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Gu, Liangcai; Erdos, Elizabeth A.; Hi-Shi, Chiang; Calderwood, Thomas S.; Tsai, Kelly; Visor, Gary C.; Duffy, J.L.; Hsu, Wen‐Chuin; Foster, Linda C.

doi:10.1023/a:1015851228163

Cited by 55 publications

(4 citation statements)

References 17 publications

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“…The loss of native protein from solution initially follows second-order kinetics (Figure 3), and then accelerates (Figure 1A). Similar acceleration also has been observed for aggregation of interleukin 1β (53). Acceleration of rhGCSF aggregation is consistent with a mechanism whereby aggregates can be formed from a structurally perturbed monomer, M*, which can react irreversibly either with itself to form dimer, M 2 , or with existing aggregates, M x , to form larger aggregates, M x+1 (Scheme 1).…”

Section: Discussionsupporting

confidence: 80%

Aggregation of Granulocyte Colony Stimulating Factor under Physiological Conditions: Characterization and Thermodynamic Inhibition

et al. 2002

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We have investigated the aggregation of recombinant human granulocyte colony stimulating factor (rhGCSF), a protein that rapidly aggregates and precipitates at pH 6.9 and 37 degrees C. We observed that native monomeric rhGCSF reversibly forms a dimer under physiological conditions and that this dimeric species does not participate in the irreversible aggregation process. Sucrose, a thermodynamic stabilizer, inhibits the aggregation of rhGCSF. We postulate that sucrose acts by reducing the concentration of structurally expanded species, consistent with the hypothesis that preferential exclusion favors most compact species in the native state ensemble. Thermodynamic stability data from unfolding curves and hydrogen-deuterium exchange experimental results support the above hypothesis. Thus, the strategy of stabilizing the native state of the protein under physiological conditions using thermodynamic stabilizers, especially ligands binding with high affinity to the native state, is expected to protect against protein aggregation occurring under such nonperturbing solution conditions.

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Section: Discussionsupporting

confidence: 80%

Aggregation of Granulocyte Colony Stimulating Factor under Physiological Conditions: Characterization and Thermodynamic Inhibition

et al. 2002

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“…Aggregation of antibodies occurs at the interface Various external factors able to induce aggregation of proteins are described in the literature, including temperature, 27,28 pH, 28 ionic strength, 29 freeze-thawing, 30,31 shearing, 32 stirring 13,18 and shaking. 18,[33][34][35] Because one can readily manage with composition and temperature parameters, most proteins can now be made highly stable under the form of liquid preparations at rest.…”

Section: Discussionmentioning

confidence: 99%

Importance of the dynamics of adsorption and of a transient interfacial stress on the formation of aggregates of IgG antibodies

et al. 2012

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It is common knowledge that aggregation of proteins may occur in aqueous solutions under mechanical stress (shaking or high shear), even in solutions that are stable at rest. Addition of surfactants is a practical generic means to prevent this stress-induced aggregation (e.g. in formulations of therapeutic proteins), which suggests that interfaces contribute to destabilization. We studied here the role of interfacial stress by applying brief mechanical impacts on air-water interface, in presence or absence of surfactants, in solutions of immunoglobulin G (IgG), a class of proteins of high importance to the developments of new therapeutics. A variety of surfactants was tested including the neutral ones Tween80, C10-C14 foscholines, alkylaminoxide, surfactin, and two ionic ones TTAB and lauroylsarcosine sodium salt. We determined the presence of aggregates in solution by light scattering. Irrespective of the type of antibody, either human polyclonal or a monoclonal one, we show that the amount of aggregated IgG increases in proportion to the number of impacts on the interface. In absence of stress, we recorded images of oblate aggregates of IgG (ca. 12 nm height and 200-1200 nm in diameter) present at the air-water interface (fluorescence microscopy using anti-Fab or anti-Fc markers, and AFM scans after transfer on freshly cleaved mica). Our results evidence that aggregates are formed at air-water interface, and are brought in solution by transient stresses applied on the water surface. Rupture of interfacial films is an important source of aggregates in solution. Finally, the role of surface dynamics in the protection brought by surfactants is discussed based on comparison of protective efficiencies with dynamic surface tension properties (measured by the maximum bubble pressure method). Our work indicates that better protection is conferred by surfactants showing the faster interfacial dynamics, which corresponds also to conditions of faster lowering of the interfacial energy at short time scale.

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“…Increase in soluble aggregates can result in change in immunogenicity of the therapeutic protein. Aggregates in certain cases can be visualized e.g., insulin and IL-1β 97,98 . Insoluble aggregates can be detected by FTIR, Raman, and electron spin resonance spectroscopy, or light scattering techniques (UV absorption).…”

Section: Aggregation and Precipitationmentioning

confidence: 99%

Stability of proteins in aqueous solution and solid state

Jacob¹,

Shirwaikar²,

Kalyanasundaram³

et al. 2006

Indian J Pharm Sci

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In the last two decades, proteins and peptides have become an important class of potent therapeutic drugs. However, their susceptibility to chemical and physical degradation presents a challenge to formulation scientists, for the development of stable pharmaceutical preparations. This is in part, due to the unique physicochemical and biological properties of the proteins and peptide drugs. The insight into the fundamental understanding of the mechanism, by which protein stabilizes, will help in the formulation of protein based pharmaceuticals.

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Cited by 55 publications

References 17 publications

Aggregation of Granulocyte Colony Stimulating Factor under Physiological Conditions: Characterization and Thermodynamic Inhibition

Aggregation of Granulocyte Colony Stimulating Factor under Physiological Conditions: Characterization and Thermodynamic Inhibition

Importance of the dynamics of adsorption and of a transient interfacial stress on the formation of aggregates of IgG antibodies

Stability of proteins in aqueous solution and solid state

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