Facile generation of drug-like conformational antibodies specific for amyloid fibrils

Alec A Desai^#^{1

2}, Jennifer M Zupancic^#^{1

2}, Hanna Trzeciakiewicz^{3

4}, Julia E Gerson⁴, Kelly N DuBois³, Mary E Skinner⁴, Lisa M Sharkey⁴, Nikki McArthur⁵, Sean P Ferris⁶, Nemil N Bhatt^{7

8}, Emily K Makowski^{2

9}, Matthew D Smith^{1

2}, Hongwei Chen^{1

2

9}, Jie Huang^{1

2

9}, Cynthia Jerez^{7

8}, Yun-Huai Kuo^{1

2}, Ravi S Kane⁵, Nicholas M Kanaan³, Henry L Paulson^{4

10

11}, Peter M Tessier^{12

13

14

15

16

17}

Affiliations

¹ Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA.
² Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA.
³ Department of Translational Neuroscience, Michigan State University, Grand Rapids, MI, USA.
⁴ Department of Neurology, University of Michigan, Ann Arbor, MI, USA.
⁵ School of Chemical & Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA, USA.
⁶ Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
⁷ Mitchell Center for Neurodegenerative Disease, University of Texas Medical Branch, Galveston, TX, USA.
⁸ Department of Neurology, University of Texas Medical Branch, Galveston, TX, USA.
⁹ Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI, USA.
¹⁰ Protein Folding Disease Initiative, University of Michigan, Ann Arbor, MI, USA.
¹¹ Michigan Alzheimer's Disease Center, University of Michigan, Ann Arbor, MI, USA.
¹² Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA. ptessier@umich.edu.
¹³ Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA. ptessier@umich.edu.
¹⁴ Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI, USA. ptessier@umich.edu.
¹⁵ Protein Folding Disease Initiative, University of Michigan, Ann Arbor, MI, USA. ptessier@umich.edu.
¹⁶ Michigan Alzheimer's Disease Center, University of Michigan, Ann Arbor, MI, USA. ptessier@umich.edu.
¹⁷ Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA. ptessier@umich.edu.

^# Contributed equally.

PMID: 40301692
PMCID: PMC12710417 (available on 2026-06-01)
DOI: 10.1038/s41589-025-01881-9

Facile generation of drug-like conformational antibodies specific for amyloid fibrils

Alec A Desai et al. Nat Chem Biol. 2025 Jun.

. 2025 Jun;21(6):916-925.

doi: 10.1038/s41589-025-01881-9. Epub 2025 Apr 29.

Authors

Affiliations

¹ Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA.
² Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA.
³ Department of Translational Neuroscience, Michigan State University, Grand Rapids, MI, USA.
⁴ Department of Neurology, University of Michigan, Ann Arbor, MI, USA.
⁵ School of Chemical & Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA, USA.
⁶ Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
⁷ Mitchell Center for Neurodegenerative Disease, University of Texas Medical Branch, Galveston, TX, USA.
⁸ Department of Neurology, University of Texas Medical Branch, Galveston, TX, USA.
⁹ Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI, USA.
¹⁰ Protein Folding Disease Initiative, University of Michigan, Ann Arbor, MI, USA.
¹¹ Michigan Alzheimer's Disease Center, University of Michigan, Ann Arbor, MI, USA.
¹² Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA. ptessier@umich.edu.
¹³ Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA. ptessier@umich.edu.
¹⁴ Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI, USA. ptessier@umich.edu.
¹⁵ Protein Folding Disease Initiative, University of Michigan, Ann Arbor, MI, USA. ptessier@umich.edu.
¹⁶ Michigan Alzheimer's Disease Center, University of Michigan, Ann Arbor, MI, USA. ptessier@umich.edu.
¹⁷ Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA. ptessier@umich.edu.

^# Contributed equally.

PMID: 40301692
PMCID: PMC12710417 (available on 2026-06-01)
DOI: 10.1038/s41589-025-01881-9

Abstract

Antibodies that recognize insoluble antigens, such as amyloid fibrils associated with neurodegenerative disorders, are important for research, diagnostic and therapeutic applications. However, these types of antibodies are difficult to generate, typically require animal immunization and also commonly require humanization in the case of therapeutic applications. Here we report a methodology for generating high-quality, fully human, conformation-specific antibodies against amyloid fibrils using a published human nonimmune library, yeast-surface display and quantitative fluorescence-activated cell sorting. Notably, this approach enables the isolation of conformation-specific antibodies against tau fibrils (Alzheimer's disease) and α-synuclein fibrils (Parkinson's disease) with combinations of high affinity, high conformational specificity and, in some cases, low off-target binding that rival or exceed those of clinical-stage antibodies specific for tau (zagotenemab) and α-synuclein (cinpanemab). This approach is expected to simplify the generation of conformation-specific antibodies against diverse protein aggregates and other insoluble antigens.

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Conflict of interest statement

Competing interests: P.M.T. is a member of the scientific advisory boards for Nabla Bio, Aureka Biotechnologies and Dualitas Therapeutics. The remaining authors declare no competing interests.

Update of

Flow cytometric isolation of drug-like conformational antibodies specific for amyloid fibrils.
Desai AA, Zupancic JM, Trzeciakiewicz H, Gerson JE, DuBois KN, Skinner ME, Sharkey LM, McArthur N, Ferris SP, Bhatt NN, Makowski EK, Smith MD, Chen H, Huang J, Jerez C, Kane RS, Kanaan NM, Paulson HL, Tessier PM. Desai AA, et al. bioRxiv [Preprint]. 2023 Jul 4:2023.07.04.547698. doi: 10.1101/2023.07.04.547698. bioRxiv. 2023. Update in: Nat Chem Biol. 2025 Jun;21(6):916-925. doi: 10.1038/s41589-025-01881-9. PMID: 37461643 Free PMC article. Updated. Preprint.

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Facile generation of drug-like conformational antibodies specific for amyloid fibrils

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Facile generation of drug-like conformational antibodies specific for amyloid fibrils

Authors

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Abstract

Conflict of interest statement

Update of

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METHODS-ONLY REFERENCES

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