Complement Activation and Intraventricular Rituximab Distribution in Recurrent Central Nervous System Lymphoma
Complement Activation and Intraventricular Rituximab Distribution in Recurrent Central Nervous System Lymphoma
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DOI：
10.1158/1078-0432.ccr-13-0474
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发表时间：
2014-02-15
影响因子：
11.5
通讯作者：
Rubenstein, James L.
中科院分区：
文献类型：
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作者：
Kadoch, Cigall;Li, Jing;Rubenstein, James L.
目的：阐明鞘内注射利妥昔单抗疗效的机制基础。我们评估了参加两项 1 期多中心研究的患者的补体激活以及心室内利妥昔单抗的药代动力学。实验设计：我们评估了补体激活作为中枢神经系统 (CNS) 内利妥昔单抗的候选介质。脑室内给予利妥昔单抗后，通过 ELISA 对连续脑脊液 (CSF) 标本中的补体 C3 和 C5b-9 进行定量。我们确定了脑脊液和血清中的利妥昔单抗浓度分布。建立了群体三室药代动力学模型来描述心室内给药后利妥昔单抗的处置。该模型源自第一次试验的结果，并用第二次试验的结果进行验证。结果：脑室内注射利妥昔单抗后，CSF 中的补体 C3 和 C5b-9 可重复激活。 CNS 淋巴瘤病灶内 C3 mRNA 和蛋白的异位表达局限于骨髓细胞。基线时 C3 的持续高激活与不良预后相关。建立了包含三个不同区室的药代动力学模型，以描述脑室内给药后利妥昔单抗在神经轴内的分布。结论：我们提供了脑室内免疫治疗神经轴内 C3 激活的第一个证据，并表明补体可能有助于中枢神经系统淋巴瘤中利妥昔单抗的免疫治疗反应。该药代动力学模型支持利妥昔单抗渗透到神经组织中，并可能有助于提高疗效。这些发现对心室内免疫治疗具有一般意义。我们的数据强调了通过调节先天免疫反应以及药物输送创新来提高心室内免疫治疗疗效的潜在创新。 (C)2013 AACR。
Purpose: To elucidate the mechanistic basis for efficacy of intrathecal rituximab. We evaluated complement activation as well as the pharmacokinetics of intraventricular rituximab in patients who participated in two phase 1 multicenter studies.Experimental Design: We evaluated complement activation as a candidate mediator of rituximab within the central nervous system (CNS). Complement C3 and C5b-9 were quantified by ELISA in serial cerebrospinal fluid (CSF) specimens after intraventricular rituximab administration. We determined rituximab concentration profiles in CSF and serum. A population three-compartment pharmacokinetic model was built to describe the disposition of rituximab following intraventricular administration. The model was derived from results of the first trial and validated with results of the second trial.Results: Complement C3 and C5b-9 were reproducibly activated in CSF after intraventricular rituximab. Ectopic expression of C3 mRNA and protein within CNS lymphoma lesions was localized to myeloid cells. Constitutive high C3 activation at baseline was associated with adverse prognosis. A pharmacokinetic model was built, which contains three distinct compartments, to describe the distribution of rituximab within the neuroaxis after intraventricular administration.Conclusions: We provide the first evidence of C3 activation within the neuroaxis with intraventricular immunotherapy and suggest that complement may contribute to immunotherapeutic responses of rituximab in CNS lymphoma. Penetration of rituximab into neural tissue is supported by this pharmacokinetic model and may contribute to efficacy. These findings have general implications for intraventricular immunotherapy. Our data highlight potential innovations to improve efficacy of intraventricular immunotherapy both via modulation of the innate immune response as well as innovations in drug delivery. (C)2013 AACR.