Abstract 2269: The anti-IL1RAP antibody CAN04 increases tumor sensitivity to platinum-based chemotherapy
Authors: Millrud Camilla Rydberg , von Wachenfeldt Karin , Falk Hanna Håkansson , Forsberg Göran , Liberg David 
Published: September 2020

Abstract
Interleukin-1 (IL1) receptor accessory protein (IL1RAP) is a co-receptor of the IL1 receptor (IL1R1) and is required for IL1 signaling. IL1RAP is overexpressed in various solid tumors, both on cancer cells and in the tumor microenvironment. CAN04 is a fully humanized antibody that binds IL1RAP with high affinity (Kd = 1.10 pM), disrupts IL1α and IL1β signaling (IC50 = 3.9 and 4.1 nM respectively) and is glycoengineered to mediate an enhanced antibody-dependent cellular cytotoxicity (ADCC, EC50 &lt; 1 nM). Currently, CAN04 is in development for non-small lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDAC), two indications with high expression of IL1RAP and where IL1 signaling has been proven important for tumor development.
IL1 has been implicated in the resistance to certain chemotherapy regimens, including gemcitabine in PDAC. However, less is known about the relationship between IL1 and platinum-based chemotherapy, which is commonly used both in NSCLC and PDAC. In order to study effects of IL1RAP targeting in combination with platinum compounds we used the syngeneic MC38 tumor model with a mouse surrogate CAN04 antibody (mCAN04). This antibody blocks IL1α and IL1β signaling and induces Antibody-Dependent Cellular Phagocytosis (ADCP) of IL1RAP-positive cells. In MC38 tumors, IL1RAP is found both on MC38 tumor cells and on infiltrating cells in the tumor stroma. Treatment of MC38 tumors showed a strong synergistic effect between mCAN04 and cisplatin, carboplatin or oxaliplatin (up to 3 times stronger tumor growth inhibition compared to either therapy alone). Interestingly, we also observed a decreased weight loss in the combination arms indicating a reduced platinum-related toxicity.
Platinum doublets, such as cisplatin/gemcitabine, are used as standard of care in NSCLC. IL1RAP is abundantly expressed in NSCLC and both IL1α and IL1β is present in the tumor stroma. We investigated a NSCLC patient-derived xenograft that express IL1RAP, IL1R1, IL1α and IL1β. In vitro, this model responds to IL1 stimulation with an increase in e.g. IL6 expression, which can be blocked completely by addition of CAN04. When combining CAN04 with cisplatin or carboplatin in this model an increased effect could be seen which was more than additive (up to 3 times either treatment alone). Again, a reduced weight loss was detected in the combination arms compared to treatment with the platinum compounds alone. Finally, the CAN04/cis/gem triplet showed an even stronger efficacy compared to either chemotherapy alone or the cis/gem doublet.
In summary, targeting IL1RAP with CAN04 blocks IL1 mediated inflammatory signaling and synergize with platinum-based chemotherapy to increase the anti-tumor effect and reduce toxicity. CAN04 is currently in phase II studies in NSCLC and PDAC in combination with chemotherapy (CANFOUR, NCT03267316), these data underscore the rationale for targeting IL1RAP with chemotherapy.
Citation Format: Camilla Rydberg Millrud, Karin von Wachenfeldt, Hanna Håkansson Falk, Göran Forsberg, David Liberg. The anti-IL1RAP antibody CAN04 increases tumor sensitivity to platinum-based chemotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2269.