Anetumab ravtansine, also known as BAY 94-9343, is a novel, selective and highly potent antibody-drug conjugate consisting of a human anti-mesothelin antibody conjugated to the maytansinoid tubulin inhibitor DM4 via a disulfide-containing linker (a reducible SPDB linker [N-succinimidyl 4-(2-pyridyldithio)butanoate]) on an average of 3 lysyl.
Mesothelia is over-expressed on all mesotheliomas as well as many ovarian and pancreatic cancers while minimally expressed on normal tissue.
The antibody binds to human mesothelin with high affinity and selectivity, thereby inducing efficient antigen internalization. Upon internalization, the DM4 moiety binds to tubulin and disrupts microtubule assembly/disassembly dynamics, resulting in inhibition of cell division and cell growth of mesothelin-expressing tumor cells.
In vitro, anetumab ravtansine has demonstrated potent and selective cytotoxicity of mesothelin-expressing cells with an IC50 of 0.72 nmol/L, without affecting mesothelin-negative or nonproliferating cells.
In vivo, anetumab ravtansine localizes specifically to mesothelin-positive tumors and inhibited tumor growth in both subcutaneous and orthotopic xenograft models. Furthermore, anetumab ravtansine was able to induce a bystander effect on neighboring mesothelin-negative tumor cells.
In clinical trials, antitumor efficacy of anetumab ravtansine correlated with the amount of mesothelin expressed and was generally superior to that of standard-of-care regimen resulting in complete tumor eradication in most of the models.
The drug is being developed by Bayer HealthCare, ImmunoGen and MorphoSys.