Development of PSMA -based recombinant protein vaccines

描述（由申请人提供）：前列腺癌是美国男性最常见的癌症，2002年约有189，000例新发病例和30，000例死亡。复发性疾病可以通过雄激素消除暂时控制。然而，几乎所有的前列腺癌最终都成为激素难治性的，然后迅速进展。前列腺癌在很大程度上对常规化疗具有耐药性，目前还没有有效的治疗晚期转移性疾病的方法。因此，迫切需要可以预防或治疗晚期前列腺癌的疗法。 前列腺特异性膜抗原（PSMA）是一种特征性很强的糖蛋白，其表达主要局限于前列腺上皮细胞。在正常前列腺中，PSMA作为缺乏跨膜结构域的剪接变体存在，从而保留在细胞质中。然而，在前列腺癌中，PSMA表达为具有大的细胞外结构域的2型膜蛋白。PSMA表达随着疾病进展增加约1000倍。PSMA还具有可能在转移中起作用的羧肽酶活性。由于这些原因，PSMA代表了前列腺癌主动免疫治疗的高度有吸引力的靶标。 该II期项目的目标是将我们的重组可溶性PSMA（rsPSMA）疫苗推进到人类临床试验中，以预防和/或逆转疾病进展。rsPSMA疫苗是一种新型构建体，其包含PSMA的胞外结构域加上免疫刺激佐剂。在I期项目中，我们开发了以保留其天然构象的方式生产和纯化rsPSMA的程序。与天然的细胞表面PSMA一样，rsPSMA蛋白被发现形成非共价二聚体，并且只有rsPSMA的二聚体形式具有酶活性并且能够诱导与PSMA表达肿瘤细胞交叉反应的高水平抗体。这些发现为我们的rsPSMA疫苗提供了重要的概念验证。此外，这些对PSMA结构-功能关系的新见解对PSMA疫苗的设计和开发具有重要意义。II期项目旨在完成启动人体试验所需的关键临床前开发和临床生产活动。我们还将优化疫苗在创新的PSMA转基因动物模型中打破耐受性的能力。这些活动在前列腺癌这种新型疫苗疗法的首次人体研究中达到高潮。如果在人类中成功诱导抗PSMA抗体，rsPSMA疫苗将代表一种有前途的新疗法模式，可单独使用或与诱导有效细胞免疫的疫苗联合使用。

DESCRIPTION (provided by applicant): Prostate cancer is the most common cancer of men in the United States with approximately 189,000 new cases and 30,000 deaths in 2002. Recurrent disease can be controlled temporarily with androgen ablation. However, almost all prostate carcinomas eventually become hormone refractory and then rapidly progress. Prostate cancer is largely resistant to conventional chemotherapy, and currently there is no effective treatment for advanced, metastatic disease. Thus, there is an urgent need for therapies that can prevent or treat advanced prostate cancer. Prostate-specific membrane antigen (PSMA) is a well-characterized glycoprotein whose expression is largely restricted to prostate epithelial cells. In normal prostate, PSMA exists as a splice variant that lacks the transmembrane domain and is thereby retained in the cytoplasm. In prostate cancer, however, PSMA is expressed as a type 2 membrane protein with a large extracellular domain. PSMA expression increases approximately 1000-fold with disease progression. PSMA also possesses carboxypeptidase activities that may play a role in metastasis. For these reasons, PSMA represents a highly attractive target for active immunotherapy of prostate cancer. The goal of this Phase II project is advance our recombinant soluble PSMA (rsPSMA) vaccine into human clinical testing to prevent and/or reverse disease progression. The rsPSMA vaccine is a novel construct that comprises the extracellular domain of PSMA plus an immunostimulatory adjuvant. In the Phase I project, we developed procedures for producing and purifying rsPSMA in a manner that preserves its native conformation. Like native, cell-surface PSMA, the rsPSMA protein was discovered to form a noncovalent dimer, and only the dimeric form of rsPSMA was enzymatically active and capable of inducing high levels of antibodies that cross-react with PSMA-expressing tumor cells. The findings provide important proof-of-concept for our rsPSMA vaccine. In addition, these novel insights into PSMA structure-function relationships have important implications for PSMA vaccine design and development. The Phase II project seeks to complete critical preclinical development and clinical manufacturing activities required to initiate human testing. We will also optimize the ability of the vaccine to break tolerance in an innovative PSMA transgenic animal model. These activities culminate in a first-in-humans study of this novel vaccine therapy in prostate cancer. If successful in inducing anti-PSMA antibodies in man, the rsPSMA vaccine would represent a promising new mode of therapy for use alone or in prime-boost combinations with vaccines that induce potent cellular immunity.