A bispecific antibody strategy to target multiple type 2 cytokines in asthma

Publication date: Available online 8 June 2018
Source:Journal of Allergy and Clinical Immunology
Author(s): Marie Godar, Kim Deswarte, Karl Vergote, Michael Saunders, Hans de Haard, Hamida Hammad, Christophe Blanchetot, Bart N. Lambrecht
BackgroundAsthma is a chronic inflammatory airway disease in which innate and adaptive immune cells act together to cause eosinophilic inflammation, goblet cell metaplasia (GCM) and bronchial hyperreactivity (BHR). In clinical trials employing biologicals against interleukin (IL)-4Rα or IL-5, only a subset of moderate-to-severe asthmatics responded favorably, suggesting that distinct pathophysiological mechanisms are at play in subgroups of patients, called endotypes. However, the effect of multiple cytokine blockade using bispecific antibodies (Ab) has not been tested.ObjectiveTo target simultaneously IL-4, IL-13 and IL-5 signaling pathways with a novel IL-4Rα/IL-5 bispecific Ab in a murine house dust mite (HDM) model of asthma.MethodsTwo monoclonal Abs neutralizing IL-4Rα and IL-5 were generated using a llama-based Ab platform. Their heavy (HC) and light chains (LC) where then co-transfected in mammalian cells, resulting in a heterogeneous Ab mixture from which the bispecific Ab was isolated using a dual anti-idiotypic purification process. C57BL/6J mice were finally sensitized and challenged to HDM extracts and treated during challenge with the Abs.ResultsWe successfully generated and characterized the monospecific and bispecific Abs targeting IL-4Rα and IL-5. The monospecific Abs could suppress eosinophilia and/or IgE synthesis whereas only the IL-4Rα/IL-5 bispecific Ab and the combination of monospecific Abs additionally inhibited GCM and BHR.ConclusionType 2 cytokines act synergistically to cause GCM and BHR in HDM-exposed mice.

Teaser

Current asthma biologicals include IL-4Rα and IL-5 monospecific Abs. Here we show the feasibility of producing an anti-IL-4Rα/IL-5 bispecific Ab that neutralizes both targets and demonstrates superior effectiveness in a murine house dust mite model.


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