ABBV-0805 Reduces Alpha-synuclein Clumping in Mice
ABBV-0805, AbbVie’s experimental antibody-based therapy for Parkinson’s disease, selectively binds to toxic clumps of the alpha-synuclein protein — a hallmark of the disease — preventing their spread and prolonging survival in mouse models of Parkinson’s, a study shows.
Also, the investigational antibody was found to bind to harmful alpha-synuclein forms in brains of deceased Parkinson’s patients.
Based on these positive findings, ABBV-0805 is now in clinical development as a potential Parkinson’s treatment, the researchers noted. Notably, a Phase 1 clinical trial (NCT04127695) testing the therapy’s safety in healthy volunteers was launched in March 2019, but withdrawn in July 2020 for “strategic considerations.”
The study, “ABBV-0805, a novel antibody selective for soluble aggregated α-synuclein, prolongs lifespan and prevents buildup of α-synuclein pathology in mouse models of Parkinson’s disease,” was published in the journal Neurobiology of Disease and conducted by BioArctic AB, the therapy’s original developer.
“I’m pleased to see the very encouraging data on ABBV-0805 published in a peer reviewed journal and we look forward to the continued development of this antibody as a potential disease-modifying treatment for patients with Parkinson’s disease,” Johanna Fälting, BioArctic’s head of research, said in a press release.
The findings also were presented at the International Parkinson and Movement Disorder Society Virtual Congress 2021, held online Sept. 17–22.
Formerly known as BAN0805, ABBV-0805 is a humanized monoclonal antibody designed to selectively bind and destroy toxic aggregates of alpha-synuclein protein, a protein abundant in the brain and thought to help regulate nerve cell function and communication.
ABBV-0805’s targets include small alpha-synuclein soluble clumps, called oligomers, and larger soluble aggregates called protofibrils, which are known to contribute to cellular damage and spread of Parkinson’s disease.
By neutralizing these toxic forms, ABBV-0805 is expected to prevent further aggregation and resulting toxicity, ultimately halting or slowing Parkinson’s progression.
In the current study, the therapy was shown to have increased binding selectivity to toxic soluble alpha-synuclein aggregates over its harmless monomer (single protein). It also resulted in a dose-dependent reduction of alpha-synuclein clumps that reached values of about 60%, relative to a control antibody.
In addition, ABBV-0805 was found to promote the uptake of toxic clumps by microglia and to protect nerve cells from alpha-synuclein oligomer-induced toxicity in a dose-dependent manner. Microglia are the brain’s immune cells that also are involved in clearing dying cells and harmful substances.
Moreover, the murine version of ABBV-0805 was found to have therapeutic effects in three different mouse models of alpha-synucleinopathies — neurodegenerative diseases, including Parkinson’s, associated with the abnormal accumulation of alpha-synuclein clumps.
Treatment, given either before or after symptom onset, resulted in a significant, dose-dependent reduction in alpha-synuclein aggregates in the mice’s brains, preventing spreading of toxic clumps, and delaying the development of severe motor symptoms.
These benefits also were associated with a significantly prolonged lifespan.
Notably, ABBV-0805 was shown to selectively bind to alpha-synuclein oligomers and protofibrils present in the brains of deceased Parkinson’s patients containing Lewy bodies, which are insoluble deposits of alpha-synuclein.
These findings highlight that ABBV-0805 “selectively targets soluble toxic [alpha-synuclein] aggregates with a [strong] affinity and demonstrates excellent [efficacy in animal models],” the researchers wrote.
“Based on the strong preclinical findings described herein, ABBV-0805 has been progressed into clinical development as a potential disease-modifying treatment for Parkinson’s disease,” the researchers concluded.
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