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-阿霉素偶联物，用于靶向治疗表达CD74抗原的b细胞癌。二期项目将重点推进该产品用于多发性骨髓瘤，多发性骨髓瘤是一种常见的浆细胞恶性肿瘤，目前无法治愈。这些患者的平均5年生存率仅为30%，因此需要不断开发新的治疗方法。该产品由一种独特的、人源化的抗cd74单克隆抗体组成，共价连接到化疗药物阿霉素的多个分子。这种药物先前被证明可以在携带人类肿瘤异种移植的免疫受损小鼠中诱导戏剧性的治愈。重点是cGMP的制作和临床前毒理学评价。使用现有的优化程序，将进行初步的非gmp共轭物制备，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产品稳定性的确定，延长存储，以及各种表征和产品释放标准的检测验证。将在体外实验中比较药物的结合形式和游离形式的心脏毒性。该产品的临床前毒理学将在食蟹猴中进行评估，食蟹猴是一种表达与人类相似的CD74抗原的非人灵长类动物。该实验将建立在先前的单剂量毒性研究的基础上，并确定如果有急性毒性，则由不断增加剂量水平的抗体-阿霉素偶联物在动物物种中产生的急性毒性，这最能预测人类毒理学。此外，还将在正常大鼠中评估非特异性毒性，使用比I期临床试验预期起始剂量大一到两个数量级的阿霉素缀合形式剂量。最后，将准备一份研究性新药申请并提交给FDA。这些基本任务的完成将推动该产品进入多发性骨髓瘤患者的临床评估阶段，预计将在SBIR III期开始。公共卫生相关性：多发性骨髓瘤（MM）是一种常见的浆细胞癌，目前是无法治愈的。平均5年生存率只有30%。该项目的目标是开发一种更安全、更有效的MM靶向化疗，使用一种独特的肿瘤选择性抗体，可以补充或增强现有的治疗方法。