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Dive into the research topics where Dietmar Berndorff is active.

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Featured researches published by Dietmar Berndorff.


Clinical Cancer Research | 2005

Radioimmunotherapy of solid tumors by targeting extra domain B fibronectin : Identification of the best-suited radioimmunoconjugate

Dietmar Berndorff; Sandra Borkowski; Stephanie Sieger; Axel Rother; Matthias Friebe; Francesca Viti; Christoph Stephan Hilger; John E. Cyr; Ludger Dinkelborg

Purpose: The expression of extra domain B (ED-B) fibronectin is always associated with angiogenic processes and can be exclusively observed in tissues undergoing growth and/or extensive remodeling. Due to this selective expression, ED-B fibronectin is an interesting target for radioimmunotherapy of malignant diseases. The aim of this study was to identify the most appropriate ED-B-targeting radioimmunoconjugate for the therapy of solid tumors. Experimental Design: Three ED-B fibronectin-binding human antibody formats of L19 were investigated: dimeric single-chain Fv (∼50 kDa), “small immunoprotein” (SIP, ∼80 kDa), and immunoglobulin G1 (IgG1, ∼150 kDa). These L19 derivatives were either labeled with I-125 or with In-111 (using MX-diethylenetriaminepentaacetic acid, MX-DTPA). Pharmacokinetics and tumor accumulation of the radiolabeled immunoconjugates were investigated in F9 (murine teratocarcinoma) tumor-bearing mice. Subsequently, dosimetry for the corresponding therapeutic isotopes I-13-1 and Y-90 was done. After testing the myelotoxicity of I-131-L19-SIP and I-131-L19-IgG1 in non-tumor-bearing mice, the therapeutic efficacy of these iodinated antibody formats was finally investigated in F9 tumor-bearing mice. Results: The most favorable therapeutic index was found for I-131-L19-SIP followed by I-131-L19-IgG1. The therapeutic index of all In-111-labeled derivatives was significantly inferior. Considering the bone marrow as the dose-limiting organ, it was calculated that activities of 74 MBq I-131-L19-SIP and 25 MBq I-131-L19-IgG1 could be injected per mouse without causing severe myelotoxicity. The best therapeutic efficacy was observed using I-131-L19-SIP, resulting in significant tumor growth delay and prolonged survival after a single injection. Conclusion: Compared with other L19-based radioimmunoconjugates, I-131-L19-SIP is characterized by superior antitumor efficacy and toxicity profile in the F9 teratocarcinoma animal model. These results indicate that ED-B fibronectin-targeted radioimmunotherapy using I-131-L19-SIP has potential to be applied to treatment of solid cancers.


Bioconjugate Chemistry | 2008

Synthesis, 18F-Labeling, and in Vitro and in Vivo Studies of Bombesin Peptides Modified with Silicon-Based Building Blocks

Aileen Höhne; Linjing Mu; Michael Honer; P. August Schubiger; Simon M. Ametamey; Keith Graham; Timo Stellfeld; Sandra Borkowski; Dietmar Berndorff; Ulrich Klar; Ulrike Voigtmann; John E. Cyr; Matthias Friebe; Ludger Dinkelborg; Ananth Srinivasan

The gastrin-releasing peptide receptor (GRPr) is overexpressed on various human tumors. The goal of our study was the synthesis of new 18F-labeled bombesin analogues for the PET imaging of GRPr expression in prostate tumor using a silicon-based one-step n. c. a. radiolabeling method. The silicon-containing building blocks were efficiently coupled to the N-terminus of the peptides via solid-phase synthesis. Radiolabeling of the obtained peptide precursors proceeded smoothly under acidic conditions (34-85% conversion). Using the di-tert-butyl silyl building block as labeling moiety, products containing a hydrolytically stable 18F-label were obtained. In in vitro receptor binding experiments 2-(4-(di-tert-butylfluorosilyl)phenyl)acetyl-Arg-Ava-Gln-Trp-Ala-Val-NMeGly-His-Sta-Leu-NH 2 ( 4b, IC50 = 22.9 nM) displayed a 12-fold higher binding affinity than 2-(4-(di-tert-butylfluorosilyl)phenyl)acetyl-Arg-Ava-Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Leu-NH2 ( 3b, IC50 = 276.6 nM), and 4b was therefore chosen for further evaluation. In vitro and ex vivo metabolite studies of [18F]4b showed no significant degradation. In biodistribution experiments, tumor uptake of [18F]4b was low and unspecific, whereas the GRPr-rich pancreas revealed a high and specific accumulation of the radiotracer. This study demonstrates the applicability of our silicon-based one-step n. c. a. radiolabeling method for the synthesis of new 18F-labeled bombesin derivatives. This innovative approach represents a general, straightforward access to radiolabeled peptides as PET imaging probes.


The Journal of Nuclear Medicine | 2009

Targeting of HER2-Expressing Tumors with a Site-Specifically 99mTc-Labeled Recombinant Affibody Molecule, ZHER2:2395, with C-Terminally Engineered Cysteine

Sara Ahlgren; Helena Wållberg; Thuy Tran; Charles Widström; Magnus Hjertman; Lars Abrahmsén; Dietmar Berndorff; Ludger Dinkelborg; John E. Cyr; Joachim Feldwisch; Anna Orlova; Vladimir Tolmachev

The detection of human epidermal growth factor receptor type 2 (HER2) expression in malignant tumors provides important information influencing patient management. Radionuclide in vivo imaging of HER2 may permit the detection of HER2 in both primary tumors and metastases by a single noninvasive procedure. Small (7 kDa) high-affinity anti-HER2 Affibody molecules may be suitable tracers for SPECT visualization of HER2-expressing tumors. The use of generator-produced 99mTc as a label would facilitate the prompt translation of anti-HER2 Affibody molecules into use in clinics. Methods: A C-terminal cysteine was introduced into the Affibody molecule ZHER2:342 to enable site-specific labeling with 99mTc. Two recombinant variants, His6-ZHER2:342-Cys (dissociation constant [KD], 29 pM) and ZHER2:2395-Cys, lacking a His tag (KD, 27 pM), were labeled with 99mTc in yields exceeding 90%. The binding specificity and the cellular processing of Affibody molecules were studied in vitro. Biodistribution and γ-camera imaging studies were performed in mice bearing HER2-expressing xenografts. Results: 99mTc-His6-ZHER2:342-Cys was capable of targeting HER2-expressing SKOV-3 xenografts in SCID mice, but the liver radioactivity uptake was high. A series of comparative biodistribution experiments indicated that the presence of the His tag caused elevated accumulation in the liver. 99mTc-ZHER2:2395-Cys, not containing a His tag, showed low uptake in the liver and high and specific uptake in HER2-expressing xenografts. Four hours after injection, the radioactivity uptake values (percentage of injected activity per gram of tissue [%IA/g]) were 6.9 ± 2.5 (mean ± SD) %IA/g in LS174T xenografts (moderate level of HER2 expression) and 15 ± 3 %IA/g in SKOV-3 xenografts (high level of HER2 expression). The corresponding tumor-to-blood ratios were 88 ± 24 and 121 ± 24, respectively. Both LS174T and SKOV-3 xenografts were clearly visualized with a clinical γ-camera 1 h after injection of 99mTc-ZHER2:2395-Cys. Conclusion: The Affibody molecule 99mTc-ZHER2:2395-Cys is a promising tracer for SPECT visualization of HER2-expressing tumors.


Bioconjugate Chemistry | 2009

Direct One-Step18F-Labeling of Peptides via Nucleophilic Aromatic Substitution

Jessica Becaud; Linjing Mu; Mylène Karramkam; Pius A. Schubiger; Simon M. Ametamey; Keith Graham; Timo Stellfeld; Lutz Lehmann; Sandra Borkowski; Dietmar Berndorff; Ludger Dinkelborg; Ananth Srinivasan; Rene Smits; Beate Koksch

Methods for the radiolabeling molecules of interest with [18F]-fluoride need to be rapid, convenient, and efficient. Numerous [18F]-labeled prosthetic groups, e.g., N-succinimidyl 4 [18F]-fluorobenzoate ([18F]-SFB), 4-azidophenacyl-[18F]-fluoride ([18F]-APF), and 1-(3-(2-[18F]fluoropyridin-3-yloxy)propyl)pyrrole-2,5-dione ([18F]-FpyMe), for conjugating to biomolecules have been developed. As the synthesis of these prosthetic groups usually requires multistep procedures, there is still a need for direct methods for the nucleophilic [18F]-fluorination of biomolecules. We report here on the development of a procedure based on the trimethylammonium (TMA) leaving group attached to an aromatic ring and activated with different electron-withdrawing groups (EWGs). A series of model compounds containing different electron-withdrawing substituents, a trimethylammonium leaving group, and carboxylic functionality for subsequent coupling to peptides were designed and synthesized. The optimal model compound, 2-cyano-4-(methoxycarbonyl)-N,N,N-trimethylbenzenaminium trifluoromethanesulfonate, was converted to carboxylic acid and coupled to peptides. The results of the one-step [18F]-fluorination of tetrapeptides and bombesin peptides show that the direct 18F-labeling of peptides is feasible under mild conditions and in good radiochemical yields.


The Journal of Nuclear Medicine | 2007

Small-animal PET of tumor angiogenesis using a (76)Br-labeled human recombinant antibody fragment to the ED-B domain of fibronectin.

Raffaella Rossin; Dietmar Berndorff; Matthias Friebe; Ludger Dinkelborg; Michael J. Welch

The aim of this study was to image the extra domain B (ED-B) of fibronectin, an angiogenesis-related target, in solid tumors using small-animal PET. Toward this aim, an ED-B fibronectin-binding human antibody derivative (L19-SIP) was labeled with 76Br via an enzymatic approach. Biodistribution and imaging studies were performed in human teratoma–bearing mice for up to 48 h after injection. Methods: L19-SIP was labeled with 76Br using bromoperoxidase/H2O2. The stability of the labeled antibody was tested both in vitro and in vivo. Biodistribution and small-animal imaging studies (PET and CT) were performed in F9-bearing 129/sv mice (n = 3 or 4). Results: The enzymatic radiobromination approach afforded the labeled antibody in high yield (>55%) under mild reaction conditions. 76Br-L19-SIP stability in mouse serum proved to be similar to that of the 125I-labeled analog (>80% of intact material at 48 h after injection). Fast and specific in vivo targeting was obtained in tumors and other organs expressing ED-B fibronectin (i.e., ovaries and uterus). However, slow renal clearance and persistent activity predominately in blood and stomach suggests partial 76Br-L19-SIP debromination in vivo. This debromination was confirmed in a metabolism study in normal mice. The F9 tumors were clearly imaged by small-animal PET at each considered time point, starting at 5 h up to 48 h after injection. Conclusion: 76Br-L19-SIP specifically accumulated at the target site, enabling detailed small-animal PET of tumor neovasculature. Therefore, targeting the angiogenesis-associated expression of ED-B fibronectin can be a valuable tool for tumor detection using molecular imaging with PET.


Clinical Cancer Research | 2006

Bispecific Antibody Pretargeting of Tumor Neovasculature for Improved Systemic Radiotherapy of Solid Tumors

Dieter Moosmayer; Dietmar Berndorff; Chien-Hsing Chang; Robert M. Sharkey; Axel Rother; Sandra Borkowski; Edmund A. Rossi; William J. McBride; Thomas M. Cardillo; David M. Goldenberg; Ludger Dinkelborg

Purpose: Extra domain B (ED-B) fibronectin is a specific tumor matrix marker for targeting angiogenesis in solid tumors. In this study, the radiotherapeutic potential of the directly radioiodinated divalent anti-ED-B antibody fragment, L19 small immunoprotein (L19-SIP; 75,000 Da), was compared with a pretargeting approach using the bispecific antibody AP39xm679 (bsMAb; 75,000 Da). Experimental Design: The bsMAb was prepared by coupling an anti-ED-B single-chain Fv (AP39) to the Fab′ of the murine antibody m679, which binds to the small peptidic hapten histamine-succinyl-glycine (HSG). As an effector molecule for the pretargeting approach, the 111In-labeled HSG-DOTA complex was injected 25 or 41 hours after the bsMAb. The kinetics of both the iodinated bsMAb and the pretargeted 111In-labeled HSG hapten were investigated in mice bearing human glioblastoma xenografts (U251) and compared with the kinetics and tumor accumulation of radioiodinated L19-SIP. 111In and 125I were used as surrogate marker for the therapeutic radioisotopes 90Y/177Lu and 131I, respectively. Results: Tumor uptake of the pretargeted 111In-labeled peptide was significantly higher than 125I-L19-SIP over 7 days. At the calculated maximally tolerated dose for each agent (with the kidney being the dose-limiting organ for pretargeting and the bone marrow for direct targeting), a mouse tumor dose of 146 Gy could be given by pretargeting versus 45 Gy delivered by the direct approach. Conclusions: These data suggest that pretargeting of ED-B with AP39xm679 and subsequent injection of the 90Y-hapten-peptide would improve the therapeutic efficacy in solid tumors by >3-fold compared with directly radiolabeled 131I-L19-SIP.


The Journal of Nuclear Medicine | 2007

Identification and Evaluation of a New Tumor Cell–Binding Peptide, FROP-1

Sabine Zitzmann; Susanne Krämer; Walter Mier; Ulrike Hebling; Annette Altmann; Axel Rother; Dietmar Berndorff; Michael Eisenhut; Uwe Haberkorn

Peptides are useful tools for the targeted delivery of radionuclides or chemotherapeutic drugs to their site of action within an organism. Given that the peptide receptor is overexpressed at the tumor, therapeutically active doses can be delivered to the tumor with reduced side effects. Because currently known peptides are restricted to a small number of tumors, new molecules and their corresponding receptors have to be identified to enlarge the spectrum of malignancies that can be diagnosed or treated using tumor-targeting peptides. Methods: A 12-amino-acid peptide phage display system was applied to identify a new peptide binding to follicular thyroid carcinoma cells. The properties of the radiolabeled peptide were assessed in binding, competition, and internalization experiments in a variety of tumor cell lines including FRO82-2 and MCF-7 cells, and the pharmacokinetic behavior of the radiolabeled peptide was evaluated in tumor-bearing mice. Peptide stability was studied in human serum. Results: After 5 selection rounds, the new peptide, FROP-1 (EDYELMDLLAYL), was identified. It showed binding to follicular thyroid carcinoma as well as anaplastic thyroid carcinoma, mammary carcinoma, cervix carcinoma, prostate carcinoma, and cell lines derived from head and neck tumors, and low affinity could be observed to control cells such as human umbilical vein endothelial cells or immortalized keratinocytes. In MCF7 cells, 78% and 86% of the bound activity was internalized after 10 and 60 min of incubation, respectively. Stability experiments in human serum showed the appearance of a degradation product after 15 min. Tumor uptake of the radioactive labeled peptide increased for 45 min in nude mouse models, reaching an accumulation level of approximately 3.6 percentage injected dose (%ID)/g for FRO82-2 tumors or approximately 3.8 %ID/g for MCF-7 tumors. Conclusion: The target of FROP-1 is most likely a molecule found generally in tumors, making this peptide highly attractive for diagnostic or therapeutic applications. However, modifications are needed to increase stability and affinity.


The Journal of Nuclear Medicine | 2010

d-18F-Fluoromethyl Tyrosine Imaging of Bone Metastases in a Mouse Model

Sabine Zitzmann-Kolbe; Anne Strube; Anna-Lena Frisk; Sanna-Maria Käkönen; Hideo Tsukada; Peter Hauff; Dietmar Berndorff; Keith Graham

The presence and localization of metastatic bone lesions is important for the staging of the disease and subsequent treatment decisions. Detecting tumor cells would have additional value over the current indirect bone scintigraphy method for detecting areas of elevated skeletal metabolic activity. d-18F-fluoromethyl tyrosine (d-18F-FMT) has recently shown good uptake and fast elimination, resulting in good tumor-to-background ratios. The potential of d-18F-FMT for imaging bone metastases has been investigated. Methods: 786-O/luciferase human renal adenocarcinoma cells were injected intracardially, resulting in the formation of bone metastases in mice. Small-animal PET was performed 51 and 65 d after tumor cell inoculation. Results: d-18F-FMT showed specific uptake in the bone metastases, giving excellent images with a little background in the pancreas. All imaged metastases were histologically confirmed. A bone scan with 18F-fluoride showed elevated skeletal metabolic activity in the areas of osteolytic lesions. Conclusion: d-18F-FMT is a useful PET tracer for the detection of bone metastases and should be evaluated in the clinical setting.


Blood | 1999

A high-affinity human antibody that targets tumoral blood vessels

Lorenzo Tarli; Enrica Balza; Francesca Viti; Laura Borsi; Patrizia Castellani; Dietmar Berndorff; Ludger Dinkelborg; Dario Neri; Luciano Zardi


The Journal of Nuclear Medicine | 2006

Imaging of Tumor Angiogenesis Using 99mTc-Labeled Human Recombinant Anti-ED-B Fibronectin Antibody Fragments

Dietmar Berndorff; Sandra Borkowski; Dieter Moosmayer; Francesca Viti; Beate Müller-Tiemann; Stephanie Sieger; Matthias Friebe; Christoph Stephan Hilger; Luciano Zardi; Dario Neri; Ludger Dinkelborg

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John E. Cyr

Bayer Schering Pharma AG

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Francesca Viti

École Polytechnique Fédérale de Lausanne

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Matthias Friebe

Free University of Berlin

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Dario Neri

Medical Research Council

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Luciano Zardi

Istituto Giannina Gaslini

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