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....
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-02-01
|
| Series: | Biomolecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2218-273X/11/2/334 |
| _version_ | 1797395576334057472 |
|---|---|
| author | Shih-Ting Hong Yu-Cheng Su Yu-Jen Wang Tian-Lu Cheng Yeng-Tseng Wang |
| author_facet | Shih-Ting Hong Yu-Cheng Su Yu-Jen Wang Tian-Lu Cheng Yeng-Tseng Wang |
| author_sort | Shih-Ting Hong |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-09T00:37:30Z |
| format | Article |
| id | doaj.art-718e4910b4734af2a847d39ec63a7f88 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-09T00:37:30Z |
| publishDate | 2021-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-718e4910b4734af2a847d39ec63a7f882023-12-11T18:04:45ZengMDPI AGBiomolecules2218-273X2021-02-0111233410.3390/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 |
| 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 |
| 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_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_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_sort | anti tnf alpha antibody humira with ph dependent binding characteristics a constant ph molecular dynamics gaussian accelerated molecular dynamics and in vitro study |
| 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 |