Targeted at particle immunotherapy for myeloid leukemia
Targeted at particle immunotherapy for myeloid leukemia
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DOI：
10.1182/blood.v100.4.1233.h81602001233_1233_1239
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发表时间：
2002-08-15
期刊：
影响因子：
20.3
通讯作者：
Scheinberg, DA
中科院分区：
文献类型：
--
作者：
Jurcic, JG;Larson, SM;Scheinberg, DA
与发射β粒子的同位素不同，阿尔法发射体可以通过单个原子衰变选择性地杀死单个癌细胞。HuM195是一种人源化的抗CD33单抗，专门针对髓系白血病细胞，具有抗微小疾病的活性。当标记有β发射体I-131和Y-90时，HuM195可以消除患者的巨大白血病负担，但它会产生长期的骨髓抑制，需要在高剂量下进行造血干细胞移植。为了增强天然HuM195的效力，同时避免β发射构建体的非特异性细胞毒性，将α发射同位素Bi213连接到HuM195上。用10.36~37.0MBq/kg的Bi2 13-HuM195治疗18例复发难治性急性髓系白血病或慢性粒单核细胞白血病。未见明显的髓外毒性。所有17名可评估的患者都出现了骨髓抑制，恢复时间的中位数为22天。几乎所有的Bi-213-HuM195都迅速定位并保留在白血病受累区域，包括骨髓、肝脏和脾。这些部位和全身之间的吸收剂量比在这个抗原系统和患者群体中看到的贝塔发射结构的吸收剂量比要大1000倍。15名可评估患者中有14名(93%)循环原始细胞减少，18名患者中有14名(78%)骨髓原始细胞百分比减少。这项研究证明了Bi-213-HuM195的安全性、可行性和抗白血病作用，这是系统靶向a粒子免疫疗法在人类中的第一次概念验证。(C)2002年，由美国血液病学会公布。
Unlike beta particle-emitting isotopes, alpha emitters can selectively kill individual cancer cells with a single atomic decay. HuM195, a humanized anti-CD33 monoclonal antibody, specifically targets myeloid leukemia cells and has activity against minimal disease. When labeled with the beta-emitters I-131 and Y-90, HuM195 can eliminate large leukemic burdens in patients, but it produces prolonged myelosuppression requiring hematopoietic stem cell transplantation at high doses.' To enhance the potency of native HuM195 yet avoid the nonspecific cytotoxicity of beta-emitting constructs, the alpha-emitting iso-tope Bi-213 was conjugated to HuM195. Eighteen patients with relapsed and refractory acute myelogenous leukemia or chronic myelomonocytic leukemia were treated with 10.36 to 37.0 MBq/kg Bi-213-HuM195. No significant extramedullary toxicity was seen. All 17 evaluable patients developed myelosuppression, with a median time to recovery of 22 days. Nearly all the Bi-213-HuM195 rapidly localized to and was retained in areas of leukemic involvement, including the bone marrow, liver, and spleen. Absorbed dose ratios between these sites and the whole body were 1000-fold greater than those seen with beta-emitting constructs in this antigen system and patient population. Fourteen (93%) of 15 evaluable patients had reductions in circulating blasts, and 14 (78%) of 18 patients had reductions in the percentage of bone marrow blasts. This study demonstrates the safety, feasibility, and antileukemic effects of Bi-213-HuM195, and it is the first proof-of-concept for systemic targeted a particle immunotherapy in humans. (C) 2002 by The American Society of Hematology.