Abstract 4548: Therapeutically targeting B7-H6 with antibody-drug conjugates for diffuse large B-cell lymphoma

Abstract Background: Diffuse large B-cell lymphoma (DLBCL) remains fatal in ∼40% of patients who relapse after first-line R-CHOP chemoimmunotherapy. Although CD19- and CD79b-targeted ADCs offer additional therapeutic options, their benefit is limited by on-target depletion of normal B cells, restricting the therapeutic window. To identify tumor-selective antigens with minimal normal-tissue expression, we performed multi-omics analyses across lymphoma datasets and identified B7-H6 (NCR3LG1) as a cancer-enriched surface protein. B7-H6 is undetectable in healthy tissues, consistently elevated in DLBCL, and further inducible by cellular stress, suggesting a therapeutically exploitable vulnerability. Methods: Monoclonal antibodies against B7-H6 were conjugated to monomethyl auristatin E (MMAE) or DXd to generate B7-H6-targeted ADCs. Antigen-dependent cytotoxicity and selectivity were evaluated across B7-H6-high DLBCL cell lines and normal epithelial or hematopoietic cells. Tumor targeting and biodistribution were assessed by IVIS imaging using fluorescently labeled antibodies. Antitumor efficacy was evaluated in subcutaneous DLBCL xenograft models by tumor growth inhibition and treatment durability. Mechanistic studies assessed NKp30 engagement, immune-evasion pathways, and Fc-dependent effector activity. Results: B7-H6 ADCs induced strong antigen-dependent cytotoxicity, eliminating B7-H6-high DLBCL cells while sparing normal cells. IVIS imaging demonstrated highly selective tumor accumulation with minimal off-tumor uptake in major organs, indicating a favorable biodistribution profile. In multiple DLBCL xenograft models, both MMAE- and DXd-based B7-H6 ADCs produced significant and sustained tumor regression, outperforming the unconjugated antibody and standard chemotherapy. Mechanistically, B7-H6 acted as an immune-modulatory ligand that engaged NKp30, enabling DLBCL cells to diminish NK-cell activity. B7-H6 ADCs counteracted this immune-evasion mechanism by directly delivering cytotoxic payloads to antigen-expressing cells. The intact Fc domain further promoted Fcγ-receptor-mediated NK- and macrophage-dependent effector functions, complementing payload-mediated killing. Conclusions: B7-H6 is a tumor-selective, immune-regulatory, and mechanistically validated target for next-generation ADC development in DLBCL. B7-H6 ADCs demonstrate potent tumor-selective activity, favorable biodistribution, and dual mechanisms of antitumor action, providing a promising strategy to overcome the limitations of existing DLBCL therapies. Citation Format: Qiaoling Ye, Ye Lu, Chulin Sha, Peng Guo. Therapeutically targeting B7-H6 with antibody-drug conjugates for diffuse large B-cell lymphoma [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 4548.