CD46-ADC Reduces the Engraftment of Multiple Myeloma Patient-Derived Xenografts.
CD46-ADC Reduces the Engraftment of Multiple Myeloma Patient-Derived Xenografts.
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CD46-ADC减少了多发性骨髓瘤患者衍生的异种移植物的植入。
DOI：
10.3390/cancers15225335
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发表时间：
2023-11-09
期刊：
影响因子：
5.2
通讯作者：
Sherbenou, Daniel W.
中科院分区：
文献类型：
--
作者：
Vanwyngarden, Michael J.;Walker, Zachary J.;Su, Yang;de Acha, Olivia Perez;Stevens, Brett M.;Forsberg, Peter A.;Mark, Tomer M.;Matsui, William;Liu, Bin;Sherbenou, Daniel W.
关键词：
多发性骨髓瘤（MM）是无法治愈的，这意味着疾病细胞对当前药物具有固有的耐药性，并不可避免地导致复发。改善治疗模式的一个策略是寻求与复发性疾病相关的新药物靶点。为此，我们开发了一种新的抗体-药物偶联物（ADC），其靶向细胞表面补体抑制剂CD 46。在这里，我们研究了这种新药物影响疾病发生的潜力。编码CD 46的基因在大多数复发性骨髓瘤患者的染色体1 q上扩增，以及含有干细胞样醛脱氢酶活性的细胞。我们通过其消除原发性MM细胞异种移植物的疾病植入的能力证明了CD 46-ADC的治疗潜力。结合最近的临床试验，该研究支持继续研究CD 46作为MM的治疗靶点。靶向CD 46的抗体-药物缀合物（ADC）与单甲基澳瑞他汀缀合，在体外和体内细胞系以及离体治疗的患者样品中具有有效的抗骨髓瘤作用。在这里，我们测试了CD 46-ADC是否可能具有靶向MM起始细胞（MM-IC）的潜力。在具有干细胞样表型的原代MM细胞上测量CD 46表达。利用植入的胎儿骨碎片实施患者来源的异种移植物（PDX）模型以提供人源化微环境。通过血清人轻链ELISA监测植入，并在处死时通过骨髓和骨碎片流式细胞术监测植入。然后，我们通过用CD 46-ADC或非结合对照ADC处理小鼠来测试PDX中的MM再生。表现出高醛脱氢酶活性的来自患者的MM祖细胞也具有高的CD 46表达。在PDX中，与复发/难治性样本相比，新诊断的MM患者样本移植显著更多。在移植有新诊断样品的小鼠中，与对照ADC治疗相比，CD 46-ADC治疗显示出显著降低的植入。据我们所知，这是第一项在MM的PDX模型中显示临床前药物疗效的研究。这是未来研究的重要领域，因为患者样本而不是细胞系准确地代表了肿瘤内异质性。
Multiple myeloma (MM) is incurable, implying that the disease cells are inherently resistant to current agents and inevitably lead to relapse. One strategy to improve the treatment paradigm is to pursue novel drug targets that are associated with relapsed disease. Towards this end, we developed a novel antibody–drug conjugate (ADC) that targets the cell surface complement inhibitor CD46. Here, we study the potential of this new agent to affect disease initiation. The gene encoding for CD46 is amplified on chromosome 1q in the majority of relapsed myeloma patients, as well as cells containing stem-like aldehyde dehydrogenase activity. We demonstrate the curative potential of CD46–ADC via its ability to abrogate disease engraftment of primary MM cell xenografts. In combination with a recent clinical trial, this study supports the continued study of CD46 as a therapeutic target in MM. 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.
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影响因子：
45.3
作者：
Martin, Thomas;Usmani, Saad Z.;Berdeja, Jesus G.;Agha, Mounzer;Cohen, Adam D.;Hari, Parameswaran;Avigan, David;Deol, Abhinav;Htut, Myo;Lesokhin, Alexander;Munshi, Nikhil C.;O'Donnell, Elizabeth;Stewart, A. Keith;Schecter, Jordan M.;Goldberg, Jenna D.;Jackson, Carolyn C.;Yeh, Tzu-Min;Banerjee, Arnob;Allred, Alicia;Zudaire, Enrique;Deraedt, William;Olyslager, Yunsi;Zhou, Changwei;Pacaud, Lida;Madduri, Deepu;Jakubowiak, Andrzej;Lin, Yi;Jagannath, Sundar
通讯作者：
Jagannath, Sundar
影响因子：
4.7
作者：
Doronina, SO;Mendelsohn, BA;Senter, PD
通讯作者：
Senter, PD
影响因子：
5.3
作者：
Ovacik, Ayse Meric;Li, Ji;Kamath, Amrita V.
通讯作者：
Kamath, Amrita V.
影响因子：
11.4
作者：
通讯作者：
--
影响因子：
11.2
作者：
Matsui, William;Wang, Qiuju;Jones, Richard J.
通讯作者：
Jones, Richard J.