한빛사논문
- 조회187
Kyuhwan Shim, Mark S. Longtine, Diane S Abou, Mark J Hoegger, Richard S Laforest, Daniel LJ Thorek and Richard L. Wahl
Mallinckrodt Institute of Radiology, Washington University School of Medicine, United States
For correspondence or reprints contact: Richard L. Wahl
Abstract
Although immunotherapies that target CD20 on most non-Hodgkin lymphoma (NHL) cells have improved patient outcomes, current therapies are inadequate as many patients are or become refractory or undergo relapse. Here, we label the third-generation human anti-CD20 antibody, ofatumumab, with lutetium-177 (177Lu), determine the in vitro characteristics of [177Lu]Lu-ofatumumab, estimate human dosimetry, and assay tumor targeting and therapeutic efficacy in a murine model of disseminated NHL. Methods: CHX-A"-DTPA-[177Lu]Lu-ofatumumab was prepared. We evaluated radiochemical yield, purity, in vitro immunoreactivity, stability, (n = 7), affinity, and killing of CD20-expressing Raji cells (n = 3). Human dosimetry was estimated from biodistribution studies as % injected activity per gram (% IA/g) using C57Bl/6N mice. Tissue/organ biodistribution was determined in R2G2 immunodeficient mice with subcutaneous Raji-cell tumors. Therapy studies used R2G2 mice with disseminated human Raji-luc tumor cells (n = 10 mice/group). Four d post cell injection, mice were untreated or treated with ofatumumab, 8.51 MBq of [177Lu]Lu-IgG or 0.74 or 8.51 MBq of [177Lu]Lu-ofatumumab. Survival, weight, and bioluminescence were tracked. Results: Radiochemical yields were 93±2%, radiochemical purities 99±1% and specific activities 401±17 MBq/mg. Immunoreactivity was substantially preserved and >75% 177Lu remained chelated after 7 d in serum. [177Lu]Lu-ofatumumab specifically killed Raji-luc cells in vitro (p<0.05). Dosimetry estimated an effective dose for human administration of 0.36 mSv/MBq and that marrow may be the dose-limiting organ. Biodistribution in subcutaneous tumors 1, 3 and 7 after [177Lu]Lu-ofatumumab injection was 11, 15, and 14% IA/g, respectively. In the therapy study, median survival of untreated mice was 19 d, not statistically different than mice treated with 8.51 MBq of [177Lu]Lu-IgG (25 d). Unlabeled ofatumumab increased survival to 46 d, similar to 0.74 MBq of [177Lu]Lu-ofatumumab (59 d), with both superior to no treatment (p<0.0003). Weight loss and increased tumor burden preceded death or sacrifice for cause. In contrast, treatment with 8.51 MBq of [177Lu]Lu-ofatumumab dramatically increased median survival (>221 d), permitted weight gain, eliminated detectable tumors, and was curative in 9/10 mice. Conclusion: [177Lu]Lu-ofatumumab shows favorable in vitro characteristics, localizes to tumor, and shows curative therapeutic efficacy in a disseminated lymphoma model, showing potential for clinical translation to treat NHL.
논문정보
- Research article
- 2022년 11월 (BRIC 등록일 2023-02-07)
- 국외 연구진
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