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Multivalency enhances the specificity of Fc-cytokine fusions

View ORCID ProfileBrian Orcutt-Jahns, View ORCID ProfilePeter C. Emmel, View ORCID ProfileEli M. Snyder, View ORCID ProfileCori Posner, View ORCID ProfileScott M. Carlson, View ORCID ProfileAaron S. Meyer
doi: https://doi.org/10.1101/2021.07.03.451002
Brian Orcutt-Jahns
1Department of Bioengineering, University of California, Los Angeles, United States of America
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Peter C. Emmel
1Department of Bioengineering, University of California, Los Angeles, United States of America
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Eli M. Snyder
1Department of Bioengineering, University of California, Los Angeles, United States of America
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Cori Posner
2Visterra, Inc., Waltham, MA, United States of America
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Scott M. Carlson
2Visterra, Inc., Waltham, MA, United States of America
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Aaron S. Meyer
1Department of Bioengineering, University of California, Los Angeles, United States of America
3Department of Bioinformatics, University of California, Los Angeles, United States of America
4Jonsson Comprehensive Cancer Center, University of California, Los Angeles, United States of America
5Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, United States of America
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  • For correspondence: ameyer@asmlab.org
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Abstract

The common γ-chain receptor cytokines are promising immune therapies due to their central role in coordinating the proliferation and activity of various immune cell populations. One of these cytokines, interleukin (IL)-2, has potential as a therapy in autoimmunity but is limited in effectiveness by its modest specificity toward regulatory T cells (Tregs). Therapeutic ligands are often made dimeric as antibody Fc fusions to confer desirable pharmacokinetic benefits, with under-explored consequences on signaling. Here, we systematically profiled the signaling responses to a panel of wild type and mutein IL-2 molecules in various Fc fusion configurations. We used a tensor-structured dimensionality reduction scheme to decompose the responses of each cell population to each ligand over a range of time points and cytokine concentrations. We found that dimeric muteins are uniquely specific for Tregs at intermediate ligand concentrations. We then compared signaling response across all treatments to a simple, two-step multivalent binding model. Our model was able to predict cellular responses with high accuracy. Bivalent Fc fusions display enhanced specificity and potency for Tregs through avidity effects toward IL-2Rα. We then utilize our model to identify the potential benefits conferred by valency engineering as an additional mechanism for cytokines with optimized therapeutic benefits. In total, these findings represent a comprehensive analysis of how ligand properties, and their consequent effects on surface receptor-ligand interactions, translate to selective activation of immune cell populations. It also identifies a new route toward engineering even more selective therapeutic cytokines.

Significance Statement Signaling in off-target immune cells has hindered the effectiveness of IL-2 as an immunotherapeutic. We show that bivalent IL-2 muteins exhibit more regulatory T cell-selective signaling than monovalent forms. This altered selectivity is explained by altered surface receptor-ligand binding kinetics and can be quantitatively predicted using a multivalent binding model. Finally, our model shows that even more selective IL-2 therapies may be developed by designing cytokines in higher valency formats, revealing valency as an unexplored mechanism for engineering specific IL-2 responses.

Competing Interest Statement

S.M.C. and C.P. are employees of Visterra Inc. A.S.M. has filed an invention disclosure on the use of multivalent cytokines to enhance cell type selective responses.

Footnotes

  • Author Emails/Contact Information: Brian Orcutt-Jahns: orcuttjahnsbrian{at}gmail.com, Peter C. Emmel: petercemmel{at}gmail.com, Eli M. Snyder: emsnyder{at}g.ucla.edu, Cori Posner: Cori.posner{at}gmail.com, Scott M. Carlson: smcarlson{at}gmail.com, Aaron S. Meyer: ameyer{at}ucla.edu

  • https://github.com/meyer-lab/gc-valent

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted July 04, 2021.
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Multivalency enhances the specificity of Fc-cytokine fusions
Brian Orcutt-Jahns, Peter C. Emmel, Eli M. Snyder, Cori Posner, Scott M. Carlson, Aaron S. Meyer
bioRxiv 2021.07.03.451002; doi: https://doi.org/10.1101/2021.07.03.451002
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Multivalency enhances the specificity of Fc-cytokine fusions
Brian Orcutt-Jahns, Peter C. Emmel, Eli M. Snyder, Cori Posner, Scott M. Carlson, Aaron S. Meyer
bioRxiv 2021.07.03.451002; doi: https://doi.org/10.1101/2021.07.03.451002

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