Anti-KIT antibody, briquilimab, induces mast cell apoptosis and depletion in nonhuman primates.

Abstract

Mast cells (MCs) play a critical role in many allergic and inflammatory reactions in healthy and disease states. Current therapeutic strategies to treat MC-mediated diseases aim to suppress MC activation by using small molecule inhibitors or antibodies targeting specific signaling receptors on MCs. However, these strategies require long-term drug exposure, which has inherent limitations including increased patient burden and potential toxicity. Moreover, the redundancy between multiple signaling pathways concomitantly regulating MC activation can lead to insufficient MC suppression. We sought to develop a novel therapeutic strategy using briquilimab, an aglycosylated anti-KIT mAb, to deplete MCs via KIT signaling inhibition. Inhibition of KIT by briquilimab was evaluated in vitro in KIT-expressing cell lines and primary human MCs. Briquilimab safety, pharmacokinetics, and MC depletion were evaluated in nonhuman primates (NHPs). Briquilimab potently blocked stem cell factor (SCF) ligand binding to KIT and inhibited SCF/KIT signaling and primary MC degranulation and survival, leading to MC apoptosis via the PI3K/AKT pathway in vitro. Additionally, aglycosylation of briquilimab mitigated unwanted MC activation. In NHPs, single- and multi-dose high, long-term exposure to briquilimab was well tolerated with mild to moderate, but reversible adverse effects and successfully depleted various tissue MCs, including lung, skin, and colon, in a dose-dependent manner. Briquilimab effectively inhibits SCF/KIT signaling and induces MC apoptosis, leading to profound and durable MC depletion in NHPs, and may provide a safe and novel therapeutic option to treat MC-mediated diseases.