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

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Abstract
Background: Asthma 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 using biologicals against IL-4 receptor (IL-4R) alpha or IL-5, only a subset of patients with moderate-to-severe asthma responded favorably, suggesting that distinct pathophysiologic mechanisms are at play in subgroups of patients called endotypes. However, the effect of multiple cytokine blockade using bispecific antibodies has not been tested. Objective: We sought to target simultaneously the IL-4, IL-13, and IL-5 signaling pathways with a novel IL-4R alpha/IL-5-bispecific antibody in a murine house dust mite (HDM) model of asthma. Methods: Two mAbs neutralizing IL-4R alpha and IL-5 were generated by using a llama-based antibody platform. Their heavy and light chains were then cotransfected in mammalian cells, resulting in a heterogeneous antibody mixture from which the bispecific antibody was isolated by using a dual anti-idiotypic purification process. C57BL/6J mice were finally sensitized and challenged to HDM extracts and treated during challenge with the antibodies. Results: We successfully generated and characterized the monospecific and bispecific antibodies targeting IL-4R alpha and IL-5. The monospecific antibodies could suppress eosinophilia, IgE synthesis, or both, whereas only the IL-4R alpha/IL-5-bispecific antibody and the combination of monospecific antibodies additionally inhibited GCM and BHR. Conclusion: Type 2 cytokines act synergistically to cause GCM and BHR in HDM-exposed mice. These preclinical results show the feasibility of generating bispecific antibodies that target multiple cytokine signaling pathways as superior inhibitors of asthma features, including the difficult-to-treat GCM.
Keywords
HOUSE-DUST MITES, EOSINOPHILIC ASTHMA, AIRWAY EPITHELIUM, T-CELLS, INTERLEUKIN (IL)-13, ALLERGIC-ASTHMA, INFLAMMATION, MEPOLIZUMAB, IMMUNITY, IL-4, Asthma, bispecific antibody, bronchial hyperreactivity, goblet cell, metaplasia, house dust mite, IL-4 receptor alpha, IL-5

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Chicago
Godar, Marie, Kim Deswarte, Karl Vergote, Michael Saunders, Hans de Haard, Hamida Hammad, Christophe Blanchetot, and Bart Lambrecht. 2018. “A Bispecific Antibody Strategy to Target Multiple Type 2 Cytokines in Asthma.” Journal of Allergy and Clinical Immunology 142 (4): 1185–1193.
APA
Godar, M., Deswarte, K., Vergote, K., Saunders, M., de Haard, H., Hammad, H., Blanchetot, C., et al. (2018). A bispecific antibody strategy to target multiple type 2 cytokines in asthma. JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 142(4), 1185–1193.
Vancouver
1.
Godar M, Deswarte K, Vergote K, Saunders M, de Haard H, Hammad H, et al. A bispecific antibody strategy to target multiple type 2 cytokines in asthma. JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. 2018;142(4):1185–93.
MLA
Godar, Marie et al. “A Bispecific Antibody Strategy to Target Multiple Type 2 Cytokines in Asthma.” JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 142.4 (2018): 1185–1193. Print.
@article{8583087,
  abstract     = {Background: Asthma 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 using biologicals against IL-4 receptor (IL-4R) alpha or IL-5, only a subset of patients with moderate-to-severe asthma responded favorably, suggesting that distinct pathophysiologic mechanisms are at play in subgroups of patients called endotypes. However, the effect of multiple cytokine blockade using bispecific antibodies has not been tested. 
Objective: We sought to target simultaneously the IL-4, IL-13, and IL-5 signaling pathways with a novel IL-4R alpha/IL-5-bispecific antibody in a murine house dust mite (HDM) model of asthma. 
Methods: Two mAbs neutralizing IL-4R alpha and IL-5 were generated by using a llama-based antibody platform. Their heavy and light chains were then cotransfected in mammalian cells, resulting in a heterogeneous antibody mixture from which the bispecific antibody was isolated by using a dual anti-idiotypic purification process. C57BL/6J mice were finally sensitized and challenged to HDM extracts and treated during challenge with the antibodies. 
Results: We successfully generated and characterized the monospecific and bispecific antibodies targeting IL-4R alpha and IL-5. The monospecific antibodies could suppress eosinophilia, IgE synthesis, or both, whereas only the IL-4R alpha/IL-5-bispecific antibody and the combination of monospecific antibodies additionally inhibited GCM and BHR. 
Conclusion: Type 2 cytokines act synergistically to cause GCM and BHR in HDM-exposed mice. These preclinical results show the feasibility of generating bispecific antibodies that target multiple cytokine signaling pathways as superior inhibitors of asthma features, including the difficult-to-treat GCM.},
  author       = {Godar, Marie and Deswarte, Kim and Vergote, Karl and Saunders, Michael and de Haard, Hans and Hammad, Hamida and Blanchetot, Christophe and Lambrecht, Bart},
  issn         = {0091-6749},
  journal      = {JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY},
  keywords     = {HOUSE-DUST MITES,EOSINOPHILIC ASTHMA,AIRWAY EPITHELIUM,T-CELLS,INTERLEUKIN (IL)-13,ALLERGIC-ASTHMA,INFLAMMATION,MEPOLIZUMAB,IMMUNITY,IL-4,Asthma,bispecific antibody,bronchial hyperreactivity,goblet cell,metaplasia,house dust mite,IL-4 receptor alpha,IL-5},
  language     = {eng},
  number       = {4},
  pages        = {1185--1193},
  title        = {A bispecific antibody strategy to target multiple type 2 cytokines in asthma},
  url          = {http://dx.doi.org/10.1016/j.jaci.2018.06.002},
  volume       = {142},
  year         = {2018},
}

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