Figure 2.

Epitope differences in therapeutic GAA from endogenously expressed native GAA predicted to drive ADA or be tolerized. CRIM-positive IOPD subjects who express residual nGAA may be tolerant to epitopes conserved, for their HLA, with the rhGAA replacement protein. (A) T cell epitopes contained within the rhGAA may be recognized as “foreign” if they are within the truncated or mutated portions of the patient-specific nGAA. (B) T cell epitopes within the rhGAA that contain T cell receptor (TCR)-facing residues that are different from those found in nGAA may be sufficient to generate a different T cell phenotype response. (C) T cell epitopes within the rhGAA that contains different MHC-facing residues but the same TCR-facing residues as epitopes found in nGAA are predicted to be tolerated by the immune system (this hypothesis was included in PIMA V3). (D) The presence of a T cell epitope in the rhGAA sequence with TCR-facing residues highly cross-conserved with several self-human proteins may not appear as foreign and would also be tolerated by the immune system. (This hypothesis was included in PIMA V3J).