VIB Scientists (dis)solve a crystal mystery and point the way towards new asthma treatments

Researchers from the VIB-UGent Center for Inflammation Research, together with the biotech  company argenx have solved a century-long puzzle about the presence of protein crystals in asthma. Normally, proteins do not crystallize in the body, but there are some instances where this process does occur. Charcot-Leyden crystals are made from the protein Galectin-10 and were discovered in the airways of asthmatics as early as 1853. However, the crystals have been largely ignored by scientists, and their actual link to disease remained unknown. Emma Persson, Kenneth Verstraete, and Ines Heyndrickx from the groups of Bart Lambrecht and Savvas Savvides have now established that the crystals are highly abundant in airway mucus, stimulate the immune system and promote the inflammation and altered mucus production that is often seen in the airways of asthmatics. Together with argenx they also developed antibodies that can dissolve these crystals to reduce key asthma features. Bart Lambrecht provides some background on the breakthrough.

Where did the idea for this research come from?
“This work started years ago when we discovered that many adjuvants that we use in vaccines have a crystalline state. We also made the striking observation that uric acid crystals induce allergy. From this, we started reasoning that there might be endogenous crystals in the airways of asthmatics that could boost type 2 immunity. I remembered these old descriptions of Charcot-Leyden crystals from my medical classes and decided to team up with Savvas to start working on this. For me, this project was my introduction to meaningful crystallography. I had never used it before in my research. The collaboration with Savvas, has really improved my understanding of crystallography, and I now see the beauty of protein structures. The project also taught me a lot about how a biotech company works.”

Savvas Savvides

Collaboration was key in this project, can you explain?
“This work was only possible because of a deep collaborative effort between the Savvides lab, the
Lambrecht/Hammad lab, and argenx, a biotech company in Ghent, which selected this project as one of their innovative access programs. Close collaboration with biotech can really bring a lot to a project. If you’re serious about bringing something to the clinic, team up with the experts in drug development. The core facilities were also continuously in the loop and were key for producing recombinant proteins, performing crucial imaging experiments, flow cytometry, etc. It is fair to say that this project would not have achieved its goals without the core facilities. It was a huge team effort, and everybody is proud of the result.”

Bart Lambrecht

What were the major challenges to overcome?
“The major challenge in this project was that it was a very high-risk project. When I first submitted the work for a grant application, the reviewers at ERC said it was going to be impossible. One year later we got the antibodies that dissolve crystals, this time the reviewers were all positive, and I received an ERC advanced grant. Ghent University believed in it from the start, so luckily we got our key funding early on.” 

At which moment did you realize that this work was going to be so significant?
“When we saw that we could engineer these protein crystals and observed that we could induce potent features of asthma I knew this was important. But what really convinced me to push this project was the fact that we can dissolve the crystals with antibodies. This was one of the nicest moments in my scientific career. We are very happy that argenx has taken the antibody into the next phase of development and announced it as their ARGX-118 program. In the coming years, we hope to see the further clinical testing of a strategy that dissolves Charcot-Leyden crystals in severe asthmatics.” 

Where do you personally think the next breakthrough lies in this field?
“Showing that altering these crystals in asthmatics changes the development of the disease and might treat the persistent airway obstruction that is often seen in these patients. This is one of the biggest unmet needs in asthma.”

Persson, Verstraete, Heyndrickx et al., Science 2019