Porcine G-CSF variants and their uses
Inventors
CANNING, Peter Connor • KNUDSEN, Nickolas • RASHID, MD HARUNUR
Assignees
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Publication Number
US-11578111-B2
Publication Date
2023-02-14
Expiration Date
Abstract
The present invention relates to variants of porcine granulocyte colony stimulating factor (pG-CSF). The pG-CSF variants are useful in treating preventing or reducing the incidence of bacterial infections in swine. Methods of treating swine are disclosed.
Core Innovation
The invention relates to porcine granulocyte colony stimulating factor (pG-CSF) variants engineered to include a para-acetyl phenylalanine (pAF) synthetic amino acid at position 43, covalently attached to a poly(ethylene glycol) (PEG). The variant sequence further includes defined substitutions at X1, X2, and X3 positions, with X1 selected from methionine, alanine, norleucine, alanine only, and no amino acids; X2 being cysteine or serine; and X3 being methionine or norleucine.
The problem addressed is bacterial infections in swine, particularly periparturient sow conditions associated with MMA syndrome (mastitis, metritis, and agalactia). The described approach uses the pG-CSF variant to provide increased porcine neutrophils and to support outcomes associated with reducing MMA incidence and improving piglet survival, while PEGylation prolongs pharmacokinetics and stability.
Documented embodiments include variant generation and experimental evaluation of potency and stability, including an in vitro neutrophil proliferation assay and measurements of porcine neutrophil responses in studies using dosing and subsequent blood analysis. Additional pAF-related variant forms, including C17A/C17S variants, are also discussed with reported potency and thermostability observations.
Claims Coverage
The independent claim covers a specific porcine granulocyte colony stimulating factor (pG-CSF) variant with defined sequence-site substitutions and a pAF-to-PEG covalent attachment at position 43. Dependent claims further refine the PEG properties and specify therapeutic method coverage for MMA syndrome in porcine animals.
Paf-pegylated pG-CSF variant with covalent attachment at position 43
A porcine granulocyte colony stimulating factor (pG-CSF) variant consisting of a sequence in which X1 is selected from methionine alanine, norleucine alanine, alanine only, and no amino acids; X2 is cysteine or serine; X3 is methionine or norleucine; and a para-acetyl phenylalanine (pAF) synthetic amino acid present at position 43 is covalently attached to a poly(ethylene glycol) (PEG).
PEG molecular-weight range
The pG-CSF variant wherein the PEG has a molecular weight in the range of about 20 kD to about 50 kD.
Treatment of MMA syndrome in a porcine
Treating MMA syndrome in a porcine by administering a therapeutically effective amount of the pG-CSF variant.
Therapeutically effective dose range
The administering is performed with a therapeutically effective dose of the pG-CSF variant of about 10 μg/kg to about 100 μg/kg of animal body weight.
Administration timing relative to farrowing
The administering is performed at least once within 7 days prior to farrowing.
Overall, the claim coverage is centered on a pG-CSF variant defined by specified sequence positions and a covalent pAF-PEG attachment at position 43, with dependent claims refining PEG molecular-weight range and adding method claims for MMA syndrome treatment, including a therapeutically effective dosing range and pre-farrowing administration timing.
Stated Advantages
Prolongs pharmacokinetics and stability through PEGylation.
Elevated porcine neutrophils after administration.
Reduced MMA incidence under an unhygienic farrowing challenge.
Improved piglet survival and related weaning outcomes.
Documented Applications
Non-antibiotic prophylaxis/treatment of bacterial infections in swine, particularly periparturient sow mastitis, metritis, and agalactia (MMA syndrome).
Use of a single intramuscular dose to increase blood neutrophils in a sow context.
A prophylactic regimen under unhygienic farrowing challenge conditions to reduce MMA incidence and affect piglet survival and weaning metrics.
In vitro neutrophil proliferation assay using M-NSF-60 cells (ATCC CRL-1838) to evaluate potency.
Rodent PK/CBC measurements of neutrophils following dosing.
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