title: Stress Tolerance of Antibody-Poly(Amino Acid) Complexes for Improving the Stability of High Concentration Antibody Formulations.
abstract: The stabilization of antibodies in aqueous solution against physical stress remains a problematic issue for pharmaceutical applications. Recently, protein-polyelectrolyte complex (PPC) formation using poly(amino acids) was proposed to prepare antibody formulation in a salt-dissociable precipitated state without protein denaturation. Here, we investigated the stabilization effect of PPC of therapeutic antibodies with poly-l-glutamic acid on agitation and thermal stress as forms of mechanical and non-mechanical stress, respectively. The precipitated state of PPC prevented the inactivation and aggregation induced by agitation. Similar results were obtained using the suspension state of PPC, but the stabilizing effects were slightly inferior to those of the PPC precipitate. PPC precipitate and PPC suspension prevented heat-induced inactivation of the antibodies, but showed little effect on heat-induced aggregation. Thus, PPC is a new candidate as a simple storage method for antibodies in aqueous solution, as an alternative state for freeze-drying.
authors.affiliation: Research and Development Center, Terumo Corporation, Nakai-machi, Ashigarakami-gun, Kanagawa, 259-0151, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Izaki
authors.affiliation: Faculty of Pure and Applied Sciences, University of Tsukuba, Tsukuba, Ibaraki, 305-8573, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Kurinomaru
authors.affiliation: Research and Development Center, Terumo Corporation, Nakai-machi, Ashigarakami-gun, Kanagawa, 259-0151, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Handa
authors.affiliation: Research and Development Center, Terumo Corporation, Nakai-machi, Ashigarakami-gun, Kanagawa, 259-0151, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Kimoto
authors.affiliation: Faculty of Pure and Applied Sciences, University of Tsukuba, Tsukuba, Ibaraki, 305-8573, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Shiraki
mesh_terms: D000068879:Adalimumab / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000737:chemistry / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000378:metabolism; D018501:Antirheumatic Agents / Q000737:chemistry / Q000378:metabolism; D011232:Chemical Precipitation; D002626:Chemistry, Pharmaceutical; D004355:Drug Stability; D004356:Drug Storage; D006358:Hot Temperature / Q000009:adverse effects; D006801:Humans; D008956:Models, Chemical; D000069444:Omalizumab / Q000737:chemistry / Q000378:metabolism; D010316:Particle Size; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000378:metabolism; D011099:Polyglutamic Acid / Q000737:chemistry* / Q000378:metabolism; D011310:Preservatives, Pharmaceutical / Q000737:chemistry* / Q000378:metabolism; D066329:Protein Aggregates; D055550:Protein Stability; D012995:Solubility; D013314:Stress, Mechanical; D013535:Suspensions
chemical_list: D018927:Anti-Asthmatic Agents; D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D004364:Pharmaceutical Preparations; D011310:Preservatives, Pharmaceutical; D066329:Protein Aggregates; D013535:Suspensions; D011099:Polyglutamic Acid; D000069444:Omalizumab; D000068879:Adalimumab
keywords: complexation; dissolution; polyelectrolytes; precipitation; protein formulation; proteins; suspensions