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

用于乳腺癌治疗的新型抗 HER2/neu IgE

• 批准号: 8759266
• 负责人: MANUEL L PENICHET
• 金额: $ 36.96万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 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/8759266
• 关键词: Acute; Affinity; Allergic Reaction; Anaphylaxis; Animal Model; Antibodies; Antigen Presentation; Antigen-Presenting Cells; Antigens; Basic Science; Binding; Binding Sites; Biological; Breast Carcinoma; CD8B1 gene; Cancer Etiology; Cancer Patient; 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; Educational process of instructing; 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; Knowledge; Lung; Macaca fascicularis; Malignant Epithelial Cell; Malignant Neoplasms; Mammary Neoplasms; Mediating; Modeling; Monitor; Mus; Neoplasm Metastasis; Oncogene Proteins; Passive Immunotherapy; Patients; Peritoneal; Phagocytosis; Pilot Projects; Process; Property; Resistance; Roche brand of trastuzumab; SCID Mice; Second Primary Neoplasms; Serum; T-Cell Activation; Therapeutic; Toxic effect; Transgenic Mice; Transgenic Organisms; Trastuzumab; Tumor Antigens; United States; Vaccination; Woman; 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

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 Fc?Rs compared to IgG for its Fc?Rs, 2) expression of Fc?Rs 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 huFc?RI 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 huFc?RI 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（由申请人提供）：乳腺癌是美国女性中诊断最多的恶性肿瘤，也是癌症死亡的第二大原因。对于那些患有过度表达癌蛋白 HER2/neu 的肿瘤的乳腺癌患者来说，预后尤其差。虽然一般来说，用于抗癌的抗体属于 IgG 类，但 IgE 类抗体具有多种特性，使其有利于癌症治疗：1) 与 IgG 对其 Fc?R 相比，IgE 对其 Fc?R 的亲和力更高，2) 负责抗体效应功能和抗原呈递的关键细胞表达 Fc?R，3) 内源性 IgE 血清水平低，导致竞争性减少 FcR 占据，4) 与 IgG 不同，IgE 不具有抑制性 FcR。本提案旨在开发一种新型 IgE 类抗 HER2/neu 抗体作为乳腺癌的可能疗法。我们假设所提出的抗 HER2/neu IgE 将靶向表达 HER2/neu 的肿瘤，并在此过程中产生局部 IgE 靶向的立即超敏反应（过敏）反应，导致肿瘤微环境中的急性炎症和快速肿瘤破坏，而癌细胞无法逃逸。死亡细胞将被树突状细胞等抗原呈递细胞 (APC) 吸收，当死亡癌细胞被 IgE 包被时，这一过程会得到增强，不仅会产生针对 HER2/neu 的适应性免疫反应，而且还会因表位扩散而产生针对其他肿瘤抗原的适应性免疫反应。我们还假设由抗 HER2/neu IgE 和 HER2/neu 可溶性胞外结构域 (ECDHER2) 组成的免疫复合物将靶向 APC，从而导致有效的抗原摄取和呈递以及随后的抗肿瘤免疫激活。我们已经开发出一种全人源抗 HER2/neu IgE (C6MH3-B1 IgE)，它不会与曲妥珠单抗 (Herceptin(R)) 竞争其抗原结合位点。这种新型IgE表现出预期的生物学特性，能够触发免疫激活和抗肿瘤保护，同时在相关动物模型中具有良好的耐受性。该提案的目标是：1) 填补先前研究中积累的知识空白，2) 开辟新的研究方向，3) 为开始将抗 HER2/neu IgE 进入临床奠定基础。我们有四个独立的具体目标： 目标 1：在效应细胞功能和体外抗原呈递的背景下定义抗 HER2/neu IgE 与抗原的相互作用；目标2：确定抗HER2/neu IgE在huFc?RI小鼠中的抗肿瘤活性；目标 3：确定抗 HER2/neu IgE 在 SCID 小鼠中的抗肿瘤活性；目标 4：确定抗 HER2/neu IgE 对 huFc?RI 小鼠和食蟹猴的毒性。目前的提案具有机械（基础科学）成分和强大的转化潜力，可能有助于治愈乳腺癌以及其他 HER2/neu 过度表达的恶性肿瘤。该项目预计将为 AllergoOncology 的新兴领域开辟一个新的领域，旨在揭示 IgE 介导的癌症免疫反应的功能，并开发基于 IgE 的新型癌症疗法，例如所提出的疗法。