CC 1065 ANALOGS--IDEAL DRUGS FOR ANTICANCER CONJUGATES

具有高度细胞毒性的CC-1065类似物双吲哚-(Seco)-CBI已经被 通过二硫键连接到单抗上。这些 免疫结合物在体外被证明是高度有效的，在一种 靶向特定方式，在体内很容易达到的浓度。 在已确定的人类肿瘤中显示了显著的疗效。 免疫缺陷小鼠异种移植存活模型的建立。这项提案现在寻求 将这些令人兴奋的结果转化为新的抗癌药物 在人类临床试验中使用。 为实现这一目标，要分阶段实现具体目标 II包括：1)开发允许放大的流程 药物和人源化抗体的生产，2)并入 将为药物提供最大溶解度的取代基，以及 它的连接物，在不失去效力的情况下，3)开发连接物 将为这些结合物提供最佳的体内稳定性，4) 优化接合和纯化工艺以实现更大规模 结合物的规模化生产5)广泛的体外和体内 最终共轭化合物的评估。预计该项目的完成 第二阶段的提案将导致临床和 具有高度靶向性的具有重要商业价值的新型抗癌药物 效力、疗效和低全身毒性。 建议的商业应用：该项目的最终目标是 创造高选择性、高效率、低成本的新型抗癌药物 癌症治疗的全身性毒性。目前，没有 由于抗体-药物偶联，该领域的主要竞争产品 在治疗上是无效的。这项建议旨在开发新的 技术，以克服使目前的方法 抗体介导的抗癌药物靶向递送未获成功。

The highly cytotoxic CC-1065 analog bis-indolyl-(seco)-CBI has been conjugated to monoclonal antibodies via disulfide bonds. These immunoconjugates have been shown to be highly potent in vitro, in a target specific manner, at concentrations readily achievable in vivo. Significant efficacy was demonstrated in an established human tumor xenograft survival model in immunodeficient mice. This proposal now seeks to translate these exciting results into new anti-cancer agents to be used in clinical trails in humans. In order to realize this goal, the specific aims to be achieve in Phase II include: 1) Development of processes that allow the scaled up production of drug and 'humanized' antibody, 2) Incorporation of substituent groups that will provide maximum solubility to the drug and its conjugates, without losing potency, 3) Development of linkers that will provide optimal in vivo stability to these conjugates, 4) Optimization of conjugation and purification processes to enable larger scale production of conjugates 5) Extensive in vitro and in vivo evaluation of final conjugates. It is expected that the completion of the Phase II proposal will lead to the production of clinically and commercially important new anti-cancer agents with high target specific potency, efficacy, and low systemic toxicity. PROPOSED COMMERCIAL APPLICATION: The ultimate goal of this project is to create new anti-cancer agents with high selectivity, efficacy, and low systemic toxicity for the treatment of cancer. Currently, there are no major competitive products in the field because antibody-drug conjugates have been therapeutically ineffective. This proposal seeks to develop new technology to overcome the problems that have made current approaches to the antibody-mediated targeted delivery of drugs for cancer unsuccessful.