Ghai Anchal, Zheleznyak Alexander, Mixdorf Matt, O'Neal Julie, Ritchey Julie, Rettig Michael, DiPersio John, Shokeen Monica, Achilefu Samuel
Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA.
Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Eur J Nucl Med Mol Imaging. 2021 May;48(5):1302-1311. doi: 10.1007/s00259-020-05097-y. Epub 2020 Nov 11.
Multiple myeloma (MM) is a bone marrow malignancy that remains mostly incurable. Elotuzumab is an FDA-approved therapeutic monoclonal antibody targeted to the cell surface glycoprotein CS1, which is overexpressed in MM cells. Identifying patients who will respond to CS1-targeted treatments such as elotuzumab requires the development of a companion diagnostic to assess the presence of CS1. Here, we evaluated [Zr]DFO-elotuzumab as a novel PET tracer for imaging CS1 expression in preclinical MM models.
Conjugation of desferrioxamine-p-benzyl-isothiocyanate (DFO-Bz-NCS) to elotuzumab enabled zirconium-89 radiolabeling. MM.1S-CG cells were intravenously injected in NOD SCID gamma (NSG) mice. Small animal PET imaging with [Zr]DFO-elotuzumab (1.11 MBq/mouse, 7 days post-injection), [Zr]DFO-IgG (1.11 MBq/mouse, 7 days post-injection), and [F]FDG (7-8 MBq, 1 h post-injection) was performed. Additionally, biodistribution of [Zr]DFO-elotuzumab post-imaging at 7 days was also done. In vivo specificity of [Zr]DFO-elotuzumab was further evaluated with a blocking study and ex vivo autoradiography.
[Zr]DFO-elotuzumab was produced with high specific activity (56 ± 0.75 MBq/nmol), radiochemical purity (99% ± 0.5), and yield (93.3% ± 1.5). Dissociation constant of 40.4 nM and receptor density of 126 fmol/mg was determined in MM.1S-CG cells. Compared to [Zr]DFO-IgG, [Zr]DFO-elotuzumab localized with a significantly higher standard uptake value in tumor-bearing bone tissue (8.59 versus 4.77). Blocking with unlabeled elotuzumab significantly reduced (P < 0.05) uptake of [Zr]DFO-elotuzumab in the bones. Importantly, while [F]FDG demonstrated similar uptake in the bone and muscle, [Zr]DFO-elotuzumab showed > 3-fold enhanced uptake in bones.
These data demonstrate the feasibility of [Zr]DFO-elotuzumab as a companion diagnostic for CS1-targeted therapies.
多发性骨髓瘤（MM）是一种骨髓恶性肿瘤，大多仍无法治愈。埃罗妥珠单抗是一种经美国食品药品监督管理局（FDA）批准的治疗性单克隆抗体，靶向细胞表面糖蛋白CS1，该蛋白在MM细胞中过表达。识别对埃罗妥珠单抗等CS1靶向治疗有反应的患者需要开发一种伴随诊断方法来评估CS1的存在情况。在此，我们评估了[Zr]DFO - 埃罗妥珠单抗作为一种新型正电子发射断层扫描（PET）示踪剂，用于在临床前MM模型中成像CS1表达。
去铁胺 - 对苄基 - 异硫氰酸酯（DFO - Bz - NCS）与埃罗妥珠单抗偶联实现了锆 - 89放射性标记。将MM.1S - CG细胞静脉注射到非肥胖糖尿病严重联合免疫缺陷（NSG）小鼠体内。用[Zr]DFO - 埃罗妥珠单抗（1.11 MBq/小鼠，注射后7天）、[Zr]DFO - 免疫球蛋白G（IgG）（1.11 MBq/小鼠，注射后7天）和[F]氟代脱氧葡萄糖（FDG）（7 - 8 MBq，注射后1小时）进行小动物PET成像。此外，还进行了成像后7天[Zr]DFO - 埃罗妥珠单抗的生物分布研究。通过阻断研究和离体放射自显影进一步评估了[Zr]DFO - 埃罗妥珠单抗的体内特异性。
[Zr]DFO - 埃罗妥珠单抗具有高比活度（56 ± 0.75 MBq/nmol）、放射化学纯度（99% ± 0.5）和产率（93.3% ± 1.5）。在MM.1S - CG细胞中测定的解离常数为40.4 nM，受体密度为126 fmol/mg。与[Zr]DFO - IgG相比，[Zr]DFO - 埃罗妥珠单抗在荷瘤骨组织中的标准化摄取值显著更高（8.59对4.77）。用未标记的埃罗妥珠单抗阻断可显著降低（P < 0.05）[Zr]DFO - 埃罗妥珠单抗在骨骼中的摄取。重要的是，虽然[F]FDG在骨骼和肌肉中的摄取相似，但[Zr]DFO - 埃罗妥珠单抗在骨骼中的摄取增强了3倍以上。
这些数据证明了[Zr]DFO - 埃罗妥珠单抗作为CS1靶向治疗的伴随诊断方法的可行性。
