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P041. Modulation of inflammatory processes in mouse colitis models and gastrointestinal acute radiation syndrome with AVX-470m, an oral polyclonal anti-TNF antibody

D. Hartman, K. Bhol, B. Lemos, E. Erlich, D. Keane, D. Tracey, B. Fox, Avaxia Biologics, Inc, Research, Lexington, United States

Background

Improved therapies for inflammatory bowel disease (IBD) require animal models that elucidate underlying mechanisms of disease. DSS-induced colitis is a well-established mouse model of the dysregulated inflammatory response in IBD. Acute radiation syndrome (ARS) also has devastating consequences in the gastrointestinal (GI) tract driven in part by cytokine-mediated inflammation, which closely resembles the pathophysiology of IBD. Tumor Necrosis Factor (TNF) is strongly implicated in both IBD and GI ARS. In this study AVX-470m, a bovine polyclonal neutralizing antibody for murine TNF, is used to characterize the pathogenesis of GI damage in models of GI ARS and IBD.

Methods

In C57BL/6 mice, colitis was induced by including 3% DSS in drinking water for five days. GI ARS was induced in C57BL/6 mice by irradiation with 15.9 Gy (∼LD80/30) from a 60-Cobalt gamma radiation source, with partial bone marrow shielding. AVX-470m (10 mg/day) or saline was administered BID by oral gavage for up to 14 days. Protein expression of inflammatory and immune cell markers was analyzed by immunohistochemistry in paraffin embedded, formalin fixed tissue sections, and relative mRNA expression measured by RT-PCR.

Results

In both the colitis and GI ARS models, mRNA and protein levels of TNF were significantly increased, in colon and jejunum tissue, respectively. IL-1-beta, IL-6, MMP9, ICAM-1, and TNFR2 mRNA levels were increased in both models; increased IL12p40 was detectable only in the colitis model. MPO protein expression was also increased in both models. CD68 and CD3 protein were increased in the colitis model, but were not detected in GI ARS, perhaps due to cell destruction by ionizing radiation. Treatment with AVX-470m in both colitis and GI ARS models resulted in a significant decrease in TNF mRNA and protein expression in colon and jejunum tissues, respectively. AVX-470m decreased MPO protein expression, and reduced MMP9 mRNA expression, in both colitis and GI ARS models.

Conclusion

These data show a strong correlation of inflammatory responses between the colitis and radiation-induced models of GI injury, with a common TNF-mediated, neutrophilic component in the colon and jejunum, respectively. Further studies will investigate time course and tissue differences. The efficacy of AVX-470m in both models highlights the central role of TNF in GI tract inflammation, and supports the therapeutic potential of an oral anti-TNF antibody in GI inflammatory disease.

This project has been funded in part by the Biomedical Advanced Research and Development Authority (BARDA), Department of Health and Human Services, under Contract No. HHSO100201100027C. This project has also been supported in part by NIH grant 2R44DK083810–02.