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

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Therapeutic Antibody-Like Immunoconjugates Against Tissue Factor with the Potential to Treat Angiogenesis-Dependent As Well As Macrophage-Associated Human Diseases antibodies Review Therapeutic Antibody-Like Immunoconjugates against Tissue Factor with the Potential to Treat Angiogenesis-Dependent as Well as Macrophage-Associated Human Diseases Zhiwei Hu ID Department of Surgery Division of Surgical Oncology, The James Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH 43210, USA; [email protected]; Tel.: +1-614-685-4606 Received: 10 October 2017; Accepted: 18 January 2018; Published: 23 January 2018 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. Keywords: tissue factor; factor VII; antibodies; antibody-like immunoconjugates (ICON and L-ICON1); solid cancer; Leukemia; age-related macular degeneration; endometriosis; rheumatoid arthritis; atherosclerosis; angiogenesis; vascular endothelial cell; cancer cell; cancer stem cell; macrophage; fibroblast; B cell 1. Introduction Tissue factor (TF) is a 47-kDa membrane-bound cell surface receptor [1–3]. It is also known as thromboplastin, coagulation factor III (fIII) or CD142. Under physiological condition, TF is not expressed by circulating peripheral blood lymphocytes and quiescent vascular endothelial cells (VECs). TF expression is restricted to the cells that are not in direct contact with the blood, such as pericytes, fibroblasts and smooth muscle cells, which are localized in the sub-endothelial vessel wall Antibodies 2018, 7, 8; doi:10.3390/antib7010008 www.mdpi.com/journal/antibodies Antibodies 2018, 7, 8 2 of 22 Antibodies 2018, 6, 8 2 of 23 andpericytes sequestered, fibroblasts from and circulating smooth coagulationmuscle cells, factor which VII are (fVII), localized the in natural the sub ligand-endothelial for TF. vessel In these wall cells, theand majority sequestered of TF isfrom localized circulating in intracellular coagulation pools factor [4 ].VII Upon (fVII) disruption, the natural of vesselligand wallfor TF integrity,. In these TF in pericytescells, the and majority smooth of muscle TF is cellslocalized is released in intracellular and can be pools bound [4] by. fVII,Upon leaking disruption from of blood vessel circulation, wall tointegrity, initiate blood TF in coagulationpericytes and in smooth order tomuscle stop bleedingcells is released [5,6]. Besidesand can itsbe rolebound as by the fVII, primary leaking initiator from of coagulation,blood circulation, TF is alsoto initiate a modulator blood coagulation of pathological in order angiogenesis to stop bleeding [7–9]. [5,6] It is. Besides worth noting its role that as the there isprimary a truncated initiator version of coagulation, of TF, called TF alternativelyis also a modulator spliced of pathological TF (asTF), which angiogenesis lacks the [7– transmembrane9]. It is worth andnoting cytoplasmic that there domains is a truncated and therefore,version of isTF, not called membrane alternatively bound spliced as a solubleTF (asTF), isoform. which Thelacks soluble the asTFtransmembrane also playsroles and incytoplasmic cancer and domains angiogenesis and therefore, [10–14]. is However, not membrane this review bound will as focusa soluble on the membrane-boundisoform. The soluble TF, asTF also also called plays full roles length in cancer TF (flTF),and angiogenesis which is an[10– angiogenic14]. However, specific this review receptor sincewill itfocus is selectively on the membrane expressed-bound on vascular TF, also endothelialcalled full length growth TF factor (flTF), (VEGF)-stimulated which is an angiogenic human microvascularspecific receptor endothelial since it cells is (HMVEC)selectively asexpressed an angiogenic on vascular VEC model endothelial (Figure 1)[growth15]. TFfactor is also the(VEGF therapeutic)-stimulated oncotarget human formicro cancervascular cells endothelial and cancer cells stem (HMVEC) cells (CSC) as an [angiogenic16] (Figures VEC2 and model3) for fVII-targeted(Figure 1) [15] immunotherapy. TF is also the therapeutic using coagulation oncotarget active for cancer site-mutated cells and fVII-IgG1 cancer stem Fc immunoconjugatecells (CSC) [16] (Figures 2 and 3) for fVII-targeted immunotherapy using coagulation active site-mutated fVII-IgG1 (called an ICON) (Figure4) and fVII-targeted photodynamic therapy (fVII-tPDT) using fVII-conjugated Fc immunoconjugate (called an ICON) (Figure 4) and fVII-targeted photodynamic therapy photosensitizers) [15,16], as summarized below. (fVII-tPDT) using fVII-conjugated photosensitizers) [15,16], as summarized below. Angiogenesis, the formation of new capillaries from pre-existing vessels, is involved in both Angiogenesis, the formation of new capillaries from pre-existing vessels, is involved in both physiological conditions (such as reproduction and tissue repair) as well as in more than 20 human physiological conditions (such as reproduction and tissue repair) as well as in more than 20 human diseasesdiseases [ 17[17]],, including including butbut notnot limited to to cancer cancer [17,18] [17,18,], age age-related-related macular macular degeneration degeneration (AMD), (AMD), endometriosisendometriosis and and rheumatoid rheumatoid arthritis arthritis (RA)(RA) [[1919––2121]].. InIn cancer,cancer, angiogenesisangiogenesis was was identified identified as as one one of theof “hallmarksthe “hallmarks of cancer” of cancer” by Hanahan by Hanahan and Weinbergand Weinberg [22,23 ][22,23] due to due the recognitionto the recognition that this that process this is crucialprocess during is crucial the transitionduring the from transition benign from hyperplastic benign hyperplastic nodules to malignantnodules to lesionsmalignant [18 ].lesions Identification [18]. ofIdentification target molecules of target specific molecules for angiogenic specific for VEC, angiogenic the inner VEC, layer the of inner pathological layer of neovasculature,pathological isneovasculature, critical for discovery is critical and for developmentdiscovery and ofdevelopment neovascular-targeting of neovascular therapy-targeting for therapy these pathological for these angiogenesis-dependent,pathological angiogenesis clinically-dependent, significant clinically human significant diseases. human diseases. Figure 1. Tissue factor (TF) is an angiogenic specific receptor. Representative confocal imaging of TF (green) and endothelial marker CD31 (red) expression on human microvascular endothelial cells (HMVEC)Figure 1. before Tissue 0-hour factor (0 h)(TF) as a is normal an angiogenic resting vascular specific endothelial receptor. cell Representative (VEC) model (a )confocal and 4 h (4 h) afterimaging vascular of endothelialTF (green) growth and factorendothelial (VEGF) marker stimulation CD31 (4–6 (red) h reaching expression peak expression) on human as an angiogenicmicrovascular VEC modelendothelial (b). Cell cells nuclei (HMVEC were counterstained) before 0-hour by (0 DAPI h) as (4 a0,6-Diamidino-2-Phenylindole, normal resting vascular Dihydrochloride)endothelial cell (blue).(VEC) Scale model bars: (a 20) andµm. 4 Modified h (4 h) fromafter ref.vascular [15]. endothelial growth factor (VEGF) stimulation (4–6 h reaching peak expression) as an angiogenic VEC model (b). Cell nuclei were counterstained by DAPI (4′,6-Diamidino-2-Phenylindole, Dihydrochloride) (blue). Scale bars: 20 μm. Modified from ref. [15]. Antibodies 2018, 7, 8 3 of 22 AntibodiesAntibodies 2018 2018, 6, 68, 8 3 of3 23 of 23 Figure 2. Tissue factor (TF) is the therapeutic target for fVII-targeted immunoconjugate Figure(ICON 2.2.). Tissue TissueRepresentative factor factor (TF) (TF is)Western theis the therapeutic therapeutic blots targetusing target formouse fVII-targeted for fVIIICON-targeted immunoconjugate(mfVII/hIgG1 immunoconjugateFc, (ICON). an Representative(ICONimmunoconjugate).
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