Abstract
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Objectives: Pretargeting is a promising procedure for improving radioimmunotherapy with less hematologic toxicity. We evaluated conditions to optimize pretargeted therapy with 90Y-DOTA-di-HSG peptide (IMP-288) and TF10, a humanized recombinant bispecific antibody with 2 Fabs that bind a pancreatic cancer mucin antigen identified by the antibody PAM4, and 1 Fab binding to the hapten HSG (histamine-succinyl-glycine).
Methods: Biodistribution and therapy studies using TF10 and radiolabeled IMP-288 were performed in nude mice bearing s.c. CaPan1 human pancreatic tumors. For therapy, TF10-pretargeted 90Y-IMP-288 was given alone or fractionated in combination with gemcitabine (human equivalent of 900 mg/m2 weekly x 3; repeated 3 times over 11 weeks).
Results: Optimal pretargeting required 10-20x molar excess of TF10 than IMP-288 given 16 h apart. 111In-IMP-288 tumor uptake was 15-25% ID/g within 1 h of injection, achieving tumor/blood, kidneys, and liver ratios >1000:1, 7:1, and >50:1, respectively. TF-10 pretargeted 90Y-IMP-288, 9.25 and 18.5 MBq, arrested the growth of established tumors, curing 3/10 and 7/10 animals, respectively, without appreciable hematologic toxicity. Three cycles of 9.25 MBq of TF10-pretargeted 90Y-IMP-288 given every 4 weeks in combination with the standard gemcitabine treatment regimen improved responses compared to pretargeted peptide alone, extending median survival from 4.9 weeks to 18.2 weeks (P = 0.004).
Conclusions: TF10-pretargeted therapy is a promising treatment for pancreatic cancer with minimal hematologic toxicity. Combination with gemcitabine further improves the response.
Research Support: In part, NCI grant CA115755.
- Society of Nuclear Medicine, Inc.