title: AG013, a mouth rinse formulation of Lactococcus lactis secreting human Trefoil Factor 1, provides a safe and efficacious therapeutic tool for treating oral mucositis.
abstract: Non-clinical studies, focusing on the pharmacodynamics (PD), pharmacokinetics (PK) and safety pharmacology of genetically modified Lactococcus lactis (L. lactis) bacteria, engineered to secrete human Trefoil Factor 1 (hTFF1), were performed to provide proof-of-concept for the treatment of oral mucositis (OM) patients. L. lactis strain sAGX0085 was constructed by stably inserting an htff1 expression cassette into the bacterial genome, and clinically formulated as a mouth rinse (coded AG013). PD studies, using different oral dosing regimens, were performed in a clinically relevant hamster model for radiation-induced OM. The PK profile was assessed in healthy hamsters and in hamsters with radiation-induced OM. In addition, in vitro and in vivo safety pharmacology studies were conducted, in pooled, complement-preserved human serum, and in neutropenic hamsters and rats respectively. Topical administration of L. lactis sAGX0085/AG013 to the oral mucosa significantly reduced the severity and course of radiation-induced OM. PK studies demonstrated that both living L. lactis bacteria, as well as the hTFF1 secreted, could be recovered from the administration site for maximum 24h post-dosing, without systemic exposure. The in vitro and in vivo safety pharmacology studies confirmed that L. lactis sAGX0085 could not survive in systemic circulation, not even under neutropenic conditions. The results from the PD, PK and safety pharmacology studies reported here indicate that in situ secretion of hTFF1 by topically administered L. lactis bacteria provides a safe and efficacious therapeutic tool for the prevention and treatment of OM.
authors.affiliation: ActoGeniX N.V., Technologiepark 4, B-9052 Ghent-Zwijnaarde, Belgium.
authors.forename: Silvia
authors.initials: S
authors.lastname: Caluwaerts
authors.forename: Klaas
authors.initials: K
authors.lastname: Vandenbroucke
authors.forename: Lothar
authors.initials: L
authors.lastname: Steidler
authors.forename: Sabine
authors.initials: S
authors.lastname: Neirynck
authors.forename: Peter
authors.initials: P
authors.lastname: Vanhoenacker
authors.forename: Sam
authors.initials: S
authors.lastname: Corveleyn
authors.forename: Brynmor
authors.initials: B
authors.lastname: Watkins
authors.forename: Stephen
authors.initials: S
authors.lastname: Sonis
authors.forename: Bernard
authors.initials: B
authors.lastname: Coulie
authors.forename: Pieter
authors.initials: P
authors.lastname: Rottiers
mesh_terms: D000818:Animals; D006224:Cricetinae; D006801:Humans; D013294:Lactococcus lactis / Q000378:metabolism*; D009067:Mouthwashes / Q000378:metabolism* / Q000493:pharmacokinetics; D010455:Peptides / Q000378:metabolism* / Q000493:pharmacokinetics; D051381:Rats; D013280:Stomatitis / Q000188:drug therapy*; D016896:Treatment Outcome; D000071164:Trefoil Factor-2
chemical_list: D009067:Mouthwashes; D010455:Peptides; D000071164:Trefoil Factor-2