Single domain antibodies for diagnosis and… (R56AG083436) – Project Grant to New York University

Abstract: Immunotherapies targeting aggregates of amyloid-SS (ASS), TAU and a-synuclein (asyn) are the most common experimental approach for diseases characterized by such depositions. Most of these potential therapies are whole antibodies. Antibody fragments have certain advantages over antibodies but their diagnostic and therapeutic potential has not been well explored. Five anti-asyn IGG antibodies and one asyn vaccine are in phase 1-2 clinical trials, and one ASS antibody recently showed clinical benefit in a phase 3 trial, which strongly supports this therapeutic approach. Regarding antibody fragments, several anti-asyn single chain variable fragments (scfvs) are effective in culture and in vivo, and two anti-asyn single domain antibodies (sdabs) have been characterized in a binding assay but their therapeutic efficacy or diagnostic imaging potential have not been reported. Sdabs have several advantages over scfvs, including higher affinity, binding to cryptic epitopes and simpler engineering. They are also more suitable for gene therapy because of uncomplicated expression and predictable protein folding, given their single domain, resulting in high solubility. We have developed 58 anti-asyn sdab clones with unique binding regions from a screen of phage display libraries generated from b-cells of a llama immunized with asyn. Three aims are proposed to clarify their potential to detect and clear asyn in vivo. Aim 1 will determine the in vivo imaging potential of sdabs targeting asyn. Aim 2 will clarify asyn clearance potential and mechanism of action of sdabs targeting asyn, and aim 3 will explore the feasibility of sdab gene therapy targeting asyn. Preliminary findings indicate that the sdabs: 1) recognize various forms of asyn with high affinity; 2) clear asyn and prevent its toxicity in culture models; 3) clear asyn from brain interstitial fluid in asyn mice; 4) bind to asyn in the brain of asyn mice after intravenous injection with in vivo brain signal that correlates well with asyn brain burden; 5) clear asyn from the brain after intravenous injection of sdab with improved clearance by its protac derivative, and; 6) clear asyn from the brain after intravenous sdab gene therapy. IT is hypothesized that the small size of the sdabs will provide diagnostic and therapeutic benefits over whole antibodies, primarily because of greater access into the brain and to the target, proper folding for gene therapy, and to some extent due to their binding to novel epitopes that the larger antibodies cannot access. Overall, the proposed studies are likely to aid in clarifying asyn pathogenesis, decipher the mechanism of action of the sdabs, and identify promising diagnostic and therapeutic sdabs for clinical trials on synucleinopathies such as lewy body dementia, parkinson's disease, alzheimer's disease with lewy bodies, and multiple system atrophy.

Action	Obligated	Date
Amendment	-$6,887	Jan 29, 2026
Original award	$717,491	Sep 21, 2023

Single domain antibodies for diagnosis and treatment of synucleinopathies

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