Targeting BCMA in multiple myeloma with a trifunctional NK cell engager

Area of Science:

• Oncology
• Immunology
• Hematology

Background:

• Multiple myeloma (MM) is a prevalent, incurable hematologic malignancy.
• There is a critical need for durable and effective therapeutic strategies.
• Natural killer (NK) cell engagers (NKCEs) are emerging as a promising alternative to T cell-based therapies due to their potent anti-tumor activity and reduced cytokine release.

Purpose of the Study:

• To evaluate SAR445514, a trifunctional NKCE targeting BCMA on MM cells and engaging NKp46 and FcγRIIIa on NK cells.
• To assess the anti-tumor efficacy and safety profile of SAR445514 in preclinical models.
• To investigate the potential of SAR445514 in activating patient-derived NK cells against autologous malignant cells.

Main Methods:

• Exploration of various molecular formats for SAR445514, focusing on BCMA and NKp46 valency.
• In vitro and in vivo studies to determine anti-tumor activity and cytokine release.
• Ex vivo analysis of NK cell activation and cytotoxicity using peripheral blood mononuclear cells from MM patients.

Main Results:

• SAR445514, a monovalent NKCE, demonstrated enhanced antibody-dependent cellular cytotoxicity (ADCC).
• The agent exhibited potent and selective anti-tumor activity in vitro and in vivo, surpassing other FcγRIIIa-immune cell engagers.
• Minimal cytokine release was observed with SAR445514 compared to T cell engagers.
• Ex vivo studies showed efficient NK cell activation and cytotoxicity against autologous MM cells, including therapy-resistant cases.

Conclusions:

• SAR445514 displays significant preclinical efficacy as an NKCE for multiple myeloma.
• Its ability to activate patient NK cells and target malignant cells supports its therapeutic potential.
• These findings provide a strong rationale for the continued clinical development of SAR445514.