专利快速检索-快速检索全球专利，免费商用专利数据库-IPRDB

1. 发明申请

US20160068825A1 Development of Protein-Based Biotherapeutics That Penetrate Cell-Membrane and Induce Anti-Cancer Effect- Cell-Permeable Glutathione Peroxidase7 (CP-GPX7) in Gastrointestinal Track (GIT), Polynucleotides Encoding the Same, and Anti-Cancer Compositions Comprising the Same 审中-公开
公开(公告)号：US20160068825A1
公开(公告)日：2016-03-10
申请号：US14846474
申请日：2015-09-04
申请人： DAEWOONG JO , Cellivery Therapeutics, Inc.
发明人： Daewoong JO , Young Sil CHOI , So Yeong LEE , Eun Kyung LEE , Mi Rin KANG
IPC分类号： C12N9/08 , A61K38/44
CPC分类号： C12N9/0065 , A61K38/00 , C07K2319/00 , C07K2319/10 , C12Y111/01009
摘要： Gastrointestinal track (GIT) including oesophageal and gastric cancers are a leading cause of cancer death worldwide. Limited therapeutic options highlight the need to understand the molecular changes responsible for the disease and to develop therapies based on this understanding. Advances in understanding the molecular changes responsible for GIT cancer etiology and progression are expected to improve disease diagnosis and treatment. The glutathione peroxidase 7 (GPX7) a candidate tumor suppressor implicated in GIT cancers including esophageal and gastric cancers has been implicated as a potential tumor suppressor gene in esophageal and gastric cancers; however, this claim is controversial. The goal of this invention is to develop cell-permeable (CP-) form of GPX7 to utilize the therapeutic potential of GPX7 in the treatment of GIT cancers. Using macromolecule intracellular transduction technology (MITT) enabled by novel hydrophobic cell-penetrating peptide (CPP) called advanced macromolecule transduction domains (aMTDs) which are able to promote protein uptake by mammalian cells and tissues, the first CP-GPX7 protein has been developed to deliver biologically active GPX7 protein into human oesophageal and gastric cancer cells, resulting in suppression of cell phenotypes and induction of changes in biomarker expression consistent with previously described effects of GPX7. CP-GPX7 recombinant protein fused to aMTD also suppresses the growth of human gastric tumors in a mouse xenograft model. The results of this art provide further evidence that GPX7 can function as an anti-cancer molecule and suggest that practical methods to augment GPX7 function could be useful in treating of some types of GIT cancers. The present art with CP-GPX7 recombinant protein illustrates the use of protein-based therapies to target GIT cancers.

2. 发明申请

US20160060314A1 Development of a Protein-Based Biotherapeutic Agent That Penetrates Cell-Membrane and Induces Anti-Tumor Effect in Solid Tumors - Improved Cell-Permeable Suppressor of Cytokine Signaling (iCP-SOCS3) Proteins, Polynucleotides Encoding the Same, and Anti-Tumor Compositions Comprising the Same 审中-公开
公开(公告)号：US20160060314A1
公开(公告)日：2016-03-03
申请号：US14838304
申请日：2015-08-27
申请人： DAEWOONG JO , Cellivery Therapeutics, Inc.
发明人： Daewoong JO , Young Sil CHOI , Seul Mee SHIN , Ju Hyun NAM
IPC分类号： C07K14/47 , C07K7/08
摘要： In principle, protein-based biotherapeutics offers a way to control biochemical processes in living cells under non-steady state conditions and with fewer off-target effects than conventional small molecule therapeutics. However, systemic protein delivery in vivo has been proven difficult due to poor tissue penetration and rapid clearance. Protein transduction exploits the ability of some cell-penetrating peptide (CPP) sequences to enhance the uptake of proteins and other macromolecules by mammalian cells. Previously developed hydrophobic CPPs, named membrane translocating sequence (MTS), membrane translocating motif (MTM) and macromolecule transduction domain (MTD), are able to deliver biologically active proteins into a variety of cells and tissues. Various cargo proteins fused to these CPPs have been used to test the functional and/or therapeutic efficacy of protein transduction. The recombinant proteins consisting of suppressor of cytokine signaling 3 (CP-SOCS3) protein fused to the fibroblast growth factor (FGF) 4-derived MTM were developed to inhibit inflammation and apoptosis. However, CP-SOCS3 fusion proteins expressed in bacteria cells were hard to be purified in soluble form. To address these critical limitations, CPP sequences called advanced MTDs (aMTDs) have been developed in this art. This is accomplished by (i) analyzing previous developed hydrophobic CPP sequences to identify specific critical factors (CFs) that affect intracellular delivery potential and (ii) constructing artificial aMTD sequences satisfied for each critical factor. In addition, solubilization domains (SDs) have been incorporated into the aMTD-fused SOCS3 recombinant proteins to enhance solubility with corresponding increases in protein yield and cell-/tissue-permeability. These recombinant SOCS3 proteins fused to aMTD/SD having much higher solubility/yield and cell-/tissue-permeability have been named as improved cell-permeable SOCS3 (iCP-SOCS3) proteins. Previously developed CP-SOCS3 proteins fused to MTM were only tested or used as anti-inflammatory agents to treat acute liver injury. In the present art, iCP-SOCS3 proteins have been tested for use as anti-cancer agents in the treatment of various cancers likes gastric, colorectal and breast cancer, and glioblastoma. Since SOCS3 is frequently deleted in and loss of SOCS3 in tumors promotes resistance to apoptosis and proliferation, we reasoned that iCP-SOCS3 could be used as a protein-based intracellular replacement therapy for the treatment of various cancers. The results demonstrated in this art support the reasoning: treatment of cancer cells with iCP-SOCS3 results in reduced cancer cell viability, enhanced apoptosis of solid tumors including gastric, colorectal and breast cancer, and glioblastoma and loss of cell migration/invasion potential. Furthermore, iCP-SOCS3 inhibits the growth of gastric and colorectal tumors in a subcutaneous xenografts model. In the present invention with iCP-SOCS3, where SOCS3 is fused to an empirically determined combination of newly developed aMTD and customized SD, macromolecule intracellular transduction technology (MITT) enabled by the advanced MTDs may provide novel protein therapy against various tumors such as gastric cancer, colorectal cancer, glioblastoma, and breast cancer.

3. 发明申请

US20160060310A1 Development of Protein-Based Biotherapeutics That Penetrates Cell-Membrane and Induces Anti-Hepatocellular Carcinoma Effect - Improved Cell-Permeable Suppressor of Cytokine Signaling (iCP-SOCS3) Proteins, Polynucleotides Encoding the Same, and Anti-Hepatocellular Carcinoma Compositions Comprising the Same 审中-公开
公开(公告)号：US20160060310A1
公开(公告)日：2016-03-03
申请号：US14838260
申请日：2015-08-27
申请人： DAEWOONG JO , Cellivery Therapeutics, Inc.
发明人： Daewoong JO , Young Sil CHOI , Youn Seo HWANG , Kyeong Soo KIM
IPC分类号： C07K14/47 , C07K7/08
摘要： Protein transduction exploits the ability of some cell-penetrating peptide (CPP) sequences to enhance the uptake of proteins and other macromolecules by mammalian cells. Previously developed hydrophobic CPPs, named membrane translocating sequence (MTS), membrane translocating motif (MTM) and macromolecule transduction domain (MTD), are able to deliver biologically active proteins into a variety of cells and tissues. Various cargo proteins fused to these CPPs have been used to test the functional and/or therapeutic efficacy of protein transduction. For example, recombinant proteins consisting of suppressor of cytokine signaling 3 protein (CP-SOCS3) fused to the fibroblast growth factor (FGF) 4-derived MTM were developed to inhibit inflammation and apoptosis. However, CP-SOCS3 fusion proteins expressed in bacteria were hard to purify in soluble form. To address these critical limitations, CPP sequences called advanced MTDs (aMTD) have been developed in this art. This is accomplished by (i) analyzing previous developed hydrophobic CPP sequences to identify specific critical factors (CFs) that affect intracellular delivery potential and (ii) constructing artificial aMTD sequences satisfied for each critical factor. In addition, solubilization domains (SDs) have been incorporated into the aMTD-fused SOCS3 recombinant proteins to enhance solubility with corresponding increases in protein yield and cell-/tissue-permeability. These recombinant SOCS3 proteins fused to aMTD/SD having much higher solubility/yield and cell-/tissue-permeability have been named as improved cell-permeable SOCS3 (iCP-SOCS3) proteins. Previously developed CP-SOCS3 proteins fused to MTM were only tested or used as anti-inflammatory agents to treat acute liver injury. In the present art, iCP-SOCS3 proteins have been tested for use as anti-cancer agents in the treatment of hepatocellular carcinoma. Since SOCS3 is frequently deleted in and loss of SOCS3 in hepatocytes promotes resistance to apoptosis and proliferation, we reasoned that iCP-SOCS3 could be used as a protein-based intracellular replacement therapy for the treatment of hepatocellular carcinoma. The results support this reasoning: treatment of hepatocellular carcinoma cells with iCP-SOCS3 results in reduced cancer cell viability, enhanced apoptosis and loss of cell migration/invasion potential. Furthermore, iCP-SOCS3 inhibits the growth of hepatocellular carcinoma in a subcutaneous xenografts model. In the present invention with iCP-SOCS3 fused to an empirically determined combination of newly developed aMTD and customized SD, macromolecule intracellular transduction technology (MITT) enabled by the advanced MTD may provide novel protein therapy against hepatocellular carcinoma.

4. 发明申请

US20160083441A1 Development of Protein-Based Biotherapeutics That Penetrate Cell-Membrane and Induce Anti-Cancer Effect - Cell-Permeable Trefoil Factor 1 (CP-TFF1) in Gastrointestinal Track (GIT) Cancer, Polynucleotides Encoding The Same, and Anti-Cancer Compositions Comprising The Same 审中-公开
标题翻译：发展渗透细胞膜并诱导抗癌作用的蛋白质生物治疗剂 - 细胞透过性三叶因子1（CP-TFF1）在胃肠道（GIT）癌症，编码其的多核苷酸和包含其的抗癌组合物
公开(公告)号：US20160083441A1
公开(公告)日：2016-03-24
申请号：US14863478
申请日：2015-09-24
申请人： DAEWOONG JO , Cellivery Therapeutics, Inc.
发明人： Daewoong JO , Young Sil CHOI , Kuy Sook LEE , Hyeon Sik KANG , Cho Hyun KIM
IPC分类号： C07K14/47 , C07K14/195 , C07K14/415 , C07K7/08
CPC分类号： C07K14/47 , A61K38/00 , C07K7/08 , C07K14/195 , C07K14/4703 , C07K2319/10 , C07K2319/35
摘要： The present study investigated the use of macromolecule intracellular transduction technology (MITT) to deliver biologically active TFF1 protein into gastric cancer cells both in vitro and in vivo. Proteins engineered to enter cancer cells are supposed to suppress cell proliferation and survival, consistent with its role as a tumor suppressor. The invention has developed new hydrophobic CPP-advanced MTDs (aMTDs) for high solubility/yield and cell-/tissue-permeability of the recombinant therapeutic fusion proteins. The TFF1 protein has been fused to aMTD165 and solubilization domains (SDs), and tested their therapeutic applicability as a gastric cancer-specific protein-based anti-cancer agent. Treatment with CP-TFF1 in gastric cancer cells reduced cancer cell viability (60%˜80% in 10 μM treatment), inhibited cell migration (approximately 50%). Furthermore, CP-TFF1 significantly inhibited the tumor growth during the treatment and the effect persisted for at least 3 weeks after the treatment was terminated (90% inhibition at day 42) in a xenografts model which were subcutaneously implanted with tumor block of gastric cancer cells (MKN45). In the present invention, CP-TFF1 recombinant protein showed the potential of novel protein therapies against gastric cancer.
摘要翻译：本研究调查了大分子细胞内转导技术（MITT）在体外和体内将生物活性TFF1蛋白递送到胃癌细胞中的应用。旨在进入癌细胞的蛋白质被认为抑制细胞增殖和存活，与其作为肿瘤抑制剂的作用一致。本发明开发了用于重组治疗融合蛋白的高溶解度/产率和细胞/组织通透性的新型疏水CPP先进MTD（aMTD）。 TFF1蛋白已经融合到MTD165和增溶结构域（SDs），并且测试了它们作为胃癌特异性蛋白质抗癌剂的治疗适用性。 CP-TFF1在胃癌细胞中的治疗降低了癌细胞活力（10μM治疗中为60％〜80％），抑制细胞迁移（约50％）。此外，CP-TFF1在治疗期间显着抑制肿瘤生长，并且在皮下植入胃癌细胞肿瘤块的异种移植物模型中，在治疗终止后至少3周持续至少3周（在第42天为90％抑制）（MKN45）。在本发明中，CP-TFF1重组蛋白显示了新的蛋白质治疗胃癌的潜力。

5. 发明申请

US20160060313A1 Development of Protein-Based Biotherapeutics That Penetrates Cell-Membrane and Induces Anti-Angiogenic Effect - Improved Cell-Permeable Suppressor of Cytokine Signaling (iCP-SOCS3) Proteins, Polynucleotides Encoding the Same, and Anti-Angiogenic Compositions Comprising the Same 审中-公开
公开(公告)号：US20160060313A1
公开(公告)日：2016-03-03
申请号：US14838295
申请日：2015-08-27
申请人： DAEWOONG JO , Cellivery Therapeutics, Inc.
发明人： Daewoong JO , Young Sil CHOI , Won Heum NA , Ki Joon OH
IPC分类号： C07K14/47 , C07K7/08
摘要： In principle, protein-based biotherapeutics offers a way to control biochemical processes in living cells under non-steady state conditions and with fewer off-target effects than conventional small molecule therapeutics. However, systemic protein delivery in vivo has been proven difficult due to poor tissue penetration and rapid clearance. Protein transduction exploits the ability of some cell-penetrating peptide (CPP) sequences to enhance the uptake of proteins and other macromolecules by mammalian cells. Previously developed hydrophobic CPPs—named membrane translocating sequence (MTS), membrane translocating motif (MTM) and macromolecule transduction domain (MTD)—are able to deliver biologically active proteins into a variety of cells and tissues. Various cargo proteins fused to these CPPs have been used to test the functional and/or therapeutic efficacy of protein transduction. Previously, recombinant proteins consisting of suppressor of cytokine signaling 3 (SOSC3) fused to the fibroblast growth factor (FGF) 4-derived MTM were developed to inhibit inflammation and apoptosis. However, this SOCS3 fusion proteins expressed in bacteria cells were hard to be purified in soluble form. To address these critical limitations, CPP sequences called advanced MTDs (aMTDs) have been developed in this art. The development of this art has been accomplished by (i) analyzing previous developed hydrophobic CPP sequences to identify specific critical factors (CFs) that affect intracellular delivery potential and (ii) constructing artificial aMTD sequences that satisfy each critical factor. Furthermore, solubilization domains (SDs) have been incorporated into the aMTD-fused SOCS3 recombinant proteins to enhance solubility with corresponding increases in protein yield and cell-/tissue-permeability. These recombinant SOCS3 proteins fused to aMTD/SD having much higher solubility/yield and cell-/tissue-permeability have been named as improved cell-permeable SOCS3 (iCP-SOCS3) proteins. Previously developed SOCS3 recombinant proteins fused to MTM were only tested or used as anti-inflammatory agents to treat acute liver injury. In the present art, iCP-SOCS3 proteins have been tested for use as anti-angiogenic agents. Since SOCS3 is known to be an endogenous inhibitor of pathological angiogenesis, we reasoned that iCP-SOCS3 could be used as a protein-based intracellular replacement therapy for inhibiting angiogenesis in tumor cells. The results demonstrated in this art support this following reasoning: Cancer treatment with iCP-SOCS3 results in reduced endothelial cell viability, loss of cell migration potential and suppressed vascular sprouting potentials. In the present invention with iCP-SOCS3, where SOCS3 is fused to an empirically determined combination of newly developed aMTD and customized SD, macromolecule intracellular transduction technology (MITT) enabled by the advanced MTDs may provide novel protein therapy against cancer cell-mediated angiogenesis.

6. 发明申请

US20160060312A1 Development of Protein-Based Biotherapeutics That Penetrates Cell-Membrane and Induces Anti-Pancreatic Cancer Effect - Improved Cell-Permeable Suppressor of Cytokine Signaling (iCP-SOCS3) Proteins, Polynucleotides Encoding the Same, and Anti-Pancreatic Cancer Compositions Comprising the Same 审中-公开
公开(公告)号：US20160060312A1
公开(公告)日：2016-03-03
申请号：US14838288
申请日：2015-08-27
申请人： Daewoong JO , Cellivery Therapeutics, Inc.
发明人： Daewoong JO , Young Sil CHOI , Eun Kyung LEE , Na Ra YOON
IPC分类号： C07K14/47 , C07K7/08
摘要： In principle, protein-based biotherapeutics offers a way to control biochemical processes in living cells under non-steady state conditions and with fewer off-target effects than conventional small molecule therapeutics. However, systemic protein delivery in vivo has been proven difficult due to poor tissue penetration and rapid clearance. Protein transduction exploits the ability of some cell-penetrating peptide (CPP) sequences to enhance the uptake of proteins and other macromolecules by mammalian cells. Previously developed hydrophobic CPPs, named membrane translocating sequence (MTS), membrane translocating motif (MTM) and macromolecule transduction domain (MTD), are able to deliver biologically active proteins into a variety of cells and tissues. Various cargo proteins fused to these CPPs have been used to test the functional and/or therapeutic efficacy of protein transduction. The recombinant proteins consisting of suppressor of cytokine signaling 3 (CP-SOCS3) protein fused to the fibroblast growth factor (FGF) 4-derived MTM were developed to inhibit inflammation and apoptosis. However, CP-SOCS3 fusion proteins expressed in bacteria cells were hard to be purified in soluble form. To address these critical limitations, CPP sequences called advanced MTDs (aMTDs) have been developed in this art. This is accomplished by (i) analyzing previous developed hydrophobic CPP sequences to identify specific critical factors (CFs) that affect intracellular delivery potential and (ii) constructing artificial aMTD sequences that satisfy each critical factor. In addition, solubilization domains (SDs) have been incorporated into the aMTD-fused SOCS3 recombinant proteins to enhance solubility with corresponding increases in protein yield and cell-/tissue-permeability. These recombinant SOCS3 proteins fused to aMTD/SD having much higher solubility/yield and cell-/tissue-permeability have been named as improved cell-permeable SOCS3 (iCP-SOCS3) proteins. Previously developed CP-SOCS3 proteins fused to MTM were only tested or used as anti-inflammatory agents to treat acute liver injury. In the present art, iCP-SOCS3 proteins have been tested for use as anti-cancer agents in the treatment of pancreatic cancer. Since SOCS3 is frequently deleted in cancer cells and loss of SOCS3 promotes resistance to apoptosis and proliferation, we reasoned that iCP-SOCS3 could be used as a protein-based intracellular replacement therapy for the treatment of pancreatic cancer. The results demonstrated in this art support this reasoning: treatment of pancreatic cancer cells with iCP-SOCS3 results in reduced cancer cell viability, enhanced apoptosis and loss of cell migration/invasion potentials. Furthermore, iCP-SOCS3 inhibits the growth of pancreatic cancer in a subcutaneous xenografts model. In the present invention with iCP-SOCS3, where SOCS3 is fused to an empirically determined combination of newly developed aMTD and customized SD, macromolecule intracellular transduction technology (MITT) enabled by the advanced MTDs may provide novel protein therapy against pancreatic cancer.

7. 发明申请

US20160060311A1 Development of Protein-Based Biotherapeutics That Penetrates Cell-Membrane and Induces Anti-Lung Cancer Effect - Improved Cell-Permeable Suppressor of Cytokine Signaling (iCP-SOCS3) Proteins, Polynucleotides Encoding the Same, and Anti-Lung Cancer Compositions Comprising the Same 审中-公开
公开(公告)号：US20160060311A1
公开(公告)日：2016-03-03
申请号：US14838280
申请日：2015-08-27
申请人： Daewoong JO , Cellivery Therapeutics, Inc.
发明人： Daewoong JO , Young Sil CHOI , Kuy Sook LEE , Min Seok JANG
IPC分类号： C07K14/47 , C07K7/08
摘要： In principle, protein-based biotherapeutics offers a way to control biochemical processes in living cells under non-steady state conditions and with fewer off-target effects than conventional small molecule therapeutics. However, systemic protein delivery in vivo has been proven difficult due to poor tissue penetration and rapid clearance. Protein transduction exploits the ability of some cell-penetrating peptide (CPP) sequences to enhance the uptake of proteins and other macromolecules by mammalian cells. Previously developed hydrophobic CPPs, named membrane translocating sequence (MTS), membrane translocating motif (MTM) and macromolecule transduction domain (MTD), are able to deliver biologically active proteins into a variety of cells and tissues. Various cargo proteins fused to these CPPs have been used to test the functional and/or therapeutic efficacy of protein transduction. Previously, recombinant proteins consisting of suppressor of cytokine signaling 3 (CP-SOCS3) protein fused to the fibroblast growth factor (FGF) 4-derived MTM were developed to inhibit inflammation and apoptosis. However, CP-SOCS3 fusion proteins expressed in bacteria cells were hard to be purified in soluble form. To address these critical limitations, CPP sequences called advanced MTDs (aMTDs) have been developed in this art. The development of this art has been accomplished by (i) analyzing previous developed hydrophobic CPP sequences to identify specific critical factors (CFs) that affect intracellular delivery potential and (ii) constructing artificial aMTD sequences that satisfy for each critical factor. In addition, solubilization domains (SDs) have been incorporated into the aMTD-fused SOCS3 recombinant proteins to enhance solubility with corresponding increases in protein yield and cell-/tissue-permeability. These recombinant SOCS3 proteins fused to aMTD/SD having much higher solubility/yield and cell-/tissue-permeability have been named as improved cell-permeable SOCS3 (iCP-SOCS3) proteins. Previously developed CP-SOCS3 proteins fused to MTM were only tested or used as anti-inflammatory agents to treat acute liver injury. In the present art, iCP-SOCS3 proteins have been tested for use as anti-cancer agents in the treatment of neoplasia in lung. Since SOCS3 is frequently deleted in cancer cells and loss of SOCS3 promotes resistance to apoptosis and proliferation, we reasoned that iCP-SOCS3 could be used as a protein-based intracellular replacement therapy for the treatment of lung cancer. The results demonstrated in this art support this reasoning: treatment of human non-small cell lung carcinoma cells with iCP-SOCS3 results in reduced cancer cell viability, enhanced apoptosis. Furthermore, iCP-SOCS3 inhibited migration/invasion of lung cancer cells. In the present invention with iCP-SOCS3, where SOCS3 is fused to an empirically determined combination of newly developed aMTD and customized SD, macromolecule intracellular transduction technology (MITT) enabled by the advanced MTDs may provide novel protein therapy against lung cancer.

8. 发明申请

US20170137482A1 CELL-PERMEABLE (ICP)-SOCS3 RECOMBINANT PROTEIN AND USES THEREOF 审中-公开
公开(公告)号：US20170137482A1
公开(公告)日：2017-05-18
申请号：US15361701
申请日：2016-11-28
申请人： Daewoong JO , CELLIVERY THERAPEUTICS, INC.
发明人： Daewoong JO , Youngsil CHOI , Kuysook LEE , Seulmee SHIN , Jihye KIM , Jeongmin KIM , Chohyun KIM
IPC分类号： C07K14/47 , C07K7/08
摘要： The present invention relates to providing improved cell-permeable (iCP)-SOCS3 recombinant protein and uses thereof. Preferably, the iCP-SOCS3 recombinant protein may be used as protein-based anti-solid tumor agent by utilizing the platform technology for macromolecule intracellular transduction.

9. 发明申请

US20170029798A1 Development of Improved Cell-Permeable (iCP) Parkin Recombinant Protein as a Protein-Based Anti-Neurodegenerative Agent for the Treatment of Parkinson's Disease-Associated Phenotypes by Utilizing BBB-Penetrating Protein Delivery System MITT, Enabled by Advanced Macromolecule Transduction Domain (aMTD) 审中-公开
标题翻译：通过使用BBB穿透蛋白递送系统MITT，通过高级大分子转导结构域（aMTD）启动，改进的细胞透过性（iCP）Parkin重组蛋白作为基于蛋白质的抗神经变性剂用于治疗帕金森病相关表型的发展
公开(公告)号：US20170029798A1
公开(公告)日：2017-02-02
申请号：US14809279
申请日：2015-07-27
申请人： DAEWOONG JO , Cellivery Therapeutics, Inc.
发明人： Daewoong JO , EUNSIN HA , JIEUN LEE , JEONGMIN JEON , KWANGJAE LEE
IPC分类号： C12N9/00 , G01N33/573
CPC分类号： C12N9/93 , C07K2319/10 , C12Y603/02019 , G01N33/573 , G01N2333/9015
摘要： Macromolecule intracellular transduction technology based on improved cell-permeable Parkin recombinant protein (iCP-Parkin) has been developed as a protein-based anti-neurodegenerative agent for efficient BBB-penetration to effectively deliver the recombinant protein into the brain. Parkin protein, a dopaminergic neuronal cell death inhibitor, has been fused with a newly developed advanced macromolecule transduction domain (aMTD) and solubilization domain (SD) to increase the solubility/yield and cell-/tissue-permeability of the recombinant protein. In addition, our newly developed aMTD/SD-fused recombinant iCP-Parkin protein has shown BBB-permeability. Both in vitro and in vivo, our iCP-Parkin recombinant protein improved motor skills, a typical phenotype of Parkinson's disease, by increasing dopamine level in the brain by suppressing apoptosis of dopaminergic neuron cells. In conclusion, iCP-Parkin could be applicable in clinical studies as a protein-based anti-neurodegenerative agent to treat Parkinson's disease by protecting dopaminergic neuron cells and regulating the secretion of dopamine.
摘要翻译：已经开发了基于改进的细胞可渗透的Parkin重组蛋白（iCP-Parkin）的大分子细胞内转导技术作为用于有效BBB穿透的蛋白质的抗神经变性剂，以有效地将重组蛋白质递送到脑中。 Parkin蛋白是一种多巴胺能神经元细胞死亡抑制剂，与新开发的高分子大分子转导结构域（aMTD）和溶解域（SD）融合，以提高重组蛋白的溶解度/产量和细胞/组织通透性。另外，我们新开发的aMTD / SD融合重组iCP-Parkin蛋白显示了BBB通透性。在体外和体内，我们的iCP-Parkin重组蛋白通过抑制多巴胺能神经元细胞的凋亡来增加大脑中多巴胺水平，从而改善运动技能，这是帕金森病的典型表型。总之，iCP-Parkin可以作为一种基于蛋白质的抗神经变性药物进行临床研究，通过保护多巴胺能神经元细胞和调节多巴胺的分泌来治疗帕金森病。

10. 发明申请

US20160060319A1 Development of Protein-Based Biotherapeutics That Induced Osteogenesis for Bone Healing Therapy: Cell-Permeable BMP2 and BMP7 Recombinant Proteins (CP-BMP2 & CP-BMP7), Polynucleotides Encoding the Same and Pro-osteogenic Compositions Comprising the Same 审中-公开
公开(公告)号：US20160060319A1
公开(公告)日：2016-03-03
申请号：US14838318
申请日：2015-08-27
申请人： DAEWOONG JO , Cellivery Therapeutics, Inc.
发明人： Daewoong JO , Eun Sin HA , Ji Hye LEE , Kyung Ae YOON , Bit Na KIM , Man Young JANG
IPC分类号： C07K14/51 , C07K7/08
摘要： The present invention is about direct protein delivery system for bone morphogenetic proteins (BMPs) to enhance bone regeneration without the need of additional delivery carrier which requires open surgery for their implantation. The cell-permeable BMP (CP-BMP) recombinant proteins are fused with advanced macromolecule transduction domain (aMTD) to give them ability for cell penetration and with solubilization domain (SD) to increase their solubility and manufacturing yield. Because existing BMP recombinant proteins have short half-life, they have been delivered with polymeric or inorganic vehicles for their sustained release. However, CP-BMPs fused to combination of aMTD and SD can easily and rapidly penetrate into the cytosol after treating on cells that likes hiding in a shelter from wash off in body fluid, and avoid rapid degradation. For the development of CP-BMP, BMP2 and BMP7 have been selected among various types of BMP family due to their potent osteo-inductivity. Both of proteins are produced in mature form (MP) as an active domain and pro-peptide form (latency associated peptide (LAP)+MP) for prolonged stability of proteins. In the present art, three strategic steps are used to prove the validity of using CP-BMPs on bone regeneration and new bone formation. First, randomly selected aMTDs and various types of SDs have been fused to BMP proteins for determine the best structural composition for highest solubility/yield and cell-/tissue-permeability. Next, aMTDs are fused to BMP2 and BMP7 proteins with optimized structure to determine the best construct for maximized cell- and tissue-permeability. Finally, biological activity of BMP2, BMP7 and combination of BMP2 and BMP7 recombinant proteins have been evaluated to enhance in vitro osteogenic differentiation and in vivo bone regeneration. The CP-BMPs can be applied to repair skeletal injuries which are by bone fracture, osteogenesis imperfecta, and bone extraction.

你已经成功收藏专利！

检索式保存成功!

IPRDB

热门服务

关于我们

友情链接

联系方式