Claudin (CLDN) 18.2, a member of a large family of transmembrane proteins with distinct functions, has been shown to have a high prevalence, predominantly in gastric and pancreatic cancer. In addition, ectopic expression of CLDN18.2 was described for other cancer types including ovarian, lung, liver and colon, whereas healthy tissue expression is restricted to the stomach. SO-N102 represents a CLDN18.2 targeting antibody-drug conjugate based on a novel proprietary highly specific monoclonal antibody conjugated to a derivative of PNU-159682 using SMACTM technology for the therapy of patients with various CLDN18.2-positive solid tumors, mainly of gastric and pancreatic origin. The CLDN18.2 protein sequence is highly conserved in mammalians with 100% identity in the targeted extracellular loop among rodents, cynomolgus monkey and human. SO-N102 showed excellent specificity for CLDN18.2, strong binding to the target followed by efficient tumor cell killing. Preferential binding to selected patient-derived tumor tissues was observed ex vivo when compared to healthy stomach tissues from mice and cynomolgus monkey. Single-agent therapeutic activity of SO-N102 was demonstrated in 10 patient-derived mouse xenografts models (gastric, pancreatic, liver, colon and lung adenocarcinomas). Complete responses were observed in all models, independent of CLDN18.2 expression levels, ranging from low (IHC1+) to high (IHC3+), with minimum efficacious doses between 0.2 mg/kg and 0.6 mg/kg. An acceptable tolerability profile was observed in preliminary toxicity studies at 10 mg/kg (mouse), 6 mg/kg (rat) and 1 mg/kg (cynomolgus monkey). SO-N102 demonstrated favorable pharmacokinetic properties with half-lives in the range of 8 days and 13 days in cynomolgus monkey and rat, respectively. Stability of SO-N102 without any significant loss of the payload was demonstrated in vitro and in animals. Further toxicology studies in rats and cynomolgus monkeys were initiated, paralleled by process development and manufacturing activities with the plan to initiate the first clinical study with SO-N102 in patients in the first half of 2022.

Citation Format: Lenka Kyrych Sadilkova, Iva Valentova, Simona Hoskova, Pavel Vopalensky, Lukas Bammert, Roger Beerli, Ulrich Moebius, Radek Spisek. SO-N102, a novel CLDN18.2-targeting antibody-drug conjugate with strong anti-tumor effect in various solid tumors expressing low target levels [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1204.