Thayer School of Engineering, Dartmouth College, Hanover, NH, USA.
Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
Immunol Cell Biol. 2020 Apr;98(4):305-317. doi: 10.1111/imcb.12324. Epub 2020 Apr 6.
Antibody-dependent complement activity is associated not only with autoimmune morbidity, but also with antitumor efficacy. In infectious disease, both recombinant monoclonal antibodies and polyclonal antibodies generated in natural adaptive responses can mediate complement activity to protective, therapeutic or disease-enhancing effect. Recent advances have contributed to the structural resolution of molecular complexes involved in antibody-mediated complement activation, defining the avid nature of participating interactions and pointing to how antibody isotype, subclass, hinge flexibility, glycosylation state, amino acid sequence and the contextual nature of the cognate antigen/epitope are all factors that can determine complement activity through impact on antibody multimerization and subsequent recruitment of complement component 1q. Beyond the efficiency of activation, complement activation products interact with various cell types that mediate immune adherence, trafficking, immune education and innate functions. Similarly, depending on the anatomical location and extent of activation, complement can support homeostatic restoration or be leveraged by pathogens or neoplasms to enhance infection or promote tumorigenic microenvironments, respectively. Advances in means to suppress complement activation by intravenous immunoglobulin (IVIG), IVIG mimetics and complement-intervening antibodies represent proven and promising exploratory therapeutic strategies, while antibody engineering has likewise offered frameworks to enhance, eliminate or isolate complement activation to interrogate in vivo mechanisms of action. Such strategies promise to support the optimization of antibody-based drugs that are able to tackle emerging and difficult-to-treat diseases by improving our understanding of the synergistic and antagonistic relationships between antibody mechanisms mediated by Fc receptors, direct binding and the products of complement activation.
抗体依赖性补体活性不仅与自身免疫发病率有关，还与抗肿瘤疗效有关。在传染病中，重组单克隆抗体和天然适应性反应产生的多克隆抗体都可以介导补体活性，从而产生保护、治疗或增强疾病的效果。最近的进展有助于解决抗体介导的补体激活中涉及的分子复合物的结构解析，确定参与相互作用的亲和力性质，并指出抗体同种型、亚类、铰链灵活性、糖基化状态、氨基酸序列和同源抗原/表位的上下文性质如何通过影响抗体多聚化以及随后招募补体成分 1q 来决定补体活性。除了激活效率外，补体激活产物还与各种介导免疫黏附、迁移、免疫教育和先天功能的细胞类型相互作用。同样，根据激活的解剖位置和程度，补体可以支持体内平衡的恢复，也可以被病原体或肿瘤利用来增强感染或促进肿瘤发生的微环境。抑制静脉注射免疫球蛋白 (IVIG)、IVIG 模拟物和补体干预抗体的补体激活的方法的进展代表了已证实和有前途的探索性治疗策略，而抗体工程同样提供了增强、消除或分离补体激活的框架，以研究体内作用机制。这些策略有望通过提高我们对 Fc 受体、直接结合和补体激活产物介导的抗体机制之间协同和拮抗关系的理解，支持优化基于抗体的药物，这些药物能够通过改善我们对 Fc 受体、直接结合和补体激活产物介导的抗体机制之间协同和拮抗关系的理解，来解决新出现的和难以治疗的疾病。
