Mechanism of Action of Anti-Her2 Monoclonal Antibodies: Scientific Update on Trastuzumab and 2c4

摘要: The HER family of transmembrane tyrosine kinase receptors is composed four members, BER1 to HER4. HER2 a ligand-orphan receptor expressed in many human tumors and overexpressed 25-30% breast cancers. amplifies the signal provided by other forming heterodimers. essential role signaling network led development anti-HER2 monoclonal antibodies (MAbs) for cancer therapy. In particular, humanized MAb trastuzumab (Herceptin) has antitumor activity against HER2-overexpressing tumor cells widely used treatment women with overexpressing Trastuzumab induces downmodulation and, as result, inhibits critical signalling pathways (i.e. ras-Raf-MAPK PI3K/Akt) blocks cell cycle progression inducing formation p27/Cdk2 complexes. also cleavage, preceding antibody-induced downmodulation, this effect might contribute its some vivo, angiogenesis antibody-dependent cellular cytotoxicity. A limitation that largely restricted cancers highest level overexpression or gene amplification. However, there large population have low moderate expression. such tumors, functions preferred coreceptor form heterodimers HER1 (EGFR), HER3 For reason, antibody, called 2C4, targets under active development. 2C4 binds different epitope ectodomain than sterically hinders recruitment receptors. This results inhibition HER2-based both high vitro vivo been reported range prostate models. Therefore, may potential wide variety solid tumors. Phase I trials are underway.