pt9b00037_si_001.pdf (487.18 kB)
Antibody-Mediated Delivery of VEGFC Ameliorates Experimental Chronic Colitis
journal contribution
posted on 2019-08-15, 15:43 authored by Carlotta Tacconi, Simon Schwager, Nikola Cousin, Davor Bajic, Marko Sesartic, John P. Sundberg, Dario Neri, Michael DetmarCrohn’s
disease (CD) and ulcerative colitis (UC) are two
distinct forms of inflammatory bowel disease (IBD) characterized by
an expanded lymphatic network with impaired functionality both in
mouse models and in human patients. In this study, we investigated
whether targeted delivery of the pro-lymphangiogenic vascular endothelial
growth factor C (VEGFC) to the site of inflammation may represent
a new, clinically feasible strategy for treating IBD. To achieve targeting
of inflamed tissue, we developed a fusion protein consisting of human
VEGFC fused to the F8 antibody (F8-VEGFC), which specifically binds
to the extradomain A (EDA) of fibronectin, a spliced isoform almost
exclusively expressed in inflamed tissues. The therapeutic activity
of intravenously administered F8-VEGFC, compared to a targeted construct
lacking VEGFC (F8-SIP), was investigated in a mouse model of dextran
sodium sulfate (DSS)-induced colitis. The presence of EDA fibronectin
was detected in both human and mouse inflamed colon tissue. Biodistribution
studies of radiolabeled F8-VEGFC revealed a specific accumulation
of the antibody in the colon of DSS-administered mice, as compared
to an untargeted VEGFC fusion protein (KSF-VEGFC) (binding the irrelevant
hen egg lysozyme antigen). Systemic treatment with F8-VEGFC significantly
reduced the clinical and histological signs of inflammation, expanded
the lymphatic vascular network, reduced the density of immune cells,
and also decreased the expression of inflammatory cytokines in the
inflamed colon. Overall, these results reveal that administration
of F8-VEGFC represents a novel and promising approach for the treatment
of IBD.