title: A novel protocol allowing oral delivery of a protein complement inhibitor that subsequently targets to inflamed colon mucosa and ameliorates murine colitis.
abstract: While there is evidence of a pathogenic role for complement in inflammatory bowel disease, there is also evidence for a protective role that relates to host defence and protection from endotoxaemia. There is thus concern regarding the use of systemic complement inhibition as a therapeutic strategy. Local delivery of a complement inhibitor to the colon by oral administration would ameliorate such concerns, but while formulations exist for oral delivery of low molecular weight drugs to the colon, they have not been used successfully for oral delivery of proteins. We describe a novel pellet formulation consisting of cross-linked dextran coated with an acrylic co-polymer that protects the complement inhibitor CR2-Crry from destruction in the gastrointestinal tract. CR2-Crry containing pellets administered by gavage, were characterized using a therapeutic protocol in a mouse model of dextran sulphate sodium (DSS)-induced colitis. Oral treatment of established colitis over a 5-day period significantly reduced mucosal inflammation and injury, with similar therapeutic benefit whether or not the proton pump inhibitor, omeprazole, was co-administered. Reduction in injury was associated with the targeting of CR2-Crry to the mucosal surface and reduced local complement activation. Treatment had no effect on systemic complement activity. This novel method for oral delivery of a targeted protein complement inhibitor will reduce systemic effects, thereby decreasing the risk of opportunistic infection, as well as lowering the required dose and treatment cost and improving patient compliance. Furthermore, the novel delivery system described here may provide similar benefits for administration of other protein-based drugs, such as anti-tumour necrosis factor-α antibodies.
authors.affiliation: Department of Microbiology and Immunology, Darby Children's Research Institute, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: M
authors.initials: M
authors.lastname: Elvington
authors.forename: P
authors.initials: P
authors.lastname: Blichmann
authors.forename: F
authors.initials: F
authors.lastname: Qiao
authors.forename: M
authors.initials: M
authors.lastname: Scheiber
authors.forename: C
authors.initials: C
authors.lastname: Wadsworth
authors.forename: I
authors.initials: I
authors.lastname: Luzinov
authors.forename: J
authors.initials: J
authors.lastname: Lucero
authors.forename: A
authors.initials: A
authors.lastname: Vertegel
authors.forename: S
authors.initials: S
authors.lastname: Tomlinson
mesh_terms: D000284:Administration, Oral; D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology*; D003106:Colon / Q000187:drug effects* / Q000276:immunology* / Q000473:pathology; D003167:Complement Activation / Q000187:drug effects / Q000276:immunology; D003169:Complement Inactivator Proteins / Q000008:administration & dosage*; D003165:Complement System Proteins / Q000276:immunology*; D016264:Dextran Sulfate / Q000009:adverse effects; D004195:Disease Models, Animal; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000276:immunology; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000276:immunology* / Q000473:pathology; D051379:Mice; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage
chemical_list: C527099:CR2-Crry fusion protein, mouse; D003169:Complement Inactivator Proteins; D011993:Recombinant Fusion Proteins; D003165:Complement System Proteins; D016264:Dextran Sulfate
keywords: colitis; complement; mouse model; oral delivery
references.citation: J Biol Chem. 2006 Dec 22;281(51):39088-95
references.pmid: 17068344
references.citation: Gut. 1989 Mar;30(3):361-6
references.pmid: 2707635
references.citation: J Clin Biochem Nutr. 2013 Jan;52(1):72-5
references.pmid: 23341701
references.citation: Gastroenterology. 1989 Jul;97(1):10-9
references.pmid: 2498144
references.citation: J Immunol. 2008 Dec 1;181(11):8068-76
references.pmid: 19017999
references.citation: J Immunol. 2003 Nov 15;171(10):5514-20
references.pmid: 14607958
references.citation: N Engl J Med. 1990 May 10;322(19):1345-9
references.pmid: 2325733
references.citation: Am J Gastroenterol. 2013 Aug;108(8):1268-76
references.pmid: 23649185
references.citation: J Immunol. 2004 Mar 15;172(6):3836-41
references.pmid: 15004190
references.citation: Lab Invest. 2011 Mar;91(3):472-83
references.pmid: 21102504
references.citation: Therap Adv Gastroenterol. 2013 Jul;6(4):269-93
references.pmid: 23814608
references.citation: Inflamm Bowel Dis. 2009 Dec;15(12):1812-23
references.pmid: 19714742
references.citation: Acta Pharm Nord. 1991;3(1):41-4
references.pmid: 1713035
references.citation: Gut. 1998 Apr;42(4):522-9
references.pmid: 9616315
references.citation: Gut. 2007 Jan;56(1):2-5
references.pmid: 17172582
references.citation: Int J Mol Med. 2005 Oct;16(4):605-8
references.pmid: 16142393
references.citation: PLoS One. 2013 Apr 26;8(4):e62257
references.pmid: 23638016
references.citation: Adv Exp Med Biol. 2013;735:137-54
references.pmid: 23402024
references.citation: Lab Invest. 1995 May;72(5):587-91
references.pmid: 7538183
references.citation: J Immunol. 2012 Jun 15;188(12):6309-18
references.pmid: 22566568
references.citation: Int J Pharm. 2009 Jan 5;365(1-2):69-76
references.pmid: 18804521
references.citation: J Control Release. 1999 Mar 29;58(2):215-22
references.pmid: 10053194
references.citation: J Clin Invest. 2005 Sep;115(9):2444-53
references.pmid: 16127466
references.citation: Gut. 1992 Jul;33(7):902-8
references.pmid: 1379568
references.citation: Clin Exp Immunol. 1996 May;104(2):286-92
references.pmid: 8625522
references.citation: Hum Pathol. 1999 Dec;30(12):1427-30
references.pmid: 10667419
references.citation: Pharm Res. 1989 Dec;6(12):995-9
references.pmid: 2622863
references.citation: Immunol Res. 1991;10(3-4):485-92
references.pmid: 1955776
references.citation: Am J Physiol Gastrointest Liver Physiol. 2010 Jun;298(6):G878-83
references.pmid: 20338925