دورية أكاديمية
أعرض في EDS

Rational affinity maturation of anti-amyloid antibodies with high conformational and sequence specificity.

التفاصيل البيبلوغرافية
العنوان: Rational affinity maturation of anti-amyloid antibodies with high conformational and sequence specificity.
المؤلفون: Desai AA; Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, Michigan, USA., Smith MD; Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, Michigan, USA., Zhang Y; Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, Michigan, USA., Makowski EK; Biointerfaces Institute, University of Michigan, Ann Arbor, Michigan, USA; Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, Michigan, USA., Gerson JE; Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA., Ionescu E; Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, Michigan, USA., Starr CG; Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, Michigan, USA; Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, Michigan, USA., Zupancic JM; Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, Michigan, USA., Moore SJ; Protein Folding Disease Initiative, University of Michigan, Ann Arbor, Michigan, USA; Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA., Sutter AB; Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA; Biophysics Program, University of Michigan, Ann Arbor, Michigan, USA., Ivanova MI; Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA; Biophysics Program, University of Michigan, Ann Arbor, Michigan, USA., Murphy GG; Protein Folding Disease Initiative, University of Michigan, Ann Arbor, Michigan, USA; Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA., Paulson HL; Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA; Protein Folding Disease Initiative, University of Michigan, Ann Arbor, Michigan, USA; Michigan Alzheimer's Disease Center, University of Michigan, Ann Arbor, Michigan, USA., Tessier PM; Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, Michigan, USA; Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, Michigan, USA; Protein Folding Disease Initiative, University of Michigan, Ann Arbor, Michigan, USA; Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan, USA. Electronic address: ptessier@umich.edu.
المصدر: The Journal of biological chemistry [J Biol Chem] 2021 Jan-Jun; Vol. 296, pp. 100508. Date of Electronic Publication: 2021 Mar 04.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.
اللغة: English
بيانات الدورية: Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE
أسماء مطبوعة: Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology
Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology
مواضيع طبية MeSH: Amyloid/*metabolism , Antibodies, Monoclonal/*immunology , Brain/*pathology, Amyloid/antagonists & inhibitors ; Amyloid/immunology ; Animals ; Antibodies, Monoclonal/chemistry ; Antibodies, Monoclonal/metabolism ; Binding Sites, Antibody ; Brain/immunology ; Case-Control Studies ; Humans ; Mice ; Models, Molecular ; Protein Conformation
مستخلص: The aggregation of amyloidogenic polypeptides is strongly linked to several neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. Conformational antibodies that selectively recognize protein aggregates are leading therapeutic agents for selectively neutralizing toxic aggregates, diagnostic and imaging agents for detecting disease, and biomedical reagents for elucidating disease mechanisms. Despite their importance, it is challenging to generate high-quality conformational antibodies in a systematic and site-specific manner due to the properties of protein aggregates (hydrophobic, multivalent, and heterogeneous) and limitations of immunization (uncontrolled antigen presentation and immunodominant epitopes). Toward addressing these challenges, we have developed a systematic directed evolution procedure for affinity maturing antibodies against Alzheimer's Aβ fibrils and selecting variants with strict conformational and sequence specificity. We first designed a library based on a lead conformational antibody by sampling combinations of amino acids in the antigen-binding site predicted to mediate high antibody specificity. Next, we displayed this library on the surface of yeast, sorted it against Aβ42 aggregates, and identified promising clones using deep sequencing. The resulting antibodies displayed similar or higher affinities than clinical-stage Aβ antibodies (aducanumab and crenezumab). Moreover, the affinity-matured antibodies retained high conformational specificity for Aβ aggregates, as observed for aducanumab and unlike crenezumab. Notably, the affinity-maturated antibodies displayed extremely low levels of nonspecific interactions, as observed for crenezumab and unlike aducanumab. We expect that our systematic methods for generating antibodies with unique combinations of desirable properties will improve the generation of high-quality conformational antibodies specific for diverse types of aggregated conformers.
Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.
(Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
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معلومات مُعتمدة: R01 AG050598 United States AG NIA NIH HHS; R01 GM104130 United States GM NIGMS NIH HHS; R35 GM136300 United States GM NIGMS NIH HHS; RF1 AG059723 United States AG NIA NIH HHS
فهرسة مساهمة: Keywords: Alzheimer; aggregate; amyloid; antibody engineering; directed evolution; fibril; mAb; neurodegeneration; scFv; yeast surface display
المشرفين على المادة: 0 (Amyloid)
0 (Antibodies, Monoclonal)
تواريخ الأحداث: Date Created: 20210306 Date Completed: 20210820 Latest Revision: 20210820
رمز التحديث: 20221213
مُعرف محوري في PubMed: PMC8081927
DOI: 10.1016/j.jbc.2021.100508
PMID: 33675750
قاعدة البيانات: MEDLINE
الوصف
تدمد:1083-351X
DOI:10.1016/j.jbc.2021.100508