VILLIGEN, Switzerland—In early June, leadXpro and the University of Zurich (UZH) announced a collaboration to generate sybodies as molecular discovery tools, therapeutic lead compounds and diagnostic reagents against disease-relevant membrane protein targets.
Membrane proteins such as transporters, ion channels and GPCRs are therapeutic targets for highly successful medicines. leadXpro’s expertise lies in the generation of membrane protein samples for biophysical analysis and structural investigation by X-ray crystallography and cryo-electron microscopy, and the company generates and applies such samples to the discovery and optimization of small-molecule and biotherapeutic lead compounds. The intent is to extend drug discovery options for previously intractable or challenging membrane protein drug targets.
According to Michael Hennig, CEO and chairman of the board of leadXpro, “leadXpro is located in a region with excellent research facilities like the ETH institutes (PSI, ETH Zürich) and Universities of Basel and Zürich. Prof. Markus Seeger and I have known each other for many years, and we had previous collaborations already. I approached Markus three years ago to use sybodies as chaperones in crystallization experiments for X-ray structure determination.”
Under this research and development collaboration, leadXpro will provide purified membrane protein and UZH will apply their sybody platform, which is unique in generating synthetic single-domain antibodies (dubbed sybodies) against challenging membrane proteins. leadXpro has the option to acquire any resulting commercial applications of the developed products.
“In this challenging project, we apply our recently developed sybody selection platform to enable drug discovery on a disease-relevant membrane protein. As an academic innovator lab, we have a strong interest in making our technology accessible to skilled and experienced industry partners, like leadXpro,” remarked Markus Seeger, project leader and a professor at UZH.
Iwan Zimmermann, co-inventor of the sybody technology, UZH, added, “The project gained quickly momentum, due to the combination of the excellent target quality delivered by leadXpro and our highly efficient sybody platform. The collaboration is an excellent validation of our binder technology towards future therapeutic applications.”
Sybodies are synthetic single-domain antibodies that have been developed in the Seeger research group at UZH. “Some animals like camels, llamas and sharks generate so-called nanobodies. They are smaller in size compared to antibodies and can be produced easily,” says Hennig.
According to the research published in eLife, the sybodies are “designed to mimic the natural shape diversity of camelid nanobodies, thus allowing for an optimal surface complementarity to the limited hydrophilic epitopes on membrane proteins. The application of ribosome display for synthetic nanobody libraries allows processing of very large diversities, thus compensating for the incremental antibody maturation taking place in vivo. Our approach permits the selection and preparative production of sybodies within three weeks and requires only standard laboratory materials.”
Sybodies have been engineered for targeting challenging integral membrane proteins and are selected entirely in vitro, thereby enabling rapid binder generation in the presence of non-covalent ligands against delicate targets. Due to their high thermal stabilities and low production costs, sybodies show promise for diagnostic as well as therapeutic applications. Sybodies are ideally suited to trap intrinsically flexible membrane proteins in defined conformational states and thereby facilitate structure determination by X-ray crystallography and cryo-EM.
Mathieu Botte, senior scientist and project leader at leadXpro, said, “Generation of high-quality membrane protein samples is a core competence of leadXpro’s lead discovery platform. Within only three weeks, our collaboration partners at UZH have successfully generated a highly diverse set of sybodies that are directed against our challenging target protein. Binding properties were characterized with our platform of biophysical methods (e.g. Creoptix’s wave-guided interferometry) and revealed up to pM affinities and favorably slow dissociation rates for several binders. Sybodies are therefore ideal candidates for the formation of stable complexes for structural studies, and they represent excellent therapeutic lead compounds.”
“In addition to employing our membrane protein samples for our biophysical and structure-based analytical tool set, we can now expand the utility of our samples as antigens for the generation of sybodies or antibodies,” Hennig adds. “While this collaboration is our first entry into the biologics discovery space, benefits from the generated sybodies as stabilization, crystallization and tools to aid our structure guided small-molecule platform are also very welcome and contribute additional value to our existing membrane protein generation platform.”
When asked about the types of possible commercial applications the researchers hope might come out of this collaboration, he notes, “Sybodies are great facilitators to crystallize challenging drug target proteins like membrane proteins. This will enable structure-based drug discovery for disease mechanisms that have not benefitted from these modern methods to discover new treatment options for patients. In addition, sybodies could be drug molecules themselves, like the many antibody treatments that are currently available.”