MAb-based targeted chemotherapy of lung cancer

描述(申请人提供)：肺癌是世界上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。利用单抗药物免疫结合物进行的单抗导向的肿瘤化疗是一个活跃的探索领域。这项拟议工作的目标是生产一种安全有效的单抗-药物结合物，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，并在人NSCLC裸鼠移植瘤中进行评估。HRS7单抗的内化提供了选择性地在肿瘤部位积累高浓度药物的机会，而单抗和药物之间的连接物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，因为与该药物相关的安全问题已经有了很好的记录。SBIR第一阶段项目的一个目标是优化已经设计的hRS7-SN-38结合物制剂，而中心目标是证明这种免疫结合物在治疗裸鼠皮下移植的人肺腺癌方面是有效的。该项目的可行性将通过以下方面证明：(1)实现每hRS7单抗分子替代6-8个药物分子的优化结合物制备，(2)证明该结合物在抗原结合和内化特性方面与未经修饰的单抗相似，(3)确定该结合物在生理条件下孵育是稳定的，(4)发现hRS7-SN-38结合物在治疗荷人肺癌裸鼠移植瘤方面具有特异而显著的疗效。这些目标的成功实现将为SBIR第二阶段计划奠定基础，以便对免疫结合物进行更详细的表征，扩大临床前治疗研究，在正常组织中进行表达EGP-1抗原的非人类灵长类物种的毒理学研究，并提交IND申请，在非小细胞肺癌患者中进行试点临床第一阶段试验。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。拟议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。

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.