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Non-invasive, whole-body anti-CD4 immunoPET can provide dynamic and spatial information (localization, proliferation, and migration) on CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells. The cys-diabody format enables site-specific radiolabeling and rapid renal clearance, which results in high-contrast images at early time points.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Procedures<\/jats:title>\n                    <jats:p>\n                      In this work, an anti-CD4 cys-diabody based on the hybridoma GK1.5 was reengineered by CDR-grafting (GK1.5 FR cDb) for higher expression in mammalian cell lines. An N-glycosylation motif in the variable light chain domain framework was removed by site-directed mutagenesis, resulting in GK1.5 N80D cDb. To investigate the impact of the variable domain glycan on the\n                      <jats:italic>in vivo<\/jats:italic>\n                      biodistribution and pharmacokinetics, both cys-diabodies were site-specifically conjugated with deferoxamine-maleimide and radiolabeled by chelation of zirconium-89. Serial immunoPET\/CT imaging was used for non-invasive, whole-body assessment of specific targeting, biodistribution, and differential clearance of the two novel anti-CD4 cys-diabodies.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The anti-CD4 cys diabody was successfully re-engineered by CDR-grafting\u00a0(GK1.5 FR cDb) and aglycosylation (GK1.5 N80D cDb), resulting in a higher expression yield (~\u2009tenfold increase) without impacting antigen specificity or affinity. Both cys-diabody variants were successfully\n                      <jats:sup>89<\/jats:sup>\n                      Zr-radiolabeled with similar specific activity and radiochemical purity. ImmunoPET imaging of\n                      <jats:sup>89<\/jats:sup>\n                      Zr-GK1.5 FR cDb and\n                      <jats:sup>89<\/jats:sup>\n                      Zr-GK1.5 N80D cDb in immunocompetent mice showed CD4 antigen-specific lymphoid tissue uptake in vivo.\n                      <jats:sup>89<\/jats:sup>\n                      Zr-GK1.5 FR cDb exhibited rapid hepatic clearance, resulting in significantly reduced uptake in lymph nodes and the spleen. Removal of the N-glycosylation motif in\n                      <jats:sup>89<\/jats:sup>\n                      Zr-GK1.5 N80D cDb restored diabody-typical biodistribution (renal clearance), resulting in higher target tissue uptake.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      The novel reengineered anti-CD4 GK1.5 N80D cDb overcomes the previous production yield bottleneck and provides same-day\n                      <jats:sup>89<\/jats:sup>\n                      Zr-immunoPET imaging for non-invasive, whole-body visualization of murine CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical Abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1007\/s11307-025-02043-y","type":"journal-article","created":{"date-parts":[[2025,8,7]],"date-time":"2025-08-07T16:54:06Z","timestamp":1754585646000},"page":"774-784","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Reengineered Anti-CD4 Cys-diabody Variants for 89Zr-immunoPET of CD4+ T Cells in Immunocompetent Mice"],"prefix":"10.1007","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-9361-1528","authenticated-orcid":false,"given":"Felix B.","family":"Salazar","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5150-5963","authenticated-orcid":false,"given":"Richard","family":"Tavar\u00e9","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7460-7951","authenticated-orcid":false,"given":"Arya","family":"\u00d6kten","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9701-5211","authenticated-orcid":false,"given":"Maciej","family":"Kujawski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8487-823X","authenticated-orcid":false,"given":"Anna M.","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4870-6603","authenticated-orcid":false,"given":"Kirstin A.","family":"Zettlitz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,8,7]]},"reference":[{"key":"2043_CR1","doi-asserted-by":"publisher","first-page":"925135","DOI":"10.1155\/2012\/925135","volume":"2012","author":"RV Luckheeram","year":"2012","unstructured":"Luckheeram RV, Zhou R, Verma AD, Xia B (2012) CD4(+)T cells: differentiation and functions. 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