Insulin-Fc fusions and methods of use
Inventors
Lancaster, Thomas M. • Zion, Todd C. • Sathiyaseelan, Thillainayagam • Murikipudi, Sylaja
Assignees
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Publication Number
US-10597435-B2
Publication Date
2020-03-24
Expiration Date
Abstract
The present disclosure relates generally to compositions of insulin-Fc (e.g., proinsulin-Fc) fusion proteins and their use to treat autoimmune disease, e.g., autoimmune diabetes, e.g., Type 1 diabetes.
Core Innovation
The invention relates to an insulin-Fc fusion protein comprising an insulin polypeptide fused to an Fc domain. The insulin polypeptide comprises a B-chain peptide, a C-chain peptide, and an A-chain peptide, and the amino acid sequence of the C-chain peptide is AAK (SEQ ID NO: 16). The B-chain peptide comprises the amino acid sequence FVNQHLCGSHLVX1ALX2LVCGEX3GFFYTPK (SEQ ID NO: 28), wherein X1 is E, X2 is A, and X3 is R.
The invention further specifies immunologic behavior in contexts that include inhibition of insulin-specific B-cell receptor binding and modulation of T-cell responses. The insulin-Fc fusion protein inhibits in vitro binding of insulin to insulin B cell receptors at an IC50 of 100 nM or less and activates T-cells to secrete IL-2 at reduced levels compared with recombinant human insulin.
The invention also addresses use in autoimmune diabetes by defining subject and indication constraints. The method scope includes treating autoimmune diabetes by administering an effective amount of the insulin-Fc fusion protein, where the subject is diagnosed with or at risk for autoimmune diabetes and is not hyperglycemic.
Claims Coverage
The patent includes two independent claims for insulin-Fc fusion protein compositions and a method claim direction for treating autoimmune diabetes. The claim coverage centers on a specific insulin polypeptide architecture with defined C-chain and B-chain sequences fused to an Fc domain, with optional competitive binding characteristics to human insulin receptor in the composition claim.
Insulin polypeptide fused to an Fc domain with defined C-chain sequence
An insulin-Fc fusion protein comprising an insulin polypeptide fused to a Fc domain, wherein the insulin polypeptide comprises a B-chain peptide, a C-chain peptide, and an A-chain peptide, wherein the amino acid sequence of the C-chain peptide is AAK (SEQ ID NO: 16).
Defined B-chain peptide substitutions within SEQ ID NO: 28
The B-chain peptide comprises the amino acid sequence FVNQHLCGSHLVX1ALX2LVCGEX3GFFYTPK (SEQ ID NO: 28), wherein X1 is E, X2 is A, and X3 is R.
Optional weak competitive binding to human insulin receptor
Optionally wherein the insulin-Fc fusion protein binds human insulin receptor at an IC50 >5,000 nM in a competitive binding assay.
Inhibits insulin B cell receptor binding with IC50 of 100 nM or less
The insulin-Fc fusion protein inhibits in vitro binding of insulin to B cell receptors with an IC50 of 100 nM or less.
Reduces T-cell IL-2 secretion compared with recombinant human insulin
The insulin-Fc fusion protein activates T-cells to secrete IL-2 at a level reduced versus T-cells activated by recombinant human insulin.
Method of treating specific autoimmune diabetes types in non-hyperglycemic subjects
A method of treating autoimmune diabetes by administering an effective amount of an insulin-Fc fusion protein, where the autoimmune diabetes is one of Type 1 diabetes, juvenile diabetes, insulin-dependent diabetes, or latent autoimmune diabetes, and the subject is diagnosed with or at risk for autoimmune diabetes and is not hyperglycemic.
Overall, the claim set covers insulin-Fc fusion protein compositions defined by an insulin polypeptide containing a C-chain AAK (SEQ ID NO: 16) and a B-chain sequence specified by SEQ ID NO: 28 substitutions (X1=E, X2=A, X3=R) fused to an Fc domain, optionally with competitive binding to human insulin receptor at IC50 >5,000 nM. Dependent claim coverage further includes inhibition of insulin B-cell receptor binding, reduced T-cell IL-2 secretion relative to recombinant human insulin, and treating defined autoimmune diabetes types in subjects who are diagnosed or at risk and not hyperglycemic.
Stated Advantages
Reduced T-cell IL-2 secretion compared with recombinant human insulin.
Inhibition of insulin-specific B-cell receptor binding in vitro (IC50 of 100 nM or less).
Documented Applications
Treating autoimmune diabetes by administering an effective amount of the insulin-Fc fusion protein, including Type 1 diabetes, juvenile diabetes, insulin-dependent diabetes, and latent autoimmune diabetes in subjects who are diagnosed with or at risk and not hyperglycemic.
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