Abstract 2875: IL1RAP-targeting antibody-drug conjugate: a novel therapeutic targeting both tumor cells and the tumor microenvironment

Abstract Background: Overexpression of Interleukin-1 receptor accessory protein (IL1RAP) has been linked to various malignancies, including acute myeloid leukemia, renal, urothelial and ovarian cancer as well as pancreatic ductal adenocarcinoma and non-small cell lung cancer, making it a promising therapeutic target. Expression on tumor cells, as well as throughout the tumor microenvironment, including expression on cancer associated fibroblasts, cancer endothelium and suppressive infiltrating immune cells sets it apart from most existing antibody-drug conjugate (ADC) targets. Here, an IL1RAP-targeting ADC was developed, consisting of a monoclonal antibody conjugated via a linker to a potent cytotoxic payload, designed to selectively deliver the cytotoxic agent to IL1RAP-expressing cells. The ADC was tested in vitro and in vivo to evaluate its therapeutic potential. Methods: A library of IL1RAP-binding clones was screened for affinity, cell binding, cynomolgus cross-reactivity and internalization. The selected antibody was conjugated to a maytansinoid using a cleavable linker. In vitro cell killing was assessed using SK-MEL5 WT and SK-MEL5 IL1RAP KO cells. The anti-IL1RAP ADC was tested in vivo using the human subcutaneous SK-MEL5 melanoma or the human BxPC3-CAF model (BxPC3 pancreatic cancer cells co-inoculated with pancreatic cancer-associated fibroblasts). Mice were treated with single (5mg/kg, SK-MEL5 and BxPC3-CAF) or multiple (3mg/kg or 10mg/kg in SK-MEL5; 5mg/kg or 10mg/kg in BxPC3-CAF) doses of the IL1RAP-targeting ADC to evaluate anti-tumor activity. A surrogate anti-mouse IL1RAP ADC was developed and used to assess toxicity in mice (C57Bl/6 1, 3, 5 or 10mg/kg antibody, Q1W x 2 doses; Balb/c 20mg/kg antibody, Q1W x 2 doses). Results and Conclusions: The selected clone showed low nanomolar affinity to human (KD 4.9nM) and cynomolgus (KD 5.4nM) IL1RAP, strong binding to IL1RAP-expressing cells (IC50 6.9nM) and robust internalization in IL1RAP-expressing cells. Conjugation to the payload did not compromise binding of the antibody to IL1RAP-expressing cells. In vitro, the IL1RAP-targeting ADC showed IL1RAP-dependent cell killing. Furthermore, the IL1RAP-targeting ADC demonstrated significant dose-dependent anti-tumor activity, with tumor regression observed in both in vivo models used. Both the anti-human IL1RAP ADC and the anti-mouse IL1RAP ADC were well tolerated in mice as indicated by kidney and liver histology, hematology assessment and body weight. These results suggest that ADCs targeting IL1RAP may have promising therapeutic potential and support clinical development for IL1RAP-targeting ADCs across a broad spectrum of cancers. Citation Format: Elin Jaensson Gyllenback, Camilla Rydberg Millrud, Olga Ab, David Liberg. IL1RAP-targeting antibody-drug conjugate: a novel therapeutic targeting both tumor cells and the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2875.