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Preclinical evaluation of anti-CD86 immunotoxin in rhesus monkeys: analysis of systemic toxicity, pharmacokinetics, and effect on primary T-cell responses

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Abstract

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 (αCD86-IT). Both αCD86-IT and αCD80-IT inhibited protein synthesis in B cell lines from rhesus monkeys and inhibited the mixed leukocyte reaction. Reactivity of the αCD86 antibody with rhesus monkey CD86 (RhCD86) was shown by cloning and transfecting RhCD86, which conferred reactivity of the αCD86 antibody used in this study. αCD86-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 αCD86-IT. No evidence could be found of significant (immunological) toxicity. The results of this study show that αCD86-IT can be applied safely in an effective dose.

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Acknowledgements

We thank Dr Louis Boon for his critical reading of this manuscript.

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Authors and Affiliations

  1. Department of Haematology, University Medical Center Utrecht, Heidelberglaan 100, F03722, 3584 CX, Utrecht, The Netherlands

    Henderikus G. Otten & Alexander P. van der Gouw

  2. Department of Internal Medicine, Netherlands Cancer Institute, Amsterdam, The Netherlands

    Gijsbert C. de Gast & Wim C. Vooijs

  3. MacroZyme, Amsterdam, The Netherlands

    Mark de Boer

  4. Department of Immunobiology, Biomedical Primate Research Centre, Rijswijk, The Netherlands

    Mirjam A. Ossevoort & Margreet Jonker

Authors
  1. Henderikus G. Otten
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  2. Gijsbert C. de Gast
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  3. Wim C. Vooijs
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  4. Alexander P. van der Gouw
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  5. Mark de Boer
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  6. Mirjam A. Ossevoort
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  7. Margreet Jonker
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Correspondence to Henderikus G. Otten.

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Otten, H.G., de Gast, G.C., Vooijs, W.C. et al. Preclinical evaluation of anti-CD86 immunotoxin in rhesus monkeys: analysis of systemic toxicity, pharmacokinetics, and effect on primary T-cell responses. Cancer Immunol Immunother 52, 569–575 (2003). https://doi.org/10.1007/s00262-003-0401-z

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  • DOI: https://doi.org/10.1007/s00262-003-0401-z

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