GC1118, a novel anti-EGFR antibody, has potent KRAS mutation-independent antitumor activity compared with cetuximab in gastric cancer

Abstract

Background EGFR overexpression in gastric cancer (GC) has been reported in about 30% of patients. However, the anti-EGFR antibodies cetuximab and panitumumab have failed to improve overall survival of GC patients in combination with cytotoxic chemotherapy compared with chemotherapy alone. GC1118, a novel anti-EGFR antibody with a distinct binding epitope compared with cetuximab or panitumumab, has not been tested in GC. Methods GC cell lines, SNU-1, SNU-5, SNU-16, SNU-216, SNU-484, SNU-601, SNU-620, SNU-638, SNU-668, SNU-719, AGS, MKN-45, NCI-N87, and KATO-III, were employed to test the effect of cetuximab or GC1118 alone, and combined with the cytotoxic agent cisplatin or 5-fluorouracil (5-FU). Cells were also treat with or without high-affinity ligands EGF 20 ng/ml or HB-EGF 100 ng/ml. Results GC1118 exhibited a more potent growth inhibition effect in the majority of cell lines than cetuximab in MTT assay, regardless of the KRAS mutation status of cell lines. Co-treatment of GC1118 and cisplatin or 5-FU inhibited colony formation and migration to a greater extent, even following EGFR ligand stimulation. Ligand-induced p-AKT and p-ERK upregulation were more potently inhibited by combination treatment with GC1118 and chemotherapeutic agents compared with cetuximab plus chemotherapeutic agents. GC1118 also showed more potent anti-tumor effects compared with cetuximab in a mouse xenograft model. Conclusion Taken together, GC1118 alone or in combination with cytotoxic chemotherapeutic agents exerted more potent anti-tumor effects than cetuximab in GC cells, regardless of KRAS status. These findings support the further clinical development of GC1118 for the treatment of GC.

Promising Therapeutic Efficacy of GC1118, an Anti-EGFR Antibody, against KRAS Mutation-Driven Colorectal Cancer Patient-Derived Xenografts

“…Low-affinity ligands EREG and AREG are predominant in CRC, whereas only a small fraction of high-affinity ligands is expressed [29]. Low expression levels of AREG and EREG associated with KRAS mutations might indicate a tumor that is less dependent on EGFR and is therefore particularly prone to developing resistance to anti-EGFR MoAbs [6,8,10,20,21]. Moreover, the expression levels of AREG and EREG were found to be significantly decreased in mutant- KRAS cases, compared to those in the wild-type cases [30].…”

“…In contrast to previous studies, we utilized the PDX platform to evaluate the efficacy of GC1118 and its mechanism of action, as the induction and expression of high-affinity EGFR ligands have been reported to be more prevalent in CRC tumor xenografts than in in vitro cultures [8]. GC1118 is a human anti-EGFR IgG1 antibody that differs from existing anti-EGFR MoAbs, such as cetuximab and panitumumab, in its constant region, affinity, mode of action, and efficacy [8,20], exhibiting superior binding affinity (resulting in ADCC) to both the low- and high-affinity variants of FcγRIIIa compared to cetuximab [8,20]. Moreover, the use of Bagg albino (BALB)/c nude mice with intact innate immune systems could allow for the evaluation of GC1118-mediated ADCC through Fc receptors present on immune effector cells such as macrophages, monocytes, and natural killer cells [8,11,38].…”

“…This is because constitutively activated RAS downstream signaling can activate multiple processes involved in tumor progression without the influence of EGFR and related receptor kinases [5,10]. There is also circumstantial evidence to suggest that an excess of high-affinity ligands drives resistance to cetuximab [6,8,20,21].…”

“…GC1118 is a human anti-EGFR IgG1 antibody that differs from existing anti-EGFR MoAbs, such as cetuximab and panitumumab, in its constant region, affinity, mode of action, and efficacy [8,20]. A recent first-in-human phase I study of GC1118 conducted on patients with refractory solid tumors, including gastric cancer and CRC, showed promising clinical antitumor efficacy and tolerability [22].…”

“…A recent first-in-human phase I study of GC1118 conducted on patients with refractory solid tumors, including gastric cancer and CRC, showed promising clinical antitumor efficacy and tolerability [22]. Notably, GC1118 exhibited superior inhibitory effects on high-affinity ligand-induced signaling in CRC and gastric cancer cells, regardless of KRAS status, triggering more potent antitumor activity than cetuximab and panitumumab [8,20]. However, persistent activation of the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)/phosphatase and tensin homolog (PTEN) pathway, one of the major downstream pathways, might lead to the activation of EGFR-independent downstream signaling pathways [10], suggesting that the combination of PI3K/mTOR/AKT inhibitors with EGFR MoAbs might be efficacious [23].…”