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-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 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.
Reiter
Y
Y
Laboratory of Molecular Biology, Division of Basic Sciences, National Cancer Institute, Building 37, Room 4E16, National Institutes of Health, Bethesda, MD 20892-4255, USA.
Di Carlo
A
A
Fugger
L
L
Engberg
J
J
Pastan
I
I
D036002:ADP Ribose Transferases; D000818:Animals; D000906:Antibodies / Q000378:metabolism / Q000494:pharmacology*; D000938:Antigen-Presenting Cells / Q000187:drug effects*; D001427:Bacterial Toxins / Q000378:metabolism / Q000494:pharmacology*; D003602:Cytotoxicity, Immunologic; D005098:Exotoxins / Q000378:metabolism / Q000494:pharmacology*; D006183:H-2 Antigens; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D000922:Immunotoxins / Q000378:metabolism / Q000494:pharmacology*; D009980:Influenza A virus / Q000187:drug effects; D051379:Mice; D010455:Peptides / Q000276:immunology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D011550:Pseudomonas aeruginosa; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012680:Sensitivity and Specificity; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D000906:Antibodies; D001427:Bacterial Toxins; D005098:Exotoxins; D006183:H-2 Antigens; D015395:Histocompatibility Antigens Class I; D000922:Immunotoxins; D010455:Peptides; D011065:Poly(ADP-ribose) Polymerases; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; C024755:H-2K(K) antigen