Evaluation of134Ce/134La as a PET Imaging Theranostic Pair for225Ac α-Radiotherapeutics

Bobba, Kondapa Naidu; Bidkar, Anil P.; Meher, Niranjan; Fong, Cyril; Wadhwa, Anju; Dhrona, Suchi; Sorlin, Alex; Bidlingmaier, Scott; Shuere, Becka; He, Jiang; Wilson, David M.; Liu, Bin; Seo, Youngho; VanBrocklin, Henry F.; Flavell, Robert R.

doi:10.2967/jnumed.122.265355

Cited by 14 publications

(13 citation statements)

References 33 publications

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“…Unchelated [ 134 Ce]CeCl 3 and [ 225 Ac]AcCl 3 are mostly similar in their biodistribution in mice, with the major difference being the higher spleen uptake found for 134 Ce. Once incorporated in a radiotracer, the radiometals make for a good pharmacokinetic match, as indicated in this study and recent literature [5, 6, 8, 10].…”

Section: Discussionmentioning

confidence: 58%

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Exploring the PET in vivo generator¹³⁴Ce as a theranostic match for²²⁵Ac

Bauer,

De Gregorio,

Pratt

et al. 2024

Preprint

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Purpose: The radionuclide pair cerium-134/lanthanum-134 (134Ce/134La) was recently proposed as a suitable diagnostic counterpart for the therapeutic alpha-emitter actinium-225 (225Ac). The unique properties of134Ce offer perspectives for developing innovative in vivo investigations not possible with225Ac. In this work,225Ac- and134Ce-labeled tracers were directly compared using internalizing and slow-internalizing cancer models to evaluate their in vivo comparability, progeny meandering, and potential as a matched theranostic pair for clinical translation. Despite being an excellent chemical match,134Ce/134La has limitations to the setting of quantitative positron emission tomography imaging.Methods: The precursor PSMA-617 and a macropa-based tetrazine-conjugate (mcp-PEG8-Tz) were radiolabelled with225Ac or134Ce and compared in vitro and in vivo using standard (radio)chemical methods. Employing biodistribution studies and positron emission tomography (PET) imaging in athymic nude mice, the radiolabelled PSMA-617 tracers were evaluated in a PC3/PIP (PC3 engineered to express a high level of prostate-specific membrane antigen) prostate cancer mouse model. The134Ac and134Ce-labeled mcp-PEG8-Tz were investigated in a BxPC-3 pancreatic tumour model harnessing the pretargeting strategy based on a trans-cyclooctene-modified 5B1 monoclonal antibody.Results: In vitro and in vivo studies with both225Ac and134Ce-labelled tracers led to comparable results, confirming the matching pharmacokinetics of this theranostic pair. However, PET imaging of the134Ce-labelled precursors indicated that quantification is highly dependent on tracer internalization due to the redistribution of134Ce's PET-compatible daughter134La. Consequently, radiotracers based on internalizing vectors like PSMA-617 are suited for this theranostic pair, while slow-internalizing225Ac-labelled tracers are not quantitatively represented by134Ce PET imaging.Conclusion: When employing slow-internalizing vectors,134Ce might not be an ideal match for225Ac due to the underestimation of tumour uptake caused by the in vivo redistribution of134La. However, this same characteristic makes it possible to estimate the redistribution of225Ac's progeny noninvasively. In future studies, this unique PET in vivo generator will further be harnessed to study tracer internalization, trafficking of receptors, and the progression of the tumour microenvironment.

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Section: Discussionmentioning

confidence: 58%

“…This PET in vivo generator is currently undergoing preclinical investigation in cancer research as a diagnostic match for actinium-225 ( 225 Ac, t ½ =9.9 d) [5][6][7][8]. Over the last decade, 225 Ac has been developed into potent drug constructs targeting various forms of mostly highly aggressive and even treatmentresistant cancers.…”

Section: Introductionmentioning

confidence: 99%

Exploring the PET in vivo generator¹³⁴Ce as a theranostic match for²²⁵Ac

Bauer,

De Gregorio,

Pratt

et al. 2024

Preprint

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“…To prepare for the TRTs, Nb HER2 (WT) and Nb HER2 (FSY) were conjugated with Macropa-PEG 4 -TFP ester (Figure A). Macropa was chosen as the chelator, as recent data have shown that it chelates 225 Ac efficiently. , Mass spectrometric analysis of the conjugated samples confirmed that both Nb HER2 (WT) and Nb HER2 (FSY) were successfully conjugated with Macropa-PEG 4 , showing two peaks of approximately equal intensity corresponding to the unlabeled and singly labeled nanobody, respectively (Figure B). To ensure that the conjugation of Macropa-PEG 4 did not affect the nanobody’s covalent cross-linking ability, we incubated Macropa-PEG 4 -Nb HER2 (WT) or Macropa-PEG 4 -Nb HER2 (FSY) with and without the HER2 ECD at 37 °C for up to 2 h and analyzed the samples via Western blot (Figure C).…”

Section: Resultsmentioning

confidence: 85%

Covalent Proteins as Targeted Radionuclide Therapies Enhance Antitumor Effects

et al. 2023

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Molecularly targeted radionuclide therapies (TRTs) struggle with balancing efficacy and safety, as current strategies to increase tumor absorption often alter drug pharmacokinetics to prolong circulation and normal tissue irradiation. Here we report the first covalent protein TRT, which, through reacting with the target irreversibly, increases radioactive dose to the tumor without altering the drug's pharmacokinetic profile or normal tissue biodistribution. Through genetic code expansion, we engineered a latent bioreactive amino acid into a nanobody, which binds to its target protein and forms a covalent linkage via the proximity-enabled reactivity, crosslinking the target irreversibly in vitro, on cancer cells, and on tumors in vivo. The radiolabeled covalent nanobody markedly increases radioisotope levels in tumors and extends tumor residence time while maintaining rapid systemic clearance. Furthermore, the covalent nanobody conjugated to the α-emitter actinium-225 inhibits tumor growth more effectively than the noncovalent nanobody without causing tissue toxicity. Shifting the protein-based TRT from noncovalent to covalent mode, this chemical strategy improves tumor responses to TRTs and can be readily scaled to diverse protein radiopharmaceuticals engaging broad tumor targets.

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“…Macropa-PEG 8 -TFP ester was synthesized by reacting the intermediate 1 in the presence of DIPEA in DMF followed by prep HPLC purification in 34% yield (Reaction scheme S1 and Figure S1 -S3). Macropa NCS was synthesized according to the reported literature 32 , and Macropa-PEG 4 -TFP was synthesized as per our prior publication 33 . With these derivatives in hand, the bifunctional chelators were conjugated to lysine residues on the antibody YS5 (Figure 1 A, B) 24 .…”

Section: Resultsmentioning

confidence: 99%

“…This isotope undergoes decay to 134 La (t 1/2 = 6.45 min) via electron capture. Subsequently, it further decays to stable 134 Ba through positron emission (63% β + ; endpoint energy, 2.69 MeV) 33 . This strategy has particular promise for the development of theranostics, owing to the chemical similarity between Ce 3+ and Ac 3+ , as well as the high fraction of positrons emitted by the daughter isotope 134 La 34 .…”

Section: Introductionmentioning

confidence: 99%

Development of CD46 targeted alpha theranostics in prostate cancer using ¹³⁴Ce/²²⁵Ac-Macropa-PEG₄-YS5

Bobba,

Bidkar,

Wadhwa

et al. 2024

Theranostics

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Rationale: 225 Ac, a long-lived α-emitter with a half-life of 9.92 days, has garnered significant attention as a therapeutic radionuclide when coupled with monoclonal antibodies and other targeting vectors. Nevertheless, its clinical utility has been hampered by potential off-target toxicity, a lack of optimized chelators for 225 Ac, and limitations in radiolabeling methods. In a prior study evaluating the effectiveness of CD46-targeted radioimmunotherapy, we found great therapeutic efficacy but also significant toxicity at higher doses. To address these challenges, we have developed a radioimmunoconjugate called 225 Ac-Macropa-PEG 4 -YS5, incorporating a stable PEGylated linker to maximize tumoral uptake and increase tumor-to-background ratios. Our research demonstrates that this conjugate exhibits greater anti-tumor efficacy while minimizing toxicity in prostate cancer 22Rv1 tumors. Methods: We synthesized Macropa.NCS and Macropa-PEG 4/8 -TFP esters and prepared Macropa-PEG 0/4/8 -YS5 (with nearly ~1:1 ratio of macropa chelator to antibody YS5) as well as DOTA-YS5 conjugates. These conjugates were then radiolabeled with 225 Ac in a 2 M NH 4 OAc solution at 30 °C, followed by purification using YM30K centrifugal purification. Subsequently, we conducted biodistribution studies and evaluated antitumor activity in nude mice (nu/nu) bearing prostate 22Rv1 xenografts in both single-dose and fractionated dosing studies. Micro-PET imaging studies were performed with 134 Ce-Macropa-PEG 0/4/8 -YS5 in 22Rv1 xenografts for 7 days. Toxicity studies were also performed in healthy athymic nude mice. Results: As expected, we achieved a >95% radiochemical yield when labeling Macropa-PEG 0/4/8 -YS5 with 225 Ac, regardless of the chelator ratios (ranging from 1 to 7.76 per YS5 antibody). The isolated yield exceeded 60% after purification. Such high conversions were not observed with the DOTA-YS5 conjugate, even at a higher ratio of 8.5 chelators per antibody (RCY of 83%, an isolated yield of 40%). Biodistribution analysis at 7 days post-injection revealed higher tumor uptake for the 225 Ac-Macropa-PEG 4 -YS5 (82.82 ± 38.27 %ID/g) compared to other conjugates, namely 225 Ac-Macropa-PEG 0/8 -YS5 (38.2 ± 14.4/36.39 ± 12.4 %ID/g) and 225 Ac-DOTA-YS5 (29.35 ± 7.76 %ID/g). The PET Imaging of 134 Ce-Macropa-PEG 0/4/8 -YS5 conjugates resulted in a high tumor uptake, and tumor to background ratios. In terms of antitumor activity, 225 Ac-Macropa-PEG 4 -YS5 exhibited a substantial response, leading to prolonged...

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Evaluation of¹³⁴Ce/¹³⁴La as a PET Imaging Theranostic Pair for²²⁵Ac α-Radiotherapeutics

Abstract: Visual Abstract

Cited by 14 publications

References 33 publications

Exploring the PET in vivo generator¹³⁴Ce as a theranostic match for²²⁵Ac

Exploring the PET in vivo generator¹³⁴Ce as a theranostic match for²²⁵Ac

Covalent Proteins as Targeted Radionuclide Therapies Enhance Antitumor Effects

Development of CD46 targeted alpha theranostics in prostate cancer using ¹³⁴Ce/²²⁵Ac-Macropa-PEG₄-YS5

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Evaluation of134Ce/134La as a PET Imaging Theranostic Pair for225Ac α-Radiotherapeutics

Abstract: Visual Abstract

Cited by 14 publications

References 33 publications

Exploring the PET in vivo generator134Ce as a theranostic match for225Ac

Exploring the PET in vivo generator134Ce as a theranostic match for225Ac

Covalent Proteins as Targeted Radionuclide Therapies Enhance Antitumor Effects

Development of CD46 targeted alpha theranostics in prostate cancer using 134Ce/225Ac-Macropa-PEG4-YS5

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Evaluation of¹³⁴Ce/¹³⁴La as a PET Imaging Theranostic Pair for²²⁵Ac α-Radiotherapeutics

Exploring the PET in vivo generator¹³⁴Ce as a theranostic match for²²⁵Ac

Exploring the PET in vivo generator¹³⁴Ce as a theranostic match for²²⁵Ac

Development of CD46 targeted alpha theranostics in prostate cancer using ¹³⁴Ce/²²⁵Ac-Macropa-PEG₄-YS5