Abstract 2710: Developing a novel doppel-targeting antibody-drug conjugate (ADC) for solid cancer

Abstract

Abstract The development of anticancer therapeutics has two main objectives: enhancing efficacy and lowering toxicity. Given these goals, an antibody-drug conjugate (ADC), which delivers highly cytotoxic payloads to tumor tissue specifically, is one of the most favorable treatments. ADC is a growing drug delivery technology, with twelve FDA-approved ADCs as of 2022. Most of ADCs in use today target particular molecules for hematologic malignancies. ADCs for solid tumors are relatively in the early stages of development due to the lack of well-defined solid tumor-specific target molecules. To put it another way, the market has an enormous unmet demand for solid cancer-specific ADCs. As seen by recently approved ADCs and ADCs in clinical trials, finding novel targets for solid cancer has drawn a lot of attention in current development trends. Doppel, a prion-like protein, is transiently expressed in the neonatal brain endothelium; in adults, it is exclusively present in testicular cells. In our previous study, we found that Doppel is specifically expressed only in tumor tissues and tumor blood vessels, but not in normal adult tissues; its expression promoted cancerous blood vessel formation. Then, we generated several monoclonal antibodies which target Doppel; the most effective clone was selected. We observed that angiogenesis-related factors were suppressed in the tumor endothelial cells treated with the Doppel-targeting antibody. In addition, we injected the antibody into mouse models and visualized the tumor-targeting efficacy using in vivo imaging system (IVIS); the antibody accumulates in the tumor significantly higher compared to non-targeting IgG. We suggest what we believe to be a novel strategy to target a molecular marker that is altered and overexpressed specifically in tumor tissues and tumor endothelial cells. Based on the above discoveries, we have developed the Doppel-targeting ADC; this drug, according to our hypothesis, will target only cancer cells that express Doppel and result in apoptotic cell death. The ADC has demonstrated remarkable anticancer efficacy in both cell and mouse models, although it is still in the early stages of research. We believe that the enhanced specificity for targeting tumors, the high tumor-to-organ ratio, and the bystander killing effect would make this Doppel-targeting ADC a successful “solid cancer-specific” one. Citation Format: Ha Kyeong Lee, Byoungmo Kim, Seho Kweon, Jeong Uk Choi, Sang Yoon Kim, Youngro Byun. Developing a novel doppel-targeting antibody-drug conjugate (ADC) for solid cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2710.