Preclinical evaluation of anti-CD86 immunotoxin in rhesus monkeys: analysis of systemic toxicity, pharmacokinetics, and effect on primary T-cell responses.
CD86 and CD80 costimulatory antigens are highly overexpressed on Hodgkin/Reed-Sternberg cells in patients with Hodgkin's disease (HD) and are candidate target antigens for immunotoxins in order to eliminate minimal residual disease. In this study we have evaluated the pharmacokinetics (and immunological) toxicity in rhesus monkeys of immunotoxins consisting of gelonin conjugated to anti-CD86 (alphaCD86-IT). Both alphaCD86-IT and alphaCD80-IT inhibited protein synthesis in B cell lines from rhesus monkeys and inhibited the mixed leukocyte reaction. Reactivity of the alphaCD86 antibody with rhesus monkey CD86 (RhCD86) was shown by cloning and transfecting RhCD86, which conferred reactivity of the alphaCD86 antibody used in this study. alphaCD86-IT was administered as single intravenous bolus injection in four rhesus monkeys, and achieved plasma concentration in 50-fold excess able to eliminate cultured Hodgkin/Reed-Sternberg cells up to 6 h. The animals were capable of generating primary immune responses to both gelonin and murine IgG within 9 days after infusion with alphaCD86-IT. No evidence could be found of significant (immunological) toxicity. The results of this study show that alphaCD86-IT can be applied safely in an effective dose.
Otten
Henderikus G
HG
Department of Haematology, University Medical Center Utrecht, Heidelberglaan 100, F03722, 3584 CX Utrecht, The Netherlands. h.g.otten@azu.nl
de Gast
Gijsbert C
GC
Vooijs
Wim C
WC
van der Gouw
Alexander P
AP
de Boer
Mark
M
Ossevoort
Mirjam A
MA
Jonker
Margreet
M
D000818:Animals; D000906:Antibodies / Q000276:immunology*; D015703:Antigens, CD / Q000276:immunology; D018122:B7-1 Antigen / Q000276:immunology; D051940:B7-2 Antigen; D000922:Immunotoxins / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D007959:Lymphocyte Culture Test, Mixed; D008253:Macaca mulatta; D008562:Membrane Glycoproteins / Q000276:immunology; D010940:Plant Proteins / Q000276:immunology; D016539:Reed-Sternberg Cells; D054789:Ribosome Inactivating Proteins, Type 1; D013601:T-Lymphocytes / Q000276:immunology; D014162:Transfection
D000906:Antibodies; D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D000922:Immunotoxins; D008562:Membrane Glycoproteins; D010940:Plant Proteins; D054789:Ribosome Inactivating Proteins, Type 1; C025674:GEL protein, Gelonium multiflorum