Ion channel modulators and uses thereof

Patent metadata

Field	Value
Publication number	US-2017166634-A1
Application number	US-201515308294-A
Country	US
Kind code	A1
Filing date	May 2, 2015
Priority date	May 2, 2014
Publication date	Jun 15, 2017
Grant date	—

Abstract

The invention provides antibodies that specifically bind a P2X4 polypeptide and modulate P2X4 channel activity, recombinant P2X4 polypeptides and methods for generating such polypeptides, as well as compositions and methods for generating anti-P2X4 antibodies, and methods of using P2X4 antibodies for the treatment of neuropathic pain and other indications.

First claim

1 . An antibody or antigen binding fragment thereof that specifically binds a human P2X4 polypeptide and modulates channel activity.

2 . The antibody of claim 1 , wherein the antibody is a P2X4 potentiator.

3 . The antibody of claim 1 , wherein the antibody is a P2X4 antagonist.

4 . (canceled)

5 . The antibody of claim 1 , wherein the antibody binds an epitope comprising human P2X4 amino acids 110-166.

6 . The antibody of claim 5 , wherein the antibody binds an epitope comprising one or more human P2X4 amino acids selected from the group consisting of amino acids 118, 122-139, 145, 159, 180, 183, 184, 231, and 244.

7 . (canceled)

8 . (canceled)

9 . The antibody of claim 1 , wherein the antibody or fragment thereof comprises:
a. a heavy chain variable region CDR1 comprising a sequence:

X 1 X 2 X 3 X 4 X 5,

 wherein
X 1 is G, N, S, D, or R;
X 2 is Y, A, H, F, or S;
X 3 is A, W, Y, S, G, F, W, E, D, or P;
X 4 is M, I, W, L, I, F, or V;
X 5 is S, G, T, H, or N; and/or
b. a heavy chain variable region CDR2 comprising a sequence:

X 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 X 12 X 13 X 14 X 15, X 16,

 wherein
X 1 is A, R, I, T, E, S, A, V, W, N, G, E, R, or Y;
X 2 is I or M;
X 3 is S, K, Y, D, N, W, or I;
X 4 is S, D, G, H, N, R, Y, or V;
X 5 is G, D, S, F, N, R, F, D, or T;
X 6 is G, S, N, or T;
X 7 is S, T, D, Y, N, A, E, M, F, or D;
X 5 is T, I, K, or A;
X 9 is Y, D, R, N, G, Q, E, H, or K;
X 10 is Y, Q, S, or V;
X 11 is A, S, N, or V;
X 12 is D, A, P, R, or Q;
X 13 is S, P, K, or N;
X 14 is V, F, L, or A;
X 15 is K, Q, or E;
X 16 is G, S, A, or D;
wherein the heavy chain variable region CDR2 optionally comprises an insertion of 1-3 amino acids, X a X b X c between amino acids X 3 and X 4 , wherein
X a is G, S, P, W, Y, E, A, R, or N; and
X b X c are KT, respectively
and/or
c. a heavy chain variable region CDR3 comprising a sequence:

X 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8,

X 1 is E, N, D, R, K, G, S, A, Y, V, P, or H;
X 2 is E, L, R, Q, T, G, F, P, Y, K, A, S, V, or F;
X 3 is R, A, T, G, V, S, M, W, Y, D, H, N, E, L, or I;
X 4 is G, L, R, D, T, G, Y, S, E, F, Q, C, I, M, V, N, K, or P;
X 5 is S, G, Y, D, W, T, S, N, I, D, V, E, or C;
X 6 is Y, A, S, W, T, L, G, E, F, K, V, I, or D;
X 7 is D, E, or G; and
X 8 is Y, S, V, L, M, Q, I, S, I, H, F, or DI wherein the heavy chain variable region CDR3 optionally comprises an insertion of 1-14 amino acids X a -X n , wherein
X a is F, R, S, Y, L, D, G, V, I, T, or A;
X b is G, R, Y, F, T, D, S, G, V, M, D, or R;
X c is F, W, A, G, T, I, S, F, Y, C, L, V, R, or N;
X d is S, F, M, G, Y, L, S, A, D, L, R, V, C, or S;
X e is G, Y, S, T, P, F, Y, R, A, E, G, Q, N, or L;
X f is Y, N, G, T, R, F, A, M, W, P, or V;
X g is Y, M, S, V, F, A, P, S, D, R, H, P, E, or R
X h is Y, G, M, F, G, P, V, F, H, T, or G,
X i is T, I G, R, or F;
X j is Y, G, H, or E;
X k is Y, G, F, or N;
X l is F, or N;
X m is Y; and
X n is F.

10 .- 16 . (canceled)

17 . The antibody of claim 1 , wherein the antibody or fragment thereof comprises,
a. a light chain variable region CDR1 comprising a sequence

X 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11,

 wherein
X 1 is T, G, R, S, or Q;
X 2 is G, A, or L;
X 3 is S, T, D, or H;
X 4 is S, N, K, A, Q, T, or V;
X 5 is G, I, L, S, or D;
X 6 is A, G, R, P, I, D, S, E, or T;
X 7 is G, N, M, D, K, S, R, Y, or T;
X 8 is Y, K, F, Q, S, N, Y, D, H, or R;
X 9 is D, N, Y, W, F, M, G, or S;
X 10 is V, A, L, I, G, or P;
X 11 is H, T, S, Y, A, Q, Y, N, or F;
wherein the light chain variable region CDR1 optionally comprises an insertion of between 1 and 3 amino acids X a -X c between X 4 and X 5 , wherein
X a is S or G;
X b is N, D or S; and
X c is I or V;
b. a light chain variable region CDR2 comprising a sequence:

X 1 X 2 X 3 X 4 X 5 X 6 X 7,

 wherein
X 1 is G, Y, Q, K, N, D, R, A, or E;
X 2 is N, D, K, A, V, G, or T;
X 3 is N, S, T, I, K, Y, or D;
X 4 is N, D, Y, K, E, T, N, S, or Q;
X 5 is R, or L;
X 6 is P, E, A, S, or Q;
X 7 is S, P, or T; and/or
c. a light chain variable region CDR3 comprising a sequence:

X 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9,

X 1 is Q, N, A, G, D, S, or L;
X 2 is S, V, A, Q, T, L, or H;
X 3 is Y, W, R, A, S, Q, T, or G;
X 4 is D, Y, I, N, M, or H;
X 5 is T, M, S, N, D, R, G, or K;
X 6 is N, T, S, G, F, L, or D;
X 7 is L, T, G, P, A, I, or N;
X 8 is K, W, V, I, P, G, L, R, or Y; and
X 9 is V, L, or T;
wherein the light chain variable region CDR3 optionally comprises an insertion of between 1 and 3 amino acids X a -X c between X 7 and X 8 , wherein
X a is D, N, A, T, S, I or H;
X b is H, Y, G, A, R, L, S, or P; and
X c is S.

18 .- 22 . (canceled)

23 . The antibody of claim 1 , wherein the antibody or fragment thereof comprises a VH comprising:
a. a heavy chain variable region CDR1 comprising the sequence: SX 1 AMS where X 1 is Y or F; b. a heavy chain variable region CDR2 comprising the sequence: AISGSG X 1 STYYADSVKG where X 1 is S or G; c. a heavy chain variable region CDR3 comprising the sequence: X 1 X 2 DX 3 WSX 4 X 5 X 6 X 7 X 8 TAFDL, where X 1 is H, D or Q; X 2 is W, M, F, H, or R; X 3 is W, Y or F; X 4 is T, N, G, or P; X 5 is R, A, S, G, or Y; X 6 is S, P, N or T; X 7 is G, S, R, or K: X 8 is P, M, A or L. optionally in combination with a VL comprising a. a light chain variable region CDR1 comprising the sequence SGDALPRQYAY b. a light chain variable region CD

Assignees

• Medlmmune Ltd
• Medimmune Ltd

Inventors

• Williams Wendy A
• Jones Clare
• Button James
• Linley John
• Snijder Harm Jan
• Huang Ling
• Shibata Yoko
• Sridharan Sudharsan
• Groves Maria
• Dobson Claire

Classifications

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title

• C07K2317/34

  Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues · CPC title

• A61K2039/505

  comprising antibodies · CPC title

• C07K2317/21

  from primates, e.g. man · CPC title

• C07K16/28 Primary

  against receptors, cell surface antigens or cell surface determinants · CPC title