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A quantitative view of strategies to engineer cell-selective ligand binding

View ORCID ProfileZhixin Cyrillus Tan, View ORCID ProfileBrian Orcutt-Jahns, View ORCID ProfileAaron S. Meyer
doi: https://doi.org/10.1101/2020.11.25.398974
Zhixin Cyrillus Tan
1Bioinformatics Interdepartmental Program, University of California, Los Angeles
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Brian Orcutt-Jahns
2Department of Bioengineering, University of California, Los Angeles
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Aaron S. Meyer
2Department of Bioengineering, University of California, Los Angeles
1Bioinformatics Interdepartmental Program, University of California, Los Angeles
3Jonsson Comprehensive Cancer Center, University of California, Los Angeles
4Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles
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Abstract

A critical property of many therapies is their selective binding to specific target populations. Exceptional specificity can arise from high-affinity binding to unique cell surface targets. In many cases, however, therapeutic targets are only expressed at subtly different levels relative to off-target cells. More complex binding strategies have been developed to overcome this limitation, including multi-specific and multi-valent molecules, but these create a combinatorial explosion of design possibilities. Therefore, guiding strategies for developing cell-specific binding are critical to employ these tools. Here, we extend a multi-valent binding model to multi-ligand and multi-receptor interactions. Using this model, we explore a series of mechanisms to engineer cell selectivity, including mixtures of molecules, affinity adjustments, and valency changes. Each of these strategies maximizes selectivity in distinct cases, leading to synergistic improvements when used in combination. Finally, we identify situations in which selectivity cannot be derived through passive binding alone to highlight areas in need of new developments. In total, this work uses a quantitative model to unify a comprehensive set of design guidelines for engineering cell-specific therapies.

Summary points

  • Affinity, valency, and other alterations to target cell binding provide enhanced selectivity in specific situations.

  • Evidence for the effectiveness and limitations of each strategy are abundant within the drug development literature.

  • Combining strategies can offer enhanced selectivity.

  • A simple, multivalent ligand-receptor binding model can help to direct therapeutic engineering.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Github cyrillustan

  • Github borcuttjahns

  • Github aarmey · twitter aarmey

  • https://github.com/meyer-lab/cell-selective-ligands

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 4.0 International license.
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Posted November 27, 2020.
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A quantitative view of strategies to engineer cell-selective ligand binding
Zhixin Cyrillus Tan, Brian Orcutt-Jahns, Aaron S. Meyer
bioRxiv 2020.11.25.398974; doi: https://doi.org/10.1101/2020.11.25.398974
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A quantitative view of strategies to engineer cell-selective ligand binding
Zhixin Cyrillus Tan, Brian Orcutt-Jahns, Aaron S. Meyer
bioRxiv 2020.11.25.398974; doi: https://doi.org/10.1101/2020.11.25.398974

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