Visualizing Galectin-3 binding protein expression with immunoPET Journal Article
| Authors: | Keinänen, O.; Sarrett, S. M.; Delaney, S.; Rodriguez, C.; Dayts, E. J.; Capone, E.; Sauniere, F.; Ippoliti, R.; Sala, G.; Iacobelli, S.; Zeglis, B. M. |
| Article Title: | Visualizing Galectin-3 binding protein expression with immunoPET |
| Abstract: | Galectin-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. © 2023 The Authors. Published by American Chemical Society. |
| Keywords: | positron emission tomography; mouse; animal; animals; mice; melanoma; carcinoma, non-small-cell lung; lung neoplasms; cell line, tumor; lung tumor; chemistry; tumor cell line; positron-emission tomography; zirconium; deferoxamine; non small cell lung cancer; galectin 3; immunopet; antibody conjugate; immunoconjugates; zr-89; procedures; antibody-drug conjugate; humans; human; galectin-3 binding protein; theranostic imaging |
| Journal Title: | Molecular Pharmaceutics |
| Volume: | 20 |
| Issue: | 6 |
| ISSN: | 1543-8384 |
| Publisher: | American Chemical Society |
| Date Published: | 2023-06-05 |
| Start Page: | 3241 |
| End Page: | 3248 |
| Language: | English |
| DOI: | 10.1021/acs.molpharmaceut.3c00241 |
| PUBMED: | 37191353 |
| PROVIDER: | scopus |
| PMCID: | PMC10245371 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Brian Zeglis -- Source: Scopus |
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