Concentration Dependent Viscosity of Monoclonal Antibody Solutions: Explaining Experimental Behavior in Terms of Molecular Properties

• Published in: Pharmaceutical research 2014-11, Vol.31 (11), p.3161-3178
• Main Authors: Li, Li, Kumar, Sandeep, Buck, Patrick M., Burns, Christopher, Lavoie, Janelle, Singh, Satish K., Warne, Nicholas W., Nichols, Pilarin, Luksha, Nicholas, Boardman, Davin
• Format: Article
• Language: English
• Subjects: Antibodies, Monoclonal - chemistry; Biochemistry; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Drug delivery systems; Immunoglobulin Variable Region - chemistry; Medical Law; Monoclonal antibodies; Pharmacology; Pharmacology/Toxicology; Pharmacy; Research Paper; Risk Assessment; Solutions - chemistry; Viscosity
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-014-1409-0

Purpose Early identification of monoclonal antibody candidates whose development, as high concentration (≥100 mg/mL) drug products, could prove challenging, due to high viscosity, can help define strategies for candidate engineering and selection. Methods Concentration dependent viscosities of 11 proprietary mAbs were measured. Sequence and structural features of the variable (Fv) regions were analyzed to understand viscosity behavior of the mAbs. Coarse-grained molecular simulations of two problematic mAbs were compared with that of a well behaved mAb. Results Net charge, ξ-potential and pI of Fv regions were found to correlate with viscosities of highly concentrated antibody solutions. Negative net charges on the Fv regions of two mAbs with poor viscosity behaviors facilitate attractive self-associations, causing them to diffuse slower than a well-behaved mAb with positive net charge on its Fv region. An empirically derived equation that connects aggregation propensity and pI of the Fv region with high concentration viscosity of the whole mAb was developed. Conclusions An Fv region-based qualitative screening profile was devised to flag mAb candidates whose development, as high concentration drug products, could prove challenging. This screen can facilitate developability risk assessment and mitigation strategies for antibody based therapeutics via rapid high throughput material-free screening.