Article Figures & Data
Figures
- FIGURE 1.
High-dose 177Lu-DOTA-daratumumab (11.1 MBq) for treatment of disseminated MM. (A) Representative bioluminescence images for each group, imaged weekly, with intensity as indicated by color bar. Single mouse survived until day 36 (not shown in A). (B) Myeloma burden as quantified on BLI images, in radiance (daratumumab, P > 0.999; 11.1 MBq of 177Lu-DOTA-daratumumab, P = 0.038) and as quantified on Kaplan–Meier survival plot (daratumumab, P > 0.999; 11.1 MBq of 177Lu-DOTA-daratumumab, P = 0.045). (C) Whole-body toxicity as measured by weight (daratumumab, P = 0.883; 11.1 MBq of 177Lu-DOTA-daratumumab, P = 0.914). n = 4 for all groups. Dara = daratumumab.
- FIGURE 2.
Dose response of 177Lu-DOTA-daratumumab (1.85, 3.7, and 7.4 MBq) for treatment of disseminated MM model. (A) Representative BLI images for each group, with intensity as indicated by color bar. (B) MM burden as quantified on BLI images, in radiance (1.85 MBq of 177Lu-DOTA-daratumumab, P = 0.91; 3.7 MBq of 177Lu-DOTA-daratumumab, P = 0.015; 7.4 MBq of 177Lu-DOTA-daratumumab, P = 0.014) and as quantified on Kaplan–Meier survival plot (1.85-MBq dose, P < 0.01; 3.7-MBq dose, P = 0.0310; 7.4-MBq dose, P < 0.01). Crosses indicate days on which mice were euthanized. (C) Whole-body toxicity as measured by weight (1.85-MBq dose, P = 0.997; 3.7-MBq dose, P = 0.821; 7.4-MBq dose, P = 0.750). n = 6 for saline group, 4 for 1.85-MBq group, and 5 for 3.7- and 7.4-MBq groups. Dara = daratumumab.
- FIGURE 3.
High dose of 225Ac-DOTA-daratumumab (11.1 and 22.2 kBq) for treatment of disseminated MM. (A) Representative BLI for each group, with intensity as indicated by color bar. To visually compare groups, >30-d separate scale was used. (B) MM burden as quantified on BLI, in radiance (22.2 kBq of 225Ac-DOTA-trastuzumab, P = 0.035; 11.1 kBq of 225Ac-DOTA-daratumumab, P = 0.015; 22.2 kBq of 225Ac-DOTA-daratumumab, P = 0.015) and as quantified on Kaplan–Meier survival plot (22.2 kBq of 225Ac-DOTA-trastuzumab, P < 0.01; 11.1 kBq of 225Ac-DOTA-daratumumab, P < 0.01; 22.2 kBq of 225Ac-DOTA-daratumumab, P < 0.01). Crosses indicate days on which mice were euthanized. (C) Whole-body toxicity as measured by weight (22.2 kBq of 225Ac-DOTA-trastuzumab, P = 0.0096; 11.1 kBq of 225Ac-DOTA-daratumumab, P = 0.0306; 22.2 kBq of 225Ac-DOTA-daratumumab, P = 0.0048). n = 8 for saline group and 4 for treated groups. Dara = daratumumab; Tras = trastuzumab.
- FIGURE 4.
Dose response of 225Ac-DOTA-daratumumab (0.925, 1.85, and 3.7 kBq) for treatment of disseminated MM. (A) Representative BLI for each group, with intensity as indicated by color bar. After day 52, single mouse survived until day 66 (not shown in A). To visually compare groups, >30-d separate scale was used. (B) MM burden as quantified on BLI, in radiance (225Ac-DOTA-trastuzumab groups: 0.925 kBq, P = 0.96; 1.85 kBq, P = 0.67; 3.7 kBq, P = 0.42) (225Ac-DOTA-daratumumab groups: 0.925 kBq, P < 0.01; 1.85 kBq, P < 0.01; 3.7 kBq, P < 0.01) and as quantified on Kaplan–Meier survival plot (225Ac-DOTA-trastuzumab groups: 0.925 kBq, P = 0.048; 1.85 kBq, P = 0.048; 3.7 kBq, P = 0.048) (225Ac-DOTA-daratumumab groups: 0.925 kBq, P < 0.01; 1.85 kBq P < 0.01; 3.7 kBq, P < 0.01). Crosses indicate days on which mice were euthanized. (C) Whole-body toxicity as measured by weight (225Ac-DOTA-trastuzumab groups: 0.925 kBq, P = 0.992; 1.85 kBq, P = 0.999; 3.7 kBq, P = 0.999) (225Ac-DOTA-daratumumab groups: 0.925 kBq, P ≥ 0.999; 1.85 kBq, P ≥ 0.999; 3.7 kBq, P = 0.995). n = 8 for saline group and 6 for therapy groups. Dara = daratumumab; Tras = trastuzumab.
- FIGURE 5.
Radiobiologic analysis of 225Ac-DOTA-daratumumab and 177Lu-DOTA-daratumumab therapy. Radiosensitivity parameter α (Gy−1) is calculated for all dose levels of 225Ac and 177Lu DOTA-daratumumab treatments. (A) We observed nonlinear relationship between radiosensitivity and dose for 225Ac. Although 0.925 kBq results in largest value of α, this dose level did not confer survival advantage. Model predicts 3.7 kBq of 225Ac-DOTA-daratumumab to provide largest radiosensitivity and therapeutic benefit relative to 1.85-, 11.1-, and 22.2-kBq doses. (B) Low-LET 177Lu results in 10-fold lower α than does high-LET 225Ac and less pronounced correlation with injected activity. (C and D) Tumor burden measured by bioluminescence over time and mathematic model fits for 3.7 kBq of 225Ac and 7.4 MBq of 177Lu, respectively. Difference in duration of response can be seen between 225Ac and 177Lu, 60–80 d vs. 30–40 d. Dara = daratumumab.
Tables
- TABLE 1
Efficacy, Toxicity, and Whole-Body Absorbed Dose for 177Lu Radioimmunotherapy in MM1-S Disseminated MM
177Lu-DOTA-daratumumab Parameter Vehicle control (n ≤ 10)* Daratumumab (n ≤ 4) 1.85 MBq (n ≤ 4) 3.7 MBq (n ≤ 5) 7.4 MBq (n ≤ 5) 11.1 MBq (n ≤ 4) Duration of tumor growth delay (days after MM1-S injection) 0 0 0 33 33 32 Start of weight loss (days after MM1-S injection) 28† 26† 33† 33‡ 33‡ 26‡ Median survival (days after MM1-S injection) 33 31 44 54 47 36 Whole-body absorbed dose (Gy) — — 0.9 1.9 4.1 6.4 - TABLE 2
Efficacy, Toxicity, and Whole-Body Absorbed Dose for 225Ac-Targeted α-Therapy in MM1-S Disseminated MM
225Ac-DOTA-trastuzumab 225Ac-DOTA-daratumumab Parameter Vehicle control (n ≤ 16)* 0.925 kBq (n ≤ 6) 1.85 kBq (n ≤ 6) 3.7 kBq (n ≤ 6) 22.2 kBq (n ≤ 4) 0.925 kBq (n ≤ 6) 1.85 kBq (n ≤ 6) 3.7 kBq (n ≤ 6) 11.1 kBq (n ≤ 4) 22.2 kBq (n ≤ 4) Duration of tumor growth delay (days after MM1-S injection) 0 0 0 0 0 16 16 29 36 43 Start of weight loss (days after MM1-S injection) 22† 22† 22† 22† 0‡ 39† 39† 73 0‡ 0‡ Median survival (days after MM1-S injection) 33 35 35 35 36 45 51 72 77 64 Whole-body absorbed dose (Gy) — 0.2 0.3 0.7 4.2 0.2 0.4 0.8 2.3 4.7
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