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Publication Number
US-9821070-B2
Publication Date
2017-11-21
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 (OXM) compositions in which PEG is linked via base-labile, reversible Fmoc or 2-sulfo-Fmoc (FMS) linkers. This design enables slow release of intact OXM and is used to provide prolonged circulation and biological half-life.
Homogeneous reverse pegylated OXM conjugates are described, including PEG-FMS-OXM variants and PEG-Fmoc-OXM variants, with PEG attachment at the amino terminus or at Lys12/Lys30. Long-acting or reversely pegylated OXM is defined using interchangeable constructions within the disclosed conjugate variants, and non-reversible PEG-EMCS-OXM control comparisons are reported.
The disclosure states that conjugation preserves GLP-1 and glucagon receptor activity while improving pharmacokinetic exposure and pharmacological outcomes. Reported effects include changes in AUC and half-life (t1/2) with Tmax/Cmax-related impacts, together with improved glucose tolerance and benefits in ob/ob mouse models including body weight, food intake, insulin sensitivity/resistance, and lipid/cholesterol-related outcomes, with variant-dependent potency differences between amino- and Lys-position variants and between PEG-FMS and PEG-Fmoc.
Claims Coverage
The claim set centers on a homogeneous conjugate with a specified structure, with a key structural limitation that R2 is hydrogen or SO3H, or a pharmaceutically acceptable salt thereof. Dependent claims further constrain PEG chain length, salt form, pharmaceutical composition, and medical uses, including obesity treatment and increased energy expenditure.
Homogeneous conjugate with R2 hydrogen or SO3H
A homogeneous conjugate represented by the structure, wherein R2 is hydrogen or SO3H, or a pharmaceutically acceptable salt thereof.
Homogeneous conjugate with PEG chain-length n equal 30, 40, or 60
The homogeneous conjugate uses a PEG whose structure is (CH2CH2O)nCH3 with n equal to 30 (PEG30), 40 (PEG40), or 60 (PEG60).
Homogeneous conjugate limited to specific pharmaceutically acceptable salts
The pharmaceutically acceptable salt form is specified to be a TFA salt, an HCl salt, or an acetate salt.
Pharmaceutical composition including the homogeneous conjugate and a carrier
A pharmaceutical composition includes the conjugate together with a pharmaceutically acceptable carrier.
Treating obesity by administering the homogeneous conjugate
Treating obesity in a subject by administering the conjugate to a subject in need.
Increasing energy expenditure by administering the homogeneous conjugate
Increasing a subject’s energy expenditure by administering the conjugate to a subject in need.
The disclosed invention centers on a homogeneous conjugate with R2 hydrogen or SO3H, further constrained by PEG chain length (30/40/60) and specific salt forms. Medical uses are claimed for treating obesity and increasing energy expenditure by administering the conjugate.
Stated Advantages
Preserves GLP-1/glucagon receptor activity while improving pharmacokinetic exposure (AUC and half-life effects stated).
Provides prolonged circulation and biological half-life through slow release of intact OXM.
Improves glucose tolerance and produces beneficial outcomes in ob/ob mouse models including body weight and food intake changes.
Improves insulin sensitivity/resistance and improves lipid/cholesterol-related outcomes.
Documented Applications
Medical use for treating obesity in a subject in need, by administering the claimed homogeneous conjugate.
Medical use to increase a subject’s energy expenditure by administering the claimed homogeneous conjugate.
Glucose tolerance improvement and metabolic outcomes are reported in ob/ob mouse models, including effects on body weight, food intake, insulin sensitivity/resistance, and lipid/cholesterol-related outcomes.
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