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Publication Number
US-12195511-B2
Publication Date
2025-01-14
Expiration Date
Abstract
The present disclosure relates to compositions of insulin-Fc fusion proteins and their use to treat diabetes.
Core Innovation
The invention provides an ultra-long acting insulin–Fc fusion protein for diabetes treatment. The fusion protein comprises an insulin polypeptide connected by a peptide linker to an Fc fragment, with emphasis on specific fusion architectures and performance criteria including manufacturability and in vivo duration of glucose-lowering activity.
The described architecture uses recombinant insulin in a single-chain form linked via defined peptide linkers to species-specific Fc fragments, including human IgG1 and canine IgG fragments. The Fc portion is designed with attention to the conserved Fc N-glycosylation site (cNg) and related Fc mutations to reduce FcγR interactions and antibody generation.
The disclosure describes that certain glycosylated and/or mutated constructs show acceptable single-dose bioactivity, but that potency decay occurs by the third repeated dose due to neutralizing anti-drug antibodies. In contrast, non-glycosylated variants that modify the cNg site and canine Fc variants that include Fc des-hinge D removal are described as aiming to preserve repeated-dose bioactivity while maintaining ultra-long acting properties.
Performance and characterization are described using measures including homodimer content and titer, insulin receptor binding potency via IC50, prolonged in vivo glucose-lowering duration and serum half-life, and reduced immunogenicity upon repeated dosing. The document further describes experimental evaluation of homodimer and potency retention and immunogenicity impacts using named analytical approaches and NAOC/NAOCR metrics.
Claims Coverage
The independent claim is clm-00001, which broadly covers an insulin–Fc fusion protein with a specifically defined Fc amino-acid sequence connected to an insulin polypeptide by a peptide linker. The claim set includes dependent claims that introduce inventive features as sequence constraints and quantitative performance/format thresholds, including homodimer percentage, homodimer titer, insulin receptor binding IC50, and pharmaceutical composition concentration.
Insulin–Fc fusion with specified Fc sequence
A fusion protein comprising an insulin polypeptide and an Fc fragment connected by a peptide linker, wherein the Fc fragment comprises the sequence of SEQ ID NO: 3.
Homodimer percentage threshold
The fusion protein where the percentage homodimer is greater than 90%.
HEK293/CHO expression with Protein A purification and homodimer titer threshold
A fusion protein recombinantly expressed in HEK293 or CHO cells, and after purification with Protein A beads or a Protein A column, its homodimer titer is greater than 150 mg/L.
Insulin receptor binding potency threshold
The fusion protein having an insulin receptor IC50 less than or equal to 5000 nM.
Pharmaceutical composition concentration threshold
A pharmaceutical composition containing the fusion protein at a concentration of about 3 mg/mL or greater.
Overall, claim coverage centers on an insulin polypeptide–peptide linker–Fc fusion defined by a specific Fc sequence (SEQ ID NO: 3), with dependent claims further narrowing to high homodimer content/titer, defined insulin receptor binding potency via IC50, and a minimum pharmaceutical composition concentration. These dependents collectively ground the fusion format in measurable performance constraints.
Stated Advantages
Ultra-long acting glucose-lowering activity for diabetes treatment.
Reduced immunogenicity upon repeated dosing.
Preservation of repeated-dose bioactivity in non-glycosylated/certain mutated variants compared with constructs that lose potency by the third repeated dose.
Prolonged in vivo glucose-lowering duration and serum half-life.
Documented Applications
Diabetes treatment using the ultra-long acting insulin–Fc fusion protein, including scheduled administration described in the dependent claim set.
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