Tumor-specific payload delivery and immune activation using a human antibody targeting a highly specific tumor cell surface antigen

Abstract

This invention provides antibodies directed against a highly specific and previously unrecognized marker for cancerous cells. In certain embodiments an isolated antibody or fragment thereof that specifically binds human placentally expressed ALPP and/or ALPPL2, but not ALPL and ALPI that are expressed outside the placenta is provided as well as immunoconjugates comprising such antibodies.

1 - 115 . (canceled) 
     
     
         116 . A chimeric antigen receptor (CAR) comprising an antibody that specifically binds human placentally expressed ALPP and/or ALPPL2, but not ALPL and ALPI that are expressed outside the placenta. 
     
     
         117 . The chimeric antigen receptor of  claim 116 , wherein said receptor comprises:
 said antibody;   a transmembrane domain;   at least one costimulatory signaling region; and   a CD3 zeta signaling domain.   
     
     
         118 . The chimeric antigen receptor of  claim 117 , wherein said costimulatory signaling region comprises the intracellular domain of a costimulatory molecule selected from the group consisting of CD27, CD2S, 4-IBB, OX40, CD30, CD40, PD-1, ICOS, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, a ligand that specifically binds with CD83, and any combination thereof. 
     
     
         119 . The chimeric antigen receptor of  claim 117 , wherein said costimulatory signaling region comprises 4-1BB. 
     
     
         120 . The chimeric antigen receptor of  claim 117 , wherein said transmembrane domain comprise the CD8 hinge domain or a fragment thereof. 
     
     
         121 . The chimeric antigen receptor of  claim 117 , wherein said antibody comprises variable light (VL) CDR1, CDR2, and CDR3, and variable heavy CDR1, CDR2, and CDR3 of an antibody selected from the group consisting of M25ADLF, M25ADLFEG, M25ADLFDS, M25FYIA, M25FYIAEG, M25FYIADS, M25, M25EG, M25DS, M25AELF, M25AELFEG, M25AELFDS, M25ADL99P, M25ADL99G, M25ADS95R, M25ADD28G, M25ADS91G, M25ADY93H, M25ADYHSRLF, M25GRITSGFYGDwtLC, M25FSITSGFYGDwtLC, M2530181A, M253018LF, M25AD, M25ADX, ALPPL2rd3 1, ALPPL2rd3 2, M25AGIA, M25AGLF, M25ASIA, M25ASLF, M25ASwt, M25AVIA, M25AVLF, M25ALIA, M25ALLF, M25wtIA, and M25wtLF. 
     
     
         122 . The chimeric antigen receptor of  claim 121 , wherein said antibody comprises variable light (VL) CDR1, CDR2, and CDR3, and variable heavy CDR1, CDR2, and CDR3 of M25FYIA. 
     
     
         123 . The chimeric antigen receptor of  claim 121 , wherein:
 said antibody comprises a heavy chain variable region (VH) of an M25ADLF antibody and a light chain variable region (VL) of an M25ADLF antibody; or .   said antibody comprises a heavy chain variable region (VH) of an M25ADLFEG antibody and a light chain variable region (VL) of an M25ADLFEG antibody; or   said antibody comprises a heavy chain variable region (VH) of an M25ADLFDS antibody and a light chain variable region (VL) of an M25ADLFDS antibody; or   said antibody comprises a heavy chain variable region (VH) of an M25FYIA antibody and a light chain variable region (VL) of an M25FYIA antibody; or   said antibody comprises a heavy chain variable region (VH) of an M25FYIAEG antibody and a light chain variable region (VL) of an M25FYIAEG antibody; or   said antibody comprises a heavy chain variable region (VH) of an M25FYIADS antibody and a light chain variable region (VL) of an M25FYIADS antibody; or   said antibody comprises a heavy chain variable region (VH) of an M25 antibody and a light chain variable region (VL) of an M25 antibody; or   said antibody comprises a heavy chain variable region (VH) of an M25EG antibody and a light chain variable region (VL) of an M25EG antibody; or   said antibody comprises a heavy chain variable region (VH) of an M25DS antibody and a light chain variable region (VL) of an M25DS antibody; or   said antibody comprises a heavy chain variable region (VH) of an M25AELF antibody and a light chain variable region (VL) of an M25AELF antibody; or   said antibody comprises a heavy chain variable region (VH) of an M25AELFEG antibody and a light chain variable region (VL) of an M25AELFEG antibody; or   said antibody comprises a heavy chain variable region (VH) of an M25AELFDS antibody and a light chain variable region (VL) of an M25AELFDS antibody; or   said antibody comprises a heavy chain variable region (VH) of an M25ADL99P antibody and a light chain variable region (VL) of an M25ADL99P antibody; or   said antibody comprises a heavy chain variable region (VH) of an M25ADL99G antibody and a light chain variable region (VL) of an M25ADL99G antibody; or   said antibody comprises a heavy chain variable region (VH) of an M25ADS95R antibody and a light chain variable region (VL) of an M25ADS95R antibody; or   said antibody comprises a heavy chain variable region (VH) of an M25ADD28G antibody and a light chain variable region (VL) of an M25ADD28G antibody; or   said antibody comprises a heavy chain variable region (VH) of an M25ADS91G antibody and a light chain variable region (VL) of an M25ADS91G antibody; or   said antibody comprises a heavy chain variable region (VH) of an M25ADY93H antibody and a light chain variable region (VL) of an M25ADY93H antibody; or   said antibody comprises a heavy chain variable region (VH) of an M25ADYHSRLF antibody and a light chain variable region (VL) of an M25ADYHSRLF antibody; or   said antibody comprises a heavy chain variable region (VH) of an M25GRITSGFYGDwtLC antibody and a light chain variable region (VL) of an M25GRITSGFYGDwtLC antibody; or   said antibody comprises a heavy chain variable region (VH) of an M25FSITSGFYGDwtLC antibody and a light chain variable region (VL) of an M25FSITSGFYGDwtLC antibody; or   said antibody comprises a heavy chain variable region (VH) of an M253018IA antibody and a light chain variable region (VL) of an M253018IA antibody; or   said antibody comprises a heavy chain variable region (VH) of an M253018LF antibody and a light chain variable region (VL) of an M253018LF antibody; or   said antibody comprises a heavy chain variable region (VH) of an M25AD antibody and a light chain variable region (VL) of an M25AD antibody; or   said antibody comprises a heavy chain variable region (VH) of an M25ADX antibody and a light chain variable region (VL) of an M25ADX antibody; or   said antibody comprises a heavy chain variable region (VH) of an ALPPL2rd3_1 antibody and a light chain variable region (VL) of an ALPPL2rd3_1 antibody; or   said antibody comprises a heavy chain variable region (VH) of an ALPPL2rd3_2 antibody and a light chain variable region (VL) of an ALPPL2rd3_2 antibody; or   said antibody comprises a heavy chain variable region (VH) of an M25AGIA antibody and a light chain variable region (VL) of an M25AGIA antibody; or   said antibody comprises a heavy chain variable region (VH) of an M25AGLF antibody and a light chain variable region (VL) of an M25AGLF antibody; or   said antibody comprises a heavy chain variable region (VH) of an M25ASIA antibody and a light chain variable region (VL) of an M25ASIA antibody; or   said antibody comprises a heavy chain variable region (VH) of an M25ASLF antibody and a light chain variable region (VL) of an M25ASLF antibody; or   said antibody comprises a heavy chain variable region (VH) of an M25ASwt antibody and a light chain variable region (VL) of an M25ASwt antibody; or   said antibody comprises a heavy chain variable region (VH) of an M25AVIA antibody and a light chain variable region (VL) of an M25AVIA antibody; or   said antibody comprises a heavy chain variable region (VH) of an M25AVLF antibody and a light chain variable region (VL) of an M25AVLF antibody; or   said antibody comprises a heavy chain variable region (VH) of an M25ALIA antibody and a light chain variable region (VL) of an M25ALIA antibody; or   said antibody comprises a heavy chain variable region (VH) of an M25ALLF antibody and a light chain variable region (VL) of an M25ALLF antibody; or   said antibody comprises a heavy chain variable region (VH) of an M25wtIA antibody and a light chain variable region (VL) of an M25wtIA antibody; or   said antibody comprises a heavy chain variable region (VH) of an M25wtLF antibody and a light chain variable region (VL) of an M25wtLF antibody.   
     
     
         124 . The chimeric antigen receptor of  claim 123 , said antibody comprises a heavy chain variable region (VH) of an M25FYIA antibody and a light chain variable region (VL) of an M25FYIA antibody. 
     
     
         125 . The chimeric antigen receptor of  claim 116 , wherein said antibody is a single chain antibody. 
     
     
         126 . The chimeric antigen receptor of  claim 125 , wherein said antibody is a human scFv. 
     
     
         127 . The chimeric antigen receptor of  claim 125 , wherein said heavy chain variable region is joined to said light chain variable region by a linker comprising or consisting of the amino acid sequence (Gly4Ser)3 (SEQ ID NO:82). 
     
     
         128 . The chimeric antigen receptor of  claim 116 , wherein chimeric antigen receptor is disposed in a mammalian cell. 
     
     
         129 . The chimeric antigen receptor of  claim 128 , wherein said chimeric antigen receptor is disposed in the cell membrane of a T cell.