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Publication Number
US-11352407-B2
Publication Date
2022-06-07
Expiration Date
Abstract
The present disclosure provides recombinantly manufactured ultra-long acting insulin-Fc fusion proteins for use in treating diabetes. The insulin-Fc fusion proteins comprise an insulin polypeptide linked via a peptide linker to an Fc-fragment of human origin. 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.
Core Innovation
The invention relates to insulin-Fc fusion proteins in which an insulin polypeptide and an Fc fragment are connected by a linker. The fusion protein is defined by specific amino-acid sequences, including SEQ ID NO: 87 for one embodiment and a human-origin Fc sequence embodiment identified as SEQ ID NO: 77.
The insulin polypeptide consists of an insulin B-chain analog linked to an insulin A-chain analog via a C-chain, and the 16th amino acid from the N-terminus of the insulin B-chain analog is alanine (B16A). The human-origin Fc fragment includes sequence variants and substitutions described as cNg and cNg-NB155-S/D/A/R/Q for altering Fc glycosylation patterns.
The described fusion proteins are configured to support ultra-long acting activity, long half-life, reduced immunogenicity, manufacturability, and bioactivity. The document further describes performance targets for insulin receptor binding, FcRn binding, and immunogenicity readouts including FcγRI, C1q, and anti-drug antibodies, and it describes non-glycosylated variants and sequence designs that restore IR/FcRn binding when B16A is added.
Claims Coverage
The provided independent claims cover 2 inventive features. Both center on an insulin-Fc fusion protein connected by a linker, with one claim defined by a specific full fusion sequence and the other adding a human-origin Fc sequence and a defined insulin architecture with B16A.
Sequence-defined insulin-fc fusion protein with linker-connected insulin polypeptide and fc fragment
A fusion protein comprising an insulin polypeptide and an Fc fragment connected by a linker, wherein the fusion protein comprises SEQ ID NO: 87.
Human-origin fc insulin fusion with b16a substitution in insulin b-chain analog
A fusion protein comprising an insulin polypeptide and a human-origin Fc fragment connected by a linker, wherein the Fc fragment comprises SEQ ID NO: 77 and the insulin polypeptide consists of an insulin B-chain analog linked to an insulin A-chain analog via a C-chain, with B16 being alanine.
Overall, the claims cover linker-connected insulin-Fc fusion proteins defined by sequence, with one claim requiring SEQ ID NO: 87 and the other requiring a human-origin Fc sequence, the B-chain analog to A-chain analog via C-chain architecture, and the B16A substitution.
Stated Advantages
Ultra-long acting activity for diabetes treatment.
Reduced immunogenicity while preserving manufacturability and bioactivity.
Long half-life associated with insulin receptor binding potency and FcRn binding.
Maintained glucose-lowering performance (NAOC and NAOCR) in repeated-dose in vivo testing.
No apparent immunogenicity reported in repeated-dose in vivo dog testing.
Unexpected resistance to enzymatic cleavage for a specified construct (SEQ ID NO: 28).
Identification of a preferred canine Fc isotype (canine IgGB) based on manufacturability (homodimer titer) and bioactivity.
Recovery of potency and repeated-dose efficacy associated with insulin B-chain mutation B16A, including after reduced FcγRI interaction approaches that otherwise produced unexpected aggregation and/or reduced potency.
Documented Applications
Diabetes treatment using ultra-long acting recombinant insulin-Fc fusion proteins.
Repeated-dose administration in dogs for evaluating glucose-lowering performance (NAOC/NAOCR) and immunogenicity testing.
Comparative evaluation of Fc isotypes (IgGA/IgGB/IgGC/IgGD) using manufacturability (homodimer titer) and bioactivity readouts.
Assay-based evaluation of receptor binding and functional activity using insulin receptor IC50, FcRn EC50, FcγRI assay OD450 ratios, and C1q assay OD450 ratios to define preferred embodiments.
Mouse PD efficacy observations for selected human Fc variants.
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