Conventional Anti-CD45 Radioimmunotherapy Comparing ⁹⁰Y or ¹⁷⁷Lu for Treatment of AML in a Syngeneic Disseminated Murine Leukemia Model,

Radioimmunotherapy (RIT) studies for the treatment of acute myeloid leukemia (AML) have mostly employed antibodies (Ab) labeled with ¹³¹I or ⁹⁰Y, but both radionuclides have limitations. The high-energy gamma component of ¹³¹I requires that patients be treated in isolation to minimize radiation exposure risk to staff and family, warranting consideration of alternative radionuclides. In contrast, ⁹⁰Y is a pure beta-emitter used in RIT, thereby not requiring extensive radiation isolation. It also has the potential of delivering improved therapeutic ratios of absorbed doses of radiation because of its higher beta energy (2.3 Median Energy [MeV] for ⁹⁰Y compared to 0.66 MeV for ¹³¹I) and shorter half-life (2.7 days for ⁹⁰Y compared to 8 days for ¹³¹I). Because ⁹⁰Y has few gamma emissions, a surrogate radioisotope is required for nuclear imaging, necessary for dosimetry calculations. In view of these limitations, and the anti-tumor effects of ¹³¹I-anti-CD45 Ab demonstrated by our group, we studied ¹⁷⁷Lu, a beta-emitting radio-metal with a half-life (6.7 days) and energetics (0.5 MeV) similar to ¹³¹I. However, ¹⁷⁷Lu has lower energy gamma emissions during its decay that is theoretically capable of reducing whole body exposure to gamma radiation while facilitating imaging. To optimize the therapeutic efficacy and minimize toxicities of RIT we compared the relative merits of ⁹⁰Y and ¹⁷⁷Lu in biodistribution, dosimetry, and therapy experiments using a mouse model of syngeneic, disseminated AML.

For biodistribution studies, we inoculated B6SJLF1/J mice with 10⁵ leukemic PBMC via tail vein injection and two days later mice received ⁹⁰Y- or ¹⁷⁷Lu-DOTA-30F11 (anti-murine CD45 Ab). Mice were euthanized at serial time-points, their organs harvested and then analyzed in a gamma counter to calculate the percent of the injected dose of radiolabeled Ab per gram of each organ (%ID/g). In therapy studies, 10 mice per group were inoculated with leukemic PBMC, and two days later treated with either 100 mCi or 300 mCi of⁹⁰Y- or ¹⁷⁷Lu-DOTA-30F11.

Biodistribution studies demonstrated excellent localization of both radioimmunoconjugates to sites of highest leukemic burden (bone marrow [BM] and spleen), while minimizing uptake in non-hematopoietic organs. After 24 hours, 67.5 ± 19.0% and 187 ± 20.2% ID/g of ⁹⁰Y-DOTA-30F11 and 9.8 ± 2.7% and 141 ± 18.3% ID/g of ¹⁷⁷Lu-DOTA-30F11 were delivered to BM and spleen, respectively. Non-hematopoietic organs such as kidneys had ≤5.2 ± 0.8% ID/g for ⁹⁰Y and ≤2.7 ± 0.3% ID/g for ¹⁷⁷Lu. This approach yielded BM-to-normal organ ratios of %ID/g as high as 36:1 (⁹⁰Y) and 39:1 (¹⁷⁷Lu) for muscle. Ratios were higher when comparing spleen to normal organs: 375:1 (⁹⁰Y) and 409:1 (¹⁷⁷Lu) for muscle. Ratios for dose limiting organs such as liver and lung were also favorable, with spleen:lung = 46.9:1 and BM:lung = 4.6:1 for ⁹⁰Y, and spleen:lung = 47.8:1 and BM:lung =4.8:1 for ¹⁷⁷Lu. In therapy studies, all untreated AML mice (Figure - No Tx group) died of disease between 33 and 56 days (median 39 days). Sixty percent of mice that received 300 mCi and twenty percent of mice that received 100 mCi of ⁹⁰Y-DOTA-30F11 are alive over 140 days after therapy (median survival not reached and 67 days, respectively). Conversely, all mice that received 300 mCi of ¹⁷⁷Lu-DOTA-30F11 died of toxicity and survived a median of only 16 days while all mice treated with 100 mCi of ¹⁷⁷Lu-DOTA-30F11 died due to progressive AML (median survival 52 days).

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These data suggest that ⁹⁰Y-anti-CD45 RIT may be more effective and better tolerated than ¹⁷⁷Lu-anti-CD45 RIT. These data also suggest that the toxicities seen in this model using ¹⁷⁷Lu may be attributed to its longer half-life compared to ⁹⁰Y, while the inferior efficacy detected may be a consequence of the lower overall dose delivered to AML cells in vivo. The superiority of ⁹⁰Y compared to ¹⁷⁷Lu for use in RIT is being confirmed using a human AML xenograft system. ⁹⁰Y and ¹⁷⁷Lu are also being compared using a pretargeted RIT approach in both murine leukemia models.

Gopal:GSK: Research Funding; Spectrum: Research Funding; Seattle Genetics: Consultancy, Research Funding; Merck: Research Funding; Piramal: Research Funding; Cephalon: Research Funding; Millenium: Speakers Bureau; Abbott: Research Funding; Pfizer: Research Funding; SBio: Research Funding; Bio Marin: Research Funding; Biogen-Idec: Research Funding.