Discovery of JNJ-87562761, a novel anti-GPRC5D enhanced effector function (eEF) antibody with multiple mechanisms of action for the treatment of multiple myeloma

Abstract Background: Antibody and cellular therapies have reshaped the multiple myeloma (MM) therapeutic landscape in recent years resulting in significantly improved clinical outcomes. These therapies target plasma cell antigens such as CD38, B cell maturation antigen (BCMA) and G-protein coupled receptor family C group 5 member D (GPRC5D). Moreover, monoclonal antibodies (mAbs) such as daratumumab (anti-CD38) demonstrate the effector function (EF) mechanisms: antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC). While EF mAbs targeting CD38 have shown clinical benefit, NK cell fratricide is a known liability due to CD38 expression on NK cells, potentially reducing the full antitumor effect of the ADCC mechanism. Targeting plasma cell-specific antigens in the hematopoietic compartment, such as GPRC5D, with an EF antibody may avoid NK cell fratricide and optimize ADCC activity. Additionally, a strategy to enhance the EF of an anti-GPRC5D antibody may provide improved outcomes for MM patients. Methods We developed JNJ-87562761, a first-in-class anti-GPRC5D enhanced-EF human IgG1 monovalent antibody that targets GPRC5D-positive MM plasma cells. JNJ-87562761 was purposefully designed to elicit ADCP, enhanced-ADCC, and enhanced-CDC. Results JNJ-87562761 induced ADCC against a panel of GPRC5D-positive but not GPRC5D-negative cells and cell lines, which correlated with NK cell activation. In contrast to an anti-CD38 mAb, no NK cell fratricide was observed with JNJ-87562761. ADCP and CDC were observed against GPRC5D-positive cell lines, which included daratumumab CDC-resistant cell lines. JNJ-87562761 demonstrated significant antitumor activity in vivo against a disseminated OPM-2-luciferase (luc) model, as well as superior efficacy compared to daratumumab in a disseminated MM.1S-luc model in NSG-IL15 mice engrafted with human NK-92.CD16 cells. Conclusion JNJ-87562761 demonstrated potent in vitro activity with 3 distinct mechanisms as well as potent in vivo activity in 2 MM xenograft models. The safety and preliminary efficacy of JNJ-87562761 is currently being evaluated in a Phase 1 study of participants with relapsed/refractory MM (NCT06604715).