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Monomethyl Auristatin E (MMAE)

Monomethyl Auristatin E

Chemical Name: (S)-N-((3R,4S,5S)-1-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptan-4-yl)-N,3-dimethyl-2-((S)-3-methyl-2-(methylamino)butanamido)butanamide
Molecular Weight: 717.98
Formula: C39H67N5O7
CAS: 474645-27-7
Solubility: DMSO up to 20 mM

Biological Activity
Monomethyl auristatin E (MMAE, vedotin) is a very potent antimitotic agent that inhibits cell division by blocking the polymerisation of tubulin. [1,2,3] The family of auristatins are synthetic analogues of the antineoplastic natural product Dolastatin 10,  ultrapotent cytotoxic microtubule inhibitors that are clinically used as payloads in antibody-drug conjugates. [6][7]

Monomethyl auristatin E or MMAE is 100-1000 times more potent than doxorubicin (Adriamycin/Rubex) and cannot be used as a drug itself. However, as part of an antibody-drug conjugate or ADC, MMAE is linked to a monoclonal antibody (mAb) that recognizes a specific marker expression in cancer cells and directs MMAE to a specific, targeted cancer cell.

The linker linking MMAE to the monoclonal antibody is stable in extracellular fluid, but is cleaved by cathepsin once the antibody-drug-conjugate has bound to the targeted cancer cell antigen and entered the cancer cell, after which the ADC releases the toxic MMAE and activates the potent anti-mitotic mechanism. Antibody-drug conjugates enhance the antitumor effects of antibodies and reduce adverse systemic effects of highly potent cytotoxic agents.[2,3,4,5]

See: ADC Review / Knowledge Center


References:
[1] Francisco JA, Cerveny CG, Meyer DL, Mixan BJ, Klussman K, Chace DF, Rejniak SX et al. cAC10-vcMMAE, an anti-CD30-monomethyl auristatin E conjugate with potent and selective antitumor activity. Blood. 2003 Aug 15;102(4):1458-65. Epub 2003 Apr 24.

[2] Junutula JR, Raab H, Clark S, Bhakta S, Leipold DD, Weir S, Chen Y, et al. Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index. Nat Biotechnol. 2008 Aug;26(8):925-32. doi: 10.1038/nbt.1480. Epub 2008 Jul 20.

[3] Asundi J, Reed C, Arca J, McCutcheon K, Ferrando R, Clark S, Luis E, Tien J, et al. An antibody-drug conjugate targeting the endothelin B receptor for the treatment of melanoma. Clin Cancer Res. 2011 Mar 1;17(5):965-75. doi: 10.1158/1078-0432.CCR-10-2340. Epub 2011 Jan 18.

[4] Younes A, Gopal AK, Smith SE, Ansell SM, Rosenblatt JD, Savage KJ, Ramchandren R, et al. Results of a Pivotal Phase II Study of Brentuximab Vedotin for Patients With Relapsed or Refractory Hodgkin’s Lymphoma. J Clin Oncol. 2012 Jun 20;30(18):2183-9. doi: 10.1200/JCO.2011.38.0410. Epub 2012 Mar 26.

[5] Monomethyl auristatin E (WikiPedia)

[6] Pettit GR, Srirangam JK, Barkoczy J, Williams MD, Durkin KP, et al Antineoplastic agents 337. Synthesis of dolastatin 10 structural modifications. Anticancer Drug Des. 1995 Oct;10(7):529-44.

[7] Doronina SO, Toki BE, Torgov MY, Mendelsohn BA, Cerveny CG, Chace DF, DeBlanc RL, et al. Development of potent monoclonal antibody auristatin conjugates for cancer therapy. Nat Biotechnol. 2003 Jul;21(7):778-84. Epub 2003 Jun 1.


Last Editorial Review: March 7, 2015

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