Characterization of the biological anti-staphylococcal functionality of hUK-66 IgG1, a humanized monoclonal antibody as substantial component for an immunotherapeutic approach
Characterization of the biological anti-staphylococcal functionality of hUK-66 IgG1, a humanized monoclonal antibody as substantial component for an immunotherapeutic approach
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DOI：
10.4161/hv.27692
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发表时间：
2014-04-01
影响因子：
4.8
通讯作者：
Ohlsen, Knut
中科院分区：
文献类型：
--
作者：
Oesterreich, Babett;Lorenz, Birgit;Ohlsen, Knut
针对金黄色葡萄球菌的多抗原免疫治疗方法，如果用于联合治疗，预计将有最大的临床成功机会，可能包括光学杀菌和毒素中和。我们最近报道了一种针对免疫优势葡萄球菌抗原A(ISAA)的鼠源性单抗，该抗体在金黄色葡萄球菌实验感染模型中显示出高效的金黄色葡萄球菌杀伤力。如果要将ISAA特异性抗体用作人类联合治疗的一个组成部分，必须保留人源化变体的结合特异性和生物活性。在这里，我们描述了人源化的单抗IgG1变异体Huk-66的功能特征。人源化抗体表现出与其亲本小鼠相似的结合动力学，并识别临床相关金黄色葡萄球菌谱系表面的靶抗原IsaA。此外，HUK-66增强了对健康受试者、易患葡萄球菌感染的患者(如糖尿病和透析患者)以及患有全身性动脉闭塞疾病的患者的全血(生理环境)样本中金黄色葡萄球菌的杀灭作用，这些患者表明不会与现有的天然抗体产生干扰。综上所述，这些数据表明，Huk-66即使在高危患者中也能介导细菌杀灭，因此，可以在免疫治疗策略中发挥作用，以对抗严重的金黄色葡萄球菌感染。
Multi-antigen immunotherapy approaches against Staphylococcus aureus are expected to have the best chance of clinical success when used in combinatorial therapy, potentially incorporating opsonic killing of bacteria and toxin neutralization. We recently reported the development of a murine monoclonal antibody specific for the immunodominant staphylococcal antigen A (IsaA), which showed highly efficient staphylococcal killing in experimental infection models of S. aureus. If IsaA-specific antibodies are to be used as a component of combination therapy in humans, the binding specificity and biological activity of the humanized variant must be preserved. Here, we describe the functional characterization of a humanized monoclonal IgG1 variant designated, hUK-66. The humanized antibody showed comparable binding kinetics to those of its murine parent, and recognized the target antigen IsaA on the surface of clinically relevant S. aureus lineages. Furthermore, hUK-66 enhances the killing of S. aureus in whole blood (a physiological environment) samples from healthy subjects and patients prone to staphylococcal infections such as diabetes and dialysis patients, and patients with generalized artery occlusive disease indicating no interference with already present natural antibodies. Taken together, these data indicate that hUK-66 mediates bacterial killing even in high risk patients and thus, could play a role for immunotherapy strategies to combat severe S. aureus infections.