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Considerations for the Design of Antibody-Based Therapeutics.

Authors
  • Goulet, Dennis R1
  • Atkins, William M2
  • 1 Department of Medicinal Chemistry, University of Washington, Seattle, Washington 98195. Electronic address: [email protected]
  • 2 Department of Medicinal Chemistry, University of Washington, Seattle, Washington 98195.
Type
Published Article
Journal
Journal of Pharmaceutical Sciences
Publisher
Elsevier
Publication Date
Jan 01, 2020
Volume
109
Issue
1
Pages
74–103
Identifiers
DOI: 10.1016/j.xphs.2019.05.031
PMID: 31173761
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Antibody-based proteins have become an important class of biologic therapeutics, due in large part to the stability, specificity, and adaptability of the antibody framework. Indeed, antibodies not only have the inherent ability to bind both antigens and endogenous immune receptors but also have proven extremely amenable to protein engineering. Thus, several derivatives of the monoclonal antibody format, including bispecific antibodies, antibody-drug conjugates, and antibody fragments, have demonstrated efficacy for treating human disease, particularly in the fields of immunology and oncology. Reviewed here are considerations for the design of antibody-based therapeutics, including immunological context, therapeutic mechanisms, and engineering strategies. First, characteristics of antibodies are introduced, with emphasis on structural domains, functionally important receptors, isotypic and allotypic differences, and modifications such as glycosylation. Then, aspects of therapeutic antibody design are discussed, including identification of antigen-specific variable regions, choice of expression system, use of multispecific formats, and design of antibody derivatives based on fragmentation, oligomerization, or conjugation to other functional moieties. Finally, strategies to enhance antibody function through protein engineering are reviewed while highlighting the impact of fundamental biophysical properties on protein developability. Copyright © 2020 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

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