Molecular reshaping of phage-displayed Interleukin-2 at beta chain receptor interface to obtain potent super-agonists with improved developability profiles

Interleukin-2 (IL-2) engineered versions, with biased immunological functions, have emerged from yeast display and rational design. Here we reshaped the human IL-2 interface with the IL-2 receptor beta chain through the screening of phage-displayed libraries. Multiple beta super-binders were obtaine...

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Bibliographic Details
Published in:Communications biology 2023-08, Vol.6 (1), p.828-828, Article 828
Main Authors: Rojas, Gertrudis, Relova-Hernández, Ernesto, Pérez-Riverón, Annia, Castro-Martínez, Camila, Diaz-Bravo, Osmany, Infante, Yanelys Cabrera, Gómez, Tania, Solozábal, Joaquín, DíazBravo, Ana Beatriz, Schubert, Maren, Becker, Marlies, Pérez-Massón, Beatriz, Pérez-Martínez, Dayana, Alvarez-Arzola, Rydell, Guirola, Osmany, Chinea, Glay, Graca, Luis, Dübel, Stefan, León, Kalet, Carmenate, Tania
Format: Article
Language:English
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Biology
Biomedical and Life Sciences
Complementarity
Cytokines
Fc receptors
Hydrophobicity
Interleukin 2
Interleukin 2 receptors
Life Sciences
Mammalian cells
Phages
Tumors
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Summary:Interleukin-2 (IL-2) engineered versions, with biased immunological functions, have emerged from yeast display and rational design. Here we reshaped the human IL-2 interface with the IL-2 receptor beta chain through the screening of phage-displayed libraries. Multiple beta super-binders were obtained, having increased receptor binding ability and improved developability profiles. Selected variants exhibit an accumulation of negatively charged residues at the interface, which provides a better electrostatic complementarity to the beta chain, and faster association kinetics. These findings point to mechanistic differences with the already reported superkines, characterized by a conformational switch due to the rearrangement of the hydrophobic core. The molecular bases of the favourable developability profile were tracked to a single residue: L92. Recombinant Fc-fusion proteins including our variants are superior to those based on H9 superkine in terms of expression levels in mammalian cells, aggregation resistance, stability, in vivo enhancement of immune effector responses, and anti-tumour effect. Engineered interleukin-2 (IL-2) variants yield better electrostatic complementarity to the IL-2 receptor beta chain and faster association kinetics leading to in vivo enhancement of immune effector responses and anti-tumor effects.
ISSN:2399-3642
2399-3642
DOI:10.1038/s42003-023-05188-0