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1. 发明申请

US20090035836A1 MODULATING PH-SENSITIVE BINDING USING NON-NATURAL AMINO ACIDS 审中-公开
标题翻译：使用非天然氨基酸调节敏感性结合
公开(公告)号：US20090035836A1
公开(公告)日：2009-02-05
申请号：US12147379
申请日：2008-06-26
申请人： Deepshikha Datta , William A. Goddard , David Tirrell , Joyce Yaochun Peng
发明人： Deepshikha Datta , William A. Goddard , David Tirrell , Joyce Yaochun Peng
IPC分类号： C12N7/00 , C07K2/00 , C07K16/00
CPC分类号： C07K16/32
摘要： The invention provides methods, systems and reagents for regulating pH-sensitive protein interaction by incorporating non-natural amino acids into the protein (e.g. an antibody, or its functional fragment, derivative, etc.). The invention also relates to specific uses in regulating pH-sensitive binding of antibodies to tumor site, by conferring enhanced tumor-specificity/selectivity. In that embodiment, the non-natural amino acids preferably have desirable side-chain pKa's, such that at below physiological pH (e.g. about pH 6.3-6.5) the non-natural amino acid confer enhanced binding to tumor antigens in acidic environments. Such non-natural amino acids can be incorporated by any suitable means, such as by utilizing a modified aminoacyl-tRNA synthetase to charge the nonstandard amino acid to a modified tRNA, which forms strict Watson-Crick base-pairing with a codon that normally forms wobble base-pairing with natural tRNAs (e.g. the degenerate codon orthogonal system.
摘要翻译：本发明提供了通过将非天然氨基酸掺入蛋白质（例如抗体或其功能片段，衍生物等）来调节pH敏感蛋白质相互作用的方法，系统和试剂。本发明还涉及通过赋予增强的肿瘤特异性/选择性来调节抗体对肿瘤部位的pH敏感结合的具体用途。在该实施方案中，非天然氨基酸优选具有所需的侧链pKa，使得在低于生理pH（例如约pH 6.3-6.5）下，非天然氨基酸在酸性环境中赋予增强的与肿瘤抗原的结合。这样的非天然氨基酸可以通过任何合适的方式并入，例如通过利用修饰的氨酰-tRNA合成酶将非标准氨基酸装入修饰的tRNA，其与通常形成的密码子形成严格的沃森 - 克里克碱基配对与天然tRNA的摆动碱基配对（如简并密码子正交系统）。

2. 发明申请

US20050260711A1 Modulating pH-sensitive binding using non-natural amino acids 审中-公开
标题翻译：使用非天然氨基酸调节pH敏感结合
公开(公告)号：US20050260711A1
公开(公告)日：2005-11-24
申请号：US11094625
申请日：2005-03-30
申请人： Deepshikha Datta , William Goddard , David Tirrell , Joyce Peng
发明人： Deepshikha Datta , William Goddard , David Tirrell , Joyce Peng
IPC分类号： C07H21/04 , C07K16/32 , C07K16/44 , C12N5/06 , C12P21/06
CPC分类号： C07K16/32
摘要： The invention provides methods, systems and reagents for regulating pH-sensitive protein interaction by incorporating non-natural amino acids into the protein (e.g. an antibody, or its functional fragment, derivative, etc.). The invention also relates to specific uses in regulating pH-sensitive binding of antibodies to tumor site, by conferring enhanced tumor-specificity/selectivity. In that embodiment, the non-natural amino acids preferably have desirable side-chain pKa's, such that at below physiological pH (e.g. about pH 6.3-6.5) the non-natural amino acid confer enhanced binding to tumor antigens in acidic environments. Such non-natural amino acids can be incorporated by any suitable means, such as by utilizing a modified aminoacyl-tRNA synthetase to charge the nonstandard amino acid to a modified tRNA, which forms strict Watson-Crick base-pairing with a codon that normally forms wobble base-pairing with natural tRNAs (e.g. the degenerate codon orthogonal system.
摘要翻译：本发明提供了通过将非天然氨基酸掺入蛋白质（例如抗体或其功能片段，衍生物等）来调节pH敏感蛋白质相互作用的方法，系统和试剂。本发明还涉及通过赋予增强的肿瘤特异性/选择性来调节抗体对肿瘤部位的pH敏感结合的具体用途。在该实施方案中，非天然氨基酸优选具有所需的侧链pKa，使得在低于生理pH（例如约pH 6.3-6.5）下，非天然氨基酸在酸性环境中赋予增强的与肿瘤抗原的结合。这样的非天然氨基酸可以通过任何合适的方式并入，例如通过利用修饰的氨酰-tRNA合成酶将非标准氨基酸装入修饰的tRNA，其与通常形成的密码子形成严格的沃森 - 克里克碱基配对与天然tRNA的摆动碱基配对（如简并密码子正交系统）。

3. 发明授权

US07139665B2 Computational method for designing enzymes for incorporation of non natural amino acids into proteins 有权
标题翻译：设计用于将非天然氨基酸掺入蛋白质的酶的计算方法
公开(公告)号：US07139665B2
公开(公告)日：2006-11-21
申请号：US10375298
申请日：2003-02-27
申请人： Deepshikha Datta , Pin Wang , Isaac Carrico , Stephen L. Mayo , David Tirrell
发明人： Deepshikha Datta , Pin Wang , Isaac Carrico , Stephen L. Mayo , David Tirrell
IPC分类号： G06F17/00 , G06F17/11 , G06F17/30
CPC分类号： C12N9/93 , C07K1/00 , C07K2299/00 , G06F19/16
摘要： The instant invention provides methods, reagents, and computational tools for designing non-natural substrate analogs for enzymes, especially for designing unnatural amino acid analogs for aminoacyl tRNA Synthetases (AARSs), such as the Phe tRNA Synthetase. The instant invention also provides methods to incorporate unnatural amino acid analogs, especially those with interesting functional groups, into protein products to generate proteins of modified or novel functions.
摘要翻译：本发明提供了用于设计用于酶的非天然底物类似物的方法，试剂和计算工具，特别是用于设计用于氨基tRNA合成酶（AARS）的非天然氨基酸类似物，例如Phe tRNA合成酶。本发明还提供了将非天然氨基酸类似物（特别是那些具有感兴趣的官能团的类似物）掺入蛋白质产物以产生修饰或新颖功能的蛋白质的方法。

4. 发明申请

US20060177865A1 Computational method for designing enzymes for incorporation of amino acid analogs into proteins 审中-公开
标题翻译：设计用于将氨基酸类似物掺入蛋白质的酶的计算方法
公开(公告)号：US20060177865A1
公开(公告)日：2006-08-10
申请号：US11399957
申请日：2006-04-07
申请人： Deepshikha Datta , Pin Wang , Isaac Carrico , Stephen Mayo , David Tirrell
发明人： Deepshikha Datta , Pin Wang , Isaac Carrico , Stephen Mayo , David Tirrell
IPC分类号： C12Q1/68 , G06F19/00 , C12N9/22
CPC分类号： C12N9/93 , C07K1/00 , C07K2299/00 , G16B15/00
摘要： The instant invention provides methods, reagents, and computational tools for designing non-natural substrate analogs for enzymes, especially for designing unnatural amino acid analogs for aminoacyl tRNA Synthetases (AARSs), such as the Phe tRNA Synthetase. The instant invention also provides methods to incorporate unnatural amino acid analogs, especially those with interesting functional groups, into protein products to generate proteins of modified or novel functions.
摘要翻译：本发明提供了用于设计用于酶的非天然底物类似物的方法，试剂和计算工具，特别是用于设计用于氨基tRNA合成酶（AARS）的非天然氨基酸类似物，例如Phe tRNA合成酶。本发明还提供了将非天然氨基酸类似物（特别是那些具有感兴趣的官能团的类似物）掺入蛋白质产物以产生修饰或新颖功能的蛋白质的方法。

5. 发明申请

US20100254943A1 AMINO ACID SUBSTITUTED MOLECULES 有权
标题翻译：氨基酸取代分子
公开(公告)号：US20100254943A1
公开(公告)日：2010-10-07
申请号：US12610909
申请日：2009-11-02
申请人： Kenneth H. Grabstein , Aijun Wang , Natalie Winblade Nairn , Thomas James Graddis , Stephen McCraith , Deepshikha Datta
发明人： Kenneth H. Grabstein , Aijun Wang , Natalie Winblade Nairn , Thomas James Graddis , Stephen McCraith , Deepshikha Datta
IPC分类号： A61K38/21 , C12P21/00 , C07H21/00 , C07K2/00 , C07K16/00 , A61K38/22 , A61K38/23 , A61K38/28
CPC分类号： C07K14/565 , A61K38/193 , A61K38/21 , A61K38/215 , A61K47/60 , C12P21/00 , C12P21/02 , Y02A50/463
摘要： The invention provides compositions and methods of identifying, modifying and producing modified target molecules, including therapeutic molecules by modification with non-natural amino acids. Certain aspects of the invention include methods of adding a chemical moiety to a target molecule, and the compositions resulting therefrom. Certain aspects of the invention also relate to kits for identifying, modifying and producing modified target molecules described herein.
摘要翻译：本发明提供通过用非天然氨基酸修饰来鉴定，修饰和产生修饰的靶分子（包括治疗分子）的组合物和方法。本发明的某些方面包括向目标分子添加化学部分的方法和由其产生的组合物。本发明的某些方面还涉及用于鉴定，修饰和产生本文所述的修饰的靶分子的试剂盒。

6. 发明授权

US08470314B2 Modified toxins 有权
标题翻译：改良毒素
公开(公告)号：US08470314B2
公开(公告)日：2013-06-25
申请号：US12335297
申请日：2008-12-15
申请人： Claude Geoffrey Davis , Deepshikha Datta , Matthew Paul Baker , Alyson Jane Rust , Simon Keen
发明人： Claude Geoffrey Davis , Deepshikha Datta , Matthew Paul Baker , Alyson Jane Rust , Simon Keen
IPC分类号： A61K39/00
CPC分类号： C07K14/34 , A61K38/00 , C07K2319/035
摘要： The present application relates to compositions of modified toxins exhibiting reduced immunogenicity and reduced binding to vascular endothelium or vascular endothelial cells, thereby reducing the incidence of Vascular Leak Syndrome. Also provided are polypeptide toxophores from a modified diphtheria toxin, where modifications are in at least one amino acid residue of at least one T-cell epitope. Another aspect relates to a polypeptide toxophore from a modified diphtheria toxin, where modifications are in at least one amino acid residue of at least one T-cell epitope and at least one amino acid residue of at least one VLS motif of an unmodified native diphtheria toxin. Another aspect relates to a fusion protein which comprises a modified diphtheria toxin and a non-diphtheria toxin fragment that is a cell binding portion. Another aspect relates to the use of a modified diphtheria toxin for the treatment of a malignant disease or a non-malignant disease.
摘要翻译：本申请涉及具有降低的免疫原性并降低与血管内皮细胞或血管内皮细胞结合的修饰毒素的组合物，从而降低血管渗漏综合征的发生率。还提供了来自修饰的白喉毒素的多肽毒素体，其中修饰在至少一个T细胞表位的至少一个氨基酸残基中。另一方面涉及来自修饰的白喉毒素的多肽毒候球体，其中修饰在至少一个T细胞表位的至少一个氨基酸残基和未修饰的天然白喉毒素的至少一个VLS基序的至少一个氨基酸残基。另一方面涉及融合蛋白，其包含修饰的白喉毒素和作为细胞结合部分的非白喉毒素片段。另一方面涉及使用修饰的白喉毒素治疗恶性疾病或非恶性疾病。

7. 发明授权

US08568706B2 Modified human interferon-beta polypeptides 有权
公开(公告)号：US08568706B2
公开(公告)日：2013-10-29
申请号：US12610909
申请日：2009-11-02
申请人： Kenneth H. Grabstein , Aijun Wang , Natalie Winblade Nairn , Thomas James Graddis , Stephen McCraith , Deepshikha Datta
发明人： Kenneth H. Grabstein , Aijun Wang , Natalie Winblade Nairn , Thomas James Graddis , Stephen McCraith , Deepshikha Datta
IPC分类号： C12N15/00 , A61K38/21 , C07K1/02
CPC分类号： C07K14/565 , A61K38/193 , A61K38/21 , A61K38/215 , A61K47/60 , C12P21/00 , C12P21/02 , Y02A50/463
摘要： The invention provides compositions and methods of identifying, modifying and producing modified target molecules, including therapeutic molecules by modification with non-natural amino acids. Certain aspects of the invention include methods of adding a chemical moiety to a target molecule, and the compositions resulting therefrom. Certain aspects of the invention also relate to kits for identifying, modifying and producing modified target molecules described herein.

8. 发明申请

US20090221500A1 MODIFIED TOXINS 有权
标题翻译：改性毒素
公开(公告)号：US20090221500A1
公开(公告)日：2009-09-03
申请号：US12335297
申请日：2008-12-15
申请人： Claude Geoffrey Davis , Deepshikha Datta , Matthew Paul Baker , Alyson Jane Rust , Simon Keen
发明人： Claude Geoffrey Davis , Deepshikha Datta , Matthew Paul Baker , Alyson Jane Rust , Simon Keen
IPC分类号： A61K38/16 , C07K14/00
CPC分类号： C07K14/34 , A61K38/00 , C07K2319/035
摘要： The present application relates to compositions of modified toxins exhibiting reduced immunogenicity and reduced binding to vascular endothelium or vascular endothelial cells, thereby reducing the incidence of Vascular Leak Syndrome. Also provided are polypeptide toxophores from a modified diphtheria toxin, where modifications are in at least one amino acid residue of at least one T-cell epitope. Another aspect relates to a polypeptide toxophore from a modified diphtheria toxin, where modifications are in at least one amino acid residue of at least one T-cell epitope and at least one amino acid residue of at least one VLS motif of an unmodified native diphtheria toxin. Another aspect relates to a fusion protein which comprises a modified diphtheria toxin and a non-diphtheria toxin fragment that is a cell binding portion. Another aspect relates to the use of a modified diphtheria toxin for the treatment of a malignant disease or a non-malignant disease.
摘要翻译：本申请涉及具有降低的免疫原性并降低与血管内皮细胞或血管内皮细胞结合的修饰毒素的组合物，从而降低血管渗漏综合征的发生率。还提供了来自修饰的白喉毒素的多肽毒素体，其中修饰在至少一个T细胞表位的至少一个氨基酸残基中。另一方面涉及来自修饰的白喉毒素的多肽毒候球体，其中修饰在至少一个T细胞表位的至少一个氨基酸残基和未修饰的天然白喉毒素的至少一个VLS基序的至少一个氨基酸残基。另一方面涉及融合蛋白，其包含修饰的白喉毒素和作为细胞结合部分的非白喉毒素片段。另一方面涉及使用修饰的白喉毒素治疗恶性疾病或非恶性疾病。

9. 发明授权

US08252897B2 Modified toxins 有权
标题翻译：改良毒素
公开(公告)号：US08252897B2
公开(公告)日：2012-08-28
申请号：US12143469
申请日：2008-06-20
申请人： Claude Geoffrey Davis , Deepshikha Datta , Matthew Paul Baker , Alyson Jane Rust , Simon Keen
发明人： Claude Geoffrey Davis , Deepshikha Datta , Matthew Paul Baker , Alyson Jane Rust , Simon Keen
IPC分类号： A61K39/02 , C07K16/46
CPC分类号： C07K14/34 , A61K38/16 , A61K39/0011 , A61K39/39 , A61K47/6415 , A61K47/642 , A61K2039/5156 , A61K2039/55533 , A61K2039/55544
摘要： The present application relates to compositions of modified toxins exhibiting reduced immunogenicity and reduced binding to vascular endothelium or vascular endothelial cells, thereby reducing the incidence of Vascular Leak Syndrome. Also provided are polypeptide toxophores from a modified diphtheria toxin, where modifications are in at least one amino acid residue of at least one T-cell epitope. Another aspect relates to a polypeptide toxophore from a modified diphtheria toxin, where modifications are in at least one amino acid residue of at least one T-cell epitope and at least one amino acid residue of at least one VLS motif of an unmodified native diphtheria toxin. Another aspect relates to a fusion protein which comprises a modified diphtheria toxin and a non-diphtheria toxin fragment that is a cell binding portion. Another aspect relates to the use of a modified diphtheria toxin for the treatment of a malignant disease or a non-malignant disease.
摘要翻译：本申请涉及具有降低的免疫原性并降低与血管内皮细胞或血管内皮细胞结合的修饰毒素的组合物，从而降低血管渗漏综合征的发生率。还提供了来自修饰的白喉毒素的多肽毒素体，其中修饰在至少一个T细胞表位的至少一个氨基酸残基中。另一方面涉及来自修饰的白喉毒素的多肽毒候球体，其中修饰在至少一个T细胞表位的至少一个氨基酸残基和未修饰的天然白喉毒素的至少一个VLS基序的至少一个氨基酸残基。另一方面涉及融合蛋白，其包含修饰的白喉毒素和作为细胞结合部分的非白喉毒素片段。另一方面涉及使用修饰的白喉毒素治疗恶性疾病或非恶性疾病。

10. 发明申请

US20090041797A1 MODIFIED TOXINS 有权
公开(公告)号：US20090041797A1
公开(公告)日：2009-02-12
申请号：US12143469
申请日：2008-06-20
申请人： Claude Geoffrey Davis , Deepshikha Datta , Matthew Paul Baker , Alyson Jane Rust , Simon Keen
发明人： Claude Geoffrey Davis , Deepshikha Datta , Matthew Paul Baker , Alyson Jane Rust , Simon Keen
IPC分类号： A61K39/02 , C07K14/195 , C07K16/46 , C07K14/55 , A61P35/00 , A61K38/16
CPC分类号： C07K14/34 , A61K38/16 , A61K39/0011 , A61K39/39 , A61K47/6415 , A61K47/642 , A61K2039/5156 , A61K2039/55533 , A61K2039/55544
摘要： The present application relates to compositions of modified toxins exhibiting reduced immunogenicity and reduced binding to vascular endothelium or vascular endothelial cells, thereby reducing the incidence of Vascular Leak Syndrome. Also provided are polypeptide toxophores from a modified diphtheria toxin, where modifications are in at least one amino acid residue of at least one T-cell epitope. Another aspect relates to a polypeptide toxophore from a modified diphtheria toxin, where modifications are in at least one amino acid residue of at least one T-cell epitope and at least one amino acid residue of at least one VLS motif of an unmodified native diphtheria toxin. Another aspect relates to a fusion protein which comprises a modified diphtheria toxin and a non-diphtheria toxin fragment that is a cell binding portion. Another aspect relates to the use of a modified diphtheria toxin for the treatment of a malignant disease or a non-malignant disease.

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