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1. 发明申请

WO2004074486A3 FUSION PROTEINS OF INTERFERON ALPHA MUTEINS WITH IMPROVED PROPERTIES 审中-公开
公开(公告)号：WO2004074486A3
公开(公告)日：2004-09-02
申请号：PCT/EP2004/001524
申请日：2004-02-18
申请人： MERCK PATENT GMBH , JONES, Tim , BAKER, Matthew , HANLON, Marian , CARR, Francis, Joseph
发明人： JONES, Tim , BAKER, Matthew , HANLON, Marian , CARR, Francis, Joseph
IPC分类号： C12N15/21
摘要： The invention concerns human interferon alpha and in particular modified forms of interferon alpha 2 with improved properties. The improved proteins contain amino acid substitutions at specific positions that confer increased relative activity in biological assays. The invention provides also modified interferon alpha with improved biological activity concomitant with reduced immunogenic potential in the protein. The improved proteins are intended for therapeutic use in the treatment of diseases in humans.

2. 发明申请

WO2002066514A2 ARTIFICIAL PROTEINS WITH REDUCED IMMUNOGENICITY 审中-公开
标题翻译：具有降低免疫原性的人造蛋白
公开(公告)号：WO2002066514A2
公开(公告)日：2002-08-29
申请号：PCT/EP2002/001690
申请日：2002-02-18
申请人： MERCK PATENT GMBH , GILLIES, Stephen , CARR, Francis, J. , JONES, Tim , CARTER, Graham , HAMILTON, Anita , WILLIAMS, Stephen , HANLON, Marian , WATKINS, John , BAKER, Matthew , WAY, Jeffrey, C.
发明人： GILLIES, Stephen , CARR, Francis, J. , JONES, Tim , CARTER, Graham , HAMILTON, Anita , WILLIAMS, Stephen , HANLON, Marian , WATKINS, John , BAKER, Matthew , WAY, Jeffrey, C.
IPC分类号： C07K16/00
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。

3. 发明申请

WO2002085941A3 MODIFIED INTERFERON ALPHA WITH REDUCED IMMUNOGENICITY 审中-公开
公开(公告)号：WO2002085941A3
公开(公告)日：2002-10-31
申请号：PCT/EP2002/002218
申请日：2002-03-01
申请人： MERCK PATENT GMBH , CARR, Francis, J. , CARTER, Graham , JONES, Tim , BAKER, Matthew , WATKINS, John , HANLON, Marian
发明人： CARR, Francis, J. , CARTER, Graham , JONES, Tim , BAKER, Matthew , WATKINS, John , HANLON, Marian
IPC分类号： C07K14/56
摘要： The present invention relates to polypeptides to be administered especially to humans and in particular for therapeutic use. The polypeptides are modified polypeptides whereby the modification results in a reduced propensity for the polypeptide to elicit an immune response upon administration to the human subject. The invention in particular to the modification of human interferon alpha and specifically interferon alpha 2(INFα2) to result in proteins that are substantially non-immunogenic or less immunogenic than any non-modified counterpart when use in vivo .

4. 发明申请

WO2002085941A2 MODIFIED INTERFERON ALPHA WITH REDUCED IMMUNOGENICITY 审中-公开
标题翻译：具有降低免疫原性的改良干扰素ALPHA
公开(公告)号：WO2002085941A2
公开(公告)日：2002-10-31
申请号：PCT/EP2002/002218
申请日：2002-03-01
申请人： MERCK PATENT GMBH , CARR, Francis, J. , CARTER, Graham , JONES, Tim , BAKER, Matthew , WATKINS, John , HANLON, Marian
发明人： CARR, Francis, J. , CARTER, Graham , JONES, Tim , BAKER, Matthew , WATKINS, John , HANLON, Marian
IPC分类号： C07K14/56
CPC分类号： C07K7/06 , A61K38/00 , C07K14/56
摘要： The present invention relates to polypeptides to be administered especially to humans and in particular for therapeutic use. The polypeptides are modified polypeptides whereby the modification results in a reduced propensity for the polypeptide to elicit an immune response upon administration to the human subject. The invention in particular to the modification of human interferon alpha and specifically interferon alpha 2(INFα2) to result in proteins that are substantially non-immunogenic or less immunogenic than any non-modified counterpart when use in vivo .
摘要翻译：本发明涉及特别用于人，特别是用于治疗用途的多肽。所述多肽是修饰的多肽，其中所述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。本发明特别涉及人干扰素α和特异性干扰素α2（INFα2）的修饰，以产生当在体内使用时与任何未修饰的对应物基本上不具有免疫原性或较低免疫原性的蛋白质。

5. 发明公开

EP1594965A2 FUSION PROTEINS OF INTERFERON ALPHA MUTEINS WITH IMPROVED PROPERTIES 审中-公开
标题翻译：干扰素α突变蛋白具有改进的性能的融合蛋白
公开(公告)号：EP1594965A2
公开(公告)日：2005-11-16
申请号：EP04712037.3
申请日：2004-02-18
申请人： Merck Patent GmbH
发明人： JONES, Tim , BAKER, Matthew , HANLON, Marian , CARR, Francis Joseph
IPC分类号： C12N15/21 , C07K14/56 , A61K38/21
CPC分类号： A61K38/212 , C07K14/56 , C07K2319/30
摘要： The invention concerns human interferon alpha and in particular modified forms of interferon alpha 2 with improved properties. The improved proteins contain amino acid substitutions at specific positions that confer increased relative activity in biological assays. The invention provides also modified interferon alpha with improved biological activity concomitant with reduced immunogenic potential in the protein. The improved proteins are intended for therapeutic use in the treatment of diseases in humans.

6. 发明公开

EP1379555A2 MODIFIED INTERFERON ALPHA WITH REDUCED IMMUNOGENICITY 审中-公开
标题翻译：免疫原性降低的修饰α干扰素
公开(公告)号：EP1379555A2
公开(公告)日：2004-01-14
申请号：EP02727340.8
申请日：2002-03-01
申请人： MERCK PATENT GmbH
发明人： CARR, Francis, J. , CARTER, Graham , JONES, Tim , BAKER, Matthew , WATKINS, John , HANLON, Marian
IPC分类号： C07K14/56 , A61K38/21 , C12N15/21 , C07K7/04 , A61K38/04
CPC分类号： C07K7/06 , A61K38/00 , C07K14/56
摘要： The present invention relates to polypeptides to be administered especially to humans and in particular for therapeutic use. The polypeptides are modified polypeptides whereby the modification results in a reduced propensity for the polypeptide to elicit an immune response upon administration to the human subject. The invention in particular to the modification of human interferon alpha and specifically interferon alpha 2(INFα2) to result in proteins that are substantially non-immunogenic or less immunogenic than any non-modified counterpart when use in vivo.

7. 发明公开

EP1361891A2 ARTIFICIAL FUSION PROTEINS WITH REDUCED IMMUNOGENICITY 审中-公开
标题翻译：免疫原性降低人工融合蛋白
公开(公告)号：EP1361891A2
公开(公告)日：2003-11-19
申请号：EP02700246.8
申请日：2002-02-18
申请人： MERCK PATENT GmbH
发明人： GILLIES, Stephen , CARR, Francis, J. , JONES, Tim , CARTER, Graham , HAMILTON, Anita , WILLIAMS, Stephen , HANLON, Marian , WATKINS, John , BAKER, Matthew , WAY, Jeffrey, C.
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.

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