ApoVax104-HPV as a Novel Vaccine for Cervical Cancer

ApoVax104-HPV 作为宫颈癌新型疫苗

• 批准号: 7538190
• 负责人: Kathryn J MacLeod
• 金额: $ 91.94万
• 依托单位: APOVAX, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-31 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7538190
• 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 Virus; 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; Numbers; Oligonucleotides; Oncogene Proteins; Oncogenes; Papillomavirus; Peptides; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Preparation; Procedures; Process; Production; Protein Isoforms; Proteins; Public Health; Purpose; Quality Control; Range; Recombinant Proteins; Role; Safety; Signal Transduction; Small Business Funding Mechanisms; 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; Woman; Work; base; cancer therapy; cancer type; crosslink; design; in vivo; interest; killings; long term memory; manufacturing process; member; monophosphoryl lipid A; novel; novel therapeutics; novel vaccines; preclinical study; prevent; protein purification; quality assurance; receptor; research study; response; success; synthetic peptide; therapeutic vaccine; tumor; uptake; vaccine development; vaccinology

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（由申请人提供）：宫颈癌是影响女性的最常见癌症之一，是一个全球性的健康问题。与大多数癌症不同，宫颈癌是由病毒引起的-人乳头瘤病毒（HPV）。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Cervarix（tm）疫苗。虽然这两种疫苗似乎都能有效预防女性HPV感染，但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，全球有2000万人感染HPV，宫颈癌是癌症死亡的第三大原因，每年约有50万妇女受到影响。因此，仍然需要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，部分原因是进展性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应答和/或增强现有免疫应答的能力，而且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）的治疗性疫苗代表了一种有吸引力的方法，因为它们的实用性以及靶向广泛的癌症类型。然而，TAA的弱抗原性与癌症患者中可能的免疫耐受和逃避机制相结合，提出了需要有效佐剂以实现治疗功效的主要障碍。 为了克服这些障碍，ApoImmune已经开发了一种专有的新型HPV疫苗ApoVax 104-HPV，其构成i）含有与核心链霉亲和素（ApoVax 104）的C-末端融合的共刺激4-1BBL的胞外结构域的嵌合分子，和ii）生物素化的HPV 16 E7癌蛋白作为通过生物素/链霉亲和素相互作用与嵌合蛋白缀合的TAA。在I期SBIR应用中，我们证明了疫苗的ApoVax 104组分i）将缀合的抗原靶向组成型表达4-1BB受体的树突状细胞（DC）中，并激活DC进行抗原摄取和呈递，从而引发适应性免疫，ii）直接作用于CD 4+和CD 8 + T效应（Teff）细胞，进一步增强适应性免疫，最重要的是iiii）克服了CD 4 + CD 25 + FoxP 3 + T调节（Treg）细胞的抑制功能。因此，4-1BBL对先天性、适应性和调节性免疫的多效性作用提供了优于正在开发或临床环境中的其他疫苗方法的独特优势。我们在I期SBIR研究中获得的强有力的数据支持了这一观点，表明用ApoVax 104与代表HPV E7癌基因（E749-57）的主导CD 8 + T细胞表位的合成肽接种疫苗比3种基准佐剂更有效（脂多糖（LPS）、单磷酰脂质A（MPL）和CpG寡核苷酸（CpG），在产生原发性和长期T细胞记忆以及根除已建立的表达E7的TC-1肿瘤方面。此外，与目前正在进行癌症临床试验的针对4-1BB受体的激动性Ab相比，用ApoVax 104接种导致更好的功效和不可检测的毒性。在I期获得的这些强有力的临床前研究的基础上，该II期SBIR申请的目标是开发含有全长HPV 16 E6和E7癌蛋白的人源化ApoVax 104-HPV疫苗，以符合美国食品药品监督管理局（FDA）对I期临床试验的要求。 公共卫生相关性：与大多数癌症不同，宫颈癌是由病毒--人乳头瘤病毒（HPV）引起的。宫颈癌是影响妇女的最常见癌症之一，是一个世界性的健康问题。据估计，全球有2000万人感染HPV，宫颈癌是癌症死亡的第三大原因，每年约有50万妇女受到影响。该项目的总体目标是将治疗性宫颈癌疫苗ApoVax 104-HPV开发成领先的商业产品，以进行I期临床试验。