An antibody–drug conjugate (ADC) targeting CD46 conjugated to monomethyl auristatin has a potent anti-myeloma effect in cell lines in vitro and in vivo, and patient samples treated ex vivo. Here, we tested if CD46–ADC may have the potential to target MM-initiating cells (MM-ICs). CD46 expression was measured on primary MM cells with a stem-like phenotype. A patient-derived xenograft (PDX) model was implemented utilizing implanted fetal bone fragments to provide a humanized microenvironment. Engraftment was monitored via serum human light chain ELISA, and at sacrifice via bone marrow and bone fragment flow cytometry. We then tested MM regeneration in PDX by treating mice with CD46–ADC or the nonbinding control–ADC. MM progenitor cells from patients that exhibit high aldehyde dehydrogenase activity also have a high expression of CD46. In PDX, newly diagnosed MM patient samples engrafted significantly more compared to relapsed/refractory samples. In mice transplanted with newly diagnosed samples, CD46–ADC treatment showed significantly decreased engraftment compared to control–ADC treatment. Our data further support the targeting of CD46 in MM. To our knowledge, this is the first study to show preclinical drug efficacy in a PDX model of MM. This is an important area for future study, as patient samples but not cell lines accurately represent intratumoral heterogeneity.
一种靶向CD46并与单甲基奥瑞他汀偶联的抗体药物偶联物（ADC），在体外细胞系、体内实验以及离体处理的患者样本中均显示出强大的抗骨髓瘤效果。本研究旨在探讨CD46-ADC是否具有靶向多发性骨髓瘤起始细胞（MM-ICs）的潜力。首先，我们在具有干细胞样表型的原代多发性骨髓瘤细胞上检测了CD46的表达水平。研究采用患者来源的异种移植模型，通过植入胎儿骨碎片以提供人源化微环境。通过血清人轻链酶联免疫吸附测定监测移植情况，并在处死小鼠后通过骨髓及骨碎片的流式细胞术进行分析。随后，我们通过给予小鼠CD46-ADC或非结合对照ADC处理，测试了PDX模型中多发性骨髓瘤的再生情况。结果显示，来自患者的具有高醛脱氢酶活性的多发性骨髓瘤祖细胞同样高表达CD46。在PDX模型中，新诊断多发性骨髓瘤患者样本的移植成功率显著高于复发/难治性样本。在移植了新诊断样本的小鼠中，与对照ADC治疗相比，CD46-ADC治疗显著降低了移植成功率。我们的数据进一步支持了在多发性骨髓瘤中靶向CD46的治疗策略。据我们所知，这是首项在多发性骨髓瘤PDX模型中展示临床前药物疗效的研究。由于患者样本（而非细胞系）能准确反映肿瘤内异质性，这一领域对未来研究具有重要意义。
CD46–ADC Reduces the Engraftment of Multiple Myeloma Patient-Derived Xenografts
肿瘤(癌症)患者之家