HLA- and genotype-based risk assessment model to identify infantile onset pompe disease patients at high-risk of developing significant anti-drug antibodies (ADA)

In Pompe disease, anti-drug antibodies (ADA) to acid alpha-glucosidase (GAA) enzyme replacement therapy contribute to early mortality. Assessing individual risk for ADA development is notoriously difficult in (CRIM-positive) patients expressing endogenous GAA. The individualized T cell epitope measu...

Full description

Saved in:

Bibliographic Details
Published in:	Clinical immunology (Orlando, Fla.) Vol. 200; pp. 66 - 70
Main Authors:	De Groot, A.S., Kazi, Z.B., Martin, R.F., Terry, F.E., Desai, A.K., Martin, W.D., Kishnani, P.S.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01-03-2019
Subjects:	ADA alpha-Glucosidases - genetics alpha-Glucosidases - immunology alpha-Glucosidases - therapeutic use Antibodies - immunology Computer Simulation Cross Reactions - immunology Enzyme Replacement Therapy Epitope Mapping Epitopes, T-Lymphocyte - immunology Glycogen Storage Disease Type II - drug therapy Glycogen Storage Disease Type II - genetics HLA-DRB1 Chains - genetics Humans Immune Tolerance - immunology Immunogenicity Immunoglobulins, Intravenous - therapeutic use Immunoinformatics Immunologic Factors - therapeutic use Infant Methotrexate - therapeutic use Pompe Disease Recombinant Proteins Risk Assessment Rituximab - therapeutic use iTEM GAA ERT Pompe Disease rhGAA GAA-iTEM nGAA CRIM Immunoinformatics Immunogenicity Enzyme replacement therapy IOPD HLA ADA ITI
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	In Pompe disease, anti-drug antibodies (ADA) to acid alpha-glucosidase (GAA) enzyme replacement therapy contribute to early mortality. Assessing individual risk for ADA development is notoriously difficult in (CRIM-positive) patients expressing endogenous GAA. The individualized T cell epitope measure (iTEM) scoring method predicts patient-specific risk of developing ADA against therapeutic recombinant human GAA (rhGAA) using individualized HLA-binding predictions and GAA genotype. CRIM-negative patients were six times more likely to develop high ADA titers than CRIM-positive patients in this retrospective study, whereas patients with high GAA-iTEM scores were 50 times more likely to develop high ADA titers than patients with low GAA-iTEM scores. This approach identifies high-risk IOPD patients requiring immune tolerance induction therapy to prevent significant ADA response to rhGAA leading to a poor clinical outcome and can assess ADA risk in patients receiving replacement therapy for other enzyme or blood factor deficiency disorders. •CRIM Status is the current method for identifying IOPD patients at high risk of ADA.•Determinants of ADA include individual patient HLA and GAA gene sequence.•Individualization of the ADA prediction can be performed using in silico tools described here (GAA-iTEM).•GAA-iTEM score predictions have better overall agreement than CRIM status predictions, in this cohort.•The GAA-iTEM approach may be useful for predicting ADA to other ERTs.
Bibliography:	Authorship Contributions: ADG and PSK conceived of the study, reviewed the data generated in the immunoinformatics analysis, wrote the manuscript and supervised the execution of the project. FT and RM developed and carried out the immunoinformatics analysis with guidance and contributions from BM and ADG. FT, RM, and BM contributed to the methods that were used and helped to write the manuscript. ZBK and AKD provided (limited) information on Pompe disease patients and access to patent HLA type and GAA genotype, wrote the ethical review and background sections, and helped to write the manuscript.
ISSN:	1521-6616 1521-7035
DOI:	10.1016/j.clim.2019.01.009