Superior Molecular Vaccine Linking the Translocation Domain of a Bacterial Toxin to an Antigen

• UNMET NEED: Enhancement of antigen presentation through the MCH class I pathway to CD8+ T cells has been a primary focus of cancer immunotherapy. DNA vaccines have emerged as attractive approaches to generate CD8+ T cell responses in vaccinated humans. Yet, lack of potency and immunogenicity has limited their clinical utility to date. Disclosed herein is a novel chimeric multidomain protein whereby a tumor-specific antigen is fused to a translocation polypeptide, exhibiting enhanced MHC class I presentation and activation of antigen-specific CD8+ T cells. Advantages include:Chimeric multidomain DNA vaccine comprised of a translocation domain and desired antigen
• Significantly enhanced MHC I presentation and antigen-specific CD8+ T cell response
• Platform to greatly enhance potency of DNA vaccines

TECHNICAL DETAILS: Domain II of Pseudomanas Exotoxin A (ETA(dII)) facilitates translocation from extracellular and vesicular compartments into the cytoplasm, which presents an opportunity to enhance MHC I presentation to CD8+ T cells. Here, ETA(dII) was fused to a model tumor antigen, HPV-16 E7, in the context of a DNA vaccine. Significantly enhanced MHC class I presentation of E7 antigen was observed in transfected, pulsed dendritic cells. Vaccination of mice generated a dramatic increase in the number of E7-specific CD8+ T cell precursors and converted a less effective DNA vaccine into one with significant potency against HPV-16 E7-expressing murine tumors via a CD8-dependent pathway. These results indicate that fusion of the translocation domain of a bacterial toxin to an antigen may greatly enhance vaccine potency.

INVENTORS: T.C. Wu Chien-Fu Hung

PATENT STATUS: Granted US Patent 8,128,922

ASSOCIATED PUBLICATIONS: Cancer Res. 2001 May 1;61(9):3698-703.