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

描述（由申请人提供）：乳腺癌是美国最常见的恶性肿瘤，也是女性癌症死亡的第二大原因。乳腺癌患者的预后特别差，在那些轴承肿瘤过表达癌蛋白HER 2/neu。虽然，一般来说，用于对抗癌症的抗体是IgG类的，但IgE类的抗体具有使其有利于癌症治疗的几种性质：1）与IgG对其Fcγ R相比，IgE对其Fcγ R的亲和力更高，2）负责抗体效应子功能和抗原呈递的关键细胞表达Fc γ R，3）内源性IgE的血清水平低，导致对FcR占据的竞争较少，和4）与IgG不同，IgE不具有抑制性FcR。本提案旨在开发一种新型的IgE类抗HER 2/neu抗体，作为乳腺癌的可能治疗方法。我们假设，拟定的抗HER 2/neu IgE将靶向HER 2/neu表达肿瘤，并在此过程中产生局部IgE靶向速发型超敏反应（过敏性），导致肿瘤微环境中的急性炎症和快速肿瘤破坏，癌细胞无逃逸。死亡细胞将被抗原呈递细胞（APC）（如树突状细胞）摄取，当死亡癌细胞被IgE包被时，这一过程可以得到增强，导致不仅针对HER 2/neu，而且由于表位扩散而针对其他肿瘤抗原的适应性免疫应答。我们还假设由抗HER 2/neu IgE和HER 2/neu的可溶性细胞外结构域（ECDHER 2）组成的免疫复合物将靶向APC，导致有效的抗原摄取和呈递，随后抗肿瘤免疫激活。我们已经开发了一种完全人源化的抗HER 2/neu IgE（C6 MH 3-B1 IgE），它不会与曲妥珠单抗（Herceptin（R））竞争抗原结合位点。这种新型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良好。该提案的目标是：1）填补以前研究中积累的知识空白，2）开辟新的研究路线，3）为开始将抗HER 2/neu IgE转移到临床奠定基础。我们有四个独立的具体目标：目标1：在体外效应细胞功能和抗原呈递的背景下定义抗HER 2/neu IgE和抗原的相互作用;目标2：在huFc IFN-γ RI小鼠中定义抗HER 2/neu IgE的抗肿瘤活性;目标3：在SCID小鼠中定义抗HER 2/neu IgE的抗肿瘤活性;以及目标4：在SCID小鼠中定义抗HER 2/neu IgE的毒性。 huFc β RI小鼠和食蟹猴。本提案具有机械（基础科学）成分和强大的转化潜力，可能有助于治愈乳腺癌和其他HER 2/neu过表达的恶性肿瘤。该项目预计将在AllergoOncology的新生领域开辟一个新的维度，旨在揭示IgE介导的免疫反应对癌症的作用，并开发基于IgE的新型癌症疗法，如拟议的治疗方法。

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 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.