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1. 发明申请

WO2006047367A2 SUPPRESSION OF ENDOGENOUS IMMUNOGLOBULIN EXPRESSION 审中-公开
标题翻译：抑制内源性免疫球蛋白表达
公开(公告)号：WO2006047367A2
公开(公告)日：2006-05-04
申请号：PCT/US2005/038095
申请日：2005-10-21
申请人： THERAPEUTIC HUMAN POLYCLONALS, INC. , BUELOW, Roland , PLATZER, Josef
发明人： BUELOW, Roland , PLATZER, Josef
IPC分类号： C12N15/85 , A01K67/027 , C07K16/00 , C12N9/00 , C12N15/62 , C07K14/085
CPC分类号： C12N9/00 , A01K67/0271 , A01K67/0275 , A01K67/0278 , A01K2207/15 , A01K2217/00 , A01K2217/05 , A01K2227/105 , A01K2227/107 , A01K2267/01 , C07K14/005 , C07K16/00 , C07K2319/00 , C12N15/8509 , C12N2770/32022 , C12N2800/30 , C12N2830/008
摘要： The invention provides anovel approach for the suppression of endogenous antibody expression in non-human transgenic animals genetically engineered to express one or several human or humanized immunoglobulin transloci. Endogenous immunoglobulin expression in transgenic non-human animals is suppressed by selective expression of a suicide gene like a toxin only in B-cells expressing endogenous immunoglobulin but not in B-cells expressing human(ized) immunoglobulins. This method allows the dominant expression of transloci coding for humanized or human antibodies in the blood, milk and eggs of transgenic animals.
摘要翻译：本发明提供了用于抑制基因工程改造以表达一种或几种人源化或人源化免疫球蛋白转基因的非人转基因动物中的内源性抗体表达的粗略方法。转基因非人动物中的内源免疫球蛋白表达通过仅在表达内源性免疫球蛋白的B细胞中选择性表达自身基因如毒素而不在表达人（免疫球蛋白）免疫球蛋白的B细胞中被抑制）。该方法允许在转基因动物的血液，牛奶和卵中编码人源化或人抗体的转座子的显性表达。

2. 发明申请

WO2004072115A2 SUPPRESSION OF ENDOGENOUS IMMUNOGLOBULIN EXPRESSION IN TRANSGENIC NON-HUMAN ANIMALS EXPRESSING HUMANIZED OR HUMAN ANTIBODIES 审中-公开
标题翻译：抑制表达人类或人类抗体的转基因非人动物内源性免疫球蛋白表达
公开(公告)号：WO2004072115A2
公开(公告)日：2004-08-26
申请号：PCT/US2004/003450
申请日：2004-02-05
申请人： THERAPEUTIC HUMAN POLYCLONALS, INC. , BUELOW, Roland , VAN SCHOOTEN, Wim
发明人： BUELOW, Roland , VAN SCHOOTEN, Wim
IPC分类号： C07K16/00
CPC分类号： C12N15/8509 , A01K67/0278 , A01K2207/15 , A01K2217/00 , A01K2217/05 , A01K2217/30 , A01K2227/10 , A01K2227/107 , A01K2227/30 , A01K2267/01 , A61K2039/505 , C07K16/4283 , C07K2317/24
摘要： The invention provides a novel approach for suppression of endogenous antibody expression in non-human transgenic animals genetically engineered to express one or several human or humanized immunoglobulin transloci. Polyclonal or one or several monoclonal antibodies specific for endogenous IgM and/or IgE heavy and/or light chains are administered to the transgenic animals such that B-cells expressing their endogenous immunoglobulin are depleted and consequently expression of endogenous immunoglobulin is suppressed. Alternatively endogenous immunoglobulin expression may be inhibited through the expression of transgenes encoding such antibodies, including antibody fragments. This method allows the dominant expression of transloci coding for humanized or human antibodies in the blood, milk and eggs of transgenic animals.
摘要翻译：本发明提供了用于抑制在遗传工程化以表达一种或几种人或人源化免疫球蛋白转座子的非人转基因动物中的内源性抗体表达的新方法。向转基因动物施用对内源性IgM和/或IgE重链和/或轻链特异性的多克隆或一种或多种单克隆抗体，使得表达其内源性免疫球蛋白的B细胞被消耗，从而抑制内源性免疫球蛋白的表达。或者内源性免疫球蛋白表达可以通过编码这种抗体的转基因（包括抗体片段）的表达来抑制。该方法允许在转基因动物的血液，牛奶和卵中编码人源化或人抗体的转座子的显性表达。

3. 发明申请

WO2007019223A1 SUPPRESSION OF B-CELL APOPTOSIS IN TRANSGENIC ANIMALS EXPRESSING HUMANIZED IMMUNOGLOBULIN 审中-公开
标题翻译：抑制表达人类免疫球蛋白的转基因动物中的B细胞凋亡
公开(公告)号：WO2007019223A1
公开(公告)日：2007-02-15
申请号：PCT/US2006/030250
申请日：2006-08-02
申请人： THERAPEUTIC HUMAN POLYCLONALS, INC. , BUELOW, Roland , PLATZER, Josef
发明人： BUELOW, Roland , PLATZER, Josef
IPC分类号： C07K14/82 , C07K14/435
CPC分类号： C07K19/00 , A01K67/0278 , A01K2267/0331 , C07K14/4747 , C07K16/00 , C07K2317/24
摘要： ABSTRACT The invention provides a novel approach to increase immunoglobulin expression in non-human transgenic animals. For instance, the invention provides a method to increase humanized immunoglobulin production in animals genetically engineered to express one or several human or humanized immunoglobulin transloci. This can be done by overexpressing the apoptosis inhibitor, i.e. a rabbit bcl-2, whose expression is driven by a B-cell specific promoter specifically in the B-cell of the animal, thereby enhancing the survival of B-cells. This invention further relates to a method for 'selectively enhancing the survival of exogenous B-cells, that is B-cells expressing any immunoglobulin transgene locus, over the survival of endogenous B-cells that do not express the transgene locus. Selectivity is achieved by expressing the apoptosis-inhibitor only within exogenous B-cells, that is, by coupling exogenous immunoglobulin expression with apoptosis inhibitor expression. This latter method allows for increased expression and production of the transgene encoded product(s) over the endogenously produced immunoglobulin of the transgenic animal. The invention also provides a novel apoptosis-inhibitor, rabbit bcl-2.
摘要翻译：摘要本发明提供了一种增加非人转基因动物免疫球蛋白表达的新方法。例如，本发明提供了一种在遗传工程化以表达一种或几种人或人源化免疫球蛋白转座子的动物中增加人源化免疫球蛋白产生的方法。这可以通过过表达凋亡抑制剂，即兔Bcl-2，其表达由特异性地在动物的B细胞中的B细胞特异性启动子驱动，从而增强B细胞的存活。本发明还涉及“选择性增强外源性B细胞的存活（即表达任何免疫球蛋白转基因座的B细胞）超过不表达转基因座的内源性B细胞的存活的方法。通过在外源性B细胞内表达凋亡抑制剂，即通过外源免疫球蛋白表达与细胞凋亡抑制剂表达的结合来实现选择性。后一种方法允许在转基因动物的内源产生的免疫球蛋白上增加转基因编码产物的表达和产生。本发明还提供了一种新的凋亡抑制剂，兔bcl-2。

4. 发明申请

WO2005038001A2 IMPROVED TRANSGENESIS BY SPERM-MEDIATED GENE TRANSFER 审中-公开
标题翻译：通过培养的基因转移改进转化
公开(公告)号：WO2005038001A2
公开(公告)日：2005-04-28
申请号：PCT/US2004/033954
申请日：2004-10-13
申请人： THERAPEUTIC HUMAN POLYCLONALS, INC. , BUELOW, Roland
发明人： BUELOW, Roland
IPC分类号： C12N
CPC分类号： C12N15/8509 , A01K67/0275 , A01K2217/05 , A01K2227/30 , A01K2267/01 , C07K14/70503 , C12N15/8773 , C12N15/907 , C12N2800/204
摘要： The invention relates to improved methods to integrate heterologous DNA into the genome of non-human animals. The transgenic constructs contain a site recognized by a site specific recombinase which can be used to catalyze the insertion of the transgene into the animal's genome. The transgenic constructs and site specific recombinase are introduced into oocytes using sperm. Fertilized oocytes are maintained under conditions that allow recombinase-mediated integration of the transgene into the genome of the non-human animal and development to term. Transgenic animals with transgenes integrated by a recombinase express transgenes at higher levels compared to transgenic animals with randomly integrated transgenes.
摘要翻译：本发明涉及将异源DNA整合到非人动物基因组中的改进方法。转基因构建体含有由位点特异性重组酶识别的位点，其可用于催化将转基因插入到动物基因组中。使用精子将转基因构建体和位点特异性重组酶导入卵母细胞。受精的卵母细胞保持在允许重组酶介导的转基因整合到非人类动物的基因组和发育期的条件下。与具有随机整合的转基因的转基因动物相比，通过重组酶整合的转基因的转基因动物以更高的水平表达转基因。

5. 发明申请

WO2005019463A1 IMPROVED TRANSGENESIS WITH HUMANIZED IMMUNOGLOBULIN LOCI 审中-公开
标题翻译：改进的人类免疫球蛋白位点转移
公开(公告)号：WO2005019463A1
公开(公告)日：2005-03-03
申请号：PCT/US2004/025933
申请日：2004-08-10
申请人： THERAPEUTIC HUMAN POLYCLONALS, INC. , BUELOW, Roland , VAN SCHOOTEN, Wim
发明人： BUELOW, Roland , VAN SCHOOTEN, Wim
IPC分类号： C12N15/85
CPC分类号： C12N15/8509 , A01K67/0278 , A01K2207/15 , A01K2217/00 , A01K2227/105 , A01K2227/107 , A01K2267/01 , C12N15/85 , C12N15/907 , C12N2800/204 , C12N2800/30 , C12N2830/42 , C12N2840/203
摘要： The invention concerns recombinase-mediated transfer of human or humanized immunoglobulin loci into the genome of non-human transgenic animals. In particular, the invention relates to improved methods to integrate human and/or humanized immunoglobulin loci into the genome of non-human animals using transgenic constructs which contain immunoglobulin loci comprising human gene sequences and a site recognized by a site specific recombinase which can be used to catalyze the insertion of the transgene into the animal's genome.
摘要翻译：本发明涉及人类或人源化免疫球蛋白基因座的重组酶介导的转移到非人转基因动物的基因组中。特别地，本发明涉及使用含有免疫球蛋白基因座的转基因构建体将人和/或人源化免疫球蛋白基因组整合到非人动物基因组中的改进方法，所述免疫球蛋白基因座包含人基因序列和可被使用的位点特异性重组酶识别的位点以催化转基因插入动物基因组中。

6. 发明申请

WO2008027986A2 ENHANCED EXPRESSION OF HUMAN OR HUMANIZED IMMUNOGLOBULIN IN NON-HUMAN TRANSGENIC ANIMALS 审中-公开
标题翻译：人类或人类免疫球蛋白在非人类转基因动物中的增强表达
公开(公告)号：WO2008027986A2
公开(公告)日：2008-03-06
申请号：PCT/US2007/077143
申请日：2007-08-29
申请人： THERAPEUTIC HUMAN POLYCLONALS, INC. , BUELOW, Roland
发明人： BUELOW, Roland
IPC分类号： C12N15/09
CPC分类号： C07K16/00 , A01K67/0278 , A01K2207/15 , A01K2217/00 , A01K2227/107 , A01K2267/01 , C07K14/70503 , C12N15/8509
摘要： The present invention describes transgenic animals with human(ized) immunoglobulin loci and transgenes encoding human(ized) Igα and/or Igβ sequences. Of particular interest are animals with transgenic heavy and light chain immunoglobulin loci capable of producing a diversified human(ized) antibody repertoire that have their endogenous production of Ig and/or endogenous Igα and/or Igβ sequences suppressed. Simultaneous expression of human(ized) immunoglobulin and human(ized) Igα and/or Igβ results in normal B-cell development, affinity maturation and efficient expression of human(ized) antibodies.
摘要翻译：本发明描述了具有编码人（ized）Iga和/或Igβ序列的人（ized）免疫球蛋白基因座和转基因的转基因动物。特别令人感兴趣的是具有转基因重链和轻链免疫球蛋白基因座的动物，其能够产生具有内源性产生Ig和/或内源性Iga和/或Igβ序列的抑制的多种人（抗体）抗体谱。人类免疫球蛋白和人（Ig）和/或Igβ的同时表达导致人（抗体）抗体的正常B细胞发育，亲和力成熟和有效表达。

7. 发明申请

WO2006065821A2 IMPROVED DNA IMMUNIZATION WITH RECOMBINASE/TRANSPOSASE 审中-公开
标题翻译：用重组酶/转移酶改进DNA免疫
公开(公告)号：WO2006065821A2
公开(公告)日：2006-06-22
申请号：PCT/US2005/045080
申请日：2005-12-12
申请人： THERAPEUTIC HUMAN POLYCLONALS, INC. , BUELOW, Roland , PLATZER, Josef
发明人： BUELOW, Roland , PLATZER, Josef
IPC分类号： A61K39/39 , C07K14/535 , C12N15/90
CPC分类号： C07K16/2896 , A61K39/0008 , A61K39/0011 , A61K2039/53 , A61K2039/55522 , A61K2039/6031 , C07K14/535 , C07K2319/00 , C07K2319/30 , C12N15/90 , A61K2300/00
摘要： The present invention relates to improved methods to immunize/vaccinate or stimulate the immune system of animals, including humans, using vectors containing expression cassettes that encode for the DNA of one or more protein/peptide antigens and/or adjuvants, in particular, cytokines like GMCSF, F1t3L, interleukins, and the like, which can be encoded by DNA as well, also recombinase mediated integration. Adjuvants known to increase immune responses following DNA vaccination. In addition, the vectors contain one or more sites recognized by a recombinase/transposase, which catalyzes the insertion of the vector into the genome of transfected cells. Stable integration of the plasmid vector into the genome of transfected cells results in higher and longer-lasting expression of the encoded protein(s), and increases the immune response in the vaccinated animal. The present invention also relates to adjuvant compositions comprising the novel polypeptide, rabbit GMCSF, for boosting antibody production in rabbits.
摘要翻译：本发明涉及使用含有编码一种或多种蛋白质/肽抗原和/或其片段的DNA的表达盒的载体免疫/接种或刺激动物（包括人）的免疫系统的改进方法，和/ 或佐剂，特别是可以由DNA编码的细胞因子如GMCSF，F1t3L，白细胞介素等，也是重组酶介导的整合。已知在DNA疫苗接种后增加免疫应答的佐剂。另外，载体含有一个或多个由重组酶/转座酶识别的位点，其催化载体插入转染细胞的基因组中。将质粒载体稳定整合到转染细胞的基因组中导致编码蛋白质的更高和更长时间的表达，并增加接种动物的免疫应答。本发明还涉及包含所述新多肽，兔GMCSF的佐剂组合物，用于加强兔中的抗体产生。

8. 发明申请

WO2005007696A2 HUMANIZED IMMUNOGLOBULIN LOCI 审中-公开
标题翻译：人源化免疫球蛋白基因
公开(公告)号：WO2005007696A2
公开(公告)日：2005-01-27
申请号：PCT/US2004/023226
申请日：2004-07-15
申请人： THERAPEUTIC HUMAN POLYCLONALS, INC. , BUELOW, Roland , VAN SCHOOTEN, Wim
发明人： BUELOW, Roland , VAN SCHOOTEN, Wim
IPC分类号： C07K16/00
CPC分类号： C12N15/67 , A01K67/0278 , A01K2207/15 , A01K2217/00 , A01K2227/105 , A01K2227/107 , A01K2267/01 , C07K16/00 , C07K16/461 , C07K2317/24 , C12N15/8509
摘要： The present invention concerns methods and means to produce humanized antibodies from transgenic non-human animals. The invention specifically relates to novel immunoglobulin heavy and light chain constructs, recombination and transgenic vectors useful in making transgenic non-human animals expressing humanized antibodies, transgenic animals, and humanized immunoglobulin preparations.
摘要翻译：本发明涉及从转基因非人动物产生人源化抗体的方法和手段。本发明具体涉及用于制造表达人源化抗体的转基因非人动物，转基因动物和人源化免疫球蛋白制剂的新型免疫球蛋白重链和轻链构建体，重组和转基因载体。

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