Abstract 6949: A novel multi-modal PD-L1-ADC could be a potential BIC candidate treatment for pan-solid tumors with enhanced tumor-specificity

Abstract PD-L1 is an immune-checkpoint frequently over-expressed oon the surface of many tumor cells, as compared to normal tissues, and it may thus be considered a tumor-associated antigen (TAA), although usually not considered a good one due to wide expression among many normal tissues. Immuno-checkpoint inhibitors (ICIs), e.g. mAbs against PD-L1 and its binding partner, PD1 on effector T-cells within tumors (TIL-Teff), become powerful modality to treat cancers. However, only 15∼30% of patients across different cancers responded to PD-(L)1 ICIs whereas most of them eventually relapse and become resistant. Combination therapies, e.g. ICIs plus chemotherapies, have been proven productive with significant clinical benefit in overall survival (OS) and have become standard practice. Chemotherapy usually comes with severe side-effects with narrow therapeutic window (TW). In recent years, ADC, as a new generation of chemo-modality with significantly improved TW due to tumor targeting specificity, witnessed great success in clinics. We hypothesized that an ADC targeting PD-L1, combining specific tumor-targeting and/or ICI, could become a new powerful multi-modality treatment of cancers, superior to existing single-modal chemotherapy or ICI. To test this, we have created a novel ADC, a PD-L1-mAb conjugated with a topoisomerase-I inhibitor as payload, which is being tested for its anti-tumor activity in preclinical settings. Specifically, although specifically binds to several PD-L1-expressing tumor cell lines with high affinity, its naked antibody exhibited poor internalization in PD-L1+ cells. The ADC showed poor cytotoxicity induction in these cells as compared to FIC SGN-PDL1V that internalized efficiently. However, in contrast, the ADC demonstrated robust cytotoxicity in PD-L1+ 3D-tumor organoids in vitro, as well as robust antitumor activity in xenograft models in vivo, even stronger than SGN-PDL1V and significantly superior to the cytotoxicity seen in 2D-cell culture. This interesting discrepancy seen between 2D cell culture and “tumor” (3D-organoid or xenograft tumor) may imply added tumor-specificity, in addition to the differential PD-L1 expression between tumors and normal tissues. It is believed that this ADC maximized its immunomodulation as well as cancer cell killing, along with the observed “tumor-specificity”, which may implicating a potential “BIC” PD-L1-ADC for treating pan-solid tumors with enhanced TW. Reference Xu, X., et al., A living biobank of matched pairs of patient-derived xenografts and organoids for cancer pharmacology. PLoS One, 2023. 18(1): p. e0279821. Citation Format: Tao Yang, Hang Ke, Feiyu Peng, Jialin Li, Cen Chen, Lei Zhang, Faming Zhang, Henry Li, . A novel multi-modal PD-L1-ADC could be a potential BIC candidate treatment for pan-solid tumors with enhanced tumor-specificity 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 6949.