Anti-TNFR2 antibody and uses thereof
The invention provides monoclonal antibodies and antigen-binding fragments thereof specific for TNFR2, and methods of using the same to treat cancer or autoimmune disorder, including combination therapy with antagonists of the PD-1/PD-L1 immune checkpoint.
1 . An isolated monoclonal antibody, or an antigen-binding fragment thereof, wherein said monoclonal antibody or antigen-binding fragment thereof is specific for human TNFR2, and wherein said monoclonal antibody comprises:
(3a) a heavy chain variable region (HCVR), comprising a HCVR CDR1 sequence of SEQ ID NO: 26, a HCVR CDR2 sequence of SEQ ID NO: 27, and a HCVR CDR3 sequence of SEQ ID NO: 28; and,
(3b) a light chain variable region (LCVR), comprising a LCVR CDR1 sequence of SEQ ID NO: 29, a LCVR CDR2 sequence of SEQ ID NO: 30, and a LCVR CDR3 sequence of SEQ ID NO: 31; or
(4a) a heavy chain variable region (HCVR), comprising a HCVR CDR1 sequence of SEQ ID NO: 39, a HCVR CDR2 sequence of SEQ ID NO: 40, and a HCVR CDR3 sequence of SEQ ID NO: 41; and,
(4b) a light chain variable region (LCVR), comprising a LCVR CDR1 sequence of SEQ ID NO: 42, a LCVR CDR2 sequence of SEQ ID NO: 43, and a LCVR CDR3 sequence of SEQ ID NO: 44; or
(5a) a heavy chain variable region (HCVR), comprising a HCVR CDR1 sequence of SEQ ID NO: 51, a HCVR CDR2 sequence of SEQ ID NO: 52, and a HCVR CDR3 sequence of SEQ ID NO: 53; and,
(5b) a light chain variable region (LCVR), comprising a LCVR CDR1 sequence of SEQ ID NO: 54, a LCVR CDR2 sequence of SEQ ID NO: 55, and a LCVR CDR3 sequence of SEQ ID NO: 56; or
(6a) a heavy chain variable region (HCVR), comprising a HCVR CDR1 sequence of SEQ ID NO: 63, a HCVR CDR2 sequence of SEQ ID NO: 64, and a HCVR CDR3 sequence of SEQ ID NO: 65; and,
(6b) a light chain variable region (LCVR), comprising a LCVR CDR1 sequence of SEQ ID NO: 66, a LCVR CDR2 sequence of SEQ ID NO: 67, and a LCVR CDR3 sequence of SEQ ID NO: 68, wherein said isolated monoclonal antibody or antigen-binding fragment thereof is a human-mouse chimeric antibody, a humanized antibody, a CDR-grafted antibody, or a resurfaced antibody.
2 . The isolated monoclonal antibody or antigen-binding fragment thereof of claim 1 , wherein:
(3A) the HCVR sequence is the HCVR sequence of a monoclonal antibody having the heavy chain sequence of SEQ ID NO: 34; and/or,
(3B) the LCVR sequence is the LCVR sequence of a monoclonal antibody having the heavy chain sequence of SEQ ID NO: 35, or,
(4A) the HCVR sequence is the HCVR sequence of a monoclonal antibody having the heavy chain sequence of SEQ ID NO: 47; and/or,
(4B) the LCVR sequence is the LCVR sequence of a monoclonal antibody having the heavy chain sequence of SEQ ID NO:48, or,
(5A) the HCVR sequence is the HCVR sequence of a monoclonal antibody having the heavy chain sequence of SEQ ID NO: 59; and/or,
(5B) the LCVR sequence is the LCVR sequence of a monoclonal antibody having the heavy chain sequence of SEQ ID NO:60, or,
(6A) the HCVR sequence is the HCVR sequence of a monoclonal antibody having the heavy chain sequence of SEQ ID NO: 71; and/or,
(6B) the LCVR sequence is the LCVR sequence of a monoclonal antibody having the heavy chain sequence of SEQ ID NO: 72.
3 . The isolated monoclonal antibody or antigen-binding fragment thereof according to claim 1 , wherein said monoclonal antibody has:
(3a) a heavy chain sequence of SEQ ID NO: 34; and/or,
(3b) a light chain sequence of SEQ ID NO: 35, or,
(4a) a heavy chain sequence of SEQ ID NO: 47; and/or,
(4b) a light chain sequence of SEQ ID NO: 48, or,
(5a) a heavy chain sequence of SEQ ID NO: 59; and/or,
(5b) a light chain sequence of SEQ ID NO: 60, or,
(6a) a heavy chain sequence of SEQ ID NO: 71; and/or,
(6b) a light chain sequence of SEQ ID NO: 72.
4 . The isolated monoclonal antibody or antigen-binding fragment thereof according to claim 1 , which is a human-mouse chimeric antibody, a humanized antibody, a CDR-grafted antibody, or a resurfaced antibody.
5 . The isolated monoclonal antibody or antigen-binding fragment thereof according to claim 1 , wherein said antigen-binding fragment thereof is an Fab, Fab′, F(ab′)2, single chain Fv or scFv, disulfide linked Fv, IgGΔCH2, minibody, F(ab′)3, tetrabody, triabody, diabody, DVD-Ig, mAb2, (scFv)2, or scFv-Fc.
6 . The isolated monoclonal antibody or antigen-binding fragment thereof of claim 1 , wherein said monoclonal antibody or antigen-binding fragment thereof does not substantially cross-react with TNFR1.
7 . The isolated monoclonal antibody or antigen-binding fragment thereof of claim 1 , wherein said monoclonal antibody or antigen-binding fragment thereof binds TNFR2 with a K d of less than about 25 nM, 20 nM, 15 nM, 10 nM, 5 nM, 2 nM, or 1 nM.
8 . The isolated monoclonal antibody or antigen-binding fragment thereof of claim 1 , which enhances binding between TNFα and TNFR2; enhances TNFα-mediated or -co-stimulated NFκB signaling and/or promotes TCR-activated effector T cell proliferation in the presence of Treg.
9 . A method of treating cancer in a patient in need thereof, the method comprising administering to the patient an effective amount of the isolated monoclonal antibody or antigen-binding fragment thereof of claim 1 .
10 . The method of claim 9 , which is for treating cancer, wherein the method further comprises administering an antagonist of an immune checkpoint.
11 . The method of claim 10 , wherein the immune checkpoint is PD-1/PD-L1 immune checkpoint.
12 . The method of claim 10 , wherein the antagonist of the immune checkpoint is:
(a) an antibody or antigen-binding fragment thereof specific for PD-1 or PD-L1, such as cemiplimab, nivolumab, pembrolizumab, avelumab, durvalumab, atezolizumab, KN035, or CK-301;
(b) a (non-antibody) peptide inhibitor of PD-1/PD-L1, such as AUNP12;
(c) a small molecule inhibitor of PD-L1 such as CA-170; or
(d) a macrocyclic peptide such as BMS-986189.
13 . The method of claim 10 , wherein the cancer is melanoma, breast cancer, colon cancer, cervical cancer, renal cancer, liver cancer (e.g., heptocellular carcinoma), lung cancer (NSCLC), ovarian cancer, skin cancer (e.g., squamous cell carcinoma or basal cell carcinoma), lymphoma, or leukemia.
14 . The method of claim 10 , further comprising administering to the patient a chemotherapeutic agent, an anti-angiogenesis agent, a growth inhibitory agent, an immune-oncology agent, and/or an anti-neoplastic composition.
15 . A polynucleotide encoding the heavy chain or the light chain or the antigen-binding portion thereof of claim 1 .
16 . The polynucleotide of claim 15 , which is codon optimized for expression in a human cell.
17 . A vector comprising the polynucleotide of claim 15 .