Work

Native structure of the monoclonal therapeutic CD20 antibody ocrelizumab

Year: 2025

Type: article

Abstract: Immunoglobulin G (IgG) is fundamental to adaptive immunity and numerous monoclonal IgGs (monoclonal antibodies (MAbs)) have been developed as therapeutics for various diseases, including ocrelizumab (OMAb), a CD20 MAb used for treating multiple sclerosis, and infliximab (IMAb), a tumor necrosis factor MAb used for treating rheumatoid arthritis and other conditions. Understanding structure-function relationships are essential for understanding the mechanisms of action of IgG MAbs and previous results have shown that IgG has a "closed", "m"-shaped conformation in native form, which may switch to an "open", "Y"-shaped conformation upon antigen binding or physico-chemical stress. Supported by immunochemical and biophysical methods and by chemical crosslinking mass spectrometry (XL-MS) we show that both OMAb and IMAb conform to this paradigm. By XL-MS, we identified eighty-five high-confidence cross-links that support the native closed state of OMAb, refining our understanding of IgG architecture. Molecular modeling based on these data further corroborates a compact IgG structure, shielding the Fc domain. This structural insight may increase our understanding of immunoglobulin biology and enhance therapeutic MAb design by optimizing stability and efficacy.

Source: Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

DOI: 10.1016/j.bbapap.2025.141084