Human epidermal growth factor receptor 2–Trastuzumab–Antibody-coupled T-cell receptor complex (HER2–Trastuzumab–ACTR)

The composite interface of Human Epidermal Growth Factor Receptor 2 (HER2), Trastuzumab, and the Antibody-Coupled T-cell Receptor (ACTR) represents a tripartite therapeutic assembly designed to redirect T-cell specificity toward HER2-positive malignancies (Kudo et al., 2014). In this system, T cells are genetically engineered to express ACTR, a chimeric receptor comprising the extracellular domain of the high-affinity Fc receptor CD16 (FcγRIIIA) fused to intracellular costimulatory and activation domains such as 4-1BB and CD3ζ. Trastuzumab, a monoclonal antibody, acts as a molecular bridge by binding to domain IV of the HER2 receptor on the surface of tumor cells while its Fc region is simultaneously engaged by the ACTR-expressing T cells (Shirasu et al., 2012). This tripartite interaction facilitates the formation of a stable immunological synapse, triggering T-cell activation, the release of cytotoxic granules such as perforin and granzymes, and the production of pro-inflammatory cytokines like IFN-gamma and TNF-alpha. This modular platform allows for the targeting of various tumor antigens by pairing ACTR T cells with different tumor-specific antibodies, though it necessitates careful management of toxicities such as cytokine release syndrome and potential on-target off-tumor effects in tissues with physiological HER2 expression (Cogent Biosciences, 2021).

Other names

HER2-Trastuzumab-ACTR complexACTR087-Trastuzumab complexAntibody-Coupled T-cell Receptor interfaceCD16-chimeric antigen receptor complexHER2-Trastuzumab-CD16-T-cell synapse

The ACTR T cell expresses a chimeric receptor (typically CD16-4-1BB-CD3ζ) that binds the Fc region of the HER2-targeting antibody Trastuzumab; Trastuzumab simultaneously binds to the HER2 receptor on tumor cells, creating a physical bridge that induces T-cell activation and directed tumor cell lysis (Kudo et al., 2014; Shirasu et al., 2012).