‘I think I know how to fix this’

Some 1 million patients in the U.S. live with a type of heart disease called heart failure with preserved ejection fraction, or HFpEF, caused by a stiffening of a chamber of the heart that makes it much more challenging to distribute blood throughout the body. The condition has few approved therapies and high mortality rates.

For years, researchers have suspected that the hormone relaxin could be an effective treatment for certain cardiovascular diseases — including possibly HFpEF. It helps counteract fibrosis, prevents veins and arteries from hardening, and promotes essential vascular and cardiac remodeling to support the mother’s heart during pregnancy. However, a major challenge has been keeping relaxin in the body long enough to be effective. The pharmaceutical industry tested a similar compound in clinical trials but encountered the same challenge as many hormone-based treatments: These molecules are generally small, and the body filters them out too quickly for them to be effective. 

“The pharmacokinetics are not really suitable to use it as a drug,” said Grant Zimmermann, director of business development at Harvard Office of Technology Development (OTD).

That started to change in 2017, soon after a discovery in the lab of Andrew Kruse, professor of biological chemistry and molecular pharmacology in the Blavatnik Institute at Harvard Medical School. “Andrew came to us,” Zimmermann recalls, “and said, ‘I think I know how to fix this.’”

Kruse had been interested in the structural biology of relaxin, which he calls a “very unusual member” of the family of proteins his lab has researched for years. Researchers in the Kruse Lab were studying the structure of the relaxin receptor to understand how it binds to its ligand and induces changes in the body. In the process, the research team made an important discovery: They were able to convert relaxin from a naturally occurring two-chain molecule to a one-chain molecule using protein engineering, and they were able to attach the Fc-domain of an antibody to extend relaxin’s half-life in the body. Native relaxin is complicated to produce in the lab because of its two-chain structure, according to Sarah Erlandson, the graduate student leading the project. Creating a single-chain design made it possible to fuse the antibody Fc to relaxin, allowing it to stay in the body longer.

There wasn’t one moment that illuminated how consequential the discovery would be, says Erlandson. Instead, the process involved the types of continuous progress that often define scientific research and development. Their work “relied on iterative design improvements,” she said. “I remember our growing excitement as we made progress on the engineered protein. That’s when it started to feel like we could have a tangible impact on relaxin therapeutics.”

What they designed as a tool to study structural biology, Kruse realized, could have significant therapeutic potential.

OTD protected the innovations related to the research and got to work on strategies to further advance the research toward commercialization opportunities. Zimmermann brought the project to his colleagues at the Blavatnik Biomedical Accelerator (BBA). That team immediately saw promise in the research and provided funding through pilot and development grants, along with business development support.

Relaxin represents a “prototypical example” of the type of innovations that the BBA funds, says Zimmermann. The accelerator specifically looks for technologies with a clear path to clinical development that need a boost to attract potential industry partners that can further the development of beneficial innovations through sponsored research or license it for commercial use.

The BBA helped fund pharmacokinetic evaluations of the molecule’s use in mice and validate the research to the point that Kruse was able to form a startup and license the technology, launching Tectonic Therapeutic to further advance the research to the clinic.

“All of these things were really critical for us to be able to out-license this molecule, to show that it actually had some real promise,” Kruse said. “The Blavatnik Accelerator is really what allowed us to go from a pure research compound to something that was ultimately a clinical candidate.”

Kruse also received guidance and ultimately partnered with Timothy A. Springer, the Latham Family Professor of Biological Chemistry and Molecular Pharmacology in the Blavatnik Institute at Harvard Medical School, whose lab studies protein-based therapeutics and who has helped found numerous biotech companies. What began as a lunchtime conversation about progressing academic discovery into a company grew into a collaboration. Springer helped co-found Tectonic, worked with Kruse on fundraising pitches, and provided pivotal early funding, along with his technical expertise.

Since licensing the relaxin technology, Tectonic has conducted additional engineering on the molecule devised in Kruse’s lab — with Kruse as an adviser and Springer on the board of directors — and created a larger platform to develop treatments targeting other G-protein coupled receptors (GPCRs), the class of receptors that Kruse’s lab studies. About 30 percent of all approved drugs target GPCRs, but currently-approved treatments target “just a small fraction” of all known GPCRs, says Alise Reicin, Tectonic’s CEO.

“There is a lot of biology there that could be important in drug discovery and development, but many of those GPCRs, for a variety of reasons, were considered hard to drug or undruggable,” said Reicin. Targeting them with unique biological engineering, the team thought, could unlock new treatments.

For cardiovascular disease, the company’s focus is the RXFP1 receptor, a GPCR that is involved in numerous processes throughout the body, including in the cardiovascular system. Relaxin binds to the RXFP1 receptor and can make tissues, including veins, stretchier and softer. Tectonic’s relaxin treatment, known as TX45, is now in a Phase 2 clinical trial.

“I think there’s lots of reason for optimism that this story is going to play out in the way we envisioned all those years ago,” said Zimmermann.

In January 2025, Tectonic received data suggesting its relaxin therapeutic could work in a subset of patients, those with pulmonary hypertension associated with HFpEF. In the fall, they received a similar dataset in patients with pulmonary hypertension associated with reduced ejection fraction heart failure. These patients typically have reduced exercise tolerance and increased mortality compared with heart failure patients without pulmonary hypertension. In the coming year, the company will also begin working on treating a new form of pulmonary hypertension, associated with interstitial lung disease, with relaxin. For patients, this would mean a potential new treatment for challenging and, at times, fatal conditions. 

“I’m a big believer that it’s the academic-pharma-biotech partnership that has driven innovation in all of the great drug-development programs over the last few decades that have improved the lives of patients,” said Reicin.