Abstract 1163: Preclinical investigation of ADCT-242, a novel exatecan-based antibody drug conjugate targeting Claudin-6, as single agent or in combination in ovarian and non-small lung cancer models

Abstract Claudin-6 expression is upregulated in ovarian cancer, testicular cancer, endometrial cancer, non-small cell lung cancer (NSCLC) and gastric cancer. ADCT-242 is a novel exatecan based antibody-drug conjugate directed against human Claudin-6. Previous preclinical data demonstrated that ADCT-242 has potent, specific anti-tumor activity in Claudin-6 expressing cell line-derived xenograft (CDX) models and exhibited a good tolerability profile up to 40 mg/kg in cynomolgus monkeys, indicative of a favourable preclinical therapeutic index. Here, we further investigated the anti-tumor activity of ADCT-242 in the OVCAR-3 CDX model, and benchmarked its activity against AB3-7-MMAE, an auristatin-based Claudin-6-targeted ADC. Furthermore, the anti-tumor activity of ADCT-242 in combination with olaparib, bevacizumab or platinum-based drug, such as cisplatin, was investigated in vitro and in vivo in Claudin-6 positive ovarian models. Finally, single agent activity of ADCT-242 in patient-derived xenograft (PDX) models of NSCLC was evaluated. In the OVCAR-3 human ovarian CDX model (H-score 164), ADCT-242 demonstrated dose-dependent anti-tumour activity across the 0.5, 1 and 2 mg/kg dose range. At 2 mg/kg, 6/8 mice were complete responders (CR), 5 of which were tumor-free survivor (TFS) at the end of the study on Day 42. In this model, a single dose at 0.5, 1 and 2 mg/kg of ADCT-242 was associated with superior anti-tumor activity when compared to AB3-7-MMAE, dosed QWx3 at 2.5 or 5 mg/kg. In vitro, ADCT-242 in combination with olaparib showed synergistic cytotoxic effects in PA-1 and OVCAR-3 cells (as assessed by the Chou-Talalay method). Anti-tumor activity of ADCT-242 in combination with bevacizumab or platinum-based drug, cisplatin, was also investigated in the OVCAR-3 CDX model in vivo. Finally, in the NSCLC PDX models, ADCT-242 showed strong anti-tumor activity in 3 models. In the LU1144 model (H-Score 231), a single dose of ADCT-242 at 10 mg/kg resulted in 1/4 partial responders at the end of the study on Day 42. In the LU2049 mode (H-Score 255), a single dose of ADCT-242 at 10 mg/kg resulted in 4/5 CR and TFS at the end of the study on Day 42. In the LU11836 mode (H-Score 240), a single dose of ADCT-242 at 10 mg/kg resulted in 3/3 CR and TFS at the end of the study on Day 42. In conclusion, the data presented provide preclinical evidence for superior anti-tumor activity of ADCT-242 vs AB3-7-MMAE in an ovarian CDX model. Furthermore, ADCT-242 was associated with strong anti-tumor activity in NSCLC PDX models, whereas synergistic combination activity with approved drugs such as the PARP inhibitor olaparib, was demonstrated. Citation Format: Nicola Tsang, Elizabeth Horsley, Narinder Janghra, Chris Pickford, Lolke de Haan, Patrick H. van Berkel. Preclinical investigation of ADCT-242, a novel exatecan-based antibody drug conjugate targeting Claudin-6, as single agent or in combination in ovarian and non-small lung cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1163.