Celgene's biologics-oriented pact with Sutro announced in October demonstrates the appeal of using a cell-free protein synthesis platform as a tool in two of biotech's hottest drug development areas: immunotherapy and antibody drug conjugates (ADCs). Summit, New Jersey–based Celgene and the S. San Francisco biotech will collaborate in developing up to six bispecific antibodies and/or ADCs directed at immuno-oncology targets. The $95-million upfront payment includes an equity investment that will increase Celgene's ownership of Sutro to 15%. Sutro is eligible to receive research and manufacturing milestones of up to $75 million, clinical and regulatory milestones that could reach $275 million per compound, and royalties on product sales.
Celgene views Sutro's platform as a potentially disruptive technology. Thomas Daniel, Celgene president, global research and early development, stated in a Sutro press release that its use will be key to building their immuno-oncology pipeline. This latest arrangement builds on a 2012 collaboration between the companies.
Sutro specializes in cell-free, in vitro protein synthesis as alternatives to conventional production methods. Using extracts of cellular lysates for protein production, instead of intact, membrane-bound cells, has been around for decades, but only for producing small volumes of antibodies and other proteins. “The big issue with a cell free–based transcriptional/translational system was [harnessing] the energy required to make a protein,” says Sutro's CSO Trevor Hallam. The problem was solved in the early 2000s through the engineering of an extract from an Escherichia coli–based strain, which contained ribosomal preparations that preserved the biochemical ability to be fed and generate energy, along with the elements necessary for catalyzing transcription, translation and protein folding. “We [can] put the DNA sequence into the extract at any volume required, and ten hours later we have [a] properly titered, folded antibody,” he says.
Cell-free protein expression may ultimately be appealing for large-scale biologics manufacturing. For now, however, drug developers are comfortable with cell-based production methods, despite the time it takes to optimize a cell line for manufacturing scale-up. “Whole cell methods are validated,” says Peter Senter, vice president, chemistry, for ADC specialist Seattle Genetics in Bothell, Washington. “All of the bugs have been worked out. It can be done reproducibly and in a very predictable manner.” Although there may be instances where a cell-free system could be advantageous, “I think much more work is going to be necessary to determine exactly where those instances are,” he says.
Drug developers also value cell-free synthesis as a discovery-to-development tool capable of creating and testing a slew of novel protein constructs quickly. The ability to tweak and optimize therapeutic peptides and proteins is shared by competitors Ambrx, in San Diego, and contract research organization Catalent's newly acquired Redwood Bioscience division in Emeryville, California. Although Ambrx's and Redwood's platforms are cell-based, all three approaches have the ability to introduce site-specific modifications—for Sutro and Ambrx, this is accomplished by inserting non-natural amino acids into antibody frameworks. Site-specific modification is particularly useful in the development of ADCs. “We can then do several hundred versions, scan the entire surface of an antibody and move a non-natural amino acid around, make them all individually, conjugate them and test them all in parallel,” Hallam says. “It's very simple. We can get an intact molecule in our system that cell-based systems struggle to find.” Sutro has been applying its platform in immuno-oncology since early 2013—programs that Celgene may ultimately take over under the deal. In September 2014, Sutro also inked an ADC development deal with the EMD Serono division of Darmstadt, Germany–based Merck.
Site-specific technologies, which also include more conventional modifications like the introduction of a unique cysteine to an antibody's heavy or light chain, are often cited as the way to reduce the heterogeneity of ADCs made using first-generation methods for conjugating cytotoxic agents. “Once it becomes possible to make homogeneous, site specific–modified ADCs with clean analytics, that's what the FDA [US Food and Drug Administration] will expect,” says Carolyn Bertozzi, professor of chemistry at the University of California at Berkeley and a founder of Redwood. “There's a manufacturing benefit but potentially there will be a regulatory benefit.” The technologies may especially add value to the ADC field as it moves beyond tubulin-targeting cytotoxic agents like maytansinoids and auristatins to the use of super-potent DNA alkylating agents, which would increase the range of tumors ADCs could attack. Those agents are much more hydrophobic, presenting thornier pharmacokinetic issues. Using cell-free synthesis, Sutro can also place two different non-natural amino acids at different places on an antibody framework to be able to add different cytotoxic drugs—a “dual warhead” ADC approach that could address issues of drug resistance or heterogeneous tumor cell populations.
“I don't think any platform will be a universal go-to technology for every next-generation biologic,” says Bertozzi. “These platform technology companies are finding a way to succeed and finding a niche where their technology might be quite perfect for the need of a particular program.”
Sutro and its peers Ambrx and Redwood are all protein synthesis companies born out of chemical biology innovations of previous decades. “They had their roots in academic labs that were trying to bridge that land between chemistry and biology,” says Bertozzi. “Those companies grew, and now bigger companies have taken notice and are assimilating the technologies into a legitimate clinical pipeline.”
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Ratner, M. Celgene wagers on Sutro's cell-free platform to ramp up bispecifics. Nat Biotechnol 32, 1175 (2014). https://doi.org/10.1038/nbt1214-1175
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