Biological pathways in respiratory conditions: T2 disease

WRITTEN BY

Professor Gary Anderson

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.

 

Key drivers

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 alpha.1

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 biomarker.2

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 pathway.3

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.

 

Branching out

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.

 

Gary Anderson, a pharmacologist, immunologist and founding Director of the Lung Health Research Centre, has authored around 180 highly cited papers. His translational research is at the interface of genetic disease models and clinical cohorts focused on understanding molecular mechanisms in asthma, COPD, lung cancer and interstitial lung disease. In 2008, he proposed the widely adopted “Endotype” concept of asthma, and his work has contributed to the development of several lung medicines used worldwide. He was awarded the Research Medal of the Thoracic Society of Australia and New Zealand in 2006, and was elected a Fellow in 2014. He has served on the NHMRC Research Committee, the Board of Directors of TSANZ where he chaired the Research Committee, and on the Council of the Australian Lung Foundation. In 2015, he was elected a Fellow of the European Respiratory Society.

View Gary Anderson’s published research


References

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.

Page ATLAS ID: 1,005,493.011
Date of next review: August 2017