PSMA Antibody-Drug Conjugate for Prostate Cancer Therapy

描述(申请人提供)：前列腺癌是美国最常见的男性癌症，2006年预计新增234,460例，死亡27,350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都对激素无效，然后迅速发展。激素难治性前列腺癌(HRPC)具有明显的化疗耐药性。唯一被批准的化疗(多西紫杉醇联合泼尼松)提供了适度的生存益处；因此，迫切需要新的、有针对性的治疗策略。抗体-药物结合物(ADC)结合了单抗的分子靶向性和强大的细胞毒药物的化疗特性，在靶向癌症治疗方面具有很大的前景。前列腺特异性膜抗原(PSMA)是前列腺癌的典型细胞表面标志。PSMA是一种完整的、不脱落的膜蛋白，几乎在所有前列腺癌中都有大量表达。PSMA的表达随着疾病进展而增加，在HRPC中表达最高。此外，PSMA在单抗结合后迅速内化，从而促进化疗药物进入胞浆。由于PSMA在正常组织中的表达有限，它是前列腺癌ADC治疗的一个引人注目的靶点。在第一阶段项目中，我们展示了一种新型ADC的令人信服的临床前概念验证，该ADC包含一种高亲和力的全人PSMA单抗，通过条件不稳定的二肽连接物连接到一种有效的金黄色药物，这是一项正在与西雅图遗传公司合作开发的新兴技术。PSMA ADC在体外通过抗分裂机制消除了表达PSMA的前列腺癌细胞，具有皮摩尔效力和近1000倍的选择性。在一个严格的HRPC异种移植模型中，耐受性良好的PSMA ADC控制了已建立的人类肿瘤，使一些动物的中位存活率和完全缓解提高了9倍。PSMA ADC在体外和体内的有效和选择性的抗肿瘤活性为在第二阶段项目中加速开发这一有希望的方法提供了强有力的理论基础。在第二阶段项目中，我们寻求完成最终的临床前安全性和药理学研究，以支持这种新制剂的人体试验。我们首先将开发和扩大生产和测试PSMA ADC毒理学批量的程序。在第二个目标中，我们将在相关的非人类灵长类物种中进行IND毒理学研究。同时，我们将对使用放大工艺制造的产品进行验证性异种移植有效性研究。第二阶段项目的成功被定义为展示良好的临床前安全性和活性特征，以支持对有前景的HRPC分子靶向治疗的人体测试。前列腺癌是美国最常见的男性癌症，是癌症死亡的第二大原因。局限性前列腺癌通常通过手术和/或放射治疗，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。激素难治性前列腺癌(HRPC)已被证明对传统化疗具有很大的耐药性。除了姑息治疗，唯一被批准的治疗HRPC的化疗是多西紫杉醇联合强的松，这种治疗提供了一个温和的(2.4个月)的生存增加。因此，迫切需要新的、分子靶向的治疗方法来治疗疾病的所有阶段，但最关键的是激素抵抗型和转移性肿瘤。

DESCRIPTION (provided by applicant): 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. Prostate cancer is the most common cancer of men in the United States and represents the second leading cause of cancer death. Localized prostate cancer typically is treated with surgery and/or radiation, and recurrent disease can be controlled temporarily with androgen ablation. However, almost all prostate carcinomas eventually become hormone refractory and then rapidly progress. Hormone-refractory prostate cancer (HRPC) has proven to be largely resistant to conventional chemotherapy. With the exception of palliative care, the only approved chemotherapy for HRPC is docetaxel in combination with prednisone, and this treatment provides a modest (2.4 month) increase in survival. Therefore, there is an urgent need for new, molecularly-targeted therapies for all stages of disease, but most critically for hormone-refractory and metastatic tumors.