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Maytansinoids

Creative Biolabs can develop various antibody-maytansinoid conjugates with different maytansinoids and linkers. Maytansinoids have been extensively used in current ADC development.

Maytansinoids

Figure: Structure of maytansine and its derivatives used in ADCs (Antibody-Drug Conjugates, 2013)


In the group of maytansinoids, maytansine is the eponymous natural cytotoxic agent which is a 19-member lactam (ansa macrolide) structure originally isolated from the Ethiopian shrub Maytenus ovatus. Maytansine and its derivatives can bind to tubulin at or near the vinblastine-binding site, which interferes the formation of microtubules, suppressing microtubule dynamic instability, inducing mitotic arrest in the intoxicated cells, similar to the mode of action of vinblastine itself. However, due to the lack of tumor specificity of the toxin, severe side effects make the use of maytansine doubtful. So, the strategy of ADCs arises to solve these problems. Many attempts with antibody-conjugated maytansine derivatives have been made, among which, some are disulfide-containing maytansinoids comprising a methyldithiopropanoyl group instead of the native N-acetyl group (Fig. 2-4). Moreover, the linker used in these ADCs also has a high influence on the usability. Three types of linker comprising a labile disulfide bond, a stable thioether bond or a hindered disulfide bond have been widely researched (Fig. 2-4). Until now, promising candidates of maytansine-based ADCs have entered clinical trials and trastuzumab-DM1 (trastuzumab emtansine, T-DM1) has approved by the FDA, which uses several molecules of DM1, a cytotoxic maytansinoid, as payloads and SMCC as the linker. In T-DM1, the antibody component does not react with rodent antigens. Some experiments have demonstrated that T-DM1 can be cleared faster than that of total corresponding tratuzumab. And other Ab-SMCC-DM1 conjugates are also shown slightly faster clearance versus antibody alone in preclinical studies. In antibody-maytansinoid conjugates, the optimized pharmacokinetics and linker characteristics facilitate efficient cytotoxin delivery to tumor cells. The success of T-DM1 also suggests that maytansinoids are potential toxins in ADC development. Now a growing number of antibody-maytansinoid conjugates (e.g. Ab-SMCC-DM1, Ab-SMCC-DM4) are in development. Based on the ADCs required and every client’s requirements, scientists from Creative Biolabs can assist your ADCs generation using optimized linker and maytansinoids combination for scientific or clinical researches.

Categories of ADC payloads that Creative Biolabs provides:

Reference:
Jan Anderl, et al. Antibody–Drug Conjugate Payloads. Antibody-Drug Conjugates, 2013:51-70.

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