Pancreatic cancer remains among the most lethal of solid tumors, due to late diagnosis and a high probability of
metastatic spread. Effective new systemic treatments are needed in order to improve outcomes in patients.
Targeted radionuclide therapy has demonstrated effectiveness cancer therapy, notably with the success of 177Lu-
dotatate in neuroendocrine tumors including those of the pancreas. Prostate Stem Cell Antigen (PSCA) is
upregulated in 60-80% of pancreatic adenocarcinomas, making it a promising target for antibody-directed
therapy. An engineered antibody fragment, the A2 scFv-Fc2 DM has been specifically designed for optimized
delivery of therapeutic radionucides in pancreatic cancer. It is based on a humanized, high-affinity anti-PSCA
antibody, and contains Fc mutations engineered to foster rapid blood clearance via the hepatobiliary route. As a
result, radiation dose to key organs/tissues (bone marrow and kidney) is minimized, enabling effective delivery
of an alpha- or beta-emitting radionuclide to tumors. In Aim 1, biodistribution studies will be undertaken in mouse
models, in order to confirm the expected tumor targeting and hepatic clearance. Formal dose estimations will be
made for the scFv-Fc2 DM radiolabeled with either 177Lu or 225Ac for therapy. Aim 2 will explore the potential
efficacy of the anti-PSCA scFv-Fc2 DM in mouse models of pancreatic cancer, including subcutaneous
xenografts of human pancreatic tumor cells, a syngeneic model of KPC-PSCA tumors in huPSCA knock-in mice,
and patient-derived pancreatic tumor xenograft models. The relative efficacies and toxicities of the alpha-emitter
225Ac and beta-emitter 177Lu will be analyzed in order to prepare for future clinical therapy studies. In Aim 3,
clinical production and conjugation of the anti-PSCA scFv-Fc2 DM will be performed, testing conducted, and an
IND filed. Finally, in Aim 4 we will conduct a first-in-human imaging study using 64Cu-DOTA-anti-PSCA scFv-
Fc2 DM in patients with advanced pancreatic cancer, to evaluate the targeting, and clearance properties and
potential radiation dose delivery of this novel engineered antibody fragment. Results from this clinical
immunoPET study will be central to guiding future development of a radioimmunotherapy agent that can be
implemented in a theranostic approach to pancreatic cancer.