Genentech BioOncology

HER2 Antibody Drug Conjugate

Genentech BioOncology is developing novel antibody—drug conjugates (ADCs) — monoclonal antibodies linked with cytotoxic agents that are designed to selectively kill cancer cells.^61,62 Through the process of targeted delivery of the cytotoxic drugs to tumor cells, ADCs have the potential to harness their antitumor effects while minimizing the impact on normal tissue.

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In the research phase of development, antibodies are chosen for their ability to selectively target cells with receptors common to tumors.⁶¹ Upon binding of the antibody—drug conjugate to cells, the ADC-receptor complex is internalized into the cell, where the cytotoxic drug is released. Cytotoxic drugs are therefore selected for their potential to induce cell death from within the tumor cell. The molecules that link the antibody to the cytotoxic agent are chosen for their ability to stabilize the conjugate and thus minimize release of the drug before the ADC is internalized into the tumor cell.^62-64

Genentech BioOncology has an ADC under development, trastuzumab-DM1, which is designed to exploit the expression of HER2. This investigational ADC has a proposed dual mechanism of action: anti-HER2 activity and targeted intracellular delivery of DM1, a maytansine derivative that is a potent antimicrotubule agent. By targeting HER2 expression on cancer cells, trastuzumab-DM1 is designed to deliver chemotherapy to tumor cells in a precise manner.⁶⁵

1: Trastuzumab-DM1 is designed to target HER2-overexpressing tumor cells by binding to HER2.⁶³

2: Antibody-bound receptors, potentially carrying trastuzumab-DM1, are internalized into the cytoplasm via endocytosis.⁶³

3: Protein components contained within the endocytic vesicle, including receptor and antibody, are proteolyzed by the lysosome, which may release the potent antimicrotubule drug.^57,63

4: When released from the antibody, the drug is then free to move to the cytoplasm of the tumor cell where it may exert its effects.⁶⁴

Journal Articles

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.

61. DiJoseph F, Goad ME, Dougher MM, et al. Potent and specific antitumour efficacy of CMC-544, a CD22-targeted immunoconjugate of calicheamicin, against systemically disseminated B cell lymphoma. Clin Cancer Res. 2004;10:8620-8629.

62. Hamann PR. Monoclonal antibody—drug conjugates. Expert Opin Ther Patents. 2005;15:1087-1103.

63. Mandler R, Kobayashi H, Hinson ER, et al. Herceptin-geldanamycin immunoconjugates: pharmacokinetics, biodistribution, and enhanced antitumor activity. Cancer Res. 2004;64:1460-1467.

64. Sanderson RJ, Hering MA, James SF, et al. In vivo drug-linker stability of an anti-CD30 dipeptide-linked auristatin immunoconjugate. Clin Cancer Res. 2005;11:843-852.

65. Parsons K, Crocker L, Leipold D, et al. Trastuzumab directed cytotoxic therapy: efficacy against HER2-positive trastuzumab-insensitive breast cancer models and enhanced response in trastuzumab-sensitive models. 2007 American Association for Cancer Research (AACR) Annual Meeting, April 14-18, 2007. Los Angeles, CA. Abstract 649.

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