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.

Synergistic interactions between antimicrobial peptides derived from plectasin and lipid nanocapsules containing monolaurin as a cosurfactant against <em>Staphylococcus aureus</em>

“…6,7,[9][10][11][12] AP138 is the product of an extensive lead optimization program based on a set of in silico generated plectasin variants. 13 In most cases, the single best antimicrobial agent should be selected for use because this minimizes side effects.…”

Esculentin-1a-Derived Peptides Promote Clearance of Pseudomonas aeruginosa Internalized in Bronchial Cells of Cystic Fibrosis Patients and Lung Cell Migration: Biochemical Properties and a Plausible Mode of Action

“…Intracellular persistence of bacteria that spread into the respiratory tract of CF patients may be one of the reasons responsible for the chronic nature of P. aeruginosa lung infections (17). It protects the bacteria from the host defense mechanisms and from the killing action of conventional antibiotics that hardly enter epithelial cells (28). Hence, the discovery of new antibiotics with new modes of action is highly demanding, and naturally occurring antimicrobial peptides (AMPs) represent potential alternatives (29,30).…”

Efficacy of NZ2114, a Novel Plectasin-Derived Cationic Antimicrobial Peptide Antibiotic, in Experimental Endocarditis Due to Methicillin-Resistant Staphylococcus aureus

“…However, plectasin has a novel mode of antimicrobial action, specifically binding to the key bacterial cell wall precursor, lipid II (21), and thereby interfering with bacterial cell wall biosynthesis. NZ2114 is a new variant of plectasin with improved in vitro activity against staphylococci and streptococci, including those resistant to clinically available antibiotics (1,4,5,(19)(20)(21). Recent studies suggested that NZ2114 has potent activities both in vitro and in a number of animal models, including rabbit meningitis, murine peritonitis, and thigh infections and against various strains of Staphylococcus aureus and of Streptococcus pneumoniae (1,5,20).…”