Confo Therapeutics Announces Publication in Nature Communications Demonstrating First-Ever Structure of a Complex Between an Antibody-based Agonist and a Class A GPCR Regulating Hunger and Satiety
Discovery of highly potent and selective antibody-based GPCR agonists targeting Melanocortin 4 Receptor (MC4R), a key regulator for hunger and satiety, using Confo’s proprietary technology platform
Resolution of first-ever structure of a complex between an antibody-based agonist, a GPCR and the G-proteins enabled by Confo’s patent-protected ConfoBody® Cb35 (Nb35)
Agonist mimics interaction of the natural ligand by binding within the orthosteric pocket of MC4R without agonising other GPCR family members
Data provides basis for further exploration to understand the contribution of MC4R stimulation to the in vivo efficacy of selective MC4R agonists for treatment of (genetic) obesity with the potential to open novel, improved therapeutic avenues
Confo Therapeutics, a leader in the discovery of novel medicines targeting G-protein coupled receptors (GPCRs), today announced a publication in Nature Communications demonstrating the world’s first structure of a complex between an antibody-based agonist and a Class A GPCR, specifically the melanocortin receptor 4 (MC4R). MC4R belongs to the melanocortin receptor family of GPCRs and is a key switch in the leptin-melanocortin molecular axis that controls hunger and satiety.
Confo applied its proprietary platform technology to enable the de novo discovery of a diverse panel of fully agonistic MC4R-specific antibody sequences. The most potent agonist, pN162, is the first reported melanocortin receptor ligand that is specific to MC4R and shows full agonist pharmacology. It does not bind to nor induce signaling by any other human melanocortin receptor subtype. Current MC4R peptide agonists for the treatment of (genetic) obesity lack this selectivity and therefore lead to off-target side effects. Confo’s discovery has the potential to be suitable for anti-obesity therapeutic intervention via MC4R.
In the publication, Confo further demonstrated the first-ever cryo-EM structure of a complex between an antibody-based agonist, a GPCR and the G-proteins. This was enabled by Confo’s patent-protected ConfoBody® Cb35 (Nb35). The structure revealed a highly distinct interaction with pN162 binding deeply in the orthosteric pocket without agonising any other melanocortin receptors. Elucidating the interaction between agonistic antibodies and GPCRs in their active state provides an important foundation for future drug discovery efforts to allow successful agonist antibody development, which has been notoriously challenging within the industry. The results put forth in the publication demonstrate the potential of Confo’s novel approach to discovering this class of therapeutic molecule.
“One of Confo’s key strengths is our unique ability to develop antibody-based GPCR agonists as an emerging class of medicines, and we continue to explore their full potential across multiple targets,” said Dr. Christel Menet, CSO of Confo Therapeutics. “The research and results published in Nature Communications will guide us as we broaden and advance our discovery efforts in metabolic and endocrine indications.”
“These data show that we are capable of unlocking a new route for developing innovative medicines targeting GPCRs,” said Cedric Ververken, Ph.D., CEO of Confo Therapeutics. “The publication of our research and scientific discovery in Nature Communications is a significant validation for our platform and a recognition of its potential to address long-standing challenges in GPCR drug discovery, with the goal of bringing novel and improved treatments to patients.”
Confo holds exclusive licenses in the field of GPCRs through the “Steyaert patents,” a patent estate comprising over 200 granted patents in 7 distinct patent families which cover various aspects of the ConfoBody® platform. This includes the recently granted US patent 12,092,646 which relates to ConfoBody®-based screening methods for small molecules and antibodies, following the earlier grant of similar patent claims in Europe.