ULTRA-LONG ACTING INSULIN-FC FUSION PROTEINS AND METHODS OF USE
The present disclosure provides recombinantly manufactured ultra-long acting insulin-Fc fusion proteins for use in treating canine and feline diabetes. The insulin-Fc fusion proteins comprise an insulin polypeptide linked via a peptide linker to an Fc-fragment of canine or feline origin. Based on the results obtained, creating a treatment that is amenable to low cost manufacturing, exhibits sufficient in vivo bioactivity, displays extended duration of bioactivity, does not induce anti-drug antibodies, and substantially retains is potency over multiple administrations, requires a non-obvious combination of insulin polypeptide, peptide linkers, and species-specific Fc fragment, in addition to selective mutations on one or more of these components. Exemplary ultra-long acting insulin-Fc fusion proteins, polynucleotides encoding these insulin-Fc fusion proteins, and pharmaceutical formulations of exemplary insulin-Fc fusion proteins are provided, in addition to methods of use and preparation.
1 . A pharmaceutical composition comprising:
i) an insulin Fc-fusion protein;
ii) 10-50 mM sodium hydrogen phosphate;
iii) 50-150 mM sodium chloride;
iv) 0.005-0.05% v/v surfactant; and
i) optionally a bacteriostat agent.
2 . The composition of claim 1 , wherein the insulin Fc-fusion protein is about 1-10 mg/ml in solution.
3 . The composition of claim 1 , wherein the bacteriostat agent is selected from a phenol, m-cresol, or methylparaben.
4 . The composition of claim 3 , wherein the bacteriostat agent when present is between about 0.02-1.00 mg/ml.
5 . The composition of claim 1 , wherein the pH is between 7.0-8.0.
6 . The composition of claim 1 , wherein a dose is about 0.08-0.80 mg insulin-Fc fusion protein/kg or 0.4-4.0 U/Kg insulin.
7 . The composition of claim 1 , wherein the insulin-Fc fusion protein is SEQ ID NO:36 or SEQ ID NO:40.
8 . The composition of claim 1 , wherein the composition is formulated for subcutaneous administration.
9 . The composition of claim 1 , wherein the composition is administered to a subject having diabetes.
10 . The composition of claim 9 , wherein the composition is for a veterinary subject.
11 . The composition of claim 10 , wherein the subject is a canine or feline.
12 . The composition of claim 9 , wherein administration of the composition lowers the blood glucose level the subject.
13 . The composition of claim 9 , wherein the fusion protein is administered daily, twice weekly, or once weekly to the subject.
14 . The composition of claim 13 , wherein the fusion protein is administered once weekly to the subject at a dose between 0.025 and 0.5 mg/kg/week.
15 . The composition of claim 1 , wherein the surfactant is a Tween-like surfactant.
16 . The composition of claim 15 , wherein the surfactant is Tween-80.