Growth Hormone Compounds

Patent metadata

Field	Value
Publication number	US-2016017017-A1
Application number	US-201414773433-A
Country	US
Kind code	A1
Filing date	Mar 11, 2014
Priority date	Mar 11, 2013
Publication date	Jan 21, 2016
Grant date	—

Abstract

The invention relates to growth hormone compounds with a long plasma half-life obtained by Fc linkage. An increased half-life is an advantage allowing a less frequent or low dosage administration of therapeutic. The invention further relates to methods of producing such compound including expression vectors for heterologous expression.

First claim

1 . A growth hormone compound comprising a growth hormone variant linked to an antibody Fc-domain (GH-variant-Fc).

2 . The growth hormone compound, according to claim 1 , wherein the growth hormone variant has reduced affinity to the human growth hormone receptor (hGHR).

3 . The growth hormone compound, according to claim 1 , wherein the growth hormone compound binds hGHR via site 1 with an affinity (K D ) between 5000-0.5 nmol.

4 . The growth hormone compound, according to claim 1 , wherein the growth hormone compound has an increased in vivo half-life compared to the equivalent hGH-Fc compound.

5 . The growth hormone compound, according to claim 1 , wherein the growth hormone compound has an increased MRT compared to the equivalent hGH-Fc compound.

6 . The growth hormone compound, according to claim 1 , wherein the growth hormone compound is capable of inducing an extended IGF-1 response.

7 . The growth hormone compound, according to claim 1 , wherein the growth hormone compound induces an extended IGF-1 response, which lasts more than 24 hours.

8 . The growth hormone compound, according claim 1 , wherein the growth hormone compound induces weight gain in hypophysectomised rats.

9 . The growth hormone compound, according to claim 1 , wherein the growth hormone variant has at least one point mutation in a position corresponding to K41, R64 and/or K172 of human growth hormone (SEQ ID NO.: 1).

10 . The growth hormone compound, according to claim 1 , wherein the compound comprises one Fc-domain and one GH variant polypeptide (monovalent).

11 . The growth hormone compound, according to claim 1 , wherein the compound comprises at least one Fc polypeptide and GH variant (GH-variant-Fc polypeptide) fusion protein.

12 . The growth hormone compound, according to claim 1 , wherein the compound comprises at least one GH variant and Fc polypeptide (GH-variant-Fc polypeptide) fusion protein wherein the GH variant and Fc polypeptide are linked by a linker peptide.

13 . The growth hormone compound, according to claim 1 , wherein the Fc-polypeptide comprises a hinge region including one or more cysteines.

14 . A method of treating GHD, AGHD, IBD or CD, comprising administering the compound of claim 1 to a subject in need thereof.

15 . An expression vector encoding the GH variant and Fc polypeptide fusion according to claim 12 .

16 . A host cell expressing the GH variant and Fc polypeptide fusion according to claim 12 .

17 . The growth hormone compound according to claim 3 , wherein the growth hormone compound binds hGHR via site 1 with an affinity (K D ) of between 4000-1.0 nmol, between 2500-10 nmol, between 1000-25 nmol, between 500-50 nmol, or between 250-75 nmol.

18 . The growth hormone compound according to claim 7 , wherein the growth hormone compound induces an extended IGF-1 response, which lasts more than 48 hours, more than 96 hours or more than 144 hours.

19 . The growth hormone compound according to claim 12 , wherein the linker peptide is a GS linker.

Assignees

• Zhao Xin
• Thygesen Peter
• Johansen Nils Langeland
• NØRSKOV LAURITSEN Leif
• Novo Nordisk Healthcare Ag
• Novo Nordisk Healthcare Ag

Inventors

• Zhao Xin
• Thygesen Peter
• Johansen Nils Langeland
• Noerskov-Lauritsen Leif

Classifications

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• C07K2319/30

  Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto · CPC title

• C07K14/61 Primary

  Growth hormone [GH], i.e. somatotropin · CPC title

• A61P5/06

  of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH · CPC title