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|HAI LAMA MTU MATUTUTUS009962408B2 KITA MAMA (12 ) United States Patent ( 10 ) Patent No. : US 9 , 962, 408 B2 Deisher ( 45 ) Date of Patent: May 8 , 2018 ( 54 ) COMPOSITIONS AND METHODS TO (52 ) U . S . CI. INHIBIT STEM CELL AND PROGENITOR CPC . .. A61K 35 /28 (2013 . 01 ) ; A61K 31/ 573 CELL BINDING TO LYMPHOID TISSUE AND ( 2013 .01 ) ; A61K 39 /3955 ( 2013 .01 ) ; CO7K FOR REGENERATING GERMINAL 16 /28 78 ( 2013 .01 ) ; AIK 35 / 12 (2013 .01 ) ; CENTERS IN LYMPHATIC TISSUES A61K 2039 /505 ( 2013 .01 ) ; C12N 5 /0602 ( 2013 .01 ) ( 71 ) Applicant : Ave Maria Biotechnology LLC , (58 ) Field of Classification Search Seattle , WA (US ) CPC .. .. A61K 31/ 573 ; A61K 35 /12 , A61K 35 / 28 ; C12N 5 /0602 ( 72 ) Inventor : Theresa Deisher, Seattle , WA (US ) USPC .. .. .. .. .. 435 /375 ; 424 /93 . 7 ; 514 / 1 ( 73 ) Assignee : AVM Biotechnology LLC , Seattle , WA See application file for complete search history . (US ) (56 ) References Cited ( * ) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 U . S . C . 154 (b ) by 0 days . days . PUBLICATIONS Kolf et al ., 2007 , Arthritis Research & Therapy, vol. 9 , p . 204, 10 ( 21 ) Appl. No .: 15 /410 , 759 pages .* Alenzi et al. , 2011 , African Journal of Biotechnology , vol. 10 ( 86 ), (22 ) Filed : Jan . 19 , 2017 pp . 19929 - 19940 . * Wu et al. , 2012 , Aging Research reviews, vol. 11 , p . 32 - 40 . * (65 ) Prior Publication Data Steinert et al. , 2007 , Arthritis Research & therapy, vol . 9 , No . 3 , 213 , p . 1 - 15 . * US 2017 /0128493 A1 May 11, 2017 Li et al. , 2009 , Transplant Immunology , vol. 21, p . 70 - 74 . * Related U . S . Application Data Sprangers et al. , 2008 , Kidney International , vol . 74 , p . 14 -21 . * (63 ) Continuation of application No . 13 /212 , 916 , filed on * cited by examiner Aug . 18 , 2011 , now abandoned . (60 ) Provisional application No .61 / 374 , 943 , filed on Aug . Primary Examiner — Shin Lin Chen 18 , 2010 , provisional application No. 61 /441 , 485 , (74 ) Attorney , Agent, or Firm — Baumgartner Patent filed on Feb . 10 , 2011 , provisional application No . Law ; Marc Baumgartner 61/ 449 , 372 , filed on Mar. 4 , 2011 . (57 ) ABSTRACT ( 51 ) Int. Cl. A01N 63 / 00 ( 2006 .01 ) The present invention relates to compositions and methods A61K 31/ 00 ( 2006 .01 ) of inhibiting stem cell binding to organs and tissues , includ C12N 5 / 00 ( 2006 . 01 ) ing the blocking of stem cell binding to germinal centers A61K 35 /28 ( 2015 . 01 ) present in lymph tissue . Disclosed are compositions and A61K 31 /573 ( 2006 .01 ) methods for regenerating germinal centers in lymphatic COZK 16 / 28 ( 2006 .01 ) tissue . Included in the compositions are adjuvants , agonists A61K 39 /395 ( 2006 .01 ) to CD40 , CD28 and the IL -21 receptor, and antagonist to A61K 39 / 00 ( 2006 . 01 ) CD20 . A61K 35 / 12 ( 2015 .01 ) C12N 5 /071 ( 2010 .01 ) 15 Claims, 1 Drawing Sheet U . S . Patent May 8 , 2018 US 9 , 962, 408 B2 - - - - Platelets Buffy coat with - - MNCs and Stem Cells HE Ficoll RBC pellet and Stem Cells Layers resulting from gradient centrifugation of whole blood US 9 , 962, 408 B2 COMPOSITIONS AND METHODS TO minal centers in the spleen . The term ‘ in conjunction with ’ INHIBIT STEM CELL AND PROGENITOR means together, before or after the stem cell treatment . CELL BINDING TO LYMPHOID TISSUE AND ‘ Stem cell treatment means the act of administering stem FOR REGENERATING GERMINAL cells to the individual, mobilizing stem cells from within the CENTERS IN LYMPHATIC TISSUES 5 individual' s endogenous stem cell stores , or relying on spontaneous release of stem cells from the individual' s CROSS -REFERENCE TO RELATED endogenous stem cell stores . For example , patients treated with stem cells to elicit APPLICATIONS organ regeneration have demonstrated reductions in mortal This application is a continuation of U . S . patent applica - 10 ity and improvements in function following stem cell tion Ser. No . 13 / 212 , 916 , filed Aug . 18 , 2011, which claims therapy , although the stem cell treatments do not generally benefit of priority to U . S . Provisional Application No. restore the patient to their functional status prior to organ 61/ 374 , 943 filed Aug . 18 , 2010 ; and to U . S . Provisional injury . Reductions in stem cell binding to the spleen and Application No . 61/ 441 , 485 filed Feb . 10 , 2011; and to U . S . other lymphatics augment the numbers of circulating stern Provisional Application No . 61 /449 , 372 filed Mar . 4 , 2011. 15 cells that can be attracted to the injured organ and thereby All of the foregoing applications are hereby incorporated by augment the degree of functional recovery induced by steal cell treatment of that patient . reference in their entirety . In administering the therapeutic agents that inhibit the FIELD OF THE INVENTION binding of stem cells to lymphatic tissues it is preferred to 20 administer the therapeutic agents 1 - 14 days prior to treat Subject matter of the disclosure concerns methods and ment, more preferably 3 - 7 days and most preferably 3 - 4 compositions to modulate stem cell binding to organs and days prior to treatment with stem cells or mobilization of tissues and for regenerating germinal centers in lymphatic stem cells . In administering the therapeutic agents that tissues . inhibit the binding of stem cells to lymphatic tissues in 25 conjunctiond with spontaneously released stem cells from the BACKGROUND OF THE INVENTION individual' s endogenous stem cell stores it is preferred to administer the therapeutic agents over a period of 1 -60 days , Regenerative Medicine is the process of creating living , more preferably 1 - 30 days , and most preferably 1 -14 days . functional tissues to repair or replace tissue or organ func - Agents that inhibit the binding of stem cells to lymphoid tion lost due to damage, or congenital defects . This field 30 tissues , particularly to the germinal centers of lymphoid holds the promise of regenerating damaged tissues and tissues , include radiation , chemotherapeutic agents , immune organs in the body by stimulating previously irreparable suppressants and antagonists to CD45 and antagonists to organs to heal themselves . CD26 . Stem cells found within the mononuclear fractions One method used to regenerate tissue or organ function is from whole blood or bone marrow , or purified stem cells the delivery of stem cells to the affected organ or tissue . 35 from whole blood or bone marrow , bind to the white pulp However , stem cells are not well retained in the organ regions in the spleen , more specifically to germinal centers targeted for tissue regeneration even when the stem cells are in the white pulp of lymphatic tissue including the spleen , directly injected into the tissue of the injured organ . Imaging and even more specifically to active germinal centers in the studies in humans and animals have demonstrated that most white pulp of the spleen . Antibodies to CD45 , particularly to of the delivered stem cells can be found within the spleen 40 the epitope identified by the 30 - F11 rat IgG2b anti -mouse within an hour after stem cell injection . Animal studies have anti -CD45 monoclonal antibody , reduce stem cell binding to also demonstrated that surgical removal of the spleen prior the identified sites in the spleen , making more stem cells to stem cell therapy after induced myocardial infarction available for biodistribution to the targeted injured organ , improved functional recovery of the damaged hearts ( Blood , and enhancing tissue regeneration and functional recovery . Vol 84 , No 5 : 1482 - 1491, 1994 ; NATURE 410 :701 -705 , 45 In another embodiment of the present invention therapeu 2001 ) . Splenectomy has also been shown to improve tic agents are administered that reduce , destroy or ablate engraftment in human patients after bone marrow transplan active germinal centers in the lymphoid tissue thus resulting tation ( Stem Cells Dev 13 ( 1 ) :51 -62 , 2004 ; Transplant Proc . in the reduction of the binding of stem cells to the lymph 28 ( 2 ): 736 - 7 , 1996 ; Am J Hematol. 22 ( 3 ) :275 - 83 , 1986 ) . tissue . Another embodiment of the present invention However , splenectomy is also associated with surgical mor - 50 describes methods to reduce the number of active germinal tality , sepsis , and lifelong thrombotic complications (Blood centers in the spleen to reduce stem cell binding to the Rev. 14 (3 ) : 121- 129, 2000 ; Leukemia . 15 ( 3 ) :465 - 467, 2001; spleen , thereby increasing the numbers of circulating stem Pediatr Transplant 13 ( 2 ) : 171 - 176 , 2009 ) cells available for delivery or homing to damaged organs in Thus, there is a need to develop methods and composi- need of repair . Agents that suppress the immune response tions that can be used to prevent localization of stem cells in 55 may reduce the numbers of active germinal centers in the the spleen and other lymphoid tissues without removal of the spleen and other lymphatic tissues . General categories of spleen . immune modulators include agents that interfere with the synthesis of purines , the anti -metabolites , radiation , radia DESCRIPTION OF THE INVENTION tion to the spleen , immunosuppressants , glucocorticoids , 60 anti -beta amyloid agents , anti -rhesus factor, anti - TNF Overview agents , anti- eotaxins, anti - T cell receptor ( TCR ) agents , The present invention fills this need by providing for anti- interferons agents , anti - interferon alpha agents, anti methods and compositions for inhibiting binding of stem interferon
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  • (12) Patent Application Publication (10) Pub. No.: US 2015/0250896 A1 Zhao (43) Pub

    (12) Patent Application Publication (10) Pub. No.: US 2015/0250896 A1 Zhao (43) Pub

    US 20150250896A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0250896 A1 Zhao (43) Pub. Date: Sep. 10, 2015 (54) HYDROPHILIC LINKERS AND THEIR USES Publication Classification FOR CONUGATION OF DRUGS TO A CELL (51) Int. Cl BNDING MOLECULES A647/48 (2006.01) (71) Applicant: Yongxin R. ZHAO, Henan (CN) Ek E. 30.8 C07D 207/216 (2006.01) (72) Inventor: R. Yongxin Zhao, Lexington, MA (US) C07D 40/12 (2006.01) C07F 9/30 (2006.01) C07F 9/572 (2006.01) (73) Assignee: Hangzhou DAC Biotech Co., Ltd., (52) U.S. Cl. Hangzhou City, ZJ (CN) CPC ........... A61K47/48715 (2013.01); C07F 9/301 (2013.01); C07F 9/65583 (2013.01); C07F (21) Appl. No.: 14/432,073 9/5721 (2013.01); C07D 207/46 (2013.01); C07D 401/12 (2013.01); A61 K3I/454 (22) PCT Filed: Nov. 24, 2012 (2013.01) (86). PCT No.: PCT/B2O12/0567OO Cell(57) binding- agent-drugABSTRACT conjugates comprising hydrophilic- S371 (c)(1), linkers, and methods of using Such linkers and conjugates are (2) Date: Mar. 27, 2015 provided. Patent Application Publication Sep. 10, 2015 Sheet 1 of 23 US 2015/0250896 A1 O HMDS OSiMe 2n O Br H-B-H HPC 3 2 COOEt essiop-\5. E B to NH 120 °C, 2h OsiMe3 J 50 °C, 2h eSiO OEt 120 oC, sh 1 2 3. 42% from 1 Bra-11a1'oet - Brn 11-1 or a 1-1 or ÓH 140 °C ÓEt ÓEt 4 5 6 - --Messio. 8 B1a-Br aus 20 cc, hP-1}^-'ot Br1-Y.