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Tumor infarction in mice by antibody-directed targeting of tissue factor to tumor vasculature
1Department of Pharmacology and Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA.
Abstract:
Selective occlusion of tumor vasculature was tested as a therapy for solid tumors in a mouse model. The formation of blood clots (thrombosis) within the tumor vessels was initiated by targeting the cell surface domain of human tissue factor, by means of a bispecific antibody, to an experimentally induced marker on tumor vascular endothelial cells. This truncated form of tissue factor (tTF) had limited ability to initiate thrombosis when free in the circulation, but became an effective and selective thrombogen when targeted to tumor endothelial cells. Intravenous administration of the antibody-tTF complex to mice with large neuroblastomas resulted in complete tumor regressions in 38 percent of the mice.
Insights
Targeting tumor blood vessels with a modified tissue factor triggered clot formation, leading to complete tumor regression in 38% of mice with neuroblastoma. This novel therapy selectively targets tumor vasculature for cancer treatment.
Area of Science:
- Oncology
- Vascular Biology
- Biotechnology
Background:
- Solid tumors rely on a vascular network for growth and metastasis.
- Targeting tumor vasculature is a promising strategy for cancer therapy.
- Developing selective methods to disrupt tumor blood supply is crucial.
Purpose of the Study:
- To evaluate the efficacy of selective tumor vasculature occlusion as a cancer therapy.
- To investigate the use of a targeted bispecific antibody-tTF complex for inducing thrombosis in tumor vessels.
- To assess the therapeutic potential of this approach in a preclinical mouse model.
Main Methods:
- A bispecific antibody was engineered to target a truncated form of human tissue factor (tTF) to a marker on tumor vascular endothelial cells.
- The antibody-tTF complex was administered intravenously to mice bearing neuroblastoma tumors.
- Tumor vascular occlusion and regression were monitored post-treatment.
Main Results:
- Targeting tTF to tumor endothelial cells effectively initiated localized thrombosis within tumor vasculature.
- The antibody-tTF complex demonstrated selective thrombogenicity in tumor vessels, with limited systemic activity.
- Intravenous administration resulted in complete tumor regression in 38% of mice with advanced neuroblastomas.
Conclusions:
- Selective occlusion of tumor vasculature using a targeted antibody-tTF complex is a viable therapeutic strategy.
- This approach offers a promising method for inducing localized thrombosis and achieving significant tumor regression.
- Further research into this targeted thrombogenic therapy could lead to new cancer treatment options.