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.

调理化疗用于消耗受体骨髓中的造血干细胞，促进供体细胞植入。虽然有效，但化疗的一个主要问题是增加继发性恶性肿瘤风险的全身遗传毒性。靶向造血细胞的抗体偶联物是一种新兴的非遗传毒性方法，可打开骨髓生态位并促进移植细胞的植入，同时保持完整的骨髓细胞结构。具体来说，该平台可用于与 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) 作为自体移植 FA 小鼠模型中的替代预处理方案。FANCA敲除小鼠在接受来自杂合健康供体的全骨髓之前，先用 CD45-SAP 或 CD117-SAP 进行调理。骨髓和外周血分析显示，与环磷酰胺治疗对照组相比，ADC 治疗组的供体移植水平相当，毒性最小。我们的研究结果表明，ADC 可能是干细胞移植中的一种有效调节策略，不仅适用于不能耐受传统化疗的疾病，而且适用于更广泛的血液和骨髓移植领域。