公开(公告)号：US20070248613A1

公开(公告)日：2007-10-25

申请号：US11628164

申请日：2005-05-31

申请人： John Shiver ,  Michael Miller ,  Romas Geleziunas ,  Daria Hazuda ,  Peter Kim ,  Debra Eckert ,  Michael Root ,  Simon Lennard ,  Elisabetta Bianchi

发明人： John Shiver ,  Michael Miller ,  Romas Geleziunas ,  Daria Hazuda ,  Peter Kim ,  Debra Eckert ,  Michael Root ,  Simon Lennard ,  Elisabetta Bianchi

IPC分类号： A61K39/395 ,  A61K33/00 ,  A61P31/18 ,  C07H21/04 ,  C07K16/00 ,  C12N15/00 ,  C12P21/06 ,  G01N33/566

CPC分类号： G01N33/56988 ,  C07K16/1063 ,  C07K2317/21 ,  C07K2317/622 ,  C07K2317/76 ,  G01N2500/00

摘要： Human scFvs are disclosed which interact with a conformational epitope along the pre-hairpin, N-helix coiled coil structure within the heptad repeat 1 (HR1) region of gp41 of HIV. These antibodies, as well as IgG conversions, are shown to neutralize diverse HIV isolates. Isolated nucleic acid molecules are also disclosed which encode relevant portions of these antibodies, as well as the purified forms of the expressed antibodies or relevant antibody fragments, such as VH and VL chains. The antibody compositions disclosed within this specification may provide for a therapeutic treatment against HIV infection by reducing viral load levels within an infected individual, thus prolonging the asymptomatic phase of HIV infection. These antibodies will also be useful in assays to identify HIV antiviral compounds as well as allowing for the identification of candidate HIV vaccines, such as HIV peptide vaccines.

摘要翻译： 披露了人scFv，其与艾滋病病毒gp41的七重复重复1（HR1）区域内的前发夹，N-螺旋卷曲螺旋结构与构象表位相互作用。 显示出这些抗体以及IgG转化中和多种HIV分离物。 还公开了分离的核酸分子，其编码这些抗体的相关部分，以及所表达的抗体或相关抗体片段的纯化形式，例如V H H和V L >链。 在本说明书中公开的抗体组合物可通过降低受感染个体内的病毒载量水平来提供抗HIV感染的治疗性治疗，从而延长HIV感染的无症状期。 这些抗体也可用于鉴定HIV抗病毒化合物的测定，以及允许鉴定候选的HIV疫苗，例如HIV肽疫苗。

公开(公告)号：US20060216272A1

公开(公告)日：2006-09-28

申请号：US10571651

申请日：2004-09-14

申请人： Emilio Emini ,  John Shiver ,  Danilo Casimiro ,  Daria Hazuda ,  William Scheilf

发明人： Emilio Emini ,  John Shiver ,  Danilo Casimiro ,  Daria Hazuda ,  William Scheilf

IPC分类号： A61K48/00

CPC分类号： A61K39/21 ,  A61K39/12 ,  A61K2039/53 ,  A61K2039/545 ,  A61K2039/55 ,  C07K14/005 ,  C12N7/00 ,  C12N15/86 ,  C12N2710/10343 ,  C12N2740/15022 ,  C12N2740/15034 ,  C12N2740/15071 ,  C12N2740/16134 ,  C12N2740/16222

摘要： The present invention provides an improved method for eliciting a therapeutic immune response in an individual infected with human immunodeficiency virus (“HIV”). The method comprises administering an adenoviral vaccine composition expressing an HIV antigen to an individual with controlled viremia. Immunization of infected individuals in this manner elicits a cellular-mediated immune response against the virus that is significant both in the level of the response and the breadth of the response. The therapeutic immune response that ensues is capable of effectively maintaining low titers of virus and, thus, offers the prospect of reducing individual dependency on antiviral therapy.

摘要翻译： 本发明提供了在感染人类免疫缺陷病毒（“HIV”）的个体中引发治疗性免疫应答的改进方法。 该方法包括向具有受控制的病毒血症的个体施用表达HIV抗原的腺病毒疫苗组合物。 以这种方式免疫感染的个体引起针对病毒的细胞介导的免疫应答，其在反应水平和反应的广度方面是显着的。 随后的治疗性免疫应答能够有效地维持低滴度的病毒，从而提供减少个体对抗病毒治疗依赖性的前景。

公开(公告)号：US20080063656A1

公开(公告)日：2008-03-13

申请号：US11659671

申请日：2005-08-05

申请人： Emilio Emini ,  John Shiver ,  Danilo Casimiro ,  Andrew Bett

发明人： Emilio Emini ,  John Shiver ,  Danilo Casimiro ,  Andrew Bett

IPC分类号： A61K31/70 ,  A61K35/00 ,  A61K39/00 ,  A61P43/00 ,  C12N15/00 ,  C12N7/00

CPC分类号： C12N15/86 ,  A61K39/12 ,  A61K39/21 ,  A61K48/00 ,  A61K48/0083 ,  A61K2039/53 ,  A61K2039/545 ,  A61K2039/57 ,  C07K14/005 ,  C12N7/00 ,  C12N2710/10343 ,  C12N2740/16134 ,  C12N2740/16334

摘要： Applicants disclose herein novel methods, vectors, and vector compositions for improving the efficiency of adenoviral vectors in the delivery and expression of heterologous nucleic acid encoding a polypeptide(s) (e.g, a protein or antigen) of interest. Adenoviral infection is quite common in the general population, and a large percentage of people have neutralizing antibodies to the more prevalent adenoviral serotypes. Such pre-existing anti-adenoviral immunity can dampen or possibly abrogate the effectiveness of this virus for the delivery and expression of heterologous proteins or antigens. The method taught herein functions to offset pre-existing immunity through the delivery of the protein or antigen by a cocktail of at least two adenoviral serotypes. Utilizing a composition of at least two adenoviral serotypes in this manner has been found to increase the effectiveness of adenoviral administration. Adenoviral vectors of utility in the elicitation of an immune response against Human Immunodeficiency Virus (“HIV”) are also disclosed.

摘要翻译： 申请人在此公开了新颖的方法，载体和载体组合物，用于提高编码感兴趣的多肽（例如，蛋白质或抗原）的异源核酸的递送和表达中腺病毒载体的效率。 腺病毒感染在普通人群中相当普遍，并且大部分人群对更普遍的腺病毒血清型具有中和抗体。 这种预先存在的抗腺病毒免疫可以抑制或可能地消除该病毒用于递送和表达异源蛋白质或抗原的有效性。 本文教导的方法通过至少两种腺病毒血清型的混合物通过递送蛋白质或抗原来抵消预先存在的免疫力。 已经发现以这种方式利用至少两种腺病毒血清型的组合物来增加腺病毒给药的有效性。 还公开了针对人类免疫缺陷病毒（“HIV”）免疫应答的效用的腺病毒载体。

公开(公告)号：US20070077257A1

公开(公告)日：2007-04-05

申请号：US11604553

申请日：2006-11-27

申请人： Emilio Emini ,  Rima Youil ,  Andrew Bett ,  Ling Chen ,  David Kaslow ,  John Shiver ,  Timothy Toner ,  Danilo Casimiro

发明人： Emilio Emini ,  Rima Youil ,  Andrew Bett ,  Ling Chen ,  David Kaslow ,  John Shiver ,  Timothy Toner ,  Danilo Casimiro

IPC分类号： A61K39/00 ,  A61K39/12

CPC分类号： A61K39/21 ,  A61K39/12 ,  A61K2039/5256 ,  A61K2039/53 ,  A61K2039/545 ,  A61K2039/55555 ,  C07K14/005 ,  C12N7/00 ,  C12N2710/10343 ,  C12N2710/10351 ,  C12N2740/16222 ,  C12N2740/16234 ,  C12N2740/16322 ,  C12N2740/16334

摘要： First generation adenoviral vectors and-recombinant adenovirus-based HIV vaccines which contain HIV-1 gag, HIV-1 pol and/or HIV-1 nef polynucleotide pharmaceutical products, and biologically relevant modifications thereof are described. The adenovirus vaccines, when directly introduced into living vertebrate tissue, express the relevant proteins, inducing a cellular immune response which specifically recognizes HIV-1. The exemplified polynucleotides of the present invention are synthetic DNA molecules encoding HIV-1 Gag, HIV-1 Pol, HIV-1 Nef, and derivatives thereof. The adenoviral vaccines of the present invention, alone or in combination, will offer a prophylactic advantage to previously uninfected individuals and/or provide a therapeutic effect by reducing viral load levels within an infected individual, thus prolonging the asymptomatic phase of HIV-1 infection.

摘要翻译： 描述了含有HIV-1 gag，HIV-1 pol和/或HIV-1 nef多核苷酸药物产品的第一代腺病毒载体和基于重组腺病毒的HIV疫苗及其生物学相关的修饰。 当直接引入活的脊椎动物组织中时，腺病毒疫苗表达相关蛋白质，诱导特异性识别HIV-1的细胞免疫应答。 本发明的示例性多核苷酸是编码HIV-1Gag，HIV-1 Pol，HIV-1 Nef的合成DNA分子及其衍生物。 本发明的单独或组合的腺病毒疫苗将对先前未感染的个体提供预防优势，和/或通过减少感染个体内的病毒载量水平提供治疗效果，从而延长HIV-1感染的无症状期。

公开(公告)号：US20060148750A1

公开(公告)日：2006-07-06

申请号：US11345127

申请日：2006-02-01

申请人： John Shiver ,  Helen Perry ,  Danilo Casimiro ,  Tong-Ming Fu

发明人： John Shiver ,  Helen Perry ,  Danilo Casimiro ,  Tong-Ming Fu

IPC分类号： A61K48/00

CPC分类号： C07K14/005 ,  A61K2039/53 ,  C07H21/02 ,  C12N2740/16222 ,  C12N2740/16234 ,  C12N2800/22

摘要： Pharmaceutical compositions which comprise HIV Pol DNA vaccines are disclosed, along with the production and use of these DNA vaccines. The pol-based DNA vaccines of the invention are administered directly introduced into living vertebrate tissue, preferably humans, and preferably express inactivated versions of the HIV Pol protein devoid of protease, reverse transcriptase activity, RNase H activity and integrase activity, inducing a cellular immune response which specifically recognizes human immunodeficiency virus-1 (HIV-1). The DNA molecules which comprise the open reading frame of these DNA vaccines are synthetic DNA molecules encoding codon optimized HIV-1 Pol and codon optimized inactive derivatives of optimized HIV-1 Pol, including DNA molecules which encode inactive Pol proteins which comprise an amino terminal leader peptide.

摘要翻译： 公开了包含HIV Pol DNA疫苗的药物组合物以及这些DNA疫苗的生产和使用。 将本发明的基于pol的DNA疫苗直接施用于活的脊椎动物组织，优选人，并且优选表达不含蛋白酶的HIV Pol蛋白，逆转录酶活性，RNase H活性和整合酶活性的失活形式，诱导细胞免疫 具体承认人体免疫缺陷病毒-1（HIV-1）的反应。 构成这些DNA疫苗的开放阅读框架的DNA分子是编码经优化的HIV-1 Pol的密码子优化的HIV-1 Pol和密码子优化的非活性衍生物的合成DNA分子，其包括编码无效Pol蛋白的DNA分子，其包含氨基末端引物 肽。

公开(公告)号：US20050106123A1

公开(公告)日：2005-05-19

申请号：US10507098

申请日：2003-03-12

申请人： Emilio Emini ,  John Shiver ,  Michael Chastain ,  Danilo Casimiro ,  Tong-Ming Fu ,  Xiaoping Liang

发明人： Emilio Emini ,  John Shiver ,  Michael Chastain ,  Danilo Casimiro ,  Tong-Ming Fu ,  Xiaoping Liang

IPC分类号： A61K39/00 ,  A61K39/21 ,  C07K14/16 ,  C12N15/861 ,  C12N15/863 ,  A61K48/00 ,  A61K39/12 ,  C12N15/867

CPC分类号： C12N15/86 ,  A61K39/12 ,  A61K39/21 ,  A61K2039/5256 ,  A61K2039/545 ,  C07K14/005 ,  C12N2710/10343 ,  C12N2710/24043 ,  C12N2710/24143 ,  C12N2740/15034 ,  C12N2740/16122 ,  C12N2740/16134 ,  C12N2740/16234 ,  C12N2830/42

摘要： An efficient means of inducing an immune response against human immunodeficiency virus (“HIV”) utilizing specific prime-boost regimes is disclosed. The specific prime-boost regimes employ a heterologous prime-boost protocol wherein recombinant adenoviral and poxvirus vectors comprising exogenous genetic material encoding a common HIV antigen are administered in that order. Vaccines administered into living vertebrate tissue in accordance with the disclosed regimes, preferably a mammalian host such as a human or a non-human mammal of commercial or domestic veterinary importance, express the HIV-1 antigen (e.g., Gag), inducing a cellular immune response which specifically recognizes HIV-1. It is believed that the disclosed prime/boost regime will offer a prophylactic advantage to previously uninfected individuals and/or provide a therapeutic effect by reducing viral load levels within an infected individual, thus prolonging the asymptomatic phase of HIV-1 infection.

摘要翻译： 公开了一种利用特定初始 - 加强方式诱导针对人类免疫缺陷病毒（“HIV”）的免疫应答的有效手段。 特异性初始 - 加强方案采用异源初始 - 加强方案，其中包含编码常见HIV抗原的外源遗传物质的重组腺病毒和痘病毒载体以该顺序施用。 根据所公开的方案，优选哺乳动物宿主例如商业或家庭兽医重要的人或非人哺乳动物施用于活的脊椎动物组织的疫苗表达HIV-1抗原（例如，Gag），诱导细胞免疫 专门承认艾滋病毒1的反应。 相信所公开的主要/加强方案将对先前未感染的个体提供预防优势，和/或通过减少感染个体内的病毒载量水平提供治疗效果，从而延长HIV-1感染的无症状期。

公开(公告)号：US20070054395A1

公开(公告)日：2007-03-08

申请号：US11599584

申请日：2006-11-13

申请人： Emilio Emini ,  Rima Youil ,  Andrew Bett ,  Ling Chen ,  David Kaslow ,  John Shiver ,  Timothy Toner ,  Danilo Casimiro

发明人： Emilio Emini ,  Rima Youil ,  Andrew Bett ,  Ling Chen ,  David Kaslow ,  John Shiver ,  Timothy Toner ,  Danilo Casimiro

IPC分类号： C12Q1/68 ,  C12N15/00

CPC分类号： C12N15/86 ,  A61K39/12 ,  A61K39/21 ,  A61K2039/5256 ,  A61K2039/53 ,  A61K2039/545 ,  A61K2039/55555 ,  A61K2039/57 ,  C07K14/005 ,  C12N7/00 ,  C12N15/63 ,  C12N2710/10343 ,  C12N2710/10351 ,  C12N2740/16122 ,  C12N2740/16134 ,  C12N2740/16222 ,  C12N2740/16234 ,  C12N2740/16322 ,  C12N2740/16334 ,  C12N2830/42

摘要： First generation adenoviral vectors and associated recombinant adenovirus-based HIV vaccines which show enhanced stability and growth properties and greater cellular-mediated immunity are described within this specification. These adenoviral vectors are utilized to generate and produce through cell culture various adenoviral-based HIV-1 vaccines which contain HIV-1 gag, HIV-1 pol and/or HIV-1 nef polynucleotide pharmaceutical products, and biologically relevant modifications thereof. These adenovirus vaccines, when directly introduced into living vertebrate tissue, preferably a mammalian host such as a human or a non-human mammal of commercial or domestic veterinary importance, express the HIV1-Gag, Pol and/or Nef protein or biologically modification thereof, inducing a cellular immune response which specifically recognizes HIV-1. The exemplified polynucleotides of the present invention are synthetic DNA molecules encoding HIV-1 Gag, encoding codon optimized HIV-1 Pol, derivatives of optimized HIV-1 Pol (including constructs wherein protease, reverse transcriptase, RNAse H and integrase activity of HIV-1 Pol is inactivated), HIV-1 Nef and derivatives of optimized HIV-1 Nef, including nef mutants which effect wild type characteristics of Nef, such as myristylation and down regulation of host CD4. The adenoviral vaccines of the present invention, when administered alone or in a combined modality regime, will offer a prophylactic advantage to previously uninfected individuals and/or provide a therapeutic effect by reducing viral load levels within an infected individual, thus prolonging the asymptomatic phase of HIV-1 infection.

摘要翻译： 在本说明书中描述了显示增强的稳定性和生长特性以及更大的细胞介导的免疫的第一代腺病毒载体和相关重组腺病毒的HIV疫苗。 这些腺病毒载体用于通过细胞培养产生和产生各种含有HIV-1 gag，HIV-1 pol和/或HIV-1 nef多核苷酸药物产品的基于腺病毒的HIV-1疫苗及其生物相关的修饰。 这些腺病毒疫苗当直接引入活的脊椎动物组织中时，优选哺乳动物宿主例如具有商业或家庭兽医重要性的人或非人哺乳动物，表达HIV1-Gag，Pol和/或Nef蛋白或其生物修饰， 诱导特异性识别HIV-1的细胞免疫应答。 本发明的示例性多核苷酸是编码HIV-1Gag的编码密码子优化的HIV-1 Pol的合成DNA分子，其优化的HIV-1 Pol的衍生物（包括其中蛋白酶，逆转录酶，RNAse H和HIV-1的整合酶活性 Pol被灭活），HIV-1 Nef和优化的HIV-1 Nef的衍生物，包括影响Nef野生型特征的nef突变体，如主体CD4的肉豆蔻酰化和下调。 本发明的腺病毒疫苗当单独施用或以组合的方式给药时，将对先前未感染的个体提供预防优势，和/或通过减少被感染个体内的病毒载量水平提供治疗效果，从而延长无症状期 HIV-1感染。

公开(公告)号：US20050215508A1

公开(公告)日：2005-09-29

申请号：US11081244

申请日：2005-03-16

申请人： John Shiver ,  Xiaoping Liang ,  Tong-Ming Fu

发明人： John Shiver ,  Xiaoping Liang ,  Tong-Ming Fu

IPC分类号： A61K48/00 ,  C07K14/16

CPC分类号： C07K14/005 ,  A61K2039/53 ,  C12N2740/16322

摘要： Pharmaceutical compositions which comprise HIV Nef DNA vaccines are disclosed, along with the production and use of these DNA vaccines. The nef-based DNA vaccines of the invention are administered directly introduced into living vertebrate tissue, preferably humans, and express the HIV Nef protein or biologically relevant portions thereof, inducing a cellular immune response which specifically recognizes human immunodeficiency virus-1 (HIV-1). The DNA molecules which comprise the open reading frame of these DNA vaccines are synthetic DNA molecules encoding codon optimized HIV-1 Nef and derivatives of optimized HIV-1 Nef, including nef modifications comprising amino terminal leader peptides, removal of the amino terminal myristylation site, and/or modification of the Nef dileucine motif. These modifications may effect wild type characteristics of Nef, such as myristylation and down regulation of host CD4.

摘要翻译： 公开了包含HIV Nef DNA疫苗的药物组合物以及这些DNA疫苗的生产和使用。 将本发明的基于nef的DNA疫苗直接施用于活的脊椎动物组织，优选人，并且表达HIV Nef蛋白或其生物相关部分，诱导特异性识别人免疫缺陷病毒-1（HIV-1 ）。 构成这些DNA疫苗的开放阅读框架的DNA分子是编码密码子优化的HIV-1 Nef和优化的HIV-1 Nef的衍生物的合成DNA分子，包括包含氨基末端前导肽的nef修饰，氨基末端的肉豆蔻酰化位点的去除， 和/或Nef二氨基酸基序的修饰。 这些修饰可能会影响Nef的野生型特征，如主要病毒的肉豆蔻酰化和下调。

公开(公告)号：US20060165664A1

公开(公告)日：2006-07-27

申请号：US10507237

申请日：2003-03-12

申请人： Emilio Emini ,  John Shiver ,  Danilo Casimiro ,  Andrew Bett ,  Xiaoping Liang ,  Tong-Ming Fu

发明人： Emilio Emini ,  John Shiver ,  Danilo Casimiro ,  Andrew Bett ,  Xiaoping Liang ,  Tong-Ming Fu

IPC分类号： A61K48/00 ,  A61K39/21

CPC分类号： C12N15/86 ,  A61K39/12 ,  A61K39/21 ,  A61K2039/5256 ,  A61K2039/545 ,  C07K14/005 ,  C12N2710/10343 ,  C12N2740/16122 ,  C12N2740/16134 ,  C12N2740/16234 ,  C12N2740/16322 ,  C12N2740/16334 ,  C12N2830/42

摘要： An efficient means of inducing an immune response against human immunodeficiency virus (HIV) utilizing specific prime-boost regimes is disclosed. The specific prime-boost regimes employ a heterologous prime-boost protocol employing recombinant adenoviral vectors of alternative and distinct serotypes comprising exogenous genetic material encoding a common HIV antigen. Vaccines administered into living vertebrate tissue in accordance with the disclosed regimes, preferably a mammalian host, such as a human or a non-human mammal of commercial or domestic veterinary importance, express the HIV-1 antigen (e.g., Gag), inducing a cellular immune response which specifically recognizes HIV-1. It is believed that the disclosed prime/boost regime will offer a prophylactic advantage to previously uninfected individuals and/or provide a therapeutic effect by reducing viral load levels within an infected individual, thus prolonging the asymptomatic phase of HIV-1 infection.

摘要翻译： 公开了一种利用特定初始 - 加强方案诱导针对人类免疫缺陷病毒（HIV）的免疫应答的有效手段。 特定的初始 - 加强方案采用异源初始 - 加强方案，其使用包含编码常见HIV抗原的外源遗传物质的替代和不同血清型的重组腺病毒载体。 根据所公开的方案，优选哺乳动物宿主，如商业或家畜兽医学重要的人或非人哺乳动物施用于活的脊椎动物组织中的疫苗表达HIV-1抗原（例如，Gag），诱导细胞 特异性识别HIV-1的免疫反应。 相信所公开的主要/加强方案将对先前未感染的个体提供预防优势，和/或通过减少感染个体内的病毒载量水平提供治疗效果，从而延长HIV-1感染的无症状期。

公开(公告)号：US20060018881A1

公开(公告)日：2006-01-26

申请号：US11115425

申请日：2005-04-27

申请人： Margaret Liu ,  John Shiver ,  Helen Perry

发明人： Margaret Liu ,  John Shiver ,  Helen Perry

IPC分类号： C12N15/867 ,  A61K48/00

CPC分类号： C07K14/005 ,  A61K39/00 ,  A61K48/00 ,  C12N15/85 ,  C12N2740/16122 ,  C12N2740/16222 ,  C12N2830/50 ,  C12N2840/203 ,  C12N2840/44 ,  Y02A50/464

摘要： Nucleic acids, including DNA constructs and RNA transcripts, capable of inducing coordinate expression of two to three cistrons upon direct introduction into animal tissues, are. bi- or tri-cistronic polynucleotides of this invention include those encoding and co-expressing HIV gene products, genes encoding antigens unrelated to HIV, and immunostimulatory gene products, including but not limited to GM-CSF, interleukins, interferon and members of the B7 family of proteins which act as T-cell costimulatory elements. The methods and polynucleotides of this invention are generally applicable to co-ordinate expression in vivo of any two or more genes in a single cell.

摘要翻译： 包括DNA构建体和RNA转录物在内的直接引入到动物组织中的能够诱导2至3个顺反子的配位表达的核酸是。 本发明的双或三顺反子多核苷酸包括编码和共表达HIV基因产物的那些，编码与HIV无关的抗原的基因和免疫刺激基因产物，包括但不限于GM-CSF，白细胞介素，干扰素和B7的成员 作为T细胞共刺激因子的蛋白家族。 本发明的方法和多核苷酸通常可用于在单个细胞中统计任何两个或更多个基因的体内表达。