A novel protocol allowing oral delivery of a protein complement inhibitor that subsequently targets to inflamed colon mucosa and ameliorates murine colitis

Abstract

SummaryWhile 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.

New Insights on Complement Inhibitor CD59 in Mouse Laser-Induced Choroidal Neovascularization: Mislocalization After Injury and Targeted Delivery for Protein Replacement

“…2). Importantly, as was shown with other CR2-fusion protein, 27,28 unaffected tissues such as the spleen did not bind CR2-CD59.…”

“…22,23 These CR2-based inhibitors have been shown to be effective in many different tissues, including spinal cord 24 and the brain, 25 and colocalization between CR2-fusion proteins and opsonins has been documented. Injury-specific targeting has been shown with all the CR2-fusion proteins made to date (CR2-fH, 26 CR2-Crry, 27 and CR2-CD59 28 ), with labeled CR2-fusion protein accumulating only in the diseased tissues and not in unaffected tissues.…”

C5a stimulates the proliferation of breast cancer cells via Akt-dependent RGC-32 gene activation

“…However, the mechanism by which breast cancer cells undergo proliferation still remains controversial. Complement is known to play important roles as a first defense against microbes, and also participates in diverse physiological processes and contributes to various immune and inflammatory diseases (4,(33)(34)(35). In addition, there is increasing evidence for the contribution of complement activation to cancer progression (12,16).…”

“…It is well established that the human complement system is a central part of the innate immune response. Complement is known to play a major role as a first defense against microbes (1,2), and also participates in diverse physiological processes and contributes to various immune and inflammatory diseases (3)(4)(5)(6). There are three conventional mechanisms of complement activation, known as the classical, lectin and alternative pathways (7,8).…”

The relative merits of therapies being developed to tackle inappropriate (‘self’-directed) complement activation

“…Formulations for transdermal or transmucosal administration generally include penetrants such as fusidic acid or bile salts in combination with detergents or surface-active agents [ 64 ]. The formulations can then be manufactured as aerosols, suppositories or patches which give the inhibitors a longer half-life and subsequently longer clearance [ 4 , 65 ]. Autoimmune diseases are often chronic, requiring lifelong care and monitoring, even when the person may look or feel well [ 8 , 10 ].…”