Purpose

Streptococcus pneumoniae (Spn) serotype 3 (Spn3) is considered one of the most virulent serotypes with resistance to conventional vaccine and treatment regimens. Pn3Pase is a glycoside hydrolase that we have previously shown to be highly effective in degrading the capsular polysaccharide of type 3 Spn, sensitizing it to host immune clearance. To begin assessing the value and safety of this enzyme for future clinical studies, we investigated the effects of high doses of Pn3Pase on host cells and immune system.

Methods

We assessed the enzyme’s catalytic activity following administration in mice, and performed septic infection models to determine if prior administration of the enzyme inhibited repeat treatments of Spn3-challenged mice. We assessed immune populations in mouse tissues following administration of the enzyme, and tested Pn3Pase toxicity on other mammalian cell types in vitro.

Results

Repeated administration of the enzyme in vivo does not prevent efficacy of the enzyme in promoting bacterial clearance following bacterial challenge, with insignificant antibody response generated against the enzyme. Immune homeostasis is maintained following high-dose treatment with Pn3Pase, and no cytotoxic effects were observed against mammalian cells.

Conclusions

These data indicate that Pn3Pase has potential as a therapy against Spn3. Further development as a drug product could overcome a great hurdle of pneumococcal infections.

中文翻译：

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3型肺炎链球菌胶囊降解酶Pn3Pase的治疗活性

目的

肺炎链球菌(Spn) 血清型 3 (Spn3) 被认为是对常规疫苗和治疗方案具有抗性的最致命的血清型之一。Pn3Pase 是一种糖苷水解酶，我们之前已经证明它在降解 3 型 Spn 的荚膜多糖方面非常有效，使其对宿主免疫清除敏感。为了开始评估这种酶对未来临床研究的价值和安全性，我们研究了高剂量 Pn3Pase 对宿主细胞和免疫系统的影响。

方法

我们评估了该酶在小鼠体内给药后的催化活性，并进行了脓毒症感染模型，以确定先前施用该酶是否会抑制 Spn3 攻击小鼠的重复治疗。我们在施用酶后评估了小鼠组织中的免疫群体，并在体外测试了 Pn3Pase 对其他哺乳动物细胞类型的毒性。

结果

体内重复施用酶不会阻止酶在细菌攻击后促进细菌清除的功效，产生的针对酶的抗体反应微不足道。在用 Pn3Pase 进行高剂量处理后，免疫稳态得以维持，并且未观察到对哺乳动物细胞的细胞毒性作用。

结论

这些数据表明 Pn3Pase 具有作为针对 Spn3 的治疗的潜力。作为药物产品的进一步开发可以克服肺炎球菌感染的一大障碍。