Development of Anti-PSMA Antibodies for Prostate Cancer

个人描述(申请人提供)：前列腺癌居第二位 导致美国男性癌症死亡的原因。尽管雄激素疗法可以 暂时控制转移疾病，大多数肿瘤变得对激素无效 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 免疫疗法。 我们建议开发抗PSMA的单抗用于治疗 前列腺癌。我们已经产生了一组抗体，可以识别天然的， 细胞表面聚甲基丙烯酸甲酯。抗体将被提纯并随后进行评估 “裸体”形式和结合时的特异性和抗肿瘤特性 新型释放α和β辐射的治疗性放射性核素。领先候选人(S) 将对本提案中确定的最佳方案进行有效性检查 第二期人类前列腺癌模型的建立以确定先导 进入人体临床试验的候选人。

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 anti-PSMA monoclonal antibodies for the treatment of prostate cancer. We have generated a panel of antibodies that recognize native, cell-surface PSMA. Antibodies will be purified and subsequently evaluated for specificity and antitumor properties in "naked" form and when conjugated to novel alpha- and beta-emitting therapeutic radionuclides. The lead candidate(s) identified in this proposal will be examined for efficacy in the best available models of human prostate cancer in Phase II in order to identify a lead candidate to advance into human clinical trials.