# US 2018/0022819 A1 · Compositions and methods for combination therapy with prostate-specific membrane antigen binding proteins

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- Number: US 2018/0022819 A1
- Document ID: US20180022819A1
- Status: Published application
- Kind: A1
- Application number: 15/550,143
- Filed: 2016-02-11
- Published: 2018-01-25
- Earliest claimed: 2015-02-11
- Applicants: Aptevo Research and Development LLC
- Inventors: John BLANKENSHIP; Elaine Todd SEWELL
- Web page: https://patentgrep.com/patent/US20180022819A1

## CPC

- C07K 16/3069: {Reproductive system, e.g. ovaria, uterus, testes, prostate}
- A61K 31/4166: having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
- A61K 31/4188: condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/58: containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin (digitoxin {A61K31/7048})
- A61K 39/39558: {against tumor tissues, cells, antigens}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/00: Antineoplastic agents
- C07K 16/2809: {against the T-cell receptor (TcR)-CD3 complex}
- A61K 2039/505: {comprising antibodies}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/31: multispecific
- C07K 2317/522: CH1 domain
- C07K 2317/53: Hinge
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/622: Single chain antibody (scFv)
- C07K 2317/73: Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present disclosure relates to combination treatments with anti-androgen therapeutics, including enzalutamide, and prostate-specific membrane antigen (PSMA)-binding polypeptides including multi-specific polypeptide therapeutics that specifically target cells expressing PSMA and are capable of redirecting T-cell cytotoxicity. Such therapeutics are useful for the treatment of prostate cancer (e.g., castration-resistant prostate cancer). In one embodiment, multi-specific polypeptide therapeutics bind both PSMA-expressing cells and the T-cell receptor complex on T-cells to induce target-dependent T-cell cytotoxicity, activation, and proliferation. The disclosure also provides compositions comprising the multi-specific polypeptide therapeutics and one or more anti-androgen therapeutics.

## Claims

### Claim 1

A method of treating a patient with a cancer, comprising administering to the patient a prostate-specific membrane antigen (PSMA)-binding polypeptide and at least one anti-androgen therapeutic.

### Claim 2 (depends on 1)

The method of claim 1, wherein said PSMA-binding polypeptide comprises a humanized PSMA-binding domain.

### Claim 3 (depends on 2)

The method of claim 2, wherein said humanized PSMA-binding domain is a single chain variable fragment (scFv).

### Claim 4 (depends on 3)

The method of claim 3, wherein the light chain variable region of said scFv is carboxy-terminal to the heavy chain variable region of said scFv.

### Claim 5 (depends on 3)

The method of claim 3, wherein the light chain variable region of said scFv is amino-terminal to the heavy chain variable region of said scFv.

### Claim 6 (depends on 2)

The method of claim 2, wherein the humanized PSMA-binding domain comprises: (i) an immunoglobulin light chain variable region comprising LCDR1, LCDR2, and LCDR3, and (ii) an immunoglobulin heavy chain variable region comprising HCDR1, HCDR2, and HCDR3, wherein
(a) the LCDR1, LCDR2 and LCDR3 have the amino acid sequences set forth in SEQ ID NOs: 15, 16 and 17, respectively, and the HCDR1, HCDR2, and HCDR3 have the amino acid sequences set forth in SEQ ID NOs: 9, 10 and 11, respectively;
(b) the LCDR1, LCDR2 and LCDR3 have the amino acid sequences set forth in SEQ ID NOs: 175, 176 and 177, respectively, and the HCDR1, HCDR2, and HCDR3 have the amino acid sequences set forth in SEQ ID NOs: 172, 173 and 174, respectively; or
(c) the LCDR1, LCDR2 and LCDR3 have the amino acid sequences set forth in SEQ ID NOs: 197, 198 and 199, respectively, and the HCDR1, HCDR2, and HCDR3 have the amino acid sequences set forth in SEQ ID NOs: 194, 195 and 196, respectively.

### Claim 7 (depends on 6)

The method of claim 6, wherein said PSMA-binding polypeptide further comprises a hinge region.

### Claim 8 (depends on 7)

The method of claim 7, wherein the hinge region comprises an amino acid sequence that is an immunoglobulin hinge region amino acid sequence or is derived from an an immunoglobulin hinge region amino acid sequence.

### Claim 9 (depends on 7, 8)

The method of claim 7 or 8, wherein said PSMA-binding polypeptide further comprises an immunoglobulin constant region.

### Claim 10 (depends on 9)

The method of claim 9, wherein the immunoglobulin constant region comprises immunoglobulin CH2 and CH3 domains of IgG1, IgG2, IgG3, IgG4, IgA1, IgA2 or IgD.

### Claim 11 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10)

The method of any one of claims 1-10, wherein the PSMA-binding polypeptide does not exhibit or exhibits minimal antibody-dependent cell-mediated cytotoxicity (ADCC) activity and/or complement-dependent cytotoxicity (CDC) activity.

### Claim 12 (depends on 7, 8, 9, 10, 11)

The method of any one of claims 7-11, wherein the PSMA-binding polypeptide comprises from amino-terminus to carboxyl-terminus or from carboxyl-terminus to amino-terminus (a) the PSMA binding domain, (b) the hinge region, and (c) the immunoglobulin constant region.

### Claim 13 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12)

The method of any one of claims 1-12, wherein said PSMA-binding polypeptide comprises an amino acid sequence that is at least 95% identical to the amino acid sequence in SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:70, or SEQ ID NO:72.

### Claim 14 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13)

The method of any one of claims 1-13, wherein said PSMA-binding polypeptide further comprises a second binding domain.

### Claim 15 (depends on 14)

The method of claim 14, wherein said PSMA-binding polypeptide comprises:
(i) in order from amino-terminus to carboxyl-terminus, (a) the PSMA binding domain, (b) a hinge region, (c) an immunoglobulin constant region, (d) a carboxyl-terminus linker, and (e) the second binding domain; or
(ii) in order from carboxyl-terminus to amino-terminus, (a) the PSMA binding domain, (b) a hinge region, (c) an immunoglobulin constant region, (d) an amino-terminus linker, and (e) the second binding domain.

### Claim 16 (depends on 15)

The method of claim 15, wherein the carboxyl-terminus linker or the amino-terminus linker comprises a flexible linker comprising glycine-serine (e.g., (Gly4Ser)) repeats or is derived from (i) a stalk region of a type II C lectin or (ii) an immunoglobulin hinge region.

### Claim 17 (depends on 14, 15, 16)

The method of any one of claims 14-16, wherein the second binding domain specifically binds a T-cell, CD3, CD3ε or a T-cell receptor (TCR) complex or a component thereof.

### Claim 18 (depends on 14, 15, 16)

The method of any one of claims 14-16, wherein the second binding domain competes for binding to CD3ε with a monoclonal antibody selected from the group consisting of CRIS-7, HuM291, and I2C.

### Claim 19 (depends on 14)

The method of claim 14, wherein the second binding domain comprises an immunoglobulin light chain variable region and an immunoglobulin heavy chain variable region derived from a monoclonal antibody selected from the group consisting of CRIS-7, HuM291, and I2C.

### Claim 20 (depends on 19)

The method of claim 19, wherein the light and heavy chain variable regions of the second binding domain are humanized variable regions of the light and heavy chain CDRs of the monoclonal antibody.

### Claim 21 (depends on 19)

The method of claim 19, wherein the light and heavy chain variable regions of the second binding domain are selected from the group consisting of:
(a) a light chain variable region comprising an amino acid sequence that is at least 95% identical to the amino acid sequence set forth in residues 139-245 of SEQ ID NO:47 and a heavy chain variable region comprising an amino acid sequence that is at least 95% identical to the amino acid sequence set forth in residues 1-121 of SEQ ID NO:47;
(b) a light chain variable region comprising an amino acid sequence that is at least 95% identical to the amino acid sequence set forth in residues 634-740 of SEQ ID NO:78 and a heavy chain variable region comprising an amino acid sequence that is at least 95% identical to the amino acid sequence set forth in residues 496-616 of SEQ ID NO:78; and
(c) a light chain variable region comprising an amino acid sequence that is at least 95% identical to the amino acid sequence set forth in residues 390-498 of SEQ ID NO:193 and a heavy chain variable region comprising an amino acid sequence that is at least 95% identical to the amino acid sequence set forth in residues 250-374 of SEQ ID NO:193.

### Claim 22 (depends on 14, 15, 16, 17, 18, 19, 20, 21)

The method of any one of claims 14-21, wherein the second binding domain is a single chain Fv (scFv).

### Claim 23 (depends on 6)

The method of claim 6, wherein said PSMA-binding polypeptide comprises an amino acid sequence that is at least 95% or 100% identical to the amino acid sequence set forth in SEQ ID NO:49, SEQ ID NO:51, SEQ ID NO:74, SEQ ID NO:76, SEQ ID NO:78, SEQ ID NO:80, SEQ ID NO:82, SEQ ID NO:84, SEQ ID NO:158, SEQ ID NO:160, SEQ ID NO:162, SEQ ID NO:164, SEQ ID NO:193, or SEQ ID NO:205.

### Claim 24 (depends on 6)

The method of claim 6, wherein the immunoglobulin light chain variable region comprises an amino acid sequence that is at least 95% identical to the amino acid sequence set forth in SEQ ID NO:5, SEQ ID NO:23, SEQ ID NO:181, or SEQ ID NO:203 and the heavy chain variable region comprises an amino acid sequence that is at least 95% identical to the amino acid sequence set forth in SEQ ID NO:2, SEQ ID NO:25, SEQ ID NO:27, SEQ ID NO:179, or SEQ ID NO:201.

### Claim 25 (depends on 24)

The method of claim 24, wherein
(a) the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:23 and the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:25 or SEQ ID NO:27;
(b) the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:181 and the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:179; or
(c) the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:203 and the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:201.

### Claim 26 (depends on 6)

The method of claim 6, wherein the PSMA-binding domain competes for binding to human PSMA with a single chain Fv (scFv) having the amino acid sequence set forth in SEQ ID NO:21.

### Claim 27 (depends on 3)

The method of claim 3, wherein the light chain variable region and heavy chain variable region of the scFv are joined by an amino acid sequence comprising (Gly4Ser)n, wherein n=1-5 (SEQ ID NO: 165).

### Claim 28 (depends on 3)

The method of claim 3, wherein the scFv comprises an amino acid sequence that is at least 95% identical to the amino acid sequence set forth in SEQ ID NO:19, SEQ ID NO:21, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:34, or SEQ ID NO:35.

### Claim 29 (depends on 6)

The method of claim 6, wherein the PSMA-binding polypeptide further comprises an immunoglobulin heterodimerization domain.

### Claim 30 (depends on 29)

The method of claim 29, wherein the immunoglobulin heterodimerization domain comprises an immunoglobulin CH1 domain or an immunoglobulin CL domain.

### Claim 31 (depends on 29)

The method of claim 29, wherein said PSMA-binding polypeptide comprises an amino acid sequence that is at least 95% identical to the amino acid sequence set forth in SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, or SEQ ID NO:61.

### Claim 32 (depends on 14, 15, 16, 17)

The method of any one of claims 14-17, wherein the second binding domain comprises:
(i) an immunoglobulin light chain variable region comprising LCDR1, LCDR2, and LCDR3, and
(ii) an immunoglobulin heavy chain variable region comprising HCDR1, HCDR2, and HCDR3, wherein
(a) the LCDR1, LCDR2 and LCDR3 has the amino acid sequences set forth in SEQ ID NOs: 169, 170 and 171, respectively, and the HCDR1, HCDR2, and HCDR3 has the amino acid sequences set forth in SEQ ID NOs: 166, 167 and 168, respectively; or
(b) the LCDR1, LCDR2 and LCDR3 has the amino acid sequences set forth in SEQ ID NOs: 185, 186 and 187, respectively, and the HCDR1, HCDR2, and HCDR3 has the amino acid sequences set forth in SEQ ID NOs: 182, 183 and 184, respectively.

### Claim 33 (depends on 1)

The method of claim 1, wherein said PSMA-binding polypeptide is a heterodimeric PSMA-binding protein comprising (1) a first polypeptide chain comprising, in order from amino-terminus to carboxyl-terminus, (a) a PSMA binding domain that specifically binds human PSMA, (b) a first hinge region, (c) a first immunoglobulin constant region, and (d) a first immunoglobulin heterodimerization domain; and (2) a second polypeptide chain comprising, in order from amino-terminus to carboxyl-terminus, (a′) a second hinge region, (b′) a second immunoglobulin constant region, and (c′) a second immunoglobulin heterodimerization domain that is different from the first immunoglobulin heterodimerization domain of the first single chain polypeptide, wherein the first and second immunoglobulin heterodimerization domains associate with each other to form a heterodimer.

### Claim 34 (depends on 33)

The method of claim 33, wherein the first immunoglobulin heterodimerization domain comprises an immunoglobulin CH1 domain and the second immunoglobulin heterodimerization domain comprises an immunoglobulin CL domain, or wherein the first immunoglobulin heterodimerization domain comprises an immunoglobulin CL domain and the second immunoglobulin heterodimerization domain comprises an immunoglobulin CH1 domain.

### Claim 35 (depends on 33)

The method of claim 33, wherein at least one of the first and second immunoglobulin constant regions comprises immunoglobulin CH2 and CH3 domains of IgG1, IgG2, IgG3, IgG4, IgA1, IgA2, IgD or any combination thereof; an immunoglobulin CH3 domain of IgG1, IgG2, IgG3, IgG4, IgA1, IgA2, IgD, IgE, IgM or any combination thereof; or immunoglobulin CH3 and CH4 domains of IgE, IgM or a combination thereof.

### Claim 36 (depends on 33, 34, 35)

The method of any one of claims 33-35, wherein the heterodimeric PSMA-binding polypeptide comprises at least one effector function selected from the group consisting of antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).

### Claim 37 (depends on 33)

The method of claim 33, wherein said second polypeptide chain further comprises a second binding domain.

### Claim 38 (depends on 37)

The method of claim 37, wherein the second binding domain is amino-terminal to the second hinge region.

### Claim 39 (depends on 33)

The method of claim 33, wherein the PSMA binding domain comprises (i) an immunoglobulin light chain variable region comprising LCDR1, LCDR2, and LCDR3, and (ii) an immunoglobulin heavy chain variable region comprising HCDR1, HCDR2, and HCDR3, wherein
(a) the LCDR1, LCDR2 and LCDR3 have the amino acid sequences set forth in SEQ ID NO: 15, 16 and 17, respectively, and the HCDR1, HCDR2, and HCDR3 have the amino acid sequences set forth in SEQ ID NO:9, 10 and 11, respectively;
(b) the LCDR1, LCDR2 and LCDR3 have the amino acid sequences set forth in SEQ ID NOs: 175, 176 and 177, respectively, and the HCDR1, HCDR2, and HCDR3 have the amino acid sequences set forth in SEQ ID NOs: 172, 173 and 174, respectively; or
(c) the LCDR1, LCDR2 and LCDR3 have the amino acid sequences set forth in SEQ ID NOs: 197, 198 and 199, respectively, and the HCDR1, HCDR2, and HCDR3 have the amino acid sequences set forth in SEQ ID NOs: 194, 195 and 196, respectively.

### Claim 40 (depends on 33)

The method of claim 33, wherein (a) the first polypeptide chain comprises an amino acid sequence that is at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 46 and the second polypeptide chain comprises an amino acid sequence that is at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 47; (b) the first polypeptide chain comprises an amino acid sequence that is at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 58 and the second polypeptide chain comprises an amino acid sequence that is at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 57; (c) the first polypeptide chain comprises an amino acid sequence that is at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 59 and the second polypeptide chain comprises an amino acid sequence that is at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 57; (d) the first polypeptide chain comprises an amino acid sequence that is at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 60 and the second polypeptide chain comprises an amino acid sequence that is at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 47; or (e) the first polypeptide chain comprises an amino acid sequence that is at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 61 and the second polypeptide chain comprises an amino acid sequence that is at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 47.

### Claim 41 (depends on 1)

The method of claim 1, wherein said PSMA-binding polypeptide is a bispecific single chain molecule comprising a PSMA binding domain and a CD3 binding domain, wherein the binding domains are arranged in the order VH PSMA-VL PSMA-VH CD3-VL CD3 or VL PSMA-VH PSMA-VH CD3-VL CD3.

### Claim 42 (depends on 41)

The method of claim 41, wherein said PSMA-binding polypeptide comprises an amino acid sequence that is at least 95% or 100% identical to the amino acid sequence set forth in SEQ ID NO:193 or SEQ ID NO:205.

### Claim 43

A method for inducing at least one of antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) against a cell expressing prostate-specific membrane antigen (PSMA), the method comprising: contacting said PSMA-expressing cell with a PSMA-binding polypeptide and with at least one anti-androgen therapeutic, wherein said contacting is under conditions whereby at least one of ADCC and CDC against the PSMA-expressing cell is induced.

### Claim 44

A method for inducing redirected T-cell cytotoxicity (RTCC) against a cell expressing prostate-specific membrane antigen (PSMA), the method comprising contacting said PSMA-expressing cell with a PSMA-binding polypeptide and with at least one anti-androgen therapeutic, wherein said PSMA-binding polypeptide comprises a T-cell binding domain and wherein contacting is under conditions whereby RTCC against the PSMA-expressing cell is induced.

### Claim 45 (depends on 44)

The method of claim 44, wherein the T-cell binding domain specifically binds CD3, CD3ε or a T-cell receptor (TCR) complex or a component thereof.

### Claim 46

A prostate-specific membrane antigen (PSMA)-binding polypeptide for the manufacture of a medicament for treatment of a cancer, wherein said PSMA-binding polypeptide is administered in combination with at least one anti-androgen therapeutic.

### Claim 47

A prostate-specific membrane antigen (PSMA)-binding polypeptide for use in treating a cancer, wherein said PSMA-binding polypeptide is to be used in combination with at least one anti-androgen therapeutic.

### Claim 48 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 46, 47)

The method of any one of claims 1-42, or the PSMA-binding polypeptide of claim 46 or 47, wherein the PSMA-binding polypeptide and the anti-androgen therapeutic are administered serially or in parallel.

### Claim 49 (depends on 43, 44, 45)

The method of any one of claims 43-45, wherein said PSMA-expressing cell is contacted with the PSMA-binding polypeptide and the anti-androgen therapeutic serially or in parallel.

### Claim 50 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 46, 47)

The method of any one of claims 1-42, or the PSMA-binding polypeptide of claim 46 or 47, wherein the cancer is prostate cancer, colorectal cancer, gastric cancer, bladder cancer, lung cancer, clear cell renal carcinoma or breast cancer.

### Claim 51 (depends on 50)

The method or the PSMA-binding polypeptide of claim 50, wherein the prostate cancer is castration-resistant prostate cancer.

### Claim 52 (depends on 50)

The method or the PSMA-binding polypeptide of claim 50, wherein the breast cancer is androgen receptor positive breast cancer.

### Claim 53 (depends on 43, 44, 45)

The method of any one of claims 43-45, wherein said PSMA-expressing cell is a prostate cancer cell.

### Claim 54 (depends on 53)

The method of claim 53, wherein the prostate cancer cell is a castration-resistant prostate cancer cell.

### Claim 55 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47)

The method of any one of claims 1-45, or the PSMA-binding polypeptide of claim 46 or 47, wherein the anti-androgen therapeutic blocks androgen synthesis or antagonizes androgen receptor signaling.

### Claim 56 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47)

The method of any one of claims 1-45, or the PSMA-binding polypeptide of claim 46 or 47, wherein the at least one anti-androgen therapeutic is selected from the group consisting of abiraterone, ketoconazole, enzalutamide, galeterone, ARN-509 and orteronel (TAK-700).

### Claim 57 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47)

The method of any one of claims 1-45, or the PSMA-binding polypeptide of claim 46 or 47, wherein the anti-androgen therapeutic is enzalutamide.

### Claim 58 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47)

The method of any one of claims 1-45, or the PSMA-binding polypeptide of claim 46 or 47, wherein the PSMA-binding polypeptide is a dimer of two identical polypeptides.

### Claim 59

A composition comprising a prostate-specific membrane antigen (PSMA)-binding polypeptide and at least one anti-androgen therapeutic.

### Claim 60 (depends on 59)

The composition of claim 59, for use in treating a patient with a cancer.

### Claim 61 (depends on 60)

The composition of claim 60, wherein the cancer is prostate cancer, colorectal cancer, gastric cancer, bladder cancer, lung cancer, clear cell renal carcinoma or breast cancer.

### Claim 62 (depends on 61)

The composition of claim 61, wherein the prostate cancer is castration-resistant prostate cancer.

### Claim 63 (depends on 61)

The composition of claim 61, wherein the breast cancer is androgen receptor positive breast cancer.

### Claim 64 (depends on 59, 60, 61, 62, 63)

The composition of any one of claims 59-63, wherein the anti-androgen therapeutic blocks androgen synthesis or antagonizes androgen receptor signaling.

### Claim 65 (depends on 59, 60, 61, 62, 63, 64)

The composition of any one of claims 59-64, wherein the at least one anti-androgen therapeutic is selected from the group consisting of abiraterone, ketoconazole, enzalutamide, galeterone, ARN-509 and orteronel (TAK-700).

### Claim 66 (depends on 59, 60, 61, 62, 63, 64)

The composition of any one of claims 59-64, wherein the anti-androgen therapeutic is enzalutamide.

### Claim 67

A pharmaceutical composition, comprising:
i. a prostate-specific membrane antigen (PSMA)-binding polypeptide;
ii. at least one anti-androgen therapeutic; and
iii. a pharmaceutically acceptable carrier.

### Claim 68 (depends on 67)

The pharmaceutical composition of claim 67, wherein said at least one anti-androgen therapeutic is selected from the group consisting of: abiraterone, ketoconazole, enzalutamide, galeterone, ARN-509 and orteronel (TAK-700).

### Claim 69 (depends on 67)

The pharmaceutical composition of claim 67, wherein the anti-androgen therapeutic is enzalutamide.

### Claim 70 (depends on 67, 68, 69)

The pharmaceutical composition of any one of claims 67-69, wherein said PSMA-binding polypeptide comprises the amino acid sequence set forth in SEQ ID NO:49, SEQ ID NO:51, SEQ ID NO:74, SEQ ID NO:76, SEQ ID NO:78, SEQ ID NO:80, SEQ ID NO:82, SEQ ID NO:84, SEQ ID NO:158, SEQ ID NO:160, SEQ ID NO:162, or SEQ ID NO:164.

### Claim 71 (depends on 67, 68, 69, 70)

The pharmaceutical composition of any one of claims 67-70 formulated in a dosage form selected from the group consisting of: an oral unit dosage form, an intravenous unit dosage form, an intranasal unit dosage form, a suppository unit dosage form, an intradermal unit dosage form, an intramuscular unit dosage form, an intraperitoneal unit dosage form, a subcutaneous unit dosage form, an epidural unit dosage form, a sublingual unit dosage form, and an intracerebral unit dosage form.

### Claim 72 (depends on 71)

The pharmaceutical composition of claim 71, formulated as an oral unit dosage form selected from the group consisting of: tablets, pills, pellets, capsules, powders, lozenges, granules, solutions, suspensions, emulsions, syrups, elixirs, sustained-release formulations, aerosols, and sprays.

### Claim 73 (depends on 59)

The pharmaceutical composition of claim 59, wherein the composition has a combination index of less than 1 as determined by the combination index theorem at inhibiting growth of cells by RTCC.

### Claim 74 (depends on 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73)

The composition of any one of claims 59-73, wherein the PSMA-binding polypeptide is a dimer of two identical polypeptides.