A therapeutic human IgG4 monoclonal antibody that depletes target cells in humans
A therapeutic human IgG4 monoclonal antibody that depletes target cells in humans
复制标题
DOI：
10.1046/j.1365-2249.1996.d01-876.x
复制
发表时间：
1996-12-01
影响因子：
4.6
通讯作者：
Waldmann, H
中科院分区：
文献类型：
--
作者：
Isaacs, JD;Wing, MG;Waldmann, H
传统上认为，人IgG 4单克隆抗体不应在体内耗尽靶细胞，因为这种同种型在许多测量效应子功能的体外测定中是无活性的。我们以前曾挑战过这一教条，目前的研究旨在研究人IgG 4同种型单克隆抗体在人体内的生物学效应。9例符合ARA标准的难治性类风湿性关节炎（RA）患者和1例强直性脊柱炎（AS）患者接受了人IgG 4 Campath-1单克隆抗体（对泛淋巴细胞抗原CD 52具有特异性）作为两阶段治疗方案的一部分。在第1阶段，患者接受单剂量的这种单克隆抗体。第2阶段，48小时后开始，包括5天的人IgG 1 Campath-1单克隆抗体与相同的V区（CAMPATH-1H），如以前在RA患者的管理。间隔48 h提供了监测IgG 4 MoAb生物学效应的机会窗口，以便与IgG 1进行比较。还比较了两种单克隆抗体的体外生物活性。IgG 4耗尽外周血淋巴细胞（PBL），尽管效率低于IgG 1。它产生了类似强度的首次给药反应，尽管相关的循环肿瘤坏死因子-α（TNF-α）水平较低。TNF-α从全血中的体外释放也更大的IgG 1单克隆抗体。研究设计不允许得出关于IgG 4 MoAb治疗有效性的结论。总之，人IgG 4 Campath-1 MoAb在体内耗尽靶细胞。重要的是，这项研究首次在人体中证明，体外试验可能无法预测治疗性MoAb的体内效应器功能。
It is traditionally held that human IgG4 MoAbs should not deplete target cells in vivo, as this isotype is inactive in a number of in vitro assays that measure effector function. We have previously challenged this dogma, and the current study was designed to investigate the in vivo biological effects in humans of a MoAb of human IgG4 isotype. Nine patients with refractory rheumatoid arthritis (RA) fulfilling ARA criteria, and one with ankylosing spondylitis (AS) received a human IgG4 Campath-1 MoAb (with specificity against the pan-lymphocyte antigen CD52) as part of a two-stage therapeutic protocol. In stage 1, patients received a single dose of this MoAb. Stage 2, starting 48 h later, comprised a 5-day course of a human IgG1 Campath-1 MoAb with identical V-region (CAMPATH-1H), as previously used in the management of RA patients. The intervening 48 h provided a window of opportunity to monitor the biological effects of the IgG4 MoAb for comparison with the IgG1. The two MoAbs were also compared for in vitro biological activity. IgG4 depleted peripheral blood lymphocytes (PBL), albeit less efficiently than IgG1. It produced a first-dose reaction of similar intensity, although associated circulating tumour necrosis factor-alpha (TNF-alpha) levels were lower. TNF-alpha release from whole blood in vitro was also greater with the IgG1 MoAb. The study design did not permit conclusions to be drawn regarding therapeutic efficacy of the IgG4 MoAb. In summary, a human IgG4 Campath-1 MoAb depletes target cells in vivo. Importantly, this study demonstrates for the first time in humans that in vitro assays may not predict the in vivo effector function of therapeutic MoAbs.