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 document describes long-acting glycoprotein hormone superagonists engineered as modified glycoprotein hormones. The modifications include conservative basic amino-acid substitutions in the glycoprotein alpha subunit and insertion of specific alpha-subunit peptides between defined alpha-residue positions, and the resulting modified bovine follicle-stimulating hormone (FSH) is designed to increase FSH receptor activation compared to bovine wild type FSH.

In particular, the disclosed modified bovine FSH comprises SEQ ID NO: 2 with arginine, histidine, or lysine substitutions at K15, K17, K20, K24, and E18, together with an insert of SEQ ID NO: 1 between F6 and T7. The insert is described using sequences such as NVTINV (SEQ ID NO:1) and variants including NV and INV, and the alpha-subunit peptide insertion is positioned within the alpha subunit based on defined residue ranges.

The document further provides rationale that the combination of alpha-subunit conservative basic substitutions and the inserted alpha-subunit peptide increases receptor activation and potency while also prolonging serum half-life through induced glycosylation, described as neoglycosylation. The disclosure includes reported in vitro cAMP bioactivity and mouse pharmacokinetic screening indicating prolonged half-life for neoglycosylated bFSH “5R” analogs, and bovine superovulation studies showing long-acting superovulatory performance with reduced dosing frequency compared to Folltropin-V.

Claims Coverage

The partial content includes two independent claims covering modified bovine FSH constructs with specific alpha-subunit substitution and peptide-insert features that increase FSH receptor activation relative to wild type. Across the independents, the inventive features focus on defined basic substitutions in SEQ ID NO: 2, an insert of SEQ ID NO: 1 at an alpha-residue position window, and a performance-based receptor activation enhancement, with optional definition of the alpha subunit sequence in dependent claims.

Overall, the claim coverage centers on modified bovine FSH molecules that combine SEQ ID NO: 2 basic amino-acid substitutions at K15/K17/K20/K24 and E18 with an SEQ ID NO: 1 alpha-subunit insert located between F6 and T7, achieving increased FSH receptor activation versus wild type. Dependent claims additionally specify alpha-subunit sequence identity and can refine pharmacokinetic aspects such as longer half-life and duration of action relative to bovine wild type.

Stated Advantages

Documented Applications