Antibody-coupled T-cell receptor (ACTR) signaling complex (ACTR)

The Antibody-coupled T-cell receptor (ACTR) signaling complex is a synthetic chimeric receptor platform designed to redirect T-cell specificity using monoclonal antibodies (mAbs). The construct typically features the extracellular domain of the high-affinity CD16 (FcγRIIIa-V158) receptor linked to intracellular signaling components of the T-cell receptor (TCR) complex, most commonly the CD3ζ chain and a co-stimulatory domain like 4-1BB (Kudo et al., 2014, Cancer Res). Unlike standard Chimeric Antigen Receptors (CARs) that are fixed to one antigen, ACTR-engineered T cells are universal and can target any cell type for which a clinical-grade mAb exists (Unum Therapeutics, 2020). When the co-administered mAb binds to its target antigen on a tumor cell, the ACTR's CD16 domain captures the antibody's Fc region, triggering the TCR/CD3-associated signaling cascade (Motohashi et al., 2019, Frontiers in Immunology). This activation leads to the release of cytotoxic granules and cytokines, resulting in the lysis of the target cell. This technology has been clinically evaluated in B-cell malignancies (e.g., ACTR087 with rituximab) and is being explored for solid tumors (NCT02776813). The modular nature of the ACTR system allows for the potential treatment of multiple indications by simply switching the antibody component.

Other names

CD16-CD3ζ chimeric receptorAntibody-Coupled T-cell ReceptorACTR T-cell signaling complexCD16V-BB-ζUniversal CAR-T

The ACTR signaling complex functions by binding the Fc region of a co-administered monoclonal antibody via its extracellular CD16 domain. This binding event clusters the intracellular CD3ζ and 4-1BB signaling domains, mimicking the natural T-cell receptor activation signal and inducing a potent cytotoxic response against cells labeled by the antibody (Kudo et al., 2014, Cancer Res).