Toll-like receptor 3 antagonists
AssigneeJanssen Biotech, Inc.
InventorsMark Cunningham, Yiqing Feng, Katharine Heeringa, Jinquan Luo, Robert Rauchenberger, Mark Rutz, Lani San Mateo, Robert Sarisky, Raymond Sweet, Fang Teng, Alexey Teplyakov, Sheng-Jiun Wu
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Abstract
Toll Like Receptor 3 (TLR3) antibody antagonists, polynucleotides encoding TLR3 antibody antagonists or fragments thereof, and methods of making and using the foregoing are disclosed.
Claims17
An isolated antibody or fragment thereof that binds toll-like receptor 3 (TLR3), wherein the antibody binds at least one TLR3 amino acid residue selected from the group consisting of residues K467, R488 and R489 of SEQ ID NO:
- 2.
An isolated antibody or fragment thereof that binds toll-like receptor 3(TLR3), 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 cynomologus TLR3 biological activity in an in vitro NF-κB reporter gene assay with IC50 <10 μg/ml;
- or
- h) inhibits cynomologus TLR3 biological activity in an in vitro ISRE reporter gene assay with IC50<5μg/ml.
An isolated monoclonal antibody or fragment reactive with TLR3 that competes for TLR3 binding with a monoclonal antibody comprising:
- a) the heavy chain variable region of SEQ ID NO:
- 216 and the light chain variable region of SEQ ID NO:
- 41;
- or
- the heavy chain CDR 1, 2 and 3 amino acid sequences as shown in SEQ ID NOs:
- 82, 86 and 84 and the light chain CDR 1, 2 and 3 amino acid sequences as shown in SEQ ID NOs:
- 79, 80 and 87.
An isolated antibody or fragment reactive with TLR3 comprising both a heavy chain and a light chain variable region and wherein the antibody comprises:
- a) the heavy chain CDR 1, 2 and 3 amino acid sequences as shown in SEQ ID NOs:
- 82, 196 and 84, wherein the HCDR2 of SEQ ID NO:
- 196 is further defined as shown in Formula (V):
- Xaa24-I-D-P-S-D-S-Y-T-N-Y-Xaa25-P-S-F-Q-G, (V)
- wherein
- Xaa24 may be Phe or Arg;
- and
- Xaa25 may be Ala or Ser;
- and
- b) the light chain CDR 1, 2 and 3 amino acid sequences as shown in SEQ ID NOs:
- 79, 80 and 195, wherein the LCDR3 of SEQ ID NO:
- 195 is further defined as shown in Formula (VI):
- Q-Q-Xaa18-Xaa19-Xaa20-Xaa21-Xaa22-Xaa23-T, (VI)
- wherein
- Xaal8 may be Tyr, Gly or Ala;
- Xaa19 may be Gly, Glu or Asn;
- Xaa20 may be Ser or Thr;
- Xaa21 may be Val, Ile or Leu;
- Xaa22 may be Ser or Leu;
- and
- Xaa23 may be Ile, Ser, Pro or Tyr.
An isolated antibody or fragment reactive with TLR3 comprising both a heavy chain and a light chain variable region and wherein the antibody comprises:
- the heavy chain CDR 1, 2 and 3 amino acid sequences as shown in SEQ ID NOs:
- 82, 86 and 84 and the light chain CDR 1, 2 and 3 amino acid sequences as shown in SEQ ID NOs:
- 79, 80 and 87.
An isolated antibody or fragment reactive with TLR3 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:
- 216;
- or
- b) the light chain variable region of SEQ ID NO:
- 41;
- or
- c) the heavy chain variable region of SEQ ID NO:
- 216 and the light chain variable region of SEQ ID NO:
- 41;
- or
- d) the heavy chain of SEQ ID NO:
- 220;
- or
- e) the light chain of SEQ ID NO:
- 156;
- or
- f) the heavy chain of SEQ ID NO:
- 220 and the light chain of SEQ ID NO:
- 156.
An isolated antibody heavy chain comprising the amino acid sequence shown in SEQ ID NO:
- 216.
An isolated antibody light chain comprising the amino acid sequence shown in SEQ ID NO:
- 41.
An isolated antibody heavy chain comprising the amino acid sequence shown in SEQ ID NO:
- 220.
An isolated antibody light chain comprising the amino acid sequence shown in SEQ ID NO:
- 156.
Dependencies are inferred from the claim text.