The Fab region of IgG impairs the internalization pathway of FcRn upon Fc engagement
Maximilian Brinkhaus, Erwin Pannecoucke et al.. Nature Communications 01 December 2022; 13(1).
AbstractBinding to the neonatal Fc receptor (FcRn) extends serum half-life of IgG, and antagonizing this interaction is a promising therapeutic approach in IgG-mediated autoimmune diseases. Fc-MST-HN, designed for enhanced FcRn binding capacity, has not been evaluated in the context of a full-length antibody, and the structural properties of the attached Fab regions might affect the FcRn-mediated intracellular trafficking pathway. Here we present a comprehensive comparative analysis of the IgG salvage pathway between two full-size IgG1 variants, containing wild type and MST-HN Fc fragments, and their Fc-only counterparts. We find no evidence of Fab-regions affecting FcRn binding in cell-free assays, however, cellular assays show impaired binding of full-size IgG to FcRn, which translates into improved intracellular FcRn occupancy and intracellular accumulation of Fc-MST-HN compared to full size IgG1-MST-HN. The crystal structure of Fc-MST-HN in complex with FcRn provides a plausible explanation why the Fab disrupts the interaction only in the context of membrane-associated FcRn. Importantly, we find that Fc-MST-HN outperforms full-size IgG1-MST-HN in reducing IgG levels in cynomolgus monkeys. Collectively, our findings identify the cellular membrane context as a critical factor in FcRn biology and therapeutic targeting.
The Latest from Antibody Journal
-
Antibody-Dependent Cellular Cytotoxicity (ADCC) – definition, mechanism & application
Antibody-dependent cellular cytotoxicity is a key process of the immune system’s arsenal to ward off cancerous cells and infections. We show you important definitions and the ADCC mechanism and key facts on ADCC antibodies in this post.
-
Afucosylated recombinant antibodies
Generally speaking, antibodies of any kind, including recombinant and afucosylated antibodies, are Y-shaped proteins produced by the human body. As they are able to identify and neutralize foreign objects – in other words viruses – they play a major contributing role in keeping our body and immune system healthy.
-
Recombinant Antibodies – 7 key insights to rAbs
From the application in medicine and science to recombinant antibody production and the advantages of recombinant Abs in contrast to traditional monoclonal antibodies, this article will teach you all you need to know about recombinant antibodies.
-
Afucosylated recombinant antibodies
Generally speaking, antibodies of any kind, including recombinant and afucosylated antibodies, are Y-shaped proteins produced by the human body. As they are able to identify and neutralize foreign objects – in other words viruses – they play a major contributing role in keeping our body and immune system healthy.
-
Recombinant Antibodies – 7 key insights to rAbs
From the application in medicine and science to recombinant antibody production and the advantages of recombinant Abs in contrast to traditional monoclonal antibodies, this article will teach you all you need to know about recombinant antibodies.
-
Antibody-Dependent Cellular Cytotoxicity (ADCC) – Definition, Mechanism & Application
Antibody-dependent cellular cytotoxicity is a key process of the immune system’s arsenal to ward off cancerous cells and infections. We show you important definitions and the ADCC mechanism and key facts on ADCC antibodies in this post.
-
AAX Biotech and evitria to expand access to Opti-mAb® technology in early antibody development
STOCKHOLM / 23 April 2026 – Biotech company AAX Biotech, a leading innovator in technologies for antibody-based therapies, today announced a partnership with evitria AG, an expert provider of antibody engineering and expression services, to enable the use of its Opti-mAb® technology in early antibody development workflows. AAX Biotech develops proprietary technologies, including Opti-mAb®, supporting antibody discovery and engineering. Through the partnership, evitria will offer its customers access to Opti-mAb® technology in the design and optimization stages of antibody candidate development across the biotech and pharmaceutical industries. Under the agreement, evitria will provide access to Opti-mAb® under a research license…
-
HEK293 vs. CHO for HTP Expression: Impact on Glycosylation and Folding
Choosing an expression host defines an antibody’s biological signature. While HEK293 is often used for convenience, it introduces significant risks in glycosylation and folding. By aligning HTP screening with CHO-native standards from the start, discovery teams eliminate host-switch leads are truly ready for clinical success.
-
Transient vs. Stable Expression in High-Throughput Antibody Screening: When to Switch
The choice between transient and stable expression defines the pace and precision of an antibody program. While transient systems provide the agility for high-throughput screening, stable cell lines offer the consistency required for clinical manufacturing. Understanding the technical triggers for this switch is essential for optimizing timelines and ensuring manufacturing success.
-
Physical Validation at Scale: How HTP Supports AI-Designed Antibody Discovery
AI accelerates antibody discovery, but physical validation remains essential to bridge the gap between digital design and biological reality. High-Throughput (HTP) platforms enable a ‘lab-in-the-loop’ approach, providing the manufacturing-relevant CHO data needed to refine predictive models and ensure that AI-generated candidates are truly developable from the earliest stage.
-
Fail Fast, Succeed Faster: The Role of Early Developability Assessment
Shifting developability assessment to the early discovery phase represents a strategic opportunity to eliminate high risk candidates before significant investment. By utilizing CHO based expression from the very first screening you ensure that early data is truly predictive of manufacturing success. This proactive approach de risks the journey from the bench to preclinical validation by identifying structural liabilities before they become costly failures.
-
Polyclonal Antibody Production: A Comprehensive Guide
This article will provide a comprehensive guide to polyclonal antibody production (pAb production), outlining the steps involved in the process, discussing the advantages and disadvantages of using polyclonal antibodies, and exploring the alternatives to polyclonal antibody production, including recombinant antibody production.
