PSMA-Targeted Immunotoxins for Prostate Cancer Therapy

描述（由申请人提供）：前列腺癌是美国男性最常见的癌症，是癌症死亡的第二大原因。局限性前列腺癌通常用手术和/或放射治疗，复发性疾病可以用雄激素消融术暂时控制。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。前列腺癌已被证明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，迫切需要新型的分子靶向治疗，可以选择性地杀死前列腺癌细胞，而没有全身毒性。 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。在正常组织中，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，在肿瘤细胞上，PSMA表达为具有大的胞外结构域的2型膜蛋白。PSMA表达随着疾病进展增加约1000倍，并且蛋白质在组成型和抗体结合后迅速内化。由于这些原因，PSMA被广泛认为是基于抗体的前列腺癌治疗的有吸引力的靶标。 我们寻求开发新的和高效的PSMA靶向免疫毒素治疗前列腺癌。我们以前开发了一种新的全人类单克隆抗体，开发一种增强化疗疗效的疗法将是一个重大进展。 克隆抗体（mAb）以高亲和力结合分散在PSMA胞外域的表位。在这个项目中，我们将利用这些单克隆抗体，在体外和体内特异性地将超强效细胞毒性剂递送到表达PSMA的肿瘤细胞。该项目提出了第一个基于强效蛋白质和药物细胞毒素的免疫毒素的头对头评估。我们将首先优化将蛋白质和药物毒素缀合到我们最有前途的全人PSMA mAb的程序。然后将比较评估蛋白质和药物免疫毒素在体外消除前列腺癌细胞中的效力和选择性。然后将在最佳的人前列腺癌临床前模型中测试优化的免疫毒素的免疫原性、药理学和抗肿瘤作用。这些研究将使我们能够确定具有整体最大治疗潜力的mAb-毒素构建体。该候选产品随后将在II期项目中进入人体临床试验。该项目的总体目标是最佳地利用PSMA作为癌症治疗的分子靶点，使用全人抗体，超强效细胞毒素和人类前列腺癌小动物模型领域的创新技术。

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.