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，也是他们癌症死亡的第二大原因。局部前列腺癌通常通过手术和/或放射治疗，复发性疾病可以通过雄激素消融术暂时控制。然而，几乎所有的前列腺癌最终成为激素难治性的，然后迅速发展。前列腺癌已被证明对常规化疗有很大的耐药性，目前对于晚期转移性疾病还没有有效的治疗方法。因此，迫切需要一种新的分子靶向治疗方法，可以选择性地杀死前列腺癌细胞而不产生全身毒性。前列腺特异性膜抗原（PSMA）是一种特征明确的糖蛋白，其表达主要局限于前列腺上皮细胞。在正常组织中，PSMA作为剪接变体存在，缺乏跨膜结构域，因此保留在细胞质中。然而，在肿瘤细胞上，PSMA表达为2型膜蛋白，具有较大的细胞外结构域。随着疾病进展，PSMA的表达增加约1000倍，并且该蛋白在构成性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一个有吸引力的靶点。

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.