Objective: To evaluate a translational free/total α-synuclein (α-syn) assay framework to quantify in vivo target engagement (TE) of anti–α-syn antibodies in preclinical models and to assess the relevance of cerebrospinal fluid (CSF) as a compartment for CNS TE.
Background: Demonstrating in vivo TE remains a central challenge in the development of anti–α-syn antibodies for synucleinopathies. Free/total α-syn assays distinguish unbound (free) α-syn from total α-syn and enable indirect quantification of antibody-bound target through reduction in the free fraction. However, interpretation of CSF-based TE and its relationship to brain exposure require further characterization.
Method: Free and total α-syn were measured in CSF following administration of distinct therapeutic antibodies in mice and were used to characterize exposure–engagement relationships. Comparative analyses were performed to assess antibody-specific differences in the magnitude and kinetics of free/total shifts. CSF-based measurements were further examined in relation to brain exposure, assessed by immunohistochemistry.
Results: Normalized free/total ratio aSyn measurements allowed to measure target engagement 24h and 72h following antibody administration. A target‑engagement exposure relationship demonstrated decreased free/total α‑syn levels with increasing CSF drug concentrations. Antibody-specific differences were identified in the magnitude and kinetics of free/total shifts. Integration with brain exposure data provided insight into the relationship between CSF-based engagement and parenchymal target interaction.
Conclusion: These findings support the translational application of free/total α-syn assays for rational dose selection and provide insight into the strengths and limitations of CSF as a compartment for assessing CNS TE.
To cite this abstract in AMA style:
M. Ramos Vega, B. Ozgur, F. Sotty, A. Jensen, K. Bjerregaard-Andersen. Translational evaluation of CSF as a relevant compartment for assessing target engagement of therapeutic anti–α-syn antibodies. [abstract]. Mov Disord. 2026; 41 (suppl 1). https://www.mdsabstracts.org/abstract/translational-evaluation-of-csf-as-a-relevant-compartment-for-assessing-target-engagement-of-therapeutic-anti-%ce%b1-syn-antibodies/. Accessed October 1, 2026.« Back to 2026 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/translational-evaluation-of-csf-as-a-relevant-compartment-for-assessing-target-engagement-of-therapeutic-anti-%ce%b1-syn-antibodies/