ACR246, a first-in-class 5T4 antibody-drug conjugate (ADC), showed promising anticancer efficacy in preclinical models and patient with esophageal cancer

Background: Advanced esophageal squamous cell carcinoma (ESCC) poses a significant therapeutic challenge, particularly after progression on first-line immune checkpoint inhibitors. The oncofetal antigen 5T4 represents a promising target due to its high expression in ESCC and limited presence in normal tissues. ACR246 is an investigational anti-5T4 ADC composed of a fully human IgG1 monoclonal antibody conjugated to a topoisomerase I inhibitor via a stable cleavable linker, with a drug-to-antibody ratio of 8. Methods: Proteomic sequencing of tumor and adjacent tissues from ESCC patients was performed to compare 5T4 protein levels and estimate immune infiltration. The antitumor efficacy of ACR246 was assessed across a panel of preclinical models, including cell lines, patient-derived organoids (PDOs), and xenografts (PDXs) of gastroesophageal cancer. Its efficacy was benchmarked against a 5T4- Deruxtecan (DXd) ADC and chemotherapy in these models. 5T4 expression level in PDX and PDO tissues was assessed by immunohistochemistry (IHC) to correlate with response. The synergistic potential of ACR246 with anti-PD-1 was investigated in 5T4-positive ESCC PDO-PBMC co-cultures and a murine ESCC model expressing human 5T4, with tumor microenvironment changes analyzed by flow cytometry. A clinical case from a heavily pretreated ESCC patient is included. Results: Proteomics confirmed significantly elevated 5T4 protein levels in ESCC tumors versus adjacent tissues. High 5T4 expression correlated with reduced infiltration of CD4+ T cells, CD8+ effector memory T cells, and dendritic cells, indicating an immunosuppressive milieu. In vitro studies showed that ACR246 exhibited high specificity for 5T4-expressing cancer cells and demonstrated superior activity over irinotecan in multiple gastroesophageal cancer PDOs. In PDX models of gastroesophageal cancer (n=9), ACR246 achieved significant tumor growth inhibition, with efficacy positively correlating with 5T4 expression. Remarkably, ACR246 outperformed the 5T4-Dxd ADC across these PDX models. Furthermore, ACR246 combined with anti-PD-1 showed enhanced antitumor activity in ESCC PDO-PBMC co-cultures and murine ESCC models, accompanied by increased IFN-gamma+ CD8+ T cells and reduced M2-like macrophages. Finally, a 5T4 positive, anti-PD-1-refractory ESCC patient (NCT06238401) receiving ACR246 (3.6 mg/kg) achieved a confirmed partial response (cycle 4) with 51% reduction in the volume of target liver and lymph node metastatic lesions. No grade ≥ 3 treatment-related adverse events (TRAEs) were observed during the treatment period. Conclusion: Integrated preclinical and clinical data establish ACR246 as a promising therapeutic for 5T4-positive ESCC and support its broader evaluation in other 5T4-expressing solid tumors.