The inverse electron-demand Diels–Alder reaction as a new methodology for the synthesis of<sup>225</sup>Ac-labelled radioimmunoconjugates

Poty, Sophie; Membreno, Rosemery; Glaser, Jonathan M.; Ragupathi, Ashwin; Scholz, Wolfgang; Zeglis, Brian M.; Lewis, Jason S.

doi:10.1039/c7cc09129j

Cited by 42 publications

(36 citation statements)

References 25 publications

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“…2A). For conventional RIT, 5B1 was radiolabeled with 225 Ac using a two-step protocol published by our groups (13). For the pretargeting technique, 5B1 was first functionalized with TCO via the incubation of the antibody with an NHS-bearing variant of TCO (18) and then injected 72 hours prior to the administration of an 225 Aclabeled Tz radioligand: 225 Ac-DOTA-PEG 7 -Tz ( Fig.…”

Section: Ac-prit Offers An Improved Biodistribution Profile Compared mentioning

confidence: 99%

“…The inverse electron-demand Diels-Alder reaction (IEDDA) between tetrazine (Tz) and trans-cyclooctene (TCO) holds promise for a variety of applications, including radiochemistry (11,12). Our laboratories reported its potential for the synthesis of 225 Aclabeled radioimmunoconjugates (13). The selectivity and rapidity of this reaction were investigated for in vivo pretargeting using TCO-bearing antibodies and Tz-containing radioligands (14).…”

Section: Introductionmentioning

confidence: 99%

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

Poty

Carter

Mandleywala

et al. 2019

Clinical Cancer Research

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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.

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Section: Ac-prit Offers An Improved Biodistribution Profile Compared mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Poty

Carter

Mandleywala

et al. 2019

Clinical Cancer Research

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“…Recently, the first Tz labeled with α‐emitting radionuclides (i. e. 212 Pb and 225 Ac) have been reported aiming at the advantages of α‐emitters over β − ‐emitting radionuclides such as the delivery of a higher radiation dose within a shorter path length …”

Section: Figurementioning

confidence: 99%

Multifunctional Clickable Reagents for Rapid Bioorthogonal Astatination and Radio‐Crosslinking

et al. 2019

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In the past decade, several developments have expanded the chemical toolbox for astatination and the preparation of 211At‐labeled radiopharmaceuticals. However, there is still a need for advanced methods for the synthesis of astatinated (bio)molecules to address challenges such as limited in vivo stability. Herein, we report the development of multifunctional 211At‐labeled reagents that can be prepared by applying a modular and versatile click approach for rapid assembly. The introduction of tetrazines as bioorthogonal tags enables rapid radiolabeling and radio‐crosslinking, which is demonstrated by steric shielding of 211At to significantly increase label stability in human blood plasma.

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“…Highly accurate quantification of RCP for 225 Ac-labeled radiopharmaceuticals requires secular equilibrium to be reached between actinium-225 and its daughter radionuclides. Secular equilibrium is reached after 20 h (24,25), but such a long analysis window is impractical in a clinical production setting. Consequently, sites producing 225 Ac-labeled radiopharmaceuticals wait between 1 h and 12 h after running the TLC plate before quantifying RCP (11,23,26,27).…”

Section: Introductionmentioning

confidence: 99%

A Consensus Time for Performing Quality Control of 225Ac-Labeled Radiopharmaceuticals

Kelly

Amor‐Coarasa

Sweeney

et al. 2020

Preprint

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Abstract Background: As 225Ac-labeled radiopharmaceuticals continue to show promise as targeted alpha therapeutics, there is a growing need to standardize quality control (QC) testing procedures. The determination of radiochemical purity (RCP) is an essential QC test. A significant obstacle to RCP testing is the disruption of the secular equilibrium between actinium-225 and its daughter radionuclides during labeling and analysis. In order to accelerate translation of actinium-225 targeted alpha therapy, we aimed to determine the earliest time point at which the RCP of an 225Ac-labeled radiopharmaceutical can be accurately calculated.Results: Six ligands were conjugated to macrocyclic metal chelators and labeled with actinium-225 under conditions designed to generate diverse incorporation yields. RCP was determined by radio thin layer chromatography (radioTLC) followed by exposure of the TLC plate on a phosphor screen either 0.5, 2, 3.5, 5, 6.5, or 26 h after the plate was developed. The dataset was used to create models for predicting the true RCP using pre-equilibrium measurements at early time points. The 585 TLC measurements span RCP values of 1.8% to 99.5%. The statistical model created from these data predicted an independent data set with high accuracy. Predictions made at 0.5 h are more uncertain than predictions made at later time points. This is primarily due to the decay of bismuth-213. At 2 h the mean average error is < 3%. A measurement of RCP > 90% at this time point predicts a true RCP > 97%.Conclusions: RCP of 225Ac-labeled radiopharmaceuticals can be quantified with acceptable accuracy at least 2 h after radioTLC. This time point best balances the need to accurately quantify RCP with the need to safely release the batch as quickly as possible.

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The inverse electron-demand Diels–Alder reaction as a new methodology for the synthesis of²²⁵Ac-labelled radioimmunoconjugates

Abstract: The inverse electron-demand Diels-Alder reaction between tetrazine (Tz) and trans-cyclooctene (TCO) facilitates the efficient radiosynthesis of Ac-labelled radioimmunoconjugates in a two-step method, outperforming conventional approaches based on isothiocyanate couplings.

Cited by 42 publications

References 25 publications

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

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

Multifunctional Clickable Reagents for Rapid Bioorthogonal Astatination and Radio‐Crosslinking

A Consensus Time for Performing Quality Control of 225Ac-Labeled Radiopharmaceuticals

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The inverse electron-demand Diels–Alder reaction as a new methodology for the synthesis of225Ac-labelled radioimmunoconjugates

Abstract: The inverse electron-demand Diels-Alder reaction between tetrazine (Tz) and trans-cyclooctene (TCO) facilitates the efficient radiosynthesis of Ac-labelled radioimmunoconjugates in a two-step method, outperforming conventional approaches based on isothiocyanate couplings.

Cited by 42 publications

References 25 publications

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

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

Multifunctional Clickable Reagents for Rapid Bioorthogonal Astatination and Radio‐Crosslinking

A Consensus Time for Performing Quality Control of 225Ac-Labeled Radiopharmaceuticals

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The inverse electron-demand Diels–Alder reaction as a new methodology for the synthesis of²²⁵Ac-labelled radioimmunoconjugates