A Novel IgE Cancer Therapeutic Specific for the Epithelial Membrane Protein-2

一种针对上皮膜蛋白 2 的新型 IgE 癌症治疗方法

基本信息

批准号：
8727497
负责人：
Tracy Ruth Daniels-Wells
金额：
$ 19.49万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8727497
关键词：
Acute Affinity Affinity Chromatography Allergic Reaction Animal Model Antibodies Antigen Presentation Antigen-Presenting Cells Antigens Basophils Binding Biological Assay Breast Cancer Cell Breast Cancer Model Breast Carcinoma Caliber Cancer cell line Cause of Death Cell Adhesion Cell Culture Techniques Cell Line Cell membrane Cells Cellular Immunity Clinic Clinical Trials Data Diagnosis Dimensions Dose ERBB2 gene Effector Cell Endometrial Carcinoma Endometrial Neoplasms Endometrial adenocarcinoma Environment Enzyme-Linked Immunosorbent Assay Epithelial Estrogen Receptors Evaluation Exhibits Flow Cytometry Foundations Funding Future Goals Grant Hela Cells Hexosaminidases Human Human Cell Line IgE IgG1 Immediate hypersensitivity Immune response Immune system Immunoglobulin G Immunoglobulin Variable Region In Vitro Induction of Apoptosis Inflammation Inflammatory Response Leukemic Cell Light Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of cervix uteri Malignant neoplasm of ovary Membrane Proteins Monitor Multiple Myeloma Mus Ovarian Endometrioid Adenocarcinoma Passive Cutaneous Anaphylaxis Patients Peptides Phagocytosis Phenotype Progesterone Receptors Property Rattus Reaction Regulation Relapse Resistance SKOV3 cells Second Primary Cancers Serous Serum Signal Transduction Staining method Stains Surface Testing Therapeutic Therapeutic Uses Therapeutic antibodies Thymidine Toxic effect Transfection Transgenic Mice Tumor Burden United States Woman Xenograft procedure annexin A5 antigen binding base beta-n-acetylhexosaminidase cancer cell cancer therapy cancer type cytotoxic cytotoxicity expression vector fighting in vivo malignant breast neoplasm meetings novel outcome forecast overexpression public health relevance therapy resistant treatment strategy tumor tumor microenvironment vector

项目摘要

DESCRIPTION (provided by applicant): Endometrial, ovarian, and breast cancers are among the top ten diagnosed and the most deadly for women in the United States. Despite advances in treatment, relapse and initial resistance to therapy continue to be problematic for these malignancies. Therefore, additional therapeutic strategies are urgently needed. The epithelial membrane protein-2 (EMP2) is a tetraspan membrane protein involved in cell adhesion, invasion, and signal transduction through the regulation of cell membrane composition. EMP2 is overexpressed on the surface of endometrial and ovarian cancers, and its expression is associated with a more aggressive phenotype and poor survival in patients with endometrial cancer. Importantly, new preliminary data show that EMP2 is overexpressed on a large number of breast cancer cells and its expression is independent of estrogen receptor, progesterone receptor, and HER2/neu status, making it an especially meaningful target for a generalized therapy. Additional preliminary data indicate that systemic administration of a human anti- EMP2 IgG1 reduces tumor load in human xenograft and syngeneic mouse breast cancer models. Although most antibody-based therapeutics used in the clinic are of the IgG class, IgE antibodies have intrinsic properties that make it attractive for anti-cancer therapy. IgE has a much higher affinity for its FcRs compared to IgG for its Fc?Rs. Additionally, these Fc¿Rs are expressed on key effector cells that are involved in the acute inflammatory response and antigen presentation. Moreover, the endogenous serum levels of IgE are very low in contrast to IgG. This decreases competition for FcR occupancy and eliminates the potential reduction in efficacy of the therapeutic antibody. Studies on the evaluation of IgE-based therapeutics for the treatment of cancer is part of the up-and-coming field of AllergoOncology. We now propose to open a new dimension in this field by developing an IgE that targets EMP2. Our central hypothesis is that a fully functional anti-EMP2 human IgE can be developed as a potential therapy of EMP2+ tumors, including endometrial, ovarian, and breast cancers. This novel antibody is expected to exhibit the intrinsic direct cytotoxicity of the anti-EMP2 IgG1 and to induce a distinct allergic reaction against the tumor consisting of a local Type I hypersensitivity reaction that leads to acute inflammation and eventually cancer cell destruction in the tumor microenvironment. It is also expected that the dead cells would be phagocytosed by antigen presenting cells and cancer antigens would be presented to the immune system resulting in a secondary cancer-targeted adaptive immune response. We propose three specific aims: Aim 1: To construct and express the fully human anti-EMP2 IgE; Aim 2: To study the functional properties of the anti-EMP2 IgE including antigen binding, Fc¿R binding, and ability to induce degranulation of effector cells; Aim 3: To evaluate the direct in vitro anti-cancer effects of the anti-EMP2 IgE. Given the high expression of EMP2 on a number of malignancies, these studies will be important to establish the anti-EMP2 IgE as a potential therapeutic for cancers in women.

描述（由适用提供）：子宫内膜，卵巢癌和乳腺癌是美国妇女被诊断出的十大，最致命的之一。尽管治疗方面的进步，继电器和对治疗的初始抵抗仍在这些恶性肿瘤上仍然存在问题。因此，迫切需要其他治疗策略。上皮膜蛋白-2（EMP2）是通过调节细胞膜组成的调节细胞粘附，侵袭和信号转导的四膜蛋白。 EMP2在子宫内膜和卵巢癌的表面过表达，其表达与子宫内膜癌患者的更具侵略性的表型和较差的生存有关。重要的是，新的初步数据表明，EMP2在大量乳腺癌细胞上过表达，其表达与雌激素受体，孕酮受体和HER2/NEU状态无关，使其成为广义治疗的特别有意义的靶标。其他初步数据表明，全身性抗EMP2 IgG1会降低人异种移植物和促成小鼠乳腺癌模型中的肿瘤负荷。尽管诊所中使用的大多数基于抗体的治疗是IgG类别的，但IgE抗体具有内在特性，使其对抗癌疗法具有吸引力。与IgG相比，IgE对其FCR具有更高的亲和力。此外，这些FCCOS在与急性炎症反应和抗原呈递有关的关键效应细胞上表达。此外，与IgG相比，IgE的内源性血清水平非常低。这减少了FCR占用率的竞争，并消除了治疗抗体有效性的潜在降低。对基于IgE治疗的癌症治疗的评估的研究是过敏剂学领域的一部分。现在，我们建议通过开发针对EMP2的IGE来打开该领域的新维度。我们的中心假设是，功能齐全的抗EMP2人IgE可以作为EMP2+肿瘤的潜在疗法，包括子宫内膜，卵巢和乳腺癌。这种新型抗体有望体验抗EMP2 IgG1的固有直接细胞毒性，并诱导针对由I型I高敏性组成的肿瘤的明显过敏反应导致急性炎症并最终在肿瘤微环境中癌细胞破坏的反应。还可以预期，将被抗原呈递细胞的死细胞吞噬，癌症抗原将被呈现给免疫系统，从而导致二级癌症的适应性免疫响应。我们提出了三个具体目标：目标1：构建和表达完全人类的抗Emp2 igE；目的2：研究抗EMP2 IgE的功能特性，包括抗原结合，FC。r结合以及影响效应细胞脱粒的能力；目标3：评估抗EMP2 IgE的直接体外抗癌作用。鉴于EMP2在许多恶性肿瘤上的高表达，这些研究对于建立抗EMP2 IgE作为女性癌症的潜在治疗方法将很重要。