CC 1065 ANALOGS--IDEAL DRUGS FOR ANTICANCER CONJUGATES

高度细胞毒性的CC-1065类似物双吲哚基-（seco）-CBI已经被研究。 通过二硫键与单克隆抗体偶联。这些 免疫缀合物已经显示出在体外、在一种 靶向特异性方式，在体内容易达到的浓度。 在已建立的人类肿瘤中证明了显著的疗效 免疫缺陷小鼠异种移植物存活模型。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， 用于人体临床试验。 为了实现这一目标，分阶段要达到的具体目标是 1）开发允许扩大规模的工艺， 药物和“人源化”抗体的生产，2） 将为药物提供最大溶解度的取代基， 其缀合物，而不丧失效力，3）开发 将为这些缀合物提供最佳的体内稳定性，4） 优化缀合和纯化过程，以实现更大的 5）广泛的体外和体内研究 最终缀合物的评价。预计， 第二阶段的建议将导致生产临床和 具有高靶点特异性的商业上重要的新抗癌剂 效力、功效和低全身毒性。 建议的商业应用：该项目的最终目标是 创造具有高选择性、有效性和低成本的新型抗癌剂， 用于治疗癌症的全身毒性。目前没有 抗体-药物缀合物是该领域的主要竞争产品， 治疗无效该提案旨在开发新的 技术，以克服问题，使目前的方法， 抗体介导的癌症靶向药物递送不成功。

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.