Human Anti-PSMA Antibodies for Prostate Cancer Therapy

描述(由申请人提供)： 前列腺癌是美国男性癌症死亡的第二大原因。 虽然雄激素疗法可以暂时控制转移性疾病，但大多数 肿瘤变得激素耐药，然后迅速发展，因为没有 其他有效的治疗方法。因此，迫切需要新的治疗方法。 前列腺特异性膜抗原(PSMA)是一种特性良好的糖蛋白。 其表达在很大程度上局限于上皮细胞。在正常组织中， PSMA以剪接变异体的形式存在，它缺乏跨膜结构域，并且 从而保留在细胞质中。但在肿瘤细胞上，PSMA包含一个单一的 跨膜区和大的胞外区。此单元格类型 特异性使PSMA的大的胞外结构域成为理想的候选者 用于免疫治疗。我们建议研制全人源性抗PSMA单抗。 用于治疗前列腺癌的抗体。使用Xenomice，它是 人免疫球蛋白GOVE基因的转基因及验证 免疫/筛查策略，我们将生成一个人类小组 识别天然细胞表面SMA的抗体。抗体将会是 评估“裸体”形式的特异性和抗肿瘤特性以及何时 与新型的阿尔法和贝塔放射治疗性核素结合。 此外，我们将在现有的最佳模型中检验抗体的效力。 人类前列腺癌将确定进入人类的主要候选 临床试验。 建议的商业应用： 本研究的总体目标是确定最有希望用于治疗前列腺癌的抗PSMA抗体，并将该治疗方法应用于临床测试。这项拟议研究确定的先导抗体结构将进入临床试验，如果对人类有效，将生产用于治疗前列腺癌的商业销售。成功的免疫疗法的市场包括有复发或转移性疾病风险的男性。这将包括相当大一部分被诊断患有前列腺癌的人，即美国的179,000人。除美国以外的市场在规模上大致相同。

DESCRIPTION (provided by applicant): Prostate cancer is the second leading cause of cancer death in American males. Although androgen therapy can temporarily control metastatic disease, most tumors become hormone refractory and then rapidly progress since there is no other effective therapy. Thus, there is an urgent need for new therapies. Prostate-specific membrane antigen (PSMA) is a well-characterized glycoprotein whose expression is largely restricted to epithelial cells. In normal tissues, PSMA exists as a splice variant that lacks the transmembrane domain and is thereby retained in the cytoplasm. But on tumor cells, PSMA contains a single transmembrane domain and a large extracellular domain. This cell-type specificity makes the large extracellular domain of PSMA an ideal candidate for immunotherapy. We propose development of fully human anti-PSMA monoclonal antibodies for the treatment of prostate cancer. Using Xenomice that are transgenic for the human immunoglobulin gone locus and proven immunization/screening strategies, we will generate a panel of human antibodies that recognize native, cell-surface SMA. Antibodies will be evaluated for specificity and antitumor properties in "naked" form and when conjugated to novel alpha- and beta-emitting therapeutic radionuclides. Furthermore, we will examine antibody efficacy in the best available models of human prostate cancer to identify a lead candidate to advance into human clinical trials. PROPOSED COMMERCIAL APPLICATION: The overall goal of this poposal is to identify the most promising anti-PSMA antibody for treating prostate cancer and advance that therapeutic into clinical testing. The lead antibody construct identified with this proposed research will be moved into clinical trials and, if effective in humans, will be manufactured for commercial sale for the treatment of prostate cancer. The market for a successful immunotherapy includes men at risk for the development of recurrent or metastatic diseases. THis would include a significant fraction of individuals diagnosed with prostate cancer, or 179,000 individuals in the U.S. The ex-U.S. market is approximately equal in magnitutde.