Anti-tnf alpha antibody humira with ph-dependent binding characteristics: A constant-ph molecular dynamics, gaussian accelerated molecular dynamics, and in vitro study

Shih Ting Hong, Yu Cheng Su, Yu Jen Wang, Tian Lu Cheng*, Yeng Tseng Wang

*Corresponding author for this work

研究成果: Article同行評審

摘要

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. Further-more, 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.

原文English
文章編號334
頁(從 - 到)1-15
頁數15
期刊Biomolecules
11
發行號2
DOIs
出版狀態Published - 二月 2021

指紋 深入研究「Anti-tnf alpha antibody humira with ph-dependent binding characteristics: A constant-ph molecular dynamics, gaussian accelerated molecular dynamics, and in vitro study」主題。共同形成了獨特的指紋。

引用此