# Vectorized scFv antibodies to treat tau pathology in Alzheimer's disease: enhancing epitope targeting and delivery strategies

> **NIH NIH R01** · FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH · 2021 · $418,750

## Abstract

PROJECT SUMMARY/ABSTRACT
Increasing evidence supports the existence of tau as an extracellular protein, and the concept of its trans-cellular
propagation as a mechanism for the initiation and progression of Alzheimer's disease (AD). In this context, using
antibodies to target tau pathology appeared as an appropriate approach to clear neurofibrillary tangles in AD
models. A conspicuous amount of data has been produced by different laboratories showing reduction of tau
pathology in transgenic animal models using tau monoclonal antibodies, with a different degree of success
according to which epitopes were targeted. Unfortunately, conventional tau immunotherapy has achieved only
incomplete clearance of tau pathology, and presents limitations in terms of potential inflammatory adverse
events, long-term sustainability, compliance and costs. Also, effective blood brain barrier penetration and choice
of the correct tau epitope are still subject of an open debate.
In this application, we will employ scFv (single chain variable fragments), to target pathological tau. scFv are
composed of the variable regions of the heavy and light chains of antibodies, joined by a short linker, preserving
the epitope specificity and affinity of the parent monoclonal antibodies (mAb), but with a much smaller size and
reduced chance of triggering unwanted inflammatory responses. scFv expression will be driven by viral vectors
(adeno-associated virus, AAV) after intracerebral or intramuscular injection. Our published data show that
intracranial administration of vectorized scFv-MC1, the recombinant version of the native anti-tau conformational
mAb MC1, significantly reduces brain pathological tau species in adult tau transgenic JNPL3 mice.
Here, we will try to further potentiate the therapeutic efficacy of scFv-MC1 preventing tau accumulation
(prevention paradigm) and reducing established tau pathology (reversion protocol): we will employ an epitope-
based dual therapy, combining scFv-MC1 with scFv directed against other tau epitopes, according to what
observed in AD pathophysiology.
We will also adopt a dual delivery strategy, intracranial or intramuscular, fulfilling both a proof of concept and a
translational approach.
Finally, our data show that microglia have a role in up-taking the scFv-tau complex and can degrade it, without
an overt inflammatory response. Here, we will deepen our understanding of the role of microglia in this process.
The overall objective of this proposal is to develop and characterize a novel therapeutic approach for AD and
tauopathies, with the goal to advance peripheral administration of engineered anti-tau antibodies, which will have
relevant translational potential.

## Key facts

- **NIH application ID:** 10260598
- **Project number:** 5R01AG061381-02
- **Recipient organization:** FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
- **Principal Investigator:** Cristina d'Abramo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $418,750
- **Award type:** 5
- **Project period:** 2020-09-15 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10260598

## Citation

> US National Institutes of Health, RePORTER application 10260598, Vectorized scFv antibodies to treat tau pathology in Alzheimer's disease: enhancing epitope targeting and delivery strategies (5R01AG061381-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10260598. Licensed CC0.

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