Open AccessAn Avidity-Based PD-L1 Antagonist Using Nanoparticle-Antibody Conjugates for Enhanced Immunotherapy
Author(s) -
JongUk Bu,
Ashita Nair,
Mari Iida,
Woo Jin Jeong,
Michael J. Poellmann,
Kara Mudd,
Luke J. Kubiatowicz,
Elizabeth W. Liu,
Deric L. Wheeler,
Seungpyo Hong
Publication year - 2020
Publication title -
nano letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.853
H-Index - 488
eISSN - 1530-6992
pISSN - 1530-6984
DOI - 10.1021/acs.nanolett.0c00953
Subject(s) - avidity , receptor–ligand kinetics , cancer immunotherapy , chemistry , dendrimer , immunotherapy , conjugate , in vivo , cancer research , pharmacology , monoclonal antibody , antibody , in vitro , immune system , biophysics , immunology , medicine , biochemistry , receptor , biology , mathematical analysis , mathematics , microbiology and biotechnology
Upregulation of programmed death ligand 1 (PD-L1) allows cancer cells to evade antitumor immunity. Despite tremendous efforts in developing PD-1/PD-L1 immune checkpoint inhibitors (ICIs), clinical trials using such ICIs have shown inconsistent benefits. Here, we hypothesized that the ICI efficacy would be dictated by the binding strength of the inhibitor to the target proteins. To assess this, hyperbranched, multivalent poly(amidoamine) dendrimers were employed to prepare dendrimer-ICI conjugates (G7-aPD-L1). Binding kinetics measurements using SPR, BLI, and AFM revealed that G7-aPD-L1 exhibits significantly enhanced binding strength to PD-L1 proteins, compared to free aPD-L1. The binding avidity of G7-aPD-L1 was translated into in vitro efficiency and in vivo selectivity, as the conjugates improved the PD-L1 blockade effect and enhanced accumulation in tumor sites. Our results demonstrate that the dendrimer-mediated multivalent interaction substantially increases the binding avidity of the ICIs and thereby improves the antagonist effect, providing a novel platform for cancer immunotherapy.