Enlaza Therapeutics marries covalent and biologic drugs

Avalon BioVentures managing partners Sergio Duron and Sandy Madigan hadn’t even left their previous start-up when they hatched the idea for Enlaza Therapeutics.

While they were both still at Nerio Therapeutics, Duron brought Madigan a promising paper from the laboratory of Lei Wang, a chemical biologist at the University of California, San Francisco. It described an unnatural amino acid that can turn a protein into a covalent binder (Cell 2020, DOI: 10.1016/j.cell.2020.05.028).

“It was pretty clear to us both very early that this was a unique opportunity,” Madigan says. Long before Nerio was acquired by Boehringer Ingelheim, the multitasking serial entrepreneurs started their next project.

Covalent drugs—small molecules that form a long-lasting covalent bond with their protein targets, in contrast to molecules that bind ephemerally and then dissociate—have been trendy in biotechnology for several years because of their prowess as irreversible inhibitors. But Duron says virtually all covalent drugs are small molecules, which are prone to off-target interactions. Large, biologic drugs, like antibodies and their many derivatives, have less-permanent effects on their targets but offer a potential advantage in more-specific target binding.

The pair perceived an opportunity to bring covalency to protein-based drugs. They licensed the technology Wang invented and founded Enlaza with Duron as CEO and Madigan as president. Their goal: to make protein drugs that could lock on to their cellular targets just as small-molecule covalent inhibitors do.

Enlaza’s approach depends on a fluorosulfated tyrosine. This unnatural amino acid can be inserted into a protein drug during synthesis. When the protein gets close to a binding partner, a nucleophile on that binding partner forms a covalent bond with the fluorosulfated tyrosine. Enlaza’s founders hope a longer-lasting interaction could enhance a drug’s ability to block signaling or improve the delivery of a drug to a specific cell.

Enlaza began in stealth mode, working out how to identify nucleophiles that make good targets and how to position the unnatural amino acid within a drug for an optimal reaction.

Covalent protein drugs have different design constraints than small-molecule covalents and traditional biologics do. Antibody developers usually try to optimize for proteins that are unlikely to dissociate from their targets after complexes are made. But with Enlaza’s technology, an antibody’s dissociation rate is less of a concern—the speed with which it can bind and form a covalent bond is more important.

Enlaza sees potential in what Duron calls “small-format protein drugs,” like single-domain antibodies. Drug developers across the industry have found that these proteins tend to be cleared from the body more quickly than full-size antibodies and require tweaks to extend their time in circulation. But the longer a drug spends circulating, the more time it has for off-target interactions that can cause side effects. Because covalent binding captures the drug only at the target, that rapid clearance can become an advantage. “You get long-term effects with short-term exposure,” Duron says.

Madigan says Enlaza is the only company he is aware of that’s developing covalent protein drugs. That distinction has appealed to investors. Earlier this year, the company raised $100 million in a series A round that was led by J.P. Morgan and included the venture arms of Amgen and Regeneron Pharmaceuticals. The start-up extended the round to accommodate an additional $10 million from the venture arm of Pfizer. The money will enable Enlaza to bring its first drug candidates, which are cancer focused, into the clinic; Duron says antibody-drug conjugates that can deliver toxins or chemotherapies only to cancer cells are a standout application for the technology. Enlaza is also looking ahead to autoimmune targets.

Meanwhile, Madigan says, development partnerships with these larger pharmaceutical companies will enable Enlaza to pursue more targets than would be feasible for a small biotechnology company working alone. “We have a business development playground,” Madigan says. “We have an opportunity here, because of the platform, to develop partnerships that will enable the technology very, very broadly.”