Peptide-antibody conjugates for tumour therapy: a MHC-class-II-restricted tetanus toxin peptide coupled to an anti-Ig light chain antibody can induce cytotoxic lysis of a human B-cell lymphoma by specific CD4 T cells.
Anti-idiotype antibody therapy of B-cell lymphomas, despite numerous promising experimental and clinical studies, has so far met with limited success. Tailor-made monoclonal anti-idiotype antibodies have been injected into a large series of lymphoma patients, with a few impressive complete tumour remissions but a large majority of negative responses. The results presented here suggest that, by coupling to antilymphoma idiotype antibodies a few molecules of the tetanus toxin universal epitope peptide P2 (830-843), one could markedly increase the efficiency of this therapy. We show that after 2-hr incubation with conjugates consisting of the tetanus toxin peptide P2 coupled by an S-S bridge to monoclonal antibodies directed to the lambda light chain of human immunoglobulin, human B-lymphoma cells can be specifically lysed by a CD4 T-lymphocyte clone specific for the P2 peptide. Antibody without peptide did not induce B-cell killing by the CD4 T-lymphocyte clone. The free cysteine-peptide was also able to induce lysis of the B-lymphoma target by the T-lymphocyte clone, but at a molar concentration 500 to 1000 times higher than that of the coupled peptide. Proliferation assays confirmed that the antibody-peptide conjugate was antigenically active at a much lower concentration than the free peptide. They also showed that antibody-peptide conjugates required an intact processing function of the B cell for peptide presentation, which could be selectively inhibited by leupeptin and chloroquine.(ABSTRACT TRUNCATED AT 250 WORDS)
Yu
Z
Z
Institute of Biochemistry, University of Lausanne, Switzerland.
Healy
F
F
Valmori
D
D
Escobar
P
P
Corradin
G
G
Mach
J P
JP
D000595:Amino Acid Sequence; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000276:immunology / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology*; D002738:Chloroquine / Q000494:pharmacology; D000949:Histocompatibility Antigens Class II / Q000276:immunology / Q000627:therapeutic use; D006801:Humans; D007147:Immunoglobulin Light Chains / Q000276:immunology / Q000627:therapeutic use; D000922:Immunotoxins / Q000378:metabolism / Q000627:therapeutic use*; D007976:Leupeptins / Q000494:pharmacology; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D010455:Peptides / Q000627:therapeutic use; D013744:Tetanus Toxin / Q000627:therapeutic use*
D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D000949:Histocompatibility Antigens Class II; D007147:Immunoglobulin Light Chains; D000922:Immunotoxins; D007976:Leupeptins; D010455:Peptides; D013744:Tetanus Toxin; D002738:Chloroquine; C032854:leupeptin