IL-1RAP plays an essential role in disease progression by contributing to the signalling of IL-1-related cytokines, such as IL-1, IL-33, and IL-36.
IL-1RAP also interacts with other plasma membrane receptors such as tyrosine kinases FLT3, c-Kit, and xCT/CD98 supporting cell survival and proliferation.
IL-1RAP is predominantly expressed on the cell surface and serves as a crucial co-receptor. It enhances intracellular signalling from IL-1-related cytokines and aids in the functioning of plasma membrane transporters, including the xCT/CD98 transporter. IL-1RAP expression is low in healthy tissue but is upregulated in the tumour microenvironment of several haematological and solid cancers on the surfaces of cancer cells and certain stromal cells. This differential expression between healthy and tumour tissues presents a significant opportunity to develop novel treatment modalities such as cell therapy (CCTx-001) and antibody-drug conjugates (ADV-101).
CCTx-001 is an IL-1RAP directed genetically modified autologous T-cell immunotherapy that is being assessed for the treatment of AML.
CCTx-001 is composed of autologous CD8+ and CD4+ T-cells that express an anti-IL-1RAP-specific CAR. The anti-IL-1RAP-specific CAR consists of an scFv binding domain derived from a proprietary anti-IL-1RAP-specific monoclonal antibody, an IgG1 hinge region, the CD28 transmembrane domain followed by the intracellular co-stimulatory domains of both CD28 and 4-1BB/CD137 and the CD3zeta activation domain.
In vitro and in vivo studies have demonstrated the ability of CCTx-001 to proliferate, produce pro-inflammatory cytokines, and exhibit antitumour activity against IL-1RAP-positive AML cells and in AML tumour-bearing mice.
The drug candidate is provided as a cryopreserved dispersion of CD8+ and CD4+ frozen T-cells for infusion. The administration of CCTx-001 will be preceded by lymphodepleting chemotherapy with fludarabine and cyclophosphamide to increase the expansion, persistence, and antitumor activity of CCTx-001 (NCT06281847).
ADV-101 is a first-in-class ADC composed of Advesya’s proprietary humanized IgG1 monoclonal antibody that binds to human IL-1RAP. ADV-101 is conjugated to a cleavable linker with a topoisomerase I inhibitor as the payload. ADV-101 was designed to achieve an optimal safety and efficacy profile with improved stability in the periphery. Once bound to a cell expressing IL-1RAP, ADV-101 is internalized and degraded, releasing the topoisomerase I inhibitor in the intracellular space.
Topoisomerase I inhibitors work by interfering with the enzyme topoisomerase I, which is responsible for relieving torsional strain in DNA during replication and transcription. By stabilizing the transient DNA-topoisomerase I complex and preventing the re-ligation of the single-strand breaks, these inhibitors cause DNA damage that ultimately leads to cell death. Further diffusion of the payload in the neighbouring tumour microenvironment allows for bystander killing.
IL-1RAP is a promising target for an ADC approach, as it is overexpressed in many hematological and solid malignancies, such as AML, Ewing Sarcoma, and various types of solid tumours. Additionally, its ability to be internalized makes it an ideal target for delivering cytotoxic agents such as topoisomerase I inhibitor directly into IL-1RAP-expressing cells, enhancing the specificity and efficacy of the cytotoxic drug while minimizing off-target effects.
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