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: 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
• 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

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(申请人提供)：乳腺癌是美国女性中诊断最多的恶性肿瘤，也是导致癌症死亡的第二大原因。乳腺癌患者的预后尤其是那些携带过表达癌蛋白HER2/neu的肿瘤的患者。虽然通常用于抗癌的抗体属于免疫球蛋白，但免疫球蛋白E类抗体有几个特性使它们有利于癌症治疗：1)与免疫球蛋白Fcϵ受体相比，免疫球蛋白E对其Fcγ受体具有更高的亲和力，2)由负责抗体效应器功能和抗原呈递的关键细胞表达Fcϵ受体，3)血清内源性Ig E水平较低，导致对FCRs的竞争较少，以及4)与Ig G不同，Ig E没有抑制性FCR。本提案旨在开发一种新型的抗HER2/neu抗体，作为乳腺癌的一种可能的治疗方法。我们假设，建议的抗HER2/neu IgE将针对表达HER2/neu的肿瘤，并在这样做的过程中，产生局部IgE靶向的即时超敏(过敏)反应，导致肿瘤微环境中的急性炎症和快速的肿瘤破坏，而癌细胞无法逃脱。死亡的细胞将被抗原提呈细胞(APC)吸收，如树突状细胞，当死亡的癌细胞被IgE包裹时，这一过程可以得到加强，导致适应性免疫反应，不仅针对HER2/neu，而且由于表位扩散而针对其他肿瘤抗原。我们还假设，由抗HER2/neu IgE和可溶性HER2/neu胞外区(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递呈，并随后激活抗肿瘤免疫。我们已经开发出一种完全人源性的抗HER2/neu IgE(C6MH3-B1 IgE)，它不与曲妥珠单抗(Herceptin(R))竞争其抗原结合部位。这种新型的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具有良好的耐受性。这项建议的目标是：1)填补先前研究积累的知识空白，2)开辟新的研究路线，3)为开始将抗HER2/neu IgE引入临床奠定基础。我们有四个独立的特异性目标：目的1：确定抗HER2/neu Ig E与抗原在体外效应细胞功能和抗原提呈方面的相互作用；目的2：确定抗HER2/neu Ig E在HuFcϵRI小鼠中的抗肿瘤活性；目标3：确定抗HER2/neu Ig E在SCID小鼠中的抗肿瘤活性；以及目标4：确定抗HER2/neu Ig E在小鼠体内的毒性 HuFcϵRI小鼠和食蟹猴。本建议具有机械性(基础科学)成分和强大的翻译潜力，这可能有助于治愈乳腺癌，也许还有其他过度表达HER2/neu的恶性肿瘤。该项目有望在新生的过敏肿瘤学领域开辟一个新的维度，旨在揭示IgE介导的抗癌免疫反应的功能，并开发新的基于IgE的癌症疗法，如拟议的治疗性疗法。