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Auristatins

Creative Biolabs provides custom services for the development of antibody-drug conjugates with auristatins and auristatin derivatives. Auristatins, the most commonly used payloads, can block tubulin assembly and cause G2/M phase cell cycle arrest. They are water-soluble dolastatin analogs of dolastatin 10. Dolastatin 10 belongs to dolastatin family and can powerfully bind to tubulin, thus inhibiting polymerization mediated through binding to the vinca alkaloid binding domain, and cause cells to accumulate in metaphase arrest.

Auristatins
Figure: Brentuximab vedotin mechanism of action (Onco Targets Ther. 2013)

Dolastatin 10 was firstly isolated from the sea hare Dolabella auricularia. It was proved to have extraordinary cytotoxicity to cause cell cycle arrest with picomolar GI50. It binds at the α,β-tubulin interphase to inhibit tubulin-dependent GTP hydrolysis and microtubule assembly. In addition to their effect on microtubules, dolastatin 10 and its auristatin analogues have strong antivascular effects. These features make auristatins chemotherapeutic agents. Based on the structure-activity relationship studies of cytotoxins, auristatin analogues can be synthesized through auristatin structural modifications including N-terminal modifications (N-terminal extensions, replacements of the N-terminal dolavaline), C-terminal modifications and central peptide core structure changes. Now a large number of antibody-drug conjugates of auristatins and auristatin derivatives have been developed in clinical trials. Among them, monomethyl auristatin-E (MMAE) and monomethyl auristatin-F (MMAF) are noteworthy. Up to now, most of auristatin-based ADCs in clinical trials use MMAE or MMAF. As auristatin derivatives, MMAE/MMAF is fully synthetic drugs and has only one methyl at its N-terminus instead of two as in auristatin E/F. In the present ADCs, MMAE or MMAF is conjugated to an antibody via a peptide linker such as dipeptide linker Val-Cit (vc). In recent years, a major breakthrough in ADCs development is brentuximab vedotin getting approved by FDABrentuximab vedotin uses MMAE as the cytotoxic payload and vc as the linker. MMAE has a free drug IC50: 10−11-10−9, allowing it to be effective in the low nanomolar range. Moreover there are at least six and three MMAE-ADCs and MMAF-ADCs that are in clinical trials respectively.

For the present, more auristatin analogues are being researched and auristatins will be one of the cornerstones in ADC development. Creative Biolabs will construct ADCs with different payloads to meet every client’s special requirements.


Categories of ADC payloads that Creative Biolabs provides:

References:
Xueyan Chen, et al. Targeted therapy for Hodgkin lymphoma and systemic anaplastic large cell lymphoma: focus on brentuximab vedotin. Onco Targets Ther. 2013 Dec 19;7:45-56. 
Nikolaos Diamantis and Udai Banerji. Antibody-drug conjugates-an emerging class of cancer treatment. Br J Cancer. 2016 Feb 16; 114(4):362-7. 
Andreas Maderna and Carolyn A. Leverett. Recent advances in the development of new auristatins: structural modifications and application in antibody drug conjugates. Mol Pharm. 2015 Jun 1; 12(6):1798-812.

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