ANTI-ANDROGEN RECEPTOR MABS FOR HUMAN PROSTATE CANCER

每年有超过10万例前列腺癌患者患有前列腺癌 在美国被确诊，是实体肿瘤中的第一个 美国男性癌症相关死亡的发病率和第二位 人口。然而，与前列腺癌有关的因素 除了雄激素的存在外，癌症的发生还不清楚。 最近，科学家们研究了癌基因扩增与肿瘤 抑制基因在前列腺组织中的表达，并未能建立 这些基因的表达与前列腺癌的关系 致癌。另一方面，已经表明转移性 前列腺癌患者治疗前血浆睾酮水平较高 当接受初级治疗时，水平往往有更高的存活率 激素治疗比那些睾酮水平低的患者要好 诊断时间。因此，雄激素和雄激素受体(AR) 在前列腺癌的发生过程中，其表达可能起着重要作用。 最近，抗AR的单抗(Mab)已经问世 这使得AR水平及其在组织中的定位得到评估 有可能。然而，这些抗AR单抗仅仅是使用 作为免疫原的多肽片段。因此，这些单抗并不总是 有效地对组织进行染色，不与AR功能域发生反应。 因此，这些单抗的应用受到了限制。此外， 缺乏高亲和力的抗AR单抗和纯化的人AR蛋白 阻碍了一种方便的临床用酶联免疫吸附试验的发展 申请。在这份提案中，我们将重点放在生产和 致病昆虫细胞全长AR蛋白的纯化 携带AR基因的杆状病毒载体；这些蛋白将被用作 制备高亲和力抗AR单抗和发展免疫分析的免疫原 用于前列腺癌的临床应用。

Each year more than one hundred thousand cases of prostate cancer have been diagnosed in the United States and which is the first in solid tumor incidence and second in cancer related death in the American male population. Yet, the factors which are involved in prostate carcinogenesis, except for the presence of androgen, remain unclear. Recently, scientists have studied oncogene amplification and tumor suppressor gene expression in prostate tissue and failed to establish a relationship between the expression of these genes and prostate carcinogenesis. On the other hand, it has been shown that metastatic prostate cancer patients with higher pretreatment plasma testosterone levels tend to have a greater survival rate when receiving primary hormonal therapy than those patients with low testosterone levels at the time of diagnosis. Thus, the androgen and androgen receptor (AR) expression may play an important role during prostate carcinogenesis. Recently, the anti-AR monoclonal antibody (Mab) has become available which make the assessment of AR levels and their localization in tissues possible. However, these anti-AR Mabs were developed using merely peptide fragments as immunogens. Consequently, these Mabs do not always stain tissue effectively and do not react with AR functional domains. Thus, the application of these Mabs has been limited. In addition, the lack of high affinity anti-Ar mabs and purified human AR proteins has hampered the development of a convenient ELISA test for clinical applications. In this proposal we will focus on the production and purification of full-length AR proteins from insect cells infected with baculovirus vector carrying the AR gene; these proteins will be used as immunogens to produce high affinity anti-AR Mabs and develop immunoassays for the clinical applications in prostate cancer.