Biodistribution and Dosimetry of 177Lu-tetulomab, a New Radioimmunoconjugate for Treatment of Non-Hodgkin Lymphoma

Abstract

The biodistribution of the anti-CD37 radioimmunoconjugate 177Lu-tetraxetan-tetulomab (177Lu-DOTA-HH1) was evaluated. Biodistribution of 177Lu-tetraxetan-tetulomab was compared with 177Lu-tetraxetan-rituximab and free 177Lu in nude mice implanted with Daudi lymphoma xenografts. The data showed that 177Lu-tetulomab had a relevant stability and tumor targeting properties in the human lymphoma model. The half-life of 177Lu allowed significant tumor to normal tissue ratios to be obtained indicating that 177Lu-tetraxetan-tetulomab could be suitable for clinical testing. The biological and effective half-life in blood was higher for 177Lu-tetraxetan-tetulomab than for 177Lu-tetraxetan-rituximab. The biodistribution of 177Lu-tetraxetan-tetulomab did not change significantly when the protein dose was varied from 0.01 to 1 mg/kg. Dosimetry calculations showed that the absorbed radiation doses to normal tissues and tumor in mice were not significantly different for 177Lu-tetraxetan-tetuloma b and 177Lu-tetraxetan-rituximab. The absorbed radiation doses were extrapolated to human absorbed radiation doses. These extrapolated absorbed radiation doses to normal tissues for 177Lu-tetraxetan-tetulomab at an injection of 40 MBq/kg were significantly lower than the absorbed radiation doses for 15 MBq/kg Zevalin, suggesting that higher tumor radiation dose can be reached with 177Lu-tetraxetan-tetulomab in the clinic.

Synthesis and Preclinical Evaluation of177Lu-CHX-A”-DTPA-Rituximab as a Radioimmunotherapeutic Agent for Non-Hodgkin's Lymphoma

“…These results compared well with the biodistribution studies of 177 Lu-DOTA-Rituximab carried out in female BALB/c-nude (nu/nu) mice with Daudi xenografts, wherein tumor uptake increased up to 2 days after injection while activity levels in blood and normal tissues cleared significantly in the first few days. 17 Accumulation of activity was found in the blood, liver, kidneys, and spleen as expected as these organs are known to catabolize antibodies. Tumor/blood, tumor/liver, tumor/muscle, and tumor/kidney ratios increased reasonably in a time-dependent manner as seen in Figure 3 indicating the preferential localization of 177 Lu is suitable to allow a favorable uptake in tumor as compared to normal tissues.…”

“…Tumor/blood, tumor/liver, tumor/muscle, and tumor/kidney ratios increased reasonably in a time-dependent manner as seen in Figure 3 indicating the preferential localization of 177 Lu is suitable to allow a favorable uptake in tumor as compared to normal tissues. 17 The in vivo stability of 177 Lu-CHX-A'' -DTPA-Rituximab is indicated by low bone uptake considering the high affinity of free 177 Lu to bone tissue. 39 …”

“…14 The 6.7 days half-life of 177 Lu could very well be exploited in radioimmunotherapy as intact antibodies have a long biological half-life. [15][16][17] Lutetium-177 emits medium-energy bparticles having a maximum path length of about 2 mm ideal for targeting small tumors, while the high-energy b -radiation emitted by 90 Y could be optimally used for bulky disease. 7,18 A number of 177 Lu radiopharmaceuticals have been developed and evaluated for radioimmunotherapy, most often using the macrocyclic bifunctional chelating agent (BFCA) DOTA and its analogues.…”

177Lu-DOTA-HH1, a Novel Anti-CD37 Radio-Immunoconjugate: A Study of Toxicity in Nude Mice

“…We have previously shown good therapeutic effects of 177 Lu-HH1 in SCID mice [19] and relatively high tumor uptake and low normal tissue uptake in nude mice [21]. The expected target organ for toxicity of 177 Lu-HH1 is bone marrow due to retention of the RIC in the blood and, binding to tumor cells if present, in the bone marrow.…”

Red Marrow–Absorbed Dose for Non-Hodgkin Lymphoma Patients Treated with 177Lu-Lilotomab Satetraxetan, a Novel Anti-CD37 Antibody–Radionuclide Conjugate

“…Estimating the absorbed dose to the RM is therefore an imperative when a new ARC is studied. Preclinical studies and preliminary phase 1/2a clinical results indicate that myelosuppression is dosage-limiting also for 177 Lu-lilotomab satetraxetan (6,7).…”