Human IgG1 Fc pH-dependent optimization from a constant pH molecular dynamics simulation analysis

Lim, Yee Ying; Lim, Theam Soon; Choong, Yee Siew

doi:10.1039/c9ra10712f

Cited by 3 publications

(1 citation statement)

References 47 publications

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“…Computer simulations can speed up antibody drug design [ 50 ]. Although molecular simulation techniques are applied in the design of pH-dependent binding antibodies, these methods cannot provide accurate predictions of antibody binding characteristics at various pH values, and these methods can only be used to perform simulations with X-ray crystals or to predict the complex structures of antibody Fab fragments and Fab–antigen complexes [ 51 , 52 ]. Therefore, antibody drug design remains a considerable challenge.…”

Section: Discussionmentioning

confidence: 99%

Anti-TNF Alpha Antibody Humira with pH-dependent Binding Characteristics: A constant-pH Molecular Dynamics, Gaussian Accelerated Molecular Dynamics, and In Vitro Study

Hong

Wang

et al. 2021

Biomolecules

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Humira is a monoclonal antibody that binds to TNF alpha, inactivates TNF alpha receptors, and inhibits inflammation. Neonatal Fc receptors can mediate the transcytosis of Humira–TNF alpha complex structures and process them toward degradation pathways, which reduces the therapeutic effect of Humira. Allowing the Humira–TNF alpha complex structures to dissociate to Humira and soluble TNF alpha in the early endosome to enable Humira recycling is crucial. We used the cytoplasmic pH (7.4), the early endosomal pH (6.0), and pKa of histidine side chains (6.0–6.4) to mutate the residues of complementarity-determining regions with histidine. Our engineered Humira (W1-Humira) can bind to TNF alpha in plasma at neutral pH and dissociate from the TNF alpha in the endosome at acidic pH. We used the constant-pH molecular dynamics, Gaussian accelerated molecular dynamics, two-dimensional potential mean force profiles, and in vitro methods to investigate the characteristics of W1-Humira. Our results revealed that the proposed Humira can bind TNF alpha with pH-dependent affinity in vitro. The W1-Humira was weaker than wild-type Humira at neutral pH in vitro, and our prediction results were close to the in vitro results. Furthermore, our approach displayed a high accuracy in antibody pH-dependent binding characteristics prediction, which may facilitate antibody drug design. Advancements in computational methods and computing power may further aid in addressing the challenges in antibody drug design.

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Section: Discussionmentioning

confidence: 99%

Anti-TNF Alpha Antibody Humira with pH-dependent Binding Characteristics: A constant-pH Molecular Dynamics, Gaussian Accelerated Molecular Dynamics, and In Vitro Study

Hong

Wang

et al. 2021

Biomolecules

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Application of Computational Techniques in Antibody Fc-Fused Molecule Design for Therapeutics

Ng,

Lim,

Choong

2023

Mol Biotechnol

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FcRn inhibitors: a novel option for the treatment of myasthenia gravis

Zhu¹,

Hou²,

Wang³

et al. 2022

Neural Regen Res

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Myasthenia gravis is an acquired, humoral immunity-mediated autoimmune disease characterized by the production of autoantibodies that impair synaptic transmission at the neuromuscular junction. The intervention-mediated clearance of immunoglobulin G (IgG) was shown to be effective in controlling the progression of the disease. The neonatal Fc receptor (FcRn) plays a key role in prolonging the serum half-life of IgG. Antagonizing FcRn to prevent its binding to IgG can accelerate the catabolism of the latter, resulting in decreased levels of IgG, including pathogenic autoantibodies, thereby achieving a therapeutic effect. In this review, we detail the substantial research progress, both basic and clinical, relating to the use of FcRn inhibitors in the treatment of myasthenia gravis.

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Human IgG1 Fc pH-dependent optimization from a constant pH molecular dynamics simulation analysis

Abstract: An in silico IgG-Fc variant with better affinity at pH 6.0 but retained the dissociation at pH 7.5 was designed.

Cited by 3 publications

References 47 publications

Anti-TNF Alpha Antibody Humira with pH-dependent Binding Characteristics: A constant-pH Molecular Dynamics, Gaussian Accelerated Molecular Dynamics, and In Vitro Study

Anti-TNF Alpha Antibody Humira with pH-dependent Binding Characteristics: A constant-pH Molecular Dynamics, Gaussian Accelerated Molecular Dynamics, and In Vitro Study

Application of Computational Techniques in Antibody Fc-Fused Molecule Design for Therapeutics

FcRn inhibitors: a novel option for the treatment of myasthenia gravis

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