Radioimmunotherapy Targeting IGF2R on Canine-Patient-Derived Osteosarcoma Tumors in Mice and Radiation Dosimetry in Canine and Pediatric Models

Background: Osteosarcoma (OS) has an overall patient survival rate of ~70% with no significant improvements in the last two decades, and novel effective treatments are needed. OS in companion dogs is phenotypically close to human OS, which makes a comparative oncology approach to developing new treatments for OS very attractive. We have recently created a novel human antibody, IF3 to IGF2R, which binds to this receptor on both human and canine OS tumors. Here, we evaluated the efficacy and safety of radioimmunotherapy with 177Lu-labeled IF3 of mice bearing canine-patient-derived tumors and performed canine and human dosimetry calculations. Methods: Biodistribution and microSPECT/CT imaging with 111In-IF3 was performed in mice bearing canine OS Gracie tumors, and canine and human dosimetry calculations were performed based on these results. RIT of Gracie-tumor-bearing mice was completed with 177Lu-IF3. Results: Biodistribution and imaging showed a high uptake of 111In-IF3 in the tumor and spleen. Dosimetry identified the tumor, spleen and pancreas as the organs with the highest uptake. RIT was very effective in abrogating tumor growth in mice with some spleen-associated toxicity. Conclusions: These results demonstrate that RIT with 177Lu-IF3 targeting IGF2R on experimental canine OS tumors effectively decreases tumor growth. However, because of the limitations of murine models, careful evaluation of the possible toxicity of this treatment should be performed via nuclear imaging and image-based dosimetry in healthy dogs before clinical trials in companion dogs with OS can be attempted.

Comparative evaluation of the chemotherapeutic efficacies of two salts of diminazene aceturate in Trypanosoma brucei brucei infected dogs

Purpose: To compare the anti-trypanosomal efficacies of 4,4-(diazoaminedibenzamidinetrihydrate) diacetate (4,4-DDBT) and 4,4-(diazoamino) benzamidine (4,4-DB) in experimental canine trypanosomosis. Methods: The efficacies of 4,4-DDBT and 4,4-DB were evaluated in 4 groups of dogs (n = 3) designated A-D. Group A was normal control without infection or drug treatment, group B did not receive any drug treatment but was infected with Trypanosoma brucei brucei, while groups C and D were infected with T. b. brucei and treated with 4,4-DDBT(3.5 mg/kg) and 4,4-DB (3.5 mg/kg), respectively. Results: The incubation period of the infection was 6 - 9 days post-infection. Treatment of the dogs with 4,4-DDBT led to zero parasitaemia 48 h post-treatment, while there was only a decrease in parasitemia to log 6 in 4,4-DB-treated dogs. Resurgence of parasite into the blood stream occurred in 4,4-DDBTtreated dogs 6 days after initial parasite clearance. Blood analyses post-treatment revealed elevated leucocytes and lymphocytes in 4,4-DB-treated dogs (p < 0.05). Packed cell volume was also observed to be higher in 4,4-DDBT-treated group when compared to 4,4-DB group (p < 0.05). Conclusion: These findings suggest that 4,4-DDBT is more efficacious in the clinical management of canine trypanosomosis caused by T. b. brucei. However, it does not prevent relapse of infection. Based on these findings, therefore, 4,4-DDBT should be the diminazene salt of choice when indicated in the clinical management of T. b. brucei infection in dogs.