Several antibodies that bind to mesothelin, intended for the treatment of malignant mesothelioma and other cancers, are in various stages of development. Because the antibody-based drugs have different properties, clinical trials will reveal which provide the most benefit to patients.
Researchers at Bayer Pharmaceuticals provided an overview of the different drugs in development in the review, “Novel Antibody Therapeutics Targeting Mesothelin In Solid Tumors.” The work was published in the journal Clinical Cancer Drugs.
There are a variety of different approaches to block mesothelin in tumors. The molecule is seen as an attractive target for cancer treatment because it’s present only in very low levels in healthy tissues.
One approach is to simply treat patients with an antibody that binds to mesothelin, in this way triggering cell toxicity. This approach has been adapted by Morphotek working together with the National Cancer Institute (NCI) in the development of amatuximab.
A completed Phase 2 clinical trial (NCT00738582) of the drug in unresectable mesothelioma patients evaluated a combination of the chemotherapies Alimta (pemetrexed) and Platinol (cisplatin) with the antibody amatuximab.
The study showed that 40 percent of patients had a partial response and 51 percent had stable disease. Importantly, the combination therapy did not cause more side effects than experienced with chemotherapy alone, and Morphotek is currently recruiting more patients for a confirmatory Phase 2 trial (NCT02357147).
Roche takes different approach
Another approach to target mesothelin has been adopted by Roche, also working with the NCI. The recombinant immunotoxins SS1P and RG7787 are antibodies bound to a toxic molecule. Once the antibodies bind to mesothelin, the toxin prevents cancer growth by blocking protein production.
SS1P has been through two Phase 1 clinical trials but failed to show significant positive responses. This was likely due to the development of so-called neutralizing antibodies — produced in an immune response toward the treatment. Although a study (NCT01362790) attempted to overcome the problem by treating patients with immunosuppressant drugs, the effects of SS1P did not improve greatly.
In contrast, when SS1P was given together with Platinol and Alimta to 13 patients with advanced pleural mesothelioma (NCT01445392), 77 percent of patients showed a partial response and 7.7 percent had stable disease. While the treatment was well-tolerated, the development of neutralizing antibodies is a problem, and Roche has continued to develop RG7787 in an attempt to lessen the immune response to the treatment. This drug is about to be explored in a Phase 1 clinical trial.
But the most common antibody-based approach is to link an antibody that targets mesothelin with a drug molecule. In this way, a cancer drug can be delivered directly to the tumor, minimizing side effects.
Bayer’s approach in targeting mesothelin
Bayer’s antibody-drug combination anetumab ravtansine (BAY 94-9343) has shown promising effects in pre-clinical studies and is currently being explored in early clinical trials.
A Phase 1 study (NCT02639091) that is currently recruiting participants with solid tumors, including mesothelioma, explores the drug in combination with Platinol and Alimta.
Meanwhile, an ongoing Phase 2 trial (NCT02610140) examines how the treatment performs compared to Navelbine (vinorelbine) in mesothelioma patients. So far, studies show that few serious adverse events have been reported. The adverse events related to the treatment have been reversible and not life-threatening, but forced patients to reduce the dosing.
In addition, Bristol-Myers Squibb initiated in June 2015 a Phase 1/2a study of a mesothelin-directed antibody-drug conjugate (BMS-986148) in solid tumors, including mesothelioma (NCT02341625), and Genentech is conducting a Phase 1 study examining DMOT4039A, another mesothelin-targeting antibody linked to a cytotoxic drug, in other cancer types (NCT01469793).