Abstract 5908: Angiosarcoma growth inhibition by targeting Doppel, a specific endothelial marker, with an antibody drug conjugate
Authors: Byoungmo Kim, Ha Kyeong Lee, Youngro Byun, Yoon Gun Ko, Sang Yoon Kim
Journal: Cancer Research (2024)

Abstract Rare cancers are defined as cancers with an annual incidence rate lower than 15/100,000 by the National Cancer Institute. Despite what the terminology may suggest, rare cancers collectively are neither very rare, accounting for about a quarter of all cancers, nor less deadly than other forms of cancer. In fact, the comparative lack of research and case studies of rare cancers compared to other forms of cancer provides both an obstacle and a unique opportunity when it comes to drug development. While finding adequate animal models and cell lines to study the disease may be more difficult, the development of innovative treatment options for rare cancers is often incentivized by the Orphan Drug Act, accelerating approval from the FDA and acting as a gateway to approval for other indications. One such rare cancer is angiosarcoma, a rare cancer that originates from the endothelium. Angiosarcoma represents about 1% of total sarcomas and can develop anywhere in the body but occurs mainly in the breast, liver, or skin of the head and neck area. Angiosarcoma is characterized by a high metastasis rate of 16% to 44%, which results in a dismal prognosis, with overall survival ranging from 6 to 16 months. Considering the high reoccurrence rate and high metastatic potential of angiosarcoma, chemotherapeutic options seem to be the obvious choice. However, mainstream chemotherapies have failed to have long-term therapeutic effects. Another approach is the use of anti-angiogenic therapy, which proved effective but was unable to lead to a complete response. Herein, we describe a novel endothelial cell-targeting therapy option for the treatment of angiosarcoma. Previously, we have discovered Doppel, a 23 kDa GPI-anchored protein that is expressed specifically in the endothelium of tumor-associated blood vessels, except for the testis. Considering the fact that angiosarcoma is a rapidly growing tumor of endothelial origin, we hypothesized that Doppel might be a viable target for both the detection and treatment of angiosarcoma. We subsequently developed an antibody-drug conjugate to Doppel by conjugating a human antibody to MMAE using a unique linker, KGDEVD. When tested on xenografts of the angiosarcoma cell lines KU-CAS3 and KU-CAS5, the tumors responded extremely well to anti-Doppel ADC treatment. Most surprisingly, even tumors exceeding 1 cm^3 went into complete remission after 6 doses of the ADC. Thus, we delved deeper into the mechanism of action behind the ADC. ADC internalization was demonstrated using confocal microscopy. Apoptosis assays show that the ADC is capable of inducing apoptosis and caspase 3 expression in angiosarcoma cells, a crucial step in the activation of the KGDEVD linker. In-vitro toxicity assays of the ADC against KU-CAS3 show an IC50 value of 7.94 nM, much lower compared to normal endothelial cell lines. Citation Format: Byoungmo Kim, Ha Kyeong Lee, Youngro Byun, Yoon Gun Ko, Sang Yoon Kim. Angiosarcoma growth inhibition by targeting Doppel, a specific endothelial marker, with an antibody drug conjugate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5908.