Gamma-delta T-cell receptor and Interleukin-3 receptor subunit alpha (CD123) bispecific interface (γδ TCR/CD123)

The gamma-delta (γδ) T-cell receptor and Interleukin-3 receptor subunit alpha (CD123) bispecific interface is a therapeutic target complex designed to redirect the cytotoxic activity of γδ T cells toward malignant cells. CD123 is a cell surface protein frequently overexpressed on leukemic stem cells and blasts in myeloid malignancies, such as acute myeloid leukemia (AML), making it a prominent target for immunotherapy (Lava Therapeutics, 2023). The Vγ9Vδ2 T-cell receptor is the most abundant γδ TCR subset in human blood and possesses natural anti-tumor properties that are independent of MHC-peptide presentation. Bispecific antibodies, known as Gammabodies (e.g., LAVA-051), facilitate the cross-linking of these two receptors, resulting in the formation of a cytolytic synapse and subsequent tumor cell death (ClinicalTrials.gov, NCT04887012). This approach is intended to provide a potent and selective immune response against CD123-positive hematologic cancers while potentially reducing the risk of systemic toxicity compared to conventional alpha-beta T-cell engagers. Clinical trials are currently exploring the efficacy and safety of targeting this interface in patients with relapsed or refractory AML, chronic myelomonocytic leukemia, and multiple myeloma (de Bruin et al., 2021).

Other names

CD123 x Vγ9Vδ2 T-cell receptor interfaceIL-3RA/γδ TCR complexCD123-Gammabody target interfaceBispecific gamma-delta T-cell engager interface

The target interface is formed by a bispecific antibody that simultaneously binds the Vγ9Vδ2 T-cell receptor and the CD123 antigen on tumor cells, facilitating the formation of an immunological synapse that triggers T-cell degranulation and MHC-independent lysis of the target cell.