An anti-CD74 MAb-drug conjugate for B-cell malignancies

用于治疗 B 细胞恶性肿瘤的抗 CD74 MAb 药物缀合物

• 批准号: 7681072
• 负责人: SERENGULAM V GOVINDAN
• 金额: $ 30.98万
• 依托单位: IMMUNOMEDICS, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7681072
• 关键词: Acute; Animals; Antibodies; B lymphoid malignancy; B-Lymphocytes; Biological Assay; Cardiac Myocytes; Cardiotoxicity; Cells; Clinical Trials; Complement; Cyclic GMP; Data; Development; Disease; Dose; Doxorubicin; Evaluation; Freeze Drying; Goals; Human; Immune; Immunoconjugates; In Vitro; Investigational New Drug Application; Life; Link; Liquid substance; Macaca fascicularis; Malignant Neoplasms; Monkeys; Monoclonal Antibodies; Multiple Myeloma; Mus; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Plasma Cells; Preparation; Procedures; Process; Radiolabeled; Rattus; Site; Small Business Innovation Research Grant; Staging; Survival Rate; Testing; Time; Tissues; Toxic effect; Toxicology; Validation; Work; Xenograft Model; antibody conjugate; chemotherapy; clinical application; comparative; humanized monoclonal antibodies; invariant chain; nonhuman primate; pre-clinical; preclinical efficacy; preclinical evaluation; radiotracer; reconstitution; research clinical testing; research study; scale up; sobriety; tumor; tumor xenograft

DESCRIPTION (provided by applicant): The goal of this work is to develop an antibody-doxorubicin conjugate for the targeted therapy of B-cell cancers that express the CD74 antigen. The Phase II project will focus on advancing this product for multiple myeloma, a common plasma cell malignancy that is incurable at this time. The average 5-year survival rate for these patients is only 30%, and there is thus a continued need for the development of newer therapies. The proposed product consists of a unique, humanized, anti-CD74 monoclonal antibody linked covalently to multiple molecules of the chemotherapeutic, doxorubicin. This agent was shown previously to induce dramatic cures in immune-compromised mice carrying human tumor xenografts of the disease. The emphasis will be on cGMP manufacture and preclinical toxicology evaluation. Using the existing optimized procedure, a preliminary non-GMP preparation of the conjugate will be undertaken to test the scale-up process under controlled conditions, followed by a 5-g preparation and a 10-g preparation under cGMP conditions. Other aspects of the project will pertain to determinations of product stabilities to protracted storage, and validation of assays for various characterization and product-release criteria. Comparative cardiotoxicity of the conjugated versus free form of the drug will be assayed in an in vitro experiment. Preclinical toxicology of the product will be evaluated in cynomolgus monkeys, non-human primate species expressing the CD74 antigen similar to humans. This experiment will build on a previous single-dose toxicity study, and determine acute toxicity, if any, engendered by repeat-administrations of the antibody-doxorubicin conjugate, at increasing dose levels, in the animal species that is most predictive of human toxicology. In addition, non-specific toxicity will also be evaluated in normal rats using doses of the conjugated form of doxorubicin that are one to two orders of magnitude greater than the anticipated starting dose in a Phase I clinical trial. Finally, an Investigational New Drug application will be prepared and submitted to the FDA. Completion of these essential tasks should advance the product to the stage of clinical evaluation in multiple myeloma patients, expected to start in the SBIR Phase III period. PUBLC HEALTH RELEVENCE: Multiple myeloma (MM), a common plasma cell cancer, is incurable at the present time. The average 5-year survival rate is just 30%. The goal of the proposed project is to develop a safer and a more efficacious targeted chemotherapy of MM using a unique tumor-selective antibody, which can complement or augment existing therapies.

描述（由申请人提供）：这项工作的目标是开发一种抗体-阿霉素缀合物，用于表达 CD74 抗原的 B 细胞癌的靶向治疗。二期项目将专注于推进该产品治疗多发性骨髓瘤，这是一种目前无法治愈的常见浆细胞恶性肿瘤。这些患者的平均 5 年生存率仅为 30%，因此持续需要开发更新的疗法。拟议的产品由一种独特的人源化抗 CD74 单克隆抗体组成，该抗体与化疗药物阿霉素的多个分子共价连接。此前研究表明，这种药物可以显着治愈携带人类肿瘤异种移植物的免疫受损小鼠。重点是 cGMP 生产和临床前毒理学评估。使用现有的优化程序，将进行缀合物的初步非 GMP 制备，以在受控条件下测试放大过程，然后在 cGMP 条件下进行 5 g 制备和 10 g 制备。该项目的其他方面将涉及确定产品长期储存的稳定性，以及验证各种表征和产品释放标准的测定。将在体外实验中测定药物的缀合形式与游离形式的比较心脏毒性。该产品的临床前毒理学将在食蟹猴（表达与人类相似的 CD74 抗原的非人类灵长类动物）中进行评估。该实验将建立在先前的单剂量毒性研究的基础上，并确定在最能预测人类毒理学的动物物种中，以不断增加的剂量水平重复施用抗体-多柔比星缀合物所产生的急性毒性（如果有的话）。此外，还将使用比 I 期临床试验中预期起始剂量大一到两个数量级的阿霉素结合形式的剂量，在正常大鼠中评估非特异性毒性。最后，将准备新药研究申请并提交给 FDA。完成这些基本任务将使该产品进入多发性骨髓瘤患者的临床评估阶段，预计在 SBIR III 期阶段开始。公共健康相关性：多发性骨髓瘤 (MM) 是一种常见的浆细胞癌，目前无法治愈。平均5年生存率仅为30%。该项目的目标是使用独特的肿瘤选择性抗体开发一种更安全、更有效的多发性骨髓瘤靶向化疗方法，该抗体可以补充或增强现有疗法。