Glycopegylated Factor IX
AssigneeNovo Nordisk A/S
InventorsShawn DeFrees, Robert J. Bayer, Caryn Bowe, Krishnasamy Paneerselvam
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Abstract
Conjugates between Factor IX and PEG moieties. are disclosed in the present application. The conjugates are linked via a glycosyl linking group interposed between and covalently attached to the peptide and the modifying group. Conjugates are formed from glycosylated peptides by the action of a glycosyltransferase. The glycosyltransferase ligates a modified sugar moiety onto a glycosyl residue on the peptide. Also provided are methods for preparing the conjugates, methods for treating various disease conditions with the conjugates, and pharmaceutical formulations including the conjugates.
Claims21
A PEGylated Factor IX protein comprising SEQ ID NO:1 and a poly(ethylene glycol) moiety, wherein the poly(ethylene glycol) moiety is conjugated to an amino acid selected from Asn 157 and Asn 167 of SEQ ID NO:1 via a glycosyl linking group of a glycosyl residue, and having a composition according to the formula:
- wherein
- R2 is COOH;
- R3 is H;
- R4 is OH;
- D is OH;
- and
- G is R1-L-
- wherein
- L is a substituted heteroalkyl linker comprising C(O)CH2NHC(O);
- R1 is the poly(ethylene glycol) moiety, wherein the poly(ethylene glycol) moiety comprises a branched poly(ethylene glycol) having a core glycerol moiety, and wherein the branched poly(ethylene glycol) has a molecular weight of about 40 kDa.
A Factor IX conjugate comprising a Factor IX protein comprising SEQ ID NO:1 and a poly(ethylene glycol) (PEG) moiety, wherein the PEG moiety is conjugated to an amino acid of SEQ ID NO:1 via a glycosyl linking group of a glycosyl residue, and having a composition according to the formula:
- wherein
- D is OH;
- and
- G has the formula
- wherein
- X2 is CH2,
- X3′ is CH2OC(O)NHCH2C(O)NH,
- X4 is a bond,
- X5 is H, and
- R16 and R17 are poly(ethylene)gycol, that compose a branched PEG moiety.
A Factor IX conjugate comprising a Factor IX protein comprising SEQ ID NO:1 and a poly(ethylene glycol) (PEG) moiety, wherein the PEG moiety is conjugated to an amino acid selected from Asn 157 and Asn 167 of SEQ ID NO:1 via a glycosyl linking group of a glycosyl residue, and having a composition according to the formula:
- wherein
- D is OH;
- and
- G is a composition according to the formula
- wherein m and n are integers independently selected from 1 to 2500.
A Factor IX conjugate comprises a glycosyl residue having the formula:
- wherein
- a, b, c, d, i, r, s, t, and u are integers independently selected from 0 and 1;
- q is 1;
- e, f, g, and h are members independently selected from the integers from 0 to 6;
- j, k, l, and m are members independently selected from the integers from 0 and 100;
- v, w, x, and y are independently selected from 0 and 1, and at least one of v, w, x, and
- y is 1;
- AA is an amino acid residue of said Factor IX peptide selected from the group consisting of Asn 157, Asn 167 and combinations thereof;
- Sia-(R) has the formula:
- wherein
- D is —OH;
- and
- G is R1-L-
- wherein
- L is a substituted heteroalkyl linker comprising C(O)CH2NHC(O);
- and
- R1 is the poly(ethylene glycol) moiety, wherein the poly(ethylene glycol) moiety comprises a branched poly(ethylene glycol) having a core glycerol moiety, and wherein the branched poly(ethylene glycol) has a molecular weight of about 40 kDa.
Dependencies are inferred from the claim text.