Department of Medicine, Infectious Disease Division, Stony Brook Universitygrid.36425.36, Stony Brook, New York, USA.
Veteran's Administration Medical Center, Northport, New York, USA.
Microbiol Spectr. 2022 Aug 31;10(4):e0176022. doi: 10.1128/spectrum.01760-22. Epub 2022 Jul 11.
The most pressing challenge for the development of anti-capsular antibodies is maximizing coverage against the heterogenous capsular polysaccharide (CPS) of carbapenem-resistant Klebsiella pneumoniae (CR-). So far, only CR- with CPS has been successfully targeted by antibodies. Here, we present murine antibody 24D11, which was developed by vaccinating mice with purified -type CPS. Cross-reactivity and protective efficacy of MAb 24D11 were confirmed against CR- that express the 3 most prevalent CPS types (, , ) using both and infection models. 24D11 induced complement-mediated and independent opsonophagocytosis in macrophages as well as killing of all CR- strains in whole blood cells derived from healthy donors. In a murine intratracheal infection model, 24D11 reduced lung burden and dissemination of CR- strains when administered 4 h pre- or postinfection. The protective efficacy of 24D11 remained effective in neutropenic mice. This is the first antibody which exhibits cross-protective efficacy against clade 1 and 2 ST258 CR- strains. It overcomes a major barrier to successfully target , a major CPS expressed by ST258 CR-. The finding that 24D11 also exhibits potent protective efficacy against CR- strains highlights its high potential as a lead agent for the development of broadly active immunotherapy. Here, we present and data for the CPS-specific monoclonal antibody MAb 24D11, demonstrating its cross-protective efficacy against three prominent types (, , and ) of the carbapenem-resistant clonal group CG258. In a murine pulmonary infection model, MAb 24D11 reduced bacterial lung burden and dissemination to other organs even if administered 4 h postinfection. Its protective efficacy was also observed in neutropenic mice, which highlights its potential value in clinical settings where oncology patients with CG258 infections may also be neutropenic.
开发抗荚膜抗体最紧迫的挑战是最大限度地覆盖对碳青霉烯类耐药肺炎克雷伯菌（CR-）异质荚膜多糖（CPS）的覆盖。到目前为止，只有具有 CPS 的 CR- 已被抗体成功靶向。在这里，我们介绍了通过用纯化的 - 型 CPS 免疫小鼠而开发的鼠抗体 24D11。使用 和 感染模型，我们证实了 MAb 24D11 对表达 3 种最常见 CPS 类型（， ， ）的 CR- 的交叉反应性和保护效力。24D11 在巨噬细胞中诱导补体介导和独立的调理吞噬作用，并在来自健康供体的全血细胞中杀死所有 CR- 菌株。在小鼠气管内感染模型中，24D11 在感染前或感染后 4 小时给药时可降低 CR- 菌株的肺部负担和传播。24D11 在中性粒细胞减少小鼠中的保护效力仍然有效。这是第一种对 1 型和 2 型 ST258 CR- 菌株表现出交叉保护效力的抗体。它克服了成功靶向 的主要障碍， 是 ST258 CR- 表达的主要 CPS。发现 24D11 对 CR- 菌株也表现出强大的保护效力，突出了其作为广泛活性免疫治疗开发的潜在主要候选药物的高潜力。在这里，我们介绍了针对 CPS 特异性单克隆抗体 MAb 24D11 的 和 数据，证明了其对三种主要的碳青霉烯类耐药克隆群 CG258 型（， ，和 ）的交叉保护效力。在小鼠肺部感染模型中，即使在感染后 4 小时给药，MAb 24D11 也可降低细菌肺部负担和向其他器官的传播。在中性粒细胞减少小鼠中也观察到其保护效力，这突出了其在临床环境中的潜在价值，患有 CG258 感染的肿瘤患者也可能中性粒细胞减少。
