ADV-101: A Topoisomerase I Inhibitor  ADC Targeting IL-1RAP Demonstrates Promising Efficacy in Preclinical Esophageal Cancer Models 

With an estimated 604,000 new cases diagnosed worldwide in 2020, Oesophageal cancer ranks as the seventh most common cancer globally and remains a challenging malignancy with poor prognosis. Chronic inflammation, driven by IL-1-related cytokines, plays a critical role in its development. The IL-1 receptor accessory protein (IL-1RAP), a key mediator in IL-1 signalling, is significantly upregulated in oesophageal squamous cell carcinoma (ESCC) while showing minimal expression in healthy tissues, making it a promising therapeutic target. 

Using in silico analysis and immunohistochemistry, we assessed IL-1RAP expression in ESCC samples. TCGA data revealed significantly higher IL-1RAP mRNA expression in ESCC compared to normal tissues, with copy number amplifications present in 54% of tumours. IHC also confirmed overexpression in over 70% of samples tested. We developed a humanized anti-IL-1RAP IgG1 monoclonal antibody to create an ADC, which was conjugated at a drug-antibody ratio (DAR) of 8 to a topoisomerase I inhibitor via a cleavable peptide-based linker. The ADC, named ADV-101, demonstrated sub-nanomolar binding affinity and effective internalization in the Kyse-270 ESCC cell line, leading to potent cytotoxicity. In vivo, ADV-101 achieved 100% complete responses in ESCC tumour-bearing mice, at 5 mg/kg, in both small and large tumours (200 and 400 mm³, respectively). 

This proof-of-concept study underscores the therapeutic potential of ADV-101 in oesophageal cancer. Further studies are ongoing to confirm its efficacy in more complex models and across different oesophageal cancer subtypes as well as assessing ADV-101 safety in relevant Tox species to prepare the clinical development of ADV-101.