Internalizing human monoclonal antibodies targeting prostate cancer cells in situ

Abstract

This invention provides a method that allows selection of antibodies against cells (e.g., tumor cells) in situ using laser capture microdissection. By restricting antibody selection to binders of internalizing epitopes, a panel of phage antibodies was generated that targets clinically represented prostate cancer antigens.

1 .- 61 . (canceled) 
     
     
         62 . An isolated antibody or antigen binding fragment thereof that specifically binds a prostate cancer cell comprising a heavy chain variable region (HCVR) CDR1 (SEQ ID NO: 62), HCVR CDR2 (SEQ ID NO: 64), HCVR CDR3 (SEQ ID NO: 66), a light chain variable region (LCVR) CDR1 (SEQ ID NO: 223), LCVR CDR2 (SEQ ID NO: 225), and LCVR CDR3 (SEQ ID NO: 227). 
     
     
         63 . The isolated antibody or antigen binding fragment thereof of  claim 62 , wherein said antibody or antigen binding fragment thereof comprises the variable heavy chain domain and the variable light chain domain of the antibody UA20 (SEQ ID NO: 8). 
     
     
         64 . The isolated antibody or antigen binding fragment thereof of  claim 62 , wherein said antigen binding fragment is selected from the group consisting of a Fab, a (Fab′)2, an scFv, and an (ScFv′)2. 
     
     
         65 . The isolated antibody or antigen binding fragment thereof of  claim 62 , wherein said antigen binding fragment is a single chain antibody UA20 (SEQ ID NO: 8). 
     
     
         66 . The isolated antibody or antigen binding fragment thereof of  claim 62  further comprising an effector attached to the isolated antibody or antigen binding fragment. 
     
     
         67 . The isolated antibody or antigen binding fragment thereof of  claim 66 , wherein said effector is selected from the group consisting of an epitope tag, a second antibody, a label, a cytotoxin, a liposome, a radionuclide, a drug, a prodrug, a viral particle, a cytokine, and a chelate. 
     
     
         68 . A pharmaceutical formulation, said formulation comprising a pharmaceutically acceptable excipient and an antibody or antigen binding fragment thereof according to  claim 62 . 
     
     
         69 . A pharmaceutical formulation, said formulation comprising a pharmaceutically acceptable excipient and a chimeric moiety comprising an effector attached to an antibody or antigen binding fragment thereof according to  claim 62 . 
     
     
         70 . The pharmaceutical formulation of  claim 69 , wherein said effector is selected from the group consisting of an epitope tag, a second antibody, a label, a cytotoxin, a liposome, a radionuclide, a drug, a prodrug, a viral particle, a cytokine, and a chelate. 
     
     
         71 . A method of treating prostate cancer in a patient in need thereof comprising administering to the patient a chimeric moiety comprising an antibody attached to an anti-cancer drug or a radionuclide,
 wherein said antibody comprises a heavy chain variable region (HCVR) CDR1 (SEQ ID NO: 62), HCVR CDR2 (SEQ ID NO: 64), HCVR CDR3 (SEQ ID NO: 66), a light chain variable region (LCVR) CDR1 (SEQ ID NO: 223), LCVR CDR2 (SEQ ID NO: 225), and LCVR CDR3 (SEQ ID NO: 227), and   wherein the prostate cancer is treated.   
     
     
         72 . The method of  claim 71 , wherein said prostate cancer is a metastatic cancer. 
     
     
         73 . The method of  claim 71 , wherein said antibody comprises the variable heavy chain domain and the variable light chain domain of the antibody UA20 (SEQ ID NO: 8). 
     
     
         74 . The method of  claim 71 , wherein said antibody is a single chain antibody. 
     
     
         75 . The method of  claim 74 , wherein the variable light chain domain is attached to the variable heavy chain domain by a (Gly 4 Ser)3 (SEQ ID NO:1) linker. 
     
     
         76 . The method of  claim 71 , wherein said antibody is an antibody selected from the group consisting of a Fab, a (Fab′)2, an scFv, and an (ScFv′)2. 
     
     
         77 . The method of  claim 76 , wherein said antibody is an scFv. 
     
     
         78 . The method of  claim 71 , wherein said chimeric moiety is internalized into a prostate cancer cell. 
     
     
         79 . The method of  claim 71 , wherein said prostate cancer is a refractory prostate cancer. 
     
     
         80 . The method of  claim 71 , wherein said chimeric moiety is formulated with a pharmaceutically acceptable excipient. 
     
     
         81 . The method of  claim 71 , wherein said antibody is an intact antibody. 
     
     
         82 . The method of  claim 71 , wherein said antibody is an IgG.