Document Detail

Effects of Ionic Strength and Sugars on the Aggregation Propensity of Monoclonal Antibodies: Influence of Colloidal and Conformational Stabilities.
MedLine Citation:
PMID:  23319172     Owner:  NLM     Status:  Publisher    
PURPOSE: To develop a general strategy for optimizing monoclonal antibody (MAb) formulations. METHODS: Colloidal stabilities of four representative MAbs solutions were assessed based on the second virial coefficient (B (2)) at 20°C and 40°C, and net charges at different NaCl concentrations, and/or in the presence of sugars. Conformational stabilities were evaluated from the unfolding temperatures. The aggregation propensities were determined at 40°C and after freeze-thawing. The electrostatic potential of antibody surfaces was simulated for the development of rational formulations. RESULTS: Similar B (2) values were obtained at 20°C and 40°C, implying little dependence on temperature. B (2) correlated quantitatively with aggregation propensities at 40°C. The net charge partly correlated with colloidal stability. Salts stabilized or destabilized MAbs, depending on repulsive or attractive interactions. Sugars improved the aggregation propensity under freeze-thaw stress through improved conformational stability. Uneven and even distributions of potential surfaces were attributed to attractive and strong repulsive electrostatic interactions. CONCLUSIONS: Assessment of colloidal stability at the lowest ionic strength is particularly effective for the development of formulations. If necessary, salts are added to enhance the colloidal stability. Sugars further improved aggregation propensities by enhancing conformational stability. These behaviors are rationally predictable according to the surface potentials of MAbs.
Shuntaro Saito; Jun Hasegawa; Naoki Kobayashi; Toshiaki Tomitsuka; Susumu Uchiyama; Kiichi Fukui
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-15
Journal Detail:
Title:  Pharmaceutical research     Volume:  -     ISSN:  1573-904X     ISO Abbreviation:  Pharm. Res.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-15     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8406521     Medline TA:  Pharm Res     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Analytical & Quality Evaluation Research Laboratories, Daiichi Sankyo Co., Ltd., 1-12-1, Shinomiya, Hiratsuka-shi, Kanagawa, 254-0014, Japan.
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