Tetravalent bispecific fusion antibody for immunotherapy

用于免疫治疗的四价双特异性融合抗体

• 批准号: 6831752
• 负责人: ZHENGXING QU
• 金额: $ 13.43万
• 依托单位: IMMUNOMEDICS, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-14 至 2005-09-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6831752
• 关键词: B lymphocyte; CD antigens; SCID mouse; antibody specificity; apoptosis; athymic mouse; biotechnology; cell growth regulation; cell line; chimeric proteins; clinical research; combination cancer therapy; crosslink; cytotoxicity; immunoglobulin G; immunologic substance development /preparation; lymphocytic leukemia; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; neoplastic cell; nonHodgkin' s lymphoma; nonhuman therapy evaluation; pharmacokinetics; protein engineering

DESCRIPTION (provided by applicant): Immunotherapy based on a naked monoclonal antibody (mAb), such as rituximab, has emerged as a safe and effective modality for treatment of indolent and aggressive non-Hodgkin's lymphomas (NHL) and chronic lymphocytic leukemias (CLL). Almost half of the patients with indolent lymphomas failed to respond to initial treatment with rituximab. To improve the therapeutic effectiveness, combination therapy with two mAbs against distinct antigens on B-lymphocytes is under active investigation, providing encouraging results in yet small pilot clinical trials. The objectives of this SBIR investigation is to develop a tetravalent bispecific fusion protein derived from two different humanized antibodies against human CD22 and CD20, and to explore the potentials of utilizing this tetravalent bispecific antibody (bsAb) as a "single agent" for treatment of patients with B-cell neoplastia to further improve the efficacy, safety, and convenience of the combination therapy. In Phase I, the fusion bsAb will be engineered by recombinant technology and expressed in a mammalian cell line, and high-level bsAb-producing clones suitable for industrial scale production will be developed. In this preliminary stage of a new drug development, the physical, biochemical, and immunological properties of the recombinant bsAb will be thoroughly characterized. In addition, in vitro and in vivo characteristics of the bsAb against neoplastic B-cells will be evaluated. Phase II will focus on detailed preclinical studies including biodistribution, pharmacokinetic and tumor therapy in animals. The ultimate goal of the Phase II application is to develop a cell line that is optimized for production in bioreactors so that clinical grade material insufficient quantities can be obtained for clinical studies.

描述（由申请人提供）：基于裸单克隆抗体（mAb）（例如利妥昔单抗）的免疫疗法已成为治疗惰性和侵袭性非霍奇金淋巴瘤（NHL）和慢性淋巴细胞白血病（CLL）的安全有效的方式。几乎一半的惰性淋巴瘤患者对利妥昔单抗的初始治疗没有反应。为了提高治疗效果，正在积极研究使用两种针对 B 淋巴细胞上不同抗原的单克隆抗体的联合疗法，在小型试点临床试验中提供了令人鼓舞的结果。这项 SBIR 研究的目的是开发一种四价双特异性融合蛋白，该融合蛋白源自两种不同的抗人 CD22 和 CD20 人源化抗体，并探索利用这种四价双特异性抗体 (bsAb) 作为“单一药物”治疗患者的潜力与 B 细胞肿瘤一起，进一步提高联合治疗的功效、安全性和便利性。第一阶段将通过重组技术改造融合bsAb并在哺乳动物细胞系中表达，并开发适合工业规模生产的高水平bsAb生产克隆。在新药开发的初步阶段，重组双特异性抗体的物理、生化和免疫学特性将得到彻底表征。此外，还将评估针对肿瘤 B 细胞的 bsAb 的体外和体内特性。第二阶段将侧重于详细的临床前研究，包括动物体内的生物分布、药代动力学和肿瘤治疗。 II期申请的最终目标是开发一种针对生物反应器生产进行优化的细胞系，以便获得数量不足的临床级材料用于临床研究。

项目成果

Bispecific anti-CD20/22 antibodies inhibit B-cell lymphoma proliferation by a unique mechanism of action.

双特异性抗 CD20/22 抗体通过独特的作用机制抑制 B 细胞淋巴瘤增殖。

• DOI: 10.1182/blood-2007-08-110072
• 发表时间: 2008
• 期刊: Blood
• 影响因子: 20.3
• 作者: Qu,Zhengxing;Goldenberg,DavidM;Cardillo,ThomasM;Shi,Victoria;Hansen,HansJ;Chang,Chien-Hsing
• 通讯作者: Chang,Chien-Hsing