Dr David Sandham

The DP₂ receptor pathway has been heralded as a novel and important therapeutic target for asthma. We sat down with Dr David Sandham, from the Novartis Institutes for Biomedical Research in Cambridge, to share the back story on targeting DP₂. Dr Sandham was in Australia for the TSANZSRS 2019 Annual Scientific Meeting on the Gold Coast.

Why is there a need to look for novel pathways in treating asthma?

When you look at the current landscape of asthma treatment, you have the inhaled corticosteroids /bronchodilator combinations which are quite effective in mild to moderate asthma.Recently, more biologics have come to Australia, meaning that anti –IgE and anti-IL5 treatments are available in Australia for severe patients.

Our research institution began to explore the DP2 pathway as we saw there was a need to bridge the gap between patients who are not controlled on high-dose inhaled combination therapies before they need to go onto biologics.

You can obviously increase the dose of inhaled steroid combinations but in the course of doing that you do get into side effect issues with the systemic exposure leading to immunosuppression and there’s a particular issue for paediatrics with growth limitation from prolonged exposure to high doses of corticosteroids. So there really is a need for non-steroidal treatments for asthma.

The DP₂ pathway has been flagged as one to watch. What’s its role in the pathophysiology of asthma?

I guess it’s important when we are talking about the DP₂ pathway, to remember DP₂ is the receptor for prostaglandin D₂ (PGD₂), which is a lipid mediator produced predominately but not exclusively by mast cells.

There is a long history of PGD₂ and asthma going back to the mid 1980s, but it’s only recently that the full inflammatory effects have been characterized and they appear to be all operating via the DP₂ receptor.

PGD₂ does have a number of homeostatic functions that are needed for normal bodily function like vasodilatation, control of body temperature and also to maintain anti-viral immunity but they are all regulated via the DP₁ receptor. You can target DP₂ selectively in order to have the anti-inflammatory effect required in asthma.

Given the DP₂ receptor is expressed on several cell types, where do we need to focus to block receptor activation?

DP₂ is expressed on the majority of inflammatory cells types that are relevant to asthma – eosinophils, Th2 cells and type-2 innate lymphoid cells (ILC2). The key thing that has emerged over the last few years is that the more severe the disease is, the higher the expression of the DP2 receptor and higher amounts of the ligand PGD₂ are produced.

Beyond inflammatory cells, the DP₂ pathway has also more recently been found to have a function in structural cells in the airways. So PGD₂ can also be released from airway epithelial cells, independent of the mast cell allergic response. And it has also been demonstrated to mediate the migration of airway smooth muscle cells. That is quite interesting because it really points towards a potential role in airway remodeling.

While DP₂ is relevant to both atopic and non-atopic asthma, is it likely to be more important in one or the other?

When the program was initiated it was very much about an allergic mast cell mediated response. That was previously where most of the PGD₂ was understood to come from – so you have IgE crosslinking stimulated by exposure to allergens and that then stimulates PGD₂ synthase within the mast cells producing the PGD₂.

More recently it has been shown there is also non-allergic activation of mast cells in response to viruses and environmental pollution. Alternative sources of PGD₂ like epithelial cells can also be non-allergically stimulated.

Blocking the DP₂ pathway will mediate the release of cytokines but also directly impacts immune cells. Is this one of the strengths of targeting DP₂?

Very definitely, as it is acting across multiple mediators. That is an interesting contrast with some of the biologics e.g. anti-IL-5 antibodies that very specifically block production of all IL-5.

The DP₂ pathway is acting across IL-4, IL-5 and IL-13 simultaneously. A DP2 receptor antagonist would not not necessarily block all three of them completely, but the given fact it impacts on them in parallel, we think will have a broader beneficial effect.