A rational approach to the use of combination biologic therapy in rheumatoid arthritis

Lead Research Organisation: Imperial College London
Department Name: Dept of Medicine

Abstract

TNF antagonists are a new class of drugs that are used to treat rheumatoid arthritis and other autoimmune diseases. These drugs act by blocking the activity of a cytokine, known as TNF, that plays an important role in the disease process. Using a mouse model of rheumatoid arthritis, we have recently discovered that one of the unexpected consequences of TNF blockade is the increased production of another cytokine, IL-17, that also contributes to the disease process. Hence, the beneficial effects of anti-TNF therapy are offset by the deleterious effects of increased IL-17 production. On this basis we would predict that a combination of a TNF antagonist and an IL-17 antagonist would have an enhanced therapeutic effect and we have obtained preliminary evidence using a mouse model of arthritis to suggest that this is the case. In this proposal we will first establish that TNF antagonists increase IL-17 levels in patients with rheumatoid arthritis and other autoimmune diseases. Next, we will validate the concept of combination therapy using a TNF antagonist and an IL-17 antagonist in mice. This will provide the scientific rationale for conducting clinical trials of combination therapy in rheumatoid arthritis. Finally, we will seek to identify industrial partners interested in testing the concept of combination therapy in patients. This study will help to establish a novel approach to treatment that will have improved long-term efficacy over existing therapies.

Technical Summary

TNF antagonists represent a major breakthrough in the treatment of a number of autoimmune and inflammatory diseases but there are serious obstacles to their more general use, including high cost and lack of durable therapeutic effect.
Using a mouse model of rheumatoid arthritis, we have recently discovered that one of the unexpected consequences of TNF blockade is the increased expression of IL-17, a potent pro-inflammatory cytokine. Thus, the beneficial effects of anti-TNF therapy are offset by the deleterious effects of increased IL-17 production. In addition, we have preliminary evidence in mice that anti-TNF and anti-IL-17 act synergistically to suppress arthritis and induce disease remission. In this proposal we will first establish that TNF blockade upregulates the IL-17 pathway in patients with rheumatoid arthritis and other autoimmune diseases. Next, we will confirm the ability of anti-TNF and anti-IL-17 to act synergistically in mice and establish the optimal form of combination therapy for use in human therapy. This will provide the scientific rationale for conducting clinical trials of combination biologic therapy in rheumatoid arthritis. The potential benefit of this study will be to establish a novel therapeutic approach which has improved long-term efficacy over existing therapies and which will increase the numbers of patients that can be treated effectively by TNF antagonists.
 
Description BBSRC CASE Studentship
Amount £92,173 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 10/2012 
End 09/2016
 
Description Merck 
Organisation Merck
Country Germany 
Sector Private 
PI Contribution This is a collaborative project in which our team are carrying out translational research. The project may lead to new treatments for rheumatoid arthritis.
Collaborator Contribution Financial, inellectual and access to data.
Impact None yet
Start Year 2012
 
Title Method of treating disease 
Description The discovery describes the synergistic effect of anti-TNF antibody therapy and anti-IL-23 antibody therapy. 
IP Reference WO2011070339 
Protection Patent granted
Year Protection Granted 2011
Licensed No
Impact None as yet.
 
Description Barts 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact 6th Gene Therapy of Arthritis and Related Disorders, London: "Anti-TNF and IL-17 in arthritis"

The presentation generated considerble interest.
Year(s) Of Engagement Activity 2011
 
Description Copenhagen 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact More than 100 scientists and clinicians attended the presentation. World Congress of Basic Clinical Pharmacology, Copenhagen: "TNF-alpha antagonists - translating molecular insights in autoimmunity into effective therapy"

A webcast was made descibing our research.
Year(s) Of Engagement Activity 2010
 
Description Presentation Liverpool 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact A presentation was given entitled 'TNFR inhibition for systemic inflammatory diseases' at a symposium focussed on drug discovery for pancreatic and GI disease. This formed a key part of the sessions on drug discovery for pancreatitis.

The meeting served as a stimulus for future collaborations.
Year(s) Of Engagement Activity 2013
 
Description Presentation, London 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Primary Audience Participants in your research and patient groups
Results and Impact Members of the ARUK User's group (comprising patients and Healthcare professionals) attended a presentation on our work.

The group reported that they found the presentation highly informative.
Year(s) Of Engagement Activity 2010