Immune Tolerance-Adjusted Personalized Immunogenicity Prediction for Pompe Disease

Area of Science:

• Biochemistry and Molecular Biology
• Immunology
• Genetics

Background:

• Infantile-onset Pompe disease (IOPD) is a genetic disorder caused by acid alpha-glucosidase (GAA) deficiency.
• Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA) is effective but can elicit anti-drug antibodies (ADA) that reduce efficacy.
• ADA development is linked to T cell responses against differing sequences between native (nGAA) and rhGAA.

Purpose of the Study:

• To develop a personalized immunogenicity risk assessment (PIMA) tool to predict ADA development in IOPD patients.
• To quantify T cell epitopes differing between nGAA and rhGAA, considering individual genetic factors (GAA gene, HLA DR haplotype).
• To assess the immunomodulatory potential of specific GAA epitopes.

Main Methods:

• Development of four PIMA versions utilizing EpiMatrix for T cell epitope identification and iTEM for HLA-restricted epitope scoring.
• Integration of JanusMatrix, a Treg epitope prediction tool, into one PIMA version (PIMA V3J).
• Logistic regression analysis of PIMA V3J scores in 48 CRIM-positive IOPD subjects to correlate scores with ADA development.

Main Results:

• PIMA V3J scores above 10 were associated with a 4-fold increased likelihood of ADA development (p<0.03).
• Confirmation that certain GAA epitopes possess immunomodulatory effects on T effector responses in vitro.
• Identification of four immunomodulatory epitopes among 21 tested GAA epitopes.

Conclusions:

• The PIMA tool, particularly PIMA V3J, can effectively predict ADA risk in IOPD patients treated with ERT.
• Implementation of PIMA V3J on a web platform can aid clinicians in personalized treatment decisions and risk stratification.
• PIMA facilitates targeted immunomodulatory strategies for ERT-naïve patients, potentially improving long-term clinical outcomes by minimizing ADA.