February 24 — Sanofi announced that its monoclonal antibody targeting IL-4Rα, dupilumab, has gained a new indication. The drug has been officially approved by the U.S. Food and Drug Administration for the treatment of allergic fungal rhinosinusitis (AFRS), becoming the first targeted therapy in this field.

Since Sanofi and Regeneron Pharmaceuticals jointly launched this first-in-class fully human monoclonal antibody targeting IL-4Rα, the commercial trajectory of dupilumab has been almost vertically upward. In 2024, dupilumab overtook Adalimumab to become the new “king of autoimmune drugs.” By 2025, its sales had surged to €15.714 billion (approximately US$18.29 billion), once again retaining the top position.

This explosive growth not only confirms the clinical value of the IL-4/IL-13 pathway as a central node in type 2 inflammation, but also accelerates its rise as a major battleground in global immunotherapy R&D. As more companies enter this arena, IL-4Rα is evolving from a deeply developed asset of a single company into a strategic high ground contested across the entire industry.

IL-4 / IL-13: The Core Engine of Type 2 Immunity

IL-4 and IL-13 are key members of the T helper type 2 (Th2) cytokine family, primarily produced by Th2 cells, ILC2 cells, eosinophils, and mast cells.

These cytokines bind to their receptor complexes to activate Janus family kinases—mainly JAK1 with JAK3 or JAK1 with TYK2—which subsequently phosphorylate signal transducer and activator of transcription 6 (STAT6). This signaling cascade ultimately drives the canonical type 2 immune response.

IL-4 can bind to two receptor complexes, whereas IL-13 can only bind to the type II receptor:

Type I receptor (IL-4Rα/γc):

Primarily expressed on hematopoietic cells. This receptor mediates IL-4–induced differentiation of Th0 cells into Th2 cells and promotes Ig class switching in B cells to IgE, representing a key mechanism in humoral immunity and allergic responses.

Type II receptor (IL-4Rα/IL-13Rα1):

Shared by IL-4 and IL-13, this receptor complex is mainly expressed on non-hematopoietic cells, including epithelial cells, fibroblasts, and smooth muscle cells. Activation of this complex triggers the JAK-STAT signaling pathway (primarily STAT6), leading to mucus secretion, mucosal barrier inflammation, tissue remodeling, and eosinophil recruitment.

Under normal physiological conditions, IL-4 and IL-13 receptor subunits are expressed at low levels under dynamic equilibrium. As key cytokines that initiate and maintain type 2 inflammatory responses, they are closely associated with a range of atopic diseases, such as atopic dermatitis (AD), asthma, and chronic rhinosinusitis with nasal polyps (CRSwNP). Currently, biologics targeting IL-4Rα, such as dupilumab, have been successfully used to treat these diseases.

It is important to note that cytokine functions are context-dependent. In rheumatoid arthritis, which is primarily driven by Th1/Th17 responses, IL-4 exhibits anti-inflammatory properties by suppressing the production of pro-inflammatory cytokines such as IL-1, IL-6, IL-8, and TNF-α by synovial cells.

In addition, studies in cancer biology have shown that several tumor types—including glioblastoma, breast cancer, and lymphoma—exhibit upregulated expression of IL-4Rα and IL-13Rα1 on tumor cells. This upregulation is associated with tumor progression and has also emerged as a potential target for immunotherapy.

Expanding Development Landscape

According to a report by Frost & Sullivan, the global market for IL-4Rα-targeted therapies is expected to reach US$28.7 billion by 2030, while the Chinese market is projected to reach US$4.08 billion.

Since 2017, dupilumab has been approved in multiple regions including the United States, European Union, and Japan. Targeting type 2 inflammatory pathways, its indications have expanded to include asthma, atopic dermatitis, chronic rhinosinusitis with nasal polyps (CRSwNP), and eosinophilic esophagitis, and have recently been extended to fungal infection–associated sinus inflammation.

February 27 marked a significant milestone for dupilumab in the global IL‑4/IL‑13 therapeutic landscape. The National Medical Products Administration (NMPA) approved two new indications: treatment of adult bullous pemphigoid (BP) and maintenance therapy for asthma in children aged 6 years and older. These approvals not only expand the clinical reach of dupilumab to previously underserved patient populations but also position China as an increasingly important market in the global development of type 2 inflammation–targeted therapies.

Dupilumab’s commercial success highlights the growing global impact of IL‑4/IL‑13–targeted strategies, yet the approaching patent expiration is already prompting a surge of “next-generation” competitors worldwide.

Internationally, numerous pipelines targeting IL-4/IL-13 are in clinical development, primarily in asthma and atopic dermatitis (AD). For example, Eli Lilly and Company’s IL-13 inhibitor Lebrikizumab is approved in multiple overseas markets and is expanding its footprint in China, aiming at the AD segment. Meanwhile, Pfizer is exploring broader respiratory applications with a Phase III trial of its IL‑4/IL‑13/TSLP trispecific antibody PF-07275315 for COPD, demonstrating the global strategy of multi-target approaches.

At the same time, China’s domestic innovation is rapidly advancing. On February 25, Akeso Biopharma’s IL-4Rα inhibitor mandokizumab (AK120), designed for moderate-to-severe atopic dermatitis, had its New Drug Application accepted by the NMPA. This signals that China is not only a major market for established biologics but also an emerging hub for novel IL‑4/IL‑13 therapeutics, with potential global implications.

Following closely, SSGJ611 from 3SBio had its New Drug Application accepted by the Center for Drug Evaluation (CDE), also targeting adult patients with moderate-to-severe atopic dermatitis (AD).

Meanwhile, next-generation approaches—including nanobodies, oral small-molecule IL-4Rα antagonists, and IL-4Rα–targeted antibody-drug conjugates (ADCs)—are still in early development. Nevertheless, these pipelines are beginning to outline a long-term innovation roadmap for the IL-4/IL-13 therapeutic space, indicating that future breakthroughs may extend beyond monoclonal antibodies and biosimilars.

Reference List

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