Pharmacology of anti-CD3 diphtheria immunotoxin in CD3 positive T-cell lymphoma trials.
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.
Woo
Jung Hee
JH
Cancer Research Institute, Scott and White Memorial Hospital, Temple, TX, USA.
Lee
Yu-Jen
YJ
Neville
David M
DM
Frankel
Arthur E
AE
D000911:Antibodies, Monoclonal / Q000097:blood / Q000276:immunology; D000912:Antibodies, Neoplasm / Q000097:blood; D017252:CD3 Complex / Q000276:immunology*; D002986:Clinical Trials as Topic; D004167:Diphtheria Toxin / Q000097:blood / Q000276:immunology* / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D007118:Immunoassay / Q000379:methods*; D000922:Immunotoxins / Q000494:pharmacology*; D016131:Lymphocyte Subsets / Q000276:immunology; D016399:Lymphoma, T-Cell / Q000276:immunology*
D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D017252:CD3 Complex; D004167:Diphtheria Toxin; D000922:Immunotoxins