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：
8584977
负责人：
Tracy Ruth Daniels-Wells
金额：
$ 16.75万
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 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8584977
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 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（由申请人提供）：子宫内膜癌、卵巢癌和乳腺癌是美国女性最常见的十种癌症，也是最致命的癌症，尽管治疗取得了进展，但复发和最初的治疗耐药性仍然是这些恶性肿瘤的问题。因此，迫切需要额外的治疗策略上皮膜蛋白2（EMP2）是一种四跨膜蛋白，通过调节细胞膜组成参与细胞粘附、侵袭和信号转导。 EMP2在子宫内膜癌和卵巢癌的表面过度表达，其表达与子宫内膜癌患者更具侵袭性的表型和较差的生存率相关，重要的是，新的初步数据表明EMP2在大量乳腺癌细胞和卵巢癌中过度表达。其表达独立于雌激素受体、孕激素受体和 HER2/neu 状态，使其成为普遍治疗特别有意义的靶标。其他初步数据表明，全身施用人抗 EMP2 IgG1。减少人类异种移植和同基因小鼠乳腺癌模型中的肿瘤负荷虽然临床上使用的大多数基于抗体的疗法都是 IgG 类，但 IgE 抗体具有使其对抗癌疗法具有更高亲和力的吸引力。与 IgG 的 FcR 相比，这些 Fc¿ Rs 在参与急性炎症反应和抗原呈递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，这减少了对 FcR 占用的竞争，并消除了潜在的功效降低。评估基于 IgE 的癌症治疗方法的研究是 AllergoOncology 新兴领域的一部分，我们现在建议通过开发一种新的方法来开辟该领域的新领域。我们的中心假设是，一种功能齐全的抗 EMP2 人类 IgE 可被开发为 EMP2+ 肿瘤（包括子宫内膜癌、卵巢癌和乳腺癌）的潜在疗法。抗 EMP2 IgG1 并诱导针对肿瘤的明显过敏反应，包括局部 I 型超敏反应导致肿瘤微环境中的急性炎症并最终破坏癌细胞的反应，预计死亡细胞将被抗原呈递细胞吞噬，并且癌症抗原将被呈递给免疫系统，从而产生二次癌症靶向适应性免疫。我们提出了三个具体目标：目标 1：构建并表达全人抗 EMP2 IgE；目标 2：研究抗 EMP2 IgE 的功能特性，包括抗原结合、Fc¿ R 结合以及诱导效应细胞脱颗粒的能力；目标 3：评估抗 EMP2 IgE 的直接体外抗癌作用，鉴于 EMP2 在许多恶性肿瘤中的高表达，这些研究对于以下方面非常重要。确定抗 EMP2 IgE 作为女性癌症的潜在治疗方法。