Targeted alpha therapy using a novel CD70 targeted thorium-227 conjugate in<i>in vitro</i>and<i>in vivo</i>models of renal cell carcinoma

Hagemann, Urs B.; Mihaylova, Dessislava; Uran, Steinar; Borrebaek, Joergen; Grant, Derek; Bjerke, Roger M.; Karlsson, Jenny; Cuthbertson, Alan S.

doi:10.18632/oncotarget.16910

Cited by 47 publications

(74 citation statements)

References 46 publications

(55 reference statements)

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“…66,70,71 A CD70-targeted 227 Th conjugate (CD70-TTC) was developed, and its activity was tested on CD70-positive human RCC cells in vitro and in vivo. 72 In vitro, exposure to CD70-TTC reduced RCC 786-O cell viability in a dose-dependent manner (Table 1). 72 In a biodistribution study using 786-O tumor-bearing mice, specific uptake and retention of CD70-TTC at 7 d after administration was observed.…”

Section: Cd70-ttcmentioning

confidence: 98%

Advances in Precision Oncology: Targeted Thorium-227 Conjugates As a New Modality in Targeted Alpha Therapy

Hagemann

Wickstroem

Hammer

et al. 2020

Cancer Biotherapy and Radiopharmaceuticals

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Targeted alpha therapy (TAT) offers the potential for the targeted delivery of potent a-particle-emitting radionuclides that emit high linear energy transfer radiation. This leads to a densely ionizing radiation track over a short path. Localized radiation induces cytotoxic, difficult-to-repair, clustered DNA double-strand breaks (DSBs). To date, radium-223 (223 Ra) is the only TAT approved for the treatment of patients with metastatic castration-resistant prostate cancer. Thorium-227 (227 Th), the progenitor nuclide of 223 Ra, offers promise as a wider-ranging alternative due to the availability of efficient chelators, such as octadentate 3,2-hydroxypyridinone (3,2-HOPO). The 3,2-HOPO chelator can be readily conjugated to a range of targeting moieties, enabling the generation of new targeted thorium-227 conjugates (TTCs). This review provides a comprehensive overview of the advances in the preclinical development of TTCs for hematological cancers, including CD22-positive B cell cancers and CD33-positive leukemia, as well as for solid tumors overexpressing renal cell cancer antigen CD70, membrane-anchored glycoprotein mesothelin in mesothelioma, prostate-specific membrane antigen in prostate cancer, and fibroblast growth factor receptor 2. As the mechanism of action for TTCs is linked to the formation of DSBs, the authors also report data supporting combinations of TTCs with inhibitors of the DNA damage response pathways, including those of the ataxia telangiectasia and Rad3-related protein, and poly-ADP ribose polymerase. Finally, emerging evidence suggests that TTCs induce immunogenic cell death through the release of danger-associated molecular patterns. Based on encouraging preclinical data, clinical studies have been initiated to investigate the safety and tolerability of TTCs in patients with various cancers.

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Section: Cd70-ttcmentioning

confidence: 98%

Advances in Precision Oncology: Targeted Thorium-227 Conjugates As a New Modality in Targeted Alpha Therapy

Hagemann

Wickstroem

Hammer

et al. 2020

Cancer Biotherapy and Radiopharmaceuticals

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“…The fully human PSMA-targeting antibody BAY 2315158 specifically recognizing human and cynomolgus PSMA was licensed from Progenics Pharmaceuticals, Inc. (16,17). The nonradiolabeled PSMA antibody-chelator conjugate (BAY 2315493) was manufactured at Bayer AG and Bayer AS by coupling an N-hydroxysuccinimideactivated 3,2-HOPO chelator covalently to the e-amino groups of the lysine residues of the PSMA antibody as described previously (12)(13)(14)(15). The radionuclide thorium-227 was manufactured at IFE and the antibody-chelator conjugate was radiolabeled with thorium-227 in citrate buffer (pH 5.5) at þ22 C for up to 60 minutes resulting in PSMA-TTC (BAY 2315497) as described in Supplementary Methods and previously (14).…”

Section: Compoundsmentioning

confidence: 99%

“…PSMA-TTC uses the alpha-particle emitter thorium-227 (half-life of 18.7 days), which is the parent nuclide of radium-223. Thorium-227 can be efficiently complexed by the 3,2-hydroxypyridinone (3,2-HOPO) octadentate chelator (10,11) covalently linked to antibodies (12)(13)(14)(15) at ambient temperature. Strong antitumor efficacy of PSMA-TTC is shown in a panel of prostate cancer models mimicking different clinical stages of prostate cancer including castration-resistant and bone metastatic disease.…”

Section: Introductionmentioning

confidence: 99%

Preclinical Efficacy of a PSMA-Targeted Thorium-227 Conjugate (PSMA-TTC), a Targeted Alpha Therapy for Prostate Cancer

Hammer¹,

Hagemann²,

Zitzmann-Kolbe³

et al. 2020

Clinical Cancer Research

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◥Purpose: Prostate-specific membrane antigen (PSMA) is an attractive target for radionuclide therapy of metastatic castrationresistant prostate cancer (mCRPC). PSMA-targeted alpha therapy (TAT) has shown early signs of activity in patients with prostate cancer refractory to beta radiation. We describe a novel, antibody-based TAT, the PSMA-targeted thorium-227 conjugate PSMA-TTC (BAY 2315497) consisting of the alpha-particle emitter thorium-227 complexed by a 3,2-HOPO chelator covalently linked to a fully human PSMA-targeting antibody.Experimental Design: PSMA-TTC was characterized for affinity, mode of action, and cytotoxic activity in vitro. Biodistribution, pharmacokinetics, and antitumor efficacy were investigated in vivo using cell line and patient-derived xenograft (PDX) models of prostate cancer.Results: PSMA-TTC was selectively internalized into PSMApositive cells and potently induced DNA damage, cell-cycle arrest, and apoptosis in vitro. Decrease in cell viability was observed dependent on the cellular PSMA expression levels. In vivo, PSMA-TTC showed strong antitumor efficacy with T/C values of 0.01 to 0.31 after a single injection at 300 to 500 kBq/kg in subcutaneous cell line and PDX models, including models resistant to standard-of-care drugs such as enzalutamide. Furthermore, inhibition of both cancer and cancer-induced abnormal bone growth was observed in a model mimicking prostate cancer metastasized to bone. Specific tumor uptake and efficacy were demonstrated using various PSMA-TTC doses and dosing schedules. Induction of DNA double-strand breaks was identified as a key mode of action for PSMA-TTC both in vitro and in vivo.Conclusions: The strong preclinical antitumor activity of PSMA-TTC supports its clinical evaluation, and a phase I trial is ongoing in mCRPC patients (NCT03724747).

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“…We have recently described the generation of targeted thorium-227 conjugates (TTC) and evaluated their potencies in in vitro and in vivo models of acute myeloid leukemia (7) and in models of renal cell carcinoma (8). The mode-of-action (MoA) of TTCs is predominantly linked to the robust induction of irreparable double-strand DNA breaks (9).…”

Section: Introductionmentioning

confidence: 99%

Mesothelin-Targeted Thorium-227 Conjugate (MSLN-TTC): Preclinical Evaluation of a New Targeted Alpha Therapy for Mesothelin-Positive Cancers

Hagemann¹,

Ellingsen

Schuhmacher

et al. 2019

Clinical Cancer Research

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150

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Purpose: Targeted thorium-227 conjugates (TTC) represent a new class of molecules for targeted alpha therapy (TAT). Covalent attachment of a 3,2-HOPO chelator to an antibody enables specific complexation and delivery of the alpha particle emitter thorium-227 to tumor cells. Because of the high energy and short penetration range, TAT efficiently induces double-strand DNA breaks (DSB) preferentially in the tumor cell with limited damage to the surrounding tissue. We present herein the preclinical evaluation of a mesothelin (MSLN)-targeted thorium-227 conjugate, BAY 2287411. MSLN is a GPI-anchored membrane glycoprotein overexpressed in mesothelioma, ovarian, pancreatic, lung, and breast cancers with limited expression in healthy tissue. Experimental Design: The binding activity and radiostability of BAY 2287411 were confirmed bioanalytically. The mode-of-action and antitumor potency of BAY 2287411 were investigated in vitro and in vivo in cell line and patient-derived xenograft models of breast, colorectal, lung, ovarian, and pancreatic cancer. Results: BAY 2287411 induced DSBs, apoptotic markers, and oxidative stress, leading to reduced cellular viability. Furthermore, upregulation of immunogenic cell death markers was observed. BAY 2287411 was well-tolerated and demonstrated significant antitumor efficacy when administered via single or multiple dosing regimens in vivo. In addition, significant survival benefit was observed in a disseminated lung cancer model. Biodistribution studies showed specific uptake and retention of BAY 2287411 in tumors and enabled the development of a mechanistic pharmacokinetic/pharmacodynamic model to describe the preclinical data. Conclusions: These promising preclinical results supported the transition of BAY 2287411 into a clinical phase I program in mesothelioma and ovarian cancer patients (NCT03507452).

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Targeted alpha therapy using a novel CD70 targeted thorium-227 conjugate inin vitroandin vivomodels of renal cell carcinoma

Cited by 47 publications

References 46 publications

Advances in Precision Oncology: Targeted Thorium-227 Conjugates As a New Modality in Targeted Alpha Therapy

Advances in Precision Oncology: Targeted Thorium-227 Conjugates As a New Modality in Targeted Alpha Therapy

Preclinical Efficacy of a PSMA-Targeted Thorium-227 Conjugate (PSMA-TTC), a Targeted Alpha Therapy for Prostate Cancer

Mesothelin-Targeted Thorium-227 Conjugate (MSLN-TTC): Preclinical Evaluation of a New Targeted Alpha Therapy for Mesothelin-Positive Cancers

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