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Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Enhanced lysis by bispecific oncolytic measles viruses simultaneously using HER2/neu or EpCAM as target receptors
Jan Rh Hanauer1, Lisa Gottschlich1, Dennis Riehl1
1Oncolytic Measles Viruses and Vaccine Vectors, Paul-Ehrlich-Institut , Langen, Germany.
Abstract:
To target oncolytic measles viruses (MV) to tumors, we exploit the binding specificity of designed ankyrin repeat proteins (DARPins). These DARPin-MVs have high tumor selectivity while maintaining excellent oncolytic potency. Stability, small size, and efficacy of DARPins allowed the generation of MVs simultaneously targeted to tumor marker HER2/neu and cancer stem cell (CSC) marker EpCAM. For optimization, the linker connecting both DARPins was varied in flexibility and length. Flexibility had no impact on fusion helper activity whereas length had. MVs with bispecific MV-H are genetically stable and revealed the desired double-target specificity. In vitro, the cytolytic activity of bispecific MVs was superior or comparable to mono-targeted viruses depending on the target cells. In vivo, therapeutic efficacy of the bispecific viruses was validated in an orthotopic ovarian carcinoma model revealing an effective reduction of tumor mass. Finally, the power of bispecific targeting was demonstrated on cocultures of different tumor cells thereby mimicking tumor heterogeneity in vitro, more closely reflecting real tumors. Here, bispecific excelled monospecific viruses in efficacy. DARPin-based targeting domains thus allow the generation of efficacious oncolytic viruses with double specificity, with the potential to handle intratumoral variation of antigen expression and to simultaneously target CSCs and the bulk tumor mass.
Insights
Engineered measles viruses (MV) armed with designed ankyrin repeat proteins (DARPins) demonstrate dual targeting of tumor and cancer stem cell markers. This bispecific approach enhances oncolytic potency and tumor selectivity for improved cancer therapy.
Area of Science:
- Oncolytic virotherapy
- Molecular engineering
- Cancer biology
Background:
- Targeting oncolytic viruses to tumors is crucial for efficacy.
- Cancer stem cells (CSCs) contribute to tumor recurrence and treatment resistance.
- Tumor heterogeneity poses a challenge for single-target therapies.
Purpose of the Study:
- To engineer measles viruses (MVs) with dual specificity for tumor and CSC markers using designed ankyrin repeat proteins (DARPins).
- To evaluate the stability, tumor selectivity, and oncolytic potency of these bispecific DARPin-MVs.
- To assess the therapeutic efficacy of bispecific DARPin-MVs in preclinical cancer models.
Main Methods:
- Designed ankyrin repeat proteins (DARPins) were engineered for specific binding to HER2/neu and EpCAM.
- DARPins were genetically incorporated into measles viruses (MVs) to create bispecific targeting vectors.
- Linker length and flexibility between DARPins were optimized.
- In vitro cytolytic activity and in vivo therapeutic efficacy in an orthotopic ovarian carcinoma model were assessed.
- Coculture models were used to mimic tumor heterogeneity.
Main Results:
- Bispecific DARPin-MVs exhibited high tumor selectivity and maintained oncolytic potency.
- Genetic stability and dual-target specificity (HER2/neu and EpCAM) were confirmed.
- In vitro cytolytic activity was superior or comparable to monospecific MVs.
- In vivo studies demonstrated significant tumor mass reduction in an ovarian carcinoma model.
- Bispecific MVs outperformed monospecific MVs in heterogeneous tumor cell cocultures.
Conclusions:
- DARPin-based dual targeting enables the generation of efficacious oncolytic viruses.
- This strategy can address intratumoral antigen expression variability.
- Simultaneous targeting of bulk tumor mass and cancer stem cells offers a promising therapeutic approach.
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