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Methods for introducing mannose 6-phosphate and other oligosaccharides onto glycoproteins
| Details |
Inventors: Zhu, Yunxiang;
Assignee: Genzyme Corporation (Cambridge, MA)
Primary Examiner: Wilson; James O.
Assistant Examiner: Khare; Devesh
Attorney, Agent or Firm: Finnegan, Henderson, Farabow, Garrett & Dunner, LLP, Linnik; Konstantin M.
Methods to introduce highly phosphorylated mannopyranosyl oligosaccharide derivatives containing mannose 6-phosphate (M6P), or other oligosaccharides bearing other terminal hexoses, to carbonyl groups on oxidized glycans of glycoproteins while retaining their biological activity are described. The methods are useful for modifying glycoproteins, including those produced by recombinant protein expression systems, to increase uptake by cell surface receptor-mediated mechanisms, thus improving their therapeutic efficacy in a variety of applications. |
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DETAILED DESCRIPTION Methods of creating neoglycoproteins are provided that increase the cellular uptake of lysosomal enzymes and other glycoproteins by covalently attaching oligosaccharide compositions to oxidized glycans of the glycoproteins through covalent bonds.
Thus, in one embodiment, the present invention is directed toward a method for coupling a highly phosphorylated mannopyranosyl oligosaccharide compound to a glycoprotein having at least one glycan, the method comprising derivatizing the highly phosphorylated manopyrosanyl oligosaccharide compound with a chemical compound containing a carbonyl-reactive group; oxidizing the glycoprotein having the at least one glycan to generate at least one aldehyde group on the glycoprotein; and reacting the oxidized glycoprotein having at least one glycan with the derivatized highly phosphorylated mannopyranosyl oligosaccharide compound to form a new compound having a hydrazone bond.
The glycoprotein in one embodiment is a lysosomal enzyme.
In one embodiment of the methods, the highly phosphorylated mannopyranosyl oligosaccharide compound contains at least one mannose 6-phosphate group, such as a compound having the formula 6-P-Mn-R wherein: M is a mannose or mannopyranosyl group; P is a phosphate group linked to the C-6 position of M; R comprises a chemical group containing at least one carbonyl-reactive group; and n is an integer from 1-15, wherein if n>1, Mn are linked to one another by alpha (1,2), alpha (1,3), alpha (1,4), or alpha (1,6).
Thus, the highly phosphorylated mannopyranosyl oligosaccharide compound includes compounds such as M6P, phosphopentamannose derived from Hansenula holstii O-phosphomannan, and 6-P-M-(alpha 1,2)-M(alpha 1,2)-M.
In another embodiment of the methods, the highly phosphorylated mannopyranosyl oligosaccharide compound comprises a compound having the formula (6-P-Mx)mLn-R wherein: M is a mannose or mannopyranosyl group; L is a mannose or other hexose or other chemical groups; P is a phosphate group linked to the C-6 position of M; R comprises a chemical group containing at least one carbonyl-reactive group; m is an integer from 2-3; n is an integer from 1-15, wherein if n>1, Ln are linked to one another by alpha (1,2), alpha (1,3), alpha (1,4), or alpha (1,6); and x is an integer from 1-15
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