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

Abstract

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.

A Mathematical Modeling Approach for Targeted Radionuclide and Chimeric Antigen Receptor T Cell Combination Therapy

“…Of the four alpha particles released by 225 Ac and its progeny, one alpha particle is attributed to 213 Bi. Daratumumab biodistribution is stable in the body over the course of hours-days [19]; this effect was negligible for the model system shown in this manuscript. Apart from the biological redistribution of daughter radionuclides, different radionuclides have different emission particles and ranges that impact on the absorbed fraction of the radiation dose.…”

“…In the presented model, the tumor burden measurement by BLI resulted in simplifying the application of the model to the data and, at the same time, resulted in the prediction of an average measure for the model parameters and responses. A better measure of the tumor burden and disease localization can be acquired by PET imaging, as has been shown for multiple myelomas both preclinically [14] and clinically [19]. Such an imaging metric can give a spatially variable estimate of the model parameters even at the voxel level.…”

ImmunoPET imaging of multiple myeloma with [68Ga]Ga-NOTA-Nb1053

“…Since Nb1053 competes with daratumumab in binding to CD38, radiotracers binding to CD38 independently of the daratumumab (or isatuximab) will more precisely monitor the dynamic change of CD38 following the antibody therapies [39]. Although the rapid clinical translation of two mAb-based CD38-targeted immunoPET probes [14,15], the development of immunoPET imaging technique with sdAbs is still in this infancy. We have demonstrated the feasibility of [ 68 Ga]Ga-NOTA-Nb1053 immunoPET in imaging MMs in preclinical models.…”

“…We have developed several immunoPET probes to facilitate the early diagnosis of advanced thyroid cancer and melanoma, among others [8][9][10][11]. In the meanwhile, daratumumab has been radiolabeled for imaging CD38 in preclinical MM models [12,13], and more recently in clinical trials [14,15]. However, the size of mAb (150 kDa) exceeds the cutoff of glomerular ltration (60 kDa) and therefore long-lived radionuclides such as 89 Zr (t 1/2 = 78.4 h) and 64 Cu (t 1/2 = 12.7 h) are needed to match the lengthy circulation.…”

A non-internalised CD38-binding radiolabelled single-domain antibody fragment to monitor and treat multiple myeloma

“…Other vectors targeting CD38 have been reported, with a few strategies already evaluated in the clinic [ 30 , 31 ]. Except for one bispecific construct, all use full-size mAbs as vector.…”