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Preclinical proof of principle for orally delivered Th17 antagonist miniproteins.
Berger, Stephanie; Seeger, Franziska; Yu, Ta-Yi; Aydin, Merve; Yang, Huilin; Rosenblum, Daniel; Guenin-Macé, Laure; Glassman, Caleb; Arguinchona, Lauren; Sniezek, Catherine; Blackstone, Alyssa; Carter, Lauren; Ravichandran, Rashmi; Ahlrichs, Maggie; Murphy, Michael; Pultz, Ingrid Swanson; Kang, Alex; Bera, Asim K; Stewart, Lance; Garcia, K Christopher; Naik, Shruti; Spangler, Jamie B; Beigel, Florian; Siebeck, Matthias; Gropp, Roswitha; Baker, David.
Afiliação
  • Berger S; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA. Electronic address: berger389@gmail.com.
  • Seeger F; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.
  • Yu TY; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; Department of Bioengineering, University of Washington, Seattle, WA 98195, USA.
  • Aydin M; Department of General, Visceral and Transplantation Surgery, LMU University Hospital, LMU Munich, 81377 Munich, Germany.
  • Yang H; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA; Translational Tissue Engineering Center, Johns Hopkins University, Baltimore, MD 21231, USA.
  • Rosenblum D; Department of Pathology, NYU Langone Health, New York, NY 10016, USA.
  • Guenin-Macé L; Department of Pathology, NYU Langone Health, New York, NY 10016, USA; Immunobiology and Therapy Unit, INSERM U1224, Institut Pasteur, Paris 75015, France.
  • Glassman C; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94304, USA.
  • Arguinchona L; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.
  • Sniezek C; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.
  • Blackstone A; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.
  • Carter L; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.
  • Ravichandran R; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.
  • Ahlrichs M; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.
  • Murphy M; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.
  • Pultz IS; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.
  • Kang A; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.
  • Bera AK; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.
  • Stewart L; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.
  • Garcia KC; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94304, USA; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94304, USA; Howard Hughes Medical Institute, Stanford School of Medicine, Stanford, CA 94305, USA.
  • Naik S; Department of Pathology, NYU Langone Health, New York, NY 10016, USA; Department of Medicine, Ronald O. Perelman Department of Dermatology, Perlmutter Cancer Center, NYU Langone Health, New York, NY 10016, USA.
  • Spangler JB; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA; Translational Tissue Engineering Center, Johns Hopkins University, Baltimore, MD 21231, USA; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
  • Beigel F; Department of Medicine II, LMU University Hospital, LMU Munich, 80336 Munich, Germany.
  • Siebeck M; Department of General, Visceral and Transplantation Surgery, LMU University Hospital, LMU Munich, 81377 Munich, Germany.
  • Gropp R; Department of General, Visceral and Transplantation Surgery, LMU University Hospital, LMU Munich, 81377 Munich, Germany.
  • Baker D; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA. Electronic address: dabaker@uw.edu.
Cell ; 2024 Jun 23.
Article em En | MEDLINE | ID: mdl-38936360
ABSTRACT
Interleukin (IL)-23 and IL-17 are well-validated therapeutic targets in autoinflammatory diseases. Antibodies targeting IL-23 and IL-17 have shown clinical efficacy but are limited by high costs, safety risks, lack of sustained efficacy, and poor patient convenience as they require parenteral administration. Here, we present designed miniproteins inhibiting IL-23R and IL-17 with antibody-like, low picomolar affinities at a fraction of the molecular size. The minibinders potently block cell signaling in vitro and are extremely stable, enabling oral administration and low-cost manufacturing. The orally administered IL-23R minibinder shows efficacy better than a clinical anti-IL-23 antibody in mouse colitis and has a favorable pharmacokinetics (PK) and biodistribution profile in rats. This work demonstrates that orally administered de novo-designed minibinders can reach a therapeutic target past the gut epithelial barrier. With high potency, gut stability, and straightforward manufacturability, de novo-designed minibinders are a promising modality for oral biologics.
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Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2024 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2024 Tipo de documento: Article