Glycoprotein hormone long-acting superagonists
Inventors
Szkudlinski, Mariusz • Weintraub, Bruce D.
Assignees
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Publication Number
US-10544200-B2
Publication Date
2020-01-28
Expiration Date
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.
Core Innovation
The invention concerns long-acting glycoprotein hormone superagonist analogs including FSH, CG/eCG, LH, and TSH. The modified hormones are engineered as modified glycoprotein hormones having an alpha subunit with substitutions in the common alpha-L1 loop using basic amino acid substitutions. Basic amino acid substitutions are introduced at species-mapped positions, including arginine/lysine substitutions at positions associated with Q13/E14/P16/Q20 or corresponding K15/E18/K20/K24.
In addition to the basic amino acid substitutions in the alpha-L1 loop, the invention introduces N-terminal alpha-subunit inserts that create neoglycosylation motifs. The inserts introduce NVTINV (SEQ ID NO: 1) glycosylation sites into the alpha subunit compared with a wild type glycoprotein hormone, including variants such as VNVTINVT (SEQ ID NO: 20) and related sequon variants, including NX1T, NX2S, NNX3X4 sequons and related NVT/NIT/NNTT/NNTS/NNSS/NNST motif variants.
The invention further reports enhanced potency and superagonist activity through receptor stimulation using in vitro assays, including cAMP/progesterone assays. It also reports prolonged serum half-life via pharmacokinetic screening in vivo, including studies in mice and bovine rFSH TR55601-like analogs.
For veterinary use, the invention reports superovulation performance in cattle using single or split dosing, including performance comparable to or improved over Folltropin-V.
Claims Coverage
The independent claim covers a modified glycoprotein hormone defined by two engineered components: basic amino acid substitutions in the alpha-L1 loop and one or more inserts between alpha-subunit positions 3 and 8 that introduce NVTINV (SEQ ID NO: 1) glycosylation sites versus a wild type glycoprotein hormone. Dependent claims refine substitution patterns and insert positioning and optionally include specific beta subunits, and further narrow use to stimulating a glycoprotein hormone receptor in an animal.
Alpha-L1 loop basic substitutions with NVTINV insert neoglycosylation sites
A modified glycoprotein hormone comprising an amino acid sequence having at least one basic amino acid substitution in the alpha-L1 loop of the alpha subunit and one or more inserts between amino acids at positions 3 and 8 of the alpha subunit, wherein the inserts introduce NVTINV (SEQ ID NO: 1) glycosylation sites into the alpha subunit compared with a wild type glycoprotein hormone.
Across the claim set provided, the inventive concept is the combination of alpha-L1 loop basic amino acid substitutions with alpha-subunit inserts between positions 3 and 8 that introduce NVTINV (SEQ ID NO: 1) glycosylation sites relative to a wild type glycoprotein hormone, with refinements specifying substitution position sets and anchoring to SEQ ID NO: 6, optional beta subunit selection, and narrowed use to receptor stimulation in an animal.
Stated Advantages
Enhanced potency and superagonist activity.
Prolonged serum half-life via pharmacokinetic screening.
Superovulation performance in cattle comparable to or improved over Folltropin-V.
Documented Applications
Stimulating a glycoprotein hormone receptor in an animal by administering a modified glycoprotein hormone.
Veterinary superovulation in cattle, including beef cows, using single or split dosing, with performance comparable to or improved over Folltropin-V.
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