Initial studies of monoclonal antibody PAM4 targeting to xenografted orthotopic pancreatic cancer.

To resemble the clinical presentation of pancreatic cancer in an animal model more closely, we developed an orthotopic xenograft of CaPan-1 human pancreatic cancer in athymic nude mice. Within 3 weeks after implantation into the body and head of the pancreas, animals had palpable tumors. By 8 weeks, metastases to the liver and spleen were observed, and at 10-14 weeks, ascites formation, with and without seeding of the diaphragm, and jaundice were evident. Thus, this tumor model exhibited many of the most common features of human pancreatic cancer. Radiolabeled monoclonal antibody PAM4 showed specific localization of the primary orthotopic and metastatic tumors. On day 3, PAM4 accumulation within the primary tumor (0.5 g) was 11.3 +/- 5.1% injected dose/g with a localization index of 11.3 +/- 4.0. The estimated tumor:blood radiation dose ratio for PAM4 was 4:1, whereas a nonspecific antibody (Ag8) would provide only 40% of the blood dose to the tumor. Based on these observations, animals bearing 4-week-old orthotopic tumors (estimated volume, 0.25 cm3) were administered either 131I-labeled PAM4, 350 microCi, or nonspecific Ag8, 350 microCi, and compared with an untreated control group. Radiolabeled PAM4 provided a significant (P < 0.001) increase in survival time with less morbidity compared with the untreated control group, whereas nonspecific Ag8 was not significantly different from the control group. These studies provide a rationale for initiating a Phase I clinical study for detection and therapy of pancreatic cancer with PAM4.