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      Identification of Anti-ErbB2 Dual Variable Domain Immunoglobulin (DVD-Ig™) Proteins with Unique Activities

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          Abstract

          Inhibiting ErbB2 signaling with monoclonal antibodies (mAbs) or small molecules is an established therapeutic strategy in oncology. We have developed anti-ErbB2 Dual Variable Domain Immunoglobulin (DVD-Ig) proteins that capture the function of a combination of two anti-ErbB2 antibodies. In addition, some of the anti-ErbB2 DVD-Ig proteins gain the new functions of enhancing ErbB2 signaling and cell proliferation in N87 cells. We further found that two DVD-Ig proteins, DVD687 and DVD688, have two distinct mechanisms of actions in Calu-3 and N87 cells. DVD687 enhances cell cycle progression while DVD688 induces apoptosis in N87 cells. Using a half DVD687, we found that avidity may play a key role in the agonist activity of DVD687 in N87 cells.

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          Most cited references31

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          Treatment of HER2-positive breast cancer: current status and future perspectives.

          The advent of HER2-directed therapies has significantly improved the outlook for patients with HER2-positive early stage breast cancer. However, a significant proportion of these patients still relapse and die of breast cancer. Trials to define, refine and optimize the use of the two approved HER2-targeted agents (trastuzumab and lapatinib) in patients with HER2-positive early stage breast cancer are ongoing. In addition, promising new approaches are being developed including monoclonal antibodies and small-molecule tyrosine kinase inhibitors targeting HER2 or other HER family members, antibodies linked to cytotoxic moieties or modified to improve their immunological function, immunostimulatory peptides, and targeting the PI3K and IGF-1R pathways. Improved understanding of the HER2 signaling pathway, its relationship with other signaling pathways and mechanisms of resistance has also led to the development of rational combination therapies and to a greater insight into treatment response in patients with HER2-positive breast cancer. Based on promising results with new agents in HER2-positive advanced-stage disease, a series of large trials in the adjuvant and neoadjuvant settings are planned or ongoing. This Review focuses on current treatment for patients with HER2-positive breast cancer and aims to update practicing clinicians on likely future developments in the treatment for this disease according to ongoing clinical trials and translational research.
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            Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941.

            Herceptin (trastuzumab) is the backbone of HER2-directed breast cancer therapy and benefits patients in both the adjuvant and metastatic settings. Here, we describe a mechanism of action for trastuzumab whereby antibody treatment disrupts ligand-independent HER2/HER3 interactions in HER2-amplified cells. The kinetics of dissociation parallels HER3 dephosphorylation and uncoupling from PI3K activity, leading to downregulation of proximal and distal AKT signaling, and correlates with the antiproliferative effects of trastuzumab. A selective and potent PI3K inhibitor, GDC-0941, is highly efficacious both in combination with trastuzumab and in the treatment of trastuzumab-resistant cells and tumors.
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              A central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy.

              Epidermal growth factor receptor (EGFR) and HER3 each form heterodimers with HER2 and have independently been implicated as key coreceptors that drive HER2-amplified breast cancer. Some studies suggest a dominant role for EGFR, a notion of renewed interest given the development of dual HER2/EGFR small-molecule inhibitors. Other studies point to HER3 as the primary coreceptor. To clarify the relative contributions of EGFR and HER3 to HER2 signaling, we studied receptor knockdown via small interfering RNA technology across a panel of six HER2-overexpressing cell lines. Interestingly, HER3 was as critical as HER2 for maintaining cell proliferation in most cell lines, whereas EGFR was dispensable. Induction of HER3 knockdown in the HER2-overexpressing BT474M1 cell line was found to inhibit growth in three-dimensional culture and induce rapid tumor regression of in vivo xenografts. Furthermore, preferential phosphorylation of HER3, but not EGFR, was observed in HER2-amplified breast cancer tissues. Given these data suggesting HER3 as an important therapeutic target, we examined the activity of pertuzumab, a HER2 antibody that inhibits HER3 signaling by blocking ligand-induced HER2/HER3 heterodimerization. Pertuzumab inhibited ligand-dependent morphogenesis in three-dimensional culture and induced tumor regression in the heregulin-dependent MDA-MB-175 xenograft model. Importantly, these activities of pertuzumab were distinct from those of trastuzumab, a monoclonal antibody currently used for treatment of HER2-amplified breast cancer patients. Our data suggest that inhibition of HER3 may be more clinically relevant than inhibition of EGFR in HER2-amplified breast cancer and also suggest that adding pertuzumab to trastuzumab may augment therapeutic benefit by blocking HER2/HER3 signaling.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                13 May 2014
                : 9
                : 5
                : e97292
                Affiliations
                [1 ]AbbVie Bioresearch Center, R&D, Worcester, Massachusetts, United States of America
                [2 ]Cancer Research, R&D, AbbVie Inc., North Chicago, Illinois, United States of America
                Tulane University, United States of America
                Author notes

                Competing Interests: All authors were employees of AbbVie Inc. (Formerly Abbott Laboratories) when this study was performed and authors may own AbbVie stock. AbbVie Inc. sponsored the study. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

                Conceived and designed the experiments: Jinming.G JY Jijie.G. Performed the experiments: Jinming.G JY QC JW MC. Analyzed the data: Jinming.G JY QC XL JW MC TG Jijie.G. Contributed reagents/materials/analysis tools: XL. Wrote the paper: Jinming.G JY QC XL JW MC TG Jijie.G.

                [¤a]

                Current address: Shire Pharmaceuticals, Lexington, Massachusetts, United States of America

                [¤b]

                Current address: Globio3S LLC, Newark, Delaware, United States of America

                Article
                PONE-D-13-42203
                10.1371/journal.pone.0097292
                4019538
                24824849
                9ba7179b-c6aa-403f-80a7-45150d230d23
                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 15 October 2013
                : 19 April 2014
                Page count
                Pages: 10
                Funding
                This study was supported by fundings from AbbVie, Inc. The funder provided support in the form of salaries for all authors and contributed to the study design, participated in the collection, analysis and interpretation of the data, and in the writing, reviewing, and approval of this publication. The specific roles of these authors are articulated in the ‘author contributions’ section (JG, JY, and JG designed the study, QC did assays in Fig. 5, other authors analyzed the data).
                Categories
                Research Article
                Biology and Life Sciences
                Biochemistry
                Proteins
                Immune System Proteins
                Antibodies
                Biotechnology
                Cell Biology
                Cell Processes
                Cell Cycle and Cell Division
                Cell Death
                Cell Growth
                Signal Transduction
                Cell Signaling
                Oncogenic Signaling
                Molecular Cell Biology
                Immunology
                Clinical Immunology
                Immunotherapy
                Medicine and Health Sciences
                Clinical Medicine
                Oncology
                Cancers and Neoplasms
                Breast Tumors
                Cancer Treatment
                Pharmacology
                Drug Research and Development
                Drug Discovery

                Uncategorized
                Uncategorized

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