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公开(公告)号：US20090298746A1
公开(公告)日：2009-12-03
申请号：US11921064
申请日：2006-06-09
IPC分类号： A61K38/16 , C07K14/435 , C07K14/76 , A61K38/38
CPC分类号： A61K47/48215 , A61K38/00 , A61K38/385 , A61K38/42 , A61K47/60 , C07K14/76 , C07K14/765 , C07K14/805
摘要： The present invention provides PEGylated hemoglobins and PEGylated albumins comprising polyethylene glycol (PEG) conjugated to hemoglobin or to albumin, wherein the PEG is a maleimide PEG, an alkylamide PEG, an iodoacetamide PEG, a p-nitro thio-phenyl PEG, a vinyl sulfone PEG, or a mixed disulfide PEG; and PEGylated albumins and PEGylated hemoglobins comprising polyethylene glycol (PEG) attached to a thiolated amino group of albumin or hemoglobin, wherein the amino group is thiolated using dithio sulfo succinimidyl propionate (DTSSP) or dithiosuccinimidyl propionate (DTSP) or dithiobispropionimidate. The invention also provides methods of preparing PEGylated hemoglobins and PEGylated albumins comprising a) reacting hemoglobin or albumin with a thiolating agent and with a PEGylating agent, and b) capping unPEGylated reactive thiols of hemoglobin or albumin with N-ethyl maleimide.
摘要翻译： 本发明提供聚乙二醇化的血红蛋白和聚乙二醇化的白蛋白，其包含与血红蛋白或白蛋白缀合的聚乙二醇（PEG），其中PEG是马来酰亚胺PEG，烷基酰胺PEG，碘乙酰胺PEG，对硝基硫代苯基PEG，乙烯基砜 PEG或混合二硫化物PEG; 和聚乙二醇化的白蛋白和聚乙二醇化血红蛋白，其包含连接到白蛋白或血红蛋白的硫醇化氨基的聚乙二醇（PEG），其中使用二硫代磺基琥珀酰亚胺基丙酸酯（DTSSP）或二硫代琥珀酰亚胺基丙酸酯（DTSP）或二硫代双丙酰亚胺酯来硫化氨基。 本发明还提供制备聚乙二醇化血红蛋白和聚乙二醇化白蛋白的方法，其包括a）使血红蛋白或白蛋白与硫醇化剂和聚乙二醇化剂反应，和b）用N-乙基马来酰亚胺封端血红蛋白或白蛋白的未PEG化的反应性硫醇。
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2.发明申请Site specific pegylated hemoglobin, method of preparing same, and uses thereof 审中-公开场地特异性聚乙二醇化血红蛋白，其制备方法及其应用公开(公告)号：US20090215670A1
公开(公告)日：2009-08-27
申请号：US11919788
申请日：2006-05-10
IPC分类号： A61K38/42 , C07K14/805
CPC分类号： C07K14/805
摘要： The present invention provides pegylated hemoglobins comprising a maleimide polyethylene glycol (PEG) conjugated to a thiol moiety of a cysteine residue of hemoglobin, methods of preparing the pegylated hemoglobins, compositions and blood substitutes comprising the pegylated hemoglobins, and methods of treating a subject which comprise administering to the subject blood substitutes comprising vasoinactive pegylated hemoglobins.
摘要翻译： 本发明提供了包含与血红蛋白的半胱氨酸残基的硫醇部分缀合的马来酰亚胺聚乙二醇（PEG）的聚乙二醇化血红蛋白，制备聚乙二醇化血红蛋白的方法，包含聚乙二醇化血红蛋白的组合物和血液代用品，以及治疗受试者的方法， 向受试者施用包含血管活性聚乙二醇化血红蛋白的血液代用品。
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公开(公告)号：US07501499B2
公开(公告)日：2009-03-10
申请号：US10538976
申请日：2003-12-18
CPC分类号： C07K14/805 , A61K38/00 , Y10T436/105831
摘要： The present invention provides a hemoglobin molecule (Hb) having six ± one PEG chains, wherein two of said PEG chains are bound to Cys-93 (β) of Hb, and the remaining PEG chains are bound to thiol groups introduced on ε-NH2 of Hb. The present invention also provides a process for preparing a modified hemoglobin molecule (Hb), comprising the steps of: (a) reacting Hb with 8-15 fold excess of iminothiolane to form thiolated Hb; and (b) reacting the thiolated Hb with 16-30 fold excess of PEG functionalized with a maleimide moiety, to form the modified Hb.
摘要翻译： 本发明提供了具有6个±1个PEG链的血红蛋白分子（Hb），其中两个所述PEG链与Hb的Cys-93（β）结合，其余的PEG链与引入到ε-NH 2上的硫醇基结合 的Hb。 本发明还提供了制备修饰的血红蛋白分子（Hb）的方法，包括以下步骤：（a）使Hb与8-15倍过量的亚氨基四氢噻吩反应以形成硫醇化的Hb; 和（b）使硫醇化的Hb与用马来酰亚胺部分官能化的16-30倍过量的PEG反应，形成改性的Hb。
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4.发明授权Pegylated non-hypertensive hemoglobins, methods of preparing same, and uses thereof 有权聚乙二醇化非高血压血红蛋白，其制备方法及其应用公开(公告)号：US07144989B2
公开(公告)日：2006-12-05
申请号：US10957200
申请日：2004-10-01
IPC分类号： A61K38/42 , C07K14/805 , C07K1/00
CPC分类号： C08B31/00 , C07C331/28 , C08B15/06 , C08B37/0021 , C08B37/0039
摘要： The present invention provides pegylated hemoglobins comprising a thiocarbamoyl-phenyl-polyethylene glycol (PEG) attached to hemoglobin, and comprising a polyethylene glycol (PEG) attached to hemoglobin by an acyl group. The invention also provides methods of preparing pegylated hemoglobins using isothiocyanato phenyl carbamate of PEG and using isothiocyanato phenyl di-PEG carbamate. The invention further provides compositions and blood substitutes comprising pegylated hemoglobins and methods of treating a subject which comprise administering to the subject blood substitutes comprising non-hypertensive pegylated hemoglobins.
摘要翻译： 本发明提供了包含与血红蛋白连接的硫代氨基甲酰基 - 苯基 - 聚乙二醇（PEG）的聚乙二醇化血红蛋白，并且包含通过酰基与血红蛋白连接的聚乙二醇（PEG）。 本发明还提供使用PEG的异硫氰酸苯酯基氨基甲酸酯制备聚乙二醇化血红蛋白的方法，并使用异硫氰酸苯酯二PEG-氨基甲酸酯。 本发明进一步提供了包含聚乙二醇化血红蛋白的组合物和血液代用品以及治疗受试者的方法，其包括向所述受试者施用包含非高血压聚乙二醇化血红蛋白的血液替代物。
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公开(公告)号：US20140256636A1
公开(公告)日：2014-09-11
申请号：US14281970
申请日：2014-05-20
IPC分类号： C07K14/805 , C07K14/765
CPC分类号： A61K38/385 , A61K38/00 , A61K38/42 , A61K47/60 , C07K14/76 , C07K14/765 , C07K14/805
摘要： The present invention provides PEGylated hemoglobins and PEGylated albumins comprising polyethylene glycol (PEG) conjugated to hemoglobin or to albumin, wherein the PEG is a maleimide PEG, an alkylamide PEG, an iodoacetamide PEG, a p-nitro thio-phenyl PEG, a vinyl sulfone PEG, or a mixed disulfide PEG; and PEGylated albumins and PEGylated hemoglobins comprising polyethylene glycol (PEG) attached to a thiolated amino group of albumin or hemoglobin, wherein the amino group is thiolated using dithio sulfo succinimidyl propionate (DTSSP) or dithiosuccinimidyl propionate (DTSP) or dithiobispropionimidate. The invention also provides methods of preparing PEGylated hemoglobins and PEGylated albumins comprising a) reacting hemoglobin or albumin with a thiolating agent and with a PEGylating agent, and b) capping unPEGylated reactive thiols of hemoglobin or albumin with N-ethyl maleimide.
摘要翻译： 本发明提供聚乙二醇化的血红蛋白和聚乙二醇化的白蛋白，其包含与血红蛋白或白蛋白缀合的聚乙二醇（PEG），其中PEG是马来酰亚胺PEG，烷基酰胺PEG，碘乙酰胺PEG，对硝基硫代苯基PEG，乙烯基砜 PEG或混合二硫化物PEG; 和聚乙二醇化的白蛋白和聚乙二醇化血红蛋白，其包含连接到白蛋白或血红蛋白的硫醇化氨基的聚乙二醇（PEG），其中使用二硫代磺基琥珀酰亚胺基丙酸酯（DTSSP）或二硫代琥珀酰亚胺基丙酸酯（DTSP）或二硫代双丙酰亚胺酯来硫化氨基。 本发明还提供制备聚乙二醇化血红蛋白和聚乙二醇化白蛋白的方法，其包括a）使血红蛋白或白蛋白与硫醇化剂和聚乙二醇化剂反应，和b）用N-乙基马来酰亚胺封端血红蛋白或白蛋白的未PEG化的反应性硫醇。
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公开(公告)号：US07521174B2
公开(公告)日：2009-04-21
申请号：US11004052
申请日：2004-12-03
IPC分类号： A01N1/02
CPC分类号： C12N5/0641 , C12N5/0006
摘要： The present invention is directed to pegylated red blood cells comprising a polyethylene glycol (PEG) attached to a thiolated amino group on a membrane protein, and to compositions comprising the pegylated red blood cells. The invention also provides methods of preparing pegylated red blood cells comprising reacting red blood cells with a compound that produces a thiolated amino group on a red blood cell membrane protein, and reacting the thiolated red blood cell with a PEG. The invention further provides methods of treatment using pegylated red blood cells.
摘要翻译： 本发明涉及包含与膜蛋白上的硫醇化氨基连接的聚乙二醇（PEG）的聚乙二醇化红细胞以及包含聚乙二醇化红细胞的组合物。 本发明还提供了制备聚乙二醇化红细胞的方法，包括使红细胞与在红细胞膜蛋白上产生硫醇化氨基的化合物反应，并将硫醇化的红细胞与PEG反应。 本发明进一步提供了使用聚乙二醇化红细胞的治疗方法。
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公开(公告)号：US07019117B2
公开(公告)日：2006-03-28
申请号：US10198732
申请日：2002-07-18
IPC分类号： C07K14/805
CPC分类号： C07K14/805 , A61K47/60
摘要： Novel modified hemoglobins comprising polyalkylene glycols and novel methods for making those hemoglobins are provided. One group of modified hemoglobins comprise polyalkylene glycols bonded to the hemoglobin with an amide linkage at Glu-43(β). Additional polyalkylene glycols can also be bonded to the Glu-22(β) and/or the Asp-47(β). These hemoglobins are made by a novel amidation procedure. A second group of modified hemoglobins comprise a polyalkylene glycol covalently bonded to the hemoglobin at the α-amino of a Val-1(β) or a Val-1(α). Additional polyalkylene glycols can optionally be covalently bonded to a limited number of ε-amino groups. This second group of hemoglobins is made using a novel reductive alkylation procedure. A third group of modified hemoglobins comprise a polyalkylene glycol bonded to a thiol group of the hemoglobin through a phenylsuccinimido linkage, wherein no polyalkylene glycol is bonded to a Cys-93(β). This third group of modified hemoglobins is made by an improvement in a hemoglobin-polyalkylene linkage procedure utilizing thiolation-mediated maleimide chemistry.
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公开(公告)号：US08741832B2
公开(公告)日：2014-06-03
申请号：US11921064
申请日：2006-06-09
CPC分类号： A61K47/48215 , A61K38/00 , A61K38/385 , A61K38/42 , A61K47/60 , C07K14/76 , C07K14/765 , C07K14/805
摘要： The present invention provides PEGylated hemoglobins and PEGylated albumins comprising polyethylene glycol (PEG) conjugated to hemoglobin or to albumin, wherein the PEG is a maleimide PEG, an alkylamide PEG, an iodoacetamide PEG, a p-nitro thio-phenyl PEG, a vinyl sulfone PEG, or a mixed disulfide PEG; and PEGylated albumins and PEGylated hemoglobins comprising polyethylene glycol (PEG) attached to a thiolated amino group of albumin or hemoglobin, wherein the amino group is thiolated using dithio sulfo succinimidyl propionate (DTSSP) or dithiosuccinimidyl propionate (DTSP) or dithiobispropionimidate. The invention also provides methods of preparing PEGylated hemoglobins and PEGylated albumins comprising a) reacting hemoglobin or albumin with a thiolating agent and with a PEGylating agent, and b) capping unPEGylated reactive thiols of hemoglobin or albumin with N-ethyl maleimide.
摘要翻译： 本发明提供聚乙二醇化的血红蛋白和聚乙二醇化的白蛋白，其包含与血红蛋白或白蛋白缀合的聚乙二醇（PEG），其中PEG是马来酰亚胺PEG，烷基酰胺PEG，碘乙酰胺PEG，对硝基硫代苯基PEG，乙烯基砜 PEG或混合二硫化物PEG; 和聚乙二醇化的白蛋白和聚乙二醇化血红蛋白，其包含连接到白蛋白或血红蛋白的硫醇化氨基的聚乙二醇（PEG），其中使用二硫代磺基琥珀酰亚胺基丙酸酯（DTSSP）或二硫代琥珀酰亚胺基丙酸酯（DTSP）或二硫代双丙酰亚胺酯来硫化氨基。 本发明还提供制备聚乙二醇化血红蛋白和聚乙二醇化白蛋白的方法，其包括a）使血红蛋白或白蛋白与硫醇化剂和聚乙二醇化剂反应，和b）用N-乙基马来酰亚胺封端血红蛋白或白蛋白的未PEG化的反应性硫醇。
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9.发明授权Second generation low oxygen affinity pegylated hemoglobins as oxygen-carrying plasma expanders 有权第二代低氧亲和力聚乙二醇化血红蛋白作为携氧血浆扩张剂公开(公告)号：US08697645B2
公开(公告)日：2014-04-15
申请号：US12449832
申请日：2008-03-12
IPC分类号： A61K38/42 , C07K14/805 , A61P7/00
CPC分类号： C07K14/805 , A61K38/42 , A61K47/62
摘要： Provided are hemoglobins having at least two chemical modifications that lower oxygen affinity, hemoglobins chemically modified by the addition of glyceraldehyde-3-phosphate, and hemoglobins having at least two specific chemical modifications. PEGylated versions of these hemoglobins are also provided, as are certain tetraPEGylated and diPEGylated hemoglobins. Methods of modifying a hemoglobin are additionally provided, as are methods of making a hemoglobin. Pharmaceutical compositions and blood substitutes using these hemoglobins are further provided, as are methods of treating a subject using these pharmaceutical compositions and blood substitutes.
摘要翻译： 提供了具有至少两种降低氧亲合力的化学修饰的血红蛋白，通过加入甘油醛-3-磷酸酯化学修饰的血红蛋白和具有至少两种特定化学修饰的血红蛋白。 还提供了这些血红蛋白的PEG化形式，以及某些四磷酸化和二磷酸化血红蛋白。 另外提供了修饰血红蛋白的方法，以及制备血红蛋白的方法。 还提供了使用这些血红蛋白的药物组合物和血液代用品，以及使用这些药物组合物和血液代用品治疗受试者的方法。
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公开(公告)号：US08071546B2
公开(公告)日：2011-12-06
申请号：US11921689
申请日：2006-06-09
CPC分类号： A61K38/38 , A61K9/0019
摘要： The present invention is directed to uses of PEGylated albumins which include methods of treating reduced functional capillary density, reduced blood volume, septic shock and cardiac arrhythmia in a subject, which comprise administering to the subject a therapeutically effective amount of a PEGylated albumin.
摘要翻译： 本发明涉及聚乙二醇化蛋白质的用途，其包括治疗受试者中功能性毛细血管密度降低，血液体积减少，败血性休克和心律失常的方法，其包括向受试者施用治疗有效量的聚乙二醇化白蛋白。
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