Type 2 immune responses offer a rich source of potential targets for therapeutic intervention in diseases such as severe asthma. Find out what AstraZeneca is doing in the T2 disease space, one of four ‘biological pathways’ that frame the company’s disruptive strategies in respiratory R&D.
The role of Type-2 (T2) immune responses in the cascade of events leading to airway inflammation is the second of four key ‘biological pathways’ that provide AstraZeneca’s researchers and key collaborators with a rational framework for stratified management of respiratory disease.
The organising principle behind the biological pathways is to identify common features or phenotypes of chronic obstructive and autoimmune conditions that reflect underlying biological mechanisms susceptible to inhibition or modification with targeted therapies.
In this way, treatment can be individualised to specific triggers of what are essentially heterogeneous diseases, enabling earlier intervention with more precise, safer and more effective molecules.
The key drivers of T2 immunity are the inflammatory cytokines interleukins 4 and 13 (IL-4 and IL-13), whose effects are mediated by the IL-4 receptor alpha1.
Activating this receptor also induces the release of characteristic biomarkers such as FeNO and periostin. Because T2 immunity can drive eosinophilia, this cell type – measured in blood, sputum or biopsies – is also a candidate biomarker2.
Serum concentrations of the protein dipeptidyl peptidase-4 (DPP-4) may provide another predictive biomarker for intervention in T2 disease.
In line with the targeted-medicine emphasis of its biological pathways strategy, AstraZeneca has been exploring potential biomarkers that can identify those asthma patients most likely to benefit from its compounds in development.
Inhibiting T2 immunity
Inhibitors of T2 immunity are of considerable interest as potential treatments for the ‘T2-high’ endotype of asthma, and as such constitute a clear biological pathway3.
Also of great interest is that, physiologically, T2 immunity is modulated by activation of Toll-like receptors (TLRs), which are key innate immunity receptors.
TLRs therefore influence the unbalanced immune response observed in asthma patients and characterised by the dominance of Type-2 over Type-1 immunity.
As with therapies targeting the eosinophilic pathway, the T2-disease space is already relatively mature, with the underlying scientific discoveries dating back to the late 1980s and early 1990s.
While largely de-risked, the segment is also highly competitive, with many different approaches to modifying Type-2 immune responses to the benefit of asthma patients.
AstraZeneca wants to mark out its own territory by not only focusing on T2 immune responses but branching out to other potential mediators of immune function and inflammation, such as innate lymphoid cells and thymic stromal lymphopoietin (TSLP) cytokines.
This is the second in a series of blogs exploring the scientific rationale behind AstraZeneca’s biological pathways framework for respiratory disease.
1. Voehringer D, Reese TA, Huang X, Shinkai K, Locksley RM. Type 2 immunity is controlled by IL-4/IL-13 expression in hematopoietic non-eosinophil cells of the innate immune system. J Exp Med. 2006. Jun 12; 203(6): 1435–1446. Doi: 10.1084/jem.20052448.
2. Kim MA, Shin YS, Pham le D, Park HS. Adult asthma biomarkers. Curr Opin Allergy Clin Immunol. 2014 Feb;14(1):49-54. Doi: 10.1097/ACI.0000000000000028.
3. Wesolowska-Andersen A, Seibold MA. Airway molecular endotypes of asthma: dissecting the heterogeneity. Curr Opin Allergy Clin Immunol. 2015. Apr; 15(2): 163–168. Doi: 10.1097/ACI.0000000000000148.
Atlas ID: 976449.011
Date of next review: May 2017