Abstract 5845: BCG010, a potentially best-in-class NKG2A blocker for cancer treatment

Abstract BCG010, a fully human IgG1κ monoclonal antibody, has been engineered with an Fc LALA (L234A/L235A) substitution to block the CD94-NKG2A inhibitory checkpoint engaged by HLA-E. This development addresses the limitations of first-generation NKG2A inhibitors, which have shown variable activity, particularly as monotherapy, highlighting the need for molecules with enhanced affinity, selectivity, pharmacokinetics (PK), and developability, as well as cynomolgus cross-reactivity to support clinical translation and combination therapies. BCG010 fulfills these requirements, exhibiting higher affinity for human NKG2A compared to a Monalizumab analog at the nanomolar level, full cross-reactivity with cynomolgus NKG2A, and no binding to human NKG2C or NKG2E. Mechanistically, BCG010 alleviates NKG2A-mediated inhibitory signaling and promotes NK-cell cytotoxicity against K562 targets in vitro, akin to the Monalizumab analog, while demonstrating favorable biophysical and developability properties under defined conditions. In vivo, BCG010 inhibited tumor growth in B-hNKG2A/hCD94 humanized mice bearing MC38-HLA-E cells, in the K562-bearing B-NDG mouse model when combined with adoptive NK-cell therapy, and in RMA-bearing B-hCD94/hNKG2A mice when combined with an Atezolizumab analog, without inducing weight loss across studies. Notably, BCG010 also exhibits a longer half-life than the Monalizumab analog in B-hNKG2A/hCD94 humanized mice. These data collectively support BCG010 as a promising, potentially best-in-class NKG2A blocker with high affinity, strict selectivity, encouraging efficacy and tolerability, and favorable PK and developability profiles, warranting clinical advancement and the exploration of combination strategies for cancer treatment. The development of the CMC cell line for BCG010 is ongoing. Citation Format: Yong Xie, Peiran Li, Huichao Liang, Tao Wang, Yanan Guo, Rongjing Zhang, Zhe Shao. BCG010, a potentially best-in-class NKG2A blocker for cancer treatment abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5845.