Antibody-Drug Conjugates Targeting the EGFR Ligand Epiregulin Elicit Robust Anti-Tumor Activity in Colorectal Cancer

皮调节素 癌症研究 单克隆抗体 结直肠癌 癌症 抗体-药物偶联物 生物素化 抗体 药理学 表皮生长因子受体 化学 医学 免疫学 生物 分子生物学 内科学 安非雷古林
作者
Joan Jacob,Yasuaki Anami,Peyton High,Zhengdong Liang,Shraddha Subramanian,Sukhen C. Ghosh,Solmaz AghaAmiri,Cara Guernsey-Biddle,H. Nicole Tran,Julie Rowe,Ali Azhdarinia,Kyoji Tsuchikama,Kendra S. Carmon
出处
期刊:Cancer Research [American Association for Cancer Research]
标识
DOI:10.1158/0008-5472.can-24-0798
摘要

Abstract As colorectal cancer (CRC) remains a leading cause of cancer-related death, identifying therapeutic targets and approaches is essential to improve patient outcomes. The EGFR ligand epiregulin (EREG) is highly expressed in RAS wildtype and mutant CRC with minimal expression in normal tissues, making it an attractive target for antibody-drug conjugate (ADC) development. In this study, we produced and purified an EREG monoclonal antibody (mAb), H231, that had high specificity and affinity for human and mouse EREG. H231 also internalized to lysosomes, which is important for ADC payload release. ImmunoPET and ex vivo biodistribution studies showed significant tumor uptake of 89Zr-labeled H231 with minimal uptake in normal tissues. H231 was conjugated to either cleavable dipeptide or tripeptide chemical linkers attached to the DNA-alkylating payload duocarmycin DM, and cytotoxicity of EREG ADCs was assessed in a panel of CRC cell lines. EREG ADCs incorporating tripeptide linkers demonstrated the highest potency in EREG-expressing CRC cells irrespective of RAS mutations. Preclinical safety and efficacy studies showed EREG ADCs were well-tolerated, neutralized EGFR pathway activity, caused significant tumor growth inhibition or regression, and increased survival in CRC cell line and patient-derived xenograft models. These data suggest EREG is a promising target for the development of ADCs for treating CRC and other cancer types that express high levels of EREG. While the efficacy of clinically approved anti-EGFR mAbs are largely limited by RAS mutational status, EREG ADCs may show promise for both RAS mutant and wildtype patients, thus improving existing treatment options.
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