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

描述（由申请人提供）：本工作的目标是开发用于表达CD 74抗原的B细胞癌的靶向治疗的抗体-多柔比星缀合物。II期项目将专注于推进该产品用于多发性骨髓瘤，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%，因此需要持续开发新的治疗方法。申报产品由一种独特的人源化抗CD 74单克隆抗体与多个化疗药物阿霉素分子共价连接组成。这种药物以前被证明可以在携带人类肿瘤异种移植物的免疫受损小鼠中诱导戏剧性的治愈。重点将放在cGMP生产和临床前毒理学评价。使用现有的优化程序，将进行结合物的初步非GMP制备，以在受控条件下检测放大工艺，然后在cGMP条件下制备5 g和10 g制剂。该项目的其他方面将涉及产品长期储存稳定性的测定，以及各种表征和产品放行标准的测定验证。将在体外实验中测定结合形式与游离形式药物的比较心脏毒性。将在食蟹猴（表达与人类相似的CD 74抗原的非人灵长类动物种属）中评价产品的临床前毒理学。该实验将建立在先前的单次给药毒性研究的基础上，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，还将在正常大鼠中使用比I期临床试验中预期的起始剂量大一到两个数量级的多柔比星缀合形式的剂量来评价非特异性毒性。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使该产品进入多发性骨髓瘤患者的临床评价阶段，预计将在SBIR III期开始。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%。拟议项目的目标是使用独特的肿瘤选择性抗体开发更安全和更有效的MM靶向化疗，该抗体可以补充或增强现有疗法。

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.