CD4/TGF-β bispecific antibody significantly reduced peritoneal melanoma tumor burden in a mouse model

Peritoneal metastasis of malignant melanoma represents a highly aggressive and often fatal disease, with limited effective treatment options. Current therapies struggle to overcome the immunosuppressive tumor microenvironment, where factors like Transforming Growth Factor-beta (TGF-β) play a crucial role in promoting tumor growth and immune evasion. Targeting TGF-β, particularly in a tumor-specific manner, offers a promising strategy to reactivate anti-tumor immunity and improve outcomes for patients facing this challenging diagnosis. This study explores a novel CD4/TGF-β bispecific antibody designed to specifically block TGF-β activity within the tumor, leveraging the CD4 receptor for targeted delivery.

Researchers evaluated the CD4/TGF-β bispecific antibody in human CD4 transgenic C57BL/6J mice. For safety, 20 mice were given intravenous injections of PBS or 2.5, 5, or 10 mg/kg antibody, observing general condition, body weight, and temperature. For efficacy, 20 mice received intraperitoneal injections of magnetized B16F10-GL melanoma cells. Some mice also had a magnet applied to the abdomen to guide tumor formation. Three days post-inoculation, mice were treated with PBS or CD4/TGF-β bispecific antibody (300 μg) twice weekly. Tumor development and dissemination were monitored via in vivo imaging and assessed on day 14 by gross observation, histopathological analysis, immunofluorescence staining, and RT-qPCR after euthanasia.

Injection of the CD4/TGF-β bispecific antibody produced no significant adverse effects in mice. In tumor-bearing mice, magnet application significantly accelerated tumor development (from 9.20±2.17 days to 3.80±1.79 days; P=0.003) and ensured precise tumor formation in the parietal peritoneum. While magnet application did not significantly affect survival, it significantly prolonged the therapeutic window (from 4.60±1.95 days to 10.00±1.73 days; P=0.002). The most impactful finding was the therapeutic efficacy of the antibody: > Mice treated with CD4/TGF-β bispecific antibody exhibited significantly reduced tumor burden, irrespective of the inoculation method. These tumors showed dense encapsulation by type III collagen, a stark contrast to the minimal type III collagen deposition and abundant tumor cells observed in PBS-treated control mice. The antibody treatment also significantly downregulated the expression of certain factors, though the abstract's description of this specific finding was incomplete.