Nucleic acid molecules encoding antibodies to the human glucagon receptor

• US 10,640,566 B2
• Filed: 01/24/2019
• Issued: 05/05/2020
• Est. Priority Date: 11/23/2010
• Status: Active Grant

• Current Assignee: Regeneron Pharmaceuticals Incorporated
• Original Assignee: Regeneron Pharmaceuticals Incorporated
• Inventors: Okamoto, Haruka, Sleeman, Mark, Harp, Joyce
• Primary Examiner(s): Landsman, Robert S
• Application Number:
  US16/256,190
• Publication Number:
  US 20190144552A1
• Time in Patent Office: 467 Days
• 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 an 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 a heavy chain variable region (HCVR) comprising the amino acid sequence set forth in SEQ ID NO 86;

and the three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within a light chain variable region (LCVR) comprising the amino acid sequence set forth in SEQ ID NO;

88.

2. The nucleic acid molecule of claim 1, wherein the nucleotide sequence encoding the HCVR is set forth in SEQ ID NO:

85.

3. The nucleic acid molecule of claim 1, wherein the nucleotide sequence encoding the LCVR is set forth in SEQ ID NO:

87.

4. The nucleic acid molecule of claim 1, wherein the antibody or antigen-binding fragment thereof comprises an HCVR comprising an amino acid sequence as set forth in SEQ ID NO:

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

88.

5. The nucleic acid molecule of claim 4, wherein the nucleic acid encoding the heavy chain variable region comprises the nucleotide sequence set forth in SEQ ID NO:

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

87.

6. The nucleic acid molecule of claim 1, wherein the antibody or antigen-binding fragment comprises:

(a) an HCDR1 domain comprising an amino acid sequence of SEQ ID NO;

72;

(b) an HCDR2 domain comprising an amino acid sequence of SEQ ID NO;

74;

(c) an HCDR3 domain comprising an amino acid sequence of SEQ ID NO;

76;

(d) an LCDR1 domain comprising an amino acid sequence of SEQ ID NO;

80;

(e) an LCDR2 domain comprising an amino acid sequence of SEQ ID NO;

82; and

(f) an LCDR3 domain comprising an amino acid sequence of SEQ ID NO;

84.

7. The nucleic acid molecule of claim 6, wherein the HCDR1 domain is encoded by a nucleotide sequence of SEQ ID NO:

71;

the HCDR2 domain is encoded by a nucleotide sequence of SEQ ID NO;

73;

the HCDR3 domain is encoded by a nucleotide sequence of SEQ ID NO;

75;

the LCDR1 domain is encoded by a nucleotide sequence of SEQ ID NO;

79;

the LCDR2 domain is encoded by a nucleotide sequence of SEQ ID NO;

81; and

the LCDR3 domain is encoded by a nucleotide sequence of SEQ ID NO;

83.

8. An isolated host cell comprising the nucleic acid molecule according to claim 1.

9. A method of producing a recombinant antibody or antigen-binding fragment thereof that specifically binds human GCGR, the method comprising introducing the nucleic acid molecule of claim 1 into an isolated host cell, growing the cell under conditions permitting production of the antibody or fragment, and recovering the antibody or fragment so produced.

10. The method of claim 9, wherein the host cell is an E. coli cell, a CHO cell, or a COS cell.