Design and development of a sortilin‐targeting miniprotein for the treatment of FTD

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BACKGROUND: Heterozygous loss-of-function mutations in the gene encoding progranulin (GRN) are causative in around 5-10% of frontotemporal dementia (FTD) cases. These mutations lead to a more than 50% reduction of progranulin levels in the plasma and cerebrospinal fluid of mutation carriers compared to healthy controls. Increasing the progranulin levels in FTD-GRN patients via inhibition of sortilin-mediated progranulin degradation has shown promise as a therapeutic strategy, as exemplified by Alector's latozinemab, currently in phase 3 clinical trials. Here we detail the development of an anti-sortilin affibody-based miniprotein as a non-immunoglobulin alternative, offering potential advantages due to its small size and cost-effective production. METHOD: Sortilin-binding affibodies were selected by phage display and subsequently genetically fused to short peptides derived from the progranulin C-terminus. The resulting miniproteins were characterized in terms of affinity, structure, stability, and their ability to increase extracellular progranulin levels in a clearance assay using progranulin-secreting, sortilin-expressing U-251 MG cells. RESULT: A set of moderate-affinity sortilin-binding affibodies were obtained from phage display selections. Following genetic fusion with short peptides derived from the progranulin C-terminus and optimization of the fusion constructs, a lead candidate with 185 pM affinity for sortilin was obtained. The affibody-peptide fusion, but not its parental affibody or peptide, was capable of elevating extracellular progranulin levels in vitro with similar potency as latozinemab. CONCLUSION: A sortilin-binding affibody-based miniprotein was developed and optimized, performing on par with latozinemab in in vitro functional studies. Affibody-based miniproteins provide a promising alternative to immunoglobulins in cases such as the present, where Fc functions are undesirable, and long-term high-dose antibody treatments risk becoming prohibitively expensive.

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