Leveraging AstraZeneca’s immunology expertise across multiple conditions with common autoimmune components is the organising principle behind the fourth ‘biological pathway’ framing AstraZeneca’s respiratory R&D.
Probably the most forward-looking of the four ‘biological pathways’ that map out AstraZeneca’s research and development efforts in respiratory disease is autoimmunity.
While autoimmunity spans a broad range of diseases, from rheumatoid arthritis and psoriasis to multiple sclerosis, inflammatory bowel disease and systemic lupus erythematosus (SLE), it also aligns strongly with the biological pathways strategy: to identify and act on common features or phenotypes underlying the strong heterogeneity of respiratory diseases.
Moreover, AstraZeneca has considerable expertise in immunology that can be leveraged to enhance its understanding of shared biological processes and molecular pathways extending across multiple inflammatory and autoimmune diseases, including those affecting the respiratory system.
That expertise has already produced assets, such as a monoclonal antibody against the type I interferon (IFN) receptor that has been investigated in Phase II trials for the treatment of moderate-to-severe SLE1.
There is also a significant degree of overlap between drivers of respiratory disease and of other conditions more readily associated with autoimmunity. For example, around one third of all patients with rheumatic disease have some degree of lung-tissue involvement.
There is strong evidence too that autoimmune conditions contribute to interstitial lung diseases such as idiopathic pulmonary fibrosis, while pathogenic autoimmune disorders have been implicated in advanced lung disease – in particular chronic obstructive pulmonary disease (COPD).
This is an emerging area of opportunity for respiratory R&D. While standard drug treatments for, say, rheumatoid arthritis – such as methotrexate or tumor necrosis factor (TNF) inhibitors – have not proved particularly effective in asthma or COPD, pathogenetic analysis does point to a genuine autoimmune component in a number of lung diseases.
The question to answer, then, is what drives these processes in the lung and whether it can be addressed with something other than classical autoimmune inhibitors or a traditional anti-inflammatory strategy.
This requires a deep understanding of the role of inflammation as a host defence mechanism, as well as finding ways to resolve inflammation – through a process known as catabasis, in which tissue-resident macrophages appear to play a key role2 – without further compromising the immune system.
Achieving the right balance is a challenging proposition. It is only through this kind of disruptive thinking, though, that researchers can arrive at new treatment paradigms for the many unmet needs which persist despite enormous scientific progress in improving the lives of people with respiratory diseases. And that is what the biological pathways strategy is all about.
This is the fourth 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
1. Clinicaltrials.gov. NCT01438489. Available at: https://clinicaltrials.gov/ct2/show/NCT01438489 Last accessed August 2016
2. Noguera A, Gomez C, Faner R et al. An investigation of the resolution of inflammation (catabasis) in COPD. Respiratory Research. 2012: 13: 101