Slide 1: Blocking IL-1, IL-33 and IL-36 Signaling with the Anti-IL1RAP Antibody mCAN10
Blocking IL-1, IL-33 and IL-36 Signaling with the Anti-IL1RAP Antibody mCAN10 Ameliorates Inflammation and Fibrosis in Preclinical Models of Systemic Sclerosis Caitriona Grönberg1, Sara Rattik1, Meik Kunz2, Thoung Trinh-Minh3, Cuong Tran- Manh3, Xiang Zhou3, Petter Skoog1, David Liberg1 and Jörg Dis
Slide 2: Disclosures
Disclosures I have the following relevant financial relationship(s) to disclose: Shareholder: Cantargia AB Employee: Cantargia AB Patent: Coinventor of patent covering the anti-IL1RAP Ab CAN10, Cantargia AB SR, PS, and DL are employees and shareholders of Cantargia AB. SR and DL are coinventors of t
Slide 3: CAN10 – a humanized monoclonal antibody blocking IL1RAP signaling
CAN10 – a humanized monoclonal antibody blocking IL1RAP signaling IL IL36R IL1RAP blockade by CAN10 for diseases involving multiple IL1RAP-dependent pathways
Slide 4: IL1RAP is involved in both inflammation and fibrosis
IL1RAP is involved in both inflammation and fibrosis Adapted from Xu et al., Front. Immunol. 2019
Slide 5: CAN10 blocks human dermal fibroblast activation by IL-1 and IL-36
CAN10 blocks human dermal fibroblast activation by IL-1 and IL-36 IL-1, IL-36 CAN10 CXCL1 Human dermal 6hrs IL-6 qPCR IL-8 fibroblasts MCP3 IL-1 stimulated IL-36 stimulated CXCL1 C X C L 1 1.0 1 IL6 IL 6 0.5 IL8 IL 8 0 0 MCP3 M C P 3 -0.5 - CAN10 - CAN10 - CAN10 - C A N 1 0 - C A N 1 0 - C A N 1 0 +
Slide 6: IL1RAP is expressed in SSc skin
IL1RAP is expressed in SSc skin 2 publicly available human SSc cohorts show differential expression of IL1RAP and associated genes in SSc skin Healthy SSc Mahoney et al. 2015 GSE59787 Skaug et al. Ann Rheum Dis 2020. GSE130955
Slide 7: Bleomycin induces IL1RAP and related genes in mouse skin
Bleomycin induces IL1RAP and related genes in mouse skin Il36r Il1r1 Il1r2 Il1b Il1rn Il1a Cxcl1 Il33 Il6 Il36g Il36a Il36b Il1rap St2 Decato et al. 2022, GSE132869
Slide 8: IL1RAP-blockade inhibits bleomycin-induced skin fibrosis
IL1RAP-blockade inhibits bleomycin- induced skin fibrosis NaCl 6wks + Isotype BLM 6wks + Isotype mCAN10 Twice W 10 mg/kg BLM 2.5mg/kg (daily s.c.) Nintedanib QD 50 mg/kg BLM 3wks + BLM 6wks + Isotype mCAN10 C57BL/6 Established fibrosis Termination N=10 per group Week 3 Week 6 Dermal thickness Myofib
Slide 9: Therapeutic treatment with mCAN10 in two additional experimental SSc models
Therapeutic treatment with mCAN10 in two additional experimental SSc models Topo I Mouse model: BLM Topo cGvHD Skin fibrosis + + + C57Bl/6 Lung fibrosis + + Topo autoantibodies + cGvHD Resemble severe patients (+) + Established fibrosis week 3
Slide 10: Therapeutic treatment with mCAN10 reduces Topo I and cGvHD skin fibrosis
Therapeutic treatment with mCAN10 reduces Topo I and cGvHD skin fibrosis Dermal thickness Myofibroblast count Hydroxyproline 3 ✱✱ ✱✱ ✱✱ No fibrosis control 3 5 ✱ ✱✱ (CFA/NaCl) ✱✱ Topo I Fold change 4 Fold change Fold change 2 2 3 1 1 2 1 0 0 PBS Iso mCAN10 Nint. 0 PBS Iso mCAN10 Nint. PBS Iso mCAN10
Slide 11: ...and lung fibrosis in the same models
...and lung fibrosis in the same models No fibrosis PBS Isotype Ab mCAN10 Ab Nintedanib Trichrome Masson Topo model cGvHD model Ashcroft score Collagen area Ashcroft score Collagen area ✱✱✱✱ ✱✱✱✱ 4 ✱ 3 6 5 ✱✱✱✱ ✱✱✱✱ ✱✱✱ ✱✱✱✱ ✱✱ 4 Fold change Fold change Fold change Fold change 3 2 4 3 2 2 1 2 1 1 0
Slide 12: mCAN10 resets gene expression in cGvHD skin
mCAN10 resets gene expression in cGvHD skin Positive regulation of humoral immune response Chemokine receptors bind chemokines Positive regulation of acute inflammatory response VCAM1 ICAM1 Regulation of lymphocyte IL-6 chemotaxis CXCL9 Cytokines and inflammatory CCL5 (RANTES) Response MCP3 (CCL7) C
Slide 13: Generation of a molecular fingerprint of CAN10 treatment
Generation of a molecular fingerprint of CAN10 treatment Differentially expressed genes in human systemic sclerosis skin were compared to differentially expressed genes in the scGvHD model 449 genes were commonly deregulated in the mouse Skaug et al 2020 40% model and the human disease, CAN10 treatm
Slide 14: IL1RAP is a novel and promising target in treatment of SSc
IL1RAP is a novel and promising target in treatment of SSc • IL1RAP is required for signaling through the IL-1, IL-33 and IL-36 receptors • IL1RAP and the IL-1/-33/-36 signaling systems have multiple roles in inflammation and fibrosis • IL1RAP and related genes are upregulated in skin of SSc patient
Slide 15: Cantargia Team and Prof J. Distler's Lab
Cantargia Team Prof J. Distlers Lab Lund, Sweden Heinrich-Heine-Universität Düsseldorf, Germany • Sara Rattik, PhD • Jörg Distler, Prof med Dr • Petter Skoog, PhD • Meik Kunz, PhD (Erlangen) • David Liberg, PhD • Thoung Trinh-Mink, PhD • Coung Tran-Manh, PhD • Xiang Zhou, PhD