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Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Reverse vaccinology and immunoinformatics approaches to design multi-epitope based vaccine against oncogenic KRAS
Prasanna Srinivasan Ramalingam1, Sivakumar Arumugam2
1Protein Engineering Lab, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, India.
Abstract:
Mutant KRAS-induced tumorigenesis is highly involved in the progression of pancreatic, lung, and breast cancer. Comparatively, KRAS G12D and KRAS G12C are the most frequent mutations that promote cancer progression and aggressiveness. Although KRAS mutant inhibitors exhibit significant therapeutic potential, day by day, they are becoming resistant among patients. Multi-epitope based cancer vaccines are a promising alternative strategy that induces an immune response against tumor antigens. In the present study, we have designed, constructed, and validated a novel multi-epitope vaccine construct against KRAS G12D and G12C mutants using reverse vaccinology and immunoinformatics approaches. In addition, the vaccine construct was structurally refined and showed significant physiochemical properties, and could induce an immune response. Furthermore, the optimized vaccine construct was cloned into a pET‑28a (+) expression vector through in silico cloning. Conclusively, the multi-epitope vaccine construct is structurally stable, soluble, antigenic, non‑allergic, and non‑toxic. Further, it has to be studied in in vitro and in vivo to evaluate its therapeutic efficacy against KRAS-mutated cancers in the near future.
Insights
This study designed a novel multi-epitope cancer vaccine targeting KRAS G12D and G12C mutations, offering a promising strategy against KRAS-mutated cancers resistant to current inhibitors.
Area of Science:
- Oncology
- Vaccinology
- Bioinformatics
Background:
- Mutant KRAS drives tumorigenesis in pancreatic, lung, and breast cancers.
- KRAS G12D and G12C mutations are key drivers of cancer progression and aggressiveness.
- Resistance to KRAS inhibitors necessitates alternative therapeutic strategies.
Purpose of the Study:
- To design and validate a novel multi-epitope vaccine construct targeting KRAS G12D and G12C mutants.
- To computationally assess the vaccine construct's structural, physiochemical, and immunological properties.
- To prepare the vaccine construct for preclinical evaluation.
Main Methods:
- Reverse vaccinology and immunoinformatics approaches were employed for vaccine design.
- In silico structural refinement and physiochemical property analysis were performed.
- In silico cloning into the pET-28a(+) expression vector was conducted.
Main Results:
- A novel multi-epitope vaccine construct targeting KRAS G12D and G12C was successfully designed and validated.
- The vaccine construct exhibited favorable physiochemical properties, structural stability, solubility, and antigenicity.
- The construct was found to be non-allergic and non-toxic in silico, and cloned into an expression vector.
Conclusions:
- The in silico designed multi-epitope vaccine is structurally stable, soluble, antigenic, non-allergic, and non-toxic.
- This vaccine construct represents a promising candidate for further in vitro and in vivo evaluation against KRAS-mutated cancers.
- The study provides a foundation for developing effective cancer vaccines against KRAS mutations.
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