Glycoprotein hormone long-acting superagonists

A glycoprotein hormone, animal technology, applied in the field of glycoprotein hormones, can solve the problems of weakening response, increasing half-life bioavailability, etc.

Inactive Publication Date: 2016-08-17
TROPHOGEN INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, previous attempts to further modify glycoprotein hormones to increase half-life and improve bioavailability were less than satisfactory, and instead the modified glycoprotein hormones exhibited only a diminished response

Method used

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  • Glycoprotein hormone long-acting superagonists
  • Glycoprotein hormone long-acting superagonists
  • Glycoprotein hormone long-acting superagonists

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0136] Design of α-subunit analogs

[0137] Human FSH superagonist glycoproteins with modifications to the α-subunit at Q13R+E14R+P16R+Q20R (human 4R) and with wild-type β-subunits showed significant binding superiority compared to their wild-type counterparts.

[0138] Table 1 shows a comparison of the primary amino acid structures of human alpha wild type (WT) and selected hFSH superagonists. The N-terminal portion of the human alpha wild-type (amino acid residues 1-28 for a total of 92 residues) and the N-terminal portion of the mutant form are shown. The positions of the four superagonist arginine (R) substitutions are shaded. Four different selected inserts introducing one or two additional N-linked carbohydrate chains were labeled between amino acids D3 and Q5 of the wild-type sequence.

[0139] Table 1.

[0140]

[0141] Fragments in Table 1 are listed below: SEQ ID NO:43:hFSH WT; SEQ ID NO:33, hFSHα(4R); SEQ ID NO:34, hFSHα(4R+Insl); SEQ ID NO:35, hFSHα( 4R+Ins2...

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Abstract

This invention provides long-acting, superactive analogs of glycoprotein hormones demonstrating enhanced bioactivity both in vitro and in vivo as compared to wild type counterparts. The analogs are particularly useful for treating subjects showing low receptor expression or poor receptor responsiveness, and for the treatment of any condition associated with glycoprotein hormone activity.

Description

technical field [0001] The present invention generally relates to modified glycoprotein hormones having superagonist activity and their use in the treatment of conditions associated with glycoprotein hormone activity. More specifically, the present invention relates to modified glycoprotein molecules that contain amino acid substitutions and one or more inserted peptides in the alpha subunit compared to the wild type alpha subunit, wherein such modified molecules are different from the wild type Glycoproteins exhibit enhanced pharmacological properties compared to glycoproteins. Background technique [0002] The gonadotropins follicle-stimulating hormone (follicle-stimulating hormone, FSH) and chorionic gonadotropin (CG), luteinizing hormone (luteinizing hormone, LH), and thyrotropin (thyroid-stimulating hormone, TSH) constitute the glycoprotein hormone family . Each hormone is a heterodimer of two non-covalently linked subunits, an alpha subunit and a beta subunit. The a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/24A61K38/16C07K14/59C07K1/00C07K14/00C07K17/00C07K16/00
CPCA61K38/00A61P15/08C07K14/59A61K38/24
Inventor M·斯库德林斯基B·D·温特劳布
Owner TROPHOGEN INC
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