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

2009; Society of Nuclear Medicine and Molecular Imaging; Volume: 50; Issue: 12 Linguagem: Inglês

10.2967/jnumed.109.067686

1535-5667

Habibe Karacay, Robert M. Sharkey, David V. Gold, Dan R. Ragland, William J. McBride, Edmund A. Rossi, Chien‐Hsing Chang, David M. Goldenberg,

Peptidase Inhibition and Analysis

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 ( 90 Y-humanized PAM4 IgG, 90 Y-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 90 Y-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 90 Y 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 90 Y-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 90 Y hapten peptide is an effective treatment for pancreatic cancer, with less toxicity than 90 Y-PAM4 IgG, in this model. Combinations with gemcitabine and dose fractionation of the PT-RAIT enhanced therapeutic responses.