Objective: To identify and characterize a human antibody against α-synuclein (α-syn) for the clinical development of an immunotherapy for Parkinson’s disease (PD).

Background: α-syn plays a crucial role in the etiology of PD, the most common neurodegenerative movement disorder. Not only is misfolded α-syn a major constituent of Lewy Bodies, but elevated gene expression due to α-syn trisomy leads to inherited PD. Transmission of α-syn pathology is believed to contribute to disease progression. Immunotherapy against α-syn is thus a promising therapeutic approach for slowing disease progression.

Methods: We generated a recombinant human antibody against α-syn based on an endogenous antibody isolated from a de-identified library of B cells collected from healthy elderly subjects using a technology platform called Reverse Translational Medicine (RTM®). The biochemical and functional properties of this antibody (BIIB054) were characterized, including its binding selectivity and ability to inhibit α-syn transmission between primary neurons cultured in a microfluidic two-chamber system. The effects of BIIB054 on α-syn spreading in vivo were assessed in mouse models that were intracerebrally inoculated with preformed α-syn fibrils.

Results: BIIB054 displayed very high selectivity for α-syn aggregates relative to soluble monomeric recombinant α-syn, and specifically immunoprecipitated pathological α-syn from human disease brain. In cultured primary neurons BIIB054 reduced transmission of α-syn from neuron to neuron. Finally, in mouse models BIIB054 attenuated the transmission of α-syn pathology and rescued motor impairments.

Conclusions: Preclinical pharmacologic data on human-derived anti-α-syn antibody BIIB054 support its clinical development for the treatment and prevention of PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/human-derived-synuclein-antibody-biib054-binds-pathologic-forms-of-synuclein-and-attenuates-transmission-of-synuclein-in-vitro-and-in-vivo/