Interleukin-4 receptor (IL-4R) has emerged as an ‘inspiring’ target for innovative therapies aimed at treating atopic diseases. This type-1 transmembrane protein plays a key role in the molecular pathway that drives a specific immune response pattern called type-2 inflammations. These inflammations are the root cause of several medical conditions including atopic dermatitis (AD) and certain types of asthma. A brief understanding the molecular pathway behind this immune response pattern is fundamental to elucidating the mechanism of drug action and recognizing the immense potential behind IL-4R alpha targeting drugs.

IL-4R cellular pathway

IL-4 and IL-13 are cytokines that have diverse biological and immunological effects on B-lymphocytes, monocytes, dendritic cells, and fibroblasts’ adjustment function. These cytokines bind to IL-4R alpha and IL-13R alpha to initiate the type-2 inflammation pathway that includes differentiation of Th2 cells, airway inflammation, and mucus production. In cases of allergic diseases such as AD, the type-2 inflammation pathway is first initiated by an abnormal secretion of cytokines stemming from an imbalance of Th1 and Th2 differentiation. Activated Th2 cells release cytokines including IL-4, 13, and 31, which activate downstream B cells to transform and produce IgE antibodies. In turn, mast cells and basophils are recruited to degranulate and produce inflammatory factors. Simultaneously, the secreted IL-4 and 13 continue to bind to its respective receptors (e. g. IL-4R) that repeatedly promotes TH2 differentiation and subsequent inflammation.

The signaling role of IL-4 and IL-13 in the type-2 inflammation pathway reveals IL-4R alpha as a prospective target for patients with abnormal type-2 inflammation responses. Unlike the single-target functions of drugs targeting IL-4 and IL-13 specifically, IL-4R alpha has an innovative mechanism similar to ‘bi-specific’ targets. Antibodies targeting IL-4R alpha prevents the binding of both IL-4 and IL-13 which blocks intracellular signaling, thereby regulating immune function through inhibition of Th2 cell differentiation, IgE synthesis, and inflammatory substances secretion. As a result, many pharmaceutical companies around the world have emphasized the development of IL-4R targeting-drugs in their pipelines.

Advances in drug research and development targeting IL-4R alpha (Sourced from Pharmacodia)

Currently, the only IL-4R alpha targeting drug available on the market is Dupilumab, which was jointly developed by Sanofi and Regeneron. In 2020, sales for Dupilumab exceeded $4 billion, with projections of over $10 billion by 2024. One of the main targets for Dupilumab is AD, otherwise known as eczema, which is a prevalent disease that affects millions of people. According to epidemiologic statistics from Frost & Sullivan, the number of patients suffering from AD has reached 649 million and is predicted to increase to 755 million people globally. Current first-line treatment for moderate-to-severe AD involves the use of topical creams and ointments to manage the severity of itching. However, for patients with uncontrolled AD, Dupilumab manages the inflammation before it even begins by inhibiting the inflammation signaling pathway. Its effectiveness has resulted in a multi-disciplinary consensus statement that emphasizes the use of Dupilumab as a first-line systemic treatment modality when topical therapy is ineffective. The success of Dupilumab in controlling severe cases of AD has helped broaden its clinical applications into other medical conditions including eosinophilic esophagitis, sinusitis, and certain cases of asthma.

Mechanism of Action of Dupilumab

Overall, IL-4R alpha is an extremely promising therapeutic target for the management and treatment of atopic diseases. ACROBiosystems has specially launched a series of IL-4R alpha/ IL-4/ IL-13 recombinant proteins, which are suitable for antibody screening and functional verification, to support the research and development of IL-4R alpha targeted drugs.

Product Features

Expressed by HEK293 cells – Recombinant proteins close to native conformation

Various species available – Human, Mouse, Cynomolgus / Rhesus macaque

Several tags offered – His & Avi Tag, His Tag, Fc Tag, Fc & Avi Tag

High purity and structural homogeneity – Verified by SDS-PAGE and SEC-MALS

High bioactivity – Verified by ELISA binding and competition experiments

Product List

Molecule	Cat. No.	Species	Product Description
IL-4 R alpha	ILR-H5221	Human	Human IL-4 R alpha / CD124 Protein, His Tag
	ILR-H82E9	Human	Biotinylated Human IL-4 R alpha / CD124 Protein, Avitag™, His Tag
	ILR-H5253	Human	Human IL-4 R alpha / CD124 Protein, Fc Tag
	ILR-H82F4	Human	Biotinylated Human IL-4 R alpha / CD124 Protein, Fc, Avitag™
	ILR-M5252	Mouse	Mouse IL-4 R alpha / CD124 Protein, Fc Tag
	ILR-M52H1	Mouse	Mouse IL-4 R alpha / CD124 Protein, His Tag
	ILR-C5258	Cynomolgus / Rhesus macaque	Cynomolgus / Rhesus    macaque IL-4 R alpha / CD124 Protein, Fc Tag
	ILR-C52H8	Cynomolgus / Rhesus macaque	Cynomolgus / Rhesus macaque IL-4 R alpha / CD124 Protein, His Tag
IL-4	IL4-H4218	Human	ActiveMax® Human IL-4 Protein, Tag Free
	IL4-H82E0	Human	Biotinylated Human IL-4 Protein, Avitag™, His Tag
	IL4-H52H9	Human	Human IL-4 Protein, His Tag (MALS verified)
	IL4-M52H5	Mouse	Mouse IL-4 Protein, His Tag
	IL4-C5259	Cynomolgus	Cynomolgus IL-4 Protein, Fc Tag (MALS verified)
IL-13	IL3-H52H4	Human	Human IL-13 Protein, His Tag
	IL3-H5256	Human	Human IL-13 Protein, Fc Tag
	IL3-H82E5	Human	Biotinylated Human IL-13 Protein, His, Avitag™
	IL3-C52H4	Canine	Canine IL-13 Protein, His Tag

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IL-2 and IL-2 Receptors

IL-2, IL-2R α, IL-2 R βγ, IL-2R αβγ

Affinity verified by SPR (Biacore)

Further Information

IL-6 and IL-6 Receptors

IL-6, IL-6 R alpha, gp130

ELISA/BLI/cell-based assay verified

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References

1. C. K. Oh, G. P. Geba, N. Molfino. Investigational therapeutics targeting the IL-4/IL-13/STAT-6 pathway for the treatment of asthma. European Respiratory Review 19, 46-54 (2010). DOI: 10.1183/09059180.00007609

2. Licari, A., Castagnoli, R., Marseglia, A. et al. Dupilumab to Treat Type 2 Inflammatory Diseases in Children and Adolescents. Pediatr Drugs 22, 295–310 (2020). https://doi.org/10.1007/s40272-020-00387-2.