Inflammatory bowel disease: exploring gut pathophysiology for novel therapeutic targets.

Ulcerative colitis and Crohn's disease are the 2 major phenotypes of inflammatory bowel disease (IBD), which are influenced by a complex interplay of immunological and genetic elements, though the precise etiology still remains unknown. With IBD developing into a globally prevailing disease, there is a need to explore new targets and a thorough understanding of the pathophysiological differences between the healthy and diseased gut could unearth new therapeutic opportunities. In this review, we provide an overview of the major aspects of IBD pathogenesis and thereafter present a comprehensive analysis of the gut pathophysiology leading to a discussion on some of the most promising targets and biologic therapies currently being explored.

Gastrointestinal stability of therapeutic anti-TNF α IgG1 monoclonal antibodies.

Monoclonal antibodies (mAbs) are highly effective therapeutic agents, administered exclusively by the parenteral route owing to their previously-documented instability in the gastrointestinal (GI) tract when delivered orally. To investigate the extent of the validity of this assumption, the stability of the tumor necrosis factor alpha (TNF-α) neutralizing IgG1 mAbs, infliximab and adalimumab, was studied in human GI conditions. In gastric fluid, infliximab and adalimumab degraded rapidly, with complete degradation occurring within 1 min.

Intranasal delivery of ESBA105, a TNF-alpha-inhibitory scFv antibody fragment to the brain.

Intranasal drug administration is an attractive route for targeted delivery of large molecular weight compounds to the central nervous system (CNS). The purpose of this study was to assess the feasibility of this non-invasive application method in mice, for delivery of ESBA105, a TNF-alpha inhibitory single-chain antibody fragment (scFv) with a molecular weight of 26.3kDa, to the brain.

Pharmacokinetics and posterior segment biodistribution of ESBA105, an anti-TNF-alpha single-chain antibody, upon topical administration to the rabbit eye.

Purpose: The purpose of this study was to characterize local distribution and systemic absorption of the tumor necrosis factor (TNF)-alpha inhibitory single-chain antibody fragment (scFv) ESBA105 following topical administration to the eye in vivo.

Methods: Rabbits received ESBA105 as topical eye drops in two dosing regimens. First, pharmacokinetics after the topical route of administration was compared to the intravenous (i.

Functional characterization of a NapA Na(+)/H(+) antiporter from Thermus thermophilus.

Na(+)/H(+) antiporters are ubiquitous membrane proteins and play an important role in cell homeostasis. We amplified a gene encoding a member of the monovalent cation:proton antiporter-2 (CPA2) family (TC 2.A.

Neutral amino acid transport mediated by ortholog of imino acid transporter SIT1/SLC6A20 in opossum kidney cells.

Most neutral l-amino acid acids are transported actively across the luminal brush-border membrane of small intestine and kidney proximal tubule epithelial cells by a Na(+) cotransport system named B(0) that has been recently molecularly identified (B(0)AT1, SLC6A19). We show here that the opossum kidney-derived cell line OK also displays a Na(+)-dependent B(0)-type neutral l-amino acid transport, although with a slightly differing substrate selectivity. We tested the hypothesis that one of the two B(0)AT1-related transporters, SLC6A18 (ortholog of orphan transporter XT2) or SLC6A20 (ortholog of the recently identified mammalian imino acid transporter SIT1), mediates this transport.

Inhibition of Borna disease virus-mediated cell fusion by monoclonal antibodies directed against the viral glycoprotein.

Borna disease virus-infected Vero cells express on their surface the major viral glycoprotein which mediates cell fusion after low pH treatment. This fusion event can be inhibited by monoclonal antibodies (mAbs) generated from chronically BDV-infected rats boosted with a recombinant vaccinia virus expressing the gp94 glycoprotein of BDV. Analysis of mAbs suggests specificity for the 43-kD C-terminal furin cleavage product of gp94 and provides evidence for the recognition of a conformational epitope.