Targeting the Tumor Stroma Using a Monoclonal Antibody Platform Technology
2021-04
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Targeting the Tumor Stroma Using a Monoclonal Antibody Platform Technology
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2021-04
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Abstract
1 in 9 men will be diagnosed with prostate cancer during their lifetime and it remains the second leading cause of cancer death among American men. Men who fail standard-of-care androgen deprivation therapy (ADT) and progress to metastatic castration resistant prostate cancer (mCRPC) are left with few therapeutic options. Current second line therapies only provide a small survival benefit and there is a critical unmet need for new and innovative approaches to treat mCRPC. Imaging is a crucial aspect of mCRPC clinical management used for the detection of recurrent or distant disease. The development of new therapies is also dependent on accurate imaging modalities for patient staging and evaluating treatment response. Our research shows fibroblast activation protein alpha (FAP) is a relevant target for imaging and treating mCRPC. FAP is emerging as the next pan-cancer target given its upregulated expression in cancer associated fibroblasts (CAFs) and localization to the tumor microenvironment. Here we document the discovery and validation of a monoclonal antibody that selectively binds to FAP. The lead antibody, B12, was identified from a naïve murine single-chain variable fragment antibody phage display library screened against recombinant human FAP. The heavy and light chains of B12 were cloned into full-length human immunoglobulin 1 vectors and expressed as a chimeric monoclonal antibody (B12 mAb). B12 mAb was shown to detect FAP expression in cell lines and was rapidly internalized by FAP-expressing cells in vitro. B12 mAb demonstrated cross-reactivity with murine FAP, but not with the highly homologous protease human dipeptidyl peptidase IV. PET/CT imaging with [89Zr]Zr-B12 mAb demonstrated high tumor uptake and long-term retention of the probe in several preclinical animal models. Furthermore, we show its superiority to other clinically investigated imaging probes which suggests clinical translation of B12 mAb as a non-invasive mCRPC imaging probe. Next, we evaluated the therapeutic potential of B12 mAb as an antibody-dependent cell-mediated cytotoxicity (ADCC) inducing agent in combination with an engineered NK-92MI CD64 cell therapy. The immunotherapy demonstrated selective cytotoxicity in vitro and treatment effectively controlled tumor growth in an animal model. Furthermore, we engineered B12 mAb as an antibody-drug conjugate (ADC) and showed cytotoxic effect in several in vitro and in vivo solid tumor models. Overall, this research represents a platform technology for the development of theranostics targeting FAP that could provide urgently needed therapies and imaging probes for mCRPC patients.
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University of Minnesota Ph.D. dissertation. April 2021. Major: Pharmacology. Advisor: Aaron LeBeau. 1 computer file (PDF); ix, 184 pages.
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Hintz, Hallie. (2021). Targeting the Tumor Stroma Using a Monoclonal Antibody Platform Technology. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/256988.
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