Everything about Monomethyl auristatin E(MMAE)

 

  1.What is Antineoplastic Agent MMAE?
  2.Monomethyl auristatin E Mechanism of Action
  3. Monomethyl auristatin E Biological Activity
  4.Monomethyl auristatin E Monoclonal Antibodies
  5.Monomethyl auristatin E research
  6.Monomethyl auristatin E(MMAE) structural features?
  7. Monomethyl auristatin E review

 


 

Monomethyl auristatin E(MMAE) powder video

 

 



 

I.Monomethyl auristatin E(MMAE) powder basic Characters:

 

Name: Monomethyl auristatin E(MMAE) powder
CAS: 474645-27-7
Molecular Formula: C39H67N5O7
Molecular Weight: 717.97858
Melt Point: 238-240°C
Storage Temp: Store in original container,between 36 to 46 degrees F
Color: White powder

 


 

1. What is Antineoplastic Agent Monomethyl auristatin E(MMAE)?aasraw

 

Monomethyl auristatin E (MMAE) is a synthetic antineoplastic agent, it is also known as Seattle Genetics and
Monomethyl auristatin F, CAS No. is 474645-27-7. Because of its toxicity, it is typically linked to a monoclonal antibody which directs it to the cancer cells. Because MMAE is covalently bound to the antibody and is intended to be released only at the target cancer cell, the plasma concentrations of free MMAE are normally quite low. In our laboratory, a LC-MS/MS method was previously developed with an LLOQ of 10 pg/mL. While using this method to support regulated sample analysis, the majority of study samples concentrations were <LLOQ, indicating that the current LLOQ is not adequate. Here we report a “heart-cut” 2D-LC-MS/MS method with peak summing for the quantitation of MMAE in monkey plasma with a calibration range of 1.0-1200 pg/mL.

 

474645-27-7

 

Name: Monomethyl auristatin E(MMAE)

Chemical name: (S)-N-((3R,4S,5S)-1-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptan-4-yl)-N,3-dimethyl-2-((S)-3-methyl-2-(methylamino)butanamido)butanamide

Molecular Weight: 717.98

Formula: C39H67N5O7

CAS: 474645-27-7

MMAE Solubility: DMSO up to 20 mM

 


 

2. Monomethyl auristatin E Mechanism of Actionaasraw

 

Monomethyl auristatin E mechanism of action is an antimitotic agent which inhibits cell division 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.

 


 

3. Monomethyl auristatin E Biological Activityaasraw

 

Monomethyl auristatin E (MMAE, vedotin) is a very potent antimitotic agent that inhibits cell division by blocking the polymerisation of tubulin.The family of auristatins are synthetic analogues of the antineoplastic natural product Dolastatin 10,  ultrapotent cytotoxic microtubule inhibitors that are clinically used as payloads in antibody-drug conjugates.

Monomethyl auristatin E or MMAE is 100-1000 times more potent than doxorubicin (Adriamycin/Rubex) and cannot be used as a drug itself. However, as part of an antibody-drug conjugate or ADC, Monomethyl auristatin E (MMAE, vedotin) is linked to a monoclonal antibody (mAb) that recognizes a specific marker expression in cancer cells and directs MMAE to a specific, targeted cancer cell.

The linker linking MMAE to the monoclonal antibody is stable in extracellular fluid, but is cleaved by cathepsin once the antibody-drug-conjugate has bound to the targeted cancer cell antigen and entered the cancer cell, after which the ADC releases the toxic MMAE and activates the potent anti-mitotic mechanism. Antibody-drug conjugates enhance the antitumor effects of antibodies and reduce adverse systemic effects of highly potent cytotoxic agents.

 

Raw Monomethyl auristatin E powder (474645-27-7) hplc≥98% | AASraw powder

 


 

4. Monomethyl auristatin E Monoclonal Antibodiesaasraw

 

MMAE has been tested with various monoclonal antibodies (usually forming an antibody-drug conjugate).

-targeting the protein CD30 which is found on malignant cells in anaplastic large cell lymphoma and Hodgkin’s lymphoma:
-Brentuximab (cAC10), 3–5 units of MMAE per molecule
-targeting the glycoprotein GPNMB which is found in aggressive melanoma, glioma, breast cancer and other tumours:
-Glembatumumab (CR011, CDX-011), investigated for the treatment of breast cancer and melanoma
-targeting CD37:
-AGS67E, to treat lymphoid malignancy

 

Examples:

  • Sofituzumab                             vedotin
  • Polatuzumab                            vedotin                         (RG7596)
  • Enfortumab                              vedotin
  • Pinatuzumab                            vedotin
  • Lifastuzumab                            vedotin
  • Brentuximab                             vedotin
  • Glembatumumab                    vedotin
  • Indusatumab                             vedotin                         (MLN-0264) in phase II trials

 


 

5. Monomethyl auristatin E researchaasraw

 

Breast cancer is a heterogeneous disease characterized by differential responses to targeted and chemotherapeutic agents. Antibody-drug conjugates are one of the promising strategies for the treatment of breast cancer. Monomethyl auristatin E (MMAE) is a highly potent microtubule inhibitor and a common payload used for development of antibody-drug conjugates. The purpose of this Monomethyl auristatin E research  was to investigate the cytotoxic effects of MMAE on breast cancer cell lines. Our findings indicated that MMAE possesses dose- and time-dependent cytotoxic activities against human breast cancer cells. The morphological features of the treated cells were supportive of the cytotoxic activity of MMAE. The results of the MTT assay showed that MMAE has a significant cytotoxicity against MDA-MB-468  and, to a lesser degree, MDA-MB-453 cells.

Breast cancer is one of the most commonly diagnosed malignancies and the leading cause of cancer-related deaths in women worldwide1, accounting for an estimated 1 million new diagnoses and 400,000 deaths  per year2. Several chemotherapeutic drugs have been approved for the treatment of breast cancer, but  effective treatment remains elusive.

Monomethyl auristatin E(MMAE),a highly potent auristatin, remains a hot topic in ADC studies. MMAE is an antimitotic agent which inhibits cell division by blocking the polymerisation of tubulin, representing as much  as  100-  to  1000-fold  more  potent  than standard chemotherapeutic   drugs   such   as   vinblastine16,17. The
drug is currently used as a payload for development of a variety of ADCs, including Brentuximab vedotin (Adcetis®, SGN-35), an FDA-approved ADC, and more than fourteen ADCs in different phases of clinical trials. More importantly, MMAE are extensively used as a payload for development of ADCs against breast cancer, including Glembatumomab vedotin (CDX-011, phase  II) and SGN-LIV1A  (phase  I)16.  Determination  of MMAE
cytotoxic potential in breast cancer cell lines may  increase the chances of successful ADCs for the  treatment of breast cancer.
In the present study, we sought to investigate the anticancer  activity  of  MMAE  in  two  kinds  of   breast cancer cell lines, MDA-MB-468 and MDA-MB-453. The cells were exposed to various concentrations of MMAE and the growth response was measured in a dose- and time-dependent manner. Then, cell Cytotoxicity was determined using the MTT assay.

 

Monomethyl auristatin E (MMAE) research

 

Effects of Monomethyl auristatin E (MMAE) on the proliferation of MDA-MB-468 (A) and MDA-MB-453 (B) cells after 48- and 72-hour treatment with Monomethyl auristatin E (MMAE). Different concentrations (1, 10, 100, and 1000 ng/ml) of MMAE were assessed on the cell lines, and the cytotoxcity rate was measured using the MTT assay after a 48- and 72-hour exposure period, as described in “Materials and Methods”. The data represent the mean and the error bars indicate standard deviation (SD) of two independent experiments (ns: P > 0.05, *: P ≤ 0.05, **: P ≤ 0.01,
***: P ≤ 0.001, and ****: P ≤ 0.0001).

 

Monomethyl auristatin E (MMAE) research

 

Comparison of the cytotoxic activity of Monomethyl auristatin E (MMAE) on MDA-MB-468 and MDA-MB-453 cell lines. The percentages for the cell cytotoxicity of MMAE-treated MDA-MB-468 cells were normalized to that of MDA-MB-453 cells. After normalization, the effect of MMAE on the two cell lines was compared.

MMAE is a synthetic antineoplastic agent, which cannot be used as a drug itself due to its high toxicity; instead, it is conjugate to a mAb to form ADCs. Although under investigation for decades, ADCs have received renewed attention with the advent of significant advances in engineering new linker and conjugation technologies together with highly potent cytotoxic drugs. The most commonly used toxins for ADCs in clinical development are  maytansine,calicheamicin,and auristatin derivatives.
In the present study, we selected the highly potent tubulin inhibitors MMAE because this agent is well  characterized and suitable for modification to facilitate coupling to an antibody25. To date, the drug MMAE has been widely used to construct various ADCs. The MMAE-based  ADCs used in the clinic trials include

Glembatumumab vedotin (phase II)26 and PSMA-ADC (phase I)27. Lately, the US FDA has approved a vc- MMAE-containing ADC, brentuximab vedotin (Adcetris®), for the treatment of CD30-positive Hodgkin lymphoma and systemic anaplastic large-cell lymphoma.

Monomethyl auristatin E research  conclusion: MMAE represents potent antitumor activities against breast cancer cells, highlighting its great potential for the development of ADCs against breast cancer.

 


 

6.  Monomethyl auristatin E(MMAE) structural featuresaasraw

 

New insight on the structural features of the cytotoxic auristatins MMAE by combined NMR spectroscopy and quantum chemical modelling.

The antineoplastic agent and antimitotic drug MMAE appears as the cytotoxic payload molecule in at least sixteen ADCs which have progressed to clinical trials21. Among these is the ADC Brentuximab vedotin which is utilised in the treatment of relapsed cases of Hodgkin’s lymphoma and anaplastic large cell lymphoma24. MMAE is composed of five peptide residues and has been reported to exist in solution as a mixture of two conformers due to a partially hindered rotation around the dolaproine-dolaisoleuine amide bond. The chemical structure of the cis/trans-isomers, information on the amino acid residues and the numbering that will be utilised in the discussion is summarised in bellow image:

 

Monomethyl auristatin E (MMAE) structure

 

While the appearance of the two conformers of MMAE have been noted before, reports on the correlation between the individual NMR signals and the molecule are absent in the literature. This was therefore the logical place to start our current work. In order to assign the individual signals in the complex NMR spectra of MMAE, a combination of NMR methods was required. In this study, we utilised an 850 MHz NMR instrument and the following set of NMR spectroscopic techniques: 1D1H and 13C; 2D COSY (correlation spectroscopy), 2D13C multiplicity edited HSQC (heteronuclear single-quantum coherence, edHSQC,), TOCSY (total correlation spectroscopy, both 1D and 2D), 2D HSQC-TOCSY, 2D HMBC (heteronuclear multiple bond correlation) and 2D ROESY (rotating-frame nuclear Overhauser effect spectroscopy). Due to the limited aqueous solubility of MMAE we used deuterated methanol as a solvent. Compared to the popular solvents DMSO-d6 and CD2Cl2, methanol better represents an aqueous environment, as it is a polar protic solvent which can participate in hydrogen bonding. In fact, Benedetti et al. concluded that the conformational properties observed for this class of compounds is solvent dependent, with a significant difference noted between CD2Cl2 and CD3OD. The key methods for identifying and assigning the signals in the complex1H- and13C-NMR spectra of 1A and 1B were high-resolution HMBC and edHSQC (See Figs 3 and 6 in the Supplementary information). COSY, TOCSY (2D) and HSQC-TOCSY were at all stages utilised to verify that the signal assignments were logical and correct. This approach was found to be solid also during the assignment of crowded areas of the spectra.

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7. Monomethyl auristatin E reviewaasraw

 

Monomethyl auristatin E review: MMAE, also known as Monomethyl auristatin E, 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 Names for MMAE-MAB-conjugates, the name vedotin refers to MMAE plus its linking structure to the antibody. MMAE is a potent antimitotic drug derived from peptides occurring in marine shell-less mollusc Dolabella auricularia called dolastatins which show potent activity in preclinical studies, both in vitro and in vivo, against a range of lymphomas, leukemia and solid tumors. MMAE show potency of up to 200 times that of vinblastine, another antimitotic drug used for Hodgkin lymphoma as well as other types of cancer.

 


 

 

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