Kim Julia G, Sandhu Sohani K, Dontula Ritesh V, Cooper Josh J, Sherman Jaden, Rochette Max, Siddiqui Rehan, Kim Lana E, Redell Michelle S, Stevens Alexandra M
Department of Pediatric Hematology/Oncology, Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
Cancers (Basel). 2025 Apr 29;17(9):1509. doi: 10.3390/cancers17091509.
Magrolimab (Magro) is a humanized naked anti-CD47 monoclonal antibody that blocks the SIRPα CD47 interaction, allowing macrophages to target and destroy cancer cells. To evaluate its preclinical efficacy in vivo, Magro was tested as a single agent and in combination with conventional chemotherapy drugs, Cytarabine (Ara-C) or Azacitidine (Aza), in three pediatric AML (pAML) patient-derived xenograft (PDX) models-AML006 (KMT2A::MLLT1), AML010 (+10, WT1), and AML013 (KMT2A::MLLT4). After PDX model establishment, mice were assigned to treatment groups hulgG4 (VC, vehicle control for Magro), Magro, Ara-C + VC, Aza + VC, Ara-C + Magro, and Aza + Magro, and then followed for survival. Mice that met humane euthanasia endpoints and at the culmination of experimental timelines had tissues harvested to measure disease burden. Magro alone significantly improved survival in AML006 ( < 0.0001) and AML013 ( = 0.003) and decreased bone marrow (BM) disease burden in AML006 ( = 0.009) and AML013 ( = 0.002). Ara-C + Magro therapy led to significantly improved survival in all three models and significantly decreased BM disease burden in AML006 ( < 0.0001) and AML013 ( = 0.048). Aza + Magro therapy led to significantly improved survival in AML013 ( = 0.047) and AML010 ( = 0.017) and significantly lower BM disease burden in AML010 ( = 0.001). : Interestingly, the two models that demonstrated improvement in survival with Magro harbored KMT2A rearrangements, suggesting a subset of patients that may be more responsive to the effects of CD47 blockade. As this drug is being evaluated for use in other malignancies, future studies may focus on investigating the importance of biomarker-based patient selection.
玛格罗利单抗（Magro）是一种人源化裸抗CD47单克隆抗体，可阻断信号调节蛋白α（SIRPα）与CD47的相互作用，使巨噬细胞能够靶向并摧毁癌细胞。为了评估其在体内的临床前疗效，在三种儿童急性髓系白血病（pAML）患者来源的异种移植（PDX）模型——AML006（KMT2A::MLLT1）、AML010（+10，WT1）和AML013（KMT2A::MLLT4）中，将玛格罗利单抗作为单一药物以及与传统化疗药物阿糖胞苷（Ara-C）或阿扎胞苷（Aza）联合进行了测试。在建立PDX模型后，将小鼠分配到治疗组：人IgG4（VC，玛格罗利单抗的溶剂对照）、玛格罗利单抗、Ara-C + VC、Aza + VC、Ara-C + 玛格罗利单抗和Aza + 玛格罗利单抗，然后跟踪其生存期。达到人道安乐死终点的小鼠以及在实验时间线结束时的小鼠，均采集组织以测量疾病负担。单独使用玛格罗利单抗可显著提高AML006（P<0.0001）和AML013（P = 0.003）的生存期，并降低AML006（P = 0.009）和AML013（P = 0.002）的骨髓（BM）疾病负担。Ara-C + 玛格罗利单抗治疗在所有三种模型中均导致生存期显著改善，并显著降低AML006（P<0.0001）和AML013（P = 0.048）的BM疾病负担。Aza + 玛格罗利单抗治疗使AML013（P = 0.047）和AML010（P = 0.017）的生存期显著改善，并使AML010（P = 0.001）的BM疾病负担显著降低。有趣的是，在生存期方面显示出改善的两个模型都存在KMT2A重排，这表明可能有一部分患者对CD47阻断的效果更敏感。由于该药物正在评估用于其他恶性肿瘤，未来的研究可能集中于调查基于生物标志物的患者选择的重要性。
