Exidavnemab binds to aggregated α-synuclein in human brains affected by α-synucleinopathies

Abnormal accumulation of α-synuclein in neuronal and/or glial cells occurs in a range of neurodegenerative conditions, including Parkinson's disease, Parkinson's disease dementia, dementia with Lewy bodies, and multiple system atrophy. Immunotherapy targeting α-synuclein is a rational treatment strategy for these α-synucleinopathies. Exidavnemab (also known as BAN0805 or ABBV-0805) is a monoclonal antibody with a high affinity and selectivity for pathological aggregated forms of α-synuclein, and a low affinity for physiological monomers. Exidavnemab is presently in clinical development as a disease-modifying treatment for patients with α-synucleinopathy. To provide information relevant to human target engagement, the present study investigated exidavnemab binding ex vivo using human post mortem brain tissues. Immunohistochemistry experiments demonstrated that exidavnemab bound to aggregated α-synuclein in tissues from individuals affected by Parkinson's disease, Parkinson's disease dementia, dementia with Lewy bodies, and multiple system atrophy. Immunoprecipitation using exidavnemab effectively removed α-synuclein aggregates from Triton-soluble brain tissue extracts. Data from these ex vivo studies using human tissues are consistent with clinical findings and provide further support for the continued development of exidavnemab as a potential treatment for multiple forms of α-synucleinopathy.