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Proc Natl Acad Sci U S A. 2014 Dec 30;111(52):18601-6. doi: 10.1073/pnas.1421779112. Epub 2014 Dec 15.

In silico selection of therapeutic antibodies for development: viscosity, clearance, and chemical stability.

Author information

1
Early Stage Pharmaceutical Development Department.
2
Protein Analytical Chemistry, and.
3
Drug Delivery, Genentech Inc., South San Francisco, CA 94080;
4
Simprota Corp., San Francisco, CA 94158; and.
5
Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, NY 11794 dill@laufercenter.org swartz.trevor@gene.com.
6
Early Stage Pharmaceutical Development Department, dill@laufercenter.org swartz.trevor@gene.com.

Abstract

For mAbs to be viable therapeutics, they must be formulated to have low viscosity, be chemically stable, and have normal in vivo clearance rates. We explored these properties by observing correlations of up to 60 different antibodies of the IgG1 isotype. Unexpectedly, we observe significant correlations with simple physical properties obtainable from antibody sequences and by molecular dynamics simulations of individual antibody molecules. mAbs viscosities increase strongly with hydrophobicity and charge dipole distribution and decrease with net charge. Fast clearance correlates with high hydrophobicities of certain complementarity determining regions and with high positive or high negative net charge. Chemical degradation from tryptophan oxidation correlates with the average solvent exposure time of tryptophan residues. Aspartic acid isomerization rates can be predicted from solvent exposure and flexibility as determined by molecular dynamics simulations. These studies should aid in more rapid screening and selection of mAb candidates during early discovery.

KEYWORDS:

degradation; monoclonal antibodies; pharmacokinetics; prediction; viscosity

PMID:
25512516
PMCID:
PMC4284567
DOI:
10.1073/pnas.1421779112
[Indexed for MEDLINE]
Free PMC Article

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