Advancing Novel Ansamitocin Payloads via Mutasynthesis: A Joint Effort by Isomerase, Regeneron, and Abzena

We’re excited to share the publication of our latest research article in ACS Omega:

“Mutasynthesis of C17- and C21-Substituted Ansamitocins for Use as ADC Payloads”

This publication highlights the impact of collaborative scientific innovation. Researchers from Isomerase, Regeneron, and Abzena have worked together to explore untapped chemical space surrounding ansamitocin — a highly potent maytansinoid microtubule inhibitor that is widely used as a payload in antibody–drug conjugates (ADCs).

Using a mutasynthesis approach, the team introduced modified biosynthetic precursors into engineered strains of Actinosynnema pretiosum. These precursor molecules were incorporated into the ansamitocin core structure by the host cells, enabling the synthesis of new derivatives featuring fluorine and bromine substituents at the C17 and C21 positions. This strategy significantly broadened the structural diversity of these important ADC payloads.

Highlights from the study on ansamitocin payload development include:

• The successful creation of halogenated ansamitocin analogs demonstrates cytotoxic activity on par with that of ansamitocin P-3.

• Evidence that the C21-fluorinated analog could be efficiently processed into an active ADC payload, maintaining its potency following derivatization and conjugation.

• Advances in strain and process engineering have led to improved production titers, helping to overcome a common limitation associated with mutasynthesis approaches.

“I am delighted that our joint paper showcasing some of the work we did with Regeneron to produce many novel ansamitocin analogs 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 programs is always a privilege.” 

— Anna Stanley-Smith, Isomerase 

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 analogs contribute to the next generation of targeted cancer treatments.