RT Journal Article
SR Electronic
T1 Pretargeted Radioimmunotherapy of Pancreatic Cancer Xenografts: TF10–<sup>90</sup>Y-IMP-288 Alone and Combined with Gemcitabine
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 2008
OP 2016
DO 10.2967/jnumed.109.067686
VO 50
IS 12
A1 Karacay, Habibe
A1 Sharkey, Robert M.
A1 Gold, David V.
A1 Ragland, Dan R.
A1 McBride, William J.
A1 Rossi, Edmund A.
A1 Chang, Chien-Hsing
A1 Goldenberg, David M.
YR 2009
UL http://jnm.snmjournals.org/content/50/12/2008.abstract
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.