Evaluation of a novel MUC1 biomarker/target antigen for pancreatic cancer

Abstract

4096 Background: Pancreatic cancer provides a major challenge in terms of diagnosis and treatment. We have developed an anti-MUC1 MAb, PAM4, which identifies an epitope that is more restricted to MUC1-expressed by pancreatic cancer than MUC1 from other forms of cancer. PAM4 has been studied for in vitro and in vivo detection and therapy of pancreatic cancer. Methods: The in vitro immunoassay consists of PAM4 as the capture reagent and an IgG fraction derived from a polyclonal, anti-MUC1 antiserum as the probe. For in vivo detection and therapy, PAM4 is either directly radiolabeled or used in a 2-step pretargeting protocol. Results: The PAM4-based immunoassay provided high sensitivity (77%) and specificity (95%), with a value ≥ 10.2 units/ml indicating a high likelihood of pancreatic cancer, as compared to normal and benign disease groups and non-pancreatic cancers. A direct pairwise comparison of the PAM4 and CA19–9 immunoassays for discrimination of pancreatic cancer and pancreatitis demonstrated a superior performance of the PAM4-immunoassay (P<0.003). Initial clinical studies with directly labeled 131I-PAM4 provided positive imaging in 8/10 patients, with one negative patient having only pancreatitis, and the other negative patient having a tumor that was MUC1-negative. A Phase I, dose-escalation study of 90Y-humanized PAM4 administered as a single dose to patients with advanced pancreatic cancer is in progress (Immunomedics, Inc), and has already achieved doses of 20 mCi/m2. Finally, pretargeting involving a bispecific MAb with one arm being PAM4 targeting MUC1 and the other arm capturing a hapten peptide carrying a radionuclide is under preclinical evaluation. This second generation targeting system has shown higher tumor/nontumor ratios and improved imaging (111In) as compared to directly radiolabeled PAM4. Conclusions: These results suggest that the PAM4-reactive MUC1 epitope may prove useful as a selective biomarker/target antigen for diagnosis, detection, imaging, and therapy of pancreatic cancer. (Supported in part by grants CA96924and CA98488 from the NIH). [Table: see text]