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女性最常见的十大癌症之一，也是最致命的癌症。尽管在治疗方面取得了进展，但这些恶性肿瘤的复发和最初对治疗的抵抗仍然是一个问题。因此，迫切需要新的治疗策略。上皮膜蛋白-2 （epithelial membrane protein-2, EMP2）是一种四跨膜蛋白，通过调节细胞膜组成参与细胞粘附、侵袭和信号转导。EMP2在子宫内膜癌和卵巢癌表面过表达，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，EMP2在大量乳腺癌细胞中过表达，且其表达不依赖于雌激素受体、孕激素受体和HER2/neu状态，这使其成为一个特别有意义的广泛治疗靶点。另外的初步数据表明，在人异种移植和同基因小鼠乳腺癌模型中，全身给药人抗EMP2 IgG1可减少肿瘤负荷。尽管临床上使用的大多数基于抗体的治疗方法都是IgG类，但IgE抗体具有内在特性，使其具有抗癌治疗的吸引力。IgE对其fcr的亲和力远高于IgG对其Fc？此外，这些Fc¿Rs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，内源性血清IgE水平非常低。这减少了对FcR占用的竞争，并消除了治疗性抗体有效性的潜在降低。基于ige的癌症治疗评价研究是变态反应肿瘤学的一个新兴领域。我们现在建议通过开发针对EMP2的IgE来开辟这一领域的新领域。我们的中心假设是一种全功能的抗EMP2人IgE可以作为EMP2阳性肿瘤的潜在治疗方法，包括子宫内膜癌、卵巢癌和乳腺癌。这种新型抗体有望表现出抗emp2 IgG1固有的直接细胞毒性，并诱导针对肿瘤的独特过敏反应，包括局部I型超敏反应

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.