Abstract I18: Retooling a blood-based biomarker into a theranostic agent

Abstract

Abstract Over the past 30 years, our ability to noninvasively diagnose, localize, and treat many forms of cancer has grown significantly. However, the biomolecular basis of many malignancies—most notably pancreatic cancer—remains convoluted, and technical advances have not translated to significantly improved survival rates. This is reflected in 1- and 5-year survival rates of 27% and 6%, respectively, for pancreatic cancer diagnoses. Given the tremendous current focus on the creation of new therapeutics for treating pancreatic cancer, the development of companion technologies that can safely, accurately, and unambiguously aid in the early diagnosis, staging, and treatment monitoring of pancreatic cancer is a vitally important—yet unmet—clinical need. The remarkable specificity and selectivity of antibodies for cancer biomarkers have made immunoglobulins some of the most flexible and adaptable tools in modern medicine. For therapeutic purposes, a wide range of nonlabeled antibodies has now entered the clinic. Antibody-based PET and SPECT imaging agents are not far behind. For example, an array of 89Zr-labeled radioimmunoconjugates has shown significant promise in both preclinical and clinical studies. CA19-9 levels in the serum are routinely used for diagnosis, risk stratification, and follow-up of PDAC. While CA19-9 is a shed antigen entering the circulation, the concentration is much higher in the tumor tissue, making it a potential target for in vivo imaging with radiolabeled antibodies. Our studies show that a tumor antigen secreted to the circulation can be used for sensitive detection of primary tumors and metastatic disease by immuno-PET. For example, in proof-of-concept preclinical studies, we were able to visualize pancreatic cancer xenograft and orthotopic models of early- and late-stage disease with excellent tumoral uptake and target-to-non-target ratios using the 89Zr-labeled human monoclonal antibody [89Zr]Zr-DFO-HuMab-5B1 (MVT-2163, NCT02687230). This 5B1 radioimmunoconjugate scaffold has also been deployed with therapeutic beta- and alpha-emitting radionuclides, creating an effective radiotherapeutic paradigm for the imaging and therapy of PDAC. In conclusion, our study shows that a tumor antigen secreted by PDAC to the circulation can be used for sensitive detection of primary tumors and metastatic disease by immuno-PET. This significantly broadens the number of molecular targets that can be used for PET imaging and provides new opportunities for noninvasive characterization of tumors in pancreatic cancer patients. Citation Format: Jason S. Lewis. Retooling a blood-based biomarker into a theranostic agent [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr I18.