Abstract LB203: Assessment of the safety, pharmacokinetics, and pharmacodynamics of a first-in-class cancer drug candidate E-602, a sialoglycan degrader, in non-human primates

E-602 is a novel, first-in-class, engineered human sialidase (Neu2) Fc fusion developed for cancer treatment by enhancing antitumor immunity through desialylating immunosuppressive sialoglycans. We have previously shown that E-602 cleaves off terminal sialic acids from surface sialoglycans on tumor and immune cells, restores the immune function of exhausted-like T cells, and enhances dendritic cell priming and activation of naïve T cells. E-602 has also demonstrated antitumor activity as a single agent in multiple syngeneic mouse tumor models. To support clinical development, we conducted a Good Laboratory Practice one-month repeat-dose toxicity study to evaluate E-602’s pharmacokinetic (PK) parameters, pharmacodynamic (PD) effects, and safety profiles in cynomolgus monkeys via weekly intravenous infusion of E-602 at 5, 30, 100, and 200 mg/kg for five doses. E-602 showed an apparent half-life (t1/2) of 4-6 hours and the terminal t1/2 of 10-30 hours with dose linearity from 30 mg/kg to 200 mg/kg. E-602 produced dose-dependent PD effects of desialylation of immune cells, such as T cells, monocytes, and dendritic cells, as monitored by flow cytometry. Despite the short half-life of E-602, the PD effect of immune cell desialylation sustained up to seven days for T cells, consistent with E-602’s enzymatic mechanism of action. Generally, E-602 was well tolerated up to 100 mg/kg with no dose-limiting adverse E-602-related changes in body weight, ophthalmology, neurological/musculoskeletal assessments, electrocardiogram parameters, respiratory rate, coagulation, urinalysis, organ weights, and histopathology. Animals in the 200 mg/kg dose group survived but showed isolated adverse histopathological changes with an uncertain relationship to E-602 administration. Therefore, the no-observed-adverse-effect-level (NOAEL) of E-602 was determined as 100 mg/kg in cynomolgus monkeys. In conclusion, the PK and PD data have supported the selection of cynomolgus monkeys as the toxicity species to evaluate E-602’s safety profile. E-602 has demonstrated sustained PD effects of immune cell desialylation up to seven days postdose and a wide safety margin with NOAEL of 100 mg/kg in cynomolgus monkeys. Citation Format: Lizhi Cao, Jenny Che, Ali Chesney, Rakesh Dixit, Nancy Zheng, Nicole Zane, James Broderick, Li Peng. Assessment of the safety, pharmacokinetics, and pharmacodynamics of a first-in-class cancer drug candidate E-602, a sialoglycan degrader, in non-human primates [abstra