Pharmacokinetics of anti-ganglioside GD2 mAb 14G2a in a phase I trial in pediatric cancer patients |
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Authors: | Martina M. Uttenreuther-Fischer Chuin-Sheng Huang Ralph A. Reisfeld Alice L. Yu |
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Affiliation: | (1) Charité Children's Hospital, Humboldt University at Berlin, Schumannstr. 20-21, D-10098 Berlin, Germany;(2) Department of Pediatrics, Division of Pediatric Hematology/Oncology, University of California San Diego, 200 West Arbor Drive, 92103 San Diego, California, USA;(3) Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan;(4) Department of Immunology, The Scripps Research Institute, 10666 North Torrey Pines Road, 92037 La Jolla, CA, USA |
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Abstract: | A phase I trial of a murine anti-ganglioside (GD2) monoclonal antibody (mAb) 14G2a was conducted in 14 neuroblastoma patients and 1 osteosarcoma patient to assess its safety, toxicity and pharmacokinetics in pediatric patients. The pharmacokinetics of mAb 14G2a were biphasic with at12/ of 2.8±2.8 h and at12/ of 18.3±11.8 h. In general,t12/ was dose-dependent with a level of significance ofP=0.036, and it reached a plateau at doses of 250 mg/m2 or more. Overall the peak serum levels were dose-dependent atP<0.001. However, they demonstrated an abrupt increase between doses of 100 mg/m2 and 250 mg/m2. The latter two suggest a saturable mechanism for mAb elimination. In addition, peak serum concentrations were observed earlier at higher mAb doses, which indicates the achievement of a steady state. Thet12/ of mAb 14G2a in children appears to be shorter than in adults. Furthermore, 2 patients demonstrated a considerable decrease int12/ following retreatment with 14G2a. This was paralleled by high human anti-(mouse Ig) antibody levels. This study represents the first comprehensive analysis of murine mAb pharmacokinetics in children and will be useful in the future design of mAb therapy.This work was supported by grants from FDA, FD-R-000377 and NIH U10 CA 28439 and in part by a grant from the general Clinical Research Center program, MOI RR00827, of the National Center for Research Resources, National Institutes of Health. M. M. U.-F. and C.-S. H. were supported in part by a grant from the Children's Cancer Research Foundation, and R. A. R. was supported in part by NIH grant CA 42508 |
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Keywords: | mAb 14G2a Pharmacokinetics Neuroblastoma Ganglioside GD2 Pediatric patients |
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