Effector mechanisms of IgA antibodies against CD20

CD20抗体利妥昔单抗显著提高了不同类型B细胞淋巴瘤患者的存活率。预计在不久的将来，新抗体的批准将取得更多进展。就其作用机制而言，CD20抗体可分为两类：I型抗体可有效地介导补体依赖性细胞毒作用(CDC)，而II型抗体尤其能有效地引发肿瘤细胞的凋亡。作为人类IgG1抗体，这两种类型的分子都能够募集NK细胞和单核/巨噬细胞，以实现抗体依赖的细胞毒作用(ADCC)。我们之前的工作已经证明，人类IgG1抗体--特别是当它们被设计成与FcGammaRIII(CD16)具有更高的亲和力时--不会通过粒细胞操纵ADCC。然而，粒细胞被人类IgA同型抗体激活得特别好。天然的IgA抗体是黏膜免疫系统的重要组成部分，但其作为治疗试剂在肿瘤免疫治疗中的作用尚未得到充分认识。最近，我们建立了生产和纯化技术，以生产足够数量的重组人IgA抗体。在拟议的项目中，选择I型(美罗华单抗和ofatumumab)和II型(Obinutuzumab)可变区将产生作为IgA1和IgA2分子的CD20抗体。然后在体外和体内将这些抗体与它们各自的IgG1分子进行功能比较。这些实验结果将加深我们对CD20抗体相关作用机制的理解，并为改进试剂的开发提供支持。此外，我们期待对IgA抗体的免疫治疗潜力有新的见解。

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.