Multifunctional PSCA Antibody Fragments for PET and Optical Prostate Cancer Imaging
Abstract
Proposal Rationale: Advances in the management of prostate cancer have been hampered by a lack of sensitive (ability to detect -- absence of false negative tests) and specific (absence of false positive tests) imaging tools to (1) stage newly diagnosed and recurrent disease, (2) visualize disease during surgery, and (3) monitor the response of metastatic disease to treatment. New imaging tools are therefore urgently needed for multiple applications in the management of this disease. Prostate Stem Cell Antigen (PSCA) is a cell surface protein present on virtually all prostate cancers and is a promising therapeutic and imaging target. In this application, we propose to develop and test multifunctional PSCA antibody fragments (small pieces of an intact antibody that are able to penetrate cancers and clear from normal body tissue more rapidly in order to produce high contrast images) that can be used for Positron Emission Tomography (PET) and/or optical (fluorescence) imaging of prostate cancer. Hypothesis/Objective: We hypothesize that PET and optical imaging of prostate cancer using PSCA antibody fragments engineered for optimal imaging properties (high tumor uptake; versatile labeling with multiple imaging or therapeutic moieties; and rapid, controlled systemic clearance) can improve clinical management of prostate cancer along the disease continuum. In this application, we propose to develop universal, multifunctional antibody-based imaging agents for PET and optical detection of PSCA-expressing prostate cancers. We will test them in metastatic, transgenic (mice into which specific genes that promote prostate cancer are introduced) and intraoperative models that mimic the human disease and can predict what will be seen in patients. These studies will guide future clinical trials of these agents. We predict that successful completion of this proposal will help solve the major unmet need for multi-purpose molecular imaging in prostate cancer. Approach: Specific Aim 1: Develop universal optimized cys-diabody and cys-minibody fragments against PSCA for PET imaging of prostate and pancreatic cancer. We have generated high affinity antibody fragments that bind strongly and specifically to PSCA on cancer cells and can image tumors beautifully in early model systems. However, these fragments have certain limitations. For example, they cannot be labeled with more than one imaging or therapeutic agent. Our goal therefore is to engineer these fragments to generate extremely versatile and universally adaptable antibody fragments that can be labeled with any radioisotope or optical agent, including dual labeling with both optical and nuclear probes so that one fragment can be used for PET and optical imaging -- a major innovation with great promise for disease staging and management. Specific Aim 2: Evaluate the ability of lead PSCA fragments to image prostate cancer disease progression in xenograft (human tumors growing in immune-deficient mice) and genetically engineered mouse models of prostate cancer. The standard approach to testing molecular imaging tracers is to image xenografts grown under the skin. However, these do not represent the actual prostate cancer disease process, which is characterized by prostate growth and bone and soft tissue metastases. They also do not model disease initiation and progression. Finally, imaging of a human antigen such as PSCA in the mouse does not assess normal tissue uptake since the PSCA antibodies do not cross-react with the mouse PSCA homologue. In this aim, we will assess the performance of our universal fragments in models of bone and lymph node metastasis. We have also generated a mouse model of prostate cancer that expresses the human PSCA protein, allowing us to evaluate PSCA imaging in the setting of normal PSCA tissue expression, disease progression, and response to therapy. Specific Aim 3: Evaluate the ability of lead PSCA fragments to visualize pr
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510724
Entities
People
- Robert Reiter
Organizations
- United States Army
- University of California, Los Angeles