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Antibody-mediated delivery of VEGF-C potently reduces chronic skin inflammation
Simon Schwager, … , Dario Neri, Michael Detmar
Simon Schwager, … , Dario Neri, Michael Detmar
Published December 6, 2018
Citation Information: JCI Insight. 2018;3(23):e124850. https://doi.org/10.1172/jci.insight.124850.
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Research Article Dermatology Therapeutics

Antibody-mediated delivery of VEGF-C potently reduces chronic skin inflammation

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Abstract

VEGF-C is an important mediator of lymphangiogenesis and has been shown to alleviate chronic inflammation in a variety of disease models. In this study, we investigated whether targeted delivery of VEGF-C to sites of inflammation and site-specific activation of lymphatic vessels would represent a clinically feasible strategy for treating chronic skin inflammation. To this end, we generated a fusion protein consisting of human VEGF-C fused to the F8 antibody (F8-VEGF-C), which is specific for the alternatively spliced, angiogenesis-marking extradomain A (EDA) of fibronectin. In two mouse models of psoriasis-like skin inflammation, mediated by transgenic VEGF-A overexpression or repeated application of imiquimod, intravenous treatment with F8-VEGF-C but not with untargeted VEGF-C significantly reduced ear skin edema and was as effective as the clinically used TNF-α receptor-Fc fusion protein (TNFR-Fc). Treatment with F8-VEGF-C led to a marked expansion of lymphatic vessels in the inflamed skin and significantly improved lymphatic drainage function. At the same time, treatment with F8-VEGF-C significantly reduced leukocyte numbers, including CD4+ and γδ T cells. In sum, our results reveal that targeted delivery of VEGF-C and site-specific induction of lymphatic vessels represent a potentially new and promising approach for the treatment of chronic inflammatory diseases.

Authors

Simon Schwager, Silvana Renner, Teresa Hemmerle, Sinem Karaman, Steven T. Proulx, Roman Fetz, Alexandra Michaela Golding-Ochsenbein, Philipp Probst, Cornelia Halin, Dario Neri, Michael Detmar

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Figure 5

F8-VEGF-C improves lymphatic clearance function.

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F8-VEGF-C improves lymphatic clearance function.
(A) In vivo imaging sys...
(A) In vivo imaging system (IVIS) images showing tracked signal decay of intradermally injected, exclusively lymphatic-drained near-infrared dye P20D800 in ears of inflamed K14-VEGF-A–transgenic mice that received either PBS or F8-VEGF-C. (B) Quantification of clearance rate of P20D800 of inflamed ear skin. (C) Quantification of half-life of P20D800 in inflamed ear skin (n = 5 animals per group, 2-tailed Student’s t test, 1 of 2 similar experiments shown). Data represent mean ± SD. *P < 0.05.

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