Peptide complex with immunodulatory and anti-inflammatory function
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Publication Number
US-11447534-B2
Publication Date
2022-09-20
Expiration Date
Abstract
The present invention relates to compositions that are effective in management of inflammatory diseases. The disclosure provides a peptide complex comprising Abeta 1-42 and undercarboxylated osteocalcin which displays anti-inflammatory and immunomodulatory functions. The disclosure further provides with processes for preparing the compositions.
Core Innovation
The disclosure describes a peptide complex comprising Abeta 1-42 peptide and undercarboxylated osteocalcin (Glu-OC) for modulating inflammation, where Abeta 1-42 is represented by SEQ ID NO: 1 and undercarboxylated osteocalcin is represented by SEQ ID NO: 2. The undercarboxylated osteocalcin is described as uncarboxylated at glutamates 17, 21, and 24.
The invention is directed to immunomodulatory/anti-inflammatory activity obtained by modulating activated macrophages and macrophage-related cells, including microglia. The disclosure states that the complex increases CD36 scavenger receptor expression and MHC class II (Cd74) expression, and reduces ConA-induced iNOS/nitrite and TNF-alpha in vitro.
In vivo support is provided in 5×FAD Alzheimer transgenic mice, where Glu-OC treatment is reported to restore cognition, reduce insoluble/plaque-associated Abeta42 while increasing soluble Abeta42, and co-localize Abeta42 with osteocalcin in brain. Additional non-toxicity and anti-inflammatory effects are described using A11 reactivity reduction, LDH assay outcomes, and carrageenan-induced paw edema/nitrite reduction.
Claims Coverage
The independent claim covers a peptide complex defined by two specific peptide sequences, Abeta 1-42 and undercarboxylated osteocalcin, for modulating inflammation. The dependent claims refine the osteocalcin uncarboxylation pattern, specify macrophage phenotype modulation and macrophage-related cell types, add immunomodulatory marker effects, and include a pharmaceutical composition formulation.
Peptide complex for modulating inflammation with defined sequences
A peptide complex comprising Abeta 1-42 peptide and undercarboxylated osteocalcin (Glu-OC) for modulating inflammation, wherein Abeta 1-42 peptide is represented by SEQ ID NO: 1, and undercarboxylated osteocalcin is represented by SEQ ID NO: 2.
Undercarboxylated osteocalcin with uncarboxylated glutamic acid residues at positions 17, 21, and 24
The peptide complex has undercarboxylated osteocalcin containing uncarboxylated glutamic acid residues at positions 17, 21, and 24.
Macrophage phenotype modulation as the inflammation modulation mechanism
The peptide complex modulates inflammation by modulating the phenotype of activated macrophages or macrophage-related cells.
Macrophage-related cells selected from peripheral blood monocyte/macrophages, microglia, dendritic cell, and osteoclasts
The macrophage-related cells are selected from peripheral blood monocyte/macrophages, microglia, dendritic cell, and osteoclasts.
Increased CD36 scavenger protein expression in macrophage-related cells
The complex increases CD36 scavenger protein expression in macrophage-related cells, thereby leading to immunomodulation.
Increased MHC class II (Cd74) molecule expression
The disclosure states increased MHC class II (Cd74) expression.
Pharmaceutical composition with pharmaceutically acceptable excipient or carrier
A composition comprises the peptide complex and at least one pharmaceutically acceptable excipient or carrier.
Overall, the claim set is centered on a defined Abeta 1-42/Glu-OC peptide complex for modulating inflammation, with refinements to the osteocalcin uncarboxylation pattern and to inflammation modulation via activated macrophage phenotype. Additional refinements specify macrophage-related cell types and immunomodulation associated with increased CD36 expression, and include formulation as a pharmaceutical composition.
Stated Advantages
Immunomodulatory/anti-inflammatory activity.
Restores cognition in 5×FAD Alzheimer transgenic mice.
Reduces insoluble/plaque-associated Abeta42 while increasing soluble Abeta42.
Reduces A11 reactivity (non-toxic oligomer species).
Reduces ConA-induced iNOS/nitrite and TNF-alpha in vitro.
Reduces carrageenan-induced paw edema and serum nitrite.
Increases CD36 scavenger protein expression and increases MHC class II (Cd74) expression.
Documented Applications
Modulating inflammation via immunomodulatory/anti-inflammatory activity, including modulation of activated macrophages and macrophage-related cells such as microglia.
Alzheimer-related context: treatment in 5×FAD Alzheimer transgenic mice with reported effects on cognition and Abeta42 solubility/plaque association.
Anti-inflammatory effects in carrageenan-induced paw edema with reduced serum nitrite.
Use in macrophage and microglia cell models to assess immunomodulatory effects and inflammation-related readouts.
Osteoblast/osteoclast co-culture gene effect assessment in the disclosure context.
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