AVX-470: a novel oral anti-TNF antibody with therapeutic potential in inflammatory bowel disease.
BACKGROUND
Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract, which is currently treated with injected monoclonal antibodies specific for tumor necrosis factor (TNF). We developed and characterized AVX-470, a novel polyclonal antibody specific for human TNF. We evaluated the oral activity of AVX-470m, a surrogate antibody specific for murine TNF, in several well-accepted mouse models of IBD.


METHODS
AVX-470 and AVX-470m were isolated from the colostrum of dairy cows that had been immunized with TNF. The potency, specificity, and affinity of both AVX-470 and AVX-470m were evaluated in vitro and compared with infliximab. AVX-470m was orally administered to mice either before or after induction of colitis, and activity was measured by endoscopy, histopathology, immunohistochemistry, and quantitative measurement of messenger RNA levels. Colitis was induced using either 2,4,6-trinitrobenzene sulfonate or dextran sodium sulfate.


RESULTS
AVX-470 and AVX-470m were shown to be functionally comparable in vitro. Moreover, the specificity, neutralizing potency, and affinity of AVX-470 were comparable with infliximab. Orally administered AVX-470m effectively reduced disease severity in several mouse models of IBD. Activity was comparable with that of oral prednisolone or parenteral etanercept. The antibody penetrated the colonic mucosa and inhibited TNF-driven mucosal inflammation with minimal systemic exposure.


CONCLUSIONS
AVX-470 is a novel polyclonal anti-TNF antibody with an in vitro activity profile comparable to that of infliximab. Oral administration of a surrogate antibody specific for mouse TNF is effective in treating mouse models of IBD, delivering the anti-TNF to the site of inflammation with minimal systemic exposure.
*Avaxia Biologics, Inc., Lexington, Massachusetts; †Biomodels, LLC, Watertown, Massachusetts; and ‡Xtal BioStructures, Natick, Massachusetts.
Kailash C
KC
Bhol
Daniel E
DE
Tracey
Brenda R
BR
Lemos
Gregory D
GD
Lyng
Emma C
EC
Erlich
David M
DM
Keane
Michael S
MS
Quesenberry
Amy D
AD
Holdorf
Lisa D
LD
Schlehuber
Shawn A
SA
Clark
Barbara S
BS
Fox
D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000906:Antibodies / Q000008:administration & dosage* / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015153:Blotting, Western; D002417:Cattle; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007124:Immunoenzyme Techniques; D007074:Immunoglobulin G / Q000008:administration & dosage* / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D000069285:Infliximab; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000276:immunology
C588404:AVX-470; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000906:Antibodies; D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D014302:Trinitrobenzenesulfonic Acid; D016264:Dextran Sulfate; D000069285:Infliximab