Binding Stability of Antibody-α-Synuclein Complexes Predicts the Protective Efficacy of Anti-α-synuclein Antibodies

Spreading of alpha-synuclein (alpha Syn) may play an important role in Parkinson's disease and related synucleinopathies. Passive immunization with anti-alpha Syn antibodies is a promising method to slow down the spreading process and thereby the progression of synucleinopathies. Currently, it remains elusive which specific characteristics are essential to render therapeutic antibodies efficacious. Here, we established a neuronal co-culture model, in which alpha Syn species are being released from alpha Syn-overexpressing cells and induce toxicity in a priori healthy GFP-expressing cells. In this model, we investigated the protective efficacy of three anti-alpha Syn antibodies. Only two of these antibodies, one C-terminal and one N-terminal, protected from alpha Syn-induced toxicity by inhibiting the uptake of spreading-competent alpha Syn from the cell culture medium. Neither the binding epitope nor the affinity of the antibodies towards recombinant alpha Syn could explain differences in biological efficacy. However, both protective antibodies formed more stable antibody-alpha Syn complexes than the non-protective antibody. These findings indicate that the stability of antibody-alpha Syn complexes may be more important to confer protection than the binding epitope or affinity to recombinant alpha Syn.

Automated summary

The spread of alpha-synuclein (alpha Syn) may be important in Parkinson's disease and related synucleinopathies. Passive immunization with specific antibodies against alpha Syn appears promising in slowing down the progression of these diseases. This study aims to identify the essential characteristics of therapeutic antibodies. A neuronal co-culture model was established to investigate the protective efficacy of three anti-alpha Syn antibodies. Results showed that two antibodies, one C-terminal and one N-terminal, protected cells from alpha Syn-induced toxicity by inhibiting the uptake of spreading-competent alpha Syn. The stability of antibody-alpha Syn complexes was found to be more important than the binding epitope or affinity to recombinant alpha Syn.