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Claude F. Meares - One of the best experts on this subject based on the ideXlab platform.

  • Are radiometal-labeled antibodies better than iodine-131-labeled antibodies: comparative pharmacokinetics and dosimetry of Copper-67-, iodine-131-, and yttrium-90-labeled Lym-1 antibody in patients with non-Hodgkin's lymphoma.
    Clinical lymphoma, 2000
    Co-Authors: Gerald L. Denardo, Claude F. Meares, Sally J Denardo, Robert T. O'donnell, Linda A. Kroger, David L. Kukis, Desiree S. Goldstein, Sui Shen
    Abstract:

    Abstract Radioimmunotherapy using radiolabeled monoclonal antibodies against tumor-associated antigens has been efficacious, particularly in the treatment of radiosensitive malignancies such as lymphoma. Antilymphoma monoclonal antibody Lym-1, labeled with Copper-67 ( 67 Cu), iodine-131 ( 131 I), or yttrium-90 ( 90 Y), has been effective salvage therapy for patients with non-Hodgkin's lymphoma. Although 131 I has had the dominant role in radioimmunotherapy thus far, several properties of radiometals are preferable. A total of 70 patients with B-lymphocytic non-Hodgkin's lymphoma were studied using 67 Cu-2IT-BAT-Lym-1, 131 I-Lym-1, or 111 In-2IT-BAD-Lym-1. Because 90 Y does not have good emissions for imaging, indium-111 ( 111 In), its analogue, was used as a surrogate to estimate 90 Y-2IT-BAD-Lym- 1 pharmacokinetics and radiation dosimetry. Subsets of four patients in each group received 67 Cu- and 131 I-labeled Lym-1 or 111 In- and 131 I-labeled Lym-1, allowing direct comparisons of the radioimmunoconjugates. Sequential blood samples and planar images were used to quantitate radioimmunoconjugate in tissues in order to determine pharmacokinetics and radiation dosimetry. 67 Cu-2IT-BAT-Lym-1 and 90 Y-2IT-BAD-Lym-1 exhibited higher cumulated activity concentrations and radiation absorbed doses per unit of administered radioactivity for tumors than did 131 I-Lym-1. The mean tumor cumulated activity (area under the time-activity curve) concentrations per unit of administered radioactivity for 67 Cu-2IT-BAT-Lym-1, 131 I-Lym-1, and 90 Y-2IT-BAD-Lym-1 were 96.89, 33.96, and 43.42 GBq-s/GBq/g, respectively. The mean tumor radiation doses from 67 Cu-2IT-BAT-Lym-1, 131 I-Lym-1, and 90 Y-2IT-BAD-Lym-1 were 2.5, 1.0, and 6.6 Gy/GBq, respectively, because 90 Y deposits more radiation per unit of administered radioactivity. Per unit of administered radioactivity, radiation doses from 67 Cu-2IT-BAT-Lym-1 and 131 I-Lym-1 to normal tissues were similar except that the liver received a higher dose from 67 Cu-2IT-BAT-Lym-1 than from 131 I-Lym-1; radiation doses to normal tissues from 90 Y-2IT-BAD-Lym-1 were generally higher. Consequently, the therapeutic indices (ratio of radiation doses to tumor and normal tissues) for 67 Cu-2IT-BAT-Lym-1, and less generally for 90 Y- 2IT-BAD-Lym-1, were more favorable when compared to those for 131 I-Lym-1. Data from the matched subsets of patients showed similar therapeutic indices to those for the groups of patients. 67 Cu-2IT-BAT-Lym-1 showed more potential than 131 I-Lym-1 or 90 Y-2IT-BADLym- 1 for non-Hodgkin's lymphoma radioimmunotherapy

  • Improved synthesis of 6-[p-(bromoacetamido)benzyl]-1,4,8,11-tetraazacyclotetradecane-N,N′, N″,N‴-tetraacetic acid and development of a thin-layer assay for thiol-reactive bifunctional chelating agents
    Bioconjugate Chemistry, 1995
    Co-Authors: Justin K. Moran, Douglas P. Greiner, Claude F. Meares
    Abstract:

    Monoclonal antibodies labeled with radiometals such as Copper-67 have applications in radioimmunodiagnosis and radioimmunotherapy. Moi et al. [(1985) Anal. Biochem. 148, 249-253] showed that 6-[p-(bromoacetamido)benzyl]-1,4,8,11-tetraazacyclotetradecane- N,N',N",N"-tetraacetic acid (BAT) is an effective reagent for linking Copper to proteins, and antibodies labeled with Copper radionuclides are currently undergoing clinical trials. Here we describe improvements in the original synthesis that increase the overall yield of BAT to 23%. We also describe a new assay useful to determine the activity of bifunctional chelating agents with thiol-reactive functional groups.

  • Improved synthesis of 6-[p-(bromoacetamido)benzyl]-1,4,8,11-tetraazacyclotetradecane- N,N',N",N"-tetraacetic acid and development of a thin-layer assay for thiol-reactive bifunctional chelating agents.
    Bioconjugate chemistry, 1995
    Co-Authors: Justin K. Moran, Douglas P. Greiner, Claude F. Meares
    Abstract:

    Monoclonal antibodies labeled with radiometals such as Copper-67 have applications in radioimmunodiagnosis and radioimmunotherapy. Moi et al. [(1985) Anal. Biochem. 148, 249-253] showed that 6-[p-(bromoacetamido)benzyl]-1,4,8,11-tetraazacyclotetradecane- N,N',N",N"-tetraacetic acid (BAT) is an effective reagent for linking Copper to proteins, and antibodies labeled with Copper radionuclides are currently undergoing clinical trials. Here we describe improvements in the original synthesis that increase the overall yield of BAT to 23%. We also describe a new assay useful to determine the activity of bifunctional chelating agents with thiol-reactive functional groups.

  • A comparative study of Copper-67 radiolabeling and kinetic stabilities of antibody-macrocycle chelate conjugates
    Cancer, 1994
    Co-Authors: L B S David Kukis, Habibe Diril, Sally J Denardo, Gerald L. Denardo, Qansy Salako, P B S Douglas Greiner, Claude F. Meares
    Abstract:

    Background. The development of new chelating agents and radiolabeling protocols is essential to progress in radioimmunotherapy with antibody-chelate conjugates. Methods. Immunoconjugates of four polyazamacrocycles with N-bonded acetate groups were prepared by conjugation via 2-iminothiolane to Lym-1, a murine anti-lymphoma immunoglobulin G 2a MoAb. To optimize 67 Cu radiolabeling, complexation conditions were explored. The kinetic stabilities in vitro in human serum of four 67 Cu labeled immunoconjugates were investigated

  • A comparative study of Copper-67 radiolabeling and kinetic stabilities of antibody-macrocycle chelate conjugates.
    Cancer, 1994
    Co-Authors: D L Kukis, Habibe Diril, D P Greiner, S J Denardo, G L Denardo, Q A Salako, Claude F. Meares
    Abstract:

    The development of new chelating agents and radiolabeling protocols is essential to progress in radioimmunotherapy with antibody-chelate conjugates. Immunoconjugates of four polyazamacrocycles with N-bonded acetate groups were prepared by conjugation via 2-iminothiolane to Lym-1, a murine antilymphoma immunoglobulin G2a MoAb. To optimize 67Cu radiolabeling, complexation conditions were explored. The kinetic stabilities in vitro in human serum of four 67Cu labeled immunoconjugates were investigated. Lym-1-2IT-6-BAT-67Cu, the chelate conjugate of 6-[p-(bromoacetamido)benzyl]-1,4,8,11-tetraazacyclotetradecane- N,N',N''N'''-tetraacetic acid, exhibited excellent kinetic stability in human serum, while Lym-1-2IT-2-BAT-67Cu, prepared from the structural isomer 2-[p-(bromoacetamido)benzyl]-1,4,8,11- tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid, exhibited a markedly higher rate of loss of radiometal. It was observed that the radiolabeling ratio of Lym-1-2IT-6-BAT-67Cu, in mCi per mg immunoconjugate, was limited solely by the specific activity of the radiometal, which varied significantly from lot to lot. This ratio for a given lot of 67Cu can be predicted by a preliminary titration. The preparation of 67Cu labeled immunoconjugates of therapeutic quality has been improved by the determination of optimum radiolabeling conditions, and by development of a titration protocol which rapidly and accurately predicts the radiolabeling ratio in mCi per mg immunoconjugate. The surprising difference in the properties of 6-BAT and 2-BAT shows the exquisite dependence of kinetic stability on structure.

Paul S. Donnelly - One of the best experts on this subject based on the ideXlab platform.

  • Harnessing 64Cu/67Cu for a theranostic approach to pretargeted radioimmunotherapy.
    Proceedings of the National Academy of Sciences of the United States of America, 2020
    Co-Authors: Outi Keinanen, Ellen Van Dam, Nicholas Zia, Kimberly Fung, James M Brennan, Matthew P Harris, Colin Biggin, Amos Hedt, Jon Stoner, Paul S. Donnelly
    Abstract:

    Over the past decade, theranostic imaging has emerged as a powerful clinical tool in oncology for identifying patients likely to respond to targeted therapies and for monitoring the response of patients to treatment. Herein, we report a theranostic approach to pretargeted radioimmunotherapy (PRIT) based on a pair of radioisotopes of Copper: positron-emitting Copper-64 (64Cu, t1/2 = 12.7 h) and beta particle-emitting Copper-67 (67Cu, t1/2 = 61.8 h). This strategy is predicated on the in vivo ligation between a trans-cyclooctene (TCO)-bearing antibody and a tetrazine (Tz)-based radioligand via the rapid and bioorthogonal inverse electron-demand Diels–Alder reaction. Longitudinal therapy studies were conducted in a murine model of human colorectal carcinoma using an immunoconjugate of the huA33 antibody modified with TCO (huA33-TCO) and a 67Cu-labeled Tz radioligand ([67Cu]Cu-MeCOSar-Tz). The injection of huA33-TCO followed 72 h later by the administration of 18.5, 37.0, or 55.5 MBq of [67Cu]Cu-MeCOSar-Tz produced a dose-dependent therapeutic response, with the median survival time increasing from 68 d for the lowest dose to >200 d for the highest. Furthermore, we observed that mice that received the highest dose of [67Cu]Cu-MeCOSar-Tz in a fractionated manner exhibited improved hematological values without sacrificing therapeutic efficacy. Dual radionuclide experiments in which a single administration of huA33-TCO was followed by separate injections of [64Cu]Cu-MeCOSar-Tz and [67Cu]Cu-MeCOSar-Tz revealed that the positron emission tomography images produced by the former accurately predicted the efficacy of the latter. In these experiments, a correlation was observed between the tumoral uptake of [64Cu]Cu-MeCOSar-Tz and the subsequent therapeutic response to [67Cu]Cu-MeCOSar-Tz.

  • Therapeutic Efficacy of a Bivalent Inhibitor of Prostate-Specific Membrane Antigen Labeled with Copper-67.
    Journal of nuclear medicine : official publication Society of Nuclear Medicine, 2020
    Co-Authors: Lachlan E. Mcinnes, Carleen Cullinane, Peter Roselt, Sue Jackson, Benjamin Blyth, Ellen Van Dam, Nicholas A. Zia, Matthew Harris, Rodney J. Hicks, Paul S. Donnelly
    Abstract:

    Radionuclide therapy targeting prostate-specific membrane antigen (PSMA) is a promising treatment for prostate cancer. We reported a ligand featuring two lysine-ureido-glutamate groups, 64Cu-CuSarbisPSMA previously. Here, we report the therapeutic potential of 67Cu-CuSarbisPSMA. Methods: Growth of PSMA-positive xenografts was evaluated following treatment with 67Cu-CuSarbisPSMA or 177Lu-LuPSMA I&T. Results: At 13 days post-injection, tumor growth was similarly inhibited by the two tracers in a dose-dependent manner. Survival was comparable after single (30 MBq) or fractionated administrations (2 x 15MBq, two weeks apart). Conclusion:67Cu-CuSarbisPSMA is efficacious in a PSMA-expressing model of prostate cancer.

  • A Bivalent Inhibitor of Prostate Specific Membrane Antigen Radiolabeled with Copper‐64 with High Tumor Uptake and Retention
    Angewandte Chemie (International ed. in English), 2019
    Co-Authors: Nicholas Zia, Lachlan E. Mcinnes, Carleen Cullinane, Peter Roselt, Rodney J. Hicks, Jessica Van Zuylekom, Kelly Waldeck, Gojko Buncic, Mohammad B. Haskali, Paul S. Donnelly
    Abstract:

    Molecules containing lysine-ureido-glutamate functional groups bind to the active site of prostate specific membrane antigen, which is overexpressed in prostate cancer. To prepare Copper radiopharmaceuticals for the diagnosis and therapy of prostate cancer, macrobicyclic sarcophagine ligands tethered to either one or two lysine-ureido-glutamate functional groups through an appropriate linker have been prepared. Sarcophagine ligands can be readily radiolabeled with positron-emitting Copper-64 at room temperature. The bivalent agent, in which two targeting groups are tethered to a single Copper complex, dramatically outperforms the monomeric agent with respect to tumor uptake and retention. The high tumor uptake, low background, and prolonged tumor retention, even at 24 hours post injection, suggest the bivalent agent is a promising diagnostic for prostate cancer and could be used for prospective dosimetry for therapy with a Copper-67 variant.

Pius A. Schubiger - One of the best experts on this subject based on the ideXlab platform.

  • Targeting Superficial Bladder Cancer by the Intravesical Administration of Copper-67–Labeled Anti-MUC1 Mucin Monoclonal Antibody C595
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2000
    Co-Authors: Owen Hughes, Malcolm Frier, M.c. Bishop, Alan C. Perkins, M.l. Wastie, G. Denton, Michael R. Price, H. Denley, R. Rutherford, Pius A. Schubiger
    Abstract:

    PURPOSE: More effective intravesical agents are required to limit the recurrence and progression of superficial bladder cancer. This study assessed the ability of Copper-67 (67Cu)-C595 murine antimucin monoclonal antibody to bind selectively to superficial bladder tumors when administered intravesically, with a view to its development for therapy. PATIENTS AND METHODS: Approximately 20 MBq of 67Cu-C595 monoclonal antibody was administered intravesically to 16 patients with a clinical indication of superficial bladder cancer. After 1 hour, the bladder was drained and irrigated. Tissue uptake was assessed by imaging and by the assay of tumor and normal tissues obtained by endoscopic resection. RESULTS: Tumor was correctly identified in the images of 12 of 15 patients who were subsequently found to have tumors. Assay of biopsy samples at 2 hours showed a mean tumor uptake of 59.4% of the injected dose per kilogram (SD = 48.0), with a tumor-to-normal tissue ratio of 14.6:1 (SD = 20). After 24 hours (n = 5), t...

  • Comparison of Copper-67- and Iodine-125-Labeled Anti-CEA Monoclonal Antibody Biodistribution in Patients with Colorectal Tumors
    Journal of nuclear medicine : official publication Society of Nuclear Medicine, 1997
    Co-Authors: Angelika Bischof Delaloye, B. Delaloye, F. Buchegger, Charles-andré Vogel, Michel Gillet, Jean-pierre Mach, Smith A, Pius A. Schubiger
    Abstract:

    Copper-67 has comparable beta-particle emissions to that of 131I, but it displays more favorable gamma emission characteristics for application in radioimmunotherapy (RIT). This study investigates the potential of 67C-labeled monoclonal antibody (MAb) 35 for RIT of colorectal carcinoma. Methods: Biokinetics of simultaneously injected 67C- and 125I-labeled MAb35 were studied in six patients scheduled for surgery of primary colorectal cancer. Results: Whole-body clearance (T1/2)of 67C, estimated from sequential anterior and posterior whole-body scans and corrected for decay of 67C, was 41 hr. Serum clearance of 67C was faster (27.41 hr) than that of 125I(38.33 hr). Mean tumor uptake of the 67C-labeled compound (0.0133 %ID/g) exceeded that of 125I(0.0095 %ID/g), and tumor-to-blood ratios were higher for 67C than for 125I, with averages of 6.07 and 2.41, respectively. The average 67C/125I ratio was 1.9 for tumor uptake, 0.7 for blood and 2.6 for tumor-to-blood ratios. Nonspecific liver uptake of 67C as calculated from whole-body scans was high in four patients, up to 25% of residual whole-body activity at 48 hr, but did not increase with time. We also observed some nonspecific bowel activity, as well as moderate to high uptake in benign polyps. Conclusion: Copper-67-labeled MAb35 is more favorable than its radioiodine-labeled counterpart for RIT of colorectal carcinoma due to higher tumor-to-blood ratios, but the problem of nonspecific liver and bowel uptake must first be overcome. The absolute accumulation of activity in tumor remains low, however, so the probability of cure with this compound alone is questionable. The use of 67C as one component of a multimodality adjuvant treatment seems to remain the most appropriate application for RIT.

  • Preclinical evaluation of Copper-67 labelled anti-MUC1 mucin antibody C595 for therapeutic use in bladder cancer.
    European journal of nuclear medicine, 1997
    Co-Authors: Owen Hughes, Malcolm Frier, M.c. Bishop, Alan C. Perkins, G. Denton, Michael R. Price, R. Rutherford, A. Smith, Pius A. Schubiger
    Abstract:

    Transitional cell carcinoma of the bladder is the fifth commonest cause of death from cancer in men in the United Kingdom. Most patients present early with superficial disease, though with current treatment up to 20% progress to invasive disease, which has a poor prognosis. Better local treatments are required to limit this tumour progression. The ease of access to the bladder via a catheter provides the ideal opportunity for antibody (Ab) targeted therapy. We have previously shown that indium-111 labelled anti-MUCI mucin Ab C595 selectively localises to bladder tumours after intravesical administration. We have selected Copper-67 as an alternative radiolabel with suitable physical characteristics for radioimmunotherapy. This communication demonstrates that C595 can be reproducibly labelled with67Cu and that the radioimmunoconjugate is both stable and maintains high immunoreactivity. Pilot studies on cystectomy specimens in a novel ex vivo system and in one patient confirmed the ability of this conjugate to localise to tumour after intravesical administration. On the basis of these studies we are now in a position to study the intravesical administration of67Cu-labelled C595 in patients with bladder cancer with a view to a therapeutic trial.

  • Tumor Uptake and Metabolism of Copper-67-Labeled Monoclonal Antibody chCE7 in Nude Mice Bearing Neuroblastoma Xenografts
    Journal of nuclear medicine : official publication Society of Nuclear Medicine, 1997
    Co-Authors: Ilse Novak-hofer, Helmut R. Maecke, Kurt Zimmermann, Hanspeter Amstutz, François Carrel, Pius A. Schubiger
    Abstract:

    lysine adduci of the Copper complex. In vivo distributions in nude mice bearing neuroblastoma xenografts were studied and extracts from tumor and tissue samples were analyzed. Results: The intact MAb showed high tumor uptake, stable over 4 days postinjection (33.7% ±2.8% ID/g),with tumor/blood ratios increasing from 4.4 on Day 1 to 23.0 on Day 7 postinjection and low levels of radioactivity in other tissues. Analysis of tumor extracts by gel filtration chromatography and high-pressure liquid chromatography (HPLC)showed that over the period of 4 days radioactivity was present both in a high Mr form, consisting of the MAb/antigen complex, as well as in a low Mr form, consisting of the Copper complex attached to short peptides, including the lys-CPTA complex. There was no evidence of aggregates or MAb/antigen complexes in the blood, radioactivity being exclusively in the form of Intact MAb, and radioactivity in the liver was found to consist of intact MAb, MAb fragments and the lys-CPTA metabolite. In the case of the F(ab')2 fragments, high accumulation of radioactivity in the kidneys was observed and analysis of kidney extracts showed it to be due to rapid accumula tion of the lys-CPTA complex. When kidney uptake and retention of the CPTA complex as well as of Its lysine and glycine adducts was investigated, the lysine complex was taken up more strongly and retained longer in the kidneys than the other com pounds. Conclusion: Copper-67-labeled MAb chCE7 F(ab')2frag ments were prepared using a novel bifunctional Copper ligand 1-(p-aminobenzyl)-l ,4,7,10-tetraazacyclodecane-4,7,10-triacetate (DO3A). Compared with MAb-chCE7 F(ab')2 fragments labeled by the CPTA ligand, labels using the DO3A ligand showed improved biodistributions resulting, 48 hr postinjection, in a 4-fold increase in tumor uptake and a 4-fold reduction of radioactivity in the kidneys.

  • Copper-67 labeled mAb chCE7 as a potential therapeutic agent for neuroblastoma: improved biodistributions of Copper-67-chCE7 F(ab’)2
    Radioactive Isotopes in Clinical Medicine and Research, 1997
    Co-Authors: Ilse Novak-hofer, Helmut R. Maecke, Kurt Zimmermann, Hanspeter Amstutz, U. Doerr, H. Bihl, A. Haldemann, Pius A. Schubiger
    Abstract:

    Neuroblastoma relapses associated with bone marrow infiltrations are considered a favorable therapeutic setting for radioimmunotherapy (RIT), because access of radiolabeled, tumor specific monoclonal antibodies (mAbs) is much better than in solid tumors. MAb chCE7 is a chimeric antibody directed against a neuroblastoma associated cell surface glycoprotein, which is internalized into its target cells (1) and first clinical results with 123 I and 131 I-labeled chCE7 have shown that it is taken up rapidly and strongly into bone marrow infiltrations (2,3).We plan to evaluate mAb chCE7 for RIT applications in such cases.

Justin K. Moran - One of the best experts on this subject based on the ideXlab platform.

P A Schubiger - One of the best experts on this subject based on the ideXlab platform.

  • targeting superficial bladder cancer by the intravesical administration of Copper 67 labeled anti muc1 mucin monoclonal antibody c595
    Journal of Clinical Oncology, 2000
    Co-Authors: Owen Hughes, M.c. Bishop, Alan C. Perkins, M.l. Wastie, G. Denton, Michael R. Price, H. Denley, R. Rutherford, M Frier, P A Schubiger
    Abstract:

    PURPOSE: More effective intravesical agents are required to limit the recurrence and progression of superficial bladder cancer. This study assessed the ability of Copper-67 (67Cu)-C595 murine antimucin monoclonal antibody to bind selectively to superficial bladder tumors when administered intravesically, with a view to its development for therapy. PATIENTS AND METHODS: Approximately 20 MBq of 67Cu-C595 monoclonal antibody was administered intravesically to 16 patients with a clinical indication of superficial bladder cancer. After 1 hour, the bladder was drained and irrigated. Tissue uptake was assessed by imaging and by the assay of tumor and normal tissues obtained by endoscopic resection. RESULTS: Tumor was correctly identified in the images of 12 of 15 patients who were subsequently found to have tumors. Assay of biopsy samples at 2 hours showed a mean tumor uptake of 59.4% of the injected dose per kilogram (SD = 48.0), with a tumor-to-normal tissue ratio of 14.6:1 (SD = 20). After 24 hours (n = 5), t...

  • Preclinical evaluation of Copper-67 labelled anti-MUC1 mutin antibody C595 for therapeutic use in bladder cancer
    European Journal of Nuclear Medicine, 1997
    Co-Authors: O. D. M. Hughes, M.c. Bishop, G. Denton, R. Rutherford, M Frier, A. C. Perkins, M. R. Price, A. Smith, P A Schubiger
    Abstract:

    Transitional cell carcinoma of the bladder is the fifth commonest cause of death from cancer in men in the United Kingdom. Most patients present early with superficial disease, though with current treatment up to 20% progress to invasive disease, which has a poor prognosis. Better local treatments are required to limit this tumour progression. The ease of access to the bladder via a catheter provides the ideal opportunity for antibody (Ab) targeted therapy. We have previously shown that indium-111 labelled anti-MUCI mucin Ab C595 selectively localises to bladder tumours after intravesical administration. We have selected Copper-67 as an alternative radiolabel with suitable physical characteristics for radioimmunotherapy. This communication demonstrates that C595 can be reproducibly labelled with^67Cu and that the radioimmunoconjugate is both stable and maintains high immunoreactivity. Pilot studies on cystectomy specimens in a novel ex vivo system and in one patient confirmed the ability of this conjugate to localise to tumour after intravesical administration. On the basis of these studies we are now in a position to study the intravesical administration of^67Cu-labelled C595 in patients with bladder cancer with a view to a therapeutic trial.