Related Experiment Video
Updated: May 14, 2026
Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
DARPin-targeting of measles virus: unique bispecificity, effective oncolysis, and enhanced safety
Katrin Friedrich1, Jan Rh Hanauer, Steffen Prüfer
1Oncolytic Measles Viruses and Vaccine Vectors, Paul-Ehrlich-Institut, Langen, Germany.
Abstract:
Oncolytic virotherapy is an emerging treatment modality that uses replication-competent viruses to destroy cancers. Many naturally occurring viruses have a preferential, although nonexclusive, tropism for tumors and tumor cells. In addition, specific targeting of cancer cells can be achieved at the virus entry level. We optimized retargeting of cell entry by elongating the measles virus attachment protein with designed ankyrin repeat proteins (DARPins), while simultaneously ablating entry through the natural receptors. DARPin-targeted viruses were strongly attenuated in off-target tissue, thereby enhancing safety, but completely eliminated tumor xenografts. Taking advantage of the unique properties of DARPins of being fused without generating folding problems, we generated a virus simultaneous targeting two different tumor markers. The bispecific virus retained the original oncolytic efficacy, while providing proof of concept for a strategy to counteract issues of resistance development. Thus, DARPin-targeting opens new prospects for the development of personalized, targeted therapeutics.
Insights
Engineered measles viruses using designed ankyrin repeat proteins (DARPins) enhance cancer cell targeting for oncolytic virotherapy. This DARPin-targeting strategy improves safety and efficacy, offering new avenues for personalized cancer treatments.
Area of Science:
- Oncolytic Virotherapy
- Molecular Engineering
- Cancer Therapeutics
Background:
- Oncolytic virotherapy utilizes replication-competent viruses to eliminate cancer cells.
- Naturally occurring viruses show some tumor tropism, but specific targeting is crucial for efficacy and safety.
- Current methods for retargeting viral entry can be complex and may face challenges.
Purpose of the Study:
- To engineer measles viruses for enhanced cancer cell targeting and improved safety profiles.
- To develop a versatile platform for oncolytic virotherapy using designed ankyrin repeat proteins (DARPins).
- To demonstrate the potential of bispecific targeting to overcome therapeutic resistance in cancer.
Main Methods:
- Modified the measles virus attachment protein by incorporating designed ankyrin repeat proteins (DARPins) to retarget viral entry.
- Ablated viral entry through natural receptors to enhance specificity and reduce off-target effects.
- Generated bispecific viruses targeting two distinct tumor markers to assess efficacy and resistance circumvention.
Main Results:
- DARPin-targeted measles viruses showed significantly reduced infectivity in off-target tissues, enhancing safety.
- These engineered viruses effectively eliminated tumor xenografts in preclinical models.
- A bispecific DARPin-targeted virus maintained oncolytic efficacy and demonstrated a strategy to combat treatment resistance.
Conclusions:
- DARPin-mediated retargeting offers a powerful strategy to enhance the safety and specificity of oncolytic measles viruses.
- This approach provides a proof-of-concept for developing bispecific oncolytic viruses to overcome cancer resistance.
- DARPin-targeting opens new possibilities for personalized and targeted cancer therapeutics.
