In silico prediction of post-translational modifications in therapeutic antibodies

Vatsa, Shabdita

doi:10.1080/19420862.2021.2023938

Cited by 21 publications

(22 citation statements)

References 136 publications

(270 reference statements)

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“…We investigate this mechanism in this work, using all-atom Molecular Dynamics (MD) simulations. Hence, our work significantly aligns with the aspirations of the community to identify low-cost approaches that can assist drug development, as reflected in recent works. − Here we quantify the interactions between mAb COE3 (and its Fab and Fc fragments) and histidine in aqueous solution and identify the preferred sites for histidine adsorption on COE3. We introduce the BSAP index, which is an extension of the Structural Aggregation Propensity (SAP) metric introduced by Chennamsetty et al .…”

Section: Introductionmentioning

confidence: 99%

Understanding the Stabilizing Effect of Histidine on mAb Aggregation: A Molecular Dynamics Study

Saurabh

Kalonia

et al. 2022

Mol. Pharmaceutics

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Histidine, a widely used buffer in monoclonal antibody (mAb) formulations, is known to reduce antibody aggregation. While experimental studies suggest a nonelectrostatic, nonstructural (relating to secondary structure preservation) origin of the phenomenon, the underlying microscopic mechanism behind the histidine action is still unknown. Understanding this mechanism will help evaluate and predict the stabilizing effect of this buffer under different experimental conditions and for different mAbs. We have used all-atom molecular dynamics simulations and contact-based free energy calculations to investigate molecular-level interactions between the histidine buffer and mAbs, which lead to the observed stability of therapeutic formulations in the presence of histidine. We reformulate the Spatial Aggregation Propensity index by including the buffer–protein interactions. The buffer adsorption on the protein surface leads to lower exposure of the hydrophobic regions to water. Our analysis indicates that the mechanism behind the stabilizing action of histidine is connected to the shielding of the solvent-exposed hydrophobic regions on the protein surface by the buffer molecules.

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Section: Introductionmentioning

confidence: 99%

Understanding the Stabilizing Effect of Histidine on mAb Aggregation: A Molecular Dynamics Study

Saurabh

Kalonia

et al. 2022

Mol. Pharmaceutics

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“…The described process is a spontaneous reaction that can occur whenever a hydrogen peroxide molecule interacts with a Met side chain. Therefore, free Met or exposed non-burial protein-bound Met are more susceptible to oxidation and, accordingly, the number of water molecules surrounding the sulfur atom is used as a common descriptor to evaluate specific Met residue liability [ 35 , 47 , 48 ]. For this reason, a further investigation of the role of water molecules in the first coordination shell has been conducted.…”

Section: Discussionmentioning

confidence: 99%

Theoretical Evaluation of Sulfur-Based Reactions as a Model for Biological Antioxidant Defense

Sciscio

D’Annibale

D’Abramo

2022

IJMS

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Sulfur-containing amino acids, Methionine (Met) and Cysteine (Cys), are very susceptible to Reactive Oxygen Species (ROS). Therefore, sulfur-based reactions regulate many biological processes, playing a key role in maintaining cellular redox homeostasis and modulating intracellular signaling cascades. In oxidative conditions, Met acts as a ROS scavenger, through Met sulfoxide formation, while thiol/disulfide interchange reactions take place between Cys residues as a response to many environmental stimuli. In this work, we apply a QM/MM theoretical–computational approach, which combines quantum–mechanical calculations with classical molecular dynamics simulations to estimate the free energy profile for the above-mentioned reactions in solution. The results obtained, in good agreement with experimental data, show the validity of our approach in modeling sulfur-based reactions, enabling us to study these mechanisms in more complex biological systems.

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“…Several in silico tools have also been developed to assess post-translational modifications (PTMs, reviewed in [ 1 ]) or other potential molecule liabilities. The early identification of potentially deleterious sequence or structural features in silico can reduce the overall experimental burden and allows for prioritization of experimental work using often limited resources.…”

Section: Developability Assessment For Lead Antibody Moleculesmentioning

confidence: 99%

Recent Advances and Future Directions in Downstream Processing of Therapeutic Antibodies

Matte¹

2022

IJMS

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Despite the advent of many new therapies, therapeutic monoclonal antibodies remain a prominent biologics product, with a market value of billions of dollars annually. A variety of downstream processing technological advances have led to a paradigm shift in how therapeutic antibodies are developed and manufactured. A key driver of change has been the increased adoption of single-use technologies for process development and manufacturing. An early-stage developability assessment of potential lead antibodies, using both in silico and high-throughput experimental approaches, is critical to de-risk development and identify molecules amenable to manufacturing. Both statistical and mechanistic modelling approaches are being increasingly applied to downstream process development, allowing for deeper process understanding of chromatographic unit operations. Given the greater adoption of perfusion processes for antibody production, continuous and semi-continuous downstream processes are being increasingly explored as alternatives to batch processes. As part of the Quality by Design (QbD) paradigm, ever more sophisticated process analytical technologies play a key role in understanding antibody product quality in real-time. We should expect that computational prediction and modelling approaches will continue to be advanced and exploited, given the increasing sophistication and robustness of predictive methods compared to the costs, time, and resources required for experimental studies.

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In silico prediction of post-translational modifications in therapeutic antibodies

Cited by 21 publications

References 136 publications

Understanding the Stabilizing Effect of Histidine on mAb Aggregation: A Molecular Dynamics Study

Understanding the Stabilizing Effect of Histidine on mAb Aggregation: A Molecular Dynamics Study

Theoretical Evaluation of Sulfur-Based Reactions as a Model for Biological Antioxidant Defense

Recent Advances and Future Directions in Downstream Processing of Therapeutic Antibodies

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