This pilot phase I clinical trial studies how well copper 64Cu-DOTA-daratumumab positron emission tomography works in diagnosing patients with multiple myeloma that has come back. Diagnostic procedures, such as copper 64Cu-DOTA-daratumumab positron emission tomography, may help evaluate the extent of multiple myeloma in patients prior to the initiation of treatment and ultimately monitor disease status/response during and post treatment.

开始日期2018-02-21

申办/合作机构

City of Hope National Medical Center

100 项与 64Cu-DOTA-daratumumab 相关的临床结果

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100 项与 64Cu-DOTA-daratumumab 相关的转化医学

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100 项与 64Cu-DOTA-daratumumab 相关的专利（医药）

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项与 64Cu-DOTA-daratumumab 相关的文献（医药）

2020-10-27·Blood Advances2区 · 医学

Identifying CD38+ cells in patients with multiple myeloma: first-in-human imaging using copper-64–labeled daratumumab

2区 · 医学

Article

作者: Caserta, Enrico ; Wong, Jeffrey ; Adhikarla, Vikram ; Sahebi, Firoozeh ; Rosenzweig, Michael ; Poku, Erasmus K. ; Chowdhury, Arnab ; Yamauchi, Dave ; Simpson, Jennifer ; Wu, Anna M. ; Palmer, Joycelynne ; Rockne, Russell ; Nathwani, Nitya ; Marcucci, Guido ; Biglang-awa, Van Eric ; Bowles, Nicole ; Colcher, David ; Parayno, Maria ; Shively, John ; Krishnan, Amrita ; Yazaki, Paul ; Sanchez, James F. ; Forman, Stephen J. ; Pichiorri, Flavia ; Karanes, Chatchada ; Chaudhry, Ammar

Abstract18F-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.

2019-01-01·American journal of translational research

ImmunoPET imaging of CD38 expression in hepatocellular carcinoma using ⁶⁴Cu-labeled daratumumab.

Article

作者: Jiang, Dawei ; Cai, Weibo ; England, Christopher G ; Engle, Jonathan W ; Ehlerding, Emily B ; Li, Shiyong ; Kutyreff, Christopher J

CD38 is expressed on the surface of many immune cells, which are closely associated with antitumor immunity and immune tolerance of tumor cells. Therefore, monitoring CD38 expression has gained great attention for tracking the progression of tumors and cancer treatment. Herein, we aim to develop a PET tracer using an anti-CD38 monoclonal antibody (daratumumab) to monitor CD38 expression in hepatocellular carcinoma (HCC). In this study, daratumumab was radiolabeled with ⁶⁴Cu (t_1/2=12.7 h) to obtain ⁶⁴Cu-NOTA-daratumumab. Relative CD38 expression in HepG2 and Huh7 HCC cell lines was assessed using western blot. The specificity of ⁶⁴Cu-NOTA-daratumumab to both cell lines was examined using an in vitro cell-binding assay. PET imaging in subcutaneous models of HCC was performed to evaluate the capability and specificity of ⁶⁴Cu-NOTA-daratumumab to target CD38 in vivo. Region-of-interest analysis and ex vivo biodistribution were performed to verify the tracer targeting capability of CD38. Through cellular studies of two HCC cell lines, CD38 expression was found to be higher in HepG2 and minimal in Huh7 cells. ⁶⁴Cu-NOTA-daratumumab showed relatively high affinity to CD38 (K_a=18.21 ± 1.74 nM), while the affinity of Huh7 was in the micromolar range for daratumumab binding to the cells (K_a=3.98 ± 0.87 μM). At 48 h post-injection, PET imaging of subcutaneous models with ⁶⁴Cu-NOTA-daratumumab revealed tumor uptakes of 12.23 ± 2.4 and 2.7 ± 1.2 %ID/g for HepG2 and Huh7, respectively (n=4), which correlated well with relative CD38 expression of the cells. Moreover, the ⁶⁴Cu-NOTA-IgG nonspecific analogue showed a significantly lower uptake in HepG2 subcutaneous model in mice, suggesting a specific binding of daratumumab with CD38 in vivo. Our cellular studies and PET imaging confirmed the capability and specificity of ⁶⁴Cu-NOTA-daratumumab for the imaging of CD38 in murine models of HCC. This study supports our claim that ⁶⁴Cu-NOTA-daratumumab is an effective PET tracer for the non-invasive evaluation of CD38 expression and sensitive detection of CD38-positive tumor lesions in HCC.

2011-06-01·Journal of Nuclear Medicine1区 · 医学

Characterization of ⁶⁴Cu-DOTA-Conatumumab: A PET Tracer for In Vivo Imaging of Death Receptor 5

1区 · 医学

Article

作者: Sharp, Terry ; Kaplan-Lefko, Paula ; Gliniak, Brian ; Rossin, Raffaella ; Chen, Qing ; Welch, Michael J. ; Kohno, Tadahiko ; Hewig, Art ; Hagooly, Aviv ; Friberg, Greg ; Arroll, Thomas ; Evelhoch, Jeffrey L. ; Radinsky, Robert ; Hwang, Dah-Ren

Conatumumab is a fully human monoclonal antibody that binds to and activates human death receptor 5 (DR5; also known as TRAIL receptor 2). The purpose of this study was to characterize (64)Cu-labeled conatumumab as a PET tracer for imaging DR5 in tumors.METHODSDOTA-conatumumab was synthesized by incubating conatumumab with 2,2',2″-(10-(2-(2,5-dioxopyrrolidin-1-yloxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (DOTA-NHS). The absolute numbers of DOTA molecules per conatumumab molecules were determined by matrix-assisted laser desorption ionization mass spectrometry and electrospray ionization quadrupole time-of-flight mass spectrometry. (64)Cu-DOTA-conatumumab was prepared by incubating (64)CuCl(2) (33-222 MBq) with DOTA-conatumumab at 37°C for 1 h. Binding of conatumumab and DOTA-conatumumab to Fc-coupled human DR5 (huTR2-Fc) was tested in a kinetic analysis assay, and the biologic activity of copper-DOTA-conatumumab was measured using a caspase-3/7 luminescent assay. In vivo evaluation of DOTA-conatumumab and copper-DOTA-conatumumab was done in severe combined immunodeficiency mice bearing Colo205 xenografts: tissue uptake was determined with biodistribution studies, and small-animal PET and autoradiography were used to determine the uptake of (64)Cu-DOTA conatumumab into tumors and other tissues.RESULTSDOTA-conatumumab was prepared with an average of 5 DOTA molecules per conatumumab molecule. The in vitro median effective concentration required to induce a 50% effect of DOTA-conatumumab and conatumumab from the assay were 389 and 320 pM, respectively. The median effective dose (±SD) of DOTA-conatumumab and conatumumab via the caspase assay was 135 ± 31 and 128 ± 30 pM, respectively. In female CB17 severe combined immunodeficiency mice bearing Colo205 xenografts, DOTA-conatumumab and conatumumab inhibited tumor growth to the same extent. Small-animal PET studies showed tumor uptake at 24 h after injection of the tracer, with a mean standardized uptake value of 3.16 (n = 2). Tumor uptake was decreased by the coadministration of 400 μg of unlabeled conatumumab (mean standardized uptake value, 1.55; n = 2), suggesting saturable uptake. Tissue uptake determined by biodistribution studies was in agreement with the small-animal PET findings.CONCLUSIONThese results suggest that (64)Cu-DOTA-conatumumab is a potential PET tracer for imaging DR5 in tumors and may be useful for measuring on-target occupancy by conatumumab.

100 项与 64Cu-DOTA-daratumumab 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
继发性淀粉样变性	临床1期	美国	City of Hope National Medical Center	2018-02-21
复发性浆细胞骨髓瘤	临床1期	美国	City of Hope National Medical Center	2018-02-21