Monomethyl auristatin E (MMAE) is a synthetic

antineoplastic agent Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (list of chemotherapeutic agents, chemotherapeutic agents or alkylating agents) as part of a standardized ...

. Because of its toxicity, it cannot be used as a drug itself; instead, it is linked to a

monoclonal antibody A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell Lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell. Monoclonal antibodies ca ...

(MAB) which directs it to the

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

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 A mitotic inhibitor is a drug that inhibits mitosis, or cell division. These drugs disrupt microtubules, which are structures that pull the chromosomes apart when a cell divides. Mitotic inhibitors are used in cancer treatment, because cancer cel ...

drug derived from peptides occurring in marine shell-less mollusc '' Dolabella auricularia'' called dolastatins which show potent activity in preclinical studies, both ''

in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...

'' and ''

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...

'', against a range of

lymphoma Lymphoma is a group of blood and lymph tumors that develop from lymphocytes (a type of white blood cell). In current usage the name usually refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include enlar ...

leukemia Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ' ...

and solid tumors. These drugs show potency of up to 200 times that of

vinblastine Vinblastine (VBL), sold under the brand name Velban among others, is a chemotherapy medication, typically used with other medications, to treat a number of types of cancer. This includes Hodgkin's lymphoma, non-small cell lung cancer, bladder ca ...

, another antimitotic drug used for

Hodgkin lymphoma Hodgkin lymphoma (HL) is a type of lymphoma, in which cancer originates from a specific type of white blood cell called lymphocytes, where multinucleated Reed–Sternberg cells (RS cells) are present in the patient's lymph nodes. The condition wa ...

as well as other types of cancer. MMAE is actually desmethyl-auristatin E; that is, the N-terminal

amino In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent s ...

group has only one

methyl In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula . In formulas, the group is often abbreviated as Me. This hydrocarbon group occurs in many ...

substituent instead of two as in auristatin E itself.

Mechanism of action

Monomethyl auristatin E is an antimitotic agent which inhibits

cell division Cell division is the process by which a parent cell (biology), cell divides into two daughter cells. Cell division usually occurs as part of a larger cell cycle in which the cell grows and replicates its chromosome(s) before dividing. In eukar ...

by blocking the polymerisation of

tubulin Tubulin in molecular biology can refer either to the tubulin protein superfamily of globular proteins, or one of the member proteins of that superfamily. α- and β-tubulins polymerize into microtubules, a major component of the eukaryotic cytoske ...

. The linker to the monoclonal antibody is stable in

extracellular fluid In cell biology, extracellular fluid (ECF) denotes all body fluid outside the cells of any multicellular organism. Total body water in healthy adults is about 60% (range 45 to 75%) of total body weight; women and the obese typically have a lower ...

, but is cleaved by

cathepsin Cathepsins (Ancient Greek ''kata-'' "down" and ''hepsein'' "boil"; abbreviated CTS) are proteases ( enzymes that degrade proteins) found in all animals as well as other organisms. There are approximately a dozen members of this family, which are d ...

once the conjugate has entered a tumor cell, thus activating the antimitotic mechanism.Seattle Genetics: Brentuximab vedotin (SGN-35)
: MMAE-MAB-conjugate skeletal

Monoclonal antibodies/ADCs

MMAE has been tested with various monoclonal antibodies (usually forming an

antibody-drug conjugate Antibody-drug conjugates or ADCs are a class of biopharmaceutical drugs designed as a targeted therapy for treating cancer. Unlike chemotherapy, ADCs are intended to target and kill tumor cells while sparing healthy cells. As of 2019, some 56 phar ...

). *targeting the protein

CD30 CD30, also known as TNFRSF8 (TNF receptor superfamily member 8), is a cell membrane protein of the tumor necrosis factor receptor family and a tumor marker. Function This receptor is expressed by activated, but not by resting, T and B cells ...

which is found on malignant cells in

anaplastic large cell lymphoma Anaplastic large cell lymphoma (ALCL) refers to a group of non-Hodgkin lymphomas in which aberrant T cells proliferate uncontrollably. Considered as a single entity, ALCL is the most common type of peripheral lymphoma and represents ~10% of all per ...

and

Hodgkin's lymphoma Hodgkin lymphoma (HL) is a type of lymphoma, in which cancer originates from a specific type of white blood cell called lymphocytes, where multinucleated Reed–Sternberg cells (RS cells) are present in the patient's lymph nodes. The condition wa ...

: **

Brentuximab Brentuximab vedotin, sold under the brand name Adcetris, is an antibody-drug conjugate medication used to treat relapsed or refractory Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (ALCL), a type of T cell non-Hodgkin lymphoma. ...

(cAC10), 3–5 units of MMAE per molecule *targeting the glycoprotein

GPNMB Transmembrane glycoprotein NMB is a protein that in humans is encoded by the ''GPNMB'' gene. Two transcript variants encoding 560 and 572 amino acid isoforms have been characterized for this gene in humans. The mouse and rat orthologues of GPNMB a ...

which is found in aggressive

melanoma Melanoma, also redundantly known as malignant melanoma, is a type of skin cancer that develops from the pigment-producing cells known as melanocytes. Melanomas typically occur in the skin, but may rarely occur in the mouth, intestines, or eye ( ...

glioma A glioma is a type of tumor that starts in the glial cells of the brain or the spine. Gliomas comprise about 30 percent of all brain tumors and central nervous system tumours, and 80 percent of all malignant brain tumours. Signs and symptoms ...

breast cancer Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a re ...

and other tumours: **

Glembatumumab Glembatumumab vedotin (also known as CDX-011 and CR011-vcMMAE) is an antibody-drug conjugate (ADC) that targets cancer cells expressing transmembrane glycoprotein NMB (GPNMB). In May 2010, the U.S FDA granted Fast Track designation to CDX-011 fo ...

(CR011, CDX-011), investigated for the treatment of breast cancer and melanoma * targeting

CD37 Leukocyte antigen CD37 is a protein that in humans is encoded by the ''CD37'' gene. Function The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell- ...

: ** AGS67E, to treat

lymphoid malignancy Tumors of the hematopoietic and lymphoid tissues (American English) or tumours of the haematopoietic and lymphoid tissues (British English) are tumors that affect the blood, bone marrow, lymph, and lymphatic system. Because these tissues are al ...

* targeting tissue factor in recurrent or persistent cervical cancers that progress on or after first line chemotherapy regimens: **

tisotumab vedotin Tisotumab vedotin, sold under the brand name Tivdak, is an antibody-drug conjugate used to treat cervical cancer. It is a combination of tisotumab, a monoclonal antibody against tissue factor, and monomethyl auristatin E (MMAE), a potent inh ...

Examples: * Sofituzumab vedotin *

Polatuzumab vedotin Polatuzumab vedotin (INN; brand name Polivy, is an antibody-drug conjugate or ADC designed for the treatment of cancer. The US Food and Drug Administration approved polatuzumab vedotin in June 2019 for treatment of diffuse large B-cell lymphoma ...

(RG7596) *

Enfortumab vedotin Enfortumab vedotin, sold under the brand name Padcev, is an antibody-drug conjugate used for the treatment of urothelial cancer. It is a nectin-4-directed antibody and microtubule inhibitor conjugate. Enfortumab refers to the monoclonal antibody ...

* Pinatuzumab vedotin * Lifastuzumab vedotin *

Brentuximab vedotin Brentuximab vedotin, sold under the brand name Adcetris, is an antibody-drug conjugate medication used to treat relapsed or refractory Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (ALCL), a type of T cell non-Hodgkin lymphoma. ...

Glembatumumab vedotin Glembatumumab vedotin (also known as CDX-011 and CR011-vcMMAE) is an antibody-drug conjugate (ADC) that targets cancer cells expressing transmembrane glycoprotein NMB (GPNMB). In May 2010, the U.S FDA granted Fast Track designation to CDX-011 ...

Tisotumab vedotin Tisotumab vedotin, sold under the brand name Tivdak, is an antibody-drug conjugate used to treat cervical cancer. It is a combination of tisotumab, a monoclonal antibody against tissue factor, and monomethyl auristatin E (MMAE), a potent inh ...

* Indusatumab vedotin (MLN-0264) in phase II trialsIndusatumab vedotin (MLN-0264) Clinical Trials. March 2015
/ref>

References

{{reflist Mitotic inhibitors

Mechanism of action

Monoclonal antibodies/ADCs

See also

References