title: Molecular and clinical rationale for therapeutic targeting of interleukin-5 and its receptor.
abstract: 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 α subunit that interacts in conformationally dynamic ways with the receptor's βc 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 antibodies are being clinically evaluated. Antisense oligonucleotide technology targeting the common βc 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.
authors.affiliation: MedImmune, LLC, Gaithersburg, MD 20878, USA. molfinon@medimmune.com
authors.forename: N A
authors.initials: NA
authors.lastname: Molfino
authors.forename: D
authors.initials: D
authors.lastname: Gossage
authors.forename: R
authors.initials: R
authors.lastname: Kolbeck
authors.forename: J M
authors.initials: JM
authors.lastname: Parker
authors.forename: G P
authors.initials: GP
authors.lastname: Geba
mesh_terms: D000818:Animals; D018926:Anti-Allergic Agents / Q000009:adverse effects / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use; D004195:Disease Models, Animal; D004804:Eosinophils / Q000276:immunology*; D006801:Humans; D006967:Hypersensitivity / Q000188:drug therapy* / Q000276:immunology*; D015848:Interleukin-5 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011485:Protein Binding; D053649:Receptors, Interleukin-5 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D018926:Anti-Allergic Agents; D000911:Antibodies, Monoclonal; D015848:Interleukin-5; D053649:Receptors, Interleukin-5