TLR3 binding agents

Patent metadata

Field	Value
Publication number	US-9388246-B2
Application number	US-201113102019-A
Country	US
Kind code	B2
Filing date	May 5, 2011
Priority date	Jul 10, 2009
Publication date	Jul 12, 2016
Grant date	Jul 12, 2016

Abstract

The present invention relates to antibodies (e.g. monoclonal antibodies), antibody fragments, and derivatives thereof that specifically bind TLR3, and that optionally further modulate, e.g. inhibit, signaling. The invention also relates to cells producing such antibodies; methods of making such antibodies; fragments, variants, and derivatives of the antibodies; pharmaceutical compositions comprising the same; methods of using the antibodies to diagnose, treat or prevent diseases, e.g. autoimmune diseases, inflammatory diseases and the like.

First claim

What is claimed is:

1. A monoclonal antibody that specifically binds a human Toll-like receptor 3 (TLR3) polypeptide, wherein said antibody inhibits signaling by said human TLR3 polypeptide without blocking binding of a double-stranded ribonucleic acid (dsRNA) TLR3 ligand to said human TLR3 polypeptide.

2. The antibody of claim 1 , wherein said antibody is conjugated or covalently bound to a toxic moiety.

3. The antibody of claim 1 , wherein said antibody is capable of being internalized by a TLR3-expressing cell.

4. The antibody of claim 3 , wherein said TLR3-expressing cell is a cancer cell.

5. The antibody of claim 1 , wherein said antibody is conjugated or covalently bound to a detectable moiety.

6. A hybridoma or recombinant host cell producing the antibody of claim 1 .

7. A pharmaceutical composition comprising an antibody of claim 1 and a pharmaceutically acceptable carrier.

8. The monoclonal antibody of claim 1 , wherein the monoclonal antibody is an antibody having the heavy chain CDR 1, 2 and 3 (HCDR1, HCDR2, HCDR3) amino acid sequences as shown in SEQ ID NO: 4, 5 and 6, respectively.

9. The monoclonal antibody of claim 8 , wherein the monoclonal antibody further comprises the light chain CDR 1, 2 and 3 (LCDR1, LCDR2, LCDR3) amino acid sequences as shown in SEQ ID NO: 8 and 9, respectively.

10. A monoclonal antibody that specifically binds a human Toll-like receptor 3 (TLR3) polypeptide, wherein said antibody specifically binds to said human TLR3 polypeptide under acidic conditions with a sub-nanomolar K D for its bivalent binding affinity.

11. The antibody of claim 10 , wherein said antibody modulates TLR3 signaling without blocking binding of a dsRNA TLR3 ligand to said human TLR3 polypeptide.

12. The antibody of claim 11 , wherein said antibody inhibits TLR3 signaling.

13. The antibody of claim 10 , wherein said antibody inhibits TLR3 signaling.

14. The antibody of claim 10 , wherein said acidic conditions comprise a pH between 4.5 and 6.5.

15. The antibody of claim 14 , wherein said antibody specifically binds to said human TLR3 polypeptide under neutral conditions with a sub-nanomolar K D for bivalent binding affinity.

16. The antibody of claim 15 , wherein said neutral conditions comprise a pH between 6.6 and 7.4.

17. The antibody of claim 10 , wherein said antibody is conjugated or covalently bound to a toxic moiety.

18. The antibody of claim 10 , wherein said antibody is capable of being internalized by a TLR3-expressing cell.

19. The antibody of claim 18 , wherein said TLR3-expressing cell is a cancer cell.

20. The antibody of claim 10 , wherein said antibody is conjugated or covalently bound to a detectable moiety.

21. A hybridoma or recombinant host cell producing the antibody of claim 10 .

22. A pharmaceutical composition comprising an antibody of claim 10 and a pharmaceutically acceptable carrier.

23. The monoclonal antibody of claim 10 , wherein the monoclonal antibody is an antibody having the heavy chain CDR 1, 2 and 3 (HCDR1, HCDR2, HCDR3) amino acid sequences as shown in SEQ ID NO: 4, 5 and 6, respectively.

24. The monoclonal antibody of claim 23 , wherein the monoclonal antibody further comprises the light chain CDR 1, 2 and 3 (LCDR1, LCDR2, LCDR3) amino acid sequences as shown in SEQ ID NO: 7, 8 and 9, respectively.

25. An isolated antibody that specifically binds a human Toll-like receptor 3 (TLR3) polypeptide, wherein said antibody has respectively a VH and VL region of SEQ ID NO: 2 and 3 (31C3), and wherein said isolated antibody is a non-naturally occurring antibody.

26. The antibody of claim 25 , wherein said antibody is an antibody having the heavy chain CDR 1, 2 and 3 (HCDR1, HCDR2, HCDR3) amino acid sequences as shown in SEQ ID NO: 4, 5 and 6, respectively.

27. The antibody of claim 26 , wherein the antibody further comprises the light chain CDR 1, 2 and 3 (LCDR1, LCDR2, LCDR3) amino acid sequences as shown in SEQ ID NO: 7, 8 and 9, respectively.

28. The antibody of claim 25 , wherein said antibody is a mouse antibody.

29. The antibody of claim 25 , wherein said antibody is a chimeric, human or humanized antibody.

30. The antibody of claim 29 , wherein said antibody is of an IgG isotype.

31. The antibody of claim 30 , wherein the isotype of said antibody is an IgG4.

32. The antibody of claim 29 , wherein said antibody is an antibody fragment selected from Fab, Fab′, Fab′-SH, F (ab′) 2, Fv, diabodies, single-chain antibody fragment, or a multispecific antibody comprising multiple different antibody fragments.

33. The antibody of claim 25 , wherein said antibody is conjugated or covalently bound to a toxic moiety.

34. The antibody of claim 25 , wherein said antibody is capable of being internalized by a TLR3-expressing cell.

35. The antibody of claim 34 , wherein said TLR3-expressing cell is a cancer cell.

36. A hybridoma or recombinant host cell producing the antibody of claim 25 .

37. A pharmaceutical composition comprising an antibody of claim 25 and a pharmaceutically acceptable carrier.

38. The isolated antibody of claim 25 , wherein said isolated antibody specifically binds under acid conditions to a human Toll-like receptor 3 (TLR3) polypeptide.

39. The isolated antibody of claim 25 , wherein said isolated antibody specifically binds under neutral conditions a human Toll-like receptor 3 (TLR3).

40. An isolated antibody that specifically binds a human Toll-like receptor 3 (TLR3) polypeptide, wherein said antibody is selected from the group consisting of:
(a) an antibody having respectively a VH and VL region of SEQ ID NO: 34 and 35 (34A3),
(b) an antibody having respectively a VH and VL region of SEQ ID NO: 10 and 11 (29H3),
(c) an antibody having respectively a VH and VL region of SEQ ID NO: 18 and 19 (28F11), and
(d) an antibody having respectively a VH and VL region of SEQ ID NO: 26 and 27 (23C8)
wherein said isolated antibody is a non-naturally occurring antibody.

41. The antibody of claim 40 , wherein the antibody is an antibody having (i) the heavy chain CDR 1, 2 and 3 (HCDR1, HCDR2, HCDR3) amino acid sequences as shown in SEQ ID NO: 12, 13 and 14, and (ii) the light chain CDR 1, 2 and 3 (LCDR1, LCDR2, LCDR3) amino acid sequences as shown in SEQ ID NO: 15, 16 and 17, respectively.

42. The antibody of claim 40 , wherein the antibody is an antibody having (i) the heavy chain CDR 1, 2 and 3 (HCDR1, HCDR2, HCDR3) amino acid sequences as shown in SEQ ID NO: 20, 21 and 22, and (ii) the light chain CDR 1, 2 and 3 (LCDR1, LCDR2, LCDR3) amino acid sequences as shown in SEQ ID NO: 23, 24 and 25, respectively.

43. The antibody of claim 40 , wherein the antibody is an anti body having (i) the heavy chain CDR 1, 2 and 3 (HCDR1, HCDR2, HCDR3) amino acid sequences as shown in SEQ ID NO: 28, 29 and 30, and (ii) the light chain CDR 1, 2 and 3 (LCDR1, LCDR2, LCDR3) amino acid sequences as shown in SEQ ID NO: 31, 32 and 33, respectively.

44. The antibody of claim 40 , wherein the antibody is an antibody having (i) the heavy chain CDR 1, 2 and 3 (HCDR1, HCDR2, HCDR3) amino acid sequences as shown in SEQ ID NO

Assignees

• Gauthier Laurent
• Massacrier Catherine
• Morel Yannis
• Paturel Carine
• Innate Pharma

Inventors

• Gauthier Laurent
• Massacrier Catherine
• Morel Yannis
• Paturel Carine

Classifications

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• A61P31/04

  Antibacterial agents · CPC title