Formulation of proteins and monoclonal antibodies (mAbs)

Shire, Steven J.

doi:10.1016/b978-0-08-100296-4.00004-x

Cited by 8 publications

(11 citation statements)

References 39 publications

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“…Tween 80 is the most common surfactant in commercial aqueous formulations of monoclonal antibodies and has a critical micelle concentration (cmc) of 0.014 mg/ mL. 30,53 At a surface ratio of 1:50 NPs:mAb, we observed that the surfactant is effective in avoiding aggregation at concentrations varying from 0.01 to 0.1 mg/mL (Figure 5A), consistent with values reported in the literature. 53 We compared the results of the HNSSA surface stress assay (under stagnant conditions) with conventional agitation studies performed in the presence of air−water interfaces in the absence of nanoparticles.…”

Section: ■ Results and Discussionsupporting

confidence: 88%

A Nanoparticle-Based Assay To Evaluate Surface-Induced Antibody Instability

2020

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Protein stability against aggregation represents a major quality attribute for the successful development of biopharmaceuticals. Increasing evidence indicates that the formation of protein aggregates in aqueous solutions is often triggered by interactions between proteins and interfaces. Yet, in contrast to a large number of methods available to test protein bulk properties, high-throughput assays to investigate protein instability at interfaces remain much less developed. Major challenges include the control of the amount and type of surfaces, as well as the presence of synergistic effects between interfaces and hydrodynamic flows. Here, we describe and develop a highly controlled surface-mediated stress assay of protein instability based on polymeric nanoparticles. We show that hydrophobic nanoparticles are remarkably powerful in destabilizing large proteins such as antibodies. We further show that this approach can be implemented on a high-throughput microfluidic platform by compartmentalizing the protein solution in picoliter droplets surrounded by an oil phase. Our method allows the evaluation of protein instability at hydrophobic interfaces in a time scale of minutes and requires amounts of the sample in the order of a few hundred micrograms. We demonstrate that our assay represents a good mimic of air–water interfaces and finds application as a screening tool to optimize protein stability toward surface-induced aggregation. We provide a concrete example by identifying the optimal concentration range of Tween 80 that prevents antibody instability in the presence of interfaces. Overall, our hydrophobic nanoparticle surface-mediated stress assay (HNSSA) represents an attractive tool for accelerated tests of protein instability at interfaces under both stagnant and flow conditions, with implications for the optimization of buffer composition and the selection of stable biotherapeutic candidate molecules during early stage development.

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Section: ■ Results and Discussionsupporting

confidence: 88%

A Nanoparticle-Based Assay To Evaluate Surface-Induced Antibody Instability

2020

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“…Before each experiment, aliquots of the two immunoglobulins were exchanged at 4°C in a 150 mM NaCl, 25 mM sodium citrate dihydrate solution (pH 6.5) by overnight dialysis using Slide‐A‐Lyzer Dialysis Cassettes (2 K MWCO, 3 ml; Thermo Fisher Scientific). This buffer composition was selected based on commercial formulations of several monoclonal antibody products (Shire, ). The resulting stock protein solutions were then diluted to the desired working protein concentrations, which were determined by both size exclusion chromatography (Superdex 200 Increase 10/300 GL) coupled with UV absorbance detection and spectrophotometer measurements (NanoDrop Lite Spectrophotometer, Witec AG; Thermo Fisher Scientific; IgG molar extinction coefficient: A [280 nm, 1%] = 13.7).…”

Section: Methodsmentioning

confidence: 99%

“…Thermo Fisher Scientific). This buffer composition was selected based on commercial formulations of several monoclonal antibody products (Shire, 2015…”

Section: Sample Preparationmentioning

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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“…Sediaan liquid adalah sediaan cair yang paling banyak dipilih dalam formulasi sediaan farmasi berbahan aktif peptide dan protein terutama antibodi monoklonal dan diadministrasikan secara parenteral baik intravena, subkutan, dan intramuskular (29) . Kelebihan sediaan liquid yang diadministrasikan secara parenteral adalah terhindar dari proses absorpsi sehingga langsung terdistribusi di peredaran darah.…”

Section: Sediaan Liquidunclassified

“…Administrasi berulang yang diberikan secara parenteral cukup membuat pasien tidak nyaman karena harus berkali-kali mendapatkan prosedur injeksi (31) . Dintinjau dari stabilitasnya, sediaan liquid memiliki stabilitas lebih rendah dibandingkan dengan sediaan solid (29) . Untuk obat-obat yang akan diadministrasikan secara parenteral namun tidak begitu stabil dalam bentuk larutan maka dibuat dalam bentuk serbuk injeksi.…”

Section: Sediaan Liquidunclassified

Tinjauan Bentuk Sediaan Farmasi Mengandung Peptida

Yuswadinata

Wathoni

2021

Maj. Farmasetika

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Peptida dan protein merupakan molekul yang memiliki fungsi vital dalam proses biokimia yang terjadi dalam tubuh. Peptida dan protein yang tidak adekuat dapat berpengaruh pada proses metabolisme dan berkaitan dengan kondisi patologis. Kemajuan ilmu pengetahuan dan teknologi membawa penemuan revolusioner dalam dunia medis yaitu menjadikan peptide dan protein sebagai terapi yang menjanjikan untuk pengobatan suatu penyakit. Penelitian di bidang farmasi terus berkembang untuk menemukan dan memproduksi berbagai sediaan farmasi dengan bahan aktif peptide dan protein. Masing-masing bentuk sediaan memiliki kelebihan dan kekurangan serta hambatan tersendiri pada rute administrasinya. Hal tersebut lebih lanjut dibahas pada review ini.

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Formulation of proteins and monoclonal antibodies (mAbs)

Cited by 8 publications

References 39 publications

A Nanoparticle-Based Assay To Evaluate Surface-Induced Antibody Instability

A Nanoparticle-Based Assay To Evaluate Surface-Induced Antibody Instability

Synergistic effects of flow and interfaces on antibody aggregation

Tinjauan Bentuk Sediaan Farmasi Mengandung Peptida

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