Blockade of IL-1α and IL-1β signaling by the anti-IL1RAP antibody nadunolimab (CAN04) mediates synergistic anti-tumor efficacy with chemotherapy

Millrud, Camilla Rydberg; Deronic, Adnan; Grönberg, Caitríona; Gyllenbäck, Elin Jaensson; Wachenfeldt, Karin von; Forsberg, G.; Liberg, David

doi:10.1007/s00262-022-03277-3

Cited by 4 publications

(5 citation statements)

References 40 publications

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“…Finally, to study if IL1RAP blockade can limit the release of chemokines in vitro , we stimulated bone marrow-derived macrophages (BMDMs) and a mouse fibroblast cell line (NIH3T3) with IL-1, IL-33, or IL-36 in the presence of anti-IL1RAP or isotype control IgG and measured release of cytokines in the cell culture supernatant ( Figure 6 E ). Previous reports have shown that IL1RAP-related cytokines also target fibroblasts, 18 , 26 , 27 and fibroblasts contribute to the inflammatory response as well as to infarct size and cardiac remodelling post-acute myocardial infarction. 28 , 29 IL1RAP expression on NIH3T3 fibroblasts and BMDM before stimulation was detected by flow cytometry ( Figure 6 F and G ).…”

Section: Resultsmentioning

confidence: 99%

Interleukin-1 receptor accessory protein blockade limits the development of atherosclerosis and reduces plaque inflammation

Mulholland,

Depuydt,

Jakobsson

et al. 2024

Cardiovascular Research

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Aims The interleukin-1 receptor accessory protein (IL1RAP) is a co-receptor required for signalling through the IL-1, IL-33, and IL-36 receptors. Using a novel anti-IL1RAP-blocking antibody, we investigated the role of IL1RAP in atherosclerosis. Methods and results Single-cell RNA sequencing data from human atherosclerotic plaques revealed the expression of IL1RAP and several IL1RAP-related cytokines and receptors, including IL1B and IL33. Histological analysis showed the presence of IL1RAP in both the plaque and adventitia, and flow cytometry of murine atherosclerotic aortas revealed IL1RAP expression on plaque leucocytes, including neutrophils and macrophages. High-cholesterol diet fed apolipoprotein E–deficient (Apoe−/−) mice were treated with a novel non-depleting IL1RAP-blocking antibody or isotype control for the last 6 weeks of diet. IL1RAP blockade in mice resulted in a 20% reduction in subvalvular plaque size and limited the accumulation of neutrophils and monocytes/macrophages in plaques and of T cells in adventitia, compared with control mice. Indicative of reduced plaque inflammation, the expression of several genes related to leucocyte recruitment, including Cxcl1 and Cxcl2, was reduced in brachiocephalic arteries of anti-IL1RAP-treated mice, and the expression of these chemokines in human plaques was mainly restricted to CD68+ myeloid cells. Furthermore, in vitro studies demonstrated that IL-1, IL-33, and IL-36 induced CXCL1 release from both macrophages and fibroblasts, which could be mitigated by IL1RAP blockade. Conclusion Limiting IL1RAP-dependent cytokine signalling pathways in atherosclerotic mice reduces plaque burden and plaque inflammation, potentially by limiting plaque chemokine production.

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Section: Resultsmentioning

confidence: 99%

Interleukin-1 receptor accessory protein blockade limits the development of atherosclerosis and reduces plaque inflammation

Mulholland,

Depuydt,

Jakobsson

et al. 2024

Cardiovascular Research

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“…The most well-known IL-1-targeting agents include the recombinant form of the receptor antagonist IL-1Ra (anakinra), the anti-IL-1β mAb (canakinumab), the anti-IL-1α mAb (bermekimab, MABp1), the fusion protein consisting of the ligand-binding regions of IL1R1 and IL-1RAP linked to the Fc region of human IgG1 (rilonacept), and Nadunolimab (CAN04) [67], a fully humanized ADCC-enhanced IgG1 antibody that targets IL1RAP and blocks IL-1α and IL-1β signaling [2,12]. All these drugs have been investigated, andhave received formal approval from the drug regulatory agencies for several immunological disorders, and show a good safety profile at clinical level [2,12].…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

IL-1 Family Members in Bone Sarcomas

Landuzzi,

Ruzzi,

Pellegrini

et al. 2024

Cells

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IL-1 family members have multiple pleiotropic functions affecting various tissues and cells, including the regulation of the immune response, hematopoietic homeostasis, bone remodeling, neuronal physiology, and synaptic plasticity. Many of these activities are involved in various pathological processes and immunological disorders, including tumor initiation and progression. Indeed, IL-1 family members have been described to contribute to shaping the tumor microenvironment (TME), determining immune evasion and drug resistance, and to sustain tumor aggressiveness and metastasis. This review addresses the role of IL-1 family members in bone sarcomas, particularly the highly metastatic osteosarcoma (OS) and Ewing sarcoma (EWS), and discusses the IL-1-family-related mechanisms that play a role in bone metastasis development. We also consider the therapeutic implications of targeting IL-1 family members, which have been proposed as (i) relevant targets for anti-tumor and anti-metastatic drugs; (ii) immune checkpoints for immune suppression; and (iii) potential antigens for immunotherapy.

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“…These oncogenes include activating mutations in the epidermal growth factor receptor (EGFR) gene and translocations of the anaplastic lymphoma kinase (ALK) gene [ 102 ]. IL-1RAP was found overexpressed in NSCLC cell lines [ 103 ], and anti-IL-1RAP immunotherapy was recently successfully assessed in an NSCLC PDX preclinical [ 28 ] model, LU2503, on Balb/c mice.…”

Section: Role Of Il-1rap In Tumorsmentioning

confidence: 99%

“… Cancer types with demonstrated IL-1RAP overexpression [ 24 , 25 , 28 , 93 , 95 , 101 , 106 , 110 , 112 ]. Created with .…”

Section: Role Of Il-1rap In Tumorsmentioning

confidence: 99%

“…As this protein shows great therapeutic potential, two therapies that target IL-1RAP are currently undergoing clinical trials with one chimeric antigen receptor T-cells (CAR-T) therapy [ 27 ] and two immunotherapies using an antibody to activate the antibody-dependent cell-mediated cytotoxicity (ADCC) or by direct blockade of IL-1RAP [ 24 , 28 ].…”

Section: Introductionmentioning

confidence: 99%

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IL-1RAP, a Key Therapeutic Target in Cancer

Frenay

Bellaye

Oudot

et al. 2022

IJMS

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Cancer is a major cause of death worldwide and especially in high- and upper-middle-income countries. Despite recent progress in cancer therapies, such as chimeric antigen receptor T (CAR-T) cells or antibody-drug conjugate (ADC), new targets expressed by the tumor cells need to be identified in order to selectively drive these innovative therapies to tumors. In this context, IL-1RAP recently showed great potential to become one of these new targets for cancer therapy. IL-1RAP is highly involved in the inflammation process through the interleukins 1, 33, and 36 (IL-1, IL-33, IL-36) signaling pathways. Inflammation is now recognized as a hallmark of carcinogenesis, suggesting that IL-1RAP could play a role in cancer development and progression. Furthermore, IL-1RAP was found overexpressed on tumor cells from several hematological and solid cancers, thus confirming its potential involvement in carcinogenesis. This review will first describe the structure and genetics of IL-1RAP as well as its role in tumor development. Finally, a focus will be made on the therapies based on IL-1RAP targeting, which are now under preclinical or clinical development.

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Blockade of IL-1α and IL-1β signaling by the anti-IL1RAP antibody nadunolimab (CAN04) mediates synergistic anti-tumor efficacy with chemotherapy

Cited by 4 publications

References 40 publications

Interleukin-1 receptor accessory protein blockade limits the development of atherosclerosis and reduces plaque inflammation

Interleukin-1 receptor accessory protein blockade limits the development of atherosclerosis and reduces plaque inflammation

IL-1 Family Members in Bone Sarcomas

IL-1RAP, a Key Therapeutic Target in Cancer

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