Biochemical and pharmacological characterization of different recombinant acid alpha-glucosidase preparations evaluated for the treatment of Pompe disease.
Pompe disease results in the accumulation of lysosomal glycogen in multiple tissues due to a deficiency of acid alpha-glucosidase (GAA). Enzyme replacement therapy for Pompe disease was recently approved in Europe, the U.S., Canada, and Japan using a recombinant human GAA (Myozyme, alglucosidase alfa) produced in CHO cells (CHO-GAA). During the development of alglucosidase alfa, we examined the in vitro and in vivo properties of CHO cell-derived rhGAA, an rhGAA purified from the milk of transgenic rabbits, as well as an experimental version of rhGAA containing additional mannose-6-phosphate intended to facilitate muscle targeting. Biochemical analyses identified differences in rhGAA N-termini, glycosylation types and binding properties to several carbohydrate receptors. In a mouse model of Pompe disease, glycogen was more efficiently removed from the heart than from skeletal muscle for all enzymes, and overall, the CHO cell-derived rhGAA reduced glycogen to a greater extent than that observed with the other enzymes. The results of these preclinical studies, combined with biochemical characterization data for the three molecules described within, led to the selection of the CHO-GAA for clinical development and registration as the first approved therapy for Pompe disease.
Biologics Research and Development, Genzyme Corporation, One Mountain Road, Framingham, MA 01701, USA.
A J
AJ
McVie-Wylie
Biologics Research and Development, Genzyme Corporation, One Mountain Road, Framingham, MA 01701, USA.
K L
KL
Lee
Biologics Research and Development, Genzyme Corporation, One Mountain Road, Framingham, MA 01701, USA.
H
H
Qiu
Biologics Research and Development, Genzyme Corporation, One Mountain Road, Framingham, MA 01701, USA.
X
X
Jin
Glycobiology Research Institute, Genzyme Corporation, Oklahoma City, OK 73104, USA.
H
H
Do
Glycobiology Research Institute, Genzyme Corporation, Oklahoma City, OK 73104, USA.
R
R
Gotschall
Biologics Research and Development, Genzyme Corporation, One Mountain Road, Framingham, MA 01701, USA.
B L
BL
Thurberg
Biologics Research and Development, Genzyme Corporation, One Mountain Road, Framingham, MA 01701, USA.
C
C
Rogers
Arthritis and Rheumatism Branch, NIAMS, National Institutes of Health, Bethesda, MD 20892, USA.
N
N
Raben
Biologics Research and Development, Genzyme Corporation, One Mountain Road, Framingham, MA 01701, USA.
M
M
O'Callaghan
Glycobiology Research Institute, Genzyme Corporation, Oklahoma City, OK 73104, USA.
W
W
Canfield
Biologics Research and Development, Genzyme Corporation, One Mountain Road, Framingham, MA 01701, USA.
L
L
Andrews
Biologics Research and Development, Genzyme Corporation, One Mountain Road, Framingham, MA 01701, USA.
J M
JM
McPherson
Biologics Research and Development, Genzyme Corporation, One Mountain Road, Framingham, MA 01701, USA.
R J
RJ
Mattaliano
D000818:Animals; D000906:Antibodies / Q000097:blood; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D004353:Drug Evaluation, Preclinical; D005347:Fibroblasts / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D006009:Glycogen Storage Disease Type II / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D006801:Humans; D037181:Lectins, C-Type / Q000378:metabolism; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000378:metabolism; D051379:Mice; D009844:Oligosaccharides / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011817:Rabbits; D017527:Receptor, IGF Type 2 / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology; D000520:alpha-Glucosidases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*
D000906:Antibodies; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D009844:Oligosaccharides; D017527:Receptor, IGF Type 2; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D006003:Glycogen; C509951:GAA protein, human; D000520:alpha-Glucosidases