Peptide-specific killing of antigen-presenting cells by a recombinant antibody–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) complexes by the T cell receptor. Such peptide/MHC 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-2K(k) molecules complexed with a H-2K(k)-restricted influenza virus-derived hemagglutinin peptide (Ha(255–262)) but does not bind to class I H-2K(k) alone, peptide alone, or H-2K(k) 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 peptide-dependent 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.