Abstract 579P
Background
MORAb-109 is an antibody-drug conjugate (ADC) that targets human mesothelin. Mesothelin has been reported to be overexpressed in a number of cancers, including mesothelioma, non-small cell lung carcinoma (NSCLC), pancreatic, ovarian, colorectal, and gastric cancers. MORAb-109 consists of the humanized anti-human mesothelin antibody 345A12 HC15 LC4 that utilizes Eisai’s site-specific conjugation technology RESPECT-L and was selected de novo as an antibody specifically for ADC generation. MORAb-109 also incorporates the tubulin-acting agent eribulin as the cytotoxic payload linked to the antibody through a cathepsin-cleavable self-immolative valine-citrulline linker. Eribulin is currently being investigated as an ADC payload in a folate-receptor alpha (FRA)-targeting ADC in an ongoing Ph 1 clinical trial (MOR202-J081-101).
Methods
For in vitro cytotoxicity assays, MORAb-109 was evaluated in 5-day assays using various tumor cell lines. Tumor-cell line-derived and patient-derived in vivo tumor effiicacy studies were performed in immunocomprimized mice, Treatment was done via i.v. injection when tumors reached ∼ 150-200 mm3. PK assays were performed in tumor-bearing mice, with detection of ADC by ligand-binding assay. Stability assays were performed in both plasma and serum from various species using a DAR-sensitive biolayer inferometry binding assay.
Results
In vitro, MORAb-109 demonstrated selective cytotoxicity on a number of mesothelin-expressing tumor cell lines compared with non-expressing lines, with an improved specificity ratio compared with a competitor ADC. MORAb-109 exhibited dose-dependent anti-tumor activity in vivo, with regression observed in multiple tumor cell line and patient-derived xenograft models, including models with heterogeneous mesothelin expression. The ADC demonstrated good stability in matrix from multiple species in vitro, with limited (< 20%) payload release after 10-day incubation.
Conclusions
Based on these findings, MORAb-109 is being considered for further development as a targeted therapy for mesothelin-expressing tumors.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Eisai Inc.
Funding
Eisai Inc.
Disclosure
E. Albone: Full/Part-time employment: Eisai Inc. X. Cheng: Full/Part-time employment: Eisai Inc. A. Verdi: Full/Part-time employment: Eisai Inc. S. Jacob: Full/Part-time employment: Eisai Inc. S. Fernando: Full/Part-time employment: Eisai Inc. K. Furuuchi: Full/Part-time employment: Eisai Inc. J. Fulmer: Full/Part-time employment: Eisai Inc. A. Soto: Full/Part-time employment: Eisai Inc. B. Drozdowski: Full/Part-time employment: Eisai Inc. Y. Mano: Full/Part-time employment: Eisai Co Ltd. Y. Nakatani: Full/Part-time employment: Eisai Co Ltd. T. Uenaka: Full/Part-time employment: Eisai Co Ltd.