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Protein Expr Purif ; 57(2): 312-9, 2008 Feb.
Article in English | MEDLINE | ID: mdl-17977014

ABSTRACT

Bone morphogenetic protein-7 (BMP-7, OP-1) is a secreted growth factor that is predominantly known for its osteoinductive properties, though it has also been implicated as having a role in mammalian kidney development. Clinical efficacy of recombinant BMP-7 has been demonstrated in the treatment of orthopedic injuries through topical application. However, the pharmaceutical development of recombinant BMP-7 for systemic delivery has presented many challenges. Specifically, the expression level of recombinant mature BMP-7 protein in mammalian cells is very low, the molecule has poor solubility at neutral pH, and intracellular proteolytic processing events result in a secreted BMP-7 having multiple amino-termini, creating a heterogeneous mixture of proteins. Utilizing structural information, we have designed and generated a number of rational BMP-7 mutations that improved both expression levels in mammalian cells and solubility at neutral pH, while limiting the amino-terminal heterogeneity of the mature protein. Introduction of these mutations did not compromise BMP-7 in vitro bioactivity. This improved BMP-7 molecule is better suited for pharmaceutical development and clinical advancement for indications where systemic delivery may be required.


Subject(s)
Bone Morphogenetic Proteins/metabolism , Mutant Proteins/metabolism , Transforming Growth Factor beta/metabolism , Alkaline Phosphatase/metabolism , Amino Acid Motifs , Amino Acid Sequence , Animals , Bone Morphogenetic Protein 7 , Bone Morphogenetic Proteins/chemistry , Bone Morphogenetic Proteins/genetics , CHO Cells , Cell Line , Cricetinae , Cricetulus , Dimerization , Humans , Models, Molecular , Molecular Sequence Data , Mutant Proteins/biosynthesis , Mutant Proteins/genetics , Mutation/genetics , Protein Precursors/chemistry , Protein Precursors/metabolism , Protein Processing, Post-Translational , Rats , Transforming Growth Factor beta/chemistry , Transforming Growth Factor beta/genetics
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