Tisotumab vedotin-tftv
Tisotumab vedotin-tftv (Tivdak®) is an antibody-drug conjugate that links an antibody directed against tissue factor to a microtubule inhibitor drug.
It indicated for the treatment of adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.
The class of therapeutics that encompasses antibody-drug conjugates contain agents with three components: the monoclonal antibody, the chemotherapy payload, and the linker which connects these molecules. Some antibodies may have multiple linkers and several payloads attached. The antibody is directed against a cell-surface receptor on the cancer cell. Essentially, antibody-drug conjugates are a sophisticated means of delivering therapeutics directly into cancer cells.
Tissue factor is highly expressed in cervical cancer cells and increased among patients with metastasis. In this way, tisotumab vedotin-tftv is a human monoclonal immunoglobulin G1 that uses tissue factor to enhance delivery of the chemotherapeutic payload more selectively to cervical cancer cells. This spares normal cells in the surrounding milieu and minimizes collateral damage, which is a major limitation of chemotherapy.
More specifically, tisotumab vedotin-tftv is composed of the human antibody conjugated to a protease-cleavable linker to a payload. The payload of tisotumab vedotin-tftv is monomethylauristatin E, which is an antimitotic agent that targets the tubulin pathway. It binds to tubulin and inhibits microtubule polymerization, causing growth arrest. Tubulin dynamics are a major target for taxane chemotherapy drugs. A benefit of tisotumab vedotin-tftv is its induction of bystander killing from freed monomethylauristatin E that impacts surrounding cancer cells.
Binding of the antibody to the receptor causes internalization of the antibody-drug conjugate into the cell. Alternatively, nonspecific endocytosis or micropinocytosis may also internalize the payload into the cell. Once inside the cell, cellular trafficking occurs and the cargo is sorted through the endosomal compartments. These compartments have sequentially lower pH which detaches the payload from the linker and the antibody. Once free, the payload interferes with a key molecular process required by the cancer cell. Usually, these processes are involved in DNA synthesis, transcription, cell replication, or tubulin dynamics required for mitosis. When these critical processes fail repeatedly, the cell dies.
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