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

Hagemann, Urs B.; Ellingsen, Christine; Schuhmacher, Joachim; Kristian, Alexander; Mobergslien, Anne; Cruciani, Véronique; Wickstroem, Katrine; Schatz, Christoph A.; Kneip, Christoph; Golfier, Sven; Smeets, Roger; Uran, Steinar; Hennekes, Hartwig; Karlsson, Jenny; Bjerke, Roger M.; Ryan, Olav B.; Mumberg, Dominik; Ziegelbauer, Karl; Cuthbertson, Alan S.

doi:10.1158/1078-0432.ccr-18-3476

Cited by 82 publications

(156 citation statements)

References 42 publications

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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%

“…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). A nonbinding radiolabeled isotype control was prepared similarly to PSMA-TTC (12,14,15).…”

Section: Compoundsmentioning

confidence: 99%

“…PSMA-TTC was analyzed for radiostability by instant thin layer chromatography and HPLC as described previously (12). The immunoreactive fraction was determined as previously described (12). The binding affinity of PSMA-TTC to recombinant human PSMA (R&D Systems) was determined with an enzyme-linked immunosorbent assay (ELISA).…”

Section: Characterization Of Psma-ttcmentioning

confidence: 99%

“…In vitro cytotoxicity and caspase experiments were performed using CellTiter-Glo or Caspase-3/7 Glo assay (Promega), respectively, in prostate cancer cell lines after a 5-day exposure to PSMA-TTC. Determination of antibodies bound per cell, cell-cycle analysis (staining C4-2 prostate cancer cells with PI RNAse), and DNA DSBs (percentage of phosphorylated histone protein g-H2AX-positive LNCaP cells) were performed by flow cytometry as previously described (12,15). Internalized radioactivity after incubation of C4-2 and PC3 cells with PSMA-TTC was determined as described in Supplementary Methods.…”

Section: Characterization Of Psma-ttcmentioning

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%

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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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Section: Compoundsmentioning

confidence: 99%

Section: Compoundsmentioning

confidence: 99%

Section: Characterization Of Psma-ttcmentioning

confidence: 99%

Section: Characterization Of Psma-ttcmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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Emerging Therapeutic Radiopharmaceuticals and Their Theranostic Pairs

Carbo-Bague

Ramogida

2021

Encyclopedia of Inorganic and Bioinorganic Chemistry

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Nuclear medicine is a rapidly evolving multidisciplinary research field that has been intensively investigated in the past decades. The successful clinical application of various metal‐based radiopharmaceuticals for cancer imaging and therapy is based on the modular assembly of the drug complex through the popular bifunctional chelate (BFC) strategy. In targeted radionuclide therapy (TRT), potent radiation is selectively delivered to the cancer cells using radiopharmaceuticals that incorporate therapeutic radiometals which emit α ‐particles, β − ‐particles, or Meitner–Auger electrons (MAEs). Radiotheranostics is an emerging concept that connects nuclear imaging (via positron emission tomography (PET) or single‐photon emission computed tomography (SPECT)) and therapy for personalized cancer diagnosis and treatment. This article outlines the fundamentals of radiopharmaceutical design and radiotheranostics and presents a general description of the therapeutic emissions accompanied by literature examples of the most promising radionuclides; 212 Pb, 213 Bi, 225 Ac, 227 Th, and 149 Tb for α therapy; 47 Sc, 67 Cu, 77 As, and 161 Tb for β − therapy; and 119 Sb, 135 La, and 197m/g Hg for MAE therapy. A comparison of the currently used or proposed theranostic pairs of each radiometal is presented.

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Recent Advances in Radiometals for Combined Imaging and Therapy in Cancer

et al. 2021

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Nuclear medicine is defined as the use of radionuclides for diagnostic and therapeutic applications. The imaging modalities positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are based on γ-emissions of specific energies. The therapeutic technologies are based on β À -particle-, α-particle-, and Auger electron emitters. In oncology, PET and SPECT are used to detect cancer lesions, to determine dosimetry, and to monitor therapy effectiveness. In contrast, radiotherapy is designed to irreparably damage tumor cells in order to eradicate or control the disease's progression. Radiometals are being explored for the development of diagnostic and therapeutic radiopharmaceuticals. Strategies that combine both modalities (diagnostic and therapeutic), referred to as theranostics, are promising candidates for clinical applications. This review provides an overview of the basic concepts behind therapeutic and diagnostic radiopharmaceuticals and their significance in contemporary oncology. Select radiometals that significantly impact current and upcoming cancer treatment strategies are grouped as clinically suitable theranostics pairs. The most important physical and chemical properties are discussed. Standard production methods and current radionuclide availability are provided to indicate whether a cost-efficient use in a clinical routine is feasible. Recent preclinical and clinical developments and outline perspectives for the radiometals are highlighted in each section.

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

Cited by 82 publications

References 42 publications

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

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

Emerging Therapeutic Radiopharmaceuticals and Their Theranostic Pairs

Recent Advances in Radiometals for Combined Imaging and Therapy in Cancer

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