Cytotoxicity against human peripheral blood mononuclear cells and T cell lines mediated by anti-T cell immunotoxins in the absence of added potentiator.
Several in vitro assays have indicated that anti-T cell immunotoxins (IT), composed of monoclonal antibodies (MoAbs) conjugated to ricin A chain (RTA), are maximally effective against T cells only in the presence of potentiators. It was thought that such IT might not be sufficiently cytotoxic to deplete T cells in vivo upon administration to patients. Therefore, we have re-evaluated the in vitro assays and report herein that even with a short exposure time (2 h), the two anti-T cell IT, H65-RTA (anti-CD5 MoAb coupled to RTA) and 4MRTA (anti-CD7 MoAb coupled to RTA30), were specifically cytotoxic for peripheral blood mononuclear cells (PBMC) in the absence of potentiators. Moreover, as has been reported for IT when tested against T cell lines, prolonging the exposure time of the IT with PBMC from 2 h to as long as 90 h, without added potentiators, enhanced their cytotoxicity from 2- to 40-fold. In contrast, most T cell lines were more sensitive to IT in the presence of potentiator, and IT cytotoxicity was much less enhanced by prolonging the exposure time. Thus, T cell lines may not serve as accurate models to determine the efficacy of IT against PBMC in vitro or in vivo. We conclude that IT-induced cytotoxicity of PBMC can be demonstrated in vitro at pharmacologically achievable concentrations in the absence of added potentiators.
Fishwild
D M
DM
Department of Immunology, Xoma Corporation, Berkeley, California 94710.
Staskawicz
M O
MO
Wu
H M
HM
Carroli
S F
SF
D000643:Ammonium Chloride / Q000494:pharmacology; D000911:Antibodies, Monoclonal; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D004306:Dose-Response Relationship, Immunologic; D006801:Humans; D007074:Immunoglobulin G; D000922:Immunotoxins; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects*; D010835:Phytohemagglutinins; D012276:Ricin; D013601:T-Lymphocytes / Q000187:drug effects*; D013997:Time Factors
D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D000922:Immunotoxins; D007376:Interleukin-2; D010835:Phytohemagglutinins; D000643:Ammonium Chloride; D012276:Ricin