GPRC5D x CD28

Class

Costimulatory bispecific antibody

Pathway

Bridges GPRC5D on myeloma cells with the CD28 costimulatory receptor on T cells, providing a second signal that amplifies T-cell activation (typically used alongside a CD3-engaging agent rather than as monotherapy)

GPRC5D is an orphan G-protein-coupled receptor whose expression is largely restricted to malignant plasma cells in multiple myeloma and to hair follicle tissue, making it an attractive tumor marker for antibody-based therapies. This mechanism is a costimulatory bispecific antibody that links GPRC5D on myeloma cells to CD28, a receptor on T cells that supplies the 'second signal' required for full T-cell activation. In normal immunity, T cells require both an antigen-recognition signal and a costimulatory signal to become fully activated, proliferate, and sustain their killing activity. Agents that engage CD3 on T cells and redirect them to tumor antigens supply the first signal alone, which can leave T cells prone to exhaustion or produce only partial activation. By bridging GPRC5D and CD28, this molecule delivers costimulation specifically at the tumor site, intended to amplify and sustain the response generated by a CD3-engaging partner drug rather than to act alone. This combination approach is being explored in multiple myeloma, where enhancing T-cell engagement without relying on a single signaling pathway may improve depth and durability of anti-tumor immune responses while potentially allowing lower doses of the CD3-directed component.