Key Points

  • GPRC5D protein is specifically expressed on the surface of plasma cells

  • GPRC5DxCD3 bispecific antibody can induce T cell-mediated killing of GPRC5D+ cells

T cell-mediated approaches have shown promise in myeloma treatment. However, there are currently a limited number of specific myeloma antigens that can be targeted, and MM remains an incurable disease. G-protein coupled receptor class 5 member D (GPRC5D) is expressed in multiple myeloma (MM) and smoldering multiple myeloma patient plasma cells. Here we demonstrate that GPRC5D protein is present on the surface of MM cells and describe JNJ-64407564, a GPRC5DxCD3 bispecific antibody that recruits CD3+ T cells to GPRC5D+ MM cells and induces killing of GPRC5D+ cells. In vitro, JNJ-64407564 induced specific cytotoxicity of GPRC5D+ cells with concomitant T cell activation and also killed plasma cells in MM patient samples ex vivo. JNJ-64407564 can recruit T cells and induce tumor regression in GPRC5D+ MM murine models which coincide with T cell infiltration at the tumor site. This antibody is also able to induce cytotoxicity of patient primary MM cells from bone marrow which is the natural site of this disease. GPRC5D is a promising surface antigen for MM immunotherapy and JNJ-64407564 is currently being evaluated in a Phase I clinical trial in patients with relapsed or refractory MM (NCT03399799).

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