Impact on chemotherapy induced peripheral neuropathy of nadunolimab, a first-in-class monoclonal antibody against IL1RAP, in patients with pancreatic cancer, with supportive mouse model data.
Authors: Van Cutsem Eric , Ochsenreither Sebastian , Collignon Joelle , Eefsen Rikke Løvendahl , Ivanauskas Audrius , Shatunova Svetlana , Vetter Irina , Gyllenbäck Elin Jaensson , Skoog Petter , Losic Nedjad , Tersago Dominique , Starobova Hana 
Published: June 2024

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Background: Chemotherapy induced peripheral neuropathy (CIPN) is one of the major nonhematological adverse events arising from chemotherapies. CIPN is a neuroinflammatory condition that can be driven by immune cell activation and interleukin-1 (IL-1) release. Nadunolimab is a fully humanized monoclonal IgG1 antibody targeting IL1 receptor accessory protein (IL1RAP). Through binding IL1RAP, nadunolimab can induce ADCC of IL1RAP-expressing tumor cells and inhibits tumor-promoting signals mediated by both IL-1α and IL-1β in the tumor microenvironment. The phase I/IIa CANFOUR trial of nadunolimab in combination with nab-paclitaxel and gemcitabine (GN) in previously untreated, unresectable, locally advanced or metastatic PDAC, showed promising efficacy with median OS: 13.2 months; median iPFS: 7.2 months; 1-year survival: 58% and iORR: 33%, with a good safety profile. Notably, only 1 of 73 patients reported a grade ≥ 3 peripheral neuropathy suggesting that targeting IL1RAP may also alleviate the neuroinflammation leading to CIPN. Methods: To assess the potential neuroprotective activity of nadunolimab, we investigated the impact of nadunolimab on CIPN in the CANFOUR trial where 73 PDAC patients received nadunolimab at 1 mg/kg (n=20), 2.5 mg/kg (n=20), 5 mg/kg (n=25) or 7.5 mg/kg (n=8) in combination with GN. Adverse events were monitored at weekly to biweekly intervals. Relations between study drugs dosing and occurrence, severity and timing of adverse events indicative of CIPN were investigated using exploratory statistical analyses. In mice, CIPN was induced by i.p. administration of vincristine at 0.5 mg/kg, or nab-paclitaxel at 4 mg/kg. The effects of an anti-mouse IL1RAP surrogate antibody (i.p. at 10 mg/kg) on CIPN were evaluated using electronic von Frey apparatus, Parallel Rod Floor apparatus and grip strength meter. Results: Among the 73 PDAC patients in CANFOUR, patients in the individual 2.5 mg/kg, 5 mg/kg and 7.5 mg/kg dose groups all had trends towards lower incidence of onset and longer time to onset of CIPN compared to the 1 mg/kg group. When pooled, patients in the 2.5-7.5 mg/kg dose groups compared to the 1 mg/kg dose group had a lower incidence of any-grade CIPN; 36% vs 60% (Chi-square test p=0.06) and a significantly longer time to onset; median not estimable vs 112 days (hazard ratio=0.48, log-rank p=0.04). In mice, vincristine and nab-paclitaxel caused long-lasting (2 weeks) CIPN. This was abrogated by co-administration of the anti-mouse IL1RAP surrogate antibody, without a negative impact on motor performance, blood values or animal body weight. Conclusions: Data from PDAC patients receiving nadunolimab + GN and experiments in preclinical models suggest that targeting IL1RAP by nadunolimab may combine antitumor activity with potent reduction of CIPN. Clinical trial information: NCT03267316 .