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

描述（由申请人提供）：子宫内膜癌，卵巢癌和乳腺癌是美国十大诊断和最致命的女性之一。尽管在治疗方面取得了进展，但复发和对治疗的初始抵抗仍然是这些恶性肿瘤的问题。因此，迫切需要额外的治疗策略。上皮细胞膜蛋白2（EMP 2）是一种通过调节细胞膜组成而参与细胞粘附、侵袭和信号转导的四面体膜蛋白。EMP 2在子宫内膜癌和卵巢癌的表面过表达，其表达与子宫内膜癌患者更具侵袭性的表型和较差的生存率相关。重要的是，新的初步数据表明，EMP 2在大量乳腺癌细胞上过表达，其表达不依赖于雌激素受体、孕激素受体和HER 2/neu状态，使其成为一种特别有意义的综合治疗靶点。额外的初步数据表明，人抗EMP 2 IgG 1的全身给药降低了人异种移植物和同基因小鼠乳腺癌模型中的肿瘤负荷。尽管临床上使用的大多数基于抗体的治疗剂是IgG类的，但IgE抗体具有使其对于抗癌治疗具有吸引力的内在性质。IgE具有更高的亲和力，其FcRs相比，IgG的Fc？卢比此外，这些Fc受体在参与急性炎症反应和抗原呈递的关键效应细胞上表达。此外，与IgG相比，IgE的内源性血清水平非常低。这减少了对FcR占据的竞争，并消除了治疗性抗体功效的潜在降低。评估IgE为基础的治疗癌症的疗法的研究是过敏肿瘤学的新兴领域的一部分。我们现在建议通过开发靶向EMP 2的IgE在该领域开辟一个新的维度。我们的中心假设是，可以开发一种全功能的抗EMP 2人IgE，作为EMP 2+肿瘤（包括子宫内膜癌、卵巢癌和乳腺癌）的潜在疗法。这种新型抗体预期表现出抗EMP 2 IgG 1的固有直接细胞毒性，并诱导针对肿瘤的独特过敏反应，包括局部I型超敏反应 这是一种导致急性炎症并最终导致肿瘤微环境中癌细胞破坏的反应。还预期死细胞将被抗原呈递细胞吞噬，并且癌抗原将被呈递给免疫系统，导致继发性癌症靶向适应性免疫应答。我们提出了三个具体目标：目的1：构建并表达全人源抗EMP 2 IgE;目的2：研究抗EMP 2 IgE的功能特性，包括抗原结合、Fc受体结合和诱导效应细胞脱粒的能力;目的3：评价抗EMP 2 IgE的直接体外抗癌作用。鉴于EMP 2在许多恶性肿瘤中的高表达，这些研究对于建立抗EMP 2 IgE作为女性癌症的潜在治疗方法将是重要的。

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.