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

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....

Full description

Bibliographic Details
Main Authors:	Shih-Ting Hong, Yu-Cheng Su, Yu-Jen Wang, Tian-Lu Cheng, Yeng-Tseng Wang
Format:	Article
Language:	English
Published:	MDPI AG 2021-02-01
Series:	Biomolecules
Subjects:	constant-pH molecular dynamics molecular simulations antibody anti-TNF alpha Gaussian accelerated molecular dynamics
Online Access:	https://www.mdpi.com/2218-273X/11/2/334

id	doaj-718e4910b4734af2a847d39ec63a7f88
record_format	Article
spelling	doaj-718e4910b4734af2a847d39ec63a7f882021-02-24T00:01:41ZengMDPI AGBiomolecules2218-273X2021-02-011133433410.3390/biom11020334Anti-TNF Alpha Antibody Humira with pH-Dependent Binding Characteristics: A Constant-pH Molecular Dynamics, Gaussian Accelerated Molecular Dynamics, and In Vitro StudyShih-Ting Hong0Yu-Cheng Su1Yu-Jen Wang2Tian-Lu Cheng3Yeng-Tseng Wang4Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 80708, TaiwanDepartment of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsin-Chu, 300, TaiwanDepartment of Mechanical and Electromechanical Engineering, National Sun Yat-Sen University, Kaohsiung 80424, TaiwanGraduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 80708, TaiwanGraduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 80708, TaiwanHumira 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 pK<sub>a</sub> 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.https://www.mdpi.com/2218-273X/11/2/334constant-pH molecular dynamicsmolecular simulationsantibodyanti-TNF alphaGaussian accelerated molecular dynamics
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Shih-Ting Hong Yu-Cheng Su Yu-Jen Wang Tian-Lu Cheng Yeng-Tseng Wang
spellingShingle	Shih-Ting Hong Yu-Cheng Su Yu-Jen Wang Tian-Lu Cheng Yeng-Tseng Wang Anti-TNF Alpha Antibody Humira with pH-Dependent Binding Characteristics: A Constant-pH Molecular Dynamics, Gaussian Accelerated Molecular Dynamics, and In Vitro Study Biomolecules constant-pH molecular dynamics molecular simulations antibody anti-TNF alpha Gaussian accelerated molecular dynamics
author_facet	Shih-Ting Hong Yu-Cheng Su Yu-Jen Wang Tian-Lu Cheng Yeng-Tseng Wang
author_sort	Shih-Ting Hong
title	Anti-TNF Alpha Antibody Humira with pH-Dependent Binding Characteristics: A Constant-pH Molecular Dynamics, Gaussian Accelerated Molecular Dynamics, and In Vitro Study
title_short	Anti-TNF Alpha Antibody Humira with pH-Dependent Binding Characteristics: A Constant-pH Molecular Dynamics, Gaussian Accelerated Molecular Dynamics, and In Vitro Study
title_full	Anti-TNF Alpha Antibody Humira with pH-Dependent Binding Characteristics: A Constant-pH Molecular Dynamics, Gaussian Accelerated Molecular Dynamics, and In Vitro Study
title_fullStr	Anti-TNF Alpha Antibody Humira with pH-Dependent Binding Characteristics: A Constant-pH Molecular Dynamics, Gaussian Accelerated Molecular Dynamics, and In Vitro Study
title_full_unstemmed	Anti-TNF Alpha Antibody Humira with pH-Dependent Binding Characteristics: A Constant-pH Molecular Dynamics, Gaussian Accelerated Molecular Dynamics, and In Vitro Study
title_sort	anti-tnf alpha antibody humira with ph-dependent binding characteristics: a constant-ph molecular dynamics, gaussian accelerated molecular dynamics, and in vitro study
publisher	MDPI AG
series	Biomolecules
issn	2218-273X
publishDate	2021-02-01
description	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 pK<sub>a</sub> 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.
topic	constant-pH molecular dynamics molecular simulations antibody anti-TNF alpha Gaussian accelerated molecular dynamics
url	https://www.mdpi.com/2218-273X/11/2/334
work_keys_str_mv	AT shihtinghong antitnfalphaantibodyhumirawithphdependentbindingcharacteristicsaconstantphmoleculardynamicsgaussianacceleratedmoleculardynamicsandinvitrostudy AT yuchengsu antitnfalphaantibodyhumirawithphdependentbindingcharacteristicsaconstantphmoleculardynamicsgaussianacceleratedmoleculardynamicsandinvitrostudy AT yujenwang antitnfalphaantibodyhumirawithphdependentbindingcharacteristicsaconstantphmoleculardynamicsgaussianacceleratedmoleculardynamicsandinvitrostudy AT tianlucheng antitnfalphaantibodyhumirawithphdependentbindingcharacteristicsaconstantphmoleculardynamicsgaussianacceleratedmoleculardynamicsandinvitrostudy AT yengtsengwang antitnfalphaantibodyhumirawithphdependentbindingcharacteristicsaconstantphmoleculardynamicsgaussianacceleratedmoleculardynamicsandinvitrostudy
_version_	1724253729406844928

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

Similar Items