Biophysical properties of the clinical-stage antibody landscape
Edited by James A. Wells, University of California, San Francisco, CA, and approved December 13, 2016 (received for review October 2, 2016)
Significance
In addition to binding to a desired target molecule, all antibody drugs must also meet a set of criteria regarding the feasibility of their manufacture, stability in storage, and absence of off-target stickiness. This suite of characteristics is often termed “developability.” We present here a comprehensive analysis of these properties for essentially the full set of antibody drugs that have been tested in phase-2 or -3 clinical trials, or are approved by the FDA. Surprisingly, many of the drugs or candidates in this set exhibit properties that indicate significant developability risks; however, the number of such red warning flags decreases with advancement toward approval. This reference dataset should help prioritize future drug candidates for development.
Abstract
Antibodies are a highly successful class of biological drugs, with over 50 such molecules approved for therapeutic use and hundreds more currently in clinical development. Improvements in technology for the discovery and optimization of high-potency antibodies have greatly increased the chances for finding binding molecules with desired biological properties; however, achieving drug-like properties at the same time is an additional requirement that is receiving increased attention. In this work, we attempt to quantify the historical limits of acceptability for multiple biophysical metrics of “developability.” Amino acid sequences from 137 antibodies in advanced clinical stages, including 48 approved for therapeutic use, were collected and used to construct isotype-matched IgG1 antibodies, which were then expressed in mammalian cells. The resulting material for each source antibody was evaluated in a dozen biophysical property assays. The distributions of the observed metrics are used to empirically define boundaries of drug-like behavior that can represent practical guidelines for future antibody drug candidates.
Acknowledgments
We thank other Adimab LLC staff members for their many contributions.
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Freely available online through the PNAS open access option.
Submission history
Published online: January 17, 2017
Published in issue: January 31, 2017
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Acknowledgments
We thank other Adimab LLC staff members for their many contributions.
Notes
This article is a PNAS Direct Submission.
Authors
Competing Interests
Conflict of interest statement: All of the authors are employed by Adimab, LLC, whose business is the discovery of antibody drugs.
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Cite this article
Biophysical properties of the clinical-stage antibody landscape, Proc. Natl. Acad. Sci. U.S.A.
114 (5) 944-949,
https://doi.org/10.1073/pnas.1616408114
(2017).
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