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:
(a) a heavy chain variable region (HCVR), comprising a HCVR CDR1 sequence of SEQ ID NO: 1, a HCVR CDR2 sequence of SEQ ID NO: 2, and a HCVR CDR3 sequence of SEQ ID NO: 3; and a light chain variable region (LCVR), comprising a LCVR CDR1 sequence of SEQ ID NO: 4, a LCVR CDR2 sequence of SEQ ID NO: 5, and a LCVR CDR3 sequence of SEQ ID NO: 6; or
(b) a heavy chain variable region (HCVR), comprising a HCVR CDR1 sequence of SEQ ID NO: 14, a HCVR CDR2 sequence of SEQ ID NO: 15, and a HCVR CDR3 sequence of SEQ ID NO: 16; and a light chain variable region (LCVR), comprising a LCVR CDR1 sequence of SEQ ID NO: 17, a LCVR CDR2 sequence of SEQ ID NO: 18, and a LCVR CDR3 sequence of SEQ ID NO: 19.
2 . The isolated monoclonal antibody or antigen-binding fragment thereof of claim 1 ,
wherein:
(a) the HCVR sequence is SEQ ID NO: 7; and/or the LCVR sequence is SEQ ID NO: 8, or
(b) the HCVR sequence is SEQ ID NO: 20; and/or the LCVR sequence is SEQ ID NO: 21.
3 . The isolated monoclonal antibody or antigen-binding fragment thereof according to claim 1 , wherein said monoclonal antibody has:
(a) a heavy chain sequence of SEQ ID NO: 9; and/or a light chain sequence of SEQ ID NO: 10, or
(b) a heavy chain sequence of SEQ ID NO: 22; and/or a light chain sequence of SEQ ID NO: 23.
4 . The isolated monoclonal antibody or antigen-binding fragment thereof according to claim 1 , which is a mouse antibody, a human-mouse chimeric antibody, a humanized antibody, a human 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, Fd, single chain Fv or scFv, disulfide linked Fv, V-NAR domain, IgNar, intrabody, IgGACH2, minibody, F(ab′)3, tetrabody, triabody, diabody, single-domain antibody, DVD-Ig, Fcab, mAb2, (scFv)2, or scFv-Fc.
6 . The isolated monoclonal antibody or antigen-binding fragment thereof according to claim 1 , wherein:
(i) said monoclonal antibody or antigen-binding fragment thereof cross-reacts with rhesus monkey TNFR2, but does not substantially cross-react with mouse TNFR2;
(ii) said monoclonal antibody or antigen-binding fragment thereof does not substantially cross-react with TNFR1;
(iii) said monoclonal antibody or antigen-binding fragment thereof binds TNFα with a Kd of less than about 25 nM;
(iv said monoclonal antibody or antigen-binding fragment thereof enhances binding between TNFα and TNFR2; enhances TNFα-mediated or TNFα-co-stimulated NFκB signaling; and/or promotes TCR-activated effector T cell proliferation in the presence of Treg;
(v) said monoclonal antibody or antigen-binding fragment thereof enhances TNFα-mediated CD25 expression on Tregs;
(vi) said monoclonal antibody or antigen-binding fragment thereof binds to an epitope of SEQ ID NO: 13;
(vii) said monoclonal antibody or antigen-binding fragment thereof inhibits binding between TNFα and TNFR2; inhibits TNFα-mediated or -co-stimulated NFκB signaling; and/or inhibits TCR-activated effector T cell proliferation in the presence of Treg;
(viii) said monoclonal antibody or antigen-binding fragment thereof promotes Treg expansion; or
(ix) said monoclonal antibody or antigen-binding fragment thereof promotes natural killer cell activation.
7 . An isolated monoclonal antibody or an antigen-binding fragment thereof, which competes with the isolated monoclonal antibody or antigen-binding fragment thereof according to claim 1 for binding to the epitope of SEQ ID NO: 13.
8 . An isolated monoclonal antibody or an antigen-binding fragment thereof, which specifically binds to the epitope of SEQ ID NO: 13.
9 . The isolated monoclonal antibody or antigen-binding fragment thereof according to claim 8 , which enhances binding between TNFα and TNFR2; enhances TNFα-mediated or TNFα-co-stimulated NFκB signaling; and/or promotes TCR-activated effector T cell proliferation in the presence of Treg.
10 . A method for treating cancer or an autoimmune disorder in a patient in need thereof, the method comprising administering the monoclonal antibody or antigen-binding fragment thereof according to claim 1 to the patient.
11 . The method according to claim 10 , wherein the method is for treating cancer, and wherein the monoclonal antibody or antigen-binding fragment thereof is administered to the patient in combination with an antagonist of an immune checkpoint protein.
12 . The method according to claim 11 , wherein the immune checkpoint protein is a PD-1 or PD-L1 immune checkpoint protein.
13 . The method according to claim 11 , wherein the antagonist of the immune checkpoint protein is an antibody or antigen-binding fragment thereof specific for PD-1 or PD-L1.
14 . The method according to claim 13 , wherein the anti-PD-1 antibody is cemiplimab, nivolumab, or pembrolizumab, or wherein the anti-PD-L1 antibody is avelumab, durvalumab, atezolizumab, KN035, or CK-301.
15 . The method according to claim 11 , wherein the antagonist of the immune checkpoint protein is a (non-antibody) peptide inhibitor of PD-1/PD-L1, or a small molecule inhibitor of PD-L1, or a macrocyclic peptide.
16 . The method according to claim 15 , wherein the peptide inhibitor is AUNP12, the small molecule inhibitor of PD-L1 is CA-170, or the macrocyclic peptide is BMS-986189.
17 . The method according to claim 10 , wherein the cancer is melanoma, breast cancer, colon cancer, cervical cancer, renal cancer, liver cancer, lung cancer (NSCLC), ovarian cancer, skin cancer, lymphoma, or leukemia.
18 . The method according to claim 10 , wherein the monoclonal antibody or antigen-binding fragment thereof is administered in combination with a chemotherapeutic agent, an anti-angiogenesis agent, a growth inhibitory agent, an immune-oncology agent, and/or an anti-neoplastic composition.
19 . A polynucleotide encoding the heavy chain or the light chain or the antigen-binding portion thereof according to claim 1 .
20 . A vector comprising the polynucleotide of claim 19 .