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Therapeutic Advantage of Pretargeted Radioimmunotherapy Using a Recombinant Bispecific Antibody in a Human Colon Cancer Xenograft

Authors' Affiliations:¹ Center for Molecular Medicine and Immunology and the Garden State Cancer Center, Belleville, New Jersey; ² IBC Pharmaceuticals, Inc.; ³ Immunomedics, Inc., Morris Plains, New Jersey; and ⁴ Cambrex Corp., Walkersville, Maryland

Requests for reprints: Robert M. Sharkey, Center for Molecular Medicine and Immunology, 520 Belleville Avenue, Belleville, NJ 07109. Phone: 973-844-7121; Fax: 973-844-7020; E-mail: rmsharkey{at}gscancer.org.

Purpose: To assess if pretargeting, using a combination of a recombinant bispecific antibody (bsMAb) that binds divalently to carcinoembryonic antigen (CEA) and monovalently to the hapten histamine-succinyl-glycine and a ⁹⁰Y-peptide, improves therapeutic efficacy in a human colon cancer-nude mouse xenograft compared with control animals given ⁹⁰Y-humanized anti-CEA immunoglobulin G (IgG).

Experimental Design: Clearance and biodistribution were monitored by whole-body readings and necropsy. Animals were monitored for 34 weeks with a determination of residual disease and renal pathology in survivors. Hematologic toxicity was assessed separately in non-tumor-bearing NIH Swiss mice.

Results: Hematologic toxicity was severe at doses of 100 to 200 µCi of ⁹⁰Y-IgG, yet mild in the pretargeted animals given 500 or 700 µCi of the ⁹⁰Y-peptide. Evidence of end-stage renal disease was found at 900 µCi of the pretargeted ⁹⁰Y-peptide whereas animals given 700 µCi showed only mild renal pathology, similar to that seen in control animals given ⁹⁰Y-IgG. Biodistribution data indicated that the average amount of tumor radioactivity by a 700-µCi dose of the pretargeted peptide over a 96-hour period was increased 2.5-fold (48 µCi/g) compared with 150 µCi of ⁹⁰Y-IgG (18.9 µCi/g). At these doses, survival (i.e., time to progression to 2.5 cm³) was significantly improved (P < 0.04) compared with ⁹⁰Y-IgG, with ablation of about one third of the tumors, whereas viable tumor was present in all of the ⁹⁰Y-IgG–treated animals.

Conclusion: Pretargeting increases the amount of radioactivity delivered to colorectal tumors sufficiently to improve the therapeutic index and responses as compared with conventional radioimmunotherapy.

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