Keywords: IL-23, IL-23R, IL-17A, Th17 cells, psoriasis, inflammatory bowel disease, biologics, oral cyclic peptides, bispecific antibodies

Autoimmune diseases represent the second-largest therapeutic area globally, and the core logic of drug development in this field is undergoing profound changes. TNF-α inhibitors pioneered targeted therapy for autoimmune diseases, but the structural market boom is primarily driven by the IL-23/IL-17A signaling axis and the Th17 pathway it represents. By 2025, the combined market size of IL-12/IL-23, IL-17, and IL-23 drugs reached $41.7 billion, far exceeding the $14.1 billion market for TNF-α inhibitors.

In 2026, this field achieved multiple technological milestones: the FDA approved the world's first oral peptide drug targeting the IL-23 receptor, Icotrokinra; clinical data for IL-17A/F dual-target antibodies continued to emerge; and a domestically developed oral IL-23R antagonist peptide completed Phase I trials with promising signals. IL-23 and IL-17A, one located at the upstream regulatory node of Th17 immune responses and the other at the downstream effector execution end, together form the "golden dual pathway" for autoimmune drug development. This article systematically explores the biological logic and industry landscape of IL-23/IL-23R and IL-17A targets from four dimensions: molecular signaling mechanisms, disease associations, drug development landscape, and technological evolution.

1.1 Molecular Structure and Receptor Signaling of IL-23

IL-23 is a member of the IL-12 cytokine family, structurally composed of a heterodimer of the p19 and p40 subunits. The p40 subunit is shared with IL-12, while the p19 subunit is unique to IL-23. IL-23 is primarily produced by activated dendritic cells, macrophages, and other antigen-presenting cells. Its core biological function is to promote the differentiation, proliferation, and maintenance of Th17 cells, as well as the secretion of multiple pro-inflammatory factors, including IL-17A/F.

IL-23 signaling begins with its binding to the IL-23 receptor complex on the cell surface. IL-23R and IL-12Rβ1 together form a functional receptor complex. Upon ligand binding, the associated JAK2 and TYK2 kinases are activated, phosphorylating and activating downstream transcription factors STAT3 and STAT4. Activated STAT3 enters the nucleus and synergizes with the retinoic acid receptor-related orphan receptor γt (RORγt) to upregulate a series of pro-inflammatory genes, ultimately driving the production of key effector cytokines such as IL-17A, IL-17F, IL-22, and TNF-α.

1.2 Expression and Target Properties of IL-23R

IL-23R is primarily expressed on the surface of immune cells such as memory T cells, Th17 cells, γδT cells, and innate lymphoid cells (ILC3). In diseases like psoriasis, inflammatory bowel disease, and ankylosing spondylitis, IL-23R gene polymorphisms are significantly associated with disease susceptibility. IL-23 itself is overproduced in lesional areas by dendritic cells and keratinocytes. Since IL-23 is upstream in the inflammatory cascade, targeting IL-23 or its receptor can achieve broader inhibition of the Th17 pathway, covering multiple downstream effectors, including IL-17A.

IL-17A is the most extensively studied member of the IL-17 family, primarily produced by Th17 cells. Additionally, CD8+ T cells, γδT cells, NK cells, neutrophils, mast cells, and macrophages also express IL-17A.

Upon binding to the IL-17RA/IL-17RC receptor complex on target cells (e.g., keratinocytes, fibroblasts, epithelial cells), IL-17A recruits the adaptor protein Act1 to TRAF6, activating NF-κB, MAPK, and C/EBP signaling pathways. This induces the expression of chemokines (CXCL1, CXCL8, CCL20), cytokines (IL-6, G-CSF), and antimicrobial peptides. The primary physiological function of this axis is to recruit and activate neutrophils to defend against extracellular pathogens, but its overactivation in autoimmune contexts directly drives tissue inflammation.

Compared to upstream IL-23 targeting, IL-17A blockade more directly antagonizes inflammatory effects, acting rapidly in Th17-driven diseases. Their biological complementarity provides a theoretical basis for combination or dual-targeting strategies.

3.1 p19-Selective Antibodies (Precision Upstream Regulation)

Globally approved IL-23-targeting drugs fall into two categories: those targeting the p40 subunit shared by IL-12/IL-23 (e.g., ustekinumab) and those more precisely targeting the p19 subunit unique to IL-23. Currently, five p19-targeting antibodies are approved worldwide, including risankizumab, guselkumab, tildrakizumab, mirikizumab, and picankibart. The advantage of p19-selective inhibition lies in preserving IL-12-mediated immune defense while reducing potential risks from non-targeted pathway inhibition.

In terms of indications, IL-23p19 inhibitors have expanded from psoriasis to psoriatic arthritis and inflammatory bowel disease. In 2026, mirikizumab became China's first IL-23p19 inhibitor approved for both ulcerative colitis and Crohn's disease. Tildrakizumab's global market size reached approximately $1.76 billion in 2025, with China's IL-23p19 inhibitor market expected to grow at a 15.8% CAGR.

3.2 Oral IL-23R Antagonists (Paradigm Shift)

In March 2026, the FDA approved Icotrokinra (brand name Icotyde), the world's first oral peptide drug targeting the IL-23 receptor, for moderate-to-severe plaque psoriasis. Developed in collaboration with Protagonist Therapeutics, this cyclic peptide selectively blocks IL-23 binding to IL-23R, precisely intervening in upstream pathway signaling. Four Phase III studies involving 2,500 patients showed that the 100mg dose regimen achieved PASI 75, PASI 90, and PASI 100 response rates of 65%, 51%, and 26%, respectively, at 52 weeks, with a safety profile comparable to biologics.

Hansoh Pharma's HS-20118, another oral peptide selectively targeting IL-23R, completed Phase I trials in China, the U.S., and Singapore with 129 participants. It demonstrated positive efficacy signals and good safety in moderate-to-severe psoriasis patients, supporting a once-weekly oral dosing regimen. Global Phase II trials are planned.

3.3 Ultra-Long-Acting Antibodies

In 2026, the ultra-long-acting antibody ORKA-001 reported positive clinical data, potentially enabling "once-a-year" dosing frequency, marking a new phase of precision and durability for IL-23-targeted therapies.

4.1 IL-17A Monoclonal Antibody Landscape

The global IL-17A inhibitor market is driven by both imported and domestic products. Secukinumab (Novartis/Sanofi) was the earliest to validate the IL-17A target, with global sales reaching $6.668 billion in 2025. Domestic IL-17A monoclonal antibodies have been densely approved: Sairizumab (approved August 2024, China's first fully human IgG4 anti-IL-17A monoclonal antibody); Anmukitab (approved February 2026, the only IL-17A inhibitor in China with an 8-week maintenance dosing interval, Phase III data showing a PASI 100 response rate of 63.6% and a 0.7% anti-drug antibody incidence); Lusechizumab submitted for approval in March 2026; and Kangfang Biotech's Gumukizumab submitted its second indication application in January 2026.

4.2 IL-17A/F Dual-Target Antibodies

UCB's bimekizumab is the world's first IL-17A/F dual-target antibody. BE BOLD Phase III data presented at EULAR 2026 showed an ACR50 of 49.1% in active psoriatic arthritis patients, demonstrating superiority over the active control. Bimekizumab entered the Chinese market in March 2026, with global sales reaching €2.227 billion in 2025, a 267% year-on-year increase. Domestically, Livzon Pharma's Laikizumab has submitted for approval, outperforming secukinumab in head-to-head studies with faster onset and longer dosing intervals.

4.3 Continued Influx of Domestic New Drugs

Junshi Biosciences' Nokokizumab achieved positive results in psoriasis Phase III trials, with its NDA accepted by the NMPA. In psoriatic arthritis Phase II studies, JS005 significantly improved nail psoriasis severity scores.

IL-23 is upstream in Th17 immune responses, while IL-17A is downstream, creating a natural biological complementarity. Upstream targets like IL-23 inhibitors enable broader Th17 pathway inhibition, covering multiple effectors, including IL-17A. IL-17A blockade more directly antagonizes inflammatory effects, acting rapidly. This complementarity provides a scientific basis for dual-targeting and combination strategies.

For example, QX Biologic's IL-23p19/TL1A bispecific antibody completed a $540 million overseas licensing deal and initiated domestic IND processes after the first overseas Phase I dosing, targeting inflammatory bowel disease. Additionally, IL-17A/F dual-target antibodies have shown superior clinical data compared to single-target IL-17A inhibitors, further validating the clinical value of multi-target coverage within the pathway.

As the "golden dual pathway" for autoimmune-targeted therapy, the technological evolution of IL-23/IL-23R and IL-17A is becoming clear. In dosing modalities, the shift from injectable monoclonal antibodies to oral peptides and ultra-long-acting antibodies continues to improve patient convenience and long-term management. In target selectivity, p19-selective antibodies are gradually replacing p40 inhibitors, while oral IL-23R antagonist peptides open new molecular avenues. In multi-target coverage, IL-17A/F dual-target inhibition and combinations like IL-23+TL1A are expanding. Meanwhile, the rise of domestic R&D molecules is reshaping the global precision therapy landscape. Over the next five years, the IL-23/IL-17A signaling axis will remain the core engine of innovation in autoimmune disease drugs.

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