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Proc Natl Acad Sci U S A. 2014 Aug 19;111(33):12008-12. doi: 10.1073/pnas.1402783111. Epub 2014 Aug 4.

Antibody-based delivery of IL4 to the neovasculature cures mice with arthritis.

Author information

1
Department of Chemistry and Applied Biosciences, ETH Zurich, CH-8093 Zürich, Switzerland.
2
Department of Chemistry and Applied Biosciences, ETH Zurich, CH-8093 Zürich, Switzerland neri@pharma.ethz.ch.

Abstract

Antibody-cytokine fusion proteins (immunocytokines) are innovative biopharmaceutical agents, which are being considered for the therapy of cancer and chronic inflammatory conditions. Immunomodulatory fusion proteins capable of selective localization at the sites of rheumatoid arthritis (RA) are of particular interest, as they may increase the therapeutic index of the cytokine payload. The F8 antibody recognizes the alternatively spliced extra domain A of fibronectin, a marker of angiogenesis, which is strongly overexpressed at sites of arthritis. In this study, we investigated the targeting and therapeutic activity of the immunocytokine F8-IL4 in the mouse model of collagen-induced arthritis. Different combination regimes were tested and evaluated by the analysis of serum and tissue cytokine levels. We show that F8-IL4 selectively localizes to neovascular structures at sites of rheumatoid arthritis in the mouse, leading to high local concentrations of IL4. When used in combination with dexamethasone, F8-IL4 was able to cure mice with established collagen-induced arthritis. Response to treatment was associated with an elevation of IL13 levels and decreased IL6 plasma concentrations. A fully human version of F8-IL4 is currently being developed for clinical investigations.

KEYWORDS:

armed antibody; interleukin 4; targeted therapy; vascular targeting

PMID:
25092334
PMCID:
PMC4143070
DOI:
10.1073/pnas.1402783111
[Indexed for MEDLINE]
Free PMC Article

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