Preclinical In Vitro and In Vivo Characterization of the Fully Human Monoclonal IgM Antibody KBPA101 Specific for Pseudomonas aeruginosa Serotype IATS-O11
Preclinical In Vitro and In Vivo Characterization of the Fully Human Monoclonal IgM Antibody KBPA101 Specific for Pseudomonas aeruginosa Serotype IATS-O11
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DOI：
10.1128/aac.01142-09
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发表时间：
2010-06-01
影响因子：
4.9
通讯作者：
Lang, Alois B.
中科院分区：
文献类型：
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作者：
Horn, Michael P.;Zuercher, Adrian W.;Lang, Alois B.
呼吸机相关性肺炎中的铜绿假单胞菌感染是重症监护病房患者的严重且通常危及生命的并发症，需要新的治疗选择。我们使用来自用铜绿假单胞菌O-多糖-毒素A缀合物疫苗免疫的志愿者的富含B细胞的外周血淋巴细胞来产生对单个铜绿假单胞菌脂多糖血清型特异性的单克隆抗体的人杂交瘤细胞系。由这些细胞系之一分泌的全人单克隆抗体KBPA 101是一种IgM/κ抗体，其以高亲合力（5.81 x 10（7）M（-1）+/- 2.8 x 10（7）M（-1））结合国际抗原分型系统（IATS）血清型O 11的铜绿假单胞菌，而不与其他血清型发生交叉反应。KBPA 101特异性调理IATS O 11血清型的铜绿假单胞菌，并在非常低的浓度（半最大吞噬作用为0.16 ng/ml）下通过人单核细胞样细胞系HL-60介导体外补体依赖性吞噬作用。KBPA 101的体内评价证明了在鼠烧伤伤口脓毒症模型中针对全身感染的保护的剂量-反应关系，其中70 - 100%的动物在低至5 μ g/动物的剂量下针对铜绿假单胞菌的致死性攻击得到保护。此外，在小鼠的急性肺部感染模型中，KBPA 101在保护免于局部呼吸道感染方面的高功效被证明。对人体组织、家兔和小鼠的临床前毒理学评价未显示KBPA 101的任何毒性。基于这些临床前发现，第一个人类临床试验已经启动。
Pseudomonas aeruginosa infection in ventilator-associated pneumonia is a serious and often life-threatening complication in intensive care unit patients, and new treatment options are needed. We used B-cell-enriched peripheral blood lymphocytes from a volunteer immunized with a P. aeruginosa O-polysaccharide-toxin A conjugate vaccine to generate human hybridoma cell lines producing monoclonal antibodies specific for individual P. aeruginosa lipopolysaccharide serotypes. The fully human monoclonal antibody secreted by one of these lines, KBPA101, is an IgM/kappa antibody that binds P. aeruginosa of International Antigenic Typing System (IATS) serotype O11 with high avidity (5.81 x 10(7) M(-1) +/- 2.8 x 10(7) M(-1)) without cross-reacting with other serotypes. KBPA101 specifically opsonized the P. aeruginosa of IATS O11 serotype and mediated complement-dependent phagocytosis in vitro by the human monocyte-like cell line HL-60 at a very low concentration (half-maximal phagocytosis at 0.16 ng/ml). In vivo evaluation of KBPA101 demonstrated a dose-response relationship for protection against systemic infections in a murine burn wound sepsis model, where 70 to 100% of animals were protected against lethal challenges with P. aeruginosa at doses as low as 5 mu g/animal. Furthermore, a high efficacy of KBPA101 in protection from local respiratory infections in an acute lung infection model in mice was demonstrated. Preclinical toxicology evaluation on human tissue, in rabbits, and in mice did not indicate any toxicity of KBPA101. Based on these preclinical findings, the first human clinical trials have been initiated.