Abstract 2704: Efficacy and candidate biomarker evaluation for the anti-MN immunoconjugate BAY 79-4620, MN-IC in MN (CAIX) positive preclinical xenograft models

Abstract

Abstract BAY 79-4620 is a novel immunoconjugate consisting of a fully human monoclonal antibody directed against MN (carbonic anhydrase IX, CAIX) conjugated with the auristatin derivative MMAE currently in Phase I clinical testing. MN is overexpressed in a range of tumor types, such as gastric cancer, non-small cell lung cancer, pancreatic cancer or colorectal cancer. CAIX expression is regulated by HIF-1α and therefore associated with tumor hypoxia. Here we report on the correlation of tumor CAIX antigen expression levels, as determined by a newly developed CAIX IHC staining protocol, and the efficacy of BAY 79-4620 in six preclinical tumor models. Further, CAIX levels in xenograft tumors were compared to those in clinical samples of human tumors. Efficacy of BAY 79-4620 in tumor models increased with their CAIX expression levels. HeLa-MaTu, HT29 and PC3mm2 models characterized by the highest expression of CAIX showed 56-92 % tumor growth inhibition, when treated with 1 mg/kg BAY 79-4620. Hs746T, the tumor model with the lowest CAIX level, did not show tumor growth inhibition at 1 mg/kg MN-IC, but responded to higher doses. Analysis of CAIX expression by IHC using human tumor samples (gastric, CRC, NSCLC and breast) demonstrated that tumor cell CAIX expression varied both within and between tumor types. IHC scoring revealed that 95% of colon cancer tumors, 55% of NSCLC tumors, and 35% of breast cancer tumors assayed had ≥10% of cells scoring 2+ or 3+ by IHC. In preclinical models analysis of serum CAIX extracellular domain (ECD) by ELISA revealed an initial rise in plasma CAIX ECD as early as 2 days after 30 mg/kg BAY 79-4620 followed by a decrease to below-baseline levels. In two out of three models tested, changes or increased levels of the apoptosis marker CK18 were observed following BAY 79-4620 administration. Changes in serum CAIX ECD levels as well as CK18 will be explored as an early pharmacodynamic (PD) response markers in clinical trials for BAY 79-4620. In summary, these results demonstrate that targeted delivery of MMAE resulted in higher efficacy of BAY 79-4620 in tumor models with high CAIX expression. Responsive xenograft models were representative of clinical samples with respect to CAIX expression scored by IHC. Quantification of MN (CAIX) by IHC is a candidate stratification biomarker for the immunoconjugate BAY 79-4620 currently in Phase I testing. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2704.