Methods for treating pain using antibodies to Kallidin and des-Arg10-Kallidin

Patent metadata

Field	Value
Publication number	US-9879079-B2
Application number	US-201615163883-A
Country	US
Kind code	B2
Filing date	May 25, 2016
Priority date	Mar 28, 2012
Publication date	Jan 30, 2018
Grant date	Jan 30, 2018

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-Kallidin 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-Kallidin activity or detect Kallidin or des-Arg10-Kallidin 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

We claim:

1. A method for treating pain, the method comprising administering to a subject in need thereof a pharmaceutical composition comprising an isolated antibody or antigen binding fragment thereof that specifically binds to Kallidin or des-Arg 10 -Kallidin, but not to Bradykinin or des-Arg 9 -Bradykinin, wherein the antibody or antigen binding fragment comprises:
i) a heavy chain variable domain comprising a heavy chain complementarity determining region 3 (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 For 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;
ii) a heavy chain variable domain comprising a heavy chain complementarity determining region 2 (HCDR2) amino acid sequence selected from the group consisting of:
h) 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;

i) 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;

j) SEQ ID NO: 14;
k) SEQ ID NO: 33;
l) SEQ ID NO: 41;
m) SEQ ID NO: 48; and
n) SEQ ID NO: 56;
iii) a heavy chain variable domain comprising a heavy chain complementarity determining region 1 (HCDR1) amino acid sequence selected from the group consisting of:
o) SEQ ID NO: 9 [GYSFTDYX 1 IY], wherein X 1 is N, W or Y;
p) SEQ ID NO: 65 [GFNIKDYYX 1 H], wherein X 1 is L, or M;
q) SEQ ID NO: 15;
r) SEQ ID NO: 34;
s) SEQ ID NO: 42;
t) SEQ ID NO: 49; and
u) SEQ ID NO: 57;
iv) a light chain variable domain comprising a light chain complementarity determining region 3 (LCDR3) amino acid sequence selected from the group consisting of:
v) 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;

w) 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;

x) SEQ ID NO: 69 [X 1 QGTHFPYT], wherein X 1 is L or M;
y) SEQ ID NO: 16;
z) SEQ ID NO: 35;
aa) SEQ ID NO: 43;
bb) SEQ ID NO: 50; and
cc) SEQ ID NO: 58, or
v) a light chain variable domain comprising a light chain complementarity determining region 2 (LCDR2) amino acid sequence selected from the group consisting of:
dd) SEQ ID NO: 11 [WASTRX 1 ], wherein X 1 is E, D, Q or N;
ee) SEQ ID NO: 67 [X 1 ASTRX 2 ], wherein
X 1 is W or G, and
X 2 is E, D, Q or N;

ff) SEQ ID NO: 17;
gg) SEQ ID NO: 36;
hh) SEQ ID NO: 51; and
ii) SEQ ID NO: 59;
and
vi) a light chain variable domain comprising a light chain complementarity determining region 1 (LCDR1) amino acid sequence selected from the group consisting of:
jj) 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;

kk) 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;

ll) SEQ ID NO: 70 [KSSQSLLYSNGX 1 TYLN], wherein X 1 is K or E;
mm) SEQ ID NO: 18;
nn) SEQ ID NO: 37;
oo) SEQ ID NO: 44;
pp) SEQ ID NO: 52; and
qq) SEQ ID NO: 60.

2. The method of claim 1 , wherein the antibody or antigen binding fragment thereof comprises: a) a heavy chain variable domain comprising the consensus HCDR3, HCDR2 and HCDR1 region amino sequences set forth in SEQ ID NOs: 7, 8, and 9, respectively; and b) a light chain variable domain comprising the consensus LCDR3, LCDR2 and LCDR1 region amino sequences set forth in SEQ ID NOs: 10, 11, and 12, respectively.

3. The method of claim 1 , wherein the antibody or antigen binding fragment thereof comprises: a) a heavy chain variable domain comprising the HCDR3, HCDR2 and HCDR1 region amino sequences set forth in SEQ ID NOs: 13, 14, and 15, respectively; and b) a light chain variable domain comprising the LCDR3, LCDR2 and LCDR1 region amino sequences set forth in SEQ ID NOs: 16, 17, and 18, respectively.

4. The method of claim 1 , wherein the antibody or antigen binding fragment thereof comprises: a) a heavy chain variable domain comprising the HCDR3, HCDR2 and HCDR1 region amino sequences set forth in SEQ ID NOs: 32, 33, and 34, respectively; and b) a light chain variable domain comprising the LCDR3, LCDR2 and LCDR1 region amino sequences set forth in SEQ ID NOs: 35, 36, and 37, respectively.

5. The method of claim 1 , wherein the antibody or antigen binding fragment thereof comprises: a) a heavy chain variable domain comprising the HCDR3, HCDR2 and HCDR1 region amino sequences set forth in SEQ ID NOs: 40, 41 and 42, respectively; and b) a light chain variable domain comprising the LCDR3, LCDR2 and LCDR1 region amino sequences set forth in SEQ ID NOs: 43, 17, and 44, respectively.

6. The method of claim 1 , wherein the antibody or antigen binding fragment thereof comprises: a) a heavy chain variable domain comprising the HCDR3, HCDR2 and HCDR1 region amino sequences set forth in SEQ ID NOs: 47, 48, and 49, respectively; and b) a light chain variable domain comprising the LCDR3, LCDR2 and LCDR1 region amino sequences set forth in SEQ ID NOs: 50, 51, and 52, respectively.

7. The method of claim 1 , wherein the antibody or antigen binding fragment thereof comprises: a) a heavy chain variable domain comprising the HCDR3, HCDR2 and HCDR1 region amino sequences set forth in SEQ ID NOs: 55, 56, and 57, respectively; and b) a light chain variable domain comprising the LCDR3, LCDR2 and LCDR1 region amino sequences set forth in SEQ ID NOs: 58, 59, and 60, respectively.

8. The method of claim 1 , wherein the antibody or antigen binding fragment thereof comprises: a) a heavy chain variable domain 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; and b) a light chain variable domain 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.

9. A method for treating pain, the method comprising administering to a subject in need thereof a pharmaceutical composition comprising an antibody or antigen binding fragment thereof that specifically binds to Kallidin or des-Arg 10 -Kallidin but not to Bradykinin or des-Arg 9 -Bradykinin, and one or more pharmaceutically acceptable carriers, wherein the antibody or antigen binding fragment thereof comprises the heavy chain and light chain variable domain amino acid sequences set forth in SEQ ID NOs: 24 and 30, respectively.

10. A method for treating pain, the method comprising administering to a subject in need thereof a pharmaceutical composition comprising an antibody or antigen binding fragment thereof that specifically binds to Kallidin or des-Arg 10 -Kallidin but not to Bradykinin or des-Arg 9 -Bradykinin, and one or more pharmaceutically acceptable carriers, wherein the antibody or antigen binding fragment thereof comprises: a) a heavy chain variable region domain amino acid sequence with at

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

• C07K2317/33

  Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity · CPC title

• C07K16/26

  against hormones {; against hormone releasing or inhibiting factors} · CPC title

• C07K2317/56

  variable (Fv) region, i.e. VH and/or VL · CPC title

• C07K2317/76

  Antagonist effect on antigen, e.g. neutralization or inhibition of binding · CPC title