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Abstract
The use of albumin fusion proteins as therapeutic drug candidates is an attractive approach to design novel biopharmaceuticals with increased circulation time in vivo. The purpose of this work was to characterize and stabilize the fusion protein sEphB4–human serum albumin (HSA), a 120 kDa protein containing the extracellular domain of EphB4 and HSA, and to identify stabilizing excipients for storage. Comparative biophysical studies combined with empirical phase diagram analysis show that both structural integrity and conformational stability of sEphB4 and sEphB4–HSA are best maintained above pH 5 and below 50°C, with different structural phases observed outside this range. A major physical degradation pathway for sEphB4–HSA is formation of soluble aggregates. Excipient studies using size‐exclusion chromatography (SEC), differential scanning calorimetry (DSC), and fluorescence spectroscopy identified disaccharide sugars (e.g., sucrose and trehalose) as effective stabilizers against protein aggregation, and NaCl as an effective stabilizer for protecting overall conformational stability. A combination of biophysical studies with sEphB4–HSA and its individual component proteins (sEphB4 and HSA), along with correlation analysis of SEC and DSC stability data in the presence of different excipients suggest that the aggregation pathway of the albumin fusion protein is primarily mediated by the sEphB4 rather than the HSA component. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:1969–1984, 2012
| Authors: | Shi, Shuai; Liu, Jing; Joshi, Sangeeta B.; Krasnoperov, Valery; Gill, Parkash; Middaugh, C. Russell; Volkin, David B. | |
| Journal: | Journal of Pharmaceutical Sciences | |
| Volume: | 101 | |
| Issue: | 6 | |
| Year: | 2012 | |
| Pages: | 1969 | |
| DOI: | 10.1002/jps.23096 | |
| Publication date: | 01-06-2012 |
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