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A homodimeric aptamer variant generated from ligand-guided selection activates T-cell receptor cluster of differentiation three complex

Lina Freage, Deana Jamal, Nicole Williams, View ORCID ProfilePrabodhika R. Mallikaratchy
doi: https://doi.org/10.1101/2020.05.18.102145
Lina Freage
1Department of Chemistry, Lehman College, The City University of New York, 250 Bedford Park Blvd., West, Bronx, NY 10468, USA
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Deana Jamal
1Department of Chemistry, Lehman College, The City University of New York, 250 Bedford Park Blvd., West, Bronx, NY 10468, USA
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Nicole Williams
3Ph.D. Program in Molecular, Cellular and Developmental Biology, CUNY Graduate Center, 365 Fifth Avenue, New York, NY 10016, USA
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Prabodhika R. Mallikaratchy
1Department of Chemistry, Lehman College, The City University of New York, 250 Bedford Park Blvd., West, Bronx, NY 10468, USA
2Ph.D. Programs in Chemistry and Biochemistry, CUNY Graduate Center, 365 Fifth Avenue, New York, NY 10016, USA
3Ph.D. Program in Molecular, Cellular and Developmental Biology, CUNY Graduate Center, 365 Fifth Avenue, New York, NY 10016, USA
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  • ORCID record for Prabodhika R. Mallikaratchy
  • For correspondence: prabodhika.mallikaratchy@lehman.cuny.edu
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Abstract

Recently, immunotherapeutic modalities with engineered cells and monoclonal antibodies have been effective in treating several malignancies. However, growing evidence suggests that immune-related adverse events (irAE) lead to severe and long-term side effects. Most iRAEs involve prolonged circulation of antibodies. To address this problem, nucleic acid aptamers can serve as alternative molecules to design immunotherapeutics with high functional diversity and predictable circulation times. Here, we report the first synthetic prototype consisting of DNA aptamers, which can activate T-cell receptor cluster of differentiation 3 (TCR-CD3) complex in cultured T-cells. We show that activation potential is similar to that of a monoclonal antibody (mAb) against TCR-CD3, suggesting the potential of aptamers in developing efficacious synthetic immunomodulators. The synthetic prototype of anti-TCR-CD3ε, as described herein, was designed using aptamer ZUCH-1 against TCR-CD3ε, generated by Ligand Guided Selection (LIGS). Aptamer ZUCH-1 was truncated and modified with nuclease-resistant RNA analogs to enhance stability. Several dimeric analogs with truncated and modified variants were designed with variable linker lengths to investigate the activation potential of each construct. Among them, dimeric aptamer with approximate dimensions similar to those of an antibody showed the highest T-cell-activation, suggesting the importance of optimizing linker lengths in engineering functional aptamers. The observed activation potential of dimeric aptamers shows the vast potential of aptamers in designing synthetically versatile immunomodulators with tunable pharmacokinetic properties, expanding immunotherapeutic designs with the use of nucleic acid-based ligands such as aptamers.

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 20, 2020.
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A homodimeric aptamer variant generated from ligand-guided selection activates T-cell receptor cluster of differentiation three complex
Lina Freage, Deana Jamal, Nicole Williams, Prabodhika R. Mallikaratchy
bioRxiv 2020.05.18.102145; doi: https://doi.org/10.1101/2020.05.18.102145
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A homodimeric aptamer variant generated from ligand-guided selection activates T-cell receptor cluster of differentiation three complex
Lina Freage, Deana Jamal, Nicole Williams, Prabodhika R. Mallikaratchy
bioRxiv 2020.05.18.102145; doi: https://doi.org/10.1101/2020.05.18.102145

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