2015
DOI: 10.1002/jps.24292
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Assessment of the Immunogenicity of Mechanically Induced Interferon Aggregates in a Transgenic Mouse Model

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Cited by 8 publications
(7 citation statements)
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“…8,9 These findings were more recently confirmed with animal models, wherein aggregates of different proteins injected in transgenic mice resulted in ADA development. This was the case for Interferon alpha or beta, [10][11][12] for Factor VIII, 13 and for monoclonal antibodies with variable magnitude of immune responses, depending on the nature of aggregates. 14,15 Other mice models also clearly demonstrated the role of hGH aggregates in the production of different IgG subtypes, suggesting that multiple mechanisms could underlie the immune response.…”
Section: Introductionmentioning
confidence: 97%
“…8,9 These findings were more recently confirmed with animal models, wherein aggregates of different proteins injected in transgenic mice resulted in ADA development. This was the case for Interferon alpha or beta, [10][11][12] for Factor VIII, 13 and for monoclonal antibodies with variable magnitude of immune responses, depending on the nature of aggregates. 14,15 Other mice models also clearly demonstrated the role of hGH aggregates in the production of different IgG subtypes, suggesting that multiple mechanisms could underlie the immune response.…”
Section: Introductionmentioning
confidence: 97%
“…Among these, aggregation of TPP carries particular concern, as it occurs under some conditions with many TPP and several studies have identified associations between aggregates and increased propensity for immunogenicity [51,[81][82][83][84][85][86]. Compared with non-aggregated forms, higher immunogenicity in mice has been observed for aggregates generated under different stress conditions for various TPPs, such as human interferon alpha2b [87][88][89], human mAbs [90][91][92], human epoetin alfa [83], human Factor VIII [93,94], human interferon beta [95], and murine growth hormone [96]. The detailed mechanisms of aggregate-induced immunogenicity are still unknown, but it has been observed that aggregation enhances antigen uptake, increases the total amount of peptides associated with MHC II molecules, and increases danger signals to maturate dendritic cells and activate T cells [52,86,91,97,98].…”
Section: Factors That Influence Immunogenicitymentioning
confidence: 97%
“…57,59 Such stresses include changes in temperature, 65 pH and ionic strength 66 during manufacture and processing, mechanical agitation stresses, such as pumping and shaking during processing and transportation, 67,68 and freeze-thawing stress from storage. 69,70 Furthermore, oxidation, which can be caused by UV light exposure 71,72 or metal contamination, 25,73 has also been associated with aggregate formation. 74,75 The stability of the protein itself, as well as the intensity and duration of one or more stresses affects the size, concentration, solubility, charge and morphology of resulting aggregates, as well as the extent of chemical modifications, unfolding and degradation.…”
Section: Reviewmentioning
confidence: 99%