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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.
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.
Figure 1: Structure 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.
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.
Figure 2: Structure of a MMAE-MAB-conjugate (from Wikipedia).
| ADC | Target | Clinical indication | Linker | Development status | Developer |
| AB-3A4 ADC | KAAG-1 | Ovarian cancer; Triple Negative Breast Cancer (TNBC); Prostate | Alethia Biotherapeutic | ||
| Anti-endosialin-MC-VC-PABC-MMAE | CD248 | Neuroblastoma; Ewing sarcoma | Maleimidocaproyl-valine-citrulline linker with a p-aminobenzylcarbamate spacer | Preclinical | Genzyme |
| Anti-ETBR (RG-7636) | Endothelin receptor (ETB) | Melanoma | Peptide linker | Phase I | Genentech/Roche |
| ASG-22CE | Nectin 4 | Metastatic Urothelial Cancer (Solid Tumors) | Valine–citrulline | Phase I | Astellas Pharma Inc/Agensys, Inc. Seattle Genetics, Inc. |
| Azintuxizumab Vedotin | ABBV-838 | SLAMF7 | Multiple myeloma (MM); Plasma cell myeloma | Maleimidocaproyl-valyl-citrullinyl-p-aminobenzyloxycarbonyl (mc-val-cit-PABC) | Phase I | AbbVie |
| BAY79-4620 | CA9 (carbonic anhydrase IX) | Various solid tumors | Valine–citrulline (vc) | Phase I; This program has been discontinued (2014) | Bayer HealthCare |
| Brentuximab Vedotin | TNFRSF8 | Hodgkin Lymphoma (HL); Anaplastic Large Cell Lymphoma (ALCL) | Valine-citrulline | Approved (FDA approval August 19, 2011) | Seattle genetics, Inc. (Bothell WA USA) / Takeda Pharmaceutical Co. Ltd. (Osaka Japan) |
| CDX-014 | TIM-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/II | Celldex Therapeutics |
| Cirmtuzumab Vedotin | ROR1 | Chronic lymphocytic leukemia (CLL); B-cell lymphomas; Acute leukemias; Many different solid-tumors | Lysine-linker with a drug to antibody ratio of 2.5 | Thomas Kipps, University of California, San Diego | |
| Enapotamab Vedotin | AXL-107-MMAE | AXL | Solid 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 II | Genmab in collaboration with Seattle Genetics |
| Enfortumab Vedotin | ASG-22ME | Cell Surface Protein Nectin 4 | Bladder, breast, lung, pancreas cancer, and solid tumor | Maleimidocaproyl-valyl-citrullinyl-p-aminobenzyloxycarbonyl (mc-val-cit-PABC) | Astellas Pharma (Agensys) / Seattle Genetics | |
| Disitamab Vedotin | EGFR2, erbB-2, EGFR2, HER2, HER-2, p185c-erbB2, NEU, CD340 | Solid tumors; Advanced Breast Cancer | Maleimidocaproyl-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 Vedotin | GPNMB | Breast cancer (TNBC); Advanced or metastatic melanoma | Maleimidocaproyl-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. |
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