Target-Specific Delivery of an Antibody That Blocks the Formation of Collagen Deposits in Skin and Lung

摘要

Regardless of the cause of organ fibrosis, its main unwanted consequence is the formation of collagen fibril-rich deposits that hamper the structure and function of affected tissues. Although many strategies have been proposed for the treatment of fibrotic diseases, no therapy has been developed, which can effectively block the formation of collagen fibril deposits. With this in mind, we recently developed an antibody-based therapy to block key interactions that drive collagen molecules into fibrils. In this study, we analyzed target specificity, which is a main parameter that defines the safe use of all antibody-based therapies in humans. We hypothesized that, regardless of the route of administration, our antibody would preferentially bind to free collagen molecules synthesized at the sites of fibrosis and have minimal off-target interactions when applied in various tissues. To test this hypothesis, we used two experimental models of organ fibrosis: (1) a keloid model, in which antibody constructs were directly implanted under the skin of nude mice and (2) an experimental model of pulmonary fibrosis, in which our antibody was administered systemically by intravenous injection. Following administration, we studied the distribution of our antibody within target and off-target sites as well as analyzed its effects on fibrotic tissue formation. We found that local and systemic application of our antibody had high specificity for targeting collagen fibrillogenesis and also appeared safe and therapeutically effective. In summary, this study provides the basis for further testing our antifibrotic antibody in a broad range of disease conditions and suggests that this treatment approach will be effective if delivered by local or systemic administration.