Targeting the drivers of immune-mediated diseases

Overview

Targeting an imbalance in immune mechanisms to halt, reverse and ultimately cure immune-mediated diseases such as Systemic Lupus Erythematosus, Inflammatory Bowel Disease, Rheumatoid Arthritis and Atopic Dermatitis is the ambitious goal of AstraZeneca’s rapidly expanding global Immunology team in BioPharmaceuticals R&D.

Building on decades of experience in unravelling complex inflammatory cell signalling pathways, our scientists are focused on the key mechanisms that turn protective immune responses into destructive forces in the joints, gastrointestinal system, skin and other vital organs.

To help drive rapid progress, we are recruiting highly skilled scientists who are eager to innovate and shape the future of Immunology at AstraZeneca. Our research teams are committed to delivering precision medicines aimed at changing the lives of patients with immune-mediated diseases.


Introduction

With an estimated 5 million people living with a form of Lupus worldwide,1 6.8 million with Inflammatory Bowel Disease,2 20 million with Rheumatoid Arthritis,3 and 15-20% of children and 1-3% of adults with Atopic Dermatitis,4 there is a well-established need for innovative therapies that target key immune mechanisms underlying these diseases. 

Acute inflammation in response to injury or infection has a natural ‘off’ switch to allow healing.  However in autoimmune diseases, some triggers may persist and faulty ‘off’ switches mean that continued inflammation leads to tissue damage, destruction and scarring.  The chronic nature of immune-mediated disease also means that next-generation therapeutics need to look beyond symptom control alone.


Key areas of focus for immunology research at AstraZeneca

  1. Raised levels of eosinophils, immune cells we already target in asthma, now investigated in disorders affecting multiple body systems, including gastrointestinal and skin diseases.
  2. Type 1 interferons, key cell signalling molecules in the immune system, now investigated in lupus and a broad range of diseases including Lupus Nephritis, Cutaneous Lupus Erythematosus and Myositis.
  3. The complement system of immune cell enhancing proteins, previously targeted mainly in rare disorders, now investigated in more common autoimmune disorders.


Shared biology, shared solutions 


We are digging deep into disease biology to develop novel and potentially transformative solutions that address broad pathology untapped by existing therapies. We aim to hit hard at multiple pathways to achieve lasting benefits for patients with immune-mediated diseases.

Tatiana Ort Head of Bioscience Immunology

In-depth research is helping us identify genetic variants in key pathways that make some people more susceptible to autoimmune diseases. This understanding is enabling us to focus on key proteins which act as a master switch for pro-inflammatory cytokines and multiple other inflammatory processes across autoimmune diseases.


In Inflammatory Bowel Disease, our researchers are investigating ways to neutralise and remove the pathological T cells that modulate inflammation in the gastrointestinal tract. The opportunity to bind chemokine receptor antigens on many of these cells – so they are labelled for destruction by other immune cells – holds considerable promise. Also, in Rheumatoid Arthritis, we are researching how inhibition of disease causing peptides linked to more severe disease could enable future treatments to target earlier stages of Rheumatoid Arthritis.


By gaining a better understanding of the biology of autoimmune diseases, our aim is to target the causes rather than the consequences of the inflammatory processes that are at work.

Mike Sheehan Senior Director, Product Development Team


Precision Immunology: right pathway, right patient, right time

As immunemediated diseases affect highly heterogeneous populations, it is essential to develop precision medicines with biomarkers that can readily identify patients most likely to benefit. 


Alongside each of the therapies we are exploring for immune-mediated disease areas we are also investigating gene and protein signature tests to enable doctors to optimise future treatment decisions for patientsining a better understanding of the biology of autoimmune diseases, our aim is to target the causes rather than the consequences of the inflammatory processes that are at work.

André da Costa Head of Precision Medicine Discovery Immunology

In Systemic Lupus Erythematosus, clinical trials of a potential antibody treatment that inhibits the activity of type 1 interferons are well advanced. Our researchers have successfully targeted the type 1 interferon signalling pathway, which is known to play a key role in Systemic Lupus Erythematosus disease activity as well as other immune-mediated diseases.5

In Inflammatory Bowel Disease, the expression of the cytokine, interleukin-23 (IL-23), has been linked with inflammatory changes in the gut, and antibody therapies are in development to inhibit the IL-23 pathway.6 Our research is investigating the use of molecular endpoints along the IL-23 pathway, as biomarkers to identify patients most likely to benefit from anti-IL-23 therapy.


Novel therapeutics: regulatory T cell therapy


At AstraZeneca, we are investigating the loss of function of regulatory T cells (Treg) within the immune system of people with autoimmune and inflammatory disorders which can lead to harmful inflammatory processes that damage healthy tissue. Re-balancing systems that have failed to maintain immune homeostasis have great potential for innovative, long term treatments for Inflammatory Bowel Disease, Systemic Lupus Erythematosus and Rheumatoid Arthritis. Our research is focused on the development of Treg cells which remain stable and retain their original function, without deteriorating, when reinfused into patients.


Future directions

In the years ahead, we will continue to draw on AstraZeneca’s cutting-edge technologies and scientific expertise for the development of novel therapies for patients with immune-mediated  diseases to stop the progression of these debilitating conditions

Artificial intelligence and machine learning technologies such as knowledge graphs and whole genome datasets will be used increasingly for big data analysis and to provide valuable insights into the next generation of promising treatment targets.


The breadth and depth of our Immunology research, the ability to integrate the latest digital, AI, CRISPR and other technologies into our projects, and the collaborations with world-leading experts at some of the finest research centres worldwide, make AstraZeneca a highly stimulating and exciting place to work. Already widely used for drug discovery at AstraZeneca R&D, our advanced CRISPR technology is expected to play a growing therapeutic role with the aim of correcting genetic mutations responsible for abnormal signalling pathways in autoimmune diseases – bringing with it the tantalising possibility of a cure for some patients, to one day, hopefully live a life without limits.

Catherine Datto Executive Director Immunology

References

1. Lupus Foundation of America. Lupus facts and statistics. https://www.lupus.org/resources/lupus-facts-and-statistics#:~:text=The%20Lupus%20Foundation%20of%20America,have%20a%20form%20of%20lupus.

2. Jairath V, Feagan BG. Global burden of inflammatory bowel disease. Lancet Gastroenterology and Hepatology 2020 Jan;5(1):2-3.

3. Safiri S, Kolahi AA, Hoy D, et al. Global, regional and national burden of rheumatoid arthritis 1990-2017: a systematic analysis of the Global Burden of Disease study 2017Ann Rheum Dis. 2019;78:1463-1471.

4. Avena-Woods C. Overview of Atopic Dermatitis. Amer J Managed Care 2017; 23(8 Suppl):S115-S123

5. Brohawn PZ, Streicher K, Higgs BW et al. Type I interferon gene signature test-low and -high patients with systemic lupus erythematosus have distinct gene expression signatures. Lupus 2019; 28 (13): 1524-1533

6. Cayatte C, Joyce-Shaikh B, Vega F et al. Biomarkers of Therapeutic Response in the IL-23 Pathway in Inflammatory Bowel Disease. Clinical and Translational Gastroenterology 2012; 3, e10


Topics:
 



You may also like

Veeva ID: Z4-34176
Date of preparation: June 2021