How M7824 works
As a fusion protein (made from a fusion gene created by joining parts of two different genes), M7824 is designed to block two signaling pathways commonly used by cancer cells to avoid being destroyed by the immune system. M7824 consists of a monoclonal antibody against a protein called programmed death-ligand 1 (PD-L1) linked to the extracellular domain of the human transforming growth factor beta (TGF-β) receptor 2 protein.
The PD-L1 and TGF-β proteins are overproduced by certain types of cancers and associated with a poor prognosis.
Upon administration, the PD-L1 monoclonal antibody part of M7854 binds PD-L1 while the TGF-β part binds to and neutralizes TGF-β receptor 2 protein. This prevents TGF-β- and PD-L1-mediated signaling, and increases T-cell-mediated immune response against cancer cells, ultimately inhibiting tumor cell growth.
M7824 in clinical trials
The safety, tolerability, pharmacokinetics (movement of the drug into, through, and out of the body), and biological and clinical activity of M7824 are being evaluated in a two-part, Phase 1 clinical trial (NCT02517398) in patients with locally advanced solid tumors or advanced solid tumors that have spread to other parts of the body.
In the first, dose-escalation part of the study, patients will receive different amounts of the compound to find the safest and most effective dose. In the second, expansion part, the anti-cancer effects of the selected dose will be assessed in many more patients .
Preliminary data from the study suggested that M7824 was generally well-tolerated when administered in doses ranging from 1−20 mg/kg and showed that the drug could bind to PD-L1 and also block TGF-β signaling, confirming early evidence of clinical activity of the compound. They also confirmed that M7824 could inhibit both PD-L1 and TGF-β signaling throughout the dosing period in a dose-dependent manner. Finally, they showed that M7824 leads to an ongoing confirmed complete response, one durable partial response, two cases of prolonged stable disease, and a 25 percent reduction in the diameter of target lesions after two doses.
The trial is still enrolling patients in the U.S., the U.K, Canada, Australia, Europe, Korea, Taiwan, and Japan.
An open-label Phase 1 trial (NCT02699515) with the same purpose as the previous one is also ongoing, but only in Japan, Taiwan, and Korea and is no longer enrolling participants.
M7824 will also be evaluated as a combination therapy in a Phase 2 clinical trial (NCT03315871) conducted by the National Cancer Institute. The aim of the trial is to verify whether the combination of Prostvac, CV301, and M7824 can induce an anti-tumor response in patients with recurrent prostate cancer. The study will take place in the U.S., but is not yet open for patient recruitment.
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