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(12) Patent Application Publication (10) Pub. No.: US 2015/0050270 A1 Li Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2015/0050270 A1 Li Et Al US 2015.005O270A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0050270 A1 Li et al. (43) Pub. Date: Feb. 19, 2015 (54) ANTIBODIES TO BRADYKININ B1 Publication Classification RECEPTOR LIGANDS (51) Int. Cl. (71) Applicant: Sanofi, Paris (FR) C07K 6/28 (2006.01) A647/48 (2006.01) (72) Inventors: Han Li, Yardley, PA (US); Dorothea Kominos, Millington, NJ (US); Jie (52) U.S. Cl. Zhang, Cambridge, MA (US); Alla CPC ........... C07K 16/28 (2013.01); A61K 47/48007 Pritzker, Cambridge, MA (US); (2013.01); C07K 2317/92 (2013.01); C07K Matthew Davison, Cambridge, MA 2317/565 (2013.01); C07K 2317/76 (2013.01); (US); Nicolas Baurin, Arpajon (FR); C07K 231 7/24 (2013.01); A61K 2039/505 Govindan Subramanian, Belle Mead, (2013.01) NJ (US); Xin Chen, Edison, NJ (US) USPC .................. 424/133.1; 530/387.3; 530/3917; 536/23.53; 435/320.1; 435/334: 435/69.6 (73) Assignee: SANOFI, Paris (FR) (21) Appl. No.: 14/382,798 (57) ABSTRACT (22) PCT Filed: Mar. 15, 2013 The invention provides antibodies that specifically bind to (86). PCT No.: PCT/US13A31836 Kallidin ordes-Arg10-Kallidin. The invention also provides S371 (c)(1), pharmaceutical compositions, as well as nucleic acids encod (2) Date: Sep. 4, 2014 ing anti-Kallidin ordes-Arg10-Kallidin antibodies, recombi nant expression vectors and host cells for making such anti Related U.S. Application Data bodies, or fragments thereof. Methods of using antibodies of (60) Provisional application No. 61/616,845, filed on Mar. the invention to modulate Kallidin or des-Arg10-Kallidin 28, 2012. activity or detect Kallidin ordes-Arg10-Kallidin or, either in vitro or in vivo, are also provided by the invention. The (30) Foreign Application Priority Data invention further provides methods of making antibodies that specifically bind to des-Arg-Bradykinin and des-Argo-Kal Feb. 4, 2013 (FR) ....................................... 1350953 lidin-like peptide. Patent Application Publication Feb. 19, 2015 Sheet 1 of 17 US 2015/0050270 A1 Iuu/6nqyuu |?Infil –09'Z 00'Z 00"| 00°0 907 CO Patent Application Publication Feb. 19, 2015 Sheet 4 of 17 US 2015/0050270 A1 Patent Application Publication Feb. 19, 2015 Sheet 5 of 17 US 2015/0050270 A1 Patent Application Publication Feb. 19, 2015 Sheet 6 of 17 US 2015/0050270 A1 Patent Application Publication Feb. 19, 2015 Sheet 8 of 17 US 2015/0050270 A1 LGT LZT GZT LZT 8ZI 8ZI Patent Application Publication Feb. 19, 2015 Sheet 9 of 17 US 2015/0050270 A1 ( 6eun61-I 6 9 8 CN y (dnouf Jed 9-1=N) WS-/+ueeu eSuOdseu e IOIAeue Patent Application Publication Feb. 19, 2015 Sheet 10 of 17 US 2015/0050270 A1 > C s - E s d c o s D s t t N r o C O e O l C 9 o 0. s 2 e s 2 9 S. Š O O O O O O Se o o S GN (%) eSuodse. Jo Aouen be Patent Application Publication Feb. 19, 2015 Sheet 11 of 17 US 2015/0050270 A1 N ed s Yd N y O (Spuooes) Aouee eMepuM Med Patent Application Publication Feb. 19, 2015 Sheet 12 of 17 US 2015/0050270 A1 2 . 2 : 2 2 O O O O O O O CO O t CN y (%) AAISueSued/ueouleuoeu Jo IeSue Ne Patent Application Publication Feb. 19, 2015 Sheet 13 of 17 US 2015/0050270 A1 O 9 d O e O . o d o 9 CD CD (spuodes) Aouee eMeupu M Aed Patent Application Publication Feb. 19, 2015 Sheet 14 of 17 US 2015/0050270 A1 izL3.Infil Patent Application Publication Feb. 19, 2015 Sheet 17 of 17 US 2015/0050270 A1 s US 2015/005O270 A1 Feb. 19, 2015 ANTIBODIES TO BRADYKINNB1 0010 c) specifically binds to Kallidin ordes-Argo-Kalli RECEPTOR LIGANDS din with a Kofless than 1x10's"; or 00.11 d) specifically binds to Kallidin ordes-Argo-Kalli RELATED APPLICATIONS din and inhibits binding to the bradykinin B1 receptor. 0001. This application claims priority to U.S. Provisional 0012. In one embodiment, the antibody or antigen binding Application No. 61/616,845, filed Mar. 28, 2012, and French fragment thereof binds to the N-terminal Lysine residue of Patent Application Number 1350953, filed Feb. 4, 2013. The Kallidin ordes-Argo-Kallidin. contents of these applications are each hereby incorporated 0013. In another embodiment, the antibody or antigen binding fragment thereof inhibits the binding of Kallidin or by reference in their entireties. des-Argo-Kallidin to a bradykinin-1 receptor. 0014. In another embodiment, the antibody or antigen SEQUENCE LISTING binding fragment thereof binds specifically to mouse Kalli 0002 The instant application contains a Sequence Listing din-like peptide (KLP). which has been submitted in ASCII format via EFS-Web and 0015. In another embodiment, the antibody or antigen is hereby incorporated by reference in its entirety. Said ASCII binding fragment thereof comprises a heavy chain variable copy, created on Mar. 15, 2013, is named 543895 SA9 domain comprising an HCDR3 amino acid sequence selected 029PC Seq List.txt and is 89,291 bytes in size. from the group consisting of 10016 a) SEQ ID NO: 7 DXY X, XD XHAMX,Y), BACKGROUND OF THE INVENTION wherein 0003. The bradykinin B1 receptor has been implicated in 0017 X is Y. For H, pathogenesis of inflammatory disease and chronic pain. By (0018 X is R, D, A, V. L., I, M, FY or W. modulating tissue inflammation and renal fibrosis, the B1 (0.019 X is Y. F. W or H, receptor has also been associated with pathogenesis of acute 0020 X is D, E or Y, and, kidney injury as well as chronic kidney diseases which are the (0021 X is D or E: main causes of end-stage renal failure. 0022 b) SEQ ID NO: 63 X EYDGXYXXLDX), 0004. In humans, the major agonists of the bradykinin B1 wherein receptor are the kinins. Kinins are bioactive peptides pro 0023 X is W or F, duced from the proteolytic cleavage of kininogen proteins. 0024 X is N or no amino acid; The major kinin agonists of bradykinin B1 receptor are the 0025 X is Y or S, decapeptide Kallidin, and the nonapeptide des-Argo-Kalli (0026 X is D or P. and din (formed by the proteolytic cleavage the c-terminal argin (0027 X is ForY. ine form Kallidin). Therefore, agents that can inhibit the 0028 c) SEQ ID NO: 13; binding of Kallidin and des-Argo-Kallidin to the bradykinin 0029 d) SEQID NO:32: B1 receptor have the potential to treat or prevent bradykinin 0030 e) SEQ ID NO: 40; B1 receptor-mediated pathologies. 0031 f) SEQID NO: 47; and 0005 Accordingly, there is a need in the art for novel 0032 g) SEQID NO. 55. agents that inhibit the binding of Kallidin and des-Argo 0033. In another embodiment, the antibody or antigen Kallidinto the bradykinin B1 receptor for use in the treatment binding fragment thereof comprises an HCDR2 amino acid of bradykinin B1 receptor-mediated human pathologies. sequence selected from the group consisting of SUMMARY OF THE INVENTION 0034) a) SEQID NO: 8 (YFXPXNGNTGYNQKFRG), wherein 0006. The present invention provides antibodies, or anti 0035 X is D, R, A, V. L. I. M. F. Y or W, and gen binding fragments thereof, that specifically bind Kallidin 003.6 X is Y, D, E, N, or Q: and des-Argo-Kallidin and prevent binding to the bradykinin 0037 b) SEQ ID NO: 64 B1 receptor. Such antibodies are particularly useful for treat ing Kallidin and des-Argo-Kallidin-associated diseases or |WXDPENGDXXYAPKFQG), wherein disorders (e.g., pain or fibrosis). The invention also provides 0038 X is I, or V. pharmaceutical compositions, as well as nucleic acids encod 0039 X is T, or S, and ing anti-Kallidin and des-Argo-Kallidin antibodies, recom 0040 X is G, or D: binant expression vectors and host cells for making Such 0041 c) SEQ ID NO: 14 antibodies, or fragments thereof. Methods of using antibod 0.042 d) SEQID NO:33; ies, or fragments thereof, of the invention to detect Kallidin 0043 e) SEQ ID NO:41: and des-Argo-Kallidin or to modulate Kallidin and des 0044 f) SEQID NO: 48; and Argo-Kallidin activity, either in vitro or in vivo, are also 0045 g) SEQID NO: 56. encompassed by the invention. The invention also provides 0046. In another embodiment, the antibody or antigen methods of making antibodies that specifically bind to des binding fragment thereof comprises an HCDR1 amino acid Argo-Bradykinin and des-Argo-Kallidin-like peptide. sequence selected from the group consisting of 0007 Accordingly, in one aspect the invention provides an 0047 a) SEQID NO: 9 (GYSFTDYXIY). In wherein X isolated monoclonal antibody or antigen binding fragment is N, W or Y: thereof that: (0.048 b) SEQID NO: 65 IGFNIKDYYXH), wherein X 0008 a) specifically binds to Kallidin ordes-Argo-Kalli is L, or M: din but not to Bradykinin ordes-Argo-Bradykinin; 0049 c) SEQ ID NO: 15; 0009 b) specifically binds to Kallidin ordes-Argo-Kalli 0050 d) SEQID NO:34: din with a KD of less than 1x10' M: 0051 e) SEQ ID NO: 42: US 2015/005O270 A1 Feb. 19, 2015 0.052 f) SEQID NO: 49; and 0101 X is Y. F., T or H, and, 0053 g) SEQID NO:57. 01.02 X is W.Y. F., H or L: 0054. In another embodiment, the antibody or antigen (0103) b) SEQID NO: 66 QXXXSXPXT, wherein binding fragment thereof comprises a light chain variable 0104 X is Q or N.
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