How GPCR agonists, including antibodies, are shaping the future of metabolic care

G protein-coupled receptors (GPCRs) represent a cornerstone of modern drug discovery due to their crucial role in regulating human physiology and their involvement in numerous diseases. Many of these receptors are key targets for addressing obesity and metabolic disorders. Confo Therapeutics, led by CEO Dr Cedric Ververken, is at the forefront of developing innovative GPCR-targeted therapies using its proprietary ConfoBody^® platform. This platform leverages nanobody-based binding domains to achieve exceptional receptor specificity and stability, offering a transformative approach to targeting GPCRs compared to traditional peptide-based therapies. In their recent publication in Nature Communications, Confo Therapeutics has demonstrated their ability to generate highly specific antibody-based agonists of MC4R, a GPCR involved in genetic obesity.

In this exclusive interview, Cedric Ververken discusses how innovative GPCR-targeted therapies are driving advancements in drug discovery to tackle pressing health challenges like obesity.

How does Confo Therapeutics’ use of nanobody-based binding domains, like ConfoBody Cb80, in their MC4R-specific agonists improve receptor selectivity compared to existing peptide-based therapies, particularly in preclinical studies?

Using its ConfoBody platform, Confo Therapeutics has been able to identify VHHs which function as orthosteric agonists of MC4R. A VHH is the antigen binding domain from naturally-occurring llama heavy-chain only antibodies. Confo’s MC4R VHHs are exquisitely selective and do not bind to or activate any of the other melanocortin receptors. By fusing Fc domains to the VHHs, Confo can produce humanized heavy-chain only antibodies for further development.

Identification of the agonistic VHHs was accomplished using an immunogen known as a ConfoGen™, which comprises a ConfoBody-stabilized chimeric version of the target GPCR. The MC4R-based ConfoGen™ was used to immunize llamas, resulting in an immune response that generated a highly diverse panel of MC4R-specific agonists.

Confo’s finely-tuned approach to GPCR antibody discovery provides several advantages. These include the use of immunogens that are highly expressed, are very immunogenic and are presented to the immune system in pharmacologically relevant conformations to generate appropriate antibodies. Confo’s approach does not require purification of the target GPCR, making it an extremely efficient and fruitful approach for a multitude of receptors.

What specific challenges has Confo Therapeutics encountered in stabilising active-state GPCR structures, such as the MC4R-β2AR hybrid, and how does this approach improve the precision of de novo drug discovery for obesity and other metabolic disorders?

In the early days, each GPCR target required its own structure-modulating ConfoBody to be identified before starting any drug discovery. This required purification of the target, which was highly time- and resource-consuming. Over several years the team developed the ConfoChimer technology which no longer requires any new ConfoBody to be discovered. Instead, chimeric receptors are generated in which intracellular loops of the target GPCR are swapped with the loops of a donor GPCR. Each of our donor GPCRs already has its own set of ConfoBodies available which remarkably are able to stabilize the new target GPCR. Despite being chimeric receptors, the team have demonstrated that the structures of their ligand binding pockets remain intact and are identical to the wild-type receptor.

The team has generated over 200 of these chimeric GPCRs and has built a tremendous amount of know-how in doing so. They are now applying the same strategy to a range of GPCRs with a focus on high value targets in obesity and other metabolic conditions. In addition to generating agonistic antibodies, Confo is also successfully applying the ConfoBody/ConfoChimer technology to drugging GPCR with small molecules.

Given the novel MC4R-specific full agonistic nanobodies, how is Confo Therapeutics addressing potential immunogenicity and long-term efficacy in preclinical models?

VHH-based therapies have been clinically-validated many times with multiple products in numerous indications, including for long-term dosing. Confo has an extensive knowledge in the optimization of VHH-based products for human use. This expertise covers humanization of the sequences, removal of potential T cell epitopes, and optimization of biophysical properties. For example, the team engineered the MC4R agonists as humanized heavy-chain only antibodies with human Fc domains to improve their overall drug-like properties.

What are the primary considerations in optimising the pharmacokinetics (PK) and biodistribution of MC4R-specific nanobodies in preclinical obesity models, and how does Confo Therapeutics plan to address challenges related to blood-brain barrier penetration?

A suitable pharmacokinetics profile can be achieved with the addition of half-life extending moieties to the molecule. For the MC4R agonists the team achieved this with the addition of human Fc domains to generate humanized heavy-chain only antibodies.

It is currently unclear whether blood-brain barrier (BBB) penetration is needed for an MC4R agonist to be active in vivo. The approved MC4R agonist setmelanotide is a peptide which also doesn’t seem to traffic across the BBB very efficiently. It is important to note that an agonist typically does not require full target engagement to be active in vivo, which contrasts with an antagonist approach which requires full (or at least 90%) target engagement throughout the dosing interval.

In light of Confo Therapeutics’ success in solving the active-state MC4R structure at 3.4 Å resolution, how do you foresee this structural insight accelerating the development of highly specific GPCR-targeted therapies, and what technical hurdles remain in translating these findings into viable therapeutic candidates?

The cryo-EM structure of our agonistic VHH, MC4R and the G-protein complex illustrates the binding mode and orthosteric activity of the VHH, which activates MC4R in a similar way as the native ligand and peptide agonists. The structure shows how the agonist binds deeply into the orthosteric pocket, in a way that would be challenging for conventional IgG antibodies with much larger paratopes.

Today there are only three GPCR antibodies on the market (2 antagonists and 1 bi-specific T cell engager for cancer targeting) and very few in development in comparison to other target classes. This demonstrates the high technical challenges for companies to discover antibodies to GPCRs, especially agonists. The advancements exemplified by the MC4R agonists is opening up this area of drug discovery and the team will continue to leverage its proprietary technology to generate high value antibodies targeting multiple GPCRs.

About the Author

Dr Cedric Ververken, CEO at Confo Therapeutics

Cedric previously served as Vice President of Business Development at Ablynx and played a key role in landmark deals. Prior to moving to business development, he worked through various R&D functions at Ablynx, first as a scientist in the pharmacology group and later as project manager, leading cross-functional project teams from discovery up to Phase II clinical studies. Cedric has a PhD in bioscience engineering from KU Leuven (Belgium).