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Monoclonal Antibody Strategies for Targeting HER2

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The Oncogenomics Handbook

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

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Abstract

The HER family is composed of four receptors, HER1 to HER4, is dysregulated, and/or shows abnormal signaling activity in a broad range of human tumors. The essential role of HER2 in the HER signaling network led to the development of anti-HER2 monoclonal antibodies (mAb) for cancer therapy. In particular, the humanized antibody trastuzumab (Herceptin™) has antitumor activity against HER2-overexpressing breast tumors and is widely used for the treatment of women with HER2-overexpressing breast cancers. However, trastuzumab activity relies on the presence of HER2 overexpression and it is not active against tumors that express moderate or normal levels of HER2.

Importantly, there is a large population of breast cancers and many other tumors that have normal (nonoverexpressed) HER2 expression yet show abnormal HER signaling activity. In such tumors, HER2 functions as a preferred coreceptor to form heterodimers with HER1 (EGFR), HER3, or HER4. For this reason, a humanized mAb, called pertuzumab (2C4; Omnitarg™), that targets HER2—the preferred pairing partner—was developed and is now in clinical development. Importantly, pertuzumab is directed at an extracellular region of HER2—the dimerization domain—and blocks HER2 from dimerizing with other receptors and prevents the activation of HER signaling cascades. Pertuzumab represents the first in a new class of targeted therapeutics known as HER dimerization inhibitors (HDIs). Given the good preclinical activity of pertuzumab and its potential to target a broad range of human tumors, including those with low HER2 expression, the antibody was recently moved to the clinic. Phase I trials with pertuzumab have shown promising results and phase Ib and II trials are ongoing against a variety of tumor types. Current results and ongoing strategies with these anti-HER2 antibodies are discussed.

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Authors and Affiliations

  1. Medical Oncology Department, ICMHO & IDIBAPS, Hospital Clínic i Provincial de Barcelona, Barcelona, Spain

    Joan Albanell MD

  2. Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, NY

    Jeffrey S. Ross MD

  3. Division of Molecular Medicine, Millennium Pharmaceuticals Inc., Cambridge, MA

    Jeffrey S. Ross MD

  4. Division Pharma, F. Hoffmann-La Roche, Basel, Switzerland

    Linda Pronk MD

  5. Division of Medical Oncology, ICMHO and IDIBAPS, Hospital Clínic i Provincial de Barcelona, Barcelona, Spain

    Pere Gascon MD (Professor and Director)

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  1. Joan Albanell MD
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  2. Jeffrey S. Ross MD
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  3. Linda Pronk MD
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  4. Pere Gascon MD
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Editors and Affiliations

  1. CuraGen Corporation, New Haven, CT

    William J. LaRochelle PhD  & Richard A. Shimkets PhD  & 

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Albanell, J., Ross, J.S., Pronk, L., Gascon, P. (2005). Monoclonal Antibody Strategies for Targeting HER2. In: LaRochelle, W.J., Shimkets, R.A. (eds) The Oncogenomics Handbook. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1385/1-59259-893-5:627

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  • DOI: https://doi.org/10.1385/1-59259-893-5:627

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