Bortezomib in the rapid reduction of high sustained antibody titers in disorders treated with therapeutic protein: lessons learned from Pompe disease.
OBJECTIVE
High sustained antibody titers complicate many disorders treated with a therapeutic protein, including those treated with enzyme replacement therapy, such as Pompe disease. Although enzyme replacement therapy with alglucosidase alfa (Myozyme) in Pompe disease has improved the prognosis of this otherwise lethal disorder, patients who develop high sustained antibody titers to alglucosidase alfa enter a prolonged phase of clinical decline resulting in death despite continued enzyme replacement therapy. Clinically effective immune-tolerance induction strategies have yet to be described in the setting of an entrenched immune response characterized by high sustained antibody titers, wherein antibody-producing plasma cells play an especially prominent role.


METHODS
We treated three patients with infantile Pompe disease experiencing marked clinical decline due to high sustained antibody titers. To target the plasma cell source of high sustained antibody titers, a regimen based on bortezomib (Velcade) was used in combination with rituximab, methotrexate, and intravenous immunoglobulin.


RESULTS
The treatment regimen was well tolerated, with no obvious side effects. Patient 1 had a 2,048-fold, and patients 2 and 3 each had a 64-fold, reduction in anti-alglucosidase alfa antibody titer, with concomitant sustained clinical improvement.


CONCLUSIONS
The addition of bortezomib to immunomodulatory regimens is an effective and safe treatment strategy in infantile Pompe disease, with potentially broader clinical implications.
Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.
Suhrad G
SG
Banugaria
Sean N
SN
Prater
Judeth K
JK
McGann
Jonathan D
JD
Feldman
Jesse A
JA
Tannenbaum
Carrie
C
Bailey
Renuka
R
Gera
Robert L
RL
Conway
David
D
Viskochil
Joyce A
JA
Kobori
Amy S
AS
Rosenberg
Priya S
PS
Kishnani
D000906:Antibodies / Q000032:analysis* / Q000276:immunology; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001897:Boronic Acids / Q000627:therapeutic use*; D000069286:Bortezomib; D002648:Child; D002675:Child, Preschool; D004359:Drug Therapy, Combination; D006009:Glycogen Storage Disease Type II / Q000276:immunology / Q000517:prevention & control*; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000627:therapeutic use*; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use*; D010950:Plasma Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D011719:Pyrazines / Q000627:therapeutic use*; D016896:Treatment Outcome
D000906:Antibodies; D000970:Antineoplastic Agents; D001897:Boronic Acids; D016756:Immunoglobulins, Intravenous; D011719:Pyrazines; D000069286:Bortezomib; D008727:Methotrexate