Therapeutic antibody targeting of CD47 eliminates human acute lymphoblastic leukemia.
Therapeutic antibody targeting of CD47 eliminates human acute lymphoblastic leukemia.
复制标题
DOI：
10.1158/0008-5472.can-10-2238
复制
发表时间：
2011-02-15
期刊：
影响因子：
11.2
通讯作者：
Majeti R
中科院分区：
文献类型：
--
作者：
Chao MP;Alizadeh AA;Tang C;Jan M;Weissman-Tsukamoto R;Zhao F;Park CY;Weissman IL;Majeti R
急性淋巴细胞白血病（ALL）是最常见的儿科恶性肿瘤，占成人白血病的15%。尽管儿童ALL的总体预后良好，但高危儿童患者和大多数成人患者的预后明显较差。多药化疗是儿童和成人ALL的标准治疗，但与全身毒性和长期副作用相关，并且对某些ALL亚型相对无效。最近的努力集中在ALL的靶向治疗的发展，包括单克隆抗体。在这里，我们报告的鉴定CD47，一种蛋白质，抑制吞噬作用，作为一个抗体的目标，在标准和高风险的急性淋巴细胞白血病。发现与正常细胞对应物相比，CD47在人类ALL患者样本的子集上更高表达，并且在几个ALL患者队列中是生存和疾病难治性的独立预测因子。此外，针对CD47的阻断性单克隆抗体能够在体外通过巨噬细胞吞噬ALL细胞，并在体内抑制肿瘤植入。值得注意的是，抗CD47抗体消除了移植了原代人ALL的小鼠的外周血、骨髓、脾脏和肝脏中的ALL。这些数据为开发用于治疗人ALL的抗CD47抗体疗法提供了临床前支持。
Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy and constitutes 15% of adult leukemias. Although overall prognosis for pediatric ALL is favorable, high-risk pediatric patients and most adult patients have significantly worse outcomes. Multi-agent chemotherapy is standard of care for both pediatric and adult ALL, but is associated with systemic toxicity and long-term side effects, and is relatively ineffective against certain ALL subtypes. Recent efforts have focused on the development of targeted therapies for ALL including monoclonal antibodies. Here we report the identification of CD47, a protein that inhibits phagocytosis, as an antibody target in standard and high-risk ALL. CD47 was found to be more highly expressed on a subset of human ALL patient samples compared to normal cell counterparts and to be an independent predictor of survival and disease refractoriness in several ALL patient cohorts. Additionally, a blocking monoclonal antibody against CD47 enabled phagocytosis of ALL cells by macrophages in vitro, and inhibited tumor engraftment in vivo. Significantly, anti-CD47 antibody eliminated ALL in the peripheral blood, bone marrow, spleen, and liver of mice engrafted with primary human ALL. These data provide pre-clinical support for the development of an anti-CD47 antibody therapy for treatment of human ALL.