SOT102, a novel CLDN18.2-targeting antibody-drug conjugate, exhibits strong therapeutic potential in solid tumors

BACKGROUND: Patients with gastric and pancreatic cancers, as well as other solid tumors including ovarian, lung, liver, and colon cancers, often lack effective therapeutic options. Claudin 18.2 (CLDN18.2) is a tumor-associated target that is predominantly expressed in gastric and pancreatic cancers but also found in several other tumor types. SOT102 is a novel antibody-drug conjugate directed against CLDN18.2, developed to provide a new therapeutic strategy for patients with CLDN18.2-positive tumors. METHODS: SOT102, composed of a proprietary monoclonal antibody (mAb) conjugated to the cytotoxic payload PNU-159682, was evaluated for binding, internalization, and cytotoxic effects in vitro. The in vivo antitumor activity was assessed in patient-derived xenograft (PDX) and cell line-derived xenograft (CDX) mouse models, both as monotherapy and the latter in combination with anti-PD1 antibody therapy. SOT102 pharmacokinetics and tolerability were further investigated in cynomolgus monkeys following intravenous administration. RESULTS: SOT102 demonstrated selective binding to CLDN18.2, with no detectable cross-reactivity to CLDN18.1, and efficient internalization into CLDN18.2-expressing cell lines, resulting in potent cytotoxic effects against tumor organoids with half-maximal activity ranging from 0.2 nM to 19.4 nM. Antitumor activity against PDX-derived mouse models was observed at a minimum effective dose of 0.2 mg/kg, with enhanced efficacy when combined with anti-PD1 antibody treatment. SOT102 exposure in cynomolgus monkeys was dose-dependent at doses between 0.3 mg/kg and 1 mg/kg with a half-life of approximately 7 days. An acceptable tolerability profile was observed, and the therapeutic window was defined between the minimum effective dose in mice and the highest non-severe toxic dose (HNSTD) of 0.6 mg/kg in cynomolgus monkeys. CONCLUSIONS: SOT102 exhibited strong antitumor activity in preclinical models of CLDN18.2-positive cancers and demonstrated a favorable pharmacokinetic and safety profile in non-human primates. These data were used to support clinical evaluation of SOT102 as a potential treatment option for patients with CLDN18.2-expressing solid tumors.