PSMA-Targeted Immunotoxins for Prostate Cancer Therapy

描述(申请人提供)：前列腺癌是美国男性最常见的癌症，是导致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。前列腺癌已被证明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，迫切需要一种新颖的、分子靶向的治疗方法，这种疗法可以选择性地杀死前列腺癌细胞，而不会产生全身毒性。前列腺特异性膜抗原(PSMA)是一种功能齐全的糖蛋白，其表达主要限于前列腺上皮细胞。在正常组织中，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，在肿瘤细胞中，PSMA表达为一种具有较大胞外结构域的2型膜蛋白。随着疾病的进展，PSMA的表达增加了大约1000倍，并且该蛋白在成分上和抗体结合后都被迅速内化。由于这些原因，PSMA被广泛认为是前列腺癌抗体治疗的一个有吸引力的靶点。 我们寻求开发新型和高度有效的PSMA靶向免疫毒素疗法来治疗前列腺癌。我们之前开发了一个完全由人类单一开发的新小组，这种治疗方法可以增强化疗的疗效，这将是一个重大的进步。与分散在PSMA胞外区的表位具有高亲和力结合的克隆性抗体。在本项目中，我们将利用这些单抗在体外和体内将超强细胞毒剂特异性地输送到表达PSMA的肿瘤细胞。该项目提出了第一个基于有效蛋白质和药物细胞毒素的免疫毒素的面对面评估。我们将首先优化将蛋白质和药物毒素与最有希望的全人PSMA单抗结合的程序。然后对蛋白质和药物免疫毒素在体外消除前列腺癌细胞的效力和选择性进行比较评估。然后，优化的免疫毒素将在最好的人类前列腺癌临床前模型中进行免疫原性、药理学和抗肿瘤效果测试。这些研究将使我们能够确定具有总体最大治疗潜力的单抗-毒素结构。然后，该候选产品将在第二阶段项目中进入人体临床测试。该项目的总体目标是利用全人类抗体、超强细胞毒素和人类前列腺癌小动物模型等领域的创新技术，以最佳方式利用PSMA作为癌症治疗的分子靶点。

DESCRIPTION (provided by applicant): Prostate cancer is the most common cancer of men in the United States and represents their 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. Prostate cancer has proven to be largely resistant to conventional chemotherapy, and currently there is no effective treatment for advanced, metastatic disease. Thus, there is an urgent need for novel, molecularly targeted therapies that can selectively kill prostate cancer cells without systemic toxicity. Prostate-specific membrane antigen (PSMA) is a well-characterized glycoprotein whose expression is largely restricted to prostate epithelial cells. In normal tissues, PSMA exists as a splice variant that lacks the transmembrane domain and is thereby retained in the cytoplasm. On tumor cells, however, PSMA is expressed as a type 2-membrane protein with a large extracellular domain. PSMA expression increases approximately 1000-fold with disease progression, and the protein is rapidly internalized both constitutively and following antibody binding. For these reasons, PSMA is widely regarded as being an attractive target for antibody-based therapy of prostate cancer. We seek to develop novel and highly potent PSMA-targeted immunotoxin therapies for prostate cancer. We previously developed a novel panel of fully human monodevelopment of a therapy that augments efficacy of chemotherapy would be a major advance. Clonal antibodies (mAbs) that bind with high affinity to epitopes scattered throughout the extracellular domain of PSMA. In this project, we will utilize these mAbs to specifically deliver ultrapotent cytotoxic agents to PSMA-expressing tumor cells in vitro and in vivo. The project proposes the first head-to-head evaluation of immunotoxins based on potent protein and drug cytotoxins. We will first optimize procedures for conjugating the protein and drug toxins to our most promising fully human PSMA mAbs. The protein and drug immunotoxins then will be comparatively evaluated for potency and selectivity in eliminating prostate cancer cells in vitro. The optimized immunotoxins then will be tested for immunogenicity, pharmacology, and antitumor effects in the best available preclinical models of human prostate cancer. These studies will enable us to identify the mAb-toxin construct that has the overall greatest therapeutic potential. This product candidate then will be advanced into human clinical testing in the Phase II project. The overall goal of this project is to optimally exploit PSMA as a molecular target for cancer therapy using innovative technologies in the areas of fully human antibodies, ultrapotent cytotoxins, and small-animal models of human prostate cancer.