A5072394114- Radiopharmaceutical Chemistry and Applications
- Prostate Cancer Treatment and Research
- Radiation Therapy and Dosimetry
- Peptidase Inhibition and Analysis
- Effects of Radiation Exposure
- Redox biology and oxidative stress
- Occupational and environmental lung diseases
- Monoclonal and Polyclonal Antibodies Research
- Mass Spectrometry Techniques and Applications
- Cancer Research and Treatments
- Lung Cancer Treatments and Mutations
- Acute Myeloid Leukemia Research
- PARP inhibition in cancer therapy
- Chemical Reactions and Isotopes
- Medical Imaging Techniques and Applications
- Nanoparticle-Based Drug Delivery
- Medical Imaging and Pathology Studies
- Chemical Synthesis and Analysis
- Cancer Immunotherapy and Biomarkers
- HER2/EGFR in Cancer Research
- DNA Repair Mechanisms
- Neuroendocrine Tumor Research Advances
- Cancer therapeutics and mechanisms
- Hematological disorders and diagnostics
- Immunotherapy and Immune Responses
Bayer (Germany)
2018-2024
Bayer (Norway)
2014-2017
University of Freiburg
2007-2009
Abstract Purpose: Prostate-specific membrane antigen (PSMA) is an attractive target for radionuclide therapy of metastatic castration-resistant prostate cancer (mCRPC). PSMA-targeted alpha (TAT) has shown early signs activity in patients with refractory to beta radiation. We describe a novel, antibody-based TAT, the thorium-227 conjugate PSMA-TTC (BAY 2315497) consisting alpha-particle emitter complexed by 3,2-HOPO chelator covalently linked fully human PSMA-targeting antibody. Experimental...
Elevated expression of the chemokine receptor CCR4 in tumors is associated with poor prognosis several cancers. Here, we have determined that was highly expressed human renal cell carcinoma (RCC) biopsies and observed abnormal levels ligands RCC patient plasma. An antagonistic anti-CCR4 antibody had antitumor activity RENCA mouse model RCC. inhibition did not reduce proportion infiltrating leukocytes tumor microenvironment but altered phenotype myeloid cells, increased NK Th1 cytokine...
Abstract Purpose: Targeted thorium-227 conjugates (TTC) represent a new class of molecules for targeted alpha therapy (TAT). Covalent attachment 3,2-HOPO chelator to an antibody enables specific complexation and delivery the particle emitter tumor cells. Because high energy short penetration range, TAT efficiently induces double-strand DNA breaks (DSB) preferentially in cell with limited damage surrounding tissue. We present herein preclinical evaluation mesothelin (MSLN)-targeted conjugate,...
Abstract The clinical efficacy of the first approved alpha pharmaceutical, Xofigo (radium-223 dichloride, 223RaCl2), has stimulated significant interest in development new alpha-particle emitting drugs oncology. Unlike radium-223 (223Ra), parent radionuclide thorium-227 (227Th) is able to form highly stable chelator complexes and therefore amenable targeted radioimmunotherapy. We describe preparation use a CD33-targeted conjugate (CD33-TTC), which binds sialic acid receptor CD33 for...
Targeted <sup>227</sup>Th conjugates (TTCs) represent a new class of therapeutic radiopharmaceuticals for targeted α-therapy. They comprise the α-emitter complexed to 3,2-hydroxypyridinone chelator conjugated tumor-targeting monoclonal antibody. The high energy and short range α-particles induce antitumor activity, driven by induction complex DNA double-strand breaks. We hypothesized that blocking damage response (DDR) pathway should further sensitize cancer cells inhibiting repair, thereby...
Background Targeted thorium-227 conjugates (TTCs) are an emerging class of targeted alpha therapies (TATs). Their unique mode action (MoA) is the induction difficult-to-repair clustered DNA double-strand breaks. However, thus far, their effects on immune system largely unknown. Here, we investigated immunostimulatory mesothelin-targeted conjugate (MSLN-TTC) in vitro and vivo monotherapy combination with inhibitor checkpoint programmed death receptor ligand 1 (PD-L1) immunocompetent mice....
// Urs B. Hagemann 1 , Dessislava Mihaylova Steinar R. Uran Joergen Borrebaek Derek Grant Roger M. Bjerke Jenny Karlsson and Alan S. Cuthbertson Thorium Conjugate Research, Bayer AS, Oslo, Norway Correspondence to: Hagemann, email: urs.hagemann@bayer.com Keywords: targeted alpha therapy (TAT), particles, radioimmunotherapy, thorium-227, renal cell carcinoma Received: January 25, 2017 Accepted: March 13, Published: April 07, ABSTRACT The surface receptor CD70 has been previously reported as a...
Despite the recent advances in treatment of ovarian cancer, it remains an area high unmet medical need. Epithelial cancer is associated with levels mesothelin expression, and therefore, attractive candidate target for this disease. Herein, we investigated antitumor efficacy mesothelin-targeting antibody-drug conjugate (ADC) anetumab ravtansine as a novel option monotherapy combination agents pegylated liposomal doxorubicin (PLD), carboplatin, copanlisib bevacizumab. Anetumab showed potent...
Initially, prostate cancer responds to hormone therapy, but eventually resistance develops. Beta emitter-based prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy is approved for the treatment of metastatic castration-resistant cancer. Here we introduce a targeted alpha (TAT) consisting PSMA antibody pelgifatamab covalently linked macropa chelator and labeled with actinium-225 compare its efficacy tolerability other TATs.
Targeted thorium-227 conjugates (TTCs) represent a novel class of therapeutic radiopharmaceuticals for the treatment cancer. TTCs consist alpha particle emitter complexed to 3,2-hydroxypyridinone chelator conjugated tumor-targeting monoclonal antibody. The high energy and short range particles induce potent selective anti-tumor activity driven by induction DNA damage in target cell. Methods: efficacy human epidermal growth factor receptor 2 (HER2)-TTC was tested combination vitro vivo with...
We have screened two coiled coil-forming libraries in which core a and electrostatic e/g positions been partially randomized. observed the relative ability of these residues to confer coil stability using protein-fragment complementation assay. Our studies continue with Jun/Fos activator protein-1 (AP-1) leucine zipper complex, as it provides valid therapeutic target, while representing one more simplistic examples quaternary structure. In mammalian cells, 28 possible dimeric interactions...
Two c-Jun leucine zipper variants that bind with high affinity to c-Fos have been selected using semirational design combined protein-fragment complementation assays (JunW) or phage display selection (JunW(Ph1)). Enriched winners differ from each other in only two of ten semi-randomized positions, DeltaT(m) values 28 degrees C and 37 over wild-type. cFos-JunW, cFos-JunW(Ph1), intermediate mutants (cFos-JunW(Q21R) cFos-JunW(E23K)) biphasic kinetics the folding direction, indicating existence...
CC chemokine receptor 4 (CCR4) represents a potentially important target for cancer immunotherapy due to its expression on tumor infiltrating immune cells including regulatory T (Tregs) and in several types role metastasis.
Abstract Purpose: Androgen receptor (AR) inhibitors are well established in the treatment of castration-resistant prostate cancer and have recently shown efficacy also castration-sensitive cancer. Although most patients respond to initial therapy, resistance eventually develops, thus, more effective therapeutic approaches needed. Prostate-specific membrane antigen (PSMA) is highly expressed presents an attractive target for radionuclide therapy. Here, we evaluated explored mode action...
Abstract Prostate-specific membrane antigen (PSMA, FOLH1) is a type II transmembrane glycoprotein of the M28 peptidase family that acts as glutamate carboxypeptidase on various substrates. PSMA well established target in prostate cancer due to its high and specific overexpression surface cells at all tumor stages, including metastatic hormone-refractory disease. Several targeting antibodies ligands are currently clinical development or compassionate use therapeutically imaging agents....
Introduction: [227Th]Th-3,2-HOPO-MSLN-mAb, a mesothelin (MSLN)-targeted thorium-227 therapeutic conjugate, is currently in phase I clinical trial; however, direct PET imaging using this conjugate technically challenging. Thus, the same MSLN antibody, we synthesized 3,2-HOPO and deferoxamine (DFO)-based zirconium-89 antibody conjugates, [89Zr]Zr-3,2-HOPO-MSLN-mAb [89Zr]Zr-DFO-MSLN-mAb, respectively, compared them vitro vivo. Methods: [89Zr]Zr-DFO-MSLN-mAb were evaluated to determine binding...
Human epidermal growth factor receptor 2 (HER2) is overexpressed in 15-30% of breast cancers but has low expression normal tissue, making it attractive for targeted alpha therapy (TAT). HER2-positive cancer typically metastasizes to bone, resulting incurable disease and significant morbidity mortality. Therefore, new strategies HER2-targeting are needed. Here, we present the preclinical vitro vivo characterization HER2-targeted thorium-227 conjugate (HER2-TTC) TAT various models. In vitro,...
Abstract The human epidermal growth factor receptor 2 (HER2) is encoded by the proto-oncogene c-erbB-2 and initiates downstream signaling pathways leading to cell proliferation tumorigenesis. HER2 overexpressed in several cancer (Ca) types one of most strongly validated targets for treatment breast gastric serving as both a prognostic predictive biomarker. Several HER2-targeting antibodies well antibody-drug conjugates are either approved or clinical development. Prolonged with monoclonal...
Abstract Radium-223 dichloride (radium-223) is a targeted alpha therapy that binds to newly formed abnormal bone in metastases and induces DNA double-strand breaks (DSBs) cancer cells, osteoblasts osteoclasts. used for the treatment of patients with metastatic castration-resistant prostate (mCRPC). Darolutamide an androgen receptor inhibitor indicated hormone-sensitive or non-metastatic CRPC. We studied antitumor effects radium-223 combination darolutamide using LNCaP human cells vitro...
Background The number of radiolabeled monoclonal antibodies (mAbs) used for medical imaging and cancer therapy is increasing. required chemical modification attaching a radioactive label all associated treatment may lead to damaged mAb subpopulation. This paper describes novel method, concentration through kinetics (CTK), rapid assessment the immunoreactive specific radioactivity, based on monitoring binding kinetics. Methods interaction with either antigen or general binder such as Protein...