Our lead candidate (KB-121) is a humanized antibody belonging to the IgG1 isotype. KB-121 binds to the extracellular domain of the transferrin receptor of the first type (TfR1) (Ki = 5.7 nM). The binding of KB-121 to the transmembrane domain causes the degradation of TfR1, and thus stops the entry of iron into the cancer cell. Binding KB-121 to the surface of the cancer cell activates the antitumor response of cellular immunity. Due to these mechanisms KB-121 suppresses tumor growth.
The transmembrane glycoprotein TfR1 is located on the plasma membrane and is a key component of the iron transport system. Extracellular transferrin (Tf) in combination with iron ions binds to TfR1, after which the iron-Tf-TfR1 triple complex is internalized. In the resulting endosomes, the work of the proton pump lowers the pH, which leads to the release of iron ions from the complex. A specific transporter located in the endosome membrane carries iron ions into the cytoplasm of the cell. The endosome returns to the cell surface, where the Tf-TfR1 complex dissociates. Thus, the recirculation of TfR ensures a steady supply of iron ions into the cell.
Iron is involved in a variety of metabolic processes important for cancer cells. Rapidly-derived cancer cells require a large amount of iron for DNA replication, since iron is a co-factor for the ribonucleotide reductase, the key enzyme of the pathway for deoxyribonucleotide biosynthesis. In addition, iron is involved in the regulation of expression of proteins – regulators of the cell cycle. A high concentration of iron ions is necessary not only for the fast-growing, but also for the dermatogenic cancer cells, since iron inhibits the cytotoxic effect of nitric oxide released by the effector cells of the immune system. Therefore, TfR1-dependent iron transport is necessary for tumor development. TfR1 mediates tumor growth and by mechanisms not associated with iron import. TfR1 interacts with the inhibitor of NF-kB kinase and thereby promotes the activation of the NF-kB signaling pathway, important for the survival of cancer cells. The involvement of TfR1 in mitochondrial respiration promotes the formation of reactive oxygen species associated with the process of tumor formation. For these reasons, many types of tumor cells, including hematologic tumor cells, overproduce TfR1. For several types of cancer, the level of expression of the TfR1 gene correlates with the prognosis or stage of the disease. Thus, TfR1 is a promising target for the therapy of various cancers.
Исследования осуществляются ООО «Гемофарм» при грантовой поддержке Фонда «Сколково»