Pretargeted Trop-2 ImmunoPET for rapid, selective detection of pancreatic tumors Journal Article
| Authors: | Pratt, E. C.; Mandleywala, K.; Bauer, D.; Bolaender, A.; Chao, G.; Castanares, M. A.; Collins, E. C.; Lewis, J. S. |
| Article Title: | Pretargeted Trop-2 ImmunoPET for rapid, selective detection of pancreatic tumors |
| Abstract: | Purpose: Recent clinical advances with the approval of antibody–drug conjugates targeting trophoblast cell-surface antigen 2 (Trop-2), such as sacituzumab govitecan and datopotamab deruxtecan, have garnered tremendous interest for their therapeutic efficacy in numerous tumor types, including breast and lung cancers. ImmunoPET can stratify tumor avidity, clarifying patient eligibility for antibody–drug conjugate therapy as well as a diagnostic companion during therapy. Slow antibody circulation requires days to reach optimal imaging timepoints. To overcome this shortfall, bioorthogonal click chemistry for pretargeting can be employed, decoupling antibody circulation time and the delivery of the radionuclide. Experimental Design: Here, we report the characterization of a new full-length Trop-2.2 antibody showing high affinity for Trop-2–positive cancers and leverage different site-selective labeling and pretargeting radionuclide combinations to yield rapid imaging with minimal radionuclide footprint after imaging. Three pretargeting strategies for fluorine-18, copper-64, and zirconium-89 were explored in addition to site-specific bioconjugation. Results: We found that pretargeting with [64Cu]Cusarcophagine-tetrazine yielded the best images, identifying Trop-2–positive tumors with optimal tumor-to-background ratios. Intriguingly, we found that the full-length antibody, when directly conjugated, yielded rapid accumulation, starting at 3 hours after injection, and led to more than 50% injected activity per gram in the tumor before 24 hours. Conclusions: [89Zr]Zr-deferoxamine-Trop-2 and pretargeting with [64Cu]Cu-sarcophagine-tetrazine are viable imaging strategies to quickly identify Trop-2–positive tumors for subsequent Trop-2 therapies. © 2025 American Association for Cancer Research. |
| Keywords: | immunohistochemistry; controlled study; protein expression; unclassified drug; human cell; nonhuman; pancreatic neoplasms; positron emission tomography; radiopharmaceuticals; mouse; animal; metabolism; animals; mice; animal experiment; animal model; pathology; cell line, tumor; diagnostic imaging; tumor antigen; membrane antigen; immunology; chemistry; antigens, neoplasm; tissue distribution; diagnosis; pancreas tumor; tumor cell line; western blotting; radioactivity; radiopharmaceutical agent; cell adhesion molecules; high performance liquid chromatography; radioisotope; fluorine 18; matrix assisted laser desorption ionization time of flight mass spectrometry; radioisotopes; surface plasmon resonance; optical density; copper 64; zirconium 89; deferoxamine; tumor diagnosis; polyacrylamide gel electrophoresis; cell adhesion molecule; immunopet; antibody conjugate; immunoconjugates; tumor-to-background ratio; tetrazine derivative; radiolabeling; humans; human; female; article; sacituzumab govitecan; tacstd2 protein, human; sacituzumab; trophoblast cell surface antigen 2; sarcophagine tetrazine |
| Journal Title: | Clinical Cancer Research |
| Volume: | 31 |
| Issue: | 13 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2025-07-01 |
| Start Page: | 2719 |
| End Page: | 2726 |
| Language: | English |
| DOI: | 10.1158/1078-0432.Ccr-24-3098 |
| PUBMED: | 39841860 |
| PROVIDER: | scopus |
| PMCID: | PMC12213220 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF (Typos) -- MSK corresponding author is Jason Lewis -- Source: Scopus |
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