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  • Review Article
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Targeting key proximal drivers of type 2 inflammation in disease

Nature Reviews Drug Discovery volume 15, pages 35–50 (2016)Cite this article

Subjects

Key Points

  • Type 2 inflammation, which encompasses systemic T helper 2 (TH2)-type responses, is emerging as a unifying feature of both classically defined allergic diseases such as asthma and a range of other inflammatory diseases.

  • Although immunological diseases may appear disparate based on their distinct organ or tissue manifestations, the tendency for diverse allergic diseases to present as co-morbidities or progressively suggests that they may share common underlying drivers.

  • The proximal type 2 cytokines interleukin-4 (IL-4), IL-5 and IL-13, produced by both innate and TH2 cells, contribute to the hallmarks of type 2-driven diseases, such as elevated immunoglobulin E (IgE) production and systemic and tissue-infiltrated eosinophilia.

  • Early clinical studies in asthma targeting IL-4, IL-5 and IL-13 did not lead to clear efficacy, possibly owing to the molecular properties of the blockers, route of administration, bioavailability and/or incorrect study patient population. However, these studies contributed to a growing understanding of the heterogeneity of asthma that led to the successful targeting of IL-4, IL-5 and/or IL-13 in subsets of patients with high biomarkers of type 2 inflammation.

  • Probing the molecular underpinnings of atopic dermatitis also revealed prominent type 2 inflammation. Although targeting IgE or IL-5 alone did not show clinical effects in atopic dermatitis, dual blockade of IL-4 and IL-13 demonstrated significant efficacy, confirming that type 2 inflammation mediates atopic dermatitis.

  • The success of systemic IL-4 and IL-13 blockade across three allergic diseases with disparate specific tissue manifestations — asthma, atopic dermatitis and chronic sinusitis with nasal polyps — suggests that the IL-4–IL-13 pathway is a key central driver pathway in immunological diseases.

  • Rather than defining atopic diseases by their apparent tissue manifestations, the identification of driver pathways in these three diseases suggests that immunological diseases can be defined and grouped based on their driver immunological pathways to enable tailored therapy.

Abstract

Systemic type 2 inflammation encompassing T helper 2 (TH2)-type responses is emerging as a unifying feature of both classically defined allergic diseases, such as asthma, and a range of other inflammatory diseases. Rather than reducing inflammation with broad-acting immunosuppressants or narrowly targeting downstream products of the TH2 pathway, such as immunoglobulin E (IgE), efforts to target the key proximal type 2 cytokines — interleukin-4 (IL-4), IL-5 and IL-13 — represent a promising strategy to achieve therapeutic benefit across multiple diseases. After several initial disappointing clinical results with therapies targeting IL-4, IL-5 or IL-13 in asthma, applying a personalized approach achieved therapeutic benefit in an asthma subtype exhibiting an 'allergic' phenotype. More recently, efficacy was extended into a broad population of people with asthma. This argues that the Type 2 inflammation is broadly relevant across the severe asthma population if the key upstream drivers are properly blocked. Moreover, the simultaneous inhibition of IL-4 and IL-13 has shown significant clinical activity in diseases that are often co-morbid with asthma — atopic dermatitis and chronic sinusitis with nasal polyps — supporting the hypothesis that targeting a central 'driver pathway' could benefit multiple allergic diseases.

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Figure 1: Receptor systems for IL-4, IL-13 and IL-5.
Figure 2: Type 2 inflammation in severe asthma, atopic dermatitis and chronic sinusitis with nasal polyps.
Figure 3: Targeting key proximal drivers of the type-2 pathway versus end-product mediators.

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Acknowledgements

The authors thank W. Brooks, J. Orengo, A. Rahmani and D. Gibson from Regeneron Pharmaceuticals.

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Authors and Affiliations

  1. Regeneron Pharmaceuticals, Tarrytown, 10591, New York, USA

    Namita A. Gandhi, Brandy L. Bennett, Neil M. H. Graham, Neil Stahl & George D. Yancopoulos

  2. Research and Development, Sanofi, Bridgewater, 08807, New Jersey, USA

    Gianluca Pirozzi

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Correspondence to Namita A. Gandhi.

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N.A.G., B.L.B., N.M.G., N.S. and G.D.Y. are employees of and shareholders of Regeneron Pharmaceuticals. G.P. is an employee and shareholder of Sanofi.

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Gandhi, N., Bennett, B., Graham, N. et al. Targeting key proximal drivers of type 2 inflammation in disease. Nat Rev Drug Discov 15, 35–50 (2016). https://doi.org/10.1038/nrd4624

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