Harnessing FcRn Biology to Degrade Pathogenic Antibodies
 
Interview with Dr Karen Silence, Vice President and Head of Preclinical Product Development, argenX
 
At the NextGen Biomed 2026 conference, Oxford Global will welcome Karen Silence, Vice President and Head of Preclinical Product Development at argenX, who will present new approaches for degrading pathogenic antibodies using FcRn biology.
 
Ahead of the conference, Karen discussed the science behind FcRn-targeting therapies, argenX’s next-generation FcRn blocker, and the company’s broader work in antibody engineering.
 
The Role of FcRn in Antibody Recycling
 
The neonatal Fc receptor (FcRn) is essential for maintaining healthy levels of IgG antibodies and albumin in the body. Initially discovered because of its role in transferring antibodies from mother to fetus during pregnancy, FcRn is now known to be widely expressed and crucial for protein recycling.
 
Cells regularly internalize proteins from the bloodstream through pinocytosis, after which most proteins are degraded. IgG and albumin are exceptions. Inside cellular endosomes, where the environment is acidic, these molecules bind to FcRn and are recycled back into circulation rather than being broken down.
 
This recycling mechanism explains why IgG and albumin have unusually long half-lives compared with other proteins.
 
Blocking FcRn to Treat Autoimmune Disease
 
Because FcRn protects IgG from degradation, blocking this interaction provides a strategy for treating diseases driven by pathogenic autoantibodies.
 
argenX’s approved therapy efgartigimod (Vyvgart) is an engineered Fc fragment containing mutations that enhance binding to FcRn. By occupying the receptor, the drug prevents IgG from binding and being recycled. As a result, IgG—including disease-causing autoantibodies—is degraded.
 
The therapy has proven safe and effective, lowering IgG levels without affecting albumin. However, it currently requires relatively frequent dosing, typically weekly or biweekly.
 
argenX therefore set out to develop a next-generation FcRn blocker that maintains efficacy while extending dosing intervals.
 
Engineering a Longer-Lasting Molecule
 
To extend the drug’s half-life, the team explored a strategy that leverages albumin’s natural longevity in circulation.
 
Their approach involved attaching albumin-binding VHH domains to the Fc fragment of efgartigimod. Although conceptually simple, the engineering process proved challenging.
 
Early designs produced excellent pharmacokinetics but lost their IgG-blocking activity. Later versions restored IgG reduction but unexpectedly lowered albumin levels as well.
 
After several iterations and careful optimization of binding affinities, linkers, and domain positioning, the team developed a final candidate that combines longer half-life, strong IgG reduction, and no effect on albumin levels.
 
Developing Therapies to Remove IgA
 
argenX is also exploring therapies that target IgA antibodies, which play a role in diseases such as IgA nephropathy, where IgA immune complexes accumulate in the kidneys and lead to progressive kidney damage.
 
Designing a therapy to remove IgA is difficult because IgA levels in serum are high and new IgA is constantly produced. Early molecules worked only when IgA levels were relatively low.
 
Through multiple rounds of engineering, the team developed a candidate capable of removing more than 90% of circulating IgA within a few days, demonstrating unexpectedly strong potency.
 
The Importance of Antibody Geometry
 
A key insight came from structural studies showing that antibodies bind upside down to FcRn, with their Fab regions pointing toward the cell membrane. This orientation created a structural clash when the therapeutic antibody attempted to bind IgA simultaneously.
 
By redesigning the antibody to maintain FcRn interaction while still allowing IgA binding, researchers were able to produce an effective IgA “sweeping” antibody.
 
Expanding the Sweeping Platform
 
The engineering work behind the IgA program has helped establish a broader antibody sweeping platform that argenX plans to apply to additional soluble targets.
 
Although IgA represented an especially challenging case due to its abundance, the company believes the platform could be adapted for other disease-driving molecules.
 
A Collaborative Approach to Innovation
 
Collaboration plays a central role in argenX’s development strategy. The company frequently works with academic and scientific partners from the earliest stages of discovery and continues those partnerships throughout development.
 
Rather than simply licensing external discoveries, argenX emphasizes co-development, allowing collaborators to remain closely involved in advancing their research into clinical therapies.
 
What’s Next for argenX
 
argenX’s preclinical pipeline currently includes several key programs:
  • ARGX-109 – an IL-6 antibody
  • ARGX-213 – a next-generation FcRn blocker with extended half-life
  • ARGX-121 – the IgA sweeping antibody
Each is designed as a pipeline-in-a-product, meaning it may be developed across multiple disease indications.
 
Karen Silence will explore these innovations in greater depth at NextGen Biomed 2026, where she will discuss the challenges and opportunities in engineering therapies that selectively remove pathogenic antibodies.