EGFR and LGR5 Dual-Targeting Antibody-Drug Conjugate-Based Therapeutic Strategies for the Improved Treatment of Colorectal Cancer

Author

• Peyton High, University of Texas Health Science Center at HoustonFollow

Author ORCID Identifier

0000-0002-4318-4490

Date of Graduation

8-2026

Document Type

Dissertation (PhD)

Program Affiliation

Molecular and Translational Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Kendra S. Carmon

Committee Member

Ali Azhdarinia

Committee Member

Rachel Miller

Committee Member

Vihang Narkar

Committee Member

Jae-Il Park

Committee Member

Kyle Poulsen

Abstract

Despite significant efforts, colorectal cancer (CRC) prognosis remains poor, exemplifying a need for improved therapies. Antibody-drug conjugates (ADCs) are a rapidly expanding class of therapeutics that utilize antibody-mediated specificity for a target antigen overexpressed on the tumor surface to deliver highly potent drug payloads to cancer cells while sparing normal tissues. Here, we describe the development of a novel topoisomerase I inhibitor-conjugated ADC (8E11-CPT2) targeting leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5), a marker of cancer stem-like cells highly overexpressed in CRC, that elicits dose- and target-dependent cytotoxicity with minimal toxicity. Furthermore, we demonstrate that cetuximab (CTX), a mAb targeting the epidermal growth factor receptor (EGFR) that is FDA-approved for KRAS^WT mCRC, increases LGR5 levels independent of KRAS mutation. Importantly, combination treatment of CTX and 8E11-CPT2 significantly reduces tumor burden and extends survival in RAS^MUT CRC patient-derived xenografts as compared to monotherapies. Having validated EGFR and LGR5 dual therapeutic targeting as an effective strategy, we then generated two EGFR:LGR5 bispecific antibodies (bsAbs; E⨯L-1 and E⨯L-2) that drive EGFR lysosomal degradation in an LGR5-driven manner. Furthermore, we produced an EGFR:LGR5 bsADC (E⨯L-1-CPT2) that demonstrates significantly enhanced cytotoxicity in EGFR- and LGR5-expressing cancer cell lines and superior anti-tumor efficacy in CRC xenografts as compared to E⨯L-1 bsAb and 8E11-CPT2 LGR5 ADC. Taken together, this work strongly rationalizes dual-targeting of EGFR and LGR5 for CRC and is in line with growing evidence that multi-targeting therapeutic strategies may prove more effective in treating cancer than single target-based approaches.

Recommended Citation

High, Peyton, "EGFR and LGR5 Dual-Targeting Antibody-Drug Conjugate-Based Therapeutic Strategies for the Improved Treatment of Colorectal Cancer" (2026). Dissertations and Theses (Open Access). 1554.
https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1554

Keywords

Colorectal cancer, antibody-drug conjugate, EGFR, LGR5, bispecific antibody, bispecific antibody-drug conjugate, combination treatment