Antibody-drug conjugates for mesothelioma: why they have failed so far and how they could work

Mesothelioma looks ideal for antibody-drug conjugates: mesothelin is on almost every tumour cell and rare elsewhere. Anetumab ravtansine, a mesothelin antibody carrying the tubulin poison DM4, proved otherwise in 248 patients, matching vinorelbine's 4.5-month progression-free survival and no more. Three explanations have evidence behind them. Mesothelioma sheds soluble mesothelin into the blood, which binds the antibody before it reaches the tumour. Expression is patchy and the tumour grows as thin sheets with dense stroma, so few cells take up enough payload. And a tubulin payload adds little to a slow-cycling tumour that already resists chemotherapy. The idea proposes conjugates built for these facts: antibodies that bind membrane mesothelin epitopes not present on the shed form, topoisomerase I payloads with a bystander effect that kill neighbouring cells that took up no drug (the DXd and SN-38 class that transformed breast and lung cancer ADCs), regional intrapleural delivery to bypass shed antigen in blood, and combination with PD-1 blockade to turn payload-induced cell death into an immune response, which the National Cancer Institute is already testing with anetumab ravtansine and pembrolizumab. Other targets present on mesothelioma, such as folate receptor alpha, on which the conjugate Rina-S is being tested across solid tumours, and B7-H3, widen the options beyond mesothelin.