Monomethyl auristatin E
Encyclopedia
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 Name
s for MMAE-MAB-conjugates, MMAE is referred to as vedotin.
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 tumour cell, thus activating the antimitotic mechanism.
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
cells. In International Nonproprietary Name
International Nonproprietary Name
An International Nonproprietary Name is the official nonproprietary or generic name given to a pharmaceutical substance, as designated by the World Health Organization...
s for MMAE-MAB-conjugates, MMAE is referred to as vedotin.
Mechanism of action
Monomethyl auristatin E is an antimitotic agent which inhibits cell divisionCell division
Cell division is the process by which a parent cell divides into two or more daughter cells . Cell division is usually a small segment of a larger cell cycle. This type of cell division in eukaryotes is known as mitosis, and leaves the daughter cell capable of dividing again. The corresponding sort...
by blocking the polymerisation of tubulin
Tubulin
Tubulin is one of several members of a small family of globular proteins. The most common members of the tubulin family are α-tubulin and β-tubulin, the proteins that make up microtubules. Each has a molecular weight of approximately 55 kiloDaltons. Microtubules are assembled from dimers of α- and...
. The linker to the monoclonal antibody is stable in extracellular fluid
Extracellular fluid
Extracellular fluid usually denotes all body fluid outside of cells. The remainder is called intracellular fluid.In some animals, including mammals, the extracellular fluid can be divided into two major subcompartments, interstitial fluid and blood plasma...
, but is cleaved by cathepsin
Cathepsin
Cathepsins are proteases: proteins that break apart other proteins, found in many types of cells including those in all animals. There are approximately a dozen members of this family, which are distinguished by their structure, catalytic mechanism, and which proteins they cleave...
once the conjugate has entered a tumour cell, thus activating the antimitotic mechanism.
Monoclonal antibodies
MMAE has been tested with various monoclonal antibodies.- targeting the protein CD30CD30CD30, also known as TNFRSF8, is a cell membrane protein of the tumor necrosis factor receptor family and tumor marker.This receptor is expressed by activated, but not by resting, T and B cells. TRAF2 and TRAF5 can interact with this receptor, and mediate the signal transduction that leads to the...
which is found on malignant cells in anaplastic large cell lymphomaAnaplastic large cell lymphomaAnaplastic large-cell lymphoma is a type of non-Hodgkin lymphoma that features in the World Health Organisation classification of lymphomas.Its name derives from anaplasia and large-cell lymphoma.-Signs and symptoms:...
and Hodgkin's lymphomaHodgkin's lymphomaHodgkin's lymphoma, previously known as Hodgkin's disease, is a type of lymphoma, which is a cancer originating from white blood cells called lymphocytes...
:- Brentuximab (cAC10): 3–5 units of MMAE per molecule
- targeting the glycoprotein GPNMBGPNMBTransmembrane glycoprotein NMB is a protein that in humans is encoded by the GPNMB gene. The mouse and rat orthologues of GPNMB are known as DC-HIL and Osteoactivin , respectively. Two transcript variants encoding 560 and 572 amino acid isoforms have been characterized for this gene in humans...
which is found in aggressive melanomaMelanomaMelanoma is a malignant tumor of melanocytes. Melanocytes are cells that produce the dark pigment, melanin, which is responsible for the color of skin. They predominantly occur in skin, but are also found in other parts of the body, including the bowel and the eye...
, gliomaGliomaA glioma is a type of tumor that starts in the brain or spine. It is called a glioma because it arises from glial cells. The most common site of gliomas is the brain.-By type of cell:...
, breast cancerBreast cancerBreast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
and other tumours:- Glembatumumab (CR011, CDX-011): investigated for the treatment of breast cancer and melanoma