BIOLOGICS


A protein synthesis platform for next-generation ADCs


By rationally designing and altering the properties of protein-protein drug interactions in order to ‘tune’ protein function, Sutro Biopharma is currently focusing on developing a new generation of multi-functional antibody drug conjugate combination therapeutics and bifunctional antibody-based therapeutics for targeted cancer therapies, as well as collaborating with pharmaceutical and biotech companies in the discovery and development of novel protein therapeutics.


Sutro Biopharma, Inc., located in South San Francisco, California, USA, is developing a new generation of multi-functional antibody drug conjugate combination therapeutics and bifunctional antibody-based therapeutics for targeted cancer therapies. The company says these therapeutics will significantly extend the clinical impact of current oncology therapeutic approaches, and are beyond what can be envisioned with current (cell-based) expression technologies.


Sutro’s biochemical synthesis technology, which underpins these therapeutics, allows the rapid and systematic exploration of many protein drug variants to identify drug candidates. The company’s make-test cycle for hundreds of protein variants, including those incorporating non-natural amino acids, takes about two weeks and, once identified, production of these protein drug candidates can be rapidly and predictably scaled up to commercial levels. In addition to supporting the development of its own drug pipeline,


Sutro Biopharma’s scalable biochemical protein synthesis technology platform


Energy required for transcription-translation is driven by glutamate catabolism via the TCA cycle to produce reducing equivalents, primarily in the form of NADH, which fuels oxidative phosphorylation providing a stable supply of ATP over the course of the 10-hour cell-free protein synthesis reaction. Addition of T7-RNA polymerase (RNAP), individual HC and LC T7-based plasmids, or linear template for scFv, with amino acids drives transcription and subsequent ribosomal translation followed by protein folding, assisted by added glutathione and disulfide isomerase chaperone. (From: Yin G, Garces ED, Yang J, Zhang J, Tran C, Steiner AR, Roos C, Bajad S, Hudak S, Penta K, Zawada J, Pollitt S, Murray


28 sp2 Inter-Active March/April 2012


Sutro is collaborating with select pharmaceutical and biotech companies in the discovery and development of novel protein therapeutics.


Cell-free protein synthesis The company was founded in 2003 by James R. Swartz, ScD, based on intellectual property he developed. Professor Swartz holds the James H. Clark Professorship in the School of Engineering at Stanford University where he is a professor in the Departments of Bioengineering and Chemical Engineering. He was interested in investigating the process by which cells make proteins, and his vision for the company was to reliably and reproducibly scale a cellfree protein synthesis process to enable the production of many different kinds of proteins from research to commercial scale. Sutro was able to develop a scalable biochemical protein synthesis technology platform, based on Professor Swartz’s pioneering work, that utilises an engineered


cell-free extract from E. coli. The open system offers rapid, high throughput optimisation of both the protein production process conditions and the exploration of multiple variants of specific product proteins. The technology enables a make-test cycle of two weeks for many hundreds of therapeutic protein variants and also provides an expression system for different types of proteins including proteins that cannot be synthesised with conventional cell-based expression systems due to their toxicity to the host cells; proteins that are insoluble; and proteins that form inclusion bodies or undergo rapid proteolytic degradation by intracellular proteases in a cellular system. Another advantage of the biochemical protein synthesis technology is the possibility of introducing site-specific chemical modifications, including non-natural amino acids (nnAA), more easily, rapidly and flexibly than in cell-based expression systems. The ability to express proteins at research scales


CJ. Aglycosylated antibodies and antibody fragments produced in a scalable in vitro


transcription-translation system. MAbs. 2012 Mar 1;4(2).)


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