LBL-054 TDC：一种首创的CDH17靶向T细胞衔接器药物偶联物用于治疗CDH17阳性胃肠道肿瘤

Background: CDH17 is a member of the cadherin superfamily. In normal tissues, CDH17 is highly restricted to the lateral membrane and concealed within intestinal tight junctions, making it inaccessible to immune cell infiltration. In contrast, it is overexpressed and redistributed in 50% to 90% of gastrointestinal cancers, leading to its exposure on the cancer cell surface, therefore becoming more accessible. This unique feature makes CDH17 a promising target for T cell engagers or antibody-drug conjugates for GI cancer. Here, we have developed a novel T cell engager drug conjugate, LBL-054 TDC, targeting CDH17 and CD3 conjugated via our proprietary TOPiKinectics TM linker-payload platform. Methods: The binding and internalization activity of LBL-054 TDC to CDH17-expressing tumor cell lines and CD3+ T cells were assessed by flow cytometry. Cytotoxicity of LBL-054 TDC against tumor cells and T cells were assessed using Cell Counting-Lite Luminescent Cell Viability Assay kit. Cytotoxicity of LBL-054 TDC against tumor cell lines with varying endogenous expression levels of CDH17 were both evaluated in absence of T cells and in T cell dependent cellular cytotoxicity (TDCC) assay system. Bystander killing of LBL-054 TDC was performed in TDCC system by flow cytometry. The anti-tumor activity of LBL-054 TDC was evaluated in human CD3 transgenic mice bearing MC38/hCDH17 syngeneic model. The safety profile of LBL-054 TDC was evaluated in a cynomolgus monkey dose-range finding (DRF) study. Results: LBL-054 TDC showed potent binding and internalization on tumor cells, but weak binding and no internalization on T cells. It demonstrated potent cytotoxicity against tumor cells, while has no cytotoxicity to naïve T cells. In TDCC assays, LBL-054 TDC induced potent cytotoxicity under various E:T ratios and CDH17 expression levels, along with lower cytokine release compared to conventional TCE. LBL-054 TDC also mediated potent bystander killing of CDH17 neg tumor cells while sparing T cells. In the MC38/hCDH17 syngeneic mouse model, LBL-054 TDC showed stronger anti-tumor effect than TCE and ADC. In a 4-week cynomolgus DRF study, LBL-054 TDC was well tolerated following repeated intravenous infusion. Conclusions: Our results demonstrate that LBL-054 TDC combines the potent, direct killing of an ADC with the T-cell redirecting activity of a TCE both in vitro and in vivo while posing a lower cytokine release than a conventional TCE. It also exhibited good safety profiles in cynomolgus monkeys. Overall, LBL-054 TDC holds promise for treating gastrointestinal cancers with varying T-cell infiltration and CDH17 expression, potentially benefiting a broad patient population.