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

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.