Design of immunogens to present a tumor-specific cryptic epitope

Area of Science:

• Oncology
• Immunology
• Structural Biology

Background:

• Epidermal growth factor receptor (EGFR) is frequently altered in various cancers.
• The monoclonal antibody mAb806 selectively targets cancer cells overexpressing EGFR or its mutant form, EGFRvIII.
• This selectivity suggests potential for developing cancer vaccines based on eliciting similar antibody responses.

Purpose of the Study:

• To design novel immunogens that present the mAb806-binding epitope in a conformation mimicking that found on cancer cells.
• To create potential vaccine candidates that elicit cancer-selective antibodies targeting EGFR.

Main Methods:

• Utilized molecular dynamics simulations to identify accessible conformations of the mAb806 epitope on EGFR.
• Engineered immunogens by substituting the epitope into a different protein scaffold.
• Generated mutants to stabilize the desired epitope conformation.
• Evaluated two stable mutants in vitro using binding kinetics experiments.

Main Results:

• Identified EGFR conformations with accessible mAb806-binding epitopes via simulations.
• Successfully designed and stabilized immunogens presenting the epitope in the target conformation.
• In vitro binding kinetics confirmed the stabilization of the mAb806-binding conformation in the designed immunogens.

Conclusions:

• Designed immunogens successfully stabilized the mAb806-binding epitope conformation.
• These immunogens show promise as a basis for developing cancer vaccines.
• The developed vaccines could elicit cancer-selective antibodies targeting EGFR.