Molecular and clinical rationale for therapeutic targeting of interleukin-5 and its receptor
Article first published online: 23 SEP 2011
© 2011 MedImmune, LLC
Clinical & Experimental Allergy
Special Issue: Special Issue on Severe Asthma
Volume 42, Issue 5, pages 712–737, May 2012
How to Cite
Cite this as: N. A. Molfino, D. Gossage, R. Kolbeck, J. M. Parker and G. P. Geba, Clinical & Experimental Allergy, 2012 (42) 712–737.
- Issue published online: 20 APR 2012
- Article first published online: 23 SEP 2011
- Manuscript Accepted: 28 JUL 2011
- Manuscript Revised: 26 JUL 2011
- Manuscript Received: 22 DEC 2010
- MedImmune, LLC
- interleukin-5 receptor;
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 antobodies 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.