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ApoVax104-HPV as a Novel Vaccine for Cervical Cancer

ApoVax104-HPV 作为宫颈癌新型疫苗

基本信息

批准号：
7665531
负责人：
Kathryn J MacLeod
金额：
$ 85.24万
依托单位：
APOVAX, INC.
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-31 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7665531
关键词：
Adjuvant Affect Agonist Animals Antigens B-Lymphocytes Benchmarking Binding Biotechnology Biotin C57BL/6 Mouse CD4 Positive T Lymphocytes CD8B1 gene Cancer Etiology Cancer Patient Cancer Vaccines Cell Line Cell physiology Cells Cervarix Cervical cancer vaccine Cessation of life Chimeric Proteins Clinical Clinical Trials Conjugate Vaccines Data Dendritic Cells Development Disease Documentation Dose Drug Formulations Effector Cell Epitopes Extracellular Domain Failure Figs - dietary Gardasil Generations Goals Grant Guidelines Health Homologous Gene Human Human Papilloma Virus Vaccine Human Papillomavirus Human papilloma virus infection Human papillomavirus 16 Immune Immune Tolerance Immune response Immunity Immunosuppressive Agents Immunotherapeutic agent Immunotherapy Lead Length Licensing Ligands Lipopolysaccharides Malignant Neoplasms Malignant neoplasm of cervix uteri Modeling Molecular Monitor Mus Nature Oligonucleotides Oncogene Proteins Oncogenes Peptides Phase Phase I Clinical Trials Phase II Clinical Trials Preparation Procedures Process Production Protein Isoforms Proteins Quality Control Recombinant Proteins Role Signal Transduction Small Business Innovation Research Grant Specificity Staining method Stains Streptavidin T memory cell T-Lymphocyte T-Lymphocyte Epitopes Technology Testing Therapeutic Toxic effect Toxicology Treatment Efficacy Treatment Protocols Tumor Antigens Tumor Necrosis Factor Receptor United States United States Food and Drug Administration Vaccinated Vaccination Vaccines Validation Virus Woman Work base cancer therapy cancer type clinical material combat crosslink design efficacy testing in vivo interest killings long term memory manufacturing process member monophosphoryl lipid A novel novel therapeutics novel vaccines preclinical study prevent protein purification public health relevance quality assurance receptor research study response safety study success synthetic peptide therapeutic development therapeutic vaccine tumor uptake vaccine development vaccinology

项目摘要

DESCRIPTION (provided by applicant): Cervical cancer is one of the most common cancers affecting women and is a worldwide health problem. Unlike most cancers, cervical cancer is caused by a virus - the human papillomavirus (HPV). Two preventative vaccines against HPV were recently licensed in the United States. Merck & Co. developed a vaccine called Gardasil(tm) and GlaxoSmithKline has developed the vaccine Cervarix(tm). Although both appear to be effective at preventing HPV infection in women, neither vaccine protects women already infected with HPV from developing cancer or afflicted with the disease. An estimated 20 million people are infected with HPV and worldwide, cervical cancer is the third leading cause of cancer death affecting an estimated 500,000 women each year. Consequently, a therapeutic approach is still necessary to combat already existing HPV infection and cervical cancer. Regardless of significant advances in vaccinology, the therapeutic potential of cancer vaccines remains to be realized, partly due to an array of evasive and immunosuppressive mechanisms employed by progressing tumors4. Therefore, the success of therapeutic vaccines is not only contingent upon their ability to generate new immune responses and/or boost the existing ones, but also to overcome immune evasion mechanisms. Therapeutic vaccines based on well-defined universal tumor associated antigens (TAAs) represent an attractive approach because of their practicality as well as targeting broad range of cancer types. However, the weak antigenic nature of TAAs combined with possible immune tolerance and evasion mechanisms in cancer patients present major hurdles that require potent adjuvants to achieve therapeutic efficacy. To overcome these obstacles, ApoImmune has developed a proprietary novel HPV vaccine, ApoVax104-HPV, that constitutes i) a chimeric molecule containing the extracellular domain of costimulatory 4-1BBL fused C-terminus to core streptavidin (ApoVax104), and ii) biotinylated HPV 16 E7 oncoprotein as a TAA conjugated to the chimeric protein via biotin/streptavidin interaction. In the Phase I SBIR application, we demonstrated that ApoVax104 component of the vaccine i) targets conjugated antigens into dendritic cells (DCs) constitutively expressing the 4-1BB receptor and activates DCs for antigen uptake and presentation, leading to initiation of adaptive immunity, ii) directly works on CD4+ and CD8+ T effector (Teff) cells further augmenting adaptive immunity, and most importantly iiii) overcomes the suppressive function of CD4+CD25+FoxP3+ T regulatory (Treg) cells. Therefore, the pleiotropic effects of 4-1BBL on innate, adaptive, and regulatory immunity provides a unique advantage over other vaccine approaches under development or in clinical settings. This notion is supported by our strong data obtained during Phase I SBIR studies demonstrating that vaccination with ApoVax104 with a synthetic peptide representing the dominant CD8+ T cell epitope for HPV E7 oncogene (E749-57) was more effective than 3 benchmark adjuvants (lipopolysaccharide, (LPS), Monophosphoryl Lipid A (MPL), and CpG oligonucleotide (CpG), in the generation of primary and long- term T cell memory as well as in the eradication of established E7-expressing TC-1 tumors. In addition, vaccination with ApoVax104 resulted in better efficacy and undetectable toxicity as compared an agonistic Ab against 4-1BB receptor, currently being pursued for cancer clinical trials. Building on these strong preclinical studies obtained from Phase I, the goal of this Phase II SBIR application is to develop a humanized ApoVax104-HPV vaccine containing full length HPV16 E6 and E7 oncoproteins to conform to the requirements of the Food and Drug Administration (FDA) for Phase I clinical trials. PUBLIC HEALTH RELEVANCE: Unlike most cancers, cervical cancer is caused by a virus - the human papillomavirus (HPV). Cervical cancer is one of the most common cancers affecting women and is a worldwide health problem. An estimated 20 million people are infected with HPV and worldwide, cervical cancer is the third leading cause of cancer death affecting an estimated 500,000 women each year. The overall goal of this project is to develop a therapeutic cervical cancer vaccine, ApoVax104-HPV, into a lead commercial product to test in a Phase I clinical trial.

描述(申请人提供)：宫颈癌是影响女性的最常见的癌症之一，是一个世界性的健康问题。与大多数癌症不同，宫颈癌是由一种病毒--人乳头瘤病毒(HPV)引起的。两种针对HPV的预防性疫苗最近在美国获得许可。默克公司开发了一种名为Gardasil(Tm)的疫苗，葛兰素史克公司开发了Cervarx(Tm)疫苗。尽管这两种疫苗似乎都能有效预防女性感染HPV，但这两种疫苗都不能保护已经感染HPV的女性免受癌症或疾病的困扰。据估计，有2000万人感染了HPV，在全球范围内，宫颈癌是癌症死亡的第三大原因，每年影响约50万女性。因此，仍然需要一种治疗方法来对抗已经存在的HPV感染和宫颈癌。尽管疫苗学取得了重大进展，但癌症疫苗的治疗潜力仍有待实现，部分原因是进展中的肿瘤采用了一系列逃避和免疫抑制机制4。因此，治疗性疫苗的成功不仅取决于它们产生新的免疫反应和/或增强现有免疫反应的能力，而且还取决于它们克服免疫逃避机制的能力。基于明确定义的通用肿瘤相关抗原(TAA)的治疗性疫苗因其实用性以及针对广泛的癌症类型而成为一种有吸引力的方法。然而，TAAs的弱抗原性以及癌症患者可能的免疫耐受和逃避机制构成了主要障碍，需要强大的佐剂才能达到治疗效果。为了克服这些障碍，ApoImmune开发了一种新型HPV疫苗ApoVax104-HPV，它包括：1)含有共刺激4-1BBL胞外区的嵌合分子，融合到核心链霉亲和素(ApoVax104)上；2)生物素化的HPV16 E7癌蛋白作为TAA通过生物素/链霉亲和素相互作用连接到嵌合蛋白上。在第一阶段的SBIR应用中，我们证明了疫苗的ApoVax104组分针对结合的抗原进入树突状细胞(DC)，组成地表达4-1BB受体并激活树突状细胞(DCs)进行抗原摄取和递呈，从而启动获得性免疫，ii)直接作用于CD4+和CD8+T效应(TEF)细胞进一步增强适应性免疫，最重要的是iiii)克服了CD4+CD25+FoxP3+T调节(Treg)细胞的抑制功能。因此，4-1BBL在天然免疫、适应性免疫和调节性免疫方面的多效性作用提供了比其他正在开发或临床环境中的疫苗方法独特的优势。这一观点得到了我们在第一阶段SBIR研究中获得的强有力数据的支持，这些数据表明，用代表HPV E7癌基因主要CD8+T细胞表位的合成肽(E749-57)接种ApoVax104疫苗在产生原代和长期T细胞记忆以及根除已建立的E7表达的TC-1肿瘤方面比3种基准佐剂(脂多糖、单磷脂A(MPL)和CpG寡核苷酸(CpG))更有效。此外，与针对4-1BB受体的激动型抗体相比，ApoVax104疫苗具有更好的疗效和不可检测的毒性，目前正在进行癌症临床试验。在第一阶段获得的这些强有力的临床前研究的基础上，这项第二阶段SBIR应用的目标是开发一种人源化ApoVax104-HPV疫苗，该疫苗包含全长HPV16E6和E7癌蛋白，以符合美国食品和药物管理局(FDA)对第一阶段临床试验的要求。与公共卫生相关：与大多数癌症不同，宫颈癌是由一种病毒--人乳头瘤病毒(HPV)引起的。宫颈癌是影响女性的最常见癌症之一，是一个世界性的健康问题。据估计，有2000万人感染了HPV，在全球范围内，宫颈癌是癌症死亡的第三大原因，每年影响约50万女性。该项目的总体目标是将一种治疗性宫颈癌疫苗ApoVax104-HPV开发成领先的商业产品，在I期临床试验中进行测试。