title: Effects of AVX-470, an Oral, Locally Acting Anti-Tumour Necrosis Factor Antibody, on Tissue Biomarkers in Patients with Active Ulcerative Colitis.
abstract: OBJECTIVE
  AVX-470 is an orally administered, bovine-derived, anti-tumour necrosis factor (TNF) antibody with local activity in the gastrointestinal tract. In the first-in-human clinical trial of AVX-470 in active ulcerative colitis, we evaluated inflammatory biomarkers in colon tissue as measures of disease activity and early response to treatment.
  
  
  METHODS
  Thirty-six patients received active drug (AVX-470 at 0.2, 1.6 or 3.5g/day) or placebo over 4 weeks. Colon biopsy samples were collected from 5 regions of colon at baseline and week 4. Tissue inflammatory biomarkers were evaluated by immunohistochemistry and quantitative reverse transcription-polymerase chain reaction (qRT-PCR), epithelial cell apoptosis by terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) and bovine immunoglobulin by immunohistochemistry and mass spectrometry. Endoscopic activity (Ulcerative Colitis Endoscopic Index of Severity [UCEIS]) at colonoscopy was assessed in each colonic region by a central reader.
  
  
  RESULTS
  Bovine immunoglobulin was observed in mucosal tissue before and after dosing in lamina propria and submucosal layers of biopsy tissue. Baseline levels of TNF, myeloperoxidase (MPO), CD68 and interleukin (IL)-1β and, to a lesser extent, IL-6 mRNA were 2- to 3-fold higher in distal vs proximal colon tissue, corresponding to the 2- to 3-fold differences in baseline severities of endoscopic scores. Reductions of >10-fold in TNF and, to lesser extents, in MPO and epithelial cell apoptosis were observed in proximal and distal colon biopsies after 4 weeks of AVX-470 3.5g/day treatment. Reductions in TNF scores were correlated with changes in MPO and CD3 immunohistochemistry scores.
  
  
  CONCLUSIONS
  These results are consistent with anti-TNF activity of orally administered AVX-470 in colon mucosal tissue in ulcerative colitis patients and demonstrate the utility of tissue biomarkers in assessing disease and treatment response in early clinical studies.
  
  
  BACKGROUND
  This trial was registered with Clinicaltrials.gov as study NCT01759056 and with EudraCT as study 2012-004859-27.
authors.affiliation: Avaxia Biologics, Inc., Lexington, MA, USA.
authors.forename: Deborah S
authors.initials: DS
authors.lastname: Hartman
authors.affiliation: Avaxia Biologics, Inc., Lexington, MA, USA.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Tracey
authors.affiliation: Avaxia Biologics, Inc., Lexington, MA, USA.
authors.forename: Brenda R
authors.initials: BR
authors.lastname: Lemos
authors.affiliation: Avaxia Biologics, Inc., Lexington, MA, USA.
authors.forename: Emma C
authors.initials: EC
authors.lastname: Erlich
authors.affiliation: Avaxia Biologics, Inc., Lexington, MA, USA.
authors.forename: Randall E
authors.initials: RE
authors.lastname: Burton
authors.affiliation: Avaxia Biologics, Inc., Lexington, MA, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Keane
authors.affiliation: Avaxia Biologics, Inc., Lexington, MA, USA.
authors.forename: Rutvij
authors.initials: R
authors.lastname: Patel
authors.affiliation: Avaxia Biologics, Inc., Lexington, MA, USA.
authors.forename: Skaison
authors.initials: S
authors.lastname: Kim
authors.affiliation: Avaxia Biologics, Inc., Lexington, MA, USA.
authors.forename: Kailash C
authors.initials: KC
authors.lastname: Bhol
authors.affiliation: Avaxia Biologics, Inc., Lexington, MA, USA.
authors.forename: M Scott
authors.initials: MS
authors.lastname: Harris
authors.affiliation: Avaxia Biologics, Inc., Lexington, MA, USA bsfox@comcast.net.
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Fox
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D000906:Antibodies / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism*; D003093:Colitis, Ulcerative / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism; D003106:Colon / Q000378:metabolism*; D003113:Colonoscopy; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012720:Severity of Illness Index; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism; D055815:Young Adult
chemical_list: C588404:AVX-470; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000906:Antibodies; D015415:Biomarkers; D014409:Tumor Necrosis Factor-alpha
keywords: TNF; biomarkers; ulcerative colitis