GI ARS model - Advances in Inflammatory Bowel Diseases

Report
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
1
Disclosures
• Employee of Avaxia Biologics, Inc.
2
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
3 1Bhol et al, Inflamm Bowel Dis. 2013 Oct;19(11):2273-81
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.
4 1Bhol et al, Inflamm Bowel Dis. 2013 Oct;19(11):2273-81
GI ARS: structural damage and mortality curve
AVX-470m treatment showed
survival benefit in the GI ARS
model, compared to saline
and control Ig.
5
DSS-induced colitis vs GI ARS:
Induction of inflammatory biomarkers
Response to injury
•
•
•
6
Biomarker
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
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
Treatment with AVX-470m reduces TNF levels
in both IBD and GI ARS models
IBD - colon tissue sections
No DSS
DSS + Saline
DSS + AVX-470m
15.9 Gy + Saline
15.9 Gy + AVX-470m
GI ARS - jejunum tissue sections
No Radiation
•
7
AVX-470m (10 mg/day, BID by oral gavage) reduced TNF
protein levels in GI tissue in both IBD and GI ARS models
AVX-470m treatment reduces inflammatory
biomarkers in both IBD & GI ARS models
Response to injury
DSS-induced
colitis (colon)
TNF
↑
TNFR1*
↑
TNFR2*
↑
MPO
↑
MMP9*
↑
CD3
↑
CD68
↑
IL-1B
↑
IL-12p40
↑
ICAM-1 (qPCR)
↑
Biomarker
GI ARS
(jejunum)
↑
─
↑
↑
↑
─
─
↑
─
↑
+ AVX-470m
DSS-induced
GI ARS
colitis (colon) (jejunum)
↓
↓
─
─
─
─
↓
↓
↓
↓
─
─
↓
─
↓
─
↓
─
─
─
↓ 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.
8
AVX-470m penetrates GI mucosal barrier
Tissue sections stained for presence of bovine Ig
Normal
Control animal with AVX-470m
•
•
9
IBD model - colon
DSS with AVX-470m
GI ARS model - jejunum
15.9 Gy with AVX-470m
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
Conclusions
• DSS colitis and GI ARS share a common TNFmediated 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.
10
Acknowledgments
• Avaxia Biologics, Inc.
–
–
–
–
–
–
Barbara Fox, PhD
Dan Tracey, PhD
Kailash Bhol, PhD
Brenda Lemos
Emma Erlich
Dave Keane
DSS-induced colitis model
• Biomodels, LLC
– Steve Sonis, DMD, DMSc
– Greg Lyng, PhD
GI ARS model
• CiToxLAB North America
– Simon Authier, PhD
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
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