In silico selection of therapeutic antibodies for development: Viscosity, clearance, and chemical stability
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- Vikas K. Sharma
- Early Stage Pharmaceutical Development Department,
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- Thomas W. Patapoff
- Early Stage Pharmaceutical Development Department,
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- Bruce Kabakoff
- Early Stage Pharmaceutical Development Department,
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- Satyan Pai
- Early Stage Pharmaceutical Development Department,
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- Eric Hilario
- Early Stage Pharmaceutical Development Department,
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- Boyan Zhang
- Protein Analytical Chemistry, and
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- Charlene Li
- Protein Analytical Chemistry, and
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- Oleg Borisov
- Protein Analytical Chemistry, and
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- Robert F. Kelley
- Drug Delivery, Genentech Inc., South San Francisco, CA 94080;
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- Ilya Chorny
- Simprota Corp., San Francisco, CA 94158; and
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- Joe Z. Zhou
- Simprota Corp., San Francisco, CA 94158; and
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- Ken A. Dill
- Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, NY 11794
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- Trevor E. Swartz
- Early Stage Pharmaceutical Development Department,
説明
<jats:title>Significance</jats:title> <jats:p>mAbs are increasingly being used for treatment of chronic diseases wherein the subcutaneous delivery route is preferred to enable self-administration and at-home use. To deliver high doses (several hundred milligrams) through a small volume (∼1 mL) into the subcutaneous space, mAb solutions need to have low viscosity. Concomitantly, acceptable chemical stability is required for adequate shelf life, and normal in vivo clearance is needed for less frequent dosing. We propose in silico tools that provide rapid assessment of atypical behavior of mAbs (high viscosity, chemical degradation, and fast plasma clearance), which are simply predicted from sequence and/or structure-derived parameters. Such analysis will greatly improve the probability of success to move mAb-based therapeutics efficiently into clinical development and ultimately benefit patients.</jats:p>
収録刊行物
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- Proceedings of the National Academy of Sciences
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Proceedings of the National Academy of Sciences 111 (52), 18601-18606, 2014-12-15
Proceedings of the National Academy of Sciences