Antibody-Mediated Delivery of VEGFC Ameliorates Experimental Chronic Colitis

Abstract

Crohn’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.

Advancements in hydrogel-based drug delivery systems for the treatment of inflammatory bowel disease: a review

“…103 GFs are proteins that can stimulate the regeneration and healing of the intestinal mucosa. 104 However direct use of growth factors tends to reduce the efficacy of the drug due to the stimulation of gastrointestinal digestive fluids. Therefore, carriers are necessary to assist in the delivery of growth factors.…”

The Role of the Lymphatic System in the Pathogenesis and Treatment of Inflammatory Bowel Disease

“…VEGFC-promoted lymphangiogenesis reduced inflammation. Similarly, blocking VEGFR-3 or the calcitonin lymphangiogenic receptors resulted in disease exacerbation [114][115][116][117][118][119]. On the contrary, it was shown that the pharmacological inhibition of lymphangiogenesis ameliorated disease activity [120,121], while lymphangiogenesis stimulation by VEGF-C overexepression in the same colitis model aggravated intestinal inflammation [122].…”

The role of lymphatics in intestinal inflammation

“…In contrast, resolution of chronic inflammation may require restoration of proper lymphatic function, removing inflammatory cells, mediators, and bacterial antigens from inflamed sites. Systemic treatment with VEGF-C significantly reduced the clinical and histological signs of inflammation, expanded the lymphatic vascular network, reduced the density of immune cells, and decreased inflammatory cytokine expression in the inflamed colon [ 60 ].…”