Jurcic Joseph G
Division of Hematology/Oncology, Department of Medicine, Columbia University Medical Center, New York- Presbyterian Hospital, Herbert Irving Comprehensive Cancer Center, New York, NY, United States.
Curr Radiopharm. 2018;11(3):192-199. doi: 10.2174/1874471011666180525102814.
Due to the shorter range and higher linear energy transfer of α-particles compared to β-particles, targeted α-particle therapy may produce more efficient tumor killing while sparing neighboring healthy cells. We will review the clinical studies using α-particle therapy for Acute Myeloid Leukemia (AML).
A series of clinical trials were conducted to assess the safety, feasibility, and anti-leukemic effects of lintuzumab, an anti-CD33 humanized monoclonal antibody, labeled with the α-emitters bismuth- 213 (213Bi) and actinium-225 (225Ac).
An initial phase I study conducted in 18 patients with relapsed or refractory AML demonstrated the safety and antitumor effects of 213Bi-lintuzumab. Subsequently, 213Bi-lintuzumab produced remissions in AML patients after partial cytoreduction with cytarabine in phase I/II trial. The 46- minute half-life of 213Bi and need for an onsite generator has limited its utility. Therefore, a secondgeneration construct was developed using 225Ac, a radiometal that yields four α-particle emissions. A phase I trial demonstrated that a single infusion of 225Ac-lintuzumab could be given safely at doses up to 111 kBq/kg with anti-leukemic activity across all dose levels studied. In a second phase I study, 28% of older patients with untreated AML had objective responses after receiving fractionated-dose 225Aclintuzumab and low-dose cytarabine.
Based upon the encouraging results seen in phase I trials of 225Ac-lintuzumab, a phase II study of 225Ac-lintuzumab monotherapy for older patients with untreated AML is now in progress and is also being studied in a subset of patients with CD33-positive multiple myeloma.
由于与β粒子相比，α粒子的射程较短且线能量转移较高，靶向α粒子治疗可能在杀死肿瘤方面更有效，同时使邻近的健康细胞免受损伤。我们将回顾使用α粒子治疗急性髓系白血病（AML）的临床研究。
进行了一系列临床试验，以评估用α发射体铋 - 213（²¹³Bi）和锕 - 225（²²⁵Ac）标记的抗CD33人源化单克隆抗体林妥珠单抗的安全性、可行性和抗白血病效果。
在18例复发或难治性AML患者中进行的初始I期研究证明了²¹³Bi - 林妥珠单抗的安全性和抗肿瘤效果。随后，在I/II期试验中，²¹³Bi - 林妥珠单抗在阿糖胞苷进行部分细胞减灭后使AML患者获得缓解。²¹³Bi的46分钟半衰期以及对现场发生器的需求限制了其应用。因此，开发了一种使用²²⁵Ac的第二代构建体，²²⁵Ac是一种产生四次α粒子发射的放射性金属。一项I期试验表明，单次输注²²⁵Ac - 林妥珠单抗，剂量高达111 kBq/kg时可安全给药，且在所研究的所有剂量水平均具有抗白血病活性。在第二项I期研究中，28%未治疗的老年AML患者在接受分次剂量的²²⁵Ac - 林妥珠单抗和低剂量阿糖胞苷后有客观反应。
基于²²⁵Ac - 林妥珠单抗I期试验中看到的令人鼓舞的结果，一项针对未治疗的老年AML患者的²²⁵Ac - 林妥珠单抗单药治疗的II期研究正在进行中，并且也在一部分CD33阳性多发性骨髓瘤患者中进行研究。
