Anti-TIM-3 antibodies and compositions
This invention relates to anti-TIM-3 antibodies and antibody compositions and their use in enhancing immunity in a patient, e.g., to treat cancer.
1 . An anti-TIM-3 antibody or an antigen-binding portion thereof, wherein said antibody comprises the H-CDR1-3 and L-CDR1-3 amino acid sequences of SEQ ID NOs: 40-45, respectively.
2 . The anti-TIM-3 antibody or antigen-binding portion of claim 1 , wherein said antibody comprises a heavy chain (HC) and a light chain (LC) whose variable domains have the amino acid sequences of SEQ ID NOs: 38 and 39, respectively.
3 . The anti-TIM-3 antibody of claim 2 , wherein said HC and said LC further comprise the amino acid sequences of:
a) SEQ ID NOs: 5 and 6, respectively;
b) SEQ ID NOs: 25 and 6, respectively;
c) SEQ ID NOs: 23 and 6, respectively; or
d) SEQ ID NOs: 24 and 6, respectively.
4 . An anti-TIM-3 antibody that comprises an HC comprising the amino acid sequences of SEQ ID NOs: 38 and 25 or SEQ ID NOs: 38 and 5 and an LC comprising the amino acid sequences of SEQ ID NOs: 39 and 6.
5 . The anti-TIM-3 antibody of claim 1 , wherein the antibody is a human IgG antibody that comprises at least one mutation in the Fc region.
6 . The anti-TIM-3 antibody of claim 5 , wherein
a) the antibody is of isotype subclass IgG 1 and one or both of the amino acid residues at positions 234 and 235 (Eu numbering) are mutated to Ala, or
b) the antibody is of isotype subclass IgG 4 and the amino acid residue at position 228 (Eu numbering) is mutated to Pro.
7 . The anti-TIM-3 antibody or antigen-binding portion of claim 1 , wherein the antibody or portion has at least one of the following properties:
a) binds to human TIM-3 with a K D of 23 nM or less as measured by surface plasmon resonance;
b) binds to cynomolgus TIM-3 with a K D of 22 nM or less as measured by surface plasmon resonance;
c) binds to human TIM-3 with an EC 50 of 1.2 nM or less as measured by ELISA;
d) binds to cynomolgus TIM-3 with an EC 50 of 46 nM or less as measured by ELISA;
e) increases IFN-γ secretion in a one-way mixed lymphocyte reaction assay;
f) increases IFN-γ secretion in a two-way mixed lymphocyte reaction assay; and
g) increases TNF-α secretion from dendritic cells.
8 . A pharmaceutical composition comprising the anti-TIM-3 antibody or antigen-binding portion of claim 1 and a pharmaceutically acceptable excipient.
9 . Isolated nucleic acid molecule(s) comprising a nucleotide sequence that encodes the heavy chain amino acid sequence and a nucleotide sequence that encodes the light chain amino acid sequence of the anti-TIM-3 antibody or antigen-binding portion of claim 1 .
10 . Vector(s) comprising the isolated nucleic acid molecule(s) of claim 9 , wherein said vector(s) further comprise an expression control sequence.
11 . A host cell comprising a nucleotide sequence that encodes the heavy chain amino acid sequence and a nucleotide sequence that encodes the light chain amino acid sequence of the anti-TIM-3 antibody or antigen-binding portion of claim 1 .
12 . A method for producing an anti-TIM-3 antibody or an antigen-binding portion thereof, comprising providing the host cell according to claim 11 , culturing said host cell under conditions suitable for expression of the antibody or portion, and isolating the resulting antibody or portion.
13 . A bispecific binding molecule having an antigen-binding portion of the anti-TIM-3 antibody of claim 1 and an antigen-binding portion of another, distinct antibody.
14 . A method for enhancing immunity in a patient in need thereof, comprising administering to said patient the anti-TIM-3 antibody or antigen-binding portion of claim 1 .
15 . The method of claim 14 , further comprising administering to the patient a chemotherapeutic agent, an anti-neoplastic agent, an anti-angiogenic agent, a tyrosine kinase inhibitor, or a TIM-3 pathway inhibitor.
16 . The method of claim 14 , further comprising administering irinotecan to the patient.
17 . A method for treating cancer in a patient, comprising administering to said patient the anti-TIM-3 antibody or antigen-binding portion of claim 1 .
18 . The method of claim 17 , wherein the cancer originates in skin, lung, intestine, ovary, brain, prostate, kidney, soft tissues, hematopoietic system, head and neck, liver, bladder, breast, stomach, uterus, or pancreas.
19 . The method of claim 17 , wherein the cancer is leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, melanoma, esophageal cancer, gastroesophageal cancer, head and neck squamous cell carcinoma, non-small cell lung cancer, pancreatic cancer, biliary tract cancer, gastric cancer, colorectal cancer, renal cell carcinoma, or mesothelioma.