Lycia Therapeutics has emerged from stealth with $50 million from Versant Ventures to develop a new generation of protein degraders, or drugs that break down rather than inhibit errant proteins. The biotech firm, which will soon open labs in the San Francisco Bay area, is founded on discoveries made in the lab of Stanford University chemical biologist Carolyn Bertozzi.
The concept of protein degradation has gained traction in recent years as a way of conquering proteins that have eluded conventional drugs, which are typically small molecule inhibitors and antibodies. Such proteins make up the lion’s share of the human proteome. Since 2017, myriad well-funded biotech firms have launched to pursue protein degraders, while big pharmaceutical companies have sunk significant cash into developing either internal research programs or external partnerships that explore protein degradation.
So far, the majority of that investment has gone into molecules that tap into the cell’s system for tagging proteins for its trash compactor, the proteasome. These degraders come in different forms, but most companies are developing bifunctional small molecules that at one end tether a protein of interest and at the other bind to an E3 ligase, a member of a family of some 600 proteins that kick off that tagging process.
But the field has a variety of limitations. One major hurdle is that the degradation machinery exploited by current protein degraders is located inside cells, whereas some 40% of proteins do their work outside the cell, Bertozzi says. “It leaves almost half the proteome on the shelf,” she says.
Bertozzi’s lab began exploring how to access those other proteins, and in March 2019 posted a paper on the preprint server ChemRxiv outlining a new form of degrader. Her group engineered an antibody to express a glycan that binds to a receptor called cation-independent mannose-6-phosphate receptor (CI-M6PR) that connects cell surfaces to the lysosome, another cellular trash system. The idea is the antibody binds to the targeted protein, then the glycan delivers it to CI-M6PR and the lysosome. Bertozzi calls the glycan-antibody construct a lysosome targeting chimera, or LYTAC.
Versant was immediately intrigued, and by summer 2019, Lycia had formed. Scientists at Versant’s San Diego-based drug discovery incubator Inception Sciences have since worked to validate and expand on the range of LYTACs. They are exploring, for example, ways to conjugate the CI-M6PR ligand to small molecules or antibody fragments.
While the initial paper takes advantage of CI-M6PR to drag proteins inside the lysosome, Lycia scientists are considering other potentially useful receptors. And although the pool of lysosomal-targeting receptors is smaller than the family of E3 ligases that direct to the proteasome, “I think the number that are going to be functionally useful for LYTACs is going to be larger,” Bertozzi says. Some of those lysosomal-targeting receptors are responsible for housekeeping functions and thus are found all over the body, while others are found in specific tissues, which Bertozzi says raises the potential of drugs that act very selectively.
Bertozzi believes the platform has other advantages. Bifunctional protein degraders are fairly large and unwieldy molecules; chemists devote lot of time to tweaking parts of the molecule to make them behave better as drugs. “By contrast, we think we have a lot more flexibility in the structures,” she explains.
Aetna Wun Trombley, who joined Lycia as CEO in April, says the company will transition out of the incubator labs and into its own building in the San Francisco Bay Area in the next month. The team is currently working on expanding their library of LYTACs, while also trying to better define the relationship between these molecules’ structures and their protein-crunching activity.
She notes that Lycia will initially focus on cancer and autoimmune disease therapies. It will explore three main categories of drugs: molecules that target challenging transmembrane proteins, others that can clear protein aggregates or pathogenic immune complexes, and those that can deplete circulating antibodies that drive autoimmunity.
“This approach has opened up a lot of targets and proteins that are currently intractable for other technologies,” Trombley says.
Researchers are intrigued by the prospect of another new protein degradation tool. “LYTACs are another example of what I see as a larger wave, likely to become a tsunami, of strategies” to hijack the cellular machinery for therapeutic use, says Milka Kostic, program director of chemical biology at the Dana-Farber Cancer Institute.
Kostic adds that, in addition to filling a therapeutic niche, the technology could be used in basic biochemistry research to precisely regulate levels of extracellular proteins to better understand their function.