Vorsetuzumab mafodotin, also known as SGN-75, is a novel antibody conjugated with a cytotoxic molecule, auristatin analogue monomethyl auristatin phenylalanine (MMAF). The antibody part of vorsetuzumab mafodotin is a monoclonal antibody targeting CD70, a member of CD70 tumor necrosis factor (TNF) superfamily. Vorsetuzumab mafodotin, developed by Seattle Genetics, has been used in the clinical treatment of Non-Hodgkin's lymphoma and renal cancer. This drug has completed a phase I clinical study in renal cell carcinoma but was discontinued in 2013. There were no reports specifying the reasons for the cessation of development. In 2014, SG had planned to reopen clinical studies related to vorsetuzumab mafodotin.
The mechanism of vorsetuzumab mafodotin is related to a humanized monoclonal antibody targeting CD70 molecule and microtubule toxin molecule MMAF. CD70 is a type II transmembrane protein, which is mainly expressed in activated T cells, B cells, natural killer (NK) cells, and dendritic cells. CD70 has the ability to regulate the activation, proliferation, and differentiation of T cells and B cells, and plays an important role in maintaining the immune response. CD70 mediated its biological function through binding to its receptor CD27. CD27, a type I transmembrane protein, is a dimer composed of two 55 000 monomers with disulfide bond chains. Under physiological conditions, CD70 is only temporarily expressed in activated lymphocytes, but it is highly expressed in a variety of tumor tissues, which provides a theoretical basis for molecular targeted therapy of tumors. MMAF is a synthetic cytotoxic drug with antitumor activity. Although it has a well-killing effect on tumor cells, it cannot be used as an anti-tumor drug directed as the lack of specificity. In general, MMAF is conjugated with certain monoclonal antibodies that specifically recognize antigens on the surface of tumor cells to form anti-drug conjugates. Vorsetuzumab mafodotin is a kind of antibody-drug conjugates composed of MMAF. After administration, the antibody part of vorsetuzumab mafodotin specifically binds to CD70, and internalization occurs. After internalization, the drug is sent to the cytoplasm, then, the linker is cleaved and MMAF is released. The released MMAF toxin binds to tubulin and interferes with the normal operation of the cell cycle, causing cell death.
Fig 1. Mechanism of Action of Vorsetuzumab mafodotin