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Pretargeted Radioimmunotherapy of Pancreatic Cancer Xenografts: TF10–⁹⁰Y-IMP-288 Alone and Combined with Gemcitabine

¹ Center for Molecular Medicine and Immunology, Belleville, New Jersey; ² National Institutes of Allergy and Infectious Disease, Ft. Detrick, Maryland; ³ Immunomedics, Inc., Morris Plains, New Jersey; and ⁴ IBC Pharmaceuticals, Inc., Morris Plains, New Jersey

Correspondence: For correspondence or reprints contact: Robert M. Sharkey, Garden State Cancer Center/Center for Molecular Medicine and Immunology, 520 Belleville Ave., Belleville, NJ 07109. E-mail: rmsharkey{at}gscancer.org

Pancreatic cancer is a silent disease that most commonly presents in an already metastatic form. Current treatment options provide little survival benefit. Radiolabeled PAM4 IgG, a monoclonal antibody that recognizes a unique epitope associated with a mucin found almost exclusively in pancreatic cancer, has shown encouraging therapeutic effects in animal models and in early clinical testing (⁹⁰Y-humanized PAM4 IgG, ⁹⁰Y-clivatuzumab tetraxetan). The studies reported herein examine a new pretargeting procedure for delivering therapeutic radionuclides. Methods: We prepared a humanized, recombinant tri-Fab bispecific monoclonal antibody (bsmAb) (TF10) using specificity for targeting pancreatic cancer of PAM4 and another Fab binding to a hapten (histamine-succinyl-glycine [HSG]) and tested this in a pretargeting setting with a ⁹⁰Y-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-di-HSG-peptide (pretargeted radioimmunotherapy [PT-RAIT]). Nude mice bearing established Capan-1 human pancreatic cancer xenografts were given TF10 and then received the ⁹⁰Y peptide as a single bolus dose 19 h later, or the therapy cycle was fractionated weekly. Other studies examined different combinations with gemcitabine. Results: PT-RAIT of 18.5 MBq (50% of its maximum tolerated dose [MTD]) was as effective as the MTD of ⁹⁰Y-PAM4 IgG (5.55 MBq). Three monthly doses of 9.25 MBq of PT-RAIT combined with a monthly cycle of gemcitabine (3 weekly, 6-mg doses) significantly enhanced survival, compared with PT-RAIT alone. Adding gemcitabine as a radiosensitizer to 9.25 MBq of PT-RAIT enhanced objective responses. Weekly fractionation of the PT-RAIT, as compared with a single treatment, improved responses. Conclusion: PAM4-based PT-RAIT with ⁹⁰Y hapten peptide is an effective treatment for pancreatic cancer, with less toxicity than ⁹⁰Y-PAM4 IgG, in this model. Combinations with gemcitabine and dose fractionation of the PT-RAIT enhanced therapeutic responses.

Key Words: bispecific antibody • gemcitabine • pancreatic cancer • pretargeting • ⁹⁰Y

COPYRIGHT © 2009 by the Society of Nuclear Medicine, Inc.

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