LFA-3/IgG1融合蛋白LFA3TIP的免疫调节作用:细胞系依赖糖基化对药代动力学和药效学标志物的影响

Therapeutic immunology Pub Date : 1995-06-01
W Meier, A Gill, M Rogge, R Dabora, G R Majeau, F B Oleson, W E Jones, D Frazier, K Miatkowski, P S Hochman
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引用次数: 0

摘要

LFA3TIP是一种融合蛋白,由LFA-3的第一个胞外结构域与人IgG1的铰链、CH2和CH3结构域融合而成,在体外抑制人和非人灵长类动物T细胞的应答。为了优化LFA3TIP的表达效率,制备大量用于灵长类动物研究的LFA3TIP蛋白,我们在CHO(中国仓鼠卵巢)和小鼠NS-0骨髓瘤细胞系中制备了该蛋白。尽管来自这些细胞系的LFA3TIP在体外CD2受体结合和T细胞试验中表现相同,但在给狒狒注射等量NS-0或CHO衍生的LFA3TIP后,药效学标记物CD2+淋巴细胞数量减少,表明NS-0衍生材料的效果不太持续。对材料在狒狒和小鼠体内的药代动力学分析表明,相对于CHO细胞的产物,NS-0细胞产生的LFA3TIP在循环中被迅速清除。不同的清除谱与不同的糖基化模式相关,来自NS-0细胞的LFA3TIP比来自CHO细胞的LFA3TIP更不广泛的唾液化,部分原因是NS-0衍生的LFA3TIP的n -连接聚糖中选择的乳糖胺部分的α -半乳糖盖顶。此外,CHO衍生的LFA3TIP的酶解脱盐作用导致小鼠和狒狒血清中的糖蛋白消失。这些结果将n -乙酰神经氨酸封顶的程度与来自两种不同细胞系的LFA3TIP清除率联系起来,并强调了在选择用于重组免疫治疗的生产细胞系时评估糖基化依赖的PK参数的重要性。
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Immunomodulation by LFA3TIP, an LFA-3/IgG1 fusion protein: cell line dependent glycosylation effects on pharmacokinetics and pharmacodynamic markers.

LFA3TIP, a fusion protein comprised of the first extracellular domain of LFA-3 fused to the hinge, CH2, and CH3 domains of human IgG1 inhibits responses of human and non-human primate T cells in vitro. In seeking to optimize the expression efficiency to prepare large quantities of LFA3TIP for primate studies, the protein was produced in both the CHO (Chinese hamster ovary) and murine NS-0 myeloma cell lines. Although LFA3TIP derived from these cell lines performs identically in vitro in CD2 receptor binding and T cell assays, examination of a pharmacodynamic marker-the reduction in CD2+ lymphocyte numbers-following the administration of equal doses of NS-0 or CHO derived LFA3TIP to baboons, suggested that the effect of the NS-0 derived material was less sustained. Pharmacokinetic analysis of the materials in baboons and mice shows that LFA3TIP produced by NS-0 cells is rapidly cleared from circulation relative to the product derived from CHO cells. The disparate clearance profiles correlate with distinct glycosylation patterns, with LFA3TIP derived from NS-0 cells being less extensively sialylated than that from CHO cells due in part to alpha-galactosyl capping of selected lactosamine moieties in the N-linked glycans of NS-0 derived LFA3TIP. Moreover, enzymatic desialylation of CHO derived LFA3TIP results in a glycoprotein with an evanescent serum profile when administered to mice and baboons. These results correlate the extent of N-acetylneuraminic acid capping with the clearance rates of LFA3TIP derived from the two distinct cell lines, and underscore the importance of evaluating glycosylation dependent PK parameters when choosing production cell lines for recombinant immunotherapeutics.

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