G protein-coupled receptor class C group 5 member D and CD3 T-cell coreceptor (GPRC5D–CD3)

GPRC5D–CD3 is a therapeutic target complex utilized primarily in the treatment of multiple myeloma through bispecific T-cell engagers. G protein-coupled receptor class C group 5 member D (GPRC5D) is an orphan receptor that is highly and selectively expressed on the surface of malignant plasma cells, while its expression in healthy tissue is restricted to hard keratinized structures like hair follicles and the tongue [1, 3]. CD3 is a critical co-receptor on T cells involved in activating the immune response [6, 13]. Bispecific antibodies targeting this pair work by simultaneously binding GPRC5D on tumor cells and CD3 on T cells, creating an immunological synapse that redirects T-cell cytotoxic activity against the myeloma cells [7, 11]. This mechanism is independent of major histocompatibility complex (MHC) presentation, allowing it to bypass common tumor escape mechanisms [1, 4]. Drugs like talquetamab have demonstrated significant clinical efficacy in relapsed or refractory multiple myeloma, providing a vital option for patients who have failed other therapies, including those targeting BCMA [10, 12]. However, the target's presence in keratinized tissues leads to unique on-target, off-tumor toxicities such as skin rashes, nail changes, and taste disturbances [11, 26].

Other names

GPRC5D/CD3GPRC5D x CD3GPRC5D-CD3 bispecific T-cell engagerGPRC5D-CD3 T-cell redirecting antibody

T-cell redirection and engagement