TARGETING A PATHOGENIC SEED, PYROGLU3 AΒ, IN ALZHEIMER’S DISEASE

Cynthia A. Lemere

Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

Abstract

Dementia, of which Alzheimer’s Disease (AD) is the most common form, currently afflicts 5.3 million Americans over 65 years of age and ~48 million people worldwide. Currently, there is no way to prevent or reverse the disease, which affects memory, speech, problem-solving, reasoning and the ability to perform daily activities. Unless an effective therapy is discovered, the number of Americans over 65 years of age with AD is expected to almost triple to 13.8 million by 2050 (www.alz.org; 2017 Facts and Figures). Cerebral accumulation of amyloid-β (Aβ) protein is the one of the earliest changes in AD. Inflammation and pathogenic changes in neuronal tau protein follow and are associated with synaptic dysfunction and neuronal loss, which correlate with cognitive decline. Recent biomarker studies, including CSF levels of Aβ42, total tau and p-tau, and PET scans for amyloid and tau, indicate that these pathological changes begin ~15-20 prior to the onset of clinical symptoms. Thus, there is a window of opportunity to therapeutically target these changes prior to the synapse and neuron loss that precedes dementia. Pyroglutamate-3 Aβ (pyroGlu3 Aβ) is an N-terminally truncated and modified, pathogenic form of Aβ protein that is formed by endopeptidase cleavage of the first two N-terminal amino acids followed by cyclization of glutamic acid at residue 3 by an enzyme, glutaminyl cyclase (QC). PyroGlu3 Aβ resists degradation and is neurotoxic. PyroGlu3 Aβ is only detectable in the brain and colocalizes with nearly every plaque in humans. In collaboration with Probiodrug AG (Halle, Germany), we have demonstrated that an anti-pyroGlu3 Aβ monoclonal antibodies (mAbs) lowered cerebral Aβ and protected cognition in both prevention and therapeutic treatment studies an AD-like mouse model. In addition, when combined with Probiodrug’s QC inhibitor, the anti-pyroGlu3 IgG2a mAb (07/2a) showed even further plaque lowering, indicating an additive effect of the two treatments such that the combination of treatments was more efficacious than either treatment alone. More recently, a CDC-mutation was introduced into the Fc region of the 07/2a mAb to block complement activation and thereby reduce potential neuroinflammation-mediated side effects of passive immunization targeting Aβ as seen in several clinical studies to date. Unlike 07/2a, the CDC-mutant antibody, 07/2a-k, did not increase uptake of a TSPO tracer (PET) 3 or 30 days following a single intraperitoneal injection of antibody, indicating that 07/2a-k treatment did not induce neuroinflammation. Similar to 07/2a, immunization with the CDC-mutant antibody, 07/2a-k, reduced cerebral plaque load in AD-like mice. Further studies are underway regarding behavioral outcomes and effects on microglia and vascular changes. Selective targeting pyroGlu3 Aβ by immunotherapy, either alone or in combination with a QC inhibitor, may be a disease-modifying treatment for AD.

Funding: NIH R01 AG040092 (past), unrestricted gift from Probiodrug AG, philanthropy.