Memorial Sloan Kettering Cancer Center, Hunter Colleg /Jason S. Lewis*,Brian M. Zeglis*,Sophie Poty*
Abstract
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.
Author information
Poty S1, Carter LM2, Mandleywala K2, Membreno R3,4, Abdel-Atti D2, Ragupathi A2, Scholz WW5, Zeglis BM1,3,4,6, Lewis JS1,6,7,8.
1
Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York. lewisj2@mskcc.org bz102@hunter.cuny.edu potys@mskcc.org.
2
Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
3
Department of Chemistry, Hunter College of the City University of New York, New York, New York.
4
Ph.D. Program in Chemistry, Graduate Center of the City University of New York, New York, New York.
5
MabVax Therapeutics, San Diego, California.
6
Departments of Radiology and Department of Pharmacology, Weill Cornell Medical College, New York, New York.
7
Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
8
Radiochemistry and Molecular Imaging Probes Core, Memorial Sloan Kettering Cancer Center, New York, New York.