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

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.

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.

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.

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).