Growth hormone receptor antagonists and fusion proteins thereof
Inventors
Park, Soon Jae • KO, Jaehyeong • You, Sun-Ah • YUN, Sang Hoon
Assignees
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Publication Number
US-11981719-B2
Publication Date
2024-05-14
Expiration Date
Abstract
The present invention relates to a growth hormone receptor antagonist comprising a growth hormone variant which is modified by substitution of one or more amino acids of growth hormone. Further, the growth hormone receptor antagonist of the present invention may further comprise a long-acting carrier which is fused to the growth hormone variant. The growth hormone receptor antagonist may have strong binding potency to growth hormone receptor and may exhibit a long-lasting antagonistic action.
Core Innovation
The invention relates to a growth hormone receptor antagonist comprising a growth hormone variant. The amino acid sequence includes specified substitutions at defined positions from the N-terminus, including substitution of the 120th amino acid from the N-terminus with lysine, the 21st amino acid from the N-terminus with asparagine, the 174th amino acid from the N-terminus with serine, the 46th amino acid from the N-terminus with lysine, the 18th amino acid from the N-terminus with aspartic acid, and substitution of the 179th amino acid from the N-terminus with threonine.
The growth hormone receptor antagonist is optionally fused with a long-acting carrier. The long-acting carrier includes alpha-1 antitrypsin (A1AT) variants, including an alpha-1 antitrypsin “NexP” variant, with fusion to the growth hormone variant directly or via a linker.
The document states that the resulting growth hormone receptor antagonism provides strong, long-lasting competitive antagonism of human growth hormone receptor binding. Comparative in vitro competitive inhibitory potency is described relative to Pegvisomant, with some variants described as showing substantially higher relative competitive inhibitory potency in assays.
Claims Coverage
The independent claim defines a growth hormone receptor antagonist through specified amino-acid substitutions at defined positions from the N-terminus, with six positions explicitly recited. Dependent claims refine the scope by specifying an exact sequence reference (SEQ ID NO: 9), optional fusion or linking to a long-acting carrier, specified linker selection, pharmaceutical compositions for enumerated diseases, and preparation by culturing cells containing a polynucleotide encoding the variant.
Growth hormone variant with defined N-terminal position substitutions
A growth hormone receptor antagonist comprising a growth hormone variant, wherein the amino acid sequence comprises the substitutions of the 120th amino acid from the N-terminus with lysine, the 21st amino acid from the N-terminus with asparagine, the 174th amino acid from the N-terminus with serine, the 46th amino acid from the N-terminus with lysine, the 18th amino acid from the N-terminus with aspartic acid, and substitution of the 179th amino acid from the N-terminus with threonine.
Growth hormone receptor antagonist defined by SEQ ID NO: 9
The growth hormone receptor antagonist comprises the amino acid sequence of SEQ ID NO: 9.
Long-acting carrier fusion or linking
The growth hormone receptor antagonist includes the growth hormone variant fused with the long-acting carrier directly or via a linker.
Non-peptidyl linker selection
A non-peptidyl linker is selected from polyethylene glycol, polypropylene glycol, copolymer of ethylene glycol and propylene glycol, polyoxyethylated polyol, polyvinyl alcohol, polysaccharide, dextran, polyvinyl ethyl ether, polylactic acid (PLA), polylactic-glycolic acid (PLGA), lipid polymer, chitins, and hyaluronic acid.
Pharmaceutical composition for a disease caused by human growth hormone
A pharmaceutical composition comprising the growth hormone receptor antagonist, wherein the disease is selected from acromegaly, gigantism, cancer, diabetic nephropathy, arthritis, lung inflammation, growth hormone deficiency (GHD), idiopathic short stature, Turner's syndrome, Prader-Willi syndrome, small for gestational age, and chronic renal insufficiency (CRI).
Polynucleotide-encoded production by culturing cells
The growth hormone receptor antagonist is prepared by culturing cells containing a polynucleotide encoding the growth hormone variant.
Overall claim coverage centers on a growth hormone receptor antagonist defined by specific N-terminus-position amino-acid substitutions in a growth hormone variant, optionally implemented as an exact sequence (SEQ ID NO: 9). The dependent claims further extend coverage to fusion or linking with a long-acting carrier using specified linker materials, pharmaceutical compositions for an enumerated set of diseases caused by human growth hormone, and preparation by culturing polynucleotide-containing cells.
Stated Advantages
Provides strong, long-lasting competitive antagonism of hGH receptor binding.
In vitro competitive inhibitory potency is described as substantially higher than Pegvisomant for certain variants.
Documented Applications
Therapeutic treatment for diseases caused by human growth hormone, including acromegaly, gigantism, growth hormone deficiency (GHD), and other enumerated conditions such as idiopathic short stature, Turner's syndrome, Prader-Willi syndrome, small for gestational age, and chronic renal insufficiency (CRI).
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