Leveraging Bioorthogonal Click Chemistry to Improve 225Ac-Radioimmunotherapy of Pancreatic Ductal Adenocarcinoma

S Poty, LM Carter, K Mandleywala, R Membreno… - Clinical Cancer …, 2019 - AACR
S Poty, LM Carter, K Mandleywala, R Membreno, D Abdel-Atti, A Ragupathi, WW Scholz…
Clinical Cancer Research, 2019AACR
Purpose: Interest in targeted alpha-therapy has surged due to α-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 α-radioimmunotherapy (PRIT) of pancreatic ductal
adenocarcinoma (PDAC). This alternative strategy is expected to reduce nonspecific …
Purpose
Interest in targeted alpha-therapy has surged due to α-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 α-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.
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