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Mechanism of Action of Anti-HER2 Monoclonal Antibodies: Scientific Update on Trastuzumab and 2C4

  • Chapter
New Trends in Cancer for the 21st Century

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 532))

Abstract

The HER family of transmembrane tyrosine kinase receptors is composed of four members, HER1 to HER4. HER2 is a ligand-orphan receptor expressed in many human tumors and overexpressed in 25-30% of breast cancers. HER2 amplifies the signal provided by other receptors of the HER family by forming heterodimers. The essential role of HER2 in the HER signaling network led to the development of anti-HER2 monoclonal antibodies (MAbs) for cancer therapy. In particular, the humanized MAb trastuzumab (Herceptin) has antitumor activity against HER2-overexpressing human breast tumor cells and is widely used for the treatment of women with HER2 overexpressing breast cancers. Trastuzumab induces HER2 receptor downmodulation and, as a result, inhibits critical signalling pathways (i.e. ras-Raf-MAPK and PI3K/Akt) and blocks cell cycle progression by inducing the formation of p27/Cdk2 complexes. Trastuzumab also inhibits HER2 cleavage, preceding antibody-induced receptor downmodulation, and this effect might contribute to its antitumor activity in some cancers.In vivotrastuzumab inhibits angiogenesis and induces antibody-dependent cellular cytotoxicity. A limitation of trastuzumab is that its activity is largely restricted to breast cancers with the highest level of HER2 overexpression or HER2 gene amplification. However, there is a large population of breast cancers and of many other tumors that have low or moderate HER2 expression. In such tumors, HER2 functions as a preferred coreceptor to form heterodimers with HER! (EGFR), HER3 or HER4. For this reason, a humanized monoclonal antibody, called 2C4, that targets the role of HER2 as a coreceptor is under active development. 2C4 binds to a different epitope of HER2 ectodomain than trastuzumab and sterically hinders HER2 recruitment in heterodimers with other HER receptors. This results in the inhibition of signalling by HER2-based heterodimers both in cells with low and high HER2 expression.In vitro andin vivo antitumor activity has been reported in a range of breast and prostate tumor models. Therefore, 2C4 may have potential against a wide variety of solid tumors. Phase I trials are underway.

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  1. ICMHO, Medical Oncology Service, Hospital Clínic i Provincial de Barcelona, C/ Villarroel 170, Barcelona, 08036, Spain

    Dr. Joan Albanell

  2. ICMHO, Laboratory of Oncology Research, Medical Oncology Service (J.A., J.C., A.R., B.M., P.G.) & IDBAPS (J.A., P.G.), Hospital Clinic i Provincial de Barcelona, Spain

    Jordi Codony, Ana Rovira, Begoña Mellado & Pere Gascón

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  1. University of Valencia, Valencia, Spain

    Antonio Llombart-Bosch

  2. Valencian Foundation for Biomedical Research, Valencia, Spain

    Vicente Felipo

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Albanell, J., Codony, J., Rovira, A., Mellado, B., Gascón, P. (2003). Mechanism of Action of Anti-HER2 Monoclonal Antibodies: Scientific Update on Trastuzumab and 2C4. In: Llombart-Bosch, A., Felipo, V. (eds) New Trends in Cancer for the 21st Century. Advances in Experimental Medicine and Biology, vol 532. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-0081-0_21

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