Antibody-Based Targeted Delivery of Interleukin-22 Promotes Rapid Clinical Recovery in Mice With DSS-Induced Colitis.

Abstract

BACKGROUND:

We have recently described the potential of the alternatively spliced extradomain A of fibronectin as a target for antibody-based pharmacodelivery applications in ulcerative colitis. Here, we report on the cloning and therapeutic properties of novel antibody-based fusion proteins, comprising the F8 antibody specific to extradomain A and murine interleukin (IL)-22, a globular cytokine belonging to the IL10 family. A protective function for IL22 in colitis has previously been described, as this cytokine induces antimicrobial, proliferative, and antiapoptotic pathways, preventing tissue damage and promoting epithelial repair.

METHODS:

Two fusion proteins comprising IL22, fused at the N- or at the C-terminus of the F8 antibody in diabody format, were expressed in mammalian cells. The ability of radiolabeled preparations of the 2 fusion proteins to localize at sites of disease was assessed by autoradiography in a murine model of dextran sodium sulfate-induced colitis and by quantitative biodistribution analysis in a syngeneic mouse teratocarcinoma model. Therapeutic activity was assessed in mice with dextran sodium sulfate-induced colitis, which received intravenous injections of antibody-cytokine fusion proteins.

RESULTS:

Both fusion proteins were able to selectively accumulate at the site of disease. The fusion protein with the cytokine moiety at the N-terminal extremity (IL22-F8) exhibited better results than the C-terminal fusion, both in terms of targeting selectivity and therapeutic efficacy. Mice treated with IL22-F8 showed a more rapid recovery from clinical symptoms compared with controls and improved macroscopic and microscopic morphology of the colon.

CONCLUSIONS:

IL22-F8 is a promising biopharmaceutical drug candidate for the treatment of ulcerative colitis.

• Authors: Franziska Bootz, Barbara Ziffels, Dario Neri
• Journal: Inflammatory bowel diseases (Inflamm Bowel Dis) Vol. 22 Issue 9 Pg. 2098-105 (09 2016) ISSN: 1536-4844 [Electronic] England
• PMID: 27482975 (Publication Type: Journal Article)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• F8 monoclonal antibody
• Fibronectins
• Interleukins
• Dextran Sulfate

Topics

• Animals
• Antibodies, Monoclonal (pharmacology)
• Antibodies, Monoclonal, Humanized
• Colitis (drug therapy, pathology)
• Dextran Sulfate (administration & dosage)
• Female
• Fibronectins (immunology)
• HT29 Cells
• Humans
• Interleukins (administration & dosage, pharmacology)
• Mice
• Mice, Inbred C57BL
• Molecular Targeted Therapy
• Interleukin-22