An IL-4/IL-13 Dual Antagonist Reduces Lung Inflammation, Airway Hyperresponsiveness, and IgE Production in Mice

Abstract

IL-4 and IL-13 comprise promising targets for therapeutic interventions in asthma and other Th2-associated diseases, but agents targeting either IL-4 or IL-13 alone have shown limited efficacy in human clinical studies. Because these cytokines may involve redundant function, dual targeting holds promise for achieving greater efficacy. We describe a bifunctional therapeutic targeting IL-4 and IL-13, developed by a combination of specific binding domains. IL-4-targeted and IL-13-targeted single chain variable fragments were joined in an optimal configuration, using appropriate linker regions on a novel protein scaffold. The bifunctional IL-4/IL-13 antagonist displayed high affinity for both cytokines. It was a potent and efficient neutralizer of both murine IL-4 and murine IL-13 bioactivity in cytokine-responsive Ba/F3 cells, and exhibited a half-life of approximately 4.7 days in mice. In a murine model of ovalbumin-induced ear swelling, the bifunctional molecule blocked both the IL-4/IL-13-dependent early-phase response and the IL-4-dependent late-phase response. In the ovalbumin-induced lung inflammation model, the bifunctional IL-4/IL-13 antagonist reduced the IL-4-dependent rise in serum IgE titers, and reduced IL-13-dependent airway hyperresponsiveness, lung inflammation, mucin gene expression, and serum chitinase responses. Taken together, these findings demonstrate the effective dual blockade of IL-4 and IL-13 with a single agent, which resulted in the modulation of a more extensive range of endpoints than could be achieved by targeting either cytokine alone.

Strategies targeting the IL-4/IL-13 axes in disease

“…Future therapeutic approaches in early preclinical development include bispecific antibodies targeting both IL-4 and IL-13 [181,182] which offer an alternative route from targeting IL-4Ra to achieve functional blockade of both IL-4 and IL-13. There is also an inhaled IL-13 antibody fragment [183,184] that could potentially offer the efficacy of systemically dosed mAbs via a more convenient route.…”

Bifunctional drugs for the treatment of asthma and chronic obstructive pulmonary disease

“…One example is a biologic agent targeting both murine IL-4 and IL-13 that was generated by combining well-characterised binding domains in an optimal configuration, using appropriate linker regions [83]. The bifunctional IL-4 and IL-13 antagonist demonstrated high affinity for both cytokines, and reduced the IL-4-dependent rise in serum IgE, and reduced IL-13-dependent airway hyperresponsiveness, lung inflammation, mucin gene expression and serum chitinase responses in mice.…”

“…The bifunctional IL-4 and IL-13 antagonist demonstrated high affinity for both cytokines, and reduced the IL-4-dependent rise in serum IgE, and reduced IL-13-dependent airway hyperresponsiveness, lung inflammation, mucin gene expression and serum chitinase responses in mice. Effective dual blockade of IL-13 and IL-4 resulted in greater therapeutic benefit than was achieved by targeting either cytokine alone [83], and clinical trial results of such an approach are awaited with interest.…”

Protein Biomarkers in Asthma

“…In particular, IL-4 is considered to be the predominant cytokine of the Th2 pathway in allergic airway inflammation. Briefly, in asthma pathogenesis, IL-4 induces differentiation of Th2 lymphocytes from naive T cells leading to Th2 cytokine release; IL-4 induces the IgE isotype switch and mucus secretion; IL-4 then induces the adhesion molecules on endothelial cells leading to the promotion of fibrosis and thrombosis and primes the vessel wall for eosinophil extravasation [44]. IL-4 has been reported as a trigger for barrier dysfunction in airway epithelial cells, but another study found that only Th1 cytokines affect epithelial barrier function [99].…”