Characterizing and Minimizing Aggregation and Particle Formation of Three Recombinant Fusion-Protein Bulk Antigens for Use in a Candidate Trivalent Rotavirus Vaccine.

Autor:	Agarwal S; Department of Pharmaceutical Chemistry, Vaccine Analytics and Formulation Center, University of Kansas, 2030 Becker Drive, Lawrence, Kansas 66047., Sahni N; Department of Pharmaceutical Chemistry, Vaccine Analytics and Formulation Center, University of Kansas, 2030 Becker Drive, Lawrence, Kansas 66047., Hickey JM; Department of Pharmaceutical Chemistry, Vaccine Analytics and Formulation Center, University of Kansas, 2030 Becker Drive, Lawrence, Kansas 66047., Robertson GA; The Center for Vaccine Innovation and Access, PATH, 455 Massachusetts Avenue NW Suite 1000, Washington, District of Columbia 20001., Sitrin R; The Center for Vaccine Innovation and Access, PATH, 455 Massachusetts Avenue NW Suite 1000, Washington, District of Columbia 20001., Cryz S; The Center for Vaccine Innovation and Access, PATH, 455 Massachusetts Avenue NW Suite 1000, Washington, District of Columbia 20001., Joshi SB; Department of Pharmaceutical Chemistry, Vaccine Analytics and Formulation Center, University of Kansas, 2030 Becker Drive, Lawrence, Kansas 66047., Volkin DB; Department of Pharmaceutical Chemistry, Vaccine Analytics and Formulation Center, University of Kansas, 2030 Becker Drive, Lawrence, Kansas 66047. Electronic address: volkin@ku.edu.
Jazyk:	angličtina
Zdroj:	Journal of pharmaceutical sciences [J Pharm Sci] 2020 Jan; Vol. 109 (1), pp. 394-406. Date of Electronic Publication: 2019 Aug 07.
DOI:	10.1016/j.xphs.2019.08.001
Abstrakt:	In a companion paper, the structural integrity, conformational stability, and degradation mechanisms of 3 recombinant fusion-protein antigens comprising a non-replicating rotavirus (NRRV) vaccine candidate (currently being evaluated in early-stage clinical trials) are described. In this work, we focus on the aggregation propensity of the 3 NRRV antigens coupled to formulation development studies to identify common frozen bulk candidate formulations. The P2-VP8-P[8] antigen was most susceptible to shaking and freeze-thaw-induced aggregation and particle formation. Each NRRV antigen formed aggregates with structurally altered protein (with exposed apolar regions and intermolecular β-sheet) and dimers containing a non-native disulfide bond. From excipient screening studies with P2-VP8-P[8], sugars or polyols (e.g., sucrose, trehalose, mannitol, sorbitol) and various detergents (e.g., Pluronic F-68, polysorbate 20 and 80, PEG-3350) were identified as stabilizers against aggregation. By combining promising additives, candidate bulk formulations were optimized to not only minimize agitation-induced aggregation, but also particle formation due to freeze-thaw stress of P2-VP8-P[8] antigen. Owing to limited material availability, stabilization of the P2-VP8-P[4] and P2-VP8-P[6] was confirmed with the lead candidate P2-VP8-P[8] formulations. The optimization of these bulk NRRV candidate formulations is discussed in the context of subsequent drug product formulations in the presence of aluminum adjuvants. (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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