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Publication Number
US-10537646-B2
Publication Date
2020-01-21
Expiration Date
Abstract
A composition which includes oxyntomodulin and polyethylene glycol polymer (PEG polymer) linked via a reversible linker such as 9-fluorenylmethoxycarbonyl (Fmoc) or 2-sulfo-9-fluorenylmethoxycarbonyl (FMS) is disclosed. Pharmaceutical compositions comprising the reverse pegylated oxyntomodulin and methods of using same are also disclosed.
Core Innovation
The invention relates to reverse pegylated oxyntomodulin conjugates in which an oxyntomodulin is conjugated with a polyethylene glycol polymer (PEG polymer) and 9-fluorenylmethoxycarbonyl (Fmoc) or 2-sulfo-9-fluorenylmethoxycarbonyl (FMS). The PEG is linked via the Fmoc or FMS group so that, under physiological conditions, the conjugate releases free OXM. This design is described as a way to prolong half-life and improve pharmacokinetics and pharmacodynamics.
The conjugates are defined with site-specific attachment of the PEG polymer to the oxyntomodulin at the amino terminus or at Lys12. The document further includes multiple site-specific variants, including amino/N-terminus and Lys12 and Lys30 variants, with PEG attachment and linker sensitivities described in the summary content.
The disclosure further describes receptor activation assays and in vivo studies showing functional and exposure-related outcomes, including GLP-1 and glucagon receptor activation with cAMP readouts and pharmacokinetic evaluation by LC-MS/MS. The stated goal of the design is to reduce OXM accumulation while maintaining extended exposure, and therapeutic effects are described for metabolic endpoints and related lipid parameters.
Claims Coverage
The independent claim covers an oxyntomodulin-PEG conjugate with a reverse pegylation design using an Fmoc or FMS linker and defines two attachment locations: the amino terminus or Lys12. Across the dependent claims, additional inventive features include specifying the oxyntomodulin sequence (SEQ ID NO: 1), adding a sulfhydryl moiety, limiting the PEG polymer to PEG30, and reciting a pharmaceutical composition and administration outcomes for metabolic control.
Fmoc or FMS-linked PEG conjugate with site-specific attachment
An oxyntomodulin conjugate consisting of an oxyntomodulin, a polyethylene glycol polymer (PEG polymer) and 9-fluorenylmethoxycarbonyl (Fmoc) or 2-sulfo-9-fluorenylmethoxycarbonyl (FMS), wherein the PEG polymer is attached to the amino terminus of the oxyntomodulin or to a lysine residue at position number twelve (Lys12) of the oxyntomodulin, via Fmoc or FMS.
Oxyntomodulin defined as SEQ ID NO: 1
The conjugate wherein the oxyntomodulin comprises the amino acid sequence of SEQ ID NO: 1.
PEG polymer containing a sulfhydryl moiety
The conjugate wherein the PEG polymer contains a sulfhydryl moiety.
PEG polymer as PEG30
The conjugate wherein the PEG polymer is PEG30.
Pharmaceutical composition with pharmaceutically acceptable carrier
A pharmaceutical composition comprising the conjugate and a pharmaceutically acceptable carrier.
Administration to induce glucose tolerance and improve metabolic outcomes
A method of inducing glucose tolerance, increasing insulin sensitivity, inducing glycemic control, and/or reducing insulin resistance in a subject who needs such treatment, by administering the pharmaceutical composition.
Overall, the claim set is directed to reverse pegylated oxyntomodulin conjugates using an Fmoc or FMS-linked PEG polymer with site-specific attachment at the amino terminus or Lys12, further narrowed by an oxyntomodulin sequence (SEQ ID NO: 1), PEG polymer functionalization (sulfhydryl moiety), and PEG30 selection. The dependent claims also extend coverage to pharmaceutical composition and administration methods targeting glucose tolerance, insulin sensitivity, glycemic control, and insulin resistance.
Stated Advantages
Prolong half-life.
Improve pharmacokinetics.
Improve pharmacodynamics.
Documented Applications
Metabolic use including glycemic control, glucose tolerance, insulin sensitivity, and insulin resistance outcomes in subjects who need such treatment.
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