Poly(glutamic acid)-Based Viscosity Reducers for Concentrated Formulations of a Monoclonal IgG Antibody - Sorbonne Université Access content directly
Journal Articles Molecular Pharmaceutics Year : 2024

Poly(glutamic acid)-Based Viscosity Reducers for Concentrated Formulations of a Monoclonal IgG Antibody

Abstract

Above a concentration threshold the viscosity of solutions of proteins increases abruptly, which hampers injectability of therapeutic formulations. Concentrations above 200 g/L is an ideal goal for subcutaneous application of antibodies. Molecular additives, such as amino acids (eg. arginine) help to decrease viscosity, but they are used at concentrations as high as about 200 mmol/L. We addressed the question of whether poly(amino acids) could be more efficient than small molecular additives. We observed marked fluidification of a model therapeutic mAb solution by poly (D,L-glutamic acid) and poly(L-glutamic acid) derivatives added at < 6.5 g/L (i.e., mAb/polymer chain molar ratio between 4:1 and 1:1 mol/mol). The bare poly(glutamate) parent chains were compared with polyethyleneglycol-grafted chains as PEGylation is a common way to enhance stability. Viscosity could be lowered down to ~ 20 mPa.s as compared to values of ~100 mPa.s in the absence of polymers at 200 g/L mAb. Formation of complexes between the mAb and the polyglutamates was characterized by capillary electrophoresis analysis in dilute solutions (1g/L mAb) and by observation of phase separation at higher concentration, suggesting tight association at about 2:1 mol/mol mAb/polymer. Altogether these results show that polyglutamate derivatives hold an untapped potential as excipient for fluidification of concentrated protein solutions.
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hal-04406095 , version 1 (19-01-2024)

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Annamaria Lapenna, Camille Dagallier, Sylvain Huille, Christophe C. Tribet. Poly(glutamic acid)-Based Viscosity Reducers for Concentrated Formulations of a Monoclonal IgG Antibody. Molecular Pharmaceutics, In press, ⟨10.1021/acs.molpharmaceut.3c01159⟩. ⟨hal-04406095⟩
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