# A Novel Antibody that Promotes Neuronal Integrity and Neurogenesis for Treating Alzheimer's Disease

> **NIH NIH R43** · VIRTICI, LLC · 2022 · $441,280

## Abstract

Project Summary
Our goal is to develop a novel neuron-penetrating bispecific antibody that promotes neuronal integrity and
neurogenesis for the treatment of AD. In the US alone, over 6 million Americans are currently living with AD,
with total economic costs around $355 billion in 20211. Despite the staggering cost, only a few mildly effective
AD symptom-treating drugs exist. As a result, treating and even reversing the effects of AD remains a
significant unmet need.
Pathologically, AD is characterized by the presence of neuritic plaques and neurofibrillary tangles in the brain.
The primary component of the extracellular neuritic plaques is the β-amyloid protein (Aβ), an approximately 4
kDa fragment proteolytically derived from the larger amyloid precursor protein (APP)2. A vast amount of
literature has implicated Aβ accumulation as being central to the progression of AD, and inhibiting Aβ
production represents a promising strategy for treating AD.
We have generated two single-chain variable domain antibody fragments (scFv), Asec and Bsec, which
respectively promote α-secretase activity and block β-secretase activity toward amyloid precursor protein
(APP) by binding to APP at either the α-site or the β-site3-5. Next, we generated a tandem bispecific antibody
that combines the Asec and Bsec scFvs and showed that it elevates levels of sAPPα, a soluble α-secretase-
associated APP fragment, and decreases levels of Aβ and sAPPβ, a soluble β-secretase-associated fragment
in cell models of AD6. An ApoB tag was added to the bispecific antibody (called VTC-939), which can facilitate
transfer across the blood-brain barrier (BBB)6-8 and neuronal targeting. Using recombinant human adeno-
associated virus (rAAV) as a vector infective to hepatic cells, VTC-939 could be secreted into the blood and
brain at high levels. When VTC-939 was tested as a therapeutic in an APP/PS1 AD mouse model, VTC-939
increased levels of sAPPα, while decreasing Aβ deposits and oligomeric Aβ levels. In addition, VTC-939
treatment increased neuronal health, substantially increased hippocampal neurogenesis and significantly
increased survival rates compared with untreated mice9. These results indicate that altering APP processing to
inhibit toxic amyloidogenic β-site activity while simultaneously promoting neuroprotective α-secretase
processing provides increased neuronal benefits and represents a promising new therapeutic approach for
treating, and potentially reversing AD.
Building from this work, our objective is to develop VTC-939 as a novel neuron-penetrating antibody that
restores neuronal integrity and promotes neurogenesis for the treatment of AD. The specific aims are to: 1)
produce antibody constructs and establish quality control assays, 2) determine the optimal effective dose of
VTC-939 to promote neuronal integrity, neurogenesis and longevity in the APP/PS1 AD mouse model, and 3)
generate acute toxicology and biodistribution profiles for VTC-939 in normal healthy mice. A t...

## Key facts

- **NIH application ID:** 10600796
- **Project number:** 1R43AG080879-01
- **Recipient organization:** VIRTICI, LLC
- **Principal Investigator:** Neil A Fanger
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $441,280
- **Award type:** 1
- **Project period:** 2022-09-30 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10600796

## Citation

> US National Institutes of Health, RePORTER application 10600796, A Novel Antibody that Promotes Neuronal Integrity and Neurogenesis for Treating Alzheimer's Disease (1R43AG080879-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10600796. Licensed CC0.

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