{"title":"Systematic analysis of Fc mutations designed to enhance binding to Fc-gamma receptors.","authors":"Geoff Hale, Alastair Douglas Davy, Ian Wilkinson","doi":"10.1080/19420862.2024.2406539","DOIUrl":null,"url":null,"abstract":"<p><p>A critical attribute of therapeutic antibodies is their ability to engage with humoral or cellular effector mechanisms, and this depends on the ability of the Fc region to bind to complement (C1q) or Fc receptors. Investigators have sought to optimize these effects by engineering the Fc region to bind to a greater or lesser extent to individual receptors. Different approaches have been used in the clinic, but they have not been systematically compared. We have now produced a matched set of anti-CD20 antibodies representing a range of variants and compared their activity in cell-based assays for complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and antibody-dependent phagocytosis using a range of individual Fc receptors. We have also compared the thermal stability of the variants by differential scanning fluorimetry (DSF). The results reveal a spectrum of activities which may be appropriate for different applications.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"16 1","pages":"2406539"},"PeriodicalIF":5.6000,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11418285/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"mAbs","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/19420862.2024.2406539","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/9/22 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0
Abstract
A critical attribute of therapeutic antibodies is their ability to engage with humoral or cellular effector mechanisms, and this depends on the ability of the Fc region to bind to complement (C1q) or Fc receptors. Investigators have sought to optimize these effects by engineering the Fc region to bind to a greater or lesser extent to individual receptors. Different approaches have been used in the clinic, but they have not been systematically compared. We have now produced a matched set of anti-CD20 antibodies representing a range of variants and compared their activity in cell-based assays for complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and antibody-dependent phagocytosis using a range of individual Fc receptors. We have also compared the thermal stability of the variants by differential scanning fluorimetry (DSF). The results reveal a spectrum of activities which may be appropriate for different applications.
治疗性抗体的一个关键属性是它们与体液或细胞效应机制结合的能力,而这取决于Fc区与补体(C1q)或Fc受体结合的能力。研究人员试图通过对 Fc 区进行工程设计,使其在更大或更小的程度上与个别受体结合,从而优化这些效应。不同的方法已用于临床,但还没有对它们进行系统的比较。现在,我们已经制备出了一组匹配的抗 CD20 抗体,代表了一系列变体,并比较了它们在基于细胞的补体依赖性细胞毒性、抗体依赖性细胞介导的细胞毒性和抗体依赖性吞噬作用试验中使用一系列单个 Fc 受体的活性。我们还通过差示扫描荧光测定法(DSF)比较了变体的热稳定性。结果表明,这些变体具有不同的活性,可能适用于不同的应用领域。
期刊介绍:
mAbs is a multi-disciplinary journal dedicated to the art and science of antibody research and development. The journal has a strong scientific and medical focus, but also strives to serve a broader readership. The articles are thus of interest to scientists, clinical researchers, and physicians, as well as the wider mAb community, including our readers involved in technology transfer, legal issues, investment, strategic planning and the regulation of therapeutics.