Targeting of glycoprotein therapeutics
AssigneeGenzyme Corporation
InventorJames STEFANO
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Abstract
Methods of making ligand-decorated polymer conjugates of therapeutic glycoproteins are described. Improved targeting of glycoproteins to specific tissues is achieved by masking the natural carbohydrate and other surface determinants with high molecular weight polymers, such as, e.g., PEG, polysialic acid, etc., which in turn are decorated with target-specific ligands. In some embodiments, acid-labile linkages in such conjugates or rapidly degradable masking groups allow for the intracellular release of the polymer from the glycoprotein, for example, under conditions found in lysosomes.
Claims13
1-67. (canceled)
A method of making a conjugate, the method comprising:
- (a) reacting a masking moiety (M) with a therapeutic glycoprotein (G), wherein the masking moiety comprises a first functional group to react with the therapeutic glycoprotein;
- and
- (b) reacting the masking moiety with a thiol group of a targeting moiety (T), wherein the masking moiety comprises a thiol-reactive group as a second functional group,
- wherein the masking moiety is covalently linked to the therapeutic glycoprotein through a first linker (L1), the targeting moiety is covalently linked to the masking moiety through a second linker (L2), and the conjugate has formula G(L1-M(L2-T)n)m, wherein 2≤m≤16, and n<1 or 1<n≤20,
- wherein the masking moiety is capable of reducing or blocking binding of the therapeutic glycoprotein to its cognate receptor, and
- wherein the conjugate is configured to release the therapeutic glycoprotein from the conjugate under lysosomal conditions.
Dependencies are inferred from the claim text.