期刊
JOURNAL OF PHARMACEUTICAL SCIENCES
卷 107, 期 5, 页码 1269-1281出版社
WILEY
DOI: 10.1016/j.xphs.2017.12.015
关键词
biopharmaceuticals characterization; biophysical models; in silico modeling; light scattering (static); monoclonal antibody; protein formulation
资金
- Bristol-Myers Squibb
- National Science Foundation [CHEM 1213728]
- National Institutes of Health [R01 EB006006]
Protein-protein interactions for solutions of an IgG1 molecule were quantified using static light scattering (SLS) measurements from low to high protein concentrations (c(2)). SLS was used to determine second osmotic virial coefficients (B-22) at low c(2), and excess Rayleigh profiles (Rex/K vs. c(2)) and zero-q structure factors (S-q = 0) as a function of c(2) at higher c(2) for a series of conditions (pH, sucrose concentration, and total ionic strength [TIS]). Repulsive (attractive) interactions were observed at low TIS (high TIS) for pH 5 and 6.5, with increasing repulsions when 5% w/w sucrose was also present. Previously developed and refined coarse-grained antibody models were used to fit model parameters from B-22 versus TIS data. The resulting parameters from low-c(2) conditions were used as the sole input to multiprotein Monte Carlo simulations to predict high-c(2) Rex/K and S-q = 0 behavior up to 150 g/L. Experimental results at high-c(2) conditions were quantitatively predicted by the simulations for the coarse-grained models that treated antibody molecules as either 6 or 12 (sub) domains, which preserved the basic shape of a monoclonal antibody. Finally, preferential accumulation of sucrose around the protein surface was identified via high-precision density measurements, which self-consistently explained the simulation and experimental SLS results. (c) 2018 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.
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