PEPTIDE-SPECIFIC KILLING OF ANTIGEN-PRESENTING CELLS BY A RECOMBINANTANTIBODY-TOXIN FUSION PROTEIN TARGETED TO MAJOR HISTOCOMPATIBILITY COMPLEX PEPTIDE CLASS-I COMPLEXES WITH T-CELL RECEPTOR-LIKE SPECIFICITY

Specificity in the immune system is dictated and regulated by specific recognition of peptide/major histocompatibility complex (MHC) complex es by the T cell receptor, Such peptide/MHC complexes are a desirable target for novel approaches in immunotherapy because of their highly r estricted fine specificity. Recently, phage display was used to isolat e an antibody that has T cell receptor-like specificity, It recognizes mouse MHC class I H-2K(k) molecules complexed with a H-2K(k)-restrict ed influenza virus-derived hemagglutinin peptide (Ha(255-262)) but doe s not bind to class I H-2K(k) alone, peptide alone, or H-2K(k) complex ed with other peptides, We have used this antibody to make a recombina nt antibody-toxin fusion protein (immunotoxin) and show herein that it specifically kills antigen-presenting cells in a peptide-dependent ma nner and with T cell receptor-like specificity, We find a striking cor relation between the fine specificity of binding of the antibody and t he cytotoxic activity of the recombinant immunotoxin. We also show spe cific killing of influenza virus infected target cells, The results su ggest that it should be possible to develop novel immunotherapeutic st rategies against human cancer by making recombinant antibodies that wi ll recognize cancer-related peptides complexed with MHC class I molecu les on the surface of cancer cells and using these to deliver toxins, radioisotopes, or cytotoxic drugs to the cancer cells.