Pharmacological Properties, Toxicology and Scientific Rationale for the use of Natalizumab (Tysabri®) in Inflammatory Diseases

Olaf Stüve, Jeffrey L. Bennett
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引用次数: 106

Abstract

Natalizumab (Tysabri®) was the first adhesion molecule antagonist to make it into clinical trial for patients with multiple sclerosis (MS) and other inflammatory disorders. Natalizumab is a humanized recombinant monoclonal antibody (MAb) that binds to the alpha (α)4 chain of the α4 beta (β)1 (very late activating antigen 4; VLA-4) and α4β7 integrins. The scientific rationale for natalizumab therapy is the reduction of leukocyte extravasation into peripheral tissues. Natalizumab, like other VLA-4 antagonists, may also interfere with the activation of T lymphocytes in secondary lymphoid organs and their reactivation in the central nervous system (CNS).

Shortly after its approval for the treatment of relapsing-remitting MS (RR-MS), three patients who were treated with natalizumab in the setting of clinical trials developed progressive multifocal leukoencephalopathy (PML), an opportunistic infection of the brain with the polyoma virus JC. It remains to be elucidated why the use of this VLA-4 antagonist is associated with an increased incidence of PML. Natalizumab was recently reapproved for the treatment of relapsing forms of MS. In this review, we outline the scientific rationale for using natalizumab in MS and other inflammatory disorders. In addition, an overview of pharmacological properties, clinical efficacy, safety, and toxicology of natalizumab is provided.

Abstract Image

Natalizumab (Tysabri®)用于炎性疾病的药理学特性、毒理学和科学原理
Natalizumab (Tysabri®)是首个进入多发性硬化症(MS)和其他炎症性疾病患者临床试验的粘附分子拮抗剂。Natalizumab是一种人源化重组单克隆抗体(MAb),结合α4 β (β)1的α (α)4链(极晚活化抗原4;VLA-4)和α4β7整合素。natalizumab治疗的科学原理是减少白细胞外渗到外周组织。与其他VLA-4拮抗剂一样,Natalizumab也可能干扰次级淋巴器官中T淋巴细胞的激活及其在中枢神经系统(CNS)中的再激活。在natalizumab被批准用于治疗复发-缓解型多发性硬化症(rm -MS)后不久,3名在临床试验中接受natalizumab治疗的患者出现了进行性多灶性白质脑病(PML),这是一种多瘤病毒JC的脑部机会性感染。为什么使用这种VLA-4拮抗剂与PML发病率增加相关还有待阐明。Natalizumab最近被重新批准用于治疗复发型多发性硬化症。在这篇综述中,我们概述了使用Natalizumab治疗多发性硬化症和其他炎症性疾病的科学依据。此外,还概述了natalizumab的药理学特性、临床疗效、安全性和毒理学。
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