CD3engaging

CD3-engaging therapies are a class of immunotherapies that activate T cells by binding CD3, a component of the T-cell receptor complex, on T cells. Most designs are bispecific, with one arm recognizing CD3 and the other recognizing a tumor-associated antigen on target cells. By bringing T cells into proximity with tumor cells, these agents trigger T-cell activation, formation of an immunological synapse, and release of cytotoxic mediators such as perforin and granzymes, leading to target cell death. This mechanism often works independently of antigen presentation on MHC molecules, enabling T cells to target cells that evade conventional T-cell recognition. However, CD3 engagement can cause systemic T-cell activation and cytokine release, requiring careful dosing and monitoring.

Formats include BiTEs (bispecific T-cell engagers) composed of two single-chain variable fragments linked together, as well as full-length bispecific antibodies, DARTs, and TandAbs; some constructs are trifunctional, designed to recruit Fc receptor-bearing accessory cells. Notable examples include blinatumomab, a CD3xCD19 BiTE approved for B-cell acute lymphoblastic leukemia; teclistamab, a BCMAxCD3 bispecific antibody approved for multiple myeloma; and catumaxomab, a CD3xEpCAM antibody with trifunctional activity that has been used in Europe for malignant ascites.

Administration varies by construct; short-half-life BiTEs often require continuous infusion, while others may use subcutaneous or intravenous dosing with step-up regimens to mitigate adverse events. Safety concerns include cytokine release syndrome and neurotoxicity, as well as on-target off-tumor toxicities when the target antigen is expressed on normal tissues. CD3-engaging agents are in active clinical development across hematologic cancers and solid tumors, with ongoing trials exploring combinations to enhance efficacy and safety.