Keina''nen, OutiSarrett, Samantha M.Delaney, SamanthaRodriguez, CindyDayts, Eric J.Capone, EmilySauniere, FredericIppoliti, RodolfoSala, GianlucaIacobelli, StefanoZeglis, Brian M.2024-03-132024-03-132023-05-16Keina''nen, O, Sarrett, S M, Delaney, S, Rodriguez, C, Dayts, E J, Capone, E, Sauniere, F, Ippoliti, R, Sala, G, Iacobelli, S & Zeglis, B M 2023, 'Visualizing Galectin-3 Binding Protein Expression with ImmunoPET', Molecular Pharmaceutics, vol. 20, no. 6, pp. 3241-3248. https://doi.org/10.1021/acs.molpharmaceut.3c00241ORCID: /0000-0002-3939-6706/work/155650625http://hdl.handle.net/10138/573059Galectin-3 binding protein (Gal-3BP) is a glycoprotein that is overexpressed and secreted by several cancers and has been implicated as a marker of both tumor progression and poor prognosis in melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, and breast cancer. The expression of Gal-3BP by a variety of neoplasms makes it an enticing target for both diagnostics and therapeutics, including immuno-positron emission tomography (immunoPET) probes and antibody-drug conjugates (ADCs). Herein, we report the development, in vitro characterization, and in vivo evaluation of a pair of Gal-3BP-targeting radioimmunoconjugates for 89Zr-immunoPET. A humanized anti-Gal-3BP antibody, 1959, and its corresponding ADC, 1959-sss/DM4 (DM4 = ravtansine), were modified with desferrioxamine (DFO) to yield DFO-1959 and DFO-1959-sss/DM4 immunoconjugates bearing 1–2 DFO/monoclonal antibody. Both DFO-modified immunoconjugates retained their affinity for Gal-3BP in enzyme-linked immunosorbent assay experiments. The chelator-bearing antibodies were radiolabeled with zirconium-89 (t1/2 ≈ 3.3 d) to produce radioimmunoconjugates ─ [89Zr]Zr-DFO-1959 and [89Zr]Zr-DFO-1959-sss/DM4 ─ with high specific activity (>444 MBq/mg, >12 mCi/mg) and stability (>80% intact after 168 h in human serum at 37 °C). In mice bearing subcutaneous Gal-3BP-secreting A375-MA1 xenografts, [89Zr]Zr-DFO-1959 clearly delineated tumor tissue, reaching a maximum tumoral activity concentration (54.8 ± 15.8%ID/g) and tumor-to-background contrast (tumor-to-blood = 8.0 ± 4.6) at 120 h post-injection. The administration of [89Zr]Zr-DFO-1959 to mice bearing subcutaneous Gal-3BP-expressing melanoma patient-derived xenografts produced similarly promising results. [89Zr]Zr-DFO-1959 and [89Zr]Zr-DFO-1959-sss/DM4 exhibited nearly identical pharmacokinetic profiles in the mice bearing A375-MA1 tumors, though the latter produced higher uptake in the spleen and kidneys. Both [89Zr]Zr-DFO-1959 and [89Zr]Zr-DFO-1959-sss/DM4 effectively visualized Gal-3BP-secreting tumors in murine models of melanoma. These results suggest that both probes could play a role in the clinical imaging of Gal-3BP-expressing malignancies, particularly as companion theranostics for the identification of patients likely to respond to Gal-3BP-targeted therapeutics such as 1959-sss/DM4.8engcc_by_nc_ndinfo:eu-repo/semantics/openAccessZr-89Antibody-drug conjugateGalectin-3 binding proteinimmunoPETPositron emission tomographyTheranostic imagingChemical sciencesArticleopenAccess702d18bd-507f-495f-b5c4-0dff7069e44537191353001014283700001