MAb-based targeted chemotherapy of lung cancer

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%。由于现有的治疗方法不能显著提高生存率，因此迫切需要开发新的治疗方法来增强现有的治疗方法。这项工作的目标是开发一种安全有效的靶向化疗药物来治疗非小细胞肺癌（NSCLC）。为此，我们设计了一种快速内化、人源化的抗egp -1单抗hRS7，它与一种有效的拓扑异构酶1抑制剂SN-38相连，并在SBIR I期研究中进行了评估。在肺腺癌裸鼠模型中，该免疫偶联物保持了其抗原结合特性和药物效力，并产生了显著的特异性治疗效果。此外，比治疗剂量大7倍的剂量是无毒的。药物成分是已经批准的抗癌药物CPT-11的药理活性形式，这是有利的，因为与药物相关的安全性问题已经有很好的记录。成功的SBIR I期可行性研究预示着将其转化为新的治疗策略的巨大潜力。二期项目将专注于cGMP生产和扩大临床前研究。具体来说，将优化缀合物的生产，最终确定其储存形式，并制备和评估该缀合物的非gmp批次（2g）和两个cGMP批次（2W5 g）的货架期稳定性。该产品将在第二种非小细胞肺癌模型和cpt -11难治模型中进行评估，测试药物和连接物的潜在免疫原性，并评估裸小鼠的治疗窗口和毒性。最重要的是，该产品的安全性将在非人类灵长类动物中确定，这将划定人类的安全起始剂量。最后，将向FDA提交一份研究性新药申请，以批准在SBIR III期的NSCLC患者中开展临床I期剂量递增试验。公共卫生相关性：肺癌是世界上最常见的恶性肿瘤之一，其5年生存率仅为15%。迫切需要继续努力开发新的治疗方法。该项目的最终目标是开发一种更安全、更有效的非小细胞肺癌靶向化疗，使用肿瘤选择性单克隆抗体和高效形式的癌症药物CPT-11。

DESCRIPTION (provided by applicant): Lung cancer is one of the most common malignancies worldwide, and the 5-year survival rate is only 15%. As existing therapies do not significantly increase survival rate, there is an urgent need to develop newer therapies that can augment the existing treatments. The goal of the proposed work is to produce a safe and effective targeted chemotherapy for the treatment of non-small cell lung cancer (NSCLC). To this end, a rapidly internalizing, humanized, anti-EGP-1 MAb, hRS7, linked to a potent topoisomerase 1 inhibitor, SN-38, was designed and evaluated in the SBIR Phase I study. The immunoconjugate, which was designed to allow for the intact intratumoral liberation of the drug, maintained its antigen-binding property and drug potency, and produced significant and specific therapeutic efficacy in a nude mouse model of lung adenocarcinoma. In addition, a 7-fold greater dose than that used for therapy was nontoxic. The drug component is the pharmacologically active form of an already approved cancer drug, CPT-11, which is advantageous in that the safety issues related to the drug are already well documented. The successful SBIR Phase I feasibility research portends a high potential for translation to novel therapeutic strategies. The Phase II program will focus on cGMP manufacture and expanded preclinical studies. Specifically, the conjugate manufacture will be optimized, its storage format will be finalized, and a non-GMP lot (2 g) and two cGMP lots (2W5 g) of the conjugate will be prepared and evaluated for shelf-life stability. The product will be evaluated in a second model of non-small cell lung cancer and a CPT-11-refractory model, tested for potential immunogenicity due to the drug and the linker, and assessed for therapeutic window and toxicity in nude mice. Most importantly, the product safety will be determined in a non-human primate species, which will delineate the safe starting dose in human. Finally, an Investigational New Drug application will be submitted to the FDA for approval to start a clinical Phase I dose-escalation trial in NSCLC patients in the SBIR Phase III period. PUBLIC HEALTH RELEVANCE: Lung cancer is one of the most common malignancies worldwide, and the 5-year survival rate is just 15%. Continued efforts with newer therapies are urgently needed. The ultimate goal of the proposed project is to develop a safer and more efficacious targeted chemotherapy of non-small cell lung cancer using a tumor-selective monoclonal antibody and the highly potent form of the cancer drug, CPT-11.