Molecular and clinical rationale for therapeutic targeting of interleukin-5 and its receptor.

来自 Semantic Scholar

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107

作者：

NA Molfino，D Gossage，R Kolbeck，JM Parker，GP Geba

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摘要：

Interleukin-5 is a Th2 homodimeric cytokine involved in the differentiation, maturation, migration, development, survival, trafficking and effector function of blood and local tissue eosinophils, in addition to basophils and mast cells.The IL-5 receptor (IL-5R) consists of an IL-5-specific subunit that interacts in conformationally dynamic ways with the receptor's c subunit, an aggregate of domains it shares with binding sites of IL-3 and granulocyte-macrophage colony-stimulating factor. IL-5 and IL-5R drive allergic and inflammatory immune responses characterizing numerous diseases, such as asthma, atopic dermatitis, chronic obstructive pulmonary disease, eosinophilic gastrointestinal diseases, hyper-eosinophilic syndrome, Churg-Strauss syndrome and eosinophilic nasal polyposis. Although corticosteroid therapy is the primary treatment for these diseases, a substantial number of patients exhibit incomplete responses and suffer side-effects.Two monoclonal antibodies have been designed to neutralize IL-5 (mepolizumab and reslizumab). Both antibodies have demonstrated the ability to reduce blood and tissue eosinophil counts. One additional monoclonal antibody, benralizumab (MEDI-563), has been developed to target IL-5R and attenuate eosinophilia through antibody-dependent cellular cytotoxicity. All three monoclonal antobodies are being clinically evaluated. Antisense oligonucleotide technology targeting the common c IL-5R subunit is also being used therapeutically to inhibit IL-5-mediated effects (TPI ASM8). Small interfering RNA technology has also been used therapeutically to inhibit the expression of IL-5 in animal models.This review summarizes the structural interactions between IL-5 and IL-5R and the functional consequences of such interactions, and describes the pre-clinical and clinical evidence supporting IL-5R as a therapeutic target.

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关键词：

asthma benralizumab eosinophils interleukin-5 interleukin-5 receptor mepolizumab reslizumab

DOI：

10.1111/j.1365-2222.2011.03854.x

被引量：

337

年份：

2012