PDGFRβ-Targeting VHH Tracer Enables Noninvasive PET Imaging of Kidney Fibrosis

With a prevalence above 10% worldwide, chronic kidney disease is one of the leading medical burdens. Independent of the underlying cause, kidney fibrosis emerges as the common final endpoint and serves as the most robust predictor of disease progression and long-term prognosis. Fibrosis is driven by extracellular matrix–producing mesenchymal cells, which are characterized by platelet-derived growth factor receptor β (PDGFRβ) expression. PDGFRβ also mediates fibrogenesis in these cells and represents a potential therapeutic target for direct intervention or a potential anchor for selective delivery of antifibrotic drugs. Diagnostic approaches assessing PDGFRβ expression in kidneys are missing. Here, we developed and evaluated a novel tracer using a PDGFRβ-targeting biparatopic variable domain of a heavy-chain-only antibody construct, designated SP02SP26-ABD, for in vivo, noninvasive, molecular imaging of kidney fibrosis. Methods: PDGFRβ expression was assessed in human kidney biopsies and publicly available transcriptomic datasets. In vivo imaging studies were performed in 2 distinct murine models of kidney fibrosis using fluorescence imaging and 89Zr-labeled PET. Specificity and dose dependency were evaluated using a nonspecific control variable domain of a heavy-chain-only antibody construct, R2R2-ABD, and coinjection of increasing amounts of unlabeled SP02SP26-ABD. Ex vivo biodistribution and correlation with histologic and molecular markers of fibrosis were performed. Results: PDGFRβ was increased in fibrotic human kidneys across multiple disease entities, predominantly localized to pericytes and fibroblasts, supporting its relevance as a translational imaging target. In vivo imaging demonstrated significantly higher tracer accumulation in fibrotic compared with nonfibrotic kidneys across both models, whereas tracer accumulation in nonrenal organs was low, with minimal uptake in the spleen. We found no difference between fibrotic and nonfibrotic kidneys when using a nonspecific R2R2-ABD control construct, whereas increasing amounts of unlabeled SP02SP26-ABD led to a dose-dependent decrease in tracer accumulation, consistent with a saturation effect. Tracer signal correlated with PDGFRβ expression, confirming the specificity of the approach. Conclusion: We provide the first proof of concept for noninvasive PET imaging of PDGFRβ-expressing fibrogenic cells in kidney disease, supporting further development of this approach for specific, noninvasive assessment of kidney fibrosis.