9MI6

Crystal structure of human FcRn in complex with nipocalimab Fab fragment

Summary for 9MI6

• Entry DOI: 10.2210/pdb9mi6/pdb
• Descriptor: IgG receptor FcRn large subunit p51, Beta-2-microglobulin, nipocalimab Fab heavy chain, ... (6 entities in total)
• Functional Keywords: neonatal fc receptor, fcrn, inhibitor, beta 2 microglobulin, b2m, complex(antibody-antigen), immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 88883.05

Authors

Xu, R.,Meador, J. (deposition date: 2024-12-12, release date: 2025-02-12, Last modification date: 2025-02-26)

Primary citation

Seth, N.P.,Xu, R.,DuPrie, M.,Choudhury, A.,Sihapong, S.,Tyler, S.,Meador, J.,Avery, W.,Cochran, E.,Daly, T.,Brown, J.,Rutitzky, L.,Markowitz, L.,Kumar, S.,Beavers, T.,Bhattacharya, S.,Chen, H.,Parge, V.,Price, K.,Wang, Y.,Sukumaran, S.,Pao, Y.,Abouzahr, K.,Elwood, F.,Duffner, J.,Roy, S.,Narayanaswami, P.,Hubbard, J.J.,Ling, L.E.
Nipocalimab, an immunoselective FcRn blocker that lowers IgG and has unique molecular properties.
Mabs, 17:2461191-2461191, 2025

PubMed 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.

PubMed: 39936406
DOI: 10.1080/19420862.2025.2461191

Experimental method

X-RAY DIFFRACTION (2.41 Å)