Abadir Edward, Silveira Pablo A, Gasiorowski Robin E, Ramesh Murari, Romano Adelina, Mekkawy Ahmed H, Lo Tsun-Ho, Kabani Karieshma, Sutherland Sarah, Pietersz Geoffrey A, Ho P Joy, Bryant Christian E, Larsen Stephen R, Clark Georgina J
Dendritic Cell Research, ANZAC Research Institute, Sydney, NSW, Australia.
Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
Blood Adv. 2020 Apr 14;4(7):1206-1216. doi: 10.1182/bloodadvances.2019001289.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) significantly reduces the rate of relapse in acute myeloid leukemia (AML) but comes at the cost of significant treatment-related mortality. Despite the reduction in relapse overall, it remains common, especially in high-risk groups. The outcomes for patients who relapse after transplant remains very poor. A large proportion of the morbidity that prevents most patients from accessing allo-HSCT is due to toxic nonspecific conditioning agents that are required to remove recipient hematopoietic stem and progenitor cells (HSPCs), allowing for successful donor engraftment. CD300f is expressed evenly across HSPC subtypes. CD300f has transcription and protein expression equivalent to CD33 on AML. We have developed an anti-CD300f antibody that efficiently internalizes into target cells. We have generated a highly potent anti-CD300f antibody-drug conjugate (ADC) with a pyrrolobenzodiazepine warhead that selectively depletes AML cell lines and colony forming units in vitro. The ADC synergizes with fludarabine, making it a natural combination to use in a minimal toxicity conditioning regimen. Our ADC prolongs the survival of mice engrafted with human cell lines and depletes primary human AML engrafted with a single injection. In a humanized mouse model, a single injection of the ADC depletes CD34+ HSPCs and CD34+CD38-CD90+ hematopoietic stem cells. This work establishes an anti-CD300f ADC as an attractive potential therapeutic that, if validated in transplant models using a larger cohort of primary AML samples, will reduce relapse rate and toxicity for patients with AML undergoing allo-HSCT.
异基因造血干细胞移植（allo-HSCT）显著降低了急性髓系白血病（AML）的复发率，但代价是显著的治疗相关死亡率。尽管总体复发率有所降低，但复发仍很常见，尤其是在高危人群中。移植后复发的患者预后仍然很差。大多数患者无法接受allo-HSCT的很大一部分发病率是由于去除受体造血干细胞和祖细胞（HSPCs）所需的毒性非特异性预处理剂，从而实现供体的成功植入。CD300f在HSPC亚型中均匀表达。CD300f的转录和蛋白表达与AML上的CD33相当。我们开发了一种能有效内化到靶细胞中的抗CD300f抗体。我们制备了一种具有吡咯并苯二氮卓弹头的高效抗CD300f抗体药物偶联物（ADC），其在体外能选择性地消耗AML细胞系和集落形成单位。该ADC与氟达拉滨协同作用，使其成为用于最小毒性预处理方案的天然组合。我们的ADC延长了移植人细胞系的小鼠的生存期，并通过单次注射消耗了原发性人AML。在人源化小鼠模型中，单次注射ADC可消耗CD34+ HSPCs和CD34+CD38-CD90+造血干细胞。这项工作确立了抗CD300f ADC作为一种有吸引力的潜在治疗方法，如果在使用更大队列的原发性AML样本的移植模型中得到验证，将降低接受allo-HSCT的AML患者的复发率和毒性。
