{
  "abstract": "IgG1 immune complexes bind to all the Fc{gamma} receptors (Fc{gamma}R) expressed on myeloid cells, making it challenging to determine the precise role of each Fc{gamma}R on Fc effector phenotypes. Here we report the engineering of Fc2KG, an aglycosylated human IgG1 Fc domain that binds with near physiological affinity to Fc{gamma}RIIa/b with no detectable binding to any other Fc{gamma}Rs. Crystallographic analysis elucidated the structural basis of how mutations in the Fc domain compensate for the absence of the N297 glycan and enable selective binding. Using single-cell phagocytosis assays, we show that particles opsonized with Fc-engineered antibodies formatted with Fc2KG or with an Fc domain that binds only Fc{gamma}RI (Fc5), are ingested by THP-1 cells with near identical kinetics. We find that with CD16+ primary human monocytes, selective Fc{gamma}RII engagement is a major contributor to the ADCP mediated by wild-type IgG1. Additionally, we showed that Fc2KG formatted antibodies induce high levels of GM-CSF. With M1-like monocyte-derived human macrophages, trastuzumab formatted with wild-type IgG1 Fc, with Fc2KG or Fc5 were all equally proficient in the trogocytotic killing of opsonized SK-BR-3 HER2+ cells but only Fc{gamma}RI engagement led to secretion of proinflammatory cytokines. Collectively, our results highlight how precisely tuned, Fc-engineered antibodies can be deployed to answer long-standing questions regarding the precise effector functions mediated by human Fc{gamma}Rs, information which is key for the optimization of therapeutic antibodies.",
  "abstract_shown": true,
  "affiliations": [
    "The University of Texas at Austin"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 14,
  "authors": [
    {
      "name": "K. George"
    },
    {
      "name": "S. Ko"
    },
    {
      "name": "S. Irani"
    },
    {
      "name": "G. Delidakis"
    },
    {
      "name": "C.-H. Lee"
    },
    {
      "name": "P. Menon"
    },
    {
      "name": "J. E. Kim"
    },
    {
      "name": "B. M. Herpers"
    },
    {
      "name": "E. Rocha"
    },
    {
      "name": "G. Soto"
    },
    {
      "name": "A. Majmudar"
    },
    {
      "name": "N. Varadarajan"
    },
    {
      "name": "Y. Zhang"
    },
    {
      "affs": [
        0
      ],
      "name": "G. Georgiou"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/5hzje2ncgrjmh.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.08.31.748147",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.08.31.748147v1.full",
  "id": "5hzje2ncgrjmh",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.08.31.748147v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "immunology"
    ],
    [
      "openalex",
      "2741|Monoclonal and Polyclonal Antibodies Research"
    ]
  ],
  "openalex": "W7208752298",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.08.31.748147v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-08-31",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/5hzje2ncgrjmh.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:28Z",
      "native_id": "10.64898/2026.08.31.748147",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.08.31.748147v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:immunology",
      "subfield": "immunology"
    }
  ],
  "title": "Antibodies with Engineered Fc Domains Having Absolute Binding Selectivity to either FcγRIIa or FcγRI Delineate the Respective Effector Phenotypes by Human Monocytes and Macrophages",
  "title_text": "Antibodies with Engineered Fc Domains Having Absolute Binding Selectivity to either FcγRIIa or FcγRI Delineate the Respective Effector Phenotypes by Human Monocytes and Macrophages",
  "type": "preprint",
  "updated_at": "2026-10-30T12:19:28Z",
  "url": "https://research.draconitic.com/paper/5hzje2ncgrjmh",
  "venue": "bioRxiv",
  "versions": []
}