First-in-human dosimetry of gastrin-releasing peptide receptor antagonist [177Lu]Lu-RM2: a radiopharmaceutical for the treatment of metastatic castration-resistant prostate cancer

Kurth, Jens; Krause, Bernd J.; Schwarzenböck, Sarah M.; Bergner, Carina; Hakenberg, Oliver W.; Heuschkel, Martin

doi:10.1007/s00259-019-04504-3

Cited by 99 publications

(101 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The dosimetry of the GRPR antagonist 177 Lu-labelled RM2 was recently studied in individuals with metastatic castration-resistant prostate cancer. The analysis showed high tumour doses (6.20 ± 3.00 Gy/GBq), with rapid clearance from normal organs, including the pancreas, which are promising attributes for therapeutic applications 212 .…”

Section: Rpt Agents In Use and In Clinical Developmentmentioning

confidence: 99%

Radiopharmaceutical therapy in cancer: clinical advances and challenges

Sgouros

Bodei

McDevitt

et al. 2020

Nat Rev Drug Discov

546

430

View full text Add to dashboard Cite

Radiopharmaceutical therapy (RPT) is emerging as a safe and effective targeted approach to treating many types of cancer. In RPT, radiation is systemically or locally delivered using pharmaceuticals that either bind preferentially to cancer cells or accumulate by physiological mechanisms. Almost all radionuclides used in RPT emit photons that can be imaged, enabling non-invasive visualization of the biodistribution of the therapeutic agent. Compared with almost all other systemic cancer treatment options, RPT has shown efficacy with minimal toxicity. With the recent FDA approval of several RPT agents, the remarkable potential of this treatment is now being recognized. This Review covers the fundamental properties, clinical development and associated challenges of RPT.

show abstract

Section: Rpt Agents In Use and In Clinical Developmentmentioning

confidence: 99%

Radiopharmaceutical therapy in cancer: clinical advances and challenges

Sgouros

Bodei

McDevitt

et al. 2020

Nat Rev Drug Discov

546

430

View full text Add to dashboard Cite

show abstract

“…The therapy was well tolerated without side effects. Pancreas was the doselimiting organ, bone metastases had the highest uptake, followed by lymph nodes and soft tissue lesions (Kurth et al 2020). These encouraging data pave the way for more intensive efforts, preclinicaly as well as in clinical settings, investigating several treatment options of PC.…”

Section: Introductionmentioning

confidence: 78%

Effect of the versatile bifunctional chelator AAZTA5 on the radiometal labelling properties and the in vitro performance of a gastrin releasing peptide receptor antagonist

Hofstetter

Moon

D'Angelo

et al. 2020

EJNMMI radiopharm. chem.

View full text Add to dashboard Cite

Background Gastrin Releasing Peptide receptor (GRPr)-based radioligands have shown great promise for diagnostic imaging of GRPr-positive cancers, such as prostate and breast. The present study aims at developing and evaluating a versatile GRPr-based probe for both PET/SPECT imaging as well as intraoperative and therapeutic applications. The influence of the versatile chelator AAZTA5 on the radiometal labelling properties and the in vitro performance of the generated radiotracers were thoroughly investigated. The GRPr-based antagonist D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 was functionalized with the chelator 6-[Bis (carboxymethyl)amino]-1,4-bis (carboyxmethyl)-6-methyl-1,4-diazepane (AAZTA5) through the spacer 4-amino-1-carboxymethyl-piperidine (Pip) to obtain AAZTA5-Pip-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 (LF1). LF1 was radiolabelled with gallium-68 (PET), indium-111 (SPECT, intraoperative applications) and lutetium-177 (therapy, SPECT). In vitro evaluation included stability studies, determination of lipophilicity, protein-binding studies, determination of Kd and Bmax as well as internalization studies using the epithelial human prostate cancer cell line PC3. In vitro monotherapy as well as combination therapy studies were further performed to assess its applicability as a theranostic compound. Results LF1 was labelled with gallium-68, indium-111 and lutetium-177 within 5 min at room temperature (RT). The apparent molar activities (Am) were ranging between 50 and 60 GBq/μmol for the 68Ga-labelled LF1, 10–20 GBq/μmol for the 111In- and 177Lu-labelled LF1. The radiotracers were stable for a period of 4 h post labeling exhibiting a hydrophilic profile with an average of a LogDoctanol/PBS of − 3, while the bound activity to the human serum protein was approximately 10%. 68/natGa-LF1, 177/natLu-LF1 and 111/natIn-LF1 exhibited high affinity for the PC3 cells, with Kd values of 16.3 ± 2.4 nM, 10.3 ± 2.73 nM and 5.2 ± 1.9 nM, respectively, and the required concentration of the radiotracers to saturate the receptors (Bmax) was between 0.5 and 0.8 nM which corresponds to approximately 4 × 105 receptors per cell. Low specific internalization rate was found in cell culture, while the total specific cell surface bound uptake always exceeded the internalized activity. In vitro therapy studies showed that inhibition of PC3 cells growth is somewhat more efficient when combination of 177Lu-labelled LF1 with rapamycin is applied compared to 177Lu-laballed LF1 alone. Conclusion Encouraged by these promising in vitro data, preclinical evaluation of the LF1 precursor are planned in tumour models in vivo.

show abstract

“…GRPR antagonists have been used for imaging GRPR-expressing tumors demonstrating high sensitivity and safety [ 8 , 17 , 18 , 19 , 29 ]. Recent clinical studies have commenced evaluating GRPR antagonists for treating patients with metastatic castration-resistant prostate cancer showing promising results [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

“…Antagonists to GRPR labelled with lutetium-177 were evaluated in preclinical studies on mice bearing prostate cancer xenografts, demonstrating a promising therapeutic efficacy with extended survival of the mice receiving the radiolabelled peptide [ 21 , 22 ]. The GRPR antagonist [ 177 Lu]Lu-RM2 was studied for the treatment of patients with metastatic castration-resistant prostate cancer by delivering at least one therapy cycle of the GRPR-targeting radioligand [ 23 ]. The therapy was deemed safe with no reported adverse effects and with the pancreas being the dose-limiting organ.…”

Section: Introductionmentioning

confidence: 99%

Preclinical Evaluation of the GRPR-Targeting Antagonist RM26 Conjugated to the Albumin-Binding Domain for GRPR-Targeting Therapy of Cancer

et al. 2020

View full text Add to dashboard Cite

The targeting of gastrin-releasing peptide receptors (GRPR) was recently proposed for targeted therapy, e.g., radiotherapy. Multiple and frequent injections of peptide-based therapeutic agents would be required due to rapid blood clearance. By conjugation of the GRPR antagonist RM26 (D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2) to an ABD (albumin-binding domain), we aimed to extend the blood circulation of peptides. The synthesized conjugate DOTA-ABD-RM26 was labelled with indium-111 and evaluated in vitro and in vivo. The labelled conjugate was stable in PBS and retained specificity and its antagonistic function against GRPR. The half-maximal inhibitory concentration (IC50) of natIn-DOTA-ABD-RM26 in the presence of human serum albumin was 49 ± 5 nM. [111In]In-DOTA-ABD-RM26 had a significantly longer residence time in blood and in tumors (without a significant decrease of up to 144 h pi) than the parental RM26 peptide. We conclude that the ABD-RM26 conjugate can be used for GRPR-targeted therapy and delivery of cytotoxic drugs. However, the undesirable elevated activity uptake in kidneys abolishes its use for radionuclide therapy. This proof-of-principle study justified further optimization of the molecular design of the ABD-RM26 conjugate.

show abstract

First-in-human dosimetry of gastrin-releasing peptide receptor antagonist [177Lu]Lu-RM2: a radiopharmaceutical for the treatment of metastatic castration-resistant prostate cancer

Cited by 99 publications

References 48 publications

Radiopharmaceutical therapy in cancer: clinical advances and challenges

Radiopharmaceutical therapy in cancer: clinical advances and challenges

Effect of the versatile bifunctional chelator AAZTA5 on the radiometal labelling properties and the in vitro performance of a gastrin releasing peptide receptor antagonist

Preclinical Evaluation of the GRPR-Targeting Antagonist RM26 Conjugated to the Albumin-Binding Domain for GRPR-Targeting Therapy of Cancer

Contact Info

Product

Resources

About