The "Dual Mission" of IL-23: Evolution from Autoimmune Diseases to Cancer Therapy

On September 26, the official website of CDE announced that the recombinant anti-interleukin-23 p19 subunit (IL-23p19) antibody, Pikanqibai (developed by Innovent Biologics), has been submitted for marketing approval as a new Class 1 drug for the treatment of moderate-to-severe plaque psoriasis. This drug is the first IL-23p19-targeted drug independently developed by a Chinese company to apply for marketing approval.

Targeted therapies against IL-23 have made significant progress in the field of autoimmune diseases, becoming a key research focus and treatment target. However, recent studies suggest that the role of IL-23 extends beyond autoimmune diseases, with its potential in cancer immunotherapy also being of growing interest. This indicates that the future of this target may intersect in both fields.

Structure and Function of IL-23

Interleukin-23 (IL-23) is an important pro-inflammatory cytokine that belongs to the interleukin-12 family. It is produced by specific cells of the immune system, such as macrophages and dendritic cells, and plays a central role in promoting inflammation during immune responses.

IL-23 consists of two subunits: IL-12p40 and IL-23p19, which typically bind to its receptor, IL-23R. This binding triggers intracellular signaling, leading to the proliferation and differentiation of Th17 cells, a process that is crucial for the development of autoimmune diseases.

The IL-23 signaling pathway involves two receptor chains and intracellular signaling proteins: Jak2 and Tyk2, as well as downstream JAK kinases, STAT3, and STAT4.

Upon stimulation, the receptor complex activates Jak2 and Tyk2, leading to phosphorylation of the receptor complex and the formation of docking sites for STAT proteins. STAT proteins are then phosphorylated, dimerize, and are transported to the cell nucleus, where they activate target genes.

Phosphorylation of STAT4 is essential for the secretion of IFN-γ and the subsequent differentiation of Th1 cells. Phosphorylation of STAT3 is crucial for the development of Th17 cells.

In summary, the IL-23 pathway can induce a cascade of cytokine responses, activate immune cells, and trigger immune reactions.

IL-23 and Autoimmune Inflammatory Diseases

IL-23 is a key cytokine that bridges innate and adaptive immune responses, playing a crucial role in driving early local immune reactions.

Initially, IL-23 was also shown to induce the production of IFN-γ, which is essential for Th1 responses and cell-mediated immunity against intracellular pathogens. Additionally, IL-23 plays a dominant role in activating NK cells, enhancing T cell proliferation, and regulating antibody production.

A substantial body of evidence suggests that elevated IL-23 levels are associated with various autoimmune diseases, including psoriasis, inflammatory bowel disease (IBD), rheumatoid arthritis (RA), and multiple sclerosis (MS).

Furthermore, IL-23 has been firmly established as a key maturation factor for Th17 cells, which are known to be major participants in autoimmune responses. As a result, IL-23 is a critical component of autoimmune disease signaling pathways. Being an upstream target for IL-17, IL-23 has become an important target for autoimmune drug development.

Global Competitive Landscape of IL-23

As autoimmune disease treatments rapidly advance, IL-23 has become a major target for global pharmaceutical companies.

Currently, five IL-23 antibodies are approved worldwide: ustekinumab, guselkumab, tildrakizumab, risankizumab, and mirikizumab. The first three have been approved in China, while risankizumab and mirikizumab's market applications are under review.

Ustekinumab

Ustekinumab is a groundbreaking drug in the field of autoimmune diseases. As one of Johnson & Johnson's best-selling products, it has maintained an 11.7% growth rate even after 14 years on the market. In 2023, its global sales reached $10.858 billion.

The patent for ustekinumab in the Chinese market has expired, and domestic biosimilars are now entering the registration/approval stages. In November 2023, HDM3001/QX001S (developed by Huadong Medicine and Qianxin Biotech) was approved for the treatment of adult moderate-to-severe plaque psoriasis, becoming the first approved biosimilar of ustekinumab in China. On November 26, CSPC Pharmaceutical Group Limited submitted the application for ustekinumab injection for domestic approval, making it the third biosimilar of ustekinumab to be submitted for marketing in China.

Tildrakizumab

Tildrakizumab was approved by the FDA in March 2018 for the treatment of moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy. It was approved in Europe in September 2018. On May 30, 2023, Tildrakizumab (marketed under the brand name Ilumya) was approved in China by NMPA after being introduced by Kangzhe Pharmaceutical.

Risankizumab

Skyrizi, developed by AbbVie, was first launched in 2019 and has gained approval for five indications: plaque psoriasis, psoriatic arthritis, Crohn’s disease, generalized pustular psoriasis, and erythrodermic psoriasis. Since its launch, Skyrizi has shown exceptional sales growth, with a 50% year-on-year increase in Q3 2024 sales, reaching $3.205 billion. It is expected to exceed $10 billion in annual sales by the end of 2024.

Guselkumab

On September 11, 2024, Johnson & Johnson announced that Guselkumab (brand name Tremfya) received FDA approval for the treatment of moderate-to-severe active ulcerative colitis (UC) in adults. Tremfya is the first and only dual-action IL-23 inhibitor approved for active UC treatment. Previously, guselkumab was approved for the treatment of moderate-to-severe plaque psoriasis and psoriatic arthritis.

On November 19, Johnson & Johnson also introduced an oral formulation of IL-23 antibody JNJ-2113 for treating inflammatory bowel disease (IBD) and a combination therapy JNJ-8408 (Tremfya + the TNF inhibitor golimumab) for refractory patients.

Mirikizumab

Mirikizumab was first approved in Japan in March 2023 and received FDA approval in October 2023 for the treatment of moderate-to-severe active ulcerative colitis (UC) in adults. It became the first IL-23p19 antagonist approved for this patient population.

On October 9, 2024, Mirikizumab (developed by Eli Lilly) submitted an application in China for approval to treat Crohn's disease (CD).

In addition to the already approved drugs, there are several domestic IL-23-targeted drugs currently under development. Some of the most advanced ones include AK101, Pikanqibai, and QX-004N. These drugs primarily work by inhibiting the active components of IL-23 to treat various autoimmune diseases.

AK101

AK101, also known as Iruoqi Monoclonal Antibody (IL-12/IL-23), is a novel, fully human monoclonal antibody targeting IL-12/IL-23 developed by Kangfang Biotech. The New Drug Application (NDA) for AK101 was accepted in August 2023. This is the first domestically developed IL-12/IL-23-targeted innovative drug to be submitted for marketing approval in China, aimed at treating moderate-to-severe plaque psoriasis and other related conditions.

Pikanqibai

On September 26, CDE announced that Innovent Biologics submitted its first-class new drug Pikanqibai (recombinant anti-IL-23p19 subunit antibody) for market approval, intended for the treatment of moderate-to-severe plaque psoriasis. This drug is the first IL-23p19-targeted drug developed by a Chinese company to apply for market approval. To date, no domestic IL-23 inhibitors have been approved for sale in China, making Pikanqibai the first in line to potentially become the first homegrown IL-23 inhibitor to hit the market.

QX-004N

In April 2024, Hansoh Pharma entered into a strategic collaboration with Qianxin Biotech regarding the latter's self-developed QX-004N monoclonal antibody. QX-004N is an IL-23p19 inhibitor in Qianxin Biotech's pipeline, under development for treating psoriasis and Crohn’s disease. The drug has already entered multiple clinical trials, with the most advanced phase being Phase 2 trials in China.

Overall, the development of IL-23-targeted drugs is highly competitive on a global scale, underscoring the significant potential of this target in treating autoimmune diseases. With several promising domestic candidates in clinical trials, China is positioning itself as a key player in the IL-23 drug development landscape.

IL-23’s "Cross-Border" Potential in Cancer Treatment

As a pro-inflammatory cytokine, could IL-23 be used in cancer treatment? Research is currently underway to investigate the roles of IL-23 in both inflammatory diseases and tumors.

Recent studies have shown that IL-23 exhibits tumor-promoting characteristics in cancer models, which are associated with poor prognosis.

On February 14, 2024, a research team from the University of Zurich, Switzerland, published a study in Nature Immunology, revealing a new role for IL-23 in the tumor microenvironment. The study found that tumor-associated macrophages (TAMs) are the primary source of IL-23, while tumor-infiltrating regulatory T cells (Tregs) are the main cells expressing the IL-23 receptor. IL-23 stabilizes the effector Treg cell program, enhancing their immunosuppressive capacity in the tumor microenvironment, which ultimately impedes anti-tumor immunity.

This study highlights the potential of the IL-23/IL-23R axis as a new target for cancer immunotherapy. By targeting this pathway, it may be possible to stimulate a more effective anti-tumor immune response.

With ongoing research, IL-23’s applications in autoimmune disease treatment continue to expand, and its potential as a therapeutic target is increasingly being explored. Now, IL-23 is "crossing over" into the cancer field, and there is growing anticipation regarding its potential in cancer therapy. In the future, IL-23 could become a major breakthrough in both cancer and autoimmune disease treatment, offering new hopes and possibilities for therapy.