Targeted Alpha-Particle Immunotherapy for Acute Myeloid Leukemia

Author(s):  
Joseph G. Jurcic ◽  
Todd L. Rosenblat

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 (213Bi)-labeled lintuzumab. In a subsequent study, 213Bi-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 213Bi, however, is limited by its short half-life. Therefore, a second-generation construct containing actinium-225 (225Ac), a radiometal that generates four alpha-particle emissions, was developed. A phase I trial demonstrated that 225Ac-lintuzumab is safe at doses of 3 μCi/kg or less and has antileukemic activity across all dose levels studied. Fractionated-dose 225Ac-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 213Bi- and astatine-211 (211At)-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.

2011 ◽  
Vol 29 (15_suppl) ◽  
pp. 6516-6516 ◽  
Author(s):  
J. G. Jurcic ◽  
T. L. Rosenblat ◽  
M. R. McDevitt ◽  
N. Pandit-Taskar ◽  
J. A. Carrasquillo ◽  
...  

2019 ◽  
Vol 95 (1) ◽  
pp. 48-56 ◽  
Author(s):  
Elizabeth F. Krakow ◽  
Boglarka Gyurkocza ◽  
Barry E. Storer ◽  
Thomas R. Chauncey ◽  
Jeannine S. McCune ◽  
...  

2013 ◽  
Vol 47 (1) ◽  
pp. 14-17 ◽  
Author(s):  
Joseph G Jurcic

ABSTRACT Lintuzumab, a humanized anti-CD33 antibody, targets myeloid leukemia cells and has modest activity against acute myeloid leukemia (AML). To increase the antibody's potency yet avoid nonspecific cytotoxicity seen with β-emitting isotopes, lintuzumab was conjugated to the α-emitters bismuth-213 (213Bi) and actinium-225 (225Ac). The 46-minute half-life of 213Bi limits its widespread use. Therefore, 225Ac was also conjugated to various antibodies using DOTA-SCN. We conducted a phase I trial of 213Bi-lintuzumab and subsequently administered cytarabine with 213Bi-lintuzumab in a phase I/II study. The toxicity and biological activity of 225Ac-linutuzumab in patients with relapsed/refractory AML in a phase I dose-escalation trial was determined. An initial phase I trial demonstrated the feasibility, safety and antileukemic activity of 213Bi-lintuzumab. 213Bi-lintuzumab produced responses in 24% of AML patients receiving doses ≥ 37 MBq/kg after partial cytoreduction with cytarabine. 225Ac-labeled immunoconjugates killed in vitro at doses at least 1,000 times lower than 213Bi analogs. Eighteen patients with relapsed/refractory AML received 18.5 to 148 kBq/kg of 225Ac-lintuzumab in a phase I study. Dose-limiting toxicities were myelosuppression lasting >35 days in one patient and death due to sepsis in two patients. The maximum tolerated dose (MTD) was 111 KBg/kg. Bone marrow blast reductions were seen across all dose levels. Targeted α- particle immunotherapy with 213Bi- and 225Ac-lintuzumab is safe, has significant antileukemic effects, and can produce remissions after partial cytoreduction. How to cite this article Jurcic JG. Targeted Alpha-Particle Immunotherapy with Bismuth-213 and Actinium-225 for Acute Myeloid Leukemia. J Postgrad Med Edu Res 2013;47(1): 14-17.


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