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An engineered 4-1BBL fusion protein with "activity on demand"
Jacqueline Mock1, Marco Stringhini1, Alessandra Villa2
1Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zürich), CH-8093 Zürich, Switzerland.
Abstract:
Engineered cytokines are gaining importance in cancer therapy, but these products are often limited by toxicity, especially at early time points after intravenous administration. 4-1BB is a member of the tumor necrosis factor receptor superfamily, which has been considered as a target for therapeutic strategies with agonistic antibodies or using its cognate cytokine ligand, 4-1BBL. Here we describe the engineering of an antibody fusion protein, termed F8-4-1BBL, that does not exhibit cytokine activity in solution but regains biological activity on antigen binding. F8-4-1BBL bound specifically to its cognate antigen, the alternatively spliced EDA domain of fibronectin, and selectively localized to tumors in vivo, as evidenced by quantitative biodistribution experiments. The product promoted a potent antitumor activity in various mouse models of cancer without apparent toxicity at the doses used. F8-4-1BBL represents a prototype for antibody-cytokine fusion proteins, which conditionally display "activity on demand" properties at the site of disease on antigen binding and reduce toxicity to normal tissues.
Insights
Engineered antibody-cytokine fusion proteins, like F8-4-1BBL, show potent antitumor activity. This novel approach targets cancer cells specifically, reducing systemic toxicity for improved cancer therapy.
Area of Science:
- Oncology
- Immunotherapy
- Protein Engineering
Background:
- Engineered cytokines are crucial in cancer therapy but often cause toxicity.
- 4-1BB (tumor necrosis factor receptor superfamily) is a therapeutic target.
- Current strategies involve agonistic antibodies or the 4-1BBL ligand.
Purpose of the Study:
- To engineer an antibody-cytokine fusion protein with conditional activity.
- To reduce systemic toxicity associated with cytokine-based therapies.
- To develop a targeted cancer treatment with "activity on demand" properties.
Main Methods:
- Engineering of the F8-4-1BBL antibody fusion protein.
- Assessment of cytokine activity in solution and on antigen binding.
- In vivo biodistribution studies to evaluate tumor localization.
- Evaluation of antitumor activity in mouse cancer models.
Main Results:
- F8-4-1BBL demonstrated antigen-specific binding to the EDA domain of fibronectin.
- Selective tumor localization was confirmed by biodistribution experiments.
- Potent antitumor activity was observed in various mouse cancer models.
- No apparent toxicity was detected at effective doses.
Conclusions:
- F8-4-1BBL functions as a prototype for "activity on demand" antibody-cytokine fusion proteins.
- Conditional activity at the disease site minimizes toxicity to normal tissues.
- This approach offers a promising strategy for safer and more effective cancer immunotherapy.
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