Numaferm’s cofounders Bürling (left) and Schwarz plan to generate kilogram quantities of peptide using E. coli within the next few years.
SYNTHESIS
How a one-year-old German start-up could be about to shake up a $1 billion market ALEX SCOTT, C&EN LONDON
erman start-up Numaferm has developed a biotech process that it claims will reduce the cost of making peptides—long chains of DNA typically used as drugs—at industrial scale by orders of magnitude. Numaferm’s fermentation technology is applicable to peptides made with natural amino acids, a family that makes up about half of the $1 billion-per-year global peptide synthesis market. The firm thinks it can squeeze pharmaceutical-grade peptide costs from an average of $1.2 million per kg for the current synthetic method to between $50,000 and $100,000. At this cost differential, leading commercial peptide firms such as Bachem, CordenPharma, and Polypeptide Laboratories would appear to have a fight on their hands. All three firms declined to talk with C&EN about the new challenger. Numaferm hopes its technology will also make peptides cheap enough to be used profitably in consumer products such as cosmetics and paints. The firm’s small team is now fully immersed in scaling up its technology. “Our clear target is to deliver peptides in the kilogram scale in a few years,” says cofounder Philipp Bürling. Even start-ups with good technology don’t always ful-
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C&EN | CEN.ACS.ORG | JANUARY 22, 2018
Numaferm at a glance ▸ Location: Düsseldorf, Germany ▸ Established: 2017 ▸ Founders: Christian Schwarz and Philipp Bürling ▸ Technology: Peptide expression using engineered E. coli. ▸ Goal: To undercut chemical synthesis of natural peptides by almost two orders of magnitude. ▸ Partner: Evonik Industries ▸ Strategy: Initially to target pharma compounds, then branch out into fields such as cosmetics, paints, adhesives. ▸ Manufacturing: Will outsource large-scale production.
fill their commercial potential. And at just a year old, Numaferm still has a way to go. Despite these potential pitfalls, some industry experts consider Numaferm well-positioned for success. Enzymes and pharmaceutical proteins are already made by genetically engineered microorganisms, but biotech production of peptides has been limited, Numaferm says, by three problems: the presence of peptide-destroying proteases, aggregation of peptides that complicates downstream processing, and the toxic effects of peptides on the production host. As a result, commercial peptide drugs are now mostly made by a multistep chemical synthesis that involves linking amino acids together via amide bonds in liquid or solid phase. The procedure is laborious as it requires a coupling reaction, along with a protection step, for each amino acid. Numaferm claims to have solved peptide fermentation’s problems by genetically inserting a transport compound into its host bacteria, Escherichia coli, that’s fused to the peptide being expressed. The firm avoids destruction of the peptide by proteases by engineering the bacteria to secrete the fused pair into the protease-free environment outside the cell. The transport compound, dubbed
C R E D I T: N UMA FE R M
Peptide makers’ new threat
though, it will have to overcome its lack of Numatag, also increases the stability and experience as well as the market presence solubility of the peptide, counteracting built up by its larger competitors over deaggregation. In addition, it prevents the cades. The company is working on scaling return of the peptide to the host, avoiding up production to hundreds of grams, but toxic effects. it has yet to make any commercial-scale Once produced, the peptide-transport products. compound combination can be easily Add to that, Schwarz, the company’s extracted, Numaferm says. Cleaving the transport compound leaves a pure peptide. CEO, is inexperienced as a business person. Until about a year “To make a new prodago he was focused on uct, the only change academic research at the needed is the genetic Institute of Biocheminformation of the target istry at Heinrich Heine peptide,” says NumaUniversity Düsseldorf, ferm’s CEO and cofoundwhere he codeveloped er Christian Schwarz. the technology. “The step The firm has one U.S. out from academia to inpatent and has one patdustry is quite a big one,” ent pending. Schwarz acknowledges, Making 1 kg of peptide “but I am loving it.” with the process requires Despite this lack of only a few hundred kiloexperience, Schwarz grams of low-cost carboand his team convinced hydrate feedstock, NuGerman specialty maferm says. In contrast, chemical giant Evonik making 1 kg of peptide using chemical synthesis —Bernhard Mohr, head of Industries—along with can consume more than venture capital for Evonik a handful of other investors—that their technol25 metric tons of raw maogy is the real deal. Last year, Evonik and terials—including some potentially toxic the other partners made an investment in and expensive compounds. Numaferm that was pegged at a little less The firm can make a sample of a chosen than $10 million. peptide within six weeks, Schwarz says. “Numaferm’s technology is highly Chemical synthesis typically takes longer, the firm claims, especially for peptides with disruptive. We expect existing markets to change dramatically and new markets more than 30 amino acids. “For us, the size does not matter, but for chemical synthesis, to develop,” says Bernhard Mohr, head of venture capital at Evonik. “A strategic fit the size has strong impact,” Schwarz says. with Evonik’s existing technology, a strong This is where Numaferm may have an scientific background and a dedicated advantage, says Belgium-based peptides team—that is what we are looking for in a consultant Alain Scarso. “Some polypepstart-up. Numaferm has it all.” tides, such as epitopes, have sequences of The start-up’s primary target is the more than 70 amino acids for which the depharmaceutical peptides market. “This is velopment of their manufacturing process where peptides are best known and where through chemical synthesis is lengthy and we can be benchmarked against chemical costly,” Scarso says. He estimates that over synthesis,” Bürling says. But Evonik notes half of the more than 200 peptides that are that the technology could open up new commercialized or in development could applications for peptides in areas such benefit from Numaferm’s technology. as cosmetics, functional coatings and Scarso figures Numaferm could cause adhesives. ripples across the sector. “The recombiNumaferm’s two cofounders say they nant DNA approach should be more atare cautious not to get ahead of themtractive in terms of costs, and have lower selves. Their near-term goals are all about environmental impact and faster develproduction scale up. Ultimately, the firm opment time, than the current chemical plans to outsource production of batches manufacturing technologies,” he says. above the gram scale. It is also willing to One shortcoming is that Numaferm’s license out its technology. technology cannot produce peptides that Established peptide producers might contain unnatural amino acids or other say that Numaferm still has much to chemical entities. But even here Scarso prove. But if the company succeeds in sees potential to start such peptides with scaling up its technology at the costs it the technology and then modify them expects, chemical synthesis of natural pepchemically. tides will quickly look very expensive. ◾ If Numaferm is to realize its potential,
“Numaferm’s technology is highly disruptive. We expect existing markets to change dramatically and new markets to develop.”
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