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Pharmacokinetics and Dosimetry Studies for Optimization of Anti-Carcinoembryonic Antigen x Anti-Hapten Bispecific Antibody-mediated Pretargeting of Iodine-131-labeled Hapten in a Phase I Radioimmunotherapy Trial¹

Nuclear Medicine Department, René Gauducheau Cancer Center, 44805 Saint Herblain, France [F. K-B., L. F., C. R., I. R., J-F. C.]; INSERM U463, 44093 Nantes, France [F. K-B., A. F-C., M. B., J-F. C., J. B.]; Nuclear Medicine Department, Michalon Hospital, 38043 Grenoble, France [J-P. V., P-Y. B.]; Nuclear Medicine Department, Eugène Marquis Cancer Center, 35062 Rennes, France [A. D., S. L.]; IBC Pharmaceuticals, Inc., Morris Plains, New Jersey 07950 [K. C., D. M. G.]; and Garden State Cancer Center, Belleville, New Jersey 07109 [R. M. S., D. M. G.]

Purpose: Pharmacokinetics and dosimetry of hMN-14 x m734 bispecific monoclonal antibody (BsMAb) and ¹³¹I-labeled di-diethylenetriaminepentaacetic acid-indium (¹³¹I-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, ¹³¹I-trace-labeled BsMAb doses were escalated from 10 to 100 mg/m², and 3.7 GBq of ¹³¹I-hapten were administered 7 days later. In a second group, 12 patients received 75 mg/m² BsMAb and 2.6–4.2 GBq of ¹³¹I-hapten 5 days later. The BsMAb dose was then reduced to 40 mg/m², and 10 patients received 1.9–5.5 GBq of ¹³¹I-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/m² BsMAb resulted in fast elimination and very low tumor uptake of hapten, whereas 50 or 100 mg/m² resulted in favorable tumor accretion. With 75 mg/m² 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/m² 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.

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