IP Library › Granted Patent US 7,452,966

Granted Patent B2

US 7,452,966 · App. 10/558,627 · Granted Nov 18, 2008

GLP-1 analog fusion proteins

Assignee: Eli Lilly and Company

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Quick Facts

Patent No.: US 7,452,966
App. No.: 10/558,627
Granted: Nov 18, 2008
Kind: B2

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Abstract

The invention provides specific GLP-1 analogs fused to specific IgG4-Fc derivatives. These fusion proteins have an increased half-life, decreased immunogenicity, and reduce effector activity. The fusion proteins are useful in treating diabetes, obesity, irritable bowel syndrome and other conditions that would be benefited by lowering plasma glucose, inhibiting gastric and/or intestinal motility and inhibiting gastric and/or intestinal emptying, or inhibiting food intake.

Claims (61)

1. A heterologous fusion protein comprising:

a GLP-1 analog comprising SEQ ID NO:1

His-Xaa 8 -Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Glu-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Gly-Gly

wherein Xaa 8 is Gly;

an Fc portion of an immunoglobulin comprising SEQ ID NO:7

Ala-Glu-Ser-Lys-Tyr-Gly-Pro-Pro-Cys-Pro-Pro-Cys-Pro-Ala-Pro-Xaa 16 -Xaa 17 -Xaa 18 -Gly-Gly-Pro-Ser-Val-Phe-Leu-Phe-Pro-Pro-Lys-Pro-Lys-Asp-Thr-Leu-Met-Ile-Ser-Arg-Thr-Pro-Glu-Val-Thr-Cys-Val-Val-Val-Asp-Val-Ser-Gln-Glu-Asp-Pro-Glu-Val-Gln-Phe-Asn-Trp-Tyr-Val-Asp-Gly-Val-Glu-Val-His-Asn-Ala-Lys-Thr-Lys-Pro-Arg-Glu-Glu-Gln-Phe-Xaa 80 -Ser-Thr-Tyr-Arg-Val-Val-Ser-Val-Leu-Thr-Val-Leu-His-Gln-Asp-Trp-Leu-Asn-Gly-Lys-Glu-Tyr-Lys-Cys-Lys-Val-Ser-Asn-Lys-Gly-Leu-Pro-Ser-Ser-Ile-Glu-Lys-Thr-Ile-Ser-Lys-Ala-Lys-Gly-Gln-Pro-Arg-Glu-Pro-Gln-Val-Tyr-Thr-Leu-Pro-Pro-Ser-Gln-Glu-Glu-Met-Thr-Lys-Asn-Gln-Val-Ser-Leu-Thr-Cys-Leu-Val-Lys-Gly-Phe-Tyr-Pro-Ser-Asp-Ile-Ala-Val-Glu-Trp-Glu-Ser-Asn-Gly-Gln-Pro-Glu-Asn-Asn-Tyr-Lys-Thr-Thr-Pro-Pro-Val-Leu-Asp-Ser-Asp-Gly-Ser-Phe-Phe-Leu-Tyr-Ser-Arg-Leu-Thr-Val-Asp-Lys-Ser-Arg-Trp-Gln-Glu-Gly-Asn-Val-Phe-Ser-Cys-Ser-Val-Met-His-Glu-Ala-Leu-His-Asn-His-Tyr-Thr-Gln-Lys-Ser-Leu-Ser-Leu-Ser-Leu-Gly-Xaa 230

wherein:

Xaa at position 16 is Glu;

Xaa at position 17 is Ala;

Xaa at position 18 is Ala;

Xaa at position 80 is Asn; and

Xaa at position 230 is Lys;

and a peptide linker comprising SEQ ID NO:8

Gly-Gly-Gly-Gly-Ser-Gly-Gly-Gly-Gly-Ser-Gly-Gly-Gly-Gly-Ser

wherein the N-terminal glycine of the peptide linker is directly fused to the C-terminal glycine residue of the GLP-1 analog and the C-terminal serine of the peptide linker is directly fused to the N-terminal alanine of the Fc portion.

2. A heterologous fusion protein comprising:

a GLP-1 analog comprising SEQ ID NO:1

His-Xaa 8 -Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Glu-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Gly-Gly

wherein Xaa 8 is Gly;

an Fc portion of an immunoglobulin comprising SEQ ID NO:7

wherein:

Xaa at position 16 is Glu;

Xaa at position 17 is Ala;

Xaa at position 18 is Ala;

Xaa at position 80 is Asn; and

Xaa at position 230 is absent;

and a peptide linker comprising SEQ ID NO:8

Gly-Gly-Gly-Gly-Ser-Gly-Gly-Gly-Gly-Ser-Gly-Gly-Gly-Gly-Ser

3. A heterologous fusion protein whose amino acid sequence consists of:

a GLP-1 analog consisting of SEQ ID NO:1

His-Xaa 8 -Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Glu-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Gly-Gly

wherein Xaa 8 is Gly;

an Fc portion of an immunoglobulin consisting of SEQ ID NO:7

Ala-Glu-Ser-Lys-Tyr-Gly-Pro-Pro-Cys-Pro-Pro-Cys-Pro-Ala-Pro-Xaa 16 -Xaa 17 -Xaa 18 -Gly-Gly-Pro-Ser-Val-Phe-Leu-Phe-Pro-Pro-Lys-Pro-Lys-Asp-Thr-Leu-Met-Ile-Ser-Arg-Thr-Pro-Glu-Val-Thr-Cys-Val-Val-Val-Asp-Val-Ser-Gln-Glu-Asp-Pro-Glu-Val-Gln-Phe-Asn-Trp-Tyr-Val-Asp-Gly-Val-Glu-Val-His-Asn-Ala-Lys-Thr-Lys-Pro-Arg-Glu-Glu-Gln-Phe-Xaa 80 -Ser-Thr-Tyr-Arg-Val-Val-Ser-Val-Leu-Thr-Val-Leu-His-Gln-Asp-Trp-Leu-Asn-Gly-Lys-Glu-Tyr-Lys-Cys-Lys-Val-Ser-Asn-Lys-Glu-Leu-Pro-Ser-Ser-Ile-Glu-Lys-Thr-Ile-Ser-Lys-Ala-Lys-Gly-Gln-Pro-Arg-Glu-Pro-Gln-Val-Tyr-Thr-Leu-Pro-Pro-Ser-Gln-Glu-Glu-Met-Thr-Lys-Asn-Gln-Val-Ser-Leu-Thr-Cys-Leu-Val-Lys-Gly-Phe-Tyr-Pro-Ser-Asp-Ile-Ala-Val-Glu-Trp-Glu-Ser-Asn-Gly-Gln-Pro-Glu-Asn-Asn-Tyr-Lys-Thr-Thr-Pro-Pro-Val-Leu-Asp-Ser-Asp-Gly-Ser-Phe-Phe-Leu-Tyr-Ser-Arg-Leu-Thr-Val-Asp-Lys-Ser-Arg-Trp-Gln-Glu-Gly-Asn-Val-Phe-Ser-Cys-Ser-Val-Met-His-Glu-Ala-Leu-His-Asn-His-Tyr-Thr-Gln-Lys-Ser-Leu-Ser-Leu-Ser-Leu-Gly-Xaa 230

wherein:

Xaa at position 16 is Glu;

Xaa at position 17 is Ala;

Xaa at position 18 is Ala;

Xaa at position 80 is Asn; and

Xaa at position 230 is Lys;

and a peptide linker consisting of SEQ ID NO:8

Gly-Gly-Gly-Gly-Ser-Gly-Gly-Gly-Gly-Ser-Gly-Gly-Gly-Gly-Ser

4. A heterologous fusion protein consisting of:

a GLP-1 analog consisting of SEQ ID NO:1

His-Xaa 8 -Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Glu-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Gly-Gly

wherein Xaa 8 is Gly;

an Fc portion of an immunoglobulin consisting of SEQ ID NO:7

wherein:

Xaa at position 16 is Glu;

Xaa at position 17 is Ala;

Xaa at position 18 is Ala;

Xaa at position 80 is Asn; and

Xaa at position 230 is absent;

and a peptide linker consisting of SEQ ID NO:8

Gly-Gly-Gly-Gly-Ser-Gly-Gly-Gly-Gly-Ser-Gly-Gly-Gly-Gly-Ser

5. The heterologous fusion protein of claim 4 wherein the fusion protein is encoded by the DNA of SEQ ID NO:20.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 29, 2005

From: GLAESNER, WOLFGANG; MILLICAN JR., ROHN LEE; VICK, ANDREW MARK

To: ELI LILLY AND COMPANY

Reel/Frame 017683/0070 →

Continuity (2)

Provisional Application 6047788000 · Jun 12, 2003

Related Publication 20070036806A1 · Feb 15, 2007