# CD98hc Brain Shuttles for Delivering Off-the-shelf Neuroprotective Antibodies in Alzheimer's Disease

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $762,048

## Abstract

Alzheimer’s disease (AD) is the most common age-related neurodegenerative disease. Biologics with potential
to affect underlying pathophysiology have failed to display significant therapeutic benefits in the clinic. The
inability of biologics to penetrate the blood-brain barrier (BBB) represents their biggest hurdle to clinical efficacy.
A promising strategy to address this challenge is to fuse IgGs to a second affinity ligand that engages a
cerebrovascular endothelial target and induces transport across the BBB. While nearly all prior efforts have
focused on the transferrin receptor (TfR-1) as the prototypical endothelial target despite inherent delivery and
safety challenges, we have developed a bispecific antibody shuttle that engages CD98hc, the heavy chain of
the large neutral amino acid transporter (LAT-1). Notably, our preliminary data show preserved affinity and
specificity of off-the-shelf IgGs incorporated into our first-generation CD98hc bispecific shuttle, superior brain
retention of IgGs shuttled via CD98hc as compared to TfR-1, and preserved endothelial levels of CD98hc and
brain uptake after saturating CD98hc shuttle doses.The overall objective of this proposal is to further the
development of the CD98hc BBB shuttle by: i) defining the optimal characteristics for maximal IgG brain
parenchymal delivery; ii) evaluating age- and disease-dependent effects on CD98hc-mediated transport; and iii)
generating proof-of-concept efficacy data in an AD mouse model using agonist (anti-TrkB) and antagonist (anti-
phospho-tau) antibodies alone and in combination. Our central hypothesis is that IgG transport via the CD98hc
shuttles will increase parenchymal delivery and achieve brain concentrations and target engagement
comparable to viral delivery, generating robust neuroprotection in a tau mouse model, including potential additive
or synergistic neuroprotective effects by targeting two different neuroprotective pathways. Therefore, we propose
in Aim 1 to optimize brain parenchymal delivery of a second-generation CD98hc antibody shuttle. We will test
the impact of the valency, affinity, and epitope of CD98hc interaction on brain uptake and parenchymal delivery.
The optimal dose and construct identified using adult mice will be tested in aged wild-type and PS19 (tau P301S)
mice to evaluate the integrity of the transport pathway. Next, in Aim 2, we will assess the efficacy of individual
neuroprotective antibody/CD98hc shuttles in PS19 mice. Validated antibodies against TrkB (C20, agonist) and
phosphorylated tau (PHF1) will be individually delivered via our best CD98hc shuttle. Efficacy outcomes will be
levels of phosphorylated and insoluble tau, neuronal and synaptic loss, and cognitive deficits. Efficacy will be
tested in three modes of treatment, beginning at early, intermediate, and late stages of progression of AD
pathology and cognitive decline. Finally, in Aim 3, the efficacy of combinations of antibody shuttles targeting
multiple neuroprotect...

## Key facts

- **NIH application ID:** 10815779
- **Project number:** 5R01AG080016-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Colin Fred Greineder
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $762,048
- **Award type:** 5
- **Project period:** 2023-04-01 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10815779

## Citation

> US National Institutes of Health, RePORTER application 10815779, CD98hc Brain Shuttles for Delivering Off-the-shelf Neuroprotective Antibodies in Alzheimer's Disease (5R01AG080016-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10815779. Licensed CC0.

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