Effective Multi-lineage Engraftment in a Mouse Model of Fanconi Anemia Using Non-genotoxic Antibody-Based Conditioning
Effective Multi-lineage Engraftment in a Mouse Model of Fanconi Anemia Using Non-genotoxic Antibody-Based Conditioning
复制标题
DOI：
10.1016/j.omtm.2020.02.001
复制
发表时间：
2020-06-12
影响因子：
4.7
通讯作者：
Kiem, Hans-Peter
中科院分区：
文献类型：
--
作者：
Srikanthan, Meera A.;Humbert, Olivier;Kiem, Hans-Peter
预处理化疗用于耗尽受体骨髓中的造血干细胞，促进供体细胞植入。尽管化疗有效，但化疗的一个主要问题是全身遗传毒性，这会增加继发性恶性肿瘤的风险。靶向造血细胞的抗体缀合物是一种新兴的非遗传毒性方法，其打开骨髓龛并促进移植细胞的植入，同时保持完整的骨髓细胞结构。具体而言，该平台将用于与DNA损伤或癌症易感性相关的疾病，例如先天性角化不良、Schwachman-Diamond综合征和范可尼贫血（FA）。我们的方法利用抗体-药物偶联物（ADC）作为FA小鼠自体移植模型的替代预处理方案。将靶向CD 45或CD 117的抗体缀合至皂草素（SAP），一种核糖体毒素。FANCA敲除小鼠在接受来自杂合健康供体的全骨髓之前，用CD 45-SAP或CD 117-SAP调节。骨髓和外周血分析显示，与环磷酰胺治疗对照组相比，ADC治疗组的供体植入水平相当，毒性最小。我们的研究结果表明，ADC可能是干细胞移植中有效的预处理策略，不仅适用于传统化疗不耐受的疾病，而且适用于更广泛的血液和骨髓移植领域。
Conditioning chemotherapy is used to deplete hematopoietic stem cells in the recipient's marrow, facilitating donor cell engraftment. Although effective, a major issue with chemotherapy is the systemic genotoxicity that increases the risk for secondary malignancies. Antibody conjugates targeting hematopoietic cells are an emerging non-genotoxic method of opening the marrow niche and promoting engraftment of transplanted cells while maintaining intact marrow cellularity. Specifically, this platform would be useful in diseases associated with DNA damage or cancer predisposition, such as dyskeratosis congenita, Schwachman-Diamond syndrome, and Fanconi anemia (FA). Our approach utilizes antibody-drug conjugates (ADC) as an alternative conditioning regimen in an FA mouse model of autologous transplantation. Antibodies targeting either CD45 or CD117 were conjugated to saporin (SAP), a ribosomal toxin. FANCA knockout mice were conditioned with either CD45-SAP or CD117-SAP prior to receiving whole marrow from a heterozygous healthy donor. Bone marrow and peripheral blood analysis revealed equivalent levels of donor engraftment, with minimal toxicity in ADC-treated groups as compared with cyclophosphamide-treated controls. Our findings suggest ADCs may be an effective conditioning strategy in stem cell transplantation not only for diseases where traditional chemotherapy is not tolerated, but also more broadly for the field of blood and marrow transplantation.