PD-L1 PET/CT imaging with radiolabeled durvalumab in patients with advanced stage non-small cell lung cancer.

Smit, Jan Maerten; Borm, Frank J.; Niemeijer, Anna-Larissa N.; Huisman, Marc C.; Hoekstra, Otto S.; Boellaard, Ronald; Oprea-Lager, Daniela E.; Vugts, Daniëlle J.; Dongen, Guus Ams van; Veen, Berlinda J. de Wit–van der; Thunnissen, Erik; Smit, Egbert F.; Langen, Adrianus J de

doi:10.2967/jnumed.121.262473

Cited by 44 publications

(68 citation statements)

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“…This effect was most pronounced with a low antibody dose of 30 µg and could be compensated for by increasing the antibody doses to 100 µg. This dose-dependent clearance from circulation has also been observed in clinical studies (20). Moreover, these results are in line with other studies that show that 10F.9G2 and other anti-PD-L1 antibodies exhibit target-mediated drug disposition (TMDD), meaning that these antibodies show nonlinear pharmacokinetics at low doses, while increasing the dose leads to linear pharmacokinetics (30,31).…”

Section: Discussionsupporting

confidence: 89%

“…Various preclinical studies in onco-immunology have demonstrated the feasibility of this approach in immunocompetent mouse models ( 17 – 19 ). Moreover, recent clinical studies using a radiolabeled anti-PD-L1 antibody ( 14 , 20 ), adnectin ( 15 ), peptide ( 21 ), or nanobody ( 22 ) demonstrated that nuclear imaging using PD-L1 targeting tracers can assess PD-L1 expression in vivo ( 18 ). Accumulation of the radiolabeled anti-PD-L1 antibodies was also observed in tissues with physiological PD-L1 expression (e.g., spleen, lymph nodes, and bone marrow) as well as in inflammatory sites ( 14 ).…”

Section: Introductionmentioning

confidence: 99%

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PD-L1 Antibody Pharmacokinetics and Tumor Targeting in Mouse Models for Infectious Diseases

et al. 2022

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BackgroundProgrammed death-ligand 1 (PD-L1) regulates immune homeostasis by promoting T-cell exhaustion. It is involved in chronic infections and tumor progression. Nuclear imaging using radiolabeled anti-PD-L1 antibodies can monitor PD-L1 tissue expression and antibody distribution. However, physiological PD-L1 can cause rapid antibody clearance from blood at imaging doses. Therefore, we hypothesized that inflammatory responses, which can induce PD-L1 expression, affect anti-PD-L1 antibody distribution. Here, we investigated the effects of three different infectious stimuli on the pharmacokinetics and tumor targeting of radiolabeled anti-PD-L1 antibodies in tumor-bearing mice.Materials/MethodsAnti-mouse-PD-L1 and isotype control antibodies were labelled with indium-111 ([111In]In-DTPA-anti-mPD-L1 and [111In]In-DTPA-IgG2a, respectively). We evaluated the effect of inflammatory responses on the pharmacokinetics of [111In]In-DTPA-anti-mPD-L1 in RenCa tumor-bearing BALB/c mice in three conditions: lipopolysaccharide (LPS), local Staphylococcus aureus, and heat-killed Candida albicans. After intravenous injection of 30 or 100 µg of [111In]In-DTPA-anti-mPD-L1 or [111In]In-DTPA-IgG2a, blood samples were collected 1, 4, and 24 h p.i. followed by microSPECT/CT and ex vivo biodistribution analyses. PD-L1 expression, neutrophil, and macrophage infiltration in relevant tissues were evaluated immunohistochemically.ResultsIn 30 µg of [111In]In-DTPA-anti-mPD-L1 injected tumor-bearing mice the LPS-challenge significantly increased lymphoid organ uptake compared with vehicle controls (spleen: 49.9 ± 4.4%ID/g versus 21.2 ± 6.9%ID/g, p < 0.001), resulting in lower blood levels (3.6 ± 1.6%ID/g versus 11.5 ± 7.2%ID/g; p < 0.01) and reduced tumor targeting (8.1 ± 4.5%ID/g versus 25.2 ± 5.2%ID/g, p < 0.001). Local S. aureus infections showed high PD-L1+ neutrophil influx resulting in significantly increased [111In]In-DTPA-anti-mPD-L1 uptake in affected muscles (8.6 ± 2.6%ID/g versus 1.7 ± 0.8%ID/g, p < 0.001). Heat-killed Candida albicans (Hk-C. albicans) challenge did not affect pharmacokinetics. Increasing [111In]In-DTPA-anti-mPD-L1 dose to 100 µg normalized blood clearance and tumor uptake in LPS-challenged mice, although lymphoid organ uptake remained higher. Infectious stimuli did not affect [111In]In-DTPA-IgG2a pharmacokinetics.ConclusionsThis study shows that anti-PD-L1 antibody pharmacokinetics and tumor targeting can be significantly altered by severe inflammatory responses, which can be compensated for by increasing the tracer dose. This has implications for developing clinical PD-L1 imaging protocols in onco-immunology. We further demonstrate that radiolabeled anti-PD-L1 antibodies can be used to evaluate PD-L1 expression changes in a range of infectious diseases. This supports the exploration of using these techniques to assess hosts’ responses to infectious stimuli.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

PD-L1 Antibody Pharmacokinetics and Tumor Targeting in Mouse Models for Infectious Diseases

et al. 2022

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“…Contradicting correlations have been found between clinical whole-body PD-L1 PET imaging and treatment response [ 22 , 23 , 60 , 61 ]. Our multimodal platform enabled us to image aPD-L1 tracer localization with cellular resolution with NIR fluorescence microscopy.…”

Section: Discussionmentioning

confidence: 99%

Multiscale imaging of therapeutic anti-PD-L1 antibody localization using molecularly defined imaging agents

et al. 2022

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Background While immune checkpoint inhibitors such as anti-PD-L1 antibodies have revolutionized cancer treatment, only subgroups of patients show durable responses. Insight in the relation between clinical response, PD-L1 expression and intratumoral localization of PD-L1 therapeutics could improve patient stratification. Therefore, we present the modular synthesis of multimodal antibody-based imaging tools for multiscale imaging of PD-L1 to study intratumoral distribution of PD-L1 therapeutics. Results To introduce imaging modalities, a peptide containing a near-infrared dye (sulfo-Cy5), a chelator (DTPA), an azide, and a sortase-recognition motif was synthesized. This peptide and a non-fluorescent intermediate were used for site-specific functionalization of c-terminally sortaggable mouse IgG1 (mIgG1) and Fab anti-PD-L1. To increase the half-life of the Fab fragment, a 20 kDa PEG chain was attached via strain-promoted azide-alkyne cycloaddition (SPAAC). Biodistribution and imaging studies were performed with 111In-labeled constructs in 4T1 tumor-bearing mice. Comparing our site-specific antibody-conjugates with randomly conjugated antibodies, we found that antibody clone, isotype and method of DTPA conjugation did not change tumor uptake. Furthermore, addition of sulfo-Cy5 did not affect the biodistribution. PEGylated Fab fragment displayed a significantly longer half-life compared to unPEGylated Fab and demonstrated the highest overall tumor uptake of all constructs. PD-L1 in tumors was clearly visualized by SPECT/CT, as well as whole body fluorescence imaging. Immunohistochemistry staining of tumor sections demonstrated that PD-L1 co-localized with the fluorescent and autoradiographic signal. Intratumoral localization of the imaging agent could be determined with cellular resolution using fluorescent microscopy. Conclusions A set of molecularly defined multimodal antibody-based PD-L1 imaging agents were synthesized and validated for multiscale monitoring of PD-L1 expression and localization. Our modular approach for site-specific functionalization could easily be adapted to other targets. Graphical Abstract

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“…to demonstrate tumor uptake in a range of advanced malignancies [93,94,102,103]. A study of [ 89 Zr]-atezolizumab, including 22 patients with advanced NSCLC, bladder or breast cancer, demonstrated tumor uptake with inter-and intra-tumoral heterogeneity, and better correlation with clinical response than with PD-L1 immunohistochemistry and RNA-sequenced immune biomarkers [94].…”

Section: Imaging Immune Checkpoint Pathwaysmentioning

confidence: 99%

¹⁸F FDG PET/CT and Novel Molecular Imaging for Directing Immunotherapy in Cancer

Hughes¹,

Subesinghe²,

Taylor³

et al. 2022

Radiology

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If citing, it is advised that you check and use the publisher's definitive version for pagination, volume/issue, and date of publication details. And where the final published version is provided on the Research Portal, if citing you are again advised to check the publisher's website for any subsequent corrections. General rightsCopyright and moral rights for the publications made accessible in the Research Portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognize and abide by the legal requirements associated with these rights. •Users may download and print one copy of any publication from the Research Portal for the purpose of private study or research. •You may not further distribute the material or use it for any profit-making activity or commercial gain •You may freely distribute the URL identifying the publication in the Research Portal Download date: 11. Jul. 2022 • [ 18 F]FDG PET/CT may help detect and facilitate monitoring of immunotherapy toxicity and help distinguish toxicity from disease progression or alternative inflammatory or infective pathology. (page 12) • Novel radiopharmaceuticals provide an opportunity to better characterize individual tumors and help define the immune tumor microenvironment. In vivo whole-body and longitudinal molecular imaging may allow dynamic real-time assessment and direct therapeutic approaches. (page 15

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PD-L1 PET/CT imaging with radiolabeled durvalumab in patients with advanced stage non-small cell lung cancer.

Cited by 44 publications

References 27 publications

PD-L1 Antibody Pharmacokinetics and Tumor Targeting in Mouse Models for Infectious Diseases

PD-L1 Antibody Pharmacokinetics and Tumor Targeting in Mouse Models for Infectious Diseases

Multiscale imaging of therapeutic anti-PD-L1 antibody localization using molecularly defined imaging agents

¹⁸F FDG PET/CT and Novel Molecular Imaging for Directing Immunotherapy in Cancer

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PD-L1 PET/CT imaging with radiolabeled durvalumab in patients with advanced stage non-small cell lung cancer.

Cited by 44 publications

References 27 publications

PD-L1 Antibody Pharmacokinetics and Tumor Targeting in Mouse Models for Infectious Diseases

PD-L1 Antibody Pharmacokinetics and Tumor Targeting in Mouse Models for Infectious Diseases

Multiscale imaging of therapeutic anti-PD-L1 antibody localization using molecularly defined imaging agents

18F FDG PET/CT and Novel Molecular Imaging for Directing Immunotherapy in Cancer

Contact Info

Product

Resources

About

¹⁸F FDG PET/CT and Novel Molecular Imaging for Directing Immunotherapy in Cancer