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Mertansine, also called DM1 (and in some of its forms emtansine), is a thiol-containing
Definition of Maytansine
/ref> The monoclonal antibody binds specifically to a structure (usually a protein) occurring in a tumour, thus directing mertansine into this tumour. This concept is called targeted therapy.
ImmunoGen: Trastuzumab-DM1
maytansinoid
Maitansine (INN), or maytansine (USAN), is a cytotoxic agent. It inhibits the assembly of microtubules by binding to tubulin at the rhizoxin binding site.
It is a macrolide of the ansamycin type and can be isolated from plants of the genus ''Mayt ...
that for therapeutic purposes is attached to a monoclonal antibody through reaction of the thiol group with a linker structure to create an antibody-drug conjugate (ADC).
ADCs with this design include trastuzumab emtansine, lorvotuzumab mertansine
Lorvotuzumab mertansine (IMGN901) is an antibody-drug conjugate. It comprises the CD56-binding antibody, lorvotuzumab (huN901), with a maytansinoid cell-killing agent, DM1, attached using a disulfide linker, SPP. (When DM1 is attached to an antib ...
, and cantuzumab mertansine
Cantuzumab mertansine (SB-408075; huC242-DM1) is an antibody-drug conjugate investigated to treat colorectal cancer and other types of cancer. It is a humanized monoclonal antibody, cantuzumab (huC242) linked to a cytotoxic agent, mertansine (DM ...
. Some are still experimental; others are in regular clinical use.
Mechanism of action
Mertansine is a tubulin inhibitor, meaning that it inhibits the assembly ofmicrotubule
Microtubules are polymers of tubulin that form part of the cytoskeleton and provide structure and shape to eukaryotic cells. Microtubules can be as long as 50 micrometres, as wide as 23 to 27 nm and have an inner diameter between 11 an ...
s by binding to tubulin (at the rhizoxin
Rhizoxin is an antimitotic agent with anti-tumor activity. It is isolated from a pathogenic plant fungus ('' Rhizopus microsporus'') which causes rice seedling blight.
Biosynthesis
Rhizoxin is biosynthesised by ''Burkholderia rhizoxinica'', a ...
binding site). National Cancer InstituteDefinition of Maytansine
/ref> The monoclonal antibody binds specifically to a structure (usually a protein) occurring in a tumour, thus directing mertansine into this tumour. This concept is called targeted therapy.
Uses and chemistry
The following (experimental) drugs are antibody-drug conjugates (ADC) combining monoclonal antibodies with mertansine as the cytotoxic component. Mertansine is linked via 4-mercaptovaleric acid. ADCs include: *Bivatuzumab mertansine
Bivatuzumab mertansine is a combination of bivatuzumab, a humanized monoclonal antibody, and mertansine, a cytotoxic agent. It is designed for the treatment of squamous cell carcinoma
Squamous-cell carcinomas (SCCs), also known as epidermoid ...
* Cantuzumab mertansine
Cantuzumab mertansine (SB-408075; huC242-DM1) is an antibody-drug conjugate investigated to treat colorectal cancer and other types of cancer. It is a humanized monoclonal antibody, cantuzumab (huC242) linked to a cytotoxic agent, mertansine (DM ...
* Lorvotuzumab mertansine
Lorvotuzumab mertansine (IMGN901) is an antibody-drug conjugate. It comprises the CD56-binding antibody, lorvotuzumab (huN901), with a maytansinoid cell-killing agent, DM1, attached using a disulfide linker, SPP. (When DM1 is attached to an antib ...
(IMGN901) for CD56 positive cancers, for example multiple myeloma
Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibodies. Often, no symptoms are noticed initially. As it progresses, bone pain, an ...
Emtansine
DM1 can also be linked via a more complicated structure – 4-(3-mercapto-2,5-dioxo-1-pyrrolidinylmethyl)-cylohexanecarboxylic acid or SMCC –, in which case the International Nonproprietary Name of the conjugate formed contains the word emtansine. The abbreviation comes from the chemical designation "succinimidyl-''trans''-4-(maleimidylmethyl) cyclohexane-1-carboxylate" which is used in the primary literature as well as by the World Health Organization (WHO) despite the fact that the linker contains only oneimide
In organic chemistry, an imide is a functional group consisting of two acyl groups bound to nitrogen. The compounds are structurally related to acid anhydrides, although imides are more resistant to hydrolysis. In terms of commercial applications, ...
group according to the WHO.
DM1 and its attachment via these linkers result from ImmunoGen Inc research.
An example is:
* Trastuzumab emtansine (T-DM1), an anti- HER2/neu antibody-drug conjugate
References
{{reflist, 35em Experimental cancer drugs