Novel and potent MICA/B antibody is therapeutically effective in KRAS LKB1 mutant lung cancer models

作者：Ryan R Kowash, Manoj Kumar Sabnani, Laura T. Gray, Qing Deng, Nusrat U A Saleh, Luc Girard, Yujiro Naito, Kentaro Masahiro, John D. Minna, David E. Gerber, Shohei Koyama, Zhiqian Lucy Liu, Hemanta Baruah, Esra A. Akbay · 发表于：Journal for ImmunoTherapy of Cancer · 年份：2025 · DOI：10.1136/jitc-2024-009867 · 被引用次数：9 · 研究领域：Immune Cell Function and Interaction、CAR-T cell therapy research、Cancer Immunotherapy and Biomarkers

BACKGROUND: (STK11, KL) mutant non-small cell lung cancers (NSCLC) do not respond well to current immune checkpoint blockade therapies, however targeting major histocompatibility complex class I-related chain A or B (MICA/B), could pose an alternative therapeutic strategy through activation of natural killer (NK) cells. METHODS: Expression of NK cell activating ligands in NSCLC cell line and patient data were analyzed. Cell surface expression of MICA/B in NSCLC cell lines was determined through flow cytometry while ligand shedding in both patient blood and cell lines was determined through ELISA. We engineered an antibody-dependent cellular cytotoxicity (ADCC) enhanced MICA/B monoclonal antibody, AHA-1031, which prevents ligand shedding without interfering with binding to natural killer group 2D while targeting cancer cells via superior ADCC. We performed in vitro assays using ELISA and flow cytometry-based assays to confirm that our antibody potently binds to and stabilizes MICA/B expression across lung cancer and other solid tumor cell lines. Additionally, we used two KL mutant NSCLC cell lines and a KL mutant patient-derived xenograft (PDX) model to demonstrate in vivo antitumor efficacy and flow cytometry analysis for immune cell activation profiling. RESULTS: NSCLC cell lines exhibit high MICA/B expression and secrete soluble MICA/B in vitro. Soluble MICA/B is also detected in patient blood samples. AHA-1031 binds to the α3 domain of MICA/B, preventing shedding and targe...