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1. 发明授权

US07430476B2 Method for identification of t-cell epitopes and use for preparing molecules with reduced immunogenicity 有权
标题翻译：用于鉴定T细胞表位的方法和用于制备具有降低的免疫原性的分子的用途
公开(公告)号：US07430476B2
公开(公告)日：2008-09-30
申请号：US10468496
申请日：2002-02-18
申请人： Francis J. Carr , Graham Carter , Tim Jones , Stephen Williams , Anita Hamilton
发明人： Francis J. Carr , Graham Carter , Tim Jones , Stephen Williams , Anita Hamilton
IPC分类号： G01N33/48 , G01N33/50 , G06F19/00 , A61K31/385
CPC分类号： G06F19/16 , A61K9/7015 , A61K38/00 , A61K47/02 , A61K47/12 , C07K14/54 , C07K16/18 , C07K16/2866 , C07K16/2896 , C07K16/30 , C07K16/3046 , C07K16/464 , C07K16/465 , C07K2319/00 , G06F19/18
摘要： This invention relates to a novel approach for identification of T-cell epitopes, that give rise to an immune reaction in a living host. By means of this novel method biological compounds can be generated which have a no or at least a reduced immunogenicity when exposed to the immune system of a given species and compared with the relevant non-modified entity. Thus the invention relates also to novel biological molecules, especially proteins and antibodies, obtained by the method according to the invention.
摘要翻译：本发明涉及用于鉴定在宿主中产生免疫反应的T细胞表位的新方法。通过这种新方法，可以产生当暴露于给定物种的免疫系统且与相关未修饰实体相比较时具有或至少具有降低的免疫原性的生物化合物。因此，本发明还涉及通过根据本发明的方法获得的新型生物分子，特别是蛋白质和抗体。

2. 发明授权

US07132511B2 Modified anti-EGFR antibodies with reduced immunogenicity 有权
标题翻译：具有降低的免疫原性的修饰的抗EGFR抗体
公开(公告)号：US07132511B2
公开(公告)日：2006-11-07
申请号：US10468528
申请日：2002-02-18
申请人： Francis J. Carr , Graham Carter , Tim Jones , Stephen Williams , Anita Hamilton
发明人： Francis J. Carr , Graham Carter , Tim Jones , Stephen Williams , Anita Hamilton
IPC分类号： C12P21/08
CPC分类号： G06F19/16 , A61K9/7015 , A61K38/00 , A61K47/02 , A61K47/12 , C07K14/54 , C07K16/18 , C07K16/2866 , C07K16/2896 , C07K16/30 , C07K16/3046 , C07K16/464 , C07K2319/00 , G06F19/18
摘要： The present invention relates to antibodies which are directed to the EGF receptor (HER1) to be administered especially to humans and in particular for therapeutic use in tumors. The antibodies are modified whereby the modification results in a reduced propensity for the antibody to elicit an immune response upon administration to the human subject. The invention in particular relates to the modification of anti-EGFR antibody 425 in its different forms and fragments thereof to result in Mab 425 variants that are substantially non-immunogenic or less immunogenic than any non-modified counterpart when used in vivo.
摘要翻译：本发明涉及针对EGF受体（HER1）的抗体，其被特别施用于人，特别是用于肿瘤的治疗用途。修饰抗体，由此修饰导致抗体在施用于人受试者时引起免疫应答的倾向降低。本发明特别涉及其不同形式和片段的抗EGFR抗体425的修饰，以产生当在体内使用时基本上不具有免疫原性或比任何未修饰的对应物更少的免疫原性的Mab 425变体。

3. 发明授权

US07392141B2 Method of preparing a modified granulocyte colony stimulating factor (G-CSF) with reduced immunogenicity 失效
标题翻译：制备具有降低免疫原性的改良粒细胞集落刺激因子（G-CSF）的方法
公开(公告)号：US07392141B2
公开(公告)日：2008-06-24
申请号：US10467396
申请日：2002-02-05
申请人： Francis J. Carr , Graham Carter , Tim Jones , Stephen Williams
发明人： Francis J. Carr , Graham Carter , Tim Jones , Stephen Williams
IPC分类号： G06F19/00 , G06F17/00 , G06G7/58 , C12P21/06 , G01N33/53 , G01N33/00 , A61K39/00
CPC分类号： C07K14/535 , A61K9/7015 , A61K38/00 , A61K47/02 , A61K47/12 , C07K14/54 , C07K16/18 , C07K16/2866 , C07K16/2896 , C07K16/30 , C07K16/3046 , C07K16/464 , C07K2319/00 , G06F19/16 , G06F19/18 , Y10S707/99943
摘要： A method of preparing a modified granulocyte colony stimulating factor (G-CSF) protein having reduced immunogenicity relative to human G-CSF comprises the steps of (i) identifying one or more potential T-cell epitopes within the amino acid sequence of human G-CSF (SEQ ID NO: 1); (ii) designing at least one sequence variant of at least one potential T-cell epitope identified in step (i), wherein the sequence variant eliminates or substantially reduces the MHC class II binding activity of the potential T-cell epitope; (iii) preparing, by recombinant DNA techniques, at least one modified G-CSF protein including a sequence variant designed in step (ii); (iv) evaluating at least one modified G-CSF protein prepared in step (iii) for G-CSF activity and immunogenicity; and (v) selecting a modified G-CSF protein evaluated in step (iv) that has substantially the same therapeutic G-CSF biological activity as, but substantially less immunogenicity than, human G-CSF.
摘要翻译：制备相对于人G-CSF具有降低的免疫原性的修饰的粒细胞集落刺激因子（G-CSF）蛋白质的方法包括以下步骤：（i）鉴定人G-蛋白的氨基酸序列内的一个或多个潜在T细胞表位， CSF（SEQ ID NO：1）; （ii）设计步骤（i）中鉴定的至少一个潜在T细胞表位的至少一个序列变体，其中所述序列变体消除或显着降低潜在T细胞表位的MHC II类结合活性; （iii）通过重组DNA技术制备至少一种修饰的G-CSF蛋白，包括在步骤（ii）中设计的序列变体; （iv）评估在步骤（iii）中制备的至少一种修饰的G-CSF蛋白质的G-CSF活性和免疫原性; 和（v）选择在步骤（iv）中评估的与人G-CSF具有基本上相同的治疗性G-CSF生物学活性但显着更低的免疫原性的修饰的G-CSF蛋白质。

4. 发明授权

US07615615B2 Modified interferon beta with reduced immunogenicity 失效
标题翻译：修饰的干扰素β具有降低的免疫原性
公开(公告)号：US07615615B2
公开(公告)日：2009-11-10
申请号：US12077120
申请日：2008-03-17
申请人： Francis J. Carr , Graham Carter , Tim Jones , John Watkins , Matthew Baker
发明人： Francis J. Carr , Graham Carter , Tim Jones , John Watkins , Matthew Baker
IPC分类号： C07K14/00 , A61K38/19 , C12N15/24
CPC分类号： C07K14/565
摘要： The present invention relates a modified human interferon beta (INFβ) which is less immunogenic than human INFβ (SEQ ID NO: 1) when administered in vivo to a human. The modified human INFβ comprises an amino acid residue sequence that differs from SEQ ID NO: 1 by an amino acid residue substitution selected from the group consisting of L57A, L57C, L57D L57E, L57G, L57H, L57K, L57N, L57P, L57Q, L57R, L57S, and L57T and an additional substitution selected from the group consisting of the H140A, H140C, H140G, and H140P.
摘要翻译：本发明涉及当在体内施用于人时，比人INFbeta（SEQ ID NO：1）具有较少的免疫原性的修饰的人干扰素β（INFbeta）。修饰的人INFbeta包含与SEQ ID NO：1不同的氨基酸残基，其选自L57A，L57C，L57D，L57E，L57G，L57H，L57K，L57N，L57P，L57Q，L57R ，L57S和L57T以及选自H140A，H140C，H140G和H140P的另外的取代基。

5. 发明申请

US20090043076A1 Modified interferon beta with reduced immunogenicity 失效
公开(公告)号：US20090043076A1
公开(公告)日：2009-02-12
申请号：US12077120
申请日：2008-03-17
申请人： Francis J. Carr , Graham Carter , Tim Jones , John Watkins , Matthew Baker
发明人： Francis J. Carr , Graham Carter , Tim Jones , John Watkins , Matthew Baker
IPC分类号： C07K14/565
CPC分类号： C07K14/565
摘要： The present invention relates a modified human interferon beta (INFβ) which is less immunogenic than human INFβ (SEQ ID NO: 1) when administered in vivo to a human. The modified human INFβ comprises an amino acid residue sequence that differs from SEQ ID NO: 1 by an amino acid residue substitution selected from the group consisting of L57A, L57C, L57D L57E, L57G, L57H, L57K, L57N, L57P, L57Q, L57R, L57S, and L57T and an additional substitution selected from the group consisting of the H140A, H140C, H140G, and H140P.

6. 发明授权

US07381795B2 Modified interferon beta with reduced immunogenicity 有权
标题翻译：修饰的干扰素β具有降低的免疫原性
公开(公告)号：US07381795B2
公开(公告)日：2008-06-03
申请号：US10471894
申请日：2002-03-15
申请人： Francis J. Carr , Graham Carter , Tim Jones , John Watkins , Matthew Baker
发明人： Francis J. Carr , Graham Carter , Tim Jones , John Watkins , Matthew Baker
IPC分类号： C07K14/00 , C12N15/24
CPC分类号： C07K14/565
摘要： A modified interferon beta (INFβ) is provided, which is less immunogenic than human INFβ (SEQ ID NO: 1) when administered to a human in vivo. The modified INFβ comprises an amino acid residue sequence that differs from SEQ ID NO: 1 by a substitution at one or more residues of SEQ ID NO: 1. Preferred substitutions are at residues selected from the group consisting of residue 50, 59, 60, 62, 63, 66, 67, 69, 70, 125, 126, 129, 130, 132, 133, and 138. Examples of suitable substitutions include F50A, L57A, I59A, Y60N, M62A, L63A, I66T, F67H, I69A, F70A, Y125A, Y126A, I129A, L130A, Y132S, L133A, Y138H, and Y138A.
摘要翻译：提供了经修饰的干扰素β（INFbeta），当其在体内施用于人时，其比人INFbeta（SEQ ID NO：1）的免疫原性较低。修饰的INFbeta包含通过在SEQ ID NO：1的一个或多个残基处的取代而与SEQ ID NO：1不同的氨基酸残基序列。优选的取代是选自残基50,59,60，合适的取代的实例包括F50A，L57A，I59A，Y60N，M62A，L63A，I66T，F67H，I69A，SEQ ID NO：6,62,63,66,67,69,70,125,126,129,130,132,133,138。 F70A，Y125A，Y126A，I129A，L130A，Y132S，L133A，Y138H和Y138A。

7. 发明授权

US07615217B2 Artificial proteins with reduced immunogenicity 有权
标题翻译：具有降低免疫原性的人造蛋白
公开(公告)号：US07615217B2
公开(公告)日：2009-11-10
申请号：US11716878
申请日：2007-03-12
申请人： Stephen Gillies , Francis J. Carr , Jones Tim , Graham Carter , Anita Hamilton , Stephen Williams , Marian Hanlon , John Watkins , Matthew Baker , Jeffrey C. Way
发明人： Stephen Gillies , Francis J. Carr , Jones Tim , Graham Carter , Anita Hamilton , Stephen Williams , Marian Hanlon , John Watkins , Matthew Baker , Jeffrey C. Way
IPC分类号： A61K39/395
CPC分类号： C07K16/30 , C07K16/28 , C07K16/2863 , C07K2317/24 , C07K2317/34 , C07K2319/00 , C07K2319/30
摘要： The invention relates to artificial modified proteins, preferably fusion proteins, having a reduced immunogenicity compared to the parent non-modified molecule when exposed to a species in vivo. The invention relates, above all, to novel immunoglobulin fusion proteins which essentially consist of an immunoglobulin molecule or a fragment thereof covalently fused via its C-terminus to the N-terminus of a biologically active non-immunoglobulin molecule, preferably a polypeptide or protein or a biologically active fragment thereof. In a specific embodiment, the invention relates to fusion proteins consisting of an Fc portion of an antibody which is fused as mentioned to the non-immunological target molecule which elicits biological or pharmacological efficacy. The molecules of the invention have amino acid sequences which are altered in one or more amino acid residue positions but have in principal the same biological activity as compared with the non-altered molecules. The changes are made in regions of the molecules which are identified as T-cell epitopes, which contribute to an immune reaction in a living host. Thus, the invention also relates to a novel method of making such fusion proteins by identifying said epitopes comprising calculation of T-cell epitope values for MHC Class II molecule binding sites in a peptide by computer-aided methods.
摘要翻译：本发明涉及人体修饰蛋白，优选融合蛋白，当与体内物种暴露时，与亲本非修饰分子相比具有降低的免疫原性。本发明首先涉及新的免疫球蛋白融合蛋白，其基本上由免疫球蛋白分子或其通过C末端与生物活性非免疫球蛋白分子，优选多肽或蛋白质的N末端共价融合的片段组成，或其生物活性片段。在一个具体的实施方案中，本发明涉及由抗体的Fc部分组成的融合蛋白，所述Fc部分如提及的非免疫靶标分子融合而引起生物学或药理学功效。本发明的分子具有氨基酸序列，其在一个或多个氨基酸残基位置被改变，但与未改变的分子相比具有相同的生物学活性。在被鉴定为T细胞表位的分子的区域中进行改变，其有助于在宿主中的免疫反应。因此，本发明还涉及通过鉴定所述表位来制备此类融合蛋白的新方法，包括通过计算机辅助方法计算肽中MHC II类分子结合位点的T细胞表位值。

8. 发明授权

US07189830B2 Anti-KSA/IL-2 fusion proteins with reduced immunogenicity 有权
标题翻译：抗KSA / IL-2融合蛋白具有降低的免疫原性
公开(公告)号：US07189830B2
公开(公告)日：2007-03-13
申请号：US10468370
申请日：2002-02-18
申请人： Stephen Gillies , Francis J. Carr , Jones Tim , Graham Carter , Anita Hamilton , Stephen Williams , Marian Hanlon , John Watkins , Matthew Baker , Jeffrey C. Way
发明人： Stephen Gillies , Francis J. Carr , Jones Tim , Graham Carter , Anita Hamilton , Stephen Williams , Marian Hanlon , John Watkins , Matthew Baker , Jeffrey C. Way
IPC分类号： C07K14/55 , C12N15/62
CPC分类号： C07K16/30 , C07K16/28 , C07K16/2863 , C07K2317/24 , C07K2317/34 , C07K2319/00 , C07K2319/30
摘要： The invention relates to artificial modified proteins, preferably fusion proteins, having a reduced immunogenicity compared to the parent non-modified molecule when exposed to a species in vivo. The invention relates, above all, to novel immunoglobulin fusion proteins which essentially consist of an immunoglobulin molecule or a fragment thereof covalently fused via its C-terminus to the N-terminus of a biologically active non-immunoglobulin molecule, preferably a polypeptide or protein or a biologically active fragment thereof. In a specific embodiment, the invention relates to fusion proteins consisting of an Fc portion of an antibody which is fused as mentioned to the non-immunological target molecule which elicits biological or pharmacological efficacy. The molecules of the invention have amino acid sequences which are altered in one or more amino acid residue positions but have in principal the same biological activity as compared with the non-altered molecules. The changes are made in regions of the molecules which are identified as T-cell epitopes, which contribute to an immune reaction in a living host. Thus, the invention also relates to a novel method of making such fusion proteins by identifying said epitopes comprising calculation of T-cell epitope values for MHC Class II molecule binding sites in a peptide by computer-aided methods.
摘要翻译：本发明涉及人体修饰蛋白，优选融合蛋白，当与体内物种暴露时，与亲本非修饰分子相比具有降低的免疫原性。本发明首先涉及新的免疫球蛋白融合蛋白，其基本上由免疫球蛋白分子或其通过C末端与生物活性非免疫球蛋白分子，优选多肽或蛋白质的N末端共价融合的片段组成，或其生物活性片段。在一个具体的实施方案中，本发明涉及由抗体的Fc部分组成的融合蛋白，所述Fc部分如提及的非免疫靶标分子融合而引起生物学或药理学功效。本发明的分子具有氨基酸序列，其在一个或多个氨基酸残基位置被改变，但与未改变的分子相比具有相同的生物学活性。在被鉴定为T细胞表位的分子的区域中进行改变，其有助于在宿主中的免疫反应。因此，本发明还涉及通过鉴定所述表位来制备此类融合蛋白的新方法，包括通过计算机辅助方法计算肽中MHC II类分子结合位点的T细胞表位值。

9. 发明授权

US07939295B2 Methods for reducing immunogenicity of polypeptides 失效
标题翻译：降低多肽免疫原性的方法
公开(公告)号：US07939295B2
公开(公告)日：2011-05-10
申请号：US10483153
申请日：2002-07-12
申请人： Francis J. Carr , Graham Carter , Koen Hellendoorn
发明人： Francis J. Carr , Graham Carter , Koen Hellendoorn
IPC分类号： C12N15/09
CPC分类号： C12N9/6472 , C07K14/47
摘要： This invention relates to the fields of immunology and protein therapeutics. The therapeutic proteins are polypeptides to be administered especially to humans. The polypeptides are modified whereby the modification results in a reduced propensity for the polypeptide to elicit an immune response upon administration to the human subject. The invention therefor provides methods for the development of therapeutic polypeptides that are less immunogenic than any non-modified counterpart when used in vivo. The modifications used according to this invention relate, for example, to the introduction of protease cleavage sites, attachment of different molecules or insertion of non-natural amino acids.
摘要翻译：本发明涉及免疫学和蛋白质治疗领域。治疗性蛋白质是特别施用于人的多肽。修饰多肽，由此修饰导致多肽在施用于人受试者时引起免疫应答的倾向降低。本发明提供了用于开发当在体内使用时比任何未修饰的对应物具有较少免疫原性的治疗性多肽的方法。根据本发明使用的修饰涉及例如引入蛋白酶切割位点，附着不同分子或插入非天然氨基酸。

10. 发明申请

US20110086422A1 HUMANIZED ANTIBODIES TO INTERFERON ALPHA RECEPTOR-1 (IFNAR-1) 失效
标题翻译：干扰素ALPHA受体-1（IFNAR-1）的人源化抗体
公开(公告)号：US20110086422A1
公开(公告)日：2011-04-14
申请号：US12972813
申请日：2010-12-20
申请人： Josephine M. Cardarelli , Tseng-hui Timothy Chen , David King , Christopher R. Bebbington , Sarah Lee Pogue , Francis J. Carr , Stephen Williams
发明人： Josephine M. Cardarelli , Tseng-hui Timothy Chen , David King , Christopher R. Bebbington , Sarah Lee Pogue , Francis J. Carr , Stephen Williams
IPC分类号： C12N5/071
CPC分类号： C07K16/2866 , A61K2039/505 , C07K2317/24 , C07K2317/56 , C07K2317/565 , C07K2317/567 , C07K2317/70 , C07K2317/76 , C07K2317/92 , C07K2317/94
摘要： Humanized monoclonal antibodies which bind to IFNAR-1, and related antibody-based compositions and molecules, are disclosed. Also disclosed are pharmaceutical compositions comprising the humanized antibodies and therapeutic and diagnostic methods for using the humanized antibodies.
摘要翻译：公开了结合IFNAR-1的人源化单克隆抗体以及相关的基于抗体的组合物和分子。还公开了包含人源化抗体和使用人源化抗体的治疗和诊断方法的药物组合物。

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