Background/Objectives: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).Methods: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.Results:Magro alone significantly improved survival in AML006 (p< 0.0001) and AML013 (p= 0.003) and decreased bone marrow (BM) disease burden in AML006 (p= 0.009) and AML013 (p= 0.002). Ara-C + Magro therapy led to significantly improved survival in all three models and significantly decreased BM disease burden in AML006 (p< 0.0001) and AML013 (p= 0.048). Aza + Magro therapy led to significantly improved survival in AML013 (p= 0.047) and AML010 (p= 0.017) and significantly lower BM disease burden in AML010 (p= 0.001).Conclusions: 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.
背景/目的：Magrolimab（Magro）是一种人源化裸抗CD47单克隆抗体，通过阻断SIRPα-CD47相互作用，使巨噬细胞能够靶向并清除癌细胞。为评估其在体内的临床前疗效，本研究在三种儿童急性髓系白血病（pAML）患者来源异种移植（PDX）模型——AML006（KMT2A::MLLT1）、AML010（+10, WT1）和AML013（KMT2A::MLLT4）中，测试了Magro单药及联合常规化疗药物阿糖胞苷（Ara-C）或阿扎胞苷（Aza）的治疗效果。 方法：建立PDX模型后，将小鼠分配至以下治疗组：hulgG4（VC，Magro的载体对照）、Magro单药、Ara-C+VC、Aza+VC、Ara-C+Magro及Aza+Magro，并进行生存期随访。对达到人道安乐死终点或实验时间截止的小鼠采集组织样本以评估疾病负荷。 结果：Magro单药治疗显著改善了AML006（p<0.0001）和AML013（p=0.003）模型的生存期，并降低了AML006（p=0.009）和AML013（p=0.002）的骨髓疾病负荷。Ara-C+Magro联合治疗在所有三种模型中均显著改善生存期，并显著降低AML006（p<0.0001）和AML013（p=0.048）的骨髓疾病负荷。Aza+Magro联合治疗显著改善了AML013（p=0.047）和AML010（p=0.017）的生存期，并显著降低AML010（p=0.001）的骨髓疾病负荷。 结论：值得注意的是，对Magro治疗呈现生存期改善的两个模型均携带KMT2A重排，提示存在可能对CD47阻断治疗更敏感的特定患者亚群。随着该药物在其他恶性肿瘤中的评估推进，未来研究可重点关注基于生物标志物的患者选择策略的重要性。
肿瘤(癌症)患者之家