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首页> 外文期刊>Antimicrobial agents and chemotherapy. >Influence of antidrug antibodies on plectasin efficacy and pharmacokinetics.
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Influence of antidrug antibodies on plectasin efficacy and pharmacokinetics.

机译：抗药物抗体对Plectasin功效和药代动力学的影响。

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摘要

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 naive 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.
机译：Plectasin是一种4.4 kDa的抗菌肽，具有治疗革兰氏阳性细菌引起的感染的潜力。由于与传统抗生素相比，Plectasin是一个大分子，因此可以预期会出现抗药物抗体（ADAs）。通过免疫研究评估了lectlectasin的免疫原性。在每天皮下注射一到两天的Plectasin治疗5天的小鼠中，未观察到抗体反应。如果在休息后再次对动物进行免疫，则大约一半的动物体内会产生低水平的抗体。此外，在弗氏不完全佐剂（FIA）中用Plectasin免疫小鼠。这些小鼠中有92％在反复免疫后发展了ADA，其中三分之二具有高水平的抗体。琼脂扩散生物测定法显示，用Plectasin免疫的动物血清不会抑制药物的功效，而在FIA中用Plectasin免疫引起免疫应答的动物的超免疫血清则在最低的测试浓度下降低了Plectasin的功效。鼠腹膜炎模型的研究表明，Plectasin可以治疗幼稚动物和ADAs动物中的肺炎链球菌感染。当用2.5 mg / kg体重的Plectasin处理动物（低于预期的治疗水平）时，细菌计数无差异。当用浓度为0.625 mg / kg的Plectasin处理动物时，在ADAs高的动物中，这种作用减弱但未被中和。没有动物表现出对Plectasin过敏或注射部位反应的迹象，并且该化合物的半衰期在有抗体和无抗体的动物之间没有变化。

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