LAUSR

NKG2A and its ligand HLA-E are increasingly recognized as an important immune checkpoint restraining multiple lymphocyte populations involved in cancer immunity. Initially described as an NK cell inhibitory receptor, NKG2A’s role in regulating T-cell functions has recently come to the fore and is increasingly viewed as a key component of its immune suppressive functions. In addition, clinical studies have also provided proof-of-concept evidence for the superiority of dual NKG2A/PD-L1 blockade over anti-PD-L1 monotherapy. As of now clinical safety and efficacy results are only available for a single NKG2A-blocking antibody. This is in contrast with other immune checkpoint receptors (e.g., PD-1) where multiple blocking agents with different pharmacological properties have been assessed in the clinic, thereby providing a broad assessment of the target therapeutic potential and benefit to patients. Here, we report the generation and preclinical characterization of a novel monoclonal antibody (mAb) disrupting the NKG2A/HLA-E interaction. The Fc-attenuated IgG1 mAb S095029 binds NKG2A with a nM-range affinity and reverses the inhibitory effects of the NKG2A/HLA-E interaction in several experimental models, both in vitro and in vivo. As a single agent S095029 enhanced the killing activity and cytokine secretion of NK and γδ T-cells in co-culture with cancer cell lines of multiple tissue origins. We also show that S095029 increased the antibody-dependent cellular cytotoxicity (ADCC) mediated by Fc-competent mAbs in different antigen systems with high HLA-E expression. Of note, these immune-activating properties of S095029 compared favorably in benchmarking experiments with other clinical-stage anti-NKG2A mAbs. Finally, S095029 combination with PD-1 blocking agents, with or without an additional ADCC mAb component, conferred superior anti-tumor activity compared to treatments without NKG2A blockade. Overall, our in vitro and in vivo data support the clinical development of S095029 in tumor settings with adequate HLA-E expression and suggest potential differentiating characteristics compared to other anti-NKG2A mAbs. S095029 is currently being evaluated in phase 1 dose escalation studies as a single agent or in combination with anti-PD-1 therapy (NCT05162755). Citation Format: Maria Melander, Bruno Laugel. S095029: a novel clinical-stage Fc-silenced NKG2A-blocking antibody with best-in-class potential [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB220.