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-11359001-B2
Publication Date
2022-06-14
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 for treating or preventing autoimmune diabetes in a subject. The fusion protein comprises an insulin polypeptide fused to an Fc domain, and the insulin polypeptide comprises a B-chain peptide, a C-chain peptide, and an A-chain peptide, where the C-chain peptide sequence is AAK. The B-chain peptide comprises the amino acid sequence FVNQHLCGSHLVX1ALX2LVCGEX3GFFYTPK (SEQ ID NO: 28), with X1 being E or Q, X2 being Y or A, and X3 being R or E.
The insulin-Fc fusion protein is characterized by binding human insulin receptor at an IC50 >3,000 nM in a competitive binding assay. The same fusion protein inhibits in vitro binding of insulin+ B cell receptors to insulin at an IC50 <300 nM, defining a profile of relatively weak competitive insulin receptor binding while providing stronger blockade of insulin+ B cell receptor binding in vitro.
The partial content further describes insulin-Fc fusion proteins including proinsulin-Fc and preproinsulin-Fc formats for autoimmune diabetes, with selective binding to insulin-specific autoantibody/B-cell receptor while avoiding significant interaction with the insulin hormone receptor to minimize in vivo glucose lowering and hypoglycemia risk. It also emphasizes targeting pathogenic insulin-reactive B cells via Fc-mediated effector functions (ADCC, CDC, and phagocytosis) and reducing IL-2 T-cell activation.
Claims Coverage
The claim coverage centers on an insulin-Fc fusion protein defined by specific insulin chain sequence constraints and IC50-defined binding behavior, with dependent refinement to proinsulin-Fc and preproinsulin-Fc formats and post-administration biological outcomes.
Insulin-fc fusion protein for treating or preventing autoimmune diabetes
An insulin-Fc fusion protein comprising an insulin polypeptide fused to an Fc domain, for treating or preventing autoimmune diabetes in a subject.
Insulin polypeptide chain composition and C-chain sequence AAK
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.
Specific B-chain peptide sequence with defined substitutions
The B-chain peptide comprises the amino acid sequence FVNQHLCGSHLVX1ALX2LVCGEX3GFFYTPK (SEQ ID NO: 28), where X1 is E or Q, X2 is Y or A, and X3 is R or E.
Weak competitive binding to human insulin receptor
The insulin-Fc fusion protein binds human insulin receptor at an IC50 >3,000 nM in a competitive binding assay.
In vitro inhibition of insulin+ B cell receptor binding
The insulin-Fc fusion protein inhibits in vitro binding of insulin+ B cell receptors to insulin at an IC50 <300 nM.
Proinsulin-fc and preproinsulin-fc formats
The partial content further describes insulin-Fc fusion proteins including proinsulin-Fc and preproinsulin-Fc formats for autoimmune diabetes.
Post-administration reductions in anti-insulin B cells and insulin autoantibodies
After at least one administration, a subject shows reduction in anti-insulin B cells and decreased insulin autoantibody levels compared to before, and blood glucose levels after administration are comparable to before.
Overall, the claim coverage centers on an insulin-Fc fusion protein defined by specific insulin chain sequence constraints, including a C-chain sequence of AAK and a B-chain sequence of SEQ ID NO: 28 with specified variable substitutions, together with an IC50-defined profile showing weak competitive binding to the human insulin receptor and strong inhibition of insulin+ B cell receptor binding in vitro. Additional claim coverage includes proinsulin-Fc and preproinsulin-Fc formats and post-administration reductions in anti-insulin B cells and insulin autoantibodies.
Stated Advantages
Minimize in vivo glucose lowering and hypoglycemia risk by avoiding significant interaction with the insulin hormone receptor.
Selectively bind to insulin-specific autoantibody/B-cell receptors while avoiding significant interaction with the insulin hormone receptor.
Target pathogenic insulin-reactive B cells via Fc-mediated effector functions (ADCC, CDC, phagocytosis).
Reduce IL-2 T-cell activation.
Documented Applications
Treating or preventing autoimmune diabetes (including Type 1 diabetes) in a subject using an insulin-Fc fusion protein.
Immunologic targeting of pathogenic insulin-reactive B cells (anti-insulin B cells/insulin-specific B cells) via ADCC, CDC, and phagocytosis.
Use with proinsulin-Fc and preproinsulin-Fc insulin-Fc fusion protein formats for autoimmune diabetes.
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