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.
Highlights
Breast cancer becomes the most lethal malignancy in women world-wide in recent years, and its incidence and mortality rate are still climbing high in both developed and developing countries
As c-Jun N-terminal kinase (JNK) pathway and reactive oxygen species (ROS) production were often involved in RIP1-dependent programmed necrosis [27, 28], we investigated the changes of pJNK and p-c
It is well known that the ability of trastuzumab to inhibit the in vitro cell proliferation correlates with ErbB3/ PI3K/AKT pathway inhibition [34]
Summary
Breast cancer becomes the most lethal malignancy in women world-wide in recent years, and its incidence and mortality rate are still climbing high in both developed and developing countries. The dimers stimulate ErbB2 phosphorylation, initiate downstream signaling events including PI3K/AKT and MAPK/ERK pathways, and culminate in tumor growth [4,5,6]. Trastuzumab (Herceptin) is a humanized monoclonal antibody directed against the extracellular domain IV of ErbB2. It is the first anti-ErbB2 antibody approved for clinical use for ErbB2-amplified metastatic breast cancer by FDA in 1998 [7] and has been the standard therapy till now. The possible mechanisms involving its action include ErbB2 downregulation and endocytosis, disruption of ErbB2-ErbB3 dimers followed by inhibition of PI3K/ AKT pathway, cell-cycle arrest and antibody-dependent, cell-mediated cytotoxicity (ADCC) [8]
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