Copper 64-labeled daratumumab as a PET/CT imaging tracer for multiple myeloma.
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ABSTRACT:
SUBMITTER: Caserta E
PROVIDER: S-EPMC5814935 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:18F-Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) is one of the most widely used imaging techniques to detect multiple myeloma (MM). Intracellular FDG uptake depicts in vivo metabolic activity, which can be seen in both malignant and nonmalignant cells, resulting in limited sensitivity and specificity. Our group showed preclinically that tracing MM dissemination using a CD38-directed human antibody, daratumumab, that is radioconjugated with 64Cu via the chelator DOTA (64Cu-daratumumab), led to improved sensitivity and specificity over that of FDG. Here, we report the results of a phase 1 trial designed to (1) assess the safety and feasibility of 64Cu-daratumumab PET/CT and (2) preliminarily evaluate and characterize the ability of 64Cu-daratumumab to accurately detect or exclude MM lesions. A total of 12 daratumumab-naive patients were imaged. Prior to the injection of 15 mCi/5 mg of 64Cu-daratumumab, patients were treated with 0 (n = 3), 10 (n = 3), 45 (n = 3), or 95 mg (n = 3) of unlabeled daratumumab to assess its effect on image quality. No significant adverse events were observed from either unlabeled daratumumab or 64Cu-daratumumab. Of the dose levels tested, 45 mg unlabeled daratumumab was the most optimal in terms of removing background signal without saturating target sites. 64Cu-daratumumab PET/CT provided safe whole-body imaging of MM. A trial comparing the sensitivity and specificity of 64Cu-daratumumab PET/CT with that of FDG PET/CT is planned. This trial was registered at www.clinicaltrials.gov as #NCT03311828.
| S-EPMC7594407 | biostudies-literature
Project description:Expression of CXCR4 in cancer has been found to correlate with poor prognosis and resistance to chemotherapy. In this study we developed a derivative of the CXCR4 peptide antagonist, T140-2D, that can be labeled easily with the PET isotope copper-64, and thereby enable in vivo visualization of CXCR4 in tumors. T140 was conjugated to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid mono (N-hydroxysuccinimide ester) (DOTA-NHS) to give T140-2D, which contains a DOTA molecule on each of the two lysine residues. (64)Cu-T140-2D was evaluated in vitro by migration and binding experiments, and in vivo by microPET imaging and biodistribution, in mice bearing CXCR4-positive and CXCR4-negative tumor xenografts. T140-2D was labeled with copper-64 to give (64)Cu-T140-2D in a high radiochemical yield of 86 ± 3% (not decay-corrected) and a specific activity of 0.28 - 0.30 mCi/µg (10.36 - 11.1 MBq/µg). (64)Cu-T140-2D had antagonistic and binding characteristics to CXCR4 that were similar to those of T140. In vivo, (64)Cu-T140-2D tended to bind to red blood cells and had to be used in a low specific activity form. In this new form (64)Cu-T140-2D enabled specific imaging of CXCR4-positive, but not CXCR4-negative tumors. Undesirably, however, (64)Cu-T140-2D also displayed high accumulation in the liver and kidneys. In conclusion, (64)Cu-T140-2D was easily labeled and, in its low activity form, enabled imaging of CXCR4 in tumors. It had high uptake, however, in metabolic organs. Further research with imaging tracers targeting CXCR4 is required.
| S-EPMC3085282 | biostudies-literature
Project description:The ability to detect and quantify macrophage accumulation can provide important diagnostic and prognostic information for atherosclerotic plaque. We have previously shown that LyP-1, a cyclic 9-amino acid peptide, binds to p32 proteins on activated macrophages, facilitating the visualization of atherosclerotic plaque with PET. Yet, the in vivo plaque accumulation of monomeric [(18)F]FBA-LyP-1 was low (0.31 ± 0.05%ID/g). To increase the avidity of LyP-1 constructs to p32, we synthesized a dendritic form of LyP-1 on solid phase using lysine as the core structural element. Imaging probes (FAM or 6-BAT) were conjugated to a lysine or cysteine on the dendrimer for optical and PET studies. The N-terminus of the dendrimer was further modified with an aminooxy group in order to conjugate LyP-1 and ARAL peptides bearing a ketone. Oxime ligation of peptides to both dendrimers resulted in (LyP-1)4- and (ARAL)4-dendrimers with optical (FAM) and PET probes (6-BAT). For PET-CT studies, (LyP-1)4- and (ARAL)4-dendrimer-6-BAT were labeled with (64)Cu (t1/2 = 12.7 h) and intravenously injected into the atherosclerotic (ApoE(-/-)) mice. After two hours of circulation, PET-CT coregistered images demonstrated greater uptake of the (LyP-1)4-dendrimer-(64)Cu than the (ARAL)4-dendrimer-(64)Cu in the aortic root and descending aorta. Ex vivo images and the biodistribution acquired at three hours after injection also demonstrated a significantly higher uptake of the (LyP-1)4-dendrimer-(64)Cu (1.1 ± 0.26%ID/g) than the (ARAL)4-dendrimer-(64)Cu (0.22 ± 0.05%ID/g) in the aorta. Similarly, subcutaneous injection of the LyP-1-dendrimeric carriers resulted in preferential accumulation in plaque-containing regions over 24 h. In the same model system, ex vivo fluorescence images within aortic plaque depict an increased accumulation and penetration of the (LyP-1)4-dendrimer-FAM as compared to the (ARAL)4-dendrimer-FAM. Taken together, the results suggest that the (LyP-1)4-dendrimer can be applied for in vivo PET imaging of plaque and that LyP-1 could be further exploited for the delivery of therapeutics with multivalent carriers or nanoparticles.
| S-EPMC4311647 | biostudies-literature
Project description:INTRODUCTION:Bone marrow is the soft tissue compartment inside the bones made up of hematopoietic cells, adipocytes, stromal cells, phagocytic cells, stem cells, and sinusoids. While [18F]-FLT has been utilized to image proliferative marrow, to date, there are no reports of particle based positron emission tomography (PET) imaging agents for imaging bone marrow. We have developed copper-64 labeled liposomal formulation that selectively targets bone marrow and therefore serves as an efficient PET probe for imaging bone marrow. METHODS:Optimized liposomal formulations were prepared with succinyl PE, DSPC, cholesterol, and mPEG-DSPE (69:39:1:10:0.1) with diameters of 90 and 140nm, and were doped with DOTA-Bn-DSPE for stable 64Cu incorporation into liposomes. RESULTS:PET imaging and biodistribution studies with 64Cu-labeled liposomes indicate that accumulation in bone marrow was as high as 15.18±3.69%ID/g for 90nm liposomes and 7.01±0.92%ID/g for 140nm liposomes at 24h post-administration. In vivo biodistribution studies in tumor-bearing mice indicate that the uptake of 90nm particles is approximately 0.89±0.48%ID/g in tumor and 14.22±8.07%ID/g in bone marrow, but respective values for Doxil® like liposomes are 0.83±0.49%ID/g and 2.23±1.00%ID/g. CONCLUSION:Our results indicate that our novel PET labeled liposomes target bone marrow with very high efficiency and therefore can function as efficient bone marrow imaging agents.
| S-EPMC5118102 | biostudies-literature
Project description:PurposeCluster of differentiation 38 (CD38) is a promising therapeutic target in multiple myeloma (MM) patients and has resulted in the development of several CD38 immunotherapies. Current methods to evaluate CD38 expression in the preclinical setting include ex vivo flow cytometry and immunohistochemistry, which can be cumbersome and do not give whole-body information. In vivo imaging technologies such as positron emission tomography rely on decay of radioisotopes, limiting the number of molecular interactions observed at any given time point. Here, we demonstrate the use of near-infrared (NIR) fluorescence imaging for spatiotemporal monitoring of CD38 expression in preclinical MM using the anti-CD38 daratumumab (DARA) conjugated to the NIR fluorophore IRDye800CW (DARA-IRDye800).ProceduresStability studies with human serum and binding assays with human myeloma cells were performed with DARA-IRDye800. Immunocompromised mice with intra- and extramedullary tumors (n = 5/group) were administered with DARA-IRDye800 for in vivo imaging up to 7 days after injection. Ex vivo biodistribution and flow cytometry studies were performed to validate in vivo imaging results. A separate therapy study was performed in mice with intramedullary tumors that were treated and not treated with DARA at a therapeutic dose (n = 7/group). DARA-IRDye800 was administered for subsequent in vivo and ex vivo imaging in both cohorts of mice.ResultsDARA-IRDye800 maintained stability and had high affinity for CD38 (KD = 3.5 ± 0.05 nM). DARA-IRDye800 demonstrated a 5- and 18-fold increase in contrast in tumor-bearing regions of mice with extra- and intramedullary MM. Finally, mice treated with therapeutic doses of DARA and imaged with DARA-IRDye800 showed an 11-fold decrease in fluorescence intensities in vivo compared with untreated controls.ConclusionsOur studies establish DARA-IRDye800 as a promising contrast agent for preclinical evaluation of CD38 expression and for further investigating myeloma engraftment and kinetics in relation to anti-CD38 therapies.
| S-EPMC8475634 | biostudies-literature
Project description:Synthesis and characterisation of a dithiadiaza chelator NSNS2A, as well as copper complexes thereof are reported in this paper. Solution structures of copper(i/ii) complexes were calculated using density functional theory (DFT) and validated by both NMR and EPR spectroscopy. DFT calculations revealed a switch in the orientation of tetragonal distortion upon protonation, which might be responsible for poor stability of the Cu(II)NSNS2A complex in aqueous media, whilst the same switch in tetragonal distortion was experimentally observed by changing the solvent. The chelator was radiolabeled with 64Cu and evaluated using PET/MRI in rats. Despite a favorable redox potential to stabilize the cuprous state in vivo, the 64Cu(II)NSNS2A complex showed suboptimal stability compared to its tetraazamacrocyclic analogue, 64Cu(TE2A), with a significant 64Cu uptake in the liver.
| S-EPMC7967274 | biostudies-literature
Project description:An observational study was set up to assess the feasibility of [18F]FPRGD2 PET/CT for imaging patients with multiple myeloma (MM) and to compare its detection rate with low dose CT alone and combined [18F]NaF/[18F]FDG PET/CT images. Four patients (2 newly diagnosed patients and 2 with relapsed MM) were included and underwent whole-body PET/CT after injection of [18F]FPRGD2. The obtained images were compared with results of low dose CT and already available results of a combined [18F]NaF/[18F]FDG PET/CT. In total, 81 focal lesions (FLs) were detected with PET/CT and an underlying bone destruction or fracture was seen in 72 (89%) or 8 (10%) FLs, respectively. Fewer FLs (54%) were detected by [18F]FPRGD2 PET/CT compared to low dose CT (98%) or [18F]NaF/[18F]FDG PET/CT (70%) and all FLs detected with [18F]FPRGD2 PET were associated with an underlying bone lesion. In one newly diagnosed patient, more [18F]FPRGD2 positive lesions were seen than [18F]NaF/[18F]FDG positive lesions. This study suggests that [18F]FPRGD2 PET/CT might be less useful for the detection of myeloma lesions in patients with advanced disease as all FLs with [18F]FPRGD2 uptake were already detected with CT alone.
| S-EPMC5612716 | biostudies-literature
Project description:1C1m-Fc, a promising anti-TEM-1 DOTA conjugate, was labeled with 64Cu to target cancer cells for PET imaging and predicting the efficacy and safety of a previously studied [177Lu]Lu-1C1m-Fc companion therapy. DOTA-conjugated 1C1m-Fc was characterized by mass spectrometry, thin layer chromatography and immunoreactivity assessment. PET/CT and biodistribution studies were performed in human neuroblastoma xenografted mice. Absorbed doses were assessed from biodistribution results and extrapolated to 177Lu based on the [64Cu]Cu-1C1m-Fc data. The immunoreactivity was ≥ 70% after 48 h of incubation in serum, and the specificity of [64Cu]Cu-1C1m-Fc for the target was validated. High-resolution PET/CT images were obtained, with the best tumor-to-organ ratios reached at 24 or 48 h and correlated with results of the biodistribution study. Healthy organs receiving the highest doses were the liver, the kidneys and the uterus. [64Cu]Cu-1C1m-Fc could be of interest to give an indication of 177Lu dosimetry for parenchymal organs. In the uterus and the tumor, characterized by specific TEM-1 expression, the 177Lu-extrapolated absorbed doses are overestimated because of the lack of later measurement time points. Nevertheless, 1C1m-Fc radiolabeled with 64Cu for imaging would appear as an interesting radionuclide companion for therapeutic application with [177Lu]Lu-1C1m-Fc.
| S-EPMC8657097 | biostudies-literature
Project description:Cardiovascular disease is the leading cause of death worldwide. PET has the potential to provide information on the biology and metabolism of atherosclerotic plaques. Natriuretic peptides (NPs) have potent antiproliferative and antimigratory effects on vascular smooth-muscle cells (VSMCs) and, in atherosclerosis, participate in vascular remodeling, in which the expression of NP clearance receptors (NPR-Cs) is upregulated both in endothelium and in VSMCs.We investigated the potential of a C-type atrial natriuretic factor (C-ANF) to image developing plaque-like lesions in vivo. C-ANF was functionalized with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and labeled with (64)Cu for noninvasive PET in a hypercholesterolemic rabbit with atherosclerotic-like lesions induced by air desiccation of a femoral artery, followed by balloon overstretch of the developing neointima. Histopathology and immunohistochemistry were performed to assess plaque development and NPR-C localization.(64)Cu-DOTA-C-ANF uptake in the atherosclerotic region was visible on small-animal PET images, with the highest target-to-background ratio (3.59 +/- 0.94) observed after the air desiccation-induced injury. Immunohistochemistry and immunofluorescence staining showed NPR-C near the luminal surface of the plaque and in VSMCs. PET and immunohistochemistry competitive blocking studies confirmed receptor-mediated tracer uptake in the plaque. With blocking, PET tracer localization of atherosclerotic to control arteries was decreased from 1.42 +/- 0.02 to 1.06 +/- 0.06 (P < 0.001).We demonstrated that (64)Cu-DOTA-C-ANF is a promising candidate tracer for in vivo PET of NPR-Cs on atherosclerotic plaques.
| S-EPMC4410353 | biostudies-literature
Project description:Vascular endothelial growth factor receptors (VEGFRs) are well recognized as significant biomarkers of tumor angiogenesis. Herein, we have developed a first-of-its-kind peptide-based VEGFR positron emission tomography (PET) tracer. The novel [64Cu]VEGF125-136 peptide possessed satisfactory radio-characteristics and showed good specificity for the visualization of VEGFR in various mouse models, in which the tumor-specific radioactivity uptake was highly correlated to the VEGFR expression level. Moreover, the tracer showed high tumor uptake (ca. 5.89 %ID/g at 20 min postinjection in B16F10 mice) and excellent pharmacokinetics, achieving the maximum imaging quality within 1 h after injection. These features convey [64Cu]VEGF125-136 as a promising, clinically translatable PET tracer for the imaging of tumor angiogenesis.
| S-EPMC7178340 | biostudies-literature