J591 minibodies and cys-diabodies for targeting human prostate specific membrane antigen (psma) and methods for their use

Abstract

In one embodiment, a minibody monomer that binds PSMA is provided. The minibody monomer is encoded by a nucleotide sequence comprising, from N-terminus to C-terminus, an scFv sequence that can bind PSMA, an artificial hinge sequence, and a human IgG CH3 sequence. In another embodiment, a CysDB monomer that binds PSMA is provided. The CysDB monomer may be encoded by a nucleotide sequence comprising, from N-terminus to C-terminus, an scFv sequence that can bind PSMA and a cysteine tail. In other embodiments, methods for diagnosing or treating a cancer associated with PSMA expression in a subject are provided.

1 . (canceled) 
     
     
         2 . A method for treating a cancer associated with prostate specific membrane antigen (PSMA) expression in a subject, the method comprising:
 administering a therapeutically effective amount of a pharmaceutical composition to the subject, the composition comprising an anti-PSMA minibody or an anti-PSMA cys-diabody, wherein   (a) the minibody comprises:
 a heavy chain CDR1 that is a CDR1 in SEQ ID NO: 10; 
 a heavy chain CDR2 that is a CDR2 in SEQ ID NO: 10; 
 a heavy chain CDR3 that is a CDR3 in SEQ ID NO: 10; 
 a light chain CDR1 that is a CDR1 in SEQ ID NO: 10; 
 a light chain CDR2 that is a CDR2 in SEQ ID NO: 10; and 
 a light chain CDR3 that is a CDR3 in SEQ ID NO: 10; 
   (b) the minibody comprises:
 a heavy chain CDR1 that is a CDR1 in SEQ ID NO: 11; 
 a heavy chain CDR2 that is a CDR2 in SEQ ID NO: 11; 
 a heavy chain CDR3 that is a CDR3 in SEQ ID NO: 11; 
 a light chain CDR1 that is a CDR1 in SEQ ID NO: 11; 
 a light chain CDR2 that is a CDR2 in SEQ ID NO: 11; and 
 a light chain CDR3 that is a CDR3 in SEQ ID NO: 11; 
   (c) the cys-diabody comprises:
 a heavy chain CDR1 that is a CDR1 in SEQ ID NO: 12; 
 a heavy chain CDR2 that is a CDR2 in SEQ ID NO: 12; 
 a heavy chain CDR3 that is a CDR3 in SEQ ID NO: 12; 
 a light chain CDR1 that is a CDR1 in SEQ ID NO: 12; 
 a light chain CDR2 that is a CDR2 in SEQ ID NO: 12; and 
 a light chain CDR3 that is a CDR3 in SEQ ID NO: 12; 
   (d) the cys-diabody comprises:
 a heavy chain CDR1 that is a CDR1 in SEQ ID NO: 13; 
 a heavy chain CDR2 that is a CDR2 in SEQ ID NO: 13; 
 a heavy chain CDR3 that is a CDR3 in SEQ ID NO: 13; 
 a light chain CDR1 that is a CDR1 in SEQ ID NO: 13; 
 a light chain CDR2 that is a CDR2 in SEQ ID NO: 13; and 
 a light chain CDR3 that is a CDR3 in SEQ ID NO: 13; 
   (e) the cys-diabody comprises:
 a heavy chain CDR1 that is a CDR1 in SEQ ID NO: 14; 
 a heavy chain CDR2 that is a CDR2 in SEQ ID NO: 14; 
 a heavy chain CDR3 that is a CDR3 in SEQ ID NO: 14; 
 a light chain CDR1 that is a CDR1 in SEQ ID NO: 14; 
 a light chain CDR2 that is a CDR2 in SEQ ID NO: 14; and 
 a light chain CDR3 that is a CDR3 in SEQ ID NO: 14; or 
   (f) the cys-diabody comprises:
 a heavy chain CDR1 that is a CDR1 in SEQ ID NO: 15; 
 a heavy chain CDR2 that is a CDR2 in SEQ ID NO: 15; 
 a heavy chain CDR3 that is a CDR3 in SEQ ID NO: 15; 
 a light chain CDR1 that is a CDR1 in SEQ ID NO: 15; 
 a light chain CDR2 that is a CDR2 in SEQ ID NO: 15; and 
 a light chain CDR3 that is a CDR3 in SEQ ID NO: 15. 
   
     
     
         3 . The method of  claim 2 , wherein the minibody comprises SEQ ID NO:10 or SEQ ID NO:11. 
     
     
         4 . The method of  claim 2 , wherein the cys-diabody, comprises SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14 or SEQ ID NO:15. 
     
     
         5 . The method of  claim 2 , wherein the anti-PSMA minibody or anti-PSMA cys-diabody is conjugated to a therapeutic agent. 
     
     
         6 . The method of  claim 5 , wherein the therapeutic agent is selected from the group consisting of chemotherapeutic agents, therapeutic antibodies and antibody fragments, toxins, radioisotopes, enzymes, nucleases, hormones, immunomodulators, antisense oligonucleotides, chelators, boron compounds, photoactive agents and dyes. 
     
     
         7 . The method of  claim 5 , wherein the therapeutic agent is a beta-emitting radiolabel. 
     
     
         8 . The method of  claim 7 , wherein the therapeutic agent is  90 Y. 
     
     
         9 . The method of  claim 2 , comprising administering the therapeutically effective amount of the pharmaceutical composition parenterally. 
     
     
         10 . The method of  claim 9 , comprising administering the therapeutically effective amount of the pharmaceutical composition intravenously. 
     
     
         11 . The method of  claim 2 , wherein the cancer associated with PSMA expression in the subject comprises a solid tumor having neovasculature that overexpresses PSMA. 
     
     
         12 . The method of  claim 2 , wherein the anti-PSMA minibody or anti-PSMA cys-diabody targets neovasculature of a solid tumor. 
     
     
         13 . The method of  claim 2 , wherein the cancer associated with PSMA expression in the subject is prostate cancer, lung cancer, colorectal cancer, breast cancer, renal cancer, liver cancer, bladder cancer, pancreatic cancer or melanoma. 
     
     
         14 . The method of  claim 2 , wherein the anti-PSMA minibody comprises:
 an scFv sequence that can bind prostate specific membrane antigen (PSMA), the scFv comprising a variable heavy domain (VH) linked to a variable light domain (VL) by a linker sequence;   an artificial hinge sequence; and   a human IgG CH3 sequence.   
     
     
         15 . The method of  claim 2 , wherein the anti-PSMA cys-diabody comprises:
 an scFv sequence that can bind PSMA, the scFv comprising a variable heavy domain (VH) linked to a variable light domain (VL) by a linker sequence; and   a cysteine tail.   
     
     
         16 . The method of  claim 2 , wherein
 (a) the minibody comprises: a variable heavy domain (VH) that is a VH of SEQ ID NO: 10 and a variable light domain (VL) that is a VL of SEQ ID NO: 10;   (b) the minibody comprises: a VH that is a VH of SEQ ID NO: 11 and a VL that is a VL of SEQ ID NO: 11;   (c) the cys-diabody comprises: a VH that is a VH of SEQ ID NO: 12 and a VL that is a VL of SEQ ID NO: 12;   (d) the cys-diabody comprises: a VH that is a VH of SEQ ID NO: 13 and a VL that is a VL of SEQ ID NO: 13;   (e) the cys-diabody comprises: a VH that is a VH of SEQ ID NO: 14 and a VL that is a VL of SEQ ID NO: 14; or   (f) the cys-diabody comprises: a VH that is a VH of SEQ ID NO: 15 and a VL that is a VL of SEQ ID NO: 15.