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Modulation of inflammatory processes in DSS-induced colitis model versus gastrointestinal acute radiation syndrome with AVX-470m , an oral polyclonal anti-TNF antibody - PowerPoint PPT PresentationTRANSCRIPT
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Modulation of inflammatory processes in DSS-induced colitis model versus gastrointestinal acute radiation syndrome with
AVX-470m, an oral polyclonal anti-TNF antibody
Kailash C Bhol, Ph.D, Brenda Lemos, B.S, Emma Erlich, B.A., David Keane, B.S, Daniel E. Tracey, Ph.D., Barbara S. Fox, Ph.D., and Deborah Hartman, Ph.D.
CCFA 2013
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Disclosures
• Employee of Avaxia Biologics, Inc.
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Introduction• AVX-470 is a gut-targeted polyclonal anti-TNF antibody
that is orally delivered and acts locally in the GI tract1
• AVX-470 is being developed for inflammatory bowel disease (IBD), and for gastrointestinal acute radiation syndrome (GI ARS) as a secondary indication
• Designed to overcome the limitations of current injectable anti-TNF therapies – direct delivery to the site of inflammation – minimal systemic exposure for reduced side effects from
untargeted immunosuppression– potential for prolonged duration of effect by avoiding
neutralizing anti-drug antibodies
1Bhol et al, Inflamm Bowel Dis. 2013 Oct;19(11):2273-81
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Background• AVX-470m is a murine-specific surrogate antibody1
– Potent and selective, neutralizes mouse TNF– Effective in DSS- and TNBS- induced colitis models
• TNF is strongly implicated in GI ARS, which results from exposure to high doses of ionizing radiation– GI ARS results from a nuclear accident, explosion,
accidental release or act of terrorism; devastating consequences in GI tract driven by cytokine-mediated inflammation closely resembling the pathophysiology of IBD
• In this study, we have profiled AVX-470m effects on biomarkers of inflammation in IBD and GI ARS models.
1Bhol et al, Inflamm Bowel Dis. 2013 Oct;19(11):2273-81
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GI ARS: structural damage and mortality curve
AVX-470m treatment showed survival benefit in the GI ARS model, compared to saline and control Ig.
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DSS-induced colitis vs GI ARS:Induction of inflammatory biomarkers
• Biomarkers measured by immunohistochemistry, and qPCR (*)• Colitis: C57BL/6 mice with 3% DSS in drinking water for five days• GI ARS: C57BL/6 mice irradiated with 15.9 Gy, partial bone marrow shielding,
60Co gamma radiation source
Biomarker
Response to injury
DSS-induced colitis (colon)
GI ARS (jejunum)
TNF ↑ ↑TNFR1 * ↑ ─TNFR2 * ↑ ↑
MPO ↑ ↑MMP9 * ↑ ↑
CD3 ↑ ─CD68 ↑ ─IL-1β ↑ ↑
IL-12p40 ↑ ─ICAM-1 * ↑ ↑
↑ indicates:
Significant increase over control in DSS colitis (p<0.05) Or, > 2-fold increase in GI ARS
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Treatment with AVX-470m reduces TNF levels in both IBD and GI ARS models
GI ARS - jejunum tissue sections
IBD - colon tissue sections
• AVX-470m (10 mg/day, BID by oral gavage) reduced TNF protein levels in GI tissue in both IBD and GI ARS models
No DSS DSS + Saline DSS + AVX-470m
No Radiation 15.9 Gy + Saline 15.9 Gy + AVX-470m
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AVX-470m treatment reduces inflammatory biomarkers in both IBD & GI ARS models
Biomarker
Response to injury + AVX-470mDSS-induced colitis (colon)
GI ARS (jejunum)
DSS-induced colitis (colon)
GI ARS (jejunum)
TNF ↑ ↑ ↓ ↓TNFR1* ↑ ─ ─ ─TNFR2* ↑ ↑ ─ ─
MPO ↑ ↑ ↓ ↓MMP9* ↑ ↑ ↓ ↓
CD3 ↑ ─ ─ ─CD68 ↑ ─ ↓ ─IL-1B ↑ ↑ ↓ ─
IL-12p40 ↑ ─ ↓ ─ICAM-1 (qPCR) ↑ ↑ ─ ─
↓ indicates p<0.05 for IBD markers or > 2-fold decrease for GI ARS markers. Control Ig had no effect on inflammatory biomarkers. *= qPCR analysis.
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AVX-470m penetrates GI mucosal barrierTissue sections stained for presence of bovine Ig
• AVX-470m penetrates into damaged tissue in both colon and jejunum, but not healthy tissue. Labeling is seen in mucosa, lamina propria, and submucosal regions.
• Minimal systemic exposure is seen with AVX-470m
Control animal with AVX-470m DSS with AVX-470m 15.9 Gy with AVX-470m
Normal IBD model - colon GI ARS model - jejunum
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Conclusions• DSS colitis and GI ARS share a common TNF-
mediated inflammatory component• AVX-470m is a novel gut-targeted anti-TNF antibody
that is delivered orally and acts locally in the GI tract• Oral delivery of AVX-470m effectively inhibits TNF
expression in DSS colitis and GI ARS• These data support the therapeutic potential of an
oral anti-TNF antibody as a gut-targeted treatment for multiple GI inflammatory diseases in both the large and small bowel.
• AVX-470 is in Phase 1b clinical trials in patients with active ulcerative colitis, results in early 2014.
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Acknowledgments
DSS-induced colitis model• Biomodels, LLC
– Steve Sonis, DMD, DMSc– Greg Lyng, PhD
GI ARS model• CiToxLAB North America
– Simon Authier, PhD
• Avaxia Biologics, Inc. – Barbara Fox, PhD– Dan Tracey, PhD– Kailash Bhol, PhD– Brenda Lemos– Emma Erlich– Dave Keane
This project has been funded in part by the Biomedical Advanced Research and Development Authority (BARDA), Office of the Assistant Secretary for Preparedness and Response, Department of Health and Human Services under Contract No. HHSO100201100027C.
This work has also been supported in part by in part by National Institutes of Health (NIH) grant 2R44DK083810-02