Human epidermal growth factor receptor 2 and Cluster of differentiation 3 complex (HER2-CD3)

The HER2–CD3 interface refers to the physical and functional coupling of Human Epidermal Growth Factor Receptor 2 (HER2) on tumor cells with the Cluster of Differentiation 3 (CD3) complex on T-cells [UniProt P04626, UniProt P07766]. This interface is typically facilitated by bispecific antibodies or T-cell engagers designed to recruit the immune system directly to malignant cells [Slaga et al., 2018]. HER2 is a proto-oncogene receptor tyrosine kinase that is frequently overexpressed in breast, gastric, and esophageal cancers, driving uncontrolled cell proliferation [UniProt P04626]. CD3 is a multi-subunit protein complex that serves as a critical co-receptor for the T-cell receptor, mediating the signal transduction required for T-cell activation [UniProt P07766]. When a therapeutic agent bridges these two molecules, it creates an artificial immunological synapse that triggers the release of cytotoxic granules, such as perforin and granzymes, from the T-cell into the tumor cell [Slaga et al., 2018; Kiewe et al., 2006]. This mechanism of action, known as redirected T-cell cytotoxicity, allows for the destruction of cancer cells independently of Major Histocompatibility Complex (MHC) presentation [Kiewe et al., 2006]. Clinical applications of targeting this interface aim to provide potent anti-tumor activity in patients who have progressed on standard HER2-targeted therapies like trastuzumab [ClinicalTrials.gov, 2024]. However, the approach carries risks such as cytokine release syndrome and potential 'on-target, off-tumor' toxicity in healthy tissues that express low levels of HER2, such as the heart and lungs [Slaga et al., 2018; ClinicalTrials.gov, 2024].

Other names

HER2/CD3ERBB2/CD3HER2-T-cell engager targetHER2-TDB interfaceHER2-CD3 bispecific target

Redirected T-cell cytotoxicity (RTCC) through the formation of a cytolytic synapse between HER2-positive tumor cells and CD3-positive T-cells, leading to MHC-independent tumor cell lysis [Slaga et al., 2018; Kiewe et al., 2006].