A novel CCK2/gastrin receptor-localizing radiolabeled peptide probe for personalized diagnosis and therapy of patients with progressive or metastatic medullary thyroid carcinoma – GRAN-T-MTC – a multicenter phase I study

Erba, Paola Anna; Maecke, Helmut R.; Mikołajczak, Renata; Decristoforo, Clemens; Zaletel, Katja; Maina, Theodosia; Peitl, Petra Kolenc; Garnuszek, Piotr; Fröberg, Alida; Goebel, Georg; Jong, Marion de; Jabrocka‐Hybel, Agata; Konijnenberg, Mark; Virgolini, Irena; Nock, Berthold A.; Lenda-Tracz, Wioletta; Pawlak, Dariusz; Rangger, C.; Trofimiuk–Müldner, Małgorzata; Sowa‐Staszczak, Anna; Tomaszuk, Monika; Guggenberg, Elisabeth von; Scarpa, Lorenza; Hubalewska‐Dydejczyk, Alicja

doi:10.20452/pamw.4387

Cited by 15 publications

(24 citation statements)

References 13 publications

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“…Most of these developments have not led to the required improvements necessary for successful clinical application. Two MG analogs, DOTA-(DGlu) 6 -Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH 2 (PP-F11) labeled with indium-111 as well as DOTA-(DGlu) 6 -Ala-Tyr-Gly-Trp-Nle-Asp-Phe-NH 2 (PP-F11N) labeled with lutetium-177, which are derived from MG0 by inversion of the configuration of the penta-Glu motif, are currently examined in clinical studies ( Identifier: NCT03246659 and NCT02088645) [ 22 , 23 , 24 ]. Besides chemical modification of the peptide, in situ stabilization by co-injection of enzyme inhibitors was investigated.…”

Section: Introductionmentioning

confidence: 99%

Initial In Vitro and In Vivo Evaluation of a Novel CCK2R Targeting Peptide Analog Labeled with Lutetium-177

et al. 2020

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Targeting of cholecystokinin-2 receptor (CCK2R) expressing tumors using radiolabeled minigastrin (MG) analogs is hampered by rapid digestion of the linear peptide in vivo. In this study, a new MG analog stabilized against enzymatic degradation was investigated in preclinical studies to characterize the metabolites formed in vivo. The new MG analog DOTA-DGlu-Pro-Tyr-Gly-Trp-(N-Me)Nle-Asp-1Nal-NH2 comprising site-specific amino acid substitutions in position 2, 6 and 8 and different possible metabolites thereof were synthesized. The receptor interaction of the peptide and selected metabolites was evaluated in a CCK2R-expressing cell line. The enzymatic stability of the 177Lu-labeled peptide analog was evaluated in vitro in different media as well as in BALB/c mice up to 1 h after injection and the metabolites were identified based on radio-HPLC analysis. The new radiopeptide showed a highly increased stability in vivo with >56% intact radiopeptide in the blood of BALB/c mice 1 h after injection. High CCK2R affinity and cell uptake was confirmed only for the intact peptide, whereas enzymatic cleavage within the receptor specific C-terminal amino acid sequence resulted in complete loss of affinity and cell uptake. A favorable biodistribution profile was observed in BALB/c mice with low background activity, preferential renal excretion and prolonged uptake in CCK2R-expressing tissues. The novel stabilized MG analog shows high potential for diagnostic and therapeutic use. The radiometabolites characterized give new insights into the enzymatic degradation in vivo.

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Section: Introductionmentioning

confidence: 99%

Initial In Vitro and In Vivo Evaluation of a Novel CCK2R Targeting Peptide Analog Labeled with Lutetium-177

et al. 2020

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“…Radiopharmaceutical research has tried to overcome these limitations by introducing various modifications in the peptide sequence of gastrin or CCK-related peptides, with the aim of reducing kidney retention and improving metabolic stability. A co-injection of plasma expanders has been proposed to reduce kidney uptake and retention, consequently minimising radiation-induced nephrotoxicity [19,20,51]. In order to reduce in vivo radiopeptide degradation, a co-injection of neutral endopeptidase inhibitors is also under investigation, since endopeptidases are the major enzymes implicated in the catabolism of gastrin/CCK-based peptides, and they are widely distributed in the body [52,53].…”

Section: Discussionmentioning

confidence: 99%

Advances in the Management of Medullary Thyroid Carcinoma: Focus on Peptide Receptor Radionuclide Therapy

Grossrubatscher

Fanciulli

Pes³

et al. 2020

JCM

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Effective treatment options in advanced/progressive/metastatic medullary thyroid carcinoma (MTC) are currently limited. As in other neuroendocrine neoplasms (NENs), peptide receptor radionuclide therapy (PRRT) has been used as a therapeutic option in MTC. To date, however, there are no published reviews dealing with PRRT approaches. We performed an in-depth narrative review on the studies published in this field and collected information on registered clinical trials related to this topic. We identified 19 published studies, collectively involving more than 200 patients with MTC, and four registered clinical trials. Most cases of MTC were treated with PRRT with somatostatin analogues (SSAs) radiolabelled with 90 yttrium (90Y) and 177 lutetium (177Lu). These radiopharmaceuticals show efficacy in the treatment of patients with MTC, with a favourable radiological response (stable disease, partial response or complete response) in more than 60% of cases, coupled with low toxicity. As MTC specifically also expresses cholecystokinin receptors (CCK2Rs), PRRT with this target has also been tried, and some randomised trials are ongoing. Overall, PRRT seems to have an effective role and might be considered in the therapeutic strategy of advanced/progressive/metastatic MTC.

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“…The central document for the clinical trial was the Clinical Trial Protocol. The trial was designed as a Phase I multicentre trial to include patients with progressive/metastatic nonoperable histologically proven MTC; details of the study design can be found in Erba et al The main objectives were (1) to establish the safety of i.v. administration of a high peptide amount of 111 In‐CP04 potentially also suitable for therapy and (2) to assess the tracer's biodistribution and to determine critical organs.…”

Section: Example Of Cp04mentioning

confidence: 99%

“…Between 2015 and 2018, in total 16 patients were successfully enrolled in the study. Safety and dosimetry of 111 In‐CP04 were established, and MTC metastases could be detected with high sensitivity which opened the way for a continuing therapeutic trial following a similar pathway with the corresponding 177 Lu‐counterpart to implement the theranostic approach.…”

Section: Example Of Cp04mentioning

confidence: 99%

Clinical translation of theranostic radiopharmaceuticals: Current regulatory status and recent examples

Peitl

Rangger

Garnuszek

et al. 2019

Labelled Comp Radiopharmac

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With the development of ever more radiopharmaceuticals suitable for theranostic applications, translation of novel compounds from the preclinical stage towards clinical application becomes a bottleneck for the advances in Nuclear Medicine. This review article summarizes the current regulatory framework for clinical trials with radiopharmaceuticals in the European Union, provides a general overview of the documentation required, and addresses quality, safety, and clinical aspects to be considered. By using a recent successful example of translating a theranostic peptide radioligand, namely 111In‐CP04, which targets receptors expressed in medullary thyroid carcinoma, the pathway from the preclinical development over establishing the required pharmaceutical documentation to designing and submitting a clinical trial is reviewed. Details regarding preclinical data, generation of the documentation, and final successful application are described. This article should provide an insight in an ever more complex process to bring innovations in the field of radiopharmaceuticals into patients.

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A novel CCK2/gastrin receptor-localizing radiolabeled peptide probe for personalized diagnosis and therapy of patients with progressive or metastatic medullary thyroid carcinoma – GRAN-T-MTC – a multicenter phase I study

Cited by 15 publications

References 13 publications

Initial In Vitro and In Vivo Evaluation of a Novel CCK2R Targeting Peptide Analog Labeled with Lutetium-177

Initial In Vitro and In Vivo Evaluation of a Novel CCK2R Targeting Peptide Analog Labeled with Lutetium-177

Advances in the Management of Medullary Thyroid Carcinoma: Focus on Peptide Receptor Radionuclide Therapy

Clinical translation of theranostic radiopharmaceuticals: Current regulatory status and recent examples

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