新型双功能抗MICA/B抗体药物偶联物NW008的临床前研究

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 gammadelta 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 alpha3 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.