2P SOT102, a novel CLDN18.2-targeting antibody-drug conjugate for gastric and pancreatic cancer with a wide range of the tumor target expression

Claudin (CLDN) 18.2, a member of a large family of transmembrane proteins with distinct functions, has been shown to have high prevalence, predominantly in gastric and pancreatic cancer. Ectopic expression of CLDN18.2 was also described in certain proportion of ovarian cancer, NSCLC, hepatocellular cancer and colorectal cancer. Healthy tissue expression is restricted to the stomach epithelium. SOT102 represents a novel CLDN18.2 targeting antibody-drug conjugate based on a proprietary monoclonal antibody conjugated to a derivative of PNU-159682 via site-specific sortase mediated conjugation. The CLDN18.2 protein sequence is highly conserved across species with a 100% identity in the targeted extracellular loop among rodents, cynomolgus monkeys and humans. SOT102 showed an excellent specificity for CLDN18.2 and strong binding to the target followed by an efficient tumor cell killing. Preferential binding to selected patient-derived tumor tissues was observed ex vivo when compared to the healthy stomach tissues from mice and cynomolgus monkeys. Single-agent therapeutic activity of SOT102 was demonstrated in numerous patient-derived xenograft models (gastric, pancreatic, liver, colon and lung adenocarcinomas). Complete responses were observed in all CLDN18.2 positive models, irrespective of the intensity of staining. models, independent of CLDN18.2 expression levels, ranging from low (IHC1+) to high (IHC3+), with minimum effective doses between 0.2 mg/kg and 0.6 mg/kg. An acceptable tolerability profile was observed in the toxicity studies at 10 mg/kg (mouse), 6 mg/kg (rat) and 1 mg/kg (cynomolgus monkey), providing a therapeutic index of approximately 10. SOT102 demonstrated favorable pharmacokinetic properties with the half-live in the range of 8 days and 13 days in cynomolgus monkeys and rats, respectively. SOT102 remains stable without any significant loss of the payload both in vitro and in animal models. SOT102 represents a novel potent ADC with the potential to treat Claudin 18.2 expressing tumors irrespective of the intensity of expression. The first in human dose escalation trial has been initiated in patients with gastric and pancreatic cancer.