Combination of novel HER2‐targeting antibody 1E11 with trastuzumab shows synergistic antitumor activity in HER2‐positive gastric cancer

Abstract

The synergistic interaction of two antibodies targeting the same protein could be developed as an effective anti-cancer therapy. Human epidermal growth factor receptor 2 (HER2) is overexpressed in 20-25% of breast and gastric cancer patients, and HER2-targeted antibody therapy using trastuzumab is effective in many of these patients. Nonetheless, improving therapeutic efficacy and patient survival is important, particularly in patients with HER2-positive gastric cancer. Here, we describe the development of 1E11, a HER2-targeted humanized monoclonal antibody showing increased efficacy in a highly synergistic manner in combination with trastuzumab in the HER2-overexpressing gastric cancer cell lines NCI-N87 and OE-19. The two antibodies bind to sub-domain IV of the receptor, but have non-overlapping epitopes, allowing them to simultaneously bind HER2. Treatment with 1E11 alone induced apoptosis in HER2-positive cancer cells, and this effect was enhanced by combination treatment with trastuzumab. Combination treatment with 1E11 and trastuzumab reduced the levels of total HER2 protein and those of aberrant HER2 signaling molecules including phosphorylated HER3 and EGFR. The synergistic antitumor activity of 1E11 in combination with trastuzumab indicates that it could be a novel potent therapeutic antibody for the treatment of HER2-overexpressing gastric cancers.

An anti-HER2 antibody conjugated with monomethyl auristatin E is highly effective in HER2-positive human gastric cancer

“…The antigen binding site is an intrinsic characteristic of therapeutic antibodies and the basis for conjugation with chemotherapeutic agents or drugs. 22,42 In the current study, we found that the hertuzumab targeted epitope was distinct from the epitope recognized by trastuzumab. We also found the affinity between HER2 and hertuzumab was higher than that of trastuzumab.…”

“…[16][17][18][19][20][21] Combination of trastuzumab with another HER2 targeting monoclonal antibody also showed synergistic antitumor activity in HER2-positive gastric cancer. 22 Thus, targeted HER2 therapy in gastric cancer is effective, although there is still a large percentage of patients with HER2-positive gastric or breast cancer presenting with a clinical resistance to trastuzumab. 17,23,24 Furthermore, the antibody-drug conjugate (ADC) is a novel class of targeting antitumor therapy that is more effective than antibodies alone and has fewer side effects, which may be due to a low concentration of free chemotherapeutic drug in the host blood system.…”

Perspectives of HER2-targeting in gastric and esophageal cancer

“…Afatinib in combination with trastuzumab appears to be promising in heavily pretreated HER2+ patients, with a disease control rate of 42% at 4 months with single agent afatinib 77 and the combination cohort ongoing. 1E11, a novel humanized monoclonal antibody that targets HER2, has been shown to have synergistic activity with trastuzumab in HER2 overexpressing gastric cancer cell lines 78 . Recently, a new anti-HER2 antibody with optimized Fc-receptor binding affinity has entered phase II of clinical testing in combination with anti-PD1 antibody pembrolizumab in advanced metastatic gastric and GEJ adenocarcinoma (NCT02689284, clinicaltrials.gov ).…”

Affinity Maturation of Monoclonal Antibody 1E11 by Targeted Randomization in CDR3 Regions Optimizes Therapeutic Antibody Targeting of HER2-Positive Gastric Cancer

“…The in vitro anti-proliferative activities of hz1E11 as a single agent and in combination with trastuzumab were also equivalent to those of ch1E11 ( Fig 2C ). In the previous study [ 22 ] it was reported that ch1E11 had in vivo antitumor activity comparable to that of trastuzumab as a single agent, and the combination of ch1E11 and trastuzumab resulted in the tumor regression index (TGI) of 95.1%. Similarly, hz1E11 as a single agent had similar in vivo antitumor activity to trastuzumab ( S1 Fig ) and the combination of hz1E11 with trastuzumab also showed dose-dependent anti-tumor activity in the NCI-N87 xenograft mouse model ( Fig 2D ).…”

“…We previously developed a murine antibody targeting HER2 (clone 1E11) that shows synergistic antitumor activity in combination with trastuzumab in HER2 overexpressing gastric cancer cell lines [ 22 ]. In this report, we describe how we optimized the 1E11 for a therapeutic antibody by CDR grafting to human germline immunoglobulin variable genes and affinity maturation through targeted randomization of CDR-H3 and CDR-L3.…”