Jin-San Yoo - Academia.edu (original) (raw)

Papers by Jin-San Yoo

Science Advances, Nov 14, 2023

Molecules and Cells, Oct 31, 1995

Kluwer Academic Publishers eBooks, Nov 19, 2005

Investigative Ophthalmology & Visual Science, Jun 16, 2013

Purpose: The study investigated the effect of intravitreally administered tanibirumab, a fully hu... more Purpose: The study investigated the effect of intravitreally administered tanibirumab, a fully human monoclonal antibody against vascular endothelial growth factor receptor 2, in a rat model of laser-induced choroidal neovascularization (CNV). Methods: CNV was induced by laser photocoagulation on day 0 in the eyes of Brown Norway rats. Intravitreal injection of tanibirumab or phosphate-buffered saline (PBS) was done on day 0 (prevention arm) or day 7 (treatment arm). Seven days after injection, the eyes were enucleated and retinal pigment epithelium-choroid-sclera flat mounts were prepared. Areas of CNV were determined in the flat mounts using tetramethylrhodamine isothiocyanate Bandeiraea simplicifolia (BS) isolectin labeling and intravenously administered fluorescein isothiocyanate-dextran and quantified using an image analysis program. Results: In the prevention arm, the mean area of CNV measured by BS isolectin labeling was reduced by 28.2% and 53.9% in tanibirumab-treated eyes (20 and 60 mg, respectively) compared with PBS-treated control eyes on day 7 (P = 0.038 and P < 0.001, respectively). In the treatment arm, the mean area of CNV measured by BS isolectin labeling was reduced by 28.7% and 46.0% in tanibirumab-treated eyes (20 and 60 mg, respectively) compared with PBS-treated control eyes on day 14 (P = 0.048 and P < 0.001, respectively). Conclusions: Intravitreally administered tanibirumab partially suppressed the formation of new CNV and partially regressed preformed laser-induced CNV in the rat model. Tanibirumab may be a feasible treatment for CNV associated with age-related macular degeneration or other causes.

Experimental & Molecular Medicine

Tumor progression is intimately associated with the vasculature, as tumor proliferation induces a... more Tumor progression is intimately associated with the vasculature, as tumor proliferation induces angiogenesis and tumor cells metastasize to distant organs via blood vessels. However, whether tumor invasion is associated with blood vessels remains unknown. As glioblastoma (GBM) is featured by aggressive invasion and vascular abnormalities, we characterized the onset of vascular remodeling in the diffuse tumor infiltrating zone by establishing new spontaneous GBM models with robust invasion capacity. Normal brain vessels underwent a gradual transition to severely impaired tumor vessels at the GBM periphery over several days. Increasing vasodilation from the tumor periphery to the tumor core was also found in human GBM. The levels of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2) showed a spatial correlation with the extent of vascular abnormalities spanning the tumor-invading zone. Blockade of VEGFR2 suppressed vascular remodeling at the tumor periphery, confir...

The Journal of Cell Biology, 2004

Archives of Pharmacal Research, 2012

Chlorpheniramine is an anti-histamine agent on IgE-mediated inflammation. In order to investigate... more Chlorpheniramine is an anti-histamine agent on IgE-mediated inflammation. In order to investigate the immunomodulatory effects of chlorpheniramine, we assessed the changes of peripheral mononuclear cell populations and other general clinical parameters, including hematology and clinical chemistry, following chlorpheniramine administration in rats. Since prednisolone is commonly co-prescribed with anti-histamine in many hypersensitive reactions, we also examined the changes to compare the results after the prednisolone administration. Chlorpheniramine (50, 100 and 200 µg/kg) and prednisolone (1, 2 and 4 mg/kg) were intramuscularly administered to female Sprague-Dawley (SD) rats 3 times, at intervals of 1 week. Except the clinical signs, such as stiffness and abnormal gait due to the local toxicity at injection sites, no other significant changes in body weights, urinalysis, and macroscopic examination were noted in the animals given chlorpheniramine. On the other hand, white blood cells, especially B cells and monocytes, showed a dose-dependent increase in the chlorpheniramine-treated animals; whereas, the numbers of both B and T cells (helper T and cytotoxic T, NKT cells) were decreased in the prednisolone-treated animals. Taken together, these results suggest that chloropheniramine administration enhances white blood cells in the peripheral blood, mostly due to increases of the B cells and monocytes, but no T cells and NK cells.

The trans-Golgi network (TGN) plays a pivotal role in directing proteins in the secretory pathway... more The trans-Golgi network (TGN) plays a pivotal role in directing proteins in the secretory pathway to the appropriate cellular destination. VAMP4, a recently discovered member of the vesicle-associated membrane protein (VAMP) family of trafficking proteins, has been suggested to play a role in mediating TGN trafficking. To better understand the function of VAMP4, we examined its precise subcellular distribution. Indirect immunofluorescence and electron microscopy revealed that the majority of VAMP4 localized to tubular and vesicular membranes of the TGN, which were in part coated with clathrin. In these compartments, VAMP4 was found to colocalize with the putative TGN-trafficking protein syntaxin 6. Additional labeling was also present on clathrin-coated and noncoated vesicles, on endosomes and the medial and trans side of the Golgi complex, as well as on immature secretory granules in PC12 cells. Immunoprecipitation of VAMP4 from rat brain detergent extracts revealed that VAMP4 exis...

Cancer Research, 2021

Background: Metastatic TNBC (mTNBC) has a poor prognosis. Preclinical data suggests benefit for c... more Background: Metastatic TNBC (mTNBC) has a poor prognosis. Preclinical data suggests benefit for combination therapy of immune checkpoint inhibitor and anti-angiogenesis. Olinvacimab (O) is a fully humanised monoclonal antibody (MAB) which binds to Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) and antiangiogenic and antitumor effects have been demonstrated. Pembrolizumab (P) is an anti-PD1 MAB. This study aimed to identify the safety and tolerability of O and P to establish a phase 2 recommended dose of O. Methods: From December 2018 to September 2020, we conducted a two-site, single arm, open-label study of O and P in pts with mTNBC. Eligible patients (pts) were >18 years, had ER, PR & HER2-negative MBC with at least one measurable lesion and adequate organ function. Pts with history of serious thromboembolism, gastrointestinal haemorrhage and prior anti-VEGF therapy were excluded. A modified Toxicity Probability Interval design was used. Pts received O 12 mg/kg q7d (dos...

The small GTPase rab5 has been shown to represent a key regulator in the endocytic pathway of mam... more The small GTPase rab5 has been shown to represent a key regulator in the endocytic pathway of mammalian cells. Using a PCR approach to identify rab5 homologs in Saccharomyces cerevisiae, two genes encoding proteins with 54 and 52 % identity to rab5, YP/51 and YF/53 have been identified. Sequencing of the yeast chromosome XI has revealed a third rab5like gene, YF/~2, whose protein product exhibits a similar identity to tab5 and the other two YPT gene products. In addition to the high degree of identity/homology shared between rab5 and Ypt51p, Ypt52p, and Ypt53p, evidence for functional homology between the mammalian and yeast proteins is provided by phenotypic characterization of single, double, and triple deletion mutants. Endocytic delivery to the vacuole of two markers, lucifer yellow CH (LY) and a-factor, was inhibited in Aypt51 mutants and aggravated in the double ypt51ypt52 and triple ypt51yptS2yptS3 mutants, suggesting a requirement for these small GTPases in endocytic membran...

Neuro-Oncology

The VEGF pathway remains an important target in GBM given its vascularity and autocrine VEGF sign... more The VEGF pathway remains an important target in GBM given its vascularity and autocrine VEGF signalling. Olinvacimab (TTAC-0001) is a fully humanised VEGFR2 Mab that binds and inhibits the receptor. This report assesses the safety, dosing schedules and efficacy of Olinvacimab in recurrent GBM. We conducted a two-site, 3 arm, open-label study of Olinvacimab in recurrent GBM. Eligible patients were ≥18 years with RANO-measurable lesion, KPS ≥ 80, and had completed chemoradiotherapy without prior bevacizumab therapy. We assessed three arms, 8 mg/kg and 12mg/kg weekly for 3 of every 4 weeks, and 12 mg/kg weekly. Three patients were treated in arms 1 and 2 and 6 in arm 3. Safety assessments were performed prior to dose escalation. The main toxicity was development of grade 1 (67%) and 2 (8%%) cutaneous haemangiomas. Common toxicities seen with other VEGF directed therapies, including hypertension, impaired wound healing, and proteinuria were not seen in this cohort. Efficacy was assessed...

Journal of Biomolecular NMR

Monoclonal antibody (mAb) drugs are clinically important for the treatment of various diseases. T... more Monoclonal antibody (mAb) drugs are clinically important for the treatment of various diseases. TTAC-0001 is under development as a new anti-cancer antibody drug targeting VEGFR-2. As the less severe toxicity of TTAC-0001 compared to Bevacizumab, likely due to the decreased in vivo half-life, seems to be related to its structural flexibility, it is important to map the exact flexible regions. Although the 13C/15N-labeled protein is required for NMR analyses, it is difficult to obtain antibody fragments (Fab and scFv) containing disulfide bonds through general cytosolic expression in Escherichia coli (E. coli). Here, we notably increased the periplasmic expression of the 13C/15N-labeled TTAC-0001-Fab (13C/15N-TTAC-Fab) through simple isopropyl β-D-1-thiogalactopyranoside (IPTG)-induction at an increased optical density (1.5 OD600nm). Through NMR triple resonance experiments, two loop insertions (LI-1 between the VH and CH1; LI-2 between the VL and CL) were confirmed to be highly flexible. The additional LIs could be another way to engineer the antibody by changing the pharmacokinetic properties.

Journal of Clinical Oncology

e14545 Background: Recurrent GBM is difficult to treat. Single agent checkpoint blockade has not ... more e14545 Background: Recurrent GBM is difficult to treat. Single agent checkpoint blockade has not improved outcomes. Angiogenesis is a rational drug target for rGBM and targeting angiogenesis may benefit pseudoprogression and cerebral oedema. O is a fully human monoclonal antibody (MAB) which binds to Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) with antiangiogenic and antitumour effects. P is an anti-PD1 MAB. This study aimed to identify the safety and tolerability of O combined with P and to establish a recommended phase 2 combination dose. Methods: From January to October 2019, we conducted a two-site, single arm, open-label study of O with P in patients with rGBM. Eligible patients (pts) were ≥18 years with at least one RANO-measurable lesion, KPS≥80, and had completed standard chemoradiotherapy and had no contraindications to O or P. No prior bevacizumab was allowed. A modified Toxicity Probability Interval design was used. Pts received O 12 mg/kg day 1/8/15 q21d (dose...

PloS one, 2018

Targeting of vascular endothelial growth factor receptors (VEGFRs) has potential anti-angiogenic ... more Targeting of vascular endothelial growth factor receptors (VEGFRs) has potential anti-angiogenic effects because VEGFR-2 is the major signaling regulator of VEGF/VEGFR pathways. We aimed to elucidate the drug mechanism and anti-tumor efficacy of TTAC-0001, a novel, fully human anti-VEGFR-2/KDR monoclonal antibody, in mouse orthotopic breast cancer model using multi-modal bioimaging. We used orthotopic xenograft tumor model in which human breast cancer cells (MDA-MB-231) were injected into the right mammary fat pad of Balb/c nude mice. We investigated its biodistribution using serial fluorescence imaging after injecting fluorescent-labelled-drug and mode of action using Matrigel plug angiogenesis assays. The anti-tumor efficacy of drug was assessed using ultrasonography and bioluminescence imaging. Histopathologic analyses, including hematoxylin and eosin staining and immunohistochemistry with anti-CD31 and anti-Ki-67 antibodies, were performed. Each experiment had four groups: contr...

mAbs, 2015

Vascular endothelial growth factor (VEGF) and its receptors are considered the primary cause of t... more Vascular endothelial growth factor (VEGF) and its receptors are considered the primary cause of tumor-induced angiogenesis. Specifically, VEGFR-2/kinase insert domain receptor (KDR) is part of the major signaling pathway that plays a significant role in tumor angiogenesis, which is associated with the development of various types of tumor and metastasis. In particular, KDR is involved in tumor angiogenesis as well as cancer cell growth and survival. In this study, we evaluated the therapeutic potential of TTAC-0001, a fully human antibody against VEGFR-2/KDR. To assess the efficacy of the antibody and pharmacokinetic (PK) relationship in vivo, we tested the potency of TTAC-0001 in glioblastoma and colorectal cancer xenograft models. Antitumor activity of TTAC-0001 in preclinical models correlated with tumor growth arrest, induction of tumor cell apoptosis, and inhibition of angiogenesis. We also evaluated the combination effect of TTAC-0001 with a chemotherapeutic agent in xenograft...

mAbs, 2015

Angiogenesis is one of the most important processes for cancer cell survival, tumor growth and me... more Angiogenesis is one of the most important processes for cancer cell survival, tumor growth and metastasis. Vascular endothelial growth factor (VEGF) and its receptor, particularly VEGF receptor-2 (VEGFR-2, or kinase insert domaincontaining receptor, KDR), play critical roles in tumor-associated angiogenesis. We developed TTAC-0001, a human monoclonal antibody against VEGFR-2/KDR from a fully human na€ ıve single-chain variable fragment phage library. TTAC-0001 was selected as a lead candidate based on its affinity, ligand binding inhibition and inhibition of VEGFR-2 signal in human umbilical vein endothelial cells (HUVEC). TTAC-0001 inhibited binding of VEGF-C and VEGF-D to VEGFR-2 in addition to VEGF-A. It binds on the N-terminal regions of domain 2 and domain 3 of VEGFR-2. It could inhibit the phosphorylation of VEGFR-2/KDR and ERK induced by VEGF in HUVEC. TTAC-0001 also inhibited VEGF-mediated endothelial cell proliferation, migration and tube formation in vitro, as well as ex vivo vessel sprouting from rat aortic rings and neovascularization in mouse matrigel model in vivo. Our data indicates that TTAC-0001 blocks the binding of VEGFs to VEGFR-2/KDR and inhibits VEGFR-induced signaling pathways and angiogenesis. Therefore, these data strongly support the further development of TTAC-0001 as an anti-cancer agent in the clinic.

The Journal of Cell Biology, 1994

The small GTPase rab5 has been shown to represent a key regulator in the endocytic pathway of mam... more The small GTPase rab5 has been shown to represent a key regulator in the endocytic pathway of mammalian cells. Using a PCR approach to identify rab5 homologs in Saccharomyces cerevisiae, two genes encoding proteins with 54 and 52% identity to rab5, YPT51 and YPT53 have been identified. Sequencing of the yeast chromosome XI has revealed a third rab5-like gene, YPT52, whose protein product exhibits a similar identity to rab5 and the other two YPT gene products. In addition to the high degree of identity/homology shared between rab5 and Ypt51p, Ypt52p, and Ypt53p, evidence for functional homology between the mammalian and yeast proteins is provided by phenotypic characterization of single, double, and triple deletion mutants. Endocytic delivery to the vacuole of two markers, lucifer yellow CH (LY) and alpha-factor, was inhibited in delta ypt51 mutants and aggravated in the double ypt51ypt52 and triple ypt51ypt52ypt53 mutants, suggesting a requirement for these small GTPases in endocyti...

Science Advances, Nov 14, 2023

Molecules and Cells, Oct 31, 1995

Kluwer Academic Publishers eBooks, Nov 19, 2005

Investigative Ophthalmology & Visual Science, Jun 16, 2013

Purpose: The study investigated the effect of intravitreally administered tanibirumab, a fully hu... more Purpose: The study investigated the effect of intravitreally administered tanibirumab, a fully human monoclonal antibody against vascular endothelial growth factor receptor 2, in a rat model of laser-induced choroidal neovascularization (CNV). Methods: CNV was induced by laser photocoagulation on day 0 in the eyes of Brown Norway rats. Intravitreal injection of tanibirumab or phosphate-buffered saline (PBS) was done on day 0 (prevention arm) or day 7 (treatment arm). Seven days after injection, the eyes were enucleated and retinal pigment epithelium-choroid-sclera flat mounts were prepared. Areas of CNV were determined in the flat mounts using tetramethylrhodamine isothiocyanate Bandeiraea simplicifolia (BS) isolectin labeling and intravenously administered fluorescein isothiocyanate-dextran and quantified using an image analysis program. Results: In the prevention arm, the mean area of CNV measured by BS isolectin labeling was reduced by 28.2% and 53.9% in tanibirumab-treated eyes (20 and 60 mg, respectively) compared with PBS-treated control eyes on day 7 (P = 0.038 and P < 0.001, respectively). In the treatment arm, the mean area of CNV measured by BS isolectin labeling was reduced by 28.7% and 46.0% in tanibirumab-treated eyes (20 and 60 mg, respectively) compared with PBS-treated control eyes on day 14 (P = 0.048 and P < 0.001, respectively). Conclusions: Intravitreally administered tanibirumab partially suppressed the formation of new CNV and partially regressed preformed laser-induced CNV in the rat model. Tanibirumab may be a feasible treatment for CNV associated with age-related macular degeneration or other causes.

Experimental & Molecular Medicine

Tumor progression is intimately associated with the vasculature, as tumor proliferation induces a... more Tumor progression is intimately associated with the vasculature, as tumor proliferation induces angiogenesis and tumor cells metastasize to distant organs via blood vessels. However, whether tumor invasion is associated with blood vessels remains unknown. As glioblastoma (GBM) is featured by aggressive invasion and vascular abnormalities, we characterized the onset of vascular remodeling in the diffuse tumor infiltrating zone by establishing new spontaneous GBM models with robust invasion capacity. Normal brain vessels underwent a gradual transition to severely impaired tumor vessels at the GBM periphery over several days. Increasing vasodilation from the tumor periphery to the tumor core was also found in human GBM. The levels of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2) showed a spatial correlation with the extent of vascular abnormalities spanning the tumor-invading zone. Blockade of VEGFR2 suppressed vascular remodeling at the tumor periphery, confir...

The Journal of Cell Biology, 2004

Archives of Pharmacal Research, 2012

Chlorpheniramine is an anti-histamine agent on IgE-mediated inflammation. In order to investigate... more Chlorpheniramine is an anti-histamine agent on IgE-mediated inflammation. In order to investigate the immunomodulatory effects of chlorpheniramine, we assessed the changes of peripheral mononuclear cell populations and other general clinical parameters, including hematology and clinical chemistry, following chlorpheniramine administration in rats. Since prednisolone is commonly co-prescribed with anti-histamine in many hypersensitive reactions, we also examined the changes to compare the results after the prednisolone administration. Chlorpheniramine (50, 100 and 200 µg/kg) and prednisolone (1, 2 and 4 mg/kg) were intramuscularly administered to female Sprague-Dawley (SD) rats 3 times, at intervals of 1 week. Except the clinical signs, such as stiffness and abnormal gait due to the local toxicity at injection sites, no other significant changes in body weights, urinalysis, and macroscopic examination were noted in the animals given chlorpheniramine. On the other hand, white blood cells, especially B cells and monocytes, showed a dose-dependent increase in the chlorpheniramine-treated animals; whereas, the numbers of both B and T cells (helper T and cytotoxic T, NKT cells) were decreased in the prednisolone-treated animals. Taken together, these results suggest that chloropheniramine administration enhances white blood cells in the peripheral blood, mostly due to increases of the B cells and monocytes, but no T cells and NK cells.

The trans-Golgi network (TGN) plays a pivotal role in directing proteins in the secretory pathway... more The trans-Golgi network (TGN) plays a pivotal role in directing proteins in the secretory pathway to the appropriate cellular destination. VAMP4, a recently discovered member of the vesicle-associated membrane protein (VAMP) family of trafficking proteins, has been suggested to play a role in mediating TGN trafficking. To better understand the function of VAMP4, we examined its precise subcellular distribution. Indirect immunofluorescence and electron microscopy revealed that the majority of VAMP4 localized to tubular and vesicular membranes of the TGN, which were in part coated with clathrin. In these compartments, VAMP4 was found to colocalize with the putative TGN-trafficking protein syntaxin 6. Additional labeling was also present on clathrin-coated and noncoated vesicles, on endosomes and the medial and trans side of the Golgi complex, as well as on immature secretory granules in PC12 cells. Immunoprecipitation of VAMP4 from rat brain detergent extracts revealed that VAMP4 exis...

Cancer Research, 2021

Background: Metastatic TNBC (mTNBC) has a poor prognosis. Preclinical data suggests benefit for c... more Background: Metastatic TNBC (mTNBC) has a poor prognosis. Preclinical data suggests benefit for combination therapy of immune checkpoint inhibitor and anti-angiogenesis. Olinvacimab (O) is a fully humanised monoclonal antibody (MAB) which binds to Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) and antiangiogenic and antitumor effects have been demonstrated. Pembrolizumab (P) is an anti-PD1 MAB. This study aimed to identify the safety and tolerability of O and P to establish a phase 2 recommended dose of O. Methods: From December 2018 to September 2020, we conducted a two-site, single arm, open-label study of O and P in pts with mTNBC. Eligible patients (pts) were >18 years, had ER, PR & HER2-negative MBC with at least one measurable lesion and adequate organ function. Pts with history of serious thromboembolism, gastrointestinal haemorrhage and prior anti-VEGF therapy were excluded. A modified Toxicity Probability Interval design was used. Pts received O 12 mg/kg q7d (dos...

The small GTPase rab5 has been shown to represent a key regulator in the endocytic pathway of mam... more The small GTPase rab5 has been shown to represent a key regulator in the endocytic pathway of mammalian cells. Using a PCR approach to identify rab5 homologs in Saccharomyces cerevisiae, two genes encoding proteins with 54 and 52 % identity to rab5, YP/51 and YF/53 have been identified. Sequencing of the yeast chromosome XI has revealed a third rab5like gene, YF/~2, whose protein product exhibits a similar identity to tab5 and the other two YPT gene products. In addition to the high degree of identity/homology shared between rab5 and Ypt51p, Ypt52p, and Ypt53p, evidence for functional homology between the mammalian and yeast proteins is provided by phenotypic characterization of single, double, and triple deletion mutants. Endocytic delivery to the vacuole of two markers, lucifer yellow CH (LY) and a-factor, was inhibited in Aypt51 mutants and aggravated in the double ypt51ypt52 and triple ypt51yptS2yptS3 mutants, suggesting a requirement for these small GTPases in endocytic membran...

Neuro-Oncology

The VEGF pathway remains an important target in GBM given its vascularity and autocrine VEGF sign... more The VEGF pathway remains an important target in GBM given its vascularity and autocrine VEGF signalling. Olinvacimab (TTAC-0001) is a fully humanised VEGFR2 Mab that binds and inhibits the receptor. This report assesses the safety, dosing schedules and efficacy of Olinvacimab in recurrent GBM. We conducted a two-site, 3 arm, open-label study of Olinvacimab in recurrent GBM. Eligible patients were ≥18 years with RANO-measurable lesion, KPS ≥ 80, and had completed chemoradiotherapy without prior bevacizumab therapy. We assessed three arms, 8 mg/kg and 12mg/kg weekly for 3 of every 4 weeks, and 12 mg/kg weekly. Three patients were treated in arms 1 and 2 and 6 in arm 3. Safety assessments were performed prior to dose escalation. The main toxicity was development of grade 1 (67%) and 2 (8%%) cutaneous haemangiomas. Common toxicities seen with other VEGF directed therapies, including hypertension, impaired wound healing, and proteinuria were not seen in this cohort. Efficacy was assessed...

Journal of Biomolecular NMR

Monoclonal antibody (mAb) drugs are clinically important for the treatment of various diseases. T... more Monoclonal antibody (mAb) drugs are clinically important for the treatment of various diseases. TTAC-0001 is under development as a new anti-cancer antibody drug targeting VEGFR-2. As the less severe toxicity of TTAC-0001 compared to Bevacizumab, likely due to the decreased in vivo half-life, seems to be related to its structural flexibility, it is important to map the exact flexible regions. Although the 13C/15N-labeled protein is required for NMR analyses, it is difficult to obtain antibody fragments (Fab and scFv) containing disulfide bonds through general cytosolic expression in Escherichia coli (E. coli). Here, we notably increased the periplasmic expression of the 13C/15N-labeled TTAC-0001-Fab (13C/15N-TTAC-Fab) through simple isopropyl β-D-1-thiogalactopyranoside (IPTG)-induction at an increased optical density (1.5 OD600nm). Through NMR triple resonance experiments, two loop insertions (LI-1 between the VH and CH1; LI-2 between the VL and CL) were confirmed to be highly flexible. The additional LIs could be another way to engineer the antibody by changing the pharmacokinetic properties.

Journal of Clinical Oncology

e14545 Background: Recurrent GBM is difficult to treat. Single agent checkpoint blockade has not ... more e14545 Background: Recurrent GBM is difficult to treat. Single agent checkpoint blockade has not improved outcomes. Angiogenesis is a rational drug target for rGBM and targeting angiogenesis may benefit pseudoprogression and cerebral oedema. O is a fully human monoclonal antibody (MAB) which binds to Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) with antiangiogenic and antitumour effects. P is an anti-PD1 MAB. This study aimed to identify the safety and tolerability of O combined with P and to establish a recommended phase 2 combination dose. Methods: From January to October 2019, we conducted a two-site, single arm, open-label study of O with P in patients with rGBM. Eligible patients (pts) were ≥18 years with at least one RANO-measurable lesion, KPS≥80, and had completed standard chemoradiotherapy and had no contraindications to O or P. No prior bevacizumab was allowed. A modified Toxicity Probability Interval design was used. Pts received O 12 mg/kg day 1/8/15 q21d (dose...

PloS one, 2018

Targeting of vascular endothelial growth factor receptors (VEGFRs) has potential anti-angiogenic ... more Targeting of vascular endothelial growth factor receptors (VEGFRs) has potential anti-angiogenic effects because VEGFR-2 is the major signaling regulator of VEGF/VEGFR pathways. We aimed to elucidate the drug mechanism and anti-tumor efficacy of TTAC-0001, a novel, fully human anti-VEGFR-2/KDR monoclonal antibody, in mouse orthotopic breast cancer model using multi-modal bioimaging. We used orthotopic xenograft tumor model in which human breast cancer cells (MDA-MB-231) were injected into the right mammary fat pad of Balb/c nude mice. We investigated its biodistribution using serial fluorescence imaging after injecting fluorescent-labelled-drug and mode of action using Matrigel plug angiogenesis assays. The anti-tumor efficacy of drug was assessed using ultrasonography and bioluminescence imaging. Histopathologic analyses, including hematoxylin and eosin staining and immunohistochemistry with anti-CD31 and anti-Ki-67 antibodies, were performed. Each experiment had four groups: contr...

mAbs, 2015

Vascular endothelial growth factor (VEGF) and its receptors are considered the primary cause of t... more Vascular endothelial growth factor (VEGF) and its receptors are considered the primary cause of tumor-induced angiogenesis. Specifically, VEGFR-2/kinase insert domain receptor (KDR) is part of the major signaling pathway that plays a significant role in tumor angiogenesis, which is associated with the development of various types of tumor and metastasis. In particular, KDR is involved in tumor angiogenesis as well as cancer cell growth and survival. In this study, we evaluated the therapeutic potential of TTAC-0001, a fully human antibody against VEGFR-2/KDR. To assess the efficacy of the antibody and pharmacokinetic (PK) relationship in vivo, we tested the potency of TTAC-0001 in glioblastoma and colorectal cancer xenograft models. Antitumor activity of TTAC-0001 in preclinical models correlated with tumor growth arrest, induction of tumor cell apoptosis, and inhibition of angiogenesis. We also evaluated the combination effect of TTAC-0001 with a chemotherapeutic agent in xenograft...

mAbs, 2015

Angiogenesis is one of the most important processes for cancer cell survival, tumor growth and me... more Angiogenesis is one of the most important processes for cancer cell survival, tumor growth and metastasis. Vascular endothelial growth factor (VEGF) and its receptor, particularly VEGF receptor-2 (VEGFR-2, or kinase insert domaincontaining receptor, KDR), play critical roles in tumor-associated angiogenesis. We developed TTAC-0001, a human monoclonal antibody against VEGFR-2/KDR from a fully human na€ ıve single-chain variable fragment phage library. TTAC-0001 was selected as a lead candidate based on its affinity, ligand binding inhibition and inhibition of VEGFR-2 signal in human umbilical vein endothelial cells (HUVEC). TTAC-0001 inhibited binding of VEGF-C and VEGF-D to VEGFR-2 in addition to VEGF-A. It binds on the N-terminal regions of domain 2 and domain 3 of VEGFR-2. It could inhibit the phosphorylation of VEGFR-2/KDR and ERK induced by VEGF in HUVEC. TTAC-0001 also inhibited VEGF-mediated endothelial cell proliferation, migration and tube formation in vitro, as well as ex vivo vessel sprouting from rat aortic rings and neovascularization in mouse matrigel model in vivo. Our data indicates that TTAC-0001 blocks the binding of VEGFs to VEGFR-2/KDR and inhibits VEGFR-induced signaling pathways and angiogenesis. Therefore, these data strongly support the further development of TTAC-0001 as an anti-cancer agent in the clinic.

The Journal of Cell Biology, 1994

The small GTPase rab5 has been shown to represent a key regulator in the endocytic pathway of mam... more The small GTPase rab5 has been shown to represent a key regulator in the endocytic pathway of mammalian cells. Using a PCR approach to identify rab5 homologs in Saccharomyces cerevisiae, two genes encoding proteins with 54 and 52% identity to rab5, YPT51 and YPT53 have been identified. Sequencing of the yeast chromosome XI has revealed a third rab5-like gene, YPT52, whose protein product exhibits a similar identity to rab5 and the other two YPT gene products. In addition to the high degree of identity/homology shared between rab5 and Ypt51p, Ypt52p, and Ypt53p, evidence for functional homology between the mammalian and yeast proteins is provided by phenotypic characterization of single, double, and triple deletion mutants. Endocytic delivery to the vacuole of two markers, lucifer yellow CH (LY) and alpha-factor, was inhibited in delta ypt51 mutants and aggravated in the double ypt51ypt52 and triple ypt51ypt52ypt53 mutants, suggesting a requirement for these small GTPases in endocyti...