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T Cell‐Signaling‐Responsive Conjugate of Antibody with siRNA to Overcome Acquired Resistance to anti‐PD‐1 Immunotherapy

T Cell‐Signaling‐Responsive Conjugate of Antibody with siRNA to Overcome Acquired Resistance to... Acquired resistance (AR) resulted from stimulated expression of AR‐related genes such as CD38 in activated T cells jeopardizes anti‐programmed death‐1 (anti‐PD‐1) immunotherapy. It remains to be explored whether the suppression of AR genes in activated T cells during anti‐PD‐1 therapy is able to overcome AR and improve the efficacy of immunotherapy. Small‐interfering RNAs (siRNAs) acting via RNA interference mechanisms are able to shut down the expression of target genes. The authors report here a T‐cell targeting conjugate of antibody‐siRNA with response to reactive oxygen species (ROS) (TCARROS) for the suppression of AR gene as well as to block the PD‐1/PD‐L1 interaction. TCARROS is able to bind with PD‐1 on T cells, then release functional siRNA to suppress AR genes in activated T cells with abundant ROS to cleave the linker in the conjugate. TCARROS comprising the siRNA targeting CD‐38 attached to PD‐1 blocking antibody (αPD‐1) via the ROS responsive linker is tested on activated T cells as well as mice bearing B16 tumor. Synergistic effect is observed on mice treated with TCARROS in anti‐PD‐1 immunotherapy, which suggests the potentials of this novel ROS responsive αPD‐1‐siRNA conjugate in anti‐PD‐1 immunotherapy to overcome AR. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Advanced Therapeutics Wiley

T Cell‐Signaling‐Responsive Conjugate of Antibody with siRNA to Overcome Acquired Resistance to anti‐PD‐1 Immunotherapy

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References (37)

Publisher
Wiley
Copyright
© 2022 Wiley‐VCH GmbH
eISSN
2366-3987
DOI
10.1002/adtp.202100161
Publisher site
See Article on Publisher Site

Abstract

Acquired resistance (AR) resulted from stimulated expression of AR‐related genes such as CD38 in activated T cells jeopardizes anti‐programmed death‐1 (anti‐PD‐1) immunotherapy. It remains to be explored whether the suppression of AR genes in activated T cells during anti‐PD‐1 therapy is able to overcome AR and improve the efficacy of immunotherapy. Small‐interfering RNAs (siRNAs) acting via RNA interference mechanisms are able to shut down the expression of target genes. The authors report here a T‐cell targeting conjugate of antibody‐siRNA with response to reactive oxygen species (ROS) (TCARROS) for the suppression of AR gene as well as to block the PD‐1/PD‐L1 interaction. TCARROS is able to bind with PD‐1 on T cells, then release functional siRNA to suppress AR genes in activated T cells with abundant ROS to cleave the linker in the conjugate. TCARROS comprising the siRNA targeting CD‐38 attached to PD‐1 blocking antibody (αPD‐1) via the ROS responsive linker is tested on activated T cells as well as mice bearing B16 tumor. Synergistic effect is observed on mice treated with TCARROS in anti‐PD‐1 immunotherapy, which suggests the potentials of this novel ROS responsive αPD‐1‐siRNA conjugate in anti‐PD‐1 immunotherapy to overcome AR.

Journal

Advanced TherapeuticsWiley

Published: Jan 1, 2022

Keywords: acquired resistance; antibody‐siRNA conjugate; cancer immunotherapy; CD38; PD‐1; T cell

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