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公开(公告)号：US09222070B2
公开(公告)日：2015-12-29
申请号：US11782264
申请日：2007-07-24
IPC分类号： C12N5/071 , C12N5/0783 , A61K48/00 , A61K38/20 , A61K38/21 , A61K39/00 , A61K41/00 , C12N5/07 , A61K35/12
CPC分类号： C12N5/0636 , A61K38/2013 , A61K38/212 , A61K39/0011 , A61K41/00 , A61K48/00 , A61K2035/124 , A61K2039/5154 , A61K2039/5156 , A61K2039/5158 , A61K2039/55527 , A61K2039/55533 , A61K2039/55538 , C12N5/0601 , C12N2501/23 , C12N2501/515 , C12N2502/99 , C12N2510/00 , A61K2300/00
摘要： T cell responses are often diminished in humans with a compromised immune system. We have developed a method to isolate, stimulate and expand naïve cytotoxic T lymphocyte precursors (CTLp) to antigen-specific effectors, capable of lysing tumor cells in vivo. This ex vivo protocol produces fully functional effectors. Artificial antigen presenting cells (AAPCs; Drosophila melanogaster) transfected with human HLA class I and defined accessory molecules, are used to stimulate CD8+ T cells from both normal donors and cancer patients. The class I molecules expressed to a high density on the surface of the Drosophila cells are empty, allowing for efficient loading of multiple peptides that results in the generation of polyclonal responses recognizing tumor cells endogenously expressing the specific peptides. The responses generated are robust, antigen-specific and reproducible if the peptide epitope is a defined immunogen. This artificial antigen expression system can be adapted to treat most cancers in a significant majority of the population.
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2.发明授权Ex-vivo priming for generating cytotoxic T lymphocytes specific for non-tumor antigens to treat autoimmune and allergic disease 有权用于产生特异于非肿瘤抗原的细胞毒性T淋巴细胞用于治疗自身免疫性和过敏性疾病的体外引发公开(公告)号：US08084256B2
公开(公告)日：2011-12-27
申请号：US12887032
申请日：2010-09-21
申请人： Zeling Cai , Michael R. Jackson , Per A. Peterson , Wei-Xing Shi , Yan Kong , Juli DeGraw
发明人： Zeling Cai , Michael R. Jackson , Per A. Peterson , Wei-Xing Shi , Yan Kong , Juli DeGraw
CPC分类号： A61K39/0008 , A61K2035/122 , C12N5/0636 , C12N2501/23 , C12N2501/51 , C12N2501/58 , C12N2502/50 , C12N2502/99
摘要： Cytotoxic T lymphocytes (CTLs) specific for antigenic peptides derived from IgE molecule can be generated in vitro by stimulating resting naive CD8 T cells with IgE peptides presented by artificial antigen presenting cells. The IgE specific CTLs lyse the target cells loaded with IgE peptides in vitro and inhibit antigen specific IgE response in vivo. In addition, adoptive transfer of the IgE specific CTL to an asthmatic mouse model can inhibit the development of lung inflammation and airway hypersensitivity. IgE specific CTL provides a treatment for allergic asthma and other IgE-mediated allergic diseases. Antigenic peptides identified from non-tumor self-antigens induce specific cytotoxic T lymphocyte (CTL) in vitro. The CTL induced by peptides identified from CD40L can kill activated CD4 T cells. In vitro generated CTL specific for CD40L inhibit CD4-dependent antibody responses of all isotypes in vivo. In contrast, CTL induced by antigenic peptides derived from IgE specifically inhibit IgE responses, and adoptive transfer of CD40L-specific CTL to NOD mice at early age delay the development of diabetes in NOD mice. In vitro generated CTL specific for non-tumor self-antigens expressed on activated CD4 T cells regulate immune responses in vivo.
摘要翻译： 可以通过用人造抗原呈递细胞呈递的IgE肽刺激静息幼稚CD8T细胞在体外产生来自IgE分子的抗原肽特异性的细胞毒性T淋巴细胞（CTL）。 IgE特异性CTL在体外裂解装载有IgE肽的靶细胞，并在体内抑制抗原特异性IgE反应。 此外，将IgE特异性CTL过继转移至哮喘小鼠模型可以抑制肺部炎症和气道超敏反应的发展。 IgE特异性CTL提供过敏性哮喘和其他IgE介导的过敏性疾病的治疗。 从非肿瘤自身抗原鉴定的抗原肽在体外诱导特异性细胞毒性T淋巴细胞（CTL）。 由CD40L鉴定的肽诱导的CTL可以杀死活化的CD4T细胞。 体外产生的CD40L特异性CTL可抑制体内所有同种型的CD4依赖性抗体反应。 相比之下，来自IgE的抗原肽诱导的CTL特异性抑制IgE应答，CD40L特异性CTL过早转移到NOD小鼠早期延迟NOD小鼠的糖尿病发展。 在活化的CD4T细胞上表达的非肿瘤自身抗原的体外产生的CTL调节体内的免疫应答。
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3.发明授权公开(公告)号：US07993638B2
公开(公告)日：2011-08-09
申请号：US12281197
申请日：2007-02-23
申请人： Zeling Cai , Ann Moriarty , Per A. Peterson , Jon M. Richards
发明人： Zeling Cai , Ann Moriarty , Per A. Peterson , Jon M. Richards
CPC分类号： A61K39/0011 , A61K35/17 , A61K38/2013 , A61K38/212 , A61K2039/5154 , A61K2039/5158 , A61K2039/55522 , A61K2039/55533 , A61K2300/00
摘要： In a cancer treatment combining cell therapy with chemotherapy, autologous CD8+ T cells are obtained from a patient, activated ex vivo by contacting them with xenogenic antigen presenting cells loaded with selected peptide antigen, thereby generating antigen-specific activated cytotoxic T lymphocytes. Such activated CTLs are administered to the patient in conjunction with a lymphodepletion and CTL maintenance regimen comprising a non-myeloblative but lymphdepleting agent, such as cladribine or denileukin diftitox, and interleukin-2 and interferon-α-2b stimulatory cytokines.
摘要翻译： 在结合细胞治疗与化疗的癌症治疗中，从患者获得自体CD8 + T细胞，通过将它们与负载选择的肽抗原的异种抗原呈递细胞接触，从而离体活化，从而产生抗原特异性激活的细胞毒性T淋巴细胞。 结合淋巴滤除和CTL维持方案向患者施用这种活化的CTL，其包括非球形性但淋巴结清除剂，例如克拉屈滨或denileukin diftitox，以及白细胞介素-2和干扰素-α-2b刺激性细胞因子。
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4.发明授权MHC class II antigen-presenting systems and methods for activating CD4+ T cells 有权MHC II类抗原呈递系统和激活CD4 + T细胞的方法公开(公告)号：US07439335B2
公开(公告)日：2008-10-21
申请号：US10822173
申请日：2004-04-08
CPC分类号： C07K14/70596 , A61K38/00 , A61K2039/5154 , A61K2039/5156 , C12N5/0601 , C12N2510/00 , Y10S424/81
摘要： The present invention relates to synthetic antigen-presenting matrices, their methods of making and their methods of use. One such matrix is cells that have been transfected to produce MHC antigen-presenting molecules with one or more accessory molecules. The matrices are used to activate naive CD4+ T cells as well as shift the ongoing activation state into a preferred differentiated population of either Th1 or Th2 cells.
摘要翻译： 本发明涉及合成抗原呈递矩阵，其制备方法及其使用方法。 一种这样的基质是已被转染以产生具有一种或多种辅助分子的MHC抗原呈递分子的细胞。 这些基质用于激活幼稚的CD4 + T细胞，以及将正在进行的激活状态转移到Th1或Th2细胞的优选的分化群体中。
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公开(公告)号：US07402430B2
公开(公告)日：2008-07-22
申请号：US10903213
申请日：2004-07-29
CPC分类号： C07K14/70596 , A61K38/00 , A61K2039/5154 , A61K2039/5156 , C12N5/0601 , C12N2510/00 , Y10S424/81
摘要： The present invention relates to synthetic antigen-presenting matrices, their methods of making and their methods of use. One such matrix is cells that have been transfected to produce MHC antigen-presenting molecules with one or more accessory molecules. The matrices are used to activate naive CD4+ T cells as well as shift the ongoing activation state into a preferred differentiated population of either Th1 or Th2 cells.
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6.发明授权MHC class II antigen-presenting systems and methods for activating CD4+ T cells 有权MHC II类抗原呈递系统和激活CD4 + T细胞的方法公开(公告)号：US06355479B1
公开(公告)日：2002-03-12
申请号：US09194285
申请日：1999-04-12
IPC分类号： C12N510
CPC分类号： C07K14/70596 , A61K38/00 , A61K2039/5154 , A61K2039/5156 , C12N5/0601 , C12N2510/00 , Y10S424/81
摘要： The present invention relates to synthetic antigen-presenting matrices, their methods of making and their methods of use. One such matrix is cells that have been transfected to produce MHC antigen-presenting molecules with one or more accessory molecules. The matrices are used to activate naive CD4+ T cells as well as shift the ongoing activation state into a preferred differentiated population of either Th1 or Th2 cells.
摘要翻译： 本发明涉及合成抗原呈递矩阵，其制备方法及其使用方法。 一种这样的基质是已被转染以产生具有一种或多种辅助分子的MHC抗原呈递分子的细胞。 这些基质用于激活幼稚的CD4 + T细胞，并将正在进行的激活状态转移到Th1或Th2细胞的优选分化群体中。
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公开(公告)号：US6001365A
公开(公告)日：1999-12-14
申请号：US103486
申请日：1998-06-24
CPC分类号： A61K38/1774 , A61K2039/5154 , A61K2039/5156
摘要： The present invention relates to a rational, elegant means of producing, loading and using Class I molecules to specifically activate CD8 cells in vitro, and their therapeutic applications in the treatment of a variety of conditions, including cancer, tumors or neoplasias, as well as viral, retroviral, autoimmune, and autoimmune-type diseases. The present invention also relates to vectors, cell lines, recombinant DNA molecules encoding human .beta.2 microglobulin or Class I MHC molecules in soluble and insoluble form, and methods of producing same.
摘要翻译： 本发明涉及生产，加载和使用I类分子以体外特异性激活CD8细胞的合理，优雅的手段，以及它们在治疗各种病症（包括癌症，肿瘤或肿瘤）中的治疗应用，以及 病毒，逆转录病毒，自身免疫和自身免疫性疾病。 本发明还涉及可溶性和不溶形式的编码人β2微球蛋白或I类MHC分子的载体，细胞系，重组DNA分子及其生产方法。
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公开(公告)号：US08133728B2
公开(公告)日：2012-03-13
申请号：US12887052
申请日：2010-09-21
申请人： Zeling Cai , Michael R. Jackson , Per A. Peterson , Wei-Xing Shi , Yan Kong , Juli DeGraw
发明人： Zeling Cai , Michael R. Jackson , Per A. Peterson , Wei-Xing Shi , Yan Kong , Juli DeGraw
IPC分类号： C12N5/08
CPC分类号： A61K39/0008 , A61K2035/122 , C12N5/0636 , C12N2501/23 , C12N2501/51 , C12N2501/58 , C12N2502/50 , C12N2502/99
摘要： Cytotoxic T lymphocytes (CTLs) specific for antigenic peptides derived from IgE molecule can be generated in vitro by stimulating resting naive CD8 T cells with IgE peptides presented by artificial antigen presenting cells. The IgE specific CTLs lyse the target cells loaded with IgE peptides in vitro and inhibit antigen specific IgE response in vivo. In addition, adoptive transfer of the IgE specific CTL to an asthmatic mouse model can inhibit the development of lung inflammation and airway hypersensitivity. IgE specific CTL provides a treatment for allergic asthma and other IgE-mediated allergic diseases. Antigenic peptides identified from non-tumor self-antigens induce specific cytotoxic T lymphocyte (CTL) in vitro. The CTL induced by peptides identified from CD40L can kill activated CD4 T cells. In vitro generated CTL specific for CD40L inhibit CD4-dependent antibody responses of all isotypes in vivo. In contrast, CTL induced by antigenic peptides derived from IgE specifically inhibit IgE responses, and adoptive transfer of CD40L-specific CTL to NOD mice at early age delay the development of diabetes in NOD mice. In vitro generated CTL specific for non-tumor self-antigens expressed on activated CD4 T cells regulate immune responses in vivo.
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9.发明授权Ex-vivo priming for generating cytotoxic T lymphocytes specific for non-tumor antigens to treat autoimmune and allergic disease 有权用于产生特异于非肿瘤抗原的细胞毒性T淋巴细胞用于治疗自身免疫性和过敏性疾病的体外引发公开(公告)号：US08133726B2
公开(公告)日：2012-03-13
申请号：US12899069
申请日：2010-10-06
申请人： Zeling Cai , Michael R. Jackson , Per A. Peterson , Wei-Xing Shi , Yan Kong , Juli DeGraw
发明人： Zeling Cai , Michael R. Jackson , Per A. Peterson , Wei-Xing Shi , Yan Kong , Juli DeGraw
IPC分类号： C12N5/08
CPC分类号： A61K39/0008 , A61K2035/122 , C12N5/0636 , C12N2501/23 , C12N2501/51 , C12N2501/58 , C12N2502/50 , C12N2502/99
摘要： Cytotoxic T lymphocytes (CTLs) specific for antigenic peptides derived from IgE molecule can be generated in vitro by stimulating resting naive CD8 T cells with IgE peptides presented by artificial antigen presenting cells. The IgE specific CTLs lyse the target cells loaded with IgE peptides in vitro and inhibit antigen specific IgE response in vivo. In addition, adoptive transfer of the IgE specific CTL to an asthmatic mouse model can inhibit the development of lung inflammation and airway hypersensitivity. IgE specific CTL provides a treatment for allergic asthma and other IgE-mediated allergic diseases. Antigenic peptides identified from non-tumor self-antigens induce specific cytotoxic T lymphocyte (CTL) in vitro. The CTL induced by peptides identified from CD40L can kill activated CD4 T cells. In vitro generated CTL specific for CD40L inhibit CD4-dependent antibody responses of all isotypes in vivo. In contrast, CTL induced by antigenic peptides derived from IgE specifically inhibit IgE responses, and adoptive transfer of CD40L-specific CTL to NOD mice at early age delay the development of diabetes in NOD mice. In vitro generated CTL specific for non-tumor self-antigens expressed on activated CD4 T cells regulate immune responses in vivo.
摘要翻译： 可以通过用人造抗原呈递细胞呈递的IgE肽刺激静息幼稚CD8T细胞在体外产生来自IgE分子的抗原肽特异性的细胞毒性T淋巴细胞（CTL）。 IgE特异性CTL在体外裂解装载有IgE肽的靶细胞，并在体内抑制抗原特异性IgE反应。 此外，将IgE特异性CTL过继转移至哮喘小鼠模型可以抑制肺部炎症和气道超敏反应的发展。 IgE特异性CTL提供过敏性哮喘和其他IgE介导的过敏性疾病的治疗。 从非肿瘤自身抗原鉴定的抗原肽在体外诱导特异性细胞毒性T淋巴细胞（CTL）。 由CD40L鉴定的肽诱导的CTL可以杀死活化的CD4T细胞。 体外产生的CD40L特异性CTL可抑制体内所有同种型的CD4依赖性抗体反应。 相比之下，来自IgE的抗原肽诱导的CTL特异性抑制IgE应答，CD40L特异性CTL过早转移到NOD小鼠早期延迟NOD小鼠的糖尿病发展。 在活化的CD4T细胞上表达的非肿瘤自身抗原的体外产生的CTL调节体内的免疫应答。
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10.发明申请EX-VIVO PRIMING FOR GENERATING CYTOTOXIC T LYMPHOCYTES SPECIFIC FOR NON-TUMOR ANTIGENS TO TREAT AUTOIMMUNE AND ALLERGIC DISEASE 有权用于产生非特异性T淋巴细胞特异性免疫抑制剂用于治疗自身免疫和过敏性疾病的EX-VIVO PRIMING公开(公告)号：US20090202506A1
公开(公告)日：2009-08-13
申请号：US11935486
申请日：2007-11-06
申请人： Zeling Cai , Michael R. Jackson , Per A. Peterson , Wei-Xing Shi , Yan Kong , Juli DeGraw
发明人： Zeling Cai , Michael R. Jackson , Per A. Peterson , Wei-Xing Shi , Yan Kong , Juli DeGraw
CPC分类号： A61K39/0008 , A61K2035/122 , C12N5/0636 , C12N2501/23 , C12N2501/51 , C12N2501/58 , C12N2502/50 , C12N2502/99
摘要： Cytotoxic T lymphocytes (CTLs) specific for antigenic peptides derived from IgE molecule can be generated in vitro by stimulating resting naive CD8 T cells with IgE peptides presented by artificial antigen presenting cells. The IgE specific CTLs lyse the target cells loaded with IgE peptides in vitro and inhibit antigen specific IgE response in vivo. In addition, adoptive transfer of the IgE specific CTL to an asthmatic mouse model can inhibit the development of lung inflammation and airway hypersensitivity. IgE specific CTL provides a treatment for allergic asthma and other IgE-mediated allergic diseases. Antigenic peptides identified from non-tumor self-antigens induce specific cytotoxic T lymphocyte (CTL) in vitro. The CTL induced by peptides identified from CD40L can kill activated CD4 T cells. In vitro generated CTL specific for CD40L inhibit CD4-dependent antibody responses of all isotypes in vivo. In contrast, CTL induced by antigenic peptides derived from IgE specifically inhibit IgE responses, and adoptive transfer of CD40L-specific CTL to NOD mice at early age delay the development of diabetes in NOD mice. In vitro generated CTL specific for non-tumor self-antigens expressed on activated CD4 T cells regulate immune responses in vivo.
摘要翻译： 可以通过用人造抗原呈递细胞呈递的IgE肽刺激静息幼稚CD8T细胞在体外产生来自IgE分子的抗原肽特异性的细胞毒性T淋巴细胞（CTL）。 IgE特异性CTL在体外裂解装载有IgE肽的靶细胞，并在体内抑制抗原特异性IgE反应。 此外，将IgE特异性CTL过继转移至哮喘小鼠模型可以抑制肺部炎症和气道超敏反应的发展。 IgE特异性CTL提供过敏性哮喘和其他IgE介导的过敏性疾病的治疗。 从非肿瘤自身抗原鉴定的抗原肽在体外诱导特异性细胞毒性T淋巴细胞（CTL）。 由CD40L鉴定的肽诱导的CTL可以杀死活化的CD4T细胞。 体外产生的CD40L特异性CTL可抑制体内所有同种型的CD4依赖性抗体反应。 相比之下，来自IgE的抗原肽诱导的CTL特异性抑制IgE应答，CD40L特异性CTL过早转移到NOD小鼠早期延迟NOD小鼠的糖尿病发展。 在活化的CD4T细胞上表达的非肿瘤自身抗原的体外产生的CTL调节体内的免疫应答。
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