Glycoprotein hormone long-acting superagonists

Inventors

Szkudlinski, Mariusz • Weintraub, Bruce D.

Assignees

Trophogen Inc

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 superagonists, including FSH/LH/CG/TSH, formed by modifying the common alpha subunit to enhance receptor activation. The modifications use conservative basic substitutions in the common alpha subunit and are applied in combination with inserted peptides to introduce neoglycosylation and/or potential glycosylation sites between defined alpha-subunit residues.

In particular examples, an insert peptide, notably NVTINV and VNVTINVT, is placed in the common alpha subunit in place of a defined residue position or between specific alpha-subunit residues. The modified alpha variants are described alongside sequence listing constructs for human, bovine, and equine alpha variants, including alpha variants with defined sets of substituted residues and insert-containing variants.

The patent reports that these modified glycoprotein hormone superagonists maintain superagonist activity while improving potency/bioactivity and increasing in vivo pharmacokinetic half-life. The document further reports in vitro and in vivo evaluations using receptor activation-related readouts, pharmacokinetic studies, and functional reproductive studies.

Claims Coverage

The partial content identifies one independent claim. Its coverage centers on a modified equine chorionic gonadotropin hormone with a defined alpha-subunit substitution pattern and a defined insert placement, where the hormone exhibits increased receptor activation compared to a wild type equine CG hormone. Dependent claims further constrain the substitution set, define the alpha-subunit sequence, optionally include the beta subunit, and specify a veterinary composition intended to decrease time to first estrous in particular animals.

Overall, the claim set is directed to a modified equine CG defined by a basic-substitution pattern in the common alpha subunit, an inserted peptide placed in the alpha subunit, and an observed increased receptor activation relative to wild type equine CG. Additional dependent coverage further narrows the substitution pattern, fixes the alpha-subunit identity, optionally adds the beta subunit, and specifies veterinary compositions aimed at decreasing time to first estrous in particular pigs.

Stated Advantages

Documented Applications