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

Humira is a monoclonal antibody that binds to TNF alpha, inactivates TNF alpha receptors, and inhibits irritation. Neonatal Fc receptors can mediate the transcytosis of Humira-TNF alpha advanced constructions and course of them towards degradation pathways, which reduces the therapeutic impact of Humira. Permitting the Humira-TNF alpha advanced constructions to dissociate to Humira and soluble TNF alpha within the early endosome to allow Humira recycling is essential.
We used the cytoplasmic pH (7.4), the early endosomal pH (6.0), and pKa of histidine aspect chains (6.0-6.4) to mutate the residues of complementarity-determining areas with histidine. Our engineered Humira (W1-Humira) can bind to TNF alpha in plasma at impartial pH and dissociate from the TNF alpha within the endosome at acidic pH.
We used the constant-pH molecular dynamics, Gaussian accelerated molecular dynamics, two-dimensional potential imply drive profiles, and in vitro strategies to analyze the traits of W1-Humira. Our outcomes 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 impartial pH in vitro, and our prediction outcomes had been near the in vitro outcomes.
Moreover, our strategy displayed a excessive accuracy in antibody pH-dependent binding traits prediction, which can facilitate antibody drug design. Developments in computational strategies and computing energy could additional support in addressing the challenges in antibody drug design.
Anti-TNF Alpha Antibody Humira with pH-dependent Binding Characteristics: A constant-pH Molecular Dynamics, Gaussian Accelerated Molecular Dynamics, and In Vitro Study

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