HUMAN ANTIBODIES TO THE GLUCAGON RECEPTOR

• US 20130344538A1
• Filed: 08/30/2013
• Published: 12/26/2013
• Est. Priority Date: 11/23/2010
• Status: Active Grant

• Current Assignee: Regeneron Pharmaceuticals Incorporated
• Original Assignee: Regeneron Pharmaceuticals Incorporated
• Inventors: Okamoto, Haruka, Harp, Joyce, Sleeman, Mark
• Granted Patent: US 9,127,068 B2
• Time in Patent Office: Days
• US Class Current: 435/69.6
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/507 Comprising a combination of two or more separate antibodies
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 39/39541 against normal tissues, cells
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/12 for cataracts
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/02 Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07K 16/2869 against hormone receptors for antibodies against neuromediator receptors C07K16/286
• CPC Class Codes: C07K 16/40 : against enzymes
• CPC Class Codes: C07K 16/468 : Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies
• CPC Class Codes: C07K 2317/21 : from primates, e.g. man
• CPC Class Codes: C07K 2317/30 : characterized by aspects of specificity or valency
• CPC Class Codes: C07K 2317/31 : multispecific
• CPC Class Codes: C07K 2317/33 : Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
• CPC Class Codes: C07K 2317/34 : Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• CPC Class Codes: C07K 2317/56 : variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/565 : Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: C07K 2317/94 : Stability, e.g. half-life, pH, temperature or enzyme-resistance
• CPC Class Codes: C12N 15/1137 : against enzymes viral enzymes C12N15/1131; receptors C12N15/1138
• CPC Class Codes: C12N 15/64 : General methods for preparing the vector, for introducing it into the cell or for selecting the vector-containing host
• CPC Class Codes: C12N 15/70 : Vectors or expression systems specially adapted for E. coli
• CPC Class Codes: C12N 2310/11 : Antisense
• CPC Class Codes: C12N 2310/14 : interfering N.A.
• CPC Class Codes: C12N 2320/31 : Combination therapy

Abstract

The present invention provides antibodies that bind to the human glucagon receptor, designated GCGR and methods of using same. According to certain embodiments of the invention, the antibodies are fully human antibodies that bind to human GCGR. The antibodies of the invention are useful for lowering blood glucose levels and blood ketone levels and are also useful for the treatment of diseases and disorders associated with one or more GCGR biological activities, including the treatment of diabetes, diabetic ketoacidosis and long-term complications associated with diabetes, or other metabolic disorders characterized in part by elevated blood glucose levels.

Claims

1. An isolated nucleic acid molecule encoding a recombinant human antibody or antigen-binding fragment thereof that specifically binds human glucagon receptor (hGCGR), wherein the antibody or antigen-binding fragment thereof comprises the three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within any one of the HCVR amino acid sequences selected from the group consisting of SEQ ID NOs:

2, 18, 34, 50, 66, 70, 86, 90, 106, 110, 126, 130 and 146; and

the three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within any one of the LCVR amino acid sequences selected from the group consisting of SEQ ID NOs;

10, 26, 42, 58, 68, 78, 88, 98, 108, 118, 128, 138 and 148.

6. An isolated nucleic acid molecule encoding the recombinant human antibody or antigen-binding fragment thereof of claim 1, wherein the antibody or antigen-binding fragment thereof comprises a HCVR having an amino acid sequence as set forth in SEQ ID NO:

86 and a LCVR having an amino acid sequence as set forth in SEQ ID NO;

88.

7. The isolated nucleic acid molecule of claim 6, wherein the nucleic acid sequence encoding the heavy chain variable region is set forth in SEQ ID NO:

85 and the nucleic acid sequence encoding the light chain variable region is set forth in SEQ ID NO;

87.

8. The isolated nucleic acid molecule of claim 1 encoding a recombinant antibody or antigen-binding fragment thereof that specifically binds human glucagon receptor (hGCGR), wherein the antibody comprises:

(a) a HCDR1 domain having an amino acid sequence selected from the group consisting of SEQ ID NO;

4, 20, 36, 52, 72, 92, 112 and 132;

(b) a HCDR2 domain having an amino acid sequence selected from the group consisting of SEQ ID NO;

6, 22, 38, 54, 74, 94, 114 and 134;

(c) a HCDR3 domain having an amino acid sequence selected from the group consisting of SEQ ID NOs;

8, 24, 40, 56, 76, 96, 116 and 136;

(d) a LCDR1 domain having an amino acid sequence selected from the group consisting of SEQ ID NO;

12, 28, 44, 60, 80, 100, 120 and 140;

(e) a LCDR2 domain having an amino acid sequence selected from the group consisting of SEQ ID NO;

14, 30, 46, 62, 82, 102, 122 and 142; and

(f) a LCDR3 domain having an amino acid sequence selected from the group consisting of SEQ ID NO;

16, 32, 48, 64, 84, 104, 124 and 144.

9. The isolated nucleic acid molecule of claim 8, wherein the HCDR1 domain is encoded by a nucleotide sequence selected from the group consisting of SEQ ID NO:

3, 19, 35, 51, 71, 91, 111 and 131;

the HCDR2 domain is encoded by a nucleotide sequence selected from the group consisting of SEQ ID NO;

5, 21, 37, 53, 73, 93, 113 and 133;

the HCDR3 domain is encoded by a nucleotide sequence selected from the group consisting of SEQ ID NO;

7, 23, 39, 55, 75, 95, 115 and 135;

the LCDR1 domain is encoded by a nucleotide sequence selected from the group consisting of SEQ ID NO;

11, 27, 43, 59, 79, 99, 119 and 139;

the LCDR2 domain is encoded by a nucleotide sequence selected from the group consisting of SEQ ID NO;

13, 29, 45, 61, 81, 101, 121 and 141; and

the LCDR3 domain is encoded by a nucleotide sequence selected from the group consisting of SEQ ID NO;

15, 31, 47, 63, 83, 103, 123 and 143.

10. The isolated nucleic acid molecule of claim 1 encoding a recombinant human antibody or antigen-binding fragment thereof that specifically binds human glucagon receptor (hGCGR), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO:

72;

HCDR2 comprises the amino acid sequence of SEQ ID NO;

74;

HCDR3 comprises the amino acid sequence of SEQ ID NO;

76;

LCDR1 comprises the amino acid sequence of SEQ ID NO;

80;

LCDR2 comprises the amino acid sequence of SEQ ID NO;

82 and LCDR3 comprises the amino acid sequence of SEQ ID NO;

84.

11. The isolated nucleic acid molecule of claim 10, wherein the nucleic acid sequence encoding the HCDR1 is set forth in SEQ ID NO:

71;

the nucleic acid sequence encoding the HCDR2 is set forth in SEQ ID NO;

73;

the nucleic acid sequence encoding the HCDR3 is set forth in SEQ ID NO;

75;

the nucleic acid sequence encoding the LCDR1 is set forth in SEQ ID NO;

79, the nucleic acid sequence encoding the LCDR2 is set forth in SEQ ID NO;

81; and

the nucleic acid sequence encoding the LCDR3 is set forth in SEQ ID NO;

83.

12. The isolated nucleic acid molecule encoding the recombinant human antibody or antigen-binding fragment thereof of claim 1, wherein the antibody comprises a heavy chain variable region (HCVR) and a light chain variable region (LCVR) amino acid sequence pair, wherein the HCVR and LCVR amino acid sequence pair consists of SEQ ID NOs:

86 and 88, respectively.

13. The isolated nucleic acid molecule of claim 12, wherein the nucleic acid sequence pair encoding the HCVR and LCVR amino acid sequence pair is set forth in SEQ ID NOs:

85 and 87, respectively.

14. An expression vector comprising the nucleic acid molecule of claim 1.

15. A host cell comprising the vector according to claim 14.

16. A method of producing a recombinant antibody or antigen-binding fragment thereof that specifically binds human GCGR, the method comprising introducing the expression vector of claim 14 into an isolated host cell, growing the cell under conditions permitting production of the antibody or antibody fragment, and recovering the antibody or antibody fragment so produced.

17. The method of claim 16, wherein the host cell is an E. coli cell, a CHO cell, or a COS cell.

2. An isolated nucleic acid molecule encoding a recombinant human antibody or fragment thereof that binds specifically to human GCGR, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) selected from the group consisting of SEQ ID NOs:

2, 18, 34, 50, 66, 70, 86, 90, 106, 110, 126, 130 and 146.

3. The isolated nucleic acid molecule of claim 2, wherein the nucleic acid sequence encoding the heavy chain variable region is selected from the group consisting of SEQ ID NO:

1, 17, 33, 49, 65, 69, 85, 89, 105, 109, 125, 129 and 145.

4. An isolated nucleic acid molecule encoding a recombinant human antibody or fragment thereof that binds specifically to human GCGR, wherein the antibody or antigen-binding fragment thereof comprises a light chain variable region (LCVR) selected from the group consisting of SEQ ID NOs:

10, 26, 42, 58, 68, 78, 88, 98, 108, 118, 128, 138 and 148.

5. The isolated nucleic acid molecule of claim 4, wherein the nucleic acid sequence encoding the light chain variable region is selected from the group consisting of SEQ ID NO:

9, 25, 41, 57, 67, 77, 87, 97, 107, 117, 127, 137 and 147.