A brain-shuttled antibody targeting alpha synuclein aggregates for the treatment of synucleinopathies

An, S.; McInnis, J. J.; Kim, D.; Li, Y.; Yilmaz, O.; Ahn, J.; Mackness, B. C.; Park, J.; Bonner, J. M.; Yun, H.; Dujardin, S.; Kwon, S.-H.; Tang, Y.; Pradier, L.; Hyeon, S.; Song, D.; Sung, B.; Krishnan, R.; Spencer, B.; Rissman, R.; Sandhu, J.; Haqqani, A.; Lee, H.; Jung, J.; You, W.-K.; Star, A. T.; Delaney, C.; Stanimirovic, D.; Sardi, S. P.; Lee, S. H.; Kayatekin, C.

doi:10.1101/2024.10.16.618734

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bioRxiv · 10.1101/2024.10.16.618734

A brain-shuttled antibody targeting alpha synuclein aggregates for the treatment of synucleinopathies

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Abstract

Parkinsons disease and multiple system atrophy are members of a class of devastating neurodegenerative diseases called synucleinopathies, which are characterized by the presence of alpha-synuclein (-Syn) rich aggregates in the brains of patients. Passive immunotherapy targeting these aggregates is an attractive disease-modifying strategy. Such an approach must not only demonstrate target selectivity towards -Syn aggregates, but also achieve appropriate brain exposure to have the desired therapeutic effect. Here we present preclinical data for a next-generation antibody for the treatment of synucleinopathies. SAR446159 (ABL301) is a bispecific antibody composed of an -Syn-binding immunoglobulin (IgG) and an engineered insulin-like growth factor receptor 1 (IGF1R) binding single-chain variable fragment (scFv), acting as a shuttle to transport an antibody across the blood-brain barrier (BBB). SAR446159 binds tightly and preferentially to -Syn aggregates and prevents their seeding capacity in vitro and in vivo. Incubation with SAR446159 reduced -Syn preformed fibrils (PFFs) uptake in neurons and facilitated uptake and clearance by microglia. In wild type mice injected in the striatum with -Syn PFFs, treatment with SAR446159 reduced the spread of aSyn pathology as measured by phosphorylated -Syn staining and lessened the severity of motor phenotypes. Additionally, in 9-month-old transgenic mice overexpressing -Syn (mThy1--Syn, Line 61), repeated treatment with SAR446159 reduced markers of -Syn aggregation in the brain. SAR446159 had significantly higher brain and CSF penetration over a sustained period than its monospecific counterpart (1E4) in rats and monkeys. The binding properties of SAR446159 combined with its brain-shuttle technology make it a potent, next-generation immunotherapeutic for treating synucleinopathies.

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An, S., McInnis, J. J., Kim, D., Li, Y., Yilmaz, O., Ahn, J., Mackness, B. C., Park, J., Bonner, J. M., Yun, H., Dujardin, S., Kwon, S.-H., Tang, Y., Pradier, L., Hyeon, S., Song, D., Sung, B., Krishnan, R., Spencer, B., Rissman, R., Sandhu, J., Haqqani, A., Lee, H., Jung, J., You, W.-K., Star, A. T., Delaney, C., Stanimirovic, D., Sardi, S. P., Lee, S. H., Kayatekin, C.. 2024-10-18. A brain-shuttled antibody targeting alpha synuclein aggregates for the treatment of synucleinopathies. https://doi.org/10.1101/2024.10.16.618734

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