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Trastuzumab Emtansine (T-DM1)

Trastuzumab emtansine is an antibody-drug conjugate (ADC) being developed by Genentech, a member of the Roche Group. ADCs are a unique combination of a precise and targeted monoclonal antibody, a stable linker, and a potent cytotoxic, and are designed to deliver potent anticancer agents to tumors in a targeted manner to limit systemic exposure.^1-3

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ADCs are designed to

• Selectively bind to specific antigens expressed on the surface of cancer cells^1,2,4

• Deliver the cytotoxic specifically to tumor cells that overexpress target tumor-associated antigens, where the cytotoxic will be released intracellularly^1,2,4

• Remain stable in circulation to prevent systemic release of the cytotoxic before reaching the target tumor cell^1,2,4

The Antibody-Drug Conjugate Trastuzumab Emtansine

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The 3 components of trastuzumab emtansine, a HER2-targeted ADC

• Trastuzumab: A monoclonal antibody that recognizes and selectively binds to HER2 antigens on the surface of tumor cells, where it exhibits anti-HER2 activity^5,6

• Cytotoxic agent DM1: A derivative of the potent antimitotic drug maytansine that inhibits tubulin polymerization.^1,5,6 In preclinical studies, maytansinoids were shown to be 24- to 270-fold more potent than paclitaxel and 2 to 3 orders of magnitude more potent than doxorubicin⁵

• Linker: A nonreducible thioether linker that is designed to remain stable in circulation prior to entering HER2-overexpressing cells⁶

Trastuzumab emtansine is designed to selectively bind to tumor-associated receptors on HER2-overexpressing cells. Receptors in the HER family play a critical role in a number of human cancers, including breast, lung, gastric, and colon cancer.^4,6,7

Based on preclinical models, trastuzumab emtansine has several proposed mechanisms of action, including anti-HER2 activity and intracellular delivery of the potent cytotoxic DM1.^4,6 Preclinical studies have demonstrated that the anticancer activities of trastuzumab emtansine may include prevention of signaling, antibody-dependent cellular toxicity, and induction of apoptosis.^5,6

The following steps illustrate the proposed mechanism of action of trastuzumab emtansine

1. Binding: In preclinical studies, trastuzumab emtansine was shown to bind to the HER2 extracellular domain with high affinity.^5,6

   

2. Endocytosis: After binding, the ADC/receptor complex is internalized into the tumor cell via endocytosis.⁶

   

3. Degradation: Once endocytosis of the ADC/receptor complex is completed, the antibody trastuzumab and the HER2 receptor are degraded, and a cytotoxic metabolite is released. The metabolite is lysine-bound emtansine, which consists of lysine, the MCC linker, and DM1.⁶

   

4. Release: DM1 is then proposed to bind to the microtubules inside the tumor cell, inhibiting their polymerization.⁶

   

5. Cell death: The inhibition of microtubule polymerization by
   trastuzumab emtansine leads to cell-cycle arrest and cell death.⁶

   

References:

1.

Chari RVJ. Targeted cancer therapy: conferring specificity to cytotoxic drugs. Acc Chem Res. 2008;41:98-107.

2.

Ducry L, Stump B. Antibody–drug conjugates: linking cytotoxic payloads to monoclonal antibodies. Bioconjug Chem. 2010;21:5-13.

3.

Jaracz S, Chen J, Kuznetsova LV, Ojima I. Recent advances in tumor-targeting
anticancer drug conjugates. Bioorg Med Chem. 2005;13:5043-5054.

4.

Carter PJ, Senter PD. Antibody-drug conjugates for cancer therapy. Cancer J. 2008;14:154-169.

5.

Junttila TT, Li G, Parsons K, Phillips GL, Sliwkowski MX. Breast Cancer Res Treat. 2011;128:347-356.

6.

Lewis Phillips GD, Li G, Dugger DL, et al. Cancer Res. 2008;68:9280-9290.

7.

Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001;2:127-137.