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Mertansine

N2'-deacetyl-N2'-(3-mercapto-1-oxopropyl)-maytansine Mertansine, also called DM1 (and in some of its forms emtansine), is a thiol-containing maytansinoid that for therapeutic purposes is attached to a monoclonal antibody through reaction of the thiol group with a linker structure to create an antibody-drug conjugate (ADC).

ADCs with this design include trastuzumab emtansine, lorvotuzumab mertansine, and cantuzumab mertansine. Some are still experimental; others are in regular clinical use.

Mechanism of action

Mertansine is a tubulin inhibitor, meaning that it inhibits the assembly of microtubules by binding to tubulin (at the rhizoxin binding site).

The monoclonal antibody binds specifically to a structure (usually a protein) occurring in a tumour, thus directing mertansine into this tumour. This concept is called targeted therapy.

Uses and chemistry

The following (experimental) drugs are antibody-drug conjugates (ADC) combining monoclonal antibodies with mertansine as the cytotoxic component. Mertansine is linked via 4-mercaptovaleric acid.

ADCs include:

  • Bivatuzumab mertansine
  • Cantuzumab mertansine
  • Lorvotuzumab mertansine (IMGN901) for CD56 positive cancers, for example multiple myeloma

Emtansine

DM1 can also be linked via a more complicated structure – 4-(3-mercapto-2,5-dioxo-1-pyrrolidinylmethyl)-cylohexanecarboxylic acid or SMCC –, in which case the International Nonproprietary Name of the conjugate formed contains the word emtansine. The abbreviation comes from the chemical designation "succinimidyl-trans-4-(maleimidylmethyl) cyclohexane-1-carboxylate" which is used in the primary literature as well as by the World Health Organization (WHO) despite the fact that the linker contains only one imide group according to the WHO.

DM1 and its attachment via these linkers result from ImmunoGen Inc research.

An example is:

  • Trastuzumab emtansine (T-DM1), an anti-HER2/neu antibody-drug conjugate

References

References

  1. Zámečník, Josef. (2019). "Patologie". PRAGER PUBLISHING.
  2. [[National Cancer Institute]]: [http://www.cancer.gov/Templates/drugdictionary.aspx?CdrID=39492 Definition of Maytansine]
  3. (2003). "International Nonproprietary Names for Pharmaceutical Substances (INN): List 89". WHO.
  4. (6 December 2009). "ImmunoGen reports encouraging clinical data of IMGN901". The Medical News.
  5. (May 2012). "Clinical pharmacology of trastuzumab emtansine (T-DM1): an antibody–drug conjugate in development for the treatment of HER2-positive cancer". Cancer Chemother Pharmacol.
  6. (2010). "International Nonproprietary Names for Pharmaceutical Substances (INN): List 103". WHO.
  7. (2012). "International Nonproprietary Names (INN) for pharmaceutical substances: Names for radicals, groups & others". WHO.
  8. National Cancer Institute: [http://www.cancer.gov/drugdictionary/?CdrID=564399 trastuzumab-MCC-DM1 antibody-drug conjugate]
  9. [http://www.immunogen.com/wt/page/trastuzumab_DM1 ImmunoGen: Trastuzumab-DM1] {{webarchive. link. (2010-10-20)
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