Costimulation of T cell proliferation by a chimeric B7-2 antibody fusion protein specifically targeted to cells expressing the erbB2 proto-oncogene.
T cells require at least two signals for activation and clonal expansion. The first signal conferring specificity is initiated by interaction of the T cell receptor with antigenic peptides in the context of MHC molecules. The second, costimulatory signal can be provided by cell surface molecules on APCs such as B7-1 (CD80) and B7-2 (CD86), which interact with their counter-receptors on T cells. The absence of costimulatory signals presents one possible mechanism for tumor cells to escape immune surveillance. In experimental models transfection of B7 genes into tumor cells can result in T cell-dependent tumor rejection. We have developed a novel approach to direct the costimulatory B7-2 molecule to the surface of target cells. Our approach is based on a chimeric fusion protein that consists of the extracellular domain of human B7-2 fused to a single-chain Ab domain (scFv) specific for the ErbB2 protein, a type I growth factor receptor overexpressed in a high percentage of human adenocarcinomas. This B7-2(225)-scFv(FRP5) molecule expressed in the yeast Pichia pastoris and purified from culture supernatants is functionally active and binds to B7 counter-receptors and to ErbB2. B7-2(225)-scFv(FRP5) localizes specifically to the surface of ErbB2-expressing target cells, thereby providing a costimulatory signal that results in enhanced proliferation of syngeneic T cells. Our results suggest that effective tumor vaccines for cancer immunotherapy could be created by targeting such chimeric ligands to the surface of tumor cells.
Gerstmayer
B
B
Institute for Experimental Cancer Research, Tumor Biology Center, Freiburg, Germany.
Altenschmidt
U
U
Hoffmann
M
M
Wels
W
W
D000069594:Abatacept; D000276:Adjuvants, Immunologic; D000818:Animals; D000906:Antibodies / Q000737:chemistry; D015703:Antigens, CD / Q000502:physiology*; D000943:Antigens, Differentiation / Q000378:metabolism; D051940:B7-2 Antigen; D016466:CHO Cells; D060908:CTLA-4 Antigen; D002478:Cells, Cultured; D006224:Cricetinae; D006801:Humans; D018796:Immunoconjugates; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D000090063:Proto-Oncogene Mas; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D011993:Recombinant Fusion Proteins; D013601:T-Lymphocytes / Q000276:immunology
D000069594:Abatacept; D000276:Adjuvants, Immunologic; D000906:Antibodies; D015703:Antigens, CD; D000943:Antigens, Differentiation; D051940:B7-2 Antigen; D060908:CTLA-4 Antigen; D018796:Immunoconjugates; D008562:Membrane Glycoproteins; D000090063:Proto-Oncogene Mas; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins; C497964:CD86 protein, human; C556706:CTLA4 protein, human; C497965:Cd86 protein, mouse; C556707:Ctla4 protein, mouse; C000715470:MAS1 protein, human