Pharmacokinetics and Dosimetry Studies for Optimization of Anti-Carcinoembryonic Antigen × Anti-Hapten Bispecific Antibody-mediated Pretargeting of Iodine-131-labeled Hapten in a Phase I Radioimmunotherapy Trial

• Published in: Clinical cancer research 2003-09, Vol.9 (10), p.3973s
• Main Authors: Françoise Kraeber-Bodéré, Alain Faivre-Chauvet, Ludovic Ferrer, Jean-Philippe Vuillez, Pierre-Yves Brard, Caroline Rousseau, Isabelle Resche, Anne Devillers, Sophie Laffont, Manuel Bardiès, Ken Chang, Robert M. Sharkey, David M. Goldenberg, Jean-François Chatal, Jacques Barbet
• Format: Article
• Language: English
• ISSN: 1078-0432; 1557-3265

Purpose: Pharmacokinetics and dosimetry of hMN-14 × m734 bispecific monoclonal antibody (BsMAb) and 131 I-labeled di-diethylenetriaminepentaacetic acid-indium ( 131 I-hapten) were studied to optimize pretargeted radioimmunotherapy. Experimental Design: Thirty-five patients with carcinoembryonic antigen-expressing tumors were included. In a first group of 12 patients, 131 I-trace-labeled BsMAb doses were escalated from 10 to 100 mg/m 2 , and 3.7 GBq of 131 I-hapten were administered 7 days later. In a second group, 12 patients received 75 mg/m 2 BsMAb and 2.6–4.2 GBq of 131 I-hapten 5 days later. The BsMAb dose was then reduced to 40 mg/m 2 , and 10 patients received 1.9–5.5 GBq of 131 I-hapten. Blood samples were collected. Biodistribution was monitored by quantitative scintigraphy. Results: Directly labeled BsMAb pharmacokinetics was described by two exponentials: half-lives were 8.1 h (2.0–18.1 h) and 48.2 h (22.8–79.4 h); blood clearance was 123 ml/h (64–195 ml/h). With a 7-day interval, 10 or 30 mg/m 2 BsMAb resulted in fast elimination and very low tumor uptake of hapten, whereas 50 or 100 mg/m 2 resulted in favorable tumor accretion. With 75 mg/m 2 BsMAb and a 5-day interval, hapten clearance was 152 ml/h (81–298 ml/h). Calculated radiation dose to tumor was 3.9 Gy/GBq (0.4–22.4 Gy/GBq) for the hapten, compared with 2.0 Gy/GBq (0.3–3.8 Gy/GBq) for the BsMAb, but hematological toxicity prevented dose escalation. Reduction of the BsMAb dose to 40 mg/m 2 accelerated hapten clearance to 492 ml/h (113–2544 ml/h) and reduced hematological toxicity without compromising tumor uptake [5.2 Gy/GBq (0.5–12.6 Gy/GBq)]. Conclusions: Optimized BsMAb doses and time interval will allow for the administration of higher, tumoricidal, activity doses.