一种新型多模态PD-L1-ADC有望成为泛实体瘤治疗中具有增强肿瘤特异性的潜在BIC候选药物

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-T eff ), 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.