# Targeting BCMA in multiple myeloma with a trifunctional NK cell engager

## TL;DR

A new trifunctional NK cell engager called SAR’514 shows strong anti-tumor effects against multiple myeloma by targeting BCMA with minimal side effects.

## Contribution

SAR’514 is a novel trifunctional NK cell engager optimized for BCMA-targeted therapy in multiple myeloma with superior efficacy and low cytokine release.

## Key findings

- SAR’514 demonstrates potent and selective anti-tumor activity in vitro and in vivo.
- It induces minimal cytokine release compared to T cell engagers targeting the same antigen.
- SAR’514 efficiently activates NK cells from multiple myeloma patients and kills resistant malignant cells ex vivo.

## Abstract

Multiple myeloma (MM), the second most common hematologic malignancy, remains incurable, highlighting the need for durable therapies. Natural killer (NK) cell engagers (NKCEs) represent a promising alternative to T cell therapies, offering potent anti-tumor activity with limited cytokine release. SAR445514 (SAR’514) is a trifunctional NKCE that co-engages NKp46 and FcγRIIIa to activate NK cells while targeting B cell maturation antigen (BCMA) on MM cells. After exploring several molecular formats with varied BCMA and NKp46 valency, we selected SAR’514, a monovalent format with enhanced antibody-dependent cellular cytotoxicity (ADCC). SAR’514 has potent and selective anti-tumor activity in vitro and in vivo, outperforming other FcγRIIIa-immune cell engagers, while inducing minimal cytokine release compared to T cell engagers targeting the same antigen. Ex vivo, SAR’514 efficiently activates NK cells from MM patients and induces cytotoxicity against autologous malignant cells, including those resistant to standard therapies. These findings support further development of SAR’514.

•SAR’514 targets BCMA in myeloma and CD16/NKp46 on NK cells via trifunctional design•Various formats and valencies have been evaluated to optimize anti-tumor activity•Monovalency for each binder shows superior efficacy against BCMA+ myeloma cells•SAR’514 outperforms standard-of-care therapies in patient samples ex vivo

SAR’514 targets BCMA in myeloma and CD16/NKp46 on NK cells via trifunctional design

Various formats and valencies have been evaluated to optimize anti-tumor activity

Monovalency for each binder shows superior efficacy against BCMA+ myeloma cells

SAR’514 outperforms standard-of-care therapies in patient samples ex vivo

Tang et al. describe SAR’514, an NK cell engager targeting BCMA in multiple myeloma. This trifunctional molecule demonstrates potent anti-tumor activity in vitro and in vivo with minimal cytokine release and efficiently activates patient NK cells against myeloma cells, including those not responding to daratumumab.