The Increasingly Human and Profitable Monoclonal Antibody Market

Grilo, Antonio; Mantalaris, A.

doi:10.1016/j.tibtech.2018.05.014

Cited by 383 publications

(282 citation statements)

References 8 publications

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“…Therapeutic proteins, including monoclonal antibodies, represent important biopharmaceutical products (Grilo & Mantalaris, ). The physical and chemical stability of these biomolecules is a crucial aspect for their large‐scale production, but importantly also for their therapeutic efficacy and clinical safety (Jiskoot et al, ; Manning, Chou, Murphy, Payne, & Katayama, ; W. Wang, ).…”

Section: Introductionmentioning

confidence: 99%

Synergistic effects of flow and interfaces on antibody aggregation

Grigolato

Arosio

2019

Biotech & Bioengineering

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During the manufacturing process, solutions of protein‐based drugs are exposed to hydrodynamic forces, which can potentially affect protein stability and aggregation. Despite being an area of extensive investigation, the effect of hydrodynamic flow on protein aggregation is still controversial. In this study, we designed an experimental setup that allowed us to investigate flow‐ and interface‐induced protein aggregation of two model immunoglobulins in the presence of well‐defined flow stresses and solid–liquid interfaces. Within the range of shear rates typically encountered in bioprocessing ( γ ̇ = 10 – 10 3 normals − 1), we observed that increasing the shear rate by three orders of magnitude had a negligible effect on protein aggregation. By contrast, changes in the materials of the syringe barrels had a dramatic effect on the monomer loss, demonstrating the key role of solid–liquid interfaces in flow‐induced aggregation. This finding was confirmed by the observed inverse dependence of the aggregation rate on the initial protein concentration, which is inconsistent with mechanisms of protein aggregation in bulk solution. Overall, our results reveal the presence of a synergistic effect of interfaces and hydrodynamic flow in flow‐induced protein aggregation, which arises from the formation of protein particles or films on interfaces followed by displacement by flow or mechanical scraping.

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Section: Introductionmentioning

confidence: 99%

Synergistic effects of flow and interfaces on antibody aggregation

Grigolato

Arosio

2019

Biotech & Bioengineering

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“…Over the past decades, monoclonal antibodies (mAbs) and derived recombinant proteins have become an important class of active pharmaceutical ingredients and are used for the treatment of a substantial variety of diseases in humans (Elgundi, Reslan, Cruz, Sifniotis, & Kayser, ; Grilo & Mantalaris, ; Kaplon & Reichert, ). At the same time, the biopharmaceutical industry has matured considerably since its inception in the 1980s, for example through the advent of generic drugs (so‐called biosimilars; Udpa & Million, ).…”

Section: Introductionmentioning

confidence: 99%

Understanding mAb aggregation during low pH viral inactivation and subsequent neutralization

Wälchli

Ressurreição

Vogg

et al. 2019

Biotech & Bioengineering

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Monoclonal antibodies (mAbs) and related recombinant proteins continue to gain importance in the treatment of a great variety of diseases. Despite significant advances, their manufacturing can still present challenges owing to their molecular complexity and stringent regulations with respect to product purity, stability, safety, and so forth. In this context, protein aggregates are of particular concern due to their immunogenic potential. During manufacturing, mAbs routinely undergo acidic treatment to inactivate viral contamination, which can lead to their aggregation and thereby to product loss. To better understand the underlying mechanism so as to propose strategies to mitigate the issue, we systematically investigated the denaturation and aggregation of two mAbs at low pH as well as after neutralization. We observed that at low pH and low ionic strength, mAb surface hydrophobicity increased whereas molecular size remained constant. After neutralization of acidic mAb solutions, the fraction of monomeric mAb started to decrease accompanied by an increase on average mAb size. This indicates that electrostatic repulsion prevents denatured mAb molecules from aggregation under acidic pH and low ionic strength, whereas neutralization reduces this repulsion and coagulation initiates. Limiting denaturation at low pH by D-sorbitol addition or temperature reduction effectively improved monomer recovery after neutralization. Our findings might be used to develop innovative viral inactivation procedures during mAb manufacturing that result in higher product yields. K E Y W O R D SANS fluorescence, downstream processing, monoclonal antibodies, protein aggregation, protein unfolding, viral inactivation

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“…The cell cycle is modeled using a three-stage single-variable PBM [6] whose mathematical description has been extensively described by Kostoglou et al [34] The formulation of the PBM for each stage is that of Equation (1). Phases G 0 /G 1 and G 2 /M were segregated using cyclins E1 and B1, respectively, while phase S was segregated using DNA.…”

Section: Cell Cyclementioning

confidence: 99%

“…Herein, a segregated unstructured model of cell culture coupling a) a cyclin‐ and DNA‐based PBM of cell cycle, b) an energy‐based kinetic metabolic model, and c) a gene expression‐based apoptosis model is described. This model is used to describe batch cultures of mAb‐producing GS–NS0 cells, an industrially relevant cell line . Once the model structure was obtained, the significant model parameters were identified through GSA and re‐estimated based on experimental data.…”

Section: Introductionmentioning

confidence: 99%

“…This model is used to describe batch cultures of mAb-producing GS-NS0 cells, an industrially relevant cell line. [1] Once the model structure was obtained, the significant model parameters were identified through GSA and re-estimated based on experimental data. Finally, the model predictive capabilities were validated against two independent experimental data sets.…”

Section: Introductionmentioning

confidence: 99%

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A Predictive Mathematical Model of Cell Cycle, Metabolism, and Apoptosis of Monoclonal Antibody‐Producing GS–NS0 Cells

Grilo

Mantalaris

2019

Biotechnology Journal

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The monoclonal antibody (mAb) industry is witnessing unprecedented growth, with an increasing range of new molecules and biosimilars as well as disease targets approved than ever before. Competition necessitates pharmaceutical companies to reduce development/production costs and time‐to‐market. To this aim, mathematical modeling can aid traditional experiment‐only‐based process development by reducing the design space, integrating scales, and assisting in identifying optimal operating conditions in less time and with lower expense. Mathematical models have been employed by other industries for control and optimization purposes and are important decisional tools for testing scenarios, process configurations, operating conditions, etc. Herein, a predictive, experimentally validated mathematical model that captures cellular metabolism and growth with cell cycle, cell death (apoptosis), and mAb production in GS–NS0 cells is presented. The model utilizes cellular, metabolic, and gene expression data, highlighting how multiple data sources can be integrated in one tool with the aim of optimizing mammalian cell bioprocessing.

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The Increasingly Human and Profitable Monoclonal Antibody Market

Cited by 383 publications

References 8 publications

Synergistic effects of flow and interfaces on antibody aggregation

Synergistic effects of flow and interfaces on antibody aggregation

Understanding mAb aggregation during low pH viral inactivation and subsequent neutralization

A Predictive Mathematical Model of Cell Cycle, Metabolism, and Apoptosis of Monoclonal Antibody‐Producing GS–NS0 Cells

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