High Throughput Formulation Screening for Global Aggregation Behaviors of Three Monoclonal Antibodies

Global aggregation behaviors of three distinct monoclonal antibodies were characterized by high throughput, multiassay analysis. First, extensive screening of formulations was performed using both incubation at elevated temperature and differential thermal scanning. In incubation studies, formulatio...

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Bibliographic Details
Published in:Journal of pharmaceutical sciences 2011-06, Vol.100 (6), p.2120-2135
Main Authors: Li, Yi, Mach, Henryk, Blue, Jeffrey T.
Format: Article
Language:English
Subjects:
Antibodies, Monoclonal - chemistry
Biological and medical sciences
Biopharmaceutics - methods
Chromatography, Gel
Fluorescence spectroscopy
General pharmacology
high throughput technologies
High-Throughput Screening Assays - methods
Immunoglobulin G - chemistry
Light
Light-scattering
Medical sciences
Molecular Weight
monoclonal antibody
Multivariate Analysis
Pharmaceutical technology. Pharmaceutical industry
Pharmacology. Drug treatments
protein aggregation
Protein Conformation
Protein Folding
protein formulation
Protein Stability
Protein Unfolding
Scattering, Radiation
Spectrometry, Fluorescence
stability
Transition Temperature
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Summary:Global aggregation behaviors of three distinct monoclonal antibodies were characterized by high throughput, multiassay analysis. First, extensive screening of formulations was performed using both incubation at elevated temperature and differential thermal scanning. In incubation studies, formulation conditions representing native favored, native favored but with particulate formation, unfolding with slow aggregation, and fast aggregation with or without phase separation were mapped across a wide range of pH and ionic strength. The sample types or aggregation kinetic scenarios were classified based on fluorescence spectroscopy, light scattering, and micron particle count. Furthermore, apparent melting point was determined for each formulation condition by differential thermal scanning. The global aggregation behaviors and their apparent melting points together highlight the common underlying aggregation pathways and kinetics for the three antibodies. Overall, incorporating multistage aggregation mechanisms in multivariate data analysis provides valuable insights to what and how high throughput techniques can be implemented. Understanding global aggregation behaviors is a key element toward development of rational screening approach. © 2011 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:2120–2135, 2011
ISSN:0022-3549
1520-6017
DOI:10.1002/jps.22450