Insulin-Fc fusion proteins and methods of use to treat cancer
Inventors
Zion, Todd C. • Lancaster, Thomas M.
Assignees
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Publication Number
US-11667689-B2
Publication Date
2023-06-06
Expiration Date
Abstract
The present disclosure relates to compositions of fusion proteins, e.g., insulin-Fc fusion proteins, and their use to treat cancer cells and cancer tumors.
Core Innovation
The invention relates to a method of downregulating insulin receptor or insulin-like growth factor 1 receptor (IGF1R), and/or decreasing phosphorylated Akt in a cancer cell in a mammal. The method comprises administering an effective amount of a fusion protein comprising an insulin polypeptide and an Fc fragment, wherein the insulin polypeptide comprises a defined amino acid sequence selected from (SEQ ID NO: 6) or (SEQ ID NO: 37). After administration, the fusion protein exhibits an anti-tumor effect on the cancer cell compared to an untreated control.
A central aspect of the invention is the performance relationship of the fusion protein versus recombinant human insulin (RHI), expressed as the ratio of IC50 for the fusion protein to IC50 for RHI. The ratio is less than or equal to 20, and in preferred embodiments the ratio is ≤48 according to the provided summary. The disclosed anti-tumor effect is selected from downregulation of insulin receptor, downregulation of IGF1R, decreased phosphorylated Akt, or combinations thereof.
The background problem addressed by the disclosed invention is the need for anti-tumor efficacy through modulation of insulin signaling pathways while avoiding hypoglycemia-associated clinical signs, as described in the provided summary. The disclosure includes mechanistic discussion of managed hypoglycemia versus non-hypoglycemia mechanisms, and it frames the approach around dimeric insulin configuration and downstream effects including downregulation of insulin receptor and/or IGF1R and reduced phosphorylated Akt. The provided summary also indicates pharmaceutical compositions and administration contexts across different cancer settings.
Claims Coverage
The independent claim is clm-00001. The coverage includes one independent method claim focused on receptor/Akt modulation in cancer cells using an insulin–Fc fusion protein with defined insulin sequences and an IC50 ratio criterion, with multiple dependent claims refining structure, administration context, and measurable response constraints.
Insulin–Fc fusion for receptor and Akt modulation in cancer
A method comprising administering an effective amount of a fusion protein comprising an insulin polypeptide and an Fc fragment to a mammal in need thereof, wherein the insulin polypeptide comprises (SEQ ID NO: 6) or (SEQ ID NO: 37), and wherein the fusion protein exhibits an anti-tumor effect on a cancer cell after administration compared to an untreated control, the anti-tumor effect selected from downregulation of insulin receptor, downregulation of insulin-like growth factor 1 receptor (IGF1R), decreased phosphorylated Akt, and a combination thereof.
IC50 ratio criterion relative to recombinant human insulin
The fusion protein has a ratio of IC50 for the fusion protein to IC50 for recombinant human insulin (RHI) that is less than or equal to 20, as part of the method for producing the anti-tumor effect compared to an untreated control.
Defined anti-tumor response outcomes in cancer cells
The method produces an anti-tumor effect on the cancer cell in the mammal selected from downregulation of insulin receptor, downregulation of IGF1R, decreased phosphorylated Akt, and a combination thereof, as compared to an untreated control cancer cell.
Overall, the claim set centers on a cancer-treatment method in a mammal that administers a defined insulin–Fc fusion protein to downregulate insulin receptor and/or IGF1R and/or decrease phosphorylated Akt, with anti-tumor effect performance constrained by an IC50 ratio relative to recombinant human insulin.
Stated Advantages
Enables an anti-tumor effect via downregulation of insulin receptor and/or IGF1R and/or decreased phosphorylated Akt in a cancer cell compared to an untreated control.
Provides an IC50 advantage of the fusion protein relative to recombinant human insulin, with an IC50 ratio ≤20 (and described preference ≤48 in the provided summary).
Aims for anti-tumor efficacy without hypoglycemia-associated clinical signs, as described in the provided summary.
Documented Applications
Treatment of cancers including breast cancer, colorectal cancer, and melanoma using the disclosed insulin–Fc fusion protein approach, with fasted versus unfasted conditions discussed in the provided summary.
Use in cancer models associated with HCT-116 and metastatic melanoma WM266.4, and discussion including breast cancer and tamoxifen-resistant models (MCF-7L TamR) in the provided summary.
Co-therapy context including chemotherapy agents, tamoxifen agonists, and antibodies against IGF1R, as described in the provided summary.
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