Neutralizing antibodies to therapeutic enzymes: considerations for testing, prevention and treatment.
Lysosomal storage diseases are characterized by deficiencies in lysosomal enzymes, allowing accumulation of target substrate in cells and eventually causing cell death. Enzyme replacement therapy is the principal treatment for most of these diseases. However, these therapies are often complicated by immune responses to the enzymes, blocking efficacy and causing severe adverse outcomes by neutralizing product activity. It is thus crucial to understand the relationships between genetic mutations, endogenous residual enzyme proteins (cross-reactive immunologic material), development of neutralizing antibodies and their impact on clinical outcomes of lysosomal storage diseases. For patients in whom neutralizing antibodies may cause severe adverse clinical outcomes, it is paramount to develop tolerance inducing protocols to preclude, where predictable, or treat such life-threatening responses.
Wang
Jinhai
J
Division of Therapeutic Proteins, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, NIH Building 29B, 8800 Rockville Pike, Bethesda, Maryland 20892, USA.
Lozier
Jay
J
Johnson
Gibbes
G
Kirshner
Susan
S
Verthelyi
Daniela
D
Pariser
Anne
A
Shores
Elizabeth
E
Rosenberg
Amy
A
D000917:Antibody Formation / Q000276:immunology*; D004791:Enzyme Inhibitors / Q000276:immunology*; D057487:Enzyme Therapy; D006801:Humans; D007108:Immune Tolerance; D007118:Immunoassay; D016464:Lysosomal Storage Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D018570:Risk Assessment; D012680:Sensitivity and Specificity
D004791:Enzyme Inhibitors