Comparative Biodistribution of 89Zr-ofatumumab and 225Ac-ofatumumab for Lymphoma Radioimmunotherapy

体内分布 拉吉细胞 放射免疫疗法 淋巴瘤 单克隆抗体 药代动力学 医学 化学 最大值 药理学 抗体 分子生物学 免疫学 生物化学 生物 体外
作者
Mark S. Longtine,Mark J. Hoegger,Diane S. Abou,Kyu-Hwan Shim,Daniel L.J. Thorek,Richard L. Wahl
出处
期刊:The Journal of Nuclear Medicine [Society of Nuclear Medicine and Molecular Imaging]
卷期号:61: 381-381 被引量:1
摘要

381 Objectives: Immunotherapies that target the CD20 protein present on most non-Hodgkins lymphoma (NHL) cells have greatly improved outcomes. However, as many patients are refractory or undergo relapse, current treatments are inadequate. Our previous work showed that 89Zr-labeled ofatumumab (Ofa), a next-generation, fully human anti-CD20 antibody, effectively targets lymphoma xenografts (Yoon et al, 2018, JNM). Here, we describe characterization of Ofa labeled with Actinium-225 (225Ac-Ofa), which emits 4 cell-killing alpha particles per decay and compare tumor targeting and biodistribution of 225Ac-Ofa with 89Zr-Ofa. 225Ac-Ofa has potential advantages over previous beta-particle-based radioimmunotherapies for NHL. Methods: DOTA was conjugated to Ofa at an 8:1 molar ratio. 225Ac was chelated and 225Ac-Ofa purified by size exclusion chromatography (SEC). Radiochemical yield was assayed by iTLC and radiochemical purity by iTLC and fast protein liquid chromatography (FPLC). Immunoreactivity was assayed by binding to Raji B-cell lymphoma cells. Stability in human serum was assayed by iTLC. Raji-luc tumor-cell killing by 225Ac-Ofa was evaluated by MTS and bioluminescence assays. 89Zr-Ofa was prepared as described (Yoon et al.). Mice with subcutaneous Raji xenografts were injected IV with 300 nCi (10 µg) 225Ac-Ofa (n=4), 100 µCi (10 µg) 89Zr-Ofa (n=3) or 300 nCi free 225Ac (n=5). Naive mice were injected IV with 225Ac-Ofa (n=4) or 89Zr-Ofa (n=4). Biodistribution in 20 organs/tissues were determined 7 d post-injection as % injected dose/gram. Results: We obtained 225Ac-Ofa (n=5) with radiochemical yields of 36±6% and >98% radiochemical purity. FPLC confirmed >98% of the 225Ac was bound to Ofa. Specific activity was >100 nCi/µg. 225Ac-Ofa immunoreactivity was >65%, similar to 89Zr-Ofa. Serum stability was 70-90% after 10 d at 37°C (n=3). 225Ac-Ofa showed potent and dose-dependent killing of Raji-luc cells at concentrations from 10-100 nCi/ml vs. 225Ac-IgG or unlabeled Ofa (p 0.05) to 89Zr-Ofa (43±13% ID/g). Biodistribution was also not statistically different between 225Ac-Ofa and 89Zr-Ofa in liver (31±6 vs. 21±2% ID/g), blood (10±3 vs. 9±2% ID/g), spleen (31±6 vs. 21±3 % ID/g), bone marrow (7±2 vs. 8±2 % ID/g) or other issues analyzed. In tumor-bearing mice, free 225Ac accumulated to high levels in the liver (64±19% ID/g), significantly (p 0.05) localizations to blood (16±1 vs. 13±2% ID/g), liver (10±2 vs. 9±1% ID/g), spleen (34±6 vs. 22±7% ID/g), bone marrow (15±8 vs. 10±4% ID/g) and other tissues. Conclusions: 225Ac-Ofa was obtained with high radiochemical purity, immunoreactivity and in vitro stability. 225Ac-Ofa showed high potency in specifically killing CD20-expressing lymphoma cells in vitro. 225Ac-Ofa specifically targeted CD20-expressing lymphoma xenografts, similar to the targeting observed by 89Zr-Ofa, and 225Ac-Ofa vs. 89Zr-Ofa showed highly similar biodistributions to non-target organs/tissues. Together, these results suggest 225Ac-Ofa has considerable potential for radioimunotherapy of non-Hodgkin lymphoma and that 89Zr-Ofa and 225Ac-Ofa may form a theranostic (imaging and therapeutic) pair for these patients.

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