Trophoblast cell-surface antigen 2 and Human epidermal growth factor receptor 3 (TROP2/HER3)

TROP2/HER3 is a dual-antigen target utilized in the development of bispecific antibody-drug conjugates (ADCs) for the treatment of various solid tumors [11, 17]. TROP2 (Trophoblast cell-surface antigen 2) is a calcium-signal transducer overexpressed in many epithelial cancers, where it promotes tumor growth and metastasis [11, 33]. HER3 (Human epidermal growth factor receptor 3) is a member of the ErbB family that lacks intrinsic kinase activity but serves as a critical co-receptor for oncogenic signaling and therapy resistance [11, 23]. By targeting both antigens simultaneously, bispecific ADCs aim to overcome tumor heterogeneity and bypass resistance mechanisms that often limit the efficacy of single-antigen targeting [21, 24]. Upon binding to the tumor cell surface, the bispecific ADC is internalized through receptor-mediated endocytosis, releasing a potent cytotoxic payload—typically a topoisomerase I inhibitor—that induces DNA damage and cell death [17, 29]. Clinical development of TROP2/HER3-targeted agents, such as JSKN016, is currently focused on indications with high unmet needs, including triple-negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC) [22, 26].

Other names

TACSTD2/ERBB3TROP-2/ErbB3EGP-1/ErbB3M1S1/ERBB3Trophoblast cell-surface antigen 2/Human epidermal growth factor receptor 3

Dual binding to TROP2 and HER3 on tumor cells, receptor-mediated endocytosis, lysosomal degradation, release of cytotoxic payload (topoisomerase I inhibitor), induction of DNA damage and apoptosis, and bystander effect.