Targeting HER2-Positive Breast Cancer with Trastuzumab-DM1, an Antibody–Cytotoxic Drug Conjugate
2008/11/14 by Gail D. Lewis Phillips, Guangmin Li, Debra L. Dugger +20 · 37 citations
Medicine · #HER2/EGFR in Cancer Research #Monoclonal and Polyclonal Antibodies Research #Peptidase Inhibition and Analysis
paper · doi:10.1158/0008-5472.can-08-1776
Abstract
HER2 is a validated target in breast cancer therapy. Two drugs are currently approved for HER2-positive breast cancer: trastuzumab (Herceptin), introduced in 1998, and lapatinib (Tykerb), in 2007. Despite these advances, some patients progress through therapy and succumb to their disease. A variation on antibody-targeted therapy is utilization of antibodies to deliver cytotoxic agents specifically to antigen-expressing tumors. We determined in vitro and in vivo efficacy, pharmacokinetics, and toxicity of trastuzumab-maytansinoid (microtubule-depolymerizing agents) conjugates using disulfide and thioether linkers. Antiproliferative effects of trastuzumab-maytansinoid conjugates were evaluated on cultured normal and tumor cells. In vivo activity was determined in mouse breast cancer models, and toxicity was assessed in rats as measured by body weight loss. Surprisingly, trastuzumab linked to DM1 through a nonreducible thioether linkage (SMCC), displayed superior activity compared with unconjugated trastuzumab or trastuzumab linked to other maytansinoids through disulfide linkers. Serum concentrations of trastuzumab-MCC-DM1 remained elevated compared with other conjugates, and toxicity in rats was negligible compared with free DM1 or trastuzumab linked to DM1 through a reducible linker. Potent activity was observed on all HER2-overexpressing tumor cells, whereas nontransformed cells and tumor cell lines with normal HER2 expression were unaffected. In addition, trastuzumab-DM1 was active on HER2-overexpressing, trastuzumab-refractory tumors. In summary, trastuzumab-DM1 shows greater activity compared with nonconjugated trastuzumab while maintaining selectivity for HER2-overexpressing tumor cells. Because trastuzumab linked to DM1 through a nonreducible linker offers improved efficacy and pharmacokinetics and reduced toxicity over the reducible disulfide linkers evaluated, trastuzumab-MCC-DM1 was selected for clinical development.
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- The ErbB/HER family of protein-tyrosine kinases and cancer
- The role of HER2 in cancer therapy and targeted drug delivery. [europepmc]
- Microtubule-binding agents: a dynamic field of cancer therapeutics. [europepmc]
- HER2-amplified breast cancer: mechanisms of trastuzumab resistance and novel targeted therapies. [europepmc]
- Targeted therapies for breast cancer. [europepmc]
- Cancer immunotherapy comes of age. [europepmc]
- Trastuzumab emtansine for HER2-positive advanced breast cancer. [europepmc]
- Implications of receptor-mediated endocytosis and intracellular trafficking dynamics in the development of antibody drug conjugates. [europepmc]
- Site-specific antibody drug conjugates for cancer therapy. [europepmc]
- ERBB receptors: from oncogene discovery to basic science to mechanism-based cancer therapeutics. [europepmc]
- Trastuzumab emtansine: mechanisms of action and drug resistance. [europepmc]
- Antibody drug conjugates: design and selection of linker, payload and conjugation chemistry. [europepmc]
- Current ADC Linker Chemistry. [europepmc]
- Antibody-drug conjugates as novel anti-cancer chemotherapeutics. [europepmc]
- A Comprehensive Review on Cyclodextrin-Based Carriers for Delivery of Chemotherapeutic Cytotoxic Anticancer Drugs. [europepmc]
- The role of HER2, EGFR, and other receptor tyrosine kinases in breast cancer. [europepmc]
- Trastuzumab Emtansine With or Without Pertuzumab Versus Trastuzumab Plus Taxane for Human Epidermal Growth Factor Receptor 2-Positive, Advanced Breast Cancer: Primary Results From the Phase III MARIANNE Study. [europepmc]
- Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial. [europepmc]
- HER2-positive breast cancer: new therapeutic frontiers and overcoming resistance. [europepmc]
- Active Targeting Strategies Using Biological Ligands for Nanoparticle Drug Delivery Systems. [europepmc]
- Antibody Structure and Function: The Basis for Engineering Therapeutics. [europepmc]
- Mechanisms of resistance to trastuzumab emtansine (T-DM1) in HER2-positive breast cancer. [europepmc]
- Targeting HER2 with Trastuzumab Deruxtecan: A Dose-Expansion, Phase I Study in Multiple Advanced Solid Tumors. [europepmc]
- Breast Cancer Treatments: Updates and New Challenges. [europepmc]
- Antibody drug conjugate: the "biological missile" for targeted cancer therapy. [europepmc]
- Targeting HER2-positive breast cancer: advances and future directions. [europepmc]
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