Pharmacology of Anti-CD3 Diphtheria Immunotoxin in CD3 Positive T-Cell Lymphoma Trials

  • Jung Hee Woo
  • Yu-Jen Lee
  • David M. Neville
  • Arthur E. Frankel
Part of the Methods in Molecular Biology book series (MIMB, volume 651)

Abstract

Anti-CD3 recombinant diphtheria immunotoxin, A-dmDT390-bisFv(UCHT1), consists of the catalytic and translocation domains of diphtheria toxin fused to two single chain Fv fragments of an anti-CD3ɛ monoclonal antibody (UCHT1). A-dmDT390-bisFv(UCHT1) is capable of killing CD3+ T-lymphoma cells and normal T cells specifically in the femtomolar concentration range. To study pharmacology of A-dmDT390-bisFv(UCHT1) in patients with CD3+ T-cell lymphoma in a phase I clinical trial, (1) highly sensitive bioassay using Jurkat cells for measuring drug levels, (2) ELISA for measuring anti-DT antibody titer, and (3) 5-color FACS analysis method for measuring changes of subtype T-cell population were developed. In addition to evaluating drug efficacy and pharmacokinetics in patients, it is important to correlate pre-existing anti-DT antibody levels with maximum drug concentration in serum and extent of T-cell depletion because pre-existing anti-DT antibodies due to DPT (Diphtheria, Pertussis, and Tetanus) immunization can neutralize diphtheria immunotoxin. We observed that at the lowest treatment dose (2.5 μg/kg: twice daily for 4 days) A-dmDT390-bisFv(UCHT1) depletes greater than 99.0% of normal T cells in all six patients for a short period of time (2–3 days) and that there is no association of C max and extent of T-cell depletion with the pre-existing anti-DT antibody titer.

Key word

UCHT1 immunotoxin CD3 diphtheria toxin T-cell depletion pre-existing anti-DT antibodies 

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Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Jung Hee Woo
    • Yu-Jen Lee
      • David M. Neville
        • 1
      • Arthur E. Frankel
        1. 1.Cancer Research InstituteScott and White Memorial HospitalTempleUSA

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