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（由申请人提供）：肺癌是全球最常见的恶性肿瘤之一，5年的生存率仅为15％。有必要以更新，更有效的疗法进行努力。单克隆抗体（MAB）指导的癌症化学疗法，使用mab-prug免疫偶联物是一个活跃的探索领域。拟议的工作的目的是生产一种安全有效的mab-grug结合物来治疗非小细胞肺癌（NSCLC）。为此，快速内在的，人源化的抗EGP-1 mAb，HRS7将共价链接到有效的拓扑异构酶1抑制剂SN-38，这是抗癌药物的药理活性形式CPT-111并在裸鼠的人NSCLC异种移植物中进行了评估。内部化HRS7 MAB提供了在肿瘤部位选择性积累高浓度的药物的机会，而MAB和药物之间的接头将确保该药物以其天然形式释放。该药物的选择是已经批准的癌症药物的主动形式，将是有利的，因为与该药物有关的安全问题已经有充分的记录。 SBIR I期项目的一个目的是优化已经设计的HRS7-SN-38共轭制剂，而核心目标是记录免疫共轭物在对皮下的人肺肺腺癌异种植物的治疗中有效。该项目的可行性将通过（1）实现优化的共轭制剂，每HRS7 mAb分子的替代6-8药物分子，（2）证明了结合物的相似性和未经修饰的mab在抗原结合和内在化方面特征，（3）确定结合物在生理条件下与孵育稳定，以及（4）发现HS7-SN-38结合物在携带人肺肿瘤异种移植物的裸小鼠治疗中发现了特定而显着的疗效。这些目标的成功实现将为SBIR II期计划奠定阶段，以对免疫缀合物的更详细特征，扩展的临床前治疗研究，非人类灵长类动物的毒理学研究，表达正常组织中EGP-1抗原的毒理学研究，以及提出的EGP-1抗原在NSCLC患者中，IND申请了试点I期试验。肺癌是全球最常见的恶性肿瘤之一，而5年的存活率仅为15％。有必要以更新，更有效的疗法进行努力。拟议项目的最终目标是使用肿瘤选择性抗体和癌症治疗性的活性药物CPT-11开发一种对非小细胞肺癌的更安全，更有效的靶向疗法。