CryoEM structure of a therapeutic antibody (favezelimab) bound to human LAG3 determined using a bivalent Fab as fiducial marker.

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Abstract

Lymphocyte activation gene 3 protein (LAG3) is an inhibitory receptor that is upregulated on exhausted T cells in tumors. LAG3 is a major target for cancer immunotherapy with many anti-LAG3 antibodies in clinical trials. However, there is no structural information on the epitopes recognized by these antibodies. We determined the single-particle cryoEM structure of a therapeutic antibody (favezelimab) bound to LAG3 to 3.5 Å resolution, revealing that favezelimab targets the LAG3-binding site for MHC class II, its canonical ligand. The small size of the complex between the conventional (monovalent) Fab of favezelimab and LAG3 (∼100 kDa) presented a challenge for cryoEM. Accordingly, we engineered a bivalent version of Fab favezelimab that doubled the size of the Fab-LAG3 complex and conferred a highly identifiable shape to the complex that facilitated particle selection and orientation for image processing. This study establishes bivalent Fabs as new fiducial markers for cryoEM analysis of small proteins.

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Author and article information

Journal

Journal ID (iso-abbrev): Structure

Title: Structure (London, England : 1993)

Publisher: Elsevier BV

ISSN (Electronic): 1878-4186

ISSN (Print): 0969-2126

Publication date (Electronic): Oct 05 2023

Volume: 31

Issue: 10

Affiliations

[1 ] W.M. Keck Laboratory for Structural Biology, University of Maryland Institute for Bioscience and Biotechnology Research, Rockville, MD 20850, USA; Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA.

[2 ] Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; University of Maryland Marlene and Stewart Greenebaum Cancer Center, University of Maryland Medical Center, Baltimore, MD 21201, USA; Center for Biomolecular Therapeutics, University of Maryland School of Medicine, Rockville, MD 20850, USA.

[3 ] W.M. Keck Laboratory for Structural Biology, University of Maryland Institute for Bioscience and Biotechnology Research, Rockville, MD 20850, USA; Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA. Electronic address: rmariuzz@umd.edu.

Article

Publisher Item ID: S0969-2126(23)00277-0

DOI: 10.1016/j.str.2023.07.013

PubMed ID: 37619561

SO-VID: 19e72982-8b6f-4fe0-984c-981b2c69086c

History

Keywords: inhibitory receptor,antibody,cryoEM,X-ray crystallography,T cell,LAG3,fiducial marker

Data availability:

Keywords: inhibitory receptor, antibody, cryoEM, X-ray crystallography, T cell, LAG3, fiducial marker

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