Abstract 2977: A first-in-class anti-HER2/TROP2 bispecific antibody-drug conjugate (YH012) exhibits potent anti-tumor efficacy

Abstract Antibody-drug conjugates (ADC) are a therapeutic modality that combines the advantages of potent killing from small molecule cytotoxic payload and highly specific targeting from monoclonal antibodies. By targeting dual tumor-associated antigens (TAA), the bispecific ADC (BsADC) serves as a promising therapeutic strategy that can further increase tissue specificity and selectivity. HER2 and TROP2 are two TAAs that are commonly expressed and co-expressed by multiple tumor types, including gastric, colorectal, bladder, breast, and non-small-cell lung cancer (NSCLC). Of note, TROP2 expression has been detected in a wide range of HER2-low expressing tumors. These data led us to predict that targeting HER2 and TROP2 with a BsADC would provide therapeutic benefit, especially for patients with HER2-low cancers. Hence, we generated YH012, a first-in-class BsADC that contains a fully human bispecific anti-HER2/TROP2 antibody conjugated with monomethyl auristatin E (MMAE) via a protease-cleavable linker. In vitro, YH012 demonstrated enhanced affinity, internalization, and tumor selectivity compared to its parental monoclonal and monovalent anti-HER2 or anti-TROP2 antibodies. In vivo, YH012 showed strong anti-tumor activity in multiple cell line-derived and patient-derived xenografts (CDX and PDX) of NSCLC, gastric, pancreatic, and breast cancer. Moreover, YH012 exhibited superior anti-tumor efficacy than benchmark antibodies in both HER2-positive and HER2-low xenograft models, indicating that YH012 has a potent and broad therapeutic effect. In summary, YH012 has the advantages of increased potency, tissue specificity, and reduced toxicity as a novel BsADC that can be further exploited to treat HER2 and TROP2 co-expressing tumors, especially HER2-low tumors. Citation Format: Chengzhang Shang, Gao An, Yuming Guo, Ellen Zhang, Qingcong Lin, Yi Yang. A first-in-class anti-HER2/TROP2 bispecific antibody-drug conjugate (YH012) exhibits potent anti-tumor efficacy [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 2977.