UCL Great Ormond Street Institute of Child Health, Zayed Centre of Research, 20 Guilford Street, London WC1N 1DZ, UK; UCL Cancer Institute, 72 Huntley Street, London, UK.
UCL Great Ormond Street Institute of Child Health, Zayed Centre of Research, 20 Guilford Street, London WC1N 1DZ, UK.
Mol Ther. 2024 Jun 5;32(6):1672-1686. doi: 10.1016/j.ymthe.2024.03.032. Epub 2024 Mar 27.
Stem cell gene therapy and hematopoietic stem cell transplantation (SCT) require conditioning to ablate the recipient's hematopoietic stem cells (HSCs) and create a niche for gene-corrected/donor HSCs. Conventional conditioning agents are non-specific, leading to off-target toxicities and resulting in significant morbidity and mortality. We developed tissue-specific anti-human CD45 antibody-drug conjugates (ADCs), using rat IgG2b anti-human CD45 antibody clones YTH24.5 and YTH54.12, conjugated to cytotoxic pyrrolobenzodiazepine (PBD) dimer payloads with cleavable (SG3249) or non-cleavable (SG3376) linkers. In vitro, these ADCs internalized to lysosomes for drug release, resulting in potent and specific killing of human CD45 cells. In humanized NSG mice, the ADCs completely ablated human HSCs without toxicity to non-hematopoietic tissues, enabling successful engraftment of gene-modified autologous and allogeneic human HSCs. The ADCs also delayed leukemia onset and improved survival in CD45 tumor models. These data provide proof of concept that conditioning with anti-human CD45-PBD ADCs allows engraftment of donor/gene-corrected HSCs with minimal toxicity to non-hematopoietic tissues. Our anti-CD45-PBDs or similar agents could potentially shift the paradigm in transplantation medicine that intensive chemo/radiotherapy is required for HSC engraftment after gene therapy and allogeneic SCT. Targeted conditioning both improve the safety and minimize late effects of these procedures, which would greatly increase their applicability.
干细胞基因治疗和造血干细胞移植（SCT）需要进行调理以消除受体的造血干细胞（HSCs）并为基因校正/供体 HSCs 创造龛位。传统的调理剂是非特异性的，导致脱靶毒性，导致发病率和死亡率显著增加。我们使用大鼠 IgG2b 抗人 CD45 抗体克隆 YTH24.5 和 YTH54.12，开发了组织特异性抗人 CD45 抗体 - 药物偶联物（ADC），将细胞毒性吡咯并苯并二氮杂卓（PBD）二聚体有效载荷与可切割（SG3249）或不可切割（SG3376）接头连接。在体外，这些 ADC 内化到溶酶体中以释放药物，导致对人 CD45 细胞的有效和特异性杀伤。在人源化 NSG 小鼠中，ADC 完全消除了人 HSCs，而对非造血组织没有毒性，从而成功植入了基因修饰的自体和同种异体人 HSCs。ADC 还延迟了 CD45 肿瘤模型中的白血病发作并提高了存活率。这些数据提供了概念验证，即用抗人 CD45-PBD ADC 调理可以在对非造血组织毒性最小的情况下植入供体/基因校正的 HSCs。我们的抗 CD45-PBD 或类似药物有可能改变移植医学的范式，即在基因治疗和同种异体 SCT 后，需要进行强化化疗/放疗以促进 HSC 植入。靶向调理既可以提高安全性，又可以最大限度地减少这些程序的晚期影响，从而大大增加其适用性。
