权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

MAb-based targeted chemotherapy of lung cancer

基于单克隆抗体的肺癌靶向化疗

基本信息

批准号：
7270215
负责人：
SERENGULAM V GOVINDAN
金额：
$ 11.43万
依托单位：
IMMUNOMEDICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2008-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7270215
关键词：
MAb based targeted chemotherapy lung

项目摘要

DESCRIPTION (provided by applicant): Lung cancer is one of the most common malignancies worldwide, and the 5-year survival rate is only 15%. Continued efforts with newer, more efficacious, therapies are warranted. Monoclonal-antibody (MAb)-directed cancer chemotherapy, using MAb-drug immunoconjugates, is an active area of exploration. The goal of the proposed work is to produce a safe and effective MAb-drug conjugate for the treatment of non-small-cell lung cancer (NSCLC). To this end, a rapidly internalizing, humanized, anti-EGP-1 MAb, hRS7, will be covalently linked to a potent topoisomerase 1 inhibitor, SN-38, which is the pharmacologically active form of the anti-cancer drug, CPT-11, and evaluated in human NSCLC xenografts in nude mice. Internalizing hRS7 MAb offers the opportunity to selectively accumulate a high concentration of the drug at the tumor sites, while the linker between the MAb and the drug will ensure that the drug is released in its native form. The choice of the drug, which is the active form of an already approved cancer drug, will be advantageous in that the safety issues related to the drug are already well documented. One objective of the SBIR Phase I project is to optimize the already designed hRS7- SN-38 conjugate preparation, while the central goal is to document that the immunoconjugate is efficacious in the therapy of subcutaneous human lung adenocarcinoma xenografts growing in athymic nude mice. The project feasibility will be documented by (1) achieving an optimized conjugate preparation with a substitution of 6-8 drug molecules per hRS7 MAb molecule, (2) demonstrating the similarity of the conjugate and the unmodified MAb in terms of antigen-binding and internalizing characteristics, (3) establishing that the conjugate is stable to incubation under physiological conditions, and (4) the finding of specific and significant efficacy of hRS7-SN-38 conjugate in the therapy of nude mice bearing human lung tumor xenografts. Successful achievement of these goals will set the stage for SBIR Phase II program for more detailed characterizations of the immunoconjugate, expanded preclinical therapy studies, toxicology studies in non-human primate species expressing the EGP-1 antigen in normal tissues, and the submission of an IND application for a pilot clinical Phase I trial in NSCLC patients. Lung cancer is one of the most common malignancies worldwide, and the 5-year survival rate is only 15%. Continued efforts with newer, more efficacious, therapies are warranted. The ultimate goal of the proposed project is to develop a safer and more efficacious targeted therapy of non-small-cell lung cancer using a tumor-selective antibody and the active drug form of the cancer therapeutic, CPT-11.

描述（申请人提供）：肺癌是世界范围内最常见的恶性肿瘤之一，5年生存率仅为15%。继续努力使用更新、更有效的治疗方法是必要的。单克隆抗体（MAb）靶向癌症化疗，使用单克隆抗体药物免疫偶联物，是一个活跃的探索领域。这项工作的目标是生产一种安全有效的单克隆抗体-药物偶联物，用于治疗非小细胞肺癌（NSCLC）。为此，一种快速内化、人源化的抗egp -1单抗hRS7将与一种有效的拓扑异构酶1抑制剂SN-38共价连接，SN-38是抗癌药物CPT-11的药理活性形式，并在裸鼠人类非小细胞肺癌异种移植中进行了评估。内化hRS7 MAb提供了选择性地在肿瘤部位积累高浓度药物的机会，而MAb和药物之间的连接将确保药物以其天然形式释放。这种药物是已经批准的抗癌药物的活性形式，选择这种药物将是有利的，因为与药物相关的安全问题已经有了很好的记录。SBIR一期项目的一个目标是优化已经设计的hRS7- SN-38偶联物制备，而中心目标是证明免疫偶联物在治疗生长在胸腺裸鼠体内的皮下人肺腺癌异种移植物方面是有效的。项目可行性将通过以下方式证明：(1)实现优化的偶联物制备，每个hRS7单抗分子取代6-8个药物分子；(2)证明偶联物与未修饰的单抗在抗原结合和内化特性方面的相似性；(3)确定偶联物在生理条件下对孵育是稳定的。(4) hRS7-SN-38偶联物对移植人肺肿瘤裸鼠的治疗具有特异性和显著的疗效。这些目标的成功实现将为SBIR II期项目奠定基础，以更详细地描述免疫偶联物的特征，扩大临床前治疗研究，在正常组织中表达EGP-1抗原的非人灵长类动物中进行毒理学研究，并为NSCLC患者的临床I期试验提交IND申请。肺癌是世界范围内最常见的恶性肿瘤之一，5年生存率仅为15%。继续努力使用更新、更有效的治疗方法是必要的。该项目的最终目标是利用肿瘤选择性抗体和癌症治疗药物CPT-11的活性药物形式，开发一种更安全、更有效的非小细胞肺癌靶向治疗方法。