CD4/TGF-β双特异性抗体在治疗恶性黑色素瘤腹膜转移小鼠模型中的疗效OA

Objective To evaluate the efficacy of CD4/TGF-β bispecific antibody in a mouse model of peritoneal metastasis of melanoma.Methods For drug safety testing,20 human CD4 transgenic C57BL/6J mice were randomized into 4 groups(n=5)for intravenous injections of PBS or 2.5,5,or 10 mg/kg CD4/TGF-β bispecific antibody,and the changes in general condition,body weight and body temperature were observed.Another 20 transgenic C57BL/6J mice were randomized into two groups to receive intraperitoneal injection of magnetized B16F10-GL melanoma cells expressing green fluorescent protein and luciferase with or without application of a magnet(3 mm in diameter)to the right abdominal skin before cell injection.Three days later,each group was further divided into two groups for treatment with PBS or CD4/TGF-β bispecific antibody(300 μg)twice a week.In vivo imaging was performed at different time points to assess fluorescence distribution and intensity.On day 14,the mice were euthanized and tumor burden and dissemination were evaluated by gross observation,histopathological analysis,immunofluorescence staining,and RT-qPCR.Results Injection of the antibody did not produce any significant adverse effects in the mice.In the tumor-bearing mice,the application of a magnet significantly accelerated tumor development(3.80±1.79 vs 9.20±2.17 days;P=0.003)and resulted in precise and consistent tumor formation in the parietal peritoneum.Magnet application did not significantly affect survival of the mice but significantly prolonged the therapeutic window(4.60±1.95 vs 10.00±1.73 days;P=0.002).The mice treated with CD4/TGF-β bispecific antibody had significantly reduced tumor burden irrespective of the inoculation approach,and showed dense encapsulation of the tumor foci by type III collagen,whereas minimal type III collagen deposition and abundant tumor cells were observed in PBS-treated mice.Treatment with the antibody significantly downregulated the expression of melanoma-associated gene MITF,and the reduction was more pronounced in the magnet group.Conclusion The CD4/TGF-β bispecific antibody shows significant antitumor efficacy and good safety in the mouse model of peritoneal metastasis of melanoma.