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

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Anti-CD3 recombinant diphtheria immunotoxin, A-dmDT(390)-bisFv(UCHT1), consists of the catalytic and translocation domains of diphtheria toxin fused to two single chain Fv fragments of an anti-CD3epsilon monoclonal antibody (UCHT1). A-dmDT(390)-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-dmDT(390)-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 microg/kg: twice daily for 4 days) A-dmDT(390)-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.

Original languageEnglish (US)
Pages (from-to)157-175
Number of pages19
JournalMethods in molecular biology (Clifton, N.J.)
Volume651
DOIs
StatePublished - 2010

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Immunotoxins
Diphtheria
T-Cell Lymphoma
Pharmacology
Anti-Idiotypic Antibodies
T-Lymphocytes
Pharmaceutical Preparations
Immunoglobulin Variable Region
Diphtheria Toxin
Single-Chain Antibodies
Clinical Trials, Phase I
Jurkat Cells
Whooping Cough
Tetanus
Biological Assay
Immunization
Catalytic Domain
Pharmacokinetics
Color
Enzyme-Linked Immunosorbent Assay

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Pharmacology of anti-CD3 diphtheria immunotoxin in CD3 positive T-cell lymphoma trials. / Woo, Jung Hee; Lee, Yu Jen; Neville, David M.; Frankel, Arthur E.

In: Methods in molecular biology (Clifton, N.J.), Vol. 651, 2010, p. 157-175.

Research output: Contribution to journalArticle

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