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Stability of Biologic Drug Formulati...

Kannan, Aadithya.

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Stability of Biologic Drug Formulations: Adsorption to Interfaces and Aggregation.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Stability of Biologic Drug Formulations: Adsorption to Interfaces and Aggregation./
作者:	Kannan, Aadithya.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2020,
面頁冊數:	145 p.
附註:	Source: Dissertations Abstracts International, Volume: 82-02, Section: B.
Contained By:	Dissertations Abstracts International82-02B.
標題:	Pharmacology. -
電子資源:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28103947
ISBN:	9798662511170

Stability of Biologic Drug Formulations: Adsorption to Interfaces and Aggregation.
Kannan, Aadithya.

Stability of Biologic Drug Formulations: Adsorption to Interfaces and Aggregation. - Ann Arbor : ProQuest Dissertations & Theses, 2020 - 145 p.

Source: Dissertations Abstracts International, Volume: 82-02, Section: B.

Thesis (Ph.D.)--Stanford University, 2020.

This item must not be sold to any third party vendors.

Monoclonal antibodies (mAbs) are therapeutic proteins that can uniquely recognize and neutralize pathogens in the body, making them well-suited for the treatment of various diseases like cancer or autoimmune disorders. These amphiphilic molecules readily adsorb to air-solution interfaces to form a viscoelastic network, which can lead to aggregation. One of the major challenges faced in the large-scale manufacture of these antibody molecules is their instability and propensity to form aggregates. This aggregation has an adverse effect on the quality and the immunogenicity of the drug and is triggered primarily due to interfacial stresses. Therefore, understanding the interfacial behavior of these antibody molecules is crucial in determining their aggregation propensity. In the biopharmaceutical industry, surfactants are typically added to mAb formulations as they competitively adsorb to the air-solution interfaces and prevent the mAbs from adsorbing and aggregating. First, we studied two mAbs, provided by our industrial collaborator Genentech, with different propensities to aggregate at air-solution interfaces. In this work, we performed interfacial stress relaxation studies under compressive step strain using a custom-built dilatational rheometer. The dilatational relaxation moduli correlated with the aggregation tendencies of the two mAbs. We also measured the time taken for bubbles laden with mAbs to coalesce with another such interface. To study the influence of surfactants in mAb formulations, polyethylene glycol (PEG) was chosen as a model surfactant. The effect of this surfactant in lowering the interfacial elasticity and the coalescence times was studied for both the mAbs. Then, we focused on the mAb that was prone to aggregation and studied the mixtures of these antibodies with three pharmaceutically relevant surfactants: polyethylene glycol, poloxamer-188 and polysorbate-20. We performed agitation studies and characterized the aggregation of both smaller (oligomeric) aggregates (< 100 nm) and larger (sub-visible) particulate aggregates using size exclusion chromatography, flow cytometry and light obscuration techniques. The air-solution interface was visualized through fluorescent confocal microscopic imaging of fluorescently-tagged mAbs and co-adsorbed surfactants. Surface tension and mAb relative surface coverage were quantified for these mixtures. Moreover, we used the dynamic fluid-film interferometer, an automated custom-built instrument, to study the thin film drainage as a bubble approached a flat interface in the presence of mAbs and surfactants in the solution. MAbs immobilized the sandwiched thin film, whereas surfactants triggered Marangoni instabilities, caused by differences in surface tension. The volume of fluid entrapped and the nature of Marangoni surface flows depended on different governing mechanisms - interfacial rheology, surface tension and surface tension gradients for different surfactants. It was shown that the level of aggregation at different length scales correlated with the surface tension, surface relative coverage, interfacial rheology and interfacial fluid mechanics.

ISBN: 9798662511170Subjects--Topical Terms:

634543
Pharmacology.
Subjects--Index Terms:

Monoclonal antibodies

Stability of Biologic Drug Formulations: Adsorption to Interfaces and Aggregation.
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