Long-acting polypeptides and methods of producing and administering same
Inventors
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-12029780-B2
Publication Date
2024-07-09
Expiration Date
Abstract
CTP-modified human growth hormone polypeptides and pharmaceutical formulations and pharmaceutical compositions comprising the same and methods of producing, and using the same are disclosed.
Core Innovation
The invention relates to CTP-modified long-acting human growth hormone (hGH) constructs in which a chorionic gonadotropin carboxy terminal peptide (CTP) is incorporated into the hGH polypeptide. The constructs include an amino terminal CTP and two carboxy terminal CTPs arranged in tandem, yielding a glycosylated polypeptide with defined amino acid sequence relationships.
The glycosylated polypeptide comprises an amino terminal CTP of SEQ ID NO:18, a human growth hormone polypeptide, and two carboxy terminal chorionic gonadotropin CTPs, each of SEQ ID NO:18 and arranged in tandem. The CTP-modified hGH polypeptide is described with an amino acid sequence as set forth in amino acids 27 to 301 of SEQ ID NO:39.
The approach is positioned as enabling maintenance of insulin-like growth factor (IGF-1) levels in a growth hormone deficient human prepubertal pediatric subject within a normal therapeutic range. The document links the CTP-modified hGH polypeptide to extended circulatory half-life, increased serum stability, and prolonged pharmacokinetics and pharmacodynamic effects, with supportive data including glycan profiling consistent with predominantly O-linked glycans and preclinical and clinical trial context.
Claims Coverage
The claim coverage centers on one independent claim directed to maintaining IGF-1 levels within a normal therapeutic range in a growth hormone deficient human prepubertal pediatric subject using a glycosylated, CTP-modified hGH polypeptide given once weekly. Dependent claims refine the IGF-1 range definition, treatment duration, measurement timing, and sequence-based definition of the polypeptide.
Maintaining IGF-1 levels within a normal therapeutic range in growth hormone deficient prepubertal pediatric subjects
Administering to the growth hormone deficient human prepubertal pediatric subject a therapeutically effective amount of a glycosylated polypeptide comprising an amino terminal chorionic gonadotropin carboxy terminal peptide (CTP) of SEQ ID NO:18, a human growth hormone polypeptide, and two carboxy terminal chorionic gonadotropin CTPs, each of SEQ ID NO:18 and arranged in tandem, wherein the CTP-modified hGH polypeptide has the amino acid sequence as set forth in amino acids 27 to 301 of SEQ ID NO:39.
Once-weekly therapeutically effective dosing
The therapeutically effective amount comprises a once a week dose of 0.66 milligrams per kilogram per week (mg/kg/week) for maintaining IGF-1 levels within the normal therapeutic range.
Defining the normal therapeutic range by IGF-1 within ±2 SDS
The normal therapeutic range of IGF-1 levels is ±2 standard deviations (SDS) of the average IGF-1 levels in non-growth hormone deficient human prepubertal pediatric subjects.
Maintaining IGF-1 within range for six months
The method maintains normal therapeutic IGF-1 levels in a growth hormone deficient human prepubertal pediatric subject for six months.
Post-dose durability using a quantified mean time interval within the IGF-1 range
The method is defined such that the mean time interval of IGF-1 levels within the normal therapeutic range after the last dose administration is at least one of the specified threshold values.
Using a narrower IGF-1 therapeutic range defined as ±1.5 SDS
The method is carried out using a normal therapeutic range for IGF-1 levels defined as ±1.5 SDS from the average IGF-1 levels in non-growth hormone deficient human prepubertal pediatric subjects.
Sampling-time constraint for measured IGF-1 four days after administration
The method includes that the measured IGF-1 levels correspond to IGF-1 levels of samples taken four days after administration of the CTP-modified hGH polypeptide.
Sequence-encoding definition for the CTP-modified hGH polypeptide
Using a CTP-modified hGH polypeptide that is encoded by a specified nucleic acid sequence (nucleotides 89 to 913 of SEQ ID NO:45).
Overall, the claim set centers on once-weekly administration of a glycosylated, tandem CTP-modified hGH polypeptide to maintain IGF-1 in a normal therapeutic range defined relative to non-growth hormone deficient prepubertal pediatric subjects. Dependent claim features further define duration, post-dose time-in-range criteria, narrower IGF-1 range criteria, a four-day sampling relationship, and a nucleic acid encoding definition for the CTP-modified hGH.
Stated Advantages
Can maintain IGF-1 within target ranges.
No excessive IGF-1 elevations.
Favorable safety/tolerability.
Improved feasibility over daily injections.
Enhances serum stability and increases in vivo potency.
Extends circulatory half-life and reduces dosing frequency.
Maintains IGF-1 within defined therapeutic ranges, including day-in-range metrics and specified SDS limits.
Documented Applications
Phase II clinical trial results in growth hormone deficient adults and children evaluating weekly or less frequent dosing to maintain IGF-1 within target ranges.
Use in growth hormone deficient human prepubertal pediatric subjects for maintaining IGF-1 levels within a normal therapeutic range.
Clinical-trial application in which adult cohorts are assessed for IGF-1 day-in-range metrics and time within ±2 SDS/+2 to -2 SDS without excessive IGF-1 above normal range.
Interested in licensing this patent?