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Antimicrobial Agents and Chemotherapy, November 2009, p. 4794-4800, Vol. 53, No. 11
0066-4804/09/$08.00+0     doi:10.1128/AAC.00440-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Influence of Antidrug Antibodies on Plectasin Efficacy and Pharmacokinetics{triangledown}

Karoline Sidelmann Brinch,1* Niels Frimodt-Møller,2 Niels Høiby,3 and Hans-Henrik Kristensen1

Novozymes A/S, Anti-Infective Discovery, Krogshøjvej 36, Bagsværd DK-2880, Denmark,1 National Center for Antimicrobials and Infection Control, Statens Serum Institut, Artillerivej 5, Copenhagen S DK-2300, Denmark,2 Department of Clinical Microbiology, Rigshospitalet, University of Copenhagen, Juliane Maries Vej 22, Copenhagen Ø DK-2100, Denmark3

Received 1 April 2009/ Returned for modification 1 June 2009/ Accepted 7 August 2009

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.

* Corresponding author. Mailing address: Novozymes A/S, Anti-Infective Discovery, Building 1A1.13, Krogshøjvej 36, Bagsværd DK-2880, Denmark. Phone: 45 4446 4787. Fax: 45 4446 3233. E-mail: kbri{at}novozymes.com

{triangledown} Published ahead of print on 17 August 2009.

Antimicrobial Agents and Chemotherapy, November 2009, p. 4794-4800, Vol. 53, No. 11
0066-4804/09/$08.00+0     doi:10.1128/AAC.00440-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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