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

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 therapy that can safely and effectively promote neuronal integrity and neurogenesis would provide a significant advancement for a clear unmet medical need.