Antibody-Drug Conjugates Targeting the EGFR Ligand Epiregulin Elicit Robust Anti-Tumor Activity in Colorectal Cancer
Joan Jacob1,2, Yasuaki Anami3, Peyton High1,2
1Center for Translational Cancer Research, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX.
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.
Insights
Epiregulin (EREG) antibody-drug conjugates (ADCs) show promise for colorectal cancer (CRC) treatment. These EREG ADCs effectively target CRC cells, regardless of RAS mutation status, and demonstrate significant anti-tumor activity in preclinical models.
Area of Science:
- Oncology
- Immunotherapy
- Drug Development
Background:
- Colorectal cancer (CRC) is a leading cause of cancer mortality, necessitating novel therapeutic strategies.
- Epiregulin (EREG), an EGFR ligand, is highly expressed in CRC but minimally in normal tissues, presenting a viable target for antibody-drug conjugates (ADCs).
- Current anti-EGFR monoclonal antibodies (mAbs) efficacy is often limited by RAS mutational status.
Purpose of the Study:
- To develop and evaluate EREG-targeted ADCs as a potential therapeutic approach for colorectal cancer.
- To assess the specificity, internalization, and tumor targeting of an EREG-specific mAb (H231).
- To determine the preclinical efficacy and safety of EREG ADCs in various CRC models.
Main Methods:
- Production and characterization of an EREG-specific monoclonal antibody (mAb), H231.
- ImmunoPET and ex vivo biodistribution studies using 89Zr-labeled H231 to assess tumor uptake.
- Conjugation of H231 to duocarmycin DM via cleavable linkers to create EREG ADCs.
- In vitro cytotoxicity assays and in vivo preclinical safety and efficacy studies in CRC cell line and patient-derived xenograft models.
Main Results:
- The H231 mAb exhibited high specificity and affinity for EREG and demonstrated effective lysosomal internalization.
- 89Zr-labeled H231 showed significant tumor uptake with minimal off-target accumulation in normal tissues.
- EREG ADCs, particularly those with tripeptide linkers, displayed potent cytotoxicity in EREG-expressing CRC cells, irrespective of RAS mutation status.
- Preclinical studies confirmed EREG ADCs were well-tolerated, inhibited EGFR pathway activity, and significantly reduced tumor growth, prolonging survival.
Conclusions:
- Epiregulin (EREG) is a promising therapeutic target for antibody-drug conjugate (ADC) development in colorectal cancer (CRC).
- EREG ADCs demonstrate potent anti-tumor activity and potential efficacy in both RAS wildtype and mutant CRC.
- These findings suggest EREG ADCs could offer an improved treatment option for CRC patients, potentially overcoming limitations of current therapies.
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