Effects of Temperature and Osmolytes on Competing Degradation Routes for an IgG1 Antibody

Roberts, Christopher J.; Nesta, Douglas P.; Kim, Nayoung

doi:10.1002/jps.23668

Cited by 26 publications

(22 citation statements)

References 34 publications

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“…Aggregates can become visible to the naked eye if they are sufficiently large and/or undergo phase separation [87–89]. If unfolding / aggregation is mediated by protein adsorption to bulk interfaces [90–92], and/or chemical changes such as deamidation [93–95], oxidation and other reactions [96,97], or fragmentation [98,99], then additional steps may also be kinetically important in the possible aggregation mechanism(s).…”

Section: Figurementioning

confidence: 99%

Therapeutic protein aggregation: mechanisms, design, and control

Roberts

2014

Trends in Biotechnology

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367

309

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While it is well known that proteins are only marginally stable in their folded states, it is often less well appreciated that most proteins are inherently aggregation-prone in their unfolded or partially unfolded states, and the resulting aggregates can be extremely stable and long-lived. For therapeutic proteins, aggregates are a significant risk factor for deleterious immune responses in patients, and can form via a variety of mechanisms. Controlling aggregation using a mechanistic approach may allow improved design of therapeutic protein stability, as a complement to existing design strategies that target desired protein structures and function. Recent results highlight the importance of balancing protein environment with the inherent aggregation propensities of polypeptide chains.

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Section: Figurementioning

confidence: 99%

Therapeutic protein aggregation: mechanisms, design, and control

Roberts

2014

Trends in Biotechnology

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367

309

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“…Lowering temperature typically has opposite effects for irreversible vs. reversible aggregation and phase separation (Box 1). Finally, one must also balance these physical degradation routes with their chemical counterparts such as deamidation [62] and oxidation [63,64], as well as fragmentation in the case of monoclonal antibodies [39,65]. In all cases, there is an argument for trying to engineer the protein (i.e., change its amino acid sequence) to have improved aggregation behavior, but historically protein engineering in industrial practice has focused to a larger extent in improving protein binding, specificity, or in vivo performance such as circulation half-life in the blood stream.…”

Section: How Can One Control or Mitigate Aggregation?mentioning

confidence: 99%

Protein aggregation and its impact on product quality

Roberts

2014

Current Opinion in Biotechnology

256

175

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Protein pharmaceutical products are typically active as folded monomers that are composed of one or more protein chains, such as the heavy and light chains in monoclonal antibodies that are a mainstay of current drug pipelines. There are numerous possible aggregated states for a given protein, some of which are potentially useful, while most of which are considered deleterious from the perspective of pharmaceutical product quality and performance. This review provides an overview of how and why different aggregated states of proteins occur, how this potentially impacts product quality and performance, fundamental approaches to control aggregate formation, and the practical approaches that are currently used in the pharmaceutical industry.

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“…This is observed in deep sea fish as a method to combat high salt and high pressure environments . It has also been determined that osmolytes can stabilize proteins and are often used in protein formulations . Influenza virus formulations can also be stabilized with concentrations of osmolytes around 0.5 M .…”

Section: Discussionmentioning

confidence: 99%

“…14,15 There are two categories of osmolytes, protecting and denaturing. Protecting osmolytes, including polyols, amino acids, and sugars, can stabilize protein structure 16 and have been shown to stabilize aggregation-prone peptides. 17 Denaturing osmolytes, like urea, are well-known for unfolding proteins.…”

Section: Introductionmentioning

confidence: 99%

A generalized purification step for viral particles using mannitol flocculation

Heldt

Saksule

Joshi

et al. 2018

Biotechnology Progress

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Vaccine manufacturing has conventionally been performed by the developed world using traditional unit operations like filtration and chromatography. There is currently a shift in the manufacturing of vaccines to the less developed world, requiring unit operations that reduce costs, increase recovery, and are amenable to continuous manufacturing. This work demonstrates that mannitol can be used as a flocculant for an enveloped and nonenveloped virus and can purify the virus from protein contaminants after microfiltration. The recovery of the virus ranges from 58 to 96% depending on virus, the filter pore size, and the starting concentration of the virus. Protein removal of 80% was achieved for the small nonenveloped virus using a 0.1 µm filter because proteins were not flocculated with the virus and flowed through the filter. It is hypothesized that mannitol dehydrates the viral surface by controlling the water structure surrounding the virus. Without the ability to become compact, as occurs with proteins, the virus aggregates in the presence of osmolytes and proteins do not. Osmolyte flocculation is a scalable process using high flux microfilters. It has been applied to both an enveloped and nonenveloped virus, making this process friendly to a variety of vaccine and gene therapy products. © 2018 American Institute of Chemical Engineers Biotechnol. Prog., 34:1027-1035, 2018.

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Effects of Temperature and Osmolytes on Competing Degradation Routes for an IgG1 Antibody

Cited by 26 publications

References 34 publications

Therapeutic protein aggregation: mechanisms, design, and control

Therapeutic protein aggregation: mechanisms, design, and control

Protein aggregation and its impact on product quality

A generalized purification step for viral particles using mannitol flocculation

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