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

MR. Zamani, M. Hadzima, K. Blažková, V. Šubr, T. Ormsby, J. Celis-Gutierrez, B. Malissen, L. Kostka, T. Etrych, P. Šácha, J. Konvalinka

. 2024 ; 300 (6) : 107325. [pub] 20240427

Language English Country United States

Document type Journal Article

Persistent link   https://www.medvik.cz/link/bmc24019995

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.

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$a Zamani, Mohammad Reza $u Faculty of Science, Department of Cell Biology, Charles University, Prague, Czech Republic; Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic
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$a 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.
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$a Hadzima, Martin $u Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic; Faculty of Science, Department of Organic Chemistry, Charles University, Prague, Czech Republic
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$a Blažková, Kristýna $u Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic
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$a Šubr, Vladimír $u Department of Biomedical polymers, Institute of Macromolecular Chemistry, Czech Academy of Sciences, Prague, Czech Republic
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$a Ormsby, Tereza $u Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic
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$a Celis-Gutierrez, Javier $u Centre d'Immunologie de Marseille-Luminy, Aix-Marseille Université, INSERM, CNRS, Marseille, France
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$a Malissen, Bernard $u Centre d'Immunologie de Marseille-Luminy, Aix-Marseille Université, INSERM, CNRS, Marseille, France
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$a Kostka, Libor $u Department of Biomedical polymers, Institute of Macromolecular Chemistry, Czech Academy of Sciences, Prague, Czech Republic
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$a Etrych, Tomáš $u Department of Biomedical polymers, Institute of Macromolecular Chemistry, Czech Academy of Sciences, Prague, Czech Republic
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$a Šácha, Pavel $u Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic. Electronic address: pavelsacha@gmail.com
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$a Konvalinka, Jan $u Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic; Faculty of Science, Department of Biochemistry, Charles University, Prague, Czech Republic. Electronic address: jan.konvalinka@uochb.cas.cz
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