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1. 发明申请

WO0240545A2 REDUCTION OF THE NONSPECIFIC ANIMAL TOXICITY OF IMMUNOTOXINS BY MUTATING THE FRAMEWORK REGIONS OF THE FV TO LOWER THE ISOELECTRIC POINT 审中-公开
标题翻译：通过打破FV的框架区域来降低免疫动力学的非特异性动物毒性以降低ISOELECTRIC POINT
公开(公告)号：WO0240545A2
公开(公告)日：2002-05-23
申请号：PCT/US0143602
申请日：2001-11-16
申请人： US GOV HEALTH & HUMAN SERV , PASTAN IRA H , ONDA MASANORI , NAGATA SATOSHI , TSUTSUMI YASUO , VINCENT JAMES J , KREITMAN ROBERT J , VASMATZIS GEORGE , LEE BYUNGKOOK
发明人： PASTAN IRA H , ONDA MASANORI , NAGATA SATOSHI , TSUTSUMI YASUO , VINCENT JAMES J , KREITMAN ROBERT J , VASMATZIS GEORGE , LEE BYUNGKOOK
IPC分类号： A61K47/48 , A61P35/00 , C07K14/21 , C07K16/00 , C07K16/18 , C07K16/28 , C07K16/30 , C12N1/21 , C07K19/00 , C12N15/62 , C12N15/70
CPC分类号： C07K16/28 , A61K47/6829 , A61K47/6849 , A61K47/6867 , A61K2039/505 , C07K14/21 , C07K16/00 , C07K16/18 , C07K16/2803 , C07K16/2866 , C07K16/2896 , C07K16/30 , C07K2317/56 , C07K2317/567 , C07K2317/624 , C07K2319/02
摘要： The invention provides recombinant immunotoxins that have been modified from a parental immunotoxin to lower liver toxicity. The immunotoxins are created by specifically mutating charged residues in the framework regions of the heavy chain, the light chain, or both, of the antibody portion or antigen-binding fragment thereof of the parental immunotoxin to reduce the pI of the antibody or fragment. In preferred forms, the antibody portion of the parental is an anti-Tac, anti-mesothelin, or anti-LewisY antigen antibody or antigen-binding fragment, and in particularly preferred forms the antibody portion is an M16 dsFv, a St6 dsFv or a Mt9 dsFv, or a sequence that has at least 90% sequence identity to one of these molecules but retain the particular mutations that lower pI without affecting antibody activity. The invention further provides nucleic acids encoding the recombinant immunotoxins of the invention, expression cassettes comprising the nucleic acids, and host cells comprising the expression cassettes. The invention also provides a method for killing a cell comprising an antigen on the surface of the cell, the method comprising contacting the cell with a recombinant immunotoxin of the invention that has an antibody or antigen-binding fragment thereof that binds specifically to the antigen on the surface of the cell, and uses of immunotoxins of the invention for the manufacture of medicaments.
摘要翻译：本发明提供已经从亲本免疫毒素修饰以降低肝毒性的重组免疫毒素。免疫毒素通过在亲本免疫毒素的抗体部分或其抗原结合片段的重链，轻链或两者的构架区中特异性突变带电残基而产生，以减少抗体或片段的pI。在优选形式中，亲本的抗体部分是抗Tac，抗间皮素或抗LewisY抗原抗体或抗原结合片段，并且在特别优选的形式中，抗体部分是M16 dsFv，St6 dsFv或 Mt9 dsFv或与这些分子之一具有至少90％序列同一性的序列，但保留降低pI而不影响抗体活性的特定突变。本发明还提供编码本发明的重组免疫毒素的核酸，包含核酸的表达盒和包含表达盒的宿主细胞。本发明还提供了一种用于杀死细胞表面上包含抗原的细胞的方法，所述方法包括使细胞与本发明的重组免疫毒素接触，所述重组免疫毒素具有抗体或其抗原结合片段，其特异性与抗原结合细胞的表面，以及本发明的免疫毒素用于制备药物的用途。

2. 发明申请

WO0240545A9 REDUCTION OF THE NONSPECIFIC ANIMAL TOXICITY OF IMMUNOTOXINS BY MUTATING THE FRAMEWORK REGIONS OF THE FV TO LOWER THE ISOELECTRIC POINT 审中-公开
标题翻译：通过打破FV的框架区域来降低免疫动力学的非特异性动物毒性以降低ISOELECTRIC POINT
公开(公告)号：WO0240545A9
公开(公告)日：2003-02-06
申请号：PCT/US0143602
申请日：2001-11-16
申请人： US GOV HEALTH & HUMAN SERV , PASTAN IRA H , ONDA MASANORI , NAGATA SATOSHI , TSUTSUMI YASUO , VINCENT JAMES J , KREITMAN ROBERT J , VASMATZIS GEORGE , LEE BYUNGKOOK
发明人： PASTAN IRA H , ONDA MASANORI , NAGATA SATOSHI , TSUTSUMI YASUO , VINCENT JAMES J , KREITMAN ROBERT J , VASMATZIS GEORGE , LEE BYUNGKOOK
IPC分类号： A61K47/48 , A61P35/00 , C07K14/21 , C07K16/00 , C07K16/18 , C07K16/28 , C07K16/30 , C12N1/21 , C07K19/00 , C12N15/62 , C12N15/70
CPC分类号： C07K16/28 , A61K47/6829 , A61K47/6849 , A61K47/6867 , A61K2039/505 , C07K14/21 , C07K16/00 , C07K16/18 , C07K16/2803 , C07K16/2866 , C07K16/2896 , C07K16/30 , C07K2317/56 , C07K2317/567 , C07K2317/624 , C07K2319/02
摘要： The invention provides recombinant immunotoxins that have been modified from a parental immunotoxin to lower liver toxicity. The immunotoxins are created by specifically mutating charged residues in the framework regions of the heavy chain, the light chain, or both, of the antibody portion or antigen-binding fragment thereof of the parental immunotoxin to reduce the pI of the antibody or fragment. In preferred forms, the antibody portion of the parental is an anti-Tac, anti-mesothelin, or anti-LewisY antigen antibody or antigen-binding fragment, and in particularly preferred forms the antibody portion is an M16 dsFv, a St6 dsFv or a Mt9 dsFv, or a sequence that has at least 90% sequence identity to one of these molecules but retain the particular mutations that lower pI without affecting antibody activity. The invention further provides nucleic acids encoding the recombinant immunotoxins of the invention, expression cassettes comprising the nucleic acids, and host cells comprising the expression cassettes. The invention also provides a method for killing a cell comprising an antigen on the surface of the cell, the method comprising contacting the cell with a recombinant immunotoxin of the invention that has an antibody or antigen-binding fragment thereof that binds specifically to the antigen on the surface of the cell, and uses of immunotoxins of the invention for the manufacture of medicaments.
摘要翻译：本发明提供已经从亲本免疫毒素修饰以降低肝毒性的重组免疫毒素。免疫毒素通过在亲本免疫毒素的抗体部分或其抗原结合片段的重链，轻链或两者的构架区中特异性突变带电残基而产生，以减少抗体或片段的pI。在优选形式中，亲本的抗体部分是抗Tac，抗间皮素或抗LewisY抗原抗体或抗原结合片段，并且在特别优选的形式中，抗体部分是M16 dsFv，St6 dsFv或 Mt9 dsFv或与这些分子之一具有至少90％序列同一性的序列，但保留降低pI而不影响抗体活性的特定突变。本发明还提供编码本发明的重组免疫毒素的核酸，包含核酸的表达盒和包含表达盒的宿主细胞。本发明还提供了一种用于杀死细胞表面上包含抗原的细胞的方法，所述方法包括使细胞与本发明的重组免疫毒素接触，所述重组免疫毒素具有抗体或其抗原结合片段，其特异性与抗原结合细胞的表面，以及本发明的免疫毒素用于制备药物的用途。

3. 发明申请

WO2004053098A2 BASE, A NEW CANCER GENE, AND USES THEREOF 审中-公开
标题翻译：基因，新癌基因及其用途
公开(公告)号：WO2004053098A2
公开(公告)日：2004-06-24
申请号：PCT/US2003/039476
申请日：2003-12-10
申请人： THE GOVERNMENT OF THE UNITED STATES, AS REPRESENTED BY THE SECRETARY OF THE DEPARTMENT OF HEALTH AND HUMAN SERVICES , PASTAN, Ira, H. , EGLAND, Kristi, A. , VINCENT, James, J. , LEE, Byungkook , STRAUSBERG, Robert
发明人： PASTAN, Ira, H. , EGLAND, Kristi, A. , VINCENT, James, J. , LEE, Byungkook , STRAUSBERG, Robert
IPC分类号： C12N
CPC分类号： C07K14/47 , A61K38/00
摘要： The invention relates to the discovery of a new gene, termed "BASE," which is expressed in some 25% of breast cancers and in salivary glands. BASE is expressed in two alternatively spliced forms: a 19.5 kD, 179 amino acid secreted protein called "base1," and a 8.4 CKD, 79 amino acid non-secreted protein called "base2." The invention provides antibodies to base l and to base2. Antibodies to the proteins can be used to detect the presence of base l or base2 in a sample, thereby detecting the presence of a BASE-expressing breast cancer. Antibodies to base2 attached to a therapeutic agent can direct the agent to base2-expressing cells. Base1 and base2, immunogenic fragments of the proteins, and analogs of the proteins can be used to raise immune responses to BASE-expressing cancer cells. The invention further provides uses for using the proteins in manufacturing medicaments and methods for using antibodies to the proteins, attached to therapeutic molecules, to inhibit the growth of cancer cells expressing BASE.
摘要翻译：本发明涉及一种称为“BASE”的新基因的发现，该基因在大约25％的乳腺癌和唾液腺中表达。 BASE以两种可变剪接形式表达：称为“碱基”的19.5kD，179个氨基酸的分泌蛋白质，以及称为“碱基2”的8.4个CKD，79个氨基酸的非分泌蛋白质。本发明提供了对碱基1和碱基2的抗体。蛋白质的抗体可用于检测样品中碱基1或碱基2的存在，从而检测表达BASE的乳腺癌的存在。与治疗剂连接的碱基2的抗体可以将该药剂引导至表达于2的细胞。 Base1和base2，蛋白质的免疫原性片段和蛋白质的类似物可用于提高对表达BASE的癌细胞的免疫应答。本发明进一步提供在制备药物中使用蛋白质的用途以及与所述蛋白质结合使用抗体的方法，所述蛋白质与治疗分子连接，以抑制表达BASE的癌细胞的生长。

4. 发明申请

WO2004053098A3 BASE, A NEW CANCER GENE, AND USES THEREOF 审中-公开
标题翻译：基因，新癌基因及其用途
公开(公告)号：WO2004053098A3
公开(公告)日：2006-01-26
申请号：PCT/US0339476
申请日：2003-12-10
申请人： HUMAN SERVICES D BY THE SECRET , PASTAN IRA H , EGLAND KRISTI A , VINCENT JAMES J , LEE BYUNGKOOK , STRAUSBERG ROBERT
发明人： PASTAN IRA H , EGLAND KRISTI A , VINCENT JAMES J , LEE BYUNGKOOK , STRAUSBERG ROBERT
IPC分类号： A61K38/00 , C07K14/47 , C07K1/00 , A01N37/18 , A61K35/12 , C07H21/02 , C07K16/00 , C12N5/00 , C12P21/00 , C12Q1/70
CPC分类号： C07K14/47 , A61K38/00
摘要： The invention relates to the discovery of a new gene, termed "BASE," which is expressed in some 25% of breast cancers and in salivary glands. BASE is expressed in two alternatively spliced forms: a 19.5 kD, 179 amino acid secreted protein called "base1," and a 8.4 CKD, 79 amino acid non-secreted protein called "base2." The invention provides antibodies to base l and to base2. Antibodies to the proteins can be used to detect the presence of base l or base2 in a sample, thereby detecting the presence of a BASE-expressing breast cancer. Antibodies to base2 attached to a therapeutic agent can direct the agent to base2-expressing cells. Base1 and base2, immunogenic fragments of the proteins, and analogs of the proteins can be used to raise immune responses to BASE-expressing cancer cells. The invention further provides uses for using the proteins in manufacturing medicaments and methods for using antibodies to the proteins, attached to therapeutic molecules, to inhibit the growth of cancer cells expressing BASE.
摘要翻译：本发明涉及一种称为“BASE”的新基因的发现，该基因在大约25％的乳腺癌和唾液腺中表达。 BASE以两种可变剪接形式表达：称为“碱基”的19.5kD，179个氨基酸的分泌蛋白质，以及称为“碱基2”的8.4个CKD，79个氨基酸的非分泌蛋白质。本发明提供了对碱基1和碱基2的抗体。蛋白质的抗体可用于检测样品中碱基1或碱基2的存在，从而检测表达BASE的乳腺癌的存在。与治疗剂连接的碱基2的抗体可以将该药剂引导至表达于2的细胞。 Base1和base2，蛋白质的免疫原性片段和蛋白质的类似物可用于提高对表达BASE的癌细胞的免疫应答。本发明进一步提供在制备药物中使用蛋白质的用途以及与所述蛋白质结合使用抗体的方法，所述蛋白质与治疗分子连接，以抑制表达BASE的癌细胞的生长。

5. 发明申请

WO2002040545A3 REDUCTION OF THE NONSPECIFIC ANIMAL TOXICITY OF IMMUNOTOXINS BY MUTATING THE FRAMEWORK REGIONS OF THE FV TO LOWER THE ISOELECTRIC POINT 审中-公开
公开(公告)号：WO2002040545A3
公开(公告)日：2002-05-23
申请号：PCT/US2001/043602
申请日：2001-11-16
申请人： THE GOVERNMENT OF THE UNITED STATES, as represented by THE SECRETARY OF THE DEPARTMENT OF HEALTH AND HUMAN SERVICES , PASTAN, Ira, H. , ONDA, Masanori , NAGATA, Satoshi , TSUTSUMI, Yasuo , VINCENT, James, J. , KREITMAN, Robert, J. , VASMATZIS, George , LEE, Byungkook
发明人： PASTAN, Ira, H. , ONDA, Masanori , NAGATA, Satoshi , TSUTSUMI, Yasuo , VINCENT, James, J. , KREITMAN, Robert, J. , VASMATZIS, George , LEE, Byungkook
IPC分类号： C07K19/00
摘要： The invention provides recombinant immunotoxins that have been modified from a parental immunotoxin to lower liver toxicity. The immunotoxins are created by specifically mutating charged residues in the framework regions of the heavy chain, the light chain, or both, of the antibody portion or antigen-binding fragment thereof of the parental immunotoxin to reduce the pI of the antibody or fragment. In preferred forms, the antibody portion of the parental is an anti-Tac, anti-mesothelin, or anti-LewisY antigen antibody or antigen-binding fragment, and in particularly preferred forms the antibody portion is an M16 dsFv, a St6 dsFv or a Mt9 dsFv, or a sequence that has at least 90% sequence identity to one of these molecules but retain the particular mutations that lower pI without affecting antibody activity. The invention further provides nucleic acids encoding the recombinant immunotoxins of the invention, expression cassettes comprising the nucleic acids, and host cells comprising the expression cassettes. The invention also provides a method for killing a cell comprising an antigen on the surface of the cell, the method comprising contacting the cell with a recombinant immunotoxin of the invention that has an antibody or antigen-binding fragment thereof that binds specifically to the antigen on the surface of the cell, and uses of immunotoxins of the invention for the manufacture of medicaments.

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