Extensive Chemical Modifications in the Primary Protein Structure of IgG1 Subvisible Particles Are Necessary for Breaking Immune Tolerance

A current concern with the use of therapeutic proteins is the likely presence of aggregates and submicrometer, subvisible, and visible particles. It has been proposed that aggregates and particles may lead to unwanted increases in the immune response with a possible impact on safety or efficacy. The...

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Published inMolecular pharmaceutics Vol. 14; no. 4; pp. 1292 - 1299
Main Authors Boll, Björn, Bessa, Juliana, Folzer, Emilien, Ríos Quiroz, Anacelia, Schmidt, Roland, Bulau, Patrick, Finkler, Christof, Mahler, Hanns-Christian, Huwyler, Jörg, Iglesias, Antonio, Koulov, Atanas V
Format Journal Article
LanguageEnglish
Published United States American Chemical Society 03.04.2017
Subjects
Amino Acid Sequence
Animals
Antibodies, Monoclonal - chemistry
Antibody Formation - immunology
Humans
Immune Tolerance - immunology
Immunoglobulin G - chemistry
Mice
Mice, Inbred C57BL
Mice, Transgenic
Particle Size
biotherapeutics
IgG1 tg mouse
subvisible protein particles
immunogenicity
chemical modifications
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Summary:A current concern with the use of therapeutic proteins is the likely presence of aggregates and submicrometer, subvisible, and visible particles. It has been proposed that aggregates and particles may lead to unwanted increases in the immune response with a possible impact on safety or efficacy. The aim of this study was thus to evaluate the ability of subvisible particles of a therapeutic antibody to break immune tolerance in an IgG1 transgenic mouse model and to understand the particle attributes that might play a role in this process. We investigated the immunogenic properties of subvisible particles (unfractionated, mixed populations, and well-defined particle size fractions) using a transgenic mouse model expressing a mini-repertoire of human IgG1 (hIgG1 tg). Immunization with proteinaceous subvisible particles generated by artificial stress conditions demonstrated that only subvisible particles bearing very extensive chemical modifications within the primary amino acid structure could break immune tolerance in the hIgG1 transgenic mouse model. Protein particles exhibiting low levels of chemical modification were not immunogenic in this model.
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ISSN:1543-8384
1543-8392
DOI:10.1021/acs.molpharmaceut.6b00816