Important roles of CD32 in promoting suppression of IL-4 induced immune responses by a novel anti-IL-4R? 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-4R? 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-4R? signaling pathway. We, therefore, devised a new strategy to increase the efficacy of the anti-IL-4R? monoclonal antibody for the treatment of asthma and other atopic diseases by co-engaging CD32 and IL-4R? 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-4R? 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-4R? signaling might result from a global network where multiple cell types that express multiple Fc?Rs 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.

SUBMITTER: Zhao J 

PROVIDER: S-EPMC6601543 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature