MAb-based targeted chemotherapy of lung cancer

基于单克隆抗体的肺癌靶向化疗

• 批准号: 7611218
• 负责人: SERENGULAM V GOVINDAN
• 金额: $ 72.47万
• 依托单位: IMMUNOMEDICS, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7611218
• 关键词: Accounting; Animals; Antibodies; Antineoplastic Agents; Area; Biodistribution; Bone Marrow; Cancer Etiology; Cancer Patient; Cell Line; Clinical; Clinical Trials; Cyclic GMP; Development; Dose; Evaluation; Gastrointestinal tract structure; Goals; Government; Human; Immunoconjugates; Investigational New Drug Application; Life; Link; Lung Adenocarcinoma; Macaca fascicularis; Malignant Neoplasms; Malignant neoplasm of lung; Modeling; Monkeys; Monoclonal Antibodies; Non-Small-Cell Lung Carcinoma; Nude Mice; Patients; Persons; Pharmaceutical Preparations; Pharmacology; Phase; Phase I Clinical Trials; Preparation; Process; Property; Public Health; Purpose; Radiolabeled; Refractory; Research; SN-38; Safety; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Survival Rate; Testing; Therapeutic; Tissues; Topoisomerase; Topoisomerase-I Inhibitor; Toxic effect; Toxicology; Translations; Treatment Efficacy; United States Food and Drug Administration; Work; Xenograft Model; antigen binding; base; cancer site; cancer therapy; chemotherapy; cross reactivity; design; immunogenicity; inhibitor/antagonist; irinotecan; mortality; mouse model; nonhuman primate; novel; novel therapeutics; pre-clinical; preclinical study; programs; radiotracer; scale up; targeted delivery; therapeutic target; tumor

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.

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％。由于现有疗法并未显着提高生存率，因此迫切需要开发可以增加现有疗法的新疗法。拟议工作的目的是生产一种安全有效的靶向化疗，以治疗非小细胞肺癌（NSCLC）。为此，在SBIR I期研究中设计和评估了与有效的拓扑异构酶1抑制剂SN-38相关的快速内在化，人性化的抗EGP-1 MAB HRS7。旨在允许该药物完整的肿瘤内解放的免疫缀合物，维持其抗原结合特性和药物效力，并在肺腺癌的裸小鼠模型中产生了显着的特定治疗功效。此外，比治疗所用的剂量大7倍是无毒的。该药物成分是已经批准的癌症药物CPT-11的药理活性形式，这是有利的，因为与该药物有关的安全问题已经有很好的证明。成功的SBIR I期可行性研究预示着将新型治疗策略转化为新型的潜力。 II期计划将重点关注CGMP制造和扩展临床前研究。具体而言，将对结合制造商进行优化，其存储格式将被最终确定，并且将准备并评估两个CGMP批次（2 g）和两个CGMP批次（2W5 g），并评估货架寿命稳定性。该产物将在第二个非小细胞肺癌和CPT-11-耐磨模型的第二个模型中进行评估，该模型测试了由于药物和接头引起的潜在免疫原性，并评估了裸鼠的治疗窗口和毒性。最重要的是，产品安全将在非人类灵长类动物中确定，该物种将描绘人类的安全起始剂量。最后，将向FDA提交一项调查新药申请，以批准在SBIR III期时期内NSCLC患者的I临床阶段剂量降低试验。公共卫生相关性：肺癌是全球最常见的恶性肿瘤之一，而5年的生存率仅为15％。迫切需要继续进行新疗法的努力。拟议项目的最终目标是使用肿瘤选择性的单克隆抗体和高度有效的癌症药物CPT-11，开发一种更安全，更有效的靶向化疗对非小细胞肺癌的化疗。