Abstract 2726: Efficacy and candidate biomarker evaluation for the anti-mesothelin antibody drug conjugate (ADC) BAY 94-9343, mesothelin-ADC in mesothelin-positive preclinical xenograft models

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL BAY 94-9343 is a novel antibody drug conjugate consisting of a fully human monoclonal antibody directed against mesothelin conjugated with the maytansinoid derivative DM4 by a linker containing a disulfide bridge (SPDB) and currently in Phase I clinical testing. Mesothelin is expressed in a range of tumor types, such as mesothelioma, ovarian cancer, pancreatic cancer and lung cancer. Membrane-anchored forms may play a role in cellular adhesion and metastasis. Here we report on the correlation of tumor mesothelin antigen expression levels, as determined by a newly developed mesothelin IHC staining protocol, and the efficacy of BAY 94-9343 in 13 preclinical tumor models. Further, mesothelin levels in xenograft tumors were compared to those in clinical samples of human tumors. Efficacy of BAY 94-9343 in tumor models with high mesothelin expression levels were generally higher compared to models with low mesothelin expression. OVCAR6677, OVCAR6668 and MIAPaCa-meso models characterized by high expression of mesothelin showed 90-100 % tumor growth inhibition, when treated with 2.5 mg/kg BAY 94-9343. PAXF736 and PAXF1881, tumor models with no mesothelin expression, did not show tumor growth inhibition at 2.5 mg/kg mesothelin-ADC, but responded to higher doses. Analysis of mesothelin expression by IHC using human tumor samples (mesothelioma, ovarian and pancreatic cancer) demonstrated that tumor cell mesothelin expression varied both within and between tumor types. IHC scoring revealed that 92% of mesothelioma tumors, 80% of ovarian tumors, and 63% of pancreatic cancer tumors assayed were mesothelin positive. Mesothelin expression was stable when comparing primary ovarian cancers with relapsing tumor tissue from the same patient. Maximum mesothelin expression in ovarian cancer is at least 400,000 antigenic sites per cell determined by Quantibrite technology. In preclinical models analysis of serum mesothelin extracellular domain (ECD) by ELISA revealed an initial rise in serum mesothelin ECD as early as 1 days after 10 mg/kg BAY 94-9343 followed by a decrease to below-baseline levels. Increased levels of the apoptosis marker CK18 were observed following BAY 94-9343 administration. Changes in serum mesothelin ECD levels as well as CK18 will be explored as an early pharmacodynamic (PD) response markers in clinical trials for BAY 94-9343. In summary, these results demonstrate that targeted delivery of DM4 resulted in higher efficacy of BAY 94-9343 in tumor models with high mesothelin expression. Responsive xenograft models were representative of clinical samples with respect to mesothelin expression scored by IHC. Quantification of mesothelin by IHC is a candidate stratification biomarker for the antibody drug conjugate BAY 94-9343 currently in Phase I testing. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2726. doi:1538-7445.AM2012-2726