Abstract 1658: Preclinical study of NW008, a novel dual-functional anti-MICA/B antibody-drug conjugate

Abstract Background: The MHC class I polypeptide-related sequences A and B (MICA and MICB; collectively MICA/B) are stress-induced antigens. They are minimally expressed in healthy tissues but overexpressed in a wide range of solid tumors. Membrane-bound MICA/B activates antitumor immunity by engaging the NKG2D receptor on immune effector cells, such as CD8-positive T cells, natural killer (NK) cells and γδ T cells. However, proteases in the tumor microenvironment (TME) cleave MICA/B from the tumor cell surface, which impairs NKG2D-mediated tumor recognition and facilitates immune evasion. Furthermore, soluble MICA/B induces sustained NKG2D activation, resulting in receptor downregulation and lymphocyte dysfunction. Elevated serum levels of soluble MICA are associated with poor patient survival, highlighting the therapeutic potential of targeting MICA/B. Methods: Mice were immunized with recombinant proteins containing the α3 domain derived from multiple MICA/B alleles. A humanized anti-MICA/B antibody that binds with high affinity to various MICA/B alleles was obtained through high-throughput screening. Each antibody molecule was site-specifically conjugated to four molecules of a highly potent topoisomerase I inhibitor via a specially designed, hydrophilic, enzyme-cleavable linker that suppresses the retro-Michael reaction, resulting in the ADC candidate NW008. The in vitro antitumor activity of NW008 was evaluated using multiple MICA/B-expressing tumor cell lines. Its in vivo efficacy was assessed in several cell-derived xenograft (CDX) models. Results: The humanized anti-MICA/B antibody exhibited high internalization efficiency and sub-nanomolar affinity for multiple MICA/B alleles. It also inhibited MICA/B shedding from tumor cells and enhanced MICA/B-NKG2D interactions. The ADC molecule NW008 demonstrated high homogeneity and favorable stability, and it showed potent cytotoxicity against a variety of MICA/B-expressing tumor cell lines, with half-maximal effective concentration (EC50) values in the nanomolar range. In multiple mouse xenograft models bearing human MICA/B-expressing tumors, NW008 exhibited significant antitumor efficacy in vivo, with maximum tumor growth inhibition (TGI) exceeding 85% in all models, and was well tolerated. Conclusion: MICA/B represents a highly attractive target for ADC development. NW008 is a first-in-class dual-functional ADC that acts by restoring antitumor immunity through inhibition of MICA/B shedding and directly eliminating tumor cells via targeted delivery of a topoisomerase I inhibitor. NW008 demonstrates robust antitumor efficacy in preclinical models, supporting its clinical development as a promising therapeutic candidate for MICA/B-positive solid tumors. Citation Format: Afang Zhou, Juanjuan Li, Changcheng Li, Xueying Zhong, Yiran Wu, Li Liu, Gang Liu, Jiaoyi Zhong, Lijia Yang, Junkui Yang, Dan Mi, Jiabao Liu, Yaolan Dai, Yan Gao, Zhijian Li, Bin Liu, Zhigang Guo, Wenting Luo. Preclinical study of NW008, a novel dual-functional anti-MICA/B antibody-drug conjugate [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 1658.