MAb-based targeted chemotherapy of lung cancer

基于单克隆抗体的肺癌靶向化疗

• 批准号: 7688493
• 负责人: SERENGULAM V GOVINDAN
• 金额: $ 23.97万
• 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/7688493
• 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; GMP lots; 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; Radiolabeled; Refractory; Research; SN-38; Safety; Small Business Innovation Research Grant; Survival Rate; Testing; Therapeutic; Tissues; Topoisomerase; Topoisomerase-I Inhibitor; Toxic effect; Toxicology; Translations; Treatment Efficacy; 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 evaluation; preclinical study; product development; programs; public health relevance; 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（申请人提供）：肺癌是全球最常见的恶性肿瘤之一，5年生存率仅为15%。由于现有疗法不能显著提高存活率，因此迫切需要开发能够增强现有疗法的更新疗法。本研究的目的是寻找一种安全有效的靶向化疗药物治疗非小细胞肺癌（NSCLC）。为此，在SBIR I期研究中设计并评价了与强效拓扑异构酶1抑制剂SN-38连接的快速内化、人源化抗EGP-1 MAb hRS 7。该免疫偶联物设计为允许药物完整的瘤内释放，保持其抗原结合特性和药物效力，并在肺腺癌的裸鼠模型中产生显著和特异性的治疗功效。此外，比治疗所用剂量大7倍的剂量是无毒的。药物成分是已经批准的癌症药物CPT-11的活性形式，这是有利的，因为与药物相关的安全性问题已经有了很好的记录。成功的SBIR I期可行性研究预示着转化为新型治疗策略的高潜力。II期项目将专注于cGMP生产和扩大的临床前研究。具体而言，将优化结合物生产，最终确定其储存格式，并制备1个非GMP批次（2 g）和2个cGMP批次（2 W 5 g）的结合物，并评价其有效期稳定性。将在第二个非小细胞肺癌模型和CPT-11难治性模型中评价产品，检测药物和接头的潜在免疫原性，并评估裸鼠中的治疗窗和毒性。最重要的是，将在非人灵长类动物种属中确定产品安全性，这将描述人体的安全起始剂量。最后，将向FDA提交研究性新药申请，以获得批准，在SBIR III期阶段在NSCLC患者中开始临床I期剂量递增试验。公共卫生相关性：肺癌是全球最常见的恶性肿瘤之一，5年生存率仅为15%。迫切需要继续努力开发新的疗法。拟议项目的最终目标是使用肿瘤选择性单克隆抗体和高效形式的抗癌药物CPT-11开发一种更安全，更有效的非小细胞肺癌靶向化疗。

项目成果

CEACAM5-targeted therapy of human colonic and pancreatic cancer xenografts with potent labetuzumab-SN-38 immunoconjugates.

• DOI: 10.1158/1078-0432.ccr-09-0586
• 发表时间: 2009-10-01
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Govindan SV;Cardillo TM;Moon SJ;Hansen HJ;Goldenberg DM
• 通讯作者: Goldenberg DM