PT  - JOURNAL ARTICLE
AU  - Karacay, Habibe
AU  - Sharkey, Robert M.
AU  - Gold, David V.
AU  - Ragland, Dan R.
AU  - McBride, William J.
AU  - Rossi, Edmund A.
AU  - Chang, Chien-Hsing
AU  - Goldenberg, David M.
TI  - Pretargeted Radioimmunotherapy of Pancreatic Cancer Xenografts: TF10–<sup>90</sup>Y-IMP-288 Alone and Combined with Gemcitabine
AID  - 10.2967/jnumed.109.067686
DP  - 2009 Dec 01
TA  - Journal of Nuclear Medicine
PG  - 2008--2016
VI  - 50
IP  - 12
4099  - http://jnm.snmjournals.org/content/50/12/2008.short
4100  - http://jnm.snmjournals.org/content/50/12/2008.full
SO  - J Nucl Med2009 Dec 01; 50
AB  - 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.