Evidence map›Paper›PMID 33675750›Full record

ArticleThe Journal of biological chemistry

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

Alec A Desai, Matthew D Smith, Yulei Zhang, Emily K Makowski, Julia E Gerson, Edward Ionescu, Charles G Starr, Jennifer M Zupancic, Shannon J Moore, Alexandra B Sutter and 4 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in The Journal of biological chemistry. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.

0numbers the graph read from it
0cells of the map it votes in
15citing papers in PubMed
3.5field-weighted citation impact, top 7% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

15 citing papers in PubMed, 32 citations in OpenAlex.

  1. Article
  2. Article
  3. Article
  4. Article
  5. Article
  6. Article
  7. Monitoring α-synuclein aggregation.Neurobiology of disease · 2023
    Review
  8. Article
  9. Review
  10. Article
  11. Review
  12. Article
  13. Isolating Anti-amyloid Antibodies from Yeast-Displayed Libraries.Methods in molecular biology (Clifton, N.J.) · 2022
    Article
  14. Article
  15. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

14 authors at 2 institutions in 1 country.

Alec A DesaiDepartment of Chemical Engineering, University of Michigan, Ann Arbor, Michigan, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, Michigan, USA.
Matthew D SmithDepartment of Chemical Engineering, University of Michigan, Ann Arbor, Michigan, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, Michigan, USA.
Yulei ZhangDepartment of Chemical Engineering, University of Michigan, Ann Arbor, Michigan, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, Michigan, USA.
Emily K MakowskiBiointerfaces Institute, University of Michigan, Ann Arbor, Michigan, USA; Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, Michigan, USA.
Julia E GersonDepartment of Neurology, University of Michigan, Ann Arbor, Michigan, USA.
Edward IonescuDepartment of Chemical Engineering, University of Michigan, Ann Arbor, Michigan, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, Michigan, USA.
Charles G StarrDepartment 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.
Jennifer M ZupancicDepartment of Chemical Engineering, University of Michigan, Ann Arbor, Michigan, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, Michigan, USA.
Shannon J MooreProtein Folding Disease Initiative, University of Michigan, Ann Arbor, Michigan, USA; Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA.
Alexandra B SutterDepartment of Neurology, University of Michigan, Ann Arbor, Michigan, USA; Biophysics Program, University of Michigan, Ann Arbor, Michigan, USA.
Magdalena I IvanovaDepartment of Neurology, University of Michigan, Ann Arbor, Michigan, USA; Biophysics Program, University of Michigan, Ann Arbor, Michigan, USA.
Geoffrey G MurphyProtein Folding Disease Initiative, University of Michigan, Ann Arbor, Michigan, USA; Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA.
Henry L PaulsonDepartment 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.
Peter M TessierDepartment 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.
BioSurfaces (United States) · USUniversity of Michigan–Ann Arbor · US

Funding

Design and Evolution of Polyvalent Domain Antibodies Specific for Tau AggregatesRF1AG059723 · NIA · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI KANE, RAVI S., TESSIER, PETER M · 2018 to 2022
$2.4M
Mechanisms transducing insulin and insulin resistance in the hippocampusR01AG050598 · NIA · STATE UNIVERSITY OF NEW YORK AT ALBANY · PI MCNAY, EWAN C · 2016 to 2020
$1.9M
Structure-guided antibody targeting of pre-selected epitopes in amyloidogenic aggregatesR35GM136300 · NIGMS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI TESSIER, PETER M · 2020 to 2024
$1.5M
Design of Antibody Fragments Specific For Amyloidogenic AggregatesR01GM104130 · NIGMS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI TESSIER, PETER M · 2014 to 2018
$1.3M
NIA NIH HHS R01 AG050598NIA NIH HHS RF1 AG059723NIGMS NIH HHS R01 GM104130NIGMS NIH HHS R35 GM136300
6 · The paper itself

Abstract

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.

Indexed as

AmyloidAnimalsAntibodies, MonoclonalBinding Sites, AntibodyBrainCase-Control StudiesHumansMiceModels, MolecularProtein ConformationAmyloidAntibodies, MonoclonalaggregateAlzheimeramyloidantibody engineeringdirected evolutionfibrilmAbneurodegenerationscFvyeast surface display

Identifiers

PMID33675750
PMCPMC8081927
OpenAlexW3135072281

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.