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Behyari M, Behyari M. Biotechnological and Pharmacological Perspectives on PD-L1 Inhibition by Single-Chain Antibodies: A Structure-Based Integrative Review. pbp 2026; 8 (4)
URL: http://pbp.medilam.ac.ir/article-1-448-en.html
URL: http://pbp.medilam.ac.ir/article-1-448-en.html
1- Department of Cancer Cell and Molecular Biology, University of Leicester, Leicester, UK , maryam.behyary@gmail.com
2- Department of Tissue Engineering, Tehran University of Medical Sciences, Tehran, Iran
2- Department of Tissue Engineering, Tehran University of Medical Sciences, Tehran, Iran
Abstract: (33 Views)
Objective: Immune checkpoint inhibitors targeting the PD-1/PD-L1 axis have transformed cancer therapy, but conventional mAbs are limited by poor tumor penetration, prolonged systemic exposure, irAEs, and high production costs. VHHs and plant molecular farming may address these limitations, yet their integration remains largely unexplored. This scoping review summarizes evidence on PD-L1 inhibition by VHHs, plant-based VHH production, ICI efficacy and safety in NSCLC, and VHH pharmacokinetics.
Methods: Peer-reviewed studies published from 2012 to 2025 were identified through PubMed/MEDLINE, Web of Science, PDB, and ClinicalTrials.gov. Eligible studies addressed PD-L1 structure, VHH engineering and production, plant-based expression, ICI outcomes in NSCLC, or nanobody pharmacokinetics. Data were systematically extracted, and methodological quality was assessed using RoB 2, ROBINS-I, and AMSTAR 2 according to study design.
Results: From 1,247 records identified, 149 full-text articles were assessed, and 62 studies were included. Structural analysis identified key PD-L1 hotspots (F19, Y56, R113, M115). The KN035 nanobody (PDB: 5JDS) competes with PD-1 for the same surface on PD-L1 through a 21-amino-acid loop with approximately 1,000-fold stronger binding than PD-1. VHHs (~15 kDa) have short half-lives (hours) due to renal filtration. Plant expression of VHH-Fc fusions in Nicotiana benthamiana has been reported at yields up to 110.90 ± 6.46 mg/kg fresh weight, depending on subcellular targeting and protein engineering. No plant-produced anti-PD-L1 VHH has been reported to date. Clinical data show that ICI combination regimens achieve HR OS as low as 0.56 (95% CI 0.45–0.70) in the updated analysis of KEYNOTE-189, with Grade ≥3 immune-mediated adverse event rates of approximately 8–11% across ICI combination trials. No human clinical trial data exist for VHHs in NSCLC.
Conclusions: Plant-produced VHHs represent a promising but currently unproven approach for PD-L1 inhibition. The structural and pharmacological rationale is strong, but clinical and biotechnological evidence is lacking. Phase I/II trials and proof-of-concept plant expression studies are warranted.
Methods: Peer-reviewed studies published from 2012 to 2025 were identified through PubMed/MEDLINE, Web of Science, PDB, and ClinicalTrials.gov. Eligible studies addressed PD-L1 structure, VHH engineering and production, plant-based expression, ICI outcomes in NSCLC, or nanobody pharmacokinetics. Data were systematically extracted, and methodological quality was assessed using RoB 2, ROBINS-I, and AMSTAR 2 according to study design.
Results: From 1,247 records identified, 149 full-text articles were assessed, and 62 studies were included. Structural analysis identified key PD-L1 hotspots (F19, Y56, R113, M115). The KN035 nanobody (PDB: 5JDS) competes with PD-1 for the same surface on PD-L1 through a 21-amino-acid loop with approximately 1,000-fold stronger binding than PD-1. VHHs (~15 kDa) have short half-lives (hours) due to renal filtration. Plant expression of VHH-Fc fusions in Nicotiana benthamiana has been reported at yields up to 110.90 ± 6.46 mg/kg fresh weight, depending on subcellular targeting and protein engineering. No plant-produced anti-PD-L1 VHH has been reported to date. Clinical data show that ICI combination regimens achieve HR OS as low as 0.56 (95% CI 0.45–0.70) in the updated analysis of KEYNOTE-189, with Grade ≥3 immune-mediated adverse event rates of approximately 8–11% across ICI combination trials. No human clinical trial data exist for VHHs in NSCLC.
Conclusions: Plant-produced VHHs represent a promising but currently unproven approach for PD-L1 inhibition. The structural and pharmacological rationale is strong, but clinical and biotechnological evidence is lacking. Phase I/II trials and proof-of-concept plant expression studies are warranted.
Type of Study: Review/Systemtic review |
Subject:
Biotechnology
Received: 2026/06/10 | Accepted: 2026/09/27 | Published: 2026/09/28
Received: 2026/06/10 | Accepted: 2026/09/27 | Published: 2026/09/28
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