Abstract
Epidermal growth factor receptor (EGFR) is a rational target for cancer therapy, because its overexpression plays an important oncogenic role in a variety of solid tumors; however, EGFR‐targeted antibody–drug conjugate (ADC) therapy for esophageal squamous cell carcinoma (ESCC) is exceedingly rare. LR004 is a novel anti‐EGFR antibody with the advantages of improved safety and fewer hypersensitivity reactions. It may be of great value as a carrier in ADCs with high binding affinity and internalization ability. Here, we prepared an EGFR‐targeting ADC, LR004‐VC‐MMAE, and evaluated its antitumor activities against ESCC and EGFR‐positive cells. LR004 was covalently conjugated with monomethyl auristatin E (MMAE) via a VC linker by antibody interchain disulfide bond reduction. VC‐MMAE was conjugated with LR004 with approximately 4.0 MMAE molecules per ADC. LR004‐VC‐MMAE showed a potent antitumor effect against ESCC and other EGFR‐positive cells with IC 50 values of nM concentrations in vitro. The in vivo antitumor effects of LR004‐VC‐MMAE were investigated in ESCC KYSE520 and A431 xenograft nude mice models. Significant activity was seen at 5 mg·kg−1, and complete tumor regression was observed at 15 mg·kg−1 in the KYSE520 xenograft nude mice after four injections, while the naked antibody LR004 had little effect on inhibiting tumor growth. Similar promising results were obtained in the A431 models. In addition, the tumors also remained responsive to LR004‐VC‐MMAE for large tumor experiments (tumor volume 400–500 mm3). The study results demonstrated that LR004‐VC‐MMAE could be a potential therapeutic agent for ESCC and other EGFR‐expressing malignancies. We also evaluated PK profile of LR004‐VC‐MMAE ADC in the mice model, which would provide qualitative guiding significance for the further research.
Highlights
The transmembrane glycoprotein epidermal growth factor receptor (EGFR) is a member of the EGFR family of receptor tyrosine kinases (TK)
The auristatin analogue monomethyl auristatin E (MMAE) is a cytotoxic agent with a pentapeptide structure that inhibits tubulin polymerization
In 2003, Doronina et al reported that MMAE combined with a target-specific monoclonal antibody increased the therapeutic index (Doronina et al, 2003)
Summary
The transmembrane glycoprotein epidermal growth factor receptor (EGFR) is a member of the EGFR family of receptor tyrosine kinases (TK). Components of the extracellular transmembrane and intracellular tyrosine kinase domains correlate with cell proliferation, progression, and metastasis. There are two distinct therapeutic strategies employed for EGFR-targeted cancer therapy: One is monoclonal antibodies and the other is small-molecule tyrosine kinase inhibitors (TKIs). Anti-EGFR antibodies exert antitumor effects by binding the receptor at the cell surface to interfere with ligand binding, which leads to the inhibition of its downstream signaling pathway. In EGFR-targeted therapy, several ADCs have entered clinical trials. AVID-100, which is composed of the maytansinoid attached to an anti-EGFR antibody, was developed to treat epithelial tumor patients in phase I/II (O’Connor-McCourt et al, 2016; Tolcher et al, 2018). ABT-414, which is composed of the monomethyl auristatin F attached to an anti-EGFRvIII antibody via a cleavable linker, has shown significant efficacy against tumors expressing amplified EGFR and EGFRvIII in phase III (van den Bent et al, 2017)
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