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 - 36 . (canceled) 
     
     
         37 . A method of inhibiting the growth or proliferation of a prostate cancer cell, said method comprising contacting said prostate cancer cell with chimeric moiety comprising an antibody that specifically binds an epitope that is specifically bound by an antibody selected from the group consisting of 3051.1 (SEQ ID NO:3), G12FC3 (SEQ ID NO:4), M6c42b (SEQ ID NO:5), 4F3YW (SEQ ID NO:6), M40pr146 (SEQ ID NO:7), UA20 (SEQ ID NO:8), UA8 (SEQ ID NO:9), 585II41 (SEQ ID NO: 10), 585II41.1 (SEQ ID NO: 11), 585II56 (SEQ ID NO:12), 3076 (SEQ ID NO::13), 3051 (SEQ ID NO:14), M49R (SEQ ID NO:15), RCI-14 (SEQ ID NO:16), II79_4 (SEQ ID NO:17), II79_3 (SEQ ID NO:18), T5II-4B.1 (SEQ ID NO:19), T5II-4B.2 (SEQ ID NO:20), RCI-11 (SEQ ID NO:21), RCI-20 (SEQ ID NO:22), CI-11A (SEQ ID NO:23), CI-14A (SEQ ID NO:24), and S95-2 (SEQ ID NO:25) attached to an anti-cancer drug or a radionuclide. 
     
     
         38 . The method of  claim 37 , wherein said prostate cancer cell is a metastatic cell. 
     
     
         39 - 61 . (canceled) 
     
     
         62 . The method of  claim 37 , wherein said antibody comprises three VH CDRs and/or three VL CDRs of an antibody selected from the group consisting of 3051.1 (SEQ ID NO:3), G12FC3 (SEQ ID NO:4), M6c42b (SEQ ID NO:5), 4F3YW (SEQ ID NO:6), M40pr146 (SEQ ID NO:7), UA20 (SEQ ID NO:8), UA8 (SEQ ID NO:9), 585II41 (SEQ ID NO: 10), 585II41.1 (SEQ ID NO: 11), 585II56 (SEQ ID NO:12), 3076 (SEQ ID NO::13), 3051 (SEQ ID NO:14), M49R (SEQ ID NO:15), RCI-14 (SEQ ID NO:16), II79_4 (SEQ ID NO:17), II79_3 (SEQ ID NO:18), T5II-4B.1 (SEQ ID NO:19), T5II-4B.2 (SEQ ID NO:20), RCI-11 (SEQ ID NO:21), RCI-20 (SEQ ID NO:22), CI-11A (SEQ ID NO:23), CI-14A (SEQ ID NO:24), and S95-2 (SEQ ID NO:25). 
     
     
         63 . The method of  claim 37 , wherein said antibody comprises a VH domain and/or a VL domain of an antibody selected from the group consisting of 3051.1 (SEQ ID NO:3), G12FC3 (SEQ ID NO:4), M6c42b (SEQ ID NO:5), 4F3YW (SEQ ID NO:6), M4Opr146 (SEQ ID NO:7), UA20 (SEQ ID NO:8), UA8 (SEQ ID NO:9), 585II41 (SEQ ID NO: 10), 585II41.1 (SEQ ID NO: 11), 585II56 (SEQ ID NO:12), 3076 (SEQ ID NO::13), 3051 (SEQ ID NO:14), M49R (SEQ ID NO:15), RCI-14 (SEQ ID NO:16), II79_4 (SEQ ID NO:17), II79_3 (SEQ ID NO:18), T5II-4B.1 (SEQ ID NO:19), T5II-4B.2 (SEQ ID NO:20), RCI-11 (SEQ ID NO:21), RCI-20 (SEQ ID NO:22), CI-11A (SEQ ID NO:23), CI-14A (SEQ ID NO:24), and S95-2 (SEQ ID NO:25). 
     
     
         64 . The method of  claim 37 , wherein said antibody is a single chain antibody. 
     
     
         65 . The method of  claim 37 , wherein the VL region is attached to the VH region by a (Gly 4 Ser) 3  (SEQ ID NO: 1) linker. 
     
     
         66 . The method of  claim 37 , wherein said antibody comprises a Fab, a (Fab′) 2 , an scFv, or an (ScFv′) 2 . 
     
     
         67 . The method of  claim 66 , wherein said antibody is an scFv. 
     
     
         68 . The method of  claim 37 , wherein said antibody comprises the VL and VH regions of SEQ ID NO: 8. 
     
     
         69 . The method of  claim 37 , wherein said antibody is internalized into said prostate cancer cell. 
     
     
         70 . The method of  claim 37 , wherein said prostate cancer cell is a refractory prostate cancer cell. 
     
     
         71 . The method of  claim 37 , wherein said antibody is further formulated with a pharmaceutically acceptable excipient.