An anti-ErbB2 fully human antibody circumvents trastuzumab resistance

Abstract

Trastuzumab, an anti-HER2/ErbB2 humanized antibody, has shown great clinical benefits in ErbB2-positive breast cancer treatment. Despite of its effectiveness, response rate to trastuzumab is limited and resistance is common. Here, we developed a new anti-ErbB2 antibody, denoted as H2-18, which was isolated from a phage display human antibody library. Previous studies have demonstrated that trastuzumab recognizes the juxtamembrane region of domain IV, and pertuzumab, another humanized ErbB2-specific antibody, binds to ErbB2 near the center of domain II. Our crystallographic analysis showed that the epitope recognized by H2-18 is within domain I of the ErbB2 molecule. H2-18 potently induced programmed cell death (PCD) in both trastuzumab-sensitive and -resistant breast cancer cell lines, while trastuzumab and pertuzumab, either used alone or in combination, only exhibits very weak PCD-inducing activity. More importantly, H2-18 could inhibit the growth of trastuzumab-resistant breast cancer cells far more effectively than trastuzumab plus pertuzumab, both in vitro and in vivo. In conclusion, H2-18 shows a unique ability to overcome trastuzumab resistance, suggesting that it has the great potential to be translated to the clinic.

The anti-ErbB2 antibody H2-18 and the pan-PI3K inhibitor GDC-0941 effectively inhibit trastuzumab-resistant ErbB2-overexpressing breast cancer

“…Extensive studies of mammary cells including breast cancer cells have revealed that 3D cell culture models could more accurately mimic the in vivo signaling, behavior and reaction of cancer cells to drugs than conventional 2D models [ 17 – 20 ]. Here, to further investigate whether the combination of H2-18 and GDC-0941 is synergistic in inhibiting cell proliferation, we treated BT-474, SKBR-3, HCC-1954 and HCC-1419 cells with various concentration ranges of GDC-0941 and H2-18 in 3D culture system.…”

“…In our recent study, we reported an ErbB2 domain I-specific fully human antibody H2-18, which exhibited a great antitumor activity in trastuzumab-resistant breast tumor-bearing nude mice [ 17 ]. However, H2-18 only had a slight inhibition effect on PI3K/AKT pathway.…”

“…Our previous study has shown that an anti-ErbB2 antibody H2-18 exhibits a unique ability to overcome trastuzumab resistance [ 17 ]. It shows a superior antitumor efficacy over trastuzumab plus pertuzumab in trastuzumab-resistant breast cancer cell lines through inducing potent programmed cell death [ 17 ]. Due to the heterogeneous nature of breast cancers, one single drug is usually not enough to overcome trastuzumab resistance.…”

Anti-ErbB2 immunotherapeutics: struggling to make better antibodies for cancer therapy

“…42 In the same fashion, the human antibody coded H2-18 recognizing an as yet untargeted epitope of the ErbB2 receptor was found to be able to circumvent trastuzumab resistance and to be more effective at inhibiting tumor growth than the combination of trastuzumab and pertuzumab in both in vitro and in vivo pre-clinical models. 43 HuA21 is a chimeric antibody targeted to subdomain I of the ErbB2 extracellular domain and it has been shown to markedly suppress the growth of trastuzumabresistant cells. 44…”

ErbB Family Signalling: A Paradigm for Oncogene Addiction and Personalized Oncology

“…Recently the Lu group used the ErbB2 domain I-specific fully human antibody H2-18 to induce programmed cell death in the trastuzumab resistant breast cancer cell line HCC-1954 [136]. Due to the absence of a kinase domain, the ErbB3 receptor has been less appreciated as a potential drug target.…”