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Development of an anti-PSA IgE to treat prostate cancer

开发抗 PSA IgE 来治疗前列腺癌

基本信息

批准号：
7608973
负责人：
MANUEL L PENICHET
金额：
$ 15.89万
依托单位：
ADVANCED IMMUNE THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-01 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7608973
关键词：
Ablation Accounting Acute Address Affinity African American American Androgens Animal Model Antibodies Antibody Formation Antigen Presentation Antigen-Antibody Complex Antigen-Presenting Cells Antigens Autologous B-Lymphocytes Binding Biochemical Biological Blood Circulation CD4 Positive T Lymphocytes CD8B1 gene Cancer Etiology Cancer Immunology Science Cell Degranulation Cell Line Cells Cessation of life Clinical Trials Complementary DNA Complex Confocal Microscopy Couples DNA Death Rate Dendritic Cells Development Disease Early Diagnosis Enzyme-Linked Immunosorbent Assay Epitopes Fc Receptor Flow Cytometry Foundations Goals Helper-Inducer T-Lymphocyte Hormones Human Hypersensitivity IgE IgG1 Immediate hypersensitivity Immune Immune response Immunoglobulin Constant Region Immunoglobulin Variable Region Immunohistochemistry In Vitro Incidence Inflammation Interferons Interleukin-4 Interleukin-5 LNCaP Light MHC Class I Genes Malignant Neoplasms Malignant neoplasm of prostate Mediating Medical Modality Modeling Monoclonal Antibodies Multiple Myeloma Mus Pathway interactions Patients Phagocytosis Phase Physiologic pulse Process Production Productivity Property Prostate Prostate-Specific Antigen Radiation therapy Reaction Refractory Research Design Second Primary Cancers Source Specificity Staging Staining method Stains Survival Rate Suspension substance Suspensions System T-Lymphocyte Testing Therapeutic Transgenic Mice Tumor Antigens Western Blotting Work anti-IgE antibody engineering antibody-dependent cell cytotoxicity antigen binding antigen processing base cancer cell cancer diagnosis cancer therapy crosslink cytokine density dosage economic cost eosinophil experience granulocyte hormone refractory prostate cancer in vivo innovation mast cell men monocyte mouse model neoplastic cell novel oncology palliative chemotherapy product development public health relevance response tumor uptake

项目摘要

DESCRIPTION (provided by applicant): The present proposal seeks to develop a novel anti-prostate specific antigen (PSA) IgE antibody for the treatment of prostate cancer (PCA) with the goal to induce a hypersensitivity reaction to the tumor. The objective of this proposal is to generate the anti-PSA IgE and to demonstrate that this anti-PSA IgE will target the tumor by two parallel pathways: a) by mediating bystander antibody-dependent cell-mediated cytotoxicity (ADCC) and phagocytosis (ADCP) effects in the tumor microenvironment and b) by activating PSA- specific T and B cells due to uptake of immune complexes (IC) composed of anti-PSA IgE and soluble PSA antigen by antigen-presenting cells (APCs). Together, these mechanisms can result in an acute inflammation of the tumor microenvironment with subsequent tumor destruction. This will initially be investigated in in vitro systems, followed by studies in relevant animal models and clinical trials in hormone refractory PCA. Specific Aims: To accomplish our goal we propose three specific aims: 1) to construct, test and produce at small-scale the human/mouse chimeric anti-PSA IgE antibody, 2) to biochemically and biologically characterize the anti-PSA IgE in vitro, and 3) to assess the direct anti-tumor effector mechanisms of the anti-PSA IgE. Study Design: The anti-PSA IgE will be constructed by genetically fusing the cDNA encoding the variable regions of the anti-PSA MAb-AR47.47 to the DNA encoding the human kappa and epsilon constant regions and transfecting the construct into murine myeloma cells. To evaluate the properties of the anti-PSA IgE in vitro, we will evaluate the antibody's ability to bind antigen of different sources. Binding to human Fc receptor will be studied by flow cytometry, using cell lines, isolated human DCs and monocytes. Antigen-presentation studies with PSA and PSA-anti-PSA-IgE IC pulsed human DCs will be used to detect T helper CTL responses by intracellular cytokine staining for IL-4 and IL-5 vs. interferon- by CD8+ and CD4+ T cells and by confocal microscopy. Finally, we will evaluate the ability of the IgE to mediate ADCC of LNCaP tumor cells by eosinophils and test for mast cell degranulation. More elaborate in vivo studies are planned for Phase II using a human IgE/human Fc receptor transgenic mouse model. The anti-tumor activity will then be studied in this model crossed to PSA-transgenic mice bearing syngeneic human PSA expressing tumor cells. Relevance: The relevance of this project relates to the limitations of current treatment options for metastatic, hormone-refractory prostate cancer and prostate cancer in African-American men. The anti-PSA IgE will be a novel molecule capable of a two-pronged attack against cancer cells, through direct elimination of tumor cells by mast cells and eosinophils and through an adaptive anti-tumor immune response. The proposed approach is expected to significantly contribute to a decrease in the human and economic cost associated with prostate cancer and to address an unmet medical need for treatment of hormone-refractory cancer. PUBLIC HEALTH RELEVANCE: With an estimated 186,320 new cases in the US for 2008, Prostate Cancer is the most frequently diagnosed cancer and the second leading cause of cancer deaths in American men. Incidence rates and death rates are significantly higher in African American men than in white men. Although the 5-year survival rate for all stages combined has increased due to earlier diagnosis, patients with metastatic disease, which account for approximately 15% of patients, often cannot be cured by chemotherapy and palliative radiotherapies once patients become refractory to androgen ablation, thus the need to develop innovative modalities of treatment.

描述(申请人提供)：本提案旨在开发一种新的抗前列腺癌(PSA)IgE抗体，用于前列腺癌(PCA)的治疗，目的是诱导对肿瘤的超敏反应。该方案的目的是产生抗PSA IgE，并证明这种抗PSA IgE将通过两条平行的途径靶向肿瘤：a)通过介导肿瘤微环境中旁观者抗体依赖的细胞介导的细胞毒(ADCC)和吞噬(ADCP)效应；b)通过抗原提呈细胞(APC)摄取由抗PSA IgE和可溶性PSA抗原组成的免疫复合物(IC)而激活PSA特异性T和B细胞。这些机制共同作用，可导致肿瘤微环境的急性炎症，进而导致肿瘤的破坏。这将首先在体外系统中进行研究，随后将在相关动物模型中进行研究，并对激素难治性前列腺癌进行临床试验。具体目标：为了实现我们的目标，我们提出了三个具体目标：1)构建、测试和小规模生产人/鼠嵌合抗PSA IgE抗体；2)体外生化和生物学鉴定抗PSA IgE；3)评价抗PSA IgE的直接抗肿瘤作用机制。研究设计：将编码抗PSA单抗AR47.47可变区的基因与编码人kappa和epsilon恒定区的DNA基因融合，构建抗PSA IgE，并将其导入小鼠骨髓瘤细胞。为了评价抗PSA-IgE抗体的体外性质，我们将评估该抗体与不同来源抗原的结合能力。使用细胞系、分离的人树突状细胞和单核细胞，将用流式细胞术研究与人Fc受体的结合。PSA和PSA-抗-PSA-IgE IC致敏的人树突状细胞的抗原提呈研究将用于通过细胞内细胞因子染色IL-4和IL-5与干扰素-CD8+和CD4+T细胞以及共聚焦显微镜来检测T辅助CTL反应。最后，我们将评估IgE通过嗜酸性粒细胞介导LNCaP肿瘤细胞ADCC的能力，并检测肥大细胞脱颗粒。计划在第二阶段使用人IgE/人Fc受体转基因小鼠模型进行更详细的体内研究。然后，将在该模型中研究该抗肿瘤活性，该模型将与携带表达肿瘤细胞的同基因人PSA的PSA转基因小鼠杂交。相关性：该项目的相关性与目前非裔美国男性转移性、激素难治性前列腺癌和前列腺癌的治疗选择的局限性有关。抗PSA IgE将成为一种新型分子，通过肥大细胞和嗜酸性粒细胞直接清除肿瘤细胞和适应性抗肿瘤免疫反应，能够双管齐下攻击癌细胞。预计拟议的方法将大大有助于降低与前列腺癌相关的人力和经济成本，并解决激素难治性癌症治疗的未得到满足的医疗需求。与公共健康相关：据估计，2008年美国新增病例为186,320例，前列腺癌是美国男性最常被诊断出的癌症，也是导致癌症死亡的第二大原因。非洲裔美国人男性的发病率和死亡率明显高于白人男性。虽然由于早期诊断，所有阶段的5年生存率都有所提高，但一旦患者对雄激素治疗无效，占患者总数约15%的转移性疾病患者往往无法通过化疗和姑息放射治疗治愈，因此需要开发创新的治疗方式。