title: BL-7010 demonstrates specific binding to gliadin and reduces gluten-associated pathology in a chronic mouse model of gliadin sensitivity.
abstract: Celiac disease (CD) is an autoimmune disorder in individuals that carry DQ2 or DQ8 MHC class II haplotypes, triggered by the ingestion of gluten. There is no current treatment other than a gluten-free diet (GFD). We have previously shown that the BL-7010 copolymer poly(hydroxyethyl methacrylate-co-styrene sulfonate) (P(HEMA-co-SS)) binds with higher efficiency to gliadin than to other proteins present in the small intestine, ameliorating gliadin-induced pathology in the HLA-HCD4/DQ8 model of gluten sensitivity. The aim of this study was to investigate the efficiency of two batches of BL-7010 to interact with gliadin, essential vitamins and digestive enzymes not previously tested, and to assess the ability of the copolymer to reduce gluten-associated pathology using the NOD-DQ8 mouse model, which exhibits more significant small intestinal damage when challenged with gluten than HCD4/DQ8 mice. In addition, the safety and systemic exposure of BL-7010 was evaluated in vivo (in rats) and in vitro (genetic toxicity studies). In vitro binding data showed that BL-7010 interacted with high affinity with gliadin and that BL-7010 had no interaction with the tested vitamins and digestive enzymes. BL-7010 was effective at preventing gluten-induced decreases in villus-to-crypt ratios, intraepithelial lymphocytosis and alterations in paracellular permeability and putative anion transporter-1 mRNA expression in the small intestine. In rats, BL-7010 was well-tolerated and safe following 14 days of daily repeated administration of 3000 mg/kg. BL-7010 did not exhibit any mutagenic effect in the genetic toxicity studies. Using complementary animal models and chronic gluten exposure the results demonstrate that administration of BL-7010 is effective and safe and that it is able to decrease pathology associated with gliadin sensitization warranting the progression to Phase I trials in humans.
authors.affiliation: Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Justin L
authors.initials: JL
authors.lastname: McCarville
authors.affiliation: BioLineRx, Ltd., Jerusalem, Israel.
authors.forename: Yotam
authors.initials: Y
authors.lastname: Nisemblat
authors.affiliation: Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Galipeau
authors.affiliation: Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Jury
authors.affiliation: BioLineRx, Ltd., Jerusalem, Israel.
authors.forename: Rinat
authors.initials: R
authors.lastname: Tabakman
authors.affiliation: BioLineRx, Ltd., Jerusalem, Israel.
authors.forename: Ad
authors.initials: A
authors.lastname: Cohen
authors.affiliation: BioLineRx, Ltd., Jerusalem, Israel.
authors.forename: Esmira
authors.initials: E
authors.lastname: Naftali
authors.affiliation: BioLineRx, Ltd., Jerusalem, Israel.
authors.forename: Bela
authors.initials: B
authors.lastname: Neiman
authors.affiliation: BioLineRx, Ltd., Jerusalem, Israel.
authors.forename: Efrat
authors.initials: E
authors.lastname: Halbfinger
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Murray
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois and Chicago and Jesse Brown VA Medical Center, Chicago, Illinois, United States of America.
authors.forename: Arivarasu N
authors.initials: AN
authors.lastname: Anbazhagan
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois and Chicago and Jesse Brown VA Medical Center, Chicago, Illinois, United States of America.
authors.forename: Pradeep K
authors.initials: PK
authors.lastname: Dudeja
authors.affiliation: Chromatography Unit, Scientific Equipment Center, The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.
authors.forename: Alexander
authors.initials: A
authors.lastname: Varvak
authors.affiliation: Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zürich, Zürich, Switzerland.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Leroux
authors.affiliation: Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Elena F
authors.initials: EF
authors.lastname: Verdu
mesh_terms: D000818:Animals; D002446:Celiac Disease / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005903:Gliadin / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010539:Permeability; D011102:Polyhydroxyethyl Methacrylate / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D011137:Polystyrenes / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D051381:Rats; D018675:Toxicity Tests
chemical_list: D011137:Polystyrenes; C571891:poly(hydroxyethyl methacrylate-co-styrene sulfonate); D011102:Polyhydroxyethyl Methacrylate; D005903:Gliadin