HITTA ETT INNUS 20170306050A1NOHTUNUT MUUT ( 19) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2017/ 0306050 A1 Degenhardt et al. (43 ) Pub . Date : Oct. 26 , 2017 (54 ) COMPOSITIONS AND METHODS FOR Publication Classification TREATING CANCER , INFLAMMATORY (51 ) Int. Cl. DISEASES AND AUTOIMMUNE DISEASES CO7K 16 / 40 ( 2006 .01 ) CO7K 16 / 28 ( 2006 . 01) (71 ) Applicant: Gilead Sciences , Inc ., Foster City , CA COZK 16 /30 ( 2006 .01 ) (US ) COZK 16 / 30 ( 2006 .01 ) (72 ) Inventors : Jeremiah D . Degenhardt, San Mateo , A61K 39 /00 (2006 .01 ) CA (US ) ; David Gossage , Seattle, WA A61K 39 /00 ( 2006 .01 ) (US ) ; Andrew Greenstein , San A61K 39 / 00 (2006 . 01) Francisco , CA (US ) ; Vladi Juric , San (52 ) U .S . CI. Francisco , CA (US ) ; Amanda CPC ...... CO7K 16 / 40 ( 2013 .01 ) ; C12Y 304 /24035 Mikels - Vigdal, San Carlos , CA (US ) ; ( 2013 .01 ) ; CO7K 16 /3046 ( 2013 .01 ) ; C07K Victoria Smith , Burlingame, CA (US ) ; 16 / 2827 ( 2013 .01 ) ; CO7K 16 / 3015 ( 2013 .01 ) ; Maria Vaysberg , Los Altos, CA (US ) ; CO7K 2317 / 34 ( 2013 . 01 ) ; A61K 2039 / 505 Peng Yue, Foster City , CA (US ) (2013 .01 ); A61K 2039 / 545 ( 2013 .01 ) ; A61K 2039/ 507 (2013 .01 ); CO7K 2317/ 56 (2013 . 01 ); (21 ) Appl. No. : 15 / 482, 452 CO7K 2317 / 565 ( 2013 .01 ) ; CO7K 2317 / 76 (2013 .01 ) ( 22 ) Filed : Apr. 7 , 2017 (57 ) ABSTRACT Related U . S . Application Data The present disclosure provides compositions and methods (60 ) Provisional application No . 62/ 408 , 673 , filed on Oct. of use comprising a matrix metalloproteinase - 9 (MMP9 ) 14 , 2016 , provisional application No . 62 /373 , 974 , binding protein , alone or in combination with one or more filed on Aug . 11 , 2016 , provisional application No . additional therapeutic agents for the treatment or prevention 62/ 320 , 441, filed on Apr. 8 , 2016 . of diseases and conditions . Patent Application Publication Oct. 26 , 2017 Sheet 1 of 25 US 2017 /0306050 A1

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COMPOSITIONS AND METHODS FOR thereof . In one aspect, the application provides a method of TREATING CANCER , INFLAMMATORY treating or preventing a disease or condition in a subject in DISEASES AND AUTOIMMUNE DISEASES need thereof, comprising administering to the subject an effective amount of an MMP9 binding protein , and option CROSS -REFERENCE TO RELATED ally an effective amount of an additional therapeutic agent, APPLICATIONS thereby treating or preventing the disease or condition in the subject. [0001 ] This application claims the benefit of U . S . Provi [0009 ] The application also provides pharmaceutical com sional Application Ser . No . 62 /408 ,673 filed Oct. 14 , 2016 , positions comprising a pharmaceutically acceptable excipi 62 / 373, 974 filed on Aug . 11 , 2016 , and 62/ 320 , 441 filed on ent, diluent or carrier ; an anti- MMP9 antibody or antigen Apr. 8 , 2016 , all of which are hereby incorporated by binding fragment thereof and optionally an additional thera reference in their entirety for all purposes . peutic agent . STATEMENT REGARDING SEQUENCE [0010 ] The application also provides kits comprising an LISTING anti -MMP9 antibody or antigen binding fragment thereof, and optionally an additional therapeutic agent. [ 0002 ] The Sequence Listing associated with this applica [0011 ] In one embodiment of any of the compositions , tion is provided in text format in lieu of a paper copy , and kits , or methods for treating or preventing a disease or is hereby incorporated by reference into the specification . condition , the MMP9 binding protein is an anti -MMP9 The name of the text file containing the Sequence Listing is antibody or antigen binding fragment thereof. In certain GILE _ 120 _ 02US _ ST25 . TXT. The text file is about 76 KB , embodiments , the anti -MMP9 antibody or antigen binding was created on Apr. 7 , 2017 , and is being submitted elec fragment thereof binds to an epitope of MMP9 . In certain tronically via EFS -Web . embodiment, the epitope comprises amino acid residues 104 - 119 , residues 159 - 166 , or residues 191 - 202 of SEQ ID FIELD OF THE INVENTION NO : 27 . In another embodiment, the epitope comprises [0003 ] This present application provides the treatment and E111 , D113 , R162, or 1198 of SEQ ID NO : 27 . In some prevention of inflammatory diseases. embodiments , the anti -MMP9 antibody or antigen binding fragment thereof competes for binding to MMP9 with a BACKGROUND OF THE INVENTION protein , wherein the protein binds to amino acid residues 104 - 119 , residues 159 - 166 , or residues 191 - 202 of SEQ ID [0004 ] Immune factors or components may play a role in NO : 27 . In one embodiment, the protein is an antibody many diseases or conditions such as cystic fibrosis (CF ) , having at least about 95 % , 96 % , 97 % , 98 % , 99 % or greater cancers, autoimmune diseases and inflammatory diseases. identity to the amino acid sequences selected from the group Some studies have suggested that neutrophils ,macrophages , consisting of SEQ ID NOs: 7 , 12 , 13 , 14 , 15 , 16 , 17 , and 18 . and T cells are involved in the infectious and pulmonary [0012 ] In one embodiment of any of the compositions , pathology of CF, accounting for the majority of CF mortality kits , or methods for treating or preventing a disease or (Rieber , N . et al. Current concepts of immune dysregulation condition , the anti -MMP9 antibody or antigen binding frag in cystic fibrosis . The International Journal of Biochemistry ment thereof comprises a heavy chain variable (VH ) region & Cell Biology (2014 ) 52 : 108 - 112 ) . comprising a complementarity determining region (CDR ) [ 0005 ] Cancer cells release chemical signals that lure having an amino acid sequence selected from the group immune cells such as macrophages and granulocytes to consisting of SEQ ID NOs: 13 , 14 and 15 . In another infiltrate the tumor. Once inside the tumor, these immune embodiment, the anti -MMP9 antibody or antigen binding cells secrete cytokines that promote angiogenesis , which in fragment thereof comprises a light chain variable ( VL ) turn provides the oxygen and nutrients necessary for the region having a complementarity determining region (CDR ) tumor to survive and grow . Inflammation might also pro having an amino acid sequence selected from the group mote metastasis by producing chemicals that help tumor consisting of SEQ ID NOs: 16 , 17 and 18 . In another cells become untethered (Lamagna , C et al. Dual role of embodiment, the anti -MMP9 antibody or antigen binding macrophages in tumor growth and angiogenesis . Journal of fragment thereof comprises a VH region comprising an leukocyte biology ( 2006 ) 80 ( 4 ) : 705 - 713 ) . amino acid sequence selected from the group consisting of [0006 ] Autoimmune diseases arise when the immune sys SEQ ID NOs: 3 , 5 , 6 , 7 and 8 . In another embodiment, the tem becomes dysregulated , mistaking the body ' s own cells anti- MMP9 antibody or antigen binding fragment thereof as invaders and attacking these cells . Dysregulation of the comprises a VL region having an amino acid sequence innate immune system , on the other hand , could cause selected from the group consisting of SEQ ID NOs: 4 , 9 , 10 , inflammation . The immune response is activated even 11 and 12 . In one embodiment, the anti -MMP9 antibody or though the body has not been exposed to autoantibodies or antigen binding fragment thereof comprises a VH region antigens . These inflammatory disorders can result in intense comprising the amino acid sequence set forth in SEQ ID episodes of inflammation with such symptoms as fever, rash , NO : 7 and a VL region comprising the amino acid sequence and swelling in the joints . set forth in SEQ ID NO : 12 . [ 0007 ] There is a need for safe and effective treatment and [0013 ] In one embodiment of any of the compositions or prevention of undesired inflammation and immune methods for treating or preventing a disease or condition , the responses. anti -MMP9 antibody or antigen binding fragment thereof is humanized , chimeric or human . In another embodiment, the SUMMARY OF THE INVENTION anti- MMP9 antibody or antigen binding fragment thereof [ 0008 ] The present application provides methods of treat inhibits the enzymatic activity of MMP9 . In some embodi ing or preventing a disease or condition in a subject in need ments , the inhibition is non -competitive . In certain embodi US 2017 /0306050 A1 Oct. 26 , 2017 ments , the anti -MMP9 antibody or antigen binding fragment therapeutic agents . The pharmaceutical composition may be thereof inhibits MMP9 proteolysis. In another embodiment, administered intravenously, intradermally , or subcutane the anti- MMP9 antibody or antigen binding fragment ously ; and may be administered once every week , once thereof inhibits activation of MMP9 . every two weeks, or once every three weeks. The pharma [0014 ] In one embodiment of any of the compositions or ceutical composition would be for use in therapy or for use methods for treating or preventing a disease or condition , the in a method of treating the disease or condition described disease or condition comprises myeloid cell - associated herein . In other aspect, the pharmaceutical composition inflammation ; cystic fibrosis ; non -cystic fibrosis bronchiec comprises an anti- MMP9 antibody or antigen binding frag tasis ; sarcoidosis ; idiopathic pulmonary fibrosis ; tuberculo ment and additional therapeutic agents for the manufacture sis ; a cancer, e . g ., a cancer selected from the group consist of a medicament for treatment of the disease or condition ing of breast cancer, pancreatic cancer , esophagogastric described herein . adenocarcinoma, non -small cell lung cancer, lung squamous cell carcinoma, lung adenocarcinoma, gastric adenocarci BRIEF DESCRIPTION OF THE DRAWINGS noma , colorectal carcinoma, pancreatic adenocarcinoma, [ 0015 ] FIG . 1A -FIG . 1C shows the specificity of an anti head and neck squamous cell carcinoma, hepatocellular body (Active AB ) raised to a neo - epitope created after carcinoma, colorectal cancer , colorectal adenocarcinoma cleavage of inactive pro -MMP9 to active MMP9 . Rabbits and hepatocellular carcinoma; an autoimmune or inflamma were immunized with the peptide NH2- FQTFEGDC conju tory disease or condition , e . g . , an autoimmune or inflam gated to keyhole limpet hemocyanin , and the resulting sera matory disease or condition selected from the group con were affinity purified . FIG . 1A , Western blot to assess Total sisting of rheumatoid arthritis , an inflammatory bowel Ab ( clone L51 /82 , Biolegend ) and Active Ab specificity for disease ( IBD ) including ulcerative colitis (UC ) , Crohn' s pro -MMP9 versus active MMP9. FIG . 1B , immunohisto disease (CD ), or indeterminate colitis ; vasculitis , including chemistry to assess Total Ab ( Abcam 76003 ) and Active Ab large vessel vasculitis ( e . g . , Takayasu arteritis and Giant cell specificity for pro -MMP9 versus active MMP9 . FIG . 1C , arteritis ), medium vessel vasculitis (e .g ., Polyarteritis peptide enzyme- linked immunosorbent assay (ELISA ) to Nodosa and Kawasaki Disease ) , immune complex small assess Active Ab specificity for a peptide corresponding to vessel vasculitis ( e . g . , Cryoglobulinemic vasculitis, IgA the N - terminus of active MMP9 ( circle ) as compared to vasculitis (Henoch - Schonlein ), and hypocomplementemic off- target peptides corresponding to cleavage at the follow urticarial vasculitis ( anti -Clq vasculitis ) ) , anti -GBM Dis ing residue ( squares ) or the uncleaved MMP9 pro -domain : ease , ANCA -associated small vessel vasculitis ( e . g ., micro catalytic domain junction region ( triangles ) . scopic polyangiitis , granulomatosis with polyangiitis [0016 ] FIG . 2A - FIG . 2B shows that MMP9 activity is (Wegner 's ) , and eosinophilic granulomatosis with poly elevated in diseased colon tissue . FIG . 2A , Endogenous angiitis (Churg - Strauss ) ) ; septicemia ; multiple sclerosis ; active MMP9 levels in ulcerative colitis and Crohn ' s disease muscular dystrophy ; lupus; allergy ; asthma; or hidradenitis tissues, measured with MMP9 activity assay (GE , MMP - 9 suppurativa . In some embodiment, the disease or condition Biotrak Activity Assay ) in the absence of APMA or other is cystic fibrosis . In another embodiment, the disease or activator. FIG . 2B , Licor Western blots of pro -MMP9 and condition is rheumatoid arthritis , an inflammatory bowel active MMP9 in non -diseased tissue and in ulcerative colitis disease ( IBD ) , septicemia , multiple sclerosis , muscular dys and Crohn ' s disease tissues . trophy , lupus , allergy or asthma. In certain embodiment, the [0017 ] FIG . 3A - FIG . 3B shows correlations between disease or condition is inflammatory bowel disease ( IBD ) , active MMP9 and disease severity by Geboes histological ulcerative colitis (UC ) , Crohn ' s disease (CD ) , or indetermi score ( FIG . 3A ) and between active MMP9 and total MMP9 nate colitis . In another embodiment, the disease or condition in matched tissue lysates from ulcerative colitis ( red circles ) , is vasculitis . Crohn ' s disease ( green circles ) , and non - IBD tissues (blue 1 . In one embodiment of any of the methods for treating or circles ) (FIG . 3B ) . preventing a disease or condition , the anti- MMP9 antibody [0018 ] FIG . 4A -FIG . 4D shows that active MMP9 and or antigen binding fragment thereof is administered concur inactive al - antitrypsin are increased in cystic fibrosis lung rently or sequentially with the additional therapeutic agent. tissue . FIG . 4A , levels of total MMP9 in lysates from In another embodiment, the anti -MMP9 antibody or antigen parenchymal lung tissue from cystic fibrosis (CF ) patients binding fragment thereof and the additional therapeutic ( squares ) compared to non -CF lung tissues (circles ) . FIG . agent are administered in one pharmaceutical composition . 4B , levels of active MMP9 in lung samples from cystic In yet another embodiment, the anti -MMP9 antibody or fibrosis (CF ) patients (squares ) compared to normal lung antigen binding fragment thereof and the additional thera samples (circles ) . * , p = 0 . 03 . FIG . 4C , ratios of cleaved to peutic agent are administered in two distinct pharmaceutical intact al- antitrypsin for CF ( squares ) and normal samples compositions. In one embodiment, the anti -MMP9 antibody ( circles ) . * * * * , p = 0 .0001 . FIG . 4D , visualization of intact or antigen binding fragment thereof is administered at a dose and inactive (cleaved ) al -antitrypsin by Licor Western blot. of about 100 mg, of about 150 mg, of about 200 mg, of about [ 0019 ] FIG . 5 shows inactivation of al- antitrypsin by 300 mg, or of about 400 mg . In another embodiment, the MMP9 in vitro . The schematic details a protocol described anti -MMP9 antibody or antigen binding fragment thereof is in Example 3 to assess the effect ofMMP9 , AB0045 , and /or administered once every week , once every two weeks , or control isotype antibody on al- antitrypsin cleavage . Intact once every three weeks . In certain embodiments , the anti al - antitrypsin is sufficient to inhibit downstream activation MMP9 antibody or antigen binding fragment thereof and/ or of neutrophil elastase , shown by elastin cleavage . the additional therapeutic agent is administered intrave [0020 ] FIG . 6A - FIG . 6B shows the correlation between nously , intradermally , or subcutaneously. Some aspect pro active MMP9 and al- antitrypsin cleavage in lysates from vides the pharmaceutical composition comprising anti parenchymal lung tissue. FIG . 6A , levels of active MMP9 MMP9 antibody or antigen binding fragment and additional for CF and non - CF patients ( line, left axis ) and ratios of US 2017 /0306050 A1 Oct. 26 , 2017 cleaved : intact al -antitrypsin (squares , right axis ). FIG . 6B isotype or aMMP9 antibodies for the first 7 days after visualization of al antitrypsin cleavage by Licor Western adoptive peripheral blood mononuclear cell (PBMC ) trans blot. fer . [ 0021] FIG . 7A - FIG . 7B shows the effectiveness of [0033 ] FIG . 14 shows MMP9 protein levels by Ashcroft MMP9 inhibition in an orthotopic murine model of colorec Score in a bleomycin - induced lung fibrosis mouse model. tal cancer . FIG . 7A , change in HCT- 116 tumor volume after No disease control ( circle ), IgG control ( square ). * * , p = 0 . treatment with antibodies inhibiting both mouse and human 008 . MMP9 as compared to Isotype control antibody . FIG . 7B , [0034 ] FIG . 15 shows the expression of CK5 , a marker of final tumor weight after study completion . lung bronchiolization , in lung tissue of bleomycin - induced [0022 ] FIG . 8 shows the efficacy of the combination of an lung fibrosis mouse model. Mice were either not treated with anti -MMP9 agent and an anti - TNF agent in a rheumatoid bleomycin (saline - treated control) or were treated with bleo arthritis mouse model. Mean clinical scores over time are mycin and indicated antibodies as described in Example 12 . shown for mice in a collagen - induced arthritis ( CIA ) model * , p < 0 .05 ; * * , p < 0 . 01 ; * * * p < 0 .001 . of rheumatoid arthritis treated with vehicle (blue circle ), [0035 ] FIG . 16 shows the results of ELISA assay to Control Ig ( square ) , methotrexate (black circle ), AB0046 measure AB0045 bound MMP9 . Sputa from two CF patients ( triangle ) , Enbrel® (upside down triangle ), or combination were incubated with : 1 ) 50 mg/ ml IgG4 control, 2 ) 50 mg/ ml AB0046 and Enbrel® ( diamond ) . AB0045 + protease inhibitor , 3 ) 50 mg/ml AB0045 and 4 ) 50 [0023 ] FIG . 9A - FIG . 9B shows the efficacy of the com mg/ ml AB0045 + 10 mg/ml HNE for 24 hours at 37° C . bination of an anti -MMP9 agent and an anti - TNF agent in a Sputum 1 ( left -hand bars ) , Sputum 2 ( right -hand bars ). rheumatoid arthritis mouse model. FIG . 9A , Number of 10036 ] FIG . 17A - FIG . 17B shows MMP9 activity as mea paws per group with clinical score < 1 . 5 (mild disease ) over sured by a peptide proteolysis assay . FIG . 17A , 0 . 97 mg/ mL time for mice in a collagen - induced arthritis ( CIA ) model of AB0045 was incubated with 10 mg/ ml HNE ( 0 . 5 U /ml ) for rheumatoid arthritis treated with vehicle (blue circle ), Con 23 hrs at 37° C . After digestion , the AB0045 mixture was trol Ig ( square ) , AB0046 ( triangle ) , Enbrel® ( upside down diluted to the concentration denoted on the x -axis , mixed triangle ) , or combination AB0046 and Enbrel® (diamond ) . with MMP9 , and MMP9 enzymatic activity was measured . * , p < 0 . 05 paired t -test to Vehicle ; # , p < 0 .05 paired t - test to AB0045 incubated with HNE ( circle ); AB0045 , no HNE Control , Ig , AB0046 or Enbrel. FIG . 9B , Number of paws ( square ). FIG . 17B , 0 . 97 mg/ ml AB0045 was incubated 1 : 1 per group with clinical scores of 0 (no disease ) over time ( v : V ) with sputa from two distinct CF patients for 23 hrs at ( graph legend as for FIG . 9A ) . * , p = 0 . 052 paired t- test to 37° C . Peptide proteolysis was measured similar to FIG . Vehicle ; # , p < 0 . 05 paired t -test to AB005123 . Areas under 17A . AB0045 , incubated with sputum # 1 ( circle ) ; AB0045 , the curve ( Total Area ) for each treatment group , with lower incubated with sputum # 2 ( square ) ; AB0045 , no sputum numbers indicating clinical efficacy of treatment, are shown ( triangle ); no AB0045 ( inverted triangle ). for both groups . 100371 FIG . 18A - FIG . 18B show median tumor volume of [0024 ] FIG . 10 shows T cell diversity analyzed by CDR3 tumors over 30 days of treatment ( FIG . 18A ) and finalmean sequences of TCRa and TCRB chains from mice treated tumor volume (FIG . 18B ) in an orthotopic , syngeneic tumor model (NeuT ) . The mice were treated with control IgG with control , aMMP9 , aPD -L1 , or combination group , as antibody, anti -MMP9 antibody, anti - PDL1 antibody , or the calculated by MiTCR /MiXCR . Results from the analysis combination of anti -MMP9 and anti - PDL1 antibodies . * * suggest combination therapy could potentially increase TCR p < 0 .01 . FIG . 18A : control IgG ( circle ) ; anti- MMP9 clonal diversity . ( square ) ; anti - PDL1 ( triangle ) ; anti -MMP9 /anti - PDL1 ( in [ 0025 ] FIG . 11 shows the relative expression ofMMP9 in verted triangle ). normal, granulomatosis with polyangiitis (Wegeneris , 10038 ] FIG . 19A - FIG . 19B shows normalized expression GPA ) , and giant cell arteritis (GCA ) arteries . of Granzyme B (FIG . 19A ) and CD69 (FIG . 19B ) , two genes [ 0026 ] FIG . 12A shows relative expression of IL6 in associated with effector T cell signature, in an orthotopic , transplanted arteries from mice with induced vasculitis syngeneic tumor model (NeuT ) treated with an anti -MMP9 treated with isotype or aMMP9 antibodies . antibody . [0027 ] FIG . 12B shows relative expression of ILlb in [0039 ] FIG . 20 shows change in TCR clonality in an transplanted arteries from mice with induced vasculitis orthotopic , syngeneic tumor model (NeuT ) treated with treated with isotype or aMMP9 antibodies . control IgG antibody, anti -MMP9 antibody, anti -PDL1 anti 10028 ] FIG . 12C shows relative expression of TNFa in body , or the combination of anti -MMP9 and anti - PDL1 transplanted arteries from mice with induced vasculitis antibodies . treated with isotype or aMMP9 antibodies . [0029 ] FIG . 12D shows relative expression of TCR in DETAILED DESCRIPTION OF THE transplanted arteries from mice with induced vasculitis INVENTION treated with isotype or aMMP9 . [0040 ] The present application provides compositions and [0030 ] FIG . 12E shows relative expression of IFNy in methods for treating and /or preventing a variety of diseases , transplanted arteries from mice with induced vasculitis conditions and disorders , including but not limited to cystic tretreated with isotype or aMMP9 antibodies. fibrosis , cancer , autoimmune diseases or conditions , inflam [ 0031 ] FIG . 12F shows relative expression of IL17 in matory diseases or conditions , and diseases and conditions transplanted arteries from mice with induced vasculitis associated with MMP9 . In one embodiment, the disease or treated with isotype or aMMP9 antibodies . disorder is associated with deregulated MMP9 expression or [0032 ] FIG . 13A - FIG . 13B shows relative expression of activity , e . g . , MMP9 overexpression . IFNY ( FIG . 13A ) and IL17 ( FIG . 13B ) in transplanted f0041 ] Practice of the present disclosure employs , unless arteries from mice with induced vasculitis treated with otherwise indicated , standard methods and conventional US 2017 /0306050 A1 Oct. 26 , 2017 techniques in the fields of cell biology, toxicology , molecu (A2aR ), Cluster of Differentiation 200 ( CD200 ) and/ or lar biology , biochemistry , cell culture, immunology, oncol Programmed cell death protein 1 (PD - 1) pathways. ogy , recombinant DNA and related fields as are within the [0047 ] As used herein , a “ recombinant molecule ” refers to skill of the art. Such techniques are described in the litera an expression vector harboring a DNA insert . In certain ture and thereby available to those of skill in the art . See , for embodiments , the “ recombinant molecule ” is designed to example , Alberts , B . et al. , “ Molecular Biology of the Cell ,” express a therapeutic agent . 5th edition , Garland Science , New York , N . Y ., 2008 ; Voet , D . et al. “ Fundamentals of Biochemistry : Life at the [0048 ] As used herein , “ treat, ” treating ” and “ treatment” Molecular Level ,” 3rd edition , John Wiley & Sons, Hobo or the like refer to stasis or a postponement of development ken , N . J . , 2008 ; Sambrook , J . et al. , “ Molecular Cloning : A of one or more symptoms associated with a disease or Laboratory Manual, ” 3rd edition , Cold Spring Harbor Labo disorder described herein , or ameliorating existing uncon ratory Press, 2001 ; Ausubel, F . et al ., " Current Protocols in trolled or unwanted symptoms, preventing additional symp Molecular Biology, " John Wiley & Sons , New York , 1987 toms, or ameliorating or preventing the underlying meta and periodic updates; Freshney , R . I. , “ Culture of Animal bolic causes of symptoms. Thus, the terms denote that a beneficial result has been conferred on a mammalian subject Cells : A Manual of Basic Technique , ” 4th edition , John with a disease or symptom , or with the potential to develop Wiley & Sons , Somerset, N .J . , 2000 ; and the series “Meth such disease or symptom . A response is achieved when the ods in Enzymology , ” Academic Press, San Diego , Calif. See patient experiences partial or total alleviation , or reduction also , for example , " Current Protocols in Immunology ," ( R . of signs or symptoms of illness , and specifically includes , Coico , series editor ), Wiley, last updated August 2010 . without limitation , prolongation of survival. The expected progression - free survival times can be measured in months Definitions to years , depending on prognostic factors including the [0042 ] As used herein , the singular form “ a ” , “ an ” , and number of relapses, stage of disease, and other factors . “ the ” includes plural references unless indicated otherwise . 00491. The first treatment given for a disease or condition [0043 ] Reference to “ about a value or parameter herein is referred to as the “ front- line therapy ," " first- line therapy, " refers to the usual error range for the respective value readily “ front- line treatment” or “ first - line treatment. ” In general, known to the skilled person in this technical field . Reference the first - line therapy is typically the one accepted as the best to “ about” a value or parameter herein includes ( and treatment that is available to healthcare provider at the time describes ) aspects that are directed to that value or parameter of treatment. If it doesn ' t cure the disease , alleviate the per se . For example , description referring to " about X ” symptoms or the extent of the disease , or it causes undesired includes description of “ X .” In certain embodiments , the or severe adverse effects, other treatment may be added or term “ about" includes the indicated amount = 1 % to 10 % . In used instead . “ First - line therapy ” may also be referred to as other embodiments , the term “ about” includes the indicated induction therapy , primary therapy , and primary treatment. amount 5 % . In certain other embodiments , the term “ about ” Any of the methods of treatment or prevention described includes the indicated amount= 1 % . In certain other embodi herein may be provided as a " first -line therapy . " " Second ments , the term “ about" includes the indicated line therapy ” refers to treatment that is given when initial amount : 10 % . treatment ( first - line therapy ) doesn ' t work , or stops working . [ 0044 ] As used herein , the term “ agent” refers to any Any of the methods of treatment or prevention described molecule, compound , nucleic acid , nucleic acid based moi herein may be provided as a " second - line therapy .” “ Add -on ety , antibody , antibody - based molecule , protein , protein therapy ” refers to any treatment given to bolster or enhance based molecule and / or substance for use in the prevention , the effectiveness of another therapy , e . g . , when the first treatment, management and /or diagnosis of a disease or treatment proved not to be hilly effective . Any of the condition . methods of treatment or prevention described herein may be [0045 ] It is understood that aspects and embodiments of the compositions and methods etc . described herein include provided as an “ add -on therapy .” " comprising ," " consisting, ” and “ consisting essentially of [0050 ] A “ prophylactically effective amount” refers to an aspects and embodiments . amount effective at the dosages and for periods of time [0046 ] As used herein , an “ immune modulating agent” is necessary , to achieve the desired prophylactic result . Typi an agent capable of modulating the immune response of a cally , but not necessarily , since a prophylactic dose is used subject. In some embodiments, an “ immune modulating in subjects prior to or at the earlier stage of disease , the agent” enhances or increases an immune response and may prophylactically effective amount can be less than the thera be referred to as “ immunostimulatory .” In other embodi peutically effective amount. ments , an “ immune modulating agent” inhibits or reduces an [ 0051 ] As used herein , the term “ subject ” refers to a immune response and may be referred to as “ immunosup mammalian subject . Exemplary subjects include , but are not pressive .” In certain embodiments , " immune modulating limited to humans, non -human primates , monkeys, dogs , agents ” include adjuvants ( substances that enhance the cats , mice , rats , cows, horses , goats and sheep . In certain body ' s immune response to an antigen ) , vaccines ( e . g . , embodiments , the subject is a human . In some embodiments , cancer vaccines ), and those agents capable ofmodulating the the subject has or is being diagnosed as having CF, an function of immune checkpoints , including the Cytotoxic inflammatory disease or condition , or an autoimmune dis T -lymphocyte -associated protein 4 (CTLA - 4 ) , Lymphocyte ease or condition , and may be treated with the agent or the activation gene 3 (LAG - 3 ), Cluster of Differentiation 276 antibody of the present application . Other embodiments ( B7 -H3 ) , V - set domain -containing T -cell activation inhibitor provide that a human in need of treatment with the antibod 1 (B7 -H4 ) , T -cell immunoglobulin and mucin domain 3 ies of the present application , wherein the human has or is ( Tim3) , B - and T - lymphocyte attenuator (BTLA ) , killer suspected to have CF, an inflammatory disease or condition , immunoglobulin receptor (KIR ) , adenosine A2a receptor or an autoimmune disease or condition . US 2017 /0306050 A1 Oct. 26 , 2017

[0052 ] As used herein , the term “ antibody ” refers to an two clearly distinct types, called kappa and lambda , based isolated or recombinant polypeptide binding agent that com on the amino acid sequences of their constant domains. prises peptide sequences (e . g. , variable region sequences) Depending on the amino acid sequence of the constant that specifically bind an antigenic epitope . The term is used domain of their heavy chains , immunoglobulins can be in its broadest sense and specifically covers monoclonal assigned to five major classes : IgA , IgD , IgE , IgG , and IgM , antibodies ( including full -length monoclonal antibodies ) , and several of these may be further divided into subclasses polyclonal antibodies , human antibodies, humanized anti ( isotypes ), e . g . , IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2 . bodies, chimeric antibodies, nanobodies , diabodies , multi [0057 ] “ Single -chain “ Fv” or “ sFv” or “ scFv” antibody specific antibodies ( e . g ., bispecific antibodies ) , and antibody fragments comprise the Vy and V , domains of antibody , fragments including but not limited to Fv , scFv, Fab , Fab ' wherein these domains are present in a single polypeptide F ( ab ') , and Fab2, so long as they exhibit the desired bio chain . In some embodiments, the Fv polypeptide further logical activity . The term “ human antibody ” refers to anti comprises a polypeptide linker between the VH and VL bodies containing sequences of human origin , except for domains, which enables the sFv to form the desired structure possible non -human CDR regions, and does not imply that for antigen binding . For a review of sFv , see Pluckthun , in the full structure of an immunoglobulin molecule be present, The Pharmacology of Monoclonal Antibodies, vol. 113 only that the antibody has minimal immunogenic effect in a (Rosenburg and Moore eds. ) Springer - Verlag , New York , pp . human (i .e ., does not induce the production of antibodies to 269 - 315 ( 1994 ). itself ) . [0058 ] The term “ diabodies ” refers to small antibody [0053 ] An “ antibody fragment” comprises a portion of a fragments with two antigen -binding sites, which fragments full - length antibody, for example , the antigen binding or comprise a heavy -chain variable domain (VH ) connected to variable region of a full - length antibody . Such antibody a light - chain variable domain ( VL ) in the same polypeptide fragments may also be referred to herein as " functional chain (VHVL ) . By using a linker that is too short to allow fragments : or “ antigen -binding fragments ” . Examples of pairing between the two domains on the same chain , the antibody fragments include Fab , Fab ', F (ab ' )2 , and Fv frag domains are forced to pair with the complementary domains ments ; diabodies; linear antibodies (Zapata et al. (1995 ) of another chain , thereby creating two antigen -binding sites . Protein Eng . 8 ( 10 ) : 1057 - 1062 ) ; single - chain antibody mol Diabodies are additionally described , for example , in EP ecules ; and multi - specific antibodies formed from antibody 404 ,097 ; WO 93111161 and Hollinger et al . (1993 ) Proc. fragments . Papain digestion of antibodies produces two Natl. Acad . Sci. USA 90 :6444 -6448 . identical antigen -binding fragments , called “ Fab ” frag [0059 ] An “ isolated ” antibody is one that has been iden ments , each with a single antigen -binding site , and a residual tified and separated and / or recovered from a component of “ Fc” fragment, a designation reflecting the ability to crys its natural environment . Components of its natural environ tallize readily . Pepsin treatment yields an F ( ab ' ) , fragment ment may include enzymes , hormones , and other proteina that has two antigen combining sites and is still capable of ceous or nonproteinaceous solutes . In some embodiments , cross - linking antigen . an isolated antibody is purified ( 1 ) to greater than 95 % by [ 0054 ] “ Fv” is a minimum antibody fragment containing a weight of antibody as determined by the Lowry method , for complete antigen - recognition and - binding site . This region example , more than 99 % by weight, (2 ) to a degree sufficient consists of a dimer of one heavy - and one light- chain to obtain at least 15 residues of N - terminal or internal amino variable domain in tight, non - covalent association . It is in acid sequence , e. g. , by use of a spinning cup sequenator, or this configuration that the three complementarity -determin ( 3 ) to homogeneity by gel electrophoresis ( e . g . , SDS - PAGE ) ing regions (CDRs ) of each variable domain interact to under reducing or nonreducing conditions , with detection by define an antigen -binding site on the surface of the V , V , Coomassie blue or silver stain . The term “ isolated antibody " dimer . Collectively , the six CDRs confer antigen -binding includes an antibody in situ within recombinant cells , since specificity to the antibody. However , even a single variable at least one component of the antibody ' s natural environ domain (or an isolated Vh or V , region comprising only ment will not be present. In certain embodiments, isolated three of the six CDRs specific for an antigen ) has the ability antibody is prepared by at least one purification step . to recognize and bind antigen , although generally at a lower [0060 ] As used herein , " immunoreactive ” refers to anti affinity than does the entire Fv fragment. bodies or fragments thereof that are specific to a sequence of [ 0055 ] The “ Fab ” fragment also contains, in addition to amino acid residues ( “ binding site” or “ epitope ” ) , yet if are heavy and light chain variable regions, the constant domain cross -reactive to other peptides/ proteins, are not toxic at the of the light chain and the first constant domain (CH ) of the levels at which they are formulated for administration to heavy chain . Fab fragments were originally observed fol human use . “ Epitope” refers to that portion of an antigen lowing papain digestion of an antibody. Fab ' fragments differ capable of forming a binding interaction with an antibody or from Fab fragments in that F (ab ' ) fragments contain several antigen binding fragment thereof. An epitope can be a linear additional residues at the carboxy terminus of the heavy peptide sequence ( i . e . , " continuous” ) or can be composed of chain CHI domain , including one or more cysteines from the noncontiguous amino acid sequences ( i . e . , " conformational ” antibody hinge region . F ( ab ') , fragments contain two Fab or " discontinuous ” ) . The term " preferentially binds ” means fragments joined , near the hinge region , by disulfide bonds, that the binding agent binds to the binding site with greater and were originally observed following pepsin digestion of affinity than it binds unrelated amino acid sequences . an antibody . Fab ' - SH is the designation herein for Fab ' 10061 ] Antibodies of the present disclosure can be fragments in which the cysteine residue ( s ) of the constant described in terms of the CDRs of the heavy and light domains bear a free thiol group . Other chemical couplings of chains. As used herein , the term “ CDR ” or “ complementar antibody fragments are also known. ity determining region ” is intended to mean the non - con [ 0056 ] The “ light chains” of antibodies ( immunoglobu tiguous antigen combining sites found within the variable lins ) from any vertebrate species can be assigned to one of region of both heavy and light chain polypeptides. These US 2017 /0306050 A1 Oct. 26 , 2017 particular regions have been described by Kabat et al. , J . can also include immunoglobulin fragments , such as Fv , Biol. Chem . 252 : 6609 - 6616 ( 1977 ) ; Kabat et al. , U . S . Dept. Fab , Fab' , F ( ab ') 2 or other antigen -binding subsequences of of Health and Human Services, “ Sequences of proteins of antibodies . immunological interest ” ( 1991) ; by Chothia et al. , J . Mol. [ 0064 ] The humanized antibody can also comprise at least Biol. 196 : 901 - 917 ( 1987 ) ; and MacCallum et al. , J . Mol. a portion of an immunoglobulin constant region (Fe ), typi Biol. 262: 732 - 745 ( 1996 ) , where the definitions include cally that of a human immunoglobulin . See , for example , overlapping or subsets of amino acid residues when com Jones et al. ( 1986 ) Nature 321 : 522 - 525 ; Riechmann et al . pared against each other. Nevertheless, application of either ( 1988 ) Nature 332 : 323 - 329 ; and Presta ( 1992 ) Curr. Op . definition to refer to a CDR of an antibody or grafted Struct. Biol. 2 :593 -596 . antibodies or variants thereof is intended to be within the [0065 Methods for humanizing non - human antibodies are scope of the term as defined and used herein . The amino acid known in the art. Generally , a humanized antibody has one or more amino acid residues introduced into it from a source residues which encompass the CDRs as defined by each of that is non - human . These non -human amino acid residues the above cited references are set forth below in Table 1A as are often referred to as “ import” or “ donor” residues , which a comparison . are typically obtained from an “ import” or “ donor” variable domain . For example , humanization can be performed TABLE 1A essentially according to the method of Winter and co CDR Definitions workers, by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody . See , for Kabat Chothia ? MacCallum3 example , Jones et al. , supra ; Riechmann et al. , supra and Vy CDR1 31 - 35 26 - 32 30 - 35 Verhoeyen et al . ( 1988 ) Science 239 :1534 - 1536 . Accord VyCDR2 50 - 65 53 - 55 47 - 58 ingly , such “ humanized " antibodies include chimeric anti VH CDR3 95 - 102 96 - 101 93 - 101 bodies ( U . S . Pat. No . 4 , 816 , 567) , wherein substantially less V? CDR1 24 - 34 26 - 32 30 - 36 Vi CDR2 50 - 56 50 - 52 46 - 55 than an intact human variable domain has been substituted V CDR3 89 - 97 91 - 96 89 - 96 by the corresponding sequence from a non -human species . In certain embodiments , humanized antibodies are human Residue numbering follows the nomenclature of Kabat et al ., supra antibodies in which some CDR residues and optionally some Residue numbering follows the nomenclature of Chothia et al. , supra framework region residues are substituted by residues from Residue numbering follows the nomenclature of MacCallum et al. , supra analogous sites in rodent antibodies ( e . g ., murine monoclo nal antibodies ) . [ 0062] As used herein , the term “ framework ” when used [0066 ] Human antibodies can also be produced , for in reference to an antibody variable region is intended to example , by using phage display libraries. Hoogenboom et mean all amino acid residues outside the CDR regions al. ( 1991 ) J. Mol . Biol, 227 : 381 ; Marks et al. ( 1991 ) J. Mol. within the variable region of an antibody . A variable region Biol. 222 :581 . Other methods for preparing human mono framework is generally a discontinuous amino acid sequence clonal antibodies are described by Cole et al. ( 1985 ) “ Mono between about 100 - 120 amino acids in length but is intended clonal Antibodies and Cancer Therapy , ” Alan R . Liss , p . 77 to reference only those amino acids outside of the CDRs. As and Boerner et al. ( 1991) J . Immunol. 147 : 86 - 95 . used herein , the term “ framework region ” is intended to [0067 ] Human antibodies can be made by introducing mean each domain of the framework that is separated by the human immunoglobulin loci into transgenic animals (e .g ., CDRs. mice ) in which the endogenous immunoglobulin genes have [0063 ] In some embodiments , an antibody is a humanized been partially or completely inactivated . Upon immunologi antibody or a human antibody . Humanized antibodies cal challenge , human antibody production is observed , include human immunoglobulins (recipient antibody ) in which closely resembles that seen in humans in all respects , which residues from a complementary - determining region including gene rearrangement, assembly , and antibody rep (CDR ) of the recipient are replaced by residues from a CDR ertoire . This approach is described , for example , in U . S . Pat. of a non -human species (donor antibody ) such as mouse , rat Nos. 5 ,545 , 807 ; 5 , 545 ,806 ; 5 , 569, 825 ; 5 ,625 , 126 ; 5 ,633 , or rabbit having the desired specificity , affinity and capacity . 425 ; 5 ,661 , 016 , and in the following scientific publications: Thus , humanized forms of non -human ( e . g . , murine ) anti Marks et al. ( 1992 ) Bio / Technology 10 : 779 -783 ( 1992 ) ; bodies are chimeric immunoglobulins which contain mini Lonberg et al. ( 1994 ) Nature 368 : 856 - 859 ; Morrison ( 1994 ) mal sequence derived from non -human immunoglobulin . Nature 368: 812 - 813 ; Fishwald et al. ( 1996 ) Nature Biotech The non - human sequences are located primarily in the nology 14 : 845 - 851 ; Neuberger ( 1996 ) Nature Biotechnology variable regions , particularly in the complementarity - deter 14 :826 ; and Lonberg et al. ( 1995 ) Intern . Rev. Immunol. mining regions (CDRs ) . In some embodiments , Fv frame 13 :65 - 93 . work residues of the human immunoglobulin are replaced by 10068 ] Antibodies can be affinity matured using known corresponding non -human residues . Humanized antibodies selection and /or mutagenesis methods as described above . In can also comprise residues that are found neither in the some embodiments , affinity matured antibodies have an recipient antibody nor in the imported CDR or framework affinity which is five times or more , ten times or more , sequences . In certain embodiments , a humanized antibody twenty times or more , or thirty times or more than that of the comprises substantially all of at least one , and typically two , starting antibody ( generally murine , rabbit , chicken , human variable domains, in which all or substantially all of the ized or human ) from which the matured antibody is pre CDRs correspond to those of a non -human immunoglobulin pared . and all or substantially all of the framework regions are [0069 ] An antibody can also be a bispecific antibody . those of a human immunoglobulin consensus sequence . For Bispecific antibodies are monoclonal, and may be human or the purposes of the present disclosure , humanized antibodies humanized antibodies that have binding specificities for at US 2017 /0306050 A1 Oct. 26 , 2017

least two different antigens . In the present case , the two al. , “ Inhibition of tumour growth by marimastat in a human different binding specificities can be directed to two different xenograft model of gastric cancer : relationship with levels of MMPs , or to two different epitopes on a single MMP ( e . g ., circulating CEA .” Br J Cancer 1999 ; 81 ( 1 ): 19 - 23 ; Sykes A MMP9) . P , et al. , “ The effect of an inhibitor of matrix metallopro [0070 ] An antibody as disclosed herein can also be an teinases on colonic inflammation in a trinitrobenzenesul immunoconjugate . Such immunoconjugates comprise an phonic acid rat model of inflammatory bowel disease .” antibody ( e . g . , to MMP9 ) conjugated to a second molecule, Aliment Pharmacol Ther 1999 ; 13 ( 11 ) : 1535 - 42 ) . Such pan such as a reporter An immunoconjugate can also comprise an antibody conjugated to a cytotoxic agent such as a inhibitors, however, can cause musculoskeletal side effects chemotherapeutic agent, a toxin ( e . g ., an enzymatically including joint stiffness, inflammation , and pain in the active toxin of bacterial, fungal, plant, or animal origin , or hands, arms, and shoulders , collectively referred to as mus fragments thereof) , or a radioactive isotope ( i. e ., a radio culoskeletal syndrome (MSS ) , typically at or near effica conjugate ) . cious dose levels of Marimastat in humans ( Peterson J T . [ 0071 ] An antibody that “ specifically binds to ” or is “ spe “ The importance of estimating the therapeutic index in the cific for” a particular polypeptide or an epitope refers to the development of matrix metalloproteinase inhibitors .” Car selective binding of the antibody to the target antigen or diovasc Res 2006 ; 69 (3 ): 677 -87 ; Tierney G M , et al. “ A epitope ; these terms, and methods for determining specific pilot study of the safety and effects of the matrix metallo binding, are well understood in the art . An antibody exhibits proteinase inhibitor marimastat in gastric cancer .” Eur J “ specific binding " for a particular target antigen or epitope Cancer 1999 ; 35 ( 4 ) : 563 - 8 ; and Wojtowicz - Fraga S , et al. if it binds with greater affinity , avidity , more readily , and/ or “ Phase I trial of Marimastat, a novel matrix metalloprotei with greater duration to that target antigen or epitope than it nase inhibitor, administered orally to patients with advanced does with other substances. In some embodiments , the lung cancer. ” J Clin Oncol 1998 ; 16 (6 ): 2150 - 6 ) . The antibody that specifically binds to the polypeptide or epitope symptoms are dose - and time- dependent , and reversible is one that that binds to that particular polypeptide or epitope shortly after cessation of treatment with the pan -MMP without substantially binding to any other polypeptide or inhibitor (Wojtowicz - Fraga S , 1998 ; Nemunaitis J , et al. , polypeptide epitope . In some embodiments , the provided “ Combined analysis of studies of the effects of the matrix antibodies specifically bind to human MMP9 or other target metalloproteinase inhibitor marimastat on serum tumor with a dissociation constant (Kd ) equal to or lower than 100 markers in advanced cancer: selection of a biologically nM , optionally lower than 10 nM , optionally lower than 1 active and tolerable dose for longer -term studies. " Clin nM , optionally lower than 0 . 5 nM , optionally lower than 0 . 1 Cancer Res 1998 ; 4 ( 5 ) : 1101 - 9 ; Hutchinson J W et al . , nM , optionally lower than 0 .01 nM , or optionally lower than “ Dupuytren ' s disease and frozen shoulder induced by treat 0 .005 nM , in certain examples, between 0 . 1 and 0 . 2 nM , or ment with a matrix metalloproteinase inhibitor. ” The Journal between 0 . 1 and 10 PM , e . g . , between 0 . 4 and 9 pm , such as of Bone and Joint Surgery , British Volume 1998 ; 80 ( 5 ) : between 0 . 4 and 8 .8 pm , in the form ofmonoclonal antibody , 907 - 8 . Marimastat and other pan -MMP inhibitors of the scFv, Fab , or other form of antibody measured at a tem same class are zinc chelators ; Peterson J T , 2006 . The perature of about 4° C . , 25° C . , 37° C . or 42° C . homozygous MMP9 knockout mouse displays no MSS - like [ 0072 ] The antibodies for use with the presently provided symptoms or MSS - like tissue changes ; and Vu T H , et al. , methods , compositions , and combinations can include but “ MMP - 9 / gelatinase B is a key regulator of growth plate are not limited to any of the antibodies described herein , angiogenesis and apoptosis of hypertrophic chondrocytes” including antibodies and antibody fragments , including Cell 1998 ; 93 ( 3 ) :411 - 22 ) . those containing any combination of the various exemplified [0076 ] Abnormal activity of certain MMPs plays a role in heavy and light chains, heavy and light chain variable tumor growth , metastasis , inflammation , autoimmunity , and regions , and CDRs. vascular disease ( see , for example , Hu et al . ( 2007 ) Nature [0073 ] All references cited herein , including patent appli Reviews: Drug Discovery 6 : 480 -498 ) . One notable source cations and publications, are hereby incorporated by refer of MMP9 is tumor -associated macrophages ( TAMs) , which ence in their entirety . support metastasis and invasion in a complex co - activation loop via paracrine interaction with the primary tumor cells . MMP9 Binding Proteins This combination of the proteolytic breakdown of physical [0074 ] Embodiments of the present application include or barriers to cell invasion plus liberation of factors that use MMP9 binding proteins, e . g ., anti -MMP9 antibodies activate growth and angiogenesis paves the way for tumor and fragments thereof that inhibit MMP9 processing or expansion , with the accompanying development of neovas activity , including but not limited to any of the MMP9 cularization to support tumor outgrowth . binding proteins described herein . [0077 ] MMP9 is a target of oncogenic signaling pathways [ 0075 ] MMP9 degrades basement membrane collagen and such as RAS/ RAF , PI3K / AKT/ NFkB , and WNT/ beta other extracellular matrix (ECM ) components (Kessenbrock catenin and functions as an upstream regulator of these K , et al. , “ Matrix metalloproteinases: regulators of the tumor pathways via modulation of integrin and receptor tyrosine microenvironment. ” Cell 2010 ; 141 ( 1 ) :52 -67 ) . Matrix deg kinase function . MMP9 is elevated in a wide variety of radation contributes to pathology in multiple diseases , tumor types and MMP9 levels are correlated with poor including arthritis, cancer , and ulcerative colitis (Roy R , et prognosis in many cancers, including gastric , lung , and al. , “ Matrix metalloproteinases as novel biomarkers and colorectal cancer. MMP9 is also implicated in chemoresis potential therapeutic targets in human cancer . ” J Clin Oncol tance and is upregulated upon loss of several tumor sup 2009 ; 27 (31 ): 5287 - 97 ). Broad - spectrum matrix metallopro pressors . MMP9 is upregulated in many diverse tumor types teinase inhibitors such as Marimastat are efficacious in and can promote primary growth and distal invasion of animal models of inflammation and cancer (Watson S A , et cancerous cells . US 2017 /0306050 A1 Oct. 26 , 2017

[0078 ] It can be desirable to inhibit the activity of one or tion of other, related matrix metalloproteinases. “ An inhibi more MMPs in certain therapeutic settings . However , the tor of MMP9 ” or “ inhibitor of MMP9 activity ” can be an activity of certain other MMPs , e . g . , MMP2 , is often antibody or an antigen binding fragment thereof that directly required for normal function and /or is protective against or indirectly inhibits activity of MMP9, including but not disease . Since most MMP inhibitors are targeted to the limited to enzymatic processing , inhibiting action of MMP9 conserved catalytic domain and , as a result , inhibit a number on it substrate ( e . g . , by inhibiting substrate binding , sub of different MMPS , use of available MMP inhibitors has strate cleavage, and the like ), and the like . caused side effects due to the inhibition of essential, non [0083 ] In one embodiment, the anti- MMP9 antibody or pathogenically - related MMPs . These side effects may likely antigen binding fragment thereof inhibits the enzymatic be also due to general zinc chelation caused by many of activity of MMP9 . In some embodiments , the inhibition is these inhibitors , including inhibiting zinc -requiring enzymes non - competitive . In certain embodiments , the anti -MMP9 more broadly . antibody or antigen binding fragment thereof inhibits 10079 ] Challenges were associated with developing MMP9 proteolysis . In another embodiment, the anti -MMP9 inhibitors specific to a particular MMP or select MMPs due antibody or antigen binding fragment thereof inhibits acti to the fact that inhibition of enzymatic activity via substrate vation of MMP9 . competitive mechanisms generally requires that the inhibitor [00841 In some embodiments , whereas treatment with be targeted to the catalytic domain . Homologies in MMP pan -MMP inhibitors , such as the small -molecule pan inhibi catalytic domains can cause inhibitors to react with more tors Marimastat, results in symptoms of musculoskeletal than one MMP. MMP9 binding proteins described herein disease , such as musculoskeletal syndrome (MSS ) , which include agents , including therapeutic reagents , such as anti can cause substantial effects on gait, posture and willingness bodies and antigen -binding fragments thereof, that specifi to move , and profound histological damage to joints , spe cally inhibit the catalytic activity of a single MMP or a select cific inhibition of MMP9 , e . g . , with the antibodies or anti plurality of MMPs , such as MMP9 and that do not react with gen -binding fragments thereof in the present application , or inhibit certain other MMPs or any other MMPs . Also among the provided embodiments are methods and uses of does not cause such symptoms and does not induce MSS . the same for treatment of various diseases, including cystic [ 0085 ] The present disclosure also provides MMP9 bind fibrosis , cancers , autoimmune diseases and conditions, and ing proteins that specifically bind to non -mouse MMP9 , inflammatory diseases and conditions . In certain embodi such as human MMP9 , Cynomolgusmonkey MMP9 , and rat ments, the MMP9 binding proteins of this disclosure binds MMP9. the general large catalytic domain , but does not bind in the [ 0086 ] The present disclosure also provides MMP9 bind substrate pocket , and appears to be acting via other , allos ing proteins ( e . g . , anti -MMP9 antibodies and functional teric mechanisms ( e. g ., certain MMP9 binding proteins of fragments thereof) that act as non -competitive inhibitors . A this disclosure do not compete with substrate for binding , “ non - competitive inhibitor ” refers to an inhibitor binds at and inhibit independently of the presence of substrate or site away from substrate binding site of an enzyme, and thus substrate concentration ) . can bind the enzyme and effect inhibitory activity regardless [ 0080 ] Certain embodiments of the compositions, kits and of whether or not the enzyme is bound to its substrate . Such methods of this application utilize binding proteins, e . g ., non - competitive inhibitors can , for example , provide for a antibodies and fragments ( e . g . , antigen - binding fragments ) level of inhibition that can be substantially independent of thereof, that bind to thematrix metalloproteinase - 9 (MMP9 ) substrate concentration . MMP9 binding proteins ( e . g ., anti protein (also referred to as gelatinase - B ) . In one embodi bodies and functional fragments thereof) of the present ment, they bind to a human MMP9, such as the human disclosure include those that bind MMP9 , e . g ., human MMP9 having an amino acid sequence set forth in SEQ ID MMP9 , and having a heavy chain polypeptide ( or functional NO : 27 or SEQ ID NO : 28 . The binding proteins of the fragment thereof) that has at least about 80 % , 85 % , 90 % , present disclosure generally comprise an immunoglobulin 95 % or more amino acid sequence identity to a heavy chain (Ig ) heavy chain (or functional fragment thereof) and an Ig polypeptide disclosed herein . In some example, MMP9 light chain (or functional fragment thereof) . binding proteins ( e . g . , antibodies and functional fragments [0081 ] The disclosure further provides MMP9 binding thereof) of the present disclosure include those that bind proteins that bind specifically to MMP9 and not to other MMP9, e . g . , human MMP9, and having a light chain poly matrix metalloproteinases such as MMP1 , MMP2 , MMP3 , peptide (or functional fragment thereof) that has at least MMP7 , MMP9, MMP10 , MMP12 , and MMP13 ( see also about 90 % , 95 % , 97 % , 98 % , 99 % or more amino acid WO 2012 /027721 , WO 2013 / 130078 and WO 2013 / 130905 , sequence identity to a light chain polypeptide disclosed each of which is herein incorporated in its entirety ) . Such herein . specific MMP9 binding proteins are generally not signifi [0087 ] MMP9 binding proteins ( e. g ., antibodies and func cantly or detectably cross - reactive with non -MMP9 matrix tional fragments thereof) of the present disclosure include metalloproteinases . MMP9 binding proteins that specifically those that bind MMP9 , e . g ., human MMP9 , and having a bind MMP9 find use in applications in which it is necessary light polypeptide (or functional fragment thereof ) that has at or desirable to obtain specific modulation ( e . g . , inhibition ) least about 80 % , 85 % , 90 % , 95 % or more amino acid of MMP9 without directly affecting the activity of other sequence identity to a heavy chain polypeptide disclosed matrix metalloproteinases. herein . [ 0082 ] In certain embodiments of the present disclosure , [0088 ] MMP9 binding proteins ( e . g ., antibodies and func an anti- MMP9 antibody is an inhibitor of the activity of tional fragments thereof) of the present disclosure include MMP9 , and it can be a specific inhibitor of MMP9 . In those that bind MMP9, e . g . , human MMP9, and have a particular, the MMP9 binding proteins disclosed herein are heavy chain polypeptide ( or functional fragment thereof ) useful for inhibition ofMMP9 while allowing normal func having the complementarity determining regions (“ CDRs” ) US 2017 /0306050 A1 Oct. 26 , 2017 of heavy chain polypeptide and the CDRs of a light chain is lysine, arginine , and histidine ; and a group of amino acids polypeptide ( or functional fragment thereof) as disclosed having sulfur- containing side chains is cysteine and methio herein . nine. [0089 ] “ Homology ” or “ identity ” or “ similarity ” as used [ 0093 ] Accordingly , the present disclosure provides , for herein in the context ofnucleic acids and polypeptides refers example , antibodies or antigen binding fragments thereof, to the relationship between two polypeptides or two nucleic comprising a heavy chain variable region polypeptide hav acid molecules based on an alignment of the amino acid ing at least 80 % , 85 % , 90 % , 95 % , 96 % , 97 % , 98 % , 99 % or sequences or nucleic acid sequences, respectively . Homol greater amino acid sequence identity to an amino acid ogy and identity can each be determined by comparing a sequence of a heavy chain variable region described herein position in each sequence which may be aligned for pur ( e . g . , SEQ ID NOS : 1 or 5 - 8 ), and a variable light chain poses of comparison . When an equivalent position in the polypeptide having at least 80 % , 85 % , 90 % , 95 % , 96 % , compared sequences is occupied by the same base or amino 97 % , 98 % , 99 % or greater amino acid sequence identity to acid , then the molecules are identical at that position ; when an amino acid sequence of a light chain polypeptide as set the equivalent site occupied by the same or a similar amino forth herein ( e . g . , SEQ ID NOS : 2 or 9 - 12 ) . In one embodi acid residue ( e . g . , similar in steric and /or electronic nature ) , ment, the present disclosure provides antibodies or antigen then the molecules can be referred to as homologous ( simi binding fragments thereof comprising a heavy chain variable lar ) at that position . Expression as a percentage of homol region polypeptide having at least about 95 % , 96 % , 97 % , ogy / similarity or identity refers to a function of the number 98 % , 99 % or greater amino acid sequence identity to an of identical or similar amino acids at positions shared by the amino acid sequence of a heavy chain variable region as set compared sequences. In comparing two sequences , the forth in SEQ ID NO : 7 , and a variable light chain polypep absence of residues ( amino acids or nucleic acids) or pres tide having at least about 95 % , 96 % , 97 % , 98 % , 99 % or ence of extra residues also decreases the identity and homol greater amino acid sequence identity to an amino acid ogy / similarity . sequence of a light chain polypeptide as set forth in SEQ ID [0090 ] As used herein , “ identity ” means the percentage of NO : 12 . In further examples , the present disclosure provides identical nucleotide or amino acid residues at corresponding antibodies or antigen binding fragments thereof comprising positions in two or more sequences when the sequences are a heavy chain variable region polypeptide having at least aligned to maximize sequence matching , i . e . , taking into 80 % , 85 % , 90 % , 95 % , 96 % , 97 % , 98 % , 99 % or greater account gaps and insertions . Sequences are generally amino acid sequence identity to an amino acid sequence of aligned for maximum correspondence over a designated a heavy chain variable region as set forth in SEQ ID NOS : region , e . g . , a region at least about 20 , 25 , 30 , 35 , 40 , 45 , 50 , 32 , 40 , or 47 , and a variable light chain polypeptide having 55 , 60 , 65 or more amino acids or nucleotides in length , and at least 80 % , 85 % , 90 % , 95 % , 96 % , 97 % , 98 % , 99 % or can be up to the full- length of the reference amino acid or greater amino acid sequence identity to an amino acid nucleotide . For sequence comparison , typically one sequence of a light chain polypeptide as set forth in SEQ ID sequence acts as a reference sequence , to which test NOS: 33 , 41 , or 48 . In some embodiments , the present sequences are compared . When using a sequence compari disclosure provides antibodies or antigen binding fragments son algorithm , test and reference sequences are input into a thereof comprising a heavy chain variable region polypep computer program , subsequence coordinates are designated , tide having at least about 95 % , 96 % , 97 % , 98 % , 99 % or if necessary , and sequence algorithm program parameters greater amino acid sequence identity to an amino acid are designated . The sequence comparison algorithm then sequence of a heavy chain variable region as set forth in calculates the percent sequence identity for the test sequence SEQ ID NOS : 32 , 40 , or 47, and a variable light chain ( s ) relative to the reference sequence , based on the desig polypeptide having at least about 95 % , 96 % , 97 % , 98 % , nated program parameters . 99 % or greater amino acid sequence identity to an amino [ 0091 ] Examples of algorithms that are suitable for deter acid sequence of a light chain polypeptide as set forth in mining percent sequence identity are the BLAST and SEQ ID NOS : 33 , 41 , or 48 . In further embodiments , the BLAST 2 .0 algorithms, which are described in Altschul et present application provides the antibodies or antigen bind al . ( 1990 ) J . Mol. Biol. 215 : 403 -410 and Altschul et al . ing fragment thereof that may compete for binding to a ( 1977 ) Nucleic Acids Res . 25 : 3389 - 3402 , respectively . protein or antibody comprising an amino acid sequence Software for performing BLAST analyses is publicly avail having at least about 95 % , 96 % , 97 % , 98 % , 99 % or greater able through the National Center for Biotechnology Infor identity to an amino acid sequence as set forth in SEQ ID mation (www .ncbi . nlm .nih . gov ) . Further exemplary algo NO : 7 , 12 , 13 , 14 , 15 , 16 , 17 , or 18 . rithms include Clustal W (Higgins D . , et al. ( 1994 ) Nucleic [0094 ] In some embodiments , an anti -MMP9 antibody or Acids Res 22 : 4673 - 4680 ), available at www .ebi . ac . uk / binding fragment thereof of the present disclosure binds to Tools / clustalw / index .html . one or more processing sites ( e . g . , sites of proteolytic [0092 ] Residue positions which are not identical can differ cleavage ) in MMP9 , thereby effectively blocking processing by conservative amino acid substitutions . Conservative of the proenzyme or preproenzyme to the catalytically active amino acid substitutions refer to the interchangeability of enzyme, and thus reducing the proteolytic activity of the residues having similar side chains . For example , a group of MMP9 . amino acids having aliphatic side chains is glycine , alanine , [0095 ] In some embodiments, an anti -MMP9 antibody or valine, leucine , and isoleucine ; a group of amino acids binding fragment thereof binds to MMP9 with an affinity at having aliphatic -hydroxyl side chains is serine and threo least 2 times , at least 5 times, at least 10 times , at least 25 nine ; a group of amino acids having amide - containing side times , at least 50 times , at least 100 times , at least 500 times, chains is asparagine and glutamine ; a group of amino acids or at least 1000 times greater than its binding affinity for having aromatic side chains is phenylalanine , tyrosine, and another MMP. Binding affinity can be measured by any tryptophan ; a group of amino acids having basic side chains method known in the art and can be expressed as, for US 2017 /0306050 A1 Oct. 26 , 2017 example , on -rate , off- rate , dissociation constant (Kd ), equi- are antibodies and fragments that specifically bind to an librium constant (Keq ) or any term in the art. epitope of MMP9 , where the epitope includes an amino acid 10096 ] In some embodiments, an anti -MMP9 antibody residue within a specific region of MMP9 or multiple according to the present disclosure is one that inhibits the regions of MMP9 . Further provided are anti -MMP9 anti enzymatic ( i . e . , catalytic ) activity of MMP9 , such as a body or antigen binding fragment thereof that compete for non -competitive inhibitor of the catalytic activity of MMP9 . binding to a protein or antibody that binds to the epitope or In some embodiments , an antibody according to the present region described herein . Such regions can include , for disclosure binds within the catalytic domain of MMP9. In example , structural loops and / or other structural domains of additional embodiments , an antibody according to the pres MMP9 , such as those shown to be important for binding to ent disclosure binds outside the catalytic domain of MMP9 . exemplary antibodies described herein . Typically , the [0097 ] Also provided are antibodies or antigen binding regions are defined according to amino acid residue posi fragments thereof that compete with any one or more of the tions on the full- length MMP9 sequence , e . g ., SEQ ID NO : anti -MMP9 antibodies or antigen binding fragments thereof 27 . In some examples , the epitope contains an amino acid described herein for binding to MMP9 . Thus , the present residue 104 - 202 of SEQ ID NO : 27 . In one example , the disclosure contemplates anti -MMP9 antibodies, and func epitope contains an amino acid residue ( i. e ., one or more tional fragments thereof, that compete for binding with , for amino acid residue ( s ) ) within a region that is residues example , an antibody having a heavy chain polypeptide of 104 - 119 residues 159 - 166 , or residues 191 - 202 of SEQ ID any of SEQ ID NOS : 1 or 5 - 8 , a light chain polypeptide of NO : 27 . In some aspects , the epitope includes an amino acid SEQ ID NOS : 2 or 9 - 12 , or combinations thereof. In one residue ( i . e ., one or more amino acid residue( s ) ) within a embodiment, the anti -MMP9 antibody , or functional frag region of MMP9 that is residues 104 - 119 of SEQ ID NO : 27 , ment thereof, competes for binding to human MMP9 with an amino acid residue within a region of MMP9 that is the antibody described herein as AB0041 . In some embodi residues 159 - 166 of SEQ ID NO : 27 , and an amino acid ments , the anti- MMP9 antibody or functional fragment residue within a region ofMMP9 that is residues 191 - 202 of thereof competes for binding to human MMP9 with the SEQ ID NO : 27 . In some cases, the epitope includes E111 , antibody described herein as AB0045 . In certain embodi D113 , R162 , or 1198 of SEO ID NO : 27 . In some cases , it ments , the anti -MMPS antibody or functional fragment includes R162 of SEQ ID NO : 27 . In some cases , it includes thereof competes for binding to human MMP9 with the E111 , D113 , R162 , and 1198 of SEO ID NO : 27 . antibody described herein as AB0046 . In additional embodi [0099 ] The amino acid sequence of human MMP9 protein ments , the anti- MMP9 antibody or functional fragment is as follows:

( SEQ ID NO : 27 ) MSLWQPLVLV LLVLGCCFAA PROROSTLVL FPGDLRTNLT DRQLAEEYLY 50 RYGYTRVAEM RGESKSLGPA LLLLQKQLSL PETGELDSAT LKAMRTPRCG 100 VPDLGRFQTF EGDLKWHHHN ITYWIQNYSE DLPRAVIDDA FARAFALWSA 150 VTPLTFTRVY SRDADIVIQF GVAEHGDGYP FDGKDGLLAH AFPPGPGIQG 200 DAHFDDDELW SLGKGVVVPT RFGNADGAAC HFPFIFEGRS YSACTTDGRS 250 DGLPWCSTTA NYDTDDRFGF CPSERLYTRD GNADGKPCOF PFIFQGQSYS 300 ACTTDGRSDG YRWCATTANY DRDKLFGFCP TRADSTVMGG NSAGELCVFP 350 FTFLGKEYST CTSEGRGDGR LWCATTSNFD SDKKWGFCPD QGYSLFLVAA 400 HEFGHALGLD HSSVPEALMY PMYRFTEGPP LHKDDVNGIR HLYGPRPEPE 450 PRPPTTTTPQ PTAPPTVCPT GPPTVHPSER PTAGPTGPPS AGPTGPPTAG 500 PSTATTVPLS PVDDACNVNI FDAIAEIGNQ LYLFKDGKYW RFSEGRGSRP 550 QGPFLIADKW PALPRKLDSV FEEPLSKKLF FFSGRQVWVY TGASVLGPRR 600 LDKLGLGADV AQVTGALRSG RGKMLLFSGR RLWRFDVKAQ MVDPRSASEV 650 DRMPPGVPLD THDVFQYREK AYFCODRFYW RVSSRSELNQ VDQVGYVTYD 700 ILQCPED thereof competes for binding to human MMP9 with the (0100 ] Protein domains of MMP9 are indicated below : antibody described herein as M4. In other embodiments , the anti -MMP9 antibody or functional fragment thereof com petes for binding to human MMP9 with the antibody Amino Acid # Feature described herein as M12 . 1 - 19 Signal Peptide [0098 ] Also provided are antibodies and fragments thereof 38 - 98 Peptidoglycan Binding Domain that bind to the same epitope , e . g . , MMP9 epitope as any one R98 / C99 Cysteine -switch active pocket or more of the antibodies described herein . Also provided US 2017 /0306050 A1 Oct. 26 , 2017

[0104 ] The present disclosure contemplates MMP9 bind - continued ing proteins that bind any portion of MMP9 , e . g . , human Amino Acid # Feature MMP9, including MMP9 binding proteins that preferen tially bind MMP9 relative to other MMPs . 112 - 445 Zn dependentmetalloproteinase domain 223 - 271 Fibronectin type II domain (gelatin binding domain ) [0105 ] Anti -MMP9 antibodies , and functional fragments 281 - 329 Fibronectin type II domain ( gelatin binding domain ) thereof, can be generated accordingly to methods well 340 - 388 Fibronectin type II domain ( gelatin binding domain ) known in the art . Exemplary anti -MMP9 antibodies are 400 -411 Zn binding region provided below . 521 -565 Hemopexin - like domain 10106 ] In related embodiments , an anti -MMP9 antibody is 613 -659 Hemopexin - like domain a heavy chain variant of AB0041 . The amino acid sequences 567 -608 Hemopexin - like domain of the variable regions of the AB0041 heavy and light chains 661 - 704 Hemopexin - like domain have been separately modified , by altering framework region sequences in the heavy and light chain variable regions. The effect of these sequence alterations was to [0101 ] The amino acid sequence of mature full- length deplete the antibody of human T -cell epitopes, thereby human MMP9 (which is the amino acid sequence of the reducing or abolishing its immunogenicity in humans ( Anti propolypeptide of SEQ ID NO : 27 without the signal tope, Babraham , UK ). peptide) is : [0107 ] Four heavy - chain variants were constructed , in a human IgG4 heavy chain background containing a S241P ( SEO ID NO : 28 ) amino acid change that stabilizes the hinge domain (Angal APRQROSTLVL FPGDLRTNLT DRQLAEEYLY RYGYTRVAEM et al . ( 1993 ) Malec . Immunol. 30 : 105 - 108 ) , and are denoted VH1 , VH2 , VH3 and VH4. The amino acid sequences of RGESKSLGPA LLLLQKQLSL PETGELDSAT LKAMRTPRCG their framework regions and CDRs are as follows: VPDLGRFQTF EGDLKWHHHN ITYWIONYSE DLPRAVIDDA FARAFALWSA VTPLTFTRVY SRDADIVIQF GVAEHGDGYP VH1 ( SEQ ID NO : 5 ) FDGKDGLLAH AFPPGPGIQG DAHFDDDELW SLGKGWVPT QVQLQESGPGLVKPSETLSLTCTVSGFSLLSYGVHWVROPPGKGLEWLG RFGNADGAAC HFPFIFEGRS YSACTTDGRS DGLPWCSTTA VIWTGGTTNYNSALMSRLTISKDDSKSTVYLKMNSLKTEDTAIYYCARY NYDTDDRFGF CPSERLYTRD GNADGKPCQF PFIFQGQSYS YYGMDYWGQGTSVTVSS ACTTDGRSDG YRWCATTANY DRDKLFGFCP TRADSTVMGG VH2 ( SEQ ID NO : 6 ) NSAGELCVFP FTFLGKEYST CTSEGRGDGR LWCATTSNFD OVOLOESGPGLVKPSETLSLTCTVSGFSLLSYGVHWVROPPGKGLEWLG SDKKWGFCPD OGYSLFLVAA HEFGHALGLD HSSVPEALMY VIWTGGTTNYNSALMSRLTISKDDSKNTVYLKMNSLKTEDTAIYYCARY PMYRFTEGPP LHKDDVNGIR HLYGPRPEPE PRPPTTTTPQ YYGMDYWGQGTLVTVSS PTAPPTVCPT GPPTVHPSER PTAGPTGPPS AGPTGPPTAG VH3 ( SEQ ID NO : 7 ) PSTATTVPLS PVDDACNVNI FDAIAEIGNQ LYLFKDGKYW QVQLQESGPGLVKPSETLSLTCTVSGFSLLSYGVHWVROPPGKGLEWLG RFSEGRGSRP QGPFLIADKW PALPRKLDSV FEEPLSKKLF VIWTGGTTNYNSALMSRFTISKDDSKNTVYLKMNSLKTEDTAIYYCARY FFSGRQVWVY TGASVLGPRR LDKLGLGADV AQVTGALRSG YYGMDYWGQGTLVTVSS RGKMLLFSGR RLWRFDVKAQ MVDPRSASEV DRMFPGVPLD VH4 ( SEQ ID NO : 8 ) THDVFQYREK AYFCQDRFYW RVSSRSELNO VDQVGYVTYD QVQLQESGPGLVKPSETLSLTCTVSGFSLLSYGVHWVROPPGKGLEWLG ILQCPED VIWTGGTTNYNSALMSRFTISKDDSKNTLYLKMNSLKTEDTAIYYCARY [0102 ] The amino acid sequence of the signal peptide is YYGMDYWGQGTLVTVSS MSLWQPLVLVLLVLGCCFA (SEQ ID NO : 29 ). [0108 ] In related embodiments , an anti -MMP9 antibody is [0103 ] Also provided are MMP9 polypeptides , including a light chain variant of AB0041 . Four light- chain variants mutant MMP9 polypeptides. Such peptides are useful, for have been constructed , in a human kappa chain background , example , in generating and selecting antibodies and frag and are denoted Vk1, Vk2 , Vk3 and Vk4. The amino acid ments as provided herein . Exemplary polypeptides include sequences of their framework regions and CDRs are as those having an amino acid sequence containing residues follows: 111 - 198 of SEQ ID NO : 27 , and those having an amino acid sequence containing residues 111 - 198 of SEO ID NO : 27 Vk1 with an amino acid substitution at residue 111, 113 , 162 , or ( SEQ ID NO : 9 ) 198 of SEQ ID NO : 27 or with an amino acid substitution DIVMTQSPSFLSASVGDRVTITCKASODVRNTVAWYOQKTGKAPKLLIY at all such residues . Such polypeptides find use , for example , in selecting antibodies that bind to epitopes containing such SSSYRNTGVPDRFTGSGSGTDFTLTISSLQAEDVAVYFCOQHYITPYTF residues and / or for which such residues of MMP9 are GGGTKVEIK important for binding, such as those described herein . US 2017 /0306050 A1 Oct. 26 , 2017

- continued 90 % or more , 95 % or more, or 99 % or more homology to the light chain variable region sequences disclosed herein are Vk2 ( SEQ ID NO : 10 ) also provided . DIVMTQSPSSLSASVGDRVTITCKASQDVRNTVAWYOQKPGKAPKLLIY [0111 ] Additional heavy chain variable region amino acid sequences having 75 % or more , 80 % or more , 90 % or more , SSSYRNTGVPDRFTGSGSGTDFTLTISSLQAEDVAVYFCOQHYITPYTF 95 % or more , or 99 % or more sequence identity to theheavy chain variable region sequences disclosed herein are also GGGTKVEIK provided . Furthermore, additional light chain variable Vk3 region amino acid sequences having 75 % or more, 80 % or ( SEO ID NO : 11 ) more , 90 % or more , 95 % or more , or 99 % or more sequence DIQMTQSPSSLSASVGDRVTITCKASQDVRNTVAWYOQKPGKAPKLLIY identity to the light chain variable region sequences dis closed herein are also provided . SSSYRNTGVPDRFSGSGSGTDFTLTISSLQAEDVAVYFCOQHYITPYTF [0112 ] In some embodiments , the CDRs of the heavy GGGTKVEIK chain of anti- MMP9 antibodies disclosed herein have the following amino acid sequences : Vk4 ( SEQ ID NO : 12 ) DIQMTQSPSSLSASVGDRVTITCKASQDVRNTVAWYOQKPGKAPKLLIY CDR1 : ( SEO ID NO : 13 ) SSSYRNTGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCOQHYITPYTF GFSLLSYGVH GGGTKVEIK CDR2 : ( SEO ID NO : 14 ) [ 0109 . According to the present disclosure , the humanized VIWTGGTTNYNSALMS . heavy and light chains may be combined in all possible CDR3 : pair -wise combinations to generate a number of functional ( SEQ ID NO : 15 ) humanized anti -MMP9 antibodies . For example , provided YYYGMDY are antibodies with a heavy chain variable (VH ) region [0113 ] Thus , among the provided anti -MMP9 antibodies having the amino acid sequence set forth in any of SEQ ID are antibodies having a heavy chain CDR1 region with an NOs: 3 , 5 , 6 , 7 , and 8 ; antibodies having a light chain amino acid sequence as set forth in SEQ ID NO : 13 , variable ( VL ) region having the amino acid sequence set antibodies having a heavy chain CDR2 region with an amino forth in any of SEQ ID NOs: 4 , 9 , 10 , 11 , and 12 ; and acid sequence set forth in SEQ ID NO : 14 , and antibodies antibodies with a heavy chain variable (VH ) region having having a heavy chain CDR3 region with an amino acid the amino acid sequence set forth in any of SEQ ID NOs: 3 , sequence as set forth in SEQ ID NO : 15 , and antibodies that 5 , 6 , 7 , and 8 and a light chain variable (VL ) region having compete for binding with or bind to the same epitope on the amino acid sequence set forth in any of SEQ ID NOs: 4 , MMP9 as such antibodies. In some cases, the antibodies 9 , 10 , 11 , and 12 , as well as antibodies that compete for contain VH CDRs having the sequences set forth in SEQ ID binding to MMP9 with such antibodies and antibodies NO : 15 . In some cases , the antibodies contain VH CDRs having at least at or about 75 % , 80 % , 85 % , 90 % , 91 % , 92 % , having the sequences set forth in SEQ ID NOs: 13 and 14 . 93 % , 94 % , 95 % , 96 % , 97 % , 98 % , 99 % or more sequence In some cases , the antibodies contain VH CDRs having the identity with such antibodies. In one example, the antibody sequences set forth in SEQ ID NOs: 13 and 15 . In some has a VH region with an amino acid sequence having at least cases , the antibodies contain VH CDRs having the at or about 75 % , 80 % , 85 % , 90 % , 91 % , 92 % , 93 % , 94 % , sequences set forth in SEQ ID NOs: 14 and 15 . In some 95 % , 96 % , 97 % , 98 % , 99 % or more sequence identity with cases , the antibodies contain VH CDRs having the SEQ ID NO : 7 and a VL region with an amino acid sequence sequences set forth in SEQ ID NOs: 13 , 14 , and 15 . having at least at or about 75 % , 80 % , 85 % , 90 % , 91 % , 92 % , [0114 ] In some embodiments , the CDRs of the light chain 93 % , 94 % , 95 % , 96 % , 97 % , 98 % , 99 % or more sequence of anti -MMP9 antibodies disclosed herein have the follow identity with SEQ ID NO : 12 , or a VH region of SEQ ID ing amino acid sequences : NO : 7 and a VL region of SEO ID NO : 12 . In an additional example, the antibody has a VH region with an amino acid CDR1 : sequence having at least at or about 95 % , 96 % , 97 % , 98 % , ( SEO ID NO : 16 ) 99 % or more sequence identity with SEQ ID NO : 7 . In a KASODVRNTVA further example , the antibody has a VL region with an amino CDR2 : acid sequence having at least at or about 95 % , 96 % , 97 % , ( SEO ID NO : 17 ) 98 % , 99 % or more sequence identity with SEQ ID NO : 12 . SSSYRNT In some example , the antibody has a VH region of SEQ ID CDR3 : NO : 7 and a VL region of SEQ ID NO : 12 . ( SEQ ID NO : 18 ) [0110 ] Additional heavy chain variable region amino acid QQ?????YT sequences having 75 % or more , 80 % or more, 90 % ormore , [0115 ] Thus , among the provided anti -MMP9 antibodies 95 % or more , or 99 % or more homology to the heavy chain are antibodies having a light chain CDR1 region with an variable region sequences disclosed herein are also pro amino acid sequence as set forth in SEQ ID NO : 16 , vided . Furthermore , additional light chain variable region antibodies having a light chain CDR2 region with an amino amino acid sequences having 75 % or more , 80 % or more , acid sequence set forth in SEQ ID NO : 17 , and antibodies US 2017 /0306050 A1 Oct. 26 , 2017 having a light chain CDR3 region with an amino acid the heavy chain ( 1gG2b ) sequence : sequence as set forth in SEQ ID NO : 18, and antibodies that MAVLVLFLCLVAFPSCVLSQVQLKESGPGLVAPSQSL compete for binding with or bind to the same epitope on SITCTVSGFSLLSYGVHWVROPPGKGLEWLGVI MMP9 as such antibodies . In some cases , the antibodies WTGGSTNYNSALMSRLSISKDDSKSQVFLK contain VL CDRs having the sequences set forth in SEQ ID MNSLQTDDTAMYYC ARYYYAMDYWGQGTSVTVS NO : 18 . In some cases , the antibodies contain VL CDRs SAKTTPPSVYPIAPGCGDTTGSSVTLGCLVKGYFPES having the sequences set forth in SEQ ID NOs: 16 and 17 . VTVTWNSGSLSSSVHTFPALLOSGLYTMSSSVT In some cases, the antibodies contain VL CDRs having the VPSSTWPSQTVTCSVAHPASSTTVDKKLEP sequences set forth in SEQ ID NOs: 16 and 18 . In some SGPISTINPCPPCKECHKCPAPNLEGGPSVFIFPPNIKD cases, the antibodies contain VL CDRs having the sequences VLMISLTPKVTCWVDVSEDDPD VRISWFVN NVEVHTAQTQTHREDYNSTIRVVSALPIQHODWMS set forth in SEQ ID NOs : 17 and 18 . In some cases , the GKEFKCKVNNKDLPSPIE antibodies contain VL CDRs having the sequences set forth RTISKIKGLVRAPOVYILPPPAEQLSRKDVSLTCLV in SEQ ID NOs: 16 , 17 , and 18 . VGFNPGDISVEWTSNGHTEENYKDTA PVLDSDGSY [ 0116 An illustrative humanized variant anti- MMP9 anti FIYSKLD IKTSKWEKTDSFSCNVRHEGLKNYYLKK body, AB0045 (humanized , modified IgG4 (S241P ) ) con TISRSPGK (SEQ ID NO : 30 ) (signal peptide set forth in tains the humanized AB0041 heavy chain variant VH3 underlined text, variable region set forth in plain text, and ( having the sequence set forth in SEQ ID NO : 7 constant region set forth in italics) , and the light chain ( OVOLOESGPGLVKPSETLSLTCTVSGFSLLSYGVH (kappa ) sequence : WVROPPGKGLEWLGVIWTGGT TNYNSALMSR MESQIQVFVFVFLWLSGVDGDIVMTQSHKFTSVGDR FTISKDDSKNTVYLKMNSLKTEDTAIYYCARYYYG VSITCKASQDVRNTVAWY QOKTGQSPKLLI MDYWGQGTLVT VSS ) and the humanized AB0041 light YSASYRNTGVPDRFTGSISGTDFTFTISSVQAEDLA chain variant Vk4 (having the light chain sequence set forth LYYCOQHYSTP YTFGGGTKLEVKRADAAPTVSIF in SEQ ID NO : 12 (DIQMTQSPSSLSASVGDRVTITCK PPSSEQLTSGGASWCFLNNFYPKDINVKWKIDGSER ASODVRNTVAWYOQKPGKAPKLLIYSSSYRNTG VP ONGVLNSWTDODSKDSTYSMSSTLTLTKDEYERHN DRFSGSGSGTDFTLTISSLQAEDVAVYYCOQHYITPY SYTCEATHKTSTSPIVKSFNRNEC (signal peptide set TFGGGTKVEIK ) ) . forth in underlined text, variable region set forth in plain [ 0117 ] The AB0045 antibody contains 1312 amino acids text, and constant region set forth in italics ) (SEQ ID NO : in length , is composed of two heavy chains and two light 31) . The M4 antibody has a variable heavy chain with an chains , and has a theoretical pl of about 7 . 90 , extinction amino acid sequence : QVOLKESGPGLVAP coefficient of about 1 .50 AU / cm at 280 nm for 1 g / L , a SOSLSITCTVSGFSLLSYGVHWVROPPGKGLEWLG molecular weight of about 144 kDa, and density of about 1 VIWTGGSTNYNSALMSRLSISKDDSKSOVFLKMNSL g /mL in formulation buffer (50 - 100 mg /mL product concen QTDDTAMYYCARYYYAMDYWGQGTSVT VSS tration ). (CDRs 1 , 2 , and 3 (SEQ ID NOs: 34, 35 , and 36 , respec [ 0118 ] The heavy chain of the AB0045 antibody has the tively ) underlined ) (SEQ ID NO : 32 ) and a variable light sequence set forth in SEQ ID NO : 49 ( chain with the amino acid sequence DIVMTQSHKFMFTS MGWSLILLFLVAVATRVHSOVOLQESGPGLVKPSETL VGDRVSITCKASODVRNTVAWYQQKTGQSPKLLIY SLTCTVSGFSLLSYGVHWVR OPPGKGLEWLGVI SASYRNTG VPDRFTGSISGTDFTFTISSVQAEDLA WTGGTTNYNSALMSRFTISKDDSKNTVYLKMNSLK LYYCQQHYSTPYTFGGGTKLEVK (CDRs 1, 2 , and 3 TEDTAIYYC ARYYYGMDYWGOGTLVTVSSASTK (SEQ ID NOs: 37 , 38 , and 39 , respectively ) underlined ) GPSVFPIAPCSRSTSESTAALGCLVKDYFPEPV (SEQ ID NO : 33 ). TVSWNSGALTSGVHTFPAVLOSSGLYSLSSWTVPSSS [0120 ] The M4 antibody heavy chain can have the amino LGTKTYTCNVDHKPSNTKVDKRVE SKYGPPCPPC acid sequence set forth in SEO ID NO : 54 : PAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCWVD MAVLVLFLCLVAFPSCVLSQVOLKESGPGLVAPSOSL VSQEDPEVOFNWYV SITCTVSGFSLLSYGVHWVROPP GKGLEWLGVI DGVEVHNAKTKPREEQFNSTYRWSVLTVLHQD WTGGSTNYNSALMSRLSISKDDSKSOVFLK WLNGKEYKCKVSNKGLPSSIEKTISKAK MNSLQTDDTAMYYCARY YYAMDYWGQGTSVTVS GOPREPOVYTLPPSQEEMTKNQVSLTCLVKGFYPS SAKTTPPSVYPLAPGCGDTTGSSVTLGCLVKGYFPES DIAVEWESNGOPENNYKTTPPVLDS DGSFFLYSRLT VTVTWNSG SL (signal peptide set forth in underlined text, VDKS RWQEGNVFSCSVMHEALHNHYTQK variable region set forth in plain text, and a part of the SLSLSLGK ( signal sequence underlined ; sequence of the constant region set forth in italics ) , and the M4 antibody constant region presented in italics ) ); the light chain of the light chain can have the amino acid sequence set forth in AB0045 antibody has the sequence set forth in SEQ ID NO : SEO ID 51 : 50 MESQIQVFVFVFLWLSGVDGDIVMTOSHKFMFTSV MRVPAQLLGLLLLWLPGARCDIQMTQSPSSLSASVG GDRVSITCKASQDVRNTVAWYQQ KTGQSPKLLI DRVTITCKASODVRNTVAWY OKPGKAPKLLIYS YSASYRNTGVPDRFTGSISGTDFTFTISSVQAEDLA SSYRNTGVPDRFSGSGSGTDFTLTISSLQAEDVAVYY LYYCQQHYSTPYTFG GGTKLEVKRADAAPTVSIF CQQHYITP YTFGGGTKVEIKRTVAAPSVFIFPPSD PPSSEQLTSG (signal peptide set forth in underlined text, EQLKSGTASVVCLLNNFYPREAKVOWKVDNALO variable region set forth in plain text, and a part of the SGNSOESVTEQDSKDSTYSLSSTLTLSKADYEKHK constant region set forth in italics ) . VYACEVTHQGLSSPVTKSFNRGEC (signal sequence [0121 ] The antibodies further include those produced by underlined ; sequence of the constant region presented in the hybridoma designated M12, i. e . , one with only a kappa italics ). chain , having the sequence : [0119 ] The antibodies further include those produced by QVFVYMLLWLSGVDGDIVMTQSQKFMSTSVGDRVS the hybridoma designated M4, i. e ., an antibody containing VTCKASQNVGTNVAWYQQKP GQSPKALIYSASYRF US 2017 /0306050 A1 Oct. 26 , 2017 14

SGVPDRFTGSGSGTDFTLTISNVOSEDLAEYFC [0125 ] The following amino acid sequence comprises the QOYNSYPYTFG GGTKLEIKRADAAPTVSIFPPSSE framework regions and complementarity -determining OLTSGGASWCFLNNFYPKDINVKWKIDGSERONGVL regions (CDRs ) of the variable region of the kappa light NSWT DODSKDSTYSMSSTLTLTKDEYERHNSYT chain of AB0046 (with CDRs underlined ): CEATHKTSTSPIVKSFNRNEC ( signal peptide set forth in underlined text, variable region set forth in plain text, and constant region set forth in italics ) (SEQ ID NO : 40 ) . The ( SEQ ID NO : 48 ) M12 antibody has a variable light chain with the amino acid DIQMTOTTSSLSASLGDRVTISCSASQGISNYLNWYQQKPDGTFKLLIY sequence DIVMTOSOKFMSTSVGDRVSVTC KASQNVGTNVAWYQQKPGQSPKALIYSASYRFS YTSILHSGVPSRFSGSGSGTDYSLTISNLEPEDIATYYCQQYGWLPRTF GVPDRFTGSGSGTDFTLTISNVOSEDLAEYFC GGGTKLEIK . QQYNSYPYTFGGGTKLEIK (CDRs 1 , 2 , and 3 (SEQ ID NOs: 42 , 43 , and 44 , respectively ) underlined ) (SEQ ID NO : [0126 ] The antibodies for use with the presently provided 41 ). methods, compositions , and combinations can include any [0122 ] The M12 antibody light chain can have the amino of the antibodies described herein , including antibodies and acid sequence set forth in SEQ ID NO : 53 : antibody fragments , including those containing any combi QVFVYMLLWLSGVDGDIVMTQSQKFMSTSVGDRVS nation of the various exemplified heavy and light chains , VTCKASONVGTNVAWYOQKPG OSPKALIYSASYRF heavy and light chain variable regions, and CDRs. By way SGVPDRFTGSGSGTDFTLTISNVOSEDLAEYFC of example, the presently provided methods, compositions , QQYNSYPYTFGGG TKLEIKRADAAPTVSIFPPSSE and combinations comprise the antibody or antigen binding QLTSG ( signal peptide set forth in underlined text, variable fragment thereof comprising an amino acid sequence of any region set forth in plain text, and constant region set forth in of SEO ID NOs: 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , italics ) . 18 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41, 42 , 43 , 44 , [0123 ] The antibodies further include the mouse antibody 45 , 46 , 47 , 48 , 49 , 50 , 51 , 53, or 54 . Some embodiments of designated AB0046 , having a kappa light chain with an the methods , compositions , and combinations comprise the amino acid sequence antibody or antigen binding fragment thereof comprising the MSSAQFLGLLLLCFQGTRCDIQMTQTTSSLSASLGDR amino acid sequences of SEO ID NOs : 7 and 12 . Certain VTISCSASQGISNYLNWYOQK PDGTFKLLI embodiments of the methods, compositions, and combina YYTSILHSGVPSRFSGSGSGTDYSLTISNLEPEDI tions comprise the antibody or antigen binding fragment ATYYCOOYGWLPRTFG GGTKLEIKRADAAPTVSIF thereof comprising the amino acid sequences of SEQ ID PPSSEOLTSGGASVVCFLNNFYPKDINVKWKIDGSER NOs: 13 , 14 , 15, 16 , 17 , and 18 . ONGVL NSWTDODSKDSTYSMSSTLTLTKDEYERHN [0127 ] In certain embodiments , an anti -MMP9 antibody is SYTCEATHKTSTSPIVKSFNRNEC (SEQ ID NO : 45 ) described in any of the following PCT applications : ( signal peptide set forth in underlined text, variable region WO2012 / 027721 , WO2013 / 130078 , and WO2013 / 130905 , set forth in plain text, and constant region set forth in italics ) herein incorporated by reference in their entireties. and an IgG1 heavy chain with an amino acid sequence [0128 ] In certain embodiments , an anti -MMP9 antibody is MGWSSIILFLVATATGVHSQVOLQOPGSVLVRPGASV described in PCT Publication Nos . WO 2016 /023979 or KLSCTASGYTFTSYWMNWV KORPGQGLEWIGEIYP WO2016 /023972 , each of which is herein incorporated by ISGRTNYNEKFKVKATLTVDTSSSTAYMDLNSLTSED reference in its entirety . SAVYY CARSRANWDDYWGOGTTLTVSSAKTTPPS VYPLAPGSAAQTNSMVTLGCLVKGYFPE [0129 ] In certain embodiments , methods of the present PVTVTWNSGSLSSGVHTFPAVLQSDLYTLSSSVT disclosure may be practiced by providing to the subject one VPSSTWPSETVTCNVAHPASSTKVDKKIV PRDCGCK or more nucleic acid encoding any of the therapeutic agents PCICTVPEVSSVFIFPPKPKDVLTITLTPKVTCVWDIS described herein , e . g ., a nucleic acid encoding an anti KDDPEVOFSWFVDDVE MMP9 antibody or binding fragment thereof, thus providing VHTAQTQPREEQFNSTFRSVSELPIMHQDWLNG to the subject the encoded polypeptide . In addition , compo KEFKCRVNSAAFPAPIEKTISKTKGRPK APOVYTIPP sitions of the present disclosure include nucleic acids that PKEQ MAKDKVSLTCMITDFFPEDITVEWQWNGO encode any of the therapeutic agents described herein , e . g . , PAENYKNTQPIMDTDGSYFVYSKLNVOKSN WE mRNA or modified mRNA or expression vectors encoding AGNTFTCSVLHEGLHNHHTEKSLSHSPGK (SEQ ID a therapeutic polypeptide described herein . In various NO : 46 ) ( signal peptide set forth in underlined text, variable embodiments , the nucleic acid is single - stranded or double region set forth in plain text, and constant region set forth in stranded , RNA or DNA , e. g ., mRNA or cDNA . italics ) . [0130 ] The present disclosure provides nucleic acids [0124 ] The following amino acid sequence comprises the encoding anti -MMP9 antibodies and functional fragments framework regions and complementarity - determining thereof and any other polypeptide therapeutic agent regions (CDRs ) of the variable region of the IgG1 heavy described herein . Accordingly , the present disclosure pro chain of AB0046 (with CDRs underlined ) : vides an isolated polynucleotide (nucleic acid ) encoding an antibody or antigen -binding fragment as described herein , vectors containing such polynucleotides , and host cells and ( SEQ ID NO : 47 ) expression systems for transcribing and translating such QVQLQQPGSVLVRPGASVKLSCTASGYTFTSYWMNWVKQRPGQGLEWIG polynucleotides into polypeptides. In certain embodiments , the nucleic acids are single -stranded , double - stranded , RNA , EIYPISGRTNYNEKFKV KATLTVDTSSSTAYMDLNSLTSEDSAVYYCAR mRNA , DNA , or cDNA , including modified forms thereof , SRANWDDYWGQGTTLTVSS . e . g . , comprising modifications to reduce immunogenicity or enhance stability . US 2017 /0306050 A1 Oct . 26 , 2017 15

[0131 ] The present disclosure contemplates constructs in the form of plasmids, vectors , transcription or expression VH1 : cassettes which comprise at least one polynucleotide as ( SEQ ID NO : 19 ) above . CAGGTGCAGC TGCAGGAATC CGGCCCTGGC CTGGTCAAGC [0132 ] The present disclosure also provides a recombinant CCTCCGAGAC ACTGTCCCTG ACCTGCACCG TGTCCGGCTT host cell which comprises one or more constructs as above , ??cccTGCTG TccTACGGCGTGCACTGGGTccGACAccc??? as well asmethods of production of the antibody or antigen binding fragments thereof described herein which method AGGGAAGGGccTGGAATG ccTGGGCGTG ????GGACCG comprises expression of nucleic acid encoding a heavy chain GCGGC????? ?????????? ?ccGcccTGA TGTcccGGCT polypeptide and a light chain polypeptide (in the same or different host cells , and from the same or different con GACCATCTcc AAGGACGACT CCAAGTCCAC CGTGTACCTG structs ) in a recombination host cell. Expression can be AAGATGAACT CCCTGAAAAC CGAGGACACC GCCATCTACT achieved by culturing under appropriate conditions recom binant host cells containing the nucleic acid . Following ACTGCGccca GTACTACTAC GGCATGGACT ACTGGGGCCA production by expression , an antibody or antigen -binding GGGCAcc??c GTGACCGTGT ccTCA fragment can be isolated and /or purified using any suitable VH2 : technique, then used as appropriate . ( SEQ ID NO : 20 ) [0133 ] Systems for cloning and expression of a polypep CAGGTGCAGC TGCAGGAATC CGGCCCTGGC CTGGTCAAGC tide in a variety of different host cells are well known . CCTCCGAGAC ACTGTCCCTG ACCTGCACCG TGTCCGGCTT Suitable host cells include bacteria , mammalian cells, yeast and baculovirus systems. Mammalian cell lines available in CTCCCTGCTG TCCTACGGCG TGCACTGGGT CCGACAGCCT the art for expression of a heterologous polypeptide include CCAGGCAAAG GCCTGGAATG GCTGGGCGTG ATCTGGACCG Chinese hamster ovary cells , HeLa cells , baby hamster kidney cells , NSO mouse melanoma cells and many others . GCGGCACCAC CAACTACAAC TCCGCCCTGA TGTCCCGGCT A common bacterial host is E . coli. GACCATCTcc AAGGACGACT cCAAGAACAC CGTGTACCTG [0134 ] Suitable vectors can be chosen or constructed , containing appropriate regulatory sequences, including AAGATGAACT cccTGAAAAC CGAGGACACC GCCATCTACT operably linked promoter sequences , terminator sequences, ACTGCGC?CG GTACTACTAC GGCATGGACT ACTGGGGCCA polyadenylation sequences, enhancer sequences , marker genes and / or other sequences as appropriate . Vectors can be GGGCAcccTG GTCAccGTGT ccTCA plasmids or viral, e . g . , phage or phagemid , as appropriate . VH3 : For further details see, for example , Molecular Cloning : a ( SEO ID NO : 21 ) Laboratory Manual: 2nd edition , Sambrook et al. , 1989 , CAGGTGCAGC TGCAGGAATC CGGCCCTGGC CTGGTCAAGC Cold Spring Harbor Laboratory Press . Many known tech niques and protocols for manipulation of nucleic acid , for CCTCCGAGAC ACTGTCCCTG ACCTGCACCG TGTCCGGCTT example in preparation of nucleic acid constructs , mutagen esis, sequencing , introduction of DNA into cells and gene ??cccTGCTG TCCTACGGCG TGCACTGGGT ccGACAGCCT expression , and analysis of proteins, are described in detail cCAGGCAAAG cccTGGAATG ccTGGGCGTG ATCTGGAccG in Short Protocols in Molecular Biology , Second Edition , Ausubel et al. eds. , John Wiley & Sons, 1992 . The disclo GCGGCACCAC CAACTACAAC TCCGCCCTGA TGTCCCGGTT sures of Sambrook et al. and Ausubel et al. are incorporated herein by reference in their entirety . CACCATCTcc AAGGACGACT CCAAGAACAC CGTGTACCTG [0135 ] The nucleic acid encoding a polypeptide of interest AAGATGAACT cccTGAAAAC CGAGGACAcc GCCATCTACT may be integrated into the genome of the host cell or can be maintained as a stable or transient episomal element. ACTGCcccca GTACTACTAC GGCATGGACT ACTGGGGCCA [ 0136 ] Any of a wide variety of expression control GGGCAcccTG GTCACCGTGT ccTCA sequences, i . e . , sequences that control the expression of a VH4 : DNA sequence operatively linked to it , can be used in these ( SEQ ID NO : 22 ) vectors to express the DNA sequences . For example , a CAGGTGCAGCTGCAGGAATCCGGCCCTGGCCTGGTCAAGC nucleic acid encoding a polypeptide of interest can be operably linked to a promoter, and provided in an expression CCTCCGAGAC ACTGTCCCTG ACCTGCACCG TGTCCGGCTT construct for use in methods of production of recombinant MMP9 proteins or portions thereof. ???ccTGCTG TCCTACGGCG TGCACTGGGT cCGACAGCCT 10137 ] Those of skill in the art are aware that nucleic acids CCAGGCAAAG GCCTGGAATG GCTGGGCGTG ATCTGGACCG encoding the antibody chains disclosed herein can be syn thesized using standard knowledge and procedures in GCGGCACCAC CAACTACAAC TCCGCCCTGA TGTCCCGGTT molecular biology . CACCATc??c AAGGACCACT cCAAGAACAC ccTGTA???? [0138 ] Examples of nucleotide sequences encoding the heavy and light chain amino acid sequences disclosed AAGATGAACT cccTGAAAAC CGAGGACAcc GCCATCTACT herein , are as follows : US 2017 /0306050 A1 Oct. 26 , 2017 16

- continued - continued ACTGCGcccG GTACTACTAC GGCATGGACT ACTGGGGCCA GAGGACGTGG ccGTGTACTA ??GCCAGCAG ?????????? GGGCACCCTG GTCACCGTGT ccTCA cccccTACAC CTTCGGCGGA GGCACCAAGG TGGAAATAAA Vkl : ( SEO ID NO : 23 ) GACATCGTGA TGACCCAGTC CCCCAGCTTC CTGTCCGCCT [0139 ] Because the structure of antibodies , including the juxtaposition of CDRs and framework regions in the vari CCGTGGGCGA CAGAGTGACC ATCACATGCA AGGCCTCTCA able region , the structure of framework regions and the GGACGTGCGG AACACCGTGG CCTGGTATCA GCAGAAAACC structure of heavy - and light- chain constant regions, is well -known in the art , it is well within the skill of the art to GGCAAGGCCC CCAAGCTGCT GATCTACTCC TCCTCCTACC obtain related nucleic acids that encode anti -MMP9 anti bodies . Accordingly , polynucleotides comprising nucleic GGAACAccGG cGTGcccGAc cGGTTTACCG GCTCTGGC?? acid sequences having at least 75 % , at least 80 % , at least CGGCAccGAC TTTAcccTGA cCATCAGCTc ccTGCAGGcc 85 % , at least 90 % , at least 95 % , at least 98 % and at least 99 % homology to any of the nucleotide sequences disclosed GAGGACGTGG ccGTGTACTT CTGCCAGCAG ?????????? herein are also provided . Accordingly , polynucleotides com cccccTACAC c??CGCCGGA GGCACCAACG TGGAAATAAA prising nucleic acid sequences having at least 75 % , at least 80 % , at least 85 % , at least 90 % , at least 95 % , at least 98 % and at least 99 % identity to any of the nucleotide sequences Vk2 : disclosed herein are also provided . In one example , the ( SEQ ID NO : 24 ) polynucleotide contains at least at or about 75 % , 80 % , 85 % , GACATCGTGA TGACCCAGTC CCCCTCCAGC CTGTCCGCCT 90 % , 91 % 92 % 93 % 94 % , 95 % , 96 % , 97 % , 98 % , 99 % or more sequence identity with SEQ ID NO : 21 or includes or ??GTGGGCGA CAGAGTGAcc ATCACATGCA AGGcc????? is SEQ ID NO : 21 and /or contains at least at or about 75 % , GGACGTGCGG AACACCGTGG CCTGGTATCA GCAGAAGCCC 80 % , 85 % , 90 % , 91 % , 92 % , 93 % , 94 % , 95 % , 96 % , 97 % , 98 % , 99 % or more sequence identity with SEQ ID NO : 26 GGCAAGGCCC CCAAGCTGCT GATCTACTCC TCCTCCTACC or includes or is SEQ ID NO : 26 . GGAACAccGG CGTGcccGAC CGGTTTACCG GC???GGC?? Methods CGGCACCGAC TTTACCCTGA CCATCAGCTC CCTGCAGGCC [0140 ] The compositions and methods of the present dis GAGGACGTGG ccGTGTACTT ??GCCAGCAG ?????????? closure , such as MMP9 binding proteins and other thera peutic agents , e . g . , TNFa inhibitors, chemotherapeutic cccccTACAC ???CGGCGGA GGCACCAAGG TGGAAATAAA agents , and immune checkpoint inhibitors , can be used , for example , for treating or preventing diseases and conditions , e . g . , pathological conditions . In certain embodiments , the Vk3 : ( SEQ ID NO : 25 ) disease or condition is selected from myeloid cell - associated GACATCCAGA TGACCCAGTC CCCCTCCAGC CTGTCCGCCT inflammation ; cystic fibrosis , non - cystic fibrosis bronchiec tasis , sarcoidosis , idiopathic pulmonary fibrosis , tuberculo CTGTGGGCGA CAGAGTGACC ATCACATGCA AGGCCTCCCA sis , a cancer, an autoimmune or inflammatory disease or condition , vasculitis , septicemia , multiple sclerosis , muscu GGACGTGCGG AACACCGTGG CCTGGTATCA GCAGAAGCCC lar dystrophy , lupus, allergy, asthma, and hidradenitis sup GGCAAGGCCC CCAAGCTGCT GATCTACTCC TCCTCCTACC purativa . In certain embodiments , the diseases and condi tions include cystic fibrosis , cancer , autoimmune diseases or GGAACACCGG CGTGCCCGAC CGGTTCTCTG GCTCTGGAAG conditions, or inflammatory diseases or conditions . Thus, in CGGCACCGAC TTTAcccTGA CCATCAGCTc CCTGCAGGCC one embodiment, the application provides therapeutic meth ods and uses of the anti -MMP9 antibodies, alone or in GAGGACGTGG ccGTGTACTT ????CAGCAG ?????????? combination with one or more additional therapeutic agents , e . g ., a chemotherapeutic agent, an anti- cancer agent, an CCCCCTACAC CTTCGGCGGA GGCACCAAGG TGGAAATAAA anti - angiogenic agent, an anti - fibrotic agent , an immuno modulating agent, an immunotherapeutic agent, an immune modulating agent, a therapeutic antibody, a radiotherapeutic Vk4 : ( SEO ID NO : 26 ) agent, an anti -neoplastic agent, an anti- proliferation agent, GACATCCAGA TGAC?CAGTc ccccTCCAGc ??GTccGcCT or any combination thereof. [0141 ] Provided herein are methods for treating or pre CTGTGGGCGA CAGAGTGACC ATCACATGCA AGGCCTCTCA venting a disease or disorder , comprising providing to the subject : an effective amount of an Matrix Metalloproteinase GGACGTGCGG AACACCGTGG CCTGGTATCA GCAGAAGCCC 9 (MMP9 ) binding protein ; and , optionally , an effective GGCAAGGccc cCAAGCTGCT GATC?????? ?????????? amount of one or more additional therapeutic agent, thereby treating or preventing the disease or condition in the subject . GGAACACCGG CGTGC?CGAC CGGT?????G GC???GGAAG Examples of MMP9 binding agents and other therapeutic agents that may be used according to the methods described CGGCACCGAC TTTAcccTGA CCATCAGCTc ccTGCAGGCC herein are provided herein . In certain embodiments, an MMP9 binding protein comprises an immunoglobulin heavy US 2017 /0306050 A1 Oct. 26 , 2017 17 chain polypeptide, or functional fragment thereof, and an cell arteritis ) , medium vessel vasculitis ( e . g . , Polyarteritis immunoglobulin light chain polypeptide , or functional frag Nodosa and Kawasaki Disease ) , immune complex small ment thereof, wherein the MMP9 binding protein specifi vessel vasculitis ( e . g . , Cryoglobulinemic vasculitis , IgA cally binds MMP9 . In some embodiments , the MMP9 vasculitis (Henoch - Schonlein ) , and hypocomplementemic binding protein and /or the additional therapeutic agent is urticarial vasculitis ( anti -Clq vasculitis )) , anti- GBM Dis selected from the group consisting of an antibody , a small ease , ANCA -associated small vessel vasculitis ( e . g . , micro molecule and a recombinant molecule. scopic polyangiitis , granulomatosis with polyangiitis [ 0142 ] Also provided is use of: a Matrix Metalloproteinase (Wegner ' s ) , and eosinophilic granulomatosis with poly 9 (MMP9 ) binding protein ; and optionally, one or more angiitis (Churg -Strauss ) ), septicemia ; multiple sclerosis ; additional therapeutic agents , in the manufacture of a medi muscular dystrophy ; lupus ; allergy ; asthma or hidradenitis cament for the treatment or prevention of a disease or suppurativa ; or an inflammatory bowel disease , optionally condition . Examples of MMP9 binding agents and other selected from the group consisting of: ulcerative colitis therapeutic agents that may be used according to the meth (UC ) , Crohn ' s disease (CD ) , or indeterminate colitis . In ods described herein are provided herein . In certain embodi another embodiment, the autoimmune or inflammatory dis ments , an MMP9 binding protein comprises an immuno ease or condition is rheumatoid arthritis , an inflammatory globulin heavy chain polypeptide , or functional fragment bowel disease (IBD ) , septicemia , multiple sclerosis , muscu thereof, and an immunoglobulin light chain polypeptide, or lar dystrophy , lupus , allergy or asthma. In a further embodi functional fragment thereof, wherein the MMP9 binding ment , the inflammatory bowel disease ( IBD ) is ulcerative protein specifically binds MMP9 . colitis (UC ) , Crohn ' s disease (CD ) , or indeterminate colitis . [ 0143 ] As demonstrated in the Examples, expression of [0146 ] In certain embodiments , each therapeutic agent of matrix metalloproteinases (MMPs ) and MMP9 in particular the present disclosure ( e . g ., an antibody that binds MMP9 or is associated with a variety of disease pathologies , including a functional fragment thereof ) is provided to a subject at the autoimmune diseases or conditions , inflammatory diseases interval of one , two or three weeks , or once every one , two , or conditions , and oncology . MMP9 can promote disease or three weeks . In certain embodiments , each therapeutic through its destructive remodeling of basement membrane agent can be provided daily or less frequently than daily, for and other structural proteins , and /or by increasing vascular example , six times a week , five times a week , four times a permeability and bioavailability of growth factors and week , three times a week , twice a week , once a week , once cytokines such as TGF, VEGF, TNFA , IL -6 , and IL - 1 . every two weeks, once every three weeks, once a month , MMP9 regulates the bioavailability of ECM - sequestered once every two months, once every three months , or once VEGF and FGF - 2 , as well as membrane - tethered EGF. As every six months. In some embodiments , the treatment described in the Examples , specific inhibition of MMP9 , includes at least one , at least two, at least three , at least four, using antibodies as described herein , was efficacious in at least five , at least six , at least seven , at least eight, at least accepted mouse models of cancer and inflammatory dis nine , or at least ten administration ( s ) . The compositions may eases, such as vasculitis , breast cancer and colorectal cancer. also be administered in a sustained release formulation , such Furthermore, the combination of an anti -MMP9 antibody as in an implant which gradually releases the composition and a TNFa inhibitor was effective at ameliorating disease for use over a period of time, and which allows for the in a mouse model of rheumatoid arthritis . composition to be administered less frequently , such as once [0144 ] Also provided are pharmaceutical compositions for a month , once every 2 - 6 months, once every year, or even a use in connection with such methods , such as those con single administration . Also , the treatment is continuous . In taining any of the MMP9 binding proteins, antibodies or one embodiment, each therapeutic agent , the composition or fragments thereof described herein , alone or in combination the formulation thereof is provided once a week . In certain with one or more additional therapeutic agent. Compositions embodiments , each therapeutic agent, the composition or the can be suitable for administration locally or systemically by formulation thereof is provided once every two weeks . In any suitable route . some embodiments , each therapeutic agent is provided at [0145 ] In general, therapeutic agents of the present dis different frequencies . In one embodiment, the antibody that closure are provided to a subject in a therapeutically effec binds MMP9 or a functional fragment thereof is adminis tive amount. In some embodiments , a therapeutic agent is tered once a week , while the TNFa inhibitor is administered provided to a subject in an amount to effect inhibition of once a month . In another embodiment, the antibody that MMP9 activity , to inhibit TNFa , to inhibit immune check binds MMP9 or a functional fragment thereof is adminis point mediators , or to treat myeloid cell -associated inflam tered once a week , while the immune checkpoint inhibitor is mation . In some embodiments , the disease or condition is : administered once a month . cystic fibrosis ; non - cystic fibrosis bronchiectasis ; sarcoido [0147 ] Each therapeutic agent of the present disclosure sis ; idiopathic pulmonary fibrosis ; tuberculosis ; a cancer , ( e . g ., an antibody that binds MMP9 or a functional fragment optionally selected from the group consisting of pancreatic thereof ) can be administered to an individual via any route , cancer, esophagogastric adenocarcinoma, non - small cell including, but not limited to , intravenous ( e . g . , by infusion lung cancer, lung squamous cell carcinoma , lung adenocar pumps ) , intraperitoneal, intra -arterial , intrapulmonary , oral, cinoma, gastric adenocarcinoma , colorectal carcinoma , pan inhalation , intravesicular, intramuscular, intra - tracheal, sub creatic adenocarcinoma , head and neck squamous cell car cutaneous, intrathecal, transdermal , transpleural, topical , cinoma, hepatocellular carcinoma, colorectal cancer, inhalational ( e . g . , as mists of sprays ) , mucosal (such as via colorectal adenocarcinoma and hepatocellular carcinoma; an nasal mucosa ) , subcutaneous , transdermal, gastrointestinal , autoimmune or inflammatory disease or condition , option intraarticular , intracisternal, or intraventricular. In some ally selected from the group consisting of rheumatoid arthri embodiments , the compositions are administered systemi tis , an inflammatory bowel disease ( IBD ) , vasculitis ( option cally ( for example by intravenous injection ) . In some ally large vessel vasculitis ( e . g . , Takayasu arteritis and Giant embodiments , each therapeutic agent is administered locally US 2017 /0306050 A1 Oct. 26 , 2017

( for example by intra - arterial or injection ). In some embodi venously at about 200 mg every two weeks. In one embodi ments , each therapeutic agent is administered subcutane ment, each therapeutic agent, the composition or the formu ously . In some embodiments, each therapeutic agent is lation thereof is administered subcutaneously ( i. e . administered intradermally . In some embodiments , each subcutaneous injection ) at about 150 mg once a week . In one therapeutic agent is administered via inhalation . In some embodiment, each therapeutic agent , the composition or the embodiments , each therapeutic agent is administered formulation thereof is administered subcutaneously at about mucosally. In one embodiment, each therapeutic agent , the 300 mg every two weeks . In some embodiments , each composition or the formulation thereof is delivered by therapeutic agent is administered at a dose , frequency and intravenous administration ( i . e . intravenous infusion ) twice route that are distinct from the dose , frequency and route of every two weeks. In certain embodiments , each therapeutic another therapeutic agent . agent, the composition or the formulation thereof is deliv 10149 ] The selected dosage regimen will depend upon a ered by subcutaneous administration once every week . In variety of factors including the activity of the therapeutic some embodiments , each therapeutic agent is administered agent, the route of administration , the time of administra via different routes. In one embodiment, the antibody that tion , the rate of excretion of the particular compound being binds MMP9 or a functional fragment thereof is adminis employed , the duration of the treatment, other drugs , com tered subcutaneously , while the TNFa inhibitor is adminis pounds and /or materials used in combination with the par tered subcutaneously or intravenously . In another embodi ticular composition employed , the age , sex, weight, condi ment, the antibody that binds MMP9 or a functional tion , general health and prior medical history of the patient fragment thereof is administered subcutaneously , while the being treated , and like factors well known in the medical immune checkpoint inhibitor is administered subcutane arts . ously or intravenously . [0150 ] In some embodiments , dosage is determined based [0148 ] In some embodiments , each therapeutic agent of on a pharmacokinetic model for antibodies displaying tar the present disclosure ( e . g . , an antibody that bindsMMP9 or get -mediated disposition . In contrast to the relatively linear a functional fragment thereof) is administered at about 25 pharmacokinetics observed for antibodies directed to mg per subject to about 800 mg per subject or at the soluble receptor targets , antibodies directed toward tissue recommended dosage for the particular therapeutic agent. In based target receptors frequently demonstrate non -linear some embodiments , each therapeutic agent is administered pharmacokinetics . Mager , D . E . ( 2006 ) , Adv Drug Deliv at about 50 mg, about 100 mg, about 200 mg, about 300 mg, Rev 58 ( 12 - 13 ) : 1326 - 1356 . The basis for non - linear dispo about 400 mg, about 500 mg, about 600 mg, about 700 mg, sition relates to the high affinity binding of antibody to target or about 800 mg per subject, including any range in between and the extent of binding ( relative to dose ) , such that the these values . In certain embodiments , each therapeutic agent interaction is reflected in the pharmacokinetic characteristics is administered at about 150 mg, about 250 mg, about 350 of the antibody. Mager , D . E . and W . J. Jusko ( 2001 ), J mg, about 450 mg, about 550 mg, about 650 mg, or about Pharmacokinet Pharmacodyn 28 (6 ): 507 - 532 . Included 750 mg per subject, including any range in between these within target mediated drug disposition is receptor- mediated values . In some embodiments , each therapeutic agent of the endocytosis (internalization ) of the antibody - receptor com above dosage is administered once a week , once every two plex . Wang , W . , E . Q . Wang , et al. ( 2008 ) , Clin Pharmacal weeks, once every three weeks , once a month , once every Ther 84 ( 5 ) : 548 -558 . two months , once every three months , or once every six [0151 ] In a pharmacokinetic model for an antibody having months. In some embodiments , each therapeutic agent is target -mediated disposition , in the absence of drug (anti administered at about 400 mg every two weeks. In certain body ) , the target receptor is synthesized at a constant rate embodiments , each therapeutic agent is administered to the and eliminated by a first- order process . As a result, the target subject at a dosage of about 200 mg every two weeks . In receptor exists at a steady - state concentration in the absence certain embodiments, each therapeutic agent is administered of drug (antibody ) . When drug is added to the body it can at about 150 mg once a week . In certain embodiments , each interact with the target receptor in a bimolecular reaction , therapeutic agent is administered at about 300 mg once a distribute into less well perfused tissue , or be eliminated via week . In certain embodiments , each therapeutic agent is first -order processes. At low drug concentrations the pre administered to the subject in a two -step procedure : first, a dominant movement of drug is onto the receptor due to the loading dose phase (more frequent dosing to cover the high affinity binding . As the amount of drug entering the " target sink ” /“ tissue and serum sink ” or high baseline con body becomes sufficient to bind the available mass of centration ofMMP9 associated with the disease , wherein the receptor the drug distributes into and out of tissue and is dosing range is administered to the subject at a dosage of eliminated . As drug concentrations fall and drug equilibrates about 200 mg, about 300 mg, or about 400 mg every week from tissue this provides an additional reservoir to binding for an interval of one , two or three weeks , or more frequent newly synthesized receptor. dosing to cover the “ target sink ” or high baseline concen [0152 ] A clinician having ordinary skill in the art can tration of MMP9 associated with the disease ) and second , readily determine and prescribe the effective amount (ED50 ) once a predictable PK has been established after the loading of the pharmaceutical composition required . For example , dose phase , a lower weekly dose such as 150 , 125 , 100 or 50 the physician or veterinarian can start doses of the com mg /week . In some embodiments, the lower weekly dose pounds of the disclosure employed in the pharmaceutical could be lower on a weekly basis , e . g . , 150 , 125 , 100 or 50 composition at levels lower than that required in order to mg/ week . In one embodiment, each therapeutic agent, the achieve the desired therapeutic effect and gradually increase composition or the formulation thereof is administered intra the dosage until the desired effect is achieved . venously ( i . e . intravenous infusion ) at about 400 mg every [0153 ] In some cases, the methods of treatment include two weeks . In one embodiment , each therapeutic agent, the parenteral administration , e. g . , intravenous, intra -arterial , composition or the formulation thereof is administered intra intradermal, intramuscular , or subcutaneous administration , US 2017 /0306050 A1 Oct. 26 , 2017 or oral administration of the agent, e . g ., anti -MMP9 anti esophagogastric adenocarcinoma, non -small cell lung can body or composition containing the same; TNFa inhibitor or cer , ulcerative colitis , colorectal cancer , Crohn ' s disease , or composition containing the same; immune checkpoint rheumatoid arthritis . In some aspects of such embodiments , inhibitor or composition containing the same. the patients are administered the anti -MMP9 antibody or [0154 ] In some embodiments , the subject treated has been antigen binding fragment thereof intravenously at a dosage diagnosed with , is diagnosed with , or is considered at risk of of 100 , 200 , 300 , 400 , 500 , 600 , 700 , 800 , 900 , 1000 , 1100 , developing a disease or condition , e . g . , cystic fibrosis ; a 1200 , 1300 , 1400 , 1500 , 1600 , 1700 , or 1800 mg, at the cancer , optionally selected from the group consisting of interval of one , two or three weeks . In some aspects , the pancreatic cancer, esophagogastric adenocarcinoma , non appropriate dosage is made with 0 . 9 % sodium chloride . In small cell lung cancer , lung squamous cell carcinoma, lung some aspects , the patients receive the antibody , e . g . , adenocarcinoma, gastric adenocarcinoma , colorectal carci AB0045 , as monotherapy or as part of a combination noma, pancreatic adenocarcinoma, head and neck squamous therapy with other therapeutic agents . cell carcinoma, hepatocellular carcinoma, colorectal cancer , [0158 ] In some embodiments , for pancreatic adenocarci colorectal adenocarcinoma and hepatocellular carcinoma ; an noma, the anti- MMP9 antibody or antigen binding fragment autoimmune or inflammatory disease or condition , option thereof is administered alone at the two -week interval or ally selected from the group consisting of rheumatoid arthri with the 28 -day cycle chemotherapy of gemcitabine and/ or tis , an inflammatory bowel disease (IBD ) , vasculitis (option nab -paclitaxel . ally large vessel vasculitis ( e . g ., Takayasu arteritis and Giant [0159 ] In some embodiments , for esophagogastric adeno cell arteritis ), medium vessel vasculitis (e . g ., Polyarteritis carcinoma, the anti -MMP9 antibody or antigen binding Nodosa and Kawasaki Disease ), immune complex small fragment thereof is administered alone at the two -week vessel vasculitis ( e . g . , Cryoglobulinemic vasculitis , IgA interval or with the 28 -day cycle chemotherapy of mFOL vasculitis (Henoch - Schonlein ), and hypocomplementemic FOX6 that is administered in a 28 -day cycle . urticarial vasculitis ( anti -C1q vasculitis )) , anti -GBM Dis [0160 ] In some embodiments , for non - small cell lung ease , ANCA -associated small vessel vasculitis ( e . g . , micro cancer, the anti -MMP9 antibody or antigen binding frag scopic polyangiitis , granulomatosis with polyangiitis ment thereof is administered alone at the three -week interval (Wegner ' s ), and eosinophilic granulomatosis with poly or with the 21 -day cycle chemotherapy of carboplatin and angiitis (Churg -Strauss ) ) , septicemia , multiple sclerosis , paclitaxel or with pemetrexed and/ or bevacizumab . muscular dystrophy, lupus, allergy, asthma or hidradenitis [0161 ] In one example , for colorectal cancer , the anti suppurativa ; or an inflammatory bowel disease , optionally MMP9 antibody or antigen binding fragment thereof is selected from the group consisting of: ulcerative colitis administered alone at a two -week interval or with a 14 - day ( UC ), Crohn ' s disease (CD ), or indeterminate colitis . In cycle chemotherapy of FOLFIRI. In some aspects of the another embodiment , the autoimmune or inflammatory dis combination treatments , the chemotherapy or immuno ease or condition is rheumatoid arthritis , an inflammatory therapy agent is administered with the known dosage and bowel disease ( IBD ) , septicemia , multiple sclerosis, muscu procedure . lar dystrophy, lupus, allergy or asthma. In a further embodi [0162 ] In some aspects , the dosage ofMMP9 antibody can ment, the inflammatory bowel disease ( IBD ) is ulcerative be adjusted and administered at about 133 , about 267, about colitis (UC ) , Crohn ' s disease (CD ) , or indeterminate colitis . 400 , about 600 or about 1200 mg. After each therapeutic In certain embodiments , the subject is a human having cystic cycle , the patients are monitored for the levels of MMP9 fibrosis , a cancer, an inflammatory disease or condition , or antibodies, MMP9 , or other suitable biomarkers . an autoimmune disease or condition , and can be treated as [0163 ] In some embodiments , the treatment methods described herein . In certain embodiments, the subject is a include steps for monitoring treatment, including for moni human . toring efficacy or activity , such as pharmacodynamic activ [0155 ] In certain embodiments , the subject or diseased ity . In some examples , such methods include detecting or cells of the subject overexpress MMP9 , e . g ., express at least measuring the presence , absence , levels , and/ or expression 1. 2 - fold , at least 1 . 5 -fold , at least 2 -fold , at least 3 -fold , at ofmarkers , such as cytokines and other inflammatory mark least 5 - fold , or at least 10 - fold higher amounts of MMPs ers that are indicative of efficacy of treatment, in biological than a control subject or non - diseased cells. test samples obtained from subjects being treated using the 101561. In certain embodiments , any of the methods methods and compositions . The samples typically are blood described herein further comprises determining an amount samples or serum samples but can include other biological of MMP9 , e . g ., active MMP9 , present in the subject or tissue samples as described herein . Among the markers for use in or cells therefrom , e . g ., diseased tissue or cells obtained such methods are Tissue Inhibitor of Metalloproteinases 1 from the subject, and comparing the amount to a control ( TIMP - 1 ) , Tumor Necrosis Factor alpha ( TNF - alpha ) , Mac amount, such as a predetermined control value or an amount rophage Inflammatory Protein - 2 (MIP - 2 ) , Interleukin - 17A determined from a normal subject or normal tissue or cells . ( IL - 17A ) , CXCL10 , Lymphotactin , Macrophage Inflamma In certain embodiments , the subject is provided with the tory Protein - 1 beta (MIP - 1 beta ) , Oncostatin - M ( OSM ) , MMP9 binding protein and immune modulatory agent if the Interleukin - 6 ( IL - 6 ) , Monocyte Chemotactic Protein 3 amount of MMP9 determined for the subject is higher than (MCP - 3 ) , Vascular EndothelialGrowth Factor A (VEGF - A ) , the control amount, e . g ., at least 1 . 2 - fold , at least 1. 5 -fold , at Monocyte Chemotactic Protein - 5 (MCP - 5 ) , Interleukin - 1 least 2 - fold , at least 3 - fold , or at least 5 - fold higher than the alpha (IL -1 alpha ), Macrophage Colony - Stimulating Fac control amount, but is not treated if the amount of MMP9 tor - 1 ( M -CSF - 1 ), Myeloperoxidase (MPO ), Growth -Regu determined for the subject is not higher than the control lated Alpha Protein (KC /GRO ), Interleukin -7 ( IL -7 ), Leu value . kemia Inhibitory Factor (LIP ) , Apolipoprotein A - I (Apo [0157 ] In some embodiments , the antibody, e . g ., AB0045 , A - I ) , C -Reactive Protein (CRP ) , Granulocyte Chemotactic is used in treating patients having advanced pancreatic or Protein - 2 (GCP - 2 ) , Interleukin - 11 ( IL - 11) , Monocyte US 2017 /0306050 A1 Oct. 26 , 2017 20

Chemotactic Protein 1 (MCP - 1 ), von Willebrand factor colorectal adenocarcinoma and hepatocellular carcinoma . In ( VWF) , and Stem Cell Factor (SCF ) gene products . In some certain embodiments , the autoimmune or inflammatory dis embodiments , the markers are selected from among ease or condition is selected from rheumatoid arthritis , an KC /GRO , LIP , CXCL10 , MPO , MIP - 2 , and MCP- 5 gene inflammatory bowel disease ( IBD ), vasculitis , septicemia , products , for example , when the diseases is IBD , such as multiple sclerosis , muscular dystrophy, lupus , allergy, UC . asthma and hidradenitis suppurativa . In certain embodi [0164 ] In some embodiments , after each therapeutic cycle , ments , the inflammatory bowel disease is selected from the the patients are monitored for the levels of MMP9 antibod group consisting of: ulcerative colitis (UC ) , Crohn ' s disease ies , MMP9 , or other suitable biomarkers . (CD ) , or indeterminate colitis . In other embodiments , the [0165 ] Among the provided methods are those that pro autoimmune or inflammatory disease or condition is rheu vide improved safety profiles compared to available treat matoid arthritis , an inflammatory bowel disease ( IBD ) , ments and therapeutic regimens and /or sustained long - term septicemia, multiple sclerosis , muscular dystrophy , lupus, efficacy in treating such diseases and conditions . allergy or asthma . In a further embodiment , the inflamma tory bowel disease (IBD ) is ulcerative colitis (UC ) , Crohn ' s Diseases and Conditions disease (CD ) , or indeterminate colitis. In yet another [ 0166 ] Compositions, methods and kits described herein embodiment, the vasculitis is large vessel vasculitis ( e. g . , are used to treat a variety of diseases and conditions, e . g . , Takayasu arteritis and Giant cell arteritis ) , medium vessel pathological conditions, including but not limited to any of vasculitis ( e .g ., Polyarteritis Nodosa and Kawasaki Dis those described herein . ease ) , immune complex small vessel vasculitis ( e . g . , Cryo [ 0167 In certain embodiments , any of the compositions globulinemic vasculitis , IgA vasculitis (Henoch - Schonlein ), and methods described herein are used to treat or prevent a and hypocomplementemic urticarial vasculitis (anti -Clq disease or condition , e .g ., a disease or condition associated vasculitis ) ), anti -GBM Disease , ANCA -associated small with MMP9 . An MMP9 -associated disease or condition vessel vasculitis (e . g ., microscopic polyangiitis , granuloma includes a disease or condition where MMP9 expression or tosis with polyangiitis (Wegner ' s ), or eosinophilic granulo activity is deregulated and /or where the disease or condition matosis with polyangiitis (Churg - Strauss ). can be treated or prevented with one or more modulators of [0169 ] In some embodiments , the methods and composi MMP9 , such as an MMP9 binding protein comprising an tions described herein , e . g ., antibodies and fragments immunoglobulin heavy chain polypeptide , or functional thereof, are used in the treatment of inflammatory and fragment thereof, and an immunoglobulin light chain poly autoimmune disease , e . g. , by inhibiting MMP9 in subjects peptide , or functional fragment thereof, wherein the MMP9 having such diseases or conditions . Among the inflamma binding protein specifically binds MMP9 , optionally in tory and autoimmune diseases are inflammatory bowel dis combination with one or more additional therapeutic agent. ease (IBD ) ( including Crohn ' s disease , ulcerative colitis In one embodiment, the disease or condition is associated (UC ) , and indeterminate colitis ) , collagenous colitis , rheu with an increase in total MMP9 protein in the subject or matoid arthritis , septicemia , multiple sclerosis , muscular diseased cells, as compared to a normal control. In yet dystrophy , lupus, allergy , septicemia , and asthma . another embodiment , the MMP9 -associated disease or con [0170 ] As described in the Examples , MMP9 and other dition is associated with an increase in , or elevated levels of, MMPs are involved in inflammatory and autoimmune dis active MMP9 protein in the subject having the disease or eases . Matrix metalloproteinase - 9 (MMP9 ) is induced in the disorder or diseased cells therefrom , as compared to a serum , synovial fluid , and synovium of RA patients , and the normal control. As described in the Examples , high levels of MMP9 / TIMP - 1 ratio is altered in favor of increased pro active MMP9 or total MMP9 are detected in tissues from teolytic activity . MMP9 is secreted by disease- mediating patients suffering from diseases such as ulcerative colitis , osteoclasts and activated cells of the monocyte /macrophage Crohn ' s disease , vasculitis , and cystic fibrosis , or in an lineage . Resistance to antibody - induced arthritis disease animalmodel of colorectal cancer. In certain embodiments , phenotypes is observed in a MMP9 knock - out mouse strain . the MMP9 - associated disease or disorder is associated with MMP9 degrades the unwound collagen II created by the a level of active MMP9 protein at least 1 . 1 - fold , at least cleavage activity of collagenases, such as MMP8 , and 1 . 2 - fold , at least 1 . 5 - fold , at least 2 - fold , at least 3 - fold , or thereby contributes to the destruction of articular cartilage . at least 5 - fold the level of active MMP9 protein in a normal [0171 ] As shown in the Examples herein , anti -MMP9 control subject or normal control cells . In certain embodi antibodies were effective in various inflammatory and auto ments , a normal control subject is a subject not diagnosed immune diseases, including vasculitis and rheumatoid with or having the disease or condition , and normal control arthritis (RA ) in animal models . Thus, in some embodi cells are non - diseased cells of the same type as the diseased ments , the methods, compositions, and kits described herein cells of the subject. are used to treat subjects having inflammatory and autoim 10168 ] In one embodiment, the MMP9 - associated disease mune diseases . In some embodiments , the methods, com or condition comprises myeloid cell -associated inflamma positions, and kits are used to treat subjects having a cancer. tion . In some embodiments , theMMP9 -associated disease or In some embodiments , the inhibitors , methods , and kits are condition is : cystic fibrosis , a cancer , or an autoimmune or used to inhibit MMP9 without inhibiting other MMPs, such inflammatory disease or condition . In certain embodiments, as without inhibiting MMP2 , or without inhibiting such the cancer is selected from the group consisting of: pancre other MMPs to a substantial degree . In one embodiment, the atic cancer , esophagogastric adenocarcinoma, non - small cell methods protect against or reduce tissue injury , systemic lung cancer, lung squamous cell carcinoma, lung adenocar inflammation , and/ or local inflammation in a subject having cinoma, gastric adenocarcinoma , colorectal carcinoma , pan such a disease or condition ; in some examples , both tissue creatic adenocarcinoma, head and neck squamous cell car - injury and inflammation are treated by the methods . In cinoma, hepatocellular carcinoma, colorectal cancer, another embodiment, the methods are associated with US 2017 /0306050 A1 Oct . 26 , 2017 21 reduced toxicity and / or reduced induction of musculoskel etal syndrome (MSS ) or similar symptoms, compared to that TABLE 1B - continued observed with pan -MMP inhibitors , such as Marimastat. In UC Mayo Score some examples , the subject has had an inadequate response to another therapy for the inflammatory disease , such as a Subscore Definition TNF -antagonist , such as an anti- TNF antibody, e . g . , inflix Moderate disease imab , i. e ., has TNF -antagonistic refractive disease . Thus, Nm Severe disease among the provided methods are those effective at treating inflammation in such subjects . Illustrative , non - limiting dis ease and disorders that may be treated or prevented using [0176 ] As described in the Examples , evidence supports a composition and methods of the present disclosure are role for MMP9 in the pathology of ulcerative colitis ( UC ) described . and other inflammatory bowel diseases (IBDs ) . Broad -spec [0172 ] Inflammatory Bowel Disease trum MMP inhibitors are efficacious in TNBS and DSS [0173 ] Inflammatory bowel diseases ( IBDs) include but models of colitis (Naito and Yoshikawa 2005 ; Medina and are not limited to Crohn 's disease , ulcerative colitis (UC ), Radomski 2006 ). While MMPI and MMP2 are the two most and indeterminate colitis ). Ulcerative colitis (UC ) is one of closely related MMPs , with similar substrate specificities , the two major IBDs, characterized by diffuse mucosal MMP9 protein and activity are induced to a greater extent in inflammation , and associated ulceration , of the colon . The IBD and preclinical colitis animalmodels and more strongly chronic course of UC includes intermittent disease exacer induced and associated with progressive disease in human bations followed by periods of remission . Many patients UC ; MMP2 is more ubiquitously expressed and plays is experience insufficient response to agents such as anti important for homeostasis of non - diseased tissue . Lack of TNFa targeted therapeutics and continue to suffer from MMP9 protects against colitis in the mouse dextran sodium disease -related symptoms. Patients with UC have a signifi sulfate (DSS ) - induced model, while MMP2 serves a pro cantly elevated risk of colon cancer after 8 - 10 years of tective function for the colon . Neutrophil and lymphocyte disease activity . accumulation in the DSS model is MMP9 - dependent; there [ 0174 ] Inflammatory bowel disease ( IBD ) therapeutics is evidence for epithelial cell -derived MMP9 contribution to can modulate disease by preventing recruitment and access tissue damage . of inflammatory cells to the disease site , preventing activa [0177 ] MMP9 was detected in human UC tissues , not in tion of cells at the disease site, and / or inhibiting the down healthy colonic crypts ( in which the distinct ring of collagen stream effects of cell activation . IV staining marked intact basement membranes ) , but in [0175 ] UC pharmacologic treatment generally proceeds areas of disorganized collagen IV , which indicates loss of by line ' based on disease severity and the location or extent basement membrane integrity . MMP9 degrades collagen IV of the disease . Disease severity is characterized as mild , and other ECM components , allowing infiltration of inflam moderate or severe based on patient symptoms, endoscopic matory cells. In colitis , MMP9 activity in the mucosa can findings , and laboratory results and in the clinical trial lead to degradation of the basementmembranes underlying setting often defined by the Mayo Score , as shown in Table crypts , and mucosal damage and exposure of the submucosa 1B . to luminal bacteria . MMP9 degradation of the basement membrane around blood vessels can promote extravasation TABLE 1B of leukocytes to the disease site. MMP9 activity in the extracellular matrix can activate and release inflammatory UC Mayo Score cytokines such as TNFO , IL - 6 , and IL1- B that contribute to Subscore Definition disease progression . Stool Frequency [0178 ] Available UC therapies have not been entirely Normal for the patient satisfactory . For example , different treatments generally are 1 - 2 stools more than normal given based on severity , location and / or extent of disease . 3 - 4 stools more than normal For less severe disease , treatments include 5 -aminosalicy WNA 25 stools more than normal late ( 5 ' -ASA ) enemas , corticosteroid enemas and oral Rectal Bleeding 5 '- ASA preparations. Patients with more severe disease ,

O No blood seen and / or those failing to respond to first line therapies are Streaks of blood with stool less than half generally treated with a course of oral corticosteroids. of the time Immunomodulators such as azathioprine and 6 -mercaptopu Obvious blood with stool most of the time rine (6 -MP ) are used to help wean subjects off steroids and Blood alone passes to maintain remission . Anti - TNFa therapy, e . g ., the chimeric IWNFindings on Endoscopy antibody Remicade® ( infliximab ) is generally used in Normal or inactive disease patients with more severe disease and for patients who are - Mild disease (erythema , decreased refractory to or dependent upon corticosteroids . Infliximab vascular pattern , mild friability ) Moderate disease (marked erythema, lack treatment generally fails to induce and maintain steroid - free of vascular pattern , friability , erosions) remission over the long term . Only 20 % of patients achieve 1 Severe disease ( spontaneous bleeding a remission by week 8 and remain in remission through 54 ulceration ) weeks , with the majority of patients relapsing by week 30 . Physician ' s global assessment Only 26 % of patients were able to achieve a long - term Normal remission completely free of corticosteroids. When the less Mild disease stringent endpoint of response is evaluated instead of remis sion (indicating an incomplete reduction in symptoms) , US 2017 /0306050 A1 Oct. 26 , 2017 approximately 60 % of patients fail to maintain this degree of point and a 30 % reduction in the Mayo Score with at least relief over 30 or 54 weeks . Thus it may be beneficial to use a 1 point reduction in the rectal bleeding subscore or an anti -MMP9 antibodies or antigen binding fragments thereof absolute rectal bleeding subscore of 0 - 1 . In some embodi as an add - on therapy with TNFa inhibitors for patients who ments , “ remission ” is defined as a Mayo scores2 , with no still have disease despite receiving anti - TNFa therapy. individual subscore > 1 . In some embodiments , “ mucosal [0179 ] Cyclosporine has helped delay the need for surgery healing ” is defined as an endoscopic subscore to sl . In some in patients hospitalized for fulminant UC , but its efficacy as embodiments , " steroid sparing" is defined as remission in a maintenance therapy has not been established . Surgery , the absence of ongoing steroid use for those patients who consisting of a two - step total colectomy with ileal pouch began on steroids . In some embodiments , quality of life is an anal anastomosis ( IPAA ) is curative. A total colectomy is , endpoint and is assessed using known methods , such as a however , is an undesirable outcome for many patients , validated quality of life measure such as the IBD -QOL or the committing them to lifelong frequent bowel movements , a SF - 36 . high risk of sexual dysfunction , and a 50 % risk of devel [0185 ] Crohn ' s disease ( CD ) is a chronic inflammatory oping pouchitisan inflamed J pouch that results in diarrhea disorder of the gastrointestinal tract defined by relapsing and with or without rectal bleeding , tenesmus, urgency, pain , remitting episodes, with progression to complications such incontinence and fevers . Furthermore , the risk of female as fistula formation , abscesses , or strictures . Extraintestinal infertility is highly increased following IPAA surgery . manifestations such as uveitis , arthritis , skin lesions , and [0180 ] As shown in WO 2013 / 130905 , which is herein kidney stones occur in upwards of 40 % of patients . The incorporated in its entirety , specific anti -MMP9 antibodies treatment paradigm for mild - to -moderate Crohn ' s has been were demonstrated as effective in an accepted UC animal antibiotics such as ciprofloxacin and flagyl, 5 - ASAs , budes model, effectively protecting against tissue destruction and onide , or systemic corticosteroids , however , the long - term aberrant tissue remodeling , as well as local and systemic side effects of systemic steroids greatly dampens their utility . downregulation of pro - inflammatory factors . The antibodies Patients with mild - to -moderate disease who fail these first had robust efficacy on multiple endpoints in treatment of line therapies are often placed on the on azathioprine remain DSS - induced colitis in mice , a well - established preclinical in remission at one -year . For patients who fail azathioprine model used for evaluation of agents being considered for or those with more severe disease , TNF - a blockade with treatment of UC . Thus, in some embodiments, the methods agents such as infliximab remain the last option . As opposed and compositions are used to treat a subject with an inflam to UC where surgical resection is curative , such therapy is matory bowel disease , such as ulcerative colitis (UC ) , more difficult for Crohn ' s patients for two reasons : 1 ) Crohn ' s disease , or indeterminate colitis . In some embodi disease is diffuse throughout the GI tract and in instances of ments , the methods and antibodies inhibit the MMP9 with isolated disease (e . g ., terminal ileum ), resection is frequently out inhibiting other MMPs, such as MMP2 . associated with recurrent disease at the site of the resection [ 0181 ] In some examples, the methods and compositions 2 ) since the disease is transmural, surgical resection places protect against destruction of basement membrane , mucosal patients at risk for future stricture and / or fistula develop damage, exposure of submucosa to luminal bacteria , inflam ment . mation , cytokine activation and leukocyte extravasation . In [0186 ] While combination therapy using azathioprine and some embodiments , the subject has moderate to severe UC , infliximab may be superior to either therapy alone for e . g . , has severe UC . In some embodiments , the subject has induction of remission and mucosal healing at 26 weeks , the steroid dependent UC . In some aspects , the treatmentmeth concurrent use of such agents increases the risk of infection ods replace or are administered as an alternative to corti and malignancy (hepatosplenic T cell lymphoma) , limiting costeroid treatment. their utility . As with UC , response , remission , mucosal [0182 ] In some embodiments , the subject treated has been healing , steroid sparing and quality of life will all be non - responsive to other UC therapies , such as TNF ( e . g . , important endpoints , but in CD the Crohn ' s Disease Activity TNF- alpha or TNF -a ) antagonists , such as anti - TNF anti Index (CDAI ) is generally the validated outcome instrument bodies ( such as infliximab and / or adalimumab ) , i . e . , TNF of choice and is described in Table 1C : antagonist- refractory patients . For example , in some embodiments , the subject is a patient who has failed to TABLE 1C achieve long - term remission on infliximab therapy or other Crohn ' s Disease Activity Index : TNF - alpha targeting treatment. In other cases , the subject has been non -responsive to another UC therapy such as oral METRIC VALUE FORMULA or rectal application treatments such as enemas , supposito Liquid stools Daily total x 7 days Total Sum x 2 ries and foam ) , 5 - aminosalicylic acid ( 5 - ASAs) , oral and Abdominal Pain Daily total 7 days Sum x 5 rectal application corticosteroids, immunosuppressants such NONE = 0 Intermediate = 1 as 6 -mercaptopurine , azathioprine , methotrexate , and / or Severe = 3 cyclosporine . In some aspects, the methods provide treat General well being Daily total 7 days Sum x 7 ment with an improved safety protocol as compared to such Well = 0 treatments , or provide treatment with more sustained , long Intermediate = 1 , 2 , term efficacy . In some embodiments , the subject is treated Extra - intestinal One point for each : Score x 20 with a combination of an anti- MMP9 therapeutic and an Arthritis / arthralgia anti - TNFa therapeutic . Iritis /uveitis Skin /mouth ulcers [0183 ] In some cases , the methods inhibit MMP9 without Peri - anal disease affecting other MMPs, such as MMP2 . Other fistula [0184 ] In some embodiments , in the context of UC , Fever > 37 . 8 C . “ response " to treatment is achieved if there is at least a 3 US 2017 /0306050 A1 Oct. 26 , 2017 23

TABLE 1C - continued trate resistant acid phosphatase (TRAP ) positive mononu clear and multinucleated cells are often found in the syn Crohn ' s Disease Activity Index : ovium at the sites of cartilage and bone destruction . TRAP positive multinucleated cells from RA patients , including METRIC VALUE FORMULA osteoclasts , secrete MMP9 and are key participants in joint Anti- diarrheal use YES /NO Value x 30 destruction . Furthermore , MMP9 has been shown to play a Abdominal Mass None = 0 Value x 10 Questionable = 2 critical role in osteoclast invasion . Studies in a variety of Hematocrit (Hct ) Males : 47 - Hct Value x 6 different disease models and correlations in human disease Females : 42 -Hct support a role for MMP9 in driving inflammation through Weight | OCCASIONALLY USED increased vascular permeability and through promoting the Score < 150 = Remission activation or increasing the bioavailability of cytokines and Moderate Disease 2220 growth factors . Selective inhibition of MMP9 has the poten Severe disease 2450 tial to slow and / or halt progression of bone and joint erosion , Response to therapy = decrease of greater than 70 or alternatively 100 point decrease can be used to define response . as well as to reduce inflammation . [ 0187 ] In some embodiments , the subject has moderate to [0192 ] Cystic Fibrosis severe CD , e . g . , has severe CD . In some embodiments , the [0193 ] Cystic fibrosis (CF ) affects approximately 100 ,000 subject has steroid dependent CD . In some aspects , the people worldwide . CF is the most common life - shortening treatment methods replace or are administered as an alter genetic disorder in Caucasians, with a median age of death native to corticosteroid treatment. of 27 . 5 years in the US and 28 . 0 years in the EU . CF is an 10188 ] In some embodiments , the subject has been non autosomal recessive disorder characterized by progressive , responsive to other CD therapies , such as TNF antagonists , obstructive pulmonary disease. Patients with CF are particu such as anti- TNF antibodies (such as infliximab and / or larly susceptible to chronic airway infections with opportu adalimumab ) , i . e . , TNF antagonist - refractory patients . For nistic bacteria such as Staphylococcus aureus, Haemophilus example , in some embodiments , the subject is a patient who influenzae , Pseudomonas aeruginosa ( PA ), Stenotrophomo has failed to achieve long -term remission on infliximab nas maltophilia , Achromobacter species , and Burkholderia therapy or other TNF - alpha targeting treatment. In other species . cases , the subject has been non -responsive to another CD [0194 ] The majority (70 % ) of patients with CF die of therapy . In some aspects , the methods provide treatment cardiorespiratory failure. This is the end result of a continu with an improved safety protocol as compared to such ous cycle of airway obstruction , inflammation , and infection treatments , or provide treatment with more sustained , long leading to bronchiectasis , parenchymal destruction , and loss term efficacy . In some embodiments , the subject suffering of pulmonary function . Patients also experience episodes of from Crohn ' s is treated with a combination of an anti acute pulmonary exacerbation , which is characterized by MMP9 therapeutic and an anti - TNFa therapeutic . worsening respiratory symptoms and an acute decline in [0189 ] Rheumatoid Arthritis lung function . [0190 ] Rheumatoid arthritis (RA ) is a chronic , systemic inflammatory disease that affects approximately 1 . 3 million [0195 ] The current standard of care in CF includes treat adults in the United States (US ) . Rheumatoid arthritis mani ment with inhaled anti -pseudomonal antibiotics ( eg , fests principally as an attack on peripheral joints and may tobramycin and Cayston® ) and mucolytics ( eg , dornase ) . lead to marked destruction and deformity of joints, with Recently , two CF transmembrane conductance regulator considerable disability and impact on quality of life . It is (CFTR ) modulator therapies have been approved for treat characterized by the production of autoantibodies , synovial ment of CF patients with select genetic mutations . Ivacaftor inflammation with formation of pannus tissue , and erosion (Kalydeco® ) has been approved for CF patients who carry of underlying cartilage and bone. Although people of any one of the G551D CFTR gating mutations . The other is a age can be affected , the onset of RA is most frequent combination product combining ivacaftor with lumacaftor between the ages of 40 and 50 years , and women are affected for CF patients who are homozygous with the most common 3 times more often than men . While the cause of RA is still CF mutation , F508del. Both drugs improve lung function not completely understood , aberrant B -cell activation , T -cell and reduced pulmonary exacerbations. While current CTFR co - stimulation , osteoclast differentiation , and cytokine modulator therapies provide clinical benefit to almost 50 % release all have been implicated in its pathogenesis . Patients of the CF population , the therapy does not represent a with RA experience a high risk of disability and mortality . complete clinical cure. [0191 ] Despite recent advances in RA treatment, including [0196 ] In certain embodiments , methods are provided for tumor necrosis factor alpha ( TNFa ) targeted therapeutics, a treating or preventing cystic fibrosis , comprising providing number of patients experience insufficient response to these to the subject an effective amount of an MMP9 binding agents and continue to suffer from disease - related symp protein , e . g ., an MMP9 binding protein comprising an toms, as well as incurring joint damage. MMP9 has been immunoglobulin heavy chain polypeptide, or functional reported to play an important role in the progression of RA , fragment thereof, and an immunoglobulin light chain poly and is known to be expressed in human RA as well as animal peptide , or functional fragment thereof, wherein the MMP9 models of disease . The role of MMP9 in disease progression binding protein specifically bindsMMP9 , thereby treating or in RA is supported by findings in the MMP9 knockout preventing cystic fibrosis in the subject. In one embodiment, mouse , which is significantly protected against increased the cystic fibrosis comprises myeloid cell - associated inflam disease severity in a collagen - induced arthritis model of RA , mation . In some embodiments , the anti -MMP9 antibody or whereas matrix metalloproteinase 2 (MMP2 ) knockout mice antigen binding fragment thereof prevents cleavage of develop more severe disease than littermate controls . Tar al- antitrypsin to an inactive form . US 2017 /0306050 A1 Oct. 26 , 2017 24

[0197 ] Idiopathic Pulmonary Fibrosis [0203 ] Using gene expression profiling in temporal artery [ 0198 ) Inflammation and fibrosis underlies many lung lesions of GCA patients , MMP9 transcript are one of the diseases from cystic fibrosis to COPD to other interstitial most abundant observed . This observation has been con lung diseases ( ILDs ). Therefore , modification of the cellular firmed by immunohistochemistry , which indicates strong microenvironment could provide broad benefit to a number immunoreactivity to macrophages localized to fragmented of lung disease patients. internal elastic membrane suggesting a pathogenic function 10199 ) One such ILD , idiopathic pulmonary fibrosis (IPF ) , in this particular form of vasculitis . The topographical is a grievous interstitial lung disease that is associated with distribution of biologically active MMPs was also assessed a median survival of 2 - 3 years from initial diagnosis (King , using in - situ gelatinase zymography . Fully -developed T . E ., Jr . et al. Idiopathic pulmonary fibrosis . Lancet (2011 ) lesions harbored the highest level of enzymatic activity 378 ( 9807 ) : 1949 - 1961; Rafii, R . et al. A review of current when compared to biopsies with adventitial involvement or and novel therapies for idiopathic pulmonary fibrosis . J control arteries . The density of inflammatory infiltrates was Thorac Dis ( 2013 ) 5 ( 1 ) : 48 -73 ) . It is characterized by found to be related to gelatinase activity . Vascular smooth fibrotic scarring of the lung and progressive loss of lung muscle cells have also been reported to express MMP9. function . Two drugs, pirfenidone and nintedanib , have been Furthermore, MMP9 serum level was found to be signifi approved for treatment of IPF in the United States on the cantly higher in untreated GCA patients compared to healthy basis that they slow the rate of disease progression , as controls . Macrophage infiltrates in GCA are believed to be measured by the rate of FVC decline over 1 year (Kreuter , essential for sustaining adaptive T cell responses in addition M . et al. Pharmacological Treatment of Idiopathic Pulmo to forming multi - nucleated giant cells . In the inflamed vessel nary Fibrosis : Current Approaches , Unsolved Issues , and wall niche of GCA patients , a large proportion of macro Future Perspectives. Biomed Res Int ( 2015 ) 2015 : 329481; phages secrete PDGF, which trigger migratory and prolif Noble , P . W . et al. Pirfenidone for idiopathic pulmonary erative signaling pathways in VSMCs. More importantly , fibrosis : analysis of pooled data from three multinational experimental systems have shown that PDGF promotes the phase 3 trials . Eur Respir J (2016 ) 47 ( 1 ) : 243 - 253 ; Richeldi, migration of smooth muscle cells by inducing MMP9 and L . et al. Nintedanib in patients with idiopathic pulmonary that the level of tissue - derived PDGF has been positively fibrosis : Combined evidence from the TOMORROW and associated with the degree of intimal hyperplasia and angio INPULSIS trials . Respir Med 2016 ) . However , the improve genesis. On a similar note , VEGF production by giant cells ments in pulmonary function seen with these treatments and macrophages is considered to be essential for the have not yet translated into improvements in mortality risk neovasculogenic process often observed in vasculitis and is or cure (Canestaro W . et al. Drug Therapy for Treatment of also a potent inducer ofMMP9 expression in T - lymphocytes Idiopathic Pulmonary Fibrosis : Systematic Review and Net and VSMCs. Finally , MMP9 is a limiting factor in the work Meta - Analysis . Chest 2016 ) . Therefore , IPF remains a process of granuloma formation , the pathologic hallmark of high unmet medical need . GCA . In light of these findings, MMP9 activity is likely to [ 0200 ) Vasculitis and Giant Cell Arteritis be a central driver of arterial stenosis in patients diagnosed [0201 ] Vasculitis is inflammation of blood vessel walls . It with GCA and is therefore an ideal drug target for experi causes changes in the walls of blood vessels , including mental therapies . thickening , weakening , narrowing and scarring . These [0204 ] Vasculitides can be categorized by the type of changes restrict blood flow , resulting in organ and tissue vessels involved . Large vessel vasculitis (LVV include damage . There are many types of vasculitis ( see below ) , and Takayasu arteritis ( TAK ), giant cell arteritis (GCA ) ; most of them are rare. Vasculitis might affect just one organ , Medium vessel vasculitis (MVV ) include polyarteritis such as the skin , or it may involve several organs . The nodosa ( PAN ) and Kawasaki disease (KD ) ; Small vessel condition can be acute or chronic . Vasculitis can affect vasculitis (SVV ) include antineutrophil cytoplasmic anti anyone, though some types are more common among certain body ( ANCA ) -associated vasculitis (AAV ) , microscopic groups . Certain patients can improve without treatment, polyangiitis (MPA ) , granulomatosis with polyangiitis (We while others will need medications to control the inflamma gener’ s ) (GPA ) , eosinophilic granulomatosis with polyangii tion and prevent flare - ups. Vasculitis is also known as tis (Churg - Strauss ) (EGPA ) , immune complex SVV , Anti angiitis and arteritis . glomerular basement membrane (anti -GBM ) disease , [0202 ] Giant cell arteritis (GCA ) is an auto - inflammatory / cryoglobulinemic vasculitis (CV ), IgA vasculitis (Henoch auto - immune disease that targets life - sustaining tissues , spe Schonlein ) ( IgAV ) , Hypocomplementemic urticarial vascu cifically the aorta and its major branches . Abnormal immune litis (HUV ) (anti -C1q vasculitis ) ; Variable vessel vasculitis response driven by T cells and macrophages lead to destruc (VVV ) include Behcet' s disease (BD ) and Cogan ' s syn tion of the vessel wall and induce maladaptive repair mecha drome (CS ) ; Single -organ vasculitis (SOV ) include cutane nisms that eventually cause vessel occlusion and resulting ous leukocytoclastic angiitis , cutaneous arteritis , primary organ ischemia . Affected patients are at high risk for suf central nervous system vasculitis , isolated aortitis , among fering ischemic optic neuropathy , CNS ischemia , aortic arch others; Vasculitis associated with systemic disease include syndrome and often have disabling systemic inflammation lupus vasculitis rheumatoid vasculitis , sarcoid vasculitis , and muscle pain (polymyalgia rheumatic ) . There is currently among others ; Vasculitis associated with probable etiology no approved medication beyond corticosteroids which can include Hepatitis C virus - associated cryoglobulinemic vas be used for induction purposes , to treat freshly diagnosed culitis , Hepatitis B virus -associated vasculitis , syphilis - as cases, or for maintenance therapy. Steroids are highly effec sociated aortitis , drug - associated immune complex vasculi tive in suppressing IL - 6 in GCA , but are only treating one tis , drug - associated ANCA - associated vasculitis , cancer part of the disease process . Therefore , alternative treatment associated vasculitis , among others . In certain embodiments , approaches are needed to prevent the progressive deteriora - compositions and methods described here treat or prevent tion of arterial function and avoid ischemic complications. any type of vasculitis . US 2017 /0306050 A1 Oct. 26 , 2017 25

[0205 ] In certain embodiments , methods are provided for appear to have locoregional tumor involvement can undergo treating or preventing vasculitis , comprising providing to the a potentially curative resection . Surgically curable early subject an effective amount of an MMP9 binding protein , gastric adenocarcinomas are usually asymptomatic and only e .g ., an MMP9 binding protein comprising an immuno infrequently detected outside the realm of a screening pro globulin heavy chain polypeptide, or functional fragment gram . Screening is not widely performed , except in coun thereof, and an immunoglobulin light chain polypeptide , or tries which have a very high incidence , such as Japan , functional fragment thereof, wherein the MMP9 binding Venezuela , and Chile . The common presenting symptoms protein specifically binds MMP9 , thereby treating or pre and diagnostic approaches to gastric adenocarcinoma venting vasculitis in the subject. In one embodiment, the include weight loss (usually results from insufficient caloric vasculitis comprises myeloid cell - associated inflammation . intake rather than increased catabolism ) and may be attrib In yet another embodiment, the vasculitis is giant cell utable to anorexia , nausea , abdominal pain , early satiety , arteritis . and / or dysphagia . Abdominal pain is often present which [ 0206 ] Hidradenitis Suppurativa tends to be epigastric , vague , and mild early in the disease [0207 ] Hidradenitis suppurativa is a chronic skin condi but more severe and constant as the disease progresses. tion that features pea- sized to marble - sized lumps under the Dysphagia is a common presenting symptom in patients skin . Also known as acne inversa , these deep - seated lumps with cancers arising in the proximal stomach or at the typically develop where skin rubs together — such as the esophagogastric junction . Patients may also present with armpits , groin , between the buttocks and under the breasts . nausea or early satiety from the tumor mass or in cases of an The lumps associated with hidradenitis suppurativa are aggressive form of diffuse -type gastric adenocarcinoma usually painful and may break open and drain foul - smelling called linitis plastica , from poor distensibility of the stom pus . In many cases , tunnels connecting the lumps will form ach . They may also present with a gastric outlet obstruction under the skin . Hidradenitis suppurativa tends to start after from an advanced distal tumor. puberty , persist for years and worsen over time . Early [0213 ] Gastric and esophageal adenocarcinomas are che diagnosis and treatment of hidradenitis suppurativa can help motherapy sensitive diseases , with several active drug manage the symptoms and prevent new lesions from devel therapy classes , including platinum , fluoropyrimidines, oping . topoisomerases inhibitors , taxanes, and anthracyclines. 0208 ] Cancer Despite significant differences in epidemiology and molecu [ 0209 ] In some embodiments , the methods and composi lar characteristics , cytotoxic chemotherapy combinations tions, e . g ., antibodies and fragments thereof, are used in the have not demonstrated significant differences in efficacy treatment of cancers and tumors and associated diseases and across gastric adenocarcinoma (Chau I , Norman AR , Cun conditions . Cancers and tumors that may be treated as ningham D , Oates J , Hawkins R , Iveson T , et al. The impact described herein include but are not limited to pancreatic of primary tumour origins in patients with advanced cancer , esophagogastric adenocarcinoma, non - small cell oesophageal, oesophago - gastric junction and gastric adeno lung cancer, lung squamous cell carcinoma, lung adenocar carcinoma - individual patient data from 1775 patients in cinoma , gastric adenocarcinoma , colorectal carcinoma , pan four randomised controlled trials . Ann Oncol 2009 ; 20 creatic adenocarcinoma, head and neck squamous cell car ( 5 ): 885 - 91 ) . cinoma, breast cancer , hepatocellular carcinoma , colorectal [0214 ] Chemotherapy clearly provides a survival advan cancer , colorectal adenocarcinoma and hepatocellular carci tage over best supportive care in both first - line and second noma. Illustrative cancers include colorectal cancers , gastric line settings (Glimelius B , Ekstrom K , Hoffman K , Graf W , adenocarcinoma, colorectal adenocarcinoma, and hepatocel Sjoden P O , Haglund U , et al . Randomized comparison lular carcinoma. between chemotherapy plus best supportive care with best [0210 ] Gastric Adenocarcinoma supportive care in advanced gastric cancer. Ann Oncol 1997 ; [0211 ] Adenocarcinoma of the stomach is the most com 8 ( 2 ) : 163 - 8 ; Murad A M , Santiago F F , Petroianu A , Rocha mon gastrointestinal cancer in the world and the third PR , Rodrigues M A , Rausch M . Modified therapy with leading cause of cancer death worldwide (Ferlay J, Soerjo 5 - fluorouracil , doxorubicin , and methotrexate in advanced mataram I , Ervik M , Dikshit R , Eser S , Mathers C , et al. gastric cancer. Cancer 1993 ; 72 ( 1 ) : 37 - 41 ; Pyrhonen S , GLOBOCAN 2012 v1 . 0 , Cancer Incidence and Mortality Kuitunen T , Nyandoto P , Kouri M . Randomised comparison Worldwide : IARC CancerBase No . 11. Available at globo of fluorouracil , epidoxorubicin and methotrexate (FEMTX ) can .iarc . fr. Accessed 9 Jul. 2014 . International Agency for plus supportive care with supportive care alone in patients Research on Cancer 2013 ) . Approximately 22 , 220 patients with non -resectable gastric cancer . Br J Cancer 1995 ; 71 are diagnosed annually in the United States , of whom 10 , 990 ( 3 ) : 587 - 91 ; Scheithauer W , Komek G , Zeh B , Stoger F X , are expected to die . While the incidence of distal gastric Schenk T , Henja M , et al. Palliative Chemotherapy vs . adenocarcinoma has recently declined in the United States , Supportive Care in Patients With Metastatic Gastric Cancer : gastric adenocarcinoma remains quite frequent in certain A Randomized Trial [ Abstract 68 ] . Conference on Biology , minority populations and it is still the second most common Prevention and Treatment of GastrointestinalMalignancies ; cause of cancer death worldwide . In addition , adenocarci 1995 09 - 12 January ; Koln , Germany ; Kang JH , Lee SI, Lim noma of the gastroesophageal junction (GEJ ) is one of the do H , Park KW , Oh S Y , Kwon H C , et al. Salvage most rapidly increasing solid tumors in the United States and chemotherapy for pretreated gastric cancer : a randomized Western Europe . phase III trial comparing chemotherapy plus best supportive [ 0212 ] Most patients with gastric adenocarcinoma in the care with best supportive care alone . J Clin Oncol 2012 ; 30 United States are symptomatic and already have advanced ( 13 ) : 1513 - 8 ; Thuss - Patience PC , Kretzschmar A , Deist T , incurable disease at the time of presentation . At diagnosis , Hinke A , Bichev D , Lebedinzew B , et al . Irinotecan versus approximately 50 percent have disease that extends beyond best supportive care (BSC ) as second - line therapy in gastric locoregional confines, and only one- half of those who cancer: A randomized phase III study of the Arbeitsgemein US 2017 /0306050 A1 Oct. 26 , 2017 26 schaft Internistische Onkologie ( AIO ) [ Abstract 4540 ) . J agent, an anti -anti - inflammatory agent, or an immune modu Clin Oncol ( ASCO Annual Meeting Abstracts ) 2009 ) . A lating agent. In some embodiment, an MMP9 binding pro meta -analysis of first- line chemotherapy versus best sup tein described herein may be used or combined with an portive case studies reported a hazard ration (HR ) of 0 . 39 anti -neoplastic agent or an anti -cancer agent. In certain ( 95 % CI, 0 .28 - 0 . 52 ; p < 0 .001 ) for overall survival in favor of embodiments , an MMP9 binding protein described herein chemotherapy. This translates to a benefit of a median of 6 may be used or combined with an immune modulating months ( Wagner A D , Grothe W , Haerting J , Kleber G , agent. In certain other embodiments , an MMP9 binding Grothey A , Fleig W E . Chemotherapy in advanced gastric protein described herein may be used or combined with an cancer: a systematic review and meta -analysis based on anti - inflammatory agent. These therapeutic agents may be in aggregate data . J Clin Oncol 2006 ; 24 ( 18 ) : 2903 - 9 ). the forms of compounds , antibodies , polypeptides , or poly [ 0215 ] Performance status often declines after first- line nucleotides . therapy . Patients with esophageal cancer often have signifi [0218 ] In some embodiments , the application provides cant comorbidities, including obesity , heart disease , emphy pharmaceutical compositions comprising an MMP9 binding sema, which when coupled with progressive dysphagia and protein and/ or one or more additional therapeutic agent, and malnutrition , often limit therapeutic opportunities after first a pharmaceutically acceptable diluent , carrier or excipient . line therapy . Gastric adenocarcinoma patients who develop In one embodiment, the pharmaceutical compositions com peritoneal carcinomatosis often have decreased bowel func prise an MMP9 binding protein , one or more additional tion that then results in GI symptoms and a decline in therapeutic agent, and a pharmaceutically acceptable excipi functional status and therefore limiting treatment options ent, carrier or diluent. In some embodiments , the pharma substantially ( Power D G , Kelsen D P , Shah MA. Advanced ceutical compositions comprise the anti- MMP9 antibody gastric cancer — slow but steady progress . Cancer treatment AB0045 . In some embodiments , the pharmaceutical com reviews 2010 ; 36 ( 5 ) : 384 - 92 ) . However , administration of positions comprise a chemotherapeutic agent, an anti -angio second - line therapy in patients who are sufficiently fit to genic agent, an anti- fibrotic agent, an anti - inflammatory receive it has demonstrated a survival advantage over sup agent, an immune modulating agent, an immunotherapeutic portive care alone (Kang et al . 2012 ; Thuss - Patience et al. agent, a therapeutic antibody , a radiotherapeutic agent , an 2009 ) . A meta - analysis of these studies demonstrated a HR anti- neoplastic agent or an anti -cancer agent, an anti -prolif for overall survival of 0 .73 (95 % CI, 058 -0 . 960 ), and in eration agent, or any combination thereof. In certain highly functioning patients (ECOG performance status of o embodiments , the pharmaceutical compositions comprise or 1 ) the HR was 0 .57 (95 % CI 0 . 36 - 0 .91 ) . the anti -MMP9 antibody AB0045 , at least one additional [0216 ] For patients who retain an adequate performance therapeutic agent that is an immunomodulating agent, and a status , there is no standard approach for second - line therapy pharmaceutically acceptable diluent, carrier or excipient. In after failure of the first - line regimen . Quality -of - life and certain other embodiments, the pharmaceutical composi minimization of side effects are key considerations when tions comprise the anti -MMP9 antibody AB0045 , at least choosing the therapeutic approach . The choice of regimen is one additional therapeutic agent that is an anti - inflammatory empiric . No single regimen has emerged as clearly superior agent, and a pharmaceutically acceptable diluent, carrier or and few trials have compared different regimens (Weso excipient. In certain other embodiments , the pharmaceutical lowski R , Lee C , Kim R . Is there a role for second - line compositions comprise the anti- MMP9 antibody AB0045 , at chemotherapy in advanced gastric cancer ? Lancet Oncol least one additional therapeutic agent that is an anti - neo 2009; 10 ( 9 ) : 903 - 12 ; Thallinger CM , Raderer M , Hejna M . plastic agent or anti -cancer agent, and a pharmaceutically Esophageal cancer: a critical evaluation of systemic second acceptable diluent, carrier or excipient. line therapy. J Clin Oncol 2011 ; 29 ( 35 ): 4709 - 14 ) . 102191. In certain embodiments , the one or more additional therapeutic agent is an immune modulating agent , e . g ., an Therapeutic Agents immunostimulant or an immunosuppressant. In certain other [0217 ] Certain embodiments of the present application embodiments , an immune modulating agent is an agent include or use one or more additional therapeutic agent. The capable of altering the function of immune checkpoints , one or more additional therapeutic agent may be an agent including the CTLA - 4 , LAG - 3 , B7 -H3 , B7 -H4 , Tim3 , useful for the treatment of cancer, inflammation , autoim BTLA , KIR , A2aR , CD200 and /or PD - 1 pathways . In other mune disease and related conditions. The one or more embodiments , the immune modulating agent is immune additional therapeutic agent may be a chemotherapeutic checkpoint modulating agents . Exemplary immune check agent, an anti - angiogenic agent, an anti- fibrotic agent , an point modulating agents include anti -CTLA - 4 antibody anti - inflammatory agent, an immune modulating agent, an ( e . g ., ipilimumab ) , anti -LAG - 3 antibody, anti -B7 -H3 anti immunotherapeutic agent, a therapeutic antibody , a radio body, anti- B7 - H4 antibody, anti - Tim3 antibody , anti -BTLA therapeutic agent, an anti - neoplastic agent or an anti - cancer antibody , anti - KIR antibody , anti- A2aR antibody, anti agent, an anti - proliferation agent , or any combination CD200 antibody, anti- PD - 1 antibody , anti - PD -L1 antibody, thereof. In some embodiments , the MMP9 binding proteins anti - CD28 antibody, anti - CD80 or - CD86 antibody, anti described herein may be used or combined with a chemo B7RP1 antibody, anti -B7 -H3 antibody, anti -HVEM anti therapeutic agent, an anti -angiogenic agent, an anti - fibrotic body , anti -CD137 or -CD137L antibody , anti -OX40 or agent , an anti - inflammatory agent , an immune modulating -OX40L antibody, anti - CD40 or - CD40L antibody , anti agent, an immunotherapeutic agent , a therapeutic antibody , GAL9 antibody, anti- IL - 10 antibody and A2aR drug . For a radiotherapeutic agent, an anti -neoplastic agent or an certain such immune pathway gene products , the use of anti -cancer agent, an anti- proliferation agent, or any com - either antagonists or agonists of such gene products is bination thereof. In certain embodiments , an MMP9 binding contemplated , as are small molecule modulators of such protein described herein may be used or combined with an gene products . In certain embodiments , the immune modu anti- neoplastic agent or an anti - cancer agent , anti - fibrotic latory agent is an anti - PD - 1 or anti - PD -L1 antibody . In some US 2017 /0306050 A1 Oct. 26 , 2017 27 embodiments , immune modulating agents include those make the PD - 1 /PD -L1 complex a central point through agents capable of altering the function of mediators in which cancer can manipulate immune responses and pro cytokine mediated signaling pathways . mote its own progression . [0224 ] The first immune - checkpoint inhibitor to be tested [ 0220 ] In certain embodiments , one or more additional in a clinical trial was ipilimumab ( Yervoy , Bristol- Myers therapeutic agent is an immune checkpoint inhibitor. Tumors Squibb ) , an CTLA - 4 mAb . CTLA - 4 belongs to the immu subvert the immune system by taking advantage of a mecha noglobulin superfamily of receptors , which also includes nism known as T - cell exhaustion , which results from chronic PD - 1 , BTLA , TIM - 3 , and V - domain immunoglobulin sup exposure to antigens and is characterized by the up - regula pressor of T cell activation ( VISTA ). Anti- CTLA - 4 mAb is tion of inhibitory receptors . These inhibitory receptors serve a powerful checkpoint inhibitor which removes “ the break ” as immune checkpoints in order to prevent uncontrolled from both naive and antigen - experienced cells . Therapy immune reactions. enhances the antitumor function of CD8 + T cells , increases the ratio of CD8 + T cells to Foxp3 + T regulatory cells , and [ 0221] PD - 1 and co - inhibitory receptors such as cytotoxic inhibits the suppressive function of T regulatory cells . T - lymphocyte antigen 4 (CTLA - 4 , B and T Lymphocyte TIM - 3 has been identified as another important inhibitory Attenuator (BTLA ; CD272 ), T cell Immunoglobulin and receptor expressed by exhausted CD8 + T cells . In mouse Mucin domain - 3 ( Tim - 3 ), Lymphocyte Activation Gene - 3 models of cancer, it has been shown that the most dysfunc ( Lag - 3 ; CD223 ) , and others are often referred to as a tional tumor - infiltrating CD8 + T cells actually co - express checkpoint regulators. They act as molecular determinants PD - 1 and TIM - 3 . LAG - 3 is another recently identified to influence whether cell cycle progression and other intra inhibitory receptor that acts to limit effector T -cell function cellular signaling processes should proceed based upon and augment the suppressive activity of T regulatory cells . extracellular information . It has recently been revealed that PD - 1 and LAG - 3 are [ 0222 ] In addition to specific antigen recognition through extensively co - expressed by tumor - infiltrating T cells in the T -cell receptor ( TCR ) , T -cell activation is regulated mice , and that combined blockade of PD -1 and LAG -3 through a balance of positive and negative signals provided provokes potent synergistic antitumor immune responses in by co - stimulatory receptors . These surface proteins are mouse models of cancer . typically members of either the TNF receptor or B7 super 102251 One embodiment includes the use of immune families. Agonistic antibodies directed against activating checkpoint inhibitors in combination with an anti -MMP9 co - stimulatory molecules and blocking antibodies against antibody or antigen binding fragment thereof to treat or negative co - stimulatory molecules may enhance T -cell prevent an MMP9 - associated disease or condition . In some stimulation to promote tumor destruction . embodiments , the immune checkpoint inhibitors may be an 10223] Programmed Cell Death Protein 1 , ( PD - 1 or anti- PD - 1 and / or an anti - PD -L1 antibody . In some embodi CD279 ), a 55 -KD type 1 transmembrane protein , is a mem ments , the anti- PD -L1 antibody may be B7 -H1 antibody , ber of the CD28 family of T cell co - stimulatory receptors BMS 936559 antibody , MPDL3280A ( atezolizumab ) anti that include immunoglobulin superfamily member CD28 , body , MEDI- 4736 antibody , MSB0010718C antibody or CTLA - 4 , inducible co - stimulator (ICOS ) , and BTLA . PD - 1 combinations thereof. According to another embodiment, is highly expressed on activated T cells and B cells . PD - 1 the anti -PD - 1 antibody may be nivolumab antibody, pem expression can also be detected on memory T - cell subsets brolizumab antibody , pidilizumab antibody or combinations with variable levels of expression . Two ligands specific for thereof. PD - 1 have been identified : programmed death - ligand 1 [0226 ] In addition , PD - 1 may also be targeted with AMP (PD - L1 , also known as B7 -H1 or CD274 ) and PD -L2 (also 224 , which is a PD - L2 - IgG recombinant fusion protein . known as B7 -DC or CD273 ) . PD -L1 and PD -L2 have been Additional antagonists of inhibitory pathways in the shown to down -regulate T cell activation upon binding to immune response include IMP321 , a soluble LAG - 3 Ig PD - 1 in both mouse and human systems (Okazaki et al. , Int fusion protein and MEW class II agonist , which is used to Immunol. , 2007 ; 19 : 813 - 824 ) . The interaction of PD - 1 with increase an immune response to tumors. Lirilumab is an its ligands, PD -L1 and PD - L2 , which are expressed on antagonist to the KIR receptor and BMS 986016 is an antigen -presenting cells (APCs ) and dendritic cells (DCs ) , antagonist of LAG3. The TIM - 3 -Galectin - 9 pathway is transmits negative regulatory stimuli to down -modulate the another inhibitory checkpoint pathway that is also a prom activated T cell immune response . Blockade of PD - 1 sup ising target for checkpoint inhibition . RX518 targets and presses this negative signal and amplifies T cell responses . activates the glucocorticoid - induced tumor necrosis factor Numerous studies indicate that the cancer microenviron receptor (GITR ), a member of the TNF receptor superfamily ment manipulates the PD -L1 / PD - 1 signaling pathway and that is expressed on the surface ofmultiple types of immune that induction of PD - L1 expression is associated with inhi cells , including regulatory T cells, effector T cells , B cells , bition of immune responses against cancer , thus permitting natural killer (NK ) cells , and activated dendritic cells . cancer progression and metastasis . The PD -L1 / PD - 1 signal [0227 ] Anti -PD -1 antibodies that may be used in the ing pathway is a primary mechanism of cancer immune compositions and methods described herein include but are evasion for several reasons . This pathway is involved in not limited to : Nivolumab (Opdivo® /MDX - 1106 / BMS negative regulation of immune responses of activated T 936558 /ONO -4538 ) , a fully human lgG4 anti -PD - 1 mono effector cells found in the periphery. PD -L1 is up -regulated clonal antibody; pidilizumab (MDV9300 /CT - 011 ) , a human in cancer microenvironments , while PD - 1 is also up -regu ized IgGl monoclonal antibody ; pembrolizumab (MK lated on activated tumor infiltrating T cells , thus possibly 3475 /Keytruda® / lambrolizumab ) , a humanized monoclonal potentiating a vicious cycle of inhibition . This pathway is IgG4 antibody ; durvalumab (MEDI - 4736 ) and atezoli also intricately involved in both innate and adaptive immune zumab . Anti -PD -L1 antibodies that may be used in compo regulation through bi- directional signaling . These factors sitions and methods described herein include but are not US 2017 /0306050 A1 Oct. 26 , 2017 limited to : avelumab ; BMS- 936559 , a fully human IgG4 phages TNFa stimulates phagocytosis , and production of antibody ; atezolizumab (MPDL3280A /RG -7446 ) , a human interleukin - 1 ( IL - 1 ) oxidants and the inflammatory lipid monoclonal antibody ; MED14736 ; MSB0010718C , and prostaglandin E ,. MDX1105 - 01 . In certain embodiments , the anti- PD - 1 anti [0232 ] Rheumatoid arthritis (RA ) is a chronic , systemic , body is nivolumab , pembrolizumab , or pidilizumab . In articular autoimmune disease of unknown etiology. Patients certain embodiments , the anti - PD -L1 antibody is BMS with RA have inflamed joints in which TNFa is produced in 936559 , atezolizumab , or avelumab . In one embodiment, the the lining and deeper layers of the synovium by cells of the immune modulating agent inhibits an immune checkpoint monocyte /macrophage lineage. It is postulated that the pro pathway . In another embodiment , the immune checkpoint duction of TNFa by cells at the cartilage - pannus junction pathway is selected from the group consisting of CTLA - 4 , could lead to cartilage degradation in RA . The inflamed joint LAG - 3 , B7 -H3 , B7 - H4, Tim3, BTLA , KIR , A2aR , CD200 in rheumatoid arthritis is known to have increased concen and PD - 1 . Additional antibodies that may be used in com trations of the pro - inflammatory cytokines TNFa and inter positions and methods described herein include the anti leukin - 1 ( IL - 1 ) in the synovial fluid . PD - 1 and anti - PD - L1 antibodies disclosed in U . S . Pat . Nos . [0233 ] The most common rheumatoid arthritis therapy involves the use of nonsteroidal anti- inflammatory drugs 8 ,008 , 449 and 7 , 943, 743 , respectively , each of which is (NSAIDs ) to alleviate symptoms. However, despite the herein incorporated by reference in its entirety . widespread use of NSAIDs, many individuals cannot toler [0228 ] In certain embodiments , one or more additional ate the doses necessary to treat the disorder over a prolonged therapeutic agent is an anti - inflammatory agent. In certain period of time. In addition , NSAIDs merely treat the symp other embodiments , the anti - inflammatory agent is a tumor toms of disorder and not the cause . When patients fail to necrosis factor alpha ( TNFa ) inhibitor . As used herein , the respond to NSAIDs, other DMARDs ( Disease Modifying terms “ TNF alpha ,” “ TNFa , ” or “ TNF - a ” are interchange Anti - Rheumatic Drugs ) such as methotrexate , gold salts , able . TNFa is a pro - inflammatory cytokine secreted primar D -penicillamine , cyclophosphamide and prednisone are ily by macrophages but also by a variety of other cell types used . These drugs have significant toxicities and their including lymphoid cells , mast cells , endothelial cells , car mechanism of action remains unknown . diac myocytes, adipose tissue , fibroblasts , and neuronal [0234 TNFa causes tumor cell necrosis ( a process that tissue . TNFa is also known as endotoxin - induced factor in involves cell swelling , organelle destruction and finally cell serum , cachectin , and differentiation inducing factor. The lysis ) and apoptosis ( a process that involves cell shrinking , tumor necrosis factor ( TNF ) family includes TNF alpha the formation of condensed bodies and DNA fragmentation ) . ( TNFa ) , TNF beta ( TNFB ), CD40 ligand (CD40L ) , Fas Additionally , TNFa plays a role in the regulation of embryo ligand (FasL ), TNF- related apoptosis inducing ligand development and the sleep -wake cycle , lymph node follicle ( TRAIL ) , and LIGHT (homologous to lymphotoxins , exhib and germinal center formation and host defense against its inducible expression , and competes with HSV glycopro pathogen infection . Importantly , TNFa is a crucial mediator tein D for HVEM , a receptor expressed by T lymphocytes ) , of both acute and chronic systematic inflammatory reac some of the most important cytokines involved in , among tions . TNFa induces its own secretion and stimulates the other physiological processes , systematic inflammation , production of other inflammatory cytokines and chemok tumor lysis , apoptosis and initiation of the acute phase ines . Animal models of septic shock implicate TNFa as a reaction . key player in this condition . TNFa is also a principal player [ 0229 ] TNFa is initially synthesized and expressed as a 26 in autoimmune diseases such as rheumatoid arthritis (RA ) ; kDa transmembrane protein (mTNFa ) , the extracellular inflammatory bowel diseases such as Crohn ' s disease and portion ofwhich is subsequently cleaved by TNFa convert ulcerative colitis; multiple sclerosis , systemic lupus erythe ing enzyme ( TACE ) , to release the soluble 17 kDa protein matosus; and systemic sclerosis . Finally , TNFa is associated ( STNFa ). TNFa is found to be present in its membrane with tumorigenesis , tumor progression , invasion and metas bound and secreted form . TNFa has a tendency to form a tasis , and is involved in cancer - associated inflammation . trimer . An increase in TNFa synthesis or release occurs in 0235 ] In certain embodiments , TNFa inhibitors are anti disorders such as inflammation . bodies , peptibodies, avimers , peptide -mimetic compounds, small molecules , or proteins . TNFa inhibitors include , but [0230 ] TNFa binds to tumor necrosis factor receptors are not limited to , broad spectrum immunosuppressants ( TNF - R ). There are two types of TNF receptors that can ( e . g . , steroids , including synthetic glucocorticoids such as either be membrane -bound or soluble: TNF - R1 ( TNF recep dexamethasone ) , curcumin , antibodies , and fusion con tor type 1 ; CD120a ; p55 /60 ) which is expressed in most structs . Antibodies such as Infliximab (REMICADE? ), tissues and TNF - R2 ( TNF receptor type 2 ; CD120b ; p '75 / Adalimumab (HUMIRA® ) , and receptor -construct fusion 80 ) which is found in cells of the immune system . Though proteins such as Etanercept ( ENBREL® , Amgen ; described both TNFR1 and TNFR2 interact with both mTNFa and in WO 91/ 03553 and WO 09 /406476 , herein incorporated by STNFa , TNFR1 signaling is strongly activated by both reference in its entirety ) are examples of TNFa inhibitors . mTNFa and sTNFa , while TNFR2 signaling can only be TNFa inhibitors also include antibodies and other agents efficiently activated by mTNFa . Each TNF receptor forms which bind to the TNF receptor, thereby inhibiting biologi homodimers , but they do not heterodimerize with each other. cal effects of TNFa . In one embodiment, the TNFa inhibitor TNF -R1 also contains a death domain that allows it to is a recombinant TNF binding protein ( r - TBP - I ) (Serono ) . interact with other death -domain containing adaptor pro (0236 ] In another embodiment, the TNFa inhibitor is a teins , whereas TNF -R2 lacks a death domain . small molecule . In yet another embodiment, the small mol [0231 ] TNFa is a potent chemoattractant for neutrophils , ecule is selected from the group consisting of pomalido and promotes the expression of adhesion molecules on mide , thalidomide , lenalidomide and bupropion . In certain endothelial cells , helping neutrophils migrate . On macro embodiments , the TNFa inhibitor is an antibody . In another US 2017 /0306050 A1 Oct. 26 , 2017 embodiment, the antibody is selected from the group con - in U .S . Pat . Nos. 6 ,593 ,458 ; 6 ,498 ,237 ; 6 ,451 , 983 ; and sisting of certolizumab pegol, adalimumab , golimumab and 6 ,448 ,380 , each of which is herein incorporated by reference infliximab . In another embodiment, the TNFa inhibitor is in its entirety . Etanercept. [0240 ] In certain embodiments , one or more additional [0237 ] Evidence that TNFa is central in the pathogenesis therapeutic agent is a chemotherapeutic agent. Chemothera of RA comes from clinical experience with either monoclo peutic agents may be categorized by their mechanism of nal antibodies against TNFa or soluble TNF receptor action into , for example , the following groups : anti- metabo immunoglobulin constructs . Five anti - TNFa biologics that lites/ anti - cancer agents such as pyrimidine analogs floxuri block the interaction of TNFa with TNF receptors have dine , capecitabine , and cytarabine; purine analogs, folate received FDA approval for treating rheumatoid arthritis , antagonists ( such as pralatrexate ), and related inhibitors ; among other indications. Etanercept (marketed as Enbrel® ) antiproliferative /antimitotic agents including natural prod is a recombinant fusion protein comprising two p75 soluble ucts such as vinca alkaloid ( vinblastine , vincristine ) and TNF - receptor domains linked to the Fc portion of a human microtubule such as taxane (paclitaxel , docetaxel) , vinblas immunoglobulin IgG1 and is produced by recombinant tin , nocodazole , epothilones, vinorelbine (NAVELBINE® ) , DNA technology in a Chinese hamster ovary mammalian and epipodophyllotoxins ( etoposide, teniposide ); DNA dam cell expression system . Adalilumab (marketed as Humira® ) aging agents such as actinomycin , amsacrine, busulfan , is a recombinant human IgG1 monoclonal antibody carboplatin , chlorambucil, cisplatin , cyclophosphamide expressed in Chinese Hamster Ovary cells. Infliximab (mar (CYTOXAN® ) , dactinomycin , daunorubicin , doxorubicin , keted as Remicade® ) is a chimeric antibody having murine epirubicin , iphosphamide, melphalan , merchlorethamine , anti - TNFa variable domains and human IgG1 Fc regions. mitomycin , mitoxantrone, nitrosourea , procarbazine, taxol, Certolizumab pegol (marketed as Cimzia® ) is a humanized taxotere , teniposide , etoposide , and triethylenethiophos antigen - binding fragment (Fab ' ) of a monoclonal antibody phoramide ; antibiotics such as dactinomycin , daunorubicin , that has been conjugated to polyethylene glycol .Golimumab doxorubicin , idarubicin , anthracyclines, mitoxantrone , bleo (marketed as Simponi® ) is a recombinant human IgG ) mycins , plicamycin (mithramycin ) and mitomycin ; monoclonal antibody that binds to both soluble and trans enzymes such as L -asparaginase which systemically membrane forms of TNFa . metabolizes L - asparagine and deprives cells which do not [0238 ] Examples of TNF antagonists include SAR have the capacity to synthesize their own asparagine ; anti 244181, denosumab , etanercept, brentuximab vedotin , platelet agents ; asparaginase stimulators , such as crisantas AVX - 470 , BIIB -023 , fulranumab , tanezumab , GBR - 830 , pase ( Erwinase® ) and GRASPA ( ERY - 001 , ERY - ASP ) ; AG -014 , lucatumumab , fasinumab , BI- 655064 , BN -006 , antiproliferative /antimitotic alkylating agents such as nitro ASKP - 1240 , RNS -60 , APG - 101 , PF -688 , APX - 005M , gen mustards cyclophosphamide and analogs (melphalan , ONL - 1204 , AFM - 13 , FFP - 104 , RPH - 203 , MEDI- 578 , chlorambucil , hexamethylmelamine , and thiotepa ) , alkyl mDTA - 1 , AVX - 1555 , TDI- 00846 , IDD -004 , APX -008 , nitrosoureas ( carmustine ) and analogs , streptozocin , and NM - 9405 , FFP - 102 , DS - 8273 , KGYY - 15 , ONL - 101, SCB triazenes ( dacarbazine ) ; antiproliferative /antimitotic antime 808 , SCB - 131 , Atu -614 , DE - 098 , FFP - 106 , p75NTR - Fc , tabolites such as folic acid analogs (methotrexate ) ; platinum ANA -02 , MEDI- 4920 , Novotarg , BMS- 986090 , VAY - 736 , coordination complexes ( cisplatin , oxiloplatinim , lobaplatin , CD40DNA Vax , GSK - 2800528 , pegsunercept, GBL -5b , and carboplatin ), procarbazine , hydroxyurea , mitotane , and NM - 2014 , Neutrolide , K - 252a , ATROSAB , ABT- 110 , SAR aminoglutethimide ; hormones , hormone analogs ( estrogen , 127963 , 5C - 11, ACE -772 , ISIS -22023 , CRB - 0089 , tamoxifen , goserelin , bicalutamide, and nilutamide ), and oxelumab , enavatuzumab , ALD - 906 , VT- 362 , F45D9, aromatase inhibitors ( letrozole and anastrozole ) ; anticoagu F61F12 , ALD - 901, AMPTIRA , APG - 103 , E -3330 , dacetu lants such as heparin , synthetic heparin salts , and other zumab , rolipram , AG - 879, onercept, D - 609 , DE - 096 , inhibitors of thrombin ; fibrinolytic agents such as tissue EC - 234 , MDX - 1401, BIM -036 , ALS - 00T2 - 0501, CZEN plasminogen activator , streptokinase, urokinase , aspirin , 001 , P -60 PLAD , PD - 90780 , LT- ZMP001 , CS - 9507 , PCM dipyridamole , ticlopidine , and clopidogrel ; antimigratory 4 , toralizumab , DOM -0100 , ReN - 1820 , solimastat , iratu agents ; antisecretory agents (breveldin ) ; immunosuppres mumab , CGEN - 40 , PN -0615 , lenercept , AUX - 202 , DOM sives tacrolimus , sirolimus , azathioprine , and mycopheno 0800 , ITF - 1779 , CEP -751 , daxalipram , B -975 , teneliximab , late ; compounds ( TNP -470 , genistein ) and growth factor ALE - 0540 , MDL - 201112 , and BB - 2275 . inhibitors (vascular endothelial growth factor inhibitors and [ 0239 ] Anti - TNFa antibodies that may be used include fibroblast growth factor inhibitors ); angiotensin receptor but are not limited to : those described in U . S . Pat. Nos. blockers , nitric oxide donors ; anti -sense oligonucleotides ; 6 ,090 ,382 ; 6 , 258 ,562 ; 6 ,509 ,015 , and in U . S . patent appli antibodies such as trastuzumab and rituximab ; cell cycle cation Ser. Nos. 09 / 801 , 185 and 10 / 302 ,356 , each of which inhibitors and differentiation inducers such as tretinoin ; is herein incorporated by reference in its entirety ; infliximab inhibitors , topoisomerase inhibitors ( doxorubicin , daunoru (Remicade® , Johnson and Johnson ; described in U . S . Pat. bicin , dactinomycin , eniposide, epirubicin , etoposide, ida No. 5 ,656 , 272 , herein incorporated by reference in its rubicin , irinotecan , mitoxantrone , topotecan , sobuzoxane , entirety ) ; CDP571 ( a humanized monoclonal anti - TNFa and irinotecan ) , and corticosteroids ( cortisone , dexametha IgG4 antibody ) ; CDP 870 ( a humanized monoclonal anti sone , hydrocortisone , methylprednisolone, prednisone , and TNFa antibody fragment) ; an anti- TNF dAb (Peptech ), prednisolone ) ; growth factor signal transduction kinase golimumab (CNTO 148 ; Medarex and Centocor , see WO inhibitors ; dysfunction inducers ; toxins such as Cholera 02 / 12502, herein incorporated by reference in its entirety ), toxin , ricin , Pseudomonas exotoxin , Bordetella pertussis and adalimumab (Humira® , Abbott Laboratories, a human adenylate cyclase toxin , diphtheria toxin , and caspase acti anti - TNF mAb , described in U . S . Pat. No. 6 ,090 ,382 as vators ; chromatin ; smoothened (SMO ) receptor inhibitors, D2E7 , herein incorporated by reference in its entirety ) . such as Odomzo® ( sonidegib , formerly LDE - 225 ) , Additional TNF antibodies which can be used are described LEQ506 , vismodegib (GDC -0449 ) , BMS - 833923, glasde US 2017 /0306050 A1 Oct. 26 , 2017 30 gib (PF -04449913 ), LY2940680 , and itraconazole ; inter as methotrexate and 5 - fluorouracil ( 5 - FU ) ; folic acid analogs feron alpha ligand modulators, such as interferon alfa - 2b , such as demopterin , methotrexate , pteropterin , and trime interferon alpha - 2a biosimilar (Biogenomics ) , ropeginter trexate ; purine analogs such as fludarabine , 6 -mercaptopu feron alfa - 2b (AOP - 2014 , P - 1101 , PEG IFN alpha - 2b ) , rine , thiamiprine , and thioguanine ; pyrimidine analogs such Multiferon ( Alfanative , Viragen ) , interferon alpha 1b , Rof as ancitabine, azacitidine, 6 - azauridine , carmofur , cytara eron - A (Canferon , Ro - 25 - 3036 ) , interferon alfa - 2a follow bine , dideoxyuridine , doxifluridine, enocitabine, and floxu on biologic (Biosidus ) ( Inmutag , Inter 2A ) , interferon alfa ridine; androgens such as calusterone, dromostanolone pro 2b follow -on biologic (Biosidus — Bioferon , Citopheron , pionate , epitiostanol, mepitiostane, and testolactone ; anti Ganapar ) ( Beijing Kawin Technology — Kaferon )( AXXO adrenals such as aminoglutethimide , mitotane , and interferon alfa - 2b ), Alfaferone , pegylated interferon alpha trilostane; folic acid replinishers such as frolinic acid ; tri 1b , peginterferon alfa - 2b follow - on biologic (Amega ) , chothecenes , especially T - 2 toxin , verracurin A , roridin A , recombinant human interferon alpha - lb , recombinant and anguidine ; taxoids such as paclitaxel ( TAXOL® ) and human interferon alpha - 2a , recombinant human interferon docetaxel ( TAXOTERE® ); platinum analogs such as cis alpha - 2b , veltuzumab - IFN alpha 2b conjugate , Dynavax platin and carboplatin ; aceglatone; aldophosphamide glyco (SD - 101) , and interferon alfa - nl ( Humoferon , SM - 10500 , side; aminolevulinic acid ; eniluracil ; amsacrine ; hestrabucil ; Sumiferon ) ; interferon gamma ligand modulators , such as bisantrene ; edatraxate ; defofamine ; demecolcine ; diazi interferon gamma (OH -6000 , Ogamma 100 ); Complement quone ; elformthine ; elliptinium acetate ; an epothilone ; eto C3 modulators, such as Imprime PGG ; IL -6 receptor modu glucid ; gallium nitrate ; hydroxyurea ; lentinan ; leucovorin ; lators, such as tocilizumab , siltuximab , AS - 101 (CB - 06 - 02 , lonidamine; maytansinoids such as maytansine and ansami IVX - Q - 101 ) ; Telomerase modulators , such as tertomotide tocins ; mitoguazone; mitoxantrone ; mopidamol; nitracrine ; (GV - 1001, HR - 2802 , Riavax ) and imetelstat (GRN - 163 , pentostatin ; phenamet ; pirarubicin ; losoxantrone ; fluoropy JNJ- 63935937 ) ; DNA methyltransferases inhibitors, such as rimidine ; folinic acid ; podophyllinic acid ; 2 -ethylhydrazide ; temozolomide (CCRG - 81045 ) , decitabine, guadecitabine procarbazine ; polysaccharide - K (PSK ) ; razoxane ; rhizoxin ; ( S - 110 , SGI- 110 ) , KRX - 0402 , and azacitidine; DNA gyrase sizofiran ; spirogermanium ; tenuazonic acid ; triaziquone; inhibitors , such as pixantrone and sobuzoxane ; and Bcl- 2 2 ,2 ', 2 " -tricUorotriemylamine ; urethane ; vindesine ; dacarba family protein inhibitor ABT- 263 , venetoclax (ABT - 199 ) , zine ; mannomustine ; mitobronitol; mitolactol ; pipobroman ; ABT- 737 , and AT- 101 . gacytosine ; arabinoside ( “ Ara - C ” ) ; cyclophosphamide; thio [0241 ] Further examples of chemotherapeutic agents peta ; chlorambucil; gemcitabine (GEMZAR® ) ; 6 - thiogua include : alkylating agents such as thiotepa and cyclophos nine ; mercaptopurine; methotrexate ; vinblastine ; platinum ; phamide (CYTOXAN® ) ; alkyl sulfonates such as busulfan , etoposide (VP - 16 ) ; ifosfamide ; mitroxantrone ; vancristine; improsulfan , and piposulfan ; aziridines such as benzodepa , vinorelbine (NAVELBINE® ) ; novantrone ; teniposide ; eda carboquone , meturedepa , and uredepa ; ethylenimines and trexate ; daunomycin ; aminopterin ; xeoloda ; ibandronate ; methylamelamines including altretamine , triethylen CPT- 11 ; topoisomerase inhibitor RFS 2000 ; difluoromethy emelamine, triethylenephosphoramide , triethylenethiophos lornithine (DFMO ); retinoids such as retinoic acid ; capecit phoramide , and trimemylolomelamine ; acetogenins, espe abine; FOLFIRI ( fluorouracil, leucovorin , and irinotecan ); cially bullatacin and bullatacinone; a camptothecin , and pharmaceutically acceptable salts , acids, or derivatives including synthetic analog topotecan ; bryostatin ; callystatin ; of any of the above . CC - 1065 , including its adozelesin , carzelesin , and bizelesin [0242 ] Also included in the definition of “ chemotherapeu synthetic analogs ; cryptophycins, e . g . , cryptophycin 1 and tic agent” are anti -hormonal agents such as anti - estrogens cryptophycin 8 ; dolastatin ; duocarmycin , including the syn and selective estrogen receptor modulators ( SERMs) , inhibi thetic analogs KW - 2189 and CBI- TMI; eleutherobin ; pan tors of the enzyme aromatase , anti- androgens , and pharma cratistatin ; a sarcodictyin ; spongistatin ; nitrogen mustards ceutically acceptable salts , acids or derivatives of any of the such as chlorambucil, chlornaphazine , cyclophosphamide , above that act to regulate or inhibit hormone action on estramustine , ifosfamide , mechlorethamine , mechlore tumors . Examples of anti - estrogens and SERMs include, for thamine oxide hydrochloride , melphalan , novembichin , example , tamoxifen (including NOLVADEXTM ) , raloxifene , phenesterine , prednimustine , trofosfamide , and uracil mus droloxifene , 4 -hydroxytamoxifen , trioxifene, keoxifene, tard ; nitrosoureas such as carmustine , chlorozotocin , fore LY117018 , onapristone , and toremifene (FARESTON® ) . mustine , lomustine , nimustine , and ranimustine ; antibiotics Inhibitors of the enzyme aromatase regulate estrogen pro such as the enediyne antibiotics ( e . g . , calicheamicin , espe duction in the adrenal glands. Examples include 4 ( 5 ) - imi cially calicheamicin gammall and calicheamicin phill ) , dazoles , aminoglutethimide , megestrol acetate dynemicin including dynemicin A , bisphosphonates such as (MEGACE® ) , exemestane , formestane , fadrozole , vorozole clodronate , an esperamicin , neocarzinostatin chromophore (RIVISOR® ), letrozole ( FEMARA? ) , and anastrozole and related chromoprotein enediyne antibiotic chromo (ARIMIDEX® ) . Examples of anti - androgens include fluta mophores , aclacinomycins, actinomycin , authramycin , aza mide , nilutamide, bicalutamide, leuprohde, and goserelin . serine, bleomycins, cactinomycin , carabicin , carrninomycin , [0243 ] Anti - angiogenic agents include, but are not limited carzinophilin , chromomycins , dactinomycin , daunorubicin , to , retinoid acid and derivatives thereof, 2 -methoxyestradiol , detorubicin , 6 - diazo - 5 - oxo - L -norleucine , doxorubicin ( in ANGIOSTATIN® , ENIDOSTATIN® , suramin , squalamine , cluding morpholino -doxorubicin , cyanomorpholino - doxo tissue inhibitor of metalloproteinase - 1 , tissue inhibitor of rubicin , 2 -pyrrolino -doxorubicin , and deoxydoxorubicin ) , metalloproteinase -2 , plasminogen activator inhibitor- 1 , epirubicin , esorubicin , idarubicin , marcellomycin , mitomy plasminogen activator inhibitor- 2 , cartilage -derived inhibi cins such as mitomycin C ,mycophenolic acid , nogalamycin , tor, paclitaxel (nab -paclitaxel ) , platelet factor 4 , protamine olivomycins , peplomycin , porfiromycin , puromycin , que sulphate (clupeine ), sulphated chitin derivatives (prepared lamycin , rodorubicin , streptonigrin , streptozocin , tubercidin , from queen crab shells ), sulphated polysaccharide peptido ubenimex , zinostatin , and zorubicin ; anti- metabolites such glycan complex ( sp -pg ) , staurosporine, modulators of US 2017 /0306050 A1 Oct. 26 , 2017 31 matrix metabolism including proline analogs such as 1 -aze bivatuzumab , blinatumomab , brentuximab , cantuzumab , tidine -2 -carboxylic acid (LACA ) , cishydroxyproline , d ,1 - 3 , catumaxomab , cetuximab , citatuzumab , cixutumumab , cli 4 - dehydroproline , thiaproline , aga '- dipyridyl, beta -amino vatuzumab , conatumumab , daratumumab , drozitumab , duli propionitrile fumarate , 4 -propyl - 5 -( 4 -pyridinyl ) - 2 (3h ) gotumab , dusigitumab , detumomab , dacetuzumab , dalotu oxazolone , methotrexate , mitoxantrone , heparin , zumab , ecromeximab , elotuzumab , ensituximab , interferons, interferon alpha ligand modulators , 2 macro ertumaxomab , etaracizumab , farletuzumab , ficlatuzumab , globulin -serum , chicken inhibitor of metalloproteinase - 3 figitumumab , flanvotumab , futuximab , ganitumab , gemtu ( ChIMP - 3 ) , chymostatin , beta - cyclodextrin tetradecasulfate , zumab , girentuximab , glembatumumab , ibritumomab , igo eponemycin , fumagillin , gold sodium thiomalate , d -penicil vomab , imgatuzumab , indatuximab , inotuzumab , intetu lamine , beta - 1 - anticollagenase -serum , alpha - 2 -antiplasmin , mumab , ipilimumab ( YERVOY® , MDX -010 , BMS bisantrene, lobenzarit disodium , n - 2 -carboxyphenyl - 4 - chlo 734016 , and MDX - 101) , iratumumab , labetuzumab , roanthronilic acid disodium or “ CCA " , thalidomide , angio lexatumumab , lintuzumab , lorvotuzumab , lucatumumab , static steroid , carboxy aminoimidazole , and metalloprotei mapatumumab , matuzumab , milatuzumab , minretumomab , nase inhibitors such as BB - 94 . Other anti - angiogenesis mitumomab , moxetumomab , narnatumab , naptumomab , agents include antibodies , preferably monoclonal antibodies necitumumab , nimotuzumab , nofetumomab , obinutuzumab , against these angiogenic growth factors: beta - FGF, alpha ocaratuzumab , ofatumumab , olaratumab , onartuzumab , FGF , FGF - 5 , VEGF isoforms, VEGF- C , HGF / SF , and Ang oportuzumab , oregovomab , panitumumab , parsatuzumab , 1 / Ang - 2 . patritumab , pemtumomab , pertuzumab , pintumomab , pritu [0244 ] Anti - fibrotic agents include, but are not limited to , mumab , racotumomab , radretumab , rilotumumab , ritux the compounds such as beta - aminoproprionitrile (BAPN ) , as imab , robatumumab , satumomab , sibrotuzumab , siltuximab , well as the compounds disclosed in U . S . Pat . No . 4 , 965, 288 solitomab , tacatuzumab , taplitumomab , tenatumomab , relating to inhibitors of lysyl oxidase and their use in the teprotumumab , tigatuzumab , tositumomab , trastuzumab , treatment of diseases and conditions associated with the tucotuzumab , ublituximab , veltuzumab , vorsetuzumab , abnormal deposition of collagen and U . S . Pat. No . 4 , 997 ,854 votumumab , zalutumumab , CC49 , and 3F8 . Rituximab can relating to compounds which inhibit LOX for the treatment be used for treating indolent B -cell cancers , including mar of various pathological fibrotic states , which are herein ginal - zone lymphoma, WM , CLL and small lymphocytic incorporated by reference . Further exemplary inhibitors are lymphoma. A combination of Rituximab and chemotherapy described in U . S . Pat. No . 4 , 943 ,593 relating to compounds agents is especially effective . The exemplified therapeutic such as 2 - isobutyl- 3 - fluoro - , chloro - , or bromo - allylamine , antibodies may be further labeled or combined with a U . S . Pat. No. 5 ,021 , 456 , U . S . Pat. No . 5 , 059 , 714 , U . S . Pat . radioisotope particle such as indium - 111, yttrium - 90 , or No . 5 , 120 , 764 , U . S . Pat. No. 5 , 182 ,297 , U . S . Pat . No . iodine- 131 . 5 , 252 , 608 relating to 2 - ( 1 - naphthyloxymemyl) - 3 - fluoroal 0247 ] In certain embodiments , the one or more additional lylamine , and US 2004 -0248871 , which are herein incorpo therapeutic agent includes and is not limited an A2B inhibi rated by reference . tor, an apoptosis signal - regulating kinase (ASK ) inhibitor, a [ 0245 ] Exemplary anti - fibrotic agents also include the Bruton ' s tyrosine kinase (BTK ) inhibitor, a BET -bromodo primary amines reacting with the carbonyl group of the main 4 (BRD4 ) inhibitor, a casein kinase inhibitor, a cyclin active site of the lysyl oxidases, and more particularly those dependent kinase (CDK ) inhibitor, a discoidin domain which produce , after binding with the carbonyl, a product receptor (DDR ) inhibitor, a histone deacetylase (HDAC ) stabilized by resonance , such as the following primary inhibitor, a protein kinase HPK1 inhibitor, an isocitrate amines : emylenemamine , hydrazine , phenylhydrazine , and dehydrogenase ( IDH ) inhibitor, an IDO1 inhibitor , a Janus their derivatives; semicarbazide and urea derivatives ; kinase ( JAK ) inhibitor, a lysyl oxidase - like protein (LOXL ) aminonitriles such as BAPN or 2 - nitroethylamine; unsatu inhibitor, a MEK inhibitor, a matrix metalloprotease (MMP ) rated or saturated haloamines such as 2 - bromo- ethylamine , inhibitor, an IKK inhibitor, phosphatidylinositol 3 -kinase 2 -chloroethylamine , 2 -trifluoroethylamine , 3 -bromopro (PI3K ) inhibitor, a protein kinase C (PKC ) activator or pylamine , and p - halobenzylamines ; and selenohomocyste inhibitor, agents that activate or reactivate latent human ine lactone . Other anti - fibrotic agents are copper chelating immunodeficiency virus (HIV ) such as panobinostat or agents penetrating or not penetrating the cells . Exemplary romidepsin , an anti- CD20 antibody such as obinutuzumab , compounds include indirect inhibitors which block the alde an anti - programmed cell death protein 1 (PD - 1 ) inhibitor hyde derivatives originating from the oxidative deamination such as nivolumab (OPDIVO? , BMS - 936558 , MDX1106 , of the lysyl and hydroxylysylresidues by the lysyl oxidases. or MK - 34775 ) , durvalumab (MEDI - 4736 ) , atezolizumab , Examples include the thiolamines, e . g . , D -penicillamine , and pembrolizumab (KEYTRODA? , MK - 3475 , SCH and its analogs such as 2 - amino - 5 -mercapto - 5 -methyl 900475 , lambrolizumab ) , an anti -programmed death - ligand hexanoic acid , D - 2 -amino - 3 -methyl - 3 - ( ( 2 -acetamidoethyl ) 1 (anti -PD - L1) inhibitor such as BMS - 936559 , dithio )butanoic acid , p - 2 - amino - 3 -methyl - 3 - ( ( 2 -amino MPDL3280A , MEDI4736 , MSB0010718C , and MDX1105 ethyl) dithio ) butanoic acid , sodium - 4 - ( ( p - 1 - dimethyl- 2 01, a spleen tyrosine kinase (SYK ) inhibitor, a serine / amino - 2 - carboxyethyl ) dithio )butane sulphurate , threonine - protein kinase 1 ( TBK1) inhibitor , a TPL2 inhibi 2 - acetamidoethyl - 2 - acetamidoethanethiol sulphanate , and tor, and a smoothened (SMO ) receptor inhibitor. These sodium - 4 -mercaptobutanesulphinate trihydrate . agents may be in the forms of compound , antibodies , 102461. Immunotherapeutic agents include and are not lim polypeptide, or polynucleotides . In the present application , ited to therapeutic antibodies suitable for treating patients . the MMP9 binding protein , including anti -MMP9 antibody Some examples of therapeutic antibodies include simtu such as AB0045 , may be used or combined with the above zumab , abagovomab , adecatumumab , afutuzumab , alemtu one or more therapeutic agent, and may be further used or zumab , altumomab , amatuximab , anatumomab , arcitu combined with a chemotherapeutic agent, an anti- angio momab , bavituximab , bectumomab , bevacizumab , genic agent , an anti - fibrotic agent, an anti- inflammatory US 2017 /0306050 A1 Oct. 26 , 2017 32 agent, an immune modulating agent , an immunotherapeutic [ 0249 ] In certain embodiments , the one or more additional agent , a therapeutic antibody, a radiotherapeutic agent, an therapeutic agents may be selected from vismodegib , maci anti- neoplastic agent or an anti - cancer agent, an anti - prolif tentan , nintedanib , tralokinumab , ambrisentan , bosentan , eration agent, or any combination thereof. It is understood interferon beta - la , everolimus , GKT- 137831 , PBI- 4050 , that some agents may be considered or used for more than PLX stem cell therapy (Pluristem / Cha Bio & Diostech ), one disease type ; for example , an agent may be considered lanreotide, tipelukast, INT- 0024 , PRM - 151, riociguat, roflu or used for anti- inflammation or anti - cancer , accordingly , milast , imatinib , serelaxin , SAR - 156597 , etanercept, AEOL may be used or combined with anti -MMP9 antibody of the 10150 , lebrikizumab , MPC - 300 - IV , FG - 3019 , carlumab , present application for treating or preventing inflammation , GR -MD -02 , AQX - 1125, MMI- 0100 , pirfenidone, deuter auto - immune, or cancers . ated pirfenidone analogs ( e . g . SD -560 ) , emricasan , Conatus , [ 0248 ] Additional examples of one or more additional BMS- 986020 , beclometasone dipropionate + formoterol therapeutic agents may include and is not limited to hedge fumarate , TD - 139 , recombinant midismase , QAX - 576 , hog protein inhibitors , smoothened receptor antagonists , bovhyaluronidase azoximer, GNI/ AFTF -351 , BG - 00011 , endothelin ET- A antagonists , endothelin ET- B antagonists, simtuzumab , SPL - 334 , pentoxifylline + N -acetyl - cysteine , FGF receptor antagonists , FGF1 receptor antagonists , FGF2 aviptadil, interferon -alpha , GSK - 2126458 , actimmune , ben receptor antagonists , PDGF receptor alpha antagonists , tamapimod , CKD - 942 , tanzisertib , interferon gamma, PDGF receptor antagonists , PDGF receptor beta antago IW -001 , PUR - 1500 , DB - 029 .01 , disitertide , fresolimumab , nists , VEGF receptor antagonists , VEGF - 1 receptor antago IVA - 337 , PBF - 1250 , P -013 , P -007 , anti - IL - 17BR human nists , VEGF - 2 receptor antagonists , VEGF -3 receptor ized antibody , triciribine , RHAMM modulators , RES - 529 , antagonists , IL - 13 antagonists , interferon beta ligands, MOR - 107 , HR -411 , HEC -00000585 , BOT- 191, GKT- 901 , mTOR complex 1 inhibitors , TGF beta antagonists , p38 USP -34 inhibitors , anti - LRP6 mAb , Gestelmir , Neumomir , MAP kinase inhibitors , NADPH oxidase 1 inhibitors, IBIO - CFB - 03 , MSM -735 , LTI- 03 , anti - WISP1 antibodies , NADPH oxidase 4 inhibitors , connective tissue growth NAS - 911B , C -301 , STNM -04 , TM -5441 , PP - 0612 , factor ligand inhibitors , IL -6 antagonists , IL - 6 agonists , QU - 100 , HR -017 , Gal- 100 , MAI- 100 , BPS -03251 , MMP9 insulin - like growth factor 1 antagonists , somatostatin recep antibodies, such as those disclosed in U . S . Pat. No . 8 , 377 , tor agonists , 5 - lipoxygenase inhibitors , PDE 3 inhibitors , 443 , ASK - 1 inhibitors, such as those disclosed in U . S . Pat . phospholipase C inhibitors , serum amyloid P stimulator, No. 8 , 378 , 108 , SYK inhibitors , such as those disclosed in guanylate cyclase stimulator, PDE 4 inhibitors, Abl tyrosine US2015 /0175616 and U . S . Pat. No. 8 ,450 ,321 , for example , kinase inhibitors , Kit tyrosine kinase inhibitors , signal trans 6 -( 1H - indazol -6 -yl ) -N - (4 -morpholinophenyl ) imidazo [ 1 ,2 duction inhibitors, angiotensin II ligand modulator, endothe a ] pyrazin - 8 - amine ) , inhibitors of Bruton ' s tyrosine kinase lin 1 ligand inhibitors , relaxin agonist, IL - 4 antagonist , TNF such as those disclosed in U . S . Pat. No . 8 ,557 , 803 , for antagonist , type II TNF receptor modulator, monocyte example , ( R ) - 6 -amino - 9 - ( 1 - ( but- 2 -ynoyl ) pyrrolidin - 3 - yl ) - 7 chemotactic protein 1 ligand inhibitors , galectin - 3 inhibi ( 4 -phenoxyphenyl ) -7H -purin - 8 ( 9H ) -one , FXR agonists tors, SH2 domain inositol phosphatase 1 stimulator, MAP such as those disclosed in US20140221659 , and PI3K KAPK2 inhibitors, caspase inhibitors , lysophosphatidate - 1 inhibitors , such as those disclosed in US20140371246 . receptor antagonist, beta 2 adrenoceptor agonist , interferon [ 0250 ] Further examples of the one or more additional gamma ligands, superoxide dismutase modulator, hyaluroni therapeutic agents may comprise a kinase or enzymemodu dase stimulator, transaminase stimulator, integrin alpha - V / lator of, but not limited to , Abl, activated CDC kinase beta - 6 antagonist , a lysyl oxidase - like protein 2 (LOXL2 ) (ACK ) such as ACK1, adenosine A2B receptor (A2B ) , inhibitor, adrenoceptor antagonist, VIP agonist, interferon apoptosis signal- regulating kinase ( ASK ) , Aurora kinase , alpha ligands, Jun N terminal kinase inhibitors, collagen V Bruton ' s tyrosine kinase (BTK ) , BET- bromodomain (BRD ) modulators , MMP9 stimulators , PPAR agonists , adenosine such as BRD4, c - Kit, c -Met , CDK -activating kinase ( CAK ) , A2b receptor antagonists , GPCR modulators, CCR7 calmodulin - dependent protein kinase (CaMK ) , cyclin - de chemokine modulators, interleukin 17E ligand inhibitors, pendent kinase (CDK ) , casein kinase (CK ) , discoidin interleukin receptor 17B antagonists , AKT protein kinase domain receptor (DDR ) , epidermal growth factor receptors inhibitors , hyaluronan mediated motility receptor modula (EGFR ) , focal adhesion kinase (FAK ) , Flt - 3 , farnesoid x tors , angiotensin II AT- 2 receptor agonists , CXC11 receptor ( FXR ), FYN , glycogen synthase kinase (GSK ) , chemokine ligand modulators , immunoglobulin Fc receptor HCK , histone deacetylase (HDAC ) , indoleamine 2 , 3 - dioxy modulators, lysophosphatidate - 1 receptor antagonists , ubiq genase (IDO ) , I -Kappa - B kinase (IKK ) such as IKKBE, uitin thioesterase inhibitors , 5 -HT 2b receptor antagonists , isocitrate dehydrogenase (IDH ) such as IDH1, Janus kinase LDL receptor related protein - 6 inhibitors , telomerase stimu ( JAK ) , KDR , lysine demethylase (KDMS ) , lymphocyte lators, endostatin modulators, Wnt- 1 induced signal path specific protein tyrosine kinase (LCK ) , lysyl oxidase protein way protein 1 inhibitors , NK1 receptor antagonists , CD95 ( LOX ) , lysyl oxidase - like protein (LOXL ) , LYN , matrix antagonists, protein tyrosine phosphatase 1E inhibitors, metalloprotease (MMP ) , mitogen - activated protein kinase plasminogen activator inhibitors 1 inhibitors , spleen tyrosine (MEK ) , mitogen - activated protein kinase (MAPK ) , mut T kinase inhibitors , MMP2 inhibitors, MMP3 inhibitors , homolog (MTH ) , NEK9, NPM -ALK , p38 kinase , platelet MMP7 inhibitors, MMP8 inhibitors , TPL2 COT Kinase derived growth factor (PDGF ) , phosphorylase kinase (PK ) , inhibitors , JAK1/ 2 inhibitors , JAK1/ 3 inhibitors , JAK2 / 3 polo - like kinase (PLK ), phosphatidylinositol 3 -kinase inhibitors , integrin alpha 4 beta 7 inhibitors, PAD4 inhibi (PI3K ), protein kinase (PK ) such as protein kinase A , B , tors, PAD2 inhibitors , IRAK4 inhibitors, ASK1 inhibitors , and / or C , PYK , spleen tyrosine kinase (SYK ) , serine / threo PIM1 inhibitors , PIM3 inhibitors , complement pathway nine kinase TPL2, serine / threonine kinase (STK ), signal inhibitors , AMPK inhibitors , IL - 17 inhibitors, PD - 1 agonist, transduction and transcription (STAT ) , SRC , serine / threo IL - 33 inhibitor, IL - 25 inhibitors , and IL -22 agonists . nine -protein kinase ( TBK ) such as TBK1 , TIE , tyrosine US 2017 /0306050 A1 Oct. 26 , 2017 33 kinase ( TK ), tank -binding kinase ( TBK ), vascular endothe entirety ) . The anti- LOXL2 antibody can be a monoclonal lial growth factor receptor (VEGFR ) , YES , or any combi antibody (including full length monoclonal antibody ) , poly nation thereof. clonal antibody, human antibody, humanized antibody, chi [0251 ] Apoptosis Signal- Regulating Kinase (ASK1 ) meric antibody, diabody, multispecific antibody (e . g ., bispe inhibitors include, but are not limited to , those described in cific antibody ), or an antibody fragment including , but not WO 2011 / 008709 and WO 2013 / 112741 . limited to , a single chain binding polypeptide, so long as it 10252 ] Examples of Bruton ' s tyrosine kinase (BTK ) exhibits the desired biological activity . Exemplified anti inhibitors include , but are not limited to , ( S ) - 6 - amino - 9 - 1 LOXL2 antibody or antigen binding fragment thereof may (but - 2 - ynoyl) pyrrolidin - 3 - yl) - 7 - ( 4 -phenoxyphenyl ) -7H - pu be found in U . S . Publication Nos. 2012 /0309020 , 2013 / rin - 8 (9H )- one, ibrutinib , HM71224 , ONO -4059 , and 0324705 , 2014 / 0079707 , 2009 /0104201 , 2009 / 0053224 . CC -292 , acalabrutinib (ACP - 196 ) , PRN - 1008 , BGB - 3111, and 2011/ 0200606 , each of which is incorporated herein by TAK - 020 , M -2951 , dasatinib , M - 2951 , HCL - 1401 , reference in the entirety ). HM -71224 , PRN - 1008, TAS -5315 , BGB - 3111, AS -550 , [0260 ] Polo - like Kinase (PLK ) inhibitors include inhibi DR - 109 , TAK -020 , SNS - 062, ONO - 4059 , X - 022 , TP -4207 , tors of PLK 1 , 2 , and 3 . KBP - 7536 , GDC -0834 , ONO - WG - 307 , and LFM - A13 . [0261 ] Phosphatidylinositol 3 -kinase ( PI3K ) inhibitors [0253 ] Mitogen - activated protein kinase (MAPK ) inhibi include inhibitors of PI3Ky, PI3KD, PI3KB , PI3Ka , and /or tors include selumetinib (AZD6244 ), MT- 144 , sorafenib , pan - PI3K . Examples of PI3K inhibitors include , but are not trametinib (GSK1120212 ) , binimetinib , antroquinonol, limited to , wortmannin , BKM120 , CH5132799 , XL756 , uprosertib + trametinib , idelalisib ( Zydelig® ) , and GDC -0980 . Examples of PI3Ky [0254 ] CK inhibitors include CK1 and / or CK2 . inhibitors include, but are not limited to , ZSTK474 , [0255 ] CDK inhibitors include inhibitors of CDK 1 , 2 , 3 , AS252424 , LY294002 , and TG100115 . Examples of PI3K8 4 , and /or 6 . Examples of CDK inhibitors include rigosertib , inhibitors include , but are not limited to , PI3K II, TGR selinexor, UCN -01 , alvocidib (HMR - 1275, flavopiridol) , 1202 , AMG -319 , GSK2269557 , X - 339, X - 414 , RP5090 , FLX - 925 , AT- 7519 , abemaciclib , palbociclib , and TG -02 . KAR4141 , XL499 , OXY111A , IPI - 145, IPI- 443 , and the ( 0256 ) Discoidin Domain Receptor (DDR ) Inhibitors compounds described in WO 2005 /113556 , WO 2013 / include inhibitors of DDR1 and /or DDR2 . Examples of 052699 , WO 2013/ 116562, WO 2014 / 100765 , WO 2014 / DDR inhibitors include, but are not limited to , those dis 100767 , and WO 2014 /201409 . Examples of P13KB inhibi closed in WO 2014 / 047624 , US 2009- 0142345 , US 2011 tors include, but are not limited to , GSK2636771 , BAY 0287011, WO 2013 /027802 , and WO 2013 / 034933 . 10824391 , and TGX221 . Examples of PI3Ka inhibitors [0257 ] Histone Deacetylase (HDAC ) inhibitors include , include , but are not limited to , buparlisib , BAY 80 -6946 , but are not limited to , pracinostat, CS -055 (HBI - 8000 ) , BYL719 , PX - 866 , RG7604, MLN1117, WX -037 , AEZA resminostat, entinostat, abexinostat , belinostat, vorinostat, 129 , and PA799 . Examples of pan - PI3K inhibitors include , riclinostat, CUDC - 907 , ACY -241 , CKD -581 , SHP - 141, val but are not limited to , LY294002 , BEZ235 , XL147 proic acid (VAL - 001 ) , givinostat , quisinostat ( JNJ (SAR245408 ) , and GDC -0941 . 26481585 ), BEBT- 908 and panobinostat. [ 0262 ] Spleen Tyrosine Kinase (SYK ) inhibitors include, [0258 ] Janus Kinase ( JAK ) inhibitors inhibit JAK1, JAK2 , but are not limited to , 6 - ( 1H - indazol- 6 - yl) - N - (4 -mor and /or JAK3, and/ or Tyk 2 . Examples of JAK inhibitors pholinophenyl ) imidazo [ 1 ,2 - a ]pyrazin - 8 -amine , tamatinib include , but are not limited to , momelotinib (CYT0387 ) , (R406 ) , fostamatinib (R788 ) , PRT062607 , BAY -61 - 3606 , ruxolitinib , filgotinib (GLPG0634 ) , peficitinib ( ASPO15K ) , NVP -QAB 205 AA , R112 , R343 , and those described in fedratinib , tofacitinib ( formerly tasocitinib ) , baricitinib , les U . S . Pat. No . 8 , 450 , 321, and those described in U . S . Pub taurtinib , pacritinib (SB1518 ) , XL019 , AZD1480 , lication No . 2015 /0175616 , which is incorporated by refer INCB039110 , LY2784544 , BMS911543 , AT9283 , and ence herein in its entirety . NS018 . Examples of Janus Kinase inhibitors ( e . g . JAK1 and 102631 Tyrosine -kinase Inhibitors ( TKIs ) may target epi JAK2) include ABT- 494 , ganetespib , tofacitinib , dermal growth factor receptors ( EGFRs ) and receptors for PF -04965842 , ruxolitinib , pacritinib , CF - 102 , momelotinib , fibroblast growth factor ( FGF ) , platelet -derived growth fac baricitinib , CS - 944X , AT- 9283 , TG - 02 , AR - 13154 , ENMD tor ( PDGF) , and vascular endothelial growth factor (VEGF ) . 2076 , VR -588 , YJC - 50018 , INCB - 39110 , NS -018 , GLPG Examples of TKIs that target EGFR include , but are not 0555 , G5 - 7 , BVB -808 , INCB - 52793 , fedratinib , limited to , gefitinib , nintedanib , and erlotinib . Sunitinib is a PF - 06263276 , TP -0413 , INCB -47986 , CT- 1578 , peficitinib , non - limiting example of a TKI that targets receptors for BMS- 911543 , XL -019 , solcitinib , MRK - 12 , AC - 410 , NMS FGF, PDGF, and VEGF. Additional TKIs include dasatinib P953 , CPL - 407 - 22 , CPL -407 - 105 , AZD - 1480 , gandotinib , and ponatinib . INCB - 016562 , CEP - 33779 , ON - 044580 , lestaurtinib , [0264 ] Toll -like Receptor ( TLR ) modulators include K - 454 , LS - 104 , SGI- 1252 , and EXEL -8232 . inhibitors of TLR - 1 , TLR - 2 , TLR - 3 , TLR - 4 , TLR - 5 , TLR - 6 , [ 0259 ] Lysyl Oxidase -Like Protein (LOXL ) inhibitors TLR - 7 , TLR - 8, TLR -9 , TLR - 10 , TLR -11 , TLR - 12 , and / or include inhibitors of LOXL1, LOXL2, LOXL3 , LOXL4 , TLR - 13 . and / or LOXL5. Examples of LOXL inhibitors include, but are not limited to , the antibodies described in WO 2009/ Therapeutic Use 017833 . Examples of LOXL2 inhibitors include , but are not [0265 ] In certain embodiments , methods are provided for limited to , the antibodies described in WO 2009 / 017833 , treating or preventing a disease or condition , including any WO 2009 /035791 , and WO 2011 /097513 . In certain of those described herein , e .g ., cystic fibrosis , cancers , embodiments , the LOXL2 inhibitor is an anti -LOXL2 anti - autoimmune or inflammatory diseases or conditions, com body ( see , e . g . , U .S . Pat. No . 8 ,461 , 303 , and U . S . Publica prising providing to the subject : an effective amount of an tion Nos . 2012 /0309020 , 2013 / 0324705 , and 2014 /0079707 , MMP9 binding protein comprising an immunoglobulin each of which are incorporated herein by reference in their heavy chain polypeptide, or functional fragment thereof, and US 2017 /0306050 A1 Oct. 26 , 2017 34 an immunoglobulin light chain polypeptide, or functional autoimmune disease or condition , or inflammatory disease fragment thereof , wherein the MMP9 binding protein spe or condition is rheumatoid arthritis , an inflammatory bowel cifically binds MMP9 ; and an effective amount of an addi disease ( IBD ) , vasculitis , septicemia , multiple sclerosis , tional therapeutic agent, thereby treating or preventing the muscular dystrophy , lupus, allergy , asthma or hidradenitis MMP9 - associated disease or condition in the subject. In one suppurativa . In yet another embodiment, the inflammatory embodiment, the disease or condition comprises myeloid bowel disease is selected from the group consisting of: cell - associated inflammation . ulcerative colitis (UC ) , Crohn ' s disease ( CD ) , or indetermi 10266 ] In another embodiment, the disease or condition is nate colitis . In yet another embodiment, the vasculitis is a cancer selected from the group consisting of: pancreatic giant cell arteritis . In certain embodiments , the TNFa inhibi cancer , esophagogastric adenocarcinoma, non - small cell tor is an antibody . In another embodiment, the antibody is lung cancer, lung squamous cell carcinoma , breast cancer , selected from the group consisting of certolizumab pegol, lung adenocarcinoma, gastric adenocarcinoma, colorectal adalimumab , golimumab and infliximab . In another embodi carcinoma, pancreatic adenocarcinoma, head and neck ment, the TNFa inhibitor is Etanercept. In certain embodi squamous cell carcinoma , hepatocellular carcinoma , col ments , the MMP9 binding protein is AB0045 or a functional orectal cancer, colorectal adenocarcinoma and hepatocellu fragment or variant thereof. lar carcinoma . In a further embodiment, the disease or [0270 ] In some embodiments , an MMP9 binding protein is condition is an autoimmune or inflammatory disease or used in treating subjects having gastric adenocarcinoma or condition . gastric cancer. In some embodiments , the subjects are [ 0267 ] In another embodiment, the autoimmune or inflam administered the MMP9 binding protein intravenously . In matory disease or condition is rheumatoid arthritis , an certain embodiments, the MMP9 binding protein is admin inflammatory bowel disease ( IBD ) , vasculitis , septicemia , istered at about 800 mg. In other embodiments , the subjects multiple sclerosis , muscular dystrophy, lupus, allergy , are administered the MMP9 binding protein every two asthma or hidradenitis suppurativa . In yet another embodi weeks . In some aspects of such embodiments , the patients ment, the inflammatory bowel disease is selected from the group consisting of: ulcerative colitis (UC ), Crohn ' s disease are administered the MMP9 binding protein intravenously at (CD ) , or indeterminate colitis . In yet another embodiment, a dosage of 800 mg every two weeks. the vasculitis is giant cell arteritis . [0271 ] In some embodiments , an MMP9 binding protein is [ 0268 ] In certain embodiments , methods are provided for used in treating subjects having cystic fibrosis , non - cystic treating or preventing one or more cancers , comprising fibrosis bronchiectasis , sarcoidosis , idiopathic pulmonary providing to the subject : an effective amount of an MMP9 fibrosis , tuberculosis , a cancer, autoimmune or inflammatory binding protein comprising an immunoglobulin heavy chain diseases or conditions . In some embodiments, the subjects polypeptide , or functional fragment thereof, and an immu are administered the MMP9 binding protein with a Janus noglobulin light chain polypeptide , or functional fragment kinase ( JAK ) inhibitor. In some embodiments , the JAK thereof, wherein the MMP9 binding protein specifically inhibitor is filgotinib . binds MMP9 ; and an effective amount of an immune check [0272 ] In certain embodiments of any of the compositions point inhibitor, thereby treating or preventing the one or or methods for treating or preventing a disease or condition , more cancers in the subject . In one embodiment, the one or the anti -MMP9 antibody or antigen binding fragment more cancers is selected from the group consisting of : thereof is AB0045 and the immune modulating agent is pancreatic cancer, esophagogastric adenocarcinoma, non etanercept. In another embodiment, the anti -MMP9 anti small cell lung cancer , lung squamous cell carcinoma, lung body or antigen binding fragment thereof is AB0045 and the adenocarcinoma, gastric adenocarcinoma , colorectal carci immune modulating agent is adalilumab . In another embodi noma , pancreatic adenocarcinoma, head and neck squamous ment, the anti -MMP9 antibody or antigen binding fragment cell carcinoma, hepatocellular carcinoma , colorectal cancer, thereof is AB0045 and the immune modulating agent is colorectal adenocarcinoma and hepatocellular carcinoma . In infliximab . In another embodiment, the anti -MMP9 anti another embodiment, the immune checkpoint inhibitor is body or antigen binding fragment thereof is AB0045 and the selected from the group consisting of an anti -PD - 1 antibody immune modulating agent is nivolumab . In another embodi and an anti -PD -L1 antibody . In certain embodiments , the ment, the anti- MMP9 antibody or antigen binding fragment anti - PD - 1 antibody is nivolumab , pembrolizumab , or pidili thereof is AB0045 and the immune modulating agent is zumab . In certain embodiments , the anti- PD -L1 antibody is pembrolizumab . In another embodiment, the anti -MMP9 BMS- 936559, atezolizumab , or avelumab . In certain antibody or antigen binding fragment thereof is AB0045 and embodiments , the MMP9 binding protein is AB0045 or a the immune modulating agent is pidilizumab . In another functional fragment or variant thereof. embodiment , the anti -MMP9 antibody or antigen binding [0269 ] In certain embodiments , methods are provided for fragment thereof is AB0045 and the immune modulating treating or preventing cystic fibrosis , autoimmune diseases agent is BMS - 936559 . In another embodiment, the anti or conditions, or inflammatory diseases or conditions , com MMP9 antibody or antigen binding fragment thereof is prising providing to the subject: an effective amount of an AB0045 and the immune modulating agent is atezolizumab . Matrix Metalloproteinase 9 (MMP9 ) binding protein com In one embodiment, the anti -MMP9 antibody or antigen prising an immunoglobulin heavy chain polypeptide , or binding fragment thereof is AB0045 and the immune modu functional fragment thereof, and an immunoglobulin light lating agent is certolizumab pegol . In one embodiment, the chain polypeptide , or functional fragment thereof, wherein anti -MMP9 antibody or antigen binding fragment thereof is the MMP9 binding protein specifically binds MMP9 ; and an AB0045 and the immune modulating agent is golimumab . In effective amount of a TNFa inhibitor, thereby treating or another embodiment, the anti -MMP9 antibody or antigen preventing cystic fibrosis, autoimmune or inflammatory binding fragment thereof is AB0045 and the immune modu diseases or conditions in the subject. In one embodiment , the lating agent is nivolumab . In another embodiment, the US 2017 /0306050 A1 Oct. 26 , 2017 35 anti -MMP9 antibody or antigen binding fragment thereof is from the group consisting of CTLA - 4 , LAG - 3 , B7 -H3 , AB0045 and the immune modulating agent is avelumab . B7- H4 , Tim3, BTLA , KIR , A2R, CD200 and PD - 1 . [ 0273 ] In one embodiment of any of the compositions or [0276 ] In certain embodiments , the anti -MMP9 antibody methods for treating or preventing a disease or condition , the or antigen binding fragment thereof and the additional additional therapeutic agent is a tumor necrosis factor alpha therapeutic agents ( s ) , e . g ., immune modulating agent, can be ( TNFa ) inhibitor selected from the group consisting of administered concurrently or sequentially . Concurrent Etanercept, pomalidomide, thalidomide, lenalidomide and administration of the anti- MMP9 antibody or antigen bind bupropion , certolizumab pegol, adalimumab , golimumab ing fragment thereof and the other therapeutic agent or their and infliximab . In one embodiment of any of the composi compositions comprises administration at the same time or tions or methods for treating or preventing a disease or at a time that overlaps . Sequential administration of the condition , the additional therapeutic agent is selected from anti -MMP9 antibody or antigen binding fragment thereof the group consisting of an anti- PD - 1 antibody and an and the immune modulating agent or their compositions anti - PD -L1 antibody . In certain embodiments , the anti - PD - 1 comprises administration of either the anti -MMP9 antibody antibody is nivolumab , pembrolizumab , or pidilizumab . In or antigen binding fragment thereof or its compositions first, certain embodiments , the anti -PD - L1 antibody is BMS followed by administration of the immune modulating agent 936559 , atezolizumab , or avelumab . In one embodiment, the or its composition second , or vice versa . additional therapeutic agent inhibits an immune checkpoint 0277 In some embodiments , the anti -MMP9 antibody or pathway . In another embodiment , the immune checkpoint antigen binding fragment thereof of the present disclosure pathway is selected from the group consisting of CTLA - 4 , may be used as the primary or front- line agent and the LAG - 3 , B7 -H3 , B7 -H4 , Tim3, BTLA , KIR , A2aR , CD200 additional agent may be used as the secondary agent . In and PD - 1 . In one embodiment of any of the compositions or other embodiments , the additional therapeutic agentmay be methods for treating or preventing a disease or condition , the used as the primary or front- line agent and the anti- MMP9 anti -MMP9 antibody or antigen binding fragment thereof is antibody or antigen binding fragment thereofmay be used as AB0045 and the immune modulating agent is etanercept . In the secondary agent. another embodiment, the anti- MMP9 antibody or antigen [0278 ] The one or more additional therapeutic agents can binding fragment thereof is AB0045 and the immune modu be an agent useful for the treatment of cancer and related lating agent is adalilumab . In another embodiment, the conditions . In some embodiments , the present disclosure anti -MMP9 antibody or antigen binding fragment thereof is provides methods for treating or preventing a disease or AB0045 and the immune modulating agent is infliximab . In condition such as cystic fibrosis, cancers , autoimmune dis another embodiment, the anti -MMP9 antibody or antigen eases or conditions , or inflammatory diseases or conditions, binding fragment thereof is AB0045 and the immune modu comprising providing to the subject : (i ) an effective amount lating agent is nivolumab . In another embodiment , the of an Matrix Metalloproteinase 9 (MMP9 ) binding protein anti -MMP9 antibody or antigen binding fragment thereof is comprising an immunoglobulin heavy chain polypeptide, or AB0045 and the immune modulating agent is pembroli functional fragment thereof, and an immunoglobulin light zumab . In another embodiment, the anti -MMP9 antibody or chain polypeptide , or functional fragment thereof, wherein antigen binding fragment thereof is AB0045 and the immune the MMP9 binding protein specifically binds MMP9; and modulating agent is pidilizumab . In another embodiment, (ii ) an effective amount of an immune modulating agent; and the anti- MMP9 antibody or antigen binding fragment ( iii ) an effective amount of one or more additional thera thereof is AB0045 and the immune modulating agent is peutic agents that is an anti - tumor agent or oncology agent, BMS - 936559 . In another embodiment, the anti -MMP9 anti thereby treating or preventing the disease or condition in the body or antigen binding fragment thereof is AB0045 and the subject. immune modulating agent is atezolizumab . [ 0279 ] In some embodiments , the present disclosure pro [0274 ] In certain embodiments , the one or more addition vides methods for treating or preventing a disease or con therapeutic agent is selected from the group consisting of an dition such as cystic fibrosis , cancers, autoimmune diseases antibody , a small molecule and a recombinant molecule . In or conditions , or inflammatory diseases or conditions , com some embodiments, the additional therapeutic agent is a prising providing to the subject an effective amount of an tumor necrosis factor alpha ( TNFa ) inhibitor. In another Matrix Metalloproteinase 9 (MMP9 ) binding protein com embodiment, the TNFa inhibitor is a small molecule . In yet prising an immunoglobulin heavy chain polypeptide , or another embodiment, the smallmolecule is selected from the functional fragment thereof, and an immunoglobulin light group consisting of pomalidomide , thalidomide , lenalido chain polypeptide , or functional fragment thereof, wherein mide and bupropion . In certain embodiments , the TNFa the MMP9 binding protein specifically binds MMP9 ; and an inhibitor is an antibody. In another embodiment, the anti effective amount of one or more additional therapeutic body is selected from the group consisting of certolizumab agents that is an oncology agent, thereby treating or pre pegol, adalimumab , golimumab and infliximab . In another venting the disease or condition in the subject. embodiment, the TNFa inhibitor is Etanercept. [0280 ] In some aspects , for treating an inflammatory or [0275 ] In some embodiments , the additional therapeutic autoimmune disease , such as IBD , UC , Crohn ' s disease , agent is selected from the group consisting of an anti -PD - 1 cancer, or rheumatoid arthritis , the monotherapy of an antibody and an anti- PD -L1 antibody . In certain embodi anti -MMP9 antibody or antigen binding fragment thereof or ments, the anti - PD - 1 antibody is nivolumab , pembroli the combination therapy of an anti -MMP9 antibody or zumab , or pidilizumab . In certain embodiments , the anti antigen binding fragment thereof and an immune modulat PD -L1 antibody is BMS- 936559 , atezolizumab , or ing agent is administered alone or with one or more addi avelumab . In one embodiment, the immune modulating tional therapeutic agents described herein . agent inhibits an immune checkpoint pathway. In another [0281 ] Each of the agents in a combination therapy can be embodiment, the immune checkpoint pathway is selected administered , via any suitable route , including any described US 2017 /0306050 A1 Oct. 26 , 2017 36 herein , simultaneously in the same composition or sepa tumor- associated tissues having MMP9 activity . The refer rately ) , or sequentially , in any order. ence sample can be a sample taken from the subject at an earlier time point or a sample from another individual. Detection of MMP9 [0288 ] In someaspects , MMP9 mRNA is detected , such as [0282 ] The present disclosure also contemplates methods by hybridization , such as by chromogenic in situ hybridiza of detecting MMP9 in a subject , e . g . , to detect tumor or tion (CISH ) . In some aspects , such detection methods are tumor -associated tissue expressing MMP9 , or tissue or fluid used when high levels of inflammatory cell - derived MMP9 or other biological sample associated with a disease as obscure signal in a desired cell type by other detection described herein , such as autoimmune or inflammatory method , e . g. , by IHC , e. g ., in tumor epithelia . disease . Thus, methods of diagnosing , monitoring , staging [0289 ] In certain embodiments , any of the methods of the or detecting a tumor having MMP9 activity are provided . present disclosure further comprise the step of determining [0283 ] Samples ( e. g ., test biological samples ) from a whether the subject, or diseased cells obtained from the subject ( e . g . , an individual suspected of having or known to subject, overexpressMMP9 as compared to a control subject have a tumor associated with MMP9 expression , or sus or non - diseased cells , e . g . , non -diseased cells of the same pected of having or known to have another disease or cell type . In certain embodiments , the subject is provided condition , such as inflammatory or autoimmune disease as with the MMP9 binding agent, alone or in combination with described herein ) , can be analyzed for MMP9 presence , an immunomodulatory agent, if the subject overexpresses absence , expression , and /or levels . For example , such MMP9 but not if the subject does not overexpress MMP9 . samples can be collected and analyzed by detecting the [0290 ] The subject who is suitable to receive or who may presence or absence ofbinding of an MMP9 binding protein , benefit from the therapy and methods of the present disclo such as an antibody or fragment as described herein , to sure may exhibit increased levels or activities of MMP9. substance ( e . g ., protein ) in the sample . In some examples , Such subjects may be identified by screening or measuring the methods further include comparing the amount of bind the levels or expression of MMP9 protein which may be ing detected to an amount of binding to a control sample, or determined by commonly - used methods such as western comparing the detected level of MMP9 to a control level of blot, ELISA , mRNA hybridization , RNAseq , or single MMP9 . In some cases , the methods indicate the presence , nucleotide polymorphism (SNP ) . Some SNPs have been absence , or severity of a disease or condition as described correlated with increased MMP9 levels . The screening or herein . identification of MMP9 levels / activities may also be used to [ 0284 ] This analysis can be performed prior to the initia monitor the patients ' responses or treatment outcome. tion of treatment using an MMP9 binding protein as described herein , or can be done as part of monitoring of Pharmaceutical Compositions and Kits progress of cancer treatment. In some embodiments , pro [0291 ] Provided herein are compositions comprising: a vided are methods of treatment, carried out by performing pharmaceutically acceptable excipient, carrier or diluent ; a the detection assays and initiating , altering , or discontinuing Matrix Metalloproteinase 9 (MMP9 ) binding protein , e . g . , treatment of the subject, for example , based on the results of comprising an immunoglobulin heavy chain polypeptide, or the diagnostic assay. Such diagnostic analysis can be per functional fragment thereof, and an immunoglobulin light formed using any sample , including but not limited to tissue , chain polypeptide , or functional fragment thereof, wherein cells isolated from such tissues , and the like . In some cases , the MMP9 binding protein specifically binds MMP9; and the methods are performed on liquid samples , such as blood , one or more additional therapeutic agent, e . g . , any of those plasma , serum , whole blood , saliva , urine , or semen . Tissue described here, such as an immune modulating agent. samples include, for example , formalin - fixed or frozen tis [0292 ]. In another aspect of the disclosure , MMP9 binding sue sections . proteins, as well as nucleic acid (e . g. , DNA or RNA ) [0285 ] Any suitable method for detection and analysis of encoding MMP9 binding proteins, can be provided as a MMP9 can be employed . Various diagnostic assay tech pharmaceutical composition , e . g ., combined with a pharma niques known in the art can be adapted for such purpose , ceutically acceptable carrier or excipient. Such pharmaceu such as competitive binding assays , direct or indirect sand tical compositions are useful for, for example , administra wich assays and immunoprecipitation assays conducted in tion to a subject in vivo or ex vivo , and for diagnosing and / or either heterogeneous or homogeneous phases . treating a subject with the MMP9 binding proteins , such as [ 0286 ] MMP9 binding proteins for use in detection meth in any of the therapeutic or diagnostic methods provided ods can be labeled with a detectable moiety . The detectable herein . moiety directly or indirectly produces a detectable signal. [0293 ] Pharmaceutically acceptable carriers or excipients For example , the detectable moiety can be any of those are physiologically acceptable to the administered patient described herein such as , for example , a radioisotope, such and retain the therapeutic properties of the antibodies or as 3H , 14C , 32P , 35S , or 1251, a fluorescent or chemilumi peptides with which it is administered . Pharmaceutically nescent compound , such as fluorescein isothiocyanate acceptable carriers or excipients and their formulations are (FITC ) , Texas red , cyanin , photocyan , rhodamine , or and generally described in , for example, Remington ' phar luciferin , or an enzyme, such as alkaline phosphatase , - ga maceutical Sciences ( 18th Edition , ed . A . Gennaro , Mack lactosidase or horseradish peroxidase. Publishing Co ., Easton , Pa . 1990 ). One exemplary pharma [0287 ] Detection can be accomplished by contacting a ceutical carrier is physiological saline . Each carrier or sample under conditions suitable for MMP9 binding protein excipient is “ pharmaceutically acceptable ” in the sense of binding to MMP9 , and assessing the presence ( e . g. , level) or being compatible with the other ingredients of the formu absence of MMP9 binding protein -MMP9 complexes. A lation and not substantially injurious to the patient. level ofMMP9 in the sample in comparison with a level of (0294 ) Pharmaceutical compositions can be formulated to a reference sample can indicate the presence of a tumor or be compatible with a particular route of administration , US 2017 /0306050 A1 Oct. 26 , 2017 37 systemic or local. Thus, pharmaceutical compositions example , by the use of a coating such as lecithin , by the include carriers, diluents , or excipients suitable for admin maintenance of the required particle size in the case of istration by various routes . dispersion and by the use of surfactants . Antibacterial and [0295 ] Pharmaceutical compositions can include pharma antifungal agents include , for example , parabens, chlorobu ceutically acceptable additives. Examples of additives tanol , phenol , ascorbic acid and thimerosal . Isotonic agents , include , but are not limited to , a sugar such as mannitol, for example , sugars, polyalcohols such as manitol, sorbitol, sorbitol, glucose , xylitol, trehalose , sorbose, sucrose, galac and sodium chloride may be included in the composition . tose , dextran , dextrose , fructose , lactose and mixtures The resulting solutions can be packaged for use as is , or thereof. Pharmaceutically acceptable additives can be com lyophilized ; the lyophilized preparation can later be com bined with pharmaceutically acceptable carriers and /or bined with a sterile solution prior to administration . excipients such as dextrose . Additives also include surfac [ 0300 ] Pharmaceutically acceptable carriers can contain a tants such as polysorbate 20 or polysorbate 80 . compound that stabilizes , increases or delays absorption or [0296 ] The formulation and delivery methods will gener clearance . Such compounds include , for example , carbohy ally be adapted according to the site and the disease to be drates , such as glucose , sucrose , or dextrans ; low molecular treated . Exemplary formulations include, but are not limited weight proteins; compositions that reduce the clearance or to , those suitable for parenteral administration , e . g ., intra hydrolysis of peptides ; or excipients or other stabilizers venous , intra - arterial, intramuscular, or subcutaneous and / or buffers . Agents that delay absorption include , for administration , or oral administration . In one embodiment, example , aluminum monostearate and gelatin . Detergents the anti- MMP9 antibody or antigen binding fragment can also be used to stabilize or to increase or decrease the thereof , the composition or the formulation thereof is deliv absorption of the pharmaceutical composition , including ered by intravenous administration (which may be referred liposomal carriers . To protect from digestion the compound to as intravenous infusion ). In some embodiment, the anti can be complexed with a composition to render it resistant MMP9 antibody or antigen binding fragment thereof, the to acidic and enzymatic hydrolysis , or the compound can be composition or the formulation thereof is delivered by complexed in an appropriately resistant carrier such as a subcutaneous administration (which may be referred to as liposome. Means of protecting compounds from digestion subcutaneous injection ) . are known in the art (see , e . g . , Fix ( 1996 ) Pharm Res . 10297 ] Pharmaceutical compositions for parenteral deliv 13: 1760 1764 ; Samanen ( 1996 ) J . Pharm . Pharmacal. 48 : 119 ery include , for example , water, saline, phosphate buffered 135 ; and U . S . Pat . No. 5 , 391, 377, describing lipid compo saline , Hank ' s solution , Ringer' s solution , dextrose / saline , sitions for oral delivery of therapeutic agents ). and glucose solutions . The formulations can contain auxil iary substances to approximate physiological conditions, [0301 ] Compositions of the present disclosure can be such as buffering agents , tonicity adjusting agents , wetting combined with other therapeutic moieties or imaging /diag agents , detergents and the like . Additives can also include nostic moieties as provided herein . Therapeutic moieties additional active ingredients such as bactericidal agents , or and / or imaging moieties can be provided as a separate stabilizers . For example , the solution can contain sodium composition , or as a conjugated moiety present on an MMP9 acetate , sodium lactate , sodium chloride , potassium chlo binding protein . ride , calcium chloride , sorbitan monolaurate or trietha [0302 ] Formulations for in vivo administration are gener nolamine oleate . Additional parenteral formulations and ally sterile . In one embodiment, the pharmaceutical compo methods are described in Bai ( 1997 ) J . Neuroimmunol. sitions are formulated to be free of pyrogens such that they 80 :65 75 ; Warren ( 1997 ) J. Neurol. Sci. 152 :31 38 ; and are acceptable for administration to human patients. Tonegawa (1997 ) J . Exp . Med . 186 : 507 515 . The parenteral 10303 ] Various other pharmaceutical compositions and preparation can be enclosed in ampules, disposable syringes techniques for their preparation and use will be known to or multiple dose vials made of glass or plastic . those of skill in the art in light of the present disclosure . For [ 0298 ] Pharmaceutical compositions for intravenous , a detailed listing of suitable pharmacological compositions intradermal or subcutaneous administration can include a and associated administrative techniques one can refer to the sterile diluent , such as water, saline solution , fixed oils , detailed teachings herein , which can be further supple polyethylene glycols , glycerin , propylene glycol or other mented by texts such as Remington : The Science and synthetic solvents ; antibacterial agents such as benzyl alco Practice of Pharmacy 20th Ed . (Lippincott , Williams & hol or methyl parabens ; antioxidants such as ascorbic acid , glutathione or sodium bisulfite ; chelating agents such as Wilkins 2003 ) . ethylenediaminetetraacetic acid ; buffers such as acetates, [0304 ] Pharmaceutical compositions can be formulated citrates or phosphates and agents for the adjustment of based on the physical characteristics of the patient/ subject tonicity such as sodium chloride or dextrose . needing treatment, the route of administration , and the like . f0299 Pharmaceutical compositions for injection include Such can be packaged in a suitable pharmaceutical package aqueous solutions (where water soluble ) or dispersions and with appropriate labels for the distribution to hospitals and sterile powders for the extemporaneous preparation of sterile clinics wherein the label is for the indication of treating a injectable solutions or dispersion . For intravenous adminis disorder as described herein in a subject . Medicaments can tration , suitable carriers include physiological saline , bacte be packaged as a single or multiple units . Instructions for the riostatic water, Cremophor ELTM (BASF , Parsippany , N .J .) dosage and administration of the pharmaceutical composi or phosphate buffered saline (PBS ) . The carrier can be a tions of the present disclosure can be included with the solvent or dispersion medium containing , for example , pharmaceutical packages and kits described below . water, ethanol, polyol ( for example , glycerol, propylene [0305 ] In one embodiment, a pharmaceutical composition glycol, and liquid polyetheylene glycol, and the like ) , and is provided for treating or preventing an MMP9 -associated suitable mixtures thereof. Fluidity can be maintained , for disease or condition in a subject in need thereof, comprising : US 2017 /0306050 A1 Oct . 26 , 2017 38 a pharmaceutically acceptable excipient, an anti -MMP9 antibody or antigen binding fragment thereof; and an - continued immune modulating agent. GKAEDNYKTTPAVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEA [ 0306 ] In one embodiment, a pharmaceutical composition is provided for treating or preventing cystic fibrosis in a LHNHYTOKSISRSPGK subject in need thereof, comprising: a pharmaceutically Active AB Light Chain : acceptable excipient; and an anti- MMP9 antibody or antigen ( SEQ ID NO : 60 ) binding fragment. AQVLTQTASPVSAAVGGTVTINCQSSQSVYNKNWLAWYOQKPGQPPK 10307 ] In one embodiment, a pharmaceutical composition RLIYSASTLDSGVSSRFKGSGSGTOFTLTISGVQCDDAA TYYCOGEF is provided for treating or preventing vasculitis in a subject in need thereof, comprising : a pharmaceutically acceptable SCSRGDCSAFGGGTEVVVQGDPVAPTVLIFPPSADLVATGTVTIVCV excipient ; and an anti- MMP9 antibody or antigen binding fragment. ANKYFPDVTVTWEVDGTTOTTGIENSKTPONSADCTYNLSSTLTLTS [ 0308 ] In one embodiment, kits comprising a compound TOYNSHKEYTCKVTQGTTSWQSFNRGDC disclosed herein , or a pharmaceutically acceptable salt [0312 ] The reagent antibodies L51/ 82 (Biolegend ) , which thereof, in combination with one or more ( e . g ., one , two , recognizes total amounts of MMP9 regardless of activation three , one or two , or one to three ) additional therapeutic state , and Abcam 76003 were also used . Specificity of agents are provided . Active AB was determined by Western blot analysis and [0309 ] Various aspects of the invention are further immunohistochemistry (IHC ) . described and illustrated by way of the several examples [0313 ] The results showed that both antibodies Active AB which follow , none of which are intended to limit the scope and L51 / 82 bound to active MMP9 (FIG . 1A ) . Addition of of the invention . an N - terminal aspartic acid reduced the binding of Active AB to active MMP9 protein and did not affect the binding EXAMPLES of the Abcam 76003 to the MMP9 protein ( FIG . 1B ) . Specificity of the Active AB was further shown by ELISA Example 1 : Activation of MMP9 Protein with peptides of the neo - epitope ( FQTFEGD ) (SEQ ID NO : [ 0310 ] Pro -MMP9 is cleaved by protease activators to 56 ), a fragment of the neo -epitope ( QTFEGD ) ( SEQ ID NO : remove the pro - domain and generate a catalytically active 57 ) , and the total fragment of cleavage site (VPDLGRFQT form of MMP9 ( i . e . active MMP9 ) . To examine whether FEGD ) ( SEQ ID NO : 58 ) . The binding of Active AB to the endogenous (MMP3 ) and exogenous (Pseudomonas neo -epitope ( FQTFEGD ) occurred at low concentrations of elastase ) proteases or activators would cleave pro -MMP9 or antibody, and the binding of Active AB to the neo -epitope activate MMP9 , a cell - free assay was used . Pro -MMP9 was fragment (QTFEGD ) and the total cleavage site (VPDLGR incubated at 37° C . with increasing concentrations of either FQTFEGD ) occurred at increased concentrations of anti active MMP3 or active Pseudomonas elastase ( 0 .0034 - 200 body ( FIG . 1C ) . nM ) . Both proteases activated MMP9 in a dose - dependent [0314 ] Moreover , the binding of Active AB to total and manner, as shown by the appearance of the active MMP9 active MMP9 in human tissues was assessed using colon fragment by Li- Cor Western blot and increase in gelati lysates from ulcerative colitis (UC ) and Crohn ' s disease nolytic activity (data not shown ). The activation of MMP9 patients. Results of Li - Cor Western blot showed that Active by MMP3 and Pseudomonas elastase was inhibited by AB specifically bound to active MMP9 and differentiated AB0045 (data not shown ) . MMP9 auto -activation was not the presence of pro - and active MMP9 in human samples observed in vitro . The result indicates that AB0045 inhibits (FIG . 2B ) . the activation of MMP9 as an MMP9 - specific protease inhibitor. Example 2 : Active MMP9 in Chronic Myeloid 10311 ] Additional antibodies specific to active MMP9 Inflammatory Disease Tissue were generated . One antibody (Active AB ) was used for [ 0315 ] To quantify endogenous or naive MMP9 activity additional studies . The heavy and light chain sequences of ( proteolysis of substrate peptide ), an MMP9 assay using the Active AB are as follows: GE MMP- 9 Biotrak assay kit was developed . Plates were coated with a monoclonal antibody specific for human Active AB Heavy Chain : MMP9 which recognized epitopes unrelated to the cleavage ( SEQ ID NO : 59 ) site . APMA was omitted to ensure endogenous or native , not OSVEESGGRLVTPGTPLTLTCTASGFTISSYHMTWVROAPMKGLEWI induced , MMP9 activity was examined . The endogenous or naïve MMP9 activity represented the MMP9 level and /or GTISSSGSTYYASWAKGRFTISKTSSTTVDLKITSPATEDTATYFCA activity in the real disease state . After sample addition and RSVPGDSSGEIWGRGTLVTVSSGQPKAPSVFPLAPCCGDTPSSTVTL incubation at 4° C . overnight, plates were washed and incubated with a substrate peptide conjugated to a fluores GCLVKGYLPEPVTVTWNSGTL TNGVRTFPSVROSSGLYSLSSVVSVT cent dye and a quencher. Cleavage of the substrate peptide removes the quencher and allows the dye to fluoresce , SSSQPVTCNVAHPATNTKVDKTVAPSTCSKPTCPPPELLGGPSVFIF indicating the presence of active MMP9 . PPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPP [0316 ] The above assay was used to examine the MMP9 activity in colon tissue lysates from ulcerative colitis (UC ) LREQOFNSTIRVVSTLPIAHODWLRGKEFKCKVHNKALPAPIEKTIS and Crohn ' s disease patients. The results showed that KARGOPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKN MMP9 activity in samples from UC and Crohn ' s disease patients was increased compared to those of non -inflamma US 2017 /0306050 A1 Oct. 26 , 2017 39

tory bowel disease ( IBD ) patients ( FIG . 2A ). Li- Cor Western Example 3 : MMP9 Activity Correlates with Blots was used to further analyze the lysates from UC , Inactivation of al - Antitrypsin in Cystic Fibrosis Crohn ' s disease , and non - diseased control tissues . The Lung Tissue results showed the levels of both pro - and active MMP9 in [0322 ] It is known that al- antitrypsin inhibits human UC and Crohn 's disease tissues were increased compared to neutrophil elastase (FINE ) , which is a key mediator of lung those of non - diseased tissues ( FIG . 2B ). destruction . Loss of function mutations in al -antitrypsin are [0317 ] After detection of both pro - and active MMP9 in associated with decreased lung function . The ability of diseased tissue lysates, correlation analyses between both MMP9 to directly inactivate al- antitrypsin was assessed in forms of the protein and disease score were determined with vitro . In reaction 1 (Rxnl ) , intact al- antitrypsin was incu matched FFPE samples analyzed histologically. As shown in bated with active MMP9 in the presence or absence of FIG . 3A , there was between the active MMP9 concentration AB0045 . Cleavage of al - antitrypsin was assessed by West and Geboes disease score (Spearman correlation = 0 .754 ). ern blot (FIG . 5 , panel 1 ) . In the presence of active MMP9 Correlation was reduced between active MMP9 and total alone , al -antitrypsin was cleaved from the active form to MMP9 for non - IBD , UC and Crohn ' s disease state (Spear the inactive form . This inactivation was inhibited by the man correlation = 0 . 21 ) FIG . 3B . This indicates that active addition of AB0045 and unaffected by the addition of an MMP9 , not total MMP9, correlates with UC histological isotype control. The digests from Rxnl were then incubated disease score . with neutrophil elastase , a key mediator of lung destruction , and its substrate , elastin ( FIG . 5 , Panel 2 ) . The ability of [ 0318 ] Endogenous or naive MMP9 activity of diseased digests from Rxnl to inhibit neutrophil elastase was mea tissue from UC and Crohn ' s disease patients was examined . sured by elastin cleavage fluorescence in reaction 2 (Rxn2 ) . The average levels of active MMP9 in the tissue of UC and Intact al- antitrypsin inhibited neutrophil elastase , indicated Crohn ' s disease patients were 14 . 8 ng /mL and 8 . 3 ng /mL , by a lack of elastin fluorescence . MMP9 - inactivated al respectively . These levels are increased compared to those of antitrypsin did not inhibit the cleavage of elastin by neutro tissue from inflammatory bowel disease and normal tissue phil elastase . Addition of AB0045 , resulting in subsequent ( < 1 ng/ mL ) . inactivation of MMP9, was sufficient to prevent downstream [0319 ] Hidradenitis suppurativa (HS ) is a prevalent elastin cleavage by neutrophil elastase . As a control, the chronic inflammatory skin condition characterized by fistu elastase inhibitor N -methoxylsuccinyl - Ala - Ala - Pro - Val lae formation . IHC analyses of tissue from HS patients chloromethyl ketone also inhibited HNE ( shown as “ i” in showed increased staining for active MMP9 . Fistulae were FIG . 5 , panel 2 ) . These results indicate that AB0045 may also characterized by significant staining for myeloperoxi prevent the inactivation of al - antitrypsin and may lead to dase (MPO ), indicative of active neutrophil infiltration . restore al- antitrypsin function and reduce HNE activity . Moderate staining for the macrophage marker, ionized cal [0323 ] Further , correlation between MMP9 activity and cium binding adaptor molecule 1 ( IBA1) , the B - cell marker al- antitrypsin inactivation was assessed in vivo . Levels of CD20 , and the T - cell marker CD3 were also detected (data active MMP9 and ratios of cleaved vs. intact al- antitrypsin not shown ) . This staining pattern indicated an active inflam were compared between lung lysates from CF and non -CF matory state characterized by MMP9 expression and patients (FIG . 6A ) . Relative ratios of cleaved vs. intact myeloid cell infiltration . al- antitrypsin were visualized by Western blots of al- an [ 0320 ) Similar to IBD and HS, cystic fibrosis (CF ) is titrypsin ( FIG . 6B ). Spearman correlations between MMP9 characterized by aberrant myeloid inflammation . Chronic activity and al - antitrypsin cleavage were calculated for all inflammation is hypothesized to result in pathologic lung patients (Spearman correlation = 0 .85 , p < 0 .0001 ) and only remodeling and decline in lung function in CF patients . As CF patients ( Spearman correlation = 0 . 7 , p < 0 . 0045 ) . shown in FIG . 4A , similar levels of total MMP9 were [0324 ] These data indicate that MMP9 may directly inac detected in lung lysates from non - CF and CF patients. tivate al -antitrypsin to allow function of inflammatory Measurements of endogenous active MMP9 showed the proteases such as neutrophil elastase . Further , the activity of increase levels of active MMP9 in samples from CF patients MMP9 correlates with inactivation of al - antitrypsin in CF as compared to those of normal controls (FIG . 4B , * lung tissue , suggesting a mechanism by which MMP9 may p = 0 .03 ). Also , samples from CF patients also exhibited mediate inflammation in CF . elevated ratios of inactive (cleaved ) vs . active intact ) al- antitrypsin , indicating an increase in levels of inactive Example 4 : MMP9 Inhibition in the Xenograft al -antitrypsin in CF lung tissue ( FIG . 4C , * * * * p = 0 . 0001 ) . Model Ratios of intact : inactive al- antitrypsin were determined by 103251 This study examines the effect of MMP9 - specific quantitative Li- Cor Western blot. Lysates from CF patients inhibition in the xenograft model. Fragments of subcutane showed decreased intact (active ) al- antitrypsin and ous tumors derived from a human colorectal cancer cell line increased levels of cleaved ( inactive ) al - antitrypsin (FIG . (HCT - 116 ) were surgically implanted into the colon in nude 4D ) . These results indicated that active MMP9 levels cor mice and allowed to grow to ~ 100 mm in volume prior to relate with CF and decreased levels of active al -antitrypsin . treatment initiation . Mice were treated with vehicle , isotype [ 0321] Together, the results suggest that active MMP9 IgG ( control) , or a 1 :1 mixture of AB0041 and AB0046 may be associated with multiple chronic myeloid inflam ( anti -mouse MMP9 and anti - human MMP9 , respectively ) matory diseases and that levels of active MMP9 may cor ( m + h ) . Treatments were administered intraperitoneally at 30 relate with disease severity, indicating a potential role for mg/ kg total antibody ( 15 mg/ kg of each AB0041 and MMP9 as a biomarker in myeloid inflammatory diseases and AB0046 ) twice a week . In the m + h group , mice were also as an active player in the inflammatory milieu of the pre -administered with AB0046 at 50 mg/ kg on the first day diseased tissue . of the treatment. US 2017 /0306050 A1 Oct. 26 , 2017 40

[ 0326 ] Primary tumor sizes were measured once a week were categorized as severe for 13 subjects (87 . 7 % ), and using a caliper . Caliper -based size estimates were obtained moderate for 2 subjects ( 13 . 3 % ) . No subjects were consid by measuring the perpendicular minor dimension ( W ) and ered mild or in remission at baseline . At Day 43 , after receiving 3 doses of IV AB0045 , disease activity was major dimension ( L ) of the palpated tumor . Approximate categorized as severe for 3 subjects ( 20 .0 % ), moderate for 8 tumor volumewas calculated by the formula (W2XL )/ 2 . The subjects (53 . 3 % ) , low for 3 subjects ( 20 . 0 % ) , and 1 subject non - parametric Mann -Whitney rank sum test was used to was in remission (6 . 7 % ) . Among placebo subjects (N = 3 ) , determine p values . Treatment with the antibody cocktail the distribution of disease activity at Baseline was severe for decreased change in tumor volume ( FIG . 7A ) and decreased 2 subjects (66 . 7 % ) and moderate for 1 subject ( 33 . 3 % ) . No final tumor weight (FIG . 7B ) . Immunohistochemistry (IHC ) subjects were considered mild or in remission . In contrast to analysis was also performed on tumors from vehicle - treated AB0045 treated subjects , at Day 43 the placebo group had mice and demonstrated production ofMMP9 by tumor cells no subjects with mild disease activity or remission . All 3 at lower levels compared to MMP9 from stromal sources placebo subjects at Day 43 exhibited moderate disease such as resident macrophages, fibroblasts , and epithelial activity . These clinical improvements and changes in addi cells (data not shown ) . tional RA disease activity measures are shown in Table 2 . TABLE 2 Subjects with 50 % improvement at Day 43 Number of Subjects with 50 % Improvement Clinical Subject Physician Assessments Subject Global Global DAS28 - CRP Swollen Tender Pain Assessment Assessment (Mean A From Joint Joint Score of Health of Health Baseline at Counts Counts ( VAS , ( VAS , (VAS , CRP Subjects Day 43 (28 -joints ) ( 28 -joints ) 0 - 100 ) 0 -100 ) 0 - 100 ) (mg / L ) AB0045 - 1. 35 ( 1. 393 ) 9 (60 % ) 7 (47 % ) 7 (47 % ) 6 (40 % ) 6 ( 40 % ) 4 ( 27 % ) ( N = 15 ) Placebo -077 (0 . 570) 0 (0 % ) 1 (33 % ) 0 (0 % ) 0 ( 0 % ) 0 (0 % ) 1 (33 % ) (N = 3 )

[0327 ] Tumor sections from isotype and AMMP9 treated [0330 ] These clinical improvements occurred despite a mice were also visualized via 2nd harmonic microscopy . The lack ofmajor change in CRP values . Among subjects treated sections were stained with picro - sirius red (PSR ) to visualize with AB0045 during the study (n = 15 ), themean ( SD ) values collagen deposition , and aKi67 antibodies were used to at baseline and Day 43 were 37 .21 (18 .688 ) mg/ L and 21 . 10 visualize cellular proliferation by IHC analysis ( data not (18 . 977) mg/ L , respectively, a mean decrease of 6 .11 (22 . shown ). Tumor sections from mice treated with aMMP9 577) mg/ L . Among subjects treated with placebo ( n = 3 ) , the antibodies showed an increased degree of fibrillar collagen mean CRP values at baseline and Day 43 were 16 . 57 remodeling adjacent to the tumor. These results indicate that ( 11. 153 ) mg / L and 12 . 46 ( 10 . 572 ) mg/ L , respectively, a targeting MMP9 with a cocktail of human -specific and mean decrease of 4 . 12 ( 5 . 922 ) mg/ L . These study results mouse -specific monoclonal antibodies in a mouse xenograft showed that AB0045 was well tolerated during the study and model reduced growth of the primary tumor and remodeled that AB0045 may be beneficial in patients with RA ( Table fibrillar collagen . 2 ). 10331 ] Additionally , the combination of an anti -MMP9 Example 5 : Treatment of Rheumatoid Arthritis agent (AB0046 ) and an anti- TNF agent (Enbrel® ) was evaluated in a murine collagen - induced arthritis ( CIA ) [0328 ] A Phase 1 , double -blind , randomized , placebo model. In this chronic model of advanced disease , therapies controlled study was conducted for RA patients ( subjects ) . ( vehicle , AB005123 control IgG , methotrexate , AB0046 , Subjects were randomized in a 4 : 1 ratio to receive an Enbrel® , or combination ) were administered after an aver intravenous (IV infusion of AB0045 at 400 mg or matched age clinical score of > 2 was reached (Day 28 ) and continued placebo every 2 weeks for a total of 3 infusions (Days 1 , 15 , through Day 43 . Score was determined using established and 29 ) . Subjects participated in the study for up to 117 days . methods on a scale of 0 - 4 . 0 ( in 0 . 5 unit increments ) and The screening visits were conducted a maximum of 15 days reflects increasing degrees of erythema and swelling across before the first infusion . Subjects exhibited a mean C - reac ankles/ wrists and paws. All 4 paws were scored , thus each tive protein (CRP ) value during screening 28 mg/ L and did mouse has a theoretical maximum score of 16 . The mean not received other concomitant RA treatments within 1- 12 represents the treatment group average at each noted time months prior to or during the study . point. Treatment with AB0046 and Enbrel® , alone or in [0329 ] The Disease Activity Score (DAS ) served as a key combination , resulted in improvement with respect to scores clinical endpoint for this study . Using the DAS - 28 CRP ( FIG . 8 * p < 0 . 05 by t - test for vehicle or control compared to score , subjects were classified by level of RA disease drug treated ). Area under the curve (AUC ) reflects cumula activity at baseline ( > 5 . 1 severe , > 3 . 255 . 1 moderate, mild tive clinical score over duration of treatment for each > 2 .6 < 3 . 2 , and remission < 2 . 6 ) (Wells et al, Annals of the therapy . As illustrated by the AUC for the course of treat rheumatic diseases 2009; 68 (6 ): 954 -60 ). Among subjects ment of the study , treatment with a combination of AB0046 treated with AB0045 ( N = 15 ) , baseline disease activity levels and Enbrel® (AUC = 107. 6 ) resulted in an improvement as US 2017 /0306050 A1 Oct. 26 , 2017 compared to vehicle (AUC = 145 . 3 ) , control IgG ( AUC = 145 . eters, the absolute change in post- bronchodilator FEV , 9 ) , AB0046 alone ( AUC = 121. 0 ) , or Enbrel® alone percent predicted from baseline to week 8 , the relative ( AUC = 114 . 9 ) . Similar results were shown in body weight change in pre -bronchodilator FEV percent predicted from and histopathology. baseline to week 8 , and the relative change in post- bron [0332 ] Further, the analysis evaluating the number of chodilator FEV1 percent predicted from baseline to week 8 . limbs scored with mild or no disease at the end of treatment Safety evaluations are assessed by adverse events (AES ) , showed that the combination therapy resulted in improve concomitant medications , clinical laboratory tests , vital ment when compared to individual agent ( mild disease, see signs, and anti- drug antibodies ( ADA ) data . Primary PK FIG . 9A , * p < 0 .05 paired t -test compared to vehicle , # parameters include Cmax (maximum concentration of drug ) , p < 0 .05 paired t - test to Control IgG , AB0046 , or Enbrel® ; Tmax (the time of Cmax ) , Clast ( last observable concentra FIG . 9B , * p = 0 .052 paired t - test to vehicle , # p < 0 .05 paired tion of drug ) , Tlast ( time of Clast ) , and AUClast ( total t - test to Control IgG ) . Furthermore , analysis of complete amount of drug absorbed by the body ) , as applicable. blood count at the end of study revealed no abnormalities in (0336 ] This study has two parts . Part 1 has a treatment arm any treatment group . These results indicate that the addition in which participants receive 600 mg of AB0045 given of anti -MMP9 to anti - TNF therapy or the combination subcutaneously once weekly for 8 weeks. Part 1 has a therapy of anti -MMP9 to anti - TNF may potentially provide placebo arm in which participants receive a placebo to an increased therapeutic benefit or efficacy . match AB0045 once weekly for 8 weeks . Part 2 has two [0333 ] A Phase 2 trial in subjects with moderate to severe treatment arms, one in which participants receive 300 mg of RA despite stable therapy with a TNF inhibitor is conducted AB0045 given subcutaneously once weekly for 8 weeks , to further evaluate the efficacy, safety , and pharmacokinetics and one in which participants receive 150 mg of AB0045 of AB0045. Subjects with moderate to severe RA are given subcutaneously once weekly for 8 weeks . Part 2 has enrolled and randomized in a 1 : 1 : 1 blinded fashion to a placebo arm , in which participants are given placebo to receive either 300 mg or 150 mg of subcutaneous (SC ) match AB0045 once weekly for 8 weeks . Some inclusion AB0045 weekly , or SC placebo weekly for 12 weeks in criteria of the study includes ( 1 ) Pre -bronchodilator addition to their current SC administration of a TNF inhibi FEV 240 % and s80 % of predicted at Screening , ( 2 ) two tor. Subjects are stratified by disease activity with those with pre - bronchodilator spirometry measures taken at least 4 days high disease activity defined as DAS -28 - CRP > 5 . 1 and those apart (one during Screening , one at Baseline ) using the with moderate disease activity defined as a DAS - 28 sponsor provided central spirometry equipment must meet CRP23 .2 and s5. 1. In addition , subjects are stratified by the following 2 criteria : (i ) the relative difference of FEV , prior treatment ( 1 to 2 treatments or 3 or more treatments ) ( L ) , calculated as the absolute value of [ ( first FEV , -second including the TNF inhibitor being administered during FEV1) / first FEV1] x100 should be < 12 % , and ( ii ) the abso screening lute difference in FEV , should be < 200 ml. Example 6 : Combination Treatment Example 8 : Treatment of Giant Cell Arteritis [0334 ] Bulk tumors from the mice injected with the HC11 [0337 ] Vasculitis is inflammation of blood vessel walls . Neut breast cancer cell line were analyzed by RNA -Seq , Giant cell arteritis (GCA ) is a form of vasculitis that regression , and Gene Set Enrichment Analysis (GSEA ). The typically affects the network of small blood vessels that expression profiles were different between the mice treated supply larger arteries . This study examined whether MMP9 with an anti- MMP9 antibody and those treated with an would be involved in vessel wall inflammation , remodeling anti- PD -L1 antibody , yet there were overlapping pathways . and myofibroblast mobilization /proliferation and the poten The results showed that immunomodulatory pathways were tial effects of MMP9 inhibition on anti - inflammatory activi upregulated in the group treated with both anti -MMP9 and ties in large vessel vasculitis . Analysis ofmRNA expression anti - PD -L1 (data not shown ) . As several of the affected revealed that MMP9 expression was increased in GCA immunomodulatory pathways centered on TCR signaling , T arteries compared to normal arteries and arteries affected by cell diversity was measured by assessing CDR3 sequence granulomatosis with polyangiitis (Wegener 's , GPA ) (FIG . diversity by application of MiTCR /MiXCR analysis to the 11 , * p < 0 .05 ). RNAseq data . The analysis revealed that the combination of 0338 ] A murine model of vasculitis was used to deter AMMP9 and aPDL1 treatment groups resulted in increased mine the potential effects ofMMP9 inhibition on the pathol overall CDR3 counts , suggesting improved T cell diversity ogy of vasculitis . Normal temporal or axillary arteries were ( FIG . 10 ). This study suggests that the combination therapy engrafted into NSG immune deficientmice . After 7 days ( i .e . of anti- MMP9 and anti - PD -L1 may potentially increase or Day 7 of the study ), 20x10 peripheral blood mononuclear enhance the overall immune response to cancer antigens cells (PBMCs ) from GCA patients were transferred into the chimeric mice . Ten days after transfer , vasculitis of the which may lead to anti- cancer responses and reduction in engrafted human arteries was evident with tissue - infiltrating tumor growth . cells populating the vessel wall lesions. No vasculitis was observed when PBMCs from normal human controls were Example 7 : Treatment of Cystic Fibrosis Patients transferred . Dexamethasone injections served as a positive [ 0335 ] This study evaluates the effect of AB0045 on control and vehicle injections as negative controls . The pre -bronchodilator forced expiratory volume in 1 second model may be useful in evaluating the potential effects in ( FEV1) in subjects with cystic fibrosis ( CF ) after 8 weeks of preventing (prior to disease development ) and /or treating the treatment. The primary outcome measure is the absolute disease (after the disease is developed or established ). change in pre -bronchodilator FEV1 percent predicted from [0339 ] An anti -MMP9 antibody AB0045 or a control baseline to week 8 . The secondary outcomemeasures are the isotype Ig antibody (Isotype ) was introduced during the safety evaluations, primary pharmacokinetics (PK ) param beginning stages of vasculitis (Day 7 , the same day as US 2017 /0306050 A1 Oct. 26 , 2017

PBMC reconstitution ) or during established vasculitis (Day 12 - lead ECG ( electrocardiogram ), ECOG ( Eastern Coop 14 , 7 days post PBMC reconstitution ) . Treating the chimeric erative Oncology Group ) performance status , prior/ con mice at Day 7 is designed to target the early phase of the comitant medication review , chemistry, hematology , and disease and to prevent vasculitic infiltrates from taking root, coagulation , adverse event ( AE ) assessment, archival or while therapeutic intervention at Day 14 mimics treatment recent biopsy FFPE ( formalin - fixed paraffin embedded ) tis of steady - state vasculitis . In each study , mice were engrafted sue block collection , and computed tomography (CT ) or with segments from the same artery and received an adop magnetic resonance imaging (MRI ) . Additional screening tive transfer of PMBC from the same patient, so that the criteria include baseline tumor lesions and archival tumor vasculitis was comparable in each of the treatment arms. The tissue adequate for PD - 1 immunohistochemical stratification antibodies were given every other day for a total of 3 times . test. Samples were collected at either Day 14 ( for early phase ) or [0345 ] Approximately 120 subjects are randomized to Day 21 (for steady state vasculitis ) . receive treatment which occurs every 2 weeks . Subjects who [0340 ] The effect of MMP9 inhibition on suppression of meet eligibility undergo CT scans or MRI every 8 weeks . vasculogenic T cell functions in the vessel wall lesions was Starting on Day 1 , subjects randomized to Arm A ( AB0045 + examined . Human arterial grafts were explanted at the end nivolumab ) receive 800 mg AB0045 via intravenous infu of the treatment period and analyzed for IL - 6 , TNF - a , sion ( IV ) infusion over approximately 30 minutes in IFN - Y , IL - 1B , T cell receptor, IL - 17 , and IFN - y expression advance of nivolumab 3 mg/ kg via IV infusion over approxi by RT- PCR and immunohistochemistry . Tissue histology mately 60 minutes on Day 1 and every 2 weeks thereafter. slides were stained with hematoxylin and eosin stain ( H & E ) Subjects randomized to Arm B (nivolumab only ) receive to visualize artery architecture and cellular infiltrate . The nivolumab 3 mg/ kg via IV over approximately 60 minutes group that received AB0045 treatment exhibited reduced on Day 1 and every 2 weeks thereafter . Treatment continues cellular infiltrate into the artery wall, prevented arterial wall every 2 weeks in the absence of disease progression or thickening , and maintained the integrity of vessel wall when toxicity , and may last for up to 2 years . compared to the Isotype treated group (data not shown ) . [0346 ] The arms and interventions of the study are These data indicate that inhibition of MMP9 may play a role described in Table 3 . to maintain the artery integrity and may reduce the inflam matory responses . TABLE 3 [ 0341] Six different arteries from the mice in Isotype or AB0045 groups were analyzed for expression of inflamma Arms and interventions tory cytokines by qPCR . Arteries from AB0045 treated Arms Assigned Interventions group exhibited decreased IL -6 expression (FIG . 12A , * Arm A AB0045 p < 0 .05 ) and decreased IL - 1ß expression ( FIG . 12B , * p < 0 . AB0045 + Nivolumab 800 mg administered via intravenous 05 ) , and decreased TNF - a expression ( FIG . 12C ) . These for up to 2 years (IV ) infusion every 2 weeks data indicate that AB0045 inhibits inflammatory cytokine Nivolumab expression in human arteries . 3 mg /kg administered via intravenous (IV ) infusion every 2 weeks [0342 ] In addition , AB0045 treatment reduced TCR Arm B Nivolumab expression in the vessel walls ( FIG . 12D , * p < 0 .05 ) , sug nivolumab for up 3 mg/ kg administered via intravenous gesting an inhibition of T cell infiltrate after vasculitis to 2 years (IV ) infusion every 2 weeks induction . Furthermore, aMMP9 treatment reduced IFN -y expression ( FIG . 12E , * p < 0 . 05 ) , suggesting that aMMP9 treatment may abrogate Th1- committed T cells . The effect [0347 ] After treatment, the study safety , efficacy , and on T cell polarization may be specific , as the group that pharmacokinetics is determined at various time points , such as 12 weeks, 48 weeks , 96 weeks , 1 year or 2 years after received AB0045 exhibited similar levels of IL17 expression treatment. Briefly , safety is evaluated by assessment of in the established vasculitis study (FIG . 12F ). Treating with clinical laboratory tests , physical examination , 12 -lead AB0045 during early disease initiation (starting treatment on ECG , vital sign measurements, and by the incidence of the same day as the PBMC adoptive transfer or Day 7 of the adverse events . Efficacy may be evaluated by objective study ) resulted in no effects on IFN - y expression ( FIG . 13A ) response rate (ORR ) which is determined from the subjects ' and decreased IL - 17 expression (FIG . 13B ) . These data best response during treatment, progression free survival suggest that aMMP9 modulates the inflammatory response (PFS ) which is defined as the interval from the date of during vasculitis . randomization to the earlier of the first documentation of definitive disease progression or death from any cause , Example 9: Treatment of Adults with Unresectable duration of response (DOR ) which is defined as the interval or Recurrent Gastric or Gastroesophageal Junction from the date the first response (CR or PR ) is achieved to the Adenocarcinoma earlier of the first documentation of definitive disease pro [ 0343] This study evaluates the potential efficacy of an gression or death from any cause , and overall survival (OS ) anti - MMP9 antibody (AB0045 ) in combination with a PD - 1 which is defined as the interval from date of randomization inhibitor (Nivolumab ) in treating unresectable or recurrent to death from any cause . Pharmacokinetics is evaluated by gastric or gastroesophageal junction (GEJ ) adenocarcinoma. blood samples collected at certain time points to measure The subjects that receive benefit from the treatment have AB0045 or anti - AB0045 antibodies . locally advanced or metastatic adenocarcinoma of the stom [0348 ] The categorical and ordinal data may be summa ach or the GEJ which is histologically confirmed inoperable rized by count and percent of subjects , and the continuous and who have received one prior line of therapy. data may be summarized by descriptive summary statistics [0344 ] The following screening criteria is used for this (mean , standard deviation , minimum , quartiles , median and study : medical history review , physical exam , vital signs, maximum ). For the analysis of ORR , a Cochran -Mantel US 2017 /0306050 A1 Oct. 26 , 2017 43

Haenszel ( CMH ) Chi- square test on odds ratio is performed inoculated into cleared mouse mammary fat pads of 3 weeks to compare the 2 treatment groups. The Kaplan -Meier (KM ) old syngeneic female Balb / c mice . method and stratified log -rank test is used to compare the [0353 ] Neut tumor growth was monitored for 3 - 4 weeks two treatment groups for time- to -event endpoints ( i. e , OS by palpation and treatments commenced when mean tumor and PFS ) . A Cox proportional hazard model is used to volume reached 200 mm ' . Each antibody ( control IgG , estimate the hazard ratio and corresponding 95 % confidence anti- PDL1, and anti- MMP9 ) was administered at 20 mg/ kg interval (CI ) . DOR is analyzed using the KM method . via i. p . injection , twice per week , in a dosing volume of 10 ml/kg . Anti -MMP9 was also administered as a single load Example 10 : MMP9 Inhibitor in a Refractory ing dose of 50 mg/ kg on the morning prior to dosing start. Model The study was completed at 7 days after treatment initiation . Tumors were collected and examined by immunostaining [ 0349] This study used an orthotopic , syngeneic tumor and flow cytometry . model of Her2 -driven breast cancer. RNA and T cell receptor [0354 ] Approximately 2x10° cells per sample were incu ( TCR ) sequencing , FACS analyses , and in vitro enzymatic bated for 30 min with rat anti -mouse CD16 /CD32 mono analyses on T cell chemoattractant CXCR3 ligands clonal antibody ( Fc Block , BD Biosciences ) and subjected ( CXCL9, CXCL10 , and CXCL11 ) were conducted . to immunostaining with T cell panel and Treg panel of [0350 ] Subjects were treated with AB0046 ( an anti -MMP9 fluorophore -conjugated monoclonal antibodies against T monoclonal antibody which inhibited mouse MMP9 as cell lineage markers . described in WO 2013 / 130905 ) alone , anti -PD -L1 antibody [0355 ] For flow cytometry, side scatter and forward scatter (LBMla mG1/mKap as described in US20100203056 ) profiles were used to eliminate debris and cell doublets , and alone, the combination of AB0046 and anti- PD -L1 antibody, live /dead stain was used to gate live cells, followed by or IgG ( control) . Results showed that the subject treated with gating for CD45 -positive cells to select for leukocytes . the combination exhibited decreased primary tumor growth Fluorescence Minus One (FMO ) control was used for each as compared to IgG - treated animals ( p < 0 .01 ) or anti - PD -L1 fluorophore in order to identify and gate cells in the context alone . Data are shown in FIG . 18A - FIG . 18B . Profiling of of data spread due to polychromatic flow cytometry . Distinct tumors by RNA sequencing revealed that inhibition of T cell subsets were identified based on co -expression of MMP9 resulted in increased expression of genes associated multiple markers : CD3€ + for CD3 + T cells ; CD3€ +/ CD8 + with immune cell activation pathways (Hallmark Interferon CD4 - for CD8 + T cells ; CD38 +/ CD8 - CD4 + for CD4 + T Gamma Response , FDR p < 0 . 001 ) . Results for Granzyme B cells ; CD38 + /CD8 - CD4 + /CD25 + FoxP3 + for Treg cells ; and CD69 are shown in FIG . 19A - FIG . 19B . Also , subjects CD38 +/ CD8 +CD4 -/ CD8 + CD44 + for CD8 +CD44 + cells ; and treated with both anti -MMP9 and anti - PD -L1 antibodies CD38 + /CD8 + CD4- 7CD4 + CD44 + for CD4 + CD44 + cells . exhibited a decrease in TCR clonality (i . e . the number of T Pairwise comparisons between treatment groups (Day 7 ) cells with the same TCR sequence ) ( p = 0 . 0047 , FIG . 20 ) . were performed using unpaired t test with Welch ' s correc Immunophenotyping of tumor- associated T cells by flow tion . A p value of s0 .05 was considered significant. cytometry showed that subjects treated with both anti 0356 ] The results showed that the subjects treated with MMP9 and anti- PD -L1 antibodies exhibited a 2 . 8 - fold both anti -MMP9 and PD -L1 antibodies exhibited increased increase in CD3 + cells in tumors ( p = 0 .01 ) , a 3 . 2 - fold levels or frequencies of tumor -associated CD3, CD4 , and increase in CD4 + T cells (p = 0 .006 ), a 2 . 8 - fold increase in CD8 T cells compared to those treated with either antibody CD8 + T cells ( p = 0 . 013 ), and a decrease in tumor - associated alone or IgG control ( Table 4 ) . Also , the subjects treated regulatory T cells (CD25 + FoxP3 + cells, p = 0 .04 ) . In vitro with both anti- MMP9 and PD - L1 antibodies exhibited enzymatic analyses showed that MMP9 cleaved T cell increased levels of CD4 and CD8 T cells with cell surface chemoattractants and inactivated them in T cell migration expression of CD44 ( Table 5 ) . The subject treated with assays (up to 88 % reduced chemotactic activity ) . MMP9 and PD -L1 inhibitors did not promote an increase in Treg ( Table 4 ) ; the subject treated with anti -MMP9 antibody alone exhibited reduced level or frequency in Treg. This Example 11: MMP9 and Pd - L1 Inhibitors on T study suggests that the combination therapy of anti -MMP9 Cells and Effector T Cell Function in Breast and anti - PD -L1 may improve T -cell mediated anti- tumor Tumors immune response . [0351 ] This study used orthotopic Neut breast tumors from the mice treated with anti -MMP9 antibody (AB0046 as TABLE 4 described in WO 2013 / 130905 ) alone , anti -PD - L1 antibody ( LBMla mG1/ mKap as described in US20100203056 ) Mean Percentage + SEM of tumor - associated T cell populations alone, or anti- MMP9 combined with anti -PD -L1 antibodies for phenotyping of tumor- associated T cells by polychro anti - PD matic flow cytometry . L1 [0352 ] HC11 -NeuT cells expressing a rat homolog of Study day - 1 Ctrl anti - anti - and anti ErbB2 were generated by transduction of HC11 mammary Treatment untreated IgG PDL1 MMP9 MMP9 epithelial cells with pBabe -puro Neut retroviral construct. N 15 15 15 15 Puromycin - selected HC11 -NeuT cells were cultured in % CD3ta Mean 10 .42 14 . 89 14 . 10 22 .51 41 .04 RPMI 1640 supplemented with 8 % HI- FBS, 1 % Gluta SEM 1. 13 5 .02 0 . 95 6 .25 7 . 34 % CD8 + a Mean 2 . 85 3 . 36 3 . 82 5 . 26 9 . 30 MAXTM , 10 ng/ mL EGF, 5 ug/ mL insulin and 1 % penicillin SEM 0 . 52 1 . 13 0 . 41 1 . 50 1 . 88 streptomycin at 5 % CO2. Early -passage HC11- NeuT cells % CD4 + a Mean 5 . 21 9 . 23 7 . 83 15 .05 29 . 90 were resuspended in serum - free medium :MatrigelTM ( 1 : 1 , SEM 0 . 45 3 . 93 0 . 81 4 . 83 5 . 58 V /v ) and 10 uL of cell suspension containing 1x10 cells was US 2017 /0306050 A1 Oct . 26 , 2017 44

TABLE 4 - continued TABLE 6 - continued Mean Percentage + SEM of tumor - associated T cell populations Treatment Groups Group # Bleomycin Treatment Dose Schedule N 2 U /kg AB0046 + 20 mg/kg + 2 x /week 10 anti - PD AB0023 50 mg/ kg loading L1 dose Study day - 1 Ctrl anti - anti- and anti 15 mg/ kg Treatment untreated IgG PDL1 MMP9 MMP9 6 2 U /kg - - 5 N 5 15 15 15 15 [0358 ] After treatments , samples were collected for leu % Trega Mean 0 .77 0 . 55 0 . 44 0 . 32 0 . 33 kocyte , protein , histology and weight analyses. Histo SEM 0 . 10 0 . 09 0 .07 0 . 05 0 . 10 pathogical staining of lung was performed by staining with Masson 's trichrome and assessed for fibrosis via Ashcroft 2 % of CD45 + non - debris scoring. In addition , lung tissues and bronchoalveolar lavage fluid (BALf ) from lung was assessed for MMP9 protein TABLE 5 levels and activity . Leukocytes were analyzed by the Trypan Blue exclusion method and hemocytometer. MMP9 concen Mean Percentage + SEM of tumor -associated CD8 and tration was measured by ELISA . Also , the inferior lung lobe CD4 T cells with cell surface expression of CD44 was homogenized for western blot analysis with anti- MMP9 ( Abeam ab38898 ) , anti - LOXL2 (GIL2570 ) , Q - SMA Study ( Abeam ab5694 ) and anti -GAPDH (Santa Cruz Biotechnol day - 1 Ctrl anti - anti - anti- PD -L1 ogy sc - 32233 ) antibodies . Body weight measurements over Treat un PDL1 MMP9 and anti the course of the study were analyzed by ordinary one -way ment treated MMP9 ANOVA with Geisser -Greenhouse correction . All groups N 5 15 15 15 15 were compared to IgG Control antibody treatment group and % CD8 + CD44 + * Mean 2 . 78 2 .84 3 . 66 4 . 14 6 .37 were found to be significantly different. Also , lung weight to SEM 0 .51 0 .67 0 . 42 0 . 96 1 . 17 body weight ratios, leukocyte counts , MMP9 protein quan % CD4 + CD44 + Mean 5 . 15 8 .62 7 .54 13 .49 24 .53 tification , and histopathological data were subjected to SEM 0 .45 3 . 37 0 . 72 4 .02 4 . 33 unpaired t -tests with Welch ' s correction . * * * * < 0 .0001 ; * * * 2 % of CD45 + non - debris < 0 .001 ; * * < 0 .01 ; * < 0 . 05 . Results for these four parameters are listed in Tables 7 - 10 and FIG . 14 - FIG . 15 . (0359 ] Results showed that bleomycin administration alone or following control antibody treatment resulted in Example 12: MMP9 Inhibitor in a Mouse Model of decreased animal body weights , increased lung weights , Lung Fibrosis increased BAL leukocyte counts , and increased MMP9 [ 0357 ] This study examined the effects of MMP9 and protein levels in BAL compared to normal control animals . LOXL2 inhibitors in a bleomycin - induced lung fibrosis This study indicated that prophylactic treatment of anti model in male C57BL / 6 mice . C57BL / 6 mice were treated MMP9 antibody may be safe and that treatment of anti prophylactically with anti -mMMP9 antibody (AB0046 ) one MMP9 antibody alone resulted in reduced animal lung day prior to administration of 2 U /kg of bleomycin to induce weights with a concomitant decrease in fibrosis. lung fibrosis via oropharyngeal route and divided into dif TABLE 7 ferent groups ( N = 5 for normal control group , N = 10 for groups treated with antibodies administered intraperitone Lung Weight to Body Weight Ratio ally ) as described in Table 6 . Subjects in group 1 ( N = 5 ) Average received saline as a control to bleomycin - induced fibrosis . Treatment Group Standard Deviation p - Value Subjects were administered with saline or antibodies twice ?? 0 . 968 0 .0377 < 0 .0001 1 . 886 0 . 2814 a week during the study . Subjects in group 6 ( normal control M??? 1 . 535 0 . 2880 0 .0130 group which did not receive any treatment ) were harvested 1 . 305 ? 0 . 1859 0 .0065 on day 10 to determine the extent of fibrosis before treat 1 . 442 0 . 2989 0 . 0463 ment. The study was completed at 21 days post -bleomycin installation when fibrosis was observed in the lungs . TABLE 8 TABLE 6 BALf Leukocyte Counts TreatmentGroups Treatment Group Average Standard Deviation p - Value Group # Bleomycin Treatment Dose Schedule N 54250 27166 0 .0005 None Buffer NA 2 x /week 5 226500 106899 ,????? 2 U / kg Control IgG 20 mg/ kg 2 x /week 10 243625 97251 ns 2 U / kg AB0046 20 mg/kg + 2 x /week 10 192375 100228 ns 50 mg/ kg loading UAWNA 167500 167500 ns dose 2 U /kg AB0023 15 mg/ kg 2 x /week 10 ns: not significant US 2017 /0306050 A1 Oct. 26 , 2017 45

TABLE 9 protein levels . Additionally, results suggested that total MMP9 levels may be associated with disease severity ( p = 0 . Ashcroft Scoring for Fibrosis Assessment 008 ) ( FIG . 14 ) . Treatment Group Average Standard Deviation p - Value Example 13 : MMP9 Inhibitor in the Presence of < 0 .0001 Human Neutrophil Elastase and Cystic Fibrosis 4 . 170 1 . 372 Sputa 2 . 640 1 .626 0 . 0358 2 . 470 1 . 725 0 . 0259 [0364 ] Proteolyzed antibodies, likely cleaved at the hinge UAWNA 3 . 140 1 . 874 ns region , were observed in CF patient sputum (Sloane , A . J. et ns: not significant al. Proteomic analysis of sputum from adults and children with cystic fibrosis and from control subjects . Am J Respir Crit Care Med ( 2005 ) 172 : 1416 - 1426 ). It was hypothesized TABLE 10 that human neutrophil elastase (HNE ) , which is elevated in the CF airway, and other proteases may mediate antibody MMP9 BALf Protein Levels proteolysis . This in vitro study characterized the stability of Treatment Group Average Standard Deviation p - Value anti -MMP9 antibody AB0045 ( an IgG4 antibody that binds and inhibits MMP9 independent of the Fc region of the - 0 . 0461 0 . 04056 0 . 0131 0 . 2643 0 . 3177 antibody ) in presence of HNE or sputum from CF subjects . 0 . 2281 0 . 1889 ns [0365 ] AB0045 was incubated with recombinant HNE 0 . 17898 0 . 1602 ( Enzo Biosciences (BML -SE284 ) or sputa from two distinct UAWNA 0 .0875 0 . 1148 ns CF subjects at 37° C . for 24 hours . AB0045 was also digested to completion at the hinge region with FabRica ns: not significant torTM enzyme . Protein degradation was monitored via Coo [0360 ] All mice treated with bleomycin lost weight as massie blue staining of non -reducing SDS -PAGE gels . Bind compared to saline - treated control mice (data not shown ) . ing affinity to MMP9 was measured by surface plasmon However , mice treated with anti- MMP9 antibody , singly or resonance , and inhibition of MMP9 proteolysis was deter in combination with anti - LOXL2 antibody, showed reduced mined by a fluorescently labeled MMP9 substrate peptide body weight loss as compared to the IgG control antibody (ES001 , R & D systems) . AB0045 bound MMP9 was mea treated group (bleomycin control arm not included in sta sured by a modified ELISA from R & D systems (DMP 900 ) . tistical analyses) (p = 0 .0130 ). Anti- LOXL2 antibody treated In addition , total MMP9 and free MMP9 (MMP9 not bound alone also resulted in a significant reduction in body weight to AB0045 ) was measured , and bound MMP9 was deter loss ( p = 0 .065 ). mined as the difference between total MMP9 and free [0361 ] At the end of the study, mouse lungs were dissected MMP9 . and weighed . Bleomycin instillation resulted in increased [ 0366 ] Results of protein degradation analysis showed that lung weight to body weight ratios in all bleomycin - treated < 20 % of AB0045 was proteolyzed after incubation with groups as compared to saline - treated controls , consistent HNE or CF sputa (data not shown) . The proteolysis products with increased lung fibrosis . Mice treated with the anti were consistent with cleavage at the hinge region ( data not MMP9 antibody , singly or in combination with anti - LOXL2 shown ). Complete digestion of the AB0045 at the hinge did antibody dosed therapeutically on day 10 , had decreased not reduce binding to MMP9 . Also , results showed that CF lung weight to body weight ratios as compared to the IgG sputum or spiked HNE did not reduce or affect the binding control antibody treated group ( p = 0 .013 and p = 0 .0463 , of AB0045 to MMP9 (FIG . 16 ) and that AB0045 inhibited respectively ) ( Table 7 ) . MMP9 activity in presence of exogenous HNE and CF ( 0362) Leukocyte counts were increased in the bleomycin sputum ( FIG . 17A - FIG . 17B ) . administered mice . However , no significant differences were [0367 ] All of the above U . S . patents , U . S . patent applica observed between the control IgG and the anti- MMP9 or tion publications, U . S . patent applications , foreign patents , anti - LOXL2 antibody treated mice ( Table 8 ) . This suggests foreign patent applications and non - patent publications that anti -MMP9 antibody treatment did nothave any anti - or referred to in this specification and / or listed in the Applica pro - inflammatory effects. tion Data Sheet are incorporated herein by reference in their [0363 ] As anti -MMP9 antibody treatment appeared to entirety . show benefit to bleomycin - treated animals as determined by [0368 ] From the foregoing it will be appreciated that, the reduction observed in final lung weights , the degree of although specific embodiments of the invention have been fibrosis present in the treated animals' lungs was assessed described herein for purposes of illustration , various modi next ( Table 9 ) . As shown in Table 10 , treatment with ficationsmay be made without deviating from the spirit and anti- MMP9 antibody did not result in decreased MMP9 total scope of the present application .

SEQUENCE LISTING

< 160 > NUMBER OF SEO ID NOS : 60 < 210 > SEQ ID NO 1 < 211 > LENGTH : 470 < 212 > TYPE : PRT < 213 > ORGANISM : Mus musculus US 2017/ 0306050 Al Oct. 26 , 2017 46

- continued < 220 > FEATURE : 1 > NAME / KEY : CHAIN 2 LOCATION : ( 1 ) . . ( 470 ) < 223 > OTHER INFORMATION : AB0041 heavy chain < 220 > FEATURE : < 221 > NAME / KEY : PEPTIDE < 222 > LOCATION : ( 1 ) . . ( 19 ) < 223 > OTHER INFORMATION : signal peptide < 220 > FEATURE : < 221 > NAME / KEY : misc _ feature < 222 > LOCATION : ( 135 ) . . ( 470 ) 23 > OTHER INFORMATION : IgG2b constant reqion < 400 > SEQUENCE : 1 Met Ala Val Leu Val Leu Phe Leu Cys Leu Val Ala Phe Pro Ser Cys 15

Val Leu Ser Gin Val 3Gln Leu Lys Glu Ser 3Gly Pro Gly Leu Val Ala 20 EJEI25 30 Pro Ser Gin Ser Leu Ser Ile Thr cys ?Thr Val Ser Gly Phe Ser Leu 35 40 1 45 d& Leu goSer SETyr Gly Val His Trp Val Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp Leu Gly Val Ile Trp Thr Gly 3Gly Thr Thr Asn Tyr Asn Ser 2 Ala Leu Met Ser Arg Leu Ser Ile Ser Lys Asp Asp Ser Lys Ser Gin 95 Val Phe Leu Lys Met Asn Ser Leu Gin Thr Asp Asp Thr Ala Ile Tyr 100 smmmm 105 110 Tyr Cys Ala Arg Tyr Tyr Tyr Gly Met Asp Tyr Trp Gly Gin Gly Thr | 115 120 125 Ser Val Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro

Leu Ala Pro Gly Cys Gly Asp Thr Thr Gly Ser Ser Val Thr Leu Gly

Cys Leu Val Lys Gly Tyr Phe Pro Glu Ser Val Thr Val Thr Trp Asn 175 Ser Gly Ser Leu Ser Ser Ser Val His Thr Phe Pro Ala Leu smsmLeu Gin 180 185 190 Ser Gly Leu Tyr Thr Met Ser Ser Ser Val Thr Val Pro Ser Ser Thr 195 200 205 Trp Pro Ser Gin Thr Val Thr Cys Ser Val Ala His Pro Ala Ser Ser

Thr Thr Val Asp Lys Lys Leu Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn Pro Cys Pro Pro Cys Lys Glu Cys His Lys Cys Pro Ala Pro Asn 255 Leu Glu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Asn Ile Lys Asp 260 265 270

Val Leu Met Ile Ser Leu Thr Pro Lys Val Thr Cys Val Val Val Asp 275 am280 285 Val Ser Glu Asp Asp Pro Asp Val Arg Ile Ser Trp Phe Val Asn Asn

Val Glu Val His Thr Ala Gin Thr Gin Thr ?His Arq Glu Asp Tyr Asn 320 mmmmmSer ?Thr Ile ??Arg Val Val Ser Ala Leu &Pro Ile Gin His mmmmmmmGin Asp Trp US 2017/ 0306050 Al Oct. 26 , 2017 47

- continued 325 330 335

?Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro . 350 Ser Pro 3ggIle Glu Arg Thr Ile Ser Lys Ile Lys Gly Leu Val Arg Ala 355 ?8 Pro Gin Val Tyr Ile Leu Pro Pro Pro Ala Glu Gln Leu Ser Arg Lys 370 AS375 Asp &SBSVal Ser Leu Thr Cys Leu Val &SRVal Gly Phe Asn Pro Gly Asp Ile 395 mmm Ser Val Glu Trp 1??Thr Ser Asn Gly His Thr Glu Glu Asn Tyr Lys Asp 410 Thr Ala &Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Ile Tyr Ser Lys 8 430

Leu Asp PIle Lys Thr Ser Lys Trp Glu Lys Thr Asp Ser Phe Ser Cys 435 E Asn Val Arg His Glu Gly Leu Lys Asn Tyr Tyr Leu Lys Lys Thr Ile 450 455 ? | ? Ser Arg Ser ?Pro Gly Lys 465 470

< 210 > SEQ ID NO 2 < 211 > LENGTH : 234 < 212 > TYPE : PRT < 213 > ORGANISM : Mus musculus < 220 > FEATURE : < 221 > NAME / KEY : CHAIN < 222 > LOCATION : ( 1 ) . . ( 234 ) < 223 > OTHER INFORMATION : AB0041 light chain FEATURE : < 221 > NAME / KEY : PEPTIDE LOCATION : ( 1 ) . . ( 20 ) < 223 > OTHER INFORMATION : signal peptide FEATURE : 21 2 NAME / KEY : misc _ feature 22 > LOCATION : ( 128 ) . . ( 234 ) < 223 > OTHER INFORMATION : kappa constant region AAAAAAAAAAAAA< 400 > SEQUENCE : 2 Met Glu Ser GinGin IleIle GinGin Valval phePhe Valval phePhe Valval Phe Leu ETrp Leu Ser Gly Val Asp Gly Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser 25 30 Thr Ser Val Gly Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gin Asp 35 Val Arg Asn Thr Val Ala Trp Tyr Gin Gin Lys Thr Gly Gin Ser Pro Lys Leu Leu Ile Tyr Ser Ser Ser Tyr Arg Asn Thr Gly Val Pro Asp 65 1?? Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser

Ser Val Gin Ala Glu Asp Leu Ala Val ETyr Phe Cys Gin Gin His ETyr 105 110 Ile Thr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg 3? 115 mem mmmm Ala Asp Ala Ala Pro Thr Val imgSer Ile Phe Pro Pro Ser Ser Glu Gin 4 ? 3 ? US 2017/ 0306050 Al Oct. 26 , 2017 48.

- continued | | Leu ?Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr 145 150 ?155 160 &Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gin mm 175 Asn Gly Val Leu Asn Ser Trp Thr Asp Gin Asp Ser Lys Asp Ser Thr 180 | 190

ETyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg 195 200 205 1 ?Egg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro 8 215 220 Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 225 230

< 210 > SEQ ID NO 3 < 21111 > LENGTH : 115 < 21212 > TYPE : PRT 1 < 2133 > ORGANISM : Mus musculus 2 < 2200 > FEATURE : A 221 > NAME KEY : CHAIN < 222 > LOCATION : ( 1 ) . . ( 115 ) < 223 > OTHER INFORMATION : variable region of the IgG2b heavy chain of AB0041 < 220 > FEATURE : < 221 > NAME / KEY : misc _ feature < 222 > LOCATION : ( 26 ) . . ( 35 ) < 223 > OTHER INFORMATION : complementarity - determining region ( CDR ) < 220 > FEATURE : < 221 > NAME / KEY : misc _ feature < 222 > LOCATION : ( 50 ) . . ( 65 ) < 223 > OTHER INFORMATION : complementarity - determining region ( CDR ) < 220 > FEATURE : < 221 > NAME / KEY : misc _ feature < 222 > LOCATION : ( 98 ) . . ( 104 ) 223 > OTHER INFORMATION : complementarity - determining region ( CDR )

< 400 > SEOUENCE : 3

Gin Val Gln Leu Lys Glu Ser Gly &Pro Gly Leu Val RAla &Pro Ser Gin

Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Leu Ser Tyr 30 Gly Val His TagTrp Val Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp Leu 40 Gly Val Ile Trp Thr Gly ?3?Gly Thr Thr Asn Tyr Asn Ser Ala Leu Met Ser Arg Leu Ser Ile Ser Lys Asp Asp Ser Lys Ser Gin Val Phe Leu Lys mmmmMet Asn Ser Leu Gin Thr Asp Asp Thr Ala Ile Tyr Tyr ??gCys amAla Arg Tyr Tyr Tyr Gly meMet Asp Tyr Trp Gly Gin Gly Thr Ser Val Thr mm 110 Val Ser Ser ?s 115 sms < 210 > SEQ ID NO 4 < 211 > LENGTH : 107 < 212 > TYPE : PRT < 213 > ORGANISM : Mus musculus < 220 > FEATURE : < 221 > NAME / KEY : CHAIN < 222 > LOCATION : ( 1 ) . . ( 107 ) A 3 > OTHER INFORMATION : variable region of the kappa light chain of US 2017/ 0306050 Al Oct. 26 , 2017 49 .

- continued AB0041 < 220 > FEATURE : 21 > NAME / KEY : misc _ feature 222 > LOCATION : ( 24 ) . . ( 34 ) < 223 > OTHER INFORMATION : complementarity - determining region ( CDR ) < 220 > FEATURE : 221OHNOAN00 > NAME / KEY : misc _ feature < 222 ^> LOCATION : ( 50 ) . . ( 56 ) < 223 ^> OTHER INFORMATION : complementarity - determining region ( CDR ) < 220 ^> FEATURE : < NNNNNNNNN221 > NAME / KEY : misc _ feature < 222 > LOCATION : ( 89 ) . . ( 97 ) < 223 > OTHER INFORMATION : complementarity - determining region ( CDR ) AAAAAAAAAAAA< 400NNNNNNNNNNNN > SEQUENCE : 4 Asp Ile Val Met Thr Gin Ser His Lys ?Phe Met Ser Thr Ser Val Gly

Asp Arg Val ?&ESer Ile Thr Cys Lys Ala Ser Gin Asp Val Arg Asn ?Thr .3? 30 Val Ala Trp Tyr Gin Gin Lys Thr Gly Gin Ser Pro Lys Leu Leu Ile 35 ?3R

Tyr Ser Ser Ser Tyr Arg Asn Thr 3Gly 3Val Pro Asp Arg Phe Thr Gly 55 &eg Ser Gly Ser 3Gly Thr Asp Phe Thr Phe ?Thr Ile Ser Ser Val Gin Ala 65 mmsGlu mmmAsp Leu Ala Val Tyr Phe Cys 3Gin Gin His Tyr Ile Thr ??Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105

A< 210 > SEQ ID No 5 A< 211 > LENGTH : 115 A< 212 > TYPE : PRT A< 213 > ORGANISM : Artificial Sequence A FEATURE : A< 223 > OTHER INFORMATION : synthetic construct A< 220 > FEATURE : A< 221 > NAME / KEY : VARIANT A2 2 2 2 > LOCATION : ( 1 ) . . ( 115 ) A< 223 > OTHER INFORMATION : VH1 heavy chain variant < 400 > SEQUENCE : 5 Gin Val Gin Leu Gin Glu Ser Gly &Pro Gly Leu Val Lys Pro Ser Glu

23 ?Thr Leu Ser Leu Thr Cys ?Thr 3Val Ser Gly Phe Ser Leu Leu Ser Tyr 8 38 30 Gly Val His Trp Val Arg 3Gin Pro Pro 3Gly Lys 3Gly Leu Glu Trp Leu 35 Gly Val Ile Trp Thr Gly Gly Thr Thr Asn Tyr Asn Ser Ala Leu Met Ser Arg Leu Thr Ile Ser Lys Asp Asp Ser Lys Ser Thr Val Tyr Leu 70 Lys mm8mmMet Asn Ser Leu Lys Thr Glu 8Asp Thr Ala Ile Tyr Tyr Cys Ala Arg Tyr Tyr Tyr Gly Met Asp Tyr Trp Gly Gin Gly Thr Ser Val Thr 110 ws 83 Val Ser Ser 11 5 mmm US 2017/ 0306050 Al Oct. 26 , 2017 50

- continued

A< 210 > SEQ ID NO 6 A< 211 > LENGTH : 115 A< 212 > TYPE : PRT A< 213 > ORGANISM : Artificial Sequence A< 220 > FEATURE : A< 223 > OTHER INFORMATION : synthetic construct < 220 > FEATURE : < 221 > NAME / KEY : VARIANT A 2 > LOCATION : ( 1 ) . . ( 115 ) < 223 > OTHER INFORMATION : VH2 heavy chain variant < 400 > SEQUENCE : 6 Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu

? Thr Leu Ser Leu Thr Cys Thr mVal Ser Gly Phe Ser Leu Leu Ser Tyr 3 25 30 Gly Val His Trp Val Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp Leu 35 ?3? RR Gly Val Ile Trp Thr Gly Gly Thr Thr Asn Tyr Asn Ser Ala Leu ?Met 50 Ser Arg Leu Thr Ile Ser Lys Asp Asp Ser Lys Asn Thr Val Tyr Leu 65 70 goA & Lys mamMet Asn Ser Leu Lys Thr Glu mmAsp Thr Ala Ile Tyr Tyr Cys Ala Arg Tyr Tyr Tyr Gly Met Asp Tyr Trp Gly Gin Gly Thr Leu GEEVal Thr 105 110 Val Ser Ser 115

A< 210 > SEQ ID NO 7 A< 211 > LENGTH : 115 A< 212 > TYPE : PRT A< 213 > ORGANISM : Artificial Sequence A FEATURE : A< 223 > OTHER INFORMATION : synthetic construct A< 220 > FEATURE : A< 221 > NAME / KEY : VARIANT A< 222 > LOCATION : ( 1 ) . . ( 115 ) A< 223 > OTHER INFORMATION : VH3 heavy chain variant < 400 > SEQUENCE : 7

Gin Val Gin Leu Gin Glu Ser Gly &Pro 3Gly Leu Val Lys Pro Ser Glu

?Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Leu Ser Tyr Gly Val His Trp Val Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp Leu 35 of Gly Val Ile Trp smThr Gly Gly Thr Thr Asn Tyr Asn Ser Ala Leu Met Ser Arg Phe Thr Ile Ser ?sLys Asp Asp Ser Lys Asn Thr Val Tyr Leu 70 ? Lys Met Asn Ser Leu meLys Thr mamGlu 8Asp ?Thr Ala Ile Tyr Tyr Cys Ala Arg Tyr Tyr Tyr Gly Met Asp Tyr Trp Gly Gin Gly Thr Leu wsVal Thr Val Ser Ser 11 5 mmm US 2017/ 0306050 Al Oct. 26 , 2017 SI

- continued

A< 210 > SEQ ID NO 8 A< 211 > LENGTH : 115 A< 212 > TYPE : PRT A< 213 > ORGANISM : Artificial Sequence A< 220 > FEATURE : A< 223 > OTHER INFORMATION : synthetic construct < 220 > FEATURE : < 221 > NAME / KEY : VARIANT A 2 > LOCATION : ( 1 ) . . ( 115 ) < 223 > OTHER INFORMATION : VH4 heavy chain variant < 400 > SEQUENCE : 8 Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys &Pro Ser Glu 15

Thr Leu Ser Leu Thr Cys Thr mVal Ser Gly Phe Ser Leu Leu Ser Tyr & 25

Gly Val His Trp Val Arg Gin Pro Pro 3Gly Lys Gly Leu Glu Trp Leu 35 ?3? RR Gly Val Ile Trp Thr Gly Gly Thr Thr Asn ETyr Asn Ser Ala Leu Met 50 8 Ser Arg Phe Thr Ile Ser Lys Asp Asp Ser Lys Asn Thr Leu Tyr Leu 65 70 goA &

Lys mamMet Asn Ser Leu Lys Thr Glu Asp ?Thr EAla Ile Tyr Tyr Cys Ala mm EE95 Arg Tyr Tyr Tyr Gly Met Asp Tyr Trp 3Gly Gin Gly Thr Leu Val Thr 100 105

Val Ser Ser 115

< 210 > SEQ ID NO 9 < 211 > LENGTH : 107 < 212 > TYPE : PRT < 213 ^> ORGANISM : Artificial Sequence 0 A2 2 FEATURE : < 223 > OTHER INFORMATION : synthetic construct < 220 > FEATURE : < 221 > NAME / KEY : VARIANT A2 2 2 2 > LOCATION : ( 1 ) . . ( 107 ) < 223 > OTHER INFORMATION : Vk1 light chain variant < 400 > SEQUENCE : 9 Asp Ile Val ?Met Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly . . ? 15

Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gin Asp Val Arg Asn ?Thr &20 25 Val RAla ggg Trp Tyr 3Gin Gin Lys Thr Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ser Ser Tyr Arg Asn Thr Gly Val R&eePro Asp Arg Phe Thr Gly &3 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gin Ala 65 mm Glu Asp Val Ala Val Tyr Phe Cys Gin Gin His Tyr Ile Thr Pro Tyr 85 95 . Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 105 ?s 100 RE

< 210 > SEQ ID NO 10 < 211 > LENGTH : 107 < 212 > TYPE : PRT US 2017/ 0306050 Al Oct. 26 , 2017

- continued < 213 > ORGANISM : Artificial Sequence < 220 > FEATURE : 23 > OTHER INFORMATION : synthetic construct < 220 > FEATURE : < 221 > NAME / KEY : VARIANT < 222 > LOCATION : ( 1 ) . . ( 107 ) 223 > OTHER INFORMATION : Vk2 light chain variant < 400 > SEQUENCE : 10 Asp Ile Val Met Thr Gin Ser &Pro Ser Ser Leu Ser Ala Ser Val Gly ?

Asp Arg Val Thr Ile Thr ECys Lys Ala Ser JGin Asp Val Arg Asn Thr & 25 23 Val Ala Trp Tyr Gin Gin Lys &Pro Rg33 Gly Lys EAla Pro Lys Leu Leu Ile Tyr Ser Ser Ser Tyr Arg Asn ?Thr Gly Val &Pro Asp Arg Phe Thr Gly 55 Ser 283Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gin Ala DB 70 mmm Glu Asp Val Ala Val Tyr Phe Cys Gin Gin His Tyr Ile Thr gggPro Tyr 85 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys mmmm 100 105

< 210 > SEQ ID No 11 < 211 > LENGTH : 107 < 212 > TYPE : PRT < 213 > ORGANISM : Artificial Sequence A< 220N)0r0HN > FEATURE : A< 223 > OTHER INFORMATION : synthetic construct A | FEATURE : A< 221 > NAME / KEY : VARIANT A< 222 > LOCATION : ( 1 ) . . ( 107 ) A< NNNNN223ANNNNNN > OTHER INFORMATION : Vk3 light chain variant < 400 > SEQUENCE : 11 Asp Ile Gln ?Met Thr Gln Ser Pro 8Ser Ser Leu Ser Ala Ser Val Gly

Asp Arg Val Thr Ile ?Thr 3Cys Lys Ala Ser Gin Asp Val Arg Asn Thr 20 25 Val Ala Trp Tyr Gin Gin Lys Pro g3Gly Lys Ala Pro Lys Leu Leu Ile &8??40 Tyr Ser Ser Ser Tyr Arg Asn Thr 3Gly Val Pro Asp Arg Phe Ser Gly 8

Ser Gly Ser 3Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gin Ala mms e75 & mmsGlu Asp Val Ala 3?Val Tyr Phe Cys 3Gin am Gin His Tyr Ile Thr &Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105

< 210 > SEQ ID NO 12 < 211 > LENGTH : 107 < 2121 > TYPE : PRT < 2131 > ORGANISM : Artificial Sequence FEATURE : < 223 > OTHER INFORMATION : synthetic construct < 220 > FEATURE : < 2212 > NAME / KEY : VARIANT

222 > LOCATION : ( 1 ) . . ( 107 ) US 2017 /0306050 A1 Oct. 26 , 2017 53

- continued < 223 > OTHER INFORMATION : Vk4 light chain variant < 400 > SEQUENCE : 12 harAsp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gin Asp Val Arg Asn Thr 20 25 eneVal beAla Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ser Ser Tyr Arg Asn Thr Gly Val Pro Asp Arg Phe Ser Gly 55 s Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gin Ala 65 Glu Asp Val Ala Val Tyr Tyr Cys Gin Gin His Tyr Ile Thr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 H

A< 210 > SEQ ID NO 13 A< 211 > LENGTH : 10 A< 212 ?> TYPE : PRT A< 213 ?> ORGANISM : Artificial Sequence A ? FEATURE : A< 223 > OTHER INFORMATION : synthetic construct A< 220 > FEATURE : A< 221 > NAME / KEY : misc _ feature A< 222 > LOCATION : ( 1 ) . . ( 10 ) A< 223 > OTHER INFORMATION : complementarity - determining region (CDR1 ) of heavy chain of anti - MMP9 antibody < 400 > SEQUENCE : 13 Gly Phe Ser Leu Leu Ser Tyr Gly Val His 10

< 210 > SEQ ID NO 14 < 211 > LENGTH : 16 < 212 > TYPE : PRT A 13 > ORGANISM : ArtificialALLILICIAL SCOUCTICSs < 220 > FEATURE : < 223 > OTHER INFORMATION : synthetic construct A 20 > FEATURE : < 221 > NAME / KEY : misc _ feature < 222MOMOHNM > LOCATION : ( 1 ) . . ( 16 ) < NNNN223NNNNNN > OTHER INFORMATION : complementarity -determining region ( CDR2 ) of heavy chain of anti - MMP9 antibody < 400 > SEQUENCE : 14 Val Ile Trp Thr Gly Gly Thr Thr Asn Tyr Asn Ser Ala Leu Met Ser 10 15

< 210 > SEQ ID NO 15 < 211 > LENGTH : 7 < 212 > TYPE : PRT < 213M??? > ORGANISM : Artificial Sequence

? N FEATURE : < 223??? > OTHER INFORMATION : synthetic construct < 220 > FEATURE : < 221> NAME / KEY : misc _ feature < 222 > LOCATION : ( 1 ) . . ( 7 ) < 223 > OTHER INFORMATION : complementarity - determining region (CDR3 ) of heavy chain of anti - MMP9 antibody < 400 > SEQUENCE : 15 US 2017 /0306050 A1 Oct. 26 , 2017 54

- continued Tyr Tyr Tyr Gly Met Asp Tyr

< 210 > SEQ ID NO 16 < 211 > LENGTH : 11 A< 212 > TYPE : PRT A< 213 > ORGANISM : Artificial Sequence A< 220 > FEATURE : A< 223 > OTHER INFORMATION : synthetic construct < 220 > FEATURE : < 221 > NAME /KEY : misc _ feature < 222 > LOCATION : ( 1 ) . . ( 11 ) < 223 > OTHER INFORMATION : complementarity - determining region ( CDR1 ) of light chain of anti - MMP9 antibody < 400 > SEQUENCE : 16 Lys Ala Ser Gln Asp Val Arq Asn Thr Val Ala 10

< 210 > SEQ ID NO 17 < 211 > LENGTH : 7 < 212 > TYPE : PRT < 213 > ORGANISM : Artificial Sequence A FEATURE : < 223 > OTHER INFORMATION : synthetic construct < 220MOMO > FEATURE : < 221 > NAME / KEY : misc _ feature < 222 > LOCATION : ( 1 ) . . ( 7 ) < 223 > OTHER INFORMATION : complementarity - determining region ( CDR2 ) of NNNNNNNNNNNN light chain of anti - MMP9 antibody < 400 > SEQUENCE : 17 Ser Ser Ser Tyr Arg Asn Thr

< 210 > SEQ ID NO 18 < 211 > LENGTH : 9 < 212 > TYPE : PRT < 213??? > ORGANISM : Artificial Sequence ?< 220? > FEATURE :

? < 223? > OTHER INFORMATION : synthetic construct < 220? > FEATURE : ?< 221 > NAME / KEY : misc _ feature ?< 222 > LOCATION : ( 1 ) . . ( 9 ) < 223 > OTHER INFORMATION : complementarity - determining region ( CDR3 ) of light chain of anti - MMP9 antibody < 400 > SEQUENCE : 18 Gin Gin His Tyr Ile Thr Pro Tyr Thr

< 210 > SEQ ID NO 19 < 211 > LENGTH : 345 < 212 > TYPE : DNA < 213?? > ORGANISM : Artificial Sequence ?< 220 > FEATURE : ?< 223 > OTHER INFORMATION : synthetic construct ?< 220 > FEATURE : ?< 221 > NAME / KEY : misc _ feature ?< 222 > LOCATION : ( 1 ) . . ( 345 ) ?< 223 > OTHER INFORMATION : nucleotide sequence encoding VH1 heavy chain amino acid sequence < 400 > SEQUENCE : 19 caggtgcagc tgcaggaatc cggccctggc ctggtcaagc cctccgagac actgtccctg 60 acctgcaccg tgtccggctt ctccctgctg tcctacggcg tgcactgggt ccgacagcct 120 US 2017 /0306050 A1 Oct. 26 , 2017 55

- continued ccagggaagg gcctggaatg gctgggcgtg atctggaccg goggcaccac caactacaac 180 tccgccctga tgtcccggct gaccatctcc aaggacgact ccaagtccac cgtgtacctg 240 aagatgaact ccctgaaaac cgaggacacc gccatctact actgcgcccg gtactactac 300 ggcatggact actggggcca gggcacctcc gtgaccgtgt cctca 345

< 210 > SEO ID NO 20 < 211 > LENGTH : 345 < 212 > TYPE : DNA A< 213 > ORGANISM : Artificial Sequence A< 220 > FEATURE : < 223 > OTHER INFORMATION : synthetic construct < 220 > FEATURE : < 221 > NAME / KEY : misc _ feature < 222 > LOCATION : ( 1 ) . . ( 345 ) < 223 > OTHER INFORMATION : nucleotide sequence encoding VH2 heavy chain amino acid sequence < 400 > SEQUENCE : 20 caggtgcagc tgcaggaatc cggccctggc ctggtcaagc cctccgagac actgtccctg 60 acctgcaccg tgtccggctt ctccctgctg tcctacggcg tgcactgggt ccgacagcct 120 ccaggcaaag gcctggaatg gctgggcgtg atctggaccg goggcaccac caactacaac 180 tccgccctga tgtcccggct gaccatctcc aaggacgact ccaagaacac cgtgtacctg 240 aagatgaact ccctgaaaac cgaggacacc gocatctact actgcgcccg gtactactac 300 ggcatggact actggggcca gggcaccctg gtcaccgtgt cctca 345

< 210 > SEQ ID NO 21 < 211 > LENGTH : 345 < 212 > TYPE : DNA < 213 > ORGANISM : Artificial Sequence A FEATURE : < 223 > OTHER INFORMATION : synthetic construct A FEATURE : A 221 > NAME / KEY : misc _ feature A 22 > LOCATION : ( 1 ) . . ( 345 )

A > OTHER INFORMATION : nucleotide sequence encoding VH3 heavy chain amino acid sequence < 400 > SEQUENCE : 21 caggtgcagc tgcaggaatc cggccctggc ctggtcaagc cctccgagac actgtccctg 60 acctgcaccg tgtccggctt ctccctgctg tcctacggcg tgcactgggt ccgacagcct 120 ccaggcaaag gcctggaatg gctgggcgtg atctggaccg goggcaccac caactacaac 180 tccgccctga tgtcccggtt caccatctcc aaggacgact ccaagaacac cgtgtacctg 240 aagatgaact ccctgaaaac cgaggacacc gccatctact actgcgcccg gtactactac 300 ggcatggact actggggcca gggcaccctg gtcaccgtgt cctca 345

< 210 > SEQ ID NO 22 < 211 > LENGTH : 345 A< 212 > TYPE : DNA A< 213 > ORGANISM : Artificial Sequence A< 220 > FEATURE : A< 223 > OTHER INFORMATION : synthetic construct A 20 > FEATURE : A< 221 > NAME / KEY : misc _ feature A< 222 > LOCATION : ( 1 ) . . ( 345 ) A< 223 > OTHER INFORMATION : nucleotide sequence encoding VH4 heavy chain amino acid sequence < 400 > SEQUENCE : 22 US 2017 /0306050 A1 Oct. 26 , 2017 56

- continued caggtgcagc tgcaggaatc cggccctggc ctggtcaagc cctccgagac actgtccctg acctgcaccg tgtccggctt ctccctgctg tcctacggcg tgcactgggt ccgacagcct 120 ccaggcaaag gcctggaatg gctgggcgtg atctggaccg goggcaccac caactacaac 180 tccgccctga tgtcccggtt caccatctcc aaggacgact ccaagaacac cctgtacctg 240 aagatgaact ccctgaaaac cgaggacacc gccatctact actgcgcccg gtactactac 300 ggcatggact actggggcca gggcaccctg gtcaccgtgt cctca 345

A< 210 > SEQ ID NO 23 A< 211 > LENGTH : 321 A< 212 > TYPE : DNA A< 213 > ORGANISM : Artificial Sequence A< 220 > FEATURE : A< 223 > OTHER INFORMATION : synthetic construct A< 220 > FEATURE : A > NAME / KEY : misc _ feature A< 222 > LOCATION : ( 1 ) . . ( 321 ) A< 223 > OTHER INFORMATION : nucleotide sequence encoding Vkl light chain amino acid sequence < 400 > SEQUENCE : 23 gacatcgtga tgacccagtc ccccagcttc ctgtccgcct ccgtgggcga cagagtgacc 60 atcacatgca aggcctctca ggacgtgcgg aacaccgtgg cctggtatca gcagaaaacc 120 ggcaaggccc ccaagctgct gatctactcc tcctcctacc ggaacaccgg cgtgcccgac 180 cggtttaccg gctctggctc cggcaccgac tttaccctga ccatcagctc cctgcaggcc 240 gaggacgtgg ccgtgtactt ctgccagcag cactacatca ccccctacac cttcggcgga 300 ggcaccaagg tggaaataaa a 321

< 210 > SEQ ID NO 24 < 211 > LENGTH : 321 < 212 > TYPE : DNA < 213 > ORGANISM : Artificial Sequence < 220 > FEATURE : < 223 > OTHER INFORMATION : synthetic construct < 220 > FEATURE : < 221 > NAME / KEY : misc _ feature < 222 > LOCATION : ( 1 ) . . ( 321 ) < 223 > OTHER INFORMATION : nucleotide sequence encoding Vk2 light chain amino acid sequence < 400 > SEQUENCE : 24 gacatcgtga tgacccagtc cccctccagc ctgtccgcct ctgtgggcga cagagtgacc 60 atcacatgca aggcctctca ggacgtgcgg aacaccgtgg cctggtatca gcagaagccc 120 ggcaaggccc ccaagctgct gatctactcc tcctcctacc ggaacaccgg cgtgcccgac 180 cggtttaccg gotctggctc cggcaccgac tttaccctga ccatcagctc cctgcaggcc 240 gaggacgtgg ccgtgtactt ctgccagcag cactacatca ccccctacac cttcggcgga 300 ggcaccaagg tggaaataaa a 321

< 210 > SEQ ID NO 25 < 211 > LENGTH : 321 < 212 > TYPE : DNA < 213 > ORGANISM : Artificial Sequence < 220 > FEATURE : < 223 > OTHER INFORMATION : synthetic construct < 220 > FEATURE : < 221 > NAME / KEY : misc _ feature US 2017 /0306050 A1 Oct. 26 , 2017 57

- continued < 222 > LOCATION : ( 1 ) . . ( 321 ) < 223 > OTHER INFORMATION : nucleotide sequence encoding Vk3 light chain amino acid sequence < 400 > SEQUENCE : 25 gacatccaga tgacccagtc cccctccagc ctgtccgcct ctgtgggcga cagagtgacc 60 atcacatgca aggcctccca ggacgtgcgg aacaccgtgg cctggtatca gcagaagccc 120 ggcaaggccc ccaagctgct gatctactcc tcctcctacc ggaacaccgg cgtgcccgac 180 cggttctctg gctctggaag cggcaccgac tttaccctga ccatcagctc cctgcaggcc 240 gaggacgtgg ccgtgtactt ctgccagcag cactacatca ccccctacac cttcggcgga 300 ggcaccaagg tggaaataaa a 321

< 210 > SEQ ID NO 26 < 211 > LENGTH : 321 < 212 > TYPE : DNA A< 213 > ORGANISM : Artificial Sequence A< 220 > FEATURE : A< 223 > OTHER INFORMATION : synthetic construct A< 220 > FEATURE : A 1 > NAME / KEY : misc _ feature A< 222 > LOCATION : ( 1 ) . . ( 321 ) A< NNNN223NNNNNN > OTHER INFORMATION : nucleotide sequence encoding Vk4 light chain amino acid sequence < 400 > SEQUENCE : 26 gacatccaga tgacccagtc cccctccagc ctgtccgcct ctgtgggcga cagagtgacc atcacatgca aggcctctca ggacgtgcgg aacaccgtgg cctggtatca gcagaagccc 120 ggcaaggccc ccaagctgct gatctactcc tcctcctacc ggaacaccgg cgtgcccgac 180 cggttctctg gotctggaag cggcaccgac tttaccctga ccatcagctc cctgcaggcc 240 gaggacgtgg ccgtgtacta ctgccagcag cactacatca ccccctacac cttcggcgga 300 ggcaccaagg tggaaataaa a 321

< 210 > SEQ ID NO 27 < 211 > LENGTH : 707 < 212 > TYPE : PRT < 213 > ORGANISM : Homo sapiens 20 > FEATURE : < 221 > NAME / KEY : misc _ feature LOCATION : ( 1 ) . . ( 707 ) < 223 > OTHER INFORMATION : matrix metalloproteinase 9 ( MMP9 ) < 220 > FEATURE : < 221 > NAME / KEY : PEPTIDE < 222 > LOCATION : ( 1 ) . . ( 19 ) 3 > OTHER INFORMATION : signal peptide < 220 > FEATURE : < 221 > NAME / KEY : DOMAIN < 222 > LOCATION : ( 38 ) . . ( 98 ) < 223 > OTHER INFORMATION : peptidoglycan binding domain < 220 > FEATURE : < 221 > NAME /KEY : SITE 22 > LOCATION : ( 98 ) . . ( 99 ) 23 > OTHER INFORMATION : propeptide cleavage site < 220 > FEATURE : < 221 > NAME / KEY : DOMAIN < 222 > LOCATION : ( 112 ) . . ( 445 ) < 223 > OTHER INFORMATION : Zn dependent metalloproteinase domain < 220 > FEATURE : < 221 > NAME / KEY : DOMAIN < 222 > LOCATION : (223 ) . . (271 ) 223 > OTHER INFORMATION : fibronectin type II domain ( gelatin binding domain ) < 220 > FEATURE : US 2017/ 0306050 Al Oct. 26 , 2017 8

- continued < 221 > NAME / KEY : DOMAIN < 222 > LOCATION : ( 281 ) . . ( 329 ) < 223 > OTHER INFORMATION : fibronectin type II domain ( gelatin binding domain ) < 220 > FEATURE : < 221 > NAME / KEY : DOMAIN < 222 > LOCATION : ( 340 ) . . ( 388 ) < 223 > OTHER INFORMATION : fibronectin type II domain ( gelatin binding domain ) < 220 > FEATURE : < 221 > NAME / KEY : misc _ feature < 222 > LOCATION : ( 400 ) . . ( 411 ) < 223 > OTHER INFORMATION : Zn binding region 20 > FEATURE : < 221 > NAME / KEY : DOMAIN LOCATION : ( 521 ) . . ( 565 ) < 223 > OTHER INFORMATION : hemopexin - like domain < 220 > FEATURE : 12 NAME / KEY : DOMAIN 22 > LOCATION : ( 567 ) . . ( 608 ) < 223 > OTHER INFORMATION : hemopexin - like domain < 220 > FEATURE : < 221 > NAME / KEY , DOMAIN < 222 > LOCATION : ( 613 ) . . ( 659 ) < 223 > OTHER INFORMATION : hemopexin - like domain < 220 > FEATURE : < 221 > NAME / KEY : DOMAIN < 222 > LOCATION : ( 661 ) . . ( 704 ) < 223 > OTHER INFORMATION : hemopexin - like domain < 400 > SEQUENCE : 27 Met Ser Leu Trp Gin Pro Leu Val Leu Val Leu Leu Val Leu Gly Cys

Cys Phe Ala Ala Pro Arg Gin Arg Gin Ser ?Thr Leu Val Leu Phe Pro 25 130 Gly Asp Leu Arg Thr Asn Leu Thr Asp Arg Gin Leu Ala Glu Glu Tyr RT 35 40 45 Leu Tyr Arg Tyr Gly Tyr Thr Arg Val Ala Glu Met Arg Gly Glu Ser 50 5 Lys Ser Leu Gly Pro Ala Leu Leu Leu Leu Gin Lys Gin Leu Ser Leu 75 80

&Pro Glu Thr Gly Glu Leu Asp Ser Ala Thr Leu Lys Ala Met Arg Thr

&Pro Arg Cys Gly Val Pro Asp Leu Gly Arg Phe Gin Thr Phe Glu Gly 105 110 Asp Leu Lys Trp His His His Asn Ile Thr Tyr Trp Ile Gin Asn Tyr 115 120 125 Ser Glu Asp Leu Pro Arg Ala Val Ile Asp Asp Ala Phe Ala Arg Ala 130 Phe Ala Leu Trp Ser Ala Val Thr Pro Leu Thr Phe Thr Arg Val Tyr mg 155 mm 160 Ser Arg Asp Ala Asp Ile mmVal Ile Gin Phe Gly Val Ala Glu His Gly Asp Gly Tyr Pro Phe Asp Gly Lys Asp Gly Leu Leu Ala His Ala Phe 185 190 Pro Pro Gly Pro Gly Ile Gin Gly Asp Ala His Phe Asp Asp Asp Glu 195 mmmm 200 205 Leu Trp Ser Leu Gly Lys Gly Val Val Val Pro Thr Arg Phe Gly Asn 210 8mm Ala Asp Gly Ala Ala Cys His Phe Pro Phe Ile Phe Glu Gly Arg Ser mmmmmmmmmm mammmmmm 235 mmmm 240 m US 2017/ 0306050 Al Oct. 26 , 2017 59 .

- continued |

? Tyr Ser Ala Cys Thr Thr Asp *Gly Arg Ser Asp Gly Leu Pro Trp Cys 255 Ser Thr Thr Ala Asn Tyr Asp Thr Asp Asp Arg Phe Gly Phe Cys Pro 265 | 270 Ser Glu Arg Leu Tyr Thr Arg Asp Gly Asn Ala Asp Gly Lys& Pro Cys 275 280 285

Gin Phe Pro Phe Ile Phe Gin Gly Gin Ser Tyr Ser Ala Cys? Thr Thr 295 Asp Gly Arg Ser Asp Gly Tyr Arg Trp Cys Ala Thr Thr Ala Asn Tyr 305 310 315 Asp Arg Asp Lys Leu Phe Gly Phe Cys Pro Thr Arg Ala Asp Ser Thr ERA 335

Val Met Gly Gly Asn Ser Ala *Gly 3JEEREGlu Leu Cys Val Phe Pro Phe Thr 345 350 Phe Leu Gly Lys Glu Tyr Ser Thr Cys Thr Ser Glu Gly Arg Gly Asp 255 360 26 Gly Arg Leu Trp Cys Ala Thr Thr Ser Asn Phe Asp Ser Asp Lys Lys 375

Trp Gly Phe Cys Pro Asp Gin *Gly Tyr Ser Leu Phe Leu Val Ala Ala 385 390 395 400 His Glu Phe Gly His Ala Leu Gly Leu Asp His Ser Ser Val Pro Glu mmmmmm 415 Ala Leu Met Tyr Pro Met Tyr Arg Phe Thr Glu Gly Pro Pro Leu His 425 430 Lys Asp Asp Val Asn Gly Ile Arg His Leu Tyr Gly Pro Arg Pro Glu 435 440 445

&Pro Glu Pro Arq Pro Pro Thr Thr Thr Thr Pro Gln Pro Thr Ala Pro 455

APro Thr Val Cys Pro Thr Gly Pro Pro Thr Val His Pro Ser Glu Arq 465 470 475 480

&Pro Thr Ala Gly Pro Thr Gly Pro Pro Ser Ala Gly Pro Thr Gly &Pro 495 Pro Thr Ala Gly Pro Ser Thr Ala Thr Thr Val Pro Leu Ser Pro Val 505 510 Asp Asp Ala Cys Asn Val Asn Ile Phe Asp Ala Ile Ala Glu Ile Gly 515 520 525 Asn Gin Leu Tyr Leu Phe Lys Asp Gly Lys Tyr Trp Arg Phe Ser Glu 535 Gly Arg Gly Ser Arg Pro Gin Gly Pro Phe Leu Ile Ala Asp Lys Trp 545 550 555 560 &Pro Ala Leu Pro Arg Lys Leu Asp Ser Val Phe Glu Glu Pro Leu Ser 575

Lys Lys Leu Phe Phe Phe Ser *Gly Arg Gin Val Trp Val Tyr Thr Gly mmm8? 585 590 Ala Ser Val Leu Gly Pro Arg Arg Leu Asp Lys Leu Gly Leu Gly Ala 595 600 605 Asp Val Ala Gin Val Thr Gly Ala Leu Arg Ser Gly Arg Gly Lys Met 615 Leu Leu Phe Ser Gly Arg Arg Leu Trp Arg Phe Asp Val Lys Ala Gin 625 mmmmmmm mmmmm 630 mm mmmm mmmmmmmmm635 mmmmm 640 US 2017/ 0306050 Al Oct. 26 , 2017

- continued | Met Val Asp Pro Arg Ser Ala Ser Glu Val Asp Arg Met Phe Pro Gly 645 650 | 655655 | Val Pro Leu Asp Thr His Asp Val Phe Gin Tyr Arg Glu Lys Ala Tyr 660 665 670 Phe Cys Gin Asp Arg Phe Tyr Trp Arg Val gSer Ser Arg Ser Glu Leu 23 675 ?23 680 685 Asn Gin Val Asp Gin Val Gly Tyr Val Thr Tyr Asp Ile Leu Gin Cys 690 695 700 Pro Glu Asp 705

< 210 > SEQ ID NO 28 < 211 > LENGTH : 688 < 2122 > TYPE : PRT < 2133 > ORGANISM : Homo sapiens < 2200 > FEATURE : < 2211 > NAME / KEY : misc _ feature < 2222 > LOCATION : ( 1 ) . . ( 688 ) < 2233 > OTHER INFORMATION : mature full - length matrix metalloproteinase 9 ( MMP9 ) < 400 > SEQUENCE : 28 Ala &Pro Arg Gin Arg Gin Ser Thr Leu Val Leu Phe &Pro Gly Asp Leu

Arg Thr Asn Leu Thr Asp Arg ?Gin Leu Ala Glu Glu Tyr Leu Tyr Arg En Tyr Gly Tyr Thr Arg Val Ala Glu Met Arg Gly Glu Ser Lys Ser Leu 35 40 |8& Gly Pro Ala Leu Leu Leu Leu Gin Lys Gin Leu Ser Leu &Pro Glu Thr Gly Glu Leu Asp Ser Ala Thr Leu Lys Ala Met Arg Thr Pro Arg Cys 65 Gly Val Pro Asp Leu Gly Arg Phe Gin Thr Phe Glu Gly Asp Leu Lys Trp His His His Asn meIle Thr Tyr Trp Ile Gln Asn Tyr Ser Glu Asp Leu Pro IArg Ala Val Ile Asp Asp Ala Phe Ala Arg Ala Phe Ala Leu 115 120 Trp Ser Ala Val Thr Pro Leu Thr Phe Thr Arg Val Tyr Ser Arg Asp RETEE&Ala Asp Ile Val Ile Gin Phe Gly Val Ala Glu His Gly Asp Gly Tyr 145 ERA Pro Phe Asp Gly Lys Asp Gly Leu Leu Ala His Ala Phe Pro Pro Gly Pro Gly Ile Gin Gly Asp Ala His Phe Asp Asp Asp Glu Leu Trp Ser

Leu Gly Lys Gly Val Val Val Pro Thr Arg Phe 3Gly Asn Ala Asp Gly 195 200 Ala Ala Cys His Phe Pro Phe Ile Phe Glu mmmGly Arg Ser Tyr Ser Ala Cys Thr Thr Asp Gly Arg Ser Asp Gly Leu Pro Trp ECys Ser Thr Thr 225 mmmmm Ala Asn Tyr Asp Thr Asp Asp Arg Phe Gly Phe Cys &Pro ?Ser Glu Arg mmmmmmm mmm mm ammmmm 8 US 2017/ 0306050m Al Oct. 26 , 2017

m - continued Leu Tyr Thr Arg Asp Gly Asn Ala Asp Gly Lys Pro Cys Gin Phe Pro 265 270 Phe Ile Phe Gin Gly Gin Ser Tyr Ser Ala Cys Thr Thr Asp Gly Arg 275 280

Ser Asp Gly Tyr Arg Trp ECys Ala Thr Thr Ala Asn Tyr Asp Arg Asp 290 295 300

Lys Leu Phe Gly Phe Cys &Pro Thr Arg Ala Asp Ser Thr Val Met Gly 305 320 Gly Asn Ser Ala Gly Glu Leu Cys Val Phe Pro Phe Thr Phe Leu Gly 330 335

Lys Glu Tyr Ser Thr Cys ?Thr Ser Glu Gly Arg Gly Asp Gly Arg Leu 345 350 Trp Cys Ala Thr Thr Ser Asn Phe Asp Ser Asp Lys Lys Trp Gly Phe 355 360 Cys Pro Asp Gin Gly Tyr Ser Leu Phe Leu Val Ala Ala His Glu Phe 370 375 380 Gly His Ala Leu Gly Leu Asp His Ser Ser Val Pro Glu Ala Leu Met 385

Tyr Pro Met Tyr Arg Phe Thr Glu Gly Pro Pro Leu His Lys Asp Asp 410 mmmmm 415 Val Asn Gly Ile Arg His Leu Tyr Gly Pro Arg Pro Glu Pro Glu Pro | 425 430 Arg Pro Pro Thr Thr 3mmThr Thr Pro Gin Pro Thr Ala Pro Pro Thr Val 435 440 Cys Pro Thr Gly Pro Pro Thr Val His Pro Ser Glu Arq Pro Thr Ala 450 455 460 Gly Pro Thr Gly Pro Pro Ser Ala Gly Pro Thr Gly Pro Pro Thr Ala 465 Gly Pro Ser Thr Ala Thr Thr Val Pro Leu Ser Pro Val Asp Asp Ala 490 495 Cys Asn Val Asn Ile Phe Asp Ala Ile Ala Glu Ile Gly Asn Gln Leu 505 510 Tyr Leu Phe Lys Asp Gly Lys Tyr Trp Arg Phe Ser Glu Gly Arg Gly 515 520 Ser Arg Pro Gin Gly Pro Phe Leu Ile Ala Asp Lys Trp Pro Ala Leu 530 535 540 Pro Arg Lys Leu Asp Ser Val Phe Glu Glu Pro Leu Ser Lys Lys Leu 545 Phe Phe Phe Ser Gly Arg Gin Val Trp Val Tyr Thr Gly Ala Ser Val 570 575 Leu Gly Pro Arg Arg Leu Asp Lys Leu Gly Leu Gly Ala Asp Val Ala mmmmm 585 590 Gin Val Thr Gly Ala Leu Arg Ser Gly Arg Gly Lys Met Leu Leu Phe 595 600 mmmm Ser Gly Arg Arg Leu Trp Arg Phe Asp Val Lys Ala Gin Met Val Asp 610 615 620 Pro Arg Ser Ala Ser Glu Val Asp Arg Met Phe Pro Gly Val Pro Leu 625 Asp Thr His gmAsp Val mmPhe Gin Tyr Arg Glu Lys Ala Tyr Phe Cys Gin 650 655 Asp Arg mmmmPhe Tyr mmmmmmmTrp Arg Val mmmmmmSer mmmmmmmmSer mmmmmmmmmmAra Ser Glu Leu mmmmmAsn mmmmmmGin Val US 2017/ 0306050 Al Oct. 26 , 2017

- continued 660 665 670 Asp Gin Val Gly Tyr Val Thr Tyr Asp Ile Leu Gin Cys Pro Glu Asp 675 680 685

< 210 > SEQ ID NO 29 < 211 > LENGTH : 19 < 212 > TYPE : PRT AAA 13 > ORGANISM : Homo gapiens < 400 > SEQUENCE : 29 | Met Ser Leu Trp Gin Pro Leu Val Leu Val Leu Leu Val Leu Gly Cys 10 15 Cys Phe Ala

< 210 > SEQ ID NO 30 < 2111 > LENGTH : 470 < 2121 > TYPE : PRT < 2131 > ORGANISM : Mus musculus A 202 > FEATURE : < 2212 > NAME / KEY : CHAIN < 2222 > LOCATION : ( 1 ) . . ( 470 ) < 2232 > OTHER INFORMATION : M4 heavy chain ( IgG2b ) < 400 > SEQUENCE : 30 Met Ala Val Leu Val Leu Phe Leu Cys Leu Val Ala Phe Pro Ser Cys 15 Val Leu Ser Gin Val Gin Leu Lys Glu Ser |23Gly Pro Gly Leu Val Ala 20 g25 8 Pro Ser Gin Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu 35 40 |8?3? Leu Ser Tyr Gly Val His Trp Val Arg Gin Pro Pro Gly Lys Gly Leu

&? Glu Trp Leu Gly Val Ile Trp Thr 3Gly Gly Ser Thr Asn Tyr Asn Ser 65 70 & Ala Leu Met Ser Arg Leu Ser Ile Ser Lys Asp Asp Ser Lys Ser Gin 2E 95 Val Phe Leu Lys mmmMet Asn Ser Leu Gin Thr Asp Asp Thr Ala Met Tyr 100 105

Tyr Cys Ala Arg Tyr Tyr Tyr Ala Met Asp Tyr Trp Gly ?Gin Gly Thr 115115 120

Ser Val Thr Val Ser Ser Ala Lys Thr Thr &Pro Pro Ser Val Tyr Pro Leu Ala Pro Gly Cys Gly Asp Thr Thr Gly Ser Ser Val Thr Leu Gly 145 150

Cys Leu Val Lys Gly Tyr Phe Pro 3Glu Ser Val Thr Val Thr Trp Asn 175

Ser Gly Ser Leu Ser Ser Ser Val His Thr Phe &Pro Ala Leu Leu Gin 180 185

Ser Gly Leu Tyr Thr Met Ser Ser Ser Val Thr Val Pro Ser Ser Thr 195 200 &E Trp Pro Ser Gin Thr Val Thr Cys Ser Val Ala His Pro Ala Ser Ser &

Thr Thr Val Asp Lys Lys Leu Glu &Pro Ser Gly Pro Ile Ser Thr Ile 225 230 mmm 8 Asn Pro mmmCys Pro Pro Cys Lys Glu Cys His Lys Cys Pro Ala Pro Asn US 2017/ 0306050 Al Oct. 26 , 2017 63

- continued 245 250 255 Leu Glu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Asn Ile Lys Asp 260

Val Leu Met °Ile Ser Leu ?Thr Pro Lys Val Thr Cys Val Val Val Asp 275 280 285 mmVal Ser Glu Asp Asp Pro 28Asp Val Arg Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gin Thr Gln Thr His Arg Glu Asp Tyr Asn &R3310 315 Ser Thr Ile Arg 8?Val Val 8Ser Ala Leu Pro Ile Gin His Gin Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu &Pro 340 EA Ser Pro Ile Glu Arg Thr Ile Ser Lys Ile Lys Gly Leu Val Arg Ala 355 360 365

Pro Gln Val Tyr Ile Leu Pro Pro Pro Ala Glu Gln Leu Ser Arg Lys

Asp Val Ser Leu Thr Cys Leu Val Val Gly Phe Asn Pro Gly Asp Ile 390 mmmmm 395 Ser Val mmmGlu Trp Thr Ser Asn Gly His Thr Glu Glu Asn Tyr Lys Asp Thr Ala Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Ile Tyr mmmmmmSer Lys 420 Leu Asp Ile Lys Thr Ser Lys Trp Glu Lys Thr Asp Ser Phe Ser Cys 435 440 mmm 445 Asn Val Arg His Glu Gly Leu Lys Asn Tyr Tyr Leu Lys Lys Thr Ile mmmm ? ? ? Ser Arg Ser Pro Gly Lys mmmm 465 470

< 210 > SED ID No 31 < 211 > LENGTH : 234 < 212 > TYPE : PRT < 213 > ORGANISM : Mus musculus < 220 > FEATURE : < 221 > NAME KEY : CHAIN < 222 > LOCATION : ( 1 ) . . ( 234 ) |AAAAA 23 > OTHER INFORMATION : M4 light chain ( kappa ) < 400 > SEQUENCE : 31 Met Glu Ser Gin Ile Gin Val Phe Val Phe Val Phe Leu Trp Leu Ser Met Giu ser Gin Ile Gin Val phe val phe val phe Leu Trp Leu15 ser Gly Val Asp Gly Asp Ile Val Met Thr Gin Ser His Lys Phe Met Phe 20 25

Thr Ser Val Gly Asp Arg Val Ser Ile ?Thr Cys Lys Ala Ser Gin Asp PR ?40 45 Val Arg Asn Thr Val Ala Trp Tyr Gin Gin Lys Thr Gly Gin Ser Pro 50 55

Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Asn Thr Gly Val Pro Asp asm 70 TO mmm ? Arg Phe Thr Gly Ser Ile Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser 95 | Ser Val Gin Ala Glu Asp Leu Ala Leu Tyr Tyr Cys Gin Gin His Tyr ama100 105 110 US 2017/ 0306050 Al Oct. 26 , 2017 64

- continued

Ser ?Thr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Val Lys Arg 115 125 RAla Asp ?Ala PE Ala &Pro Thr Val REESer Ile Phe Pro Pro Ser Ser Glu Gln Leu ?Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe ETyr 150 Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gin

Asn Gly Val Leu Asn Ser Trp Thr Asp Gin Asp Ser Lys Asp Ser ?Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg 195 205

His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser 8Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 225 230 mmm < 210 > SEQ ID NO 32 < 2111 > LENGTH : 115 < 2122 > TYPE : PRT < 2133 > ORGANISM : Mus musculus < 400 > SEQUENCE : 321

Gin Val Gin Leu Lys Glu Ser Gly &Pro Gly Leu Val Ala Pro Ser Gin

Ser Leu Ser Ile Thr Cys ?Thr Val Ser Gly Phe Ser Leu Leu Ser ETyr 25 Gly Val His Trp Val Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp Leu

Gly Val Ile ?Trp Thr Gly Gly Ser Thr Asn Tyr Asn Ser Ala Leu Met ? Ser Arg Leu Ser Ile Ser Lys Asp Asp Ser Lys Ser Gin Val Phe Leu

Lys Met Asn Ser Leu Gin Thr Asp Asp Thr Ala Met Tyr Tyr ECys Ala Arg Tyr Tyr Tyr Ala HeMet Asp Tyr Trp Gly Gin Gly Thr Ser Val Thr 105 smVal Ser Ser sms < 210 > SEO ID NO 33 < 211 > LENGTH : 107 < 212 > TYPE : PRT < 213 > ORGANISM : Mus musculus < 400 > SEQUENCE : 33

Asp Ile Val Met Thr Gln Ser His Lys Phe Met ?Phe Thr Ser Val Gly 15

Asp Arg Val Ser Ile ?Thr ECys 5Lys Ala Ser Gin Asp Val Arg Asn Thr 20 ?3? 25 30 3? Val Ala Trp Tyr Gin Gin Lys Thr Gly Gin Ser Pro Lys Leu Leu Ile 8 8 CEPE Tyr Ser Ala Ser Tyr Arg Asn Thr Gly Val Pro Asp Arg Phe ?Thr Gly 55 | US 2017 /0306050 A1 Oct. 26 , 2017 65

- continued

Ser Ile Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Val Gln Ala 65 70 75 80 Glu Asp Leu Ala Leu Tyr Tyr cys Gin Gin His Tyr Ser Thr Pro Tyr 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Val Lys 100 105

< 210 > SEQ ID NO 34 < 211 > LENGTH : 10 < 212 > TYPE : PRT < 213 > ORGANISM : Mus musculus < 400 > SEQUENCE : 34 Gly Phe Ser Leu Leu Ser Tyr Gly Val His 10

< 210 > SEQ ID NO 35 < 211 > LENGTH : 16 < 212 > TYPE : PRT < 213 > ORGANISM : Mus musculus < 400 > SEQUENCE : 35 Val Ile Trp Thr Gly Gly Ser Thr Asn Tyr Asn Ser Ala Leu Met Ser 10 15

< 210 > SEO ID NO 36 < 211 > LENGTH : 7 < 212 > TYPE : PRT < 213 > ORGANISM : Mus musculus < 400 > SEQUENCE : 36 Tyr Tyr Tyr Ala Met Asp Tyr

< 210 > SEQ ID NO 37 < 211 > LENGTH : 11 ?M 12 > TYPE : PRT ?M 13 > ORGANISM : Mus musculus < 400 > SEQUENCE : 37 Lys Ala Ser Gin Asp Val Arg Asn Thr Val Ala 5 10

< 210 > SEQ ID NO 38 < 211 > LENGTH : 7 < 212 > TYPE : PRT < 213 > ORGANISM : Mus musculus < 400 > SEQUENCE : 38 Ser Ala Ser Tyr Arg Asn Thr

< 210 > SEQ ID NO 39 < 211 > LENGTH : 9 < 212 > TYPE : PRT < 213 > ORGANISM : Mus musculus < 400 > SEQUENCE : 39 Gin Gin His Tyr Ser Thr Pro Tyr Thr 1 US 2017/ 0306050 Al Oct. 26 , 2017 66

- continued

< 210 > SEQ ID NO 40 < 211 > LENGTH : 229 < 212 > TYPE : PRT < 213 > ORGANISM : Mus musculus < 220 > FEATURE : < 221 > NAME KEY : CHAIN 22 > LOCATION : ( 1 ) . . ( 229 ) < 223 > OTHER INFORMATION : M12 kappa chain < 400 > SEQUENCE : 40 Gin Val ?Phe Val Tyr ?Met Leu Leu Trp Leu Ser Gly Val Asp Gly Asp

Ile Val Met Thr Gin Ser Gin ?Lys Phe Met Ser Thr Ser Val Gly Asp 30

Arg Val Ser Val ?Thr Cys Lys Ala Ser Gin Asn Val Gly Thr Asn Val mmasm 40 Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ser Pro Lys Ala Leu ?Ile Tyr 55

Ser Ala Ser Tyr Arg Phe Ser Gly Val Pro Asp Arg Phe ?Thr Gly Ser mmsGly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Val Gln Ser Glu Asp Leu Ala Glu Tyr Phe Cys Gin Gin Tyr Asn Ser Tyr &Pro Tyr Thr 110 Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ala Asp Ala Ala Pro 120 Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gin Leu Thr Ser Gly Gly 135 Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile Asn

Val Lys Trp Lys Ile Asp Gly Ser Glu 1Arg Gin Asn Gly Val Leu mmmmAsn Ser Trp Thr Asp Gin Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser Ser 190

Thr Leu Thr Leu ?Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr Thr 200 Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser Phe 215 Asn Arg Asn Glu Cys mmmmm < 210 > SEO ID NO 41 < 211 > LENGTH : 107 < 212 > TYPE : PRT < 213 > ORGANISM : Mus musculus mmm < 400 > SEQUENCE : 41 Asp Ile Val Met Thr Gln Ser Gln Lys ?Phe Met Ser Thr Ser Val Gly 10 15

Asp Arg Val Ser Val ?Thr ECys Lys Ala Ser Gin Asn Val Gly Thr Asn 20 25 Val Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ser Pro Lys Ala Leu Ile 8 40 CEPE Tyr Ser Ala Ser Tyr Arg Phe Ser Gly Val Pro Asp Arg Phe Thr Gly 55 US 2017/ 0306050 Al Oct. 26 , 2017 67

- continued

Ser Gly Ser Gly Thr Asp Phe Thr Leu ?Thr Ile Ser Asn Val Gln Ser 65 70 75 80 Glu Asp Leu Ala Glu Tyr Phe Cys Gin Gin Tyr Asn Ser Tyr Pro Tyr 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105

< 210 > SEQ ID NO 42 < 211 > LENGTH : 11 < 212 > TYPE : PRT < 213 > ORGANISM : Mus musculus < 400 > SEOUENCE : 42 Lys Ala Ser Gln Asn Val Gly Thr Asn Val Ala al Gly Thr Agn val10 Ala

< 210 > SEQ ID NO 43 < 211 > LENGTH : 7 < 212 > TYPE : PRT < 213 > ORGANISM : Mus musculus < 400 > SEQUENCE : 43 Ser Ala Ser Tyr Arg Phe Ser

< 210 > SEQ ID NO 44 < 211 > LENGTH : 9 < 212 > TYPE : PRT < 213 > ORGANISM : Mus musculus < 400 > SEQUENCE : 44 Gin Gin Tyr Asn Ser Tyr Pro Tyr Thr

< 210 > SEQ ID NO 45 < 21111 > LENGTH : 233

1 < 21223 > TYPE : PRT

< 2131 > ORGANISM : Mus musculus < 220 > FEATURE : < 221 > NAME KEY : CHAIN < 222 > LOCATION : ( 1 ) . . ( 233 ) < 223 > OTHER INFORMATION : AB0046 kappa light chain < 400 > SEQUENCE : 45

Met Ser Ser Ala Gln Phe Leu Gly Leu Leu Leu Leu Cys ?Phe ?Gln &Gly - 15

?Thr Arg Cys Asp Ile Gin Met Thr Gin Thr Thr Ser Ser Leu Ser Ala 20 25

Ser Leu Gly Asp Arg Val Thr Ile Ser ECys Ser Ala Ser Gin Gly Ile 35 am Ser Asn Tyr Leu Asn Trp Tyr Gin Gin Lys Pro Asp Gly ?Thr Phe Lys

%m Leu Leu Ile Tyr Tyr Thr Ser Ile Leu His Ser meGly Val &Pro Ser Arg AR 80 Re Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn mms 95 Leu Glu Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gin Gin Tyr Gly Trp 38 100 mms sm 105 US 2017/ 0306050 Al Oct. 26 , 2017

- continued | Leu &Pro Arg Thr ?Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ala ? 120 125

Asp AAla Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gin Leu Set Ile Phe Pro Pro 140 Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro | 150 160 Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gin Asn 165 175 Gly Val Leu Asn Ser Trp Thr Asp Gin Asp Ser Lys Asp Ser Thr Tyr 180 185 190 Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His 200 205 Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile 220 | Val Lys Ser Phe Asn Arg Asn Glu Cys 225 230

< 210 > SEO ID NO 46 < 211 > LENGTH : 460 < 212 > TYPE : PRT < 213 > ORGANISM : Mus musculus < 220 > FEATURE : 21 2 NAME / KEY : CHAIN < 222 > LOCATION : ( 1 ) . . ( 460 ) AAAAAAAA223 > OTHER INFORMATION : AB0046 IgG1 heavy chain < 400 > SEQUENCE : 46 Met ?Gly Trp Ser Ser Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly 101 9 Val His Ser Gin Val Gin Leu Gin |SEGin Pro Gly Ser Val Leu Val Arq 25

3.?Pro Gly Ala Ser Val Lys Leu Ser Cys Thr Ala Ser Gly Tyr Thr Phe 35 45 Thr Ser Tyr Trp Met Asn Trp Val Lys Gin Arg Pro Gly Gin Gly Leu am 60 Glu Trp Ile Gly Glu Ile Tyr Pro Ile Ser Gly Arg Thr Asn Tyr Asn am 70 Glu Lys Phe Lys Val Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser 90 Thr Ala Tyr Met Asp Leu Asn Ser Leu Thr mmsSer Glu Asp Ser Ala Val 105 3?ETyr Tyr Cys Ala Arg Ser Arg Ala Asn Trp Asp Asp Tyr Trp Gly Gin 115 125 Gly Thr Thr Leu Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val mmm 140 Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gin Thr Asn Ser Met Val Thr 145 smmmm 150 Leu Gly cys Leu Val Lys Gly Tyr Phe amaPro Glu Pro Val ?Thr Val Thr 165 170 Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val 185 gSea&A Leu Gin Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser 195 205 Ser Thr Trp Pro Ser Glu Thr Val Thr Cys Asn Val Ala His Pro Ala ? mm mmmm mmmm US 2017/ 0306050 Al Oct. 26 , 2017 69

- continued | 215 220 Ser Ser Thr Lys Val Asp Lys Lys ?Ile Val Pro RArg AAsp Cys Gly Cys 225 8235 Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe pgIle Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val 265

Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp &Pro Glu Val Gin Phe 275 280 mmm 83 Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gin ?Thr 3Gin Pro

Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro 305 mm 315 Ile Met His Gin Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala mm??Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr 345 Lys Gly Arg Pro Lys Ala Pro Gin Val Tyr Thr Ile Pro Pro Pro Lys 355 360 Glu Gin Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gin Trp Asn Gly Gin Pro 385 395 Ala Glu Asn Tyr Lys Asn Thr Gin Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe Val Tyr Ser mmmmmLys Leu Asn Val Gin Lys Ser Asn Trp Glu Ala 425 Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His 435 440 mmmm His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys 450 ?

< 210 > SED ID No 47 ama < 211 > LENGTH : 117 < 212 > TYPE : PRT 213 > ORGANISM : Mus musculus < 400 > SEQUENCE : 47 Gln Val Gln Leu ?Gin Gin Pro Gly Ser Val Leu Val Arq &Pro Gly Ala

?2 Ser Val Lys Leu Ser Cys Thr Ala Ser Gly ETyr Thr Phe Thr Ser ?Tyr &

Trp Met Asn Trp Val Lys 3Gin Arg Pro 3Gly Gin Gly Leu Glu Trp Ile 35 40 45 ?3 R&RE 3we ? 3Gly Glu Ile Tyr Pro Ile Ser Gly Arg Thr Asn Tyr Asn Glu Lys Phe 8

Lys Val Lys Ala Thr Leu Thr Val Asp ?Thr Ser Ser Ser Thr Ala Tyr 70 ne Met Asp Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

Ala Arg Ser Arg Ala Asn Trp Asp Asp Tyr 9Trp Gly Gin Gly Thr Thr mmmm m? ? TIE US 2017/ 0306050 Al Oct. 26 , 2017

- continued Leu Thr Val Ser Ser 115

< 210 > SEQ ID NO 48 < 211 > LENGTH : 107 < 212 > TYPE : PRT 213 > ORGANISM : Mus musculus < 400 > SEQUENCE : 48 Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly 5 | Asp Arg 3Val Thr Ile Ser Cys Ser Ala Ser Gin Gly Ile Ser Asn Tyr 20 g25 &E Leu Asn Trp Tyr Gin 3Gin ? Lys &Pro Asp Gly Thr Phe Lys Leu Leu °Ile 40 Tyr Tyr Thr Ser ?3?Ile Leu His Ser 3Gly Val Pro Ser Arg Phe Ser Gly 55 &ep Ser 3Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu ggggGlu Pro 2

Glu ?Asp ?Ile Ala Thr Tyr Tyr ECys JGin Gin Tyr Gly Trp Leu Pro Arg 3? 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 ?105

< 2102 SEO ID NO 49 < 211 > LENGTH : 461 < 21212 > TYPE : PRT

1133 5 ORGANISM : Artificial sequence < 220 > FEATURE : < 2233 > OTHER INFORMATION : synthetic construct 0 22 0 ) FEATURE : < 221 > NAME / KEY : CHAIN < 222 > LOCATION : ( 1 ) . . (461 ) < 223 > OTHER INFORMATION : AB0045 heavy chain < 400 > SEQUENCE : 49 Met Gly Trp Ser Leu Ile1 Leu Leu Phe Leu Val Ala Val aAla Thr Arq ?

Val His Ser Gin Val Gin Leu 3Gln Glu Ser Gly .Pro 3Gly Leu Val Lys His Ser Gin Val Gin Leu Gin | 30

Pro Ser Glu Thr Leu Ser Leu ?Thr cys Thr Val Ser Gly Phe Ser Leu 35 gRIT gg& Leu Ser Tyr Gly Val His Trp 3Val Arg Gln Pro Pro Gly Lys Gly Leu . ER Glu Trp Leu Gly Val Ile Trp ?Thr Gly Gly Thr Thr Asn Tyr Asn Ser 70 80

Ala Leu Met Ser Arg .Phe Thr Ile Ser Lys Asp Asp Ser Lys Asn Thr

Val Tyr Leu Lys Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Ile Tyr mmmm 110 Tyr Cys Ala Arg Tyr Tyr Tyr Gly Met Asp Tyr Trp Gly Gin Gly Thr 115 ?E emmLeu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala &Pro Cys Ser Ara Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly mmm 150 160 US 2017/ 0306050 Al Oct. 26 , 2017

- continued | | | | Cys Leu gVal Lys Asp Tyr Phe Pro Glu ?Pro Val Thr Val Ser Trp Asn 175 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gin 180 185 190 g& Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 195 200 205 Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser

Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly &Pro Pro Cys 230 240 Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu 255 ?8 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Ara Thr Pro Glu E&EEE 260 265 270 Val Thr Cys Val Val Val Asp Val Ser ?Gin Glu Asp Pro Glu Val Gin 275 280 285 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

Pro Arq Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu 310 320 Thr Val Leu His Gin Asp Trp Leu Asn Gly 1?DELys Glu Tyr Lys Cys Lys 335 Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys 340 mmmm 345 3?? 350 Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser 355 360 365 Gin Glu Glu Met Thr Lys Asn Gin Val gSer Leu Thr cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gin 390 Se 400 Pro Glu Asn Asn Tyr mmmLys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly mmmmm 415 Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg mmmmmTrp Gin 420 425 430 Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 435 440 445 ? His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Leu Gly Lys ?

< 210 > SEO ID NO 50 mmmg < 211 > LENGTH : 234 < 212 > TYPE : PRT < 2133 > ORGANISM : Artificial Sequence A< 220 > FEATURE : A< 223 > OTHER INFORMATION : synthetic construct A< 220 > FEATURE : A< 221 > NAME KEY : CHAIN A< 222 > LOCATION : ( 1 ) . . ( 234 ) A< 223 > OTHER INFORMATION : AB0045 light chain < 400 > SEQUENCE : 50 Met Arg Val Pro Ala Gin Leu Leu Gly Leu Leu Leu Leu Trp Leu Pro 10 . 15 Gly Ala Arg Cys Asp Ile Gin Met Thr Gin Ser Pro Ser Ser Leu Ser 20 25 30 US 2017/ 0306050 Al Oct. 26 , 2017

- continued

Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gin Asp 8 45

Val Arg Asn Thr Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys RAla& Pro 5

Lys Leu Leu Ile Tyr Ser Ser Ser Tyr Arg RAsn ?Thr 3Gly 3Val &Pro Asp 70 75 80

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe ?Thr Leu Thr pIle Ser Ser Leu Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Gin Gin His Tyr 110 Ile Thr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 125

Thr Val Ala Ala Pro Ser Val Phe Ile Phe &Pro Pro Ser Asp 3Glu Gln

Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 150 mmm 155 160. Pro Arg Glu Ala Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr mmm Egg?? 190 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys LEE| 205 His Lys Val Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro 210 28 Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 225 mam230 < 210 > SEQ ID NO 51 < 211 > LENGTH : 148 ) mmmm< 212 > TYPE : PRT < 213 > ORGANISM : Mus musculusmm mmmmm < 400 > SEQUENCE : 51

? Met Glu Ser |Gin Ile Gin Val Phe Val Phe Val Phe Leu ?Trp Leu Ser o ?

Gly Val Asp Gly Asp Ile Val ?Met Thr Gin Ser His Lys Phe ?Met Phe 25 30

Thr Ser Val Gly Asp Arg Val Ser Ile Thr ECys Lys Ala Ser 3Gin Asp 35 ? 45

Val Arg Asn Thr Val Ala Trp Tyr Gin Gin Lys Thr 2Gly Gin Ser &Pro

Lys Leu Leu Ile Tyr Ser Ala 8Ser Tyr Arg Asn Thr Gly Val Pro AAsp 70 80

D Arg Phe Thr Gly Ser Ile Ser 3Gly Thr Asp Phe Thr Phe Thr Ile Ser

Ser Val Gin Ala Glu Asp Leu Ala Leu Tyr ETyr Cys 3Gin Gin His ETyr mmm 105 110 3EA Ser Thr APro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Val Lys Arg 115 125

Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gin mmm gg & Leu Thr Ser Gly US 2017/ 0306050 Al Oct. 26 , 2017 73.

- continued 145

< 210 > SEO ID NO 52 < 400 > SEQUENCE : 52 000

< 210 > SEQ ID NO 53 < 211 > LENGTH : 143 < 212 > TYPE : PRT 4213 > ORGANISM : Mus musculus < 400 > SEQUENCE : 53 | Gin Val Phe Val Tyr Met Leu Leu Trp Leu Ser Gly Val Asp 3Gly Asp a

Ile Val Met Thr Gin Ser Gin Lys Phe Met Ser Thr Ser 2?Val Gly Asp Arg Val Ser Val Thr Cys Lys Ala Ser Gin Asn Val ggGly Thr Asn Val am 40 Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ser Pro Lys Ala Leu Ile Tyr 55 Ser Ala Ser Tyr Arg Phe Ser 2Gly Val Pro Asp memArg Phe ?Thr Gly ARE&Ser Gly Ser Gly Thr Asp Phe ?Thr Leu Thr Ile Ser Asn Val Gin Ser Glu mms ?6 Asp mmm8mmLeu Ala Glu BamTyr Phe Cys Gin Gin smTyr Asn Ser Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ala Asp Ala Ala Pro 120 Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gin Leu Thr Ser Gly 135 140

< 210 > SED ID No 54 < 211 > LENGTH : 180 < 212 > TYPE : PRT < 213 > ORGANISM : Mus musculus < 400 > SEQUENCE : 54 Met Ala Val Leu Val Leu Phe Leu Cys Leu Val Ala Phe &Pro Ser Cys

93 Val Leu Ser Gin Val Gin Leu Lys Glu Ser Gly Pro Gly Leu Val RAla 20 25 Pro Ser Gin Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu 35 Leu Ser Tyr Gly Val His Trp val Arg Gin Pro Pro Gly Lys Gly Leu 55 Glu Trp Leu Gly Val Ile Trp ?Thr Gly Gly Ser Thr Asn Tyr Asn Ser 70 & smAla Leu Met Ser smmmArg Leu Ser Ile Ser Lys Asp Asp Ser Lys Ser Gin Val Phe Leu Lys Met Asn Ser Leu Gin Thr Asp Asp Thr Ala Met Tyr 100 105 Tyr Cys Ala amArg Tyr Tyr Tyr Ala Met Asp mmmTyr Trp Gly Gin Gly Thr US 2017/ 0306050 Al Oct. 26 , 2017 74

- continued | Ser Val Thr Val Ser ?Ser Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro 130 135 Leu Ala Pro Gly Cys Gly Asp Thr Thr Gly Ser Ser Val Thr Leu Gly 145 150 160

3Cys Leu Val Lys Gly Tyr Phe Pro Glu Ser Val Thr Val Thr Trp Asn 165 170 175 1 Ser Gly Ser Leu 180

< 210 > SEQ ID NO 55 < 400 > SEQUENCE : 55 000

< 210 > SED ID No 56 < 211 > LENGTH : 7 < 212 > TYPE : PRT < 213 > ORGANISM : Homo sapiens < 400 > SEQUENCE : 56 Phe Gin Thr Phe Glu Gly Asp

< 210 > SEQ ID NO 57 < 211 > LENGTH : 6 < 212 > TYPE : PRT < 213 > ORGANISM : Homo sapiens < 400 > SEQUENCE : 57 | Gin Thr Phe Glu Gly Asp

< 210 > SEQ ID NO 58 < 211 > LENGTH : 13 < 212 > TYPE : PRT < 213 > ORGANISM : Homo sapiens < 400 > SEQUENCE : 58 Val Pro Asp Leu Gly Arg Phe Gin Thr Phe Glu Gly Asp 10

< 210 > SEQ ID NO 59 < 211 > LENGTH : 439 < 212 > TYPE : PRT < 213 > ORGANISM : Oryctolagus cuniculus < 400 > SEQUENCE : 59 Gin Ser Val Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro ? 15 Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Thr Ile Ser Ser Tyr His 30

Met Thr Trp Val Arg ?Gin Ala Pro Met Lys Gly Leu Glu Trp Ile Gly am 40 Thr Ile Ser Ser Ser Gly Ser Thr Tyr Tyr Ala Ser Trp Ala Lys Gly 55 Arg Phe Thr Ile ggSer Lys Thr Ser Ser Thr Thr Val Asp Leu Lys Ile 0

Thr Ser Pro Ala Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala .Arg Ser