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Visualizing cell-cell interactions between immune effector and tumor cells induced by antibodies using a proximity-dependent biosensor system

Yu Tang, View ORCID ProfileYanguang Cao
doi: https://doi.org/10.1101/2022.05.04.490615
Yu Tang
1Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. 27599, United States
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Yanguang Cao
1Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. 27599, United States
2Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States
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  • ORCID record for Yanguang Cao
  • For correspondence: yanguang@unc.edu
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Abstract

Therapeutic antibodies can engage innate (NK) and adaptive (T) immune cells to eliminate pathogenic or malignant cells. Activated NK or T cells exert cytotoxic effects dependent upon direct cell-cell contact and subsequent formation of immunological synapses (IS) with target cells. Therefore, understanding antibody-mediated cell-cell interactions is crucial to optimizing antibody pharmacology and efficacy across all therapeutic areas. To date, most investigations around antibody-mediated cell-cell interactions have primarily focused on molecular-scale interactions. In this study, we developed a biosensor system to evaluate direct cell-cell contact and interactions and the formation of IS at the cell population level. In this biosensor system, two structural complementary luciferase units (SmBit and LgBit) were respectively expressed on immune effector and target cell membranes with optimized spacer lengths. Upon cell-cell contact, two subunits come together to form active NanoLuc, generating a luminescent signal for longitudinal monitoring. The selectivity of the system were optimized by adjusting the spacer lengths to assure the signal is from stable cell-cell interactions with minimal interference from nonspecific and transient intercellular contact. This system was then applied to longitudinally quantify cell-cell interactions between NK and target cells induced by an anti-CD20 antibody (rituximab) and between T and target cells induced by a bispecific (anti-CD3/CD19) T cell engaging antibody (blinatumomab) in a three-dimensional cell culture system. This biosensor system shows promise for monitoring cell-cell interactions in physiologically relevant environments and provides insights into the environmental factors that impede cell-cell interaction and antibody efficacy.

Competing Interest Statement

The authors have declared no competing interest.

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 May 04, 2022.
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Visualizing cell-cell interactions between immune effector and tumor cells induced by antibodies using a proximity-dependent biosensor system
Yu Tang, Yanguang Cao
bioRxiv 2022.05.04.490615; doi: https://doi.org/10.1101/2022.05.04.490615
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Visualizing cell-cell interactions between immune effector and tumor cells induced by antibodies using a proximity-dependent biosensor system
Yu Tang, Yanguang Cao
bioRxiv 2022.05.04.490615; doi: https://doi.org/10.1101/2022.05.04.490615

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