US2018100021A1PendingUtilityA1

Prostate-specific membrane antigen binding proteins and related compositions and methods

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Assignee: APTEVO RES & DEVELOPMENT LLCPriority: Apr 22, 2011Filed: Sep 8, 2017Published: Apr 12, 2018
Est. expiryApr 22, 2031(~4.8 yrs left)· nominal 20-yr term from priority
Inventors:John W. BlankenshipElaine T. SewellPhilip Tan
A61P 9/00A61P 37/02A61P 35/00A61P 37/00A61P 13/08A61P 1/04A61P 11/00A61P 13/12C07K 16/2809C07K 2317/53C07K 2317/73C07K 16/40C07K 2317/31C07K 2317/622C07K 2317/64C07K 2317/565C07K 2317/24C07K 2317/77C07K 2317/56C07K 16/3069C12Y 304/17021A61K 2039/505C07K 2317/35
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Claims

Abstract

The present invention relates to mono-specific and multi-specific polypeptide therapeutics that specifically target cells expressing prostate-specific membrane antigen (PSMA) and are useful for the treatment of prostate cancer (e.g., castrate-resistant prostate cancer), tumor-related angiogenesis or benign prostatic hyperplasia (BPH). In one embodiment, the multi-specific poly-peptide 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.

Claims

exact text as granted — not AI-modified
1 .- 153 . (canceled) 
     
     
         154 . A dimeric prostate-specific membrane antigen (PSMA)-binding protein comprising two identical PSMA-binding polypeptide chains, wherein each polypeptide chain comprises, in order from amino-terminus to carboxyl-terminus or in order from carboxyl-terminus to amino-terminus:
 (a) a PSMA-binding domain that specifically binds human PSMA,   (b) a hinge, and   (c) an immunoglobulin constant region,   wherein the PSMA-binding domain comprises (i) an immunoglobulin light chain variable region, and (ii) an immunoglobulin heavy chain variable region;   wherein the light chain variable region comprises an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO:5 or SEQ ID NO:23;   wherein the heavy chain variable region comprises an amino acid sequence that is at least 85% identical to the amino add sequence set forth in SEQ ID NO:2, SEQ ID NO:25, or SEQ ID NO:27.   
     
     
         155 . The PSMA-binding protein of  claim 154 , 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. 
     
     
         156 . The PSMA-binding protein of  claim 154 , wherein at least one of the light chain variable and heavy chain variable regions is humanized. 
     
     
         157 . The PSMA-binding protein of  claim 154 , wherein the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:5 or SEQ ID NO:23. 
     
     
         158 . The PSMA-binding protein of  claim 154 , wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:2, SEQ ID NO:25, or SEQ ID NO:27. 
     
     
         159 . The PSMA-binding protein of  claim 154 , wherein the PSMA-binding domain is an scFv. 
     
     
         160 . The PSMA-binding protein of  claim 159 , 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. 
     
     
         161 . The PSMA-binding protein of  claim 159 , wherein the scFv comprises 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. 
     
     
         162 . The PSMA-binding protein of  claim 159 , wherein the heavy chain variable region of said scFv is carboxy-terminal to the light chain variable region. 
     
     
         163 . The PSMA-binding protein of  claim 159 , wherein the light chain variable region of said scFv is carboxy-terminal to the heavy chain variable region. 
     
     
         164 . The PSMA-binding protein of  claim 159 , wherein the light chain variable region and heavy chain variable region of the scFv are joined by an amino acid sequence comprising (Gly 4 Ser) n , wherein n=1-5 (SEQ ID NO:165). 
     
     
         165 . The PSMA-binding protein of  claim 154 , wherein the hinge is derived from an immunoglobulin hinge region. 
     
     
         166 . The PSMA-binding protein of  claim 154 , wherein the immunoglobulin constant region comprises immunoglobulin CH2 and CH3 domains of IgG1, IgG2, IgG3, IgG4, IgA1, IgA2 or IgD. 
     
     
         167 . The PSMA-binding protein of  claim 154 , wherein the hinge is derived from an immunoglobulin hinge region and the immunoglobulin constant region comprises immunoglobulin CH2 and CH3 domains of IgG1, IgG2, IgG3, or IgG4. 
     
     
         168 . The PSMA-binding protein of  claim 154 , wherein each PSMA-binding polypeptide chain comprises an amino acid sequence that is at least 95% identical to the amino acid sequence set forth 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. 
     
     
         169 . The PSMA-binding protein of  claim 154 , wherein each PSMA-binding polypeptide chain comprises the amino acid sequence set forth 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. 
     
     
         170 . A dimeric prostate-specific membrane antigen (PSMA)-binding protein comprising two identical PSMA-binding polypeptide chains, wherein each polypeptide chain comprises, in order from amino-terminus to carboxyl-terminus or in order from carboxyl-terminus to amino-terminus,
 (a) a PSMA-binding domain that specifically binds human PSMA,   (b) a hinge,   (c) an immunoglobulin constant region, and   (d) a second binding domain that specifically binds a T cell receptor (TCR) complex or a component thereof;   wherein the PSMA-binding domain comprises an immunoglobulin light chain variable region and an immunoglobulin heavy chain variable region.   
     
     
         171 . The PSMA-binding protein of  claim 170 , wherein the light chain variable region comprises an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO:5 or SEQ ID NO:23; and
 wherein the heavy chain variable region comprises an amino acid sequence that is at least 85% identical to the amino add sequence set forth in SEQ ID NO:2, SEQ ID NO:25, or SEQ ID NO:27.   
     
     
         172 . The PSMA-binding protein of  claim 170 , wherein the second binding domain comprises an immunoglobulin light chain variable region and an immunoglobulin heavy chain variable region. 
     
     
         173 . The PSMA-binding protein of  claim 170 , wherein the hinge is derived from an immunoglobulin hinge region and the immunoglobulin constant region comprises immunoglobulin CH2 and CH3 domains of IgG1, IgG2, IgG3, or IgG4. 
     
     
         174 . The PSMA-binding protein of  claim 170 , wherein the second binding domain specifically binds CD3. 
     
     
         175 . The PSMA-binding protein of  claim 172 , wherein the immunoglobulin 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; and   (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.   
     
     
         176 . The PSMA-binding protein of  claim 172 , wherein the immunoglobulin 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 the amino acid sequence set forth in residues 139-245 of SEQ ID NO:47 and a heavy chain variable region comprising the amino acid sequence set forth in residues 1-121 of SEQ ID NO:47; and   (b) a light chain variable region comprising the amino acid sequence set forth in residues 634-740 of SEQ ID NO:78 and a heavy chain variable region comprising the amino acid sequence set forth in residues 496-616 of SEQ ID NO:78.   
     
     
         177 . The PSMA-binding protein of  claim 170 , wherein the second binding domain is a scFv. 
     
     
         178 . The PSMA-binding protein of  claim 177 , wherein the second binding domain is a scFv comprising an amino acid sequence that is at least 95% identical to an amino acid sequence selected from the group consisting of (i) the amino acid sequence set forth in residues 1-245 of SEQ ID NO:47, and (ii) the amino acid sequence set forth in residues 496-742 of SEQ ID NO:78. 
     
     
         179 . The PSMA-binding protein of  claim 177 , wherein the second binding domain comprises the amino acid sequence selected from the group consisting of (i) the amino acid sequence set forth in residues 1-245 of SEQ ID NO:47, and (ii) the amino acid sequence set forth in residues 496-742 of SEQ ID NO:78. 
     
     
         180 . The PSMA-binding protein of  claim 170 , wherein each PSMA-binding polypeptide chain comprises an amino acid sequence that is at least 95% 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, or SEQ ID NO:164. 
     
     
         181 . The PSMA-binding protein of  claim 170 , wherein each PSMA-binding polypeptide chain 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. 
     
     
         182 . An isolated nucleic acid encoding the PSMA-binding polypeptide chain of  claim 154 . 
     
     
         183 . A composition comprising
 the PSMA-binding protein of  claim 154 ; and   a pharmaceutically acceptable carrier, diluent, or excipient.   
     
     
         184 . A composition comprising
 the PSMA-binding protein of  claim 170 ; and   a pharmaceutically acceptable carrier, diluent, or excipient.   
     
     
         185 . 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 the PSMA-binding protein of  claim 170 , and wherein said contacting is under conditions whereby RTCC against the PSMA-expressing cell is induced.   
     
     
         186 . A method for treating a disorder in a subject, wherein the disorder is characterized by overexpression of PSMA and wherein the disorder is a cancer, a prostate disorder, or a neovascular disorder, the method comprising administering to the subject a therapeutically effective amount of the PSMA-binding protein of  claim 170  under conditions whereby RTCC in the subject is induced against a cell expressing PSMA, thereby treating said disorder in the subject. 
     
     
         187 . The method of  claim 186 , wherein the disorder is prostate cancer, colorectal cancer, gastric cancer, castrate-resistant prostate cancer, benign prostatic hyperplasia, solid tumor growth, clear cell renal carcinoma, colorectal cancer, bladder cancer, or lung cancer.

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