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Abstract Multiple myeloma (MM), characterized by clonal accumulation of malignant plasma cells in the bone marrow, is the second most prevalent hematopoietic malignancy. Despite emerging therapies, MM remains an incurable disease with a 5-year overall survival of 56% for relapsed and/or refractory disease (RRMM) patients. Thus, innovative approaches that would be safe and potent are required. GPRC5D (G Protein-Coupled Receptor Class C Group 5 Member D) is an orphan GPCR protein involved in keratin synthesis with limited expression in healthy tissues. GPRC5D is expressed at very high prevalence among MM patients and its expression on tumor cells is maintained after treatments with standard of care agents such as anti-CD38, or BCMA-targeting therapies. The ability of NK cells to kill tumor cells leaving other cells unharmed and to induce minimal pro-inflammatory cytokine release as compared to T cell-based therapies, makes NK cells ideal immune cells for a safe and efficacious therapeutic approach. Like Sarclisa®, other therapies engaging NK cells and mediating tumor cell killing through antibody-dependent cell-mediated cytotoxicity (ADCC) mechanism have demonstrated their efficacy in clinic. Here we report the design, preclinical characterization, and development of a novel anti-GPRC5D antibody inducing potent cytotoxic activity against MM cells. SAR446523 is an IgG1-based antibody with an engineered Fc domain for enhanced ADCC function and targeting human GPRC5D on tumoral plasma cells. SAR446523 demonstrated high affinity for GPRC5D target and increased affinity for both high and low affinity FCGR3A-158V and 158F variants of CD16a receptor. The ability of SAR446523 to induce ADCC in vitro was assessed in a panel of MM cell lines exhibiting low, medium, and high GPRC5D expression. SAR446523 induced strong potency against all tested cell lines (picomolar range), regardless of the levels of GPRC5D. In addition, SAR446523 induced higher cytotoxic activity compared to a clinical benchmark compound. This anti-tumor activity was associated with very low IL-6, TNFa and IFNg pro-inflammatory cytokine release, much lower compared to a CD3xGPRC5D T-cell engager in in vitro assay using human peripheral blood mononuclear cells (PBMC) in presence of GPRC5D positive cells. In addition, the in vivo anti-tumor activity of SAR446523 was investigated in a NK humanized NOG huIL15 transgenic mouse model bearing disseminated MM cells. SAR446523 led to a robust antitumoral efficacy with a significant improved mouse survival. These data demonstrating potent anti-tumor activity and favorable safety profile of this novel anti-GPRC5D antibody suggest that SAR446523 may be a promising therapy for patients with RRMM and provide consistent support for clinical development. Citation Format: Helene Bonnevaux, Elisabeth Remy, Theo Pizette, Sophie Bouvier, Klervi Desrumeaux, Laurent Bassinet, Celine Nicolazzi, Pauline Rettman, Zandra Klippel, Marco Meloni, Marielle Chiron, Angela Virone-Oddos. Pre-clinical development of a novel anti-GPRC5D inducing potent anti-tumor effect through enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) for multiple myeloma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 2727.
Bonnevaux et al. (Fri,) studied this question.