Proteins with insulin-like activity useful in the treatment of diabetes

• US 6,746,853 B1
• Filed: 05/19/2000
• Issued: 06/08/2004
• Est. Priority Date: 05/19/1999
• Status: Expired due to Fees

• Current Assignee: Xencor, Inc.
• Original Assignee: Xencor, Inc.
• Inventors: Morton, Andrew G., Dahiyat, Bassil I.
• Primary Examiner(s): Saoud, Christine J.
• Application Number:
  US09/574,443
• Time in Patent Office: 1,481 Days
• Field of Search: 514/3, 530/303, 435/69.1, 435/320.1, 435/69.4, 435/325, 435/243, 536/235
• US Class Current: 435/69.1
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: C07K 14/62 Insulins

Abstract

The invention relates to novel insulin activity (IA) proteins and nucleic acids. The Invention further relates to the use of the IA proteins in the treatment of insulin related disorders such as type 1 diabetes and type 2 diabetes.

Claims

1. A protein having insulin activity comprising an amino acid sequence of SEQ ID NO:

2, wherein said protein has at least one substitution selected from B4-Y and B4F.

2. A protein having insulin activity comprising an amino acid sequence of SEQ ID NO:

2 wherein said protein has at least one substitution selected from the group of B5-F, B5-W, B14-F, B14-W, B14-Y, and B14-L.

3. A protein having insulin activity comprising an amino acid sequence selected from the group of amino acid sequence shown in SEQ ID NO:

7, SEQ ID NO;

8, SEQ ID NO;

9, SEQ ID NO;

10, SEQ ID NO;

11, SEQ ID NO;

12, SEQ ID NO;

13, SEQ ID NO;

14, SEQ ID NO;

15, SEQ ID NO;

16, SEQ ID NO;

17, SEQ ID NO;

18, SEQ ID NO;

19, SEQ ID NO;

20, SEQ ID NO;

21, SEQ ID NO;

22, SEQ SEQ ID NO;

23.

4. A recombinant nucleic acid encoding said protein of claim 3.

5. An expression vector comprising the recombinant nucleic acid of claim 4.

6. A host cell comprising the expression vector of claim 5.

7. A host cell comprising the recombinant nucleic acid of claim 4.

8. A method of producing a protein having insulin activity comprising culturing the host cell of claim 7 under conditions suitable for expression of said nucleic acid.

9. A method according to claim 8 further comprising recovering said protein.

10. A pharmaceutical composition comprising a protein according to claim 3 and a pharmaceutical carrier.

11. A protein according to claim 3 wherein said protein comprises the amino acid sequence shown in (SEQ ID NO:

7).

12. A protein having insulin activity comprising an amino acid sequence of SEQ ID NO:

2, wherein said protein comprises an least 2 amino acid substitutions from the A-chain and at least 5 amino acid substitutions from the B-chain and said substitutions are selected from the group consisting of A1N, A10Q, A16Y, A17Y, A17L, A17W, A17Q, A19F, B1D, B2E, B2T, B2K, B2Q, B2D, B2R, B2N, B2F, B4Y, B4F, B4E, B4K, B4R, B8L, B8L, B8K, B8E, B11I, B12R, B12K, B14F, B14W, B14Y, B14I, B14B, B14R, B14K, B14L, B25N, B26F, B27D, B28N, and B28F.

13. A protein according to claim 12, wherein said substitutions are selected from the group consisting of A1-N, A10-Q, A16-Y, A17-Y, A19-F, B1-D, B2-K, B4-F, B8-L, B11-I, B12-R, B14-W, B25-N, B26-F, B27-D, and B28-N.

14. A recombinant nucleic acid encoding the non-naturally occurring IA protein selected from the group consisting of:

SEQ ID NO;

7, SEQ ID NO;

8, SEQ ID NO;

9, SEQ ID NO;

10, SEQ ID NO;

11, SEQ ID NO;

12, SEQ ID NO;

13, SEQ ID NO;

14, SEQ ID NO;

15, SEQ ID NO;

16, SEQ ID NO;

17, SEQ ID NO;

18, SEQ ID NO;

19, SEQ ID NO;

20, SEQ ID NO;

21, SEQ ID NO;

22, and SEQ ID NO;

23.