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EP-4735055-A1 - UROKINASE-TYPE PLASMINOGEN ACTIVATOR RECEPTOR (UPAR)-PET/CT IN BRAIN TUMOURS

EP4735055A1EP 4735055 A1EP4735055 A1EP 4735055A1EP-4735055-A1

Abstract

The present invention relates to positron-emitting imaging agents for use in the prognosis of brain tumours in a patient by PET imaging of the cancer, wherein said imaging agent comprises an uPAR binding peptide coupled to a radionuclide. The invention also relates to compositions comprising a radiopharmaceutical for use in the treatment or alleviation of a brain tumour in a subject, wherein said radiopharmaceutical comprises a radionuclide and an uPAR binding peptide.

Inventors

  • KJAER, ANDREAS

Assignees

  • Curasight A/S

Dates

Publication Date
20260506
Application Date
20240626

Claims (20)

  1. 1. A positron-emitting imaging agent for use in the prognostication of Progression-Free Survival (PFS) and/or Overall Survival (OS) of a brain tumour in a patient by PET imaging of the cancer, wherein said imaging agent comprises a uPAR binding peptide coupled to a radionuclide; and wherein the uPAR binding peptide is (D-Asp)-([beta]-cyclohexyl-L-alanine)- (Phe)-(D-Ser)-(D-Arg)-(Tyr)-(Leu)-(Trp)-(Ser) or a uPAR binding variant thereof; wherein the uPAR binding variant is selected from the group consisting of • (D-Asp)-([ beta] -cyclohexyl-L-a Ian ine)-(Phe)-(D-Ser)-(D-Arg)- (Tyr)-(Leu)-(Trp)-(Ser), • (Ser)-(Leu)-([ beta] -cyclohexyl-L-a Ian ine)-(Phe)-(D-Ser)-(Gln)- (Tyr)(Leu)-(Trp)-(Ser), • (D-Glu)-([ beta] -cyclohexyl-L-a Ian ine)-(Phe)-(D-Ser)-(D-Tyr)- (Tyr)-(Leu)-(Trp)-(Ser), • (Asp)-( [beta] -cyclohexyl-L-a Ian ine)-(Phe)-(D-Ser)-(D-Arg)- (Tyr)-(Leu)-(Trp)-(Ser), • (Asp)-( [beta] -cyclohexyl-L-a Ian ine)-(Phe)-(Ser)-(D-Arg)-(Tyr)- Leu)-(Trp)-(Ser), • (D-Asp)-([ beta] -cyclohexyl-L-a Ian ine)-(Phe)-(Ser)-(D-Arg)- (Tyr)-Leu)-(Trp)-(Ser), • (D-Th r)-([ beta] -cyclohexyl-L-a la n ine)-(Phe)-(D-Ser)-(D-Arg)- (Tyr)-(Leu)-(Trp)-(Ser), • (D-Asp)-([ beta] -cyclohexyl-L-a Ian ine)-(Phe)-(D-Ser)-(D-Arg)- (Tyr)-(Leu)-([ beta] -2-naphthyl-L-a Ian ine)-(Ser), • (Asp)-( [beta] -cyclohexyl-L-a Ian ine)-(Phe)-(D-Ser)-(Arg)-(Tyr)- (Leu)-(Trp)-(Ser), • (Asp)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(D-Arg)- (Tyr)-(Leu)([beta]-l-naphthyl-L-alanine)-(Ser), • (D-Glu)-([ beta] -cyclohexyl-L-a Ian ine)-(Phe)-(D-Ser)-(Tyr)- (Tyr)-(Leu)-(Trp)-(Ser), • (Asp)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(D-Arg)- (Leu)-(Leu)-(Trp)-(D-His), • (Asp)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(D-Arg)- ([beta]-cyclohexyl-L-alanine)-(Leu)-(Trp)-(Ile), • (Asp)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(D-Arg)- (Tyr)-(Leu)([beta]-l-naphthyl-L-alanine)-(D-His), • (Asp)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(D-Arg)-(N- (2,3-dimethoxybenzyl)glycine)-(D-Phe)-(N-(3- indolylethyl)glycine)-(N-(2-methoxyethyl)glycine), • (Asp)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(D-Arg)-(N- (2,3-dimethoxybenzyl)glycine)-(D-Phe)-(N-benzylglycine)-(N- (2 [beta]thoxyethyl)g lycine), • (Asp)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(D-Arg)-(N- (2,3-dimethoxybenzyl)glycine)-(D-Phe)-(N- (methylnaphthalyl)glycine)-(N-(2-methoxyethyl)glycine), and • (Asp)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(D-Arg)-(N- (2,3-dimethoxybenzyl)glycine)-(D-Phe)-(N-(2,3- dimethoxybenzyl)glycine)-(Ile); wherein a SUVmax and/or SUVmean level above a threshold level is indicative of a poor PFS prognosis and/or poor OS prognosis; and wherein a SUVmax and/or SUVmean level equal to or below a threshold level is indicative of good PFS prognosis and/or good OS prognosis.
  2. 2. The imaging agent for use according to claim 1, wherein the peptide is (D- Asp)-( [beta] -cyclohexyl-L-a la n ine)-(Phe)-(D-Ser)-(D-Arg)-(Tyr)-(Leu)-(Trp)- (Ser).
  3. 3. The imaging agent for use according to claim 1 or 2, wherein the radionuclide is selected from the group consisting of 68 Ga and 64 Cu.
  4. 4. The imaging agent for use according to any of the preceding claims, wherein the radionuclide is coupled to the uPAR binding peptide via a chelating agent, such as DOTA or NOTA.
  5. 5. The imaging agent for use according to any of the preceding claims, wherein the radionuclide is 68 Ga coupled to the uPAR binding peptide via a chelating agent NOTA.
  6. 6. The imaging agent for use according to any of the preceding claims, having the formula
  7. 7. The imaging agent for use according to any of the preceding claims 1-4, wherein the radionuclide is 64 Cu coupled to the uPAR binding peptide via a chelating agent DOTA or NOTA.
  8. 8. The imaging agent for use according to any of the preceding claims, wherein the imaging agent is to be administered in a dose of 10-500 MBq followed by PET scanning 10 min to 24 hours after the imaging agent has been administered, and quantification through SUVmax and/or SUVmean.
  9. 9. The imaging agent for use according to any of the preceding claims, wherein - said SUVmax and/or SUVmean threshold in relation to PFS for all gliomas is in the range 0.3-1, preferably 0.4-0.8, more preferably around 0.64; and/or said SUVmax and/or SUVmean threshold in relation to OS for all gliomas is in the range 0.7-1.5, preferably 0.9-1.3, more preferably around 1.1.
  10. 10. The imaging agent for use according to any of the preceding claims 1-8, wherein - said SUVmax and/or SUVmean threshold in relation to PFS for high-grade gliomas is in the range 0.7-1.5, preferably 0.9-1.3, more preferably around 1.1; and/or - said SUVmax and/or SUVmean threshold in relation to OS for all high-grade gliomas is in the range 0.7-1.5, preferably 0.9-1.3, more preferably around 1.1.
  11. 11. The imaging agent for use according to any of the preceding claims, wherein the brain tumor is a high-grade glioma (WHO grade 3 and 4) or a low-grade glioma (WHO grade 1 and 2), preferably a high-grade glioma (WHO grade 4) (glioblastoma).
  12. 12. The imaging agent for use according to any of the preceding claims, wherein the brain tumor is a high-grade glioma (glioblastoma).
  13. 13. A positron-emitting imaging agent for use as companion diagnostic of a brain tumour patient by PET imaging of the cancer, wherein said imaging agent comprises a uPAR binding peptide coupled to a radionuclide; and wherein the uPAR binding peptide is (D-Asp)-([beta]-cyclohexyl-L-alanine)- (Phe)-(D-Ser)-(D-Arg)-(Tyr)-(Leu)-(Trp)-(Ser) or a uPAR binding variant thereof; wherein o a SUVmax and/or SUVmean level above a threshold level is indicative of that a uPAR binding drug, such as a uPAR binding radiopharmaceutical will be effective against said brain tumour; and o a SUVmax and/or SUVmean level equal to or below a threshold level is indicative of that a uPAR drug, such as a uPAR binding radiopharmaceutical will not be effective against said brain tumour; wherein the uPAR binding variant is selected from the group consisting of • (D-Asp)-([ beta] -cyclohexyl-L-a Ian ine)-(Phe)-(D-Ser)-(D-Arg)- (Tyr)-(Leu)-(Trp)-(Ser), • (Ser)-(Leu)-([ beta] -cyclohexyl-L-a Ian ine)-(Phe)-(D-Ser)-(Gln)- (Tyr)(Leu)-(Trp)-(Ser), • (D-Glu)-([ beta] -cyclohexyl-L-a Ian ine)-(Phe)-(D-Ser)-(D-Tyr)- (Tyr)-(Leu)-(Trp)-(Ser), • (Asp)-( [beta] -cyclohexyl-L-a Ian ine)-(Phe)-(D-Ser)-(D-Arg)- (Tyr)-(Leu)-(Trp)-(Ser), • (Asp)-( [beta] -cyclohexyl-L-a Ian ine)-(Phe)-(Ser)-(D-Arg)-(Tyr)- Leu)-(Trp)-(Ser), • (D-Asp)-([ beta] -cyclohexyl-L-a Ian ine)-(Phe)-(Ser)-(D-Arg)- (Tyr)-Leu)-(Trp)-(Ser), • (D-Th r)-([ beta] -cyclohexyl-L-a la n ine)-(Phe)-(D-Ser)-(D-Arg)- (Tyr)-(Leu)-(Trp)-(Ser), • (D-Asp)-([ beta] -cyclohexyl-L-a Ian ine)-(Phe)-(D-Ser)-(D-Arg)- (Tyr)-(Leu)-([ beta] -2-naphthyl-L-a Ian ine)-(Ser), • (Asp)-( [beta] -cyclohexyl-L-a Ian ine)-(Phe)-(D-Ser)-(Arg)-(Tyr)- (Leu)-(Trp)-(Ser), • (Asp)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(D-Arg)- (Tyr)-(Leu)([beta]-l-naphthyl-L-alanine)-(Ser), • (D-Glu)-([ beta] -cyclohexyl-L-a Ian ine)-(Phe)-(D-Ser)-(Tyr)- (Tyr)-(Leu)-(Trp)-(Ser), • (Asp)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(D-Arg)- (Leu)-(Leu)-(Trp)-(D-His), • (Asp)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(D-Arg)- ([beta]-cyclohexyl-L-alanine)-(Leu)-(Trp)-(Ile), • (Asp)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(D-Arg)- (Tyr)-(Leu)([beta]-l-naphthyl-L-alanine)-(D-His), • (Asp)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(D-Arg)-(N- (2,3-dimethoxybenzyl)glycine)-(D-Phe)-(N-(3- indolylethyl)glycine)-(N-(2-methoxyethyl)glycine), • (Asp)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(D-Arg)-(N- (2,3-dimethoxybenzyl)glycine)-(D-Phe)-(N-benzylglycine)-(N- (2 [beta]thoxyethyl)g lycine), • (Asp)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(D-Arg)-(N- (2,3-dimethoxybenzyl)glycine)-(D-Phe)-(N- (methylnaphthalyl)glycine)-(N-(2-methoxyethyl)glycine), and • (Asp)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(D-Arg)-(N- (2,3-dimethoxybenzyl)glycine)-(D-Phe)-(N-(2,3- dimethoxybenzyl)glycine)-(Ile).
  14. 14. The positron-emitting imaging agent for use according to claim 13, wherein the radionuclide and chelator are 68 Ga-NOTA.
  15. 15. The positron-emitting imaging agent for use according to claim 13, wherein the radionuclide and chelator are 64 Cu-DOTA.
  16. 16. The positron-emitting imaging agent for use according to any of claims 13-15, being a companion diagnostic for a radiopharmaceutical.
  17. 17. The positron-emitting imaging agent for use according to any of claims 13-16, being a companion diagnostic for a radiopharmaceutical as defined in any of claims 24-30.
  18. 18 The positron-emitting imaging agent for use according to claim 17, being a companion diagnostic for a radiopharmaceutical as defined in claim 24, wherein the radionuclide and chelator of the radiopharmaceutical is 177 Lu- DOTA.
  19. 19. The positron-emitting imaging agent for use according to any of claims 13-18, being a companion diagnostic for a radiopharmaceutical having the formula:
  20. 20. The positron-emitting imaging agent for use according to any of claims 13-19, wherein the companion diagnostic is for determining the applicability of a radiopharmaceutical to a specific person, such as a radiopharmaceutical as defined in any of claims 24-30.

Description

UROKINASE-TYPE PLASMINOGEN ACTIVATOR RECEPTOR (UPARJ-PET/CT IN BRAIN TUMOURS Technical field of the invention The present invention relates to a positron-emitting imaging agent for use in the prognostication of a brain cancer patient by PET imaging of the cancer, wherein said imaging agent comprises a uPAR binding peptide coupled via the chelating agent NOTA or DOTA to the radionuclide 68Ga or 64Cu. The invention also relates to compositions comprising a radiopharmaceutical for use in the treatment or alleviation of a brain cancer in a subject, wherein said radiopharmaceutical comprises a radionuclide and a uPAR binding peptide. Finally, the invention relates to the use of said imaging agents as companion diagnostic for the radiopharmaceutical for therapy. Background of the invention Gliomas are among the most common types of brain cancers, with an annual incidence of 6 cases per 100.000 individuals (1). These highly heterogenous tumors are graded in a multilayered approach into 4 distinct WHO grades. Grade 1-2 gliomas are referred to as low-grade (LGG) while grade 3-4 tumors are referred to as high-grade gliomas (HGG). Increasing WHO grade is correlated with increased tumor aggressiveness and poorer survival (2-4). In the era of many oncological advances, survival among patients with gliomas remains essentially unchanged with a 5-year survival rate of 82% for LGG to the most dismissal survival expectancy of 3-10 % among HGG (4-6). The treatment of gliomas is highly variable depending on tumor subtype. For LGGs treatment varies from watchful waiting after surgery (biopsy, partial, or gross total resection) to radiotherapy alone or concomitant chemotherapy including a procarbazine, lomustine, vincristine regime (PCV) or temozolomide (TMZ). For HGG, treatment aims at gross total tumor resection followed by concomitant radiotherapy and chemotherapy with TMZ or PCV (3). This variability in treatment regimens underlines the need for phenotyping and risk stratification of gliomas before treatment initiation in order to ensure more precise management of these tumors. Magnetic resonance imaging (MRI) is the standard imaging modality to detect gliomas and can be complemented by positron emission tomography (PET), where particularly the use of amino acid tracers, such as O-(2-[18F]fluoroethyl)-l-tyrosine (FET), has been recommended (7-9). FET-PET has multiple applications, including diagnosis, prognostication, target delineation, and determination of tumor recurrence (9). Additionally, PET imaging with the tracer [68Ga]Ga-NOTA-Asp-Cha-Phe-D-Ser-D- Arg-Tyr-Leu-Trp-Ser-OH (68Ga-NOTA-AE105) targeting the proteolytic urokinase plasminogen activator (uPA) system is emerging as a promising new imaging biomarker for diagnosis, prognostication, risk stratification as well as a therapeutic target for solid cancers. Over the years, several studies have shown the applicability of uPA receptor (uPAR) as a diagnostic biomarker in cancer associated with poor disease prognosis (10). uPAR is highly upregulated in most solid cancers with limited expression in normal tissue. It is located on the surface of the cell where it binds the serine protease uPA. This facilitates cell proliferation, angiogenesis, proteolysis, motility resulting in tumor progression and invasion into the surrounding tissue 10-12). To target uPAR, the PET radiotracers 68Ga-NOTA-AE105 and 64Cu-DOTA-AE105 where the targeting peptide is a high-affinity antagonist for uPAR was developed (13-15). The safety, biodistribution, and radioligand accumulation of 68Ga-NOTA- AE105 and 64Cu-DOTA-AE105 in cancer tissue in two Phase 1 trials involving primary tumors and metastases has previously been established. Tracer accumulation was histopathologically confirmed to correspond with cancer tissue and uPAR expression using immunohistochemistry (13, 36). Furthermore, the utility of 68Ga-NOTA-AE105 for uPAR-PET as a promising method for non-invasive evaluation of localized prostate cancer with high diagnostic accuracy in differentiating between low-risk and intermediate-risk Gleason score profiles have been demonstrated (16). uPAR-PET has also been found to be highly prognostic in neuroendocrine neoplasms (17) and head-and-neck cancer (18). In gliomas, uPAR-PET has been highlighted as an effective imaging biomarker for tumour visualization using an orthotopic human xenograft model of glioblastoma (19). From a therapeutic perspective, uPAR has been identified as a promising target for peptide receptor radionuclide therapy (PRRT) and therapeutic efficacy of uPAR- targeted PRRT in preclinical models of prostate and colorectal cancers has previously been demonstrated the (20,21). Moreover, recent work has revealed a high correlation between uPAR expression on uPAR-PET and both Overall Survival (OS) and Progression-Free Survival (PFS) in patients with neuroendocrine neoplasms underscoring uPAR as a promising target for PRRT treatment. Actually, 68% of these patients across tumor