Nature: Autoimmune Drug Target Landscape and Development Strategies

Over the past 25 years, targeting the immune system by modulating cytokine signaling has been the cornerstone of innovation in autoimmune disease treatment. TNF inhibitors such as infliximab and adalimumab have become standard therapies for various indications. With the successful development of interleukin (IL) inhibitors and kinase inhibitors (e.g., JAKs) involved in downstream cytokine receptor signaling, pharmaceutical interest in cytokine modulation has further expanded.

On April 3, Nature Reviews Drug Discovery published an article titled "Trends in the drug target landscape for autoimmune diseases", analyzing the evolving pipeline for autoimmune diseases. It focused on the top 15 targets of products in Phase II, Phase III, and on the market in 2024, and compared them to the landscape in 2020.

▌Newly Approved Drugs

Since 2020, several first-in-class drugs for skin diseases have been approved, expanding the pool of druggable targets in autoimmune disease, including:

• IL-13 inhibitors tralokinumab and lebrikizumab for moderate-to-severe atopic dermatitis,
• IL-31Rα inhibitor nemolizumab for atopic dermatitis and prurigo nodularis,
• IL-36R inhibitor spesolimab for generalized pustular psoriasis.

The first selective TYK2 inhibitor deucravacitinib for psoriasis and the first JAK3/TEC inhibitor ritlecitinib for alopecia were approved in 2022 and 2023, respectively. JAK inhibitors continue to expand their indications, especially in rheumatology, such as ankylosing spondylitis and rheumatoid arthritis.

Progress in respiratory diseases includes the launch of:

• Tezepelumab, the first drug targeting TSLP for severe asthma,
• Dupilumab, the first biologic approved for chronic obstructive pulmonary disease (COPD).

The most competitive area is the development of innovative therapies for type 2 inflammatory diseases, including atopic dermatitis, chronic prurigo, chronic urticaria, asthma, and chronic rhinosinusitis with nasal polyps. Key targets include IL-5, IL-4, IL-13, TSLP, IL-25, IL-33, IgE, IL-31, BTK, and JAKs.

▌Research Hotspots and Strategies

In recent years, the most notable progress has been made in targeting members of the TNF superfamily beyond TNF-α. In 2020, the CD40/CD40 ligand axis was one of the few in Phase III trials. By 2024, drugs targeting OX40 and TL1A have entered Phase III trials—for instance, TL1A inhibitors are being developed for Crohn’s disease and ulcerative colitis.

Innovations in IL-targeting drugs include enhancing selectivity of marketed drugs (e.g., IL-17A/F inhibitors), extending dosing intervals (e.g., GSK's long-acting IL-5 inhibitor depemokimab), and new delivery methods (e.g., Eli Lilly's oral small molecules targeting IL-17). First-in-class opportunities exist for targets such as IL-4, IL-33, and IL-18.

IRAK4 has drawn significant interest due to its potential to suppress the entire IL-1 family (IL-1, IL-18, IL-33, IL-36—linked to psoriasis and asthma) and toll-like receptors with a single agent. TSLP is also gaining traction for its upstream role in type 2 inflammation, promoting IL-5, IL-4, and IL-13 secretion.

Downstream in immune signaling, TYK2 inhibitors targeting IL-12 and IL-23

Reference

[1] https://www.nature.com/articles/d41573-025-00061-7