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Consulter Le Mémoire 19 ORGANISATION AFRICAINE DE LA PROPRIETE INTELLECTUELLE 51 8 . C07K 16/26 Inter. CI A61K 39/395 11 17139 C07K 7/18 N° A61P 29/00 FASCICULE DE BREVET D’INVENTION : 1201400447 21 Numéro de dépôt 73 Titulaire(s) : (PCT/US13/031836) SANOFI, 54, Rue La Boétie, 22 Date de dépôt : 15/03/2013 75008 PARIS (FR) 30 Priorité(s) : US n° 61/616 845 du 28/03/2012 FR n° 1350953 du 04/02/2013 72 Inventeur(s) : LI Han (US) KOMINOS Dorothea (US) PRITSKER Alla (US) DAVISON Matthew (US) BAURIN Nicolas (US) SUBRAMANIAN Govindan (US) CHEN Xin (US) ZHANG Jie (US). 74 Mandataire : Cabinet CAZENAVE SARL, Délivré le : 31/07/2015 24 B.P. 500, YAOUNDE (CM). 45 Publié le : 28.03.2016 54 Titre : Antibodies to bradykinin B1 receptor ligands. 57 Abrégé : The disclosure provides antibodies that specifically bind to Kallidin or des-Arg 10-Kallidin. The disclosure also provides pharmaceutical compositions, as well as nucleic acids encoding anti-Kallidin or des- Arg10-Kallidin antibodies, recombinant expression vectors and host cells for making such antibodies, or fragments thereof. Methods of using antibodies of the disclosure to modulate Kallidin or des- Arg10- Kallidin activity or detect Kallidin or des-Arg10- Kallidin or, either in vitro or in vivo, are also provided by the disclosure. The disclosure further provides methods of making antibodies that specifically bind to des-Argg- Bradykinin and des-Arg10-Kallidin-like peptide. Fig. 1 O.A.P.I. – B.P. 887, YAOUNDE (Cameroun) – Tel. (237) 22 20 57 00– Fax: (237) 22 20 57 27– Site web: http:/www.oapi.int – Email: [email protected] 17139 1 ANTIBODIES TO BRADYKININ B1 RECEPTOR LIGANDS RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 61/616,845, filed March 5 28, 2012, and French Patent Application Number 1350953, filed February 4, 2013. The contents of these applications are each hereby incorporated by reference In their entireties. SEQUENCE LISTING The Instant application contains a Sequence Listing which has been submitted in ASCII 10 format via EFS-Web and is hereby Incorporated by reference In its entirety. Said ASCII copy, created on March 15, 2013, is named 543895_5A9-029PC_Seq_Ust.txt and Is 89,291 bytes in size. BACKGROUND OF THE INVENTION 15 The bradykinin B1 receptor has been implicated in pathogenesis of inflammatory disease and chronic pain. By modulating tissue Inflammation and renal fibrosis, the 81 receptor has also been associated with pathogenesis of acute kidney Injury as well as chronic kidney diseases which are the main causes of end-stage renal failure. In humans, the major agonists of the bradykinin 81 receptor are the kinins. Kinins are bioactive 20 peptides produced from the proteolytic cleavage of kininogen proteins. The major kinin agonists of bradykinin 81 receptor are the decapeptide Kallidin, and the nonapeptide des-Argio-Kallidin (formed by the proteolytic cleavage the c-terminal arginine form Kallidin). Therefore, agents that can Inhibit the binding of Kallidin and des-Argio-Kallidin to the bradykinin 81 receptor have the potential to treat or prevent bradykinin 81 receptor-mediated pathologies. 25 Accordingly, there is a need in the art for novel agents that Inhibit the binding of Kallidin and des-Argio-Kallidin to the bradykinin 131 receptor for use in the treatment of bradykinin 81 receptor- mediated human pathologies. SUMMARY OF THE INVENTION 30 The present invention provides antibodies, or antigen binding fragments thereof, that specifically bind Kallidin and des-Argio-Kallidin and prevent binding to the bradykinin 81 receptor. Such antibodies are particularly useful for treating Kallidin and des-Argio-Kallidin-associated diseases or disorders (e.g., pain or fibrosis). The Invention also provides pharmaceutical compositions, as well as nucleic acids encoding anti-Kallidin and des-Argio-Kallidin antibodies, 35 recombinant expression vectors and host cells for making such antibodies, or fragments thereof. Methods of using antibodies, or fragments thereof, of the invention to detect Kallidin and des-Argio- Kallidin or to modulate Kallidin and des-Argio-Kallidin activity, either in vitro or in vivo, are also encompassed by the Invention. The invention also provides methods of making antibodies that specifically bind to des-Argr Bradykinin and des-Argio-Kallidin-like peptide. • , a 17139 2 Accordingly, in one aspect the invention provides an isolated monoclonal antibody or antigen binding fragment thereof that: a) specifically binds to Kallidin or des-Argio-Kallidin but not to Bradykinin or des-Argr Bradykinin; 5 b) specifically binds to Kallidin or des-Argio-Kallidin with a KD of less than 1x10 -" M; c) specifically binds to Kallidin or des-Argio-Kallidin with a Kw of less than 1x10 4 s-1 ; or d) specifically binds to Kallidin or des-Argio-Kallidin and inhibits binding to the bradykinin B1 receptor. 10 In one embodiment, the antibody or antigen binding fragment thereof binds to the N-terminal Lysine residue of Kallidin or des-Argio-Kallidin. In another embodiment, the antibody or antigen binding fragment thereof Inhibits the binding of Kallidin or des-Argio-Kallidin to a bradylcinin-1 receptor. 15 In another embodiment, the antibody or antigen binding fragment thereof binds specifically to mouse Kallidin-like peptide (KLP). In another embodiment, the antibody or antigen binding fragment thereof comprises a heavy chain 20 variable domain comprising an HCDR3 amino acid sequence selected from the group consisting of: a) SEQ ID NO: 7 [XIV X2 X3D X4HAM )(Ca wherein Xi Is Y, F or H, X2Is R, D, A, V. L, I, M, F, Y or W, X3 is V. F, W or H, 25 Is D, E or Y, and, Xs Is 0 or E; b) SEQ ID NO: 63 VIEYDGX2YX3X4LDX51, wherein XI is W or F, X2 is N or no amino acid; 30 X3IsYorS, X4is D or P, and X5 Is F or Y; c) SEQ ID NO: 13; d) SEQ ID NO: 32; 35 e) SEQ ID NO: 40; U SEQ ID NO: 47; and g) SEQ ID NO: 55. 17139 3 In another embodiment, the antibody or antigen binding fragment thereof comprises an HCDR2 amino add sequence selected from the group consisting of: a) SEQ ID NO: 8 [YFX113X2NGNTGYNOKFRG], wherein X1 Is D, R, A, V. L, I, M, F, Y or W, and 5 X2is Y, D, E, N, or Q; b) SEQ ID NO: 64 [WXIDPENGDX2X3YAPKFOG], wherein X1 is I, or V, X2 IS T, or S, and X3 is G, or D; 10 c) SEQ ID NO: 14 d) SEQ ID NO: 33; e) SEQ ID NO: 41; f) SEQ ID NO: 48; and g) SEQ ID NO: 56. 15 In another embodiment, the antibody or antigen binding fragment thereof comprises an HCDR1 amino acid sequence selected from the group consisting of: a) SEQ ID NO: 9 [GYSFTDYXIIY], wherein Xi is N, W or V; b) SEQ ID NO: 65 [GFNIKDYYX,H]. wherein XI is L, or M; 20 c) SEQ ID NO: 15; d) SEQ ID NO: 34; e) SEQ ID NO: 42; I) SEQ ID NO: 49; and g) SEQ ID NO: 57. 25 In another embodiment, the antibody or antigen binding fragment thereof comprises a light chain variable domain comprising an LCDR3 amino add sequence selected from the group consisting of: a) SEQ ID NO: 10 [QQ Xi X2S )(313 X4T], wherein Xi is Y, F or H, 30 X2is Y, F, H or W, XI is Y, F, T or H, and, X4 is W, Y, F, H or L: b) SEC) ID NO: 66 (QX,X2X3SX4PX511, wherein Xi Is Q or N, 35 X2 is Y, F, D or H, X3 IS Y, F, H or W, X. is Y, F, T or H, and X5 iS W, Y, F, H or L; c) SEQ ID NO: 69 [XIQGTHFPYTJ, wherein Xi is L or M; 17139 4 d) SEQ ID NO: 16; e) SEQ ID NO: 35; I) SEQ ID NO: 43; g) SEQ ID NO: 50; and 5 h) SEQ ID NO: 58. In another embodiment, the antibody or antigen binding fragment thereof comprises an LCDR2 amino acid sequence selected from the group consisting of: a) SEQ ID NO: 11 (WASTRM, wherein Xi is E, D, Q or N; 10 b) SEQ ID NO: 67 VIASTRX21, wherein Xi Is W or G, and X2 is E, D, Q or N; c) SEQ ID NO: 17; d) SEQ ID NO: 36; 15 e) SEQ ID NO: 51; and f) SEQ ID NO: 59. In another embodiment, the antibody or antigen binding fragment thereof comprises an LCDR1 amino acid sequence selected from the group consisting of: 20 a) SEQ ID NO: 12 [KSSQSLL XISSNOKN X2LAI, wherein Xi Is W, H, Y or F, and X2 Is H or Y; b) SEQ ID NO: 68 [KSSQSLLXIX2SX3QXINX5LA], wherein Xi is W, H, Y or F, 25 X2 IS S or G, X3 Is N or D, Is K or R, X5 is H or Y. c) SEQ ID NO: 70 [KSSQSLLYSNGXITYLN],wherein Xi Is K or E; 30 b) SEQ ID NO: 18; c) SEQ ID NO: 37; d) SEQ ID NO: 44; e) SEQ ID NO: 52; and f) SEQ ID NO: 60. 35 In another embodiment, the antibody or antigen binding fragment comprises a light chain variable domain comprising an LCDR3 amino acid sequence selected from the group consisting of: a) SEQ ID NO: 10 [QQ Xi X2S X3P X11], wherein X1 Is Y, F or H, • 17139 5 X2 is V. F, H or W, X3 is Y, F. T or H, and, X4 Is W, Y, F, H or L: b) SEQ ID NO: 66 [QX1X2X3SX413X5T1 wherein 5 XtisQorN, X2is Y, F, D or H, X3 is Y, F.
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