Maytansinoids

With years of experience and our advanced “DrugLnk” synthetic chemistry platform, Creative Biolabs has established a comprehensive service program for antibody-drug conjugates (ADCs) developments. Our scientists can help design and provide clients with customized antibody-drug conjugates (ADCs) containing different maytansinoid variants using optimized linkers and suitable conjugation strategies.

Maytansine and its derivatives (named as maytansinoids in general) are members of the ansamycins superfamily and contains a 19-member macrocyclic lactams attached to a chlorinated benzene. Maytansine is originally isolated from an Ethiopian shrub Maytenus ovatus and exerts extremely high anti-mitotic potency. Maytansinoids are microtubule-targeting agents that share same binding site with vinca and function by depolymerizing microtubules and arresting cells in the mitosis stage. Maytansinoids reveal over 100-fold elevated cytotoxicity in cells than vinca alkaloids, making them suitable candidates in anti-cancer therapies utilizing tissue-specific drug delivery strategies, particularly as ADCs. The form of ADC significantly increases the therapeutic window of maytansinoids comparing to the free drugs, enabling the usage of an otherwise highly toxic drug in cancer treatments.

Maytansinoids Chemical structures of maytansine and its derivatives. Both DM1 and DM4 have been used as payloads for ADC development (Mol. Cancer Ther, 2010).

Maytansine Mode of Action (MOA)

As tubulin inhibitors, maytansinoids and its analogues inhibit the assembly of microtubules by binding to tubulin at or near the vinblastine-binding site. They can decrease microtubule dynamic instability and cause mitotic arrest in cells, similar to the MOA of vinblastine. Furthermore, maytansinoids exert cytotoxicity against a number of tumor cell lines and inhibit tumor growth in vivo. However, in human clinical trials, maytansine showed a small therapeutic window due to its neurotoxicity and harmful effects on the gastrointestinal tract. In the form of an antibody-drug conjugate, the toxicity as well as the side-effects caused by free maytansine could be reduced. By far, numerous attempts have been made to conjugate maytansine and its analogues to an antibody. Chemical modifications on maytansinoids are common to facilitate the conjugation, for instance the native N-acetyl group in many disulfide-containing maytansinoids are often replaced with methyldithio-propanoyl group for this very purpose.

Maytansinoids Maytansine mode of action. Maytansine binds to tubulin and decrease microtubule dynamic instability, arresting the cells in the mitosis stage (Nat. Rev. Mol. Cell Biol., 2015)

Antibody-maytansinoid Conjugates

Several antibody-maytansinoid conjugates have emerged as good anti-cancer candidates. T-DM1 (trastuzumab-MCC-DM1), an ADC in which maytansinoid was conjugated to the anti-HER2 antibody trastuzumab showed superb efficacy against metastatic breast cancer while lorvotuzumab mertansine (huN901-SPP-DM1), a CD-56 targeting ADC, has also revealed hopeful results in solid and liquid tumors that express CD56. Chemical versatility of maytansinoids enables the use of various linkers in antibody-maytansinoid conjugate preparation: for instance, T-DM1 uses a non-cleavable thioether-based linker, while lorvotuzumab mertansine uses a disulfide-based cleavable linker.

Maytansinoids Antibody-maytansinoid conjugates for cancer treatments. Maytansinoids were conjugated with lorvotuzumab (left) or trastuzumab (middle) via linkers bearing different release mechanisms (Mol Cancer Ther, 2010). Cleavable linkers undergo distinguished metabolism routes than non-cleavable linkers once internalized (right, Bioconjugate Chem, 2011).

Currently, several antibody-maytansinoid conjugates are under evaluation in clinical trial stages while many more are under active development in pre-clinical pipelines. Based on our well-established “DrugLnk” synthesis platform and extensive experience in ADC preparation, Creative BioLabs can help create unique antibody-maytansinoid conjugates with optimized linkers to meet your requirements. In the meantime, Creative BioLabs also provides various other ADC-related services. Please feel free to contact us for more information and a detailed quote regarding your ADC design and production.

References:

  1. Sun, X.; et al. Design of antibody−maytansinoid conjugates allows for efficient detoxification via liver metabolism. Bioconjugate Chem. 2011, 22(4): 728-735.
  2. Oroudjev, E.; et al. Maytansinoid-antibody conjugates induce mitotic arrest by suppressing microtubule dynamic instability. Mol. Cancer Ther. 2010, 9(10): 2700-2713.
  3. Akhmanova, A.; et al. Control of microtubule organization and dynamics: two ends in the limelight. Nat. Rev. Mol. Cell Biol. 2015, 16: 711-726.
  4. Lopus, M.; et al. Maytansine and cellular metabolites of antibody-maytansinoid conjugates strongly suppress microtubule dynamics by binding to microtubules. Mol. Cancer Ther. 2010, 9(10): 2689-2699.

For Research Use Only. NOT FOR CLINICAL USE.



Related Sections

Drug Module: DrugLnk™ Custom Synthesis: One-stop ADC Development Service: Services:
Online Inquiry
Name:
*Phone:
*E-mail Address:
*Products or Services Interested:
Company/Institution
Project Description:









Customized FluoroAb™

Welcome! For price inquiries, please feel free to contact us through the form on the left side. We will get back to you as soon as possible.

Contact us
USA
 
 Tel:
 Fax:
 Email:
Europe
 
 Tel:
 Email:
Germany
 
 Tel:
 Email:


Inquiry

Top