Human PSMA MAb Radioimmunotherapy for Prostate Cancer

前列腺癌是美国最常见的男性癌症，2002年新增病例约18.9万例，死亡3万例。复发的疾病可以通过雄激素消融暂时控制。然而，几乎所有的前列腺癌最终都会变成激素耐药，然后迅速发展。前列腺癌在很大程度上对传统化疗耐药，目前还没有有效的治疗晚期转移性疾病的方法。 因此，迫切需要治疗晚期前列腺癌。前列腺特异性膜抗原(PSMA)是一种广泛表达的糖蛋白。 仅限于前列腺上皮细胞。在正常前列腺中，PSMA以剪接变异体的形式存在，缺乏跨膜区，因此保留在细胞质中。然而，在前列腺癌中，PSMA以II型膜蛋白的形式表达，具有较大的胞外结构域。随着疾病的进展，PSMA的表达增加约1000倍。PSMA还具有羧肽酶活性，可能在肿瘤转移中发挥作用。出于这些原因，PSMA是前列腺癌免疫治疗的一个极具吸引力的靶点。 在第一阶段项目中，我们产生并鉴定了一组新的全人单抗(MAb)，它们识别人前列腺肿瘤细胞表面的PSMA。在对单抗进行了严格的分析后，我们选择了一种领先的候选抗体(称为PSMAb)，以推进临床开发。PSMAb以亚摩尔亲和力识别人PSMA的构象表位。重要的是，放射性标记形式的PSMAb可以 在体外和体内选择性地靶向并有效地杀伤表达PSMA的肿瘤细胞。 这一第二阶段项目的总体目标是推动PSMAb进入人体临床试验。为此，我们将在开发和实施生产临床级抗体的方法的同时，优化我们的铅放射性标记PSMAb构建在体外和最佳可用人类前列腺癌动物模型中的效力和特异性。在完成毒理学和额外的IND研究后，我们将开始 第一阶段人类临床试验旨在评估PSMAb在激素抵抗型前列腺癌中的安全性和靶向性。第二阶段项目的成功被定义为将一种有前景的新的分子靶向疗法引入到目前无法治疗的晚期前列腺癌的临床测试中。

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 for advanced prostate cancer. Prostate-specific membrane antigen (PSMA) is a well-characterized glyeoprotein 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 II membrane protein with a large extraeellular 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 immunotherapy of prostate cancer. In the Phase I project, we generated and characterized a novel panel of fully human monoclonal antibodies (MAbs) that recognize PSMA on the surface of human prostate tumor cells. After a rigorous analysis of the MAbs, we have selected a lead candidate (termed "PSMAb") to advance into clinical development. PSMAb specifically recognizes a conformational epitope of human PSMA with subnamolar affinity. Importantly, radiolabeled forms of PSMAb can selectively target and potently kill PSMA-expressing tumor cells both in vitro and in vivo. The overall goal of this Phase II project is to advance PSMAb into human clinical testing. To this end, we will optimize our lead radiolabeled PSMAb construct for potency and specificity in vitro and in the best available animal models of human prostate cancer in parallel with the development and implementation of methods for producing clinical-grade antibody. Following completion of toxicology and additional IND-enabling studies, we will commence a Phase 1 human clinical trial designed to evaluate the safety and targeting of PSMAb in hormone-refractory prostate cancer. Successin the Phase II project is defined as the introduction of a promising new molecularly targeted therapy into clinical testing for a currently untreatable form of advanced prostate cancer.