Influence of endogenous Thy1.1 cells upon the efficacy of an anti-Thy1.1 antibody-diphtheria toxin conjugate.
The chemical conjugation of antibodies to protein toxins results in cell-specific cytotoxic agents that can be defined in terms of in vitro potency and efficacy; however, it is the in vivo utilities that are largely being pursued in clinical trials. The nature of in vivo target cell depletion by toxin conjugates is largely unknown. The anti-murine Thy1.1 antibody-diphtheria toxin conjugate possesses high in vitro efficacy, and because mice are remarkably resistant to the native toxin, the conjugate possesses in vivo efficacy. When administered intravenously, the conjugate is shown to deplete peripheral blood Thy1.1+ target cells in a concentration-dependent fashion. When the log kill of Thy1.1+ tumor cells was analyzed by the life span extension method, it was determined, however, that the log kill is inversely proportional to the number of target cells. That is, the presence of an endogenous cell population, which is expressing the same surface antigen targeted by the antibody conjugate as on the pathological cell, may drastically lower the clinical efficacy of the immunotoxin. Thus, the greatest potential for antibody-toxin conjugates will be for low target cell burdens and for pathogenic cell populations expressing unique surface antigens. These are important considerations in the design of bioconjugates to insure high in vivo efficacy in elimination of intended target cells.
Yan
B
B
Laboratory of Molecular Biology, National Institute of Mental Health, Bethesda, Maryland 20892.
Baker
P D
PD
Evans
C H
CH
Marsh
J W
JW
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D000954:Antigens, Surface / Q000032:analysis* / Q000276:immunology; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D004167:Diphtheria Toxin / Q000494:pharmacology*; D004306:Dose-Response Relationship, Immunologic; D000922:Immunotoxins / Q000627:therapeutic use*; D007518:Isoantibodies; D007942:Leukemia, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008806:Mice, Inbred AKR; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018800:Thy-1 Antigens; D014407:Tumor Cells, Cultured / Q000276:immunology*
D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D004167:Diphtheria Toxin; D000922:Immunotoxins; D007518:Isoantibodies; D018800:Thy-1 Antigens; C035678:anti-Thy antibody