Despite the rise of CAR-T and other cell therapies, small molecules and antibody treatments remain the bread and butter of cancer treatment. Lassogen thinks it’s found a way to combine the power of antibodies and small molecules while overcoming their weaknesses—lasso peptides.
The San Diego-based startup launches with a $4.5 million seed round led by Playground Global to develop its namesake peptides, starting with a program that turns “cold” tumors “hot.” Its approach is based on the work of academic founders Douglass Mitchell, Ph.D., of the University of Illinois at Urbana-Champaign and Tracy Handel, Ph.D., of the University of California, San Diego.
Bacteria produce lasso peptides as “small evolvable units” that serve many different functions, Lassogen CEO Mark Burk, Ph.D., said. As their name suggests, they are folded into a lasso structure, which makes them stable to all kinds of things that would ordinarily degrade a peptide, such as protease enzymes, low pH or high temperatures.
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“You can boil them in water and they retain their folded conformation,” he said. “They’re very different than antibodies, protein therapeutics and other peptides that are readily broken down in the body, which has been particularly challenging in the past for peptide therapeutics.”
Classified as proteins made up of 40 or fewer amino acids, peptides are in between small molecules and large biologics in size. Approved peptide drugs include GLP-1 meds Byetta, Trulicity and Victoza, all of which are given by injection because the stomach and small intestine begin to break them down.
“What this represents is a unique structure and novel modality that has been validated in nature, but hasn’t been developed yet from a human therapeutic standpoint,” Burk said. “We are looking at natural lasso peptides and using advanced tools of computational design, synthetic biology and molecular evolution engineer lasso peptides as drugs. These technologies are available today butt weren’t available 15 years ago to. We couldn’t even think about doing this 10 or 15 years ago.”
Lassogen’s goal is to create modular treatments that can be “programmed” for different diseases. Lasso peptides could be particularly useful in targeting GPCRs and chemokine receptors, which have been challenging targets for other drug types.
“Lasso peptides have the right size and shape to mimic ligands in the body much more closely than antibodies or small molecules,” Burk said. Those ligands include hormones, growth factors, chemokines and cytokines—all small proteins—which antibodies and small molecules look “nothing like.”
These peptides comprise a ring, which ranges in nature from seven to 10 amino acids in length; a loop, which can be three to 18 amino acids long; and a tail, which can be almost any length, Burk said.
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“We can conjugate many different things to the tail and, on top of that, we can change over 80% of the amino acids of a given lasso peptide,” he said. All of these tweaks can change the properties of a lasso peptide, which is what makes them programmable, he said.
Another advantage is the number of interactions a lasso peptide can have with its target, compared to other drugs.
“That structure, that 3-D object you’re creating allows many points of contact inside the pocket of a receptor, whereas a small molecule typically has two to three main interactions,” Burk said. “A lasso peptide can have eight or nine interactions and thereby, we can regulate the selectivity, potency and residence times of lasso peptides in a way that is challenging with small molecules.”
With a total of $5.1 million raised, Lassogen plans to advance a pair of programs: lead asset LAS-103, an endothelin receptor type be antagonist, and LAS-20x, which targets the chemokine receptor CCR4.
“Tumors have learned that if they overexpress the endothelin B receptor in their vasculature, they can shut down the infiltration of lymphocytes into the tumor microenvironment, rendering the tumor immunologically cold,” Burk said.
Blocking those receptors could pave the way for tumor-infiltrating lymphocytes to enter the tumor, turning it “hot” and setting up the immune system for success. The approach could come in handy alongside immunotherapies like checkpoint inhibitors, which have dramatically transformed treatment for some cancer patients, but don’t work for everyone.
Although cancer is Lassogen’s first focus, the company thinks lasso peptides could become new treatments for autoimmune disease, pain and inflammation.