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Chimeric Protein Shows Promise in a Mouse Model of IBD

From Reuters Health Information

A chimeric protein designed to target activated T lymphocytes mitigates colitis in mice and might provide a novel approach to the treatment of inflammatory bowel disease (IBD) in humans, scientists from Hebrew University of Jerusalem report in the June issue of the journal Gut.

The interleukin-2 (IL2)-caspase 3 chimeric protein both prevented experimental colitis and was an effective therapy in active, ongoing colitis in mice.

These observations, Dr. Haya Lorberboum-Galski told Reuters Health, "suggest that the chimeric protein IL2-caspase 3, designed to specifically target and kill activated lymphocytes...opens a window to a promising new future for the therapy of human IBD."

"Moreover," she added, "this approach may be applied to the treatment of a variety of pathological conditions that involve uncontrolled expansion of activated T cells."

The IL2-caspase 3 chimeric protein uses human IL2 as its targeting moiety and caspase 3, the primary executor enzyme of apoptosis, as its killing moiety. Because IL2-caspase 3 is constructed of human proteins, it is expected to show reduced or no immunogenicity in human recipients, the researchers note.

Colitis was induced in the study mice by adding dextran sodium sulfate (DSS) to their drinking water from day 0 to day 7. In one part of the study, groups of mice were given IL2-caspase 3 intravenously 5, 10, 15 or 20 mg/day, or 15 mg/day intraperitoneally, for the same period and were killed on day 8.

In another part of the study, assessing the chimeric protein's therapeutic potential, DSS was added to the drinking water for 7 days and replaced with a lower dose for a second week. These mice received 10 mg/day intravenous IL2-caspase 3 during the second week only.

Each part of the study was performed in parallel with a control group of untreated mice.

In mice treated in the first 7 days of the study, IL2-caspase 3 mitigated the DSS-induced colitis in a dose-dependent manner, with the IV 15 mg/day dose being the most effective.

In addition, the mice treated after full onset of colitis experienced a significant decrease in disease activity, compared with controls.

Gut 2009;58:790-798.