Abstract LB214: A first-in-class bispecific antibody-drug conjugate (DM002) targeting HER3 and the juxtamembrane domain of MUC1

作者：Yifu Zhang, Chenzhang Shang, Nannan Wang, Gao An, Ellen Zhang, Qingcong Lin, Yi Yang · 发表于：Cancer Research · 年份：2023 · DOI：10.1158/1538-7445.am2023-lb214 · 被引用次数：4 · 研究领域：Monoclonal and Polyclonal Antibodies Research、Glycosylation and Glycoproteins Research、Advanced Biosensing Techniques and Applications

Abstract Despite the entry of new anti-cancer drugs into the market, there were more than 10 million deaths from cancer globally in 2021, with cancers of the lung, stomach, breast, and pancreas contributing to the most cancer-related deaths in China and the USA. Accordingly, there is an urgent need for improved therapeutic interventions. Antibody-drug conjugates (ADC) are novel drugs that exploit the specificity of a monoclonal antibody for target antigens expressed on cancer cells in order to achieve targeted delivery of a potent cytotoxic payload. More recently, bispecific ADCs (BsADC) targeting two tumor-associated antigens (TAA) have been developed to further amplify tumor cell specificity while minimizing toxicity to normal tissue, thus allowing for broader therapeutic windows. HER3 and MUC1 are two TAAs that are commonly expressed/co-expressed on multiple tumor types, including lung, gastric, breast and pancreatic cancer; however, neither antigen has been successfully targeted by effective drugs: of the candidates targeting HER3 antigen being evaluated in human clinical studies, most are well-tolerated, but with limited efficacy. On the other hand, high levels of MUC1 in diseased tissues can undergo auto-proteolysis, so that drugs targeting the MUC1-N region will be neutralized before reaching the tumor tissues, thereby limiting the recognition of tumor cells. To overcome these challenges, we generated fully human bispecific antibody candidates with human-monkey cross-s...