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

描述(申请人提供)：这项工作的目标是开发一种抗体-阿霉素结合物，用于表达CD74抗原的B细胞癌的靶向治疗。第二阶段项目将专注于推动该产品治疗多发性骨髓瘤，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年存活率只有30%，因此需要继续开发新的治疗方法。建议的产品包括一种独特的人源化抗CD74单抗，与化疗药物阿霉素的多个分子共价连接。这种药物之前被证明可以在携带人类肿瘤移植瘤的免疫受损小鼠身上诱导戏剧性的治愈。重点将放在cGMP的制造和临床前毒理学评价上。使用现有的优化程序，将进行结合物的初步非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5g制备和10g制备。该项目的其他方面将涉及产品稳定性的确定和长期储存，以及各种表征和产品释放标准的分析验证。该药物的偶联形式和游离形式的心脏毒性将在体外实验中进行比较。该产品的临床前毒理学将在食蟹猴身上进行评估，食蟹猴是表达CD74抗原的非人类灵长类物种，与人类相似。这项实验将建立在之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，重复注射抗体-阿霉素结合物以增加剂量水平所产生的急性毒性(如果有的话)。此外，非特异性毒性也将在正常大鼠身上进行评估，使用的阿霉素结合形式的剂量比I期临床试验中预期的起始剂量大一到两个数量级。最后，将准备一份调查性新药申请，并提交给FDA。这些基本任务的完成将使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第三阶段开始。公共卫生报道：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年存活率仅为30%。该项目的目标是使用一种独特的肿瘤选择性抗体来开发一种更安全、更有效的MM靶向化疗，这种抗体可以补充或增强现有的治疗方法。

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.