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.
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.
Authors: Eva Y Chi; Sampathkumar Krishnan; Brent S Kendrick; Byeong S Chang; John F Carpenter; Theodore W Randolph Journal: Protein Sci Date: 2003-05 Impact factor: 6.725
Authors: Joseph J Valente; Robert W Payne; Mark Cornell Manning; W William Wilson; Charles S Henry Journal: Curr Pharm Biotechnol Date: 2005-12 Impact factor: 2.837
Authors: Santosh V Thakkar; Sangeeta B Joshi; Matthew E Jones; Hasige A Sathish; Steven M Bishop; David B Volkin; C Russell Middaugh Journal: J Pharm Sci Date: 2012-05-11 Impact factor: 3.534
Authors: Priscilla Kheddo; Matthew J Cliff; Shahid Uddin; Christopher F van der Walle; Alexander P Golovanov Journal: MAbs Date: 2016-08-11 Impact factor: 5.857
Authors: Sanjeev Agarwal; Neha Sahni; John M Hickey; George A Robertson; Robert Sitrin; Stanley Cryz; Sangeeta B Joshi; David B Volkin Journal: J Pharm Sci Date: 2019-08-07 Impact factor: 3.534
Authors: Priscilla Kheddo; Malgorzata Tracka; Jonathan Armer; Rebecca J Dearman; Shahid Uddin; Christopher F van der Walle; Alexander P Golovanov Journal: Int J Pharm Date: 2014-06-30 Impact factor: 5.875