Preclinical characterization of S095029, a novel clinical-stage Fc-attenuated NKG2A-blocking antibody for cancer immunotherapy
Year: 2026
Type: article
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.
Source: Frontiers in Oncology
Authors: Maria Carlsen Melander, Franziska Uhlenbrock, Anne Worsaae, Randi W. Hansen, Julien Mafille, Daniel Andersen, Samantha Knockaert, Wendy Philippon, Nikolaj Dietrich, Michael M. Grandal, Agnete Marie Granau, Chris D. Madsen, Alba Diaz-Herrero, Fabien Melchiore, Johanna Verneau, Soraia Cerqueira, Matthieu Bouaziz, Mathieu Boucher, Tania Køllgaard, Jamila Elhmouzi-Younes, Niels Jørgen Skartved, Pierre Tonnerre, Céline Lefebvre, Véronique Blanc, Trine Lindsted, Camilla Frölich, Bruno Laugel
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7214066985