Enhancement of Gene Knockdown on CD22-Expressing Cells by Chemically Modified Glycan Ligand–siRNA Conjugates

Abstract

Extrahepatic targeted delivery of oligonucleotides, such as small interfering RNA (siRNA) and antisense oligonucleotides (ASOs), is an attractive technology for the development of nucleic acid-based medicines. To target CD22-expressing B cells, several drug platforms have shown promise, including antibodies, antibody–drug conjugates, and nanoparticles, but to date CD22-targeted delivery of oligonucleotide therapeutics has not been reported. Here we report the uptake and enhancement of siRNA gene expression knockdown in CD22-expressing B cells using a chemically stabilized and modified CD22 glycan ligand-conjugated siRNA. This finding has the potential to broaden the use of siRNA technology, opening up novel therapeutic opportunities, and presents an innovative approach for targeted delivery of siRNAs to B cell lymphomas.

Targeted delivery to macrophages and dendritic cells by chemically modified mannose ligand-conjugated siRNA

“…The selectivity of the target mRNA was also confirmed using three types of target sequences. The gene silencing activity of the siB2M(h) conjugate was weaker than that of the siHPRT1-a conjugate in our previous report ( 57 ), and the same tendency was observed in this study. Although optimization of the sequence and modification pattern in this study has not been fully investigated, these results indicate that siRNA optimization is also important for validating the conjugate.…”

“…Our CMM–siRNAs exhibited enhanced uptake and gene silencing effects compared with siRNA and C3N-siRNA as non-CD206-binding compounds (Figures 4 and 5 ). In other studies, multivalent sugar ligand-conjugated siRNAs have been shown to enhance gene silencing, accompanied by increased valency-dependent uptake ( 56 , 57 ). As expected, valency-dependent uptake, gene silencing, and protein downregulation were observed compared with CMM1–siRNA and CMM4–siRNA.…”

Glycomimetics for the inhibition and modulation of lectins

“…Adopted from lit. 367,693,694 direct insertion of the glycomimetic lipid conjugate, similar effects on B cells could be induced. Inhibition of cellular activation, reduction of cytokine secretion and cellular proliferation were achieved.…”

PAF‐induced inflammatory and immuno‐allergic ophthalmic diseases and their mitigation with PAF receptor antagonists: Cell and nuclear effects

“…The elucidation of the precise role of nuclear PAF receptors 92,142,143 and orphan receptors, 144 and receptor dimers 145 that may recognize PAF and Lyso‐PAF as their cognate ligands is also needed. We eagerly await more progress in the PAF receptor mechanisms of action and the creation of next generation of PAF receptor antagonists, 8 perhaps those that can be conjugated to other disease‐modifying drugs, siRNAs and/or antibodies 146–149 . In fact, PAF‐neutralizing antibodies may prove effective in some of the diseases caused by PAF akin to what has been achieved by anti‐VEGF biologics, 150–152 and more recently by use of bispecific antibodies 153 .…”

“…We eagerly await more progress in the PAF receptor mechanisms of action and the creation of next generation of PAF receptor antagonists, 8 perhaps those that can be conjugated to other disease‐modifying drugs, siRNAs and/or antibodies. 146 , 147 , 148 , 149 In fact, PAF‐neutralizing antibodies may prove effective in some of the diseases caused by PAF akin to what has been achieved by anti‐VEGF biologics, 150 , 151 , 152 and more recently by use of bispecific antibodies. 153 Exciting new technologies and other forms of therapeutic agents as mentioned above need to be applied to PAF and its receptors to help advance this field of study.…”