An EGFR‐targeting antibody–drug conjugate LR004‐VC‐MMAE: potential in esophageal squamous cell carcinoma and other malignancies

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.

Tumor-targeting anti-EGFR x anti-PD1 bispecific antibody inhibits EGFR-overexpressing tumor growth by combining EGFR blockade and immune activation with direct tumor cell killing

“…Novel mAb to other immune checkpoint targets, for example antagonistic antibodies to LAG3, TIM3 and TIGIT, and agonistic antibodies to CD40, OX40 and 4-1BB, are being identified and developed [27 , 28] . Anti-EGFR antibody-based bispecific antibodies (BsAb) and antibody-drug conjugates (ADC) are also being studied [29 – 31] . Recently, combination therapies of two or more tumor-targeting mAbs, for example, anti-HER2 mAbs, trastuzumab and pertuzumab, in breast cancer, or two or more immune checkpoint inhibitor mAbs, for instance, an anti-PD1 mAb (nivolumab) and an anti-CTLA4 mAb (ipilimumab) in melanoma and NSCLC, or others, such as an anti-vascular endothelial growth factor (VEGF) mAb (bevacizumab) and an anti-PDL1 mAb (atezolizumab) in liver cancer, have been shown to be more efficacious than single antibody agents in the clinic [32 , 33] .…”

Lapachol is a novel ribosomal protein S6 kinase 2 inhibitor that suppresses growth and induces intrinsic apoptosis in esophageal squamous cell carcinoma cells

“…Recently, FGF‐mediated MAPK signaling activation was shown to promote tumor growth in ESCC (Chen et al, ; Maehara et al, ), and EGFR inhibitors have been used for ESCC chemotherapeutics (Hu et al, ; Lee et al, ). Therefore, the FGF or EGF signaling pathway is important for ESCC therapy.…”

High‐throughput membrane‐anchored proteome screening reveals PIEZO1 as a promising antibody‐drug target for human esophageal squamous cell carcinoma

“…26 For instance, EGFR has been identified as a potential ADC target for several cancer treatments including ESCC. 27 In the past, most ADC targets' development was restricted within well-characterized membrane-anchored proteins on tumors, which might miss the novel or unknown targets. 28 Proteome Epitope Tag Antibody Library array is a powerful platform for high-throughput and multiplexed protein profiling with a collection of immobilized antibodies targeting different cellular components.…”

“…An ideal ADC antigen should be particularly enriched on the tumor cells’ surface and can be internalized when bound with its monoclonal antibody 26 . For instance, EGFR has been identified as a potential ADC target for several cancer treatments including ESCC 27 …”

“… 26 For instance, EGFR has been identified as a potential ADC target for several cancer treatments including ESCC. 27 …”