Abstract 1769: Antibody blockade of IL1RAP signaling reduces metastasis in a breast cancer model

Abstract Blockade of tumor inflammation has potential for cancer therapy, both as a primary mechanism to counter tumor growth but also in combination with other therapeutics. IL-1 signaling has been shown preclinically to be involved in tumor development and chemoresistance of pancreatic cancer, and blockade of IL-1 was recently shown to have a significant clinical impact on development of lung cancer. IL-1 receptor associated protein (IL1RAP) is a coreceptor for the IL-1 receptor (IL1R1) and is required for IL-1 signaling. IL1RAP is expressed in a number of tumor tissues, including lung and pancreatic cancer, both on tumor cells and on infiltrating immune cells. We have, using antibodies directed against IL1RAP, shown the ability to target and kill IL1RAP-expressing tumor cells by ADCC, to inhibit IL-1 signaling in those cells and to reduce growth of transplanted human tumors in vivo. To study effects of IL1RAP targeting on the tumor microenvironment and in an immune competent setting, an antibody towards mouse IL1RAP was generated. This antibody potently blocks mouse IL-1 (IC50 = 13 nM), binds to IL1RAP protein with high affinity (Kd = 4,2 nM), labels IL1RAP-expressing cells and can be administered to mice with good pharmacokinetics. In vivo imaging shows that the antibody is not generally distributed in tissues but localizes to tumor sites after injection. Treatment of mice with orthotopically implanted 4T1 breast cancer cells did not reduce primary tumor growth significantly but reduced both the number of (47% reduction, p=0.02) and size of lung metastases. Interestingly, 4T1 tumor cells express low levels of IL1RAP and are not responsive to IL1RAP blockade, but the effects instead relate to effects on the tumor microenvironment. We conclude that targeting of IL1RAP can, in addition to induce ADCC of tumor cells and block their response to IL-1, also inhibit metastasis by affecting the tumor microenvironment. Citation Format: David Liberg, Per-Ola Önnervik, Matteo Riva, Liselotte Larsson, Göran Forsberg, Karin von Wachenfeldt. Antibody blockade of IL1RAP signaling reduces metastasis in a breast cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1769.