# Epitope-Specific Targeting of Tau Aggregates

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2022 · $677,295

## Abstract

Ten tau immunotherapies are currently in clinical trials. One of the most studied tau epitopes
preclinically, including in our original reports, phospho-serine 396,404, is being targeted in two of these trials.
We have generated several antibodies against it, which have unique binding profiles to these two phospho-
sites and varying efficacy in preventing tau toxicity and promoting tau clearance. It is not clear why the subtle
epitope differences within this region can greatly influence antibody efficacy. Another important issue to
explore is which antibody isotype to choose for clinical trials. To date, these have either strong or limited
effector function with regard to promoting microglial phagocytosis of the tau-antibody complex, but this key
isotype efficacy/safety issue has not been well examined in tauopathy models. The few reports on it differ in
their conclusion. A third matter that needs to be studied further has to do with where to target pathological tau,
intra- and/or extracellularly. Most companies have focused on extracellular clearance but since almost all of
pathological tau resides intracellularly (>99%), targeting it there in addition to extracellularly should be more
efficacious, as we have advocated over the years. Specifically, we have shown that neuronal uptake of tau
antibodies and thereby their efficacy in clearing tau and preventing its toxicity is influenced by their electrical
charge. The relationship between antibody charge and efficacy has been well studied in the cancer field but
has received little attention in the tau field. Finally, it is not clear which forms of tau are most toxic and should
ideally be targeted with therapies. Our recent preliminary data indicates that we have been able to stabilize a
toxic conformation of tau. We would like to clarify this phenomenon, which may have major implications for
understanding tau pathogenesis and for development of therapies. To address these related very important
issues we propose to clarify: 1) the pronounced influence of subtle epitope differences and antibody isotype on
the efficacy of tau antibodies; 2) the robust influence of affinity and electrical charge on antibody efficacy, and;
3) why engineering an effective single domain tau antibody (sdAb) to a full size antibody (Fc-(sdAb)2 renders it
toxic, whereas the same modification for a different effective tau sdAb does not. The scientific premise of these
aims is highly supported by our publications and preliminary data, and the approach is very feasible based on
this foundation and the use of technologies that are well established in our laboratories, reflecting strong rigor
and reproducibility. Together, the outcome of these studies is likely to guide further development of tau
immunotherapies and provide valuable insight into tau pathogenesis in Alzheimer's disease and related
tauopathies that may be applicable to other targets in various protein aggregation diseases.

## Key facts

- **NIH application ID:** 10467481
- **Project number:** 2R01NS077239-11
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Einar M Sigurdsson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $677,295
- **Award type:** 2
- **Project period:** 2011-09-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10467481

## Citation

> US National Institutes of Health, RePORTER application 10467481, Epitope-Specific Targeting of Tau Aggregates (2R01NS077239-11). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10467481. Licensed CC0.

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