{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T23:31:12Z","timestamp":1783467072963,"version":"3.55.0"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,3,10]],"date-time":"2022-03-10T00:00:00Z","timestamp":1646870400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003246","name":"Nederlandse Organisatie voor Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["91617039"],"award-info":[{"award-number":["91617039"]}],"id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004622","name":"KWF Kankerbestrijding","doi-asserted-by":"publisher","award":["10099"],"award-info":[{"award-number":["10099"]}],"id":[{"id":"10.13039\/501100004622","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Programmed 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials\/Methods<\/jats:title><jats:p>Anti-mouse-PD-L1 and isotype control antibodies were labelled with indium-111 ([<jats:sup>111<\/jats:sup>In]In-DTPA-anti-mPD-L1 and [<jats:sup>111<\/jats:sup>In]In-DTPA-IgG2a, respectively). We evaluated the effect of inflammatory responses on the pharmacokinetics of [<jats:sup>111<\/jats:sup>In]In-DTPA-anti-mPD-L1 in RenCa tumor-bearing BALB\/c mice in three conditions: lipopolysaccharide (LPS), local <jats:italic>Staphylococcus aureus<\/jats:italic>, and heat-killed <jats:italic>Candida albicans<\/jats:italic>. After intravenous injection of 30 or 100 \u00b5g of [<jats:sup>111<\/jats:sup>In]In-DTPA-anti-mPD-L1 or [<jats:sup>111<\/jats:sup>In]In-DTPA-IgG2a, blood samples were collected 1, 4, and 24 h p.i. followed by microSPECT\/CT and <jats:italic>ex vivo<\/jats:italic> biodistribution analyses. PD-L1 expression, neutrophil, and macrophage infiltration in relevant tissues were evaluated immunohistochemically.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In 30 \u00b5g of [<jats:sup>111<\/jats:sup>In]In-DTPA-anti-mPD-L1 injected tumor-bearing mice the LPS-challenge significantly increased lymphoid organ uptake compared with vehicle controls (spleen: 49.9 \u00b1 4.4%ID\/g versus 21.2 \u00b1 6.9%ID\/g, p &amp;lt; 0.001), resulting in lower blood levels (3.6 \u00b1 1.6%ID\/g versus 11.5 \u00b1 7.2%ID\/g; p &amp;lt; 0.01) and reduced tumor targeting (8.1 \u00b1 4.5%ID\/g versus 25.2 \u00b1 5.2%ID\/g, p &amp;lt; 0.001). Local <jats:italic>S. aureus<\/jats:italic> infections showed high PD-L1<jats:sup>+<\/jats:sup> neutrophil influx resulting in significantly increased [<jats:sup>111<\/jats:sup>In]In-DTPA-anti-mPD-L1 uptake in affected muscles (8.6 \u00b1 2.6%ID\/g versus 1.7 \u00b1 0.8%ID\/g, p &amp;lt; 0.001). Heat-killed <jats:italic>Candida albicans<\/jats:italic> (Hk-<jats:italic>C. albicans<\/jats:italic>) challenge did not affect pharmacokinetics. Increasing [<jats:sup>111<\/jats:sup>In]In-DTPA-anti-mPD-L1 dose to 100 \u00b5g normalized blood clearance and tumor uptake in LPS-challenged mice, although lymphoid organ uptake remained higher. Infectious stimuli did not affect [<jats:sup>111<\/jats:sup>In]In-DTPA-IgG2a pharmacokinetics.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This 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\u2019 responses to infectious stimuli.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2022.837370","type":"journal-article","created":{"date-parts":[[2022,3,10]],"date-time":"2022-03-10T14:35:59Z","timestamp":1646922959000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["PD-L1 Antibody Pharmacokinetics and Tumor Targeting in Mouse Models for Infectious Diseases"],"prefix":"10.3389","volume":"13","author":[{"given":"Gerwin G. W.","family":"Sandker","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gosse","family":"Adema","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janneke","family":"Molkenboer-Kuenen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Wierstra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johan","family":"Bussink","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Heskamp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik H. J. 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