Long-acting conjugates of GLP-2 derivatives
A glucagon-like peptide-2 (GLP-2) derivative, a conjugate thereof, and a use thereof are disclosed. Additionally, a method for preparing a glucagon-like peptide-2 (GLP-2) derivative and a conjugate thereof is disclosed.
1 . A glucagon-like peptide-2 (GLP-2) conjugate, wherein a GLP-2 derivative and an immunoglobulin Fc region are each covalently linked via a non-peptidyl polymer at both termini of the non-peptidyl polymer,
wherein the GLP-2 derivative consists of the amino acid sequence of SEQ ID NO: 4;
wherein the non-peptidyl polymer is polyethylene glycol,
wherein a molecular weight of the non-peptidyl polymer is in a range of 3.4 kDa to 10 kDa; and
wherein one end of the non-peptidyl polymer is conjugated to the immunoglobulin Fc region and the other end of the non-peptidyl polymer is conjugated to lysine of the GLP-2 derivative at position 34 of SEQ ID NO: 4.
2 . The GLP-2 conjugate according to claim 1 , wherein the immunoglobulin Fc region is non-glycosylated.
3 . The GLP-2 conjugate according to claim 1 , wherein the immunoglobulin Fc region comprises a hinge region.
4 . The GLP-2 conjugate according to claim 1 , wherein the immunoglobulin Fc region is an IgG4 Fc region.
5 . The GLP-2 conjugate according to claim 1 , wherein the molecular weight of the non-peptidyl polymer is 3.4 kDa or 10 kDa.
6 . A method for preparing the GLP-2 conjugate of claim 1 , comprising:
(a) preparing a complex by reacting a non-peptidyl polymer having two or more terminal reactive groups with one of the GLP-2 derivative as defined in claim 1 and an immunoglobulin Fc region such that the complex has the GLP-2 derivative or the immunoglobulin Fc region attached to one terminal end of the non-peptidyl polymer, and a reactive group at the other terminal end; and
(b) preparing a conjugate by reacting the complex prepared in step (a) with one of the immunoglobulin Fc region and the GLP-2 derivative not attached to the complex such that the GLP-2 derivative and the immunoglobulin Fc region are linked via the non-peptidyl polymer,
wherein the non-peptidyl polymer is polyethylene glycol,
wherein a molecular weight of the non-peptidyl polymer is in a range of 3.4 kDa to 10 kDa, and
wherein one end of the non-peptidyl polymer is conjugated to the immunoglobulin Fc region and the other end of the non-peptidyl polymer is conjugated to lysine of the GLP-2 derivative at position 34 of SEQ ID NO: 4.
7 . The method according to claim 6 , wherein the non-peptidyl polymer comprises one or more reactive groups selected from the group consisting of an aldehyde group, a propionaldehyde group, a butyraldehyde group, a maleimide group, and a succinimide derivative.
8 . The method according to claim 7 , wherein the succinimide derivative is succinimidyl carboxymethyl, succinimidyl valerate, succinimidyl methylbutanoate, succinimidyl methylpropionate, succinimidyl butanoate, succinimidyl propionate, N-hydroxysuccinimide, or succinimidyl carbonate.
9 . A method for treating one or more diseases selected from intestinal disease, intestinal injury, and gastrosia, comprising administering an effective amount of a composition comprising the GLP-2 conjugate according to claim 1 to a subject in need thereof.
10 . The method according to claim 9 , wherein the intestinal disease is short-bowel syndrome, hypersensitive intestinal disease, inflammatory intestinal disease, Crohn's disease, colonitis, colitis, pancreatitis, ileitis, mucositis, or intestine atrophy.
11 . The method according to claim 9 , wherein the gastrosia is stomach cramps, gastritis, gastric ulcer, duodenitis, or duodenal ulcer.