Petersen Kenneth Ahrend, Matthiesen Finn, Agger Teit, Kongerslev Leif, Thiel Steffen, Cornelissen Karen, Axelsen Mads
NatImmune A/S, Fruebjergvej 3, Box 3 DK-2100 , Copenhagen, Denmark.
J Clin Immunol. 2006 Sep;26(5):465-75. doi: 10.1007/s10875-006-9037-z. Epub 2006 Aug 9.
Mannan-binding lectin (MBL), a human plasma protein, plays an important role in the innate immune defence. MBL recognizes microorganisms through surface carbohydrate structures. Due to genetic polymorphisms, MBL plasma concentrations range from 5 to 10,000 ng/mL. Approximately 30% of the human population have low levels of MBL (below 500 ng/mL). MBL deficiency is associated with increased susceptibility to infections in immunosuppressed individuals, e.g., during chemotherapeutically induced neutropenia. Replacement therapy with MBL may be beneficial in this patient group, and recombinant human MBL (rhMBL) is in development as a novel therapeutic approach. To assess the safety, tolerability, and pharmacokinetics of rhMBL, a placebo-controlled double-blinded study was performed in MBL-deficient healthy male subjects. rhMBL was administered as both single intravenous (i.v.) infusions (0.01, 0.05, 0.1, and 0.5 mg/kg) and repeated i.v. infusions (0.1 or 0.3 mg/kg given at 3-day intervals). There were no difference in incidence and type of adverse events reported in the study between the groups of subjects receiving rhMBL and the placebo group. All adverse events reported as drug-related were mild and no serious adverse events were recorded. There were no clinically significant changes in laboratory evaluations, ECG or vital signs, and no anti-MBL antibodies were detected following rhMBL administration. After single i.v. doses of rhMBL the maximal plasma levels increased in a dose-dependent manner reaching a geometric mean of 9710 ng/mL+/-10.5% in the highest dose group (0.5 mg/kg), with an elimination half-life of approximately 30 h. No rhMBL accumulation in plasma was observed following repeat dosing. Administration of rhMBL restored the ability to activate the MBL pathway of the complement system without non-specific activation of the complement cascade. In conclusion, no safety or tolerability concern was raised following rhMBL administration no signs of immunogenicity detected, and an rhMBL plasma level judged sufficient to achieve therapeutic benefit (>1000 ng/mL) can be achieved.
甘露聚糖结合凝集素（MBL）是一种人类血浆蛋白，在先天性免疫防御中发挥重要作用。MBL通过表面碳水化合物结构识别微生物。由于基因多态性，MBL血浆浓度范围为5至10,000 ng/mL。大约30%的人群MBL水平较低（低于500 ng/mL）。MBL缺乏与免疫抑制个体（如化疗诱导的中性粒细胞减少期间）感染易感性增加有关。对该患者群体进行MBL替代治疗可能有益，重组人MBL（rhMBL）正在作为一种新型治疗方法进行研发。为评估rhMBL的安全性、耐受性和药代动力学，在MBL缺乏的健康男性受试者中进行了一项安慰剂对照双盲研究。rhMBL以单次静脉注射（i.v.）输注（0.01、0.05、0.1和0.5 mg/kg）和重复i.v.输注（0.1或0.3 mg/kg，每3天给药一次）的方式给药。接受rhMBL的受试者组与安慰剂组之间在研究中报告的不良事件发生率和类型没有差异。所有报告为与药物相关的不良事件均为轻度，未记录到严重不良事件。实验室评估、心电图或生命体征无临床显著变化，rhMBL给药后未检测到抗MBL抗体。单次静脉注射rhMBL剂量后，最大血浆水平呈剂量依赖性增加，最高剂量组（0.5 mg/kg）达到几何平均值9710 ng/mL±10.5%，消除半衰期约为30小时。重复给药后未观察到rhMBL在血浆中蓄积。rhMBL给药恢复了激活补体系统MBL途径的能力，而没有补体级联反应的非特异性激活。总之，rhMBL给药后未引起安全性或耐受性问题，未检测到免疫原性迹象，并且可以达到判断足以实现治疗益处（>1000 ng/mL）的rhMBL血浆水平。
