Copper-67 radioimmunotheranostics for simultaneous immunotherapy and immuno-SPECT (original) (raw)
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Pharmaceutical Biology, 1995
biological behavior (Mausner, 1993). Physical properties that are important to consider include the radionuclide half-life, the type, energy and branching ratio of particulate radiation and the gamma-ray energies and abundances. The physical half-life should be matched with the in vivo pharmacokinetics of the molecule under consideration. Time-dose fractionation is also an important criterion . For equal radioactivity concentrations in the target, radionuclides with long half lives will produce a lower absorbed dose rate than those with short half lives. The type of particulate emission also must be considered. Although Auger and low-energy conversion electrons can be potentially lethal , this effect can best be realized with intranuclear localization of the radionuclide, which does not generally occur with radiolabeled MAbs. Beta particles are less densely ionizing and have a range longer than a's or the Auger and conversion electrons so that the distribution requirements are less restrictive for RIT of bulky disease or for macrometastases. The gamma-ray energies and abundances are also important physical properties, because the presence of gamma rays allows the possibility of external imaging.
Monoclonal antibodies for copper-64 PET dosimetry and radioimmunotherapy
Cancer Biology & Therapy, 2011
Copper-64 emits b þ and bparticles suitable for positron emission tomography and radioimmunotherapy (RIT) of cancer. Copper-64-labelled antibodies have caused complete responses in laboratory animal RIT studies at far lower radiation doses than traditionally prescribed. The intracellular localization of copper radioisotopes may lead to cytotoxic effects by mechanisms beyond ionizing radiation damage. The purpose of this research was to develop a model using both internalizing and non-internalizing antibodies for direct comparison in future RIT studies using the same animal model of cancer. The monoclonal antibodies, cBR96 and cT84.66, were conjugated with N-hydroxysulfosuccinimidyl DOTA. All conjugates retained high immunoreactivity and labelled efficiently with 64 Cu with high specific activity and radiochemical purity. Twenty-four hour biodistributions determined in LS174T tumour-bearing nude mice demonstrated low organ and high tumour uptakes for both monoclonal antibodies. This model constitutes a promising system for elucidating whether internalization of 64 Cu is responsible for an enhanced tumour cytotoxicity in vivo.
Development of a two-antibody model for the evaluation of copper-64 radioimmunotherapy
Veterinary and Comparative Oncology, 2004
Copper-64 emits b þ and bparticles suitable for positron emission tomography and radioimmunotherapy (RIT) of cancer. Copper-64-labelled antibodies have caused complete responses in laboratory animal RIT studies at far lower radiation doses than traditionally prescribed. The intracellular localization of copper radioisotopes may lead to cytotoxic effects by mechanisms beyond ionizing radiation damage. The purpose of this research was to develop a model using both internalizing and non-internalizing antibodies for direct comparison in future RIT studies using the same animal model of cancer. The monoclonal antibodies, cBR96 and cT84.66, were conjugated with N-hydroxysulfosuccinimidyl DOTA. All conjugates retained high immunoreactivity and labelled efficiently with 64 Cu with high specific activity and radiochemical purity. Twenty-four hour biodistributions determined in LS174T tumour-bearing nude mice demonstrated low organ and high tumour uptakes for both monoclonal antibodies. This model constitutes a promising system for elucidating whether internalization of 64 Cu is responsible for an enhanced tumour cytotoxicity in vivo.
Radioimmunotherapy with a 64 Cu-labeled monoclonal antibody : A comparison with 67 Cu JUDITH
2005
67Cu (tl2 = 62 h) has demonstrated potential as a radionuclide for radioimmunotherapy, but limited availability severely restricts its widespread use. 6"Cu (t1l2 = 12.8 h) has been shown to have comparable effectiveness in vitro and in vivo. The present study was undertaken to examine the therapeutic potential of 64Cuand 67Cu-bromoacetamidobenzyl-1,4,8,1 1-tetraazacyclotetradecane-N,N',N",N'"-tetraacetic acid (BAT)-2-iminothiolane (2IT)-1A3 (1A3 is a mouse anti-human colorectal cancer mAb) for treatment of GW39 human colon carcinoma carried in hamster thighs. Hamsters were injected with 64Cuor 67Cu-BAT-21T-1A3 or Cu-labeled nonspecific IgG (MOPC) or saline. Hamsters were killed 6-7 months after therapy or when tumors were 210 g. Of the hamsters with small tumors (mean weight 0.43 ± 0.25 g), 87.5% were disease-free 7 months after treatment with 2 mCi (1 Ci = 37 GBq) of 64Cu-BAT-21T-1A3 or 0.4 mCi of 67CuBAT-2IT-1A3. The mean tumor doses at these activities of 6...
Copper-64-labeled antibodies for PET imaging
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 1992
In the imaging of tumors using radiolabeled monoclonal antibodies, the use of PET gives increased sensitivity over conventional gamma camera imaging techniques. Copper-64, a positron-emitting radionuclide, has been labeled to 1A3, an anticolorectal carcinoma monoclonal antibody, and its fragments 1A3-F(ab')2 utilizing the bifunctional chelate Br-benzyl-TETA. The 64Cu-labeled intact 1A3 and 1A3-F(ab')2 have been evaluated as potential imaging agents for PET. Biodistribution studies of 64Cu-benzyl-TETA-1A3 and 64Cu-benzyl-TETA-1A3-F(ab')2 in tumor-bearing hamsters were compared with those of 111In-Br phi HBED-1A3, 111In-Br phi HBED-1A3-F(ab')2 and 125I-labeled intact 1A3 and 1A3-F(ab')2. Tumor uptake of 64Cu-labeled intact 1A3 and fragments in the hamster model was superior to both 111In- and 125I-labeled intact 1A3 and fragments. Human dosimetry data for 64Cu- and 123I-labeled 1A3 and 1A3-F(ab')2 were calculated from biodistribution data in rats. High kidney u...
Radioimmunotherapy with a 64Cu-labeled monoclonal antibody: a comparison with 67Cu
Proceedings of the National Academy of Sciences, 1996
67Cu (t1/2 = 62 h) has demonstrated potential as a radionuclide for radioimmunotherapy, but limited availability severely restricts its widespread use. 64Cu (t1/2 = 12.8 h) has been shown to have comparable effectiveness in vitro and in vivo. The present study was undertaken to examine the therapeutic potential of 64Cu- and 67Cu-bromoacetamidobenzyl-1,4,8,11-tetraazacyclotetradeca ne-N, N',N",N"'-tetraacetic acid (BAT)-2-iminothiolane (2IT)-1A3 (1A3 is a mouse anti-human colorectal cancer mAb) for treatment of GW39 human colon carcinoma carried in hamster thighs. Hamsters were injected with 64Cu- or 67Cu-BAT-2IT-1A3 or Cu-labeled nonspecific IgG (MOPC) or saline. Hamsters were killed 6-7 months after therapy or when tumors were > or = 10 g. Of the hamsters with small tumors (mean weight 0.43 +/- 0.25 g), 87.5% were disease-free 7 months after treatment with 2 mCi (1 Ci = 37 GBq) of 64Cu-BAT-2IT-1A3 or 0.4 MCi of 67Cu-BAT-2IT-1A3. The mean tumor doses at these ac...
Bioconjugate Chemistry, 2008
Radiolabeled anti-carcinoembryonic antigen (CEA) antibodies have the potential to give excellent images of a wide variety of human tumors, including tumors of the colon, breast, lung, and medullar thyroid. In order to realize the goals of routine and repetitive clinical imaging with anti-CEA antibodies, it is necessary that the antibodies have high affinity for CEA, low cross reactivity and uptake in normal tissues, and low immunogenicity. The humanized anti-CEA antibody hT84.66-M5A (M5A) fulfills these criteria with an affinity constant >10 10 M −1 , no reactivity with CEA crossreacting antigens found in normal tissues, and >90% human protein sequence. A further requirement for routine clinical use of radiolabeled antibodies is a versatile method of radiolabeling that allows the use of multiple radionuclides that differ in their radioemissions and half-lives. We describe a versatile bifunctional chelator, DO3A-VS (1, 4, 7-tris(carboxymethyl)-10-(vinylsulfone)-1, 4, 7, 10tetraazacyclododecane) that binds a range of radiometals including 111 In for gamma-ray imaging and 64 Cu for Positron Emission Tomography (PET), and which can be conjugated with negligible loss of immunoreactivity either to sulfhydryls (SH) in the hinge region of lightly reduced immunoglobulins or surface lysines (NH) of immunoglobulins.
Comparison of bifunctional chelates for 64Cu antibody imaging
European Journal of Nuclear Medicine and Molecular Imaging, 2010
Purpose Improved bifunctional chelates (BFCs) are needed to facilitate efficient 64 Cu radiolabeling of monoclonal antibodies (mAbs) under mild conditions and to yield stable, target-specific agents. The utility of two novel BFCs, 1-Oxa-4,7,10-triazacyclododecane-5-S-(4-isothiocyanatobenzyl)-4,7,10-triacetic acid (p-SCN-Bn-Oxo-DO3A) and 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1 (15),11,13-triene-4-S-(4-isothiocyanatobenzyl)-3,6,9-triacetic acid (p-SCN-Bn-PCTA), for mAb imaging with 64 Cu were compared to the commonly used S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-tetraacetic acid (p-SCN-Bn-DOTA). Methods The BFCs were conjugated to trastuzumab, which targets the HER2/neu receptor. 64 Cu radiolabeling of the conjugates was optimized. Receptor binding was analyzed using flow cytometry and radioassays. Finally, PET imaging and biodistribution studies were done in mice bearing either HER2/neu-positive or HER2/neu-negative tumors.
Nuclear Medicine and Biology, 2005
Copper-64-labeled monoclonal antibodies (mAbs) have previously demonstrated unexpectedly effective tumor control in rodent models of cancer at relatively low tumor-absorbed radiation doses. This property has been associated with delivery platforms resulting in cellular internalization. The purpose of the present studies was to evaluate the in vitro internalization and in vivo distribution of a two-antibody model of 64 Cu radioimmunotherapy (RIT) in the same cell and animal models of cancer. Biodistributions of an internalizing antibody, cBR96, and a noninternalizing antibody, cT84.66, labeled with 64 Cu, were obtained in nude mice bearing LS174T colon carcinoma xenografts from 15 min to 48 h. The 64 Cu-DOTA-cBR96 conjugate demonstrated rapid tumor uptake, reaching 20.2% ID/g at 3 h and peaking at 35.4% ID/g by 24 h. Tumor accumulation of 64 Cu-DOTA-cT84.66 was more gradual, 8.19% ID/g at 3 h and 43.8% ID/g by 24 h, but maximum uptake was not statistically different from 64 Cu-DOTA-cBR96. Mouse xenograft dosimetry was estimated to be 1128 rad/mCi (304.9 mGy/MBq) for 64 Cu-DOTA-cBR96 and 1409 rad/mCi (380.5 mGy/MBq) for 64 Cu-DOTA-cT84.66. In LS174T cells, internalized radioactivity increased by a factor of 3.8 over 4 h for 64 Cu-DOTA-cBR96, but remained unchanged 64 Cu-DOTA-cT84.66. When normalized to uptake at 1 h, cellular efflux of 64 Cu was essentially identical for both mAbs. The biodistributions and tumor dosimetry of these internalizing and noninternalizing radiolabeled mAbs were sufficiently similar for direct comparison of the therapeutic efficacies of low doses of 64 Cu RIT agents in the same animal model of cancer. D 2005 Elsevier Inc. All rights reserved.