IL1RAP: Background, Research Mechanisms, Signaling Pathways, Related Diseases, and Latest Advances in Drug Development

1. Background and Significance of IL1RAP Research

Interleukin-1 receptor accessory protein (IL1RAP) is a key co-receptor in the IL-1 family signaling pathways, extensively involved in immune and inflammatory responses. Recent studies have revealed that the functions of IL1RAP extend far beyond this: it directly regulates cell proliferation by interacting with receptor tyrosine kinases such as FLT3 and c-KIT ^[1-3]. In various diseases, including acute myeloid leukemia (AML), solid tumors, atherosclerosis, and fibrotic diseases, IL1RAP is highly expressed and closely associated with poor prognosis ^[4-6]. These findings establish IL1RAP as a highly potential therapeutic target, driving the development of various targeted drugs.

2. Molecular Structure, Expression, and Physiological Functions of IL1RAP

IL1RAP is a core member of the IL-1 receptor family, acting as a co-receptor in the signal transduction of IL-1, IL-33, and IL-36 ^[1,2]. By binding to IL-1R1, IL-33R, and IL-36R, it activates downstream signaling pathways such as NF-κB and MAPK, regulating inflammatory responses ^[3]. Under normal physiological conditions, IL1RAP expression is low, but it is significantly upregulated in many diseases, particularly immune-related and oncological diseases ^[7]. For example, in AML, IL1RAP is highly expressed in leukemia stem cells (LSCs) and is associated with poor prognosis ^[4].

3. Signaling Pathways Mediated by IL1RAP

Within cells, IL1RAP cooperates with IL-1 family cytokine receptors to activate several important inflammatory and immune signaling pathways. By binding to IL-1R1, IL-33R, and IL-36R, it triggers MyD88-dependent signaling pathways, further activating NF-κB and MAPK, and promoting inflammatory responses ^[2,9].

3.1 Signaling Pathways of IL1RAP with IL-1 Family Cytokines

The IL-1 signaling pathway is the primary functional pathway for IL1RAP. In this pathway, after IL-1β binds to IL-1R1, IL1RAP cooperates to form a receptor complex, recruiting MyD88 and IRAK, and activating downstream signaling ^[9]. Activation of this signaling pathway leads to the expression of inflammatory genes such as IL-6 and IL-8, involved in various immune and inflammatory responses ^[9].

3.2 Interaction of IL1RAP with Receptor Tyrosine Kinases

Beyond IL-1 family cytokines, IL1RAP also directly interacts with receptor tyrosine kinases (such as FLT3 and c-KIT), promoting the proliferation of AML cells ^[4]. This IL-1-independent signaling pathway indicates that IL1RAP may play a more complex role in tumorigenesis and progression ^[4].

3.3 Regulatory Role of Non-coding RNAs on IL1RAP

Non-coding RNAs, particularly miRNAs and circRNAs, have been found to regulate IL1RAP expression. For example, circMAN1A2 affects IL1RAP expression by regulating miR-135a-3p, thereby promoting tumor cell proliferation ^[12].

4. Role of IL1RAP in Diseases

IL1RAP plays important roles in various diseases, especially in tumors, inflammatory diseases, and neurological disorders. Its high expression in many diseases is closely associated with poor prognosis ^[1,2]. The role of IL1RAP in different diseases is detailed below.

4.1 Hematologic Malignancies

The high expression of IL1RAP in acute myeloid leukemia (AML) makes it a key therapeutic target. Leukemia stem cells (LSCs) in AML overly rely on IL1RAP for proliferation and survival. IL1RAP enhances the growth of these tumor cells through interactions with FLT3 and c-KIT receptor tyrosine kinases ^[4]. Targeting IL1RAP has been shown to effectively inhibit the growth of LSCs and improve AML treatment outcomes ^[5]. For instance, the anti-IL1RAP antibody BOS-371 demonstrated promising anti-leukemic effects in preclinical studies, particularly in treating resistant AML ^[14].

4.2 Solid Tumors

IL1RAP is highly expressed in many solid tumors, such as pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), and melanoma, and is closely related to malignant characteristics and poor prognosis ^[3,4]. IL1RAP promotes tumor growth and metastasis by interacting with immune cells in the tumor microenvironment. Therapeutic strategies targeting IL1RAP, such as Nadunolimab (CAN10), have shown significant anti-tumor activity in clinical trials, especially in enhancing anti-tumor immunity and remodeling the tumor microenvironment ^[8].

4.3 Inflammatory and Autoimmune Diseases

IL1RAP plays a significant role in inflammatory and autoimmune diseases. By cooperating with IL-1 family cytokine receptors, it promotes inflammatory responses. For example, in atherosclerosis, IL1RAP promotes the secretion of inflammatory factors and chemokines, thereby exacerbating plaque formation ^[2]. In systemic sclerosis (SSc), upregulated IL1RAP expression drives the progression of fibrosis and immune responses ^[1]. Targeting IL1RAP has successfully reduced inflammatory responses and slowed disease progression in animal models ^[1,2].

4.4 Neurological Diseases

The role of IL1RAP in neurological diseases is gaining increasing attention. Studies have found that IL1RAP shows significant expression and functional roles in Alzheimer's disease (AD) and age-related macular degeneration (AMD). In AD, IL1RAP accelerates neurodegenerative pathology by promoting inflammatory responses ^[11][10]. Genetic polymorphisms of IL1RAP are closely related to the onset and progression of AD, where its expression may exacerbate pathological processes under specific genotypes ^[11].

4.5 Other Diseases

IL1RAP is also closely associated with the pathogenesis of other diseases. For instance, in sepsis and myocarditis, IL1RAP significantly influences disease progression by modulating immune and inflammatory responses ^[9,13]. Furthermore, high expression of IL1RAP in Ewing sarcoma promotes tumor metastasis by inhibiting apoptosis ^[7]. These findings indicate that IL1RAP plays important roles in various pathological processes, making it a potential therapeutic target for these diseases.

5. Research Progress on IL1RAP-Targeted Drugs

Innovative drug development targeting IL1RAP has become a hotspot in the treatment of tumors and inflammatory diseases. Currently, diverse drug modalities are being actively explored: Monoclonal antibodies, represented by Nadunolimab, have progressed to Phase II clinical trials for various solid tumors including pancreatic cancer; CAR-T cell therapies (e.g., CCTx-001) show potential in hematologic malignancies like relapsed acute myeloid leukemia; simultaneously, various IL1RAP-targeting antibody-drug conjugates (ADCs) and bispecific antibodies (e.g., BiF-002) have entered preclinical or early clinical research stages, aiming to eliminate cancer cells more precisely. Furthermore, this target shows broad therapeutic prospects in emerging autoimmune and inflammatory diseases such as hidradenitis suppurativa and psoriasis, attracting research involvement from several renowned institutions including Cantargia, AbbVie, and Sanofi, collectively promoting the expansion of this target into more disease areas.

Selected pipelines are listed in the table below:

Drug	Mechanism of Action	Drug Type	Indication (Disease Name)	Research Institution	Highest Phase
LAD191	IL1RAP inhibitor	Monoclonal antibody	Hidradenitis Suppurativa \| Autoimmune Diseases	Almirall SA	Phase 2
Nadunolimab	IL1RAP inhibitor \| Natural killer cells stimulator	Monoclonal antibody	Pancreatic Cancer \| Advanced Triple-Negative Breast Cancer \| Colorectal Cancer \| PDAC etc.	Cantargia AB	Phase 2
CCTx-001	IL1RAP inhibitor	Autologous CAR-T	Relapsed Acute Myeloid Leukemia	Advesya Ltd.	Phase 1/2
Anti-IL1RAP CAR-T cells (Zhongshan Hospital Fudan University)	IL1RAP modulators	CAR-T	Advanced Hepatocellular Carcinoma	-	Phase 1
ISB-880	IL1RAP inhibitor	Monoclonal antibody	Hidradenitis Suppurativa	Ichnos Glenmark Innovation, Inc. \| Almirall SA	Phase 1
CAN-10	IL1RAP inhibitor	Monoclonal antibody	Plaque Psoriasis \| Hidradenitis Suppurativa \| Systemic Sclerosis \| Myocarditis \| Atherosclerosis	Cantargia AB	Phase 1
AK-135	IL1RAP inhibitor	Biologics	Peripheral Nervous System Diseases	Zhongshan Kangfang Biopharmaceutics Co., Ltd.	Phase 1
SAR-445399	IL1RAP inhibitor	Monoclonal antibody	Inflammation	Sanofi	Phase 1
GSK3903371	IL1RAP inhibitor	Monoclonal antibody	Tumors	GSK Plc	Phase Indeterminate
CAN03	IL1RAP inhibitor	Monoclonal antibody	Autoimmune Diseases \| Inflammation \| Tumors	Innovagen AB \| University of Maryland School of Medicine \| Cantargia AB	Preclinical
Anti-IL1RAP ADC (Cantargia)	IL1RAP inhibitor	ADC	Tumors	Cantargia AB \| AbbVie, Inc.	Preclinical
BOS-371	IL1RAP inhibitor	Monoclonal antibody	Adult Acute Myeloid Leukemia	Zhongshan Genewise Biopharmaceutics Co., Ltd. \| Boston Pharmaceuticals, Inc.	Preclinical
ADV-101	IL1RAP inhibitor \| TOP1 inhibitor	ADC	Solid Tumors	Advesya Ltd.	Preclinical
3G-5	IL1RAP inhibitor	Monoclonal antibody	Inflammation	Cantargia AB	Preclinical
DXP-106	IL1RAP inhibitor	Monoclonal antibody	Tumors	Beijing Danxu Biopharmaceutical Co., Ltd.	Preclinical
STLX-2012	IL1RAP modulators	Biologics	Chronic Myelomonocytic Leukemia \| Myelodysplastic Syndromes \| Myelofibrosis etc.	Stelexis Therapeutics LLC	Preclinical
CSC-012-ADC	IL1RAP inhibitor	ADC	Acute Myeloid Leukemia	Cellerant Therapeutics, Inc.	Preclinical
IL1RAP ADC (Pfizer)	IL1RAP inhibitor	ADC	Solid Tumors	Pfizer Inc.	Preclinical
STLX-2400	IL1RAP modulators	Biologics	-	Stelexis Therapeutics LLC	Preclinical
BiF-002	CD3 stimulator \| IL1RAP inhibitor \| Immunoglobulin G modulator	Bispecific T cell engager	Acute Myeloid Leukemia	City of Hope National Medical Center	Preclinical
DX-2206	IL1RAP inhibitor	Monoclonal antibody	Tumors	Beijing Danxu Biopharmaceutical Co., Ltd.	Preclinical
Anti-IL-1RAcP Antibody (LEO Pharma)	IL1RAP inhibitor	Monoclonal antibody	Skin Diseases	LEO Pharma A/S	Preclinical

(Data as of November 6, 2025, source: synapse)

6. IL1RAP Research Tools

CUSABIO provides IL1RAP recombinant proteins and antibody products to assist you in developing drugs specifically targeting IL1RAP and exploring its application potential in the treatment of tumors and autoimmune diseases.

● IL1RAP Recombinant Proteins

Recombinant Human Interleukin-1 receptor accessory protein (IL1RAP), partial (Active); CSB-MP878844HU

Recombinant Macaca fascicularis Interleukin 1 receptor accessory protein(IL1RAP), partial (Active); CSB-MP5268MOV

Recombinant Rat Interleukin-1 receptor accessory protein (Il1rap), partial (Active); CSB-MP733954RA

Recombinant Mouse Interleukin-1 receptor accessory protein (Il1rap), partial (Active); CSB-MP730751MO

● IL1RAP Antibody

IL1RAP Recombinant Monoclonal Antibody; CSB-RA878844MA1HU

IL1RAP Recombinant Monoclonal Antibody; CSB-RA878844MA2HU

References

[1] C. Grönberg, S. Rattik, C. Tran-Manh, Xiang Zhou, Aleix Rius Rigau, Yi-Nan Li, A. Györfi, Nicholas Dickel, Meik Kunz, Alexander Kreuter, Emil-Alexandru Matei, Honglin Zhu, Petter Skoog, D. Liberg, J. Distler, T. Trinh-Minh.(2024). Combined inhibition of IL-1, IL-33 and IL-36 signalling by targeting IL1RAP ameliorates skin and lung fibrosis in preclinical models of systemic sclerosis.

[2] Megan Mulholland, M. Depuydt, G. Jakobsson, I. Ljungcrantz, A. Grentzmann, Fong To, E. Bengtsson, Elin Jaensson Gyllenbäck, C. Grönberg, S. Rattik, D. Liberg, A. Schiopu, H. Björkbacka, J. Kuiper, I. Bot, B. Slütter, D. Engelbertsen.(2024). Interleukin-1 receptor accessory protein blockade limits the development of atherosclerosis and reduces plaque inflammation.

[3] Qinghao Liu, Yaqi Ru, Yan Jiang, Huimin Li, Wenbo Li, Lan Yang, Qian Shi.(2024). Abstract 5794: DX2206, a humanized monoclonal antibody that targets IL1RAP, exhibits potent inhibition of IL-1 pathways and activities against tumors in vitro and in vivo.

[4] K. Mitchell, Laura Barreyro, Tihomira I. Todorova, Samuel J. Taylor, I. Antony-Debré, Swathi-Rao Narayanagari, L. Carvajal, Joana Leite, Zubair Piperdi, Gopichand Pendurti, Ioannis Mantzaris, E. Paietta, A. Verma, K. Gritsman, U. Steidl.(2018). IL1RAP potentiates multiple oncogenic signaling pathways in AML.

[5] Bauke de Boer, S. Sheveleva, K. Apelt, E. Vellenga, A. Mulder, G. Huls, J. Schuringa.(2020). The IL1-IL1RAP axis plays an important role in the inflammatory leukemic niche that favors acute myeloid leukemia proliferation over normal hematopoiesis.

[6] Yu Zhang, Zi-tong Zhang, Shiwei Wan, Jing Yang, Yu-Juan Wei, Huijing Chen, Wanzhu Zhou, Qiu-Yi Song, Shu-Xuan Niu, Ling Zheng, Kun Huang.(2023). ANGPTL3 negatively regulates IL-1β-induced NF-κB activation by inhibiting the IL1R1-associated signaling complex assembly.

[7] Hai-Feng Zhang, Christopher S. Hughes, Wei Li, Jianzhong He, Didier Surdez, Amal M. El-Naggar, Hongwei Cheng, A. Prudova, A. Delaidelli, G. Negri, Xiaojun Li, Maj Sofie Orum-Madsen, Michael M Lizardo, H. Oo, Shane Colborne, Taras Shyp, Renata Scopim-Ribeiro, C. Hammond, Anne-Chloé Dhez, Sofya Langman, J. Lim, Sonia H Y Kung, Amy Li, A. Steinø, M. Daugaard, Seth J. Parker, Ramon I. Klein Geltink, R. Orentas, Li-Yan Xu, G. Morin, O. Delattre, D. Dimitrov, P. Sorensen.(2021). Proteomic Screens for Suppressors of Anoikis Identify IL1RAP as a Promising Surface Target in Ewing Sarcoma.

[8] Eric Van Cutsem, S. Ochsenreither, J. Collignon, R. Eefsen, A. Ivanauskas, Svetlana Shatunova, Irina Vetter, E. Gyllenbäck, Petter Skoog, N. Losic, D. Tersago, Hana Starobova.(2024). Impact on chemotherapy induced peripheral neuropathy of nadunolimab, a first-in-class monoclonal antibody against IL1RAP, in patients with pancreatic cancer, with supportive mouse model data.

[9] D. Lema, G. Jakobsson, A. Daoud, David Elias, M. Talor, S. Rattik, C. Grönberg, Hannah Kalinoski, Elin Jaensson Gyllenbäck, Nadan Wang, D. Liberg, A. Schiopu, D. Čiháková.(2024). IL1RAP Blockade With a Monoclonal Antibody Reduces Cardiac Inflammation and Preserves Heart Function in Viral and Autoimmune Myocarditis.

[10] Elizabeth S Fisher, Kate Tubbesing, T. Bertucci, Katherine Stevens, J. Tcw, Alison M. Goate, Sally Temple.(2023). Investigation of IL1RAP in vascular endothelial and microglia interactions.

[11] Elizabeth S Fisher, Kate Tubbesing, Katherine Stevens, Steven A. Lotz, T. Bertucci, Sally Temple.(2024). Basic Science and Pathogenesis.

[12] Bo Li, Chuancui Hu, Da Zhao, Mingchao Nie, Xiaoli Wang.(2024). Circular RNA circMAN1A2 promotes ovarian cancer progression through the microRNA-135a-3p/IL1RAP/TAK1 pathway.

[13] Liou Huang, Chunrong Wu, Dan Xu, Yu-hui Cui, Jianguo Tang.(2024). IL1RAP Exacerbates Sepsis-Induced Pulmonary and Spleen Injury Through Regulating CD4+ T Lymphocyte Differentiation.

[14] K. West, Susheel Kumar, M. Scott, J. Emery, U. Steidl, Swathi-Rao Narayanagari, K. Mitchell, Fang Ren, Hua-Zong Ying, Qi Fei, T. Yang, Eric C. Svensson, G. Rosen.(2023). BOS-371, a monoclonal antibody against IL1RAP: Characterization in preclinical models of AML.