Genentech BioOncology

 

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HER Dimerization Inhibition

HER dimerization — pairing of human epidermal receptors — is essential for the activation of HER signaling pathways and represents a potential therapeutic target.⁵⁶ Genentech has developed a humanized monoclonal antibody, pertuzumab, designed to inhibit the process of HER dimerization. Pertuzumab is the first in a new class of targeted agents known as HER dimerization inhibitors.⁵⁷

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Inhibition of the formation of HER2 dimer pairs may prevent inappropriate activation of HER intracellular signaling cascades in tumor cells.⁵⁷ Preclinical experiments in a number of solid tumor types have identified HER dimerization as a key step in the ability of cells to independently proliferate, whether or not HER2 is overexpressed.^57,58 These preclinical studies suggest that it may be possible to develop antibodies with the potential to inhibit HER dimerization regardless of HER2 expression levels.^58,59

1: Pertuzumab is a humanized monoclonal antibody designed to bind to the dimerization domain of HER2 — a region essential for HER protein pairing.⁵⁵

2: Pertuzumab, the first in a new class of targeted anticancer therapeutic agents known as HER dimerization inhibitors, is designed to bind to HER2 and prevent it from forming homo- or heterodimers with any other HER family members.^55,60

3: HER2 is the preferred dimerization partner in the activation of HER signaling. Inhibition of HER2 dimer pairs may prevent the activation of several intracellular signaling cascades that can drive carcinogenesis, including the PI3K and MAPK pathways.^55,59

Journal Articles

55. Franklin MC, Carey KD, Vajdos FF, et al. Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell. 2004;5:317-328.

56. Baselga J. A new anti-ErbB2 strategy in the treatment of cancer: prevention of ligand-dependent ErbB2 receptor heterodimerization. Cancer Cell. 2002;2:92-95.

57. Adams CW, Allison DE, Flagella K, et al. Humanization of a recombinant monoclonal antibody to produce a therapeutic HER dimerization inhibitor, pertuzumab. Cancer Immunol Immunother. 2006;55:717-727.

58. Johnson BE, Janne PA. Rationale for a Phase II trial of pertuzumab, a HER2 dimerization inhibitor, in patients with non-small cell lung cancer. Clin Cancer Res. 2006;12:4436s-4440s.

59. Agus DB, Gordon MS, Taylor C, et al. Phase I clinical study of pertuzumab, a novel HER dimerization inhibitor, in patients with advanced cancer. J Clin Oncol. 2005;23:2534-2543.

60. Agus DB, Akita RW, Fox WD, et al. Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. Cancer Cell. 2002;2:127-137.

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