Method of treating or ameliorating metabolic disorders using GLP-1 receptor agonists conjugated to antagonists for gastric inhibitory peptide receptor (GIPR)

Patent metadata

Field	Value
Publication number	US-10905772-B2
Application number	US-201815872841-A
Country	US
Kind code	B2
Filing date	Jan 16, 2018
Priority date	Jan 17, 2017
Publication date	Feb 2, 2021
Grant date	Feb 2, 2021

Abstract

Methods of treating metabolic diseases and disorders using a composition comprising an antigen binding protein specific for the GIPR polypeptide conjugated to a GLP-1 receptor agonist are provided. In various embodiments the metabolic disease or disorder is type 2 diabetes, obesity, dyslipidemia, elevated glucose levels, elevated insulin levels and diabetic nephropathy. In certain embodiments the composition comprises an antibody or functional fragment thereof comprising a cysteine at one or more conjugation site(s) wherein the GLP-1 receptor agonist is conjugated to the antibody or functional fragment thereof through the side-chain of the cysteine residue.

First claim

What is claimed is:

1. A composition comprising
a) an antibody or functional fragment thereof that specifically binds to human GIPR, wherein said antibody comprises a CDRL1, a CDRL2, a CDRL3, a CDRH1, a CDRH2, and a CDRH3, wherein each CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3, respectively, comprise SEQ ID NO: 702, SEQ ID NO: 859, SEQ ID NO: 1016, SEQ ID NO: 1173, SEQ ID NO: 1330, and SEQ ID NO: 1487; and wherein
the antibody or functional fragment thereof comprises a cysteine or non-canonical amino acid amino acid substitution at one or more conjugation site(s); and
b) a GLP-1 receptor agonist, wherein the GLP-1 receptor agonist is conjugated to the antibody or functional fragment thereof through the side-chain of the cysteine residue or non-canonical amino acid residue substituted at the one or more conjugation site(s).

2. The composition of claim 1 , wherein said human GIPR has a sequence comprising a sequence selected from the group consisting of SEQ ID NO: 3141, SEQ ID NO: 3143, and SEQ ID NO: 3145.

3. The composition of claim 1 , wherein said antibody or functional fragment thereof is a monoclonal antibody, a recombinant antibody, a human antibody, a humanized antibody, a chimeric antibody, a multispecific antibody, or an antibody fragment thereof.

4. The composition of claim 3 , wherein said antibody fragment is a Fab fragment, a Fab′ fragment, or a F(ab′)2 fragment.

5. The composition of claim 3 , wherein said antibody or functional fragment thereof is a human antibody.

6. The composition of claim 3 , wherein said antibody or functional fragment thereof is a monoclonal antibody.

7. The composition of claim 3 , wherein said antibody or functional fragment thereof is of the IgG1-, IgG2- IgG3- or IgG4-type.

8. The composition of claim 7 , wherein said antibody or functional fragment thereof is of the IgG1- or the IgG2-type.

9. The composition of one of claim 3 , wherein said antibody or functional fragment thereof inhibits binding of GIP to the extracellular portion of human GIPR.

10. The composition of claim 3 , wherein said antibody or functional fragment thereof is an antibody, and wherein said antibody comprises a combination of a light chain and a heavy chain, wherein the the light chain comprises the amino acid sequence of SEQ ID NO: 338 and the heavy chain comprises the amino acid sequence of SEQ ID NO: 545, wherein
the antibody or functional fragment thereof comprises a cysteine or non-canonical amino acid amino acid substitution at one or more conjugation site(s) selected from the group consisting of
D70 of the antibody light chain relative to reference sequence SEQ ID NO: 455,
E276 of the antibody heavy chain relative to reference sequence SEQ ID NO: 612, and
T363 of the antibody heavy chain relative to reference sequence SEQ ID NO: 612.

11. The composition of claim 1 , wherein
the antibody or functional fragment thereof comprises a cysteine or non-canonical amino acid amino acid substitution at one or more conjugation site(s) selected from the group consisting of
D70 of the antibody light chain relative to reference sequence SEQ ID NO: 455,
E276 of the antibody heavy chain relative to reference sequence SEQ ID NO: 612, and
T363 of the antibody heavy chain relative to reference sequence SEQ ID NO: 612.

12. The composition of claim 1 , wherein said antibody or functional fragment thereof comprises a combination of a light chain variable region and a heavy chain variable region, wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO: 74 and the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 231.

13. The composition of claim 12 , wherein
the antibody or functional fragment thereof comprises a cysteine or non-canonical amino acid amino acid substitution at one or more conjugation site(s) selected from the group consisting of
D70 of the antibody light chain relative to reference sequence SEQ ID NO: 455,
E276 of the antibody heavy chain relative to reference sequence SEQ ID NO: 612, and
T363 of the antibody heavy chain relative to reference sequence SEQ ID NO: 612.

14. The composition of any one of claims 1 - 11 and 12 , 13 , 10 , wherein the GLP-1 receptor agonist is GLP-1(7-37) or a GLP-1(7-37) analog.

15. The composition of claim 14 , wherein receptor agonist or GLP-1(7-37) analog is selected from the group consisting of GLP-1(7-37) (SEQ ID NO: 3184); GLP-1(7-36)-NH 2 (SEQ ID NO: 3185); liraglutide; albiglutide; taspoglutide; dulaglutide, semaglutide; LY2428757; Exendin-4 (SEQ ID NO: 3163); Exendin-3 (SEQ ID NO: 3164); Leu 14 -exendin-4 (SEQ ID NO: 3165); Leu 14 ,Phe 25 -exendin-4 (SEQ ID NO: 3166); Leu 14 ,Ala 19 ,Phe 25 -exendin-4 (SEQ ID NO: 3167); exendin-4(1-30) (SEQ ID NO: 3168); Leu 14 -exendin-4(1-30) (SEQ ID NO: 3169); Leu 14 ,Phe 25 -exendin-4(1-30) (SEQ ID NO: 3170); Leu 14 ,Ala 19 ,Phe 25 -exendin-4(1-30) (SEQ ID NO: 3171); exendin-4(1-28) (SEQ ID NO: 3172); Leu 14 -exendin-4(1-28) (SEQ ID NO: 3173); Leu 14 ,Phe 25 -exendin-4(1-28) (SEQ ID NO: 3174); Leu 14 ,Ala 19 ,Phe 25 -exendin-4 (1-28) (SEQ ID NO: 3175); Leu 14 ,Lys 17,20 ,Ala 19 ,Glu 21 ,Phe 5 ,Gln 28 -exendin-4 (SEQ ID NO: 3176); Leu 14 ,Lys 17,20 ,Ala 19 ,Glu 21 ,Gln 28 -exendin-4 (SEQ ID NO: 3177); octylGly 14 ,Gln 28 -exendin-4 (SEQ ID NO: 3178); Leu 14 ,Gln 28 ,octylGly 34 -exendin-4 (SEQ ID NO: 3179); Phe 4 ,Leu 14 ,Gln 28 ,Lys 33 ,Glu 34 , Ile 35,36 ,Ser 37 -exendin-4(1-37) (SEQ ID NO: 3180); Phe 4 ,Leu 14 ,Lys 17,20 ,Ala 19 ,Glu 21 ,Gln 28 -exendin-4 (SEQ ID NO: 3181); Val 11 ,Ile 13 ,Leu 14 ,Ala 16 ,Lys 21 ,Phe 25 -exendin-4 (SEQ ID NO: 3182); exendin-4-Lys 40 (SEQ ID NO: 3183); GLP-1(7-37) (SEQ ID NO: 3184); GLP-1(7-36)-NH 2 (SEQ ID NO: 3185); Aib 8,35 ,Arg 26,34 ,Phe 31 -GLP-1(7-36)) (SEQ ID NO: 3186); HXaa 8 EGTFTSDVSSYLEXaa 22 Xaa 23 AAKEFIXaa 30 WLXaa 33 Xaa 34 G Xaa 36 Xaa 37 ; wherein Xaa 8 is A, V, or G, Xaa 22 is G, K, or E; Xaa 23 is Q or K; Xaa 30 is A or E; Xaa 33 is V or K Xaa 34 is K, N, or R; Xaa 36 is R or G; and Xaa 37 is G, H, P, or absent (SEQ ID NO: 3187); Arg 34 -GLP-1(7-37) (SEQ ID NO: 3188); Glu 30 -GLP-1(7-37) (SEQ ID NO: 3189); Lys 22 -GLP-1(7-37) (SEQ ID NO: 3190); Gly 8,36 ,Glu 22 -GLP-1(7-37) (SEQ ID NO: 3191); Val 8 ,Glu 22 ,Gly 36 -GLP-1(7-37) (SEQ ID NO: 3192); Gly 8,36 ,Glu 22 ,Lys 33 ,Asn 34 -GLP-(7-37) (SEQ ID NO: 3193); Val 8 ,Glu 22 ,Lys 33 ,Asn 34 ,Gly 36 -GLP-1(7-37) (SEQ ID NO: 3194); Gly 8,36 ,Glu 22 ,Pro 37 -GLP-1(7-37) (SEQ ID NO: 3195); Val 8 ,Glu 22 ,Gly 36 ,Pro 37 -GLP-1(7-37) (SEQ ID NO: 3196); Gly 8,36 ,Glu 22 ,Lys 33 , Asn 34 ,Pro 37 -GLP-1(7-37) (SEQ ID NO: 3197); Val 8 ,Glu 22 ,Lys 33 ,Asn 34 ,Gly 36 ,Pro 37 -GLP-1(7-37) (SEQ ID NO: 3198); Gly 8,36 ,Glu 22 -GLP-1(7-36) (SEQ ID NO: 3199); Val 8 ,Glu 22 ,Gly 36 -GLP-1(7-36) (SEQ ID NO: 3200); Val 8 ,Glu 22 ,Asn 34 ,Gly 36 -GLP-1(7-36) (SEQ ID NO: 3201); Gly 8,36 ,Glu 22 ,Asn 34 -GLP-1(7-36) (SEQ ID NO: 3202); GLP-1 analog (SEQ ID NO: 3206); GLP-1 analog (SEQ ID NO: 3207); [N e -(17-carboxyheptadecanoic acid)Lys 20 ]exendin-4-NH 2 (SEQ ID NO: 3208); [N e -(17-carboxyhepta-decanoyl)Lys 32 ]exendin-4-NH 2 (SEQ ID NO: 3209); [desamino-His 1 ,N e -(17-carboxyheptadecanoyl)Lys 20 ]exendin-4-NH 2 (SEQ ID NO: 3210); [Arg 12,27 ,NLe 14 ,N e -(17-carboxy-heptadecanoyl)Lys 32 ]exendin-4-NH 2 (SEQ ID NO: 3211); [N e -(19-carboxy-nonadecanoylamino)Lys 20 ]-exendin-4-NH 2 (SEQ ID NO: 3212); [N e -(15-carboxypentadecanoylamino)Lys 20 ]-exendin-4-NH 2 (SEQ ID NO: 3213); [N e -(13-carboxytridecanoylamino)Lys 20 ]exendin-4-NH 2 (SEQ ID NO: 3214); [N e -(11-carboxy-undecanoyl-amino)Lys 20 ]exendin-4-NH 2 (SEQ ID NO: 3215); exendin-4-Lys 40 (e-MPA)-NH 2 (SEQ ID NO: 3

Assignees

• Amgen Inc

Inventors

• Cheng Yuan
• Netirojjanakul Chawita
• Holder Jerry Ryan
• Wu Bin
• Falsey James R
• Herberich Bradley J
• Sham Kelvin
• Miranda Leslie P
• Lu Shu-Chen
• Veniant-Ellison Murielle M
• Stanislaus Shanaka
• Yie Junming
• Xu Jing

Classifications

• C07K2317/76

  Antagonist effect on antigen, e.g. neutralization or inhibition of binding · CPC title

• A61K38/00

  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 title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• C07K16/2869 Primary

  against hormone receptors (for antibodies against neuromediator receptors C07K16/286) · CPC title

• C07K14/605 Primary

  Glucagons · CPC title