Important roles of CD32 in promoting suppression of IL-4 induced immune responses by a novel anti-IL-4Rα therapeutic antibody.

Abstract

Asthma is characterized by airway hyperresponsiveness and inflammation, as well as underlying structural changes to the airways. Interleukin-4 (IL-4) is a key T-helper type 2 (Th2) cytokine that plays important roles in the pathogenesis of atopic and eosinophilic asthma. We developed a novel humanized anti-IL-4Rα antibody that can potently inhibit IL-4/IL-13-mediated TF-1 cell proliferation. Using monocytes isolated from human peripheral blood mononuclear cells (PBMCs), we revealed a critical role of CD32 in modulating the immune responses of monocytes in response to blockade of IL-4Rα signaling pathway. We, therefore, devised a new strategy to increase the efficacy of the anti-IL-4Rα monoclonal antibody for the treatment of asthma and other atopic diseases by co-engaging CD32 and IL-4Rα on monocytic cells by choosing IgG classes or Fc mutations with higher affinities for CD32. The antibody with selectively enhanced affinity for CD32A displayed superior suppression of IL-4-induced monocytes' activities, including the down-regulation of CD23 expression. Intriguingly, further analysis demonstrated that both CD32A and CD32B contributed to the enhancement of antibody-mediated suppression of CD23 expression from monocytes in response to blockade of IL-4Rα signaling. Furthermore, inhibition of IgE secretion from human PBMC by the antibody variants further suggests that the complex allergic inflammation mediated by IL-4/IL-4Rα signaling might result from a global network where multiple cell types that express multiple FcγRs are all involved, of which CD32, especially CD32A, is a key mediator. In this respect, our study provides new insights into designing therapeutic antibodies for targeting Th2 cytokine-mediated allergic pathogenesis.

• Authors: Jie Zhao, Liangfeng Jiang, Lan Deng, Wei Xu, Yang Cao, Chen Chen, Yan Yang, Huiling Wu, Yuping Huang, Zhenping Zhu, Haomin Huang
• Journal: mAbs (MAbs) Vol. 11 Issue 5 Pg. 837-847 (07 2019) ISSN: 1942-0870 [Electronic] United States
• PMID: 30950681 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Asthmatic Agents
• Antibodies, Monoclonal, Humanized
• FCGR2A protein, human
• IL4R protein, human
• Interleukin-4 Receptor alpha Subunit
• Receptors, IgE
• Receptors, IgG
• Interleukin-4
• Immunoglobulin E

Topics

• Animals
• Anti-Asthmatic Agents (immunology, metabolism, pharmacology)
• Antibodies, Monoclonal, Humanized (immunology, metabolism, pharmacology)
• Cell Line
• Humans
• Immunoglobulin E (metabolism)
• Interleukin-4 (antagonists & inhibitors, pharmacology)
• Interleukin-4 Receptor alpha Subunit (antagonists & inhibitors, immunology)
• Mice
• Monocytes (cytology, drug effects, immunology, metabolism)
• Receptors, IgE (metabolism)
• Receptors, IgG (immunology)