Generation of nanometer-size aggregates using Solubility Controlling Peptide tags and their ability to increase a proteins immunogenicity in vivo
RAHMAN, N.; ISLAM, M. M.; UNZAI, S.; MIURA, S.; KURODA, Y.
Show abstract
Sub-visible aggregates of proteins are suspected to cause adverse immune response, and a recent FDA guideline has recommended the monitoring of micrometer-size aggregates (2-10 m) though recognizing that the underlying mechanism behind aggregation and immunogenicity remains unclear. Here, we report a correlation between the immunogenicity and the size of nanometer-scale aggregates of a small 6.5 kDa model protein, Bovine Pancreatic Trypsin Inhibitor (BPTI) variant. BPTI-19A, a monomeric and non-immunogenic protein, was oligomerized into sub-visible aggregates with hydrodynamic radii (Rh) of 3~4 nm by attaching hydrophobic solubility controlling peptide (SCP) tags to its C-terminus. The results showed that the association of non-immunogenic BPTI into nanometer-size aggregates made it highly immunogenic, as assessed by the IgG antibody titers of the mices sera. Overall, the study emphasizes that sub-visible aggregates, as small as a few nanometers, which are presently ignored, are worth monitoring for deciphering the origin of undesired immunogenicity of therapeutic proteins.
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