title: Feasibility of antibody-poly(glutamic acid) complexes: preparation of high-concentration antibody formulations and their pharmaceutical properties.
abstract: Development of high-concentration antibody formulations for subcutaneous administration remains challenging. Recently, a precipitation-redissolution method was proposed to prepare suspensions or precipitates of salt-dissociable protein-poly(amino acid) complexes. To elucidate the utility of this method for protein therapy, we investigated the feasibility of a precipitation-redissolution method using poly(amino acid) for high-concentration antibody formulation. Omalizumab and adalimumab formulations of 150 mg/mL could be prepared using poly-l-glutamic acid (polyE) from low-concentration stock solutions. Enzyme-linked immunosorbent assay, circular dichroism, and size-exclusion chromatography revealed that the formation of antibody-polyE complex and precipitation-redissolution process did not significantly affect the immunoreactivity or secondary structure of the antibodies. The precipitation-redissolution method was less time-consuming and more effective than lyophilization-redissolution, evaporation-redissolution, and ultrafiltration from the viewpoint of final yield. Scalability was confirmed from 400 μL to 1.0 L. The general toxicity and pharmacokinetic profiles of the antibody-polyE complex formulations were similar to those of conventional antibody formulations. These results suggested that the precipitation-redissolution method using poly(amino acid) has great potential as a concentration method for antibody formulation and medicinal use.
authors: Research and Development Center, Terumo Corporation, Ashigarakamigun, Kanagawa 259-0151, Japan.
authors: Shunsuke
authors: S
authors: Izaki
authors: Faculty of Pure and Applied Sciences, University of Tsukuba, Ibaraki 305-8573, Japan.
authors: Takaaki
authors: T
authors: Kurinomaru
authors: Faculty of Pure and Applied Sciences, University of Tsukuba, Ibaraki 305-8573, Japan.
authors: Takuya
authors: T
authors: Maruyama
authors: Research and Development Center, Terumo Corporation, Ashigarakamigun, Kanagawa 259-0151, Japan.
authors: Takayuki
authors: T
authors: Uchida
authors: Research and Development Center, Terumo Corporation, Ashigarakamigun, Kanagawa 259-0151, Japan.
authors: Kenji
authors: K
authors: Handa
authors: Research and Development Center, Terumo Corporation, Ashigarakamigun, Kanagawa 259-0151, Japan.
authors: Tomoaki
authors: T
authors: Kimoto
authors: Faculty of Pure and Applied Sciences, University of Tsukuba, Ibaraki 305-8573, Japan. Electronic address: shiraki@bk.tsukuba.ac.jp.
authors: Kentaro
authors: K
authors: Shiraki
mesh_terms: D000068879:Adalimumab / Q000097:blood / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000097:blood / Q000737:chemistry* / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000097:blood / Q000737:chemistry* / Q000494:pharmacology; D011232:Chemical Precipitation; D006801:Humans; D000069444:Omalizumab / Q000097:blood / Q000737:chemistry* / Q000494:pharmacology; D011099:Polyglutamic Acid / Q000097:blood / Q000737:chemistry* / Q000494:pharmacology; D017433:Protein Structure, Secondary; D051381:Rats
chemical_list: D018927:Anti-Asthmatic Agents; D000893:Anti-Inflammatory Agents; D011099:Polyglutamic Acid; D000069444:Omalizumab; D000068879:Adalimumab
keywords: complexation; dissolution; formulation; polyelectrolytes; precipitation; suspensions