Leveraging Bioorthogonal Click Chemistry to Improve 225Ac-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 225 Ac-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 225 Ac-PRIT and conventional RIT using a directly 225 Ac-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 225 Ac-radioimmunoconjugate but-importantly-further allowed for the ex vivo monitoring of 225 Ac's radioactive daughters' redistribution. Human dosimetry was extrapolated from the mouse biodistribution and confirms the clinical translatability of 225 Ac-PRIT. Furthermore, longitudinal therapy studies performed in subcutaneous and orthotopic PDAC models confirm the therapeutic efficacy of 225 Ac-PRIT with the observation of prolonged median survival compared with control cohorts. Finally, a comparison with conventional RIT highlighted the potential of 225 Ac-PRIT to reduce hematotoxicity while maintaining therapeutic effectiveness.Conclusions: The ability of 225 Ac-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.

Radioimmunotherapy of Pancreatic Ductal Adenocarcinoma: A Review of the Current Status of Literature

“…The current paucity in the literature regarding clinical α RIT studies for PDAC limits comparison. The primary concern regarding α RIT is the potential for nephrotoxicity due to the elimination pathway of the radioimmunoconjugates and localisation of recoiling daughter products [57,60]. The use of nano-carriers, fast tumour uptake of the radioimmunoconjugate and direct tumour administration may be beneficial for reducing the potential toxicity of α RIT [75].…”

“…The process of pre-targeting improves blood clearance and tumour localisation of the radioimmunoconjugate to minimise radiation damage to normal tissues. Pre-targeting has already shown value in reducing the incidence of nephrotoxicity in α RIT due to the fast uptake of the radioimmunoconjugate [57]. On the other hand, some inhibitors act as radiosensitisers to block relevant tumour signalling processes [50].…”

“…Nephrotoxicity was observed in some mice receiving α RIT yet not β RIT [57,60]. The effect of α RIT on renal function is likely due to the elimination pathway of the radioimmunoconjugate and recoiling daughter radionuclides.…”

“…Typically, survival improved with higher RIT doses, multiple treatment cycles and the use of a combination therapy approach when delivered within tolerable limits. As an emerging approach, α RIT was primarily assessed as a stand-alone therapy for PDAC, with only Poty et al [57] evaluating the influence of a pre-targeted approach. In comparison, few in vivo studies focused directly on investigating a single β RIT cycle, with the majority assessing different administration routes, pre-targeting and various combination therapies including the addition of chemotherapy and inhibitors.…”

“…The primary side effects observed in both in vivo α and β RIT studies were transient weight loss and haemotoxicities. More severe side effects such as disseminated intravascular coagulation, diarrhea, nephrotoxicity and decreasing activity were also observed in both RIT approaches in a limited number of animals [48,56,57,60]. For β RIT, the presence of side effects typically increased with dose or the addition of chemotherapy to the RIT regime.…”