Novel Complex of PD-L1 Aptamer and Albumin Enhances Antitumor Efficacy In Vivo

Abstract

The PD-1/PD-L1 pathway blockade can generate a good clinical response by reducing immunosuppression and provoking durable antitumor immunity. In addition to antibodies, aptamers can also block the interaction between PD-1 and PD-L1. For the in vivo application, however, free aptamers are usually too small in size and quickly removed from blood via glomerular filtration. To avoid renal clearance of aptamer, we conjugated the PD-L1 aptamer to albumin to form a larger complex (BSA-Apt) and evaluated whether BSA-Apt would enhance the in vivo antitumor efficacy. The PD-L1 aptamer was thiol-modified and conjugated to the amino group of BSA via a SMCC linker. The average size of BSA-Apt was 11.65 nm, which was above the threshold for renal clearance. Functionally, BSA-Apt retained the capability of the PD-L1 aptamer to bind with PDL1-expressing tumor cells. Moreover, both the free aptamer and BSA-Apt augmented the PBMC-induced antitumor cytotoxicity in vitro. Furthermore, BSA-Apt generated a significantly stronger antitumor efficacy than the free PD-L1 aptamer in vivo without raising systemic toxicity. The results indicate that conjugating the PD-L1 aptamer to albumin may serve as a promising strategy to improve the in vivo functionality of the aptamer and that BSA-Apt may have application potential in cancer immunotherapy.

Aptamers Targeting the PD-1/PD-L1 Axis: A Perspective

“…MP7-PEG suppressed tumor growth in PD-L1 + colon carcinoma cells in C57Bl/6 mice. An et al coupled BSA through succinyl-maleimide chemistry, as in Figure A, to a sulfur-modified PD-L1 aptamer (5′-SH-TTTTTTACGG­GCCACATCAA­CTCATTGATA­GACAATGCGT­CCACTGCCCGT-3′) with close to 60% efficacy using an aptamer:BSA ratio of 5:1 . The particle size (11.6 nm) was expected to limit kidney clearance, and binding of the anti-PD-L1 aptamer to the CT26 cell line was maintained after its modification.…”

Novel Nanotherapeutics for Cancer Immunotherapy by PD-L1-Aptamer-Functionalized and Fexofenadine-Loaded Albumin Nanoparticles

“…Lai et al developed a high-affinity aptamer for human PD-L1 [ 15 ]. Several studies have demonstrated that this aptamer generates good antitumor efficacy in preclinical researches [ 16 , 17 ], indicating that the PD-L1 aptamer has potential for clinical application.…”

Preliminary evaluation of a 64Cu-labeled DNA aptamer for PET imaging of glioblastoma

“…Ever since their discovery, DNA or RNA-based aptamers have been designed to act against a wide variety of targets present on the surface of cells, ranging from small molecules [1,2], oligonucleotides [3,4], peptides [5][6][7], to complex proteins [8][9][10]. DNA/RNA aptamers have been incredibly useful in biomedical applications, such as biosensing [11,12], biomarker discovery [13,14], medical imaging [15][16][17], and drug delivery [18,19].…”