Therapeutic Antibody-Like Immunoconjugates against Tissue Factor with the Potential to Treat Angiogenesis-Dependent as Well as Macrophage-Associated Human Diseases

Abstract

Accumulating evidence suggests that tissue factor (TF) is selectively expressed in pathological angiogenesis-dependent as well as macrophage-associated human diseases. Pathological angiogenesis, the formation of neovasculature, is involved in many clinically significant human diseases, notably cancer, age-related macular degeneration (AMD), endometriosis and rheumatoid arthritis (RA). Macrophage is involved in the progression of a variety of human diseases, such as atherosclerosis and viral infections (human immunodeficiency virus, HIV and Ebola). It is well documented that TF is selectively expressed on angiogenic vascular endothelial cells (VECs) in these pathological angiogenesis-dependent human diseases and on disease-associated macrophages. Under physiology condition, TF is not expressed by quiescent VECs and monocytes but is solely restricted on some cells (such as pericytes) that are located outside of blood circulation and the inner layer of blood vessel walls. Here, we summarize TF expression on angiogenic VECs, macrophages and other diseased cell types in these human diseases. In cancer, for example, the cancer cells also overexpress TF in solid cancers and leukemia. Moreover, our group recently reported that TF is also expressed by cancer-initiating stem cells (CSCs) and can serve as a novel oncotarget for eradication of CSCs without drug resistance. Furthermore, we review and discuss two generations of TF-targeting therapeutic antibody-like immunoconjugates (ICON and L-ICON1) and antibody-drug conjugates that are currently being tested in preclinical and clinical studies for the treatment of some of these human diseases. If efficacy and safety are proven in current and future clinical trials, TF-targeting immunoconjugates may provide novel therapeutic approaches with potential to broadly impact the treatment regimen of these significant angiogenesis-dependent, as well as macrophage-associated, human diseases.

Tissue factor as a new target for CAR-NK cell immunotherapy of triple-negative breast cancer

“…On the other end, in normal physiological conditions, TF is not expressed on normal leukocytes in circulation 23 , such as B, T, NK cells and monocytes, and not on quiescent VECs of normal blood vessels in normal org ans 22,23,29,48,49 . TF occurs only in cells that are not in direct contact with the blood, such as pericytes, which are localized in the sub-endothelial vessel wall, and the epithelial cells of the skin, mucosa and glomeruli 22,23 . Thus, under normal conditions, TF expression is sequestered from its natural ligand 17,19,50 , fVII 22,23 , in circulation.…”

“…TF occurs only in cells that are not in direct contact with the blood, such as pericytes, which are localized in the sub-endothelial vessel wall, and the epithelial cells of the skin, mucosa and glomeruli 22,23 . Thus, under normal conditions, TF expression is sequestered from its natural ligand 17,19,50 , fVII 22,23 , in circulation. Upon disruption of vessel wall integrity, TF in pericytes and smooth muscle cells is released and can be bound by fVII, leaking from blood circulation, to initiate coagulation 20,51 .…”

“…In particular, this study established the proof of concept of targeting TF as a new target for CAR-NK cellular immunotherapy for the treatment of TNBC and may warrant further investigation in TNBC patients. If the efficacy and safety can be proven in clinical trials, TF-targeted therapeutics may represent a novel therapeutic approach for TNBC and can potentially impact the treatment regimen for pathological angiogenesis-dependent human diseases (notably cancer, age-related macular degeneration, endometriosis and rheumatoid arthritis) and macrophage-associated human disease (such as atherosclerosis, HIV and Ebola viral transduction) 23 , in which TF is selectively expressed on angiogenic VECs and/or disease-associated macrophages 23 .…”

“…Its best known function involves the initiation of blood coagulation upon disruption of vessel wall integrity 18,19 . Under physiological conditions, TF is not expressed on peripheral blood lymphocytes and quiescent vascular endothelial cells (the inner layer) of normal blood vessels in normal tissues and organs [20][21][22][23] . Besides its role as the primary initiator of coagulation, TF is also a modulator of pathological angiogenesis [24][25][26] .…”

“…We and our collaborators along with other groups have identified TF as an angiogenesis-specific receptor on VEGF-stimulated angiogenic microvascular endothelial models in vitro as well as in vivo in angiogenic VECs (the inner layer) of the pathological neovasculature of endometriosis, age-related macular degeneration (AMD) and solid cancers, including melanoma 27,28 , lung cancer 29 and breast cancer 29 , and from tumor xenografts in mice and breast cancer tissues from patients 14,16 . In cancer, TF is highly expressed on the cancer cells in many types of solid cancers 14,23,[30][31][32] , acute myeloid and lymphoblastic leukemia (AML and ALL) and sarcoma 23,32 as well as in Hodgkin's lymphoma 33 and multiple myeloma (MM, TF detected in 10 out of 18 patients with MM and 3 MM lines) 34 .…”