Leveraging bioorthogonal click chemistry to improve (225)Ac-radioimmunotherapy of pancreatic ductal adenocarcinoma Journal Article

Authors: Poty, S.; Carter, L. M.; Mandleywala, K.; Membreno, R.; Abdel-Atti, D.; Ragupathi, A.; Scholz, W. W.; Zeglis, B. M.; Lewis, J. S.
Article Title: Leveraging bioorthogonal click chemistry to improve (225)Ac-radioimmunotherapy of pancreatic ductal adenocarcinoma
Abstract: Purpose: Interest in targeted alpha-therapy has surged due to a-particles' high cytotoxicity. However, the widespread clinical use of this approach could be limited by on-/off-target toxicities. Here, we investigated the inverse electron-demand Diels–Alder ligation between an 225Ac-labeled tetrazine radioligand and a trans-cyclooctene–bearing anti-CA19.9 antibody (5B1) for pretargeted a-radioimmunotherapy (PRIT) of pancreatic ductal adenocarcinoma (PDAC). This alternative strategy is expected to reduce nonspecific toxicities as compared with conventional radioimmunotherapy (RIT). Experimental Design: A side-by-side comparison of 225Ac-PRIT and conventional RIT using a directly 225Ac-radiolabeled immunoconjugate evaluates the therapeutic efficacy and toxicity of both methodologies in PDAC murine models. Results: A comparative biodistribution study of the PRIT versus RIT methodology underscored the improved pharmacokinetic properties (e.g., prolonged tumor uptake and increased tumor-to-tissue ratios) of the PRIT approach. Cerenkov imaging coupled to PRIT confirmed the in vivo biodistribution of 225Ac-radioimmunoconjugate but—importantly—further allowed for the ex vivo monitoring of 225Ac's radioactive daughters' redistribution. Human dosimetry was extrapolated from the mouse biodistribution and confirms the clinical translatability of 225Ac-PRIT. Furthermore, longitudinal therapy studies performed in subcutaneous and orthotopic PDAC models confirm the therapeutic efficacy of 225Ac-PRIT with the observation of prolonged median survival compared with control cohorts. Finally, a comparison with conventional RIT highlighted the potential of 225Ac-PRIT to reduce hematotoxicity while maintaining therapeutic effectiveness. Conclusions: The ability of 225Ac-PRIT to deliver a radiotherapeutic payload while simultaneously reducing the off-target toxicity normally associated with RIT suggests that the clinical translation of this approach will have a profound impact on PDAC therapy. © 2018 American Association for Cancer Research.
Journal Title: Clinical Cancer Research
Volume: 25
Issue: 2
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2019-01-15
Start Page: 868
End Page: 880
Language: English
DOI: 10.1158/1078-0432.Ccr-18-1650
PUBMED: 30352909
PROVIDER: scopus
PMCID: PMC6343144
Notes: Article -- Export Date: 1 February 2019 -- Source: Scopus
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MSK Authors
  1. Brian Zeglis
    61 Zeglis
  2. Jason S Lewis
    239 Lewis
  3. Lukas M Carter
    6 Carter
  4. Sophie Poty
    5 Poty