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Monomethyl auristatin E

Monomethyl auristatin E (MMAE) is a synthetic antineoplastic agent. Because of its toxicity, it cannot be used as a drug itself; instead, it is linked to a monoclonal antibody (MAB) which directs it to the cancer cells. In International Nonproprietary Names for MMAE-MAB-conjugates, the name vedotin refers to MMAE plus its linking structure to the antibody. It is a potent antimitotic drug derived from peptides occurring in marine shell-less mollusc Dolabella auricularia called dolastatins which show potent activity in preclinical studies, both in vitro and in vivo, against a range of lymphomas, leukemia and solid tumors. These drugs show potency of up to 200 times that of vinblastine, another antimitotic drug used for Hodgkin lymphoma as well as other types of cancer.

MMAE is actually desmethyl-auristatin E; that is, the N-terminal amino group has only one methyl substituent instead of two as in auristatin E itself.

Mechanism of action

Monomethyl auristatin E is an antimitotic agent which inhibits cell division by blocking the polymerisation of tubulin. The linker to the monoclonal antibody is stable in extracellular fluid, but is cleaved by cathepsin once the conjugate has entered a tumor cell, thus activating the antimitotic mechanism.

:[File:MMAE-MAB-conjugate skeletal.svg|thumb|left|600px|Structure of a MMAE-MAB-conjugate. The linker, consisting of the amino acids [valine (Val) and citrulline (Cit), is cleaved by cathepsin inside tumour cells. The spacer (para-aminobenzylcarbamate) is marked green, the cathepsin-cleavable linker is blue, and the attachment group (consisting of maleimide and caproic acid) is brown. The whole radical inside the four boxes is called vedotin.]]

Monoclonal antibodies/ADCs

MMAE has been tested with various monoclonal antibodies (usually forming an antibody-drug conjugate).

  • targeting the protein CD30 which is found on malignant cells in anaplastic large cell lymphoma and Hodgkin's lymphoma:
    • Brentuximab (cAC10), 3–5 units of MMAE per molecule
  • targeting the glycoprotein GPNMB which is found in aggressive melanoma, glioma, breast cancer and other tumours:
    • Glembatumumab (CR011, CDX-011), investigated for the treatment of breast cancer and melanoma
  • targeting CD37:
    • AGS67E, to treat lymphoid malignancy
  • targeting tissue factor in recurrent or persistent cervical cancers that progress on or after first line chemotherapy regimens:
    • tisotumab vedotin

Examples:

  • Sofituzumab vedotin
  • Polatuzumab vedotin (RG7596)
  • Enfortumab vedotin
  • Pinatuzumab vedotin
  • Lifastuzumab vedotin
  • Brentuximab vedotin
  • Glembatumumab vedotin
  • Tisotumab vedotin
  • Indusatumab vedotin (MLN-0264) in phase II trials

References

References

  1. [http://www.ama-assn.org/resources/doc/usan/vedotin.pdf Statement on a nonproprietary name adopted by the USAN Council: Vedotin]
  2. (2011). "Immunotoxins and Anticancer Drug Conjugate Assemblies: The Role of the Linkage between Components". Toxins.
  3. [http://www.seagen.com/clinical_trials_sgn35.shtml Seattle Genetics: Brentuximab vedotin (SGN-35)] {{webarchive. link. (2011-07-16)
  4. Francisco, Joseph A. (2003). "cAC10-vcMMAE, an anti-CD30–monomethyl auristatin E conjugate with potent and selective antitumor activity". Blood.
  5. A. Klement. (13 May 2013). "Sprunginnovation beim Hodgkin-Lymphom: Adcetris". Österreichische Apothekerzeitung.
  6. [http://www.medicalnewstoday.com/articles/154376.php Medical News Today: CuraGen Announces Expansion Of CR011-vcMMAE Phase II Trial In Advanced Breast Cancer]
  7. [[National Cancer Institute
  8. (2015). "AGS67E, an Anti-CD37 Monomethyl Auristatin E Antibody-Drug Conjugate as a Potential Therapeutic for B/T-Cell Malignancies and AML: A New Role for CD37 in AML". Mol Cancer Ther.
  9. [https://clinicaltrials.gov/ct2/show/NCT02175433 A study of Escalating Doses of AGS67E Given as Monotherapy in Subjects With Refractory or Relapsed Lymphoid Malignancies]
  10. (May 2021). "Efficacy and safety of tisotumab vedotin in previously treated recurrent or metastatic cervical cancer (innovaTV 204/GOG-3023/ENGOT-cx6): a multicentre, open-label, single-arm, phase 2 study". The Lancet Oncology.
  11. [http://adcreview.com/indusatumab-vedotin-mln-0264-clinical-trials/ Indusatumab vedotin (MLN-0264) Clinical Trials. March 2015]
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