Glycoprotein hormone long-acting superagonists
Inventors
Szkudlinski, Mariusz • Weintraub, Bruce D.
Assignees
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Publication Number
US-10457713-B2
Publication Date
2019-10-29
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 relates to long-acting glycoprotein hormone superagonist analogs engineered from follicle-stimulating hormone (FSH) by modifying the alpha (α) subunit. The engineered FSH α-subunit comprises conservative basic amino-acid substitutions in selected positions, including arginine, histidine, or lysine substitutions at at least one of T11, Q13, E14, P16, and Q20.
In addition to the conservative basic substitutions, the invention includes an insert of a specific peptide sequence within the α-subunit. An insert such as NVTINVT (SEQ ID NO: 46) is inserted between V4 and Q5, and related NVTINV/VNVTINVT-type peptides are also described.
The modified FSH is evaluated using cAMP stimulation, receptor binding, Steelman-Pohley bioassay, and pharmacokinetics analyses. Nonclinical and animal study contexts are explicitly referenced, along with charge heterogeneity analyses and comparative performance for engineered FSH α-subunit analogs with or without inserts.
Claims Coverage
The provided claim set includes one independent claim directed to a modified human FSH, with dependent claims that further specify particular substitution patterns, an alternative α-subunit sequence definition, and formulation/composition limitations. Across the dependency described, there are four inventive features focused on an α-subunit substitution pattern, a defined peptide insert position and sequence, pharmaceutical composition and carrier aspects, and adding an associated β subunit to form a full complex.
Modified human FSH alpha subunit with basic substitutions at selected positions
A modified human follicle stimulating hormone (FSH) wherein the α subunit comprises arginine, histidine, or lysine substitutions at at least one of T11, Q13, E14, P16, and Q20.
NVTINVT peptide insert between V4 and Q5 in the alpha subunit
A modified human follicle stimulating hormone (FSH) wherein the α subunit includes an insert of NVTINVT (SEQ ID NO: 46) between V4 and Q5.
Pharmaceutical composition with carrier
A pharmaceutical composition comprising the modified human FSH together with a carrier, including a pharmaceutically acceptable carrier.
Associated beta subunit
An associated β subunit is described as forming a full complex.
Overall, the claim coverage centers on a modified human FSH defined by a specific α-subunit substitution scheme combined with a defined NVTINVT insert between V4 and Q5. The dependent claims further narrow the substitution pattern and add pharmaceutical composition limitations including a carrier and a pharmaceutically acceptable carrier, with optional inclusion of the β subunit described in the family summary.
Stated Advantages
Increased potency and maintained superagonist activity in vitro and in vivo.
Increased serum half-life, including effects described as neoglycosylation-driven half-life extension.
Prolonged plasma levels.
Observed improvements in reproductive outcomes described as superovulation and IVF/embryo development improvements.
Documented Applications
Administration to mammals for subjects with low receptor expression/responsiveness and reproductive disorders.
Reproductive use contexts involving superovulation and IVF, including embryo development improvements.
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