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• W2493433222 abstract "There is growing interest in the use of pegylated therapeutic proteins due to the improved therapeutic efficacy, with much greater serum circulation half-life leading to lower dosage requirements and dosing frequency. One of the challenges in producing pegylated proteins is the low product yield and difficult purification of the desired (typically mono-pegylated) product. The overall objective of this thesis was to examine the use of ultrafiltration for the production and purification of a desired mono-pegylated protein product. The specific aims included: (1) evaluate the effects of electrostatic and solute-solute intermolecular interactions on transmission of pegylated proteins through both neutral and charged ultrafiltration membranes, (2) develop an ultrafiltration process to purify pegylated proteins with different degree of pegylation, and (3) develop a combined reaction and membrane-based separation process to enhance the yield of a desired pegylated product. Experiments were performed using a model pegylated system produced by covalent attachment of activated PEG to α-lactalbumin. Ultrafiltration experiments were performed with UltracelTM cellulosic membranes, with a negatively charged version generated by covalent attachment of sulfonic acid groups to the base cellulose. The ultrafiltration data showed strong electrostatic exclusion of the pegylated proteins from a charged membrane. A theoretical model was developed to describe the sieving behavior of the pegylated proteins accounting for the increase in the effective protein size, the elimination of the protonatable –NH2 group due to the pegylation reaction, and the alteration of the electrostatic potential field around the protein due to the PEG layer. The transmission of the pegylated proteins also increases with increasing PEG concentration due to the increase in free energy of the pegylated protein in the bulk solution associated with the strong intermolecular interactions. These intermolecular interactions also affect the bulk mass transfer, which could be described theoretically using a modified concentration polarization model. These models provide an appropriate framework to describe / optimize the performance of ultrafiltration and diafiltration processes for the purification and formulation of pegylated proteins. The sieving data were used to develop a diafiltration process to purify the mono-pegylated protein. Unreacted (native) protein and PEG were removed via a single diafiltration step using a highly charged membrane with relatively large pore size (300 kDa); the high retention of the mono-pegylated protein was due to a combination of steric and electrostatic exclusion. The process provided greater than 90% yield with purification factors of more than 20. A similar diafiltration process was developed for purification of a mono-pegylated protein from the di- and tri-pegylated forms, with greater than 95% yield and more than 20-fold purification. A combined reaction-membrane based separation system was developed to produce a mono-pegylated…" @default.
• W2493433222 created "2016-08-23" @default.
• W2493433222 creator A5065584472 @default.
• W2493433222 date "2013-07-16" @default.
• W2493433222 modified "2023-09-28" @default.
• W2493433222 title "Purification and Production of Pegylated Proteins using Membrane Processes" @default.
• W2493433222 hasPublicationYear "2013" @default.
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