An Avidity-Based PD-L1 Antagonist Using Nanoparticle-Antibody Conjugates for Enhanced Immunotherapy.

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.

Enhanced detection of cell-free DNA (cfDNA) enables its use as a reliable biomarker for diagnosis and prognosis of gastric cancer.

Although circulating cell-free DNA (cfDNA) is a promising biomarker for the diagnosis and prognosis of various tumors, clinical correlation of cfDNA with gastric cancer has not been fully understood. To address this, we developed a highly sensitive cfDNA capture system by integrating polydopamine (PDA) and silica. PDA-silica hybrids incorporated different molecular interactions to a single system, enhancing cfDNA capture by 1.34-fold compared to the conventional silica-based approach (p = 0.001), which was confirmed using cell culture supernatants. A clinical study using human plasma samples revealed that the diagnostic accuracy of the new system to be superior than the commercially available cfDNA kit, as well as other serum antigen tests. Among the cancer patients, plasma cfDNA levels exhibited a good correlation with the size of a tumor. cfDNA was also predicative of distant metastasis, as the median cfDNA levels of metastatic cancer patients were ~60-fold higher than those without metastasis (p = 0.008). Furthermore, high concordance between tissue biopsy and cfDNA genomic analysis was found, as HER2 expression in cfDNA demonstrated an area under ROC curve (AUC) of 0.976 (p <0.001) for detecting patients with HER2-positive tumors. The new system also revealed high prognostic capability of cfDNA, as the concentration of cfDNA was highly associated with the survival outcomes. Our novel technology demonstrates the potential to achieve efficient detection of cfDNA that may serve as a reliable biomarker for gastric tumor.