Effector mechanisms of IgA antibodies against CD20

抗CD20 IgA抗体的效应机制

• 批准号: 278247522
• 负责人: Professor Dr. Matthias Peipp
• 金额: --
• 依托单位: Cancer Sciences Unit
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/278247522?language=en
• 关键词: Effector; mechanisms; IgA; antibodies; against

The CD20 antibody rituximab has significantly contributed to the improved survival of patients with different types of B cell lymphomas. Additional progress is expected in the near future from the approval of novel antibodies. With respect to their mechanisms of action, CD20 antibodies can be grouped into two different types: type I antibodies are efficient in mediating complement dependent cytotoxicity (CDC), while type II antibodies are particularly efficient in triggering tumor cell apoptosis. As human IgG1 antibodies, both types of molecules are able to recruit NK cells and monocytes/macrophages for antibody-dependent cellular cytotoxicity (ADCC). Our own previous work has demonstrated that human IgG1 antibodies - particularly when they were engineered to achieve higher affinity for FcgammaRIII (CD16) - do not rigger ADCC by granulocytes. However, granulocytes are particularly well activated by antibodies of human IgA isotypes. Natural IgA antibodies constitute an integral part of the mucosal immune system, but their role as therapeutic reagents in tumor immunotherapy has not been adequately addressed. Recently, we established production and purification technologies to generate sufficient amounts of recombinant human IgA antibodies. Within the proposed project variable regions of select type I (rituximab and ofatumumab) and type II (obinutuzumab) CD20 antibodies shall be produced as IgA1 and IgA2 molecules. These antibodies shall then be functionally compared to their respective IgG1 molecules in vitro and in vivo. Results of these experiments shall improve our understanding of the relevant mechanisms of action of CD20 antibodies and support the development of improved reagents. Additionally, we expect novel insights into the immunotherapeutic potential of IgA antibodies.

CD20抗体利妥昔单抗对提高不同类型B细胞淋巴瘤患者的生存率做出了显着贡献。预计新型抗体的批准将在不久的将来取得更多进展。就其作用机制而言，CD20抗体可分为两种不同类型：I型抗体可有效介导补体依赖性细胞毒性（CDC），而II型抗体在触发肿瘤细胞凋亡方面特别有效。作为人类 IgG1 抗体，两种类型的分子都能够招募 NK 细胞和单核细胞/巨噬细胞以实现抗体依赖性细胞毒性 (ADCC)。我们自己之前的工作已经证明，人类 IgG1 抗体 - 特别是当它们被设计为对 FcgammaRIII (CD16) 具有更高的亲和力时 - 不会通过粒细胞操纵 ADCC。然而，粒细胞特别容易被人类 IgA 同种型抗体激活。天然 IgA 抗体构成粘膜免疫系统的组成部分，但它们作为肿瘤免疫治疗中的治疗试剂的作用尚未得到充分解决。最近，我们建立了生产和纯化技术来产生足够量的重组人 IgA 抗体。在拟议的项目中，选择 I 型（利妥昔单抗和奥法木单抗）和 II 型（obinutuzumab）可变区的 CD20 抗体应以 IgA1 和 IgA2 分子的形式产生。然后，这些抗体应在体外和体内与它们各自的 IgG1 分子进行功能比较。这些实验结果将提高我们对 CD20 抗体相关作用机制的理解，并支持改进试剂的开发。此外，我们期望对 IgA 抗体的免疫治疗潜力有新的见解。