Preclinical and first-in-human evaluation of 18F-labeled D-peptide antagonist for PD-L1 status imaging with PET

Zhou, Ming; Wang, Xiaobo; Chen, Bei; Xiang, Shijun; Rao, Wanqian; Zhang, Zhe; Liu, Huanhuan; Fang, Jianyang; Yin, Xian‐Hong; Deng, Pengbo; Zhang, Xianzhong; Hu, Shuo

doi:10.1007/s00259-022-05876-9

Cited by 22 publications

(18 citation statements)

References 33 publications

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“… 7 29 However, preclinical and clinical data showed that WL12-derived tracers had low spleen uptake and high liver accumulation 26 ; similar results went to 18 F-NOTA-NF12. 27 Whether or not the varying pharmacokinetic profile potentially affects their diagnostic efficacies needs to be elucidated. In general, sufficient antibody concentrations are required to overcome distribution to PD-L1-positive normal tissues to provide circulating tracer levels needed for specific tumor accumulation.…”

Section: Discussionmentioning

confidence: 99%

Preclinical development of novel PD-L1 tracers and first-in-human study of [⁶⁸Ga]Ga-NOTA-RW102 in patients with lung cancers

Zhang,

Cao,

et al. 2024

J Immunother Cancer

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BackgroundThe programmed cell death protein-1 (PD-1)/programmed death receptor ligand 1 (PD-L1) axis critically facilitates cancer cells’ immune evasion. Antibody therapeutics targeting the PD-1/PD-L1 axis have shown remarkable efficacy in various tumors. Immuno-positron emission tomography (ImmunoPET) imaging of PD-L1 expression may help reshape solid tumors’ immunotherapy landscape.MethodsBy immunizing an alpaca with recombinant human PD-L1, three clones of thevariable domain of theheavy chain ofheavy-chain only antibody (VHH) were screened, and RW102 with high binding affinity was selected for further studies. ABDRW102, a VHH derivative, was further engineered by fusing RW102 with the albumin binder ABD035. Based on the two targeting vectors, four PD-L1-specific tracers ([68Ga]Ga-NOTA-RW102, [68Ga]Ga-NOTA-ABDRW102, [64Cu]Cu-NOTA-ABDRW102, and [89Zr]Zr-DFO-ABDRW102) with different circulation times were developed. The diagnostic efficacies were thoroughly evaluated in preclinical solid tumor models, followed by a first-in-human translational investigation of [68Ga]Ga-NOTA-RW102 in patients with non-small cell lung cancer (NSCLC).ResultsWhile RW102 has a high binding affinity to PD-L1 with an excellent KDvalue of 15.29 pM, ABDRW102 simultaneously binds to human PD-L1 and human serum albumin with an excellent KDvalue of 3.71 pM and 3.38 pM, respectively. Radiotracers derived from RW102 and ABDRW102 have differentin vivocirculation times. In preclinical studies, [68Ga]Ga-NOTA-RW102 immunoPET imaging allowed same-day annotation of differential PD-L1 expression with specificity, while [64Cu]Cu-NOTA-ABDRW102 and [89Zr]Zr-DFO-ABDRW102 enabled longitudinal visualization of PD-L1. More importantly, a pilot clinical trial shows the safety and diagnostic value of [68Ga]Ga-NOTA-RW102 immunoPET imaging in patients with NSCLCs and its potential to predict immune-related adverse effects following PD-L1-targeted immunotherapies.ConclusionsWe developed and validated a series of PD-L1-targeted tracers. Initial preclinical and clinical evidence indicates that immunoPET imaging with [68Ga]Ga-NOTA-RW102 holds promise in visualizing differential PD-L1 expression, selecting patients for PD-L1-targeted immunotherapies, and monitoring immune-related adverse effects in patients receiving PD-L1-targeted treatments.Trial registration numberNCT06165874.

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Section: Discussionmentioning

confidence: 99%

Preclinical development of novel PD-L1 tracers and first-in-human study of [⁶⁸Ga]Ga-NOTA-RW102 in patients with lung cancers

Zhang,

Cao,

et al. 2024

J Immunother Cancer

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“…They demonstrated that this tracer is safe for humans and that PET imaging can be completed in less than an hour. However, it should be noted that the uptake of 18 F-NOTA-NF12 by tumors in animal models and patients is relatively low, which may be related to the insufficient affinity of 18 F-NOTA-NF12 for PD-L1 (K D = 85.08 nM) 152 .…”

Section: Detection Methodsmentioning

confidence: 99%

Recent Advancement of PD-L1 Detection Technologies and Clinical Applications in the Era of Precision Cancer Therapy

Zhang¹,

Wu²,

Zhao³

et al. 2023

J. Cancer

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Programmed death-1 is a protein found on the surface of immune cells that can interact with its ligand, programmed death-ligand 1 (PD-L1), which is expressed on the plasma membrane, the surface of secreted cellular exosomes, in cell nuclei, or as a circulating soluble protein. This interaction can lead to immune escape in cancer patients. In clinical settings, PD-L1 plays an important role in tumor disease diagnosis, determining therapeutic effectiveness, and predicting patient prognosis. PD-L1 inhibitors are also essential components of tumor immunotherapy. Thus, the detection of PD-L1 levels is crucial, especially in the era of precision cancer therapy. In recent years, innovations have been made in traditional immunoassay methods and the development of new immunoassays for PD-L1 detection. This review aims to summarize recent research progress in tumor PD-L1 detection technology and highlight the clinical applications of PD-L1.

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“…The cyclic peptide WL12 is such an example, showing excellent affinity and specificity, along with suitable pharmacokinetics in vivo (Chatterjee et al 2017 ; De Silva et al 2018 ; Lesniak et al 2019 ). Hence, this peptide has recently been advanced to clinical trials, marking a significant step forward in this field (Zhou et al 2022 ). In contrast, small molecule-based PD-L1 radiotracers yielded fewer promising outcomes (Ważyńska et al 2023 ), mainly caused by high nonspecific binding, relatively low in vivo tumor uptake, and primarily hepatobiliary clearance (Miao et al 2020 ; Maier et al 2022 ; Xu et al 2023 ).…”

Section: Introductionmentioning

confidence: 99%

Chelator impact: investigating the pharmacokinetic behavior of copper-64 labeled PD-L1 radioligands

Krutzek,

Donat,

Stadlbauer

2024

EJNMMI radiopharm. chem.

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Background Programmed cell death ligand 1 (PD-L1) plays a critical role in the tumor microenvironment and overexpression in several solid cancers has been reported. This was associated with a downregulation of the local immune response, specifically of T-cells. Immune checkpoint inhibitors showed a potential to break this localized immune paralysis, but only 30% of patients are considered responders. New diagnostic approaches are therefore needed to determine patient eligibility. Small molecule radiotracers targeting PD-L1, may serve as such diagnostic tools, addressing the heterogeneous PD-L1 expression between and within tumor lesions, thus aiding in therapy decisions. Results Four biphenyl-based small-molecule PD-L1 ligands were synthesized using a convergent synthetic route with a linear sequence of up to eleven steps. As a chelator NODA-GA, CB-TE2A or DiAmSar was used to allow radiolabeling with copper-64 ([64Cu]Cu-14–[64Cu]Cu-16). In addition, a dimeric structure based on DiAmSar was synthesized ([64Cu]Cu-17). All four radioligands exhibited high proteolytic stability (> 95%) up to 48 h post-radiolabeling. Saturation binding yielded moderate affinities toward PD-L1, ranging from 100 to 265 nM. Real-time radioligand binding provided more promising KD values around 20 nM for [64Cu]Cu-14 and [64Cu]Cu-15. In vivo PET imaging in mice bearing both PC3 PD-L1 overexpressing and PD-L1-mock tumors was performed at 0–2, 4–5 and 24–25 h post injection (p.i.). This revealed considerably different pharmacokinetic profiles, depending on the substituted chelator. [64Cu]Cu-14, substituted with NODA-GA, showed renal clearance with low liver uptake, whereas substitution with the cross-bridged cyclam chelator CB-TE2A resulted in a primarily hepatobiliary clearance. Notably, the monomeric DiAmSar radioligand [64Cu]Cu-16 demonstrated a higher liver uptake than [64Cu]Cu-15, but was still renally cleared as evidenced by the lack of uptake in gall bladder and intestines. The dimeric structure [64Cu]Cu-17 showed extensive accumulation and trapping in the liver but was also cleared via the renal pathway. Of all tracer candidates and across all timepoints, [64Cu]Cu-17 showed the highest accumulation at 24 h p.i. in the PD-L1-overexpressing tumor of all timepoints and all radiotracers, indicating drastically increased circulation time upon dimerization of two PD-L1 binding motifs. Conclusions This study shows that chelator choice significantly influences the pharmacokinetic profile of biphenyl-based small molecule PD-L1 radioligands. The NODA-GA-conjugated radioligand [64Cu]Cu-14 exhibited favorable renal clearance; however, the limited uptake in tumors suggests the need for structural modifications to the binding motif for future PD-L1 radiotracers.

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Preclinical and first-in-human evaluation of 18F-labeled D-peptide antagonist for PD-L1 status imaging with PET

Cited by 22 publications

References 33 publications

Preclinical development of novel PD-L1 tracers and first-in-human study of [⁶⁸Ga]Ga-NOTA-RW102 in patients with lung cancers

Preclinical development of novel PD-L1 tracers and first-in-human study of [⁶⁸Ga]Ga-NOTA-RW102 in patients with lung cancers

Recent Advancement of PD-L1 Detection Technologies and Clinical Applications in the Era of Precision Cancer Therapy

Chelator impact: investigating the pharmacokinetic behavior of copper-64 labeled PD-L1 radioligands

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Preclinical and first-in-human evaluation of 18F-labeled D-peptide antagonist for PD-L1 status imaging with PET

Cited by 22 publications

References 33 publications

Preclinical development of novel PD-L1 tracers and first-in-human study of [68Ga]Ga-NOTA-RW102 in patients with lung cancers

Preclinical development of novel PD-L1 tracers and first-in-human study of [68Ga]Ga-NOTA-RW102 in patients with lung cancers

Recent Advancement of PD-L1 Detection Technologies and Clinical Applications in the Era of Precision Cancer Therapy

Chelator impact: investigating the pharmacokinetic behavior of copper-64 labeled PD-L1 radioligands

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Preclinical development of novel PD-L1 tracers and first-in-human study of [⁶⁸Ga]Ga-NOTA-RW102 in patients with lung cancers

Preclinical development of novel PD-L1 tracers and first-in-human study of [⁶⁸Ga]Ga-NOTA-RW102 in patients with lung cancers