US 2008O193414A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0193414 A1 Proudfoot et al. (43) Pub. Date: Aug. 14, 2008

(54) USE OF AN IMMUNOGLOBULIN (30) Foreign Application Priority Data DOMAN-CONTAINING CELL SURFACE RECOGNITION MOLECULE FOR TREATING May 6, 2005 (EP) ...... 05103791.9 DISEASES Publication Classification (76) Inventors: Amanda Proudfoot, Chens Sur (51) Int. Cl. Leman (FR); Bruno Antonsson, A638/17 (2006.01) Billiat (FR); Linda Kontula, A638/2 (2006.01) Geneva (CH); Francis Vilbois, A63L/7088 (2006.01) Minzier (FR) A6IR 39/44 (2006.01) A6IR 48/00 (2006.01) Correspondence Address: A6IP3L/2 (2006.01) SALWANCHIK LLOYD & SALWANCHIK A6IP3L/00 (2006.01) A PROFESSIONAL ASSOCATION A6IP33/00 (2006.01) PO BOX 142950 A6IP37/00 (2006.01) A6IP35/00 (2006.01) GAINESVILLE, FL 32614-2950 (US) A6IP 9/00 (2006.01) (21) Appl. No.: 11/913,620 A6IP 7/00 (2006.01) (52) U.S. Cl...... 424/85.6; 514/12: 514/13: 514/8: (22) PCT Filed: May 4, 2006 514/11: 514/44; 424/178.1; 424/85.4; 424/93.2 (57) ABSTRACT (86). PCT No.: PCT/EPO6/62O63 The invention relates to the use of INSP052 for treatment and/or prevention of infectious disease, properdin-related S371 (c)(1), disease, MBL2-related disease, MASP1-related disease, (2), (4) Date: Nov. 5, 2007 MASP2-related disease, Antithrombin III-related disease, Complement factor H-related disease and/or Albumin-related Related U.S. Application Data disease. Combinations of INSP052 with an interferon, a TNF (60) Provisional application No. 60/681,651, filed on May antagonist or a further anti-infectious or anti-blood clotting 17, 2005. agent are also within the present invention. US 2008/O 1934.14 A1 Aug. 14, 2008

USE OF AN IMMUNOGLOBULIN MASP1-related disease, MASP2-related disease, Antithrom DOMAN-CONTAINING CELL SURFACE bin III-related disease, Complement factor H-related disease RECOGNITION MOLECULE FOR TREATING and/or Albumin-related disease, wherein said polypeptide is DISEASES selected from the group consisting of: 0007) a) A polypeptide consisting of SEQID NO: 16, or FIELD OF THE INVENTION 0008 b) A polypeptide comprising any of SEQID NO: 0001. The invention relates to the use of INSP052 for the 2, SEQID NO: 4, SEQID NO: 6, SEQID NO: 8, SEQ treatment and/or prevention of infectious disease, properdin ID NO: 10, SEQ ID NO: 12, SEQID NO: 14, SEQ ID related disease, MBL2-related disease, MASP1-related dis NO:16, SEQID NO: 18, SEQID NO:20, SEQID NO: ease, MASP2-related disease, Antithrombin III-related dis 22, SEQID NO: 24, SEQID NO:26, SEQID NO: 27, ease, Complement factor H-related disease and/or Albumin SEQID NO:28, SEQID NO:29, SEQID NO:30, SEQ related disease. ID NO:31, SEQID NO:32 or SEQ ID NO:33, or 0009 c) A soluble form consisting of any of SEQ ID BACKGROUND OF THE INVENTION NO:20, SEQID NO:22, SEQID NO:27, SEQID NO: 0002. The protein INSP052 was disclosed in WO2003/ 28, SEQID NO: 29, SEQID NO:30, SEQID NO:31, 093316 and International Application No. PCT/GB2004/ SEQID NO:32 or SEQ ID NO:33, or 004772 as an immunoglobulin domain-containing cell Sur 0.010 d) A mature form consisting of any of SEQ ID face recognition molecule, and more particularly, as a NO: 22, SEQID NO: 24 or SEQID NO: 26, or cytokine antagonist. 0.011 e) A histidine tag form consisting of SEQID NO: 29, or SUMMARY OF THE INVENTION 0012 f) A glycosylated form of any of the polypeptides of (a) to (e), wherein the polypeptide is glycosylated at 0003. The invention is based on the unexpected finding that INSP052 interacts with proteins of the complement path one or more sites, or way, namely properdin, mannose-binding lectin C (MBL-C), 0013 g) A mutein of any of the polypeptides of(a) to (f), MASP1, MASP2, antithrombin III, complement factor Hand wherein the amino acid sequence has at least 40% or albumin. 50% or 60% or 70% or 80% or 90% identity to at least 0004. It is therefore a first object of the invention to use one of the corresponding sequences in (a) to (f), and INSP052 for the preparation of a medicament for the treat retaining INSP052 biological activity, or ment and/or prevention of infectious disease, properdin-re 0.014 h) A mutein of any of the polypeptides of (a) to (f) lated disease, MBL2-related disease, MASP1-related dis wherein any changes in the amino acid sequence are ease, MASP2-related disease, Antithrombin III-related conservative amino acid substitutions to the amino acid disease, Complement factor H-related disease and/or Albu sequences in (a) to (f), and retaining INSP052 biological min-related disease. It is a second object of the invention to activity, or use a cell expressing INSP052, or an expression vector com 0.015 i) A salt or an isoform, fusion protein, functional prising the coding sequence of INSP052, for the preparation derivative, active fraction or circularly permutated of a medicament for the treatment and/or prevention of infec derivative of any of the polypeptides of (a) to (h). tious disease, properdin-related disease, MBL2-related dis 0016. In a second aspect, the invention relates to the use of ease, MASP1-related disease, MASP2-related disease, Anti an INSP052 nucleic acid molecule for the preparation of a thrombin III-related disease, Complement factor H-related medicament for the treatment and/or prevention of infectious disease and/or Albumin-related disease. The present inven disease, properdin-related disease, MBL2-related disease, tion is also directed towards the use of INSP052 for the MASP1-related disease, MASP2-related disease, Antithrom preparation of a pharmaceutical composition for the treat bin III-related disease, Complement factor H-related disease ment and/or prevention of infectious disease, properdin-re and/or Albumin-related disease, wherein said nucleic acid is lated disease, MBL2-related disease, MASP1-related dis selected from the group consisting of: ease, MASP2-related disease, Antithrombin III-related 0017 a) A nucleic acid sequence as set forth in any of disease, Complement factor H-related disease and/or Albu SEQ ID NO: 1, SEQID NO:3, SEQID NO:5, SEQID min-related disease. NO:7, SEQID NO:9, SEQID NO:11, SEQID NO:13, SEQID NO:15, SEQID NO: 17, SEQID NO: 19, SEQ DESCRIPTION OF THE INVENTION ID NO: 21, SEQID NO: 23, or SEQ ID NO: 25, or 0005. The invention is based on the unexpected finding 0.018 b) A nucleic acid sequence which hybridizes to that INSP052 interacts with proteins of the complement path the complement of the nucleic acid sequence of (a) way, namely properdin, mannose-binding lectin C (MBL-C), under moderately stringent conditions or under highly MASP1, MASP2, antithrombin III, complement factor Hand stringent conditions, or albumin. These Surprising properties presently characterized 0.019 c) A nucleic acid sequence of any of (a) or (b) of the polynucleotides or the corresponding polypeptides of wherein said nucleic acid sequence encodes an amino WO2003/093316 and International Application No. PCT/ acid sequence having conservative amino acid Substitu GB2004/004772 make them particularly suitable for the tions to the amino acid sequences in any of SEQID NO: preparation of a medicament or of a pharmaceutical compo 2, SEQID NO: 4, SEQID NO: 6, SEQID NO: 8, SEQ sition. ID NO: 10, SEQ ID NO: 12, SEQID NO: 14, SEQ ID 0006. In a first aspect, the invention therefore relates to the NO:16, SEQID NO: 18, SEQID NO:20, SEQID NO: use of an INSP052 polypeptide for the preparation of a medi 22, SEQID NO: 24, SEQID NO:26, SEQID NO: 27, cament for the treatment and/or prevention of infectious dis SEQID NO:28, SEQID NO:29, SEQID NO:30, SEQ ease, properdin-related disease, MBL2-related disease, ID NO:31, SEQID NO:32 or SEQ ID NO:33. US 2008/O 1934.14 A1 Aug. 14, 2008

0020. In a third aspect, the invention relates to the use of an 22, SEQID NO: 24, SEQID NO:26, SEQID NO: 27, INSP052 polypeptide for the preparation of a pharmaceutical SEQID NO:28, SEQID NO:29, SEQID NO:30, SEQ composition for the treatment and/or prevention of infectious ID NO:31, SEQID NO:32 or SEQ ID NO:33. disease, properdin-related disease, MBL2-related disease, 0034 Preferably, a soluble INSP052 is used for the prepa MASP1-related disease, MASP2-related disease, Antithrom ration of a medicament or of a pharmaceutical composition. bin III-related disease, Complement factor H-related disease and/or Albumin-related disease, wherein said polypeptide is 0035. The term “soluble INSP052” or “sINSP052 herein selected from the group consisting of: refers to an INSP052 polypeptide which is not membrane 0021 a) A polypeptide consisting of SEQID NO: 16, or bound or to an INSP052 polypeptide which doesn't contain 0022 b) A polypeptide comprising any of SEQID NO: one or more transmembrane domains. 2, SEQID NO: 4, SEQID NO: 6, SEQID NO: 8, SEQ 0036. It will be appreciated by the person skilled in the art ID NO: 10, SEQ ID NO: 12, SEQID NO: 14, SEQ ID that in accordance with the present invention, a Substance NO:16, SEQID NO: 18, SEQID NO:20, SEQID NO: which stimulates release or potentiates the activity of endog 22, SEQID NO: 24, SEQID NO: 26, SEQID NO:27, enous INSP052 can equally be used for treatment and/or SEQID NO: 28, SEQID NO:29, SEQID NO:30, SEQ prevention of infectious disease, properdin-related disease, ID NO:31, SEQID NO:32 or SEQ ID NO:33, or MBL2-related disease, MASP1-related disease, MASP2-re 0023 c) A soluble form consisting of any of SEQ ID lated disease, Antithrombin III-related disease, Complement NO:20, SEQID NO:22, SEQID NO:27, SEQID NO: factor H-related disease and/or Albumin-related disease. 28, SEQID NO: 29, SEQID NO:30, SEQID NO:31, 0037. The invention is based on the unexpected finding SEQID NO:32 or SEQID NO:33, or that a soluble INSP052 consisting of the extracellular part of 0024 d) A mature form consisting of any of SEQ ID the membrane-bound INSP052 (SEQ ID NO: 22) interacts NO: 22, SEQID NO: 24 or SEQID NO: 26, or with proteins of the complement pathway, namely properdin, 0025 e) A histidine tag form consisting of SEQID NO: mannose-binding lectin C (MBL-C), MASP1, MASP2, anti 29, or thrombin III, complement factor H and albumin. 0026 f) A glycosylated form of any of the polypeptides 0038. The term “complement-pathway protein herein of (a) to (e), wherein the polypeptide is glycosylated at refers to as protein selected from properdin, mannose-bind one or more sites, or ing lectin C (MBL-C), MASP1, MASP2, antithrombin III, 0027 g) A mutein of any of the polypeptides of(a) to (f), complement factor Hand albumin. These complement-path wherein the amino acid sequence has at least 40% or way proteins are associated with infectious disease, proper 50% or 60% or 70% or 80% or 90% identity to at least din-related disease, MBL2-related disease, MASP1-related one of the corresponding sequences in (a) to (f), and disease, MASP2-related disease, Antithrombin III-related retaining INSP052 biological activity, or disease, Complement factor H-related disease and/or Albu 0028 h) A mutein of any of the polypeptides of (a) to (f) min-related disease. wherein any changes in the amino acid sequence are 0039. Preferably, the infectious disease is selected from conservative amino acid Substitutions to the amino acid Systemic Fungal Disease, Rickettsial Disease, Chlamydial sequences in (a) to (f), and retaining INSP052 biological Disease, Parasitic Infection, Viral Disease, Abscess, Human activity, or Immunodeficiency Virus Infection, Bacteremia, Septic 0029 i) A salt or an isoform, fusion protein, functional Shock, Sexually Transmitted Disease or Bacterial Disease. derivative, active fraction or circularly permutated 0040 Preferably, the bacterial disease is selected from a derivative of any of the polypeptides of (a) to (h). disease caused by Gram-Positive Cocci, caused by Gram 0030. In a fourth aspect, the invention relates to an Negative Aerobic Cocci, caused by Gram-Positive Bacilli, INSP052 nucleic acid for the preparation of a pharmaceutical caused by Gram-Negative Bacilli, caused by Anaerobic composition for the treatment and/or prevention of infectious Bacilli, caused by Spirochetes or caused by Mycobacteria. disease, properdin-related disease, MBL2-related disease, 0041. In one embodiment, a “Gram-Negative Aerobic MASP1-related disease, MASP2-related disease, Antithrom Cocci” refers herein to an organism of the genus Neisseria bin III-related disease, Complement factor H-related disease including N. meningitidis, N. gomorrhoeae, and numerous and/or Albumin-related disease, wherein said nucleic acid is saprophytic Neisseria sp that commonly inhabit the orophar selected from the group consisting of: ynx, Vagina, or colon. 0031 a) A nucleic acid sequence as set forth in any of 0042 Preferably, the disease caused by Gram-Negative SEQID NO: 1, SEQID NO:3, SEQID NO:5, SEQID Aerobic Cocci is selected from meningitis, bacteremia, ure NO:7, SEQID NO:9, SEQID NO:11, SEQID NO:13, thritis, cerviciitis, proctitis, pharyngitis, salpingitis, epid SEQID NO: 15, SEQID NO: 17, SEQID NO: 19, SEQ idymitis, gonorrheal infection, acute cacterial meningitis or ID NO: 21, SEQID NO: 23, or SEQID NO: 25, or 0032 b) A nucleic acid sequence which hybridizes to Meningococcal infection. the complement of the nucleic acid sequence of (a) 0043 “Bacteremia' herein refers to bacteria in the blood under moderately stringent conditions or under highly Stream. stringent conditions, or 0044) “Septic shock’ herein refers to sepsis with hypop 0033 c) A nucleic acid sequence of any of (a) or (b) erfusion and hypotension refractory to fluid therapy. “Sepsis” wherein said nucleic acid sequence encodes an amino or “systemic inflammatory response syndrome' herein refers acid sequence having conservative amino acid Substitu to a serious infection, localized or bacteremic, that is accom tions to the amino acid sequences in any of SEQID NO: panied by Systemic manifestations of inflammation. Sepsis 2, SEQID NO: 4, SEQID NO: 6, SEQID NO: 8, SEQ due to bacteremia herein refers to septicemia. ID NO: 10, SEQ ID NO: 12, SEQID NO: 14, SEQ ID 0045 Preferably, the Parasitic Infections is selected from NO:16, SEQID NO: 18, SEQID NO:20, SEQID NO: Extraintestinal Protozoa infection, infection with Free-Liv US 2008/O 1934.14 A1 Aug. 14, 2008

ing Amebas, Intestinal Protozoa infection, Nematode Swiss type, glomerular disease, ametropia, wiskott-aldrich (Roundworm) Infection, Trematode (Fluke) infection or Ces syndrome, IgA glomerulonephritis, protein c deficiency, todes (Tapeworms) infection. nephritis, chronic granulomatous disease, bacterial infection, 0046 Preferably, the Extraintestinal Protozoa infection is proteinuria, septic shock, hemolysis, Systemic infection, sep malaria. ticemia, immunologic deficiency syndrome, systemic lupus 0047 Preferably, the Viral disease is selected from Respi erythematosus, malaria, thrombosis, diabetes mellitus, ratory Viral Disease, Herpesvirus Infection, Central Nervous necrosis, acquired immunodeficiency syndrome. System Viral Disease, Arbovirus or Arenavirus Disease. 0.058 Preferably, the glomerular disease is selected from 0048. In addition, each complement-pathway protein has nephritic syndrome, nephrotic syndrome, primary glomeru been shown to be associated with specific diseases, as lar disease, or secondary renal disease. described below. 0059 Preferably, the primary glomerular disease is 0049. As such, in one embodiment, the invention related to selected from minimal change disease, focal segmental glom the use of INSP052 for the preparation of a medicament or of erulosclerosis, membranous glomerulonelhritis, membrano a pharmaceutical composition for the treatment of a proper proliferative glomerulonephritis, mesangial proliferative din-related disease. glomerulonephritis, IgA nephropathy, rapidly progressive 0050. In one embodiment, the invention relates to the use glomerulonephritis, or fibrillary glomerulonephritis. of INSP052 for the preparation of a medicament or of a 0060 Preferably, the nephritic syndrome is selected from pharmaceutical composition for the treatment of a MBL2 hematuria, hypertension, renal insufficiency, edema, acute related disease. glomerulonephritis, transient glomerulonephritis, postinfec 0051. In one embodiment, the invention relates to the use tious glomerulonephritis, fulminant glomerulonephritis, rap of INSP052 for the preparation of a medicament or of a idly progressive glomerulonephritis (RPGN), indolent Glom pharmaceutical composition for the treatment of a MASP1 erulonephritis, IgA nephropathy, Crescentic related disease. glomerulonephritis, Pauci-immune RPGN, Immune complex 0.052. In one embodiment, the invention relates to the use RPGN, Anti-GBM antibody disease autoimmunity, primary of INSP052 for the preparation of a medicament or of a renal hematuric-proteinuric syndrome, asymptomatic hema pharmaceutical composition for the treatment of a MASP2 turic-proteinuric syndrome, chronic nephritic-proteinuric related disease. syndrome, chronic glomerulonephritis, slowly progressive 0053. In one embodiment, the invention relates to the use glomerular disease. of INSP052 for the preparation of a medicament or of a 0061. Mannose-binding lectin 2 gene (MBL2: 248 amino pharmaceutical composition for the treatment of an Anti acids; 26143 Da; Subunit: oligomeric complex of 6 set of thrombin III-related disease. homotrimers) encodes a mannose-binding lectin (MBL), or 0054. In one embodiment, the invention relates to the use protein (MBP), that is secreted by the liver as part of the of INSP052 for the preparation of a medicament or of a acute-phase response and is involved in innate immune pharmaceutical composition for the treatment of a Comple defense. The ligands for MBL are expressed by a wide variety ment factor H-related disease. of microorganisms, and binding of the protein leads to 0055. In one embodiment, the invention relates to the use opSonization resulting in Susceptibility to frequent and of INSP052 for the preparation of a medicament or of a chronic infections as well as activation of the complement pharmaceutical composition for the treatment of an Albumin system. MBL2 has been linked to many diseases as set forth related disease. by the term “MBL2-related disease'. 0056 Properdin (factor P; 469 amino acids; 51276 Da) is 0062 A“MBL2-related disease' is selected from vascular a plasma protein that is active in the alternative complement disease, atherosclerotic disease, mannose-binding protein pathway of the innate immune system. It is a positive regula deficiency, chronic infection due to opsonin defect, menin tory factor that binds to many microbial surfaces to stabilize gococcal infection, systemic lupus erythematosus, comple the C3b. Bb convertase. The C3b. Bb convertase then rapidly ment deficiency, acute-phase reaction, meningococcal men cleaves more C3 to C3b, which acts either as an opsonin or to ingitis, IgA glomerulonephritis, IgG subclass deficiency, reinitiate the pathway in an amplification loop that proceeds cystic fibrosis, cutaneous Subacute lupus erythematosus, on the bacterial cell, but not on the host cell. In the alternative rheumatoid arthritis, immunologic deficiency syndrome, res pathway, C3 is thus activated through factor B, factor D, and piratory tract infection, Swollen joint, influenza, primary properdin P. under the control of factors I and H. Deficiency Sjogrens syndrome, hemolysis, cystic fibrosis, bacterial of properdin is associated in particular with a heightened infection, mucocutaneous lymph node syndrome, common susceptibility to Neisseria species. Defects in properdin are variable immunodeficiency, lupus nephritis, polyarthritis, the cause of properdin deficiency (pfd), resulting in higher inflammation, septic shock, tuberculosis, virus infection, Susceptibility to bacterial infections; especially to meningo pneumococcal infection, hiv infection, otitis media, nephritis, coccal infections. Three phenotypes have been reported: systemic infection, malaria, membranous glomerulonephri complete deficiency (type I), incomplete deficiency (type II). tis, sepsis syndrome, adenocarcinoma of the colon, hepatitis and dysfunction of properdin (type III). Properdin has been c, spontaneous abortion, sjogrens syndrome, acute otitis linked to many diseases as set forth by the term “properdin media, glomerulonephritis, herpes simplex, dermatomyosi related disease'. tis, necrosis, aspergillosis, atherosclerosis, epstein-barr virus 0057. A “properdin-related disease' is selected from infection, pneumonia, primary biliary cirrhosis, hepatitis b, complement deficiency, complete deficiency (type I), incom liver disease, osteomyelitis, cardiovascular disease, hepatitis, plete deficiency (type II), dysfunction of properdin (type III), neutropenia, sarcoidosis, acquired immunodeficiency syn meningococcal infection, Neisseria infection, hypocomple drome, cirrhosis, meningitis, colitis ulcerative, glioma, kid mentemia, afibrinogenemia, acute poststreptococcal glom ney disease, coronary arteriosclerosis, chronic kidney failure, erulonephritis, agammaglobulinemia, agammaglobulinemia colorectal cancer, shock, Kawasaki disease, Acute respiratory US 2008/O 1934.14 A1 Aug. 14, 2008

tract infection, Vulvar vestibulitis syndrome, Behcet’s dis presence of heparin. Defects in antithrombin III are the cause ease, Crohn's disease, Restenosis, human t-cell leukemia of antithrombin iii deficiency (at-iii deficiency). AT-III defi virus type i (hTLV-i) provirus infection, dermatomyositis, ciency is a form of thrombophilia, an autosomal dominant HBV infection, IgA nephropathy, COPD infections, gesta disorder in which affected individuals are prone to develop tional Diabetes Mellitus, giant cell arteritis, dental caries, serious spontaneous thrombosis. AT-III deficiency is classi Chlamydia trachomatis infection, chorioamnionitis, Primary fied into 4 types. Type I is characterized by a 50% decrease in Biliary Cirrhosis, Chlamydia pneumoniae infection, celiac antigenic and functional levels. Type II has defects affecting disease, post-Q fever fatigue syndrome, or chronic Q fever. the thrombin-binding domain. Type III is an alteration of the 0063 Preferably, the cardiovascular disorder is selected heparin-binding domain. Plasmaat-iii antigen levels are nor from Cardiac and Respiratory Arrest, Valvular Heart Disease, Arterial Hypertension, Endocarditis, Orthostatic Hypoten mal in type II and III. Type IV consists of miscellaneous Sion, Syncope, Pericardial Disease, Arteriosclerosis, Cardiac group of unclassifiable mutations. AT-III Basel, Tours/Alger/ Tumor, Coronary Artery Disease, Disease of the Aorta and Its Amiens/Toyama, Rouen-1, -2, -3 and -4, have decreased (or Branches, Heart Failure, Peripheral Vascular Disorder, lack) heparin-binding properties. At-lii Hamilton, Glasgow/ Shock, Athletic Heart Syndrome or Arrhythmia. Sheffield/Chicago, Northwick-Park/Milano-1, Pescara, Den 0064. The Ra-reactive factor (RARF) is a complement ver/Milano-2, and Utah are deprived of inhibitory activity. dependent bactericidal factor that binds to the Ra and R2 (0071 Antithrombin III has been linked to diseases as set polysaccharides expressed by certain enterobacteria. RARF forth by the term 'Antithrombin III-related disease'. activity is found in the sera of a diverse group of vertebrates, 0072 An Antithrombin III-related disease' is selected Suggesting that it is an evolutionarily conserved mechanism from a hematology-related disorder, antithrombin III defi to resist infection by these bacterial strains. RARF includes a ciency, thrombophilia, proteins deficiency, activated protein 100-kD component, CRARF, also called MASP1 or p 100, c resistance, disseminated intravascular coagulation, throm that was thought to activate the complement components C4 bosis, protein c deficiency, venous thrombosis, familial anti (C4F: C4S), C2, and C3. Subsequent work, however, sepa thrombin III deficiency, blood coagulation disorder, throm rated MASP1 from MASP2 and showed that MASP1 acti boembolism, congenital dysfibrinogenemia, deep vein vates C3 and C2, whereas MASP2 activates C4 and C2. The other component of RARF is mannan-binding lectin, a thrombosis of lower limb, arterial thrombosis, hemorrhage, plasma protein member of the complement system that binds hypercortisonism, mesenteric vein thrombosis, pre-eclamp to microbial carbohydrates and activates the MASPs. The sia, cerebral thrombosis, purpura fulminans, pulmonary MASPs then recruit C4 and C2 to generate the C3 convertase embolism, nephrotic syndrome, systemic infection, fibrin or directly activate C3. olytic defect, antiphospholipid syndrome, cerebral venous 0065. Alternate splicing of MASP1 results in two tran thrombosis, factor XII deficiency, help syndrome, portal Script variants encoding two RARF components that are vein thrombosis, pulmonary thromboembolism, multiple involved in the mannan-binding lectin (MBL) pathway of organ failure, Superior Sagittal sinus thrombosis, Venous complement activation. Each isoform is cleaved into two occlusion, postoperative hemorrhage, homocystinuria, septic chains which form a heterodimer linked by a disulfide bond. shock, abruptio placentae hyperhomocysteinemia, thromb The encoded proteins are members of the trypsin family of ocytopenia, spontaneous platelet aggregation disease, renal peptidases. MASP1 (699 amino acids: 79258 Da) is therefore vein thrombosis, Veno-occlusive disease, cerebral infarction, a component of the bactericidal Ra-reactive factor RARF pregnancy toxemia, postphlebitic syndrome, thrombocytosis, which specifically binds to Ra and R2 polysaccharides livedo reticularis, atherosclerosis, platelet dysfunction, expressed by certain enterobacteria. MASP1 has been linked hepatic veno-occlusive disease, stasis, retinal vein occlusion, to a few diseases as set forth by the term “MASP1-related promyelocytic acute leukemia, shwartzman phenomenon, disease'. skin necrosis, liver cirrhosis, increased bleeding time disor 0066. A “MASP1-related disease” is selected from glom der, Sneddon syndrome, polycythemia Vera, purpura, eclamp erulonephritis, IgA glomerulonephritis, Systemic lupus sia, hemophilia a, sepsis syndrome, legg-perthes disease, erythematosus or immunologic deficiency syndrome. myocardial infarction, cerebrovascular accident, meningo 0067. MASP2 (686 amino acids; 75685 Da; Isoform 2 coccemia, inherited blood coagulation disorder, angina pec binds to MASP-1; belongs to the peptidase S1 family) is a toris, mediastinal fibrosis, thrombophlebitis, cardiovascular trypsin protease that presumably plays an important role in disease, fetal growth retardation, pulmonary vein trombosis, the initiation of the mannose-binding lectin (MBL) comple hyperlipoproteinemia, Vascular disease, liver dysfunction, ment activation pathway. After activation it cleaves C4 gen hepatic vein thrombosis, acute myocardial infarction, hemor erating C4A and C4B. MASP2 has been linked to diseases as rhagic fever with renal syndrome, infarction, central retinal set forth by the term “MASP2-related disease”. vein occlusion, liver disease, hematoma Subcutaneous, Beh 0068 A“MASP2-related disease' is selected from immu cets syndrome, acute lymphocytic leukemia, hypoprothrom nologic deficiency syndrome or MASP2 deficiency. binemia, mesenteric infarction, proteinuria, cerebral embo 0069 Preferably, an “immunologic deficiency sydrome' lism, myeloproliferative disorder, habitual abortion, is selected from acquired immunodeficiency syndrome or disseminated intravascular coagulation sepsis, thromboem immunodeficiency linked to the Mannose-binding protein bolism, Marburg virus infection, Ebola virus infection or (MBP) locus. Thrombosis Burns. 0070 Antithrombin III (464 amino acids; 52602 Da; 0073 Preferably, the hematology-related disorder is belongs to the serpin family) is the most important serine selected from Anemia, Histiocytic Syndrome, Iron Overload protease inhibitor in plasma that regulates the blood coagul related disorder, Leukemia, Lymphoma, Myeloproliferative lation cascade. AT-III inhibits thrombinas well as factors IXa, Disorder, Plasma Cell Dyscrasia, Hemostasis and Coagula Xa and XIa. Its inhibitory activity is greatly enhanced in the tion Disorder, Disorder of the Spleen, Thrombotic Disorder, US 2008/O 1934.14 A1 Aug. 14, 2008

Platelet Disorder, Vascular Bleeding Disorder, Leukopenia, cleaved in the Golgivesicles to produce the secreted albumin. Lymphocytopenia or AIDS-Associated Hematologic Disor Defects in ALB are a cause of familial dysalbuminemic der and Malignancy. hyperthyroxinemia (fdh). FDH is a form of euthyroid hyper 0074 There is an interest to develop drugs related to Anti thyroxinemia that is due to increased affinity of ALB for T(4). thrombin III. For example, Advantek Biologics has tried to It is the most common cause of inherited euthyroid hyperthy develop a drug with an antithrombin III peptide for genetic roxinemia in caucasian population. Defects in ALB might be disorder. Aventis Behring has discontinued to work on an a cause of hyperZincemia. A variant structure of albumin antithrombin III peptide for disseminated intravascular could, in fact, lead to increased binding of Zinc resulting in an coagulation sepsis. Bayer has launched an antithrombin III asymptomatic augmentation of Zinc concentration in the drug for thromboembolism. GTC Biotherapeutics has pre blood. Albumin has been linked to diseases as set forth by the registered a transgenic antithrombin III for Marburg virus term "Albumin-related disease'. infection, Ebola virus infection and Thrombosis Burns. 0078. There is an interest to develop drugs related to Albu Myriad Genetics has tried to develop MPC-1203 (Coagula min. For example, Mitsubishi Pharma has pre-registered a tion inhibitor Antithrombin III) for thrombosis. recombinant serum albumin for Hematological disease, 0075 Complement factor H (1231 amino acids; 139125 Renal disease and Wound healing Hemophilia. Pharming Da) is a member of the Regulator of Complement Activation Group NV tried to develop human serum albumin for Anemia (RCA) gene cluster and encodes a protein with twenty short Bleeding. concensus repeat (SCR) domains. Alternate transcriptional 0079 An Albumin-related disease' is selected from splice variants, encoding different isoforms, have been char Microalbuminuria, albuminuria, diabetic nephropathy, acterized. This protein is secreted into the bloodstream and hypoalbuminemia, kidney disease, proteinuria, insulin-de has an essential role in the regulation of complement activa pendent diabetes mellitus, malnutrition, non-insulin-depen tion, restricting this innate defense mechanism to microbial dent diabetes mellitus, retinal disease, nephrotic syndrome, infections. Factor H functions as a cofactor in the inactivation ascites, chronic kidney failure, hypoproteinemia, kidney fail of C3b by factor I and also increases the rate of dissociation of ure, cirrhosis, diabetes mellitus, protein-energy malnutrition, the C3bBb complex (C3 convertase) and the (C3b)NBB com liver cirrhosis, hepatorenal syndrome, essential hypertension, plex (C5 convertase) in the alternative complement pathway. kwashiorkor, cardiovascular disease, bisalbuminemia, bron Mutations in this gene have been associated with hemolytic choalveolar lavage fluid, ovarian hyperstimulation syndrome, uremic syndrome (HUS) and chronic hypocomplementemic hyperthyroxinemia, liver disease, diabetic retinopathy, nephropathy. HUS is a microvasculature disorder leading to inflammation, protein-losing enteropathy, hypovolemia, bac microangiopathic hemolytic anemia associated with dis terial peritonitis, liver failure, diabetic microangiopathy, torted erythrocytes (burr cells), thrombocytopenia, and hepatopulmonary syndrome, chronic liver disease, primary acute renal failure. Both dominant and recessive modes of carcinoma of the liver cells, uremia, edema, focal segmental inheritance have been reported. Most cases of HUS are asso glomerulosclerosis 1, kernicterus, severe malnutrition, lipoid ciated with epidemics of diarrhea caused by verocytotoxin nephrosis, hepatic encephalopathy, marasmus, anemia, liver producing bacteria, but atypical cases of HUS not associated dysfunction, peripheral vascular disease, hypervolemia, auto with diarrhea (aHUS) also occur. Complement Factor H is nomic neuropathy, hypertensive renal disease, acute liver fail associated with Membroproliferative glomerulonephritis and ure, glomerulosclerosis, hyperglycemia, atherosclerosis, Factor H deficiency. Complement factor H has been linked to alcoholic liver cirrhosis, cyclic edema, primary biliary cirrho diseases as set forth by the term “Complement factor H-re sis, glomerulonephritis, liver fibrosis, abnormal kidney func lated disease'. tion, insulin resistance, peritonitis, nephrosis, hypocalcemia, 0076. A “Complement factor H-related disease” is systemic infection, hyperbilirubinemia, chronic glomerulo selected from uremic syndrome, thrombotic thrombocy nephritis, dyslipidemia, metabolic acidosis, hyperhomocys topenic purpura, hemolytic-uremic syndrome, hemolytic teinemia, left ventricular hypertrophy, arterial hypertension, microangiopathic anemia, membranoproliferative glomeru diabetic glomerulosclerosis, chronic hepatitis, encephalopa lonephritis, hypocomplementemia, primary hyperoxaluria, thy, portal hypertension, hemolysis, allergic rhinitis, systolic acute kidney failure, thrombocytopenia, cancer of bladder, hypertension, pulmonary edema, hyponatremia, hypoten hemolytic anemia, antiphospholipid syndrome, hemolysis, Sion, glycosuria, coronary disease, hypertensive retinopathy, systemic lupus erythematosus, inflammation, malignant neo hypocholesteremia, proximal renal tubular dysfunction, plasm, liver disease, thrombosis, malignant neoplasm of hypomagnesemia, alcoholic liver disease, secondary hyper lung, chronic hypocomplementemic nephropathy, Factor H parathyroidism, idiopathic membranous nephropathy, ict deficiency or Age-Related Macular Degeneration. erus, analbuminemia, familial dysalbuminemic hyperthyroX 0077 Albumin (ALB: 609 amino acids; 69366 Da) is a inemia, hyperZincemia, hematological disease, renal disease, soluble, monomeric protein which comprises about one-half wound healing Hemophilia, or bleeding anemia. of the blood serum protein. Albumin functions primarily as a 0080. The term “treatment as used herein encompasses carrier protein for steroids, fatty acids, and thyroid hormones any attenuation, reduction, or partial, Substantial or complete and plays a role in stabilizing extracellular fluid Volume prevention or blockage of disease formation, development, (regulation of the colloidal osmotic pressure of blood). Serum progression or of the formation, development or progression albumin has a good binding capacity for water, Ca(2+), of any one or several or all of the symptoms of the disease. Na(+), K(+), fatty acids, hormones, bilirubin and drugs. 0081. The term “INSP052 herein refers to an INSP052 Mutations in this gene on chromosome 4 result in various polypeptide or to an INSP052 nucleic acid molecule. anomalous proteins. Albumin is synthesized in the liver as I0082) An “INSP052 polypeptide' may refer to: preproalbumin which has an N-terminal peptide that is The polypeptide having the sequence recited in SEQID NO:2 removed before the nascent protein is released from the rough is referred to hereafter as “the INSP052 exon 1 polypeptide'. endoplasmic reticulum. The product, proalbumin, is in turn The polypeptide having the sequence recited in SEQID NO:4 US 2008/O 1934.14 A1 Aug. 14, 2008

is referred to hereafter as “the INSP052 exon 2 polypeptide'. consists of amino acids 34-240 of INSPO52. This latter The polypeptide having the sequence recited in SEQID NO:6 sequence is similar to two sequences disclosed in the litera is referred to hereafter as “the INSP052 exon 3 polypeptide'. ture as SEQIDNO434 and SEQIDNO880 (WO 04/009834; The polypeptide having the sequence recited in SEQID NO:8 SEQID NO: 27 and 28). The intracellular domain of mem is referred to hereafter as “the INSP052 exon 4 polypeptide'. brane-bound INSP052 corresponds to amino acids 264 to The polypeptide having the sequence recited in SEQ ID 416. NO:10 is referred to hereafter as “the INSPO52 exon 5 I0086. It is considered highly likely that the extracellular polypeptide'. The polypeptide having the sequence recited in domain and or “soluble form” of INSP052 will fold correctly SEQID NO:12 is referred to hereafter as “the INSP052 exon and show biological activity if additional residues C terminal 6 polypeptide'. The polypeptide having the sequence recited and/or N terminal of these boundaries in the polypeptide in SEQ ID NO:14 is referred to hereafter as “the INSP052 sequence are included in the polypeptide fragment. In one exon 7 polypeptide'. Combining SEQ ID NO:2, SEQ ID embodiment, the INSP052 polypeptide includes additional NO:4, SEQID NO:6, SEQIDNO:8, SEQID NO:10, SEQID residues C terminal and/or N terminal. For example, an addi NO:12 and SEQID NO:14 produces the sequence recited in tional 5, 10, 20, 30, 40, 50 or even 100 amino acid residues SEQID NO:16. The polypeptide having the sequence recited from the INSP052 polypeptide sequence, or from a homolo in SEQ ID NO:16 is referred to hereafter as the INSP052 gous sequence, may be included at either or both the C ter polypeptide. The polypeptide having the sequence recited in minal and/or N terminal of the boundaries of the receptor SEQ ID NO:20 is the extracellular domain of INSP052. The binding domain, without prejudicing the ability of the polypeptide having the sequence recited in SEQID NO:22 is polypeptide fragment to fold correctly and exhibit biological referred to hereafter as the extracellular domain of the mature activity. Extensions as large as 100 or 200 residues may be INSP052 polypeptide. The polypeptide having the sequence necessary due to the presence of large loops between second recited in SEQID NO:24 is referred to hereafter as the mature ary structural elements. INSP052 exon 2 polypeptide. The polypeptide having the 0087. In one embodiment, for truncated variants of the sequence recited in SEQID NO:26 is referred to hereafter as INSP052 extracellular domain, one or a few amino acid resi the mature INSP052 polypeptide. The polypeptide having the dues (for example, 2, 3, 4, 5, 10, 15, 20, 25, 30 or more) may sequence recited in SEQID NO:29 is referred to hereafter as be deleted at either or both the C terminus or the N terminus the histidine-tagged, extracellular domain of mature of the domain without prejudicing biological activity. INSP052. The polypeptide having the sequence recited in I0088 A preferred truncated variant of the INSP052 extra SEQID NO:30 is referred to hereafter as the Fc fusion of the cellular domain may be the Ig domain containing fragment of extracellular domain of mature INSP052. The polypeptide INSP052 (INSP052Ig2) having the sequence shown in SEQ having the sequence recited in SEQID NO:31 is referred to ID NO:31. hereafter as the Ig domain containing fragment of INSP052 I0089. A preferred truncated variant of the INSP052 extra (INSP052Ig2). The polypeptide having the sequence recited cellular domain may be the extracellular INSP052 lacking the in SEQID NO:32 is referred to hereafter as the extracellular first Ig domain (INSP052-EC-DELIG1) having the sequence INSP052 lacking the first Ig domain (INSP052-EC-DEL shown in SEQID NO:32. IG1). The polypeptide having the sequence recited in SEQID (0090. A preferred truncated variant of the INSP052 extra NO:33 is referred to hereafter as the extracellular INSP052 cellular domain may be the extracellular INSP052 lacking the lacking the second Ig domain (INSP052-EC-DEL IG2). A second Ig domain (INSP052-EC-DEL IG2) having the “soluble INSP052” or “soluble form”herein refers to SEQID sequence shown in SEQID NO:33. NO: 20, SEQID NO: 22, SEQID NO: 27, SEQID NO; 28, 0091. As discussed below, in one embodiment, the SEQID NO: 29, SEQ ID NO:30, SEQID NO:31, SEQ ID polypeptides of the invention may be provided in the form of NO:32 and/or SEQID NO:33. a fusion protein or as “free-standing protein. Accordingly, I0083. In one embodiment, the INSP052 polypeptide one embodiment of the invention provides a polypeptide according to this embodiment consists of the amino acid which consists of the extracellular domain of INSP052. sequence recited in SEQ ID NO:16 (the INSP052 polypep Another embodiment of the invention provides a polypeptide tide) or is a fragment of or functional equivalent thereof. In which consists of INSP052 (the full length protein or the another embodiment, the INSP052 polypeptide consists of extracellular domain thereof, including the mature version the amino acid sequence recited in any one of SEQID NO:2. and truncated variants thereof) fused with at least one other SEQID NO:4, SEQIDNO: 6, SEQID NO:8, SEQID NO:10, polypeptide to form a fusion protein. SEQ ID NO:12, or SEQID NO:14, or is a variant thereof. 0092. The “INSP052 nucleic acid molecule' may refer to I0084. The amino acid sequence recited in SEQID NO:20 a nucleic acid which comprises or consists of the nucleic acid represents the extracellular domain of INSP052 and corre sequence as recited in SEQID NO:1 (encoding the INSP052 sponds to amino acids 1-240 of the full length protein. SEQ exon 1 polypeptide), SEQID NO:3 (encoding the INSP052 ID NO:22 represents the extracellular domain of mature exon 2 polypeptide), SEQID NO:5 (encoding the INSP052 INSPO52. exon 3 polypeptide), SEQID NO:7 (encoding the INSP052 0085. As indicated in WO 03/93316, the INSP052 full exon 4 polypeptide), SEQID NO:9 (encoding the INSP052 length prediction encodes a type I membrane protein of 416 exon 5 polypeptide), SEQID NO:11 (encoding the INSP052 amino acids, related to the VEGF/PDGF receptors, belonging exon 6 polypeptide), SEQID NO:13 (encoding the INSP052 to the immunoglobulin Superfamily. The putative signal exon 7 polypeptide), SEQID NO:15 (encoding the INSP052 sequence consists of amino acids 1-33 of INSP052. The Ig polypeptide), SEQ ID NO:17 (encoding the mouse virtual like domain consists of amino acids 48 to 124. The Ig domain INSP055 polypeptide), SEQID NO:19 (encoding the extra consists of amino acids 161 to 216. The predicted transmem cellular domain of the INSP052 polypeptide), SEQID NO:21 brane (TM) domain consists of amino acids 241-263 of (encoding the extracellular domain of the INSP052 mature INSPO52. Thus the mature extracellular domain of INSP052 polypeptide), SEQID NO:23 (encoding the mature INSP052 US 2008/O 1934.14 A1 Aug. 14, 2008

exon 2 polypeptide), SEQ ID NO:25 (encoding the mature 6, SEQID NO:8, SEQID NO: 10, SEQID NO: 12, SEQ ID INSP052 polypeptide) or is a redundant equivalent or frag NO: 14, SEQID NO: 16, SEQID NO: 18, SEQID NO: 20, ment of any one of these sequences. SEQID NO: 22, SEQID NO: 24, SEQID NO: 26, SEQ ID 0093 Combining the sequences recited in SEQID NO:1, NO: 27, SEQID NO: 28, SEQID NO: 29, SEQID NO:30, SEQID NO:3, SEQID NO:5, SEQID NO:7, SEQID NO:9, SEQ ID NO: 31, SEQID NO:32, or SEQID NO:36 (all SEQ ID NO:11 and SEQ ID NO:13 produces the sequence human except for SEQID NO: 18) showing the desired activ recited in SEQID NO:15. ity in infectious disease, properdin-related disease, MBL2 0094 Combining the sequences recited in SEQID NO:23, related disease, MASP1-related disease, MASP2-related dis SEQID NO:5, SEQID NO:7, SEQID NO:9, SEQID NO:11 ease, Antithrombin III-related disease, Complement factor and SEQID NO:13 produces the sequence recited in SEQID H-related disease and/or Albumin-related disease. In one NO:25. embodiment, protein fragments, isoforms, differentially gly 0.095. In one embodiment of the invention, the nucleic acid cosylated or sialylated forms or one or more domains of the molecule encodes a polypeptide which comprises or consists protein may be used according to the invention, as long as of the extracellular domain of INSP052 (SEQ ID NO:20). Preferably, the nucleic acid molecule comprises or consists of they exhibit any beneficial effect on infectious disease, the nucleic acid sequence set forth in SEQID NO:19. This is properdin-related disease, MBL2-related disease, MASP1 also set out in FIG. 7 of co-pending patent application WOO3/ related disease, MASP2-related disease, Antithrombin III 0933 16, although these sequences include histidine residues related disease, Complement factor H-related disease and/or added to the C terminal. Albumin-related disease, preferably an effect which is at least 0096. In one embodiment of the invention, the nucleic acid comparable of the full length protein. The beneficial effect molecule encodes a polypeptide which comprises or consists can be measured in any invitro or in vivo tests described in the of the extracellular domain of mature INSP052 (SEQ ID literature adequate to demonstrate an effect in infectious dis NO:22). Preferably, the nucleic acid molecule comprises or ease, properdin-related disease, MBL2-related disease, consists of the nucleic acid sequence set forth in SEQ ID MASP1-related disease, MASP2-related disease, Antithrom NO:21. This is also set out in FIG. 7 of co-pending patent bin III-related disease, Complement factor H-related disease application WO03/0933 16, although these sequences include and/or Albumin-related disease. The biological activity of histidine residues added to the C terminal. INSP052 can e.g. be measured by assaying INSP052 in its 0097. In one embodiment of the invention, the nucleic acid capacity to reduce infection, for example of Neisseria spe molecule encodes a polypeptide which comprises of consists cies, or to prevent blood clotting or platelet aggregation, or to of the variant of the extracellular domain of mature INSP052 act on the dilatation or constriction of blood vessels, or to which is the Ig-domain containing fragment of INSP052 modulate blood pressure, blood coagulation, fluid retention, (SEQ ID NO:31). opSonization, complement activation or osmotic pressure. 0098. In one embodiment of the invention, the nucleic acid 0102) In one embodiment, INSP052 may be a naturally molecule encodes a polypeptide which comprises of consists occurring, i.e. native protein, or a recombinant protein. of the variant of the extracellular domain of mature INSP052 Recombinant production may be carried out in eukaryotic which is the extracellular INSP052 lacking the first Ig domain cells, such as yeast cells or mammalian cells, preferably in (INSP052-EC-DELIG1) having the sequence shown in SEQ CHO cells, HEK cells (human embryonic kidney cells) or in ID NO:32. human fibroblast cells or cell lines. It may further be produced 0099. In one embodiment of the invention, the nucleic acid in prokaryotic cells such as E. coli. molecule encodes a polypeptide which comprises of consists (0103 Preferably, INSP052 is glycosylated at one or more of the variant of the extracellular domain of mature INSP052 sites. It may also be unglycosylated, depending on the given which is the extracellular INSP052 lacking the second Ig needs and the Source of production or isolation of the protein. domain (INSP052-EC-DELIG2) having the sequence shown 0104 Preferably, the polypeptides of the invention are in SEQID NO:33. glycosylated at residues 2, 71, 105, 134, 139 and/or 156 of 0100. In one embodiment, the term “INSP052 polypep SEQID NO: 22 (SEQIDNO:22 is taken as a reference for the tide' may relate to a protein comprising all, or a portion of the residues numbering). sequence of SEQID NO: 2, SEQID NO: 4, SEQID NO: 6, 0105. The term “salts' herein refers to both salts of car SEQ ID NO: 8, SEQ ID NO: 10, SEQ ID NO: 12, SEQID boxyl groups and to acid addition salts of amino groups of NO: 14, SEQID NO: 16, SEQID NO: 18, SEQID NO:20, INSP052 molecule or analogs thereof. Salts of a carboxyl SEQID NO: 22, SEQID NO: 24, SEQID NO: 26, SEQ ID group may be formed by means known in the art and include NO: 27, SEQID NO: 28, SEQID NO: 29, SEQID NO:30, inorganic salts, for example, Sodium, calcium, ammonium, SEQ ID NO: 31, SEQ ID NO:32, or SEQ ID NO:36 (all ferric or Zinc salts, and the like, and salts with organic bases as human except for SEQID NO: 18) of the enclosed sequence those formed, for example, with amines. Such as triethanola listing, as well as to salts, isoforms, muteins, active fractions, mine, arginine or lysine, piperidine, procaine and the like. functional derivatives and circularly permutated derivatives Acid addition salts include, for example, salts with mineral thereof. In one embodiment, INSP052 from species other acids, such as, for example, hydrochloric acidor Sulfuric acid, than human, such as mouse (e.g. SEQID NO: 18) or rat, may and salts with organic acids, such as, for example, acetic acid be used in accordance with the present invention, as long as or oxalic acid. Of course, any such salts must retain the there is a sufficient identity between the proteins as to allow biological activity of INSP052 relevant to the present inven the protein to exhibit its biological activity, and without elic tion, i.e., exert a beneficial effect on infectious disease, iting a substantial immune response in a human being. properdin-related disease, MBL2-related disease, MASP1 0101. In one embodiment, the term “INSP052 polypep related disease, MASP2-related disease, Antithrombin III tide' may further relate to any fragment, portion, domain or related disease, Complement factor H-related disease and/or sub-domain of SEQID NO: 2, SEQID NO: 4, SEQID NO: Albumin-related disease. US 2008/O 1934.14 A1 Aug. 14, 2008

0106. In one embodiment, isoforms or splice variants of 0112. In a preferred embodiment, any such mutein has at INSP052 may also be used according to the invention, as long least 40% identity or homology with the sequence of SEQID as they are capable of inhibiting disease progression and/or NO: 16. More preferably, it has at least 50%, at least 60%, at symptoms of that disease. least 70%, at least 80% or, most preferably, at least 90% 0107. In one embodiment, the term “muteins’ refers to identity or homology thereto. analogs of INSP052, in which one or more of the amino acid 0113 Identity reflects a relationship between two or more residues of natural INSP052 are replaced by different amino polypeptide sequences or two or more polynucleotide acid residues, or are deleted, or one or more amino acid sequences, determined by comparing the sequences. In gen residues are added to the natural sequence of INSP052, hav ing preferably at least the same activity as wild type INSP052 eral, identity refers to an exact nucleotide to nucleotide or or even having a much more potent activity. The biological amino acid to amino acid correspondence of the two poly activity of INSP052 can e.g. be measured by assaying nucleotides or two polypeptide sequences, respectively, over INSP052 in its capacity to reduce infection, for example of the length of the sequences being compared. Neisseria species, or to prevent blood clotting or platelet 0114 For sequences where there is not an exact correspon aggregation, or to act on the dilatation or constriction of blood dence, a “% identity” may be determined. In general, the two vessels, or to modulate blood pressure, blood coagulation, sequences to be compared are aligned to give a maximum fluid retention, opSonization, complement activation or correlation between the sequences. This may include insert osmotic pressure. Assays for assessing protein-protein inter ing 'gaps' in either one or both sequences, to enhance the actions are well known by the person skilled in the art. degree of alignment. A% identity may be determined over the Examples for Such assays are ELISA type binding assays, whole length of each of the sequences being compared (so immuno-precipitation assays, or measurement in any other called global alignment), that is particularly Suitable for suitable system such as the BIAcore system. These muteins sequences of the same or very similar length, or over shorter, are prepared by known synthesis and/or by site-directed defined lengths (so-called local alignment), that is more Suit mutagenesis techniques, or any other known technique Suit able for sequences of unequal length. able therefor. 0108 Preferably, such mutein has a sequence of amino 0115 Methods for comparing the identity and homology acids sufficiently duplicative of SEQID NO: 22, such as to of two or more sequences are well known in the art. Thus for have at least a substantially similar activity of SEQID NO: instance, programs available in the Wisconsin Sequence 22. The activity of an INSP052 mutant can further be tested Analysis Package, version 9.1 (Devereux J et al., 1984), for by assaying INSP052 in its capacity to reduce infection, for example the programs BESTFIT and GAP may be used to example of Neisseria species, or to prevent blood clotting or determine the '% identity between two polynucleotides and platelet aggregation, or to act on the dilatation or constriction the '% identity and the '% homology between two polypeptide of blood vessels, or to modulate blood pressure, blood coagu sequences. BESTFIT uses the “local homology' algorithm of lation, fluid retention, opSonization, complement activation Smith and Waterman (1981) and finds the best single region or osmotic pressure. of similarity between two sequences. Other programs for 0109. In one embodiment, muteins in accordance with the determining identity and/or similarity between sequences are present invention include proteins encoded by a nucleic acid, also known in the art, for instance the BLAST family of such as DNA or RNA, which hybridizes to DNA or RNA, programs (Altschul S Fetal, 1990, Altschul S Fetal, 1997, which encodes INSP052, in accordance with the present accessible through the home page of the NCBI at www.ncbi. invention, under Stringent conditions. The term "stringent nlm.nih.gov) and FASTA (Pearson W R, 1990; Pearson conditions' refers to hybridization and Subsequent washing 1988). conditions, which those of ordinary skill in the art conven 0116. Muteins of INSP052, which can be used in accor tionally refer to as “stringent'. See Ausubel et al., Current dance with the present invention, or nucleic acids encoding Protocols in Molecular Biology, supra, Interscience, N.Y., them, include a finite set of Substantially corresponding SS6.3 and 6.4 (1987, 1992), and Sambrook et al. (Sambrook, sequences as Substitution peptides or polynucleotides which J. C., Fritsch, E. F., and Maniatis, T. (1989) Molecular Clon can be routinely obtained by one of ordinary skill in the art, ing: A Laboratory Manual, Cold Spring Harbor Laboratory without undue experimentation, based on the teachings and Press, Cold Spring Harbor, N.Y.). guidance presented herein. 0110. Without limitation, examples of stringent condi 0117. In one embodiment, preferred changes for muteins tions include washing conditions 12-20°C. below the calcu in accordance with the present invention are what are known lated Tm of the hybrid under study in, e.g., 2xSSC and 0.5% as "conservative' substitutions. Conservative amino acid SDS for 5 minutes, 2XSSC and 0.1% SDS for 15 minutes: substitutions of INSP052 polypeptides or proteins, may 0.1xSSC and 0.5% SDS at 37°C. for 30-60 minutes and then, include synonymous amino acids within a group which have a 0.1XSSC and 0.5% SDS at 68°C. for 30-60 minutes. Those Sufficiently similar physicochemical properties that Substitu of ordinary skill in this art understand that stringency condi tion between members of the group will preserve the biologi tions also depend on the length of the DNA sequences, oli cal function of the molecule (Grantham, 1974). It is clear that gonucleotide probes (such as 10-40 bases) or mixed oligo insertions and deletions of amino acids may also be made in nucleotide probes. If mixed probes are used, it is preferable to the above-defined sequences without altering their function, use tetramethylammonium chloride (TMAC) instead of SSC. particularly if the insertions or deletions only involve a few See Ausubel, Supra. amino acids, e.g., under thirty, and preferably under ten, and 0111 Preferably, any such mutein has a sequence of do not remove or displace amino acids which are critical to a amino acids sufficiently duplicative of that of SEQ ID NO: functional conformation, e.g., cysteine residues. Proteins and 22, such as to have substantially similar, or even better, bio muteins produced by Such deletions and/or insertions come logical activity as SEQID NO: 22. within the purview of the present invention. US 2008/O 1934.14 A1 Aug. 14, 2008

0118 Preferably, the synonymous amino acid groups are those defined in Table I. More preferably, the synonymous TABLE III-continued amino acid groups are those defined in Table II; and most preferably the synonymous amino acid groups are those Most Preferred Groups of Synonymous Amino Acids defined in Table III. Amino Acid Synonymous Group Gly Gly TABLE I Ile Ile, Met, Leu Phe Phe Preferred Groups of Synonymous Amino Acids Tyr Tyr Cys Cys, Ser Amino Acid Synonymous Group His His Gln Gln Ser Ser, Thr, Gly, ASn ASn ASn Arg Arg, Gln, Lys, Glu, His Lys Lys Leu Ile, Phe, Tyr, Met, Val, Leu Asp Asp Pro Gly, Ala, Thr, Pro Thr Pro, Ser, Ala, Gly, His, Gln, Thr Glu Glu Ala Gly, Thr, Pro, Ala Met Met, Ile, Leu Wall Met, Tyr, Phe, Ile, Leu, Val Trp Met Gly Ala, Thr, Pro, Ser, Gly Ile Met, Tyr, Phe, Val, Leu, Ile Phe Trp, Met, Tyr, Ile, Val, Leu, Phe 0119 Examples of production of amino acid substitutions Tyr Trp, Met, Phe, Ile, Val, Leu, Tyr in proteins which can be used for obtaining muteins of Cys Ser, Thr, Cys INSP052 polypeptides or proteins, for use in the present His Glu, Lys, Gln, Thr, Arg, His Gln Glu, Lys, ASn, His, Thr, Arg, Gln invention include any known method steps, such as presented ASn Gln, Asp, Ser, ASn in U.S. Pat. Nos. 4,959,314, 4,588,585 and 4,737,462, to Lys Glu, Gln, His, Arg, Lys Market al; U.S. Pat. No. 5,116,943 to Koths et al., U.S. Pat. Asp Glu, ASn, Asp Glu Asp, Lys, ASn, Gln, His, Arg, Glu No. 4,965,195 to Namen et al; U.S. Pat. No. 4,879,111 to Met Phe, Ile, Val, Leu, Met Chong et al; and U.S. Pat. No. 5,017,691 to Lee et al; and Trp Trp lysine substituted proteins presented in U.S. Pat. No. 4,904, 584 (Shaw et al). I0120. The term “fusion protein” refers to a polypeptide comprising INSP052, or a mutein thereof, fused with another TABLE II protein, which, e.g., has an extended residence time in body More Preferred Groups of Synonymous Amino Acids fluids. Fusion proteins comprising all or a functional part of INSP052 fused to all or a functional part of a protein capable Amino Acid Synonymous Group of improving the biological activities of the molecule, like Ser Ser half-life in the human body, for instance, are preferred Arg His, Lys, Arg according to the invention. In a preferred embodiment the Leu Leu, Ile, Phe, Met fusion protein comprises an immunoglobulin (Ig) fusion. Pro Ala, Pro Thr Thr Fusion proteins comprising all or part of INSP052 fused to all Ala Pro, Ala or part of an immunoglobulin are highly preferred. They can Wal Val, Met, Ile be monomeric or multimeric, hetero- or homomultimeric. Gly Gly Advantageously, the fusion protein comprises the constant Ile Ile, Met, Phe, Val, Leu Phe Met, Tyr, Ile, Leu, Phe region of an immunoglobulin, in particular of the Fc portion Tyr Phe, Tyr of the immunoglobulin. Embodiments in which the immuno Cys Cys, Ser globulin is of the IgG1 or IgG2 isotype are further preferred His His, Gln, Arg according to the invention. Preferably, the fusion is an Fc Gln Glu, Gln, His ASn Asp, ASn fusion. Preferably, the fusion protein consists of SEQID NO: Lys LyS, Arg 3O. Asp Asp, ASn I0121 INSP052 may thus be fused to another protein, Glu Glu, Gln Met Met, Phe, Ile, Val, Leu polypeptide or the like, e.g., an immunoglobulin or a frag Trp Trp ment thereof. The fusion may be direct, or via a short linker peptide which can be as short as 1 to 3 amino acid residues in length or longer, for example, 13 amino acid residues in length. Said linker may be a tripeptide of the sequence E-F-M TABLE III (Glu-Phe-Met), for example, or a 13-amino acid linker Most Preferred Groups of Synonymous Amino Acids sequence comprising Glu-Phe-Gly-Ala-Gly-Leu-Val-Leu Gly-Gly-Gln-Phe-Met introduced between the INSP052 Amino Acid Synonymous Group sequence and the immunoglobulin sequence. Ser Ser 0.122 "Functional derivatives” as used herein cover Arg Arg derivatives of INSP052, and their muteins and fusion pro Leu Leu, Ile, Met teins, which may be prepared from the functional groups Pro Pro Thr Thr which occur as side chains on the residues or the N- or Ala Ala C-terminal groups, by means known in the art, and are Wal Wall included in the invention as long as they remain pharmaceu tically acceptable, i.e. they do not destroy the activity of the US 2008/O 1934.14 A1 Aug. 14, 2008

protein which is at least substantially similar to the activity of related disease, MBL2-related disease, MASP1-related dis SEQID NO: 22, and do not confer toxic properties on com ease, MASP2-related disease, Antithrombin III-related dis positions containing it. Therefore, in a preferred embodiment ease, Complement factor H-related disease and/or Albumin the functional derivative comprises at least one moiety related disease. A cell that has been genetically modified to attached to one or more functional groups, which occuras one produce a polypeptide according to the invention is also or more side chains on the amino acid residues. within the scope of the present invention. 0123. In accordance with the present invention, polyeth I0128. The use of an expression vector for inducing and/or ylene glycol (PEG) side-chains are highly preferred moieties. enhancing the endogenous production of INSP052 in a cell PEG side chains may mask antigenic sites and extend the normally silent or expressing amounts of the inhibitor which residence of the substance they are attached to in body fluids. are not sufficient, are also contemplated according to the Other derivatives include aliphatic esters of the carboxyl invention. Thus, the invention makes use of a technology groups, amides of the carboxyl groups by reaction with known as endogenous gene activation (EGA) for the produc ammonia or with primary or secondary amines, N-acyl tion of the desired protein. derivatives of free amino groups of the amino acid residues I0129. According to the invention, INSP052 can be admin formed with acyl moieties (e.g. alkanoyl or carbocyclic aroyl istered alone or in combination with several other therapeutic groups) or O-acyl derivatives of free hydroxyl groups (for regimens or agents (e.g. multiple drug regimens) to obtain an example that of seryl or threonyl residues) formed with acyl additive or synergistic effect for the treatment and/or preven moieties. tion of infectious disease, properdin-related disease, MBL2 0.124 “Active fractions of INSP052 and its muteins and related disease, MASP1-related disease, MASP2-related dis fusion proteins, cover any fragment or precursors of the ease, Antithrombin III-related disease, Complement factor polypeptide chain of the protein molecule alone or together H-related disease and/or Albumin-related disease. Therefore, with associated molecules or residues linked thereto, e.g., preferably, the medicament of the invention further com Sugar or phosphate residues, or aggregates of the protein prises: molecule or the Sugar residues by themselves, provided said active fraction has at least a substantially similar activity to 0.130 Interferon, in particular interferon-C., interferon SEQID NO. 22. B, or interferon-Y, or (0.125. In accordance with the present invention, INSP052 0.131. A Tumor Necrosis Factor (TNF) antagonist, in may also be administered to the human body in form of a particular soluble TNFRs, such as soluble p55 (TBPI) vector comprising said nucleic acid molecule. Therefore, the and/or soluble p75 (TBP II), or invention further relates to the use of a vector comprising said 0.132. An anti-infectious agent, or nucleic acid molecule for the manufacture of a medicament 0.133 An anti-blood clotting agent. for the treatment and/or prevention of infectious disease, I0134. The anti-blood clotting agent may be selected from properdin-related disease, MBL2-related disease, MASP1 Nitrates, nitroglycerin, isosorbide dinitrate, isosorbide mono related disease, MASP2-related disease, Antithrombin III nitrate, vitamin C or E. Beta-blockers, propranolol (Inderal, related disease, Complement factor H-related disease and/or Ciplar), labetalol (Normadate), acebutolol (Sectral), atenolol Albumin-related disease. Preferably, the vector is an expres (Aten, Tenormin, Betacard, Tensimin), metoprolol (Betaloc, sion vector, comprising a promoter operably linked to all or Metolar), bisoprolol (Concor), Carvedilol (Carvedil, Carloc, part of the coding sequence of INSP052. Inafurther preferred Carvil), anticoagulants, heparin, warfarin, anti-platelet drug, embodiment, the vector is a gene therapy vector. Gene aspirin, glycoprotein IIb/IIIa receptor antagonists, clopi therapy vectors are known in the art, most of them are virally dogrel, NSAIDs, Enoxaparin (Clexane), dalteparin (Frag derived vectors, such as adenoviral or lentiviral vectors. min), reviparin (Clivarine), abciximab (ReoPro, Centocor), 0126. According to the invention, INSP052 may also be eptifibatide, lamifiban, tirofiban, abciximab, Clopidogrel administered to the human body in form of a cell producing (Deplatt, Clopilet), ticlopidine (Tyklid, Ticlop), Hirudin, and/or secreting INSP052. Therefore, the invention further Bivalirudin, argatroban, danaparoid, Statins, Angiotensin relates to the use of a cell expressing INSP052 for the manu Converting Enzyme Inhibitors Angiotensin converting facture of a medicament for the treatment and/or prevention enzyme (ACE) inhibitors, ramipril (Cardace), captopril (Ca of infectious disease, properdin-related disease, MBL2-re potril, Aceten), enalapril (Envas, Vasonorm), lisinopril (Pre lated disease, MASP1-related disease, MASP2-related dis vace, Lipril, Zestril), fosinopril, Calcium Channel Blockers, ease, Antithrombin III-related disease, Complement factor Verapamil (Calan, Isoptin), nifedipine (Adalat, Depin), nica H-related disease and/or Albumin-related disease, i.e. to cell rdipine (Cardene), amlodipine (Amdepin, Corvadil), dilt therapy for the treatment and/or prevention of infectious dis iazem (Cardizem, Dilzem), bepridil (Vascor), Ranolazine, ease, properdin-related disease, MBL2-related disease, Nicorandil, Antibiotics, tetracyclines, quinolones. Folic acid, MASP1-related disease, MASP2-related disease, Antithrom Thrombolytics, recombinant tissue plasminogen activators bin III-related disease, Complement factor H-related disease (rt-Pas), alteplase (Activase and reteplase (Retavase)). Fibrin and/or Albumin-related disease. The cell may be a naturally Depleting Agent, ancrod, batroXobin (Defibrase). Thienopy producing INSP052 and/or a transfected cell that produces ridines, Clopidogrel (Plavix), ticlopidine (Ticlid), thienopy recombinant INSP052. Preferred are cells expressing and ridines, (Clopidogrel), Direct Thrombin Inhibitors (DTIs), secreting high amounts of the protein, such as over-express hirudin, argatroban (Novastan), bivalirudin (Angiomax), ing cells carrying high copy numbers of an expression vector danaproid (Orgaran), lepirudin (Refludan), desirudin (Re comprising a nucleic acid molecule encoding INSP052. vasc), inogatran, efegatran, Ximelagatran (EXanta), antifi 0127. The invention further relates to a cell comprising a brinolytics, tranexamic acid, or epsilon amino-caproic acid. vector comprising a nucleic acid molecule encoding all or 0.135 The anti-infectious agent may be selected from pen part of INSP052 for the preparation of a medicament for tamidine, antibiotics, colistine, aminoglycosides or amphot treatment and/or prevention of infectious disease, properdin ericin B. US 2008/O 1934.14 A1 Aug. 14, 2008 11

0136 All treatments are intended for simultaneous, simultaneous, sequential, or separate use of INSP052 with the sequential or separate use. TNFantagonistand/oran Interferonis preferred, according to 0.137 Pharmaceutical compositions comprising one or the invention. more of the above substances, together with INSP052, are 0143. According to the invention, TBPI and TBPII are within the scope of the present invention. preferred TNF antagonists to be used in combination with 0.138. In yet a further embodiment of the invention, INSP052. Derivatives, fragments, regions and biologically INSP052 is used in combination with an interferon. Prefer active portions of the receptor molecules functionally ably, the interferon is selected among interferon-C., inter resemble the receptor molecules that can also be used in the feron-?3, or interferon-Y. Interferons have also been associated present invention. Such biologically active equivalent or to infectious disease, properdin-related disease, MBL2-re derivative of the receptor molecule refers to the portion of the lated disease, MASP1-related disease, MASP2-related dis polypeptide, or of the sequence encoding the receptor mol ease, Antithrombin III-related disease, Complement factor ecule, that is of sufficient size and able to bind TNF with such H-related disease and/or Albumin-related disease. For an affinity that the interaction with the membrane-bound TNF example, interferon-C. has been involved in neutropenia, receptor is inhibited or blocked. thrombocytopenia, hepatitis C or hepatitis B. For example, 0144. In a further preferred embodiment, human soluble interferon-?3 has been involved in hepatitis B, hepatitis C, TNF-RI (TBPI) is the TNF antagonist to be used according to virus diseases, hiv-infections and influenza. For example, the invention. The natural and recombinant soluble TNF interferon-Y has been associated with Tuberculosis, virus dis receptor molecules and methods of their production have eases, visceral or cutaneous leishmaniasis, hiv infections, been described in the European Patents EP308 378, EP398 hepatitis B, hepatitis C, influenza, diabetes, malaria, bacterial 327 and EP 433 900. infections, mycobacterium infections and filarial elephantia (0145 Whilst it may be beneficial to block TNF-C. in early stages of the disease, it has been discussed that in later stages, S1S. TNF itself may exert a beneficial effect on disease progres 0.139. In yet a further embodiment of the invention, sion (Abraham et al., 2000). Therefore, the invention further INSP052 is used in combination with a TNFantagonist. TNF relates to a combination of INSP052 and TNF for treatmentor antagonists exert their activity in several ways. First, antago prevention of infectious disease, properdin-related disease, nists can bind to or sequester the TNF molecule itself with MBL2-related disease, MASP1-related disease, MASP2-re sufficient affinity and specificity to partially or substantially lated disease, Antithrombin III-related disease, Complement neutralise the TNF epitope or epitopes responsible for TNF factor H-related disease and/or Albumin-related disease, in receptor binding (hereinafter termed “sequestering antago particular in advanced stages of disease. TNF-C. or TNF-B nists'). A sequestering antagonist may be, for example, an may be used in accordance with the invention. antibody directed against TNF. For example, TNF-C. has been 0146 The invention further relates to a pharmaceutical involved in virus diseases, malaria, septic shock, bacterial composition comprising INSP052, optionally together with infections, mycobacterium infections, bacterial meningitis, one or more pharmaceutically acceptable carriers, diluents or hiv infections and tuberculosis. excipients, for the treatment and/or prevention of infectious 0140 Alternatively, TNF antagonists can inhibit the TNF disease, properdin-related disease, MBL2-related disease, signalling pathway activated by the cell Surface receptor after MASP1-related disease, MASP2-related disease, Antithrom TNF binding (hereinafter termed “signalling antagonists”). bin III-related disease, Complement factor H-related disease TNFantagonists are easily identified and evaluated by routine and/or Albumin-related disease. The pharmaceutical compo screening of candidates for their effect on the activity of sition may further comprise any of the above-identified fur native TNF on susceptible cell lines in vitro, for example ther components, and preferably an interferon. human B cells, in which TNF causes proliferation and immu 0147 The pharmaceutical composition according to the noglobulin secretion. The assay contains TNF formulation at invention may also comprise a vector comprising a nucleic varying dilutions of candidate antagonist, e.g. from 0.1 to 100 acid molecule according to the invention, or a cell expressing times the molar amount of TNF used in the assay, and controls INSPO52. with no TNF or only antagonist (Tucci et al., 1992). 0.148. The active ingredients of the pharmaceutical, i.e. 0141 Sequestering antagonists are the preferred TNF polypeptides, nucleic acids or cells according to the inven antagonists to be used according to the present invention. tion, or combinations thereof, as well as the combinations of Amongst sequestering antagonists, those polypeptides that Substances mentioned above, may be administered to an indi bind TNF with high affinity and possess low immunogenicity vidual in a variety of ways. The routes of administration are preferred. Soluble TNF receptor molecules and neutral include intradermal, transdermal (e.g. in slow release formu ising antibodies to TNF are particularly preferred. For lations), intramuscular, intraperitoneal, intravenous, Subcuta example, soluble forms of TNF-RI (p55) and TNF-RII (p75) neous, oral, epidural, topical, and intranasal routes. Any other are useful in the present invention. Truncated forms of these therapeutically efficacious route of administration can be receptors, comprising the extracellular domains of the recep used, for example absorption through epithelial or endothelial tors or functional portions thereof, are more particularly pre tissues or by genetherapy wherein a DNA molecule encoding ferred antagonists according to the present invention. Trun the active agent is administered to the patient (e.g. via a cated soluble TNF type-I and type-II receptors are described vector), which causes the active agent to be expressed and in EP914431, for example. secreted in vivo. In addition, the protein(s) according to the 0142 Truncated forms of the TNF receptors are soluble invention can be administered together with other compo and have been detected in urine and serum as about 30 kDa or nents of biologically active agents such as pharmaceutically 40 kDa TNF inhibitory binding proteins, which are called acceptable Surfactants, excipients, carriers, diluents and TBPI and TBPII, respectively (Engelmann et al., 1990). The vehicles. US 2008/O 1934.14 A1 Aug. 14, 2008

014.9 The definition of “pharmaceutically acceptable' is or a nucleic acid molecule of the invention, optionally com meant to encompass any carrier, which does not interfere with prised in an expression vector, may be administered accord effectiveness of the biological activity of the active ingredient ing to the invention. and that is not toxic to the host to which it is administered. For 0157. The expression vector may be administered sys example, for parenteral administration, the active protein(s) temically. Preferably the expression vector is administered by may be formulated in a unit dosage form for injection in intramuscular injection. A further preferred route of admin vehicles such as saline, dextrose solution, serum albuminand istration is inhalation, in particular if the lungs are involved in Ringer's solution. the disease (e.g. infectious diseases of the lung). Topical 0150. For parenteral (e.g. intravenous, subcutaneous, administration of an expression vector comprising INSP052 intramuscular) administration, the active protein(s) can be sequences, or of an INSP052 polypeptide according to the formulated as a solution, Suspension, emulsion or lyophilised invention, is a further preferred route of administration, in powder in association with a pharmaceutically acceptable particular if there is an involvement of the skin. parenteral vehicle (e.g. water, Saline, dextrose solution) and 0158. The invention further relates to a method for the additives that maintain isotonicity (e.g. mannitol) or chemical preparation of a pharmaceutical composition comprising stability (e.g. preservatives and buffers). The formulation is admixing an effective amount of INSP052 with a pharmaceu sterilized by commonly used techniques. tically acceptable carrier, and to a method of treatment and/or prevention of infectious disease, properdin-related disease, 0151. The bioavailability of the active protein(s) accord MBL2-related disease, MASP1-related disease, MASP2-re ing to the invention can also be ameliorated by using conju lated disease, Antithrombin III-related disease, Complement gation procedures which increase the half-life of the molecule factor H-related disease and/or Albumin-related disease com in the human body, for example linking the molecule to poly prising administering to a host in need thereof an effective ethylenglycol, as described in the PCT Patent Application amount of INSPO52. WO 92/13095. 0159 All references cited herein, including journal 0152 The therapeutically effective amount of the active articles or abstracts, published or unpublished patent appli protein(s) will be a function of many variables, including the cations, issued patents or any other references, are entirely type of receptor, the affinity of the Substance according to the incorporated by reference herein, including all data, tables, invention to its receptor, any residual cytotoxic activity exhib figures and text presented in the cited references. Addition ited thereby, the route of administration, the clinical condition ally, the entire contents of the references cited within the of the patient. references cited herein are also entirely incorporated by ref 0153. A “therapeutically effective amount' is such that CCC. when administered, the Substance according to the invention 0160 Reference to known method steps, conventional results in a beneficial effect on disease development or pro methods steps, known methods or conventional methods is gression in vivo. The dosage administered, as single or mul not any way an admission that any aspect, description or tiple doses, to an individual will vary depending upon a vari embodiment of the present invention is disclosed, taught or ety of factors, including the pharmacokinetic properties of Suggested in the relevant art. INSP052, the route of administration, patient conditions and 0.161 The foregoing description of the specific embodi characteristics (sex, age, body weight, health, size), extent of ments will so fully reveal the general nature of the invention symptoms, concurrent treatments, frequency of treatment and that others can, by applying knowledge within the skill of the the effect desired. Adjustment and manipulation of estab art (including the contents of the references cited herein), lished dosage ranges are well within the ability of those readily modify and/or adapt for various application Such spe skilled in the art. cific embodiments, without undue experimentation, without 0154 The dose of the polypeptide according to the inven departing from the general concept of the present invention. tion required will vary from about 0.0001 to 100 mg/kg or Therefore, Suchadaptations and modifications are intended to about 0.01 to 10 mg/kg or about 0.1 to 5 mg/kg or about 1 to be within the meaning an range of equivalents of the disclosed 3 mg/kg, although as noted above this will be subject to a embodiments, based on the teaching and guidance presented great deal of therapeutic discretion. The medicament of the herein. It is to be understood that the phraseology or termi invention may be administered daily, every other day, or three nology herein is for the purpose of description and not of times per week. limitation, such that the terminology or phraseology of the 0155 The daily doses are usually given individed doses or present specification is to be interpreted by the skilled artisan in sustained release form effective to obtain the desired in light of the teachings and guidance presented herein, in combination with the knowledge of one of ordinary skill in results. Second or Subsequent administrations can be per the art. formed at a dosage, which is the same, less than or greater 0162 Having now described the invention, it will be more than the initial or previous dose administered to the indi readily understood by reference to the following examples vidual. A second or Subsequent administration can be admin that are provided by way of illustration and are not intended to istered during or prior to onset of the disease. be limiting of the present invention. 0156 The invention further relates to a method for treating and/or preventing infectious disease, properdin-related dis EXAMPLES ease, MBL2-related disease, MASP1-related disease, MASP2-related disease, Antithrombin III-related disease, Example 1 Complement factor H-related disease and/or Albumin-related disease, comprising administering to a patient in need thereof Cloning and Expression an effective amount of a Substance according to the invention, (0163 Cloning of extracellular INSP052, construction of optionally together with a pharmaceutically acceptable car mammalian cell expression vectors, expression in mamma rier. Alternatively, or additionally, a cell producing INSP052 lian cells and purification of extracellular INSP052 and his US 2008/O 1934.14 A1 Aug. 14, 2008

tidine tagged version of extracellular domain are described in performed by SELDI-TOF-MS, using the ProteinChipTM Examples 2 and 3 of International Application WO2003/ Biology System II. Spectra were generated using laser inten O933 16. and No. PCTFGB2004/OO.4772. sity 200, sensitivity 9 and 10 and mass focus between 10-40 0164. The polypeptide having the sequence recited in SEQ kDa and 20-160 kDa. ID NO:30 (referred to hereafter as the Fc fusion of the extra 0176 Spectra of controls and samples from different chips cellular domain of mature INSP052) has been purified twice (500 ml each) and 7.9 mg and 2.4 mg were recovered. The were merged into the same file and treated identically for polypeptide having the sequence recited in SEQ ID NO:32 analysis. The spectra were calibrated using the all-in-1 pro (referred to as the extracellular INSP052 lacking the first Ig tein standard from Ciphergen biosystems Inc. following domain or INSP052-EC-DEL IG1) has been purified and manufacturers indications. For comparison between spectra, recovered (2 purifications (500 ml) of recovery 0.7 mg and 0.3 they were normalized to total ion current. Differentially mg, respectively and 1 purification (3000 ml) of recovery 7 expressed peaks were identified using the Ciphergen Biom mg). The polypeptide having the sequence recited in SEQID arker Wizard software. NO:33 (referred to hereafter as the extracellular INSP052 0177. For identification of binding proteins, IDM affinity lacking the second Ig domain or INSP052-EC-DELIG2) has beads (Ciphergen biosystems) were used, applying a similar been purified (500 ml) and recovered at Western Blot levels. protocol as the one used on the RS100 chip. 1 mg bait protein (sINSP052) in 50 mM NaAcetate buffer pH 5.0 was incu Example 2 bated on 600 ul beads overnight at room temperature. The Binding Partners of INSP052 beads were washed 2x5 min 50 mMNa Acetate buffer pH 5.0 and blocked with 0.5M Tris-HCl pH 9.0, 0.1% Triton-X100 I. Introduction for 2 hours. They were washed 3x10 min 0.1% Triton-X100 (0165. The SELDI-TOF MS technique (Surface-enhanced in PBS and 2x10 minin PBS. Plasma samples were diluted in Laser Desorption/Ionization Time-of-flight Mass Spectrom 1:1 in PBS, 0.1% Triton X-100, and incubated on the beads etry/ProteinChipTM Arrays) was used to identify potential (overnight, room temperature). Washed 2x5 min with 0.2M binding partners of soluble INSP052 (sINSP052 corre Urea/0.1% CHAPS/0.2M NaCl/50 mM Tris pH 7.5 and 2x5 sponding to the mature extracellular part of membrane bound min with PBS. Interacting proteins were eluted with 50% INSP052, SEQID NO: 22). Briefly, the following steps were acetonitrile, 0.3%TFA (Tri-phosphatidic acid). Eluates were performed: examined using the NP20 protein chip. 5ul eluate was added 0166 1. Acquiring the sample from mouse, per spot. Spots were washed with deionised water and undi 0.167 2. SELDI analysis and optimization, luted Sinapinic acid was added. Spectra were generated using 0168 3. Scale-up to beads, laser intensity 180/200, sensitivity 8 and mass focus between (0169. 4. Analyse eluate on SELDI, 2-30 kDa and 20-160 kDa. (0170 5. HPLC of bead eluate, 0.178 The eluate was further fractionated on a C4 (butyl) 0171 6. Analyse HPLC fractions on chip and gel, column (reverse phase), with a 2.1 mm diameter (VYDAC 0172 7. Digestion of isolated proteins and 214TPTM Series, Grace Vydac) at a flowrate of 0.2 ml/min. (0173 8. Nano LC MS/MS and identification of pro The column was developed with a continuous linear acetoni teins. trile gradient 0 to 90% in 0.1% TFA. 1 min fractions were collected. The fractions were lyophilized and the protein con II. Material and Methods tent determined using the NP20 protein chip. (0174 First, intravenous LPS or NaCl (control) was 0179 RP-HPLC fractions containing the proteins of inter injected in female CH3 mice and blood was collected through est were trypsin digested for identification, using RapigestTM intra cardiac puncuration after 3 hours. The mice were SF (Waters) following manufacturers protocol. injected i.p. with 300 ug/Kg LPS. For plasma the blood was 0180. The pooled fractions were also analysed by gel elec collected in heparin treated tubes and for serum in untreated trophoresis and silverstain. tubes. The tubes were centrifuged at 13,000 rpm for 10 min. 0181 Mass spectrometric experiments were conducted The Supernatant (serum or plasma samples) was collected and using a Q-Star quadrupole/time-of-flight instrument (MDS/ used for the experiment. Sciex). The interface was connected to an Ultimate HPLC (0175. Then, 1.25 ug of the bait protein sINSP052 or con system (LC-Packings), equipped with a capillary C-18 RP trol IL-18 (IL-18 as a control proteinbinding of IL-18BP) was column (75 um inner diameter, 150 mm length). Peptide applied to each spot on RS100 ProteinChipTM Arrays (Cipher digests were injected onto the column using a Famos gen Biosystems Inc., Fremont, Calif.) and incubated 2 h autosampler (LC-Packings) and separated on the column by a (room temperature) in a humidified chamber. Non-specific gradient of acetonitrile in water in the presence of 0.1% binding sites were blocked with 0.5 M ethanolamine/PBS for formic acid at a flow rate of 200 ml/min. The column was 1 hour (room temperature). Arrays were washed 3 times for 5 connected to a nano-emitter and the eluent sprayed towards min with PBS, 0.1% Triton X-100. Plasma samples were the orifice of the mass spectrometer using a current of 2400 V. diluted 1:1 in PBS, 0.1% Triton X-100, and incubated on the The mass spectrometer is operated in a data dependent acqui arrays (2 h, room temperature). Optimal conditions for the sition mode. A second survey scans are performed in the MS samples are achieved with an incubation time of 4 hours. The mode followed by 4 MS/MS scans when M+2H]?" or arrays were then washed for 2x5 min with PBS, 0.1% Triton M+3H" precursor ions are detected above a signal of 20 X-100 and 1x3 min with 1MUrea/2%CHAPS/0.5MNaC/50 counts/second. Tandem mass spectra were obtained using mM Tris pH 9. They were rinsed with 5 mM HEPES pH 7.2 nitrogen as a target gas at collision energies that were set (15 Sec room temperature). The matrix. Sinapinic acid was automatically depending on the mass and the charge of the applied to each spot on the array and mass analysis was precursor ion. US 2008/O 1934.14 A1 Aug. 14, 2008

0182 Peptide sequences were determined after transfer of 0214 a. Ctrl serum the MS/MS data to the Mascot program and searches per 0215 b. LPS serum formed in protein databases available in house. 0216 and incubate for of n at RT (18 hours) 0183 The protocols used are presented below: 0217 iii) Washing and Eluting from the Beads a) Fishing Protein Binding Partners Using the Ciphergen 0218 13. Prepared washing and elution solutions and fil RS100 Protein Chip tered them 0184 1. Added 5 ul of 1 mg/ml protein diluted 1:3 in 0219. 14. Removed supernatant and store at -80°C. for a NaHCO3 to each spot possible incubation with a new set of bound beads 0185. 2. Incubated for 2 h in a humidified chamber. 0220 15. Added 2x100 ul of PBS into eacheppi to transfer 0186 3. Added 50 ul 0.5M ethanolamine and blocked for same samples into only one eppi, giving total of 2 eppis. 1 hat RT by mixing (Micromix520/02/60). 0221) 16. Washed beads 1x5 min 400 ul & 1x5min 500 ul 0187. 4. Washed 2x5 min with 0.1% TritonX100 in PBS with 0.2M Urea/0.1% CHAPS/0.2M NaCl/50 mM Tris pH (micromix520/3/5) 7.5. Kept wash solution and examined with SELDI. 0188 5. Prepared samples and added 50 ul of plasma 0222 17. Washed beads 2x5 min with 1 ml of 1xPBS Solution/spot 0223 18. Eluted with 200 ul 50% acetonitrile, 0.3%TFA (0189 i. Plasma from LPS stimulated mice diluted 1:1 in (0.2 ml H2O, 0.5 ml 100% ACN, 0.3 ml 1% TFA). Vortexed PBS70.1% Triton gently for 30 sec, rotate for 3 min and Vortexed again gently 0190. 6. Centrifuged the bioprocessor 1 min at 500 rpm. for 30 sec. Placed eluate in a separate eppi. Incubated for 2 hat RT, shaking (Micromix5 20/2/120) 0224) 19. Left beads in 4C for 3 h, added 200 ul 50% (0191) 7. Washed acetonitrile, 0.3% TFA and redid elution procedure. (0192 i. 3x5 min with 0.1% TritonX100 in PBS. (0193 ii. 1x3 min with 1M Urea/2%CHAPS/0.5M 0225. 20. Added additional 200ul 50% acetonitrile, 0.3% NaC1/50 mM Tris pH 9 TFA and redid elution procedure. 0194 8. Removed the array from the holder and placed it 0226, 21. Placed 3 ul for eluate 1 and 6 ul for eluates 2 and in a 15 ml falcon containing 5 mM Hepes pH 7.5. (10 sec) 3 on a NP20 spot. Let dry. Wash 2x5x up-and-down with (0195 9. Added 2x0.5 ul SPA solution. H2O. Let dry. Add 0.8 ul 100% SPA 0196) 10. Let airdry and analyzed the samples. 0227. 22. Analysed low and high molecular weight pro (0197) 11. The chips were analysed with the Ciphergen teins with separate SELDI protocols SELDI using the following reading conditions: 200-10-40 0228 a. Low: 800-8-2-30-160-16 65-100-51 or 200-9-20-160-160-50 laser intensity-sensitiv ity-massfocus low-massfocus high-Maximum mass-mass 0229 b. High: 200-8-20-160-160-50 focus) 0230 23. Looked at the various solution with gel electro b) Binding INSP052 to Affinity Beads and Incubating with phoresis and silverstain Mouse Plasma (0198 i) Binding the Bait Protein to Beads c) Reverse-HPLC Fractionation of the Bead Eluate (0199. 1. Took out the beads and kept at RT for 30 min 0231. The eluate of INSP052 bound beads, incubated with 0200 2. Mixed beads for 5 min on roller LPS plasma (from 21 1204) was run through a HPLC column. 0201 3. Added 200ul of beads into two 1.5 mileppendorff Using parameters: tubes 0202 4. Washed 6 times with 1 ml water 0232 Column: 0203 5. Added 600 ul 0233 C4 (butyl) column (reverse phase), 2.1 0204 a. 2.2 mg/ml INSP052 (13495F13P1 1.7 mg/ml 0234 Solvant A: 0.1% TFA concentrated to 4 mg/ml) (1320 ug total) 0235 Solvant B: 0.1% TFA, 90% acetonitrile (0205 b. 1.95 mg/ml IL 18 (hIL 18mature, E. Coli, Batch Wash column: LM10821-1101 mg/ml concentrated to 4 mg/ml) (1170 0236 ug total) in 50 mM Na Acetate buffer pH 5.0 and incu 0237) 30 min 0-90% acetonitrile, 0.1% TFA, 0.2 ml/min bate overnight at RT on the roller 0238 Inject sample: 0206 ii) Saturating Unbound Sites and Incubating with 0239) 100 ul of lyophilized sample resuspended in 0.1% Plasma TFA 0207 6. Removed supernatant, determined protein con 0240 followed by 5 min solvant A (0.1% TFA) centration and stored (See below for protein concentration) 0208 7. Washed 2x1 ml 50 mM NaAcetate buffer pH 5.0 0241 Elution: 0209 8. Add 600 ul of 0.5M Tris-HCl pH 9, 0.1% Tri 0242 105 min elution 0-90% acetonitrile, 0.1% TFA, 0.2 tonX100 (to deactivate possible remaining active groups) and ml/min incubate for 2 h on a roller at RT 0243 5 min elution 90% acetonitrile, 0.1% TFA, 0.2 0210 9. Wash 3x10 min with 1 ml 0.1% TritonX100 in ml/min PBS 0244 10 min wash 0.1% TFA 0211 10. Wash 2x10 min with 1 ml PBS 0245 1 min fractions were collected. Each fraction was 0212 11. Put 20 ul of INSP052 bound beads into eight 1.5 analysed on the SELDI. When 10 ul of 200 ul was absorbed mleppitubes on the NP20 protein chip spot only the highest HPLC peaks 0213 12. Mix 600 ul of serum+600 ul 0.1% Triton in could be visualized. Therefore, the fractions corresponding to PBS-56 ul 25xprotease inhibitor (complete mix) and added the smaller peaks were lyophilized, resuspended in 15 ul to beads 0.3% TFA, 50% acetonitrile and 5ul was added to the chip US 2008/O 1934.14 A1 Aug. 14, 2008 d) Rapigest Protein Digestion for MALDI manipulation and functional analysis of the cardiovascular system in mice. Chang Gung Med J. December 2003; 26(12): 0246 1. The fractions (200ul) were lyophilized separately 868-78.), in Ma et al. (Neurocardiovascular regulation in 0247 2.50 ul was used to resuspend and merge 4 frac mice: experimental approaches and novel findings. Clin Exp tions. The tubes were washed further with 50 ul that was Pharmacol Physiol. November 2003; 30(11):885-93.) or added to the previous volume. Svenson etal. (Invited review: Identifying new mouse models 0248 3. The samples were lyophilised of cardiovascular disease: a review of high-throughput 0249. The samples were resuspended in 50 ul 0.2 w/v. screens of mutagenized and inbred strains. J Appl Physiol. Rapigest and the Rapigest protocol was followed. April 2003: 94(4): 1650-9; discussion 1673.). III. Results 0261 Alternatively, biological activity of INSP052 polypeptides can be tested in mouse models of infectious (0250 Protein peaks of 20, 50, 53 and 56 kDa were seen to diseases as described in Cluffetal. (Synthetic toll-like recep bind to array spots with immobilized sINSP052 but not to tor 4 agonists stimulate innate resistance to infectious chal array spots with the immobilized control protein, IL-18. LPS lenge. Infect Immun. May 2005: 73(5):3044-52), Ahmed et stimulated plasma generally showed higher peaks of the bind al. (Mycetoma caused by Madurella mycetomatis: a ing partners (more binding) compared to the control plasma. neglected infectious burden. Lancet Infect Dis. September Plasma samples gave higher peaks when incubated on immo 2004; 4(9):566-74), in Schriewer et al. (Mouse models for bilized sINSP052 compared to serum. studying orthopoxvirus respiratory infections. Methods Mol 0251. The mouse peptide sequences were thus determined Biol. 2004; 269:289-308.) or Davis and (Breaking the species after transfer of the MS/MS data to the Mascot program and barrier: use of SCID mouse-human chimeras for the study of searches performed in protein databases available in house. human infectious diseases. Cell Microbiol. December 2003; Several binding partners were identified as follows: 5(12):849-60.). (0252) Properdin. The properdin size (49959 Da) fits 0262 Alternatively, biological activity of INSP052 with the observed SELDI mass of 56 kDa (the protein is polypeptides can be tested in mouse models of glomerulone glycosylated), phritis as described in Kikuchi et al. (A transgenic mouse 0253 Mannose-binding lectin C precursor (MBL-C). model of autoimmune glomerulonephritis and necrotizing The size of 25 kDa correlates with the gel band (ca 30 arteritis associated with cryoglobulinemia. J Immunol. Octo kDa). The protein forms tight polymers through disul ber 2002; 169(8):4644-50.), Nordstrand et al. (Streptokinase fide bonds, explaining the 50.6 kDa peak on SELDI. as a mediator of acute post-streptococcal glomerulonephritis (0254 MUSCRARF NID or P100 serine protease of the in an experimental mouse model. Infect Immun. January Ra reactive factor (RaRF), with a size of 81 kDa, 1998; 66(1):315-21.), or Rondeau E. (A new model of (0255 Antithrombin III (52 kDa), extramembranous glomerulonephritis in the mouse after a 0256 Complement factor H precursor (143 kDa), single injection of anti-aminopeptidase A monoclonal anti (0257 Albumin 1 (Fragment) (67kDa) and bodies Nephrologie. 1992: 13(3):138.). 0258 Mannose-binding lectin associated serine pro tease-2 (77 kDa). REFERENCES 0259 Unexpectedly, all the binding partners correspond to proteins from the complement pathway, namely to human 0263. 1. Abraham DJ, Shiwen X, Black CM, Sa S, Xu Y, properdin, mannose-binding lectin C (MBL-C), MASP1, Leask A. J. Biol Chem. 2000 May 19: 275(20): 15220-5. MASP2, antithrombin III, complement factor Hand albumin. 0264. 2. Altschul S Fetal, J Mol Biol, 215, 403-410, 1990 These surprising properties presently characterized of the 0265 3. Altschul S Fetal, Nucleic Acids Res., 25:389 polynucleotides or the corresponding polypeptides of Inter 3402, 1997 national Applications WO2003/093316 and No. PCT/ 0266 4. Devereux Jetal, Nucleic Acids Res, 12,387-395, GB2004/004772 make them particularly suitable for the 1984. preparation of a medicament or of a pharmaceutical compo 0267 5. Engelmann, H., Novick, D., and Wallach, D., sition. 1990, J. Biol. Chem. 265, 1531-1536. 0268 6. Pearson W R, Methods in Enzymology, 183, Example 3 63-99, 1990 0269. 7. Pearson W Rand Lipman DJ, Proc Nat Acad Sci Mouse Models USA, 85, 2444-2448, 1988. 0260. The biological activity of INSP052 polypeptides 0270 8. Tucci, A., James, H., Chicheportiche, R., Bonne can be tested in mouse models of cardiovascular diseases as foy, J.Y., Dayer, J. M., and Zubler, R. H., 1992, J. Immunol. described in Chu et al. (Gene-engineered models for genetic 148, 2778-2784.

SEQUENCE LISTING

<16 Oc NUMBER OF SEO ID NOS: 33

<210 SEQ ID NO 1 <211 LENGTH: 85 &212> TYPE: DNA <213> ORGANISM: homo sapiens US 2008/O 1934.14 A1 Aug. 14, 2008 16

- Continued

<4 OO SEQUENCE: 1 atgaagagag aaaggggagc cctgtc.ca.ga gcct C caggg C cctg.cgc.ct tcct cct titt 6 O gtctacct tc ttctgatcca gacag 85

<210 SEQ ID NO 2 <211 LENGTH: 29 &212> TYPE: PRT <213> ORGANISM: homo sapiens <4 OO SEQUENCE: 2 Met Lys Arg Glu Arg Gly Ala Lieu. Ser Arg Ala Ser Arg Ala Lieu. Arg 1. 5 1O 15 Lieu Ala Pro Phe Val Tyr Lieu. Lieu. Lieu. Ile Glin Thr Asp 2O 25

<210 SEQ ID NO 3 <211 LENGTH: 342 &212> TYPE: DNA <213> ORGANISM: homo sapiens

<4 OO SEQUENCE: 3 accc cctgga gggggtgaac at Caccagcc ccgtgcgc.ct gatccatggc accgtgggga 6 O agtcggct ct gctittctgtg cagtacagca gtaccagcag cacaggcct gtagtgaagt 12 O ggcagotgaa goggga caag C cagtgaccg tdgtgcagtic cattggcaca gaggt catcg 18O gcaccctg.cg gcc tigacitat cqagaccgta t cogact citt tdaaaatggc ticcictgcttic 24 O t cagcgacct gcagotggcc gatgagggca cct atgaggit Cagatct cc at Caccgacg 3OO acacct tcac tdggagaag accat calacc titact.gtaga tig 342

<210 SEQ ID NO 4 <211 LENGTH: 114 &212> TYPE: PRT <213> ORGANISM: homo sapiens

<4 OO SEQUENCE: 4 Pro Leu Glu Gly Val Asn Ile Thr Ser Pro Val Arg Lieu. Ile His Gly 1. 5 1O 15 Thr Val Gly Lys Ser Ala Lieu. Leu Ser Val Glin Tyr Ser Ser Thr Ser 2O 25 3 O Ser Asp Arg Pro Val Val Llys Trp Glin Lieu Lys Arg Asp Llys Pro Val 35 4 O 45 Thr Val Val Glin Ser Ile Gly Thr Glu Val Ile Gly Thr Lieu. Arg Pro SO 55 6 O Asp Tyr Arg Asp Arg Ile Arg Lieu. Phe Glu Asn Gly Ser Lieu. Lieu. Lieu 65 70 7s 8O Ser Asp Lieu. Glin Lieu Ala Asp Glu Gly Thr Tyr Glu Val Glu Ile Ser 85 9 O 95 Ile Thr Asp Asp Thr Phe Thr Gly Glu Lys Thr Ile Asn Lieu. Thr Val 1 OO 105 11O Asp Wall

<210 SEQ ID NO 5 <211 LENGTH: 282 &212> TYPE: DNA US 2008/O 1934.14 A1 Aug. 14, 2008 17

- Continued <213> ORGANISM: homo sapiens <4 OO SEQUENCE: 5 tgcc catttic gaggccacag gtgttggtgg Cttcaac cac ttgctggag ct cagcgagg 6 O

CCtt Caccitt gaactgctica catgagaatg gCaccaa.gcc cagct acacic tigctgaagg 12 O atggcaa.gcc cct cotcaat gactic gagaa tdctic ctdtc ccc.cgaccala aaggtgctica 18O c cat cacccg cgtgct catg gaggatgacg acctgtacag Ctgcatggtg gagaaccc.ca 24 O t cagcc aggg cc.gcagcctg cctgtcaaga t caccgtata Ca 282

<210 SEQ ID NO 6 <211 LENGTH: 94 &212> TYPE: PRT <213> ORGANISM: homo sapiens

<4 OO SEQUENCE: 6 Pro Ile Ser Arg Pro Glin Val Lieu Val Ala Ser Thr Thr Val Lieu. Glu 1. 5 1O 15 Lieu. Ser Glu Ala Phe Thr Lieu. Asn. Cys Ser His Glu Asn Gly. Thir Lys 2O 25 3 O Pro Ser Tyr Thir Trp Lieu Lys Asp Gly Llys Pro Lieu. Lieu. Asn Asp Ser 35 4 O 45 Arg Met Lieu. Lieu. Ser Pro Asp Gln Llys Val Lieu. Thir Ile Thr Arg Val SO 55 6 O Lieu Met Glu Asp Asp Asp Lieu. Tyr Ser Cys Met Val Glu Asn Pro Ile 65 70 7s 8O Ser Glin Gly Arg Ser Leu Pro Val Lys Ile Thr Val Tyr Arg 85 9 O

<210 SEQ ID NO 7 <211 LENGTH: 94 &212> TYPE: DNA <213> ORGANISM: homo sapiens

<4 OO SEQUENCE: 7 gaagaa.gctic cctttacatc atc.ttgtcta caggaggcat citt cotcctt gtgaccttgg 6 O tgacagtctg. tcctgctgg aaacccticca aaag 94

<210 SEQ ID NO 8 <211 LENGTH: 31 &212> TYPE: PRT <213> ORGANISM: homo sapiens

<4 OO SEQUENCE: 8 Arg Ser Ser Leu Tyr Ile Ile Leu Ser Thr Gly Gly Ile Phe Lieu. Leu 1. 5 1O 15 Val Thr Lieu Val Thr Val Cys Ala Cys Trp Llys Pro Ser Lys Arg 2O 25 3 O

<210 SEQ ID NO 9 <211 LENGTH: 74 &212> TYPE: DNA <213> ORGANISM: homo sapiens <4 OO SEQUENCE: 9 gaaacagaag aagctagaaa agcaaaactic cctggaatac atggat Caga atgatgaccg 6 O

US 2008/O 1934.14 A1 Aug. 14, 2008 20

- Continued Lieu Ala Pro Phe Val Tyr Lieu. Lieu. Lieu. Ile Glin Thr Asp Pro Lieu. Glu 2O 25 3 O Gly Val Asn Ile Thr Ser Pro Val Arg Lieu. Ile His Gly Thr Val Gly 35 4 O 45 Llys Ser Ala Lieu Lleu Ser Val Glin Tyr Ser Ser Thr Ser Ser Asp Arg SO 55 6 O Pro Val Val Lys Trp Glin Lieu Lys Arg Asp Llys Pro Val Thr Val Val 65 70 7s 8O Gln Ser Ile Gly Thr Glu Val Ile Gly Thr Lieu. Arg Pro Asp Tyr Arg 85 9 O 95 Asp Arg Ile Arg Lieu. Phe Glu Asn Gly Ser Lieu Lleu Lleu Ser Asp Lieu OO OS 1O Glin Lieu Ala Asp Glu Gly. Thir Tyr Glu Val Glu Ile Ser Ile Thr Asp 15 2O 25 Asp Thr Phe Thr Gly Glu Lys Thr Ile Asn Lieu. Thr Val Asp Val Pro 3O 35 4 O le Ser Arg Pro Glin Val Lieu Val Ala Ser Thr Thr Val Lieu. Glu Lieu. 45 SO 55 160 Ser Glu Ala Phe Thr Lieu. Asn Cys Ser His Glu Asn Gly Thr Llys Pro 65 70 7s Ser Tyr Thir Trp Lieu Lys Asp Gly Llys Pro Lieu. Lieu. Asn Asp Ser Arg 8O 85 90 Met Lieu. Lieu. Ser Pro Asp Gln Llys Val Lieu. Thir Ile Thr Arg Val Lieu. 95 2 OO 2O5 Met Glu Asp Asp Asp Lieu. Tyr Ser Cys Met Val Glu Asn Pro Ile Ser 210 215 22O Glin Gly Arg Ser Lieu Pro Wall Lys Ile Thr Val Tyr Arg Arg Ser Ser 225 23 O 235 24 O Lieu. Tyr Ile Ile Leu Ser Thr Gly Gly Ile Phe Lieu. Leu Val Thr Lieu. 245 250 255 Val Thr Val Cys Ala Cys Trp Llys Pro Ser Lys Arg Lys Glin Llys Llys 26 O 265 27 O Lieu. Glu Lys Glin Asn. Ser Lieu. Glu Tyr Met Asp Glin Asn Asp Asp Arg 27s 28O 285 Lieu Lys Pro Glu Ala Asp Thr Lieu Pro Arg Ser Gly Glu Glin Glu Arg 290 295 3 OO Lys Asn Pro Met Ala Lieu. Tyr Ile Lieu Lys Asp Lys Asp Ser Pro Glu 3. OS 310 315 32O Thr Glu Glu Asn Pro Ala Pro Glu Pro Arg Ser Ala Thr Glu Pro Gly 3.25 330 335 Pro Pro Gly Tyr Ser Val Ser Pro Ala Val Pro Gly Arg Ser Pro Gly 34 O 345 350 Lieu Pro Ile Arg Ser Ala Arg Arg Tyr Pro Arg Ser Pro Ala Arg Ser 355 360 365 Pro Ala Thr Gly Arg Thr His Ser Ser Pro Pro Arg Ala Pro Ser Ser 37O 375 38O Pro Gly Arg Ser Arg Ser Ala Ser Arg Thr Lieu. Arg Thr Ala Gly Val 385 390 395 4 OO His Ile Ile Arg Glu Glin Asp Glu Ala Gly Pro Val Glu Ile Ser Ala 4 OS 410 415

US 2008/O 1934.14 A1 Aug. 14, 2008 22

- Continued

OO OS 1O

Glin Luell Ala Asp Glu Thir Glu Wall Ile Ser Ile Thir Asp 15 25

Thir Phe Thr Gly Glu Thir Ile Asn Lel Thir Wall Asp Wall Pro 35

Ser Arg Pro Glin Wall Lell Wall Ala Ser Thir Wall Luell Glu Lieu. SO 160

Glu Ala Phe Thir Lell Asn Ser His Glu Asn Gly Thir Llys Pro 70

Thir Trp Lieu Asp Pro Lell Asn Asp Ser Arg 85

Met Luell Luell Ser Pro Asp Glin Wall Luell Ile Thir Arg Wall Lieu 95 2 OO

Met Glu Asp Asp Asp Lell Ser Wall Glu Asn Pro Ile Ser 210 215

Glin Wall Arg Ser Luell Pro Wall Ile Thir Wall Arg Arg Ser Ser 225 23 O 235 24 O

Lell Ile Ile Lieu. Ser Thir Gly Ile Phe Lell Lell Wall Thir Lieu. 245 250 255

Wall Thir Wall Cys Ala Cys Trp Pro Ser Lys Ser Arg 26 O 265 27 O

Arg Lel Glu Lys Glin Asn Ser Luell Glu Tyr Met Asp Glin ASn Asp 27s 28O 285

Asp Arg Lel Llys Ser Glu Ala Asp Thir Luell Pro Arg Ser Gly Glu Glin 290 295 3 OO

Glu Arg Asn. Pro Met Ala Luell Ile Luell Asp Asp Ser 3. OS 310 315 32O

Ser Glu Asp Glu Asn Pro Ala Thir Glu Pro Arg Ser Thir Thr Glu 3.25 330 335

Pro Gly Pro Gly Tyr Ser Wall Ser Pro Pro Wall Pro Gly Arg Ser 34 O 345 350

Pro Gly Lel Pro Ile Arg Ser Ala Arg Arg Tyr Pro Arg Ser Pro Ala 355 360 365

Arg Ser Ala Thr Gly Arg Thir His Thir Ser Pro Pro Arg Ala Pro 37O 375 38O

Ser Ser Gly Arg Ser Arg Ser Ser Ser Arg Ser Lell Arg Thir Ala 385 390 395 4 OO

Gly Wall Glin Arg Ile Arg Glu Glin Asp Glu Ser Gly Glin Wall Glu Ile 4 OS 410 415

Ser Ala

SEQ ID NO 19 LENGTH: 720 TYPE: DNA ORGANISM: homo sapiens SEQUENCE: 19 atgaagagag aaaggggagc cctgtc.ca.ga gcct c caggg c cctd.cgc.ct tgctccttitt 6 O gtctacct tc ttctgatcca gacagacic cc Ctggaggggg tgaacat cac Cagcc.ccgtg 12 O cgc.ctgat co atggcaccgt. ggggaagttcg gctctgctitt Ctgtgcagta Cagcagtacc 18O agcagcgaca ggcctgtagt galagtggcag acaa.gc.cagt gaccgtggtg 24 O US 2008/O 1934.14 A1 Aug. 14, 2008 23

- Continued

Cagt cc attg gcacagaggt catcggcacc Ctgcggcctg act at Caga cc.gitatc.cga 3OO Ctctttgaaa atggct coct gct tcticago gacctgcagc tiggc.cgatga gggcaccitat 360 gaggtogaga t ct coatcac cacgacacic titcactgggg agaagac cat Caacct tact 42O gtagatgtgc C cattt cag gcc acaggtg ttggtggctt Calaccactgt gctggagctic 48O agcgaggcct t caccittgaa citgct cacat gagaatggca C caagcc cag Ctacacctgg 54 O Ctgaaggatg gcaa.gc.ccct cct caatgac togagaatgc ticctgtc.ccc caccaaaag 6OO gtgcticacca t caccc.gc.gt gct catggag gatgacgacc titacagctg catggtggag 660 alacc cc at ca gcc agggc.cg cagcctgcct gtcaagat.ca ccgtata cag aagaa.gct cc 72 O

<210 SEQ ID NO 2 O <211 LENGTH: 24 O &212> TYPE: PRT <213> ORGANISM: homo sapiens

<4 OO SEQUENCE: 2O Met Lys Arg Glu Arg Gly Ala Lieu. Ser Arg Ala Ser Arg Ala Lieu. Arg 1. 5 1O 15 Lieu Ala Pro Phe Val Tyr Lieu. Lieu. Lieu. Ile Glin Thr Asp Pro Lieu. Glu 2O 25 3 O Gly Val Asn Ile Thr Ser Pro Val Arg Lieu. Ile His Gly Thr Val Gly 35 4 O 45 Llys Ser Ala Lieu Lleu Ser Val Glin Tyr Ser Ser Thr Ser Ser Asp Arg SO 55 6 O Pro Val Val Lys Trp Glin Lieu Lys Arg Asp Llys Pro Val Thr Val Val 65 70 7s 8O Gln Ser Ile Gly Thr Glu Val Ile Gly Thr Lieu. Arg Pro Asp Tyr Arg 85 9 O 95 Asp Arg Ile Arg Lieu. Phe Glu Asn Gly Ser Lieu Lleu Lleu Ser Asp Lieu OO OS 1O Glin Lieu Ala Asp Glu Gly. Thir Tyr Glu Val Glu Ile Ser Ile Thr Asp 15 2O 25 Asp Thr Phe Thr Gly Glu Lys Thr Ile Asn Lieu. Thr Val Asp Val Pro 3O 35 4 O le Ser Arg Pro Glin Val Lieu Val Ala Ser Thr Thr Val Lieu. Glu Lieu. 45 SO 55 160 Ser Glu Ala Phe Thr Lieu. Asn Cys Ser His Glu Asn Gly Thr Llys Pro 65 70 7s Ser Tyr Thir Trp Lieu Lys Asp Gly Llys Pro Lieu. Lieu. Asn Asp Ser Arg 8O 85 90 Met Lieu. Lieu. Ser Pro Asp Gln Llys Val Lieu. Thir Ile Thr Arg Val Lieu. 95 2 OO 2O5 Met Glu Asp Asp Asp Lieu. Tyr Ser Cys Met Val Glu Asn Pro Ile Ser 210 215 22O Glin Gly Arg Ser Lieu Pro Wall Lys Ile Thr Val Tyr Arg Arg Ser Ser 225 23 O 235 24 O

<210 SEQ ID NO 21 <211 LENGTH: 621 &212> TYPE: DNA <213> ORGANISM: homo sapiens US 2008/O 1934.14 A1 Aug. 14, 2008 24

- Continued <4 OO SEQUENCE: 21 gtgaac at Ca C cagcc.ccgt gcgc.ctgatc catggcaccg tdgggaagtic ggctctgctt 6 O tctgtgcagt acagoagtac Cagcagogac aggcctgtag taagtggca gctgaag.cgg 12 O gacaa.gc.cag taccgtggit gcagt ccatt ggcacagagg to atcggcac cctgcggcct 18O gacitat coag accitatic cq act ctittgaaaatggct coc togcttct cag cqacctgcag 24 O Ctggc.cgatgagggcaccita taggtogag atct c catca ccgacgacac Ctt cactggg 3OO gagalagacca t caaccttac titagatgtg cc cattt cqa ggccacaggt gttggtggct 360 t calaccactg. tctggagct cagcgaggcc titcaccttga actgct caca tagaatggc 42O accalagcc.ca gct acacctg gctgaaggat ggcaa.gc.ccc ticcitcaatga Citcgagaatg 48O

CtcCtgtc.cc ccgaccaaaa ggtgct cacc at Caccc.gcg tdot catgga ggatgacgac 54 O Ctgtacagct gcatggtgga galaccc.catc agc.cagggcc gcagcct gcc ttcaagat C 6OO accgtataca gaagaa.gctic C 621

<210 SEQ ID NO 22 <211 LENGTH: 2O7 &212> TYPE: PRT <213> ORGANISM: homo sapiens <4 OO SEQUENCE: 22 Val Asn. Ile Thr Ser Pro Val Arg Lieu. Ile His Gly Thr Val Gly Lys 1. 5 1O 15 Ser Ala Leu Lleu Ser Val Glin Tyr Ser Ser Thr Ser Ser Asp Arg Pro 2O 25 3 O Val Val Lys Trp Gln Lieu Lys Arg Asp Llys Pro Val Thr Val Val Glin 35 4 O 45 Ser Ile Gly. Thr Glu Val Ile Gly. Thir Lieu. Arg Pro Asp Tyr Arg Asp SO 55 6 O Arg Ile Arg Lieu. Phe Glu Asn Gly Ser Lieu. Lieu Lleu Ser Asp Lieu. Glin 65 70 7s 8O Lieu Ala Asp Glu Gly Thr Tyr Glu Val Glu Ile Ser Ile Thir Asp Asp 85 9 O 95 Thr Phe Thr Gly Glu Lys Thr Ile Asn Lieu. Thr Val Asp Val Pro Ile OO OS 1O Ser Arg Pro Glin Val Lieu Val Ala Ser Thr Thr Val Lieu. Glu Lieu Ser 15 2O 25 Glu Ala Phe Thr Lieu. Asn Cys Ser His Glu Asn Gly Thr Llys Pro Ser 3O 35 4 O yr Thir Trp Lieu Lys Asp Gly Llys Pro Lieu. Lieu. Asn Asp Ser Arg Met 45 SO 55 160 Lieu. Lieu. Ser Pro Asp Glin Llys Val Lieu. Thir Ile Thr Arg Val Lieu Met 65 70 7s Glu Asp Asp Asp Lieu. Tyr Ser Cys Met Val Glu ASn Pro Ile Ser Glin 8O 85 90 Gly Arg Ser Lieu Pro Wall Lys Ile Thr Val Tyr Arg Arg Ser Ser 95 2 OO 2O5

<210 SEQ ID NO 23 <211 LENGTH: 328 &212> TYPE: DNA <213> ORGANISM: homo sapiens

US 2008/O 1934.14 A1 Aug. 14, 2008 26

- Continued gaaaagcaaa act Coctgga atacatggat Cagaatgatg accgc.ctgaa accagaa.gca 78O gacacic ct co Ctcgaagtgg tagcaggala C9gaagaac C C catggcact ctatat cctg 84 O aaggacaagg act coccgga gaccgaggag aaccc.ggc.cc cagcctic aag.cgcgacg 9 OO gaggcc.ggcc cqC ccggcta Ctc.cgtgtct ccc.gc.cgtgc ccggcc.gctic gcc.ggggctg 96.O cc catc.cgct Ctgc.ccgc.cg ct accc.gc.gc. tcc cc agcgc gct coccagc Caccggc.cgg 1 O2O acacacticgt. c9ccgcc.cag ggcc.ccgagc ticgc.ccggcc gct cqcgcag cqc ct cqcgc 108 O acactg.cgga citgcgggcgt gcacataatc. c9cgagcaag acgaggc.cgg ccc.ggtggag 114 O atcagcgc.ct ga 1152

<210 SEQ ID NO 26 <211 LENGTH: 383 &212> TYPE: PRT <213> ORGANISM: homo sapiens <4 OO SEQUENCE: 26 Val Asn Ile Thr Ser Pro Val Arg Lieu. Ile His Gly Thr Val Gly Lys 1. 5 1O 15 Ser Ala Leu Lleu Ser Val Glin Tyr Ser Ser Thr Ser Ser Asp Arg Pro 2O 25 3 O Val Val Lys Trp Gln Lieu Lys Arg Asp Llys Pro Val Thr Val Val Glin 35 4 O 45 Ser Ile Gly. Thr Glu Val Ile Gly. Thir Lieu. Arg Pro Asp Tyr Arg Asp SO 55 6 O Arg Ile Arg Lieu. Phe Glu Asn Gly Ser Lieu. Lieu Lleu Ser Asp Lieu. Glin 65 70 7s 8O Lieu Ala Asp Glu Gly Thr Tyr Glu Val Glu Ile Ser Ile Thir Asp Asp 85 9 O 95 Thr Phe Thr Gly Glu Lys Thr Ile Asn Lieu. Thr Val Asp Val Pro Ile OO OS 1O Ser Arg Pro Glin Val Lieu Val Ala Ser Thr Thr Val Lieu. Glu Lieu Ser 15 2O 25 Glu Ala Phe Thr Lieu. Asn Cys Ser His Glu Asn Gly Thr Llys Pro Ser 3O 35 4 O yr Thir Trp Lieu Lys Asp Gly Llys Pro Lieu. Lieu. Asn Asp Ser Arg Met 45 SO 55 160 Lieu. Lieu. Ser Pro Asp Glin Llys Val Lieu. Thir Ile Thr Arg Val Lieu Met 65 70 7s Glu Asp Asp Asp Lieu. Tyr Ser Cys Met Val Glu ASn Pro Ile Ser Glin 8O 85 90 Gly Arg Ser Lieu Pro Wall Lys Ile Thr Val Tyr Arg Arg Ser Ser Lieu. 95 2 OO 2O5 Tyr Ile Ile Leu Ser Thr Gly Gly Ile Phe Leu Lleu Val Thr Lieu Val 210 215 22O Thr Val Cys Ala Cys Trp Llys Pro Ser Lys Arg Lys Glin Llys Llys Lieu. 225 23 O 235 24 O Glu Lys Glin Asn. Ser Lieu. Glu Tyr Met Asp Glin Asn Asp Asp Arg Lieu. 245 250 255 Llys Pro Glu Ala Asp Thir Lieu Pro Arg Ser Gly Glu Glin Glu Arg Llys 26 O 265 27 O Asn Pro Met Ala Lieu. Tyr Ile Lieu Lys Asp Lys Asp Ser Pro Glu Thr US 2008/O 1934.14 A1 Aug. 14, 2008 27

- Continued

27s 28O 285 Glu Glu Asn Pro Ala Pro Glu Pro Arg Ser Ala Thr Glu Pro Gly Pro 290 295 3 OO Pro Gly Tyr Ser Val Ser Pro Ala Val Pro Gly Arg Ser Pro Gly Lieu. 3. OS 310 315 32O Pro Ile Arg Ser Ala Arg Arg Tyr Pro Arg Ser Pro Ala Arg Ser Pro 3.25 330 335 Ala Thr Gly Arg Thr His Ser Ser Pro Pro Arg Ala Pro Ser Ser Pro 34 O 345 350 Gly Arg Ser Arg Ser Ala Ser Arg Thr Lieu. Arg Thr Ala Gly Val His 355 360 365 Ile Ile Arg Glu Glin Asp Glu Ala Gly Pro Val Glu Ile Ser Ala 37O 375 38O

<210 SEQ ID NO 27 <211 LENGTH: 256 &212> TYPE: PRT <213> ORGANISM: homo sapiens <4 OO SEQUENCE: 27 Met Lys Arg Glu Arg Gly Ala Lieu. Ser Arg Ala Ser Arg Ala Lieu. Arg 1. 5 1O 15 Lieu Ala Pro Phe Val Tyr Lieu. Lieu. Lieu. Ile Glin Thr Asp Pro Lieu. Glu 2O 25 3 O Gly Val Asn Ile Thr Ser Pro Val Arg Lieu. Ile His Gly Thr Val Gly 35 4 O 45 Llys Ser Ala Lieu Lleu Ser Val Glin Tyr Ser Ser Thr Ser Ser Asp Arg SO 55 6 O Pro Val Val Lys Trp Glin Lieu Lys Arg Asp Llys Pro Val Thr Val Val 65 70 7s 8O Gln Ser Ile Gly Thr Glu Val Ile Gly Thr Lieu. Arg Pro Asp Tyr Arg 85 9 O 95 Asp Arg Ile Arg Lieu. Phe Glu Asn Gly Ser Lieu Lleu Lleu Ser Asp Lieu OO OS 1O Glin Lieu Ala Asp Glu Gly. Thir Tyr Glu Val Glu Ile Ser Ile Thr Asp 15 2O 25 Asp Thr Phe Thr Gly Glu Lys Thr Ile Asn Lieu. Thr Val Asp Val Pro 3O 35 4 O le Ser Arg Pro Glin Val Lieu Val Ala Ser Thr Thr Val Lieu. Glu Lieu. 45 SO 55 160 Ser Glu Ala Phe Thr Lieu. Asn Cys Ser His Glu Asn Gly Thr Llys Pro 65 70 7s Ser Tyr Thir Trp Lieu Lys Asp Gly Llys Pro Lieu. Lieu. Asn Asp Ser Arg 8O 85 90 Met Lieu. Lieu. Ser Pro Asp Gln Llys Val Lieu. Thir Ile Thr Arg Val Lieu. 95 2 OO 2O5 Met Glu Asp Asp Asp Lieu. Asp Ser Cys Val Val Glu Asn Pro Ile Asn 210 215 22O Gln Gly Arg Thr Lieu Pro Cys Lys Ile Thr Val Tyr Lys Llys Ser Ser 225 23 O 235 24 O Lieu. Ser Ser Ile Trp Leu Gln Glu Ala Phe Ser Ser Lieu. Gly Pro Trp 245 250 255 US 2008/O 1934.14 A1 Aug. 14, 2008 28

- Continued

<210 SEQ ID NO 28 <211 LENGTH: 256 &212> TYPE: PRT <213> ORGANISM: homo sapiens <4 OO SEQUENCE: 28 Met Lys Arg Glu Arg Gly Ala Lieu. Ser Arg Ala Ser Arg Ala Lieu. Arg 1. 5 1O 15 Lieu Ala Pro Phe Val Tyr Lieu. Lieu. Lieu. Ile Glin Thr Asp Pro Lieu. Glu 2O 25 3 O Gly Val Asn Ile Thr Ser Pro Val Arg Lieu. Ile His Gly Thr Val Gly 35 4 O 45 Llys Ser Ala Lieu Lleu Ser Val Glin Tyr Ser Ser Thr Ser Ser Asp Arg SO 55 6 O Pro Val Val Lys Trp Glin Lieu Lys Arg Asp Llys Pro Val Thr Val Val 65 70 7s 8O Gln Ser Ile Gly Thr Glu Val Ile Gly Thr Lieu. Arg Pro Asp Tyr Arg 85 9 O 95 Asp Arg Ile Arg Lieu. Phe Glu Asn Gly Ser Lieu Lleu Lleu Ser Asp Lieu OO OS 1O Glin Lieu Ala Asp Glu Gly. Thir Tyr Glu Val Glu Ile Ser Ile Thr Asp 15 2O 25 Asp Thr Phe Thr Gly Glu Lys Thr Ile Asn Lieu. Thr Val Asp Val Pro 3O 35 4 O le Ser Arg Pro Glin Val Lieu Val Ala Ser Thr Thr Val Lieu. Glu Lieu. 45 SO 55 160 Ser Glu Ala Phe Thr Lieu. Asn Cys Ser His Glu Asn Gly Thr Llys Pro 65 70 7s Ser Tyr Thir Trp Lieu Lys Asp Gly Llys Pro Lieu. Lieu. Asn Asp Ser Arg 8O 85 90 Met Lieu. Lieu. Ser Pro Asp Gln Llys Val Lieu. Thir Ile Thr Arg Val Lieu. 95 2 OO 2O5 Met Glu Asp Asp Asp Lieu. Asp Ser Cys Val Val Glu Asn Pro Ile Asn 210 215 22O Gln Gly Arg Thr Lieu Pro Cys Lys Ile Thr Val Tyr Lys Llys Ser Ser 225 23 O 235 24 O Phe Tyr Ile Ile Cys Lieu Lys Glu Ala Ser Ser Ser Phe Gly Pro Trp 245 250 255

<210 SEQ ID NO 29 <211 LENGTH: 213 &212> TYPE: PRT <213> ORGANISM: homo sapiens

<4 OO SEQUENCE: 29 Val Asn Ile Thr Ser Pro Val Arg Lieu. Ile His Gly Thr Val Gly Lys 1. 5 1O 15 Ser Ala Leu Lleu Ser Val Glin Tyr Ser Ser Thr Ser Ser Asp Arg Pro 2O 25 3 O Val Val Lys Trp Gln Lieu Lys Arg Asp Llys Pro Val Thr Val Val Glin 35 4 O 45 Ser Ile Gly. Thr Glu Val Ile Gly. Thir Lieu. Arg Pro Asp Tyr Arg Asp SO 55 6 O US 2008/O 1934.14 A1 Aug. 14, 2008 29

- Continued Arg Ile Arg Lieu. Phe Glu Asn Gly Ser Lieu. Lieu Lleu Ser Asp Lieu. Glin 65 70 7s 8O Lieu Ala Asp Glu Gly Thr Tyr Glu Val Glu Ile Ser Ile Thir Asp Asp 85 9 O 95 Thr Phe Thr Gly Glu Lys Thr Ile Asn Lieu. Thr Val Asp Val Pro Ile OO OS 1O Ser Arg Pro Glin Val Lieu Val Ala Ser Thr Thr Val Lieu. Glu Lieu Ser 15 2O 25 Glu Ala Phe Thr Lieu. Asn Cys Ser His Glu Asn Gly Thr Llys Pro Ser 3O 35 4 O yr Thir Trp Lieu Lys Asp Gly Llys Pro Lieu. Lieu. Asn Asp Ser Arg Met 45 SO 55 160 Lieu. Lieu. Ser Pro Asp Glin Llys Val Lieu. Thir Ile Thr Arg Val Lieu Met 65 70 7s Glu Asp Asp Asp Lieu. Tyr Ser Cys Met Val Glu ASn Pro Ile Ser Glin 8O 85 90 Gly Arg Ser Leu Pro Val Lys Ile Thr Val Tyr Arg Arg Ser Ser His 95 2 OO 2O5

His His His His His 210

<210 SEQ ID NO 3 O <211 LENGTH: 439 &212> TYPE: PRT <213> ORGANISM: homo sapiens

<4 OO SEQUENCE: 30 Val Asn Ile Thr Ser Pro Val Arg Lieu. Ile His Gly Thr Val Gly Lys 1. 5 1O 15 Ser Ala Leu Lleu Ser Val Glin Tyr Ser Ser Thr Ser Ser Asp Arg Pro 2O 25 3 O Val Val Lys Trp Gln Lieu Lys Arg Asp Llys Pro Val Thr Val Val Glin 35 4 O 45 Ser Ile Gly. Thr Glu Val Ile Gly. Thir Lieu. Arg Pro Asp Tyr Arg Asp SO 55 6 O Arg Ile Arg Lieu. Phe Glu Asn Gly Ser Lieu. Lieu Lleu Ser Asp Lieu. Glin 65 70 7s 8O Lieu Ala Asp Glu Gly Thr Tyr Glu Val Glu Ile Ser Ile Thir Asp Asp 85 9 O 95 Thr Phe Thr Gly Glu Lys Thr Ile Asn Lieu. Thr Val Asp Val Pro Ile OO OS 1O Ser Arg Pro Glin Val Lieu Val Ala Ser Thr Thr Val Lieu. Glu Lieu Ser 15 2O 25 Glu Ala Phe Thr Lieu. Asn Cys Ser His Glu Asn Gly Thr Llys Pro Ser 3O 35 4 O yr Thir Trp Lieu Lys Asp Gly Llys Pro Lieu. Lieu. Asn Asp Ser Arg Met 45 SO 55 160 Lieu. Lieu. Ser Pro Asp Glin Llys Val Lieu. Thir Ile Thr Arg Val Lieu Met 65 70 7s Glu Asp Asp Asp Lieu. Tyr Ser Cys Met Val Glu ASn Pro Ile Ser Glin 8O 85 90 Gly Arg Ser Lieu Pro Wall Lys Ile Thr Val Tyr Arg Arg Ser Ser Glu 95 2 OO 2O5 US 2008/O 1934.14 A1 Aug. 14, 2008 30

- Continued

Pro Llys Ser Cys Asp Llys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 210 215 22O Glu Lieu. Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Llys Pro Llys 225 23 O 235 24 O Asp Thr Lieu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 245 250 255 Asp Wal Ser His Glu Asp Pro Glu Val Llys Phe Asn Trp Tyr Val Asp 26 O 265 27 O Gly Val Glu Val His Asn Ala Lys Thr Llys Pro Arg Glu Glu Glin Tyr 27s 28O 285 Asn Ser Thr Tyr Arg Val Val Ser Val Lieu. Thr Val Lieu. His Glin Asp 290 295 3 OO Trp Lieu. Asn Gly Lys Glu Tyr Lys Cys Llys Val Ser Asn Lys Ala Lieu. 3. OS 310 315 32O Pro Ala Pro Ile Glu Lys Thir Ile Ser Lys Ala Lys Gly Glin Pro Arg 3.25 330 335 Glu Pro Glin Val Tyr Thr Lieu Pro Pro Ser Arg Glu Glu Met Thr Lys 34 O 345 350 Asn Glin Val Ser Lieu. Thr Cys Lieu Val Lys Gly Phe Tyr Pro Ser Asp 355 360 365 Ile Ala Val Glu Trp Glu Ser Asn Gly Glin Pro Glu Asn. Asn Tyr Lys 37O 375 38O Thir Thr Pro Pro Val Lieu. Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 385 390 395 4 OO Llys Lieu. Thr Val Asp Llys Ser Arg Trp Glin Glin Gly Asn Val Phe Ser 4 OS 410 415 Cys Ser Val Met His Glu Ala Lieu. His Asn His Tyr Thr Glin Lys Ser 42O 425 43 O Lieu. Ser Lieu. Ser Pro Gly Lys 435

<210 SEQ ID NO 31 <211 LENGTH: 186 &212> TYPE: PRT <213> ORGANISM: homo sapiens <4 OO SEQUENCE: 31 Val Arg Lieu. Ile His Gly Thr Val Gly Lys Ser Ala Lieu. Lieu. Ser Val 1. 5 1O 15 Gln Tyr Ser Ser Thr Ser Ser Asp Arg Pro Val Val Lys Trp Glin Leu 2O 25 3 O Lys Arg Asp Llys Pro Val Thr Val Val Glin Ser Ile Gly Thr Glu Val 35 4 O 45 Ile Gly. Thir Lieu. Arg Pro Asp Tyr Arg Asp Arg Ile Arg Lieu. Phe Glu SO 55 6 O Asn Gly Ser Lieu Lleu Lleu Ser Asp Lieu. Glin Lieu Ala Asp Glu Gly Thr 65 70 7s 8O Tyr Glu Val Glu Ile Ser Ile Thr Asp Asp Thr Phe Thr Gly Glu Lys 85 9 O 95 Thir Ile Asn Lieu. Thr Val Asp Val Pro Ile Ser Arg Pro Glin Val Lieu. 1 OO 105 11O

Wall Ala Ser Thir Thir Wall Lieu. Glu Lieu. Ser Glu Ala Phe Thir Lieu. Asn US 2008/O 1934.14 A1 Aug. 14, 2008 31

- Continued

115 12O 125 Cys Ser His Glu Asn Gly Thr Llys Pro Ser Tyr Thr Trp Leu Lys Asp 13 O 135 14 O Gly Llys Pro Lieu. Lieu. Asn Asp Ser Arg Met Lieu Lleu Ser Pro Asp Glin 145 150 155 160 Llys Val Lieu. Thir Ile Thr Arg Val Lieu Met Glu Asp Asp Asp Lieu. Tyr 1.65 17O 17s Ser Cys Met Val Glu Asn Pro Ile Ser Glin 18O 185

<210 SEQ ID NO 32 <211 LENGTH: 131 &212> TYPE: PRT <213> ORGANISM: homo sapiens

<4 OO SEQUENCE: 32 Val Asn Ile Thr Ser Pro Val Arg Lieu. Ile His Gly Thr Val Gly Ser 1. 5 1O 15 Ile Thr Asp Asp Thr Phe Thr Gly Glu Lys Thr Ile Asn Lieu. Thr Val 2O 25 3 O Asp Val Pro Ile Ser Arg Pro Glin Val Lieu Val Ala Ser Thr Thr Val 35 4 O 45 Lieu. Glu Lieu. Ser Glu Ala Phe Thr Lieu. Asn. Cys Ser His Glu Asn Gly SO 55 6 O Thir Lys Pro Ser Tyr Thir Trp Lieu Lys Asp Gly Llys Pro Lieu. Lieu. Asn 65 70 7s 8O Asp Ser Arg Met Lieu Lleu Ser Pro Asp Glin Llys Val Lieu. Thir Ile Thr 85 9 O 95 Arg Val Lieu Met Glu Asp Asp Asp Lieu. Tyr Ser Cys Met Val Glu Asn 1 OO 105 11O Pro Ile Ser Glin Gly Arg Ser Leu Pro Val Lys Ile Thr Val Tyr Arg 115 12O 125

Arg Ser Ser 13 O

<210 SEQ ID NO 33 <211 LENGTH: 150 &212> TYPE: PRT <213> ORGANISM: homo sapiens

<4 OO SEQUENCE: 33 Val Asn Ile Thr Ser Pro Val Arg Lieu. Ile His Gly Thr Val Gly Lys 1. 5 1O 15 Ser Ala Leu Lleu Ser Val Glin Tyr Ser Ser Thr Ser Ser Asp Arg Pro 2O 25 3 O Val Val Lys Trp Gln Lieu Lys Arg Asp Llys Pro Val Thr Val Val Glin 35 4 O 45 Ser Ile Gly. Thr Glu Val Ile Gly. Thir Lieu. Arg Pro Asp Tyr Arg Asp SO 55 6 O Arg Ile Arg Lieu. Phe Glu Asn Gly Ser Lieu. Lieu Lleu Ser Asp Lieu. Glin 65 70 7s 8O Lieu Ala Asp Glu Gly Thr Tyr Glu Val Glu Ile Ser Ile Thir Asp Asp 85 9 O 95 Thr Phe Thr Gly Glu Lys Thr Ile Asn Lieu. Thr Val Asp Val Pro Ile US 2008/O 1934.14 A1 Aug. 14, 2008 32

- Continued

1 OO 105 11O Ser Arg Pro Glin Val Lieu Val Ala Ser Thr Thr Val Lieu. Glu Lieu Met 115 12O 125 Val Glu Asn Pro Ile Ser Glin Gly Arg Ser Leu Pro Val Lys Ile Thr 13 O 135 14 O Val Tyr Arg Arg Ser Ser 145 150

1-32. (canceled) tive Cocci, caused by Gram-Negative Aerobic Cocci, caused 33. A method of treating a disease comprising administer by Gram-Positive Bacilli, caused by Gram-Negative Bacilli, ing to a patient in need thereof an effective amount of a caused by Anaerobic Bacilli, caused by Spirochetes or caused composition comprising an INSP052 polypeptide and a phar by Mycobacteria. maceutically acceptable carrier, said INSP052 polypeptide: 36. The method according to claim 35, wherein the disease a) consisting of SEQID NO: 16; caused by Gram-Negative Aerobic Cocci is selected from the b) comprising SEQID NO: 2, SEQID NO: 4, SEQID NO: group consisting of meningitis, bacteremia, urethritis, cervi 6, SEQID NO: 8, SEQID NO: 10, SEQID NO: 12, SEQ citis, proctitis, pharyngitis, salpingitis, epididymitis, gonor ID NO: 14, SEQ ID NO: 16, SEQID NO: 18, SEQ ID rheal infection, acute cacterial meningitis, and Meningococ NO:20, SEQID NO:22, SEQID NO:24, SEQID NO: cal infection. 26, SEQID NO: 27, SEQID NO: 28, SEQID NO:29, 37. The method according to claim 34, wherein the Para SEQ ID NO:30, SEQ ID NO:31, SEQID NO:32 or sitic Infection is selected from the group consisting of SEQID NO:33; Extraintestinal Protozoa infection, infection with Free-Liv c) consisting of any of SEQ ID NO: 20, SEQID NO: 22, ing Amebas, Intestinal Protozoa infection, Nematode SEQID NO:27, SEQID NO: 28, SEQID NO: 29, SEQ (Roundworm) Infection, Trematode (Fluke) infection, and ID NO:30, SEQID NO:31, SEQID NO:32 or SEQID Cestodes (Tapeworms) infection. NO:33 in a soluble form: 38. The method according to claim 34, wherein the Viral d) being a mature form of SEQID NO:22, SEQID NO:24 Disease is selected from the group consisting of Respiratory or SEQID NO: 26; Viral Disease, Herpesvirus Infection, Central Nervous Sys tem Viral Disease, Arbovirus, and Arenavirus Disease. e) consisting of SEQID NO:29: 39. The method according to claim 33, wherein the proper f) being a glycosylated form of any of the polypeptides of din-related disease is a glomerular disease. (a) to (e), wherein the polypeptide is glycosylated at one 40. The method according to claim 39, wherein the glom or more sites; erular disease is selected from the group consisting of g) comprising a mutein of any of the polypeptides of (a) to nephritic syndrome, nephrotic syndrome, primary glomeru (f), wherein the amino acid sequence has at least 40% or lar disease, and secondary renal disease. 50% or 60% or 70% or 80% or 90% identity to at least 41. The method according to claim 40, wherein the primary one of the corresponding sequences in (a) to (f), and glomerular disease is selected from the group consisting of wherein said mutein retains INSP052 biological activ minimal change disease, focal segmental glomerulosclerosis, ity; membranous glomerulonelhritis, membranoproliferative h) comprising a mutein of any of the polypeptides of (a) to glomerulonephritis, mesangial proliferative glomerulone (f) wherein any changes in the amino acid sequence are phritis, IgA nephropathy, rapidly progressive glomerulone conservative amino acid Substitutions to the amino acid phritis, and fibrillary glomerulonephritis. sequences in (a) to (f), and wherein said mutein retains 42. The method according to claim 40, wherein the INSP052 biological activity; or nephritic syndrome is selected from the group consisting of i) comprising a salt, isoform, fusion protein, functional hematuria, hypertension, renal insufficiency, edema, acute derivative, active fraction or circularly permutated glomerulonephritis, transient glomerulonephritis, postinfec derivative of any of the polypeptides of (a) to (h); and tious glomerulonephritis, fulminant glomerulonephritis, rap said disease being selected from infectious disease, proper idly progressive glomerulonephritis (RPGN), indolent glom din-related disease, MBL2-related disease, MASP1-related erulonephritis, IgA nephropathy, crescentic disease, MASP2-related disease, Antithrombin III-related glomerulonephritis, Pauci-immune RPGN, Immune complex disease, Complement factor H-related disease or Albumin RPGN, Anti-GBM antibody disease autoimmunity, primary related disease. renal hematuric-proteinuric syndrome, asymptomatic hema 34. The method according to claim 33, wherein the infec turic-proteinuric syndrome, chronic nephritic-proteinuric tious disease is selected from a group consisting of Systemic syndrome, chronic glomerulonephritis, and slowly progres Fungal Disease, Rickettsial Disease, Chlamydial Disease, sive glomerular disease. Parasitic Infection, Viral Disease, Abscess, Human Immuno 43. The method according to claim 33, wherein the deficiency Virus Infection, Bacteremia, Septic Shock, Sexu INSP052 polypeptide is: ally Transmitted Disease, and Bacterial Disease. a) glycosylated at residues 2,71, 105, 134, 139 and/or 156 35. The method according to claim 34, wherein the bacte of SEQID NO: 22: rial disease is selected from a disease caused by Gram-Posi b) fused to an immunoglobulin (Ig); US 2008/O 1934.14 A1 Aug. 14, 2008 33

c) fused to a Fc region of an immunoglobulin; 51. A method of treating a disease comprising administer d) SEQID NO:30; ing to a patient in need thereof an effective amount of a composition comprising a nucleic acid encoding an INSP052 e) a functional derivative that includes at least one moiety polypeptide and a pharmaceutically acceptable carrier, said attached to one or more functional groups; or INSP052 polypeptide: f) a functional derivative that includes a polyethylene moi a) consisting of SEQID NO: 16: ety. b) comprising SEQID NO: 2, SEQID NO: 4, SEQID NO: 44. The method according to claim 33, wherein said com 6, SEQID NO: 8, SEQID NO: 10, SEQID NO: 12, SEQ position further comprises an interferon, for simultaneous, ID NO: 14, SEQ ID NO: 16, SEQID NO: 18, SEQ ID sequential, or separate use. NO:20, SEQID NO:22, SEQID NO:24, SEQID NO: 45. The method according to claim 44, wherein the inter 26, SEQID NO: 27, SEQID NO: 28, SEQID NO: 29, feron is interferon-?3. SEQ ID NO:30, SEQ ID NO:31, SEQID NO:32 or 46. The method according to claim 33, wherein pharma SEQ ID NO:33; ceutical composition further comprises a Tumor Necrosis c) consisting of any of SEQID NO: 20, SEQID NO: 22, Factor (TNF) antagonist for simultaneous, sequential, or SEQ ID NO:27, SEQID NO: 28, SEQID NO: 29, SEQ separate use. ID NO:30, SEQID NO:31, SEQID NO:32 or SEQID NO:33 in a soluble form: 47. The method according to claim 46, wherein the TNF d) being a mature form of SEQID NO:22, SEQIDNO: 24 antagonist is TBPI and/or TBPII. or SEQID NO: 26; 48. The method according to claim 33, wherein the com e) consisting of SEQID NO:29: position further comprises an anti-infectious agent and/or an f) being glycosylated form of any of the polypeptides of(a) anti-blood clotting agent for simultaneous, sequential, or to (e), wherein the polypeptide is glycosylated at one or separate use. more sites; 49. The method according to claim 48, wherein the anti g) comprising a mutein of any of the polypeptides of (a) to infectious agent is selected from the group consisting of pen (f), wherein the amino acid sequence has at least 40% or tamidine, antibiotics, colistine, aminoglycosides, and 50% or 60% or 70% or 80% or 90% identity to at least amphotericin B. one of the corresponding sequences in (a) to (f), and 50. The method according to claim 47, wherein the anti wherein said mutein retains INSP052 biological activ blood clotting agent is selected from the group consisting of ity; nitrates, nitroglycerin, isosorbide dinitrate, isosorbide mono h) comprising a mutein of any of the polypeptides of (a) to nitrate, vitamin C or E, beta-blockers, propranolol, labetalol, (f) wherein any changes in the amino acid sequence are acebutolol, atenolol, metoprolol, bisoprolol, carvedilol, anti conservative amino acid substitutions to the amino acid coagulants, heparin, warfarin, anti-platelet drug, aspirin, gly sequences in (a) to (f), and wherein said mutein retains coprotein IIb/IIIa receptorantagonists, clopidogrel, NSAIDs, INSP052 biological activity; or enoxaparin, dalteparin, reviparin, abciximab, eptifibatide, i) comprising a salt, isoform, fusion protein, functional lamifiban, tirofiban, abciximab, clopidogrel, ticlopidine, derivative, active fraction or circularly permutated hirudin, bivalirudin, argatroban, danaparoid, statins, Angio derivative of any of the polypeptides of (a) to (h); and tensin Converting Enzyme Inhibitors Angiotensin converting said disease being selected from infectious disease, proper enzyme (ACE) inhibitors, ramipril, captopril, enalapril, lisi din-related disease, MBL2-related disease, MASP1-related nopril, fosinopril, calcium channel blockers, Verapamil, nife disease, MASP2-related disease, Antithrombin III-related dipine, nicardipine, amlodipine, diltiazem, bepridil, ranola disease, Complement factor H-related disease or Albumin Zine, nicorandil, antibiotics, tetracyclines, quinolones, folic related disease. acid, thrombolytics, recombinant tissue plasminogen activa 52. The method according to claim 51, wherein said tors (rt-Pas), alteplase, activase, reteplase, fibrin-depleting nucleic acid encoding an INSP052 polypeptide is a vector. agent, ancrod, batroXobin, thienopyridines, clopidogrel, 53. The method according to claim 51, wherein said ticlopidine, thienopyridines, direct thrombin inhibitors nucleic acid encoding an INSP052 polypeptide is integrated (DTIs), lepirudin, desirudin, inogatran, efegatran, Ximelagat into a host cell. ran, antifibrinolytics, tranexamic acid, and epsilon amino caproic acid.