Antibodies to kallidin and des-arg9-kallidin

Patent metadata

Field	Value
Publication number	US-2016368976-A1
Application number	US-201615163883-A
Country	US
Kind code	A1
Filing date	May 25, 2016
Priority date	Mar 28, 2012
Publication date	Dec 22, 2016
Grant date	—

Abstract

The invention provides antibodies that specifically bind to Kallidin or des-Arg10-Kallidin. The invention also provides pharmaceutical compositions, as well as nucleic acids encoding anti-Kallidin or des-Arg10-Kanidin antibodies, recombinant expression vectors and host cells for making such antibodies, or fragments thereof. Methods of using antibodies of the invention to modulate Kallidin or des-Arg10-Kanidin activity or detect Kallidin or des-Arg10-Kanidin or, either in vitro or in vivo, are also provided by the invention. The invention further provides methods of making antibodies that specifically bind to des-Arg 9 -Bradykinin and des-Arg 10 -Kallidin-like peptide.

First claim

1 . An isolated monoclonal antibody or antigen binding fragment thereof that:
a) specifically binds to Kallidin or des-Arg 10 -Kallidin but not to Bradykinin or des-Arg 9 -Bradykinin; b) specifically binds to Kallidin or des-Arg 10 -Kallidin with a KD of less than 1×10 −1 ° M; c) specifically binds to Kallidin or des-Arg 10 -Kallidin with a K off of less than 1×10 4 s −1 ; and/or d) specifically binds to Kallidin or des-Arg 10 -Kallidin and inhibits binding to the bradykinin B1 receptor.

2 . The antibody or antigen binding fragment thereof of claim 1 , that
binds to the N-terminal Lysine residue of Kallidin or des-Arg10-Kallidin, or inhibits the binding of Kallidin or des-Arg10-Kallidin to a bradykinin-1 receptor, or binds specifically to mouse Kallidin-like peptide (KLP).

3 - 4 . (canceled)

5 . The antibody or antigen binding fragment thereof of claim 1 , comprising
a heavy chain variable domain comprising an HCDR3 amino acid sequence selected from the group consisting of: a) SEQ ID NO: 7 [X 1 Y X 2 X 3 D X 4 HAM X 5 Y], wherein
X 1 is Y, For H,
X 2 is R, D, A, V, L, I, M, F, Y or W,
X 3 is Y, F, W or H,
X 4 is D, E or Y, and,
X 5 is D or E;
b) SEQ ID NO: 63 [X 1 EYDGX 2 YX 3 X 4 LDX 5 ], wherein
X 1 is W or F,
X 2 is N or no amino acid;
X 3 is Y or S,
X 4 is D or P, and
X 5 is F or Y;
c) SEQ ID NO: 13; d) SEQ ID NO: 32; e) SEQ ID NO: 40; f) SEQ ID NO: 47; and g) SEQ ID NO: 55 or an HCDR2 amino acid sequence selected from the group consisting of: a) SEQ ID NO: 8 [YFX 1 PX 2 NGNTGYNQKFRG], wherein
X 1 is D, R, A, V, L, I, M, F, Y or W, and
X 2 is Y, D, E, N, or Q;
b) SEQ ID NO: 64 [WX 1 DPENGDX 2 X 3 YAPKFQG], wherein
X 1 is I, or V,
X 2 is T, or S, and X 3 is G, or D;
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, or an HCDR1 amino acid sequence selected from the group consisting of: a) SEQ ID NO: 9 [GYSFTDYX 1 IY], wherein X 1 is N, W or Y; b) SEQ ID NO: 65 [GFNIKDYYX 1 H], wherein X 1 is L, or M; c) SEQ ID NO: 15; d) SEQ ID NO: 34; e) SEQ ID NO: 42; f) SEQ ID NO: 49; and g) SEQ ID NO: 57, or a light chain variable domain comprising an LCDR3 amino acid sequence selected from the group consisting of: a) SEQ ID NO: 10 [QQ X 1 X 2 S X 3 P X 4 T], wherein
X 1 is Y, F or H,
X 2 is Y, F, H or W,
X 3 is Y, F, T or H, and,
X 4 is W, Y, F, H or L;
b) SEQ ID NO: 66 [QX 1 X 2 X 3 SX 4 PX 5 T], wherein
X 1 is Q or N,
X 2 is Y, F, D or H,
X 3 is Y, F, H or W,
X 4 is Y, F, T or H, and
X 5 is W, Y, F, H or L;
c) SEQ ID NO: 69 [X 1 QGTHFPYT], wherein X 1 is L or M; d) SEQ ID NO: 16; e) SEQ ID NO: 35; f) SEQ ID NO: 43; g) SEQ ID NO: 50; and h) SEQ ID NO: 58, or an LCDR2 amino acid sequence selected from the group consisting of: a) SEQ ID NO: 11 [WASTRX 1 ], wherein X 1 is E, D, Q or N; b) SEQ ID NO: 67 [X1ASTRX 2 ], wherein
X 1 is W or G, and
X 2 is E, D, Q or N;
c) SEQ ID NO: 17; d) SEQ ID NO: 36; e) SEQ ID NO: 51; and f) SEQ ID NO: 59, or an LCDR1 amino acid sequence selected from the group consisting of: a) SEQ ID NO: 12 [KSSQSLL X 1 SSNQKN X 2 LA], wherein
X1 is W, H, Y or F, and
X2 is H or Y;
b) SEQ ID NO: 68 [KSSQSLLX 1 X 2 SX 3 QX 4 NX 5 LA], wherein
X 1 is W, H, Y or F,
X 2 is S or G,
X 3 is N or D,
X 4 is K or R,
X 5 is H or Y,
c) SEQ ID NO: 70 [KSSQSLLYSNGX 1 TYLN], wherein X 1 is K or E; d) SEQ ID NO: 18; e) SEQ ID NO: 37; f) SEQ ID NO: 44; g) SEQ ID NO: 52; and h) SEQ ID NO: 60.

6 - 10 . (canceled)

11 . The antibody or antigen binding fragment thereof of claim 1 , comprising a light chain variable domain comprising an LCDR3 amino acid sequence selected from the group consisting of:
a) SEQ ID NO: 10 [QQ X1 X25 X 3 P X 4 T], wherein
X 1 is Y, F or H,
X 2 is Y, F, H or W,
X 3 is Y, F, T or H, and,
X 4 is W, Y, F, H or UM
b) SEQ ID NO: 66 [QX 1 X 2 X 3 SX 4 PX 5 T], wherein
X 2 is Y, F, D or H,
X 3 is Y, F, H or W,
X 4 is Y, F, T or H, and
X 5 is W. Y, F, H or L;
c) SEQ ID NO: 69 [X 1 QGTHFPYT], wherein X 1 is L or M; d) SEQ ID NO: 16; e) SEQ ID NO: 35; f) SEQ ID NO: 43; g) SEQ ID NO: 50; and h) SEQ ID NO: 58 optionally further comprising an LCDR2 amino acid sequence selected from the group consisting of: a) SEQ ID NO: 11 [WASTRX 1 ], wherein is E, D, Q or N; b) SEQ ID NO: 67 [X 2 ASTRX 2 ], wherein
X 1 is W or G, and
X 2 is E, D, Q or N;
c) SEQ ID NO: 17; d) SEQ ID NO: 36; e) SEQ ID NO: 51; and f) SEQ ID NO: 59, and optionally further comprising an LCDR1 amino acid sequence selected from the group consisting of: a) SEQ ID NO: 12 [KSSQSLL X 1 SSNQKN X 2 LA], wherein
X 1 is W, H, Y or F, and X 2 is H or Y;
b) SEQ ID NO: 68 [KSSQSLLX 1 X 2 SX 3 QX 4 NX 5 LA], wherein
X 1 is W, H, Y or F,
X 2 is S or G,
X 3 is N or D,
X 4 is K or R,
X 5 is H or Y,
c) SEQ ID NO: 70 [KSSQSLLYSNGX 1 TYLN], wherein X 1 is K or E; 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.

12 - 13 . (canceled)

14 . The antibody or antigen binding fragment thereof of claim 1 comprising a heavy chain variable region comprising the HCDR3, HCDR2 and HCDR1 region amino sequences set forth in SEQ ID NOs 13, 14, and 15, respectively, and one or more amino acid substitution at positions selected from the group consisting of H1, H5, H9, H11, H12, H16, H38, H40, H41, H43, H44, H66, H75, H79, H81, H82A, H83, H87, and H108 according to Kabat, optionally further comprising a light chain variable region comprising the LCDR3, LCDR2 and LCDR1 region amino sequences set forth in SEQ ID NOs 16, 17, and 18, respectively, and one or more amino acid substitution at positions selected from the group consisting of L5, L9, L15, L18, L19, L21, L22, L43, L63, L78, L79, L83, L85, L100 and L104, according to Kabat.

15 . (canceled)

16 . The antibody or antigen binding fragment thereof of claim 1 comprising
a light chain variable region comprising the LCDR3, LCDR2 and LCDR1 region amino sequences set forth in SEQ ID NOs 16, 17, and 18, respectively, and one or more amino acid substitution at positions selected from the group consisting of L5, L9, L15, L18, L19, L21, L22, L43, L63, L78, L79, L83, L85, L100 and L104 according to Kabat, or
a heavy chain variable region amino acid sequence with at least 90% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 19, 20, 21, 22, 24, 25, 38, 45, 53, and 61, and optionally further comprising a light chain variable domain amino acid sequence with at least 90% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 26, 27, 28, 29, 29, 30, 31, 39, 46, 54, and 62.

17 . (canceled)

18 . (canceled)

19 . The antibody or antigen binding fragment thereof of claim 1 , comprising
a light chain variable region amino acid sequence with at least 90% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 26, 27, 28, 29, 29, 30, 31, 39, 46, 54, and 62, or a heavy chain variable domain comprising an amino acid sequence selected from the group consisting of: SEQ ID NO: 19, 20, 21, 22, 24, 25, 38, 45, 53, and 61, optionally further comprising a light chain variable domain amino acid sequence selected from the group consisting of: SEQ ID NO: 26, 27, 28, 29, 29, 30, 31, 39, 46, 54, and 62, or an amino acid sequence selected from the group consisting of: SEQ ID NO: 26, 27, 28, 29, 29, 30, 31, 39, 46, 54, and 62.

20 - 22 . (canceled)

23 . The antibody or antigen binding fragme

Assignees

• Sanofi Sa

Inventors

• Li Han
• KOMINOS Dorothea
• Zhang Jie
• Pritsker Alla
• Davison Matthew
• Baurin Nicolas
• Subramanian Govindan
• Chen Xin

Classifications

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• C07K2317/24

  containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered · CPC title

• C07K2317/92

  Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value · CPC title

• A61K2039/505

  comprising antibodies · CPC title

• C07K7/18

  Kallidins; Bradykinins; Related peptides · CPC title