DARPA’s Reimagining Protein Manufacturing (RPM) Program seeks to revolutionize the production of protein based medical countermeasures to significantly advance the DoD’s ability to rapidly manufacture proteins in a fully distributed setting.
The Defense Advanced Research Projects Agency (DARPA) announced that Ginkgo Bioworks has been awarded a 4-year contract worth up to $18 million to reimagine how to manufacture complex therapeutic proteins. As a performer on DARPA’s Reimagining Protein Manufacturing (RPM) project, Ginkgo aims to deliver revolutionary advances in on-demand protein manufacturing by leveraging Cell-Free Protein Synthesis (CFPS) to enable rapid, high-yield, distributed production of human therapeutic proteins that support national security objectives.
Ginkgo will lead a team comprising representatives from Imperial College London, led by Prof. Paul Freemont, Nature’s Toolbox, Inc., led by Alex Koglin, and consultant Michael Feldhaus (former Executive VP of Antibody Discovery at Adimab).
Therapeutic proteins bearing so-called “post-translational modifications,” such as antibodies, cytokines, and clotting factors are particularly important in the marketplace and to DARPA, as are subunit and conjugate vaccines. Half of the top-selling drugs used to treat cancer and autoimmune diseases are such therapeutic proteins; many are also used as medical countermeasures to treat or prevent disease, injury, or death related to chemical, biological, radiological, or nuclear threats. Through this program, Ginkgo hopes to transform how therapeutic proteins are made, replacing cell-based methods with cell-free methods. Traditional centralized, large-scale manufacturing methods have usually sufficed, but increasingly there are use cases where rapid distributed or on-demand manufacturing is needed, such as supplying of therapeutic proteins to geographically isolated locales, providing hospitals and clinics with point-of-need rapid production of medicines from common precursors, and improving our ability to mount rapid and targeted responses to natural or man-made biological threats and emergencies.
Traditional production methods rely on weeks- to months-long construction of bespoke cellular organisms that have been engineered to produce the desired therapeutic protein during days-long fermentation processes. Even with standardized methods, it typically takes months to achieve the first useful production of a biological drug. Post-expression isolation and purification are equally challenging: each unique process is costly and time-consuming to develop.
Cell-Free Protein Synthesis (CFPS), by contrast, brings the key advantages of greater speed and flexibility than cell- and fermentation-based production. Significant improvements are needed to make CFPS competitive with traditional therapeutic protein production, however, primarily with respect to efficiency and the identity and homogeneity of post-translational modifications.
In this program, Ginkgo seeks to address these challenges and hopes to enable the rapid prototyping of enzymes and other proteins for diverse therapeutic and nontherapeutic projects. One aim of the project is to create production methods that are compatible with Good Manufacturing Practices, thereby facilitating adoption by the pharmaceutical industry.
About DARPA’s Reimagining Protein Manufacturing (RPM) Program
DoD access to critical proteins is currently limited by the slow response times of protein production methods. State-of-the-art (SOA) protein-based medical countermeasure (MCM) production relies on massive centralized infrastructure and complex pipelines that require lengthy cellular engineering, sufficient growth of cells for production, and intensive purification and quality control. Current response times are several months for production alone, with additional time needed for dispersing MCMs to vulnerable populations. Distributed manufacturing paradigms may transform these timelines into those relevant to DoD response, especially in denied, degraded, or disrupted operational environments.
To significantly advance the DoD’s ability to rapidly manufacture proteins in a fully distributed setting, RPM will address the following biochemistry challenges: achieving relevant quantities of MCM; ensuring initiation of protein production within ~24 hours of receiving DNA/RNA template; and producing fully bioactive complex proteins by ensuring correct folding and controlled addition of post-translational modifications.
The RPM program seeks to revolutionize the production of protein based MCMs and lay the foundation for the fully distributed manufacturing paradigms of the future.