title: Influence of antidrug antibodies on plectasin efficacy and pharmacokinetics.
abstract: Plectasin is a 4.4-kDa antimicrobial peptide with the potential to be a treatment of infections caused by gram-positive bacteria. Since plectasin is a large molecule compared to conventional antibiotics, the development of antidrug antibodies (ADAs) could be anticipated. The immunogenic properties of plectasin were assessed through immunization studies. In mice treated for 5 days with one to two daily subcutaneous doses of plectasin, no antibody response was observed. If the animals were immunized again, after a rest period, low levels of antibodies developed in approximately half the animals. Additionally, mice were immunized with plectasin in Freund's incomplete adjuvant (FIA). Ninety-two percent of these mice developed ADAs after repeated immunizations, with two-thirds having high levels of antibodies. An agar diffusion bioassay showed that sera from animals immunized with plectasin did not inhibit the efficacy of the drug, while hyperimmune sera from animals in which an immune response was provoked by immunization with plectasin in FIA reduced the efficacy of plectasin at the lowest concentration tested. Studies in the murine peritonitis model showed an excellent efficacy of plectasin for the treatment of Streptococcus pneumoniae infections both in naïve animals and in animals with ADAs. No difference in bacterial counts was seen when the animals were treated with plectasin at 2.5 mg/kg of body weight, a dose below the expected therapeutic level. When animals were treated with plectasin at 0.625 mg/kg, the effect was reduced but not neutralized in animals with high levels of ADAs. No animals showed signs of hypersensitivity or injection site reactions toward plectasin, and the half-life of the compound did not vary between animals with and without antibodies.
authors.affiliation: Novozymes A/S, Anti-Infective Discovery, Building 1A1.13, Krogshøjvej 36, Bagsvaerd DK-2880, Denmark. kbri@novozymes.com
authors.forename: Karoline Sidelmann
authors.initials: KS
authors.lastname: Brinch
authors.forename: Niels
authors.initials: N
authors.lastname: Frimodt-Møller
authors.forename: Niels
authors.initials: N
authors.lastname: Høiby
authors.forename: Hans-Henrik
authors.initials: HH
authors.lastname: Kristensen
mesh_terms: D000818:Animals; D000906:Antibodies / Q000097:blood / Q000502:physiology*; D005260:Female; D006207:Half-Life; D007114:Immunization; D051379:Mice; D010455:Peptides / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010538:Peritonitis / Q000188:drug therapy; D011008:Pneumococcal Infections / Q000188:drug therapy*
chemical_list: D000906:Antibodies; D010455:Peptides; C504857:plectasin
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