Immune checkpoint blockade (ICB) using monoclonal antibodies against programmed cell death protein 1 (PD-1) or programmed death-ligand 1 (PD-L1) is the treatment of choice for cancer immunotherapy. However, low tissue permeability, immunogenicity, immune-related adverse effects, and high cost could be possibly improved using alternative approaches. On the other hand, synthetic low-molecular-weight (LMW) PD-1/PD-L1 blockers have failed to progress beyond in vitro studies, mostly due to low binding affinity or poor pharmacological characteristics resulting from their limited solubility and/or stability. Here, we report the development of polymer-based anti-human PD-L1 antibody mimetics (α-hPD-L1 iBodies) by attaching the macrocyclic peptide WL12 to a N-(2-hydroxypropyl)methacrylamide copolymer. We characterized the binding properties of iBodies using surface plasmon resonance, enzyme-linked immunosorbent assay, flow cytometry, confocal microscopy, and a cellular ICB model. We found that the α-hPD-L1 iBodies specifically target human PD-L1 (hPD-L1) and block the PD-1/PD-L1 interaction in vitro, comparable to the atezolizumab, durvalumab, and avelumab licensed monoclonal antibodies targeting PD-L1. Our findings suggest that iBodies can be used as experimental tools to target hPD-L1 and could serve as a platform to potentiate the therapeutic effect of hPD-L1-targeting small molecules by improving their affinity and pharmacokinetic properties.

• Klíčová slova
• HPMA copolymer, PD-1, PD-L1, T-cell, antibody mimetic, immune checkpoint, immunosuppression, immunotherapy, inhibitor, tumor immunology,
• MeSH
• antigeny CD274 * antagonisté a inhibitory   imunologie   metabolismus   MeSH
• inhibitory kontrolních bodů * farmakologie   chemie   MeSH
• lidé MeSH
• monoklonální protilátky chemie   farmakologie   MeSH
• nádorové buněčné linie MeSH
• polymery chemie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antigeny CD274 * MeSH
• CD274 protein, human MeSH Prohlížeč
• inhibitory kontrolních bodů * MeSH
• monoklonální protilátky MeSH
• polymery MeSH