SCR-A008, a novel CDH17-targeted ADC, exhibited potent tumor inhibition in CDH17-positive gastric cancer PDX model

Gastric cancer (GC) is a leading cause of cancer-related deaths worldwide. Despite continuous updates to clinical guidelines, chemotherapy remains the primary treatment option for most gastric cancer patients, including those with pMMR/MSS, HER2-low/negative expression, and HER2-targeted drug resistance. This emphasizes the urgent need to investigate better predictive and prognostic biomarkers. Cadherin 17 (CDH17) has emerged as a promising target for gastric cancers, as it is highly expressed in gastric cancer tissues but has limited expression in normal tissues. In this study, we conducted research on a CDH17 moderate expression GC patient-derived xenograft (PDX) model, selected from a bank of 59 PDX model using IHC, to explore the antitumor efficacy of the CDH17-ADC, SCR-A008, as a monotherapy and in combination with chemotherapy. Additionally, we determined the pharmacokinetics (PK) profile of SCR-A008 using a TAA or ADC assay, and assessed pharmacodynamic biomarkers using IHC. Furthermore, we evaluated the concordance between AI-scoring and manual pathologist-based scoring. SCR-A008 demonstrated sustained tumor inhibition after a single administration at various doses, with 1 mg/kg chosen as the dosage for combination studies. Additionally, the TGI of the SCR-A008 combined with paclitaxel group was 95% at 42 days post treatment, significantly better than that of the SCR-A008 monotherapy group, the 5-Fu combined with L-OHP group, and the paclitaxel monotherapy group, with TGI values of 86%, 47%, and 61%, respectively. Meanwhile, PK profiles were investigated in this study, with no significant differences between SCR-A008 as a single drug and SCR-A008 in combination with chemotherapy drugs. Notably, the SCR-A008 plus paclitaxel group exhibited significantly elevated p-ERK expression, along with relatively higher p-NBS1 levels at 336 h post treatment. The study investigated the selective expression of CDH17 in tumors, and provided vital insights into the efficacy and safety of SCR-A008, which may potentially address a significant unmet medical need of gastric cancer.