^99mTc-CD3813: A Nanobody-Based Single Photon Emission Computed Tomography Radiotracer with Clinical Potential for Myeloma Imaging and Evaluation of CD38 Expression

Abstract

Daratumumab (DARA) is an anti-CD38 monoclonal antibody for the treatment of multiple myeloma (MM). The tumor CD38 expression level is one of the important factors in determining the efficacy of DARA treatment. Therefore, there is an urgent clinical need for a noninvasive tool to evaluate the CD38 levels in cancer patients before, during, and after DARA treatment. In this study, we prepared a new molecular imaging probe 99m Tc-CD3813, the 99m Tc-labeled nanobody CD3813, for noninvasive imaging of CD38 expression by single photon emission computed tomography (SPECT). We evaluated 99m Tc-CD3813 for its CD38 affinity and specificity and its capacity to image the CD38 expression in the MM and lymphoma xenografts models. 99m Tc-CD3813 SPECT/CT is able to visualize subcutaneous/orthotopic myeloma lesions in animal models and has advantages over 18 Ffluorodeoxyglucose ( 18 F-FDG) positron emission tomography. Excess DARA has less impact on its tumor uptake (3.14 ± 0.83 vs 2.29 ± 0.91 %ID/g, n.s.), strongly suggesting that there is no competition between 99m Tc-CD3813 and DARA in binding to CD38. 99m Tc-CD3813 SPECT/CT revealed significant reduction in CD38 expression in the Ramos-bearing mice under DARA treatment, as evidenced by their reduced tumor uptake (3.04 ± 0.70 vs 1.07 ± 0.28 %ID/cc, P < 0.001). 99m Tc-CD3813 SPECT/CT was also able to detect the increased tumor uptake (0.79 ± 0.29 vs 2.12 ± 0.12 %ID/cc, P < 0.001) due to the upregulation of CD38 levels caused by all-trans retinoic acid infection. 99m Tc-CD3813 is a promising SPECT radiotracer for imaging the CD38-positive tumors and has clinical potential as a molecular imaging tool for evaluation of the CD38 expression level in patients before, during, and after DARA treatment.

Noninvasive Evaluation of Tumoral PD-L1 Using a Novel 99mTc-Labeled Nanobody Tracer with Rapid Renal Clearance

“…The N 3 S structure can provide residualizing and nonresidualizing properties, depending on the amino acids adjacent to the thiol-bearing moiety and the −GGGC chelator, with a minimal number of stabilizing side chains, has provided a low residualizing property to 99m Tc. 26 However, there are limited studies on 99m Tc labeling of the nanobody using the N 3 S structure from our group, 15,27,28 and whether the metabolic properties have similar characteristics to the affibody remains to be investigated. We have tried to label 99m Tc with GGEC at the C-terminus of the nanobody MIRC208 as a chelator, and the renal uptake of 99m Tc-MIRC208 remained high at 2 h p.i.…”

Single-Domain Antibody Theranostics on the Horizon

“…CD38 (12,24,25), B-cell maturation antigen (26), CS1 (27,28), and paraprotein (29) are promising targets exploited for molecular imaging of multiple myeloma. 68 Ga-NOTA-Nb1053 is the firstgeneration CD38-specific sdAb tracer that realized precise delineation of disseminated multiple myeloma in preclinical settings (Fig.…”

Microarray-Based CD38 Peptide Probe Screening for Multiple Myeloma Imaging

“…Radiolabeled Daratumumab has been used to display the expression of CD38 in several tumor models such as MM and B-cell lymphoma. − The long half-life of radiolabeled antibodies also limits the injected dose and carries with it the risk of giving the patient an unnecessary radiation dose. However, both CD38 recognition is based on the recognition interaction between monoclonal antibodies and antigens, and antibodies are slowly consumed and cleared in vivo, requiring a longer time to obtain an adequate imaging signal. ,− Therefore, the development of small-molecule ligands targeting CD38 with shorter half-lives for diagnostic imaging has a high clinical value.…”