# US 2020/0399372 A1 · Use of bispecific antigen-binding molecules that bind psma and cd3 in combination with 4-1bb co-stimulation > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2020/0399372 A1 - Document ID: US20200399372A1 - Status: Published application - Kind: A1 - Application number: 16/906,943 - Filed: 2020-06-19 - Published: 2020-12-24 - Earliest claimed: 2019-06-21 - Assignees: Regeneron Pharmaceuticals, Inc. - Applicants: Regeneron Pharmaceuticals, Inc. - Inventors: Jessica R. Kirshner; Alison Crawford; Danica Chiu - Web page: https://patentgrep.com/patent/US20200399372A1 ## CPC - C07K 16/2809: {against the T-cell receptor (TcR)-CD3 complex} - C07K 16/468: {Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies} - A61K 47/6849: {the antibody targeting a receptor, a cell surface antigen or a cell surface determinant} - A61K 47/6869: {the tumour determinant being from a cell of the reproductive system: ovaria, uterus, testes, prostate} - A61K 47/6887: {Antibody-chelate conjugates using chelates for therapeutic purposes (radioactive substances, e.g. for use in radio diagnosis or radiotherapy, A61K51/10; antibody-chelates for use in MRI A61K49/14)} - A61K 51/1042: {against T-cell receptor (TcR)-CD3 complex} - A61K 51/1072: {the tumor cell being from the reproductive system, e.g. ovaria, uterus, testes or prostate} - C07K 16/2878: {against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95} - C07K 16/3069: {Reproductive system, e.g. ovaria, uterus, testes, prostate} - A61K 2039/505: {comprising antibodies} - A61K 2039/507: {Comprising a combination of two or more separate antibodies} - C07K 2317/31: multispecific - C07K 2317/56: variable (Fv) region, i.e. VH and/or VL - C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00) - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) ## Abstract Provided herein are methods of treating cancer using bispecific antigen-binding molecules that bind to prostate-specific membrane antigen (PSMA) and CD3. According to certain embodiments, the antibodies useful herein bind human PSMA with high affinity and bind CD3 to induce human T cell proliferation. According to certain embodiments, bispecific antigen-binding molecules comprising a first antigen-binding domain that specifically binds human CD3, and a second antigen-binding molecule that specifically binds human PSMA are particularly useful herein. In certain embodiments, the bispecific antigen-binding molecules in combination with an anti-4-1BB agonist are capable of inhibiting the growth of prostate tumors expressing PSMA. The bispecific antigen-binding molecules in combination with an anti-4-1BB agonist are useful for the treatment of diseases and disorders in which an upregulated or induced targeted immune response is desired and/or therapeutically beneficial, for example, in the treatment of various cancers. ## Claims ### Claim 1 A method of treating a cancer or inhibiting the growth of a tumor comprising administering to a subject in need thereof a therapeutically effective amount of each of (a) an anti-CD3/anti-PSMA bispecific antigen-binding molecule; and (b) an anti-4-1BB agonist. ### Claim 2 (depends on 1) The method of claim 1, wherein the cancer is selected from the group consisting of prostate cancer, kidney cancer, bladder cancer, colorectal cancer, and gastric cancer. ### Claim 3 (depends on 2) The method of claim 2, wherein the cancer is prostate cancer. ### Claim 4 (depends on 3) The method of claim 3, wherein the prostate cancer is castrate-resistant prostate cancer. ### Claim 5 (depends on 1) The method of claim 1, wherein the anti-CD3/anti-PSMA bispecific antibody and the anti-4-1BB agonist are administered separately. ### Claim 6 (depends on 1) The method of claim 1, wherein the anti-CD3/anti-PSMA bispecific antibody and the anti-4-1BB agonist are co-administered. ### Claim 7 (depends on 1) The method of claim 1, wherein the anti-CD3/anti-PSMA bispecific antibody is administered prior to, concurrent with or after the anti-4-1BB agonist. ### Claim 8 (depends on 7) The method of claim 7, wherein the anti-CD3/anti-PSMA bispecific antibody is administered prior to the anti-4-1BB agonist. ### Claim 9 (depends on 7) The method of claim 7, wherein the anti-CD3/anti-PSMA bispecific antibody is administered the same day as the anti-4-1BB agonist. ### Claim 10 (depends on 1) The method of claim 1, wherein the anti-CD3/anti-PSMA bispecific antibody is administered in combination with the anti-4-1BB agonist. ### Claim 11 (depends on 1) The method of claim 1, wherein the anti-4-1BB agonist is selected from a small molecule or an antibody. ### Claim 12 (depends on 11) The method of claim 11, wherein the anti-4-1BB agonist is an antibody selected from the group consisting of urelumab and utomilumab. ### Claim 13 (depends on 1) The method of claim 1, wherein the bispecific antigen-binding molecule comprises a first antigen-binding domain, and the first antigen-binding domain specifically binds human CD3 and comprises a heavy chain variable region (HCVR-1) amino acid sequence of SEQ ID NO: 2. ### Claim 14 (depends on 1) The method of claim 1, wherein the bispecific antigen-binding molecule comprises a second antigen-binding domain, and the second antigen-binding domain specifically binds human PSMA and comprises a heavy chain variable region (HCVR-2) amino acid sequence of SEQ ID NO: 1. ### Claim 15 (depends on 1) The method of claim 1, wherein the bispecific antigen-binding molecule comprises a first antigen-binding domain that specifically binds CD3 and comprises a HCVR-1 amino acid sequence of SEQ ID NO: 2 and a second antigen-binding domain that specifically binds PSMA and comprises a HCVR-2 amino acid sequence of SEQ ID NO: 1. ### Claim 16 (depends on 1) The method of claim 1, wherein the bispecific antigen-binding molecule comprises a common LCVR of SEQ ID NO: 3. ### Claim 17 (depends on 1) The method of claim 1, wherein the tumor volume is decreased relative to treatment in the absence of an anti-4-1BB agonist. ### Claim 18 (depends on 1) The method of claim 1, wherein tumor free survival is increased relative to treatment in the absence of an anti-4-1BB agonist. ### Claim 19 (depends on 1) The method of claim 1, wherein expression of TRAF1 in the tumor of a subject is increased by at least about 4 fold relative to TRAF1 expression in the tumor of a subject administered the anti-CD3/anti-PSMA bispecific antigen-binding molecule in the absence of an anti-4-1BB agonist. ### Claim 20 (depends on 1) The method of claim 1, wherein expression of Bcl2 in the tumor of a subject is increased by at least about 2 fold relative to Bcl2 expression in the tumor of a subject administered the anti-CD3/anti-PSMA bispecific antigen-binding molecule in the absence of an anti-4-1BB agonist. ### Claim 21 (depends on 1) The method of claim 1, wherein expression of BFL-1 in the tumor of a subject is increased by at least about 3 fold relative to BFL-1 expression in the tumor of a subject administered the anti-CD3/anti-PSMA bispecific antigen-binding molecule in the absence of an anti-4-1BB agonist. ### Claim 22 (depends on 1) The method of claim 1, wherein expansion of CD8+ T cells in the tumor of a subject is increased and/or survival of CD8+ T cells increases relative to CD8+ T cells in the tumor of a subject administered the anti-CD3/anti-PSMA bispecific antigen-binding molecule in the absence of an anti-4-1BB agonist. ### Claim 23 A method of increasing expansion of CD8+ T cells in tumor tissue, the method comprising administering to a subject in need thereof a therapeutically effective amount of each of (a) an anti-CD3/anti-PSMA bispecific antigen-binding molecule; and (b) an anti-4-1BB agonist. ### Claim 24 (depends on 23) The method of claim 23, wherein the CD8+ T cells to Treg ratio increases in the tumor tissue of a subject treated with an anti-CD3/anti-PSMA bispecific antigen-binding molecule plus an anti-4-1BB agonist as compared to the CD8+ T cells to Treg ratio in the tumor tissue of a subject treated with an anti-CD3/anti-PSMA bispecific antigen-binding molecule in the absence of an anti-4-1BB agonist. ### Claim 25 (depends on 1) The method of claim 1, wherein subsequent exposure to tumor cells elicits a memory response in the subject treated with the anti-CD3/anti-PSMA bispecific antigen-binding molecule in the presence of an anti-4-1BB agonist. ### Claim 26 A method of eliciting and/or enhancing a T cell response to a tumor, the method comprising administering to a subject in need thereof a therapeutically effective amount of each of (a) an anti-CD3/anti-PSMA bispecific antigen-binding molecule; and (b) an anti-4-1BB agonist. ### Claim 27 A pharmaceutical composition comprising: (a) a bispecific antigen-binding molecule comprising: (i) first antigen-binding domain that specifically binds human CD3 and comprises a HCVR-1 amino acid sequence of SEQ ID NO: 2 and (ii) a second antigen-binding domain that specifically binds human PSMA and comprises a HCVR-2 amino acid sequence of SEQ ID NO: 1; (b) an anti-4-1BB agonist; and (c) a pharmaceutically acceptable carrier or diluent. ### Claim 28 (depends on 27) The pharmaceutical composition of claim 27, wherein the bispecific antigen-binding molecule of part (a) comprises a common LCVR amino acid of SEQ ID NO: 3. ### Claim 29 A radiolabeled bispecific antibody conjugate comprising a bispecific antigen-binding molecule that binds PSMA and CD3, a chelating moiety, and a positron emitter. ### Claim 30 (depends on 29) The conjugate of claim 29, wherein the bispecific antigen-binding molecule is covalently bonded to the chelating moiety, L, of formula (A): -L-Mz (A) wherein M is the positron emitter; and z, independently at each occurrence, is 0 or 1; and wherein at least one of z is 1. ### Claim 31 (depends on 29) The conjugate of claim 29, wherein the chelating moiety comprises desferrioxamine. ### Claim 32 (depends on 29) The conjugate of claim 29, wherein the positron emitter is 89Zr. ### Claim 33 (depends on 30) The conjugate of claim 30, wherein -L-M is and wherein the positron emitter Zr is 89Zr. ### Claim 34 (depends on 30) The conjugate of claim 30, wherein the bispecific antigen-binding molecule is covalently bonded to one, two, or three moieties of Formula (A). ### Claim 35 (depends on 29) The conjugate of claim 29, wherein the bispecific antigen-binding molecule comprises a first antigen-binding domain that specifically binds CD3 and comprises a HCVR-1 amino acid sequence of SEQ ID NO: 2 and a second antigen-binding domain that specifically binds PSMA and comprises a HCVR-2 amino acid sequence of SEQ ID NO: 1. ### Claim 36 (depends on 29) A method of imaging a tissue that expresses PSMA comprising administering a radiolabeled bispecific antibody conjugate of claim 29 to the tissue; and visualizing PSMA expression by positron emission tomography (PET) imaging.