Preclinical characterization of S095029, a novel clinical-stage Fc-attenuated NKG2A-blocking antibody for cancer immunotherapy

Abstract

Natural killer group 2 family of receptor A (NKG2A) and its ligand human leukocyte antigen-E (HLA-E) are increasingly recognised as an important immune checkpoint restraining lymphocyte populations involved in cancer immunity. Recent clinical studies investigating dual NKG2A/programmed death ligand 1 (PD-L1) blockade versus anti-PD-L1 monotherapy suggest that the combination may be beneficial in immunotherapy-responsive disease settings. To date, clinical safety and efficacy results are only available for a single NKG2A-blocking monoclonal antibody (mAb). Here, we report on the generation and preclinical characterization of a novel NKG2A-blocking agent. The fully human Fc-attenuated immunoglobulin G1 mAb S095029, selected via functional antibody repertoire screening, was tested against benchmark clinical-stage antibodies in in vitro binding and functional NKG2A/HLA-E blockade assays. S095029 bound human NKG2A with a low nanomolar-range affinity and efficiently reversed the inhibitory effects of NKG2A/HLA-E interaction. As a single agent, S095029 enhanced the activation, cytotoxicity, and cytokine secretion of natural killer (NK) and γδ T cells. S095029 improved NK cell antibody-dependent cellular cytotoxicity and other effector functions triggered by Fc-competent mAbs. In vivo investigations in syngeneic mouse models showed that S095029 inhibited tumour growth by harnessing the anti-tumour activity of both NK and CD8+ T cells. Overall, our results support the clinical development of S095029 in immuno-oncology-responsive tumour settings with adequate HLA-E expression. Phase 1b/2 dose escalation studies are currently underway to evaluate S095029 in combination with anti-PD-1 in non-small cell lung cancer and gastric cancer.