{
  "abstract": "Complex antibody formats are advancing in the biotherapeutic landscape to address the need for multi-specificity, tailored valency, and novel mechanisms of action. However, understanding how non-canonical architectures impact fundamental pharmacokinetic pathways remains a critical challenge. While canonical IgGs experience steric hindrance at the endosomal membrane during FcRn engagement, whether -- and how strongly -- this constraint impacts FcRn-mediated recycling across the expanding diversity of non-canonical antibody architectures has remained unknown. By systematically evaluating a diverse panel of rationally designed antibody geometries utilizing orthogonal in vitro assays we demonstrate that spatial layout profoundly influences FcRn-recycling efficiency; inverting the antibody structure by positioning the Fab-domains to the C-terminus (invertbodies) maximizes recycling, whereas crowding the N-terminus severely impairs it. In contrast, non-specific endocytosis was only modestly and inconsistently affected by Fab number, dependent on the Fv-sequence, but not by the spatial architecture itself. Notably, antibody architecture and affinity-enhancing Fc-FcRn mutations act independently yet cooperatively, ultimately revealing a physiological recycling ceiling. These FcRn-recycling dynamics translate with high fidelity to in vivo clearance (CL) in a humanized FcRn mouse model. Across the antibody panel, architecture drove a near 15-fold variance in CL, an effect that collapsed in FcRn-knockout mice. As proof of concept, we applied the invertbody design to a variant of the marketed antibody golimumab, achieving a three-fold reduction in clearance without compromising potency. These findings reveal the magnitude and predictability with which the antibody architecture governs FcRn-recycling and non-specific CL, establishing a rational, generalizable framework to optimize the pharmacokinetics of biotherapeutics.",
  "abstract_shown": true,
  "affiliations": [
    "Roche Pharma Research and Early Development, Roche Innovation Center Munich"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 16,
  "authors": [
    {
      "name": "S. C. Weise"
    },
    {
      "name": "C. Jany"
    },
    {
      "name": "S. Imhof-Jung"
    },
    {
      "name": "C. Simonneau"
    },
    {
      "name": "J. Fraidling"
    },
    {
      "name": "A.-L. Bolender"
    },
    {
      "name": "A. Padamsey"
    },
    {
      "name": "E. Di Lenarda"
    },
    {
      "name": "A. C. Cascais"
    },
    {
      "name": "T. Emrich"
    },
    {
      "name": "T. Schlothauer"
    },
    {
      "name": "A. Indlekofer"
    },
    {
      "name": "H. Kettenberger"
    },
    {
      "name": "V. Haucke"
    },
    {
      "name": "W. F. Richter"
    },
    {
      "affs": [
        0
      ],
      "name": "T. E. Kraft"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/0g63d6fxktpw7.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.11.02.763654",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.11.02.763654v1.full",
  "id": "0g63d6fxktpw7",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.11.02.763654v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "pharmacology and toxicology"
    ]
  ],
  "openalex": null,
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.11.02.763654v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-11-02",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/0g63d6fxktpw7.ris",
  "sources": [
    {
      "first_seen": "2026-11-05T00:21:52Z",
      "native_id": "10.64898/2026.11.02.763654",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.11.02.763654v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "biorxiv:pharmacology and toxicology",
      "subfield": "pharmacology-toxicology"
    }
  ],
  "title": "Spatial architecture of complex antibody formats dictates pharmacokinetics via FcRn-recycling",
  "title_text": "Spatial architecture of complex antibody formats dictates pharmacokinetics via FcRn-recycling",
  "type": "preprint",
  "updated_at": "2026-11-06T00:21:39Z",
  "url": "https://research.draconitic.com/paper/0g63d6fxktpw7",
  "venue": "bioRxiv",
  "versions": []
}