PROJECT SUMMARY AND ABSTRACT
The goal of this proposal is to develop a novel immunoPET imaging method for the detection of CD46 positive
malignancy in men with prostate cancer. CD46 is a novel therapeutic target, with a cognate antibody-drug
conjugate, FOR46, now in phase 1 clinical trials. Our preliminary data suggests high expression of CD46 in the
most advanced, lethal forms of prostate cancer, including adenocarcinoma and neuroendocrine prostate cancer
phenotypes. Encouragingly, expression of CD46 is increased in forms of disease with loss of prostate specific
membrane antigen (PSMA) expression, suggesting opportunity for improved theranostic agent development. In
this proposal, we develop and implement [89Zr]DFO-YS5, a novel immunoPET agent based on YS5, the parent
antibody of the FOR46 ADC, in preclinical models, and in a subsequent pilot clinical study. The central
hypothesis of this proposal is that CD46 expression, as measured by [89Zr]DFO-YS5 PET, is a
characteristic feature of metastatic prostate cancer.
In order to test this hypothesis, we have assembled an experienced team of chemists, imaging scientists,
physicists, and physicians to evaluate this method in preclinical models and to perform initial feasibility testing in
men with metastatic prostate cancer. In specific aim 1, we will test if [89Zr]DFO-YS5 PET can detect CD46
expression in preclinical models of adenocarcinoma and neuroendocrine prostate cancer, including patient
derived xenografts. In specific aim 2, we leverage the ongoing clinical trial of FOR46 to obtain GMP antibody for
labeling, and also to recruit patients for a correlative translational imaging study of [89Zr]DFO-YS5. In aim 3, we
analyze these imaging data to determine the landscape of CD46 expression in mCRPC, to test the central
hypothesis of this proposal. These experiments will help aid the development and implementation of CD46
targeted therapeutic and theranostic agents, thereby improving patient care for men with prostate cancer.