Polymer-based antibody mimetics (iBodies) target human PD-L1 and function as a potent immune checkpoint blocker.

0586357 - ÚOCHB 2025 RIV NL eng J - Článek v odborném periodiku
Zamani, Mohammad Reza - Hadzima, Martin - Blažková, Kristýna - Šubr, Vladimír - Ormsby, Tereza - Celis-Gutierrez, J. - Malissen, B. - Kostka, Libor - Etrych, Tomáš - Šácha, Pavel - Konvalinka, Jan
Polymer-based antibody mimetics (iBodies) target human PD-L1 and function as a potent immune checkpoint blocker.
Journal of Biological Chemistry. Roč. 300, č. 6 (2024), č. článku 107325. ISSN 0021-9258. E-ISSN 1083-351X
Grant CEP: GA MŠMT LX22NPO5102; GA ČR(CZ) GA23-05642S
Institucionální podpora: RVO:61388963 ; RVO:61389013
Klíčová slova: antibody mimetic * HPMA copolymer * mmune checkpoint * immunosuppression * immunotherapy * inhibitor * PD-1 * PD-L1 * T-cell * tumor immunology
Kód oboru RIV: CD - Makromolekulární chemie (UMCH-V)
Obor OECD: Polymer science (UMCH-V)
Impakt faktor: 4.8, rok: 2022
Způsob publikování: Open access
https://doi.org/10.1016/j.jbc.2024.107325

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 invitro 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 (alpha-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 alpha-hPD-L1 iBodies specifically target human PD-L1 (hPD-L1) and block the PD-1/PD-L1 interaction invitro, 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.
Trvalý link: https://hdl.handle.net/11104/0353904