IL-1 inhibitor

“Chronic inflammation mediated by IL-1 signaling leads to tumor immuno-suppression by myeloid cells (MDSCs)”

• • Driving chronic non-resolving inflammation
  • Tumor angiogenesis
  • Activation of the IL-17 pathway,
  • Induction of myeloid-derived suppressor cells (MDSC)
    • IL-1 promotes recruitment of myeloid cells in tumors and their tumor promoting function
    • IL-1β neutralization leads to differentiation of MDSCs into M1 anti-tumor macrophages, and it prevents the differentiation of inflammatory monocytes into suppressive macrophages.

• Macrophage recruitment
• Invasion
• Metastasis (EMT)

• IL-1α is constitutively expressed by mesenchymal and epithelial cells and is released as an alarmin to signal cellular damage/necrosis or as a signal of DNA damage
• IL-1β is not constitutively expressed, but is upregulated, primarily in monocytes and macrophages, following NFκB activation
• IL-1 initiates a signaling cascade which results in NFκB-mediated transcription, Cox-2 induction and production of pro-inflammatory mediators such as IL-6, IL-8 and prostaglandin E2
• Endogenous regulation of signaling occurs via tight control of IL-1α and IL-1β activation and release as well as production of the IL-1 receptor antagonist (IL-1RA)

In the tumor: Interleukin-1 release from tumor cells and macrophages

• Polymorphisms of interleukin-1β (IL-1β) are associated with an increased risk of developing solid malignancies
• Stomach-specific expression of human IL-1β in transgenic mice leads to spontaneous gastric inflammation and cancer that correlates with early recruitment of myeloid-derived suppressor cells (MDSCs)
• IL-1β activates MDSCs ina vitro and in vivo through an IL-1RI/NF-kappaB pathway
• IL-1β transgenic mice deficient in T and B lymphocytes develop gastric dysplasia accompanied by a marked increase in MDSCs in the stomach
• Antagonism of IL-1 receptor signaling inhibits the development of gastric preneoplasia and suppresses MDSC mobilization
• These results demonstrate that pathologic elevation of a single proinflammatory cytokine may be sufficient to induce neoplasia and provide a direct link between IL-1β, MDSCs, and carcinogenesis

Read further: Tu et al. Cancer Cell. 2008 Nov 4;14(5):408-19.

• In a mouse model of RCC (RENCA), treatment with an anti-IL-1β antibody resulted in a significant decrease in tumor growth from day 10 to 18 compared to vehicle or anti-PD-1
• Combination treatment anti-IL-1β/anti-PD-1 or anti-IL-1β/cabozantinib potentiated the monotherapy effects
• anti-IL-1β therapy decreased the infiltration of granulocytic MDSCs (Gr-MDSC) (p=0.014) and increased M1-like TAM
• Based on these result the group at Columbia is conducting a clinical trial of neoadjuvant anti-IL-1β and anti-PD-1 in patients with high-risk RCC (NCT04028245)

Read further: Aggen et al Clin Cancer Res 2020.

• Isunakinra (EBI-005) was selected from a range of chimeric proteins based on the sequences of IL1Ra and IL-1β
• Both cytokines bind to separate parts of the IL1 receptor (IL1R1)
• Isunakinra was selected to show:
  • High potency (up to 20 x IL-1Ra)
  • No agonistic effect
  • Thermal stability

Read further: Hou et al PNAS 2013.

• In Buzzard’s phase I/II trial we will use IL-6, IL-8 and hsCRP as pharmacodynamic biomarkers of IL-1 inhibition. IL-6 and IL-8 are downstream of IL-1 and CRP is downstream of IL-6.
• A recent study of IL-6 and CRP levels in melanoma patients on checkpoint blockade – showed that high IL-6/CRP correlated with poor response and poor prognosis:
• “High levels of CRP and IL-6 at baseline were associated with a poor response and shorter survival after nivolumab alone, and CRP with ipilimumab alone or the combination of both drugs. High levels of CRP were also associated with shorter overall survival in the randomized CheckMate 066 study of chemotherapy compared to nivolumab. CRP and IL-6 are prognostic factors for checkpoint inhibition.”

Weber et al. Abstract presented at the 2019 ASCO Annual Meeting. J Clin Oncol. (2019) 37(15 Suppl):100.

• Buzzard is conducting a phase I/IIa trial in solid tumor patients Isunakinra taken as a daily subcutaneous injection (patient self-injection)
• Objectives:
  • Establish safety and PK of isunakinra in patients at different doses
  • Dose selection based on safety and effect on PD markers: CRP and IL-6 in plasma
  • Establish safety and efficacy on biomarkers in combination with a PD-1/PD-L1 inhibitor
  • Biomarkers include cytokines, Gr-MDSCs, CD8+ T cells and other leukocyte subsets in tumor biopsies, Circulating tumor cells (CTCs)
• Study to be conducted under an IND in collaboration with dr Carlos Becerra at Baylor University, Dallas, TX
• Enrollment is ongoing
• See study description at: https://clinicaltrials.gov/ct2/show/NCT04121442.