# Design and Evolution of Polyvalent Domain Antibodies Specific for Tau Aggregates

> **NIH NIH RF1** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $421,875

## Abstract

Protein misfolding and aberrant self-assembly into toxic species ranging from small oligomers to large amyloid
fibrils are pathologically linked to neurodegenerative disorders such as Alzheimer’s disease. Conformational
antibodies with specificity for protein aggregates are important for investigating the role of different types of
aggregates in neurodegenerative diseases as well as for potentially treating these debilitating diseases. It
has, however, been extremely difficult to generate conformational antibodies against protein aggregates due
to several factors: i) the limitations of immunization (lack of control over antigen presentation); ii) the fixed
number of binding sites per antibody, which limits the use of polyvalency for targeting multimeric protein
aggregates; and iii) the difficulty in using naïve antibody libraries to obtain conformational antibodies via in
vitro selection methods. To address these challenges, we have recently developed a systematic approach for
generating domain antibodies with specificity for protein aggregates. The goal of this proposal is to use this
approach to generate conformational domain antibodies specific for tau oligomers and fibrils, and to use these
antibodies to evaluate the relative importance of different types of tau aggregates in mediating tau pathology
in animal models. Our proposed approach builds on our collective experience in: i) designing domain
antibodies with specificity for protein aggregates based on homotypic interactions between identical peptide
motifs; ii) enhancing the affinity and specificity of domain antibodies using directed evolution; iii) designing
polyvalent molecules that bind to oligomeric proteins with high affinity and specificity; iv) assembling and
isolating tau oligomers and fibrils; and v) evaluating the ability of antibodies to prevent and reverse pathology
in tau animal models. In Aim 1, we will test our hypothesis that domain antibodies with enhanced
conformational specificity and affinity for tau oligomers and fibrils can be readily selected from antibody
libraries with tau amyloidogenic peptides grafted into the main binding loop (CDR3). Next, in Aim 2A, we will
evaluate our hypothesis that polyvalency can be used to increase the conformational specificity and affinity
of tau domain antibodies by generating polyvalent versions in a manner that affords control over the number
and spacing of domain antibodies. In Aim 2B, we will generate bispecific domain antibodies that combine tau
and blood-brain barrier (BBB) targeting domain antibodies, and evaluate their pharmacokinetics and target
engagement in tau transgenic (PS19) mice. Finally, in Aim 3, we will test the ability of the most specific and
inhibitory tau/BBB bispecific antibodies generated in Aim 2, which are best at engaging tau in the mouse
brain, to inhibit tau seeding, spontaneous aggregation and pathology in vivo using tau mouse models.
Significant outcomes of our studies will be systematic methods for ...

## Key facts

- **NIH application ID:** 10585480
- **Project number:** 3RF1AG059723-01S1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Ravi S. Kane
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $421,875
- **Award type:** 3
- **Project period:** 2018-08-15 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10585480

## Citation

> US National Institutes of Health, RePORTER application 10585480, Design and Evolution of Polyvalent Domain Antibodies Specific for Tau Aggregates (3RF1AG059723-01S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10585480. Licensed CC0.

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