A Novel IgE Cancer Therapeutic Specific for the Epithelial Membrane Protein-2

描述(申请人提供)：子宫内膜癌、卵巢癌和乳腺癌是美国女性确诊的十大癌症之一，也是最致命的癌症。尽管在治疗方面取得了进展，但对于这些恶性肿瘤来说，复发和最初的治疗抵抗仍然是一个问题。因此，迫切需要更多的治疗策略。上皮膜蛋白-2(EMP2)是一种通过调节细胞膜成分参与细胞黏附、侵袭和信号转导的四聚体蛋白。EMP2在子宫内膜癌和卵巢癌的表面过表达，它的表达与子宫内膜癌患者更具侵袭性的表型和低生存率有关。重要的是，新的初步数据显示，EMP2在大量乳腺癌细胞上过表达，并且其表达独立于雌激素受体、孕激素受体和HER2/neu状态，使其成为广泛治疗的特别有意义的靶点。更多的初步数据表明，在人类异种移植和同基因小鼠乳腺癌模型中，系统地给药人抗EMP2 IgG1可以降低肿瘤负荷。虽然临床上使用的大多数基于抗体的治疗药物都是免疫球蛋白G类，但IgE抗体具有固有的特性，使其在抗癌治疗中具有吸引力。IgE对其FCRs的亲和力远高于Ig G对其Fcr的亲和力。此外，这些Fc？R表达在参与急性炎症反应和抗原呈递的关键效应细胞上。此外，与免疫球蛋白相比，内源性血清中的免疫球蛋白E水平很低。这减少了对FCR占有率的竞争，并消除了治疗性抗体有效性的潜在降低。以IgE为基础的治疗癌症的评价研究是过敏肿瘤学新兴领域的一部分。我们现在建议通过开发针对EMP2的IgE来打开这一领域的新维度。我们的中心假设是，可以开发一种功能齐全的抗EMP2人IgE，作为EMP2+肿瘤的潜在治疗方法，包括子宫内膜癌、卵巢癌和乳腺癌。这种新的抗体有望表现出抗EMP2 IgG1的内在直接细胞毒性，并诱导对肿瘤的独特过敏反应，包括局部I型超敏反应 在肿瘤微环境中导致急性炎症并最终摧毁癌细胞的反应。预计死亡的细胞将被抗原提呈细胞吞噬，癌症抗原将被提呈给免疫系统，从而产生二次针对癌症的适应性免疫反应。我们提出三个具体目标：目的1：构建和表达全人抗EMP2 IgE；目的2：研究抗EMP2 IgE的功能特性，包括抗原结合、Fc？R结合和诱导效应细胞脱颗粒的能力；目的3：评价抗EMP2 IgE的体外直接抗癌作用。鉴于EMP2在许多恶性肿瘤上的高表达，这些研究将对建立抗EMP2 IgE作为潜在的女性癌症治疗药物具有重要意义。

DESCRIPTION (provided by applicant): Endometrial, ovarian, and breast cancers are among the top ten diagnosed and the most deadly for women in the United States. Despite advances in treatment, relapse and initial resistance to therapy continue to be problematic for these malignancies. Therefore, additional therapeutic strategies are urgently needed. The epithelial membrane protein-2 (EMP2) is a tetraspan membrane protein involved in cell adhesion, invasion, and signal transduction through the regulation of cell membrane composition. EMP2 is overexpressed on the surface of endometrial and ovarian cancers, and its expression is associated with a more aggressive phenotype and poor survival in patients with endometrial cancer. Importantly, new preliminary data show that EMP2 is overexpressed on a large number of breast cancer cells and its expression is independent of estrogen receptor, progesterone receptor, and HER2/neu status, making it an especially meaningful target for a generalized therapy. Additional preliminary data indicate that systemic administration of a human anti- EMP2 IgG1 reduces tumor load in human xenograft and syngeneic mouse breast cancer models. Although most antibody-based therapeutics used in the clinic are of the IgG class, IgE antibodies have intrinsic properties that make it attractive for anti-cancer therapy. IgE has a much higher affinity for its FcRs compared to IgG for its Fc?Rs. Additionally, these Fc¿Rs are expressed on key effector cells that are involved in the acute inflammatory response and antigen presentation. Moreover, the endogenous serum levels of IgE are very low in contrast to IgG. This decreases competition for FcR occupancy and eliminates the potential reduction in efficacy of the therapeutic antibody. Studies on the evaluation of IgE-based therapeutics for the treatment of cancer is part of the up-and-coming field of AllergoOncology. We now propose to open a new dimension in this field by developing an IgE that targets EMP2. Our central hypothesis is that a fully functional anti-EMP2 human IgE can be developed as a potential therapy of EMP2+ tumors, including endometrial, ovarian, and breast cancers. This novel antibody is expected to exhibit the intrinsic direct cytotoxicity of the anti-EMP2 IgG1 and to induce a distinct allergic reaction against the tumor consisting of a local Type I hypersensitivity reaction that leads to acute inflammation and eventually cancer cell destruction in the tumor microenvironment. It is also expected that the dead cells would be phagocytosed by antigen presenting cells and cancer antigens would be presented to the immune system resulting in a secondary cancer-targeted adaptive immune response. We propose three specific aims: Aim 1: To construct and express the fully human anti-EMP2 IgE; Aim 2: To study the functional properties of the anti-EMP2 IgE including antigen binding, Fc¿R binding, and ability to induce degranulation of effector cells; Aim 3: To evaluate the direct in vitro anti-cancer effects of the anti-EMP2 IgE. Given the high expression of EMP2 on a number of malignancies, these studies will be important to establish the anti-EMP2 IgE as a potential therapeutic for cancers in women.