期刊
MABS
卷 8, 期 6, 页码 1088-1097出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/19420862.2016.1189048
关键词
Aggregation; colloidal stability; diffusion interaction parameter; fragmentation; Immunoglobulin; monoclonal antibody; thermal stability; zeta potential
资金
- National Institutes of Health under Ruth L. Kirschstein National research Service Award from the NIGMS [T32 GM8339]
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM008339] Funding Source: NIH RePORTER
With the rapid growth of biopharmaceutical product development, knowledge of therapeutic protein stability has become increasingly important. We evaluated assays that measure solution-mediated interactions and key molecular characteristics of 9 formulated monoclonal antibody (mAb) therapeutics, to predict their stability behavior. Colloidal interactions, self-association propensity and conformational stability were measured using effective surface charge via zeta potential, diffusion interaction parameter (k(D)) and differential scanning calorimetry (DSC), respectively. The molecular features of all 9 mAbs were compared to their stability at accelerated (25 degrees C and 40 degrees C) and long-term storage conditions (2-8 degrees C) as measured by size exclusion chromatography. At accelerated storage conditions, the majority of the mAbs in this study degraded via fragmentation rather than aggregation. Our results show that colloidal stability, self-association propensity and conformational characteristics (exposed tryptophan) provide reasonable prediction of accelerated stability, with limited predictive value at 2-8 degrees C stability. While no correlations to stability behavior were observed with onset-of-melting temperatures or domain unfolding temperatures, by DSC, melting of the Fab domain with the C(H)2 domain suggests lower stability at stressed conditions. The relevance of identifying appropriate biophysical assays based on the primary degradation pathways is discussed.
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