PSMA Antibody-Drug Conjugate for Prostate Cancer Therapy

摘要 前列腺癌是美国男性最常见的癌症，预计新增234，460例 2006年有27，350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都变得激素难治，然后迅速进展。荷尔蒙- 难治性前列腺癌（HRPC）明显具有化学抗性。唯一批准的化疗（多西他赛， 联合泼尼松）提供了适度的生存益处;因此， 迫切需要战略。抗体-药物缀合物（ADC）联合收割机结合了抗体的分子靶向作用， 单克隆抗体（mAb）具有强效细胞毒性药物的化疗特性， 作为靶向癌症治疗的前景。 前列腺特异性膜抗原（PSMA）是前列腺癌的原型细胞表面标志物。 PSMA是一种完整的非脱落膜蛋白，在几乎所有的前列腺增生中大量表达。 癌PSMA表达随着疾病进展而增加，并且在HRPC中最高。此外，本发明还提供了一种方法， PSMA在mAb结合后迅速内化，从而促进将化疗药物引入细胞内。 细胞质鉴于其在正常组织中的有限表达，PSMA代表了ADC的一个引人注目的靶点。 前列腺癌的治疗 在I期项目中，我们展示了新型ADC的令人信服的临床前概念验证 包含通过条件不稳定的寡核苷酸连接到有效的澳瑞他汀药物的高亲和力、完全人PSMA mAb， 二肽接头，这是与西雅图遗传学公司合作开发的一种新兴技术。PSMA ADC以皮摩尔效力消除了PSMA表达的前列腺癌细胞， 通过抗有丝分裂机制的体外选择性。在严格的HRPC异种移植模型中，耐受良好的剂量 PSMA ADC控制已建立的人类肿瘤，导致中位生存期提高9倍， 一些动物完全缓解。PSMA ADC在体外和体内的有效和选择性抗肿瘤活性 vivo为II期项目中加速开发这种有前途的方法提供了强有力的理由。 在II期项目中，我们寻求完成明确的临床前安全性和药理学研究， 支持对这种新药剂进行人体测试我们首先将开发和扩大生产程序， 测试PSMA ADC的毒理学批次在第二个目标中，我们将在一个 相关的非人类灵长类物种。与此同时，我们将进行确认性异种移植有效性研究， 使用放大工艺生产的产品。第二阶段项目的成功定义为： 证明了有利的临床前安全性和活性特征，以支持有前途的 HRPC的分子靶向治疗。

ABSTRACT Prostate cancer is the most common cancer of men in the United States with an expected 234,460 new cases and 27,350 deaths in 2006. Recurrent disease can be controlled temporarily with androgen ablation. However, almost all prostate carcinomas become hormone refractory and then rapidly progress. Hormone- refractory prostate cancer (HRPC) is notably chemoresistant. The only approved chemotherapy (docetaxel in combination with prednisone) provides a modest survival benefit; therefore, novel, targeted therapeutic strategies are urgently needed. Antibody-drug conjugates (ADCs) combine the molecular targeting of a monoclonal antibody (mAb) with the chemotherapeutic properties of a potent cytotoxic drug and hold great promise as targeted cancer therapies. Prostate-specific membrane antigen (PSMA) is the prototypic cell-surface marker of prostate cancer. PSMA is an integral, non-shed membrane protein that is expressed abundantly in nearly all prostatic carcinomas. PSMA expression increases with disease progression and is highest in HRPC. In addition, PSMA internalizes rapidly upon mAb binding, thus facilitating the introduction of chemotherapeutic drugs into the cytosol. Given its limited expression in normal tissues, PSMA represents a compelling target for ADC therapy of prostate cancer. In the Phase I project, we demonstrated compelling preclinical proof-of-concept for a novel ADC comprising a high-affinity, fully human PSMA mAb linked to a potent auristatin drug via a conditionally labile dipeptide linker, an emerging technology being developed in collaboration with Seattle Genetics, Inc. PSMA ADC eliminated PSMA-expressing prostate cancer cells with picomolar potency and nearly 1000-fold selectivity in vitro via antimitotic mechanisms. In a stringent xenograft model of HRPC, well-tolerated doses of PSMA ADC controlled established human tumors resulting in a 9-fold improvement in median survival and complete remission in some animals. The potent and selective antitumor activity of PSMA ADC in vitro and in vivo provides strong rationale for accelerated development of this promising approach in the Phase II project. In the Phase II project, we seek to complete definitive preclinical safety and pharmacology studies to support human testing of this new agent. We first will develop and scale-up procedures for manufacturing and testing a toxicology lot of PSMA ADC. In a second aim, we will perform IND-enabling toxicology studies in a relevant non-human primate species. In parallel, we will perform confirmatory xenograft efficacy studies of the product manufactured using the scaled-up process. Success in the Phase II project is defined as demonstrating favorable preclinical safety and activity profiles to support human testing of a promising molecularly targeted therapy for HRPC.