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

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。肿瘤蛋白HER2/neu过表达的乳腺癌患者预后尤其差。尽管通常用于抗癌的抗体是IgG类抗体，但IgE类抗体具有几个特性，使其对癌症治疗有利：1)IgE对其Fc？相对于IgG的Fc？Rs, 2) Fc？3)血清内源性IgE水平较低，导致对FcR占用的竞争较少；4)与IgG不同，IgE不具有抑制FcR的作用。目前的建议旨在开发一种新的抗her2 / IgE类抗体，作为乳腺癌的可能治疗方法。我们假设提出的抗HER2/neu IgE将靶向表达HER2/neu的肿瘤，并在此过程中产生局部靶向IgE的即时超敏（过敏）反应，导致肿瘤微环境中的急性炎症和肿瘤的快速破坏，癌细胞无法逃脱。死亡的癌细胞会被抗原呈递细胞（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，也针对其他肿瘤抗原。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，导致有效的抗原摄取和递呈，随后的抗肿瘤免疫激活。我们已经开发了一种完全人类抗her2 /neu IgE (C6MH3-B1 IgE)，它不会与曲妥珠单抗（赫赛汀(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)填补以前研究中积累的知识空白，2)开辟新的研究领域，3)为开始将抗her2 /新IgE推向临床创造基础。我们有四个独立的特异性目标：目标1：在体外效应细胞功能和抗原呈递的背景下，确定抗her2 /新IgE与抗原的相互作用；目的2：确定抗her2 /新IgE在huFc中的抗肿瘤活性？国际扶轮的老鼠;目的3：明确抗her2 /neu IgE在SCID小鼠体内的抗肿瘤活性；目的4：确定抗her2 /新IgE在huFc中的毒性？小鼠和食蟹猴。目前的建议具有机制（基础科学）成分和强大的转化潜力，可以潜在地为乳腺癌和其他HER2/neu过表达恶性肿瘤的治疗做出贡献。该项目有望在新兴的变态反应肿瘤学领域开辟一个新的维度，该领域旨在揭示ige介导的免疫反应对癌症的作用，并开发新的基于ige的癌症治疗方法，如所提出的治疗方法。

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.