21
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Targeting HER3 using mono- and bispecific antibodies or alternative scaffolds

      review-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          ABSTRACT

          The human epidermal growth factor receptor 3 (HER3) has in recent years been recognized as a key node in the complex signaling network of many different cancers. It is implicated in de novo and acquired resistance against therapies targeting other growth factor receptors, e.g., EGFR, HER2, and it is a major activator of the PI3K/Akt signaling pathway. Consequently, HER3 has attracted substantial attention, and is today a key target for drugs in clinical development. Sophisticated protein engineering approaches have enabled the generation of a range of different affinity proteins targeting this receptor, including antibodies and alternative scaffolds that are either mono- or bispecific. Here, we describe HER3 and its role as a key tumor target, and give a comprehensive review of HER3-targeted proteins currently in development, including discussions on the opportunities and challenges of targeting this receptor.

          Related collections

          Most cited references101

          • Record: found
          • Abstract: found
          • Article: not found

          Novel anticancer targets: revisiting ERBB2 and discovering ERBB3.

          Aberrant receptor expression or functioning of the epidermal growth factor receptor (Erbb) family plays a crucial part in the development and evolution of cancer. Inhibiting the signalling activity of individual receptors in this family has advanced the treatment of a range of human cancers. In this Review we re-evaluate the role of two important family members, ERBB2 (also known as HER2) and ERBB3 (also known as HER3), and explore the mechanisms of action and preclinical and clinical data for new therapies that target signalling through these pivotal receptors. These new therapies include tyrosine kinase inhibitors, antibody-chemotherapy conjugates, heat-shock protein inhibitors and antibodies that interfere with the formation of ERBB2-ERBB3 dimers.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            ErbB receptors and signaling pathways in cancer.

            The ErbB receptor tyrosine kinases play important roles in normal physiology and in cancer. Epidermal growth factor receptor (EGFR) and ErbB2 in particular are mutated in many epithelial tumors, and clinical studies suggest that they play roles in cancer development and progression. These receptors have been intensely studied, not only to understand the mechanisms underlying their oncogenic potential, but also to exploit them as therapeutic targets. ErbB receptors activate a multiplicity of intracellular pathways via their ability to interact with numerous signal transducers. Furthermore, there are now many ErbB-targeted inhibitors used in the clinic. In this review we will concentrate on breast tumors with ERBB2 gene amplification/receptor overexpression and non-small cell lung cancer (NSCLC) with activating EGFR mutations. We will discuss data showing the important role that the PI3K/Akt pathway plays, not only in cancer development, but also in response to targeted therapies. Finally, mechanisms contributing to resistance to ErbB-targeted therapeutics will also be discussed.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              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.
                Bookmark

                Author and article information

                Journal
                MAbs
                MAbs
                KMAB
                kmab20
                mAbs
                Taylor & Francis
                1942-0862
                1942-0870
                October 2016
                17 August 2016
                17 August 2016
                : 8
                : 7
                : 1195-1209
                Affiliations
                [a ]Division of Protein Technology, School of Biotechnology, KTH-Royal Institute of Technology, SE , Stockholm
                [b ]Affibody AB, SE, Stockholm, Sweden
                [c ]Department of Immunology, Genetics and Pathology, Uppsala University , Uppsala, Sweden
                Author notes
                CONTACT Magdalena Malm mamalm@ 123456kth.se
                Article
                1212147
                10.1080/19420862.2016.1212147
                5058629
                27532938
                a405a287-1d60-4036-aea9-1f1eaf9f91cd
                © 2016 The Author(s). Published with license by Taylor & Francis Group, LLC

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s) have been asserted.

                History
                : 12 February 2016
                : 30 June 2016
                : 6 July 2016
                Page count
                Figures: 2, Tables: 1, References: 147, Pages: 15
                Categories
                Review

                Immunology
                affibody molecules,alternative scaffolds,bispecific antibodies,erbb3,her3,monoclonal antibodies,protein therapeutics,tumor targeting

                Comments

                Comment on this article