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%。由于现有的治疗方法不能显著提高存活率，因此迫切需要开发新的治疗方法来增强现有的治疗方法。这项拟议工作的目标是为非小细胞肺癌(NSCLC)的治疗提供一种安全有效的靶向化疗。为此，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第一阶段研究中进行了评估。该免疫结合物的设计允许药物在肿瘤内的完整释放，保持了其抗原结合特性和药物效力，并在裸鼠肺腺癌模型中产生了显著和特异的治疗效果。此外，比用于治疗的剂量大7倍的剂量是无毒的。该药物成分是一种已获批准的抗癌药物CPT-11的药理活性形式，其优势在于与该药物相关的安全性问题已经得到了很好的证明。成功的SBIR第一阶段可行性研究预示着转化为新的治疗策略的潜力很大。第二阶段计划将侧重于cGMP的制造和扩大的临床前研究。具体地说，将优化结合物的制造，最后确定其存储格式，并将制备一批非GMP批次(2克)和两批cGMP批次(2W5克)的结合物，并对其货架期稳定性进行评估。该产品将在第二个非小细胞肺癌模型和CPT-11耐药模型中进行评估，测试药物和连接物的潜在免疫原性，并评估裸鼠的治疗窗口和毒性。最重要的是，产品的安全性将在非人类灵长类物种中确定，这将描绘出人类的安全起始剂量。最后，研究性新药申请将提交FDA批准，以便在SBIR III期在非小细胞肺癌患者中启动I期临床剂量递增试验。与公共卫生相关：肺癌是世界上最常见的恶性肿瘤之一，5年存活率仅为15%。迫切需要用新的疗法继续努力。拟议项目的最终目标是利用肿瘤选择性单抗和高度有效的抗癌药物CPT-11开发一种更安全、更有效的非小细胞肺癌靶向化疗。

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.