Peptide-specific killing of antigen-presenting cells by a recombinant antibody-toxin fusion protein targeted to major histocampatibility complex/peptide class I complexes with T cell receptor-like specificity

Specificity in the immune system is dictated and regulated by specific recognition of peptideymajor histocompatibility complex (MHC) complexes by the T cell receptor. Such peptideyMHC complexes are a desirable target for novel approaches in immunotherapy because of their highly restricted fine specificity. Recently, phage display was used to isolate an antibody that has T cell receptor-like specificity. It recognizes mouse MHC class I H-2Kk molecules complexed with a H-2Kk-restricted influenza virus-derived hemagglutinin peptide (Ha255–262) but does not bind to class I H-2Kk alone, peptide alone, or H-2Kk complexed with other peptides. We have used this antibody to make a recombinant antibody– toxin fusion protein (immunotoxin) and show herein that it specifically kills antigen-presenting cells in a peptidedependent manner and with T cell receptor-like specificity. We find a striking correlation between the fine specificity of binding of the antibody and the cytotoxic activity of the recombinant immunotoxin. We also show specific killing of influenza virus-infected target cells. The results suggest that it should be possible to develop novel immunotherapeutic strategies against human cancer by making recombinant antibodies that will recognize cancer-related peptides complexed with MHC class I molecules on the surface of cancer cells and using these to deliver toxins, radioisotopes, or cytotoxic drugs to the cancer cells.