Potent efficacy of an IgG-specific endoglycosidase against IgG-mediated pathologies

Affiliations

• Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA
• Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065, USA

PMID:  #  DOI: 10.1016/j.cell.2024.09.038

Abstract

Endo-β-N-acetylglucosaminidases (ENGases) that specifically hydrolyze the Asn297-linked glycan on immunoglobulin G (IgG) antibodies, the major molecular determinant of fragment crystallizable (Fc) γ receptor (FcγR) binding, are exceedingly rare. All previously characterized IgG-specific ENGases are multi-domain proteins secreted as an immune evasion strategy by Streptococcus pyogenes strains. Here, using in silico analysis and mass spectrometry techniques, we identified a family of single-domain ENGases secreted by pathogenic corynebacterial species that exhibit strict specificity for IgG antibodies. By X-ray crystallographic and surface plasmon resonance analyses, we found that the most catalytically efficient IgG-specific ENGase family member recognizes both protein and glycan components of IgG. Employing in vivo models, we demonstrated the remarkable efficacy of this IgG-specific ENGase in mitigating numerous pathologies that rely on FcγR-mediated effector functions, including T and B lymphocyte depletion, autoimmune hemolytic anemia, and antibody-dependent enhancement of dengue disease, revealing its potential for treating and/or preventing a wide range of IgG-mediated diseases in humans.

特异性水解免疫球蛋白G（IgG）上Asn297连接的糖链的酶（ENGases）极为稀少，而这些糖链是与FcγR结合的主要分子决定因素。目前已知的IgG特异性ENGases均为多结构域蛋白，主要由化脓性链球菌（Streptococcus pyogenes）分泌，以实现免疫逃逸。在本研究中，我们通过生物信息学分析和质谱技术，鉴定出了一类由致病性棒状杆菌（corynebacterial species）分泌的单域ENGases，它们对IgG表现出严格的特异性。通过X射线晶体学和表面等离子体共振分析，我们发现该类ENGases中催化效率最高的成员能够识别IgG的蛋白质和糖链成分。利用体内模型实验，我们证明了这一IgG特异性ENGase在减轻多种依赖于FcγR介导的病理效应方面的显著功效，包括T细胞和B细胞的耗竭、自身免疫性溶血性贫血以及登革热的抗体依赖性增强，显示了其在治疗和/或预防多种IgG介导疾病方面的潜力。

关键词：抗体, IgG, 糖苷酶, EndoS, Endo S, EndoS2, Endo S2, PNGase F, ENGase, 棒状杆菌, corynebacterial species, 化脓性链球菌, Streptococcus pyogenes, 佰乐博, 佰乐博生物