Wolfgang Becker

Georg-August-Universität Göttingen, Göttingen, Lower Saxony, Germany

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Publications (39)192.63 Total impact

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    ABSTRACT: Uptake of radiolabeled peptides in the kidneys may obscure abdominal tumors in radiopeptide scintigraphy. This problem is much more pronounced in peptide receptor radionuclide therapy (i.e., radiopeptide therapy), possibly leading to renal damage or even failure. Cationic peptide uptake in the kidneys can be reduced by the application of cationic amino acids, such as lysine or arginine. The aim of this study was to develop a suitable method to reduce anionic peptide uptake in the kidneys. (111)In-Diethylenetriaminepentaacetic acid dGlu(1)-minigastrin ((111)In-DTPA-dGlu-Glu-Glu-Glu-Glu-Glu-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH(2)) was chosen as a model compound with a sequence of 6 negatively charged glutamic acids in a chain and an additional aspartic acid. TT (human medullary carcinoma cells)-bearing nu/nu mice of the Institute of Cancer Research genotype received intraperitoneal injections of different chain lengths and weights of glutamic acids, aspartic acids, and derivatives of glutamic acids. Uptake in tumors and organs was determined and compared with the values for untreated control mice. Accretion of (111)In-DTPA-dGlu(1)-minigastrin in the kidneys could be reduced by up to 90%. The uptake values for all other organs and the tumors were not affected. These results were obtained with a chain of 5 or more glutamic acids, whereas uptake in kidneys was affected not at all or only slightly with poly-d-glutamic or polyaspartic acids and with Glu(x) (x = 1-4). These studies indicated a specific blocking of uptake by Glu(5) sequences in the kidneys. Application of polyglutamic acids is a new, successful method of reducing uptake of negatively charged peptides in the kidneys during radiopeptide therapy.
    Journal of Nuclear Medicine 07/2005; 46(6):1012-5. · 5.56 Impact Factor
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    ABSTRACT: The development of monofunctional DTPA derivatives has been a major breakthrough in the labelling of proteins or peptides with a variety of radiometals. Although this methodology is simple and useful for indium-111 labelling, the stability of these conjugates is too low for most therapeutic nuclides. Cyclic chelators, such as DOTA, have shown excellent kinetic stability with a variety of radiometals, but the labelling procedure is more difficult, requiring ultra-pure reagents and a heating step that sometimes endangers the biomolecule's integrity. The aim of this work was twofold: (a) to develop a novel, open chain chelator which can be easily labelled with various radiometals, displaying higher kinetic stability than monofunctional DTPA, and (b) to evaluate this chelator in vitro and in vivo when conjugated to a CCK-B receptor ligand as a detection modality for receptor-(over-)expressing tumours. DTPA derivatives of Leu(1)- and dGlu(1)-minigastrin were synthesised. All conjugates could be labelled with (111)In or (88/90)Y at high specific activities (8.5-44.4 GBq/micro mol) and with high radiochemical purity. Serum stability testing was performed, and the labelled conjugates were compared concerning their stability against DTPA challenge. The biodistribution of the radiolabelled Leu(1)- and dGlu(1)-minigastrin derivatives was studied in tumour-bearing nude mice, in one healthy human volunteer and in three patients with metastatic medullary thyroid carcinoma. The transchelation of all tested radiometals to serum proteins was significantly slower with the DTPA-Glu conjugates as compared with their Leu analogues (e.g. transchelation t(1/2) of DTPA- dGlu(1)-minigastrin vs its Leu(1) analogue at 37 degrees C in human serum for (111)In: 239 h vs 91 h; for (90)Y: 130 h vs 53 h). In animals, all labelled CCK-B receptor ligands showed fast and specific uptake in CCK-B-receptor-positive tissues, such as the stomach and tumour, as well as a fast renal clearance pattern. However, DTPA-Leu(1)-minigastrin showed higher background activity in the whole body and those organs known to accumulate the respective free radiometal (e.g. (88)Y-DTPA-Leu(1)-minigastrin had bone uptake of 22%ID/g as compared to only 1.2%ID/g with its dGlu(1) analogue). In humans, fast tumour and stomach uptake was observed for both (111)In-labelled compounds, but DTPA- dGlu(1)-minigastrin lacked the liver, spleen and bone marrow uptake observed with its Leu(1) analogue. In conclusion, anionic amino acid derivatives of DTPA may display improved metabolic stability as compared with monofunctional DTPA conjugates. DTPA- dGlu(1)-minigastrin is preferred to "monofunctional" DTPA-Leu(1)-minigastrin for diagnostic application with (111)In for the in vivo detection of CCK-B receptor-expressing tissues.
    European journal of nuclear medicine and molecular imaging 09/2003; 30(8):1140-6. DOI:10.1007/s00259-003-1178-1 · 5.22 Impact Factor
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    ABSTRACT: Nuclear medicine (scintigraphy) studies that are performed in patients being prepared for regular dialysis treatment include the measurement of renal clearance and dynamic studies of renal perfusion and function. Static scintigraphy with 99mTc-DMSA may be used in the evaluation of children at risk of renal damage and further functional deterioration. In patients on peritoneal dialysis, nuclear medicine procedures enable the diagnosis of structural complications such as intra-abdominal herniations and leaks. Diagnosis of infections of the vascular access sites in patients on hemodialysis and of the catheter tunnel in patients on peritoneal dialysis can be made with high diagnostic accuracy using radiolabeled, autologous leukocytes. Scintigraphy is valuable in delineating the extent of deposits of amyloid and parenchymal microcalcifications, and may be helpful in the functional evaluation of organs and tissues involved in the pathophysiology of renal impairment and dialysis. If radioiodine therapy with 131I is performed in patients on hemodialysis with benign or malignant thyroid disease, then pretherapeutic dosimetry is necessary to avoid over- and undertreatment. Radioiodine therapy in the dialysis patient leads to only insignificant contamination of dialysis equipment and marginal exposure to the medical staff.
    Seminars in Dialysis 07/2002; 15(4):269-76. DOI:10.1046/j.1525-139X.2002.00069.x · 2.07 Impact Factor
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    ABSTRACT: CD20 has been used successfully as a target molecule for conventional low-dose, as well as high-dose, myeloablative radioimmunotherapy (RIT) of B-cell non-Hodgkin lymphoma (NHL). Mantle cell lymphoma (MCL) is an especially aggressive, prognostically unfavorable subtype of B-cell NHL, associated with an overall 5-year survival rate of less than 20%. Recent evidence has failed to show convincing therapeutic efficacy of conventional, nonmyeloablative RIT in patients with MCL. The aim of this pilot study was to investigate whether high-dose, myeloablative RIT with the iodine-131 ((131)I)-labeled chimeric anti-CD20 antibody C2B8 (rituximab, obtained as Mabthera from Roche Pharma, Reinach, Switzerland) is therapeutically effective in MCL patients. A total of seven patients with chemorefractory or relapsed MCL were studied in this pilot trial. All had relapsed after high-dose chemotherapy with autologous stem cell transplantation (four of them combined with 12 grays (Gy) total-body irradiation). A diagnostic-dosimetric study was performed with approximately 10 mCi of (131)I-labeled C2B8 at a protein dose of 2.5 mg per kg body weight, in order to assess its biodistribution and dosimetry. If splenic pooling was observed, as is typically the case in patients with splenomegaly, the protein dose was doubled in additional studies until a "favorable" biodistribution was obtained. Therapy was performed with myeloablative doses of 261-495 mCi of (131)I-labeled C2B8 at the previously optimized protein dose, aiming at lung doses less-than-or-equal 27 Gy. Homologous stem cell support was provided. Clinical follow-up was obtained at 3-month intervals for up to 38 months (median observation time, 25 months). Overall, in six patients the 2.5 mg/kg protein dose was used, whereas in one patient with splenomegaly, 10 mg/kg was necessary to overcome the splenic antigenic sink. Blood cell nadirs were reached at 2-3 weeks after therapy infusion, but all patients reengrafted at 7-10 days after stem cell reinfusion. Nonhematologic toxicity was restricted to mild-to-moderate nausea, fever, transient bilirubin, or liver enzyme elevations. One patient with preexisting alcoholic cirrhosis experienced a deterioration of liver function. Despite thyroid blocking, 5 of 7 patients developed hypothyroidism, requiring thyroxine substitution at 6-18 months after RIT. Six patients experienced a complete and one a good partial remission. Five patients were still in CR at the time this article was written, and six are still alive for more than 3 years; one patient relapsed locally at 3 months and one systemically at 26 months after RIT. High-dose myeloablative radioimmunotherapy with (131)I-labeled anti-CD20 antibodies seems to be associated with a high response rate and moderate toxicity in patients with MCL. Further follow-up to monitor the long-term outcome as well as systematic prospective clinical studies are indicated.
    Cancer 03/2002; 94(4 Suppl):1363-72. · 4.90 Impact Factor
  • European journal of nuclear medicine and molecular imaging 03/2002; 29(2):277-9. · 5.22 Impact Factor
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    ABSTRACT: BACKGROUND Whereas radioimmunotherapy (RIT) has shown disappointing results in bulky, solid tumors, preclinical results in small-volume disease and in an adjuvant setting are promising. In a previous Phase I study, the authors had encouraging results with the iodine-131 (131I)–labeled humanized anti–carcinoembryonic antigen (anti-CEA) antibody (MAb) hMN-14 in small-volume disease of colorectal cancer. The aim of this study was to evaluate, in a subsequent Phase II trial, the therapeutic efficacy of this 131I-labeled humanized anti-CEA antibody in colorectal cancer patients with small-volume disease or in an adjuvant setting.METHODS Thirty colorectal cancer patients, with small-volume metastatic disease (n = 21; all lesions ≤ 3.0 cm, and chemorefractory to 5-fluorouracil and folinic acid) or in an adjuvant setting (n = 9), 4–6 weeks after surgical resection of liver metastases with curative intention, were studied. The patients were given a single injection of 131I-hMN-14 immunoglobulin G at a 60 mCi/m2 dose level, which was shown to be the maximum tolerated dose in the previous Phase I study. Follow-up was obtained at 3-month intervals for as long as 36 months.RESULTSAt a mean blood-based red marrow dose of 1.8 ± 0.8 Gy, myelotoxicity was the only toxicity observed, but only 1 of 28 assessable patients developed transient Grade 4 thrombocytopenia. Of the 21 patients with radiologically documented lesions, 19 were assessable. Three experienced partial remission and eight showed minor responses up to 15 months in duration (corresponding to an objective response rate of 16% and an overall response rate of 58%; the mean duration of response was 9 months). At the time this article was written, seven of nine patients in the adjuvant setting had remained free of disease for up to 36 months (one patient relapsed after 6 months and another after 30 months), whereas the relapse rate in a historical control group receiving chemotherapy was 67% over the same time period. Five patients with radiologically documented lesions, having experienced at least disease stabilization as a consequence of RIT, were retreated at the same 60-mCi/m2 dose level at 8–16 months after the first therapy. No evidence of increased toxicity was observed (no hematologic toxicity was higher than Grade 3). Two of four assessable retreated patients experienced partial remissions; one of these four again experienced disease stabilization as a consequence of the second radioantibody therapy injection.CONCLUSIONS These data suggest that RIT is a safe and effective form of therapy for small-volume colorectal cancer and has potential as treatment for colorectal cancer in an adjuvant setting. Toxicity is restricted to mild and transient leuko- and thrombocytopenia. Retreatment seems to be a feasible option. A prospective randomized comparison with standard chemotherapy is indicated. Cancer 2002;94:1373–81. © 2002 American Cancer Society.DOI 10.1002/cncr.10308
    Cancer 02/2002; 94(S4):1373 - 1381. DOI:10.1002/cncr.10308 · 4.90 Impact Factor
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    Johannes Meller, C O Sahlman, Wolfgang Becker
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    ABSTRACT: Since 1942, therapy with radioiodine (RIT) has gained a major role in the treatment of benign thyroid disorders, notably hyperthyroidism caused by Graves' disease or toxic multinodular goitre (thyroid autonomy). In iodine deficient areas thyroid autonomy accounts for 40-50% of all cases with hyperthyroidism. RIT has become a cost-effective first-line procedure in autonomy-patients with latent or overt hyperthyroidism, especially in the absence of a large goitre, after thyroid surgery and in elderly patients with associated conditions who carry a high intra- or perioperative risk. Decisions concerning the definitive treatment of thyroid autonomy should take into account previous episodes of hyperthyroidism, objective parameters of risk stratification in euthyroid patients as well as concomitant diseases and the probability of iodine exposure in the future. In Central Europe the majority of investigators prefer to estimate the therapeutic activity individually by a radioiodine test. TCTUs (global 99m-Tc-pertechnetate thyroid uptake under suppression)-based dose concepts have been proven to be highly effective in the elimination of autonomy and carry a low (< 10%) risk of post-radioiodine-therapeutic hypothyroidism. Radioiodine therapy for autonomy has been found to be both effective and safe and without major early or late side effects. The most frequent complication is hypothyroidism requiring lifelong follow-up.
    Nuclear medicine review. Central & Eastern Europe: journal of Bulgarian, Czech, Macedonian, Polish, Romanian, Russian, Slovak, Yugoslav societies of nuclear medicine and Ukrainian Society of Radiology 01/2002; 5(1):1-10.
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    Johannes Meller, Wolfgang Becker
    06/2001;
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    ABSTRACT: Derivatives of somatostatin (sms) are attracting increasing interest as part of the treatment of several cancer diseases expressing sms receptors (srs). Radiolabeled sms analogs can additionally be used for systemic radiotherapy and for diagnostic investigations. Glycosylated sms-14 (sms-dextran70) was characterized regarding in vitro srs binding, biodistribution, and blood half-life in mice. Rat brain cortex membranes (expressing srs 2) were used for the srs binding study. Tyr3-Octreotide was used as positive control. The binding data were analyzed by competition curve analysis. In the biodistribution study, the Bolton-Hunter reagent was used for the radioiodination of sms-dextran70. Organs and blood were collected at different time-points and the percentage of the injected dose per gram of tissue (%ID/g) was calculated. The conjugate was administered subcutaneously (sc). The sms-dextran70 showed high srs binding affinity (i.e., in the same nanomolar range as the reference ligand Tyr3-octreotide (IC50 approximately 2.5 nM). The blood half-life was approx 27 h after reaching maximum blood concentration 24 h postinjection. Because of the molecular weight of the conjugate (i.e., approx 75,000) being above the kidney threshold for dextran (i.e., 50,000), the digestion and excretion is assumed to be mainly through the hepatobiliary system. Increased uptake was seen in the adrenals, which are receptor-positive organs. Some accumulation was seen in the stomach, indicating certain deiodination of the conjugate label. The sms-dextran70 showed promising properties and its clinical relevance is currently being evaluated in clinical phase I-II studies.
    Medical Oncology 02/2001; 18(1):59-64. DOI:10.1385/MO:18:1:59 · 2.06 Impact Factor
  • Johannes Meller, Wolfgang Becker
    1st edited by Stoppe G, Hentschel F, Munz DL, 06/2000; Thieme.
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    ABSTRACT: Recent studies suggest a higher anti-tumour efficacy of internalizing monoclonal antibodies (MAbs) when labelled with Auger electron emitters, as compared with β-emitters. The aim of this study was to compare the anti-tumour efficacy and toxicity of the internalizing MAb, CO17-1A, labelled with Auger electron emitters (125I, 111In) versus conventional β–-emitters (131I, 90Y) in a colon cancer model, and to assess whether the residualizing radiometals may have therapeutic advantages over the conventionally iodinated conjugates. Biodistribution studies of 125I-, 111In- or 88Y-labelled CO17-1A were performed in nude mice bearing subcutaneous human colon cancer xenografts. For therapy, the mice were injected with either unlabelled or 125I-, 131I-, 111In- or 90Y-labelled CO17-1A IgG2a, whereas control groups were left untreated or were given a radiolabelled isotype-matched irrelevant antibody. The influence of internalization was assessed by comparing the results with those obtained with an anti-carcinoembryonic antigen (CEA) antibody which does not internalize to a relevant extent. The maximum tolerated activities (MTA) and doses (MTD) of each agent were determined. Myelotoxicity and potential second-organ toxicities, as well as tumour growth, were monitored. Bone marrow transplantation (BMT) was performed in order to enable dose intensification. Radiometals showed significantly better tumour-to-blood ratios than the respective iodinated conjugates. The MTAs of 131I- and 125I-CO17-1A without artificial support were 11.1 MBq (300 µCi) and 111 MBq (3 mCi), respectively; the MTA of the metals was reached at 4 MBq (100 µCi) for 90Y-, and at 85 MBq (2.3 mCi) for 111In-CO17-1A. Myelotoxicity was dose limiting in all cases. BMT enabled an increase in the MTA to 15 MBq (400 µCi) of 131I-labelled CO17-1A, to 4.4 MBq (120 µCi) of 90Y-labelled CO17-1A, and to 118 MBq (3.2 mCi) of 111In-labelled CO17-1A, while the MTA of 125I-CO17-1A had not been reached at 185 MBq (5 mCi) with BMT. Whereas no significant therapeutic effects were seen with unlabelled CO17-1A, tumour growth was retarded significantly with its radiolabelled forms. The therapeutic results were significantly (P<0.01) better with both Auger electron emitters (125I and 111In) than with the β-emitters, and, in accordance with the biodistribution data, a trend towards better therapeutic results was found with radiometals (more complete remissions) as compared with radioiodine. In contrast, at equitoxic doses, no significant difference was observed in the therapeutic efficacy of 131I- versus 125I-labelled non-internalizing anti-CEA antibody, F023C5. These data suggest that, at equitoxic doses, the therapeutic efficacy of internalizing MAbs labelled with Auger electron emitters, such as 125I or 111In, is superior to that of internalizing MAbs labelled with conventional β-emitters. The lower toxicity of Auger electron emitters may be due to the short path length of their low-energy electrons, which can reach the nuclear DNA only if the antibody is internalized (as is the case in antigen-expressing tumour tissue, but not in the stem cells of the red marrow).
    European journal of nuclear medicine and molecular imaging 05/2000; 27(7):753-765. DOI:10.1007/s002590000272 · 5.22 Impact Factor
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    ABSTRACT: To assess the involvement of the contralateral knee joint in monarticular antigen-induced arthritis (AIA) by scintigraphy with the cationic (pI >10), 123I-labeled, serine proteinase inhibitor antileukoproteinase (123I-ALP) and to compare the scintigraphic findings with those of radiography and high-resolution ex vivo magnetic resonance imaging (MRI). Lewis rats with chronic AIA were examined 2.5 months following arthritis induction (injection of 500 microg of methylated bovine serum albumin/saline into the ipsilateral [arthritic] knee joint and injection of phosphate buffered saline into the contralateral knee joint following systemic immunization). 123I-ALP was injected intravenously into normal rats (n = 4) or rats with AIA (n = 6). The ipsilateral and contralateral knee joints and both ankles were examined by scintigraphy and radiography. Joint cartilage was examined by high-resolution ex vivo MRI, histopathology, and measurement of tissue radioactivity. ALP accumulation (typically observed in normal articular cartilage) was lost in both the ipsilateral and the contralateral knee joints, but not in the clinically unaffected ankles of rats with AIA. In both knee joints, 123I-ALP target:background ratios and cartilage radioactivity correlated negatively with the loss of toluidine blue staining in cartilage, which documents the depletion of charged matrix molecules. Findings of histopathology confirmed mild alterations in the ipsilateral knee joint and even milder alterations in the contralateral knee joint, while the ankles were normal. Radiography and high-resolution ex vivo MRI failed to detect abnormalities in the contralateral knee joint. Loss of ALP accumulation appears to document proteoglycan depletion, even in the microscopically altered cartilage of the contralateral knee joint in AIA. These findings underscore the high sensitivity of 123I-ALP for in vivo detection of biochemical cartilage alterations in arthritis, and furthermore, question the use of the contralateral knee joint as a normal control in AIA.
    Arthritis & Rheumatology 01/2000; 43(2):298-310. DOI:10.1002/1529-0131(200002)43:2<298::AID-ANR9>3.0.CO;2-G · 7.87 Impact Factor
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    ABSTRACT: Imaging of cartilage alterations was attempted in joints of rats with chronic antigen-induced arthritis (AIA) using the cationic 123I-labeled serine proteinase inhibitor antileukoproteinase (123I-ALP; pI > 10), which selectively accumulates in normal cartilage, presumably through interaction with negatively charged proteoglycans. Iodine-123-ALP or 123I-myoglobin, a control protein of comparable size but with different isoelectric point (pI=7.3) was injected intravenously into normal or AIA rats. Joint accumulation was followed by scintigraphy for 14 hr. Tissue radioactivity was assessed by well-counter measurements after dissection. The content of charged molecules in articular cartilage was determined by toluidine blue staining; the degree of joint destruction was assessed in parallel by x-ray, ex vivo MRI and histopathology. In intact articular cartilage, ALP accumulated to a significantly higher degree than myoglobin. This preferential accumulation was lost in rats with chronic AIA. The target-to-background ratio for 123I-ALP negatively correlated with the loss of toluidine blue staining in cartilage, which documents depletion of charged matrix molecules (r=-0.92, p < 0.01 at 4 hr; r=-0.97, p < 0.01 at 13 hr). ALP scintigraphy was sensitive in detecting cartilage alterations, even though the degree of joint destruction and inflammatory infiltration was mild, as demonstrated by x-ray, MRI and histopathology. In rat AIA, loss of ALP accumulation appears to document proteoglycan depletion in mildly altered arthritic cartilage. ALP scintigraphy may represent a functional assay for early, premorphological cartilage alterations in human arthritis as well.
    Journal of Nuclear Medicine 10/1998; 39(9):1638-45. · 5.56 Impact Factor
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    ABSTRACT: The aim of our study was to evaluate the clinical value of immunoscintigraphy with the monoclonal antibody 99mTc-BW 250/183 in patients with fever of unknown origin (FUO). The antibody BW 250/183 is an immunoglobulin G1 subtype that binds to the antigen NCA-95, which is expressed on the cell membrane surface of granulocytes. We studied 51 patients who were referred with the diagnosis of FUO. Thirty-five percent of the patients suffered from infection, 17% had autoimmune diseases, 14% had neoplasms and 8% had other diseases. The remaining 28% of the patients did not have a diagnosis. Planar imaging was performed in all patients, and 19 patients underwent SPECT. In our analysis, both cold and hot spots were considered diagnostic. Pyogenic infections were visualized correctly in 13 foci. The diagnosis of endocarditis (n = 4) could be determined only by SPECT. False-negative results were found in 4 patients and false-positive uptake was seen in 2 patients. No false-positive uptake or cold spots in the central bone marrow were found in patients with viral, granulomatous and autoimmune diseases or in those patients in whom no FUO cause was found in a 6-mo follow-up. In these patients, a negative scan did not change their diagnostic work-up. Cold spots in the central bone marrow were correctly interpreted in 5 of 6 patients. Sensitivity in detecting pyogenic foci was 73% and specificity was 97%. Positive and negative predictive values were 93% and 87%, respectively. Including areas of decreased uptake in the analysis, sensitivity for detecting an underlying inflammatory or malignant process for FUO was 81 % and specificity was 87%. Positive and negative predictive values were 81% and 87%, respectively. Immunoscintigraphy with 99mTc-BW 250/183 in patients with FUO has clinical potential for the diagnosis and exclusion of pyogenic causes of FUO. Metastatic malignant disease and high-grade spondylodiskitis could be diagnosed early in a diagnostic work-up by a characteristic cold spot pattern in the bone marrow. SPECT is indispensible for scintigraphic imaging of endocarditis.
    Journal of Nuclear Medicine 08/1998; 39(7):1248-53. · 5.56 Impact Factor
  • International Journal of Cancer 05/1998; 76(5):738-748. DOI:10.1002/(SICI)1097-0215(19980529)76:53.3.CO;2-Q · 5.01 Impact Factor
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    ABSTRACT: Elevated renal uptake and prolonged retention of radiolabeled antibody fragments and peptides is a problem in the therapeutic application of such agents. Over recent years, one of the focuses of research has therefore been to develop suitable methods to reduce this renal uptake, and to evaluate whether the resulting methodology will benefit therapy with antibody fragments and peptides. In these studies it has been shown that the kidney uptake of antibody fragments in animals can be reduced in a dose-dependent manner by almost one order of magnitude by the systemic administration of cationic amino acids and their derivatives, whereas the uptake in all other organs, as well as the tumor, remains unaffected. A similar reduction in renal retention is achieved for all intracellularly retained radionuclides (e.g., radiometals) or radioiodinated immunoconjugates, as well as for smaller peptides. Lysine is usually the preferred agent, and its d- and l-isomers are equally effective whether given intraperitoneally or orally. Amino sugars are effective, but their N-acetyl derivatives, lacking the positive charge, are not. Basic polypeptides are also effective, and their potency increases with increasing molecular weight (i.e., the amount of positive charges per molecule). Urine analysis of treated individuals shows the excretion of unmetabolized, intact fragments or peptides, in contrast to mostly low-molecular-weight metabolites in untreated controls. In therapy studies using radiometal-conjugated Fab fragments, the kidney is the first dose-limiting organ. Administration of cationic amino acids results in a substantial increase in the maximum tolerated dose of such Fab fragments. No biochemical or histological evidence of renal damage has been observed under these conditions. As was the case in animal studies, in pilot clinical trials the renal uptake in patients injected with Fab′ fragments and given amino acids could be decreased significantly, whereas the uptake by all other organs remained unaffected. These recent studies indicate that a variety of basic compounds are capable of inhibiting the tubular reabsorption of peptides and proteins, thus significantly lowering the renal uptake of antibody fragments or peptides in both animals and patients. On a molecular basis, the effect seems to rely essentially on the presence of a positively charged amino group. Thus, radiation nephrotoxicity of antibody fragments and peptides can be overcome successfully; this may provide new prospects for cancer therapy with radiolabeled antibody fragments and peptides.
    European journal of nuclear medicine and molecular imaging 01/1998; 25(2):201-212. DOI:10.1007/s002590050216 · 5.22 Impact Factor
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    ABSTRACT: The outstanding sensitivity of pentagastrin in detecting the presence of primary, recurrent or metastatic medullary thyroid cancer (MTC) suggests widespread expression of the corresponding receptor type in human MTC. Indeed, recent autoradiographic studies have demonstrated the presence of cholecystokinin (CCK)-B (= gastrin) receptors not only in more than 90% of MTCs but also in a high percentage of small cell lung cancers, stromal ovarian cancers, astrocytomas and several other tumour types. The aim of this study was to evaluate whether radiolabelled gastrin may be suitable for targeting CCK-B receptor-expressing tumours in vivo. For this purpose, the biodistribution of the radioiodinated human heptadecapeptide gastrin-I was studied in nude mice bearing subcutaneous xenografts of the human MTC cell line, TT. Initial therapy experiments were undertaken. Finally, the biodistribution of iodine-131- labelled gastrin-I was studied in a patient with metastatic MTC. At a peptide amount of approximately 1μg, maximum tumour uptake (8.9±2.9%ID/g) was observed in animals at 1h post injection, with tumour-to-blood ratios as high as 6.3±1.9. Physiological CCK-B receptors in the stomach, gallbladder and pancreas of the mice were targeted as well. The major route of excretion was renal, but strong evidence for a biliary excretion pathway also exists. Pilot therapy studies with 131I-labelled gastrin showed significant anti-tumour efficacy as compared with untreated controls. In accordance with the preclinical data, good receptor targeting was observed in the tumour sites, stomach, gallbladder and pancreas of a patient with metastatic MTC. These data suggest that gastrin and its analogues may represent a useful new class of receptor binding peptides for diagnosis and therapy of a variety of tumour types, including MTC and small cell lung cancer. Future preclinical and clinical studies will address in more detail the molecular features that render CCK-B receptor binding agents potentially useful candidates for in vivo scintigraphy and radionuclide therapy.
    European journal of nuclear medicine and molecular imaging 01/1998; 25(4):424-430. DOI:10.1007/s002590050241 · 5.22 Impact Factor
  • Klinische Pädiatrie 01/1998; 210(05):373-378. DOI:10.1055/s-2008-1043907 · 1.90 Impact Factor
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    ABSTRACT: Whereas bivalent fragments have been widely used for radio-immunotherapy, no systematic study has been published on the therapeutic performance of monovalent conjugates in vivo. The aim of our study was, therefore, to determine the therapeutic performance of 131I-labeled Fab as compared to bivalent conjugates and to analyze factors that influence dose-limiting organ toxicity and anti-tumor efficacy. The maximum tolerated doses (MTDs) and dose-limiting organ toxicities of the 131I-labeled anti-CEA antibody MN-14 [IgG, F(ab′)2 and Fab] were determined in nude mice bearing s.c. human colon cancer xenografts. Mice were treated with or without bone marrow transplantation (BMT) or inhibition of the renal accretion of antibody fragments by D-lysine or combinations thereof. Toxicity and tumor growth were monitored. Radiation dosimetry was calculated from biodistribution data. With all 3 131I-labeled immunoconjugates [IgG, F(ab′)2 and Fab], the red marrow was the only dose-limiting organ; MTDs were 260 μCi for IgG, 1,200 μCi for F(ab′)2 and 3 mCi for Fab, corresponding to blood doses of 17 Gy, 9 Gy and 4 Gy, respectively. However, initial dose rates were 10 times higher with Fab as compared to IgG and 3 times higher as compared to F(ab′)2. The MTD of all 3 immunoconjugates was increased by BMT by approximately 30%. In accordance with renal doses below 10 Gy, no signs of nephrotoxicity were observed. Despite lower absorbed tumor doses, at equitoxic dosing, Fab fragments were more effective at controlling tumor growth than the respective bivalent fragment or IgG, probably due to higher intratumoral dose rates. Our data indicate that the improved anti-tumor effectiveness of antibody fragments as compared to IgG and the higher myelotoxicity at comparably lower red marrow doses are most likely due to the higher initial dose rates observed with antibody fragments. Int. J. Cancer 77:787–795, 1998. © 1998 Wiley-Liss, Inc.
    International Journal of Cancer 01/1998; 77(5):787 - 795. DOI:10.1002/(SICI)1097-0215(19980831)77:5<787::AID-IJC19>3.0.CO;2-Z · 5.01 Impact Factor
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    ABSTRACT: BACKGROUND Elevated renal uptake and extended retention of radiolabeled antibody fragments and peptides is a problem in the therapeutic application of such agents. However, cationic amino acids have been shown to reduce renal accretion. The aims of the current study were to evaluate whether this methodology would benefit therapy with yttrium 90 (90Y)-labeled antibody fragments (Fab, F(ab)2), to establish the relationship between radiation dosimetry and observed biologic effects, and to compare the antitumor efficacy of antibody fragments with that of whole immunoglobulin (Ig)G.METHODS The maximum tolerated dose (MTD) and the dose-limiting organ toxicity of 90Y-labeled anti-carcinoembryonic antigen (CEA) MN-14 monoclonal antibodies (Fab, F(ab)2, and IgG) were determined in nude mice bearing GW-39 human colon carcinoma xenografts. The mice were treated with or without kidney protection by administration of D-lysine, with or without bone marrow transplantation (BMT), or with combinations of each. Toxicity and tumor growth were monitored at weekly intervals after radioimmunotherapy. Dosimetry was calculated from biodistribution studies using 88Y-labeled antibody. Three different dosimetric models were examined: 1) taking solely self-to-self doses into account, using S factors for 90Y in spheroids from 0.1 to 1 g; 2) correcting for cross-organ radiation; and 3) using actual mouse anatomy as represented by nuclear magnetic resonance imaging with a three-dimensional internal dosimetry package (3D-ID).RESULTSThe kidney was the first dose-limiting organ with the use of Fab fragments. Acute radiation nephritis occurred at injected activities ≥325 μCi, and chronic nephrosis at doses ≥250 μCi. Activities of 200 μCi were tolerated by 100% of the animals (i.e., the MTD). Application of lysine decreased the renal dose by approximately fivefold, facilitating a 25% increase in the MTD (to 250 μCi), because myelotoxicity became dose-limiting despite red marrow doses of less than 5 gray (Gy). By using BMT and lysine, the MTD could be doubled from 200 to 400 μCi, where no biochemical or histologic evidence of renal damage was observed (kidney dose, ≤40 Gy). With injected activities of ≥325 μCi without kidney protection, and with a hepatic self-to-self dose of only 4 Gy, rising liver enzymes were observed, which could be explained only by cross-organ radiation from radioactivity in the kidneys (in the immediate neighborhood of the right kidney up to ≥150 Gy). The MTD of F(ab)2 fragments could be elevated only by a combination of BMT and lysine. With IgG, the bone marrow alone was dose-limiting. Tumor dosimetry correlated well with antitumor effects; Fab was more effective than F(ab)2, which was consistent with its more favorable dosimetry, and it may also be more effective than IgG due to its higher dose rate and more homogenous distribution. Dosimetry Model 1 was insufficient for predicting biologic effects. Model 2 seemed to be more accurate, accounting for interorgan crossfire. However, Model 3 showed an additional substantial contribution to the red bone marrow dose due to crossfire from the abdominal organs.CONCLUSIONS These data show that radiation nephrotoxicity is an important effect of cancer therapy with radiometal-conjugated antibody fragments or peptides. However, this effect can be overcome successfully with the application of cationic amino acids, which substantially increase the anti-tumor efficacy of radiometal-labeled immunoconjugates. For understanding the biologic effects (e.g., liver toxicity) of 90Y in a mouse model, accounting for cross-organ radiation is essential. Further studies with radiometal-conjugated monoclonal antibody fragments and peptides are necessary to determine the MTD, dose-limiting organs, antitumor effectiveness, and nephroprotective effects of cationic amino acids in humans. Cancer 1997; 80:2591-610. © 1997 American Cancer Society.
    Cancer 12/1997; 80(S12):2591 - 2610. DOI:10.1002/(SICI)1097-0142(19971215)80:12+<2591::AID-CNCR35>3.0.CO;2-5 · 4.90 Impact Factor

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Institutions

  • 1997–2005
    • Georg-August-Universität Göttingen
      Göttingen, Lower Saxony, Germany
  • 1992–1997
    • Friedrich-Alexander Universität Erlangen-Nürnberg
      • Department of Nuclear Medicine
      Erlangen, Bavaria, Germany
  • 1996
    • Universitätsklinikum Erlangen
      • Department of Nuclear Medicine
      Erlangen, Bavaria, Germany