Jurcic Joseph G, Rosenblat Todd L
From the Division of Hematology/Oncology, Department of Medicine, Columbia University Medical Center; the New York-Presbyterian Hospital, and the Herbert Irving Comprehensive Cancer Center, New York, NY.
Am Soc Clin Oncol Educ Book. 2014:e126-31. doi: 10.14694/EdBook_AM.2014.34.e126.
Because alpha-particles have a shorter range and a higher linear energy transfer (LET) compared with beta-particles, targeted alpha-particle immunotherapy offers the potential for more efficient tumor cell killing while sparing surrounding normal cells. To date, clinical studies of alpha-particle immunotherapy for acute myeloid leukemia (AML) have focused on the myeloid cell surface antigen CD33 as a target using the humanized monoclonal antibody lintuzumab. An initial phase I study demonstrated the safety, feasibility, and antileukemic effects of bismuth-213 ((213)Bi)-labeled lintuzumab. In a subsequent study, (213)Bi-lintuzumab produced remissions in some patients with AML after partial cytoreduction with cytarabine, suggesting the utility of targeted alpha-particle therapy for small-volume disease. The widespread use of (213)Bi, however, is limited by its short half-life. Therefore, a second-generation construct containing actinium-225 ((225)Ac), a radiometal that generates four alpha-particle emissions, was developed. A phase I trial demonstrated that (225)Ac-lintuzumab is safe at doses of 3 μCi/kg or less and has antileukemic activity across all dose levels studied. Fractionated-dose (225)Ac-lintuzumab in combination with low-dose cytarabine (LDAC) is now under investigation for the management of older patients with untreated AML in a multicenter trial. Preclinical studies using (213)Bi- and astatine-211 ((211)At)-labeled anti-CD45 antibodies have shown that alpha-particle immunotherapy may be useful as part conditioning before hematopoietic cell transplantation. The use of novel pretargeting strategies may further improve target-to-normal organ dose ratios.
与β粒子相比，α粒子的射程较短且线性能量传递（LET）较高，因此靶向α粒子免疫疗法有可能更有效地杀死肿瘤细胞，同时使周围正常细胞免受损伤。迄今为止，针对急性髓系白血病（AML）的α粒子免疫疗法的临床研究主要聚焦于将髓系细胞表面抗原CD33作为靶点，使用人源化单克隆抗体林妥珠单抗。一项初始的I期研究证明了铋-213（²¹³Bi）标记的林妥珠单抗的安全性、可行性及抗白血病作用。在随后的一项研究中，²¹³Bi-林妥珠单抗在部分患者中经阿糖胞苷进行部分细胞减灭后产生了缓解，这表明靶向α粒子疗法对小体积疾病有用。然而，²¹³Bi的广泛应用受到其半衰期短的限制。因此，开发了一种含有锕-225（²²⁵Ac）的第二代构建体，²²⁵Ac是一种能产生四次α粒子发射的放射性金属。一项I期试验表明，²²⁵Ac-林妥珠单抗在剂量为3μCi/kg或更低时是安全的，并且在所有研究剂量水平下均具有抗白血病活性。目前正在一项多中心试验中研究分次剂量的²²⁵Ac-林妥珠单抗联合小剂量阿糖胞苷（LDAC）用于治疗未治疗的老年AML患者。使用²¹³Bi和砹-211（²¹¹At）标记的抗CD45抗体的临床前研究表明，α粒子免疫疗法可能作为造血细胞移植前的部分预处理有用。使用新型预靶向策略可能会进一步提高靶器官与正常器官的剂量比。
