Monoclonal Antibody Therapy Targeting
Alpha-Synuclein in Parkinson’s Disease: A
Comprehensive Review

Abstract

​Parkinson’s disease (PD) is a prevalent neurodegenerative disorder characterized by motor and non-motor
symptoms resulting from the progressive loss of dopaminergic neurons. A key contributor to PD pathology
is the misfolding and aggregation of alpha-synuclein (α-syn) into insoluble fibrils that accumulate
as Lewy bodies, disrupting cellular homeostasis, impairing mitochondrial function, and triggering neuroinflammation. Monoclonal antibody (mAb) therapy has emerged as a promising strategy to target α-syn
pathology, aiming to mitigate its toxic effects by enhancing proteolytic degradation, inhibiting intercellular transmission, and reducing microglial activation. This review evaluates the mechanisms, efficacy,
and limitations of prominent mAbs under clinical investigation, including prasinezumab, BIIB054 (Cinpanemab),
and MEDI1341. Prasinezumab targets the C-terminus of α-syn, showing potential in slowing
motor progression. BIIB054 binds the N-terminal of α-syn, inhibiting oligomer formation. MEDI1341
specifically targets aggregated α-syn to reduce neuroinflammation. Despite promising outcomes, challenges
such as limited blood-brain barrier penetration, high costs, and variable patient responses remain
significant barriers to clinical translation. Future research should focus on improving mAb design, enhancing
blood-brain barrier permeability, and developing reliable biomarkers for patient stratification.
Collectively, mAb therapy represents a potential paradigm shift in managing PD by directly targeting the
underlying disease mechanisms associated with α-syn aggregation.

Keywords: ​Parkinson’s disease, Prasinezumab, Cinpanemab, Monoclonal antibody.