AUTHOR=Ek Moira , Nilvebrant Johan , Nygren Per-Åke , Ståhl Stefan , Lindberg Hanna , Löfblom John 

TITLE=An anti-sortilin affibody-peptide fusion inhibits sortilin-mediated progranulin degradation

JOURNAL=Frontiers in Immunology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1437886

DOI=10.3389/fimmu.2024.1437886

ISSN=1664-3224

ABSTRACT=<p>Heterozygous loss-of-function mutations in the <italic>GRN</italic> gene are a common cause of frontotemporal dementia. Such mutations lead to decreased plasma and cerebrospinal fluid levels of progranulin (PGRN), a neurotrophic factor with lysosomal functions. Sortilin is a negative regulator of extracellular PGRN levels and has shown promise as a therapeutic target for frontotemporal dementia, enabling increased extracellular PGRN levels through inhibition of sortilin-mediated PGRN degradation. Here we report the development of a high-affinity sortilin-binding affibody-peptide fusion construct capable of increasing extracellular PGRN levels <italic>in vitro</italic>. By genetic fusion of a sortilin-binding affibody generated through phage display and a peptide derived from the progranulin C-terminus, an affinity protein (A3-PGRN<sub>C</sub>15*) with 185-pM affinity for sortilin was obtained. Treating PGRN-secreting and sortilin-expressing human glioblastoma U-251 cells with the fusion protein increased extracellular PGRN levels up to 2.5-fold, with an EC<sub>50</sub> value of 1.3 nM. Our results introduce A3-PGRN<sub>C</sub>15* as a promising new agent with therapeutic potential for the treatment of frontotemporal dementia. Furthermore, the work highlights means to increase binding affinity through synergistic contribution from two orthogonal polypeptide units.</p>