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Nipocalimab, an immunoselective FcRn blocker that lowers IgG and has unique molecular properties
Nilufer P Seth1, Rui Xu1, Matthew DuPrie1
1Johnson & Johnson, USA.
Insights
Nipocalimab, an antibody targeting the neonatal Fc receptor (FcRn), effectively reduces pathogenic immunoglobulin G (IgG) levels. Nonclinical studies confirm its potential for treating IgG-mediated autoimmune and alloantibody diseases.
Area of Science:
- Immunology
- Pharmacology
- Structural Biology
Background:
- Nipocalimab is a human IgG1 monoclonal antibody designed to target the neonatal Fc receptor (FcRn).
- FcRn plays a crucial role in IgG homeostasis and recycling.
- Dysregulation of IgG levels is implicated in various autoimmune and alloantibody-mediated diseases.
Purpose of the Study:
- To characterize the molecular, cellular, and nonclinical properties of nipocalimab.
- To support the clinical pharmacology and potential therapeutic applications of nipocalimab.
- To elucidate the binding mechanism of nipocalimab to FcRn.
Main Methods:
- X-ray crystallography to determine the structure of the nipocalimab Fab/FcRn complex.
- Cell-based assays to assess FcRn occupancy and IgG reduction.
- In vivo studies in mice and cynomolgus monkeys to evaluate pharmacokinetic and pharmacodynamic effects.
Main Results:
- Crystal structure revealed nipocalimab binds a unique FcRn epitope, explaining its high, pH-independent affinity.
- Demonstrated dose- and time-dependent FcRn occupancy and reduction of circulating IgG levels.
- Confirmed selective IgG reduction without impacting other immune functions.
Conclusions:
- Nipocalimab exhibits high-affinity, pH-independent binding to FcRn.
- Nonclinical data support nipocalimab's efficacy in reducing pathogenic IgG.
- Nipocalimab shows potential as a therapeutic agent for IgG-driven diseases.
Abstract:
Nipocalimab is a human immunoglobulin G (IgG)1 monoclonal antibody that binds to the neonatal Fc receptor (FcRn) with high specificity and high affinity at both neutral (extracellular) and acidic (intracellular) pH, resulting in the reduction of circulating IgG levels, including those of pathogenic IgG antibodies. Here, we present the molecular, cellular, and nonclinical characteristics of nipocalimab that support the reported clinical pharmacology and potential clinical application in IgG-driven, autoantibody- and alloantibody-mediated diseases. The crystal structure of the nipocalimab antigen binding fragment (Fab)/FcRn complex reveals its binding to a unique epitope on the IgG binding site of FcRn that supports the observed pH-independent high-binding affinity to FcRn. Cell-based and in vivo studies demonstrate concentration/dose- and time-dependent FcRn occupancy and IgG reduction. Nipocalimab selectively reduces circulating IgG levels without detectable effects on other adaptive and innate immune functions. In vitro experiments and in vivo studies in mice and cynomolgus monkeys generated data that align with observations from clinical studies of nipocalimab in IgG autoantibody- and alloantibody-mediated diseases.
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