A Novel Anti-HER2/neu IgE for Breast Cancer Therapy

用于乳腺癌治疗的新型抗 HER2/neu IgE

基本信息

批准号：
9331321
负责人：
MANUEL L PENICHET
金额：
$ 55.41万
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：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9331321
关键词：
Acute Affinity Allergic Reaction Anaphylaxis Animal Model Antibodies Antigen Presentation Antigen Targeting Antigen-Presenting Cells Antigens Basic Science Binding Binding Sites Biological Breast Cancer Patient Breast Cancer therapy Breast Carcinoma CD8-Positive T-Lymphocytes Cancer Etiology Cancer cell line Carcinomatosis Cell Degranulation Cell Line Cell physiology Cells Cessation of life Clinic Complex Cytotoxic T-Lymphocytes Data Dendritic Cells Diagnosis Dimensions Dose ERBB2 gene Effector Cell Environment Epitopes Exhibits Extracellular Domain FDA approved Fc Receptor Glycocalyx Goals Human IgE IgG1 Immediate hypersensitivity Immune response Immune system Immunocompetent Immunoglobulin G In Vitro Inflammation Inflammatory Response Irradiated tumor Knowledge Macaca fascicularis Malignant Neoplasms Mammary Neoplasms Mediating Metastatic Neoplasm to the Lung Modeling Monitor Mus Oncoproteins Passive Immunotherapy Patients Peritoneal Phagocytosis Pilot Projects Process Property Resistance SCID Mice Serum Therapeutic Toxic effect Transgenic Mice Transgenic Organisms Trastuzumab Tumor Antigens United States Woman adaptive immune response antibody-dependent cell cytotoxicity antigen binding base cancer cell cancer therapy cell killing clinically relevant eosinophil fighting immune activation improved intraperitoneal killings macrophage malignant breast neoplasm mast cell monocyte neoplastic cell novel novel therapeutics outcome forecast overexpression public health relevance response subcutaneous tumor tumor microenvironment uptake vaccine trial

项目摘要

DESCRIPTION (provided by applicant): Breast cancer is the most diagnosed malignancy and the second cause of cancer death in women in the United States. The prognosis for breast cancer patients is particularly poor in those bearing tumors that overexpress the oncoprotein HER2/neu. Although, in general, antibodies used against cancer are of the IgG class, antibodies of the IgE class have several properties that make them advantageous for cancer therapy: 1) higher affinity of IgE for its FcϵRs compared to IgG for its FcγRs, 2) expression of FcϵRs by key cells responsible for antibody effector functions and antigen presentation, 3) low serum levels of endogenous IgE, resulting in less competition for FcR occupancy, and 4) unlike IgG, IgE does not have an inhibitory FcR. The present proposal seeks to develop a novel anti-HER2/neu antibody of the IgE class as a possible therapy of breast cancer. We hypothesize that the proposed anti-HER2/neu IgE will target HER2/neu expressing tumors and, in so doing, create a local IgE-targeted immediate hypersensitivity (anaphylactic) reaction resulting in acute inflammation in the tumor microenvironment and in rapid tumor destruction, with no escape of cancer cells. The dead cells will be taken up by antigen presenting cells (APC), such as dendritic cells, a process that can be enhanced when dead cancer cells are coated by IgE, resulting in an adaptive immune response not only against HER2/neu, but also against other tumor antigens due to epitope spreading. We also hypothesize that immunocomplexes composed of anti-HER2/neu IgE and soluble extracellular domain of HER2/neu (ECDHER2) will target APC, resulting in efficient antigen uptake and presentation with subsequent anti-tumor immune activation. We have already developed a totally human anti-HER2/neu IgE (C6MH3-B1 IgE) that does not compete with trastuzumab (Herceptin(R)) for its antigen-binding site. This novel IgE exhibits the expected biological properties and is capable of triggering immune activation and anti-tumor protection, while being well tolerated in relevant animal models. The goals of this proposal are: 1) Fill the gaps in the knowledge accrued from the previous studies, 2) open new lines of studies, and 3) create the basis to start moving the anti-HER2/neu IgE into the clinic. We have four independent specific aims: Aim 1: Define the interaction of anti-HER2/neu IgE and antigen in the context of effector cell functions and antigen presentation in vitro; Aim 2: Define the anti-tumor activity of anti-HER2/neu IgE in huFcϵRI mice; Aim 3: Define the anti-tumor activity of anti-HER2/neu IgE in SCID mice; and Aim 4: Define the toxicity of anti-HER2/neu IgE in huFcϵRI mice and cynomolgus monkeys. The present proposal has a mechanistic (basic science) component and a strong translational potential, which can contribute, potentially, to the cure of breast cancer and perhaps other HER2/neu overexpressing malignancies. The project is expected to open a new dimension in the nascent field of AllergoOncology, which aims to reveal the function of IgE-mediated immune responses against cancer and develop novel IgE-based cancer therapies such as the proposed therapeutic.

描述（由适用提供）：乳腺癌是美国妇女诊断最多的恶性肿瘤和癌症死亡的第二个原因。乳腺癌患者的预后在那些过表达癌蛋白HER2/NEU的肿瘤中尤为较差。虽然通常，抗癌使用的抗体是IgG类别的，但IgE类的抗体具有多种特性，使其对癌症治疗有利：1）与IgG相比，IgE对IgG的FCγR与FCγR相比较高，2）对FCϵRS的表达较少，对抗体效应和抗体功能的表达较少，而在抗体效应中，抗体效应和抗体的表现，3），3），3）抗体效应，3） FCR占用率和4）与IgG不同，IgE没有抑制性FCR。本提案旨在开发一种新型的抗HER2/NEU抗体，以作为乳腺癌的一种可能的疗法。我们假设所提出的抗HER2/neu IgE将靶向HER2/NEU表达肿瘤，这样就产生了局部IGE的立即性高敏性（过敏性）反应，从而导致肿瘤微环境和快速肿瘤破坏的急性炎症，而癌细胞没有逃脱。死细胞将被抗原呈递细胞（APC）（例如树突状细胞）吸收，当死亡癌细胞被IgE覆盖时，该过程不仅可以对HER2/NEU产生适应性免疫响应，而且还会产生针对HER2/NEU的适应性免疫响应，而且还会针对其他肿瘤抗原引起的其他肿瘤抗原。我们还假设由HER2/NEU（ECDHER2）的抗HER2/NEU IGE和固体外细胞结构域组成的免疫复合物将靶向APC，从而有效地进行抗原摄取和呈现，并带有随后的抗肿瘤免疫激活。我们已经开发了完全人类的抗HER2/neu IgE（C6MH3-B1 IgE），该抗原结合位点没有与曲妥珠单抗（Herceptin（R））竞争。这款新型IgE具有预期的生物学特性，能够触发免疫激活和抗肿瘤保护，同时在相关动物模型中耐受性良好。该提案的目标是：1）填补以前研究中积累的知识的空白，2）开放新的研究线，3）创建基础，开始将抗HER2/neu igE移至诊所。我们有四个独立的特定目的：目标1：在效应细胞功能和抗原表现的背景下定义抗HER2/neu IgE和抗原的相互作用； AIM 2：定义HUFCϵRI小鼠中抗HER2/neu IgE的抗肿瘤活性； AIM 3：定义SCID小鼠中抗Her2/neu IgE的抗肿瘤活性；目标4：定义抗HER2/neu igE的毒性 Hufcϵri小鼠和cynomolgus猴子。本提案具有机械性（基础科学）组成部分和强大的翻译潜力，这可能有助于治愈乳腺癌以及其他HER2/NEU过表达的恶性肿瘤。预计该项目将在过敏剂学的新生领域开设一个新的维度，该项目旨在揭示IgE介导的对癌症的免疫反应的功能，并开发出新型的基于IGE的癌症疗法，例如拟议的疗法。