Toll-like receptor 3 antagonists

1. An isolated antibody that binds toll-like receptor 3 (TLR3), wherein the antibody competes for TLR3 binding with a monoclonal antibody comprising:

a) the heavy chain variable region of SEQ ID NO: 214 and the light chain variable region of SEQ ID NO: 211; or

b) the heavy chain CDR 1, 2 and 3 amino acid sequences as shown in SEQ ID NOs: 70, 77 and 72 and the light chain CDR 1, 2 and 3 amino acid sequences as shown in SEQ ID NOs: 67, 68 and 78,

wherein the isolated antibody comprises

the heavy chain CDR 1, 2 and 3 amino acid sequences as shown in SEQ ID NOs: 70, 194 and 72, wherein the HCDR2 of SEQ ID NO: 194 is further defined as shown in Formula (III): I-I-Q-Xaa 15 -R-S-K-W-Y-N-Xaa 16 -Y-A-Xaa 17 -S-V-K-S, (III) wherein

i) Xaa 15 may be Lys, Thr or Ile;

ii) Xaa 16 may be Asn or Asp; and

iii) Xaa 17 may be Val or Leu; and

the light chain CDR 1, 2 and 3 amino acid sequences as shown in SEQ ID NOs: 67, 68 and 193, wherein the LCDR3 of SEQ ID NO: 193 is further defined as shown in Formula (IV): Xaa 10 -S-Y-D-Xaa 11 -P-Xaa 12 -Xaa 13 -Xaa 14 -V, (IV) wherein

iv) Xaa 10 may be Gln or Ser;

v) Xaa 11 may be Thr, Glu or Asp;

vi) Xaa 12 may be Val or Asn;

vii) Xaa 13 may be Tyr or Phe; and

viii) Xaa 14 may be Ser, Asn or Gln.

2. The isolated antibody of claim 1 , wherein

the antibody has at least one of the following properties:

a) reduces human TLR3 biological activity in an in vitro poly(I:C) NF-κB reporter gene assay >50% at <1 μg/ml;

b) inhibits >60% of IL-6 or CXCL10/IP-10 production from BEAS-2B cells stimulated with <100 ng/ml poly(I:C) at <10 μg/ml;

c) inhibits >50% of IL-6 or CXCL10/IP-10 production from BEAS-2B cells stimulated with <100 ng/ml poly(I:C) at <0.4 μg/ml;

d) inhibits >50% of IL-6 production from NHBE cells stimulated with 62.5 ng/ml poly(I:C) at <5 μg/ml;

e) inhibits >50% of IL-6 production from NHBE cells stimulated with 62.5 ng/ml poly(I:C) at <1 μg/ml;

f) inhibits >20% of poly(I:C)-induced IFN-γ, IL-6 or IL-12 production by PBMC at <1 μg/ml;

g) inhibits cynomolgus TLR3 biological activity in an in vitro NF-kB reporter gene assay with IC50<10 μg/ml; or

h) inhibits cynomolgus TLR3 biological activity in an in vitro ISRE reporter gene assay with IC50<5 μg/ml.

3. The isolated antibody of claim 1 , comprising both a heavy chain and a light chain variable region and wherein the antibody comprises:

a) the heavy chain variable region of SEQ ID NO: 214 and the light chain variable region of SEQ ID NO: 211; or

b) the heavy chain CDR 1, 2 and 3 amino acid sequences as shown in SEQ ID NOs: 70, 77 and 72 and the light chain CDR 1, 2 and 3 amino acid sequences as shown in SEQ ID NOs: 67, 68 and 78.

4. The isolated antibody of claim 1 comprising both a heavy chain and a light chain variable region and wherein the antibody comprises:

a) the heavy chain variable region of SEQ ID NO: 32 and the light chain variable region of SEQ ID NO: 31.

5. The isolated antibody of claim 1 comprising both a heavy chain and a light chain variable region and wherein the antibody comprises:

a) the heavy chain variable region of SEQ ID NO: 34 and the light chain variable region of SEQ ID NO: 33; or

b) the heavy chain CDR 1, 2 and 3 amino acid sequences as shown in SEQ ID NOs: 70, 77 and 72 and the light chain CDR 1, 2 and 3 amino acid sequences as shown in SEQ ID NOs: 67, 68 and 76.

6. The isolated antibody of claim 1 , wherein the antibody is fully human or human-adapted.

7. The isolated antibody of claim 6 , wherein the antibody is conjugated to polyethylene glycol.

8. The isolated antibody of claim 6 having an IgG4 isotype.

9. The isolated antibody of claim 6 , wherein the Fc domain comprises S229P, P235A or L236A mutations.

10. A pharmaceutical composition comprising the isolated antibody of claim 1 and a pharmaceutically acceptable carrier.