# Structure-guided antibody targeting of pre-selected epitopes in amyloidogenic aggregates

> **NIH NIH R35** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $269,727

## Abstract

Amyloidogenic protein aggregation is a key event in seemingly disparate biological phenomena, including
those ranging from bacterial biofilms to neurodegenerative diseases. Intriguingly, amyloidogenic proteins do
not form aggregates with a single 3D structure, but rather with several related yet distinct 3D structures that
are linked to unique biological activities (akin to prion strains). How these structurally-unique aggregates
mediate different toxic or beneficial activities is one of the most important questions in the protein aggregation
field. Conformational antibodies specific for amyloidogenic aggregates are invaluable for investigating this
intriguing problem and, more generally, for their potential use as disease-specific diagnostic and therapeutic
agents. The utility of such antibodies stems from their ability to sensitively detect specific types of protein
aggregates and selectively interfere with their biological activities. However, these types of antibodies are
difficult to generate because of issues common to many antigens (immunodominant epitopes) and those
specific to protein aggregates (multivalent, highly hydrophobic and, in some cases, kinetically unstable). The
goals of this proposal are to develop structure-guided approaches for in vitro generation of antibodies against
six classes of predicted conformational epitopes in amyloidogenic aggregates, and to use these antibodies to
evaluate conformational differences between disease-associated aggregates formed in vivo. The predicted
epitopes – which include the leading candidates for generic antibody epitopes in oligomers and fibrils – have
not been specifically targeted or verified previously using monoclonal antibodies. We will primarily target a-
synuclein (associated with Parkinson’s disease), which forms multiple types of oligomers and fibrils. These
studies will address four key fundamental (Q1, Q2) and methodological (Q3, Q4) questions. 1) Which generic
classes of predicted conformational antibody epitopes exist in oligomers and fibrils of a-synuclein and other
amyloidogenic proteins? 2) Which protein-specific classes of predicted conformational epitopes exist in
different structural (strain) variants of a-synuclein aggregates? 3) What are optimal design parameters for
generating in vitro antibody libraries that maximize the likelihood of isolating antibodies with high specificity in
addition to high affinity? 4) What are the most effective in vitro methods for targeting antibody libraries to pre-
selected epitopes in protein aggregates in order to overcome common problems associated with
immunodominant epitopes and poor antigen quality? These proposed studies are based on multiple
discoveries in the Tessier lab: i) novel in vitro library design and sorting methods for isolating yeast-displayed
antibodies with extremely high specificity; ii) bioinformatics methods for predicting antibody specificity; and iii)
identification of multiple classes of conformational epitopes ...

## Key facts

- **NIH application ID:** 10129400
- **Project number:** 5R35GM136300-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Peter M Tessier
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $269,727
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10129400

## Citation

> US National Institutes of Health, RePORTER application 10129400, Structure-guided antibody targeting of pre-selected epitopes in amyloidogenic aggregates (5R35GM136300-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10129400. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*