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.

Public Health Relevance

This proposal describes the development and implementation of a novel immunoPET imaging agent targeting CD46, an exciting new therapeutic target which is highly expressed in the most lethal forms of prostate cancer. We will demonstrate the ability of this agent to detect CD46 expression in preclinical models and in a pilot clinical study of men with metastatic prostate cancer. The imaging will demonstrate the landscape of CD46 expression across these heterogeneous tumors, and support the development of CD46 targeted therapies and theranostics.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Method to Extend Research in Time (MERIT) Award (R37)
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Imaging Probes and Contrast Agents Study Section (IPCA)
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Zhang, Yantian
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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