Exploring Novel Ansamitocin Payloads Through Mutasynthesis: Abzena & Isomerase Collaboration

We’re delighted to announce the publication of our latest research in ACS Omega:  “Mutasynthesis of C17- and C21-Substituted Ansamitocins for Use as ADC Payloads”

This paper showcases the power of collaborative innovation. Scientists from Isomerase, Regeneron, and Abzena joined forces to unlock new chemical space around ansamitocin, a potent maytansinoid microtubule inhibitor widely used as an antibody–drug conjugate (ADC) payload. 

Leveraging mutasynthesis, the team fed engineered Actinosynnema pretiosum strains with modified biosynthetic precursors, allowing the cells to incorporate new building blocks into the ansamitocin scaffold. This approach enabled the production of fluorinated and brominated derivatives at positions C17 and C21, expanding the structural diversity of these valuable ansamitocin payloads.

Key findings from the ansamitocin payloads paper include: Successful generation of halogenated ansamitocin analogues with cytotoxic activity comparable to ansamitocin P-3. Demonstration that the C21 fluoro analogue could be fully processed into a functional ADC payload, retaining potency after derivatisation and conjugation. Process and strain-engineering improvements to increase titres, addressing a common bottleneck in mutasynthesis. “I am delighted that our joint paper showcasing some of the work we did with Regeneron to produce many novel ansamitocin analogues via mutasynthesis to enable new ADCs has been published in ACS Omega. This paper represents a great collaborative effort between three companies (Isomerase, Abzena, and Regeneron) in one of the several different chemical classes that we have worked on together. It has been an absolute pleasure to work with Tom and his team over the years, and being able to support Regeneron with their programmes is always a privilege.” 

— Anna Stanley-Smith, Isomerase 

“I have worked with Isomerase for a number of years across different target compounds. It is great to see this publication out that demonstrates some of the value they added to our programs, allowing us to access novel chemical space around known payload compounds.” 

— Tom Nittoli, Regeneron 

By combining strain engineering, natural product biosynthesis, and payload chemistry, this collaboration underscores how multidisciplinary partnerships can accelerate the discovery of innovative therapeutics. 

We’re proud of this achievement and look forward to seeing how these new analogues contribute to the next generation of targeted cancer treatments.