Biology subjects

High, P.

Publications and source records attributed to High, P..

2 recordsLinked to original sources

bioRxiv2026

Bispecific antibody-drug conjugates targeting EGFR and LGR5 exert potent antitumor activity in colorectal cancer models

Colorectal cancer (CRC) remains a significant contributor to cancer-associated deaths worldwide, indicating the need for new therapeutic targets and modalities. Antibody-drug conjugates (ADCs) have demonstrated remarkable potential for the treatment of various cancer types, although their efficacy as monotherapies is often limited by insufficient targeting of tumor heterogeneity, dose-limiting toxicities, and drug resistance. Accordingly, multi-targeting therapeutic strategies, such as bispecific ADCs (bsADCs), which simultaneously target two cancer-associated antigens or non-overlapping epitopes on the same antigen, may prove more effective at overcoming resistance and eliminating tumors compared to monospecific ADCs. In this work, we describe the development of EGFR:LGR5 bispecific antibodies (bsAbs) and bsADCs. EGFR:LGR5 bsAbs were shown to internalize to the lysosome to a greater extent than EGFR- and LGR5-targeting monoclonal antibodies (mAbs) and drive EGFR lysosomal degradation in an LGR5-mediated fashion. However, EGFR:LGR5 bsAbs exerted suboptimal cytotoxicity in CRC cell lines. We therefore engineered an EGFR:LGR5 bsADC that demonstrated 100- to 1000-fold enhanced efficacy over a previously developed LGR5-targeting monospecific ADC (8E11-CPT2) with an identical linker-payload in CRC cell lines of various genetic backgrounds and EGFR and LGR5 expression levels. EGFR:LGR5 bsADC potency was strongly correlated with cell line sensitivity to the CPT2 payload. EGFR:LGR5 bsADC induced tumor regression in select RASMUT CRC xenograft models and demonstrated superior antitumor activity and prolonged survival benefit in all evaluated models versus EGFR mAb cetuximab (CTX), bsAb, and 8E11-CPT2. These findings strongly support the further development of EGFR and LGR5 dual-targeting approaches for CRC and other EGFR- and LGR5-expressing malignancies. One Sentence SummaryEGFR:LGR5 bsADCs exert robust antitumor activity and outperform EGFR:LGR5 bsAb and LGR5 monospecific ADC in RASWT and RASMUT colorectal cancer models.

Cancer Biology↗

bioRxiv2024

Antibody-drug conjugates targeting EGFR ligand Epiregulin inhibit colorectal tumor growth irrespective of RAS mutational status

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. Significance: EREG-targeting antibody-drug conjugates demonstrate acceptable safety and robust therapeutic efficacy in RAS mutant and wildtype colorectal cancer, suggesting their potential as an alternative to EGFR-targeted therapy to benefit a broader patient population.

cancer biology↗