Correspondence
Elimination of Antibodies to Recombinant Enzyme in Pompe's Disease
N Engl J Med 2009; 360:194-195January 8, 2009
- Article
To the Editor:
Infantile Pompe's disease is due to a deficiency of lysosomal acid alpha glucosidase (GAA). In patients in whom GAA is not produced, a status called cross-reacting immunologic material (CRIM)–negative, enzyme-replacement therapy with recombinant human GAA (rhGAA) has uniformly led to high titers of anti-rhGAA antibody, with an ultimately fatal outcome.1 Previous attempts at eliminating rhGAA antibodies in these patients have failed.1-3 We report the successful induction of immune modulation in a CRIM-negative patient with Pompe's disease who continues to be antibody-free at 24 months of age and continues to gain motor milestones.
A baby boy of African-American descent presented at 5 weeks of age with cardiomyopathy and decreased muscle tone. The diagnosis of Pompe's disease was confirmed by means of enzymatic analysis and molecular evidence of the homozygote R854 stop mutation in the GAA gene. No GAA was detected on a Western blot skin-fibroblast assay, confirming the infant's CRIM-negative status. Enzyme-replacement therapy with rhGAA (Myozyme, Genzyme) was initiated when the patient was 7 weeks of age (Figure 1Figure 1
Antibodies against Recombinant Human Acid Alpha Glucosidase (rhGAA) in the Patient.).1 Levels of IgG antibodies against rhGAA, measured with the use of an enzyme-linked immunosorbent assay,1 increased rapidly, reaching a titer of 1:1600 at 23 weeks of age. Immune modulation with the anti-CD20 monoclonal antibody rituximab plus methotrexate4 and intravenous gamma globulin was initiated at 25 weeks of age, resulting in rapid elimination of the anti-rhGAA antibody (Figure 1). Intravenous gamma globulin was used as an immune modulator, but since rituximab induces generalized severe B-cell suppression, intravenous gamma globulin was also administered to preserve normal immune function. With this approach, the patient has maintained undetectable antibody titers against rhGAA through 22 months of enzyme-replacement therapy (Figure 1).At 13 months of age, persistent carbon dioxide retention developed in the patient, and he became ventilator-dependent and required a tracheostomy. However, his ventilator settings have been stable, and he now tolerates brief periods of ventilator-free time. After the initiation of enzyme-replacement therapy, the patient's cardiomyopathy resolved, and he has shown continued neurologic improvement.
Historically, CRIM-negative patients with Pompe's disease receiving enzyme-replacement therapy fare poorly, and when treated with enzyme-replacement therapy, all have died or were ventilator-dependent, with major motor and cardiac decline. These CRIM-negative patients with Pompe's disease all had early seroconversion; in all, persistent high-titer antibodies developed within 12 months after the start of enzyme-replacement therapy. In contrast, our patient, at 24 months of age, shows ongoing clinical benefit from enzyme-replacement therapy, with undetectable antibody titers. Although the follow-up of this patient is limited to 24 months, previously studied CRIM-negative patients have all died or dramatically declined by this age.
Successful immune modulation permitting rhGAA therapy to be continued in this CRIM-negative patient with Pompe's disease appears to be a promising approach to the treatment of this refractory disorder. This case suggests that tolerance induction may be achieved. We speculate that this strategy could be applied in patients with other severe deficiency disorders, such as hemophilia A and B, Gaucher's disease, Fabry's disease, and mucopolysaccharidosis type I, in whom the replacement protein elicits robust antibody responses that can interfere with product efficacy.
Nancy J. Mendelsohn, M.D.
Yoav H. Messinger, M.D.
Children's Hospitals and Clinics of Minnesota, Minneapolis, MN 55404
nancy.mendelsohn@childrensmn. org Amy S. Rosenberg, M.D.
Food and Drug Administration, Bethesda, MD 20892Priya S. Kishnani, M.D.
Duke University Medical Center, Durham, NC 27710Supported in part by Genzyme (for the rhGAA antibody testing).
Drs. Mendelsohn and Kishnani report receiving research or grant support from Genzyme; and Dr. Kishnani, honoraria and consulting fees from Genzyme and being a member of the Pompe Disease and the Gaucher Disease Registry Advisory Boards. Duke University and the inventors of the method of treatment and precursors of the cell lines used to generate the enzyme (rhGAA) used commercially all receive royalties pursuant to the university's policy on inventions, patents, and technology transfer. No other potential conflict of interest relevant to this letter was reported.
4 References1
Kishnani PS ,Corzo D ,Nicolino M , et al. Recombinant human acid [alpha]-glucosidase: major clinical benefits in infantile-onset Pompe disease. Neurology 2007;68:99-109
CrossRef | Web of Science | Medline2
Amalfitano A ,Bengur AR ,Morse RP , et al. Recombinant human acid alpha-glucosidase enzyme therapy for infantile glycogen storage disease type II: results of a phase I/II clinical trial. Genet Med 2001;3:132-138
CrossRef | Web of Science | Medline3
Hunley TE ,Corzo D ,Dudek M , et al. Nephrotic syndrome complicating alpha-glucosidase replacement therapy for Pompe disease. Pediatrics 2004;114:e532-e535
CrossRef | Web of Science | Medline4
Joseph A ,Munroe K ,Housman M ,Garman R ,Richards S . Immune tolerance induction to enzyme-replacement therapy by co-administration of short-term, low-dose methotrexate in a murine Pompe disease model. Clin Exp Immunol 2008;152:138-146
CrossRef | Web of Science | Medline
- Citing Articles (24)
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Corrado Angelini, Claudio Semplicini. (2012) Enzyme Replacement Therapy for Pompe Disease. Current Neurology and Neuroscience Reports 12:1, 70-75
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Emanuela Lacaná, Lynne P. Yao, Anne R. Pariser, Amy S. Rosenberg. (2012) The role of immune tolerance induction in restoration of the efficacy of ERT in Pompe disease. American Journal of Medical Genetics Part C: Seminars in Medical Geneticsn/a-n/a
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Barbara K. Burton. (2012) Newborn screening for Pompe disease: An update, 2011. American Journal of Medical Genetics Part C: Seminars in Medical Geneticsn/a-n/a
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Deeksha S. Bali, Jennifer L. Goldstein, Suhrad Banugaria, Jian Dai, Joanne Mackey, Catherine Rehder, Priya S. Kishnani. (2012) Predicting cross-reactive immunological material (CRIM) status in Pompe disease using GAA mutations: Lessons learned from 10 years of clinical laboratory testing experience. American Journal of Medical Genetics Part C: Seminars in Medical Geneticsn/a-n/a
CrossRef6
Suhrad G. Banugaria, Trusha T. Patel, Joanne Mackey, Stuti Das, Andrea Amalfitano, Amy S. Rosenberg, Joel Charrow, Y.-T. Chen, Priya S. Kishnani. (2012) Persistence of high sustained antibodies to enzyme replacement therapy despite extensive immunomodulatory therapy in an infant with Pompe disease: Need for agents to target antibody secreting plasma cells. Molecular Genetics and Metabolism
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Lainie Friedman Ross. (2011) Newborn screening for lysosomal storage diseases: an ethical and policy analysis. Journal of Inherited Metabolic Disease
CrossRef8
Mary-Alice Abbott, Sean N. Prater, Suhrad G. Banugaria, Susan M. Richards, Sarah P. Young, Amy S. Rosenberg, Priya S. Kishnani. (2011) Atypical immunologic response in a patient with CRIM-negative Pompe disease. Molecular Genetics and Metabolism 104:4, 583-586
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R. Wynn. (2011) Stem Cell Transplantation in Inherited Metabolic Disorders. Hematology 2011:1, 285-291
CrossRef10
Emmanuel Richard, Gaëlle Douillard-Guilloux, Catherine Caillaud. (2011) New insights into therapeutic options for Pompe disease. IUBMB Life 63:11, 979-986
CrossRef11
Suhrad G. Banugaria, Sean N. Prater, Yiu-Ki Ng, Joyce A. Kobori, Richard S. Finkel, Roger L. Ladda, Yuan-Tsong Chen, Amy S. Rosenberg, Priya S. Kishnani. (2011) The impact of antibodies on clinical outcomes in diseases treated with therapeutic protein: Lessons learned from infantile Pompe disease. Genetics in Medicine 13:8, 729-736
CrossRef12
T. Ohashi, S. Iizuka, Y. Shimada, Y. Eto, H. Ida, S. Hachimura, H. Kobayashi. (2011) Oral administration of recombinant human acid α-glucosidase reduces specific antibody formation against enzyme in mouse. Molecular Genetics and Metabolism 103:1, 98-100
CrossRef13
Raymond Y Wang, Olaf A Bodamer, Michael S Watson, William R Wilcox. (2011) Lysosomal storage diseases: Diagnostic confirmation and management of presymptomatic individuals. Genetics in Medicine 13:5, 457-484
CrossRef14
B. J. Byrne, D. J. Falk, C. A. Pacak, S. Nayak, R. W. Herzog, M. E. Elder, S. W. Collins, T. J. Conlon, N. Clement, B. D. Cleaver, D. A. Cloutier, S. L. Porvasnik, S. Islam, M. K. Elmallah, A. Martin, B. K. Smith, D. D. Fuller, L. A. Lawson, C. S. Mah. (2011) Pompe disease gene therapy. Human Molecular Genetics 20:R1, R61-R68
CrossRef15
Juna M. de Vries, Nadine A.M.E. van der Beek, Marian A. Kroos, Lale Özkan, Pieter A. van Doorn, Susan M. Richards, Crystal C.C. Sung, Jan-Dietert C. Brugma, Adrienne A.M. Zandbergen, Ans T. van der Ploeg, Arnold J.J. Reuser. (2010) High antibody titer in an adult with Pompe disease affects treatment with alglucosidase alfa. Molecular Genetics and Metabolism 101:4, 338-345
CrossRef16
Marianne Rohrbach, Andrea Klein, Alice Köhli-Wiesner, Dorothe Veraguth, Ianina Scheer, Christian Balmer, Roger Lauener, Matthias R. Baumgartner. (2010) CRIM-negative infantile Pompe disease: 42-month treatment outcome. Journal of Inherited Metabolic Disease 33:6, 751-757
CrossRef17
Salvatore DiMauro, Caterina Garone, Ali Naini. (2010) Metabolic Myopathies. Current Rheumatology Reports 12:5, 386-393
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Karen M. Ashe, Kristin M. Taylor, Qiuming Chu, Elizabeth Meyers, Allen Ellis, Varvara Jingozyan, Katherine Klinger, Patrick F. Finn, Christopher G.F. Cooper, Wei-Lien Chuang, John Marshall, John M. McPherson, Robert J. Mattaliano, Seng H. Cheng, Ronald K. Scheule, Rodney J. Moreland. (2010) Inhibition of glycogen biosynthesis via mTORC1 suppression as an adjunct therapy for Pompe disease. Molecular Genetics and Metabolism 100:4, 309-315
CrossRef19
Baodong Sun, Michael D Kulis, Sarah P Young, Amy C Hobeika, Songtao Li, Andrew Bird, Haoyue Zhang, Yifan Li, Timothy M Clay, Wesley Burks, Priya S Kishnani, Dwight D Koeberl. (2010) Immunomodulatory Gene Therapy Prevents Antibody Formation and Lethal Hypersensitivity Reactions in Murine Pompe Disease. Molecular Therapy 18:2, 353-360
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CrossRef21
John Schloendorn, Tim Webb, Kent Kemmish, Mark Hamalainen, David Jackemeyer, Lijing Jiang, Jacques Mathieu, Justin Rebo, Jonathan Sankman, Lindsey Sherman, Lauri Tontson, Ateef Qureshi, Pedro Alvarez, Bruce Rittmann. (2009) Medical Bioremediation: A Concept Moving Toward Reality. Rejuvenation Research 12:6, 411-419
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PRIYA S. KISHNANI, DEYA CORZO, NANCY D. LESLIE, DANIEL GRUSKIN, ANS van der PLOEG, JOHN P. CLANCY, ROSELLA PARINI, GILLES MORIN, MICHAEL BECK, MISLEN S. BAUER, MIKAEL JOKIC, CHEN-EN TSAI, BRIAN W. H. TSAI, CLAIRE MORGAN, TARA O’MEARA, SUSAN RICHARDS, ELISA C. TSAO, HANNA MANDEL. (2009) Early Treatment With Alglucosidase Alfa Prolongs Long-Term Survival of Infants With Pompe Disease. Pediatric Research 66:3, 329-335
CrossRef23
Sarah P Young, Haoyue Zhang, Deyanira Corzo, Beth L Thurberg, Deeksha Bali, Priya S Kishnani, David S Millington. (2009) Long-term monitoring of patients with infantile-onset Pompe disease on enzyme replacement therapy using a urinary glucose tetrasaccharide biomarker. Genetics in Medicine 11:7, 536-541
CrossRef24
Gregory M Pastores, Derralynn A Hughes. (2009) Enzyme-replacement therapy for Pompe disease. Pediatric Health 3:1, 41-49
CrossRef
