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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（由申请人提供）：本提案旨在开发一种新型抗前列腺特异性抗原（PSA）IgE抗体，用于治疗前列腺癌（PCA），目的是诱导对肿瘤的超敏反应。本提案的目的是产生抗PSA IgE，并证明该抗PSA IgE将通过两种平行途径靶向肿瘤：a）通过介导肿瘤微环境中的旁观者抗体依赖性细胞介导的细胞毒性（ADCC）和吞噬作用（ADCP）效应，和B）通过由于摄取由抗-PSA组成的免疫复合物（IC）而激活PSA特异性T和B细胞，PSA IgE和可溶性PSA抗原通过抗原呈递细胞（APC）。总之，这些机制可导致肿瘤微环境的急性炎症以及随后的肿瘤破坏。这将首先在体外系统中进行研究，然后在相关动物模型中进行研究，并在激素难治性PCA中进行临床试验。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/小鼠嵌合抗PSA IgE抗体，2）体外生物化学和生物学表征抗PSA IgE，和3）评估抗PSA IgE的直接抗肿瘤效应机制。研究设计：通过将编码抗PSA MAb-AR 47.47可变区的cDNA与编码人κ和κ恒定区的DNA遗传融合，并将构建体转染入鼠骨髓瘤细胞，构建抗PSA IgE。为了评价抗PSA IgE的体外性质，我们将评价抗体结合不同来源抗原的能力。将使用细胞系、分离的人DC和单核细胞通过流式细胞术研究与人Fc受体的结合。使用PSA和PSA-抗-PSA-IgE IC脉冲的人DC的抗原呈递研究将用于通过CD 8+和CD 4 + T细胞的IL-4和IL-5相对于干扰素的细胞内细胞因子染色以及通过共聚焦显微镜检测T辅助CTL应答。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，并检测肥大细胞脱粒。计划使用人IgE/人Fc受体转基因小鼠模型进行II期更详细的体内研究。然后将在与携带表达同基因人PSA的肿瘤细胞的PSA转基因小鼠杂交的该模型中研究抗肿瘤活性。相关性：该项目的相关性与目前转移性、难治性前列腺癌和非裔美国男性前列腺癌治疗选择的局限性有关。抗PSA IgE将是一种新型分子，能够通过肥大细胞和嗜酸性粒细胞直接消除肿瘤细胞以及通过适应性抗肿瘤免疫应答双管齐下地攻击癌细胞。预计所提出的方法将显著有助于降低与前列腺癌相关的人力和经济成本，并解决治疗难治性癌症的未满足的医疗需求。公共卫生相关性：据估计，2008年美国有186，320例新发病例，前列腺癌是美国男性中最常诊断的癌症，也是癌症死亡的第二大原因。非裔美国男性的发病率和死亡率明显高于白色男性。尽管由于早期诊断，所有分期的5年生存率都有所增加，但转移性疾病患者（约占患者的15%）一旦雄激素消融术难治，通常无法通过化疗和姑息性放疗治愈，因此需要开发创新的治疗方式。