Synthetic Agonistic Receptor (SAR) (SAR)

The Synthetic Agonistic Receptor (SAR) is a modular, MHC-unrestricted synthetic receptor engineered into autologous T cells to provide a controllable and versatile platform for cancer immunotherapy [2, 12]. Unlike traditional Chimeric Antigen Receptors (CARs) that directly bind tumor antigens, the SAR features an inert extracellular domain (such as EGFRvIII or Cripto-1) that remains inactive until engaged by a bridging bispecific antibody (BiAb) [6, 11]. This BiAb simultaneously binds the SAR and a specific tumor-associated antigen (TAA), such as mesothelin or EpCAM, triggering T cell activation, proliferation, and targeted tumor cell lysis [1, 10]. This design allows for precise control over T cell activity through the dosing and half-life of the BiAb, potentially reducing the risk of systemic toxicity and cytokine release syndrome [2, 5]. Furthermore, the modular nature of the SAR platform enables the targeting of multiple or shifting tumor antigens simply by switching the bispecific antibody adapter, addressing the challenge of tumor heterogeneity and antigen escape in solid malignancies [4, 7].

Other names

SARSynthetic Agonistic Receptor-transduced T cellsSAR-TAdaptor CARModular CAR platform

The bispecific antibody acts as a bridge, simultaneously binding the inert extracellular domain of the Synthetic Agonistic Receptor (SAR) on engineered T cells and a tumor-associated antigen on cancer cells. This cross-linking induces SAR clustering, which triggers intracellular signaling through CD3ζ and CD28 domains, leading to T cell activation, cytokine release, and targeted tumor cell destruction.