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1. 发明申请

US20120237517A1 Antibody Substituting for Function of Blood Coagulation Factor VIII 审中-公开
标题翻译：抗体代替血液凝固因子VIII的功能
公开(公告)号：US20120237517A1
公开(公告)日：2012-09-20
申请号：US13434643
申请日：2012-03-29
申请人： Kunihiro Hattori , Tetsuo Kojima , Hiroyuki Saito , Taro Miyazaki , Tetsuhiro Soeda
发明人： Kunihiro Hattori , Tetsuo Kojima , Hiroyuki Saito , Taro Miyazaki , Tetsuhiro Soeda
IPC分类号： C07K16/36 , A61P7/02 , A61K39/395
CPC分类号： C07K16/36 , C07K16/40 , C07K16/468 , C07K2317/24 , C07K2317/31 , C07K2317/56 , C07K2317/622 , C07K2317/75
摘要： The present inventors produced a variety of bispecific antibodies that specifically bind to both F. IX/F. IXa and F. X, and functionally substitute for F. VIIIa, i.e., have a cofactor function to promote F. X activation via F. IXa. Among these antibodies, the antibody A44/B26 reduced coagulation time by 50 seconds or more as compared to that observed when the antibody was not added. The present inventors produced a commonly shared L chain antibody from this antibody using L chains of A44, and showed that A44L can be used as commonly shared L chains, although the activity of the resulting antibody is reduced compared to the original antibody (A44HL-B26HL). Further, with appropriate CDR shuffling, the present inventors successfully produced highly active multispecific antibodies that functionally substitute for coagulation factor VIII.
摘要翻译：本发明人生产了特异性结合F.IX / F两种的各种双特异性抗体。 IXa和F.X，并且功能上替代F.CⅧa，即具有辅因子功能以通过F.Ixa促进F.X活化。在这些抗体中，与未添加抗体时相比，抗体A44 / B26的凝固时间缩短了50秒以上。本发明人使用A44的L链从该抗体生产共同的L链抗体，并且表明尽管与原始抗体（A44HL-B26HL）相比，所得抗体的活性降低，但A44L可以用作共同的L链）。此外，通过适当的CDR改组，本发明人成功地制备了功能性替代凝血因子VIII的高活性多特异性抗体。

2. 发明申请

US20080075712A1 Double Specific Antibodies Substituting For Functional Proteins 审中-公开
标题翻译：双功能抗体替代功能蛋白
公开(公告)号：US20080075712A1
公开(公告)日：2008-03-27
申请号：US10575905
申请日：2003-10-14
申请人： Kunihiro Hattori , Tetsuo Kojima , Taro Miyazaki , Tetsuhiro Soeda , Chiaki Senoo , Osamu Natori , Keiko Kasutani , Shinya Ishii
发明人： Kunihiro Hattori , Tetsuo Kojima , Taro Miyazaki , Tetsuhiro Soeda , Chiaki Senoo , Osamu Natori , Keiko Kasutani , Shinya Ishii
IPC分类号： A61K39/395 , A61P31/12 , A61P35/00 , A61P37/00 , A61P7/00 , C07K16/00 , C07K16/36
CPC分类号： C07K16/36 , C07K16/2866 , C07K2317/31 , C07K2317/622
摘要： The present inventors succeeded in separating bispecific antibodies that functionally substitute for ligands of type I interferon receptors comprising two types of molecules: AR1 chain and AR2 chain. Furthermore, the present inventors succeeded in producing bispecific antibodies that substitute for the enzyme reaction-accelerating function of blood coagulation factor VIII/activated blood coagulation factor VIII, which bind to both blood coagulation factor IX/activated blood coagulation factor IX and blood coagulation factor X.
摘要翻译：本发明人成功地分离了功能上代替包含两种类型的分子：AR1链和AR2链的I型干扰素受体的配体的双特异性抗体。此外，本发明人成功地制备了代替凝血因子VIII /活化凝血因子VIII的酶反应促进功能的双特异性抗体，其结合凝血因子IX /活化凝血因子IX和凝血因子X 。

3. 发明授权

US08062635B2 Bispecific antibody substituting for functional proteins 有权
标题翻译：替代功能蛋白的双特异性抗体
公开(公告)号：US08062635B2
公开(公告)日：2011-11-22
申请号：US10575193
申请日：2004-10-08
申请人： Kunihiro Hattori , Tetsuo Kojima , Taro Miyazaki , Tetsuhiro Soeda
发明人： Kunihiro Hattori , Tetsuo Kojima , Taro Miyazaki , Tetsuhiro Soeda
IPC分类号： A61K39/395
CPC分类号： C07K16/36 , C07K16/2866 , C07K2317/24 , C07K2317/31 , C07K2317/622
摘要： The present inventors succeeded in constructing bispecific antibodies, which bind to both the blood coagulation factor IX/activated blood coagulation factor IX and blood coagulation factor X, and functionally substitute for blood coagulation factor VIII/activated blood coagulation factor VIII which enhances the enzymatic reaction.
摘要翻译：本发明人成功构建了结合凝血因子IX /活化凝血因子IX和血液凝固因子X两者的双特异性抗体，并且功能性地代替增强酶促反应的凝血因子VIII /活化凝血因子VIII。

4. 发明申请

US20070041978A1 Bispecific antibody substituting for functional proteins 有权
标题翻译：替代功能蛋白的双特异性抗体
公开(公告)号：US20070041978A1
公开(公告)日：2007-02-22
申请号：US10575193
申请日：2004-10-08
申请人： Kunihiro Hattori , Tetsuo Kojima , Taro Miyazaki , Tetsuhiro Soeda
发明人： Kunihiro Hattori , Tetsuo Kojima , Taro Miyazaki , Tetsuhiro Soeda
IPC分类号： A61K39/395 , C12N9/00 , C07K16/40
CPC分类号： C07K16/36 , C07K16/2866 , C07K2317/24 , C07K2317/31 , C07K2317/622
摘要： The present inventors succeeded in constructing bispecific antibodies, which bind to both the blood coagulation factor IX/activated blood coagulation factor IX and blood coagulation factor X, and functionally substitute for blood coagulation factor VIII/activated blood coagulation factor VIII which enhances the enzymatic reaction.
摘要翻译：本发明人成功构建了结合凝血因子IX /活化凝血因子IX和血液凝固因子X两者的双特异性抗体，并且功能性地代替增强酶促反应的凝血因子VIII /活化凝血因子VIII。

5. 发明申请

US20100003254A1 Antibody Substituting for Function of Blood Coagulation Factor VIII 审中-公开
标题翻译：抗体代替血液凝固因子VIII的功能
公开(公告)号：US20100003254A1
公开(公告)日：2010-01-07
申请号：US11910836
申请日：2006-03-31
申请人： Kunihiro Hattori , Tetsuo Kojima , Hiroyuki Saito , Taro Miyazaki , Tetsuhiro Soeda
发明人： Kunihiro Hattori , Tetsuo Kojima , Hiroyuki Saito , Taro Miyazaki , Tetsuhiro Soeda
IPC分类号： A61K39/395 , C07K16/00 , A61P7/00
CPC分类号： C07K16/36 , C07K16/40 , C07K16/468 , C07K2317/24 , C07K2317/31 , C07K2317/56 , C07K2317/622 , C07K2317/75
摘要： The present inventors produced a variety of bispecific antibodies that specifically bind to both F. IX/F. IXa and F. X, and functionally substitute for F. VIIIa, i.e., have a cofactor function to promote F. X activation via F. IXa. Among these antibodies, the antibody A44/B26 reduced coagulation time by 50 seconds or more as compared to that observed when the antibody was not added. The present inventors produced a commonly shared L chain antibody from this antibody using L chains of A44, and showed that A44L can be used as commonly shared L chains, although the activity of the resulting antibody is reduced compared to the original antibody (A44HL-B26HL). Further, with appropriate CDR shuffling, the present inventors successfully produced highly active multispecific antibodies that functionally substitute for coagulation factor VIII.
摘要翻译：本发明人生产了特异性结合F.IX / F两种的各种双特异性抗体。 IXa和F.X，并且功能上替代F.CⅧa，即具有辅因子功能以通过F.Ixa促进F.X活化。在这些抗体中，与未添加抗体时相比，抗体A44 / B26的凝固时间缩短了50秒以上。本发明人使用A44的L链从该抗体生产共同的L链抗体，并且表明尽管与原始抗体（A44HL-B26HL）相比，所得抗体的活性降低，但A44L可以用作共同的L链）。此外，通过适当的CDR改组，本发明人成功地制备了功能性替代凝血因子VIII的高活性多特异性抗体。

6. 发明申请

US20060269989A1 Process for producing antibodies 失效
标题翻译：生产抗体的方法
公开(公告)号：US20060269989A1
公开(公告)日：2006-11-30
申请号：US10560098
申请日：2004-06-11
申请人： Taro Miyazaki , Tetsuo Kojima
发明人： Taro Miyazaki , Tetsuo Kojima
IPC分类号： C12P21/06 , C07H21/04 , C07K16/18 , C12N5/06
CPC分类号： C07K16/468 , C07K16/00 , C07K16/2866 , C07K2317/626 , C12N2510/02
摘要： Focusing on the fact that antibody molecules with one H chain are not secreted when using the “knobs-into-holes” method, the present inventors revealed that desired bispecific antibodies can be preferentially formed by first expressing the H and L chains of one arm, and then suppressing their expression, followed by expressing the H and L chains of the other arm so that first desired HL molecules (HaLa and HbLb) are constructed, and then the H chains are paired with each other (H2L2). The present invention was thus completed.
摘要翻译：关注当使用“旋钮孔”方法时，不分泌具有一个H链的抗体分子的事实，本发明人揭示了可以通过首先表达一个臂的H和L链来优先形成所需的双特异性抗体，然后抑制其表达，随后表达另一臂的H和L链，使得构建第一所需的HL分子（HaLa和HbLb），然后H链彼此配对（H 2' SUB＆gt; 2＆lt; 2＆gt;）。从而完成了本发明。

7. 发明授权

US08597911B2 Process for producing antibodies 失效
标题翻译：生产抗体的方法
公开(公告)号：US08597911B2
公开(公告)日：2013-12-03
申请号：US10560098
申请日：2004-06-11
申请人： Taro Miyazaki , Tetsuo Kojima
发明人： Taro Miyazaki , Tetsuo Kojima
IPC分类号： C12N15/13
CPC分类号： C07K16/468 , C07K16/00 , C07K16/2866 , C07K2317/626 , C12N2510/02
摘要： Focusing on the fact that antibody molecules with one H chain are not secreted when using the “knobs-into-holes” method, the present inventors revealed that desired bispecific antibodies can be preferentially formed by first expressing the H and L chains of one arm, and then suppressing their expression, followed by expressing the H and L chains of the other arm so that first desired HL molecules (HaLa and HbLb) are constructed, and then the H chains are paired with each other (H2L2). The present invention was thus completed.
摘要翻译：关注当使用“旋钮孔”方法时，不分泌具有一个H链的抗体分子的事实，本发明人揭示了可以通过首先表达一个臂的H和L链来优先形成所需的双特异性抗体，然后抑制其表达，然后表达另一臂的H链和L链，使得构建第一所需的HL分子（HaLa和HbLb），然后H链彼此配对（H2L2）。从而完成了本发明。

8. 发明申请

US20050153412A1 Aldehyde dehydrogenase II 审中-公开
标题翻译：醛脱氢酶II
公开(公告)号：US20050153412A1
公开(公告)日：2005-07-14
申请号：US10511426
申请日：2003-04-14
申请人： Tatsuo Hoshino , Taro Miyazaki , Teruhide Sugisawa
发明人： Tatsuo Hoshino , Taro Miyazaki , Teruhide Sugisawa
IPC分类号： C12N9/02 , C12P7/40 , C12P7/60 , C12P17/04 , C07H21/04 , C12N1/21 , C12N15/74
CPC分类号： C12N9/0008 , C12P7/40 , C12P7/60 , C12P17/04
摘要： The present invention concerns a novel aldehyde dehydrogenase having the following physico-chemical properties: a molecular weight of 100,000±10,000 Da which comprises two homologous subunits or a molecular weight of 150,000±15,000 Da which comprises three homologous subunits, each subunit having a molecular weight of 55,000±2,000 Da; dehydrogenase activity on L-sorbosone, D-Glucosone, D-glucose and D-xylose; utilizes as cofactor pyrroloquinoline quinone; has an optimum pH of from 6.5 to 8.0 for the production of vitamin C and an optimum pH of about 9.0 for the production of 2-keto-L-gulonic acid from L-sorbosone; and is inhibited by Co2+, Cu2+, Fe3+, Ni2+, Zn2+, and monoiodoacetate, is derived from a microorganism belonging to the genus Gluconobacter.
摘要翻译：本发明涉及具有以下物理化学性质的新型醛脱氢酶：分子量为100,000±10,000Da，其包含两个同源亚基或分子量为150,000±15,000Da，其包含三个同源亚基，每个亚基具有分子量 55,000±2,000 Da; L-山梨糖酮，D-葡萄糖酮，D-葡萄糖和D-木糖的脱氢酶活性; 用作辅因子吡咯并喹啉醌; 维生素C的最佳pH为6.5〜8.0，L-山梨糖酮生产2-酮-L-古洛糖酸的最佳pH为9.0左右; 并且被Co 2+，Cu 2+，Fe 3+，Ni 2+，Zn 2+抑制， SUP + 2 +和单碘乙酸酯衍生自属于葡糖杆菌属的微生物。

9. 发明申请

US20060121582A1 Process for producing vitamin c 失效
标题翻译：生产维生素C的方法
公开(公告)号：US20060121582A1
公开(公告)日：2006-06-08
申请号：US10528885
申请日：2003-09-22
申请人： Tatsuo Hoshino , Taro Miyazaki , Teruhide Sugisawa
发明人： Tatsuo Hoshino , Taro Miyazaki , Teruhide Sugisawa
IPC分类号： C12P17/04 , C12N9/02 , C12N1/20
CPC分类号： C12P17/04
摘要： The present invention relates to a process for the production of vitamin C from L sorbosone using an aldehyde dehydrogenase which is isolated from Gluconobacter oxydans DSM 4025 (FERM BP-3812), said enzyme having the following physicochemical properties: (a) molecular weight of 150,000±6,000 Da or 230,000±9,000 Da (consisting of 2 or 3 homologous subunits, each subunit having a molecular weight of 75,000±3,000 Da); (b) substrate specificity as active on aldehyde compounds; (c) Cofactors are pyrroloquinoline quinone and heme c; (d) Optimum pH between 6.4 and 8.2 for vitamin C production from L-sorbosone; and (e) as inhibitors Co2+, Cu2+, Fe2+, Ni2+, Zn2+, monoiodoacetate and ethylendiamine tetraacetic acid. The process is performed in the presence of a suitable electron acceptor and the vitamin C isolated from the reaction mixture.
摘要翻译：本发明涉及使用从脱氧氧化葡糖杆菌DSM 4025（FERM BP-3812）中分离的醛脱氢酶从L山梨糖酮生产维生素C的方法，所述酶具有以下物理化学性质：（a）分子量为15万 ±6,000Da或230,000±9,000Da（由2或3个同源亚基组成，每个亚基具有75,000±3,000Da的分子量）; （b）对醛化合物具有活性的底物特异性; （c）辅因子是吡咯并喹啉醌和血红素c; （d）从L-山梨糖酮生产维生素C的最佳pH在6.4和8.2之间; 和（e）作为抑制剂Co 2+，Cu 2+，Fe 2+，Ni 2+， Zn2 +，一碘乙酸酯和乙二胺四乙酸。该方法在合适的电子受体和从反应混合物中分离的维生素C的存在下进行。

10. 发明授权

US06846660B2 Method of making an aldehyde dehydrogenase with gluconobacter 有权
标题翻译：用葡萄糖酸生成醛脱氢酶的方法
公开(公告)号：US06846660B2
公开(公告)日：2005-01-25
申请号：US09815695
申请日：2001-03-23
申请人： Tatsuo Hoshino , Taro Miyazaki , Teruhide Sugisawa
发明人： Tatsuo Hoshino , Taro Miyazaki , Teruhide Sugisawa
IPC分类号： C12N9/04 , C12N9/02 , C12P7/50 , C12P7/60 , C12R1/01
CPC分类号： C12N9/0008 , C12P7/60
摘要： A new aldehyde dehydrogenase having the physico-chemical properties: molecular weight:150,000±6,000 or 230,000±9,000; substrate specificity active on aldehyde compounds; cofactors:pyrroloquinoline quinone and heme c; optimum pH: 7.0-8.5; and inhibitors: Co2+, Cu2+, Fe2+, Ni2+, Zn2+, monoiodoacetate and EDTA, is derived from a microorganism belonging to the genus Gluconobacter. Said aldehyde dehydrogenase can be produced by cultivating a microorganism of the genus Gluconobacter which is capable of producing an aldehyde dehydrogenase having the above properties, in an aqueous nutrient medium under aerobic conditions, disrupting the cells of the microorganism and isolating and purifying the aldehyde dehydrogenase from the cell-free extract of the disrupted cells of the microorganism. 2-Keto-L-gulonic acid (2-KGA) can be produced from L-sorbosone by contacting L-sorbosone with (i) the aldehyde dehydrogenase in the presence of an electron acceptor, (ii) a Gluconobacter microorganism capable of producing the aldehyde dehydrogenase in an aqueous medium under aerobic conditions or (iii) a cell-free extract of said microorganism, and in each case isolating the resulting 2-KGA from the reaction mixture.
摘要翻译：具有物理化学性质的新型醛脱氢酶：分子量：150,000±6,000或230,000±9,000; 对醛化合物具有活性的底物特异性; 辅因子：吡咯并喹啉醌和血红素c; 最适pH：7.0-8.5; 和抑制剂：Co 2+，Cu 2+，Fe 2+，Ni 2+，Zn 2+，一碘乙酸酯和EDTA，衍生自属于葡糖杆菌属的微生物。所述醛脱氢酶可以通过在需氧条件下在水性营养培养基中培养能够产生具有上述性质的醛脱氢酶的葡糖杆菌属的微生物，破坏微生物的细胞并从其中分离和纯化醛脱氢酶微生物破碎的细胞的无细胞提取物。 2-酮-L-古洛糖酸（2-KGA）可以由L-山梨糖酮通过在电子受体存在下将L-山梨醇与（i）醛脱氢酶接触，（ii）能产生醛脱氢酶在有氧条件下在水性介质中或（iii）所述微生物的无细胞提取物，并且在每种情况下从反应混合物中分离得到的2-KGA。

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