What is Monomethyl Auristatin E (MMAE)?

What is Monomethyl Auristatin E (MMAE)?

Monomethyl auristatin E (MMAE, the commercial name is Vedotin) is a very effective anti-mitotic agent, which can inhibit cell division by preventing the polymerization of tubulin. It is a synthetic anti-tumor drug. Due to its high toxicity, it cannot be used as a medicine by itself. Instead, it is linked to monoclonal antibodies (MAB) that direct it to cancer cells.

Structure of MMAE

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

Structure of MMAE. Figure 1: Structure of MMAE.

Biological Activity of MMAE

MMAE is 100-1000 times more potent than doxorubicin and cannot be used as a drug alone. At present, researches on MMAE conjugated with monoclonal antibodies (mAbs) through chemical linkers to form antibody-drug conjugates or ADCs have been widely carried out. The monoclonal antibodies can recognize the expression of specific markers in cancer cells and direct MMAE to specific targets.

Mechanism of action

Monomethyl auristatin E is an anti-mitotic agent that inhibits cell division by preventing the polymerization of tubulin. The linker that connects the MMAE to the monoclonal antibody is stable in the extracellular fluid, but once the antibody-drug conjugate binds to the target cancer cell antigen and enters the cancer cell, cathepsin will cleave the ADC, and then the ADC will release the toxic MMAE and effectively activate its anti-mitotic mechanism. Antibody-drug conjugates can enhance the anti-tumor effects of antibodies and reduce the adverse systemic effects of highly effective cytotoxic agents.

Structure of a MMAE-MAB-conjugate Figure 2: Structure of a MMAE-MAB-conjugate (from Wikipedia).

ADCs drugs with MMAE

ADCTarget Clinical indicationLinker Development statusDeveloper
AB-3A4 ADCKAAG-1Ovarian cancer; Triple Negative Breast Cancer (TNBC); ProstateAlethia Biotherapeutic
Anti-endosialin-MC-VC-PABC-MMAECD248Neuroblastoma; Ewing sarcomaMaleimidocaproyl-valine-citrulline linker with a p-aminobenzylcarbamate spacer  PreclinicalGenzyme
Anti-ETBR (RG-7636)Endothelin receptor (ETB)MelanomaPeptide linkerPhase IGenentech/Roche
ASG-22CENectin 4Metastatic Urothelial Cancer (Solid Tumors)Valine–citrullinePhase IAstellas Pharma Inc/Agensys, Inc. Seattle Genetics, Inc.
Azintuxizumab Vedotin | ABBV-838SLAMF7Multiple myeloma (MM); Plasma cell myelomaMaleimidocaproyl-valyl-citrullinyl-p-aminobenzyloxycarbonyl (mc-val-cit-PABC)Phase IAbbVie
BAY79-4620CA9 (carbonic anhydrase IX)Various solid tumorsValine–citrulline (vc)Phase I; This program has been discontinued (2014)Bayer HealthCare
Brentuximab VedotinTNFRSF8Hodgkin Lymphoma (HL); Anaplastic Large Cell Lymphoma (ALCL)Valine-citrullineApproved (FDA approval August 19, 2011)    Seattle genetics, Inc. (Bothell WA USA) / Takeda Pharmaceutical Co. Ltd. (Osaka Japan)
CDX-014TIM-1 (Transmembrane protein T-cell immunoglobulin mucin-1)Kidney cancer, Clear Cell Renal Cell Carcinoma, Papillary Cell Renal Cell Carcinoma, Renal cell carcinoma (RCC)Maleimidocaproyl-valyl-citrullinyl-p-aminobenzyloxycarbonyl (mc-val-cit-PABC)Preclinical, Phase I/IICelldex Therapeutics
Cirmtuzumab VedotinROR1Chronic lymphocytic leukemia (CLL); B-cell lymphomas; Acute leukemias; Many different solid-tumorsLysine-linker with a drug to antibody ratio of 2.5Thomas Kipps, University of California, San Diego
Enapotamab Vedotin | AXL-107-MMAEAXLSolid tumors including - Ovarian cancer; - Non-small Cell Lung Cancer (NSCLC); - Endometrial cancer; - Cervical cancer; - Thyroid Cancer.Maleimidocaproyl-valyl-citrullinyl-p-aminobenzyloxycarbonyl (mc-val-cit-PABC)Phase I  Phase IIGenmab in collaboration with Seattle Genetics
Enfortumab Vedotin | ASG-22MECell Surface Protein Nectin 4Bladder, breast, lung, pancreas cancer, and solid tumorMaleimidocaproyl-valyl-citrullinyl-p-aminobenzyloxycarbonyl (mc-val-cit-PABC)Astellas Pharma (Agensys)  /  Seattle Genetics
Disitamab VedotinEGFR2, erbB-2, EGFR2, HER2, HER-2, p185c-erbB2, NEU, CD340Solid tumors; Advanced Breast CancerMaleimidocaproyl-valyl-citrullinyl-p-aminobenzyloxycarbonyl (mc-val-cit-PABC)Phase I (Sold Tumors) Phase II (Advanced Breast Cancers)Yantai Rongchang Biological Engineering, RemeGen (Shandong China) and MabPlex
Glembatumumab VedotinGPNMBBreast cancer (TNBC); Advanced or metastatic melanomaMaleimidocaproyl-valyl-citrullinyl-p-aminobenzyloxycarbonyl (mc-val-cit-PABC)Phase I Phase II Phase III (Breast Cancer); Phase II (Unresectable Melanoma at stage III or IV)Celldex Therapeutics, Inc.

References:

  1. Dosio, F.; Brusa, P.; Cattel, L. Immunotoxins and Anticancer Drug Conjugate Assemblies: The Role of the Linkage between Components. Toxins. 2011; 3(12):848-883.
  2. Francisco, Joseph A; et al. cAC10-vcMMAE, an anti-CD30–monomethyl auristatin E conjugate with potent and selective antitumor activity. Blood. 2003; 102(4):1458-1465.
  3. 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;26(8):925-32.
* Only for research. Not suitable for any diagnostic or therapeutic use.
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