Redirecting anti-viral CTL against cancer cells by surface targeting of monomeric MHC class I-viral peptide conjugated to antibody fragments.
To combine the advantage of both the tumor targeting capacity of high affinity monoclonal antibodies (mAbs) and the potent killing properties of cytotoxic T lymphocytes (CTL), we investigated the activity of conjugates made by coupling single Fab' fragments, from mAbs specific for tumor cell surface antigens, to monomeric HLA-A2 complexes containing the immunodominant influenza-matrix peptide 58-66. In solution, the monovalent 95 kDa Fab-HLA-A2/Flu conjugates did not activate influenza-specific CTL. However, when targeted to tumor cells expressing the relevant tumor-associated antigen, the conjugates induced CTL activation and efficient tumor cell lysis, as a result of MHC/peptide surface oligomerization. The highly specific and sensitive in vitro cytotoxicity results presented suggest that injection of Fab-MHC/peptide conjugates could represent a new form of immunotherapy, bridging antibody and T lymphocyte attack on cancer cells.
Robert
B
B
Institute of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland.
Guillaume
P
P
Luescher
I
I
Doucey
M A
MA
Cerottini
J C
JC
Romero
P
P
Mach
J P
JP
D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D005434:Flow Cytometry / Q000379:methods; D015789:HLA-A2 Antigen / Q000235:genetics / Q000276:immunology*; D006801:Humans; D018796:Immunoconjugates / Q000276:immunology; D007128:Immunoglobulin Fragments / Q000276:immunology; D020128:Inhibitory Concentration 50; D009369:Neoplasms / Q000276:immunology / Q000473:pathology; D010446:Peptide Fragments / Q000276:immunology*; D011994:Recombinant Proteins / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000276:immunology; D014763:Viral Matrix Proteins / Q000276:immunology*
D000911:Antibodies, Monoclonal; D015789:HLA-A2 Antigen; D018796:Immunoconjugates; D007128:Immunoglobulin Fragments; D010446:Peptide Fragments; D011994:Recombinant Proteins; D014763:Viral Matrix Proteins; C448634:influenza matrix peptide (58-66); D002118:Calcium