Glp-1 receptor agonists and medical uses thereof

Abstract

This disclosure relates to improved GLP-1 receptor agonist peptides and molecules comprising such improved GLP-1 receptor agonist peptides, such as molecules comprising one or more GLP-1 receptor agonist peptides conjugated to an anti-gastric inhibitory peptide receptor (GIPR) antibody. This disclosure also relates to the use of these improved GLP-1 receptor agonist peptides and conjugate molecules comprising such peptides for the treatment or prevention of obesity, obesity-related conditions, type 2 diabetes, and / or type 2 diabetes-related conditions.

Description

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 566,857, filed March 18, 2024, pursuant to 35 USC §119(e).

[0002] By incorporating materials submitted electronically. By reference incorporated in its entirety is a computer-readable nucleotide / amino acid sequence list submitted with this application, and identified as follows: a 1.51 MB (XML) file named “10889-WO01-SEC_Sequence_Listing.xml”; created on March 13, 2025. Technical Field

[0003] This disclosure relates to improved glucagon-like peptide-1 (GLP-1) receptor agonist peptides and molecules comprising these improved GLP-1 receptor agonist peptides, such as conjugate molecules comprising one or more GLP-1 receptor agonist peptides conjugated to an anti-gastric inhibitory peptide receptor (GIPR) antibody. This disclosure also relates to the use of these improved GLP-1 receptor agonist peptides and conjugate molecules comprising these peptides for the treatment or relief of metabolic disorders such as obesity and type 2 diabetes. These improved GLP-1 receptor agonist peptides and conjugate molecules comprising these peptides may also be used to treat or relieve obesity-related conditions and type 2 diabetes-related conditions. Background Technology

[0004] Glucose-dependent insulinotropic peptide (GIP) is a single 42-amino acid peptide secreted by K cells in the small intestine (duodenum and jejunum). Human GIP is derived from the processing of proGIP, a 153-amino acid precursor encoded by a gene located on chromosome 17q (Inagaki et al., Mol Endocrinol [Journal of Molecular Endocrinology] 1989; 3:1014-1021; Fehmann et al., Endocr Rev. [Endocrinology Review] 1995; 16:390-410). Previously, GIP was known as a gastric inhibitory peptide.

[0005] Food intake induces GIP secretion. In tissues, GIP plays multiple physiological roles, including promoting fat storage in adipocytes and promoting pancreatic β-cell function and glucose-dependent insulin secretion. GIP and glucagon-like peptide-1 (GLP-1) are the only known insulinotropic factors (“incretins”). Intact GIP is rapidly degraded into an inactive form by DPPIV. GIP loses its insulinotropic effect in subjects with type 2 diabetes, while the incretin effect of GLP-1 remains intact (Nauck et al., J. Clinc. Invest. [Journal of Clinical Research] 1993; 91:301-307).

[0006] The GIP receptor (GIPR) is a member of the secretin-glucagon family of G protein-coupled receptors (GPCRs). This GPCR has an extracellular N-terminus, seven transmembrane domains, and an intracellular C-terminus. The N-terminal extracellular domain of this receptor family is typically glycosylated to form the receptor's recognition and binding domains. GIPR is highly expressed in many tissues, including the pancreas, intestine, adipose tissue, heart, pituitary gland, adrenal cortex, and brain (Usdin et al., Endocrinology 1993, 133:2861-2870). The human GIPR contains 466 amino acids and is encoded by a gene located on chromosome 19q13.3 (Gremlich et al., Diabetes 1995; 44:1202-8; Volz et al., FEBS Lett. 1995, 373:23-29). Studies have shown that variable mRNA splicing leads to the production of GIP receptor variants of varying lengths in humans, rats, and mice.

[0007] GIPR knockout mice (GIPR - / - It exhibits resistance to high-fat diet-induced weight gain and improves insulin sensitivity and lipid profile (Yamada et al., Diabètes. [Diabetes] 2006, 55:S86; Miyawaki et al., Nature Med. [Nature Medicine] 2002, 8:738-742). Furthermore, the novel small-molecule GIPR antagonist SKL-14959 prevents obesity and insulin resistance (Diabetologia [Diabetology] 2008, 51:S373, poster presentation at the 44th EASD Annual Meeting).

[0008] In conclusion, these associations with obesity and insulin resistance suggest that GIPR inhibition is a useful therapeutic intervention.

[0009] Glucagon-like peptide-1 (GLP-1) is a 31-amino acid peptide derived from the proglucagon gene. It is secreted by L cells in the gut and released in response to food intake, thereby inducing insulin secretion from pancreatic β cells (Diabetes 2004, 53:S3, 205-214). In addition to its glucagon-lowering effect, GLP-1 also reduces glucagon secretion, delays gastric emptying, and reduces calorie intake (Diabetes Care, 2003, 26(10): 2929-2940). GLP-1 exerts its effects by activating the GLP-1 receptor, a class B G protein-coupled receptor (Endocrinology, 1993, 133(4):1907-10). Rapid degradation by the DPP-IV enzyme limits GLP-1 function, resulting in a half-life of approximately 2 minutes. Recently, long-acting GLP-1 receptor agonists (GLP-1RAs) (such as exenatide, liraglutide, and duraglutide) have been developed and are now used clinically to improve glycemic control in subjects with type 2 diabetes. Furthermore, GLP-1 receptor agonists also promote weight loss and lower blood pressure and plasma cholesterol levels in subjects (Bioorg. Med. Chem. Lett [Bioorganic Chemistry and Medicinal Chemistry Letters] 2013, 23:4011-4018). Summary of the Invention

[0010] This disclosure relates to improved GLP-1 receptor agonist peptides. This disclosure also relates to molecules comprising these improved GLP-1 receptor agonist peptides, such as molecules comprising one or more GLP-1 receptor agonist peptides conjugated to an antagonist antigastric inhibitory peptide receptor (GIPR) antibody.

[0011] Therefore, the first aspect of this disclosure relates to a human glucagon-like peptide-1 (GLP-1) receptor agonist polypeptide comprising H[Aib]EGTFTSDYSSYLEEX 17 AAX 20 EFIX 24 WLX 27 X 28 The amino acid sequence of GGG (SEQ ID NO: 1575), where Aib at position 2 is α-amino-isobutyric acid (also known as 2-amino-isobutyric acid), X 17 It is Q, K, E, or R; X 20 It is K, R, Q or high in arginine (hArg); X 24It is A, E, Q, D, d-Ala, G, N, K, (1S,2S)-2-aminocyclopentanecarboxylic acid (ACPC), (3S,4R)-4-amino-3-pyrrolidinecarboxylic acid (APCA), T, S, or Y; X 27 It is V, K, Aib, N, S, T, Y, Q, or R; and X 28 It is K, E, R, Q, D, N, G, S, or T; and wherein the GLP-1 receptor agonist polypeptide does not contain the amino acid sequence H[Aib]EGTFTSDYSSYLEEQAAKEFIAWLVKGGG (SEQ ID NO: 1574).

[0012] In one embodiment, the GLP-1 receptor agonist peptide disclosed herein comprises H[Aib]EGTFTSDYSSYLEEX 17 AAX 20 EFIX 24 WLX 27 X 28 The amino acid sequence of GGG (SEQ ID NO: 1576), where X 17 Is it Q or K; X 20 It is K or R; X 24 It is A, E, or Q; X 27 It is V or K; and X 28 It is K, E, or R, wherein the GLP-1 receptor agonist peptide does not contain the amino acid sequence H[Aib]EGTFTSDYSSYLEEQAAKEFIAWLVKGGG (SEQ ID NO: 1574).

[0013] In one embodiment, the GLP-1 receptor agonist peptide disclosed herein comprises H[Aib]EGTFTSDYSSYLEEX 17 AAREFIX 24 WLX 27 X 28 The amino acid sequence of GGG (SEQ ID NO: 1577), where X 17 Is it Q or K; X 24 It is A, E, or Q; X 27 It is V or K; and X 28 It is K, E, or R.

[0014] In one embodiment, the GLP-1 receptor agonist peptide disclosed herein comprises H[Aib]EGTFTSDYSSYLEEX 17 AAX 20 EFIX 24 WLKX 28 The amino acid sequence of GGG (SEQ ID NO: 1578), where X17 Is it Q or K; X 20 It is K or R; X 24 It is A, E, or Q; and X 28 It is K, E, or R.

[0015] In one embodiment, the GLP-1 receptor agonist polypeptide disclosed herein comprises the amino acid sequence of any one of SEQ ID NO: 1579, SEQ ID NO: 1580, SEQ ID NO: 1581, SEQ ID NO: 1582 or SEQ ID NO: 1583 as provided herein.

[0016] On the other hand, the GLP-1 receptor agonist polypeptide disclosed herein comprises 31 amino acids, including an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO:1580, and including Aib at position 2; tyrosine at position 10; glutamic acid at positions 16, 24 and 28; arginine at position 20; lysine at positions 17 and 27; and glycine at position 30.

[0017] On the other hand, the GLP-1 receptor agonist polypeptide disclosed herein comprises 31 amino acids, including an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO:1579, and includes Aib at position 2; tyrosine at position 10; glutamic acid at positions 16 and 24; arginine at position 20; lysine at position 27; and glycine at position 30.

[0018] On the other hand, the GLP-1 receptor agonist polypeptide disclosed herein comprises 31 amino acids, including an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO:1581, and including Aib at position 2; tyrosine at position 10; glutamic acid at positions 16 and 24; arginine at position 20; lysine at positions 17 and 27; and glycine at position 30.

[0019] On the other hand, the GLP-1 receptor agonist polypeptide disclosed herein comprises 31 amino acids, including an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO:1583, and including Aib at position 2; tyrosine at position 10; glutamic acid at positions 16 and 28; arginine at position 20; lysine at positions 17 and 27; glutamine at position 24; and glycine at position 30.

[0020] On the other hand, the GLP-1 receptor agonist polypeptide disclosed herein comprises 31 amino acids, including an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO:1582, and includes Aib at position 2; tyrosine at position 10; glutamic acid at positions 16 and 24; arginine at positions 20 and 28; lysine at position 27; and glycine at position 30.

[0021] Another aspect of this disclosure relates to molecules comprising a first-human glucagon-like peptide-1 (GLP-1) receptor agonist polypeptide as described herein and a half-life extension moiety.

[0022] In one embodiment, the first GLP-1 receptor agonist peptide of the molecule comprises H[Aib]EGTFTSDYSSYLEEX 17 AAX 20 EFIX 24 WLX 27 X 28 The amino acid sequence of GGG (SEQ ID NO: 1575), where X 17 It is Q, K, E, or R; X 20 It is K, R, Q or high in arginine (hArg); X 24 It is A, E, Q, D, d-Ala, G, N, K, (1S,2S)-2-aminocyclopentanecarboxylic acid (ACPC), (3S,4R)-4-amino-3-pyrrolidinecarboxylic acid (APCA), T, S, or Y; X 27 It is V, K, Aib, N, S, T, Y, Q, or R; and X 28 It is K, E, R, Q, D, N, G, S, or T; and wherein the GLP-1 receptor agonist polypeptide does not contain the amino acid sequence of SEQ ID NO: 1574.

[0023] In one embodiment, the first GLP-1 receptor agonist peptide of the molecule comprises H[Aib]EGTFTSDYSSYLEEX 17 AAX 20 EFIX 24 WLX 27 X 28 The amino acid sequence of GGG (SEQ ID NO: 1576), where X 17 Is it Q or K; X 20 It is K or R; X 24 It is A, E, or Q; X 27 It is V or K; and X 28 It is K, E, or R, wherein the GLP-1 receptor agonist polypeptide does not contain the amino acid sequence of SEQ ID NO:1574.

[0024] In one embodiment, the first GLP-1 receptor agonist peptide of the molecule comprises H[Aib]EGTFTSDYSSYLEEX 17 AAREFIX 24 WLX 27 X 28 The amino acid sequence of GGG (SEQ ID NO: 1577), where X 17 Is it Q or K; X 24 It is A, E, or Q; X 27 It is V or K; and X 28 It is K, E, or R.

[0025] In one embodiment, the first GLP-1 receptor agonist peptide of the molecule comprises H[Aib]EGTFTSDYSSYLEEX 17 AAX 20 EFIX 24 WLKX 28 The amino acid sequence of GGG (SEQ ID NO: 1578), where X 17 Is it Q or K; X 20 It is K or R; X 24 It is A, E, or Q; and X 28 It is K, E, or R.

[0026] In one embodiment, the first GLP-1 receptor agonist polypeptide of the molecule comprises the amino acid sequence of any one of SEQ ID NO: 1579, SEQ ID NO: 1580, SEQ ID NO: 1581, SEQ ID NO: 1582 or SEQ ID NO: 1583.

[0027] In one embodiment, the extended half-life portion of the molecule is an antibody.

[0028] Another aspect of this disclosure relates to a conjugate molecule comprising a first human glucagon-like peptide-1 (GLP-1) receptor agonist polypeptide as described herein, which is conjugated to an antagonist antiglucose-dependent insulinotropic peptide receptor (GIPR) antibody.

[0029] In one embodiment, the conjugate molecule comprises a first GLP-1 receptor agonist polypeptide conjugated to an antagonist anti-GIPR antibody, the polypeptide comprising the amino acid sequence of any one of SEQ ID NO: 1575-1583. The anti-GIPR antibody of the conjugate molecule comprises a first cysteine ​​conjugate site located within the light or heavy chain of the antibody, and the first GLP-1 receptor agonist polypeptide is conjugated at its C-terminus to the first cysteine ​​conjugate site of the anti-GIPR antibody. In one embodiment, the first cysteine ​​conjugate site of the anti-GIPR antibody is located at position 88 of the light chain, position 384 of the heavy chain, or position 487 of the heavy chain according to AHo number.

[0030] In one embodiment, the first GLP-1 receptor agonist polypeptide of the conjugate molecule is conjugated at its C-terminus to the first cysteine ​​conjugate site of the anti-GIPR antibody via a first linker portion. In one embodiment, the first linker portion is a peptide linker, and the peptide linker comprises the amino acid sequence of any one of SEQ ID NO: 1585-1593. In one embodiment, the first linker portion is a PEG linker.

[0031] In one embodiment, the conjugate molecule further comprises a second GLP-1 receptor agonist peptide. The second GLP-1 receptor agonist peptide is conjugated at its C-terminus to the second cysteine ​​conjugate site of the anti-GIPR antibody.

[0032] In one embodiment, the second GLP-1 receptor agonist polypeptide comprises any GLP-1 receptor agonist polypeptide disclosed herein. In one embodiment, the second GLP-1 receptor agonist polypeptide comprises the amino acid sequence of any one of SEQ ID NO: 1575-1583. In one embodiment, the second GLP-1 receptor agonist polypeptide comprises the same amino acid sequence as the first GLP-1 receptor agonist polypeptide.

[0033] In one embodiment of this aspect of the disclosure, the second GLP-1 receptor agonist peptide of the conjugate molecule is conjugated at its C-terminus to the second cysteine ​​conjugate site of the anti-GIPR antibody via a second linker portion. In one embodiment, the second linker portion is a peptide linker, and the peptide linker comprises the amino acid sequence of any one of SEQ ID NO: 1585-1593. In one embodiment, the second peptide linker comprises the same amino acid sequence as the first peptide linker. In one embodiment, the second linker portion is a PEG linker.

[0034] In one embodiment, the first and second conjugation sites of the anti-GIPR antibody in the conjugated molecule are located at position 88 of each light chain, position 384 of each heavy chain, or position 487 of each heavy chain according to the AHo number.

[0035] In one embodiment, the anti-GIPR antibody of the conjugate molecule comprises CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3, wherein CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3 respectively comprise the amino acid sequences of 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.

[0036] In one embodiment, the anti-GIPR antibody of the conjugate molecule contains V L and V H The V L and V H It contains the amino acid sequences of SEQ ID NO: 74 and SEQ ID NO: 231, respectively.

[0037] In one embodiment, the anti-GIPR antibody of the conjugate molecule comprises a light chain and a heavy chain, the light chain and the heavy chain comprising the amino acid sequences of SEQ ID NO: 388 and SEQ ID NO: 545, respectively, wherein, according to the AHo number, a cysteine ​​substitution is present at position 88 of each light chain, position 384 of each heavy chain, or position 487 of each heavy chain.

[0038] Another aspect of this disclosure relates to a molecule comprising an antagonist anti-glucose-dependent insulinotropic peptide receptor (GIPR) antibody, wherein said antibody comprises: a first light chain and a second light chain, each light chain comprising CDRL1, CDRL2, and CDRL3 of SEQ ID NO: 702, SEQ ID NO: 859, and SEQ ID NO: 1016, respectively; and a first heavy chain and a second heavy chain, each heavy chain comprising CDRH1, CDRH2, and CDRH3 of SEQ ID NO: 1173, SEQ ID NO: 1330, and SEQ ID NO: 1487, respectively. The molecule further comprises a first GLP-1 receptor agonist peptide and a second GLP-1 receptor agonist peptide, wherein each GLP-1 receptor agonist peptide comprises the amino acid sequence of SEQ ID NO: 1579; and a first peptide linker and a second peptide linker, wherein each peptide linker comprises the amino acid sequence of SEQ ID NO: 1592. The first GLP-1 receptor agonist polypeptide of the molecule is conjugated at its C-terminus to a cysteine ​​residue at position 384 of the first heavy chain of the anti-GIPR antibody according to AHo number 384 (corresponding to position 275 of SEQ ID NO: 1571) via a first linker, and the second GLP-1 receptor agonist polypeptide is conjugated at its C-terminus to a cysteine ​​residue at position 384 of the second heavy chain of the anti-GIPR antibody according to AHo number 384 (corresponding to position 275 of SEQ ID NO: 1571) via a second linker. In one embodiment, each light chain of the antibody comprises VL of SEQ ID NO: 74, and each heavy chain of the antibody comprises VH of SEQ ID NO: 231. In another embodiment, each light chain of the antibody comprises the amino acid sequence of SEQ ID NO: 388, and each heavy chain of the antibody comprises the amino acid sequence of SEQ ID NO: 1571.

[0039] Another aspect of this disclosure relates to a molecule comprising an antagonist anti-glucose-dependent insulinotropic peptide receptor (GIPR) antibody, wherein said antibody comprises: a first light chain and a second light chain, each light chain comprising CDRL1, CDRL2, and CDRL3 of SEQ ID NO: 702, SEQ ID NO: 859, and SEQ ID NO: 1016, respectively; and a first heavy chain and a second heavy chain, each heavy chain comprising CDRH1, CDRH2, and CDRH3 of SEQ ID NO: 1173, SEQ ID NO: 1330, and SEQ ID NO: 1487, respectively. The molecule further comprises a first GLP-1 receptor agonist peptide and a second GLP-1 receptor agonist peptide, wherein each GLP-1 receptor agonist peptide comprises the amino acid sequence of SEQ ID NO: 1580; and a first peptide linker and a second peptide linker, wherein each peptide linker comprises the amino acid sequence of SEQ ID NO: 1591. The first GLP-1 receptor agonist polypeptide of the molecule is conjugated at its C-terminus to a cysteine ​​residue at position 384 of the first heavy chain of the anti-GIPR antibody according to AHo number 384 (corresponding to position 275 of SEQ ID NO: 1571) via a first linker, and the second GLP-1 receptor agonist polypeptide is conjugated at its C-terminus to a cysteine ​​residue at position 384 of the second heavy chain of the anti-GIPR antibody according to AHo number 384 (corresponding to position 275 of SEQ ID NO: 1571) via a second linker. In one embodiment, each light chain of the antibody comprises VL of SEQ ID NO: 74, and each heavy chain of the antibody comprises VH of SEQ ID NO: 231. In another embodiment, each light chain of the antibody comprises the amino acid sequence of SEQ ID NO: 388, and each heavy chain of the antibody comprises the amino acid sequence of SEQ ID NO: 1571.

[0040] Another aspect of this disclosure relates to a molecule comprising an antagonist anti-glucose-dependent insulinotropic peptide receptor (GIPR) antibody, wherein said antibody comprises: a first light chain and a second light chain, each light chain comprising CDRL1, CDRL2, and CDRL3 of SEQ ID NO: 702, SEQ ID NO: 859, and SEQ ID NO: 1016, respectively; and a first heavy chain and a second heavy chain, each heavy chain comprising CDRH1, CDRH2, and CDRH3 of SEQ ID NO: 1173, SEQ ID NO: 1330, and SEQ ID NO: 1487, respectively. The molecule further comprises a first GLP-1 receptor agonist peptide and a second GLP-1 receptor agonist peptide, wherein each GLP-1 receptor agonist peptide comprises the amino acid sequence of SEQ ID NO: 1581; and a first peptide linker and a second peptide linker, wherein each peptide linker comprises the amino acid sequence of SEQ ID NO: 1586. The first GLP-1 receptor agonist polypeptide of the molecule is conjugated at its C-terminus to a cysteine ​​residue at position 384 of the first heavy chain of the anti-GIPR antibody according to AHo number 384 (corresponding to position 275 of SEQ ID NO: 1571) via a first linker, and the second GLP-1 receptor agonist polypeptide is conjugated at its C-terminus to a cysteine ​​residue at position 384 of the second heavy chain of the anti-GIPR antibody according to AHo number 384 (corresponding to position 275 of SEQ ID NO: 1571) via a second linker. In one embodiment, each light chain of the antibody comprises VL of SEQ ID NO: 74, and each heavy chain of the antibody comprises VH of SEQ ID NO: 231. In another embodiment, each light chain of the antibody comprises the amino acid sequence of SEQ ID NO: 388, and each heavy chain of the antibody comprises the amino acid sequence of SEQ ID NO: 1571.

[0041] Another aspect of this disclosure relates to a molecule comprising an antagonist anti-glucose-dependent insulinotropic peptide receptor (GIPR) antibody, wherein said antibody comprises: a first light chain and a second light chain, each light chain comprising CDRL1, CDRL2, and CDRL3 of SEQ ID NO: 702, SEQ ID NO: 859, and SEQ ID NO: 1016, respectively; and a first heavy chain and a second heavy chain, each heavy chain comprising CDRH1, CDRH2, and CDRH3 of SEQ ID NO: 1173, SEQ ID NO: 1330, and SEQ ID NO: 1487, respectively. The molecule further comprises a first GLP-1 receptor agonist peptide and a second GLP-1 receptor agonist peptide, wherein each GLP-1 receptor agonist peptide comprises the amino acid sequence of SEQ ID NO: 1581; and a first peptide linker and a second peptide linker, wherein each peptide linker comprises the amino acid sequence of SEQ ID NO: 1585. The first GLP-1 receptor agonist polypeptide of the molecule is conjugated at its C-terminus to a cysteine ​​residue at position 384 of the first heavy chain of the anti-GIPR antibody according to AHo number 384 (corresponding to position 275 of SEQ ID NO: 1571) via a first linker, and the second GLP-1 receptor agonist polypeptide is conjugated at its C-terminus to a cysteine ​​residue at position 384 of the second heavy chain of the anti-GIPR antibody according to AHo number 384 (corresponding to position 275 of SEQ ID NO: 1571) via a second linker. In one embodiment, each light chain of the antibody comprises VL of SEQ ID NO: 74, and each heavy chain of the antibody comprises VH of SEQ ID NO: 231. In another embodiment, each light chain of the antibody comprises the amino acid sequence of SEQ ID NO: 388, and each heavy chain of the antibody comprises the amino acid sequence of SEQ ID NO: 1571.

[0042] Another aspect of this disclosure relates to pharmaceutical compositions comprising or containing the GLP-1 receptor agonist peptide disclosed herein, and pharmaceutically acceptable excipients.

[0043] Another aspect of this disclosure relates to methods for reducing the weight and / or food intake of subjects in need. These methods include administering to subjects in need the GLP-1 receptor agonist peptide disclosed herein, a molecule containing the GLP-1 receptor agonist peptide disclosed herein, or a pharmaceutical composition disclosed herein.

[0044] Another aspect of this disclosure relates to a method for treating obesity or obesity-related conditions in a subject of need. This method includes administering to a subject of need the GLP-1 receptor agonist peptide disclosed herein, a molecule containing the GLP-1 receptor agonist peptide disclosed herein, or a pharmaceutical composition disclosed herein.

[0045] Another aspect of this disclosure relates to a method for treating type 2 diabetes or type 2 diabetes-related conditions in a subject of need. The method includes administering to the subject of need the GLP-1 receptor agonist peptide disclosed herein, a molecule containing the GLP-1 receptor agonist peptide disclosed herein, or a pharmaceutical composition disclosed herein.

[0046] This article describes novel GLP-1 receptor agonist peptides and molecules comprising antagonist anti-GIPR antibodies conjugated to one or more novel GLP-1 receptor agonist peptides. The GLP-receptor agonist peptides described herein contain one or more defined amino acid substitutions that enhance the stability and / or efficacy of the agonist peptides and molecules containing these peptides. Attached Figure Description

[0047] Figure 1 The reaction protocol for preparing the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule disclosed herein is shown.

[0048] Figure 2 The structure of the disclosed GLP-1 receptor agonist peptide covalently linked to a peptide linker is shown. The GLP-1 receptor agonist peptide comprises the amino acid sequence of SEQ ID NO: 1579. The C-terminal amino acid residue of the GLP-1 receptor agonist peptide is covalently linked to the N-terminal amino acid residue of the linker peptide of SEQ ID NO: 1592. The C-terminus of the peptide linker has been brominated (ε-amino group on the lysine residue side chain) to allow further conjugation to an anti-GIPR antibody via a bromoacetyl-thiol reaction with the thiol group of the cysteine ​​residue.

[0049] Figure 3 The structure of the disclosed GLP-1 receptor agonist peptide covalently linked to a peptide linker is shown. The GLP-1 receptor agonist peptide comprises the amino acid sequence of SEQ ID NO: 1580. As shown, the C-terminal amino acid residue of the GLP-1 receptor agonist peptide is covalently linked to the α-amino group of the lysine residue of the linker peptide of SEQ ID NO: 1591. The N-terminus of the peptide linker has been bromoacetylated to allow further conjugation to an anti-GIPR antibody via a bromoacetyl-thiol reaction with the thiol group of the cysteine ​​residue.

[0050] Figure 4The structure of the disclosed GLP-1 receptor agonist peptide covalently linked to a peptide linker is shown. The GLP-1 receptor agonist peptide comprises the amino acid sequence of SEQ ID NO: 1581. As shown, the C-terminal amino acid residue of the GLP-1 receptor agonist peptide is covalently linked to the N-terminal amino acid residue of the linker peptide of SEQ ID NO: 1585. The C-terminal lysine residue of the peptide linker has been brominated (ε-amino group on the side chain of the lysine residue) to allow further conjugation to the anti-GIPR antibody via a bromoacetyl-thiol reaction with the thiol group of the cysteine ​​residue.

[0051] Figure 5 The structure of the disclosed GLP-1 receptor agonist peptide covalently linked to a peptide linker is shown. The GLP-1 receptor agonist peptide comprises the amino acid sequence of SEQ ID NO: 1581. As shown, the C-terminal amino acid residue of the GLP-1 receptor agonist peptide is covalently linked to the N-terminal amino acid residue of the linker peptide of SEQ ID NO: 1586. The C-terminal lysine residue of the peptide linker has been bromoacetylated (ε-amino group on the side chain of the lysine residue) to allow further conjugation to the anti-GIPR antibody via a bromoacetyl-thiol reaction with the thiol group of the cysteine ​​residue.

[0052] Figure 6 The structure of the disclosed GLP-1 receptor agonist peptide covalently linked to a peptide linker is shown. The GLP-1 receptor agonist peptide comprises the amino acid sequence of SEQ ID NO: 1581. As shown, the C-terminal amino acid residue of the GLP-1 receptor agonist peptide is covalently linked to the N-terminal amino acid residue of the linker peptide of SEQ ID NO: 1593. The C-terminal lysine residue of the peptide linker has been bromoacetylated (ε-amino group on the side chain of the lysine residue) to allow further conjugation to the anti-GIPR antibody via a bromoacetyl-thiol reaction with the thiol group of the cysteine ​​residue.

[0053] Figure 7 The structure of the disclosed GLP-1 receptor agonist peptide covalently linked to a PEG linker is shown. The GLP-1 receptor agonist peptide comprises the amino acid sequence of SEQ ID NO: 1581. As shown, the C-terminal amino acid residue of the GLP-1 receptor agonist peptide is covalently linked to the PEG20 linker via the α-amino group of the lysine residue. The PEG20 linker is covalently linked to the ε-amino group of the lysine side chain. The glycine residue at the other end of the PEG linker has been bromoacetylated to allow further conjugation to the anti-GIPR antibody via a bromoacetyl-thiol reaction with the thiol group of the cysteine ​​residue.

[0054] Figure 8 The structure of the disclosed GLP-1 receptor agonist peptide covalently linked to a PEG linker is shown. The GLP-1 receptor agonist peptide comprises the amino acid sequence of SEQ ID NO: 1582. As shown, the C-terminal amino acid residue of the GLP-1 receptor agonist peptide is covalently linked to the PEG20 linker via the α-amino group of the lysine residue. The PEG20 linker is covalently linked to the ε-amino group of the lysine side chain. The glycine residue at the other end of the PEG linker has been bromoacetylated to allow further conjugation to the anti-GIPR antibody via a bromoacetyl-thiol reaction with the thiol group of the cysteine ​​residue.

[0055] Figure 9 The structure of the disclosed GLP-1 receptor agonist peptide covalently linked to a PEG linker is shown. The GLP-1 receptor agonist peptide comprises the amino acid sequence of SEQ ID NO: 1583. As shown, the C-terminal amino acid residue of the GLP-1 receptor agonist peptide is covalently linked to the PEG20 linker via the α-amino group of the lysine residue. The PEG20 linker is covalently linked to the ε-amino group of the lysine side chain. The glycine residue at the other end of the PEG linker has been bromoacetylated to allow further conjugation to the anti-GIPR antibody via a bromoacetyl-thiol reaction with the thiol group of the cysteine ​​residue.

[0056] Figure 10 The study illustrates the weight loss over 12 days in diet-induced obese C57BL6 mice following a single dose of 0.5 mg / kg of an alternative anti-GIPR / GLP-1 agonist conjugate (i.e., reference conjugate molecule 1238 and conjugate molecule 62207 disclosed herein) or a mediator (A52Su) on day 0.

[0057] Figure 11 The study demonstrates the weight loss over 18 days in diet-induced obese C57BL6 mice following a single dose of 0.5 mg / kg of an alternative anti-GIPR / GLP-1 agonist conjugate (i.e., reference conjugate molecule 1238 and conjugate molecule 65296 disclosed herein) or a mediator (A52Su) on day 0.

[0058] Figure 12 The study demonstrates the weight loss over 18 days in diet-induced obese C57BL6 mice following a single dose of 0.5 mg / kg of an alternative anti-GIPR / GLP-1 agonist conjugate (i.e., reference conjugate molecule 1238 and conjugate molecules 69730 and 69850 disclosed herein) or a mediator (A52Su) administered on day 0.

[0059] Figure 13The study demonstrates the weight loss over 16 days in diet-induced obese C57BL6 mice following a single dose of 0.5 mg / kg of an alternative anti-GIPR / GLP-1 agonist conjugate (i.e., reference conjugate molecule 1238 and conjugate molecules 59112 and 59117 disclosed herein) or a mediator (A52Su) on day 0.

[0060] Figure 14 The study demonstrates the weight loss over 20 days in diet-induced obese C57BL6 mice following a single dose of 0.5 mg / kg of an alternative anti-GIPR / GLP-1 agonist conjugate (i.e., reference conjugate molecule 1238 and conjugate molecule 65300 disclosed herein) or a mediator (A52Su) on day 0.

[0061] Figure 15 The study demonstrates the weight loss over 24 days in diet-induced obese C57BL6 mice following administration of 0.5 mg / kg of alternative anti-GIPR / GLP-1 agonist conjugates (i.e., reference conjugate molecule 1238 and conjugate molecule 59112 disclosed herein) or mediators on days 0 and 10.

[0062] Figure 16 The study illustrates the weight loss over 24 days in diet-induced obese C57BL6 mice following administration of 0.5 mg / kg of alternative anti-GIPR / GLP-1 agonist conjugates (i.e., reference conjugate molecule 1238 and conjugate molecules 62207, 65296, and 65300 disclosed herein) or mediators on days 0 and 10.

[0063] Figure 17 The study demonstrates the weight loss over 24 days in diet-induced obese C57BL6 mice following administration of 0.5 mg / kg of alternative anti-GIPR / GLP-1 agonist conjugates (i.e., reference conjugate molecule 1238 and conjugate molecules 59117, 69730, 69850, and 73313 disclosed herein) or mediators on days 0 and 10. Detailed Implementation

[0064] This disclosure relates to improved GLP-1 receptor agonists and molecules comprising these improved GLP-1 receptor agonists. This disclosure further relates to the efficacy of these improved protein therapeutics in treating or alleviating metabolic disorders such as obesity, type 2 diabetes, elevated blood glucose levels, elevated insulin levels, non-alcoholic fatty liver disease, cardiovascular disease, and diabetic nephropathy, as described herein, including type 1 and type 2 diabetes-related conditions. This disclosure also relates to the efficacy of these improved protein therapeutics in treating or alleviating obesity-related conditions and type 2 diabetes-related conditions.

[0065] The chapter titles used in this article are for organizational purposes only and should not be considered as limiting the subject matter described.

[0066] Unless otherwise defined herein, scientific and technical terms used in connection with this application shall have the meanings commonly understood by one of ordinary skill in the art. Furthermore, unless the context otherwise requires, singular terms will include plural forms and plural terms will include singular forms.

[0067] Except as provided in operational examples or otherwise indicated, all figures used herein to indicate the amount of an ingredient or reaction conditions should be understood to be modified by the term “about” in all cases. When used in conjunction with percentages, the term “about” means ±1%.

[0068] By convention, unless otherwise explicitly indicated, as used in this article, “a / an” means “one or more”.

[0069] As used herein, the terms “amino acid” and “residue” are used interchangeably and, when used in the context of a peptide or polypeptide, refer to both naturally occurring and synthetic amino acids, as well as amino acid analogs, amino acid mimics, and non-naturally occurring amino acids that are chemically similar to naturally occurring amino acids.

[0070] "Naturally occurring amino acids" refer to amino acids encoded by the human genetic code, as well as those genetically encoded amino acids that are modified after synthesis, such as hydroxyproline, γ-carboxyglutamic acid, and O-phosphoserine. Amino acid analogs are compounds that have the same basic chemical structure as naturally occurring amino acids (i.e., the α-carbon is bonded to hydrogen, a carboxyl group, an amino group, and an R group), such as homoserine, ortholeucine, methionine sulfoxide, and methionine methylsulfonium. Such analogs may have modified R groups (e.g., ortholeucine) or modified peptide backbones, but will retain the same basic chemical structure as naturally occurring amino acids.

[0071] "Amino acid mimics" are chemical compounds that have a structure different from the general chemical structure of amino acids but function in a manner similar to naturally occurring amino acids. Examples include methacryloyl or acryloyl derivatives of amides, β-imino acids, γ-imino acids, δ-imino acids (such as piperidine-4-carboxylic acid), etc.

[0072] "Non-naturally occurring amino acids" are compounds that have the same basic chemical structure as naturally occurring amino acids but are not incorporated into the growing polypeptide chain by the translation complex. Non-naturally occurring amino acids also include, but are not limited to, amino acids produced by modification (e.g., post-translational modification) of naturally encoded amino acids (including, but not limited to, 20 common amino acids) but which are not incorporated into the growing polypeptide chain by the translation complex in their natural state. A non-limiting list of examples of non-naturally occurring amino acids that can be inserted into or replace wild-type residues in a polypeptide sequence includes β-amino acids, high-molecular-weight amino acids, cyclic amino acids, and amino acids with derivatized side chains. Examples include (in L or D form; abbreviations as shown in parentheses): citrulline (Cit), high-citrulline (hCit), Nα-methylcitrulline (NMeCit), Nα-methylhigh-citrulline (Nα-MeHoCit), ornithine (Orn), Nα-methylornithine (Nα-MeOrn or NMeOrn), sarcosine (Sar), high-lysine (hLys or hK), high-arginine (hArg or hR), high-glutamine (hQ), Nα-methylarginine (NMeR), Nα-methylleucine (Nα- MeL or NMeL), N-methylholysine (NMeHoK), Nα-methylglutamine (NMeQ), leucine (Nle), valine (Nva), 1,2,3,4-tetrahydroisoquinoline (Tic), octahydroindole-2-carboxylic acid (Oic), 3-(1-naphthyl)alanine (1-Nal), 3-(2-naphthyl)alanine (2-Nal), 1,2,3,4-tetrahydroisoquinoline (Tic), 2-dihydroindole-glycine (IgI), p-iodophenylalanine (pI-Phe), p-aminophenylalanine (4 AmP or 4-amino-Phe), 4-guanidinophenylalanine (Guf), glycyl lysine (abbreviated as "K(Nε-glycyl)" or "K(gly)" or "K(gly)"), nitrophenylalanine (nitrophe), aminophenylalanine (aminophe or amino-Phe), benzylphenylalanine (benzylphe), γ-carboxyglutamic acid (γ-carboxyglu), hydroxyproline (hydroxypro), p-carboxyphenylalanine (Cpa), α-aminoadipic acid (Aad), Nα-methylvaline (NMeVa) l), N-α-methylleucine (NMeLeu), Nα-methylortholeucine (NMeNle), cyclopentylglycine (Cpg), cyclohexylglycine (Chg), acetylargine (acetylarg), α,β-diaminopropionic acid (Dpr), α,γ-diaminobutyric acid (Dab), diaminopropionic acid (Dap), cyclohexylalanine (Cha), 4-methyl-phenylalanine (MePhe), β,β-diphenylalanine (BiPhA), aminobutyric acid (Abu), 4-phenyl-phenylalanine (or biphenylalanine);4-Bip), α-amino-isobutyric acid (Aib), β-alanine, β-aminopropionic acid, piperidinecarboxylic acid, aminohexanoic acid, aminoheptanoic acid, aminopimelic acid, desmodium, diaminopimelic acid, N-ethylglycine, N-ethylarginine, hydroxylysine, allohydroxylysine, isodesmodium, alloiseleucine, N-methylglycine, N-methylisoleucine, N-methylvaline, 4-hydroxyproline (Hyp), γ-carboxyglutamic acid, ε-N,N,N-trimethyllysine, ε-N-acetyllysine, O-phosphoserine, N-acetylserine, N-formylmethionine, 3-methylhistidine, 5-hydroxylysine, ω-methylarginine, 4-amino-O-phthalic acid (4APA) and other similar amino acids, as well as derivatized forms of any of the amino acids specifically listed.

[0073] As used herein, the term "polypeptide" refers to a polymer of amino acid residues. Polypeptides containing between twenty and fifty amino acids may also be referred to herein as "peptides". "Polypeptide" further encompasses amino acid polymers in which one or more amino acid residues are analogs or mimics of the corresponding naturally occurring amino acids, as well as naturally occurring amino acid polymers. The term may also encompass amino acid polymers that have been modified, for example, by adding carbohydrate residues to form glycoproteins, or by adding phosphate groups to form phosphorylated polypeptides. Polypeptides can be produced by naturally occurring and non-recombinant cells, or by genetically engineered or recombinant cells, and comprise molecules having the amino acid sequence of a natural protein or molecules having one or more amino acids with a natural sequence that have been omitted, added, and / or substituted. Polypeptides can also be produced synthetically.

[0074] As used herein, a “variant” of a polypeptide comprises an amino acid sequence in which one or more amino acid residues are inserted into, deleted from, and / or substituted into a reference polypeptide sequence relative to the reference polypeptide sequence.

[0075] As used herein, a “derivative” of a polypeptide is a polypeptide that has been chemically modified in a manner different from insertion, deletion, or substitution variants, such as, for example, by conjugation with another chemical moiety.

[0076] The compositions of the present invention, including GLP-1 receptor agonist peptides as described herein (which are covalently linked, attached, or bound to the anti-GIPR antibody of the present invention directly or indirectly through a linker portion), are referred to herein as “conjugates,” “conjugate molecules,” “conjugate proteins,” or “antibody conjugates.”

[0077] As used herein, the term "connector moiety" refers to a biologically acceptable (i.e., safe and non-toxic) peptide or non-peptide organic group that is covalently linked to a first molecule (e.g., a first polypeptide) and covalently linked or conjugated to a second molecule (e.g., a second polypeptide). When the connector moiety consists of a polypeptide or polypeptide derivative (e.g., a polypeptide that has been chemically modified at one or both of its N-terminus and C-terminus to incorporate functional groups that allow conjugation to the first or second molecule), it may be referred to herein as a "connector polypeptide". For example, in one embodiment, the connector polypeptide may comprise an acetylated terminus (e.g., when the derivatized terminus of the connector polypeptide is conjugated to a cysteine ​​residue of the polypeptide by forming a thioether linker containing the sulfur atom of the cysteine ​​residue using a thiol-bromoacetyl reaction).

[0078] In the context of two or more polypeptide sequences, the phrase "sequence identity percentage" refers to the ratio, expressed as a percentage, of the number of identical amino acid residues between two or more aligned amino acid (peptide or protein) sequences along their alignment length. To calculate the sequence identity percentage of two sequences, the sequences are aligned along their length. Sequence alignment algorithms (e.g., BLAST (Myers et al., J. Mol. Biol. [Journal of Molecular Biology] 215(3):403-10 (1990)) can be used to align the two sequences to ensure that the corresponding amino acids are correctly positioned relative to each other. The number of identical amino acids at each position in the alignment is divided by the total number of aligned positions and then multiplied by 100.

[0079] The terms “GIPR polypeptide” and “GIPR protein” are used interchangeably to refer to a naturally occurring glucose-dependent insulinotropic polypeptide receptor protein expressed in mammals (e.g., humans or mice) and include naturally occurring allelic variants (e.g., the naturally occurring allelic form of human GIPR protein). For the purposes of this disclosure, the term “GIPR polypeptide” is used interchangeably to refer to any full-length GIPR polypeptide (UniProt accession number P48546-1), for example, SEQ ID NO: 1572, which consists of 466 amino acid residues and is encoded by the nucleotide sequence SEQ ID NO: 1573. The term also covers known isoforms of GIPR proteins (see, for example, UniProt accession numbers P48546-2 and P48546-3).

[0080] The term "GIPR polypeptide" also encompasses naturally occurring GIPR polypeptide variants. Such variants may include modifications to a naturally occurring GIPR sequence (SEQ ID NO: 1572), including but not limited to one or more amino acid substitutions, deletions, and / or insertions. A GIPR polypeptide encompasses an amino acid sequence having at least about 85% identity with a naturally occurring GIPR polypeptide (e.g., SEQ ID NO: 1572). In other embodiments, a GIPR polypeptide comprises an amino acid sequence having at least about 90% or about 95%, 96%, 97%, 98%, or 99% identity with a naturally occurring GIPR polypeptide amino acid sequence (e.g., SEQ ID NO: 1572). Such GIPR polypeptides preferably, but not necessarily, possess at least one activity of wild-type GIPR polypeptides, such as the ability to bind to GIP receptors. The invention also covers nucleic acid molecules encoding such GIPR polypeptide sequences.

[0081] The terms “GIP,” “gastric inhibitory peptide,” “glucose-dependent insulinotropic peptide,” and “GIP ligand” are used interchangeably and refer to naturally occurring wild-type peptides expressed in mammals (e.g., humans or mice), and include naturally occurring alleles (e.g., the naturally occurring allele form of human GIP protein). GIP is the natural ligand of GIPR. For the purposes of this disclosure, the term “GIP” is used interchangeably to refer to any mature GIP peptide.

[0082] As used herein, the term "antibody" refers to a complete immunoglobulin. An antibody consists of two full-length heavy chains and two full-length light chains. Antibodies may originate from a single source or may be "chimeric" antibodies, meaning that different parts of an antibody may originate from two different antibodies, as further described below.

[0083] As used herein, the term "light chain" or "immunoglobulin light chain" refers to a polypeptide comprising a single immunoglobulin light chain variable region (VL) and a single immunoglobulin light chain constant domain (CL) from the amino terminus (N-terminus) to the carboxyl terminus (C-terminus). The immunoglobulin light chain constant domain (CL) may be a human κ (kappa) or human λ (lambda) constant domain.

[0084] As used herein, the term "heavy chain" or "immunoglobulin heavy chain" refers to a polypeptide comprising a single immunoglobulin heavy chain variable region (VH), immunoglobulin heavy chain constant domain 1 (CH1), immunoglobulin hinge region, immunoglobulin heavy chain constant domain 2 (CH2), immunoglobulin heavy chain constant domain 3 (CH3), and optionally immunoglobulin heavy chain constant domain 4 (CH4) from the N-terminus (N-terminus) to the C-terminus (C-terminus). Heavy chains are classified as μ (mu), Δ (delta), γ (gamma), α (alpha), and ε (epsilon) chains, which respectively define antibody isotypes as IgM, IgD, IgG, IgA, and IgE. According to this disclosure, the antibody is an IgG isotype. IgG has several subclasses, including but not limited to IgG1, IgG2, IgG3, and IgG4.

[0085] The variable regions of immunoglobulin chains typically exhibit the same overall structure, comprising relatively conserved frame regions (FRs) linked by three hypervariable regions (more commonly referred to as "complementarity-determining regions" or CDRs). The CDRs from each heavy and light chain pair are typically aligned via the frame regions to form a structure that specifically binds to a particular epitope on the target antigen or protein. From the N-terminus to the C-terminus, both the naturally occurring light and heavy chain variable regions of antibodies typically follow this order of elements: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. A numbering system has been designed to assign numbers to the amino acids occupying positions in each of these domains. Exemplary numbering systems are defined in the following literature: Kabat Sequences of Proteins of Immunological Interest (1987 and 1991, NIH, Bethesda, Maryland); and Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987); Chothia et al., Nature 342:878-883 (1989). Other numbering systems used to identify amino acids in immunoglobulin chains include IMGT® (International ImMunoGeneTics Information System; Lefranc et al., Dev. Comp. Immunol. 29:185-203; 2005) and AHo (Honegger and Pluckthun, J. Mol. Biol. 309(3):657-670; 2001).

[0086] As used herein, “antagonist anti-GIPR antibody” and “anti-GIPR antibody” refer to intact immunoglobulins of the IgG isotype that partially or completely block, inhibit, or neutralize the biological activity of GIPR proteins. The antagonist activity of the anti-GIPR antibodies disclosed herein was determined using GIPR activity assays and GIPR binding assays as defined herein.

[0087] As used herein, an "antibody fragment" is a portion of an antibody that lacks at least some of the amino acids present in the full-length chain but is capable of binding to the same epitope of the same antigen with the corresponding full-length antibody (regardless of how the portion is obtained or synthesized). Exemplary antibody fragments include, but are not limited to, Fab, Fab', and F(ab')2 fragments.

[0088] As used herein, an "Fc domain" refers to the portion of an antibody that contains the second and third constant domains (i.e., CH2 and CH3) of the heavy chain, and optionally includes a CH4 domain. The Fc domain may be an Fc domain derived from IgG1, IgG2, IgG3, or IgG4 immunoglobulins. In some embodiments, the Fc region contains CH2 and CH3 domains derived from human IgG1 or human IgG2 immunoglobulins. The Fc region may retain effector functions such as C1q binding, complement-dependent cytotoxicity (CDC), Fc receptor binding, antibody-dependent cell-mediated cytotoxicity (ADCC), and phagocytosis. In other embodiments, the Fc region may be modified to reduce or eliminate effector functions. "An Fc-containing polypeptide" refers to a polypeptide that contains an Fc domain as defined herein.

[0089] As used herein, the terms “GLP-1 receptor agonist” and “GLP-1 receptor agonist peptide” are used interchangeably and refer to molecules that mimic the biological activity of naturally occurring glucagon-like peptide (GLP-1) molecules relative to the GLP-1 receptor.

[0090] As used herein, the term “pharmaceutical acceptable” means a substance or component that is generally safe, non-toxic, and biologically and otherwise not intended for use in subjects.

[0091] As used herein, the term "pharmaceuticalally acceptable excipient" refers to a broad range of ingredients that can be combined with the polypeptide or conjugate molecules disclosed herein to prepare pharmaceutically acceptable compositions or formulations. Excipients include, for example, mediators (e.g., solvents, dispersion media), coating agents, isotonic agents and absorption delay agents, diluents, colorants, flow aids, disintegrants, flavoring agents, coating agents, binders, sweeteners, lubricants, adsorbents, and preservatives (e.g., antibacterial and antifungal agents).

[0092] As used herein, the term "therapeuticly effective amount" refers to the amount of a polypeptide or conjugate molecule disclosed herein that elicits the desired biological or medical response in cells, tissues, systems, or subjects. The desired biological or medical response may not occur with a single dose and may only occur after a series of doses. Therefore, a therapeutically effective amount can be administered in one or more doses.

[0093] As used herein, the term "subject" refers to humans and other mammals. As used herein, the term "mammal" includes, for example, humans, non-human primates, cattle, sheep, goats, pigs, horses, cats, dogs, rabbits, rodents (e.g., rats or mice), and monkeys. Human subjects include newborns, infants, adolescents, adults, and elderly subjects. In one embodiment, the subject is a human. In one embodiment, the subject is an adult.

[0094] It should be understood that the present invention is not limited to the specific methods, schemes, and reagents described herein, and therefore can be varied. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of this disclosure, which is defined only by the claims.

[0095] GLP-1 receptor agonist peptide This disclosure relates to GLP-1 receptor agonist peptides and molecules comprising such GLP-1 receptor agonist peptides, such as protein conjugates. These GLP-1 receptor agonist peptides, also referred herein as GLP-1 receptor agonists and GLP-1R agonist peptides, encompass molecules that mimic one or more biological activities exhibited by natural human GLP-1 peptides upon binding to the human GLP-1 receptor. Furthermore, these GLP-1 receptor agonist peptides possess one or more advantageous properties relative to natural GLP-1 protein and / or other GLP-1 receptor agonist peptides known in the art.

[0096] The natural human GLP-1 peptide is produced from proglucagon via post-translational processing in intestinal cells. Cleavage of proglucagon by PCSK1 / PC1 yields a peptide containing residues 71-108 of proglucagon or a C-terminal amidated form containing residues 71-107 of an amide. Further N-terminal truncation of this proglucagon-derived peptide fragment is required within intestinal cells to form the active GLP-1 peptide. Therefore, the active human GLP-1 peptide (referred to as GLP-1(7-37)) contains the amino acid sequence HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG (SEQ ID NO: 1584). The C-terminal amidated version of this peptide is referred to as GLP-1(7-36)amide.

[0097] In one embodiment of this disclosure, the GLP-1 receptor agonist peptide is an analog of the natural human GLP-1 (7-37) peptide, specifically an analog of the amino acid sequence of SEQ ID NO: 1584. As used herein, “GLP-1 analog” refers to a molecule that, when evaluated by a GLP-1 receptor agonist activity assay as described in Example 3 herein or using other methods known in the art (e.g., receptor binding assays or in vivo blood glucose assays, such as those described, for example, by Hargrove et al., Regulatory Peptides, 141:113-119 (2007) (the disclosure of which is incorporated herein by reference)), exhibits improved biological activity (e.g., improved stability or agonist potency) relative to the corresponding biological activity of GLP-1 (7-37). In one embodiment, a GLP-1 analog refers to a peptide that, compared to the amino acid sequence of GLP-1 (7-37), contains an amino acid sequence having at least 4, 5, 6, 7, 8, or 9 amino acid substitutions, insertions, or deletions (or combinations of two or more substitutions, insertions, or deletions). In one embodiment, the GLP-1 analog disclosed herein contains an amino acid sequence having 5, 6, 7, 8, or 9 amino acid substitutions, insertions, or deletions (or combinations of two or more substitutions, insertions, or deletions) compared to the amino acid sequence of GLP-1 (7-37) (SEQ ID NO: 1584). In one embodiment, the GLP-1 analog disclosed herein contains an amino acid sequence having 5, 6, 7, 8, or 9 amino acid substitutions in the amino acid sequence of the GLP-1 (7-37) polypeptide of SEQ ID NO: 1584. In one embodiment, the 5, 6, 7, 8, or 9 amino acid substitutions comprise substitutions at any 5 or more positions of A2, V10, G16, Q17, K20, A24, V27, K28, and R30 of the GLP-1 (7-37) peptide selected from SEQ ID NO: 1584. In one embodiment, the GLP-1 analog comprises substitutions at A2, V10, G16, and R30, and one or more additional amino acid substitutions at residues selected from Q17, K20, A24, V27, and K28 of SEQ ID NO: 1584. In one embodiment, the GLP-1 analog comprises substitutions at A2, V10, G16, and R30, and two additional amino acid substitutions at residues selected from Q17, K20, A24, V27, and K28 of SEQ ID NO: 1584. In one embodiment, the GLP-1 analog comprises substitutions at A2, V10, G16, and R30, and three additional amino acid substitutions at residues selected from Q17, K20, A24, V27, and K28 of SEQ ID NO: 1584.In one embodiment, the GLP-1 analog comprises substitutions at A2, V10, G16, and R30, and four additional amino acid substitutions at residues selected from Q17, K20, A24, V27, and K28 of SEQ ID NO: 1584. In another embodiment, the GLP-1 analog comprises substitutions at A2, V10, G16, R30, Q17, K20, A24, V27, and K28 of the GLP-1 (7-37) peptide of SEQ ID NO: 1584. The GLP-1 analogs disclosed herein include any of the aforementioned analogs in an amidated form, an acidic form, a pharmaceutically acceptable salt form, and any other physiologically active form of the molecule.

[0098] In one embodiment, the GLP-1 receptor agonist peptide disclosed herein comprises H[Aib]EGTFTSDYSSYLEEX 17 AAX 20 EFIX 24 WLX 27 X 28 The amino acid sequence of GGG (SEQ ID NO: 1575), wherein Aib at position 2 is α-amino-isobutyric acid; X 17 Selected from glutamine (Q), lysine (K), glutamic acid (E), or arginine (R), X 20 Selected from K, R, Q or high arginine (hArg), X 24 Selected from alanine (A), E, ​​Q, aspartic acid (D), d-Ala, glycine (G), asparagine (N), K, (1S,2S)-2-aminocyclopentanecarboxylic acid (ACPC), (3S,4R)-4-amino-3-pyrrolidinecarboxylic acid (APCA), threonine (T), serine (S), or tyrosine (Y); X 27 Selected from valine (V), K, α-amino-isobutyric acid (Aib), N, S, T, Y, Q, or R; and X 28 Selected from K, E, R, Q, D, N, G, S, or T. According to this embodiment and all embodiments disclosed herein, the GLP-1 receptor agonist disclosed herein does not contain the amino acid sequence of SEQ ID NO: 1574 (H[Aib]EGTFTSDYSSYLEEQAAKEFIAWLVKGGG).

[0099] In one embodiment, the GLP-1 receptor agonist peptide disclosed herein comprises H[Aib]EGTFTSDYSSYLEEX 17 AAX 20 EFIX 24 WLX 27 X 28The amino acid sequence of GGG (SEQ ID NO: 1576), where X 17 Is it Q or K; X 20 It is K or R; X 24 It is A, E, or Q; X 27 It is V or K; and X 28 It is K, E, or R. As stated above, the GLP-1 receptor agonist disclosed herein does not contain the amino acid sequence of SEQ ID NO: 1574.

[0100] In one embodiment, the GLP-1 receptor agonist peptide disclosed herein comprises the amino acid sequence H[Aib]EGTFTSDYSSYLEEX 17 AAREFIX 24 WLX 27 X 28 GGG (SEQ ID NO: 1577), where X 17 Is it Q or K; X 24 It is A, E, or Q; X 27 It is V or K; and X 28 It is K, E, or R. Alternatively, the GLP-1 receptor agonist disclosed herein comprises H[Aib]EGTFTSDYSSYLEEX 17 AAX 20 EFIX 24 WLKX 28 The amino acid sequence of GGG (SEQ ID NO: 1578), where X 17 Is it Q or K; X 20 It is K or R; X 24 It is A, E, or Q; and X 28 It is K, E, or R.

[0101] Non-limiting examples of GLP-1 receptor agonists disclosed herein are given in Table 1 below. The explanatory columns of Table 1 provide the amino acid substitutions present at specified positions in the specific GLP-1 receptor agonist polypeptide sequences (relative to GLP-1(7-37)).

[0102] Table 1. GLP-1 receptor agonist peptide sequences Aib is α-amino-isobutyric acid. In one embodiment, the human glucagon-like peptide-1 (GLP-1) receptor agonist polypeptide disclosed herein comprises 31 amino acids, including an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 1580. The GLP-1 receptor agonist polypeptide further comprises α-amino-isobutyric acid (Aib) at position 2; tyrosine at position 10; glutamic acid at positions 16, 24, and 28; arginine at position 20; lysine at positions 17 and 27; and glycine at position 30. In one embodiment, the GLP-1 receptor agonist polypeptide comprises an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 1580. In another embodiment, the GLP-1 receptor agonist polypeptide comprises an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 1580. In one embodiment, the GLP-1 receptor agonist peptide comprises the amino acid sequence of SEQ ID NO: 1580.

[0103] In one embodiment, the human glucagon-like peptide-1 (GLP-1) receptor agonist polypeptide disclosed herein comprises 31 amino acids, and includes an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 1579. The GLP-1 receptor agonist polypeptide further comprises Aib at position 2; tyrosine at position 10; glutamic acid at positions 16 and 24; arginine at position 20; lysine at position 27; and glycine at position 30. In one embodiment, the GLP-1 receptor agonist polypeptide comprises an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 1579. In one embodiment, the GLP-1 receptor agonist polypeptide comprises an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 1579. In one embodiment, the GLP-1 receptor agonist polypeptide comprises the amino acid sequence of SEQ ID NO: 1579.

[0104] In one embodiment, the human glucagon-like peptide-1 (GLP-1) receptor agonist polypeptide disclosed herein comprises 31 amino acids, including an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 1581. The GLP-1 receptor agonist polypeptide further comprises Aib at position 2; tyrosine at position 10; glutamic acid at positions 16 and 24; arginine at position 20; lysine at positions 17 and 27; and glycine at position 30. In one embodiment, the GLP-1 receptor agonist polypeptide comprises an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 1581. In one embodiment, the GLP-1 receptor agonist polypeptide comprises an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 1581. In one embodiment, the GLP-1 receptor agonist polypeptide comprises the amino acid sequence of SEQ ID NO: 1581.

[0105] In one embodiment, the human glucagon-like peptide-1 (GLP-1) receptor agonist polypeptide disclosed herein comprises 31 amino acids, including an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 1583. The GLP-1 receptor agonist polypeptide further comprises Aib at position 2; tyrosine at position 10; glutamic acid at positions 16 and 28; arginine at position 20; lysine at positions 17 and 27; glutamine at position 24; and glycine at position 30. In one embodiment, the GLP-1 receptor agonist polypeptide comprises an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 1583. In another embodiment, the GLP-1 receptor agonist polypeptide comprises an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 1583. In one embodiment, the GLP-1 receptor agonist peptide comprises the amino acid sequence of SEQ ID NO: 1583.

[0106] In one embodiment, the human glucagon-like peptide-1 (GLP-1) receptor agonist polypeptide disclosed herein comprises 31 amino acids, including an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 1582. The GLP-1 receptor agonist polypeptide further comprises Aib at position 2; tyrosine at position 10; glutamic acid at positions 16 and 24; arginine at positions 20 and 28; lysine at position 27; and glycine at position 30. In one embodiment, the GLP-1 receptor agonist polypeptide comprises an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 1582. In one embodiment, the GLP-1 receptor agonist polypeptide comprises an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 1582. In one embodiment, the GLP-1 receptor agonist polypeptide comprises the amino acid sequence of SEQ ID NO: 1582.

[0107] In one embodiment, the GLP-1 receptor agonist comprises the amino acid sequence of SEQ ID NO: 1579. In one embodiment, the GLP-1 receptor agonist comprises the amino acid sequence of SEQ ID NO: 1580. In one embodiment, the GLP-1 receptor agonist comprises the amino acid sequence of SEQ ID NO: 1581. In one embodiment, the GLP-1 receptor agonist comprises the amino acid sequence of SEQ ID NO: 1582. In one embodiment, the GLP-1 receptor agonist comprises the amino acid sequence of SEQ ID NO: 1583.

[0108] In one embodiment, a GLP-1 receptor agonist activates the human GLP-1 receptor. In another embodiment, a GLP-1 receptor agonist peptide activates the ECGs of the human GLP-1 receptor. 50 Less than or equal to 50 pM, as measured using the GLP-1 receptor agonist activity assay described in Example 3 of this document. For example, the EC50 of a GLP-1 receptor agonist peptide. 50 Less than or equal to 45 pM, less than or equal to 40 pM, less than or equal to 35 pM, less than or equal to 30 pM, less than or equal to 25 pM, less than or equal to 20 pM, less than or equal to 15 pM. In one embodiment, GLP-1 EC 50 It was measured in the GLP-1 receptor agonist activity assay described in Example 3 of this article.

[0109] In one embodiment, a GLP-1 receptor agonist peptide activates the EC50 of the human GLP-1 receptor.50 The value is approximately 10 pM, as measured using the GLP-1 receptor agonist activity assay described in Example 3 of this document. In one embodiment, the GLP-1 receptor agonist peptide activates the EC50 of the human GLP-1 receptor. 50 The values ​​were approximately 15 pM, approximately 20 pM, approximately 25 pM, approximately 30 pM, approximately 35 pM, approximately 40 pM, approximately 45 pM, approximately 50 pM, approximately 55 pM, approximately 60 pM, approximately 65 pM, approximately 70 pM, and approximately 75 pM, as measured using the GLP-1 receptor agonist activity assay described in Example 3 of this document.

[0110] In one embodiment, the GLP-1 receptor agonist disclosed herein is chemically derivatized at one or more amino acid residues using known organic chemistry techniques. According to this embodiment and all embodiments of this disclosure, "chemical derivative" or "chemically derived" refers to a peptide (e.g., a peptide linker as described herein), polypeptide (e.g., a GLP-1 receptor agonist polypeptide), or other protein (e.g., an anti-GIPR antibody as described herein) having one or more residues chemically derived via a reaction of a functional side group. For example, such derived molecules include those in which the free amino group has been derivatized to form an amine hydrochloride, p-toluenesulfonyl, benzyloxycarbonyl, tert-butoxycarbonyl, chloroacetyl, or formyl group. The free carboxyl group can be derivatized to form a salt, methyl ester, ethyl ester, or other types of ester or hydrazide. The free hydroxyl group can be derivatized to form an O-acyl or O-alkyl derivative. The imidazole nitrogen of histidine can be derivatized to form N-im-benzylhistidine. Also included as chemical derivatives are polypeptides containing one or more naturally occurring amino acid derivatives of the twenty standard amino acids (whether in L- or D-form). For example, 4-hydroxyproline can replace proline; 5-hydroxylysine can replace lysine; 3-methylhistidine can replace histidine; homoserine can replace serine; and ornithine can replace lysine.

[0111] In one embodiment, useful derivatization includes derivatization in which the amino terminus of the peptide is chemically blocked, thereby preventing conjugation with Fc-containing peptides or antibodies at the free amino group at the N-terminus of the GLP-1 receptor agonist peptide. Such modification may have other beneficial effects, such as reducing the sensitivity of the peptide agonist to enzymatic proteolysis. The N-terminus may be acylated or modified to a substituted amine, or derivatized with another functional group, such as an aromatic moiety (e.g., indoleic acid, benzyl (Bzl or Bn), dibenzyl (DiBzl or Bn2), or benzyloxycarbonyl (Cbz or Z)), N,N-dimethylglycine, or creatine. For example, in one embodiment, an acyl moiety (e.g., but not limited to formyl, acetyl (Ac), propionyl, butyryl, heptayl, hexanoyl, octanoyl, or nonanoyl) is covalently linked to the N-terminus of the peptide, which can prevent undesirable side reactions during the conjugation of the peptide with Fc-containing peptides or antibodies. Other exemplary N-terminal derivative groups include -NRR1 (other than -NH2), -NRC(O)R1, -NRC(O)OR1, -NRS(O)2R1, -NHC(O)NH1, succinimide, or benzyloxycarbonyl-NH—(Cbz-NH—), wherein R and R1 are each independently hydrogen or a lower alkyl group, and wherein the benzene ring may be substituted by one to three substituents selected from C1-C4 alkyl, C1-C4 alkoxy, chlorine, and bromine.

[0112] In one embodiment, one or more individual amino acid residues of the GLP-1 receptor agonist peptide as described herein are derivatized. Various derivatizing agents are known to react specifically with selected side chain or terminal residues, as detailed in the examples below.

[0113] The lysine residues and amino-terminal residues of the GLP-1 receptor agonist peptides described herein can react with succinic anhydride or other carboxylic anhydrides, reversing the charge of the lysine residues. Other suitable reagents for derivatizing α-amino residues include imine esters such as methylpyridinium imide; pyridoxal phosphate; pyridoxal; chlorine borohydride; trinitrobenzenesulfonic acid; O-methylisourea; 2,4-pentanedione; and transaminase-catalyzed reactions with glyoxylates.

[0114] Arginyl residues can be modified by reacting with any one or a combination of several common reagents, including benzoylformaldehyde, 2,3-butanedione, 1,2-cyclohexanedione, and ninhydrin. Due to the high pKa of the guanidine functional group, the derivatization of arginyl residues requires the reaction to be carried out under basic conditions. Furthermore, these reagents can react with lysine groups as well as arginine ε-amino groups.

[0115] Specific modifications of tyrosine residues have been extensively studied, with particular interest in introducing spectral labeling into tyrosine residues through reactions with aromatic diazo compounds or tetranitromethane. Most commonly, N-acetylimidazolium and tetranitromethane are used to form O-acetyltyrosine compounds and 3-nitro derivatives, respectively.

[0116] The carboxyl side chain groups (aspartic or glutamic) of the GLP-1 receptor agonist peptide described herein can be selectively modified by reacting with carbodiimides (R′—N═C═N—R′) (e.g., 1-cyclohexyl-3-(2-morpholino-(4-ethyl)carbodiimide or 1-ethyl-3-(4-azainium-4,4-dimethylpentyl)carbodiimide). Furthermore, the aspartic and glutamic residues can be converted to asparagyl and glutamicyl residues by reacting with ammonium ions.

[0117] Glutamine acyl and asparagine acyl residues can be deamidated to the corresponding glutamine acyl and asparagine acyl residues. Alternatively, these residues undergo deamidation under weakly acidic conditions.

[0118] Cysteine ​​residues can be replaced with amino acid residues or other parts to eliminate disulfide bonds, or conversely, they can be used to stabilize crosslinks.

[0119] In one embodiment, one or more peptide [—C(O)NR—] links (bonds) between amino acid residues of the GLP-1 receptor agonist peptide are replaced by non-peptide links. Exemplary non-peptide links are —CH2-carbamate [—CH2—OC(O)NR—], phosphonate, —CH2-sulfonamide [—CH2—S(O)2NR—], urea [—NHC(O)NH—], —CH2-secondary amine, and alkylated peptide [—C(O)NR6—, where R6 is a lower alkyl group].

[0120] Other possible modifications to GLP-1 receptor agonist peptides include hydroxylation of proline and lysine, phosphorylation of the hydroxyl groups of serine or threonine residues, oxidation of the sulfur atom in Cys, and methylation of the α-amino groups of the lysine, arginine, and histidine side chains.

[0121] Conjugate molecules containing GLP-1 receptor agonist peptides Another aspect of this disclosure relates to molecules comprising the GLP-1 receptor agonist peptide as described above.

[0122] In one embodiment, the molecule comprises a first GLP-1 receptor agonist peptide, wherein the first GLP-1 receptor agonist peptide is conjugated to a half-life extension domain. The half-life extension domain may be conjugated directly to the GLP-1 receptor agonist peptide or conjugated via a linker portion.

[0123] In one embodiment, the half-life extension domain is a peptide (e.g., an antibody, antibody fragment, or peptide) that alters the pharmacodynamics and pharmacokinetics of a GLP-1 receptor agonist peptide relative to an unconjugated peptide. For example, in one embodiment, the half-life extension domain extends the elimination half-life relative to an unconjugated peptide. Additionally, in one embodiment, the half-life extension domain alters one or more pharmacodynamic properties of the peptide, such as tissue distribution, penetration, or diffusion.

[0124] In one embodiment, the extended half-life domain is a molecule that specifically binds to circulating plasma proteins.

[0125] In one embodiment, the extended half-life domain is a molecule that specifically binds to albumin. In another embodiment, the extended half-life domain is a polypeptide (e.g., an antibody, antibody fragment, or peptide) that specifically binds to albumin.

[0126] In one embodiment, the extended half-life domain is a molecule that specifically binds to human serum albumin (HSA). In another embodiment, the extended half-life domain is a polypeptide (e.g., an antibody, antibody fragment, or peptide) that specifically binds to HSA.

[0127] In one embodiment, the extended half-life domain is an HSA or a variant thereof.

[0128] In one embodiment, the extended half-life domain is a molecule that specifically binds to the neonatal Fc receptor (FcRn). In another embodiment, the extended half-life domain is a polypeptide (e.g., an antibody, antibody fragment, or peptide) that specifically binds to FcRn.

[0129] In one embodiment, the extended half-life domain is the Fc domain.

[0130] In one embodiment, the half-life extension domain is an Fc-containing polypeptide. In one embodiment, the half-life extension domain is an antibody. In one embodiment, the half-life extension domain is an antibody fragment.

[0131] In one embodiment, the half-life extension domain is an antibody.

[0132] Another aspect of this disclosure relates to a conjugate molecule comprising the GLP-1 receptor agonist peptide disclosed herein and an antagonist antibody against glucose-dependent insulinotropic peptide receptor (GIPR). In one embodiment, the conjugate molecule comprises a first GLP-1 receptor agonist peptide comprising H[Aib]EGTFTSDYSSYLEEX 17 AAX 20 EFIX 24 WLX 27 X 28The amino acid sequence of GGG (SEQ ID NO: 1575), where X 17 It is Q, K, E, or R; X 20 It is K, R, Q or high in arginine (hArg); X 24 It is A, E, Q, D, d-Ala, G, N, K, (1S,2S)-2-aminocyclopentanecarboxylic acid (ACPC), (3S,4R)-4-amino-3-pyrrolidinecarboxylic acid (APCA), T, S, or Y; X 27 It is V, K, Aib, N, S, T, Y, Q, or R; and X 28 It is K, E, R, Q, D, N, G, S or T, and wherein the GLP-1 receptor agonist polypeptide does not contain the amino acid sequence of SEQ ID NO: 1574; and the antagonist anti-GIPR human antibody.

[0133] The exemplary molecule disclosed herein comprises a first GLP-1 receptor agonist polypeptide conjugated to an antagonist anti-GIPR human antibody. This molecule is referred herein as an “anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule,” “conjugate molecule,” or “anti-GIPR / GLP-1 conjugate molecule.” An exemplary antagonist anti-GIPR antibody is disclosed below.

[0134] According to this embodiment of the disclosure, the antagonist anti-GIPR antibody of the anti-GIPR / GLP-1 conjugate molecule contains a first cysteine ​​conjugate site located within the light or heavy chain of the anti-GIPR antibody. The first GLP-1 receptor agonist polypeptide of the molecule is conjugated at its C-terminus to the first cysteine ​​conjugate site of the anti-GIPR antibody.

[0135] In one embodiment, the anti-GIPR / GLP-1 conjugate molecule further comprises a second GLP-1 receptor agonist polypeptide. The second GLP-1 receptor agonist polypeptide is conjugated at its C-terminus to a second cysteine ​​conjugate site of the anti-GIPR antibody. The second cysteine ​​conjugate site of the anti-GIPR antibody is also located within the light or heavy chain of the anti-GIPR antibody. Preferably, the first and second cysteine ​​conjugate sites of the anti-GIPR antibody are located at corresponding positions within each light chain or each heavy chain.

[0136] In one embodiment, the first GLP-1 receptor agonist peptide and the second GLP-1 receptor agonist peptide conjugated to the anti-GIPR antibody in the conjugate molecule contain the same amino acid sequence. In another embodiment, the first GLP-1 receptor agonist peptide and the second GLP-1 receptor agonist peptide in the conjugate molecule contain different amino acid sequences.

[0137] In one embodiment, the first GLP-1 receptor agonist polypeptide and / or the second GLP-1 receptor agonist polypeptide of the anti-GIPR / GLP-1 receptor agonist conjugate molecule (or any conjugate molecule disclosed herein) comprises H[Aib]EGTFTSDYSSYLEEX 17 AAX 20 EFIX 24 WLX 27 X 28 The amino acid sequence of GGG (SEQ ID NO: 1575), wherein Aib at position 2 is α-amino-isobutyric acid; X 17 Selected from glutamine (Q), lysine (K), glutamic acid (E), or arginine (R), X 20 Selected from K, R, Q or high arginine (hArg), X 24 Selected from alanine (A), E, ​​Q, aspartic acid (D), d-Ala, glycine (G), asparagine (N), K, (1S,2S)-2-aminocyclopentanecarboxylic acid (ACPC), (3S,4R)-4-amino-3-pyrrolidinecarboxylic acid (APCA), threonine (T), serine (S), or tyrosine (Y); X 27 Selected from valine (V), K, α-amino-isobutyric acid (Aib), N, S, T, Y, Q, R; and X 28 Selected from K, E, R, Q, D, N, G, S, T. According to this embodiment and all embodiments disclosed herein, the GLP-1 receptor agonist of the anti-GIPR / GLP-1 conjugate molecule disclosed herein does not contain the amino acid sequence of SEQ ID NO: 1574 (H[Aib]EGTFTSDYSSYLEEQAAKEFIAWLVKGGG).

[0138] In one embodiment, the incorporation of amino acid substitutions at designated locations, particularly residues 17, 20, 24, 27, and 28 (SEQ ID NO: 1575), improves the in vivo stability of the conjugate molecule. For example, the designated amino acid substitutions make the GLP-1 peptide less susceptible to cleavage from the conjugate in vivo, as indicated by the AUC of the intact GIPR-GLP-1 molecule versus the total GIPR-GLP-1 molecule. 0-t The efficacy is measured by a high ratio (≥ 0.65) (see Example 5). In one embodiment, the incorporation of amino acid substitutions at designated sites on the GLP-1 receptor agonist peptide, particularly at sites 17, 20, 24, 27, and 28, improves the potency of the conjugate molecule. For example, designated amino acid substitutions give the conjugate molecule greater therapeutic potency, as measured by weight loss after in vivo administration (see Example 4).

[0139] In one embodiment, the first GLP-1 receptor agonist peptide and / or the second GLP-1 receptor agonist peptide of the anti-GIPR / GLP-1 receptor agonist conjugate molecule comprise H[Aib]EGTFTSDYSSYLEEX 17 AAX 20 EFIX 24 WLX 27 X 28 The amino acid sequence of GGG (SEQ ID NO: 1576), where X 17 Is it Q or K; X 20 It is K or R; X 24 It is A, E, or Q; X 27 It is V or K; and X 28 It is K, E, or R. As mentioned above, the GLP-1 receptor agonist in the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule does not contain the amino acid sequence of SEQ ID NO: 1574.

[0140] In one embodiment, the first GLP-1 receptor agonist peptide and / or the second GLP-1 receptor agonist peptide of the anti-GIPR / GLP-1 receptor agonist conjugate molecule comprise H[Aib]EGTFTSDYSSYLEEX 17 AAREFIX 24 WLX 27 X 28 The amino acid sequence of GGG (SEQ ID NO: 1577), where X 17 Is it Q or K; X 24 It is A, E, or Q; X 27 It is V or K; and X 28 It is K, E, or R. Alternatively, the first and / or second GLP-1 receptor agonist of the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule contains H[Aib]EGTFTSDYSSYLEEX 17 AAX 20 EFIX 24 WLKX 28 The amino acid sequence of GGG (SEQ ID NO: 1578), where X 17 Is it Q or K; X 20 It is K or R; X 24 It is A, E, or Q; and X 28 It is K, E, or R.

[0141] In one embodiment, the first GLP-1 receptor agonist polypeptide and / or the second GLP-1 receptor agonist polypeptide of the conjugate molecule comprises 31 amino acids, and includes an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 1580. The GLP-1 receptor agonist polypeptide further comprises Aib at position 2; tyrosine at position 10; glutamic acid at positions 16, 24, and 28; arginine at position 20; lysine at positions 17 and 27; and glycine at position 30. In one embodiment, the first GLP-1 receptor agonist polypeptide and / or the second GLP-1 receptor agonist polypeptide comprises an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 1580. In one embodiment, the first GLP-1 receptor agonist peptide and / or the second GLP-1 receptor agonist peptide of the conjugate molecule comprises an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 1580. In one embodiment, the first GLP-1 receptor agonist and / or the second GLP-1 receptor agonist of the anti-GIPR / GLP-1 conjugate molecule comprises the amino acid sequence of SEQ ID NO: 1580.

[0142] In one embodiment, the first GLP-1 receptor agonist polypeptide and / or the second GLP-1 receptor agonist polypeptide of the conjugate molecule comprises 31 amino acids, and includes an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 1579. The GLP-1 receptor agonist polypeptide further comprises Aib at position 2; tyrosine at position 10; glutamic acid at positions 16 and 24; arginine at position 20; lysine at position 27; and glycine at position 30. In one embodiment, the first GLP-1 receptor agonist polypeptide and / or the second GLP-1 receptor agonist polypeptide comprises an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 1579. In one embodiment, the first GLP-1 receptor agonist polypeptide and / or the second GLP-1 receptor agonist polypeptide comprises an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 1579. In one embodiment, the first GLP-1 receptor agonist and / or the second GLP-1 receptor agonist of the anti-GIPR / GLP-1 conjugate molecule comprises the amino acid sequence of SEQ ID NO: 1579.

[0143] In one embodiment, the first GLP-1 receptor agonist polypeptide and / or the second GLP-1 receptor agonist polypeptide of the conjugate molecule comprises 31 amino acids, and includes an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 1581. The first GLP-1 receptor agonist polypeptide and / or the second GLP-1 receptor agonist polypeptide further comprises Aib at position 2; tyrosine at position 10; glutamic acid at positions 16 and 24; arginine at position 20; lysine at positions 17 and 27; and glycine at position 30. In one embodiment, the first GLP-1 receptor agonist polypeptide and / or the second GLP-1 receptor agonist polypeptide comprises an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 1581. In one embodiment, the first GLP-1 receptor agonist peptide and / or the second GLP-1 receptor agonist peptide comprises an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 1581. In one embodiment, the first GLP-1 receptor agonist and / or the second GLP-1 receptor agonist of the anti-GIPR / GLP-1 conjugate molecule comprises the amino acid sequence of SEQ ID NO: 1581.

[0144] In one embodiment, the first GLP-1 receptor agonist polypeptide and / or the second GLP-1 receptor agonist polypeptide of the conjugate molecule comprises 31 amino acids, and includes an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 1583. The GLP-1 receptor agonist polypeptide further comprises Aib at position 2; tyrosine at position 10; glutamic acid at positions 16 and 28; arginine at position 20; lysine at positions 17 and 27; glutamine at position 24; and glycine at position 30. In one embodiment, the first GLP-1 receptor agonist polypeptide and / or the second GLP-1 receptor agonist polypeptide comprises an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 1583. In one embodiment, the first GLP-1 receptor agonist peptide and / or the second GLP-1 receptor agonist peptide comprises an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 1583. In one embodiment, the first GLP-1 receptor agonist and / or the second GLP-1 receptor agonist of the anti-GIPR / GLP-1 conjugate molecule comprises the amino acid sequence of SEQ ID NO: 1583.

[0145] In one embodiment, the first GLP-1 receptor agonist polypeptide and / or the second GLP-1 receptor agonist polypeptide of the conjugate molecule comprises 31 amino acids, and includes an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 1582. The GLP-1 receptor agonist polypeptide further comprises Aib at position 2; tyrosine at position 10; glutamic acid at positions 16 and 24; arginine at positions 20 and 28; lysine at position 27; and glycine at position 30. In one embodiment, the first GLP-1 receptor agonist polypeptide and / or the second GLP-1 receptor agonist polypeptide comprises an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 1582. In one embodiment, the first GLP-1 receptor agonist polypeptide and / or the second GLP-1 receptor agonist polypeptide comprises an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 1582. In one embodiment, the first GLP-1 receptor agonist and / or the second GLP-1 receptor agonist of the anti-GIPR / GLP-1 conjugate molecule comprises the amino acid sequence of SEQ ID NO: 1582.

[0146] In one embodiment, the first GLP-1 receptor agonist peptide of the conjugate molecule is directly conjugated at its C-terminus to the first cysteine ​​conjugate site of the anti-GIPR antibody. In another embodiment, each of the first and second GLP-1 receptor agonist peptides of the molecule is directly conjugated at its C-terminus to the first and second cysteine ​​conjugate sites of the anti-GIPR antibody, respectively. The locations of the first and second cysteine ​​conjugate sites within the anti-GIPR antibody are described in more detail below.

[0147] In one embodiment, the first GLP-1 receptor agonist peptide of the conjugate molecule is conjugated to the first cysteine ​​conjugate site of the anti-GIPR antibody via a linker portion at its C-terminus. In another embodiment, each of the first GLP-1 receptor agonist peptide and the second GLP-1 receptor agonist peptide of the conjugate molecule is conjugated to the first cysteine ​​conjugate site and the second cysteine ​​conjugate site of the anti-GIPR antibody via a first linker portion and a second linker portion, respectively.

[0148] In one embodiment, the linker portion couples the C-terminus of a GLP-1 receptor agonist peptide to a conjugation site on an anti-GIPR antibody. The presence of any linker portion in the GLP-1 receptor agonist conjugate molecule described herein is optional. In one embodiment, the linker portion primarily serves as a spacer region to localize, connect, link, or optimize the presentation or position of functional portions of the molecule (e.g., the GLP-1 receptor agonist peptide and / or the anti-GIPR antibody). In another embodiment, the linker portion is used to optimize the pharmacological activity or stability of the GLP-1 receptor agonist-containing molecule disclosed herein. In a preferred embodiment, the linker portion of the anti-GIPR antibody / GLP-1 receptor agonist peptide conjugate molecule described herein contributes to enhanced stability of the molecule in terms of resistance to cleavage after in vivo administration.

[0149] In one embodiment, the linker portion is a peptide linker portion. The peptide linker typically consists of amino acids linked together by peptide bonds and has a length of 1 to about 40 amino acid residues, preferably 10 to about 30 amino acid residues, and more preferably 10 to about 20 amino acid residues. In some embodiments, the peptide linker may contain amino acid residues, wherein one or more amino acid residues are not linked by peptide bonds (i.e., the amino acid residues of the linker are selected from twenty standard amino acids). More preferably, the amino acid residues of the linker are selected from glycine, alanine, proline, asparagine, glutamine, and / or serine. Even more preferably, the peptide linker is composed of a majority of sterically unhindered amino acids, such as glycine, serine, and alanine linked by peptide bonds. Also ideally, if present, the peptide linker should not be easily degraded by rapid proteolytic hydrolysis during cycling.

[0150] Exemplary linker portions of the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecules described herein include the linker peptides of SEQ ID NO: 1585, SEQ ID NO: 1586, SEQ ID NO: 1587, SEQ ID NO: 1588, SEQ ID NO: 1589, SEQ ID NO: 1590, SEQ ID NO: 1591, SEQ ID NO: 1592, and SEQ ID NO: 1593. Additional peptide linkers suitable for inclusion in the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecules described herein are provided in Table 2 herein.

[0151] In one embodiment, the connection between the GLP-1 receptor peptide and the peptide linker is a peptide bond between the C-terminal amino acid residue of the GLP-1 agonist peptide and the N-terminal amino acid residue of the peptide linker. In another embodiment, the connection between the GLP-1 receptor peptide and the peptide linker is an amide bond between the C-terminal amino acid residue of the GLP-1 agonist peptide and the side chain of a lysine residue on the peptide linker (i.e., at the ε-amino group of the lysine). In yet another embodiment, the connection between the GLP-1 receptor peptide and the peptide linker is an amide bond between the C-terminal amino acid residue of the GLP-1 agonist peptide and the α-amino group of a C-terminal lysine residue on the peptide linker.

[0152] In one embodiment, an exemplary adapter peptide comprises an amino acid residue sequence coupled via a standard peptide bond (e.g., the peptide adapters of SEQ ID NO: 1585-1587 and 1592-1654). In one embodiment, an exemplary adapter peptide comprises at least a non-standard peptide bond. In this embodiment, the adapter peptide comprises an amino acid residue sequence coupled via a standard peptide bond, wherein the C-terminal residue of the sequence is coupled to the ε-amino group of a lysine residue via an amide bond. For example, the exemplary adapter peptide of SEQ ID NO: 1588-1591 comprises a non-standard amino acid link at the lysine residue. In particular, for the adapter peptides of SEQ ID NO: 1588 and 1590, the glutamine residue at position 15 of these peptides is linked to the ε-amino group of an adjacent lysine residue via an amide bond. This unique link is represented in the adapter peptides provided in Table 2 by the lysine residue located outside the brackets enclosing the remainder of the adapter sequence. Similarly, for the linker peptides of SEQ ID NO: 1589 and 1591, the serine residue at position 15 of these peptides is linked to the ε-amino group of the adjacent lysine residue via an amide bond. The linking between the GLP-1 receptor peptide and the peptide linkers of SEQ ID NO: 1588, SEQ ID NO: 1589, SEQ ID NO: 1590, or SEQ ID NO: 1591 occurs via an amide bond between the C-terminal amino acid residue of the GLP-1 agonist peptide and the α-amino group of the lysine residue of the linker. In these embodiments, the N-terminal amino acid residue of the linker peptide is coupled to a cysteine ​​conjugate site on an anti-GIPR antibody residue. The N-terminal amino acid residue of the linker peptide can be modified (e.g., bromoacetylated) to facilitate coupling with the cysteine ​​conjugate site on the anti-GIPR antibody.

[0153] In one embodiment, the molecule disclosed herein comprises the GLP-1 receptor agonist polypeptide of SEQ ID NO: 1579, which is covalently linked to the adaptor peptides of SEQ ID NO: 1585, SEQ ID NO: 1586, SEQ ID NO: 1587, SEQ ID NO: 1588, SEQ ID NO: 1589, SEQ ID NO: 1590, SEQ ID NO: 1591, SEQ ID NO: 1592, or SEQ ID NO: 1593. In one embodiment, the molecule disclosed herein comprises the GLP-1 receptor agonist polypeptide of SEQ ID NO: 1579, wherein the C-terminal amino acid residue of the polypeptide is covalently linked to the N-terminal amino acid residue of the adaptor peptide of SEQ ID NO: 1592, such as... Figure 2 As depicted. In one embodiment, the C-terminal lysine of the linker peptide is modified (e.g., bromoacetylated) to couple with a cysteine ​​residue at a conjugation site on the anti-GIPR antibody.

[0154] In one embodiment, the molecule disclosed herein comprises the GLP-1 receptor agonist polypeptide of SEQ ID NO: 1580, which is covalently linked to the adaptor peptides of SEQ ID NO: 1585, SEQ ID NO: 1586, SEQ ID NO: 1587, SEQ ID NO: 1588, SEQ ID NO: 1589, SEQ ID NO: 1590, SEQ ID NO: 1591, SEQ ID NO: 1592, or SEQ ID NO: 1593. In one embodiment, the molecule disclosed herein comprises the GLP-1 receptor agonist polypeptide of SEQ ID NO: 1580, wherein the C-terminal amino acid residue of the polypeptide is covalently linked to the α-amino group of the lysine residue of the adaptor peptide of SEQ ID NO: 1591, such as... Figure 3 As depicted. As described above, the adjacent serine residue of the linker (i.e., the serine at position 15 of the linker peptide in SEQ ID NO: 1591) is linked to the ε-amino group of the lysine residue via an amide bond, as... Figure 3 As shown. In this embodiment, the N-terminal glycine residue of the linker peptide is modified (i.e., bromoacetylated) to couple with the cysteine ​​residue at the conjugation site on the anti-GIPR antibody.

[0155] In one embodiment, the molecule disclosed herein comprises the GLP-1 receptor agonist polypeptide of SEQ ID NO: 1581, which is covalently linked to the adaptor peptides of SEQ ID NO: 1585, SEQ ID NO: 1586, SEQ ID NO: 1587, SEQ ID NO: 1588, SEQ ID NO: 1589, SEQ ID NO: 1590, SEQ ID NO: 1591, SEQ ID NO: 1592, or SEQ ID NO: 1593. In one embodiment, the molecule disclosed herein comprises the GLP-1 receptor agonist polypeptide of SEQ ID NO: 1581, wherein the C-terminal amino acid residue of the polypeptide is covalently linked to the N-terminal amino acid residue of the adaptor peptide of SEQ ID NO: 1585, such as... Figure 4 As depicted. In one embodiment, the C-terminal lysine of the linker peptide is modified (e.g., bromoacetylated), as... Figure 4 As shown, it is coupled to cysteine ​​residues at the conjugation site on the anti-GIPR antibody.

[0156] In one embodiment, the molecule disclosed herein comprises the GLP-1 receptor agonist peptide of SEQ ID NO: 1581, wherein the C-terminal amino acid residue of the peptide is covalently linked to the N-terminal amino acid residue of the linker peptide of SEQ ID NO: 1586, as follows: Figure 5 As depicted. In one embodiment, the C-terminal lysine of the linker peptide is modified (e.g., bromoacetylated), as... Figure 5 As shown, it is coupled to cysteine ​​residues at the conjugation site on the anti-GIPR antibody.

[0157] In one embodiment, the molecule disclosed herein comprises the GLP-1 receptor agonist peptide of SEQ ID NO: 1581, wherein the C-terminal amino acid residue of the peptide is covalently linked to the N-terminal amino acid residue of the linker peptide of SEQ ID NO: 1593, as follows: Figure 6 As depicted. In one embodiment, the C-terminal lysine of the linker peptide is modified on the side chain (e.g., bromoacetylated), as shown. Figure 6 As shown, it is coupled to cysteine ​​residues at the conjugation site on the anti-GIPR antibody.

[0158] In one embodiment, the molecule disclosed herein comprises the GLP-1 receptor agonist peptide of SEQ ID NO: 1582, which is covalently linked to the adaptor peptide of SEQ ID NO: 1585, SEQ ID NO: 1586, SEQ ID NO: 1587, SEQ ID NO: 1588, SEQ ID NO: 1589, SEQ ID NO: 1590, SEQ ID NO: 1591, SEQ ID NO: 1592, or SEQ ID NO: 1593.

[0159] In one embodiment, the molecule disclosed herein comprises a GLP-1 receptor agonist peptide of SEQ ID NO: 1583, which is covalently linked to a adaptor peptide of SEQ ID NO: 1585, SEQ ID NO: 1586, SEQ ID NO: 1587, SEQ ID NO: 1588, SEQ ID NO: 1589, SEQ ID NO: 1590, SEQ ID NO: 1591, SEQ ID NO: 1592, or SEQ ID NO: 1593.

[0160] Other peptide linkers applicable to molecules contained in this article are provided in Table 2.

[0161] Table 2. Linker peptide sequences In one embodiment, the connector portion (if present) is a non-peptide connector portion. A non-limiting category of suitable non-peptide connectors is polyethylene glycol (PEG) connectors, such as, Wherein n causes the linker to have a molecular weight of about 100 Daltons (Da) to about 5000 Da, preferably about 100 Da to about 500 Da. Further non-peptide linker moieties suitable for incorporation into molecules containing GLP-1 agonist peptides are disclosed below. In one embodiment, the PEG linker is a PEG20 linker comprising K-(G-PEG20), K-(PEG20), or (G-PEG20)-K.

[0162] In one embodiment, the molecule disclosed herein comprises the GLP-1 receptor agonist peptide of SEQ ID NO: 1581, which is covalently linked to the α-amino group of a lysine residue of a PEG20 linker (G-PEG20)-K, such as Figure 7 As shown. At the other end of the PEG20 molecule are brominated glycine residues that promote conjugation to cysteine ​​conjugation sites on the anti-GIPR antibody.

[0163] In one embodiment, the molecule disclosed herein comprises the GLP-1 receptor agonist peptide of SEQ ID NO: 1582, which is covalently linked to the α-amino group of a lysine residue of a PEG20 linker (G-PEG20)-K, such as Figure 8 As shown. At the other end of the PEG20 molecule are brominated glycine residues that promote conjugation to cysteine ​​conjugation sites on the anti-GIPR antibody.

[0164] In one embodiment, the molecule disclosed herein comprises the GLP-1 receptor agonist peptide of SEQ ID NO: 1583, which is covalently linked to the α-amino group of a lysine residue of a PEG20 linker (G-PEG20)-K, such as Figure 9 As shown. At the other end of the PEG20 molecule are brominated glycine residues that promote conjugation to cysteine ​​conjugation sites on the anti-GIPR antibody.

[0165] Additional non-peptide linker moieties suitable for incorporation into molecules containing GLP-1 agonist peptides include alkyl linkers, such as -NH-(CH2). s -C(O), where s = 2-20. These alkyl links can be further substituted with any sterically unhindered group, such as lower alkyl groups (e.g., C1-C6), lower acyl groups, halogens (e.g., Cl, Br), CN, NH2, phenyl, etc.

[0166] Other suitable non-peptide linkers comprise a length-controlled rigid polyhedrally core. Such linkers can be chemically differentiated at either end to accommodate orthogonal coupling chemistry (i.e., azide "click", amide coupling, thioether formation via alkylation with maleimide or haloacetamide, oxime formation, reductive amination, etc.).

[0167] Non-peptide linkers can be synthesized through conventional organic chemical reactions.

[0168] The above is merely illustrative and not an exhaustive list of non-peptide connector types that may be optionally used under this disclosure.

[0169] In one embodiment, the antagonist anti-GIPR antibody of the conjugate molecule disclosed herein comprises at least one conjugate site. In one embodiment, the anti-GIPR antibody of the conjugate molecule disclosed herein comprises at least two conjugate sites (e.g., a first conjugate site and a second conjugate site). One or more conjugate sites of the anti-GIPR antibody are suitable for conjugation with the GLP-1 receptor agonist peptide disclosed herein via a defined conjugate chemistry, through the side chain of an amino acid residue at the conjugate site. The GLP-1 receptor agonist peptide can be conjugated or coupled to selected conjugate sites of the anti-GIPR antibody via a variety of different conjugate chemistry known in the art. For example, in one embodiment, a maleimide-activated conjugate pairing group targeting cysteine ​​thiols accessible on the anti-GIPR antibody can be used. In one embodiment, a conjugate or coupling chemistry targeting the side chain of a classical or non-classical amino acid (e.g., a non-natural amino acid) in the sequence of the anti-GIPR antibody can be used.

[0170] Chemistry for the chemoselective conjugation of anti-GIPR antibodies with GLP-1 receptor agonist peptides includes, but is not limited to, copper(I)-catalyzed azide-alkyne [3+2] dipolar cycloaddition, Staudinger linkage, other acyl transfer processes, oxime, hydrazone formation, and other suitable organic chemical reactions, such as cross-coupling using water-soluble palladium catalysts (see, for example, Bong et al., Organic Letters 3(16):2509-11 (2001); Dibowski et al., Angew. Chem. Int. Ed. 37(4):476-78 (1998); DeVasher et al., J. Org. Chem. 69:7919-27 (2004); Shaugnessy et al., J. Org. Chem. 68, 6767-6774 (2003); Prescher et al., Nature Chemical Biology [Nature Chemical Biology] 1(1); 13-21 (2005)).

[0171] In one embodiment, the conjugation (or covalent binding) with the anti-GIPR antibody is via a side chain of an amino acid residue (e.g., but not limited to, a cysteine ​​residue) at the conjugation site. The amino acid residue at the selected internal conjugation site, such as a cysteine ​​residue, can be an amino acid residue occupying the same position in the native Fc domain sequence, or it can be an amino acid residue engineered into the Fc domain by substitution or insertion.

[0172] Non-limiting examples of non-natural amino acid residues that can be used as conjugation sites include: amino acid residues containing an azide group, such as azide-homoalanine and p-azidophenylalanine; ketone-containing amino acid residues, such as p-acetylphenylalanine; alkyne-containing amino acid residues, such as p-ethynylphenylalanine, homoargylated glycine, and p-(propynyl)-tyrosine; olefin-containing amino acid residues, such as homoallyl glycine; aryl halide-containing amino acid residues, such as p-iodophenylalanine and p-bromophenylalanine; and amino acid residues containing 1,2-aminothiols.

[0173] Non-standard amino acid residues (e.g., non-natural amino acid residues) can be incorporated into anti-GIPR antibodies through amino acid substitution or insertion. Non-standard amino acid residues can be incorporated into antibodies through chemical peptide synthesis rather than through synthesis in biological systems such as recombinant expression cells, or alternatively, those skilled in the art can employ known protein engineering techniques using recombinant expression cells (see, for example, Link et al., Current Opinion in Biotechnology, 14(6):603-609 (2003); U.S. Patent No. 7,045,337 to Schultz).

[0174] Any exposed amino acid residue on an anti-GIPR antibody can be a potentially useful conjugation site. Such sites may naturally contain cysteine ​​or another reactive amino acid for site-selective coupling. Other sites may be mutated to cysteine ​​or another reactive amino acid for site-selective coupling. In some embodiments, the conjugation site is located within the light chain constant region (CL), heavy chain constant region 1 (CH1), CH2, or CH3 of the anti-GIPR antibody.

[0175] In one embodiment, the anti-GIPR antibody contains a cysteine ​​amino acid at one or more conjugation sites. In one embodiment, the one or more conjugation sites are located within the CL, CH1, CH2, or CH3 region of the anti-GIPR antibody. In one embodiment, the one or more conjugation sites are located at positions independently selected from the group consisting of: position 88 (e.g., D88) of the light chain, position 384 (e.g., E384) of the heavy chain, and position 487 (e.g., T487) of the heavy chain. For clarity, position 88 of the light chain according to the AHo number corresponds to position 70 according to the Kabat number. Position 88 of the light chain according to the AHo number corresponds to position 70 in the reference light chain antibody sequence of SEQ ID NO: 455 (light chain of anti-GIPR antibody 5G12.006). Position 88 of the light chain according to the AHo number corresponds to position 70 in the reference light chain antibody sequence of SEQ ID NO: 388 (light chain of anti-GIPR antibody 2G10.006).

[0176] Position 384 in the heavy chain, according to the AHo number, is another suitable conjugation site within the anti-GIPR antibody. Position 384 in the heavy chain, according to the AHo number, corresponds to position 272 according to the EU number. Position 384 in the heavy chain, according to the AHo number, corresponds to position 276 in the reference heavy chain antibody sequence of SEQ ID NO: 612 (heavy chain of anti-GIPR antibody 5G12.006) and position 275 in the reference heavy chain antibody sequence of SEQ ID NO: 545 (heavy chain of anti-GIPR antibody 2G10.006).

[0177] Position 487 in the heavy chain, according to the AHo number, is another suitable conjugation site within the anti-GIPR antibody. Position 487 in the antibody heavy chain, according to the AHo number, corresponds to position 359 according to the EU number. Position 487, according to the AHo number, also corresponds to position 363 in the reference heavy chain antibody sequence of SEQ ID NO: 612 (heavy chain of anti-GIPR antibody 5G12.006) and position 362 in the reference heavy chain antibody sequence of SEQ ID NO: 545 (heavy chain of anti-GIPR antibody 2G10.006).

[0178] Exemplary antibodies that bind to and antagonize GIPRs (including human GIPRs (hGIPRs)) for inclusion in conjugate molecules described herein are provided below and disclosed in U.S. Patent No. 10,294,303, which is hereby incorporated by reference in its entirety.

[0179] In one embodiment, the antagonist anti-GIPR antibody of the conjugate molecule binds to the extracellular portion of human GIPR. In one embodiment, the antagonist anti-GIPR antibody inhibits the binding of GIP to the extracellular portion of human GIPR. In one embodiment, the human GIPR has the amino acid sequence of SEQ ID NO: 1572.

[0180] In one embodiment, the antagonist anti-GIPR antibody of the conjugate molecule binds to the N-terminal extracellular domain of human GIPR. In another embodiment, the antagonist anti-GIPR antibody inhibits the binding of GIP to the N-terminal extracellular domain of human GIPR. In yet another embodiment, the human GIPR has the amino acid sequence SEQ ID NO: 1572.

[0181] In one embodiment, the antagonist anti-GIPR antibody of the conjugate molecule binds to one or more amino acids at positions 1-139 of human GIPR. In one embodiment, the antagonist anti-GIPR antibody inhibits the binding of GIP to amino acids at positions 1-139 of human GIPR. In one embodiment, human GIPR has the amino acid sequence of SEQ ID NO: 1572.

[0182] In one embodiment, the antagonist anti-GIPR antibody of the conjugate molecule disclosed herein prevents or reduces the binding of GIP to GIPR, wherein the level of prevention or reduction can be measured, for example, by a GIPR binding assay (e.g., a radiolabeled or fluorescently labeled GIP ligand binding study). The GIPR binding assay can be an FMAT or FACS assay that measures the binding of fluorescently labeled GIP to GIPR-expressing cells, and the antagonistic activity of the anti-GIPR antibody is measured by its ability to substitute for the binding of fluorescently labeled GIP to GIPR-expressing cells. Alternatively, the GIPR binding assay can measure the binding of radiolabeled GIP to GIPR-expressing cells, and the antagonistic activity of the anti-GIPR antibody is measured by its ability to substitute for the binding of radiolabeled GIP to GIPR-expressing cells (see, for example, Biochimica et Biophysica Acta [Chinese Journal of Biochemistry and Biophysics] (2001) 1547:143-155). The reduction in GIP binding can be at least 10%, 25%, 50%, 100%, or more under comparable conditions relative to treatment with a non-GIPR control antibody.

[0183] In one embodiment, the antagonist anti-GIPR antibody of the conjugate molecule disclosed herein prevents or reduces the binding of GIP to GIPR, wherein the level of prevention or reduction is measured using a GIPR activity assay that measures the activity of GIP-binding proteins in the cellular environment. In one embodiment, the GIPR activity assay is a cAMP assay in GIPR-expressing cells, wherein GIP induces cAMP signaling, and the antagonistic activity of the anti-GIPR antibody is measured in the presence / absence of GIP ligand, wherein the IC50 / EC50 and the degree of inhibition / activation can be obtained (see, for example, Gault et al., Biochem. Biophys. Res. Commun. [Biochemical and Biophysical Research Communications] (2002) 290:1420-1426). In another embodiment, the GIPR activity assay is an insulin secretion assay in pancreatic β-cells. GIP induces glucose-dependent insulin secretion, and the antagonistic activity of anti-GIPR antibodies can be determined in the presence / absence of GIP ligands, and the IC50 / EC50 and the degree of GIP inhibition can be obtained (see, for example, Gault et al., Biochem. Biophys. Res. Commun. [Biochemical and Biophysical Research Communications] (2002) 290:1420-1426).

[0184] Using the anti-GIPR antibody-GLP-1 conjugate molecule disclosed herein to prevent or reduce the binding of GIP to GIPR, one or more of the following pharmacodynamic effects are produced upon in vivo administration: increased glucose tolerance; increased insulin sensitivity; decreased weight loss or reduced weight gain; decreased fat mass or reduced adipose tissue inflammation; decreased circulating cholesterol levels; decreased circulating triglyceride levels; reduced hepatic steatosis or decreased hepatic triglyceride levels; and decreased levels of one or more hepatic enzymes (e.g., aspartate aminotransferase (AST), alanine aminotransferase (ALT), and / or alkaline phosphatase (ALP)). Methods for determining and validating the foregoing properties are known in the art and are disclosed in U.S. Patent No. 10,294,303 (which is hereby incorporated by reference in its entirety).

[0185] In one embodiment, the antagonist anti-GIPR antibody disclosed herein is characterized by its binding affinity to GIPR. In one embodiment, the anti-GIPR antibody disclosed herein, when conjugated with a GLP-1 receptor agonist disclosed herein, binds to human GIPR with an equilibrium dissociation constant (KD) of ≤ 200 nM, ≤ 150 nM, ≤ 100 nM, ≤ 50 nM, ≤ 10 nM, ≤ 5 nM, ≤ 2 nM, or ≤ 1 nM, for example, as measured by surface plasmon resonance or kinetic exclusion assays. In one embodiment, the KD of the anti-GIPR antibody against human GIPR is 1 nM, 2 nM, 3 nM, 4 nM, 5 nM, 6 nM, 7 nM, 8 nM, 9 nM, 10 nM, 15 nM, 20 nM, 25 nM, 30 nM, 35 nM, 40 nM, 45 nM, 50 nM, 55 nM, 60 nM, 65 nM, 70 nM, 75 nM, 80 nM, 85 nM, 90 nM, 95 nM, 100 nM, 110 nM, 120 nM, 130 nM, 140 nM, 150 nM, 160 nM, 170 nM, 180 nM, 190 nM, 200 nM, 210 nM, 220 nM, 230 nM, 240 nM, 250 nM, 260 nM, 270 nM. nM, 280 nM, 290 nM, 300 nM, 310 nM, 320 nM, 330 nM, 340 nM, 350 nM, 360 nM, 370 nM, 380 nM, 390 nM, 400 nM, 410 nM, 420 nM, 430 nM, 440 nM, 450 nM, 460 nM, 470 nM, 480 nM, 490 nM or 500 nM.

[0186] In one embodiment, the antagonist anti-GIPR antibody disclosed herein has a slow dissociation rate (or off-rate). For example, in one embodiment, the antagonist anti-GIPR antibody has a kd (dissociation rate) of 1 x 10⁻⁶. -2 s -1 or 1 x 10 -3 s -1 or 1 x 10 -4 s -1 or 1 x 10 -5 s -1 .

[0187] In one embodiment, the antagonist anti-GIPR antibody is a monoclonal antibody, a recombinant antibody, a human antibody, or a multispecific antibody. In one embodiment, the anti-GIPR antibody is a monoclonal antibody. In one embodiment, the anti-GIPR antibody is a recombinant antibody. In one embodiment, the anti-GIPR antibody is a human antibody.

[0188] As defined herein, the antagonist anti-GIPR antibody belongs to the IgG isotype. In one embodiment, the antagonist anti-GIPR antibody belongs to the IgG1, IgG2, IgG3, or IgG4 subclass. In one embodiment, the antibody belongs to the IgG1, IgG2, or IgG4 subclass. In one embodiment, the antibody belongs to the IgG1 or IgG2 subclass. In one embodiment, the antibody belongs to the IgG1 subclass.

[0189] Non-limiting examples of anti-GIPR antibodies for the IgG1 subclass are summarized in Table 3. In one embodiment, an anti-GIPR antibody is an antibody having a CDR, variable domain, and light and heavy chain sequences as specified in one of the rows of Table 3.

[0190] SEQ ID NO has been assigned to the variable light chain, variable heavy chain, light chain, heavy chain, CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3 sequences of the exemplary antagonist anti-GIPR antibodies provided in Table 3-11. These antibodies can be identified by SEQ ID NO, but also by construct name (e.g., 2C2.005) or identifier number (e.g., iPS:336175). The anti-GIPR antibodies identified in Table 3-11 below can be classified into different families based on construct name. For example, the “4B1 family” includes constructs 4B1, 4B1.010, 4B1.011, 4B1.012, 4B1.013, 4B1.014, 4B1.015, and 4B1.016.

[0191] The various light and heavy chain variable regions described in this article are presented in Tables 4 and 5, respectively. Each of these variable regions can be attached to a heavy or light chain constant region to form the complete antibody heavy and light chains, respectively. Furthermore, each of the resulting heavy and light chain sequences can be combined to form the complete antibody structure.

[0192] In one embodiment, the antagonist anti-GIPR antibody of the conjugate molecule comprises a light chain variable region, wherein the light chain variable region comprises light chain complementarity-determining regions 1 (CDRL1), 2, and 3. In one embodiment, CDRL1 of the antibody comprises the amino acid sequence of any one of SEQ ID NOs: 629-785 in Table 6; CDRL2 comprises the amino acid sequence of any one of SEQ ID NOs: 786-942 in Table 6; and CDRL3 comprises the amino acid sequence of any one of SEQ ID NOs: 943-1099 in Table 6. In one embodiment, the antagonist anti-GIPR antibody of the conjugate molecule comprises a heavy chain variable region, wherein the heavy chain variable region comprises heavy chain complementarity-determining regions 1 (CDRH1), 2, and 3. In one embodiment, the antibody CDRH1 comprises the amino acid sequence of any one of SEQ ID NO: 1100-1256 disclosed in Table 7; CDRH2 comprises the amino acid sequence of any one of SEQ ID NO: 1257-1413 in Table 7; and CDRH3 comprises the amino acid sequence of any one of SEQ ID NO: 1414-1570 in Table 7.

[0193] In one embodiment, the anti-GIPR antibody of the conjugate molecule includes a light chain variable region comprising the CDRL1, CDRL2, and CDRL3 amino acid sequences listed in the corresponding row of any antibody in Table 3. In another embodiment, the anti-GIPR antibody of the conjugate molecule includes a heavy chain variable region comprising the CDRH1, CDRH2, and CDRH3 amino acid sequences listed in the corresponding row of any antibody in Table 3.

[0194] In one embodiment, the anti-GIPR antibody of the conjugate molecule described herein comprises a combination of the CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3 sequences listed in the corresponding row of any antibody in Table 3. In one embodiment, the CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3 of the antagonist anti-GIPR antibody comprise an amino acid sequence selected from the following: i. These are SEQ ID NO: 629, SEQ ID NO: 786, SEQ ID NO: 943, SEQ ID NO: 1100, SEQ ID NO: 1257 and SEQ ID NO: 1414, respectively; ii. These are SEQ ID NO: 630, SEQ ID NO: 787, SEQ ID NO: 944, SEQ ID NO: 1101, SEQ ID NO: 1258 and SEQ ID NO: 1415, respectively; iii. These are SEQ ID NO: 631, SEQ ID NO: 788, SEQ ID NO: 945, SEQ ID NO: 1102, SEQ ID NO: 1259 and SEQ ID NO: 1416, respectively; iv. These are SEQ ID NO: 632, SEQ ID NO: 789, SEQ ID NO: 946, SEQ ID NO: 1103, SEQ ID NO: 1260 and SEQ ID NO: 1417, respectively; v. are SEQ ID NO: 633, SEQ ID NO: 790, SEQ ID NO: 947, SEQ ID NO: 1104, SEQ ID NO: 1261 and SEQ ID NO: 1418 respectively; vi. These are SEQ ID NO: 634, SEQ ID NO: 791, SEQ ID NO: 948, SEQ ID NO: 1105, SEQ ID NO: 1262 and SEQ ID NO: 1419, respectively; vii. These are SEQ ID NO: 635, SEQ ID NO: 792, SEQ ID NO: 949, SEQ ID NO: 1106, SEQ ID NO: 1263 and SEQ ID NO: 1420, respectively; viii. These are SEQ ID NO: 636, SEQ ID NO: 793, SEQ ID NO: 950, SEQ ID NO: 1107, SEQ ID NO: 1264 and SEQ ID NO: 1421, respectively; ix. are SEQ ID NO: 637, SEQ ID NO: 794, SEQ ID NO: 951, SEQ ID NO: 1108, SEQ ID NO: 1265 and SEQ ID NO: 1422 respectively; x. are SEQ ID NO: 638, SEQ ID NO: 795, SEQ ID NO: 952, SEQ ID NO: 1109, SEQ ID NO: 1266 and SEQ ID NO: 1423 respectively; xi. are SEQ ID NO: 639, SEQ ID NO: 796, SEQ ID NO: 953, SEQ ID NO: 1110, SEQ ID NO: 1267 and SEQ ID NO: 1424 respectively; xii. These are SEQ ID NO: 640, SEQ ID NO: 797, SEQ ID NO: 954, SEQ ID NO: 1111, SEQ ID NO: 1268 and SEQ ID NO: 1425, respectively; xiii. These are SEQ ID NO: 641, SEQ ID NO: 798, SEQ ID NO: 955, SEQ ID NO: 1112, SEQ ID NO: 1269 and SEQ ID NO: 1426, respectively; xiv. are SEQ ID NO: 642, SEQ ID NO: 799, SEQ ID NO: 956, SEQ ID NO: 1113, SEQ ID NO: 1270 and SEQ ID NO: 1427 respectively; xv. are SEQ ID NO: 643, SEQ ID NO: 800, SEQ ID NO: 957, SEQ ID NO: 1114, SEQ ID NO: 1271 and SEQ ID NO: 1428 respectively; xvi. are SEQ ID NO: 644, SEQ ID NO: 801, SEQ ID NO: 958, SEQ ID NO: 1115, SEQ ID NO: 1272 and SEQ ID NO: 1429 respectively; xvii. are SEQ ID NO: 645, SEQ ID NO: 802, SEQ ID NO: 959, SEQ ID NO: 1116, SEQ ID NO: 1273 and SEQ ID NO: 1430 respectively; xviii. are SEQ ID NO: 646, SEQ ID NO: 803, SEQ ID NO: 960, SEQ ID NO: 1117, SEQ ID NO: 1274 and SEQ ID NO: 1431, respectively; xix. are SEQ ID NO: 647, SEQ ID NO: 804, SEQ ID NO: 961, SEQ ID NO: 1118, SEQ ID NO: 1275 and SEQ ID NO: 1432 respectively; xx. are SEQ ID NO: 648, SEQ ID NO: 805, SEQ ID NO: 962, SEQ ID NO: 1119, SEQ ID NO: 1276 and SEQ ID NO: 1433 respectively; xxi. are SEQ ID NO: 649, SEQ ID NO: 806, SEQ ID NO: 963, SEQ ID NO: 1120, SEQ ID NO: 1277 and SEQ ID NO: 1434 respectively; xxii. are SEQ ID NO: 650, SEQ ID NO: 807, SEQ ID NO: 964, SEQ ID NO: 1121, SEQ ID NO: 1278 and SEQ ID NO: 1435 respectively; xxiii. These are SEQ ID NO: 651, SEQ ID NO: 808, SEQ ID NO: 965, SEQ ID NO: 1122, SEQ ID NO: 1279 and SEQ ID NO: 1436, respectively; xxiv. are SEQ ID NO: 652, SEQ ID NO: 809, SEQ ID NO: 966, SEQ ID NO: 1123, SEQ ID NO: 1280 and SEQ ID NO: 1437 respectively; The xxv. are SEQ ID NO: 653, SEQ ID NO: 810, SEQ ID NO: 967, SEQ ID NO: 1124, SEQ ID NO: 1281 and SEQ ID NO: 1438, respectively; xxvi. are SEQ ID NO: 654, SEQ ID NO: 811, SEQ ID NO: 968, SEQ ID NO: 1125, SEQ ID NO: 1282 and SEQ ID NO: 1439 respectively; xxvii. are SEQ ID NO: 655, SEQ ID NO: 812, SEQ ID NO: 969, SEQ ID NO: 1126, SEQ ID NO: 1283 and SEQ ID NO: 1440 respectively; xxviii. are SEQ ID NO: 656, SEQ ID NO: 813, SEQ ID NO: 970, SEQ ID NO: 1127, SEQ ID NO: 1284 and SEQ ID NO: 1441, respectively; xxix. are SEQ ID NO: 657, SEQ ID NO: 814, SEQ ID NO: 971, SEQ ID NO: 1128, SEQ ID NO: 1285 and SEQ ID NO: 1442 respectively; The numbers xxx are SEQ ID NO: 658, SEQ ID NO: 815, SEQ ID NO: 972, SEQ ID NO: 1129, SEQ ID NO: 1286 and SEQ ID NO: 1443, respectively. xxxi are SEQ ID NO: 659, SEQ ID NO: 816, SEQ ID NO: 973, SEQ ID NO: 1130, SEQ ID NO: 1287 and SEQ ID NO: 1444 respectively; xxxii. are SEQ ID NO: 660, SEQ ID NO: 817, SEQ ID NO: 974, SEQ ID NO: 1131, SEQ ID NO: 1288 and SEQ ID NO: 1445 respectively; xxxiii. are SEQ ID NO: 661, SEQ ID NO: 818, SEQ ID NO: 975, SEQ ID NO: 1132, SEQ ID NO: 1289 and SEQ ID NO: 1446 respectively; xxxiv. are SEQ ID NO: 662, SEQ ID NO: 819, SEQ ID NO: 976, SEQ ID NO: 1133, SEQ ID NO: 1290 and SEQ ID NO: 1447 respectively; xxxv. are SEQ ID NO: 663, SEQ ID NO: 820, SEQ ID NO: 977, SEQ ID NO: 1134, SEQ ID NO: 1291 and SEQ ID NO: 1448 respectively; xxxvi. are SEQ ID NO: 664, SEQ ID NO: 821, SEQ ID NO: 978, SEQ ID NO: 1135, SEQ ID NO: 1292 and SEQ ID NO: 1449 respectively; xxxvii. are SEQ ID NO: 665, SEQ ID NO: 822, SEQ ID NO: 979, SEQ ID NO: 1136, SEQ ID NO: 1293 and SEQ ID NO: 1450 respectively; xxxviii. are SEQ ID NO: 666, SEQ ID NO: 823, SEQ ID NO: 980, SEQ ID NO: 1137, SEQ ID NO: 1294 and SEQ ID NO: 1451 respectively; xxxix. are SEQ ID NO: 667, SEQ ID NO: 824, SEQ ID NO: 981, SEQ ID NO: 1138, SEQ ID NO: 1295 and SEQ ID NO: 1452 respectively; xl. are SEQ ID NO: 668, SEQ ID NO: 825, SEQ ID NO: 982, SEQ ID NO: 1139, SEQ ID NO: 1296 and SEQ ID NO: 1453 respectively; xli. are SEQ ID NO: 669, SEQ ID NO: 826, SEQ ID NO: 983, SEQ ID NO: 1140, SEQ ID NO: 1297 and SEQ ID NO: 1454 respectively; xlii. are SEQ ID NO: 670, SEQ ID NO: 827, SEQ ID NO: 984, SEQ ID NO: 1141, SEQ ID NO: 1298 and SEQ ID NO: 1455 respectively; xliii. are SEQ ID NO: 671, SEQ ID NO: 828, SEQ ID NO: 985, SEQ ID NO: 1142, SEQ ID NO: 1299 and SEQ ID NO: 1456 respectively; xliv. are SEQ ID NO: 672, SEQ ID NO: 829, SEQ ID NO: 986, SEQ ID NO: 1143, SEQ ID NO: 1300 and SEQ ID NO: 1457 respectively; The xlv. are SEQ ID NO: 673, SEQ ID NO: 830, SEQ ID NO: 987, SEQ ID NO: 1144, SEQ ID NO: 1301 and SEQ ID NO: 1458, respectively; xlvi. are SEQ ID NO: 674, SEQ ID NO: 831, SEQ ID NO: 988, SEQ ID NO: 1145, SEQ ID NO: 1302 and SEQ ID NO: 1459 respectively; xlvii. are SEQ ID NO: 675, SEQ ID NO: 832, SEQ ID NO: 989, SEQ ID NO: 1146, SEQ ID NO: 1303 and SEQ ID NO: 1460 respectively; xlviii. are SEQ ID NO: 676, SEQ ID NO: 833, SEQ ID NO: 990, SEQ ID NO: 1147, SEQ ID NO: 1304 and SEQ ID NO: 1461, respectively; xlix. are SEQ ID NO: 677, SEQ ID NO: 834, SEQ ID NO: 991, SEQ ID NO: 1148, SEQ ID NO: 1305 and SEQ ID NO: 1462 respectively; l. These are SEQ ID NO: 678, SEQ ID NO: 835, SEQ ID NO: 992, SEQ ID NO: 1149, SEQ ID NO: 1306 and SEQ ID NO: 1463, respectively; The li are SEQ ID NO: 679, SEQ ID NO: 836, SEQ ID NO: 993, SEQ ID NO: 1150, SEQ ID NO: 1307 and SEQ ID NO: 1464 respectively; The lii. are SEQ ID NO: 680, SEQ ID NO: 837, SEQ ID NO: 994, SEQ ID NO: 1151, SEQ ID NO: 1308 and SEQ ID NO: 1465 respectively; liii. are SEQ ID NO: 681, SEQ ID NO: 838, SEQ ID NO: 995, SEQ ID NO: 1152, SEQ ID NO: 1309 and SEQ ID NO: 1466 respectively; The liv. are SEQ ID NO: 682, SEQ ID NO: 839, SEQ ID NO: 996, SEQ ID NO: 1153, SEQ ID NO: 1310 and SEQ ID NO: 1467 respectively; The lv. are SEQ ID NO: 683, SEQ ID NO: 840, SEQ ID NO: 997, SEQ ID NO: 1154, SEQ ID NO: 1311 and SEQ ID NO: 1468 respectively; lvi. are SEQ ID NO: 684, SEQ ID NO: 841, SEQ ID NO: 998, SEQ ID NO: 1155, SEQ ID NO: 1312 and SEQ ID NO: 1469 respectively; lvii. are SEQ ID NO: 685, SEQ ID NO: 842, SEQ ID NO: 999, SEQ ID NO: 1156, SEQ ID NO: 1313 and SEQ ID NO: 1470 respectively; lviii. are SEQ ID NO: 686, SEQ ID NO: 843, SEQ ID NO: 1000, SEQ ID NO: 1157, SEQ ID NO: 1314 and SEQ ID NO: 1471, respectively; The lix. are SEQ ID NO: 687, SEQ ID NO: 844, SEQ ID NO: 1001, SEQ ID NO: 1158, SEQ ID NO: 1315 and SEQ ID NO: 1472 respectively; lx. are SEQ ID NO: 688, SEQ ID NO: 845, SEQ ID NO: 1002, SEQ ID NO: 1159, SEQ ID NO: 1316 and SEQ ID NO: 1473 respectively; lxi. are SEQ ID NO: 689, SEQ ID NO: 846, SEQ ID NO: 1003, SEQ ID NO: 1160, SEQ ID NO: 1317 and SEQ ID NO: 1474 respectively; lxii. are SEQ ID NO: 690, SEQ ID NO: 847, SEQ ID NO: 1004, SEQ ID NO: 1161, SEQ ID NO: 1318 and SEQ ID NO: 1475 respectively; lxiii. are SEQ ID NO: 691, SEQ ID NO: 848, SEQ ID NO: 1005, SEQ ID NO: 1162, SEQ ID NO: 1319 and SEQ ID NO: 1476 respectively; The lxiv. are SEQ ID NO: 692, SEQ ID NO: 849, SEQ ID NO: 1006, SEQ ID NO: 1163, SEQ ID NO: 1320 and SEQ ID NO: 1477, respectively; lxv. are SEQ ID NO: 693, SEQ ID NO: 850, SEQ ID NO: 1007, SEQ ID NO: 1164, SEQ ID NO: 1321 and SEQ ID NO: 1478 respectively; lxvi. are SEQ ID NO: 694, SEQ ID NO: 851, SEQ ID NO: 1008, SEQ ID NO: 1165, SEQ ID NO: 1322 and SEQ ID NO: 1479 respectively; lxvii. are SEQ ID NO: 695, SEQ ID NO: 852, SEQ ID NO: 1009, SEQ ID NO: 1166, SEQ ID NO: 1323 and SEQ ID NO: 1480 respectively; lxviii. are SEQ ID NO: 696, SEQ ID NO: 853, SEQ ID NO: 1010, SEQ ID NO: 1167, SEQ ID NO: 1324 and SEQ ID NO: 1481, respectively; lxix. are SEQ ID NO: 697, SEQ ID NO: 854, SEQ ID NO: 1011, SEQ ID NO: 1168, SEQ ID NO: 1325 and SEQ ID NO: 1482 respectively; lxx. are SEQ ID NO: 698, SEQ ID NO: 855, SEQ ID NO: 1012, SEQ ID NO: 1169, SEQ ID NO: 1326 and SEQ ID NO: 1483 respectively; lxxi. are SEQ ID NO: 699, SEQ ID NO: 856, SEQ ID NO: 1013, SEQ ID NO: 1170, SEQ ID NO: 1327 and SEQ ID NO: 1484 respectively; lxxii. are SEQ ID NO: 700, SEQ ID NO: 857, SEQ ID NO: 1014, SEQ ID NO: 1171, SEQ ID NO: 1328 and SEQ ID NO: 1485 respectively; lxxiii. are SEQ ID NO: 701, SEQ ID NO: 858, SEQ ID NO: 1015, SEQ ID NO: 1172, SEQ ID NO: 1329 and SEQ ID NO: 1486 respectively; lxxiv. are 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 respectively; lxxv. are SEQ ID NO: 703, SEQ ID NO: 860, SEQ ID NO: 1017, SEQ ID NO: 1174, SEQ ID NO: 1331 and SEQ ID NO: 1488 respectively; lxxvi. are SEQ ID NO: 704, SEQ ID NO: 861, SEQ ID NO: 1018, SEQ ID NO: 1175, SEQ ID NO: 1332 and SEQ ID NO: 1489 respectively; lxxvii. are SEQ ID NO: 705, SEQ ID NO: 862, SEQ ID NO: 1019, SEQ ID NO: 1176, SEQ ID NO: 1333 and SEQ ID NO: 1490 respectively; lxxviii. are SEQ ID NO: 706, SEQ ID NO: 863, SEQ ID NO: 1020, SEQ ID NO: 1177, SEQ ID NO: 1334 and SEQ ID NO: 1491, respectively; lxxix. are SEQ ID NO: 707, SEQ ID NO: 864, SEQ ID NO: 1021, SEQ ID NO: 1178, SEQ ID NO: 1335 and SEQ ID NO: 1492 respectively; lxxx. are SEQ ID NO: 708, SEQ ID NO: 865, SEQ ID NO: 1022, SEQ ID NO: 1179, SEQ ID NO: 1336 and SEQ ID NO: 1493 respectively; lxxxi. are SEQ ID NO: 709, SEQ ID NO: 866, SEQ ID NO: 1023, SEQ ID NO: 1180, SEQ ID NO: 1337 and SEQ ID NO: 1494 respectively; lxxxii. are SEQ ID NO: 710, SEQ ID NO: 867, SEQ ID NO: 1024, SEQ ID NO: 1181, SEQ ID NO: 1338 and SEQ ID NO: 1495 respectively; lxxxiii. are SEQ ID NO: 711, SEQ ID NO: 868, SEQ ID NO: 1025, SEQ ID NO: 1182, SEQ ID NO: 1339 and SEQ ID NO: 1496 respectively; lxxxiv. are SEQ ID NO: 712, SEQ ID NO: 869, SEQ ID NO: 1026, SEQ ID NO: 1183, SEQ ID NO: 1340 and SEQ ID NO: 1497 respectively; lxxxv. are SEQ ID NO: 713, SEQ ID NO: 870, SEQ ID NO: 1027, SEQ ID NO: 1184, SEQ ID NO: 1341 and SEQ ID NO: 1498 respectively; lxxxvi. are SEQ ID NO: 714, SEQ ID NO: 871, SEQ ID NO: 1028, SEQ ID NO: 1185, SEQ ID NO: 1342 and SEQ ID NO: 1499 respectively; lxxxvii. are SEQ ID NO: 715, SEQ ID NO: 872, SEQ ID NO: 1029, SEQ ID NO: 1186, SEQ ID NO: 1343 and SEQ ID NO: 1500 respectively; lxxxviii. are SEQ ID NO: 716, SEQ ID NO: 873, SEQ ID NO: 1030, SEQ ID NO: 1187, SEQ ID NO: 1344 and SEQ ID NO: 1501, respectively; lxxxix. are SEQ ID NO: 717, SEQ ID NO: 874, SEQ ID NO: 1031, SEQ ID NO: 1188, SEQ ID NO: 1345 and SEQ ID NO: 1502 respectively; xc. are SEQ ID NO: 718, SEQ ID NO: 875, SEQ ID NO: 1032, SEQ ID NO: 1189, SEQ ID NO: 1346 and SEQ ID NO: 1503 respectively; xci. are SEQ ID NO: 719, SEQ ID NO: 876, SEQ ID NO: 1033, SEQ ID NO: 1190, SEQ ID NO: 1347 and SEQ ID NO: 1504 respectively; xcii. are SEQ ID NO: 720, SEQ ID NO: 877, SEQ ID NO: 1034, SEQ ID NO: 1191, SEQ ID NO: 1348 and SEQ ID NO: 1505 respectively; xciii. are SEQ ID NO: 721, SEQ ID NO: 878, SEQ ID NO: 1035, SEQ ID NO: 1192, SEQ ID NO: 1349 and SEQ ID NO: 1506 respectively; xciv. are SEQ ID NO: 722, SEQ ID NO: 879, SEQ ID NO: 1036, SEQ ID NO: 1193, SEQ ID NO: 1350 and SEQ ID NO: 1507 respectively; xcv. are SEQ ID NO: 723, SEQ ID NO: 880, SEQ ID NO: 1037, SEQ ID NO: 1194, SEQ ID NO: 1351 and SEQ ID NO: 1508 respectively; xcvi. are SEQ ID NO: 724, SEQ ID NO: 881, SEQ ID NO: 1038, SEQ ID NO: 1195, SEQ ID NO: 1352 and SEQ ID NO: 1509 respectively; xcvii. are SEQ ID NO: 725, SEQ ID NO: 882, SEQ ID NO: 1039, SEQ ID NO: 1196, SEQ ID NO: 1353 and SEQ ID NO: 1510 respectively; xcviii. are SEQ ID NO: 726, SEQ ID NO: 883, SEQ ID NO: 1040, SEQ ID NO: 1197, SEQ ID NO: 1354 and SEQ ID NO: 1511, respectively; xcix. are SEQ ID NO: 727, SEQ ID NO: 884, SEQ ID NO: 1041, SEQ ID NO: 1198, SEQ ID NO: 1355 and SEQ ID NO: 1512 respectively; c. These are SEQ ID NO: 728, SEQ ID NO: 885, SEQ ID NO: 1042, SEQ ID NO: 1199, SEQ ID NO: 1356 and SEQ ID NO: 1513, respectively; Ci. are SEQ ID NO: 729, SEQ ID NO: 886, SEQ ID NO: 1043, SEQ ID NO: 1200, SEQ ID NO: 1357 and SEQ ID NO: 1514 respectively; cii. are SEQ ID NO: 730, SEQ ID NO: 887, SEQ ID NO: 1044, SEQ ID NO: 1201, SEQ ID NO: 1358 and SEQ ID NO: 1515 respectively; ciii. are SEQ ID NO: 731, SEQ ID NO: 888, SEQ ID NO: 1045, SEQ ID NO: 1202, SEQ ID NO: 1359 and SEQ ID NO: 1516 respectively; civ. are SEQ ID NO: 732, SEQ ID NO: 889, SEQ ID NO: 1046, SEQ ID NO: 1203, SEQ ID NO: 1360 and SEQ ID NO: 1517 respectively; cv. are SEQ ID NO: 733, SEQ ID NO: 890, SEQ ID NO: 1047, SEQ ID NO: 1204, SEQ ID NO: 1361 and SEQ ID NO: 1518 respectively; cvi. are SEQ ID NO: 734, SEQ ID NO: 891, SEQ ID NO: 1048, SEQ ID NO: 1205, SEQ ID NO: 1362 and SEQ ID NO: 1519 respectively; cvii. are SEQ ID NO: 735, SEQ ID NO: 892, SEQ ID NO: 1049, SEQ ID NO: 1206, SEQ ID NO: 1363 and SEQ ID NO: 1520 respectively; cviii. are SEQ ID NO: 736, SEQ ID NO: 893, SEQ ID NO: 1050, SEQ ID NO: 1207, SEQ ID NO: 1364 and SEQ ID NO: 1521, respectively; cix. are SEQ ID NO: 737, SEQ ID NO: 894, SEQ ID NO: 1051, SEQ ID NO: 1208, SEQ ID NO: 1365 and SEQ ID NO: 1522 respectively; cx. are SEQ ID NO: 738, SEQ ID NO: 895, SEQ ID NO: 1052, SEQ ID NO: 1209, SEQ ID NO: 1366 and SEQ ID NO: 1523 respectively; cxi. are SEQ ID NO: 739, SEQ ID NO: 896, SEQ ID NO: 1053, SEQ ID NO: 1210, SEQ ID NO: 1367 and SEQ ID NO: 1524 respectively; cxii. are SEQ ID NO: 740, SEQ ID NO: 897, SEQ ID NO: 1054, SEQ ID NO: 1211, SEQ ID NO: 1368 and SEQ ID NO: 1525 respectively; cxiii. are SEQ ID NO: 741, SEQ ID NO: 898, SEQ ID NO: 1055, SEQ ID NO: 1212, SEQ ID NO: 1369 and SEQ ID NO: 1526 respectively; cxiv. are SEQ ID NO: 742, SEQ ID NO: 899, SEQ ID NO: 1056, SEQ ID NO: 1213, SEQ ID NO: 1370 and SEQ ID NO: 1527 respectively; cxv. are SEQ ID NO: 743, SEQ ID NO: 900, SEQ ID NO: 1057, SEQ ID NO: 1214, SEQ ID NO: 1371 and SEQ ID NO: 1528 respectively; cxvi. are SEQ ID NO: 744, SEQ ID NO: 901, SEQ ID NO: 1058, SEQ ID NO: 1215, SEQ ID NO: 1372 and SEQ ID NO: 1529 respectively; cxvii. are SEQ ID NO: 745, SEQ ID NO: 902, SEQ ID NO: 1059, SEQ ID NO: 1216, SEQ ID NO: 1373 and SEQ ID NO: 1530 respectively; cxviii. are SEQ ID NO: 746, SEQ ID NO: 903, SEQ ID NO: 1060, SEQ ID NO: 1217, SEQ ID NO: 1374 and SEQ ID NO: 1531, respectively; cxix. are SEQ ID NO: 747, SEQ ID NO: 904, SEQ ID NO: 1061, SEQ ID NO: 1218, SEQ ID NO: 1375 and SEQ ID NO: 1532 respectively; cxx. are SEQ ID NO: 748, SEQ ID NO: 905, SEQ ID NO: 1062, SEQ ID NO: 1219, SEQ ID NO: 1376 and SEQ ID NO: 1533 respectively; cxxi. are SEQ ID NO: 749, SEQ ID NO: 906, SEQ ID NO: 1063, SEQ ID NO: 1220, SEQ ID NO: 1377 and SEQ ID NO: 1534 respectively; cxxii. are SEQ ID NO: 750, SEQ ID NO: 907, SEQ ID NO: 1064, SEQ ID NO: 1221, SEQ ID NO: 1378 and SEQ ID NO: 1535 respectively; cxxiii. are SEQ ID NO: 751, SEQ ID NO: 908, SEQ ID NO: 1065, SEQ ID NO: 1222, SEQ ID NO: 1379 and SEQ ID NO: 1536 respectively; cxxiv. are SEQ ID NO: 752, SEQ ID NO: 909, SEQ ID NO: 1066, SEQ ID NO: 1223, SEQ ID NO: 1380 and SEQ ID NO: 1537 respectively; cxxv. are SEQ ID NO: 753, SEQ ID NO: 910, SEQ ID NO: 1067, SEQ ID NO: 1224, SEQ ID NO: 1381 and SEQ ID NO: 1538 respectively; cxxvi. are SEQ ID NO: 754, SEQ ID NO: 911, SEQ ID NO: 1068, SEQ ID NO: 1225, SEQ ID NO: 1382 and SEQ ID NO: 1539 respectively; cxxvii. are SEQ ID NO: 755, SEQ ID NO: 912, SEQ ID NO: 1069, SEQ ID NO: 1226, SEQ ID NO: 1383 and SEQ ID NO: 1540 respectively; cxxviii. are SEQ ID NO: 756, SEQ ID NO: 913, SEQ ID NO: 1070, SEQ ID NO: 1227, SEQ ID NO: 1384 and SEQ ID NO: 1541, respectively; cxxix. are SEQ ID NO: 757, SEQ ID NO: 914, SEQ ID NO: 1071, SEQ ID NO: 1228, SEQ ID NO: 1385 and SEQ ID NO: 1542 respectively; cxxx. are SEQ ID NO: 758, SEQ ID NO: 915, SEQ ID NO: 1072, SEQ ID NO: 1229, SEQ ID NO: 1386 and SEQ ID NO: 1543 respectively; cxxxi. are SEQ ID NO: 759, SEQ ID NO: 916, SEQ ID NO: 1073, SEQ ID NO: 1230, SEQ ID NO: 1387 and SEQ ID NO: 1544 respectively; cxxxii. are SEQ ID NO: 760, SEQ ID NO: 917, SEQ ID NO: 1074, SEQ ID NO: 1231, SEQ ID NO: 1388 and SEQ ID NO: 1545 respectively; cxxxiii. are SEQ ID NO: 761, SEQ ID NO: 918, SEQ ID NO: 1075, SEQ ID NO: 1232, SEQ ID NO: 1389 and SEQ ID NO: 1546 respectively; cxxxiv. are SEQ ID NO: 762, SEQ ID NO: 919, SEQ ID NO: 1076, SEQ ID NO: 1233, SEQ ID NO: 1390 and SEQ ID NO: 1547 respectively; cxxxv. are SEQ ID NO: 763, SEQ ID NO: 920, SEQ ID NO: 1077, SEQ ID NO: 1234, SEQ ID NO: 1391 and SEQ ID NO: 1548 respectively; cxxxvi. are SEQ ID NO: 764, SEQ ID NO: 921, SEQ ID NO: 1078, SEQ ID NO: 1235, SEQ ID NO: 1392 and SEQ ID NO: 1549 respectively; cxxxvii. are SEQ ID NO: 765, SEQ ID NO: 922, SEQ ID NO: 1079, SEQ ID NO: 1236, SEQ ID NO: 1393 and SEQ ID NO: 1550 respectively; cxxxviii. are SEQ ID NO: 766, SEQ ID NO: 923, SEQ ID NO: 1080, SEQ ID NO: 1237, SEQ ID NO: 1394 and SEQ ID NO: 1551, respectively; cxxxix. are SEQ ID NO: 767, SEQ ID NO: 924, SEQ ID NO: 1081, SEQ ID NO: 1238, SEQ ID NO: 1395 and SEQ ID NO: 1552 respectively; cxl. are SEQ ID NO: 768, SEQ ID NO: 925, SEQ ID NO: 1082, SEQ ID NO: 1239, SEQ ID NO: 1396 and SEQ ID NO: 1553 respectively; cxli. are SEQ ID NO: 769, SEQ ID NO: 926, SEQ ID NO: 1083, SEQ ID NO: 1240, SEQ ID NO: 1397 and SEQ ID NO: 1554 respectively; cxlii. are SEQ ID NO: 770, SEQ ID NO: 927, SEQ ID NO: 1084, SEQ ID NO: 1241, SEQ ID NO: 1398 and SEQ ID NO: 1555 respectively; cxliii. are SEQ ID NO: 771, SEQ ID NO: 928, SEQ ID NO: 1085, SEQ ID NO: 1242, SEQ ID NO: 1399 and SEQ ID NO: 1556 respectively; cxliv. are SEQ ID NO: 772, SEQ ID NO: 929, SEQ ID NO: 1086, SEQ ID NO: 1243, SEQ ID NO: 1400 and SEQ ID NO: 1557 respectively; cxlv. are SEQ ID NO: 773, SEQ ID NO: 930, SEQ ID NO: 1087, SEQ ID NO: 1244, SEQ ID NO: 1401 and SEQ ID NO: 1558 respectively; cxlvi. are SEQ ID NO: 774, SEQ ID NO: 931, SEQ ID NO: 1088, SEQ ID NO: 1245, SEQ ID NO: 1402 and SEQ ID NO: 1559 respectively; cxlvii. are SEQ ID NO: 775, SEQ ID NO: 932, SEQ ID NO: 1089, SEQ ID NO: 1246, SEQ ID NO: 1403 and SEQ ID NO: 1560 respectively; cxlviii. are SEQ ID NO: 776, SEQ ID NO: 933, SEQ ID NO: 1090, SEQ ID NO: 1247, SEQ ID NO: 1404 and SEQ ID NO: 1561, respectively; cxlix. are SEQ ID NO: 777, SEQ ID NO: 934, SEQ ID NO: 1091, SEQ ID NO: 1248, SEQ ID NO: 1405 and SEQ ID NO: 1562 respectively; Cl. are SEQ ID NO: 778, SEQ ID NO: 935, SEQ ID NO: 1092, SEQ ID NO: 1249, SEQ ID NO: 1406 and SEQ ID NO: 1563 respectively; The cli. are SEQ ID NO: 779, SEQ ID NO: 936, SEQ ID NO: 1093, SEQ ID NO: 1250, SEQ ID NO: 1407 and SEQ ID NO: 1564 respectively; The clii are SEQ ID NO: 780, SEQ ID NO: 937, SEQ ID NO: 1094, SEQ ID NO: 1251, SEQ ID NO: 1408 and SEQ ID NO: 1565, respectively; cliii. are SEQ ID NO: 781, SEQ ID NO: 938, SEQ ID NO: 1095, SEQ ID NO: 1252, SEQ ID NO: 1409 and SEQ ID NO: 1566 respectively; cliv. are SEQ ID NO: 782, SEQ ID NO: 939, SEQ ID NO: 1096, SEQ ID NO: 1253, SEQ ID NO: 1410 and SEQ ID NO: 1567 respectively; The clv. are SEQ ID NO: 783, SEQ ID NO: 940, SEQ ID NO: 1097, SEQ ID NO: 1254, SEQ ID NO: 1411 and SEQ ID NO: 1568 respectively; Clvi. are SEQ ID NO: 784, SEQ ID NO: 941, SEQ ID NO: 1098, SEQ ID NO: 1255, SEQ ID NO: 1412 and SEQ ID NO: 1569 respectively; and clvii. are SEQ ID NO: 785, SEQ ID NO: 942, SEQ ID NO: 1099, SEQ ID NO: 1256, SEQ ID NO: 1413 and SEQ ID NO: 1570 respectively.

[0195] In one embodiment, the antagonist anti-GIPR antibody of the conjugate molecule described herein comprises light chains CDRL1, CDRL2, and CDRL3 (containing the amino acid sequences of SEQ ID NO: 702, 859, and 1016, respectively) and heavy chains HCDR1, HCDR2, and HCDR3 (containing the amino acid sequences of SEQ ID NO: 1173, 1330, and 1487, respectively). An exemplary antibody comprising these light and heavy chain CDRs disclosed herein is referred to as the 2G10_LC1.006 anti-GIPR antibody.

[0196] In one embodiment, the anti-GIPR antibody of the conjugate molecule comprises a light chain variable region and a heavy chain variable region, the light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 1-157, and the heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 158-314.

[0197] In one embodiment, the antagonist anti-GIPR antibody of the conjugate molecule comprises a light chain variable region and a heavy chain variable region, the light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 1-157, and the heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 158-314, wherein the antibody comprises at least one cysteine ​​conjugate site located at a position selected from all of the following groups according to AHo numbering: light chain position 88 (e.g., D88), heavy chain position 384 (e.g., E384), and heavy chain position 487 (e.g., T487).

[0198] In one embodiment, the anti-GIPR antibody of the conjugate molecule comprises the light chain variable region and heavy chain variable region described in the corresponding row of any antibody listed in Table 3. In one embodiment, the anti-GIPR antibody comprises the light chain variable region and heavy chain variable region described in the corresponding row of any antibody listed in Table 3, except that one or both of the light chain variable region and the heavy chain variable region differ from the sequence specified in Table 4 (VL) or Table 5 (VH) at 1, 2, 3, 4 or 5 amino acid residues (combinations), wherein each such sequence difference is independently a single amino acid deletion, insertion or substitution, wherein such deletion, insertion and / or substitution causes no more than 1, 2, 3, 4 or 5 amino acid changes (combinations) relative to the light chain variable region and heavy chain variable region sequences specified in Table 4 (VL) or Table 5 (VH).

[0199] In one embodiment, the anti-GIPR antibody of the conjugate molecule comprises the light chain variable region and heavy chain variable region described in the corresponding row of any antibody listed in Table 3, except that one or both of these variable regions differ from the amino acid sequence specified in Table 5 (VH) or Table 4 (VL) in that the heavy chain variable region and / or light chain variable region comprises or consists of the following: an amino acid sequence having at least 95%, 96%, 97%, 98%, or 99% sequence identity with the amino acid sequence of the heavy chain variable region or light chain variable domain region specified in Table 5 or Table 4, respectively.

[0200] In one embodiment, the antagonist antiGIPR of the molecule described herein comprises a combination of a light chain variable region and a heavy chain variable region selected from the group consisting of: a light chain variable region comprising SEQ ID NO: 1 and a heavy chain variable region comprising SEQ ID NO: 158; a light chain variable region comprising SEQ ID NO: 2 and a heavy chain variable region comprising SEQ ID NO: 159; a light chain variable region comprising SEQ ID NO: 3 and a heavy chain variable region comprising SEQ ID NO: 160; a light chain variable region comprising SEQ ID NO: 4 and a heavy chain variable region comprising SEQ ID NO: 161; a light chain variable region comprising SEQ ID NO: 5 and a heavy chain variable region comprising SEQ ID NO: 162; a light chain variable region comprising SEQ ID NO: 6 and a heavy chain variable region comprising SEQ ID NO: 163; a light chain variable region comprising SEQ ID NO: 7 and a heavy chain variable region comprising SEQ ID NO: 164; a light chain variable region comprising SEQ ID NO: 8 ...164; a light chain variable region comprising SEQ ID NO: 165; a heavy chain variable region comprising SEQ ID NO: 164; a light chain variable region comprising SEQ ID NO: 165; a heavy chain variable region comprising SEQ ID NO: 165; a light chain variable region comprising SEQ ID NO: 165; a heavy chain variable region comprising SEQ ID NO: 165; a light chain variable region comprising SEQ ID NO: 165; a heavy chain variable region comprising SEQ ID NO: 165; a light chain variable region comprising SEQ ID NO: 165; a heavy chain variable region comprising SEQ ID NO: The heavy chain variable region of SEQ ID NO: 165; containing the light chain variable region of SEQ ID NO: 9 and the heavy chain variable region of SEQ ID NO: 166; containing the light chain variable region of SEQ ID NO: 10 and the heavy chain variable region of SEQ ID NO: 167; containing the light chain variable region of SEQ ID NO: 11 and the heavy chain variable region of SEQ ID NO: 168; containing the light chain variable region of SEQ ID NO: 12 and the heavy chain variable region of SEQ ID NO: 169; containing the light chain variable region of SEQ ID NO: 13 and the heavy chain variable region of SEQ ID NO: 170; containing the light chain variable region of SEQ ID NO: 14 and the heavy chain variable region of SEQ ID NO: 171; containing the light chain variable region of SEQ ID NO: 15 and the heavy chain variable region of SEQ ID NO: 172; containing the light chain variable region of SEQ ID NO: 16 and the heavy chain variable region of SEQ ID NO: 173; containing SEQ ID NO: The light chain variable region of SEQ ID NO: 17 and the heavy chain variable region containing SEQ ID NO: 174; the light chain variable region containing SEQ ID NO: 18 and the heavy chain variable region containing SEQ ID NO: 175; the light chain variable region containing SEQ ID NO: 19 and the heavy chain variable region containing SEQ ID NO: 176; the light chain variable region containing SEQ ID NO: 20 and the heavy chain variable region containing SEQ ID NO: 177; the light chain variable region containing SEQ ID NO: 21 and the heavy chain variable region containing SEQ ID NO: 178;The following regions are included: the light chain variable region containing SEQ ID NO: 22 and the heavy chain variable region containing SEQ ID NO: 179; the light chain variable region containing SEQ ID NO: 23 and the heavy chain variable region containing SEQ ID NO: 180; the light chain variable region containing SEQ ID NO: 24 and the heavy chain variable region containing SEQ ID NO: 181; the light chain variable region containing SEQ ID NO: 25 and the heavy chain variable region containing SEQ ID NO: 182; the light chain variable region containing SEQ ID NO: 26 and the heavy chain variable region containing SEQ ID NO: 183; the light chain variable region containing SEQ ID NO: 27 and the heavy chain variable region containing SEQ ID NO: 184; the light chain variable region containing SEQ ID NO: 28 and the heavy chain variable region containing SEQ ID NO: 185; the light chain variable region containing SEQ ID NO: 29 and the heavy chain variable region containing SEQ ID NO: 186; and the region containing SEQ ID NO: 179. The light chain variable region of SEQ ID NO: 30 and the heavy chain variable region containing SEQ ID NO: 187; the light chain variable region containing SEQ ID NO: 31 and the heavy chain variable region containing SEQ ID NO: 188; the light chain variable region containing SEQ ID NO: 32 and the heavy chain variable region containing SEQ ID NO: 189; the light chain variable region containing SEQ ID NO: 33 and the heavy chain variable region containing SEQ ID NO: 190; the light chain variable region containing SEQ ID NO: 34 and the heavy chain variable region containing SEQ ID NO: 191; the light chain variable region containing SEQ ID NO: 35 and the heavy chain variable region containing SEQ ID NO: 192; the light chain variable region containing SEQ ID NO: 36 and the heavy chain variable region containing SEQ ID NO: 193; the light chain variable region containing SEQ ID NO: 37 and the heavy chain variable region containing SEQ ID NO: 194; the light chain variable region containing SEQ ID NO: 38 and the heavy chain variable region containing SEQ ID NO: 199; the light chain variable region containing SEQ ID NO: 30 ... heavy chain variable region containing SEQ ID NO: 199; the light chain variable region containing SEQ ID NO: 30 and the heavy chain variable region containing SEQ ID NO: 199 The heavy chain variable region of SEQ ID NO: 195; the light chain variable region of SEQ ID NO: 39 and the heavy chain variable region of SEQ ID NO: 196; the light chain variable region of SEQ ID NO: 40 and the heavy chain variable region of SEQ ID NO: 197; the light chain variable region of SEQ ID NO: 41 and the heavy chain variable region of SEQ ID NO: 198; the light chain variable region of SEQ ID NO: 42 and the heavy chain variable region of SEQ ID NO: 199; the light chain variable region of SEQ ID NO: 43 and the heavy chain variable region of SEQ ID NO: 200;The following regions are included: the light chain variable region containing SEQ ID NO: 44 and the heavy chain variable region containing SEQ ID NO: 201; the light chain variable region containing SEQ ID NO: 45 and the heavy chain variable region containing SEQ ID NO: 202; the light chain variable region containing SEQ ID NO: 46 and the heavy chain variable region containing SEQ ID NO: 203; the light chain variable region containing SEQ ID NO: 47 and the heavy chain variable region containing SEQ ID NO: 204; the light chain variable region containing SEQ ID NO: 48 and the heavy chain variable region containing SEQ ID NO: 205; the light chain variable region containing SEQ ID NO: 49 and the heavy chain variable region containing SEQ ID NO: 206; the light chain variable region containing SEQ ID NO: 50 and the heavy chain variable region containing SEQ ID NO: 207; the light chain variable region containing SEQ ID NO: 51 and the heavy chain variable region containing SEQ ID NO: 208; the region containing SEQ ID NO: The light chain variable region of SEQ ID NO: 52 and the heavy chain variable region containing SEQ ID NO: 209; the light chain variable region containing SEQ ID NO: 53 and the heavy chain variable region containing SEQ ID NO: 210; the light chain variable region containing SEQ ID NO: 54 and the heavy chain variable region containing SEQ ID NO: 211; the light chain variable region containing SEQ ID NO: 55 and the heavy chain variable region containing SEQ ID NO: 212; the light chain variable region containing SEQ ID NO: 56 and the heavy chain variable region containing SEQ ID NO: 213; the light chain variable region containing SEQ ID NO: 57 and the heavy chain variable region containing SEQ ID NO: 214; the light chain variable region containing SEQ ID NO: 58 and the heavy chain variable region containing SEQ ID NO: 215; the light chain variable region containing SEQ ID NO: 59 and the heavy chain variable region containing SEQ ID NO: 216; the light chain variable region containing SEQ ID NO: 60 and the heavy chain variable region containing SEQ ID NO: 219; The heavy chain variable region of SEQ ID NO: 217; the light chain variable region of SEQ ID NO: 61 and the heavy chain variable region of SEQ ID NO: 218; the light chain variable region of SEQ ID NO: 62 and the heavy chain variable region of SEQ ID NO: 219; the light chain variable region of SEQ ID NO: 63 and the heavy chain variable region of SEQ ID NO: 220; the light chain variable region of SEQ ID NO: 64 and the heavy chain variable region of SEQ ID NO: 221; the light chain variable region of SEQ ID NO: 65 and the heavy chain variable region of SEQ ID NO: 222;Containing the light chain variable region of SEQ ID NO: 66 and the heavy chain variable region of SEQ ID NO: 223; containing the light chain variable region of SEQ ID NO: 67 and the heavy chain variable region of SEQ ID NO: 224; containing the light chain variable region of SEQ ID NO: 68 and the heavy chain variable region of SEQ ID NO: 225; containing the light chain variable region of SEQ ID NO: 69 and the heavy chain variable region of SEQ ID NO: 226; containing the light chain variable region of SEQ ID NO: 70 and the heavy chain variable region of SEQ ID NO: 227; containing the light chain variable region of SEQ ID NO: 71 and the heavy chain variable region of SEQ ID NO: 228; containing the light chain variable region of SEQ ID NO: 72 and the heavy chain variable region of SEQ ID NO: 229; containing the light chain variable region of SEQ ID NO: 73 and the heavy chain variable region of SEQ ID NO: 230; containing SEQ ID NO: The light chain variable region of SEQ ID NO: 74 and the heavy chain variable region containing SEQ ID NO: 231; the light chain variable region containing SEQ ID NO: 75 and the heavy chain variable region containing SEQ ID NO: 232; the light chain variable region containing SEQ ID NO: 76 and the heavy chain variable region containing SEQ ID NO: 233; the light chain variable region containing SEQ ID NO: 77 and the heavy chain variable region containing SEQ ID NO: 234; the light chain variable region containing SEQ ID NO: 78 and the heavy chain variable region containing SEQ ID NO: 235; the light chain variable region containing SEQ ID NO: 79 and the heavy chain variable region containing SEQ ID NO: 236; the light chain variable region containing SEQ ID NO: 80 and the heavy chain variable region containing SEQ ID NO: 237; the light chain variable region containing SEQ ID NO: 81 and the heavy chain variable region containing SEQ ID NO: 238; the light chain variable region containing SEQ ID NO: 82 and the heavy chain variable region containing SEQ ID NO: 233; The heavy chain variable region of SEQ ID NO:239; the light chain variable region of SEQ ID NO:83 and the heavy chain variable region of SEQ ID NO:240; the light chain variable region of SEQ ID NO:84 and the heavy chain variable region of SEQ ID NO:241; the light chain variable region of SEQ ID NO:85 and the heavy chain variable region of SEQ ID NO:242; the light chain variable region of SEQ ID NO:86 and the heavy chain variable region of SEQ ID NO:243; the light chain variable region of SEQ ID NO:87 and the heavy chain variable region of SEQ ID NO:244;The following regions are included: the light chain variable region containing SEQ ID NO: 88 and the heavy chain variable region containing SEQ ID NO: 245; the light chain variable region containing SEQ ID NO: 89 and the heavy chain variable region containing SEQ ID NO: 246; the light chain variable region containing SEQ ID NO: 90 and the heavy chain variable region containing SEQ ID NO: 247; the light chain variable region containing SEQ ID NO: 91 and the heavy chain variable region containing SEQ ID NO: 248; the light chain variable region containing SEQ ID NO: 92 and the heavy chain variable region containing SEQ ID NO: 249; the light chain variable region containing SEQ ID NO: 93 and the heavy chain variable region containing SEQ ID NO: 250; the light chain variable region containing SEQ ID NO: 94 and the heavy chain variable region containing SEQ ID NO: 251; the light chain variable region containing SEQ ID NO: 95 and the heavy chain variable region containing SEQ ID NO: 252; and the region containing SEQ ID NO: 89. The light chain variable region of SEQ ID NO: 96 and the heavy chain variable region containing SEQ ID NO: 253; the light chain variable region containing SEQ ID NO: 97 and the heavy chain variable region containing SEQ ID NO: 254; the light chain variable region containing SEQ ID NO: 98 and the heavy chain variable region containing SEQ ID NO: 255; the light chain variable region containing SEQ ID NO: 99 and the heavy chain variable region containing SEQ ID NO: 256; the light chain variable region containing SEQ ID NO: 100 and the heavy chain variable region containing SEQ ID NO: 257; the light chain variable region containing SEQ ID NO: 101 and the heavy chain variable region containing SEQ ID NO: 258; the light chain variable region containing SEQ ID NO: 102 and the heavy chain variable region containing SEQ ID NO: 259; the light chain variable region containing SEQ ID NO: 103 and the heavy chain variable region containing SEQ ID NO: 260; the light chain variable region containing SEQ ID NO: 259; the heavy chain variable region containing SEQ ID NO: 259 ... The light chain variable region of SEQ ID NO: 104 and the heavy chain variable region containing SEQ ID NO: 261; the light chain variable region containing SEQ ID NO: 105 and the heavy chain variable region containing SEQ ID NO: 262; the light chain variable region containing SEQ ID NO: 106 and the heavy chain variable region containing SEQ ID NO: 263; the light chain variable region containing SEQ ID NO: 107 and the heavy chain variable region containing SEQ ID NO: 264; the light chain variable region containing SEQ ID NO: 108 and the heavy chain variable region containing SEQ ID NO: 265; the light chain variable region containing SEQ ID NO: 109 and the heavy chain variable region containing SEQ ID NO: 266;Containing the light chain variable region of SEQ ID NO: 110 and the heavy chain variable region of SEQ ID NO: 267; containing the light chain variable region of SEQ ID NO: 111 and the heavy chain variable region of SEQ ID NO: 268; containing the light chain variable region of SEQ ID NO: 112 and the heavy chain variable region of SEQ ID NO: 269; containing the light chain variable region of SEQ ID NO: 113 and the heavy chain variable region of SEQ ID NO: 270; containing the light chain variable region of SEQ ID NO: 114 and the heavy chain variable region of SEQ ID NO: 271; containing the light chain variable region of SEQ ID NO: 115 and the heavy chain variable region of SEQ ID NO: 272; containing the light chain variable region of SEQ ID NO: 116 and the heavy chain variable region of SEQ ID NO: 273; containing the light chain variable region of SEQ ID NO: 117 and the heavy chain variable region of SEQ ID NO: 274; containing the light chain variable region of SEQ ID NO: 110 and the heavy chain variable region of SEQ ID NO: 267; containing the light chain variable region of SEQ ID NO: 110 and the heavy chain variable region of SEQ ID NO: 267; containing the heavy chain variable region of SEQ ID NO: 268; containing the light chain variable region of SEQ ID NO: 110 and the heavy chain variable region of SEQ ID NO: 269 ... heavy chain variable region of SEQ ID NO: 110 and the heavy chain variable region of SEQ ID NO: 2 The light chain variable region of SEQ ID NO: 118 and the heavy chain variable region containing SEQ ID NO: 275; the light chain variable region containing SEQ ID NO: 119 and the heavy chain variable region containing SEQ ID NO: 276; the light chain variable region containing SEQ ID NO: 120 and the heavy chain variable region containing SEQ ID NO: 277; the light chain variable region containing SEQ ID NO: 121 and the heavy chain variable region containing SEQ ID NO: 278; the light chain variable region containing SEQ ID NO: 122 and the heavy chain variable region containing SEQ ID NO: 279; the light chain variable region containing SEQ ID NO: 123 and the heavy chain variable region containing SEQ ID NO: 280; the light chain variable region containing SEQ ID NO: 124 and the heavy chain variable region containing SEQ ID NO: 281; the light chain variable region containing SEQ ID NO: 125 and the heavy chain variable region containing SEQ ID NO: 282; the light chain variable region containing SEQ ID NO: 125 and the heavy chain variable region containing SEQ ID NO: 282; the light chain variable region containing SEQ ID NO: 123 and the heavy chain variable region containing SEQ ID NO: 280; the light chain variable region containing SEQ ID NO: 124 and the heavy chain variable region containing SEQ ID NO: 281 ... The light chain variable region of SEQ ID NO: 126 and the heavy chain variable region containing SEQ ID NO: 283; the light chain variable region containing SEQ ID NO: 127 and the heavy chain variable region containing SEQ ID NO: 284; the light chain variable region containing SEQ ID NO: 128 and the heavy chain variable region containing SEQ ID NO: 285; the light chain variable region containing SEQ ID NO: 129 and the heavy chain variable region containing SEQ ID NO: 286; the light chain variable region containing SEQ ID NO: 130 and the heavy chain variable region containing SEQ ID NO: 287;The following regions are included: a light chain variable region containing SEQ ID NO: 131 and a heavy chain variable region containing SEQ ID NO: 288; a light chain variable region containing SEQ ID NO: 132 and a heavy chain variable region containing SEQ ID NO: 289; a light chain variable region containing SEQ ID NO: 133 and a heavy chain variable region containing SEQ ID NO: 290; a light chain variable region containing SEQ ID NO: 134 and a heavy chain variable region containing SEQ ID NO: 291; a light chain variable region containing SEQ ID NO: 135 and a heavy chain variable region containing SEQ ID NO: 292; a light chain variable region containing SEQ ID NO: 136 and a heavy chain variable region containing SEQ ID NO: 293; a light chain variable region containing SEQ ID NO: 137 and a heavy chain variable region containing SEQ ID NO: 294; a light chain variable region containing SEQ ID NO: 138 and a heavy chain variable region containing SEQ ID NO: 295; and a region containing SEQ ID NO: The light chain variable region of SEQ ID NO: 139 and the heavy chain variable region containing SEQ ID NO: 296; the light chain variable region containing SEQ ID NO: 140 and the heavy chain variable region containing SEQ ID NO: 297; the light chain variable region containing SEQ ID NO: 141 and the heavy chain variable region containing SEQ ID NO: 298; the light chain variable region containing SEQ ID NO: 142 and the heavy chain variable region containing SEQ ID NO: 299; the light chain variable region containing SEQ ID NO: 143 and the heavy chain variable region containing SEQ ID NO: 300; the light chain variable region containing SEQ ID NO: 144 and the heavy chain variable region containing SEQ ID NO: 301; the light chain variable region containing SEQ ID NO: 145 and the heavy chain variable region containing SEQ ID NO: 302; the light chain variable region containing SEQ ID NO: 146 and the heavy chain variable region containing SEQ ID NO: 303; the light chain variable region containing SEQ ID NO: 149 and the heavy chain variable region containing SEQ ID NO: 303; the light chain variable region containing SEQ ID NO: 149 and the heavy chain variable region containing SEQ ID NO: 296; the heavy chain variable region containing SEQ ID NO: 149 and the heavy chain variable region containing SEQ ID NO: 299; the light chain variable region containing SEQ ID NO: 149 and the heavy chain variable region containing SEQ ID NO: 299; the heavy ... The light chain variable region of SEQ ID NO: 147 and the heavy chain variable region containing SEQ ID NO: 304; the light chain variable region containing SEQ ID NO: 148 and the heavy chain variable region containing SEQ ID NO: 305; the light chain variable region containing SEQ ID NO: 149 and the heavy chain variable region containing SEQ ID NO: 306; the light chain variable region containing SEQ ID NO: 150 and the heavy chain variable region containing SEQ ID NO: 307; the light chain variable region containing SEQ ID NO: 151 and the heavy chain variable region containing SEQ ID NO: 308;The antibody comprises the light chain variable region of SEQ ID NO: 152 and the heavy chain variable region of SEQ ID NO: 309; the light chain variable region of SEQ ID NO: 153 and the heavy chain variable region of SEQ ID NO: 310; the light chain variable region of SEQ ID NO: 154 and the heavy chain variable region of SEQ ID NO: 311; the light chain variable region of SEQ ID NO: 155 and the heavy chain variable region of SEQ ID NO: 312; the light chain variable region of SEQ ID NO: 156 and the heavy chain variable region of SEQ ID NO: 313; and the light chain variable region of SEQ ID NO: 157 and the heavy chain variable region of SEQ ID NO: 314. Any of the above combinations of light chain variable regions and heavy chain variable regions may further comprise cysteine ​​or non-standard amino acid substitutions at one or more conjugation sites. In one embodiment, the conjugation site is located at position 88 in the light chain according to AHo number.

[0201] In one embodiment, the antagonist anti-GIPR antibody of the conjugate molecule described herein comprises the amino acid sequence of the light chain variable region of SEQ ID NO: 74 and the amino acid sequence of the heavy chain variable region of SEQ ID NO: 231. The exemplary antibody disclosed herein comprising these light and heavy chain variable regions is referred to as the 2G10_LC1.006 anti-GIPR antibody.

[0202] In one embodiment, the antagonist antiGIPR of the conjugate molecule described herein comprises a light chain and a heavy chain, the light chain comprising a sequence selected from the group consisting of SEQ ID NO: 315-471, and the heavy chain comprising a sequence selected from the group consisting of SEQ ID NO: 472-628, wherein the antibody or its functional fragment comprises a cysteine ​​or non-standard amino acid substitution at one or more conjugate sites selected from the group consisting of: position 88 of the antibody light chain according to AHo number, position 384 of the antibody heavy chain according to AHo number, and position 487 of the antibody heavy chain according to AHo number.

[0203] Antagonistic anti-GIPR antibodies suitable for incorporation into the conjugate molecules described herein (i.e., molecules containing GLP-1 receptor agonist peptides conjugated with anti-GIPR antibodies) may comprise the full-length light chain and full-length heavy chain described in the corresponding row of any antibody listed in Table 3. Some of the antibodies provided comprise the full-length light chain and full-length heavy chain described in the corresponding row of any antibody listed in Table 3, except that one or both of these chains differ from the sequence specified in the table at only 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid residues, wherein each such sequence difference is independently a single amino acid deletion, insertion, or substitution, wherein such deletion, insertion, and / or substitution causes a change of no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid residues relative to the full-length sequences specified in Tables 8 and 9. In one embodiment, the anti-GIPR antibody comprises the full-length light chain from Table 8 and / or the full-length heavy chain from Table 9, wherein the N-terminal methionine (if present) is deleted. In one embodiment, an anti-GIPR antibody comprises a full-length light chain from Table 8 and / or a full-length heavy chain from Table 9, wherein a C-terminal lysine (if present) is deleted. Other anti-GIPR antibodies also comprise the full-length light chain and full-length heavy chain described in the corresponding row of any antibody listed in Table 3, except that one or both of these chains differ from the sequences specified in the table in that the light chain and / or heavy chain comprises or consists of a sequence of amino acids having at least 95%, 96%, 97%, 98%, or 99% sequence identity with the amino acid sequence of the light chain or heavy chain as specified in Table 3.

[0204] In one embodiment, the antagonist anti-GIPR antibody of the conjugate molecule described herein comprises a combination of light and heavy chains selected from the group consisting of: a light chain comprising SEQ ID NO: 315 and a heavy chain comprising SEQ ID NO: 472; a light chain comprising SEQ ID NO: 316 and a heavy chain comprising SEQ ID NO: 473; a light chain comprising SEQ ID NO: 317 and a heavy chain comprising SEQ ID NO: 474; a light chain comprising SEQ ID NO: 318 and a heavy chain comprising SEQ ID NO: 475; a light chain comprising SEQ ID NO: 319 and a heavy chain comprising SEQ ID NO: 476; a light chain comprising SEQ ID NO: 320 and a heavy chain comprising SEQ ID NO: 477; a light chain comprising SEQ ID NO: 321 and a heavy chain comprising SEQ ID NO: 478; a light chain comprising SEQ ID NO: 322 and a heavy chain comprising SEQ ID NO: 479; a light chain comprising SEQ ID NO: 322; a heavy chain comprising SEQ ID NO: 323; a light chain comprising SEQ ID NO: 323 ... light chain comprising SEQ ID NO: 3 The light chain of SEQ ID NO: 323 and the heavy chain containing SEQ ID NO: 480; the light chain containing SEQ ID NO: 324 and the heavy chain containing SEQ ID NO: 481; the light chain containing SEQ ID NO: 325 and the heavy chain containing SEQ ID NO: 482; the light chain containing SEQ ID NO: 326 and the heavy chain containing SEQ ID NO: 483; the light chain containing SEQ ID NO: 327 and the heavy chain containing SEQ ID NO: 484; the light chain containing SEQ ID NO: 328 and the heavy chain containing SEQ ID NO: 485; the light chain containing SEQ ID NO: 329 and the heavy chain containing SEQ ID NO: 486; the light chain containing SEQ ID NO: 330 and the heavy chain containing SEQ ID NO: 487; the light chain containing SEQ ID NO: 331 and the heavy chain containing SEQ ID NO: 488; the light chain containing SEQ ID NO: 332 and the heavy chain containing SEQ ID NO: 480; The heavy chain containing SEQ ID NO: 489; the light chain containing SEQ ID NO: 333 and the heavy chain containing SEQ ID NO: 490; the light chain containing SEQ ID NO: 334 and the heavy chain containing SEQ ID NO: 491; the light chain containing SEQ ID NO: 335 and the heavy chain containing SEQ ID NO: 492; the light chain containing SEQ ID NO: 336 and the heavy chain containing SEQ ID NO: 493; the light chain containing SEQ ID NO: 337 and the heavy chain containing SEQ ID NO: 494;The following chains are included: a light chain containing SEQ ID NO: 338 and a heavy chain containing SEQ ID NO: 495; a light chain containing SEQ ID NO: 339 and a heavy chain containing SEQ ID NO: 496; a light chain containing SEQ ID NO: 340 and a heavy chain containing SEQ ID NO: 497; a light chain containing SEQ ID NO: 341 and a heavy chain containing SEQ ID NO: 498; a light chain containing SEQ ID NO: 342 and a heavy chain containing SEQ ID NO: 499; a light chain containing SEQ ID NO: 343 and a heavy chain containing SEQ ID NO: 500; a light chain containing SEQ ID NO: 344 and a heavy chain containing SEQ ID NO: 501; a light chain containing SEQ ID NO: 345 and a heavy chain containing SEQ ID NO: 502; a light chain containing SEQ ID NO: 346 and a heavy chain containing SEQ ID NO: 503; and a heavy chain containing SEQ ID NO: 340 and a heavy chain containing SEQ ID NO: 497. The light chain of SEQ ID NO: 347 and the heavy chain containing SEQ ID NO: 504; the light chain containing SEQ ID NO: 348 and the heavy chain containing SEQ ID NO: 505; the light chain containing SEQ ID NO: 349 and the heavy chain containing SEQ ID NO: 506; the light chain containing SEQ ID NO: 350 and the heavy chain containing SEQ ID NO: 507; the light chain containing SEQ ID NO: 351 and the heavy chain containing SEQ ID NO: 508; the light chain containing SEQ ID NO: 352 and the heavy chain containing SEQ ID NO: 509; the light chain containing SEQ ID NO: 353 and the heavy chain containing SEQ ID NO: 510; the light chain containing SEQ ID NO: 354 and the heavy chain containing SEQ ID NO: 511; the light chain containing SEQ ID NO: 355 and the heavy chain containing SEQ ID NO: 512; the light chain containing SEQ ID NO: 356 and the heavy chain containing SEQ ID NO: 504; The heavy chain containing SEQ ID NO: 513; the light chain containing SEQ ID NO: 357 and the heavy chain containing SEQ ID NO: 514; the light chain containing SEQ ID NO: 358 and the heavy chain containing SEQ ID NO: 515; the light chain containing SEQ ID NO: 359 and the heavy chain containing SEQ ID NO: 516; the light chain containing SEQ ID NO: 360 and the heavy chain containing SEQ ID NO: 517; the light chain containing SEQ ID NO: 361 and the heavy chain containing SEQ ID NO: 518; the light chain containing SEQ ID NO: 362 and the heavy chain containing SEQ ID NO: 519;The following chains are included: a light chain containing SEQ ID NO: 363 and a heavy chain containing SEQ ID NO: 520; a light chain containing SEQ ID NO: 364 and a heavy chain containing SEQ ID NO: 521; a light chain containing SEQ ID NO: 365 and a heavy chain containing SEQ ID NO: 522; a light chain containing SEQ ID NO: 366 and a heavy chain containing SEQ ID NO: 523; a light chain containing SEQ ID NO: 367 and a heavy chain containing SEQ ID NO: 524; a light chain containing SEQ ID NO: 368 and a heavy chain containing SEQ ID NO: 525; a light chain containing SEQ ID NO: 369 and a heavy chain containing SEQ ID NO: 526; a light chain containing SEQ ID NO: 370 and a heavy chain containing SEQ ID NO: 527; a light chain containing SEQ ID NO: 371 and a heavy chain containing SEQ ID NO: 528; and a heavy chain containing SEQ ID NO: 520. The light chain of SEQ ID NO: 372 and the heavy chain containing SEQ ID NO: 529; the light chain containing SEQ ID NO: 373 and the heavy chain containing SEQ ID NO: 530; the light chain containing SEQ ID NO: 374 and the heavy chain containing SEQ ID NO: 531; the light chain containing SEQ ID NO: 375 and the heavy chain containing SEQ ID NO: 532; the light chain containing SEQ ID NO: 376 and the heavy chain containing SEQ ID NO: 533; the light chain containing SEQ ID NO: 377 and the heavy chain containing SEQ ID NO: 534; the light chain containing SEQ ID NO: 378 and the heavy chain containing SEQ ID NO: 535; the light chain containing SEQ ID NO: 379 and the heavy chain containing SEQ ID NO: 536; the light chain containing SEQ ID NO: 380 and the heavy chain containing SEQ ID NO: 537; the light chain containing SEQ ID NO: 381 and the heavy chain containing SEQ ID NO: 529; The heavy chain containing SEQ ID NO: 538; the light chain containing SEQ ID NO: 382 and the heavy chain containing SEQ ID NO: 539; the light chain containing SEQ ID NO: 383 and the heavy chain containing SEQ ID NO: 540; the light chain containing SEQ ID NO: 384 and the heavy chain containing SEQ ID NO: 541; the light chain containing SEQ ID NO: 385 and the heavy chain containing SEQ ID NO: 542; the light chain containing SEQ ID NO: 386 and the heavy chain containing SEQ ID NO: 543; the light chain containing SEQ ID NO: 387 and the heavy chain containing SEQ ID NO: 544;The light chain containing SEQ ID NO: 388 and the heavy chain containing SEQ ID NO: 545; the light chain containing SEQ ID NO: 389 and the heavy chain containing SEQ ID NO: 546; the light chain containing SEQ ID NO: 390 and the heavy chain containing SEQ ID NO: 547; the light chain containing SEQ ID NO: 391 and the heavy chain containing SEQ ID NO: 548; the light chain containing SEQ ID NO: 392 and the heavy chain containing SEQ ID NO: 549; the light chain containing SEQ ID NO: 393 and the heavy chain containing SEQ ID NO: 550; the light chain containing SEQ ID NO: 394 and the heavy chain containing SEQ ID NO: 551; the light chain containing SEQ ID NO: 395 and the heavy chain containing SEQ ID NO: 552; the light chain containing SEQ ID NO: 396 and the heavy chain containing SEQ ID NO: 553; the light chain containing SEQ ID NO: 398 and the heavy chain containing SEQ ID NO: 545; the light chain containing SEQ ID NO: 399 and the heavy chain containing SEQ ID NO: 546; the light chain containing SEQ ID NO: 399 and the heavy chain containing SEQ ID NO: 547; the light chain containing SEQ ID NO: 391 and the heavy chain containing SEQ ID NO: 548; the light chain containing SEQ ID NO: 392 and the heavy chain containing SEQ ID NO: 549; the light chain containing SEQ ID NO: 393 and the heavy chain containing SEQ ID NO: 549; the heavy chain containing SEQ ID NO: 399 and the heavy chain containing SEQ ID NO: 549; the light chain containing SEQ ID NO: 399 and the heavy chain containing SEQ ID NO: 549; the heavy chain containing SEQ ID NO: 399 and the heavy chain containing SEQ ID NO: 549; the heavy chain containing SEQ ID The light chain containing SEQ ID NO: 397 and the heavy chain containing SEQ ID NO: 554; the light chain containing SEQ ID NO: 398 and the heavy chain containing SEQ ID NO: 555; the light chain containing SEQ ID NO: 399 and the heavy chain containing SEQ ID NO: 556; the light chain containing SEQ ID NO: 400 and the heavy chain containing SEQ ID NO: 557; the light chain containing SEQ ID NO: 401 and the heavy chain containing SEQ ID NO: 558; the light chain containing SEQ ID NO: 402 and the heavy chain containing SEQ ID NO: 559; the light chain containing SEQ ID NO: 403 and the heavy chain containing SEQ ID NO: 560; the light chain containing SEQ ID NO: 404 and the heavy chain containing SEQ ID NO: 561; the light chain containing SEQ ID NO: 405 and the heavy chain containing SEQ ID NO: 562; the light chain containing SEQ ID NO: 406 and the heavy chain containing SEQ ID NO: 554; The heavy chain containing SEQ ID NO: 563; the light chain containing SEQ ID NO: 407 and the heavy chain containing SEQ ID NO: 564; the light chain containing SEQ ID NO: 408 and the heavy chain containing SEQ ID NO: 565; the light chain containing SEQ ID NO: 409 and the heavy chain containing SEQ ID NO: 566; the light chain containing SEQ ID NO: 410 and the heavy chain containing SEQ ID NO: 567; the light chain containing SEQ ID NO: 411 and the heavy chain containing SEQ ID NO: 568; the light chain containing SEQ ID NO: 412 and the heavy chain containing SEQ ID NO: 569;The following chains are included: a light chain containing SEQ ID NO: 413 and a heavy chain containing SEQ ID NO: 570; a light chain containing SEQ ID NO: 414 and a heavy chain containing SEQ ID NO: 571; a light chain containing SEQ ID NO: 415 and a heavy chain containing SEQ ID NO: 572; a light chain containing SEQ ID NO: 416 and a heavy chain containing SEQ ID NO: 573; a light chain containing SEQ ID NO: 417 and a heavy chain containing SEQ ID NO: 574; a light chain containing SEQ ID NO: 418 and a heavy chain containing SEQ ID NO: 575; a light chain containing SEQ ID NO: 419 and a heavy chain containing SEQ ID NO: 576; a light chain containing SEQ ID NO: 420 and a heavy chain containing SEQ ID NO: 577; a light chain containing SEQ ID NO: 421 and a heavy chain containing SEQ ID NO: 578; and a heavy chain containing SEQ ID NO: 570. The light chain of SEQ ID NO: 422 and the heavy chain containing SEQ ID NO: 579; the light chain containing SEQ ID NO: 423 and the heavy chain containing SEQ ID NO: 580; the light chain containing SEQ ID NO: 424 and the heavy chain containing SEQ ID NO: 581; the light chain containing SEQ ID NO: 425 and the heavy chain containing SEQ ID NO: 582; the light chain containing SEQ ID NO: 426 and the heavy chain containing SEQ ID NO: 583; the light chain containing SEQ ID NO: 427 and the heavy chain containing SEQ ID NO: 584; the light chain containing SEQ ID NO: 428 and the heavy chain containing SEQ ID NO: 585; the light chain containing SEQ ID NO: 429 and the heavy chain containing SEQ ID NO: 586; the light chain containing SEQ ID NO: 430 and the heavy chain containing SEQ ID NO: 587; the light chain containing SEQ ID NO: 431 and the heavy chain containing SEQ ID NO: 579. The heavy chain containing SEQ ID NO: 588; the light chain containing SEQ ID NO: 432 and the heavy chain containing SEQ ID NO: 589; the light chain containing SEQ ID NO: 433 and the heavy chain containing SEQ ID NO: 590; the light chain containing SEQ ID NO: 434 and the heavy chain containing SEQ ID NO: 591; the light chain containing SEQ ID NO: 435 and the heavy chain containing SEQ ID NO: 592; the light chain containing SEQ ID NO: 436 and the heavy chain containing SEQ ID NO: 593; the light chain containing SEQ ID NO: 437 and the heavy chain containing SEQ ID NO: 594;The following chains are included: a light chain containing SEQ ID NO: 438 and a heavy chain containing SEQ ID NO: 595; a light chain containing SEQ ID NO: 439 and a heavy chain containing SEQ ID NO: 596; a light chain containing SEQ ID NO: 440 and a heavy chain containing SEQ ID NO: 597; a light chain containing SEQ ID NO: 441 and a heavy chain containing SEQ ID NO: 598; a light chain containing SEQ ID NO: 442 and a heavy chain containing SEQ ID NO: 599; a light chain containing SEQ ID NO: 443 and a heavy chain containing SEQ ID NO: 600; a light chain containing SEQ ID NO: 444 and a heavy chain containing SEQ ID NO: 601; a light chain containing SEQ ID NO: 445 and a heavy chain containing SEQ ID NO: 602; a light chain containing SEQ ID NO: 446 and a heavy chain containing SEQ ID NO: 603; and a heavy chain containing SEQ ID NO: 440 and SEQ ID NO: 597. The light chain of SEQ ID NO: 447 and the heavy chain containing SEQ ID NO: 604; the light chain containing SEQ ID NO: 448 and the heavy chain containing SEQ ID NO: 605; the light chain containing SEQ ID NO: 449 and the heavy chain containing SEQ ID NO: 606; the light chain containing SEQ ID NO: 450 and the heavy chain containing SEQ ID NO: 607; the light chain containing SEQ ID NO: 451 and the heavy chain containing SEQ ID NO: 608; the light chain containing SEQ ID NO: 452 and the heavy chain containing SEQ ID NO: 609; the light chain containing SEQ ID NO: 453 and the heavy chain containing SEQ ID NO: 610; the light chain containing SEQ ID NO: 454 and the heavy chain containing SEQ ID NO: 611; the light chain containing SEQ ID NO: 455 and the heavy chain containing SEQ ID NO: 612; the light chain containing SEQ ID NO: 456 and the heavy chain containing SEQ ID NO: 604; The heavy chain containing SEQ ID NO: 613; the light chain containing SEQ ID NO: 457 and the heavy chain containing SEQ ID NO: 614; the light chain containing SEQ ID NO: 458 and the heavy chain containing SEQ ID NO: 615; the light chain containing SEQ ID NO: 459 and the heavy chain containing SEQ ID NO: 616; the light chain containing SEQ ID NO: 460 and the heavy chain containing SEQ ID NO: 617; the light chain containing SEQ ID NO: 461 and the heavy chain containing SEQ ID NO: 618; the light chain containing SEQ ID NO: 462 and the heavy chain containing SEQ ID NO: 619;The following chains are included: a light chain containing SEQ ID NO: 463 and a heavy chain containing SEQ ID NO: 620; a light chain containing SEQ ID NO: 464 and a heavy chain containing SEQ ID NO: 621; a light chain containing SEQ ID NO: 465 and a heavy chain containing SEQ ID NO: 622; a light chain containing SEQ ID NO: 466 and a heavy chain containing SEQ ID NO: 623; a light chain containing SEQ ID NO: 467 and a heavy chain containing SEQ ID NO: 624; a light chain containing SEQ ID NO: 468 and a heavy chain containing SEQ ID NO: 625; a light chain containing SEQ ID NO: 469 and a heavy chain containing SEQ ID NO: 626; a light chain containing SEQ ID NO: 470 and a heavy chain containing SEQ ID NO: 627; and a light chain containing SEQ ID NO: 471 and a heavy chain containing SEQ ID NO: 620. The heavy chain of 628, wherein the antibody contains one or more cysteine ​​amino acid substitutions at one or more positions selected from the following according to AHo numbers: position 88 of the light chain, position 384 of the heavy chain, or position 487 of the heavy chain.

[0205] In one embodiment, the antagonist anti-GIPR antibody of the conjugate molecule described herein comprises the light chain amino acid sequence of SEQ ID NO: 388 and the heavy chain amino acid sequence of SEQ ID NO: 545, wherein the antibody contains one or more cysteine ​​amino acid substitutions at one or more positions selected according to AHo numbers: position 88 of the light chain, position 384 of the heavy chain, or position 487 of the heavy chain. An exemplary antibody disclosed herein comprising these light and heavy chains is referred to as 2G10_LC1.006 anti-GIPR antibody.

[0206] In one embodiment, the antagonist anti-GIPR antibody of a conjugate molecule containing a cysteine ​​amino acid substitution (i.e., a conjugate site) at position 88 (according to AHo number) on the light chain comprises the light chain amino acid sequence of SEQ ID NO: 1594 and the heavy chain amino acid sequence of SEQ ID NO: 612.

[0207] In one embodiment, the antagonist anti-GIPR antibody of a conjugate molecule containing a cysteine ​​amino acid substitution (i.e., a conjugation site) at position 384 (according to AHo number) on the heavy chain comprises the light chain amino acid sequence of SEQ ID NO: 388 and the heavy chain amino acid sequence of SEQ ID NO: 1571.

[0208] In one embodiment, the antagonist anti-GIPR antibody of a conjugate molecule containing a cysteine ​​amino acid substitution (i.e., a conjugation site) at position 384 (according to AHo number) on the heavy chain comprises the light chain amino acid sequence of SEQ ID NO: 389 and the heavy chain amino acid sequence of SEQ ID NO: 1596.

[0209] In one embodiment, the exemplary anti-GIPR / GLP-1 conjugate molecule disclosed herein comprises an antagonist anti-GIPR antibody, wherein the antibody comprises: a first light chain and a second light chain, each light chain comprising CDRL1, CDRL2, and CDRL3 of SEQ ID NO: 702, SEQ ID NO: 859, and SEQ ID NO: 1016, respectively; and a first heavy chain and a second heavy chain, each heavy chain comprising CDRH1, CDRH2, and CDRH3 of SEQ ID NO: 1173, SEQ ID NO: 1330, and SEQ ID NO: 1487, respectively. The molecule further comprises a first GLP-1 receptor agonist peptide and a second GLP-1 receptor agonist peptide, wherein each GLP-1 receptor agonist peptide comprises the amino acid sequence of SEQ ID NO: 1579; and a first peptide linker and a second peptide linker, wherein each peptide linker comprises the amino acid sequence of SEQ ID NO: 1592. The first GLP-1 receptor agonist polypeptide of the molecule is conjugated at its C-terminus to a cysteine ​​residue at position 384 of the first heavy chain of the GIPR antibody according to AHo number (corresponding to position 275 of SEQ ID NO: 1571) via a first linker, and the second GLP-1 receptor agonist polypeptide is conjugated at its C-terminus to a cysteine ​​residue at position 384 of the second heavy chain of the GIPR antibody according to AHo number (corresponding to position 275 of SEQ ID NO: 1571) via a second linker. In one embodiment, each light chain contains the VL of SEQ ID NO: 74, and each heavy chain contains the VH of SEQ ID NO: 231. In one embodiment, each light chain contains the amino acid sequence of SEQ ID NO: 388, and each heavy chain contains the amino acid sequence of SEQ ID NO: 1571.

[0210] In one embodiment, the exemplary anti-GIPR / GLP-1 conjugate molecule disclosed herein comprises an antagonist anti-GIPR antibody, wherein the antibody comprises: a first light chain and a second light chain, each light chain comprising CDRL1, CDRL2, and CDRL3 of SEQ ID NO: 702, SEQ ID NO: 859, and SEQ ID NO: 1016, respectively; and a first heavy chain and a second heavy chain, each heavy chain comprising CDRH1, CDRH2, and CDRH3 of SEQ ID NO: 1173, SEQ ID NO: 1330, and SEQ ID NO: 1487, respectively. The molecule further comprises a first GLP-1 receptor agonist peptide and a second GLP-1 receptor agonist peptide, wherein each GLP-1 receptor agonist peptide comprises the amino acid sequence of SEQ ID NO: 1580; and a first peptide linker and a second peptide linker, wherein each peptide linker comprises the amino acid sequence of SEQ ID NO: 1591. The first GLP-1 receptor agonist polypeptide of the molecule is conjugated at its C-terminus to a cysteine ​​residue at position 384 of the first heavy chain of the GIPR antibody according to AHo number (corresponding to position 275 of SEQ ID NO: 1571) via a first linker, and the second GLP-1 receptor agonist polypeptide is conjugated at its C-terminus to a cysteine ​​residue at position 384 of the second heavy chain of the GIPR antibody according to AHo number (corresponding to position 275 of SEQ ID NO: 1571) via a second linker. In one embodiment, each light chain contains the VL of SEQ ID NO: 74, and each heavy chain contains the VH of SEQ ID NO: 231. In one embodiment, each light chain contains the amino acid sequence of SEQ ID NO: 388, and each heavy chain contains the amino acid sequence of SEQ ID NO: 1571.

[0211] In one embodiment, the exemplary anti-GIPR / GLP-1 conjugate molecule disclosed herein comprises an antagonist anti-GIPR antibody, wherein the antibody comprises: a first light chain and a second light chain, each light chain comprising CDRL1, CDRL2, and CDRL3 of SEQ ID NO: 702, SEQ ID NO: 859, and SEQ ID NO: 1016, respectively; and a first heavy chain and a second heavy chain, each heavy chain comprising CDRH1, CDRH2, and CDRH3 of SEQ ID NO: 1173, SEQ ID NO: 1330, and SEQ ID NO: 1487, respectively. The molecule further comprises a first GLP-1 receptor agonist peptide and a second GLP-1 receptor agonist peptide, wherein each GLP-1 receptor agonist peptide comprises the amino acid sequence of SEQ ID NO: 1581; and a first peptide linker and a second peptide linker, wherein each peptide linker comprises the amino acid sequence of SEQ ID NO: 1586. The first GLP-1 receptor agonist polypeptide of the molecule is conjugated at its C-terminus to a cysteine ​​residue at position 384 of the first heavy chain of the GIPR antibody according to AHo number (corresponding to position 275 of SEQ ID NO: 1571) via a first linker, and the second GLP-1 receptor agonist polypeptide is conjugated at its C-terminus to a cysteine ​​residue at position 384 of the second heavy chain of the GIPR antibody according to AHo number (corresponding to position 275 of SEQ ID NO: 1571) via a second linker. In one embodiment, each light chain contains the VL of SEQ ID NO: 74, and each heavy chain contains the VH of SEQ ID NO: 231. In one embodiment, each light chain contains the amino acid sequence of SEQ ID NO: 388, and each heavy chain contains the amino acid sequence of SEQ ID NO: 1571.

[0212] In one embodiment, the exemplary anti-GIPR / GLP-1 conjugate molecule disclosed herein comprises an antagonist anti-GIPR antibody, wherein the antibody comprises: a first light chain and a second light chain, each light chain comprising CDRL1, CDRL2, and CDRL3 of SEQ ID NO: 702, SEQ ID NO: 859, and SEQ ID NO: 1016, respectively; and a first heavy chain and a second heavy chain, each heavy chain comprising CDRH1, CDRH2, and CDRH3 of SEQ ID NO: 1173, SEQ ID NO: 1330, and SEQ ID NO: 1487, respectively. The molecule further comprises a first GLP-1 receptor agonist peptide and a second GLP-1 receptor agonist peptide, wherein each GLP-1 receptor agonist peptide comprises the amino acid sequence of SEQ ID NO: 1581; and a first peptide linker and a second peptide linker, wherein each peptide linker comprises the amino acid sequence of SEQ ID NO: 1585. The first GLP-1 receptor agonist polypeptide of the molecule is conjugated at its C-terminus to a cysteine ​​residue at position 384 of the first heavy chain of the GIPR antibody according to AHo number (corresponding to position 275 of SEQ ID NO: 1571) via a first linker, and the second GLP-1 receptor agonist polypeptide is conjugated at its C-terminus to a cysteine ​​residue at position 384 of the second heavy chain of the GIPR antibody according to AHo number (corresponding to position 275 of SEQ ID NO: 1571) via a second linker. In one embodiment, each light chain contains the VL of SEQ ID NO: 74, and each heavy chain contains the VH of SEQ ID NO: 231. In one embodiment, each light chain contains the amino acid sequence of SEQ ID NO: 388, and each heavy chain contains the amino acid sequence of SEQ ID NO: 1571.

[0213] In one embodiment, the antagonist anti-GIPR antibody of the conjugate molecule described herein is a monoclonal antibody that binds to GIPR. The monoclonal antibody can be produced using any technique known in the art, e.g., by immortalizing spleen cells harvested from a transgenic animal capable of producing human antibodies (e.g., XenoMouse®) after the completion of the immunization protocol. Spleen cells can be immortalized using any technique known in the art, e.g., by fusing spleen cells with myeloma cells to produce a hybridoma. The myeloma cells used in the fusion procedure for producing the hybridoma are preferably antibody-free, have high fusion efficiency, and are enzyme-deficient, preventing them from growing in certain selective culture media that only support the growth of the desired fusion cells (hybridomas). Examples of suitable cell lines for use in mouse fusions include Sp-20, P3-X63 / Ag8, P3-X63-Ag8.653, NS1 / 1.Ag41, Sp210-Ag14, FO, NSO / U, MPC-11, MPC11-X45-GTG1.7, and S194 / 5XXO Bul; examples of cell lines for use in rat fusions include R210.RCY3, Y3-Ag1.2.3, IR983F, and 4B210. Other cell lines that can be used for cell fusions are U-266, GM1500-GRG2, LICR-LON-HMy2, and UC729-6.

[0214] In some cases, hybridoma cell lines are generated by: immunizing an animal (e.g., a transgenic animal capable of producing human immunoglobulin sequences) with a GIPR immunogen; harvesting spleen cells from the immunized animal; fusing the harvested spleen cells with a myeloma cell line to generate hybridoma cells; establishing hybridoma cell lines from the hybridoma cells; and identifying hybridoma cell lines that produce antibodies that bind GIPR peptides. Anti-GIPR monoclonal antibodies produced by these hybridoma cells are suitable for inclusion in the molecules described herein.

[0215] Anti-GIPR monoclonal antibodies secreted by hybridoma cell lines can be purified using any technique known in the art. Hybridomas or mAbs can be further screened to identify mAbs with specific properties, such as the ability to antagonize GIPR activity.

[0216] Anti-GIPR chimeric antibodies and humanized antibodies are also applicable to the conjugate molecules described herein. The anti-GIPR antibody sequences disclosed herein can be modified in various ways prior to use. One example is a chimeric antibody, which is an antibody composed of protein segments from different antibodies covalently linked to produce a functional immunoglobulin light chain or heavy chain, or its immunofunctional portion. Generally, a portion of the heavy chain and / or light chain is identical or homologous to a corresponding sequence in an antibody derived from a specific species or belonging to a specific antibody class or subclass, while the remainder of the chain is identical or homologous to a corresponding sequence in an antibody derived from another species or belonging to another antibody class or subclass. For methods relating to chimeric antibodies, see, for example, U.S. Patent No. 4,816,567; and Morrison et al., 1985, Proc. Natl. Acad. Sci. USA [Proceedings of the National Academy of Sciences of the United States of America]. 81 References 6851-6855 are hereby incorporated by reference. CDR porting is described, for example, in U.S. Patent Nos. 6,180,370, 5,693,762, 5,693,761, 5,585,089, and 5,530,101.

[0217] Typically, the goal of preparing chimeric antibodies is to generate chimeras where the number of amino acids from a predetermined subject species is maximized. One example is a “CDR-transplanted” antibody, where the antibody contains one or more complementarity-determining regions (CDRs) derived from a specific species or belonging to a specific antibody class or subclass, while the remainder of the antibody chain is identical or homologous to the corresponding sequence in an antibody derived from another species or belonging to another antibody class or subclass. For use in humans, variable regions or selected CDRs from rodent antibodies are typically transplanted into human antibodies, replacing the naturally occurring variable regions or CDRs of that human antibody.

[0218] In one aspect, the CDRs of the light and heavy chain variable regions of the antibodies presented in this paper are transplanted into the framework regions (FRs) of antibodies from the same or different phylogenetic species. For example, the heavy and light chain variable regions V... H 1. V H 2. V H 3. V H 4. V H 5. V H 6. V H 7. V H 8. V H 9. V H 10. V H 11. V H 12 and / or V L 1 and V LThe CDR of 2 was transplanted into a common human FR. To generate a common human FR, FRs from several human heavy or light chain amino acid sequences can be compared to identify common amino acid sequences. In other embodiments, the FRs of the heavy or light chain disclosed herein are replaced with FRs from different heavy or light chains. In one aspect, rare amino acids in the heavy and light chain FRs of the GIPR antibody are not replaced, but the remaining FR amino acids are replaced. A “rare amino acid” is a specific amino acid located at a position in the FR where this particular amino acid is not commonly found. Alternatively, a transplanted variable region from one heavy or light chain can be used with a constant region that is different from the constant region of the specific heavy or light chain disclosed herein.

[0219] Human antagonist anti-GIPR antibodies are also provided. These methods can be used to produce human antibodies specific to a given antigen without exposing a person to that antigen. One specific method provided for generating human antibodies is the "humanization" of the mouse humoral immune system. Introducing the human immunoglobulin (Ig) locus into mice with inactivated endogenous Ig genes is one way to generate human monoclonal antibodies (mAbs) in mice, which are animals that can be immunized with any desired antigen. Using human antibodies minimizes immunogenicity and allergic responses, which are sometimes induced by the administration of mouse or mouse-derived mAbs to humans as therapeutic agents.

[0220] Human antibodies can be generated by immunizing transgenic animals (typically mice) that produce human antibody lineages without producing endogenous immunoglobulins. The antigens used for this purpose typically have six or more consecutive amino acids and are optionally conjugated to a carrier, such as a hapten. See, for example, Jakobovits et al., 1993, Proc. Natl. Acad. Sci. USA [Proceedings of the National Academy of Sciences of the United States of America]. 90 2551-2555; Jakobovits et al., 1993, Nature. 362 :255-258; and Bruggermann et al., 1993, Year in Immunol. 7:33. In one example of such a method, transgenic animals are produced by deactivating an endogenous mouse immunoglobulin locus encoding the mouse heavy and light chain immunoglobulin chains and inserting a larger fragment of a locus containing human genomic DNA encoding human heavy and light chain proteins into the mouse genome. Animals with less complete complement modification than the human immunoglobulin locus are then crossbred to obtain animals with all the desired immune system modifications. When an immunogen is administered, these transgenic animals produce antibodies that are immune-specific to that immunogen and possess a human, not mouse, amino acid sequence, including the variable region. For further details on such methods, see, for example, WO 96 / 33735 and WO 94 / 02602. Further methods for preparing transgenic mice with human antibodies are described in U.S. Patent Nos. 5,545,807, 6,713,610, 6,673,986, 6,162,963, 5,545,807, 6,300,129, 6,255,458, 5,877,397, 5,874,299 and 5,545,806; PCT Publications WO 91 / 10741, WO 90 / 04036; and EP 546073 B1 and EP 546073A1.

[0221] Suitable human antibodies can be alternatively derived from phage display libraries (e.g., Hoogenboom et al., 1991, J.Mol. Biol. [Journal of Molecular Biology]). 227 :381; and Marks et al., 1991, J. Mol. Biol. [Journal of Molecular Biology] 222 (Disclosed in :581). Phage display technology mimics immune selection by displaying antibody lineages on the surface of filamentous phages and subsequently selecting phages by binding to selected antigens. One such technology is described in PCT Publication No. WO 99 / 10494 (incorporated hereby by reference).

[0222] The anti-GIPR antibodies used in the molecules described herein can be prepared using any of a variety of conventional techniques. For example, antibodies can be generated using a recombinant expression system. See, for example, Monoclonal Antibodies, Hybridomas: A New Dimension in Biological Analyses, Kennet et al. (eds.), Plenum Press, New York (1980); and Antibodies: A Laboratory Manual, Harlow and Lane (eds.), Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York (1988).

[0223] In one embodiment, the anti-GIPR antibody provided herein is expressed in a hybridoma cell line or a cell line other than a hybridoma. The expression construct encoding the anti-GIPR antibody can be used to transform mammalian, insect, or microbial host cells. Transformation can be performed using any known method for introducing polynucleotides into host cells, including, for example, encapsulating polynucleotides in viruses or bacteriophages and transducing host cells with the construct using transfection procedures known in the art, such as those exemplified in U.S. Patent Nos. 4,399,216, 4,912,040, 4,740,461, and 4,959,455. The choice of transformation procedure will depend on the type of host cells being transformed. Methods for introducing heterologous polynucleotides into mammalian cells are well known in the art and include, but are not limited to, dextran-mediated transfection, calcium phosphate precipitation, polybrene-mediated transfection, protoplast fusion, electroporation, encapsulation of polynucleotides in liposomes, mixing nucleic acids with positively charged lipids, and direct microinjection of DNA into the cell nucleus.

[0224] Recombinant expression constructs typically contain a nucleic acid molecule encoding a polypeptide that includes one or more of the following: one or more light chain CDRs; one or more heavy chain CDRs; a light chain constant region; a light chain variable region; a heavy chain constant region (e.g., CDRs). H 1. C H 2 and / or C H3) and the heavy chain variable region. These nucleic acid sequences are inserted into an appropriate expression vector using standard ligation techniques. In one embodiment, the heavy chain or light chain constant region is attached to the C-terminus of the anti-GIPR specific heavy chain or light chain variable region and ligated into the expression vector. Typically, vectors that are functional in the specific host cell used are selected (i.e., the vector is compatible with the host cell structure, thereby allowing gene amplification and / or expression to occur).

[0225] Typically, expression vectors used in any host cell will contain sequences for plasmid maintenance and for cloning and expressing exogenous nucleotide sequences. Such sequences (collectively referred to as "sidelink sequences") may include one or more of the following nucleotide sequences: promoter, one or more enhancer sequences, origin of replication, transcription termination sequence, complete intron sequences containing donor and acceptor splicing sites, sequence encoding a leader sequence for polypeptide secretion, ribosome binding site, polyadenylated sequence, multi-connector region for inserting a nucleic acid encoding the polypeptide to be expressed, and optional marker elements.

[0226] Lateral sequences can be homologous (i.e., from the same species and / or strain as the host cell), heterologous (i.e., from a different species or strain than the host cell), hybrid (i.e., a combination of lateral sequences from more than one source), synthetic, or natural. Therefore, the source of a lateral sequence can be any prokaryotic or eukaryotic organism, any vertebrate or invertebrate organism, or any plant, as long as the lateral sequence functions within the host cell machinery and can be activated by the host cell machinery.

[0227] Useful side sequences in the vector can be obtained by methods known in the art. Typically, the side sequences are pre-identified by localization and / or digestion with restriction endonucleases and thus isolated from appropriate tissue sources using suitable restriction endonucleases. In some cases, the full nucleotide sequence of the side sequence may be known. Side sequences can be synthesized using conventional nucleic acid synthesis or cloning methods.

[0228] Origin of replication (OCR) is typically a component of commercially available prokaryotic expression vectors; it facilitates vector amplification within host cells. If the chosen vector does not contain an OCR, it can be chemically synthesized based on a known sequence and ligated into the vector. For example, the OCR from plasmid pBR322 (New England Biolabs, Beverly, Massachusetts) is suitable for most Gram-negative bacteria and various viral OCRs (e.g., SV40, polyomaviruses, adenoviruses, vesicular stomatitis virus (VSV), or papillomaviruses (such as, for example, HPV or BPV)). Generally, mammalian expression vectors do not require an OCR component (e.g., typically only the SV40 OCR is used because it also contains an early viral promoter).

[0229] Transcription termination sequences are typically located at the 3′ end of the polypeptide coding region and are used to terminate transcription. In prokaryotic cells, the transcription termination sequence is usually a GC-rich fragment followed by a poly-T sequence. Although this sequence is readily available from library cloning or even commercially available as part of a vector, it can also be easily synthesized using conventional nucleic acid synthesis methods.

[0230] Selectable marker genes encode proteins required for the survival and growth of host cells grown in selective media. Typical selectable marker genes encode proteins that: (a) confer resistance to antibiotics or other toxins (e.g., ampicillin, tetracycline, or kanamycin for prokaryotic host cells); (b) compensate for cellular nutritional deficiencies; or (c) provide essential nutrients not available in complex or limited media. Specific selectable markers include kanamycin resistance genes, ampicillin resistance genes, and tetracycline resistance genes. Advantageously, neomycin resistance genes can also be used for selection in both prokaryotic and eukaryotic host cells.

[0231] Genes to be expressed can be amplified using other selectable genes. Amplification is the process of tandem replication of genes required to produce proteins necessary for growth or cell survival within the chromosomes of recombinant cells across successive generations. Examples of selectable markers suitable for mammalian cells include dihydrofolate reductase (DHFR) and the promoterless thymidine kinase gene. Transformed mammalian cells are subjected to selection pressure, where only the transformant is uniquely suited for survival due to the presence of the selectable gene in the vector. Selection pressure is applied by culturing transformed cells under conditions of continuously increasing concentrations of the selectant in the culture medium, resulting in the amplification of the selectable gene and the DNA encoding another gene (e.g., an antibody binding a GIPR peptide). Consequently, an increased amount of peptide (e.g., an anti-GIPR antibody) is synthesized from the amplified DNA.

[0232] Ribosome binding sites are typically required for the initiation of mRNA translation and are characterized by a Shine-Dalgarno sequence (prokaryotes) or a Kozak sequence (eukaryotes). This element is typically located at the 3' end of the promoter and at the 5' end of the coding sequence of the polypeptide to be expressed.

[0233] In some cases, such as when glycosylation is desired in eukaryotic host cell expression systems, various pre-sequences can be manipulated to improve glycosylation or yield. For example, the peptidase cleavage site of a specific signal peptide can be altered, or pre-sequences can be added, which can also affect glycosylation. The final protein product may have one or more additional amino acids readily expressible at the -1 position (relative to the first amino acid of the mature protein), which may not be completely removed. For example, the final protein product may have one or two amino acid residues attached to the amino terminus found in the peptidase cleavage site. Alternatively, when the enzyme cleaves in such a region within the mature polypeptide, using some enzyme cleavage sites may produce a slightly truncated form of the desired polypeptide.

[0234] Expression and cloning typically involve a promoter containing a molecule operatively linked to a host organism that is recognized by the host organism and encodes an anti-GIPR antibody. A promoter is a non-transcribed sequence located upstream (i.e., 5') of the start codon of a structural gene that controls transcription of structural genes. Promoters are generally grouped into one of two categories: inducible promoters and constitutive promoters. Inducible promoters elicit an increased level of transcription in response to a change in culture conditions (such as the presence or absence of nutrients, or a change in temperature) by the DNA under their control. Constitutive promoters, on the other hand, consistently transcribe the gene to which they are operatively linked, i.e., they have minimal or no control over gene expression. Many promoters recognized by a variety of potential host cells are well known. The promoter is operatively linked to DNA encoding a heavy or light chain containing the GIPR antibody by removing the appropriate promoter from the source DNA through restriction enzyme digestion and inserting the desired promoter sequence into a vector.

[0235] Suitable promoters for yeast hosts are well known in the art. Yeast enhancers are preferred for use with yeast promoters. Suitable promoters for mammalian host cells are well known and include, but are not limited to, promoters derived from viral genomes, such as polyomaviruses, infectious epitheliomaviruses, adenoviruses (e.g., adenovirus 2), bovine papillomaviruses, avian sarcomaviruses, cytomegaloviruses, retroviruses, hepatitis B viruses, and simian virus 40 (SV40). Other suitable mammalian promoters include, but are not limited to, heterologous mammalian promoters, such as heat shock promoters and actin promoters.

[0236] Enhancer sequences can be inserted into vectors to increase transcription of light or heavy chain DNA encoding anti-GIPR antibodies in higher eukaryotes. Enhancers are cis-acting elements of DNA, typically about 10–300 bp in length, that act on promoters to increase transcription. Enhancers are relatively independent in orientation and location, and have been found at the 5' and 3' positions of transcription units. Several enhancer sequences are known to be derived from mammalian genes (e.g., globin, elastase, albumin, alpha-fetoprotein, and insulin). Alternatively, enhancers derived from viruses can be used. SV40 enhancers, cytomegalovirus early promoter enhancers, polyomavirus enhancers, and adenovirus enhancers known in the art are non-limiting examples of enhancing elements for activating eukaryotic promoters. Although enhancers can be located at the 5' or 3' of the coding sequence in a vector, they are typically located at the 5' site of the promoter. Sequences encoding appropriate native or heterologous signal sequences (lead sequences or signal peptides) can be incorporated into expression vectors, for example, to promote the extracellular secretion of antibodies. The choice of signal peptide or leader sequence depends on the type of host cell from which the antibody is to be produced, and a heterologous signal sequence can replace the native signal sequence. Non-limiting examples of functional signal peptides in mammalian host cells include the following: the signal sequence of interleukin-7 (IL-7) described in U.S. Patent No. 4,965,195; Cosman et al., 1984, Nature. 312 Interleukin-2 receptor signaling sequence as described in :768; interleukin-4 receptor signaling peptide as described in European Patent No. 0367 566; type I interleukin-1 receptor signaling peptide as described in US Patent No. 4,968,607; type II interleukin-1 receptor signaling peptide as described in European Patent No. 0460 846.

[0237] In one embodiment, the leader sequence comprises SEQ ID NO: 1655 (MDMRVPAQLL GLLLLWLRGA RC). In another embodiment, the leader sequence comprises SEQ ID NO: 1656 (MAWALLLLTL LTQGTGSWA).

[0238] Expression vectors can be constructed from starter vectors, such as commercially available vectors. These vectors may or may not contain all the desired side sequences. In the absence of one or more of the side sequences described herein, they can be obtained independently and ligated into the vector. Methods for obtaining the respective side sequences are well known to those skilled in the art.

[0239] Optionally, the vector may contain a "tag" encoding sequence, i.e., an oligonucleotide molecule located at the 5′ or 3′ end of the GIPR antibody encoding sequence; this oligonucleotide sequence encodes polyHis (e.g., hexameric His), or another "tag" for a commercially available antibody targeting it, such as a FLAG, may be present. ® The tag is HA (hemagglutinin influenza virus) or myc. This tag is typically fused to the peptide during expression and can be used as a means of affinity purification or detection of antibodies from host cells. Affinity purification can be achieved, for example, by column chromatography using an antibody against the tag as an affinity matrix. Optionally, the tag can then be removed from the purified antibody by various methods, such as using certain peptidase cleavage.

[0240] After the vector has been constructed and nucleic acid molecules encoding the light chain, heavy chain, or a combination of light and heavy chains have been inserted into the appropriate sites within the vector, the intact vector can be inserted into suitable host cells for amplification and / or peptide expression. Transformation of antibody-encoding expression vectors into selected host cells can be achieved using conventional methods, including but not limited to transfection, infection, calcium phosphate co-precipitation, electroporation, microinjection, lipid transfection, DEAE-glucan-mediated transfection, or other known techniques. The chosen method will vary in part depending on the type of host cells used.

[0241] When cultured under appropriate conditions, host cells synthesize anti-GIPR antibodies, which can then be collected from the culture medium (if the host cell secretes it into the medium) or directly from the host cell that produced the anti-GIPR antibody (if it is not secreted). The selection of a suitable host cell will depend on various factors, such as the desired expression level, the desired or necessary peptide modifications (e.g., glycosylation or phosphorylation) for activity, and ease of folding into a biologically active molecule.

[0242] Mammalian cell lines that can be used as hosts for expression are well known in the art and include, but are not limited to, immortalized cell lines available from the American Type Culture Collection (ATCC), including, but not limited to, Chinese hamster ovary (CHO) cells, HeLa cells, young hamster kidney (BHK) cells, monkey kidney cells (COS) cells, human hepatocellular carcinoma cells (e.g., Hep G2), and a variety of other cell lines. In one embodiment, host cell lines can be selected by identifying which cell lines have high expression levels and constitutively produce the desired anti-GIPR antibody. In one embodiment, cell lines that do not produce autoantibodies but are capable of preparing and secreting heterologous antibodies can be selected from B cell lineages.

[0243] Additionally, in one embodiment, a mammalian cell line modified to provide reduced cleavage of peptides conjugated to a cell-expressed polypeptide can be used (e.g., a cathepsin D knockout cell line). In one embodiment, a mammalian cell line in which both alleles of cathepsin D are knocked out (e.g., using CRISPR or zinc finger technology) can be used (e.g., a CHO cell line). Examples of cathepsin D knockout cells that can be used to generate antibody-peptide conjugates of the present disclosure are described in WO 2023 / 086790 (which is incorporated herein by reference).

[0244] Pharmaceutical Composition While the GLP-1 receptor agonist peptides or anti-GIPR / GLP-1 conjugates disclosed herein may be administered alone in the uses described herein, GLP-1 receptor agonist peptides or conjugates are typically administered as the active ingredient in a pharmaceutical composition. Therefore, this document further provides pharmaceutical compositions comprising the GLP-1 receptor agonist peptides or anti-GIPR / GLP-1 conjugates disclosed herein, along with pharmaceutically acceptable excipients. Non-limiting examples of pharmaceutically acceptable excipients include calcium carbonate, calcium phosphate, sugars (e.g., lactose, glucose, or sucrose), starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycol, and physiologically compatible solvents. See, for example, Remington: The Science and Practice of Pharmacy, Volumes I and II, 22nd ed., edited by Loyd V. Allen Jr., Philadelphia, PA, Pharmaceutical Press, 2012; Pharmaceutical Dosage Forms (Vols. 1–3), edited by Liberman et al., Marcel Dekker, NY, 1992; Handbook of Pharmaceutical Excipients (3rd ed.), edited by Arthur H. Kibbe, American Pharmaceutical Association, Washington, 2000; Pharmaceutical Formulation: The Science and Technology of Dosage Forms (Drug Discovery), 1st ed., edited by GD Tovey, Royal Society of Chemistry. 2018.

[0245] In some cases, the pharmaceutical compositions described herein comprise a therapeutically effective amount of the GLP-1 receptor agonist peptide or anti-GIPR / GLP-1 conjugate molecule disclosed herein. In one embodiment, the pharmaceutical composition is prepared in a dosage unit containing a specific amount of the active ingredient.

[0246] The GLP-1 receptor agonist peptides or anti-GIPR / GLP-1 conjugate molecules disclosed herein can be administered via any suitable route in the form of pharmaceutical compositions suited to such routes and at a dose effective for the intended treatment. The peptides, molecules, and compositions described herein can be formulated in dose units containing conventionally pharmaceutically acceptable excipients, and administered, for example, orally, via mucosae, dermis, parenteral, intravenous, intraperitoneal, subcutaneous, intramuscular, or by infusion techniques. For example, in one embodiment, the pharmaceutical compositions disclosed herein can be provided for peripheral administration, such as parenteral administration (e.g., subcutaneous, intravenous, intramuscular), continuous infusion (e.g., intravenous drip, intravenous bolus, intravenous infusion), topical, nasal, or oral administration.

[0247] The pharmaceutical compositions disclosed herein can be sterilized using conventional sterilization techniques or by filtration sterilization. In one embodiment, such a composition comprises sterile water. In another embodiment, such a composition may contain pharmaceutically acceptable adjuvants to approximate physiological conditions, such as pH buffers (e.g., acetate buffer).

[0248] In one embodiment, the pharmaceutical composition comprises sterile water and sodium chloride. In one embodiment, the pharmaceutical composition comprises sterile water and dextrose. In another embodiment, the pharmaceutical composition comprises sterile water, sodium chloride, and dextrose.

[0249] In one embodiment, the pharmaceutical composition comprises an aqueous carrier. In one embodiment, the aqueous carrier is an isotonic buffer solution with a pH in the range of 3.0 to 8.0 (e.g., in the range of 3.0 to 5.0).

[0250] In one embodiment, the pharmaceutical composition is a parenteral composition. In one embodiment, the pharmaceutical composition is a parenteral composition for injection. In one embodiment, the pharmaceutical composition is a parenteral composition for infusion.

[0251] In one embodiment, a reservoir or “reservoir” sustained-release formulation may be used to deliver a therapeutically effective amount of the formulation into the bloodstream hours or days after subcutaneous injection, percutaneous injection, or other delivery methods. The required isotonicity may be achieved using sodium chloride or other pharmaceutically acceptable excipients, such as dextran, boric acid, sodium tartrate, propylene glycol, polyols (e.g., mannitol and sorbitol), or other inorganic or organic solutes.

[0252] Treatment The GLP-1 receptor agonist peptides disclosed herein and their conjugates (e.g., anti-GIPR antibody / GLP-1 receptor agonist conjugates) may be used to reduce weight in subjects in need. The GLP-1 receptor agonist peptides disclosed herein and their conjugates may also be used to reduce food intake in subjects in need. The GLP-1 receptor agonist peptides disclosed herein and their conjugates may also be used to lower hypertension and / or glycemic levels in subjects in need. The GLP-1 receptor agonist peptides and their conjugates may also be used to treat obesity in subjects in need, and to treat and prevent obesity-related conditions in subjects in need. Obesity-related conditions include, but are not limited to, cardiovascular disease, particularly hypertension, heart failure, and atherosclerotic cardiovascular disease (ASCVD); sleep apnea; dyslipidemia; chronic kidney disease; and metabolic dysfunction-associated steatohepatitis (MASH). GLP-1 receptor agonist peptides and conjugates containing these GLP-1 receptor agonist peptides may also be used to treat type 2 diabetes in subjects in need, as well as to treat and prevent type 2 diabetes-related conditions in subjects in need. Type 2 diabetes-related conditions include, but are not limited to, hypertension, hyperglycemia, cardiovascular disease, diabetic nephropathy, and diabetic kidney failure.

[0253] Therefore, in one aspect, this disclosure provides methods for preventing or treating obesity, obesity-related conditions, type 2 diabetes, and / or type 2 diabetes-related conditions in a subject of need. In one embodiment, the method involves administering to a subject the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule disclosed herein or a pharmaceutical composition comprising thereof at a dose of about 21 mg to about 840 mg. In one embodiment, the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule or a pharmaceutical composition comprising thereof is administered to the subject at a dose of about 21 mg to about 840 mg every four weeks, at a dose of about 21 mg to about 840 mg every six weeks, at a dose of about 21 mg to about 840 mg every eight weeks, or at a dose of about 21 mg to about 840 mg every twelve weeks. In one embodiment, an anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule or a pharmaceutical composition comprising therethe is administered to the subject at a dose of about 21 mg to about 840 mg per month, about 21 mg to about 840 mg every half month, about 21 mg to about 840 mg every two months, or about 21 mg to about 840 mg every three months. In one embodiment, the subject is obese. In one embodiment, the subject has an obesity-related condition or is at risk of having an obesity-related condition. In one embodiment, the subject has sleep apnea. In one embodiment, the subject has dyslipidemia. In one embodiment, the subject has cardiovascular disease or is at risk of having cardiovascular disease. In one embodiment, the subject has ASCVD or is at risk of having ASCVD. In one embodiment, the subject has heart failure. In one embodiment, the subject has hypertension. In one embodiment, the subject has chronic renal failure. In one embodiment, the subject has MASH. In one embodiment, the subject has type 2 diabetes. In one embodiment, the subject has type 2 diabetes-related conditions. In one embodiment, the subject has hypertension and / or hyperglycemia. In one embodiment, the subject has diabetic nephropathy or diabetic renal failure. In one embodiment, the subject has cardiovascular disease.

[0254] On the other hand, this disclosure provides methods for reducing the weight or food intake of a subject in need. The method involves administering the disclosed anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule or a pharmaceutical composition comprising thereof to a subject at a dose of about 21 mg to about 840 mg. In one embodiment, the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule or a pharmaceutical composition comprising thereof is administered to the subject at a dose of about 21 mg to about 840 mg every four weeks, at a dose of about 21 mg to about 840 mg every six weeks, at a dose of about 21 mg to about 840 mg every eight weeks, or at a dose of about 21 mg to about 840 mg every twelve weeks. In one embodiment, the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule or a pharmaceutical composition comprising thereof is administered to the subject at a dose of about 21 mg to about 840 mg per month, at a dose of about 21 mg to about 840 mg every half month, at a dose of about 21 mg to about 840 mg every two months, or at a dose of about 21 mg to about 840 mg every three months. In one embodiment, the subject has an obesity-related condition or is at risk of having an obesity-related condition. In one embodiment, the subject has sleep apnea. In one embodiment, the subject has dyslipidemia. In one embodiment, the subject has cardiovascular disease or is at risk of having cardiovascular disease. In one embodiment, the subject has ASCVD or is at risk of having ASCVD. In one embodiment, the subject has heart failure. In one embodiment, the subject has hypertension. In one embodiment, the subject has chronic renal failure. In one embodiment, the subject has MASH. In one embodiment, the subject has type 2 diabetes. In one embodiment, the subject has type 2 diabetes-related conditions. In one embodiment, the subject has hypertension and / or hyperglycemia. In one embodiment, the subject has diabetic nephropathy or diabetic renal failure. In one embodiment, the subject has cardiovascular disease.

[0255] On the other hand, this disclosure provides methods for lowering blood pressure and / or blood glucose levels in subjects in need. The method involves administering the disclosed anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule or a pharmaceutical composition comprising thereof to a subject at a dose of about 21 mg to about 840 mg. In one embodiment, the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule or a pharmaceutical composition comprising thereof is administered to the subject at a dose of about 21 mg to about 840 mg every four weeks, at a dose of about 21 mg to about 840 mg every six weeks, at a dose of about 21 mg to about 840 mg every eight weeks, or at a dose of about 21 mg to about 840 mg every twelve weeks. In one embodiment, the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule or a pharmaceutical composition comprising thereof is administered to the subject at a dose of about 21 mg to about 840 mg per month, at a dose of about 21 mg to about 840 mg every half month, at a dose of about 21 mg to about 840 mg every two months, or at a dose of about 21 mg to about 840 mg every three months. In one embodiment, the subject is obese. In one embodiment, the subject has an obesity-related condition or is at risk of having an obesity-related condition. In one embodiment, the subject has sleep apnea. In one embodiment, the subject has dyslipidemia. In one embodiment, the subject has cardiovascular disease or is at risk of having cardiovascular disease. In one embodiment, the subject has ASCVD or is at risk of having ASCVD. In one embodiment, the subject has heart failure. In one embodiment, the subject has hypertension. In one embodiment, the subject has chronic renal failure. In one embodiment, the subject has MASH. In one embodiment, the subject has type 2 diabetes. In one embodiment, the subject has type 2 diabetes-related conditions. In one embodiment, the subject has hypertension and / or hyperglycemia. In one embodiment, the subject has diabetic nephropathy or diabetic renal failure. In one embodiment, the subject has cardiovascular disease.

[0256] On the other hand, this disclosure provides the use of the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule disclosed herein in the preparation of a medicament for the prevention or treatment of obesity, obesity-related conditions, type 2 diabetes, or type 2 diabetes-related conditions in a subject of need. In one embodiment, the medicament is formulated for administration at a dose of about 21 mg to about 840 mg. In one embodiment, the medicament (formulated at a dose of about 21 mg to about 840 mg) is administered to the subject once every four weeks, every six weeks, every eight weeks, or every twelve weeks. In one embodiment, the medicament (formulated at a dose of about 21 mg to about 840 mg) is administered to the subject once a month, every half month, every two months, or every three months. In one embodiment, the subject is obese. In one embodiment, the subject has an obesity-related condition or is at risk of having an obesity-related condition. In one embodiment, the subject has sleep apnea. In one embodiment, the subject has dyslipidemia. In one embodiment, the subject has cardiovascular disease or is at risk of having cardiovascular disease. In one embodiment, the subject has ASCVD or is at risk of having ASCVD. In one embodiment, the subject has heart failure. In one embodiment, the subject has hypertension. In one embodiment, the subject has chronic renal failure. In one embodiment, the subject has MASH. In one embodiment, the subject has type 2 diabetes. In one embodiment, the subject has type 2 diabetes-related conditions. In one embodiment, the subject has high blood pressure and / or high blood sugar. In one embodiment, the subject has diabetic nephropathy or diabetic kidney failure. In one embodiment, the subject has cardiovascular disease.

[0257] In another aspect, this disclosure relates to the use of the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule disclosed herein in the preparation of a medicament for reducing the weight or food intake of a subject in need. The medicament is formulated for administration at a dose of about 21 mg to about 840 mg. In one embodiment, the medicament (formulated at a dose of about 21 mg to about 840 mg) is administered to the subject once every four weeks, every six weeks, every eight weeks, or every twelve weeks. In one embodiment, the medicament (formulated at a dose of about 21 mg to about 840 mg) is administered to the subject once a month, every half month, every two months, or every three months. In one embodiment, the subject is obese. In one embodiment, the subject has an obesity-related condition or is at risk of having an obesity-related condition. In one embodiment, the subject has sleep apnea. In one embodiment, the subject has dyslipidemia. In one embodiment, the subject has cardiovascular disease or is at risk of having cardiovascular disease. In one embodiment, the subject has ASCVD or is at risk of having ASCVD. In one embodiment, the subject has heart failure. In one embodiment, the subject has hypertension. In one embodiment, the subject has chronic renal failure. In one embodiment, the subject has MASH. In one embodiment, the subject has type 2 diabetes. In one embodiment, the subject has type 2 diabetes-related conditions. In one embodiment, the subject has hypertension and / or hyperglycemia. In one embodiment, the subject has diabetic nephropathy or diabetic kidney failure. In one embodiment, the subject has cardiovascular disease.

[0258] In another aspect, this disclosure relates to the use of the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule disclosed herein in the preparation of a medicament for lowering blood pressure and / or lowering blood glucose levels in a subject in need. The medicament is formulated for administration at a dose of about 21 mg to about 840 mg. In one embodiment, the medicament (formulated at a dose of about 21 mg to about 840 mg) is administered to the subject once every four weeks, every six weeks, every eight weeks, or every twelve weeks. In one embodiment, the medicament (formulated at a dose of about 21 mg to about 840 mg) is administered to the subject once a month, every half month, every two months, or every three months. In one embodiment, the subject is obese. In one embodiment, the subject has an obesity-related condition or is at risk of having an obesity-related condition. In one embodiment, the subject has sleep apnea. In one embodiment, the subject has dyslipidemia. In one embodiment, the subject has cardiovascular disease or is at risk of having cardiovascular disease. In one embodiment, the subject has ASCVD or is at risk of having ASCVD. In one embodiment, the subject has heart failure. In one embodiment, the subject has hypertension. In one embodiment, the subject has chronic renal failure. In one embodiment, the subject has MASH. In one embodiment, the subject has type 2 diabetes. In one embodiment, the subject has type 2 diabetes-related conditions. In one embodiment, the subject has high blood pressure and / or high blood sugar. In one embodiment, the subject has diabetic nephropathy or diabetic kidney failure. In one embodiment, the subject has cardiovascular disease.

[0259] In one embodiment, the weekly and monthly dosing schedules for the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule are similar among subjects and are not affected by weight. Alternatively, the monthly dose of the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule may be based on the subject's weight.

[0260] The dosage of the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule described herein can be administered as a single dose or distributed between multiple doses during a dosing frequency cycle. For example, in one embodiment, a therapeutically effective dose of the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule is administered as a single dose in each frequency cycle. Thus, in one embodiment, any dose of the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule described herein can be administered to the subject once monthly (QM dosing). Subjects receiving a QM dosing regimen typically receive the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule every 24 to 36 days, preferably every 28 to 35 days, more preferably every 28 to 31 days, or even more preferably every 28 days or every 30 days. In these and other embodiments, the monthly dose is administered to the subject by bolus injection (e.g., using a self-injection device as described herein).

[0261] In alternative embodiments, the dose of the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule may be allocated between two or more administrations during a dosing frequency cycle. For example, for a monthly dosing frequency cycle, the monthly dose may be divided into four doses administered weekly, or into two doses administered every two weeks. Any dose of the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule described herein may be allocated between two or more administrations. The number of administrations and the interval between interventions may be tailored to specific subjects based on the severity of the condition (e.g., obesity, type 2 diabetes, or obesity or type 2 diabetes-related conditions), the subject's age, the subject's physical condition, concomitant treatment with other medications, and / or the presence of other conditions.

[0262] In one embodiment, a subject suitable for treatment according to the methods and compositions described herein is a subject who has or has been diagnosed with type 2 diabetes. In one embodiment, a subject with type 2 diabetes is a subject with a hemoglobin A1C (HbA1c) level ≥ 6.5% and ≤ 10% (48 to 86 mmol / mol), wherein administration of the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule at the doses and frequencies disclosed herein reduces the subject's HbA1c level. In one embodiment, administration of the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule at the doses and frequencies disclosed herein reduces the subject's HbA1c level by about 0.5%, about 1%, about 1.5%, about 2%, or > 2%. In one embodiment, a subject suitable for treatment according to the methods and compositions described herein is a subject with type 2 diabetes who has been treated with metformin, sulfonylureas, or sodium-glucose cotransporter 2 (SGLT2) inhibitors as monotherapy or in combination therapy.

[0263] In one embodiment, the subject was obese but did not have type 2 diabetes. In another embodiment, the subject had not previously received any treatment for obesity.

[0264] In one embodiment, a subject suitable for treatment according to the methods and compositions described herein is a body mass index (“BMI”) ≥ 25 kg / m². 2 Subjects. In one embodiment, the subject's BMI ≥ 27 kg / m². 2 In one embodiment, the subject's BMI was ≥ 30 kg / m². 2 Body mass index (BMI) is calculated by dividing a person's weight (in kilograms (or pounds)) by the square of their height (in meters (or feet)). A high BMI can indicate high body fat. In one embodiment, a subject's BMI is ≥ 35 kg / m². 2 In one embodiment, the subject's BMI was ≥ 40 kg / m². 2 In one embodiment, the subject's BMI is greater than 25 kg / m² and less than 40 kg / m². In another embodiment, the subject's BMI is greater than 27 kg / m² and less than 40 kg / m². In yet another embodiment, the subject's BMI is greater than 30 kg / m² and less than 35 kg / m². Measurements can also be converted to lbs / in. 2 In one embodiment, BMI ≥ 25 kg / m² 2 ≥ 27 kg / m 2 or ≥ 30 kg / m 2 The subjects also had one or more obesity-related conditions, such as hypertension, dyslipidemia, sleep apnea, or cardiovascular disease.

[0265] In one embodiment, treating obesity includes promoting weight loss in a subject. Therefore, this disclosure relates to a method of treating obesity in which a subject loses approximately 5% of their body weight within 52 weeks, approximately 10% within 52 weeks, approximately 15% within 52 weeks, approximately 20% within 52 weeks, approximately 25% within 52 weeks, or approximately 30% within 52 weeks. As used in the foregoing context, “weight” refers to the subject’s weight prior to the first administration of the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule disclosed herein or a pharmaceutical composition comprising therethe.

[0266] In one embodiment, treating obesity includes maintaining a subject's weight by administering a maintenance dose of an anti-GIPR antibody / GLP-1 receptor agonist. Therefore, this disclosure relates to a method for maintaining a subject's weight where the subject's weight fluctuation does not exceed ±0.5%, ±1.0%, ±1.5%, ±2.0%, ±2.5%, ±3.0%, ±3.5%, ±4.0%, ±4.5%, or ±5.0% of a target weight. As used in the foregoing context, "target weight" refers to the weight the subject intends to maintain. The maintenance dose may be the same amount and frequency as the dose that promotes weight loss. Alternatively, the maintenance dose may be 1) an amount of the anti-GIPR antibody / GLP-1 receptor agonist conjugate lower than the dose that promotes weight loss, 2) a dose administered at a frequency lower than the dose that promotes weight loss, or 3) an amount and frequency lower than the dose that promotes weight loss.

[0267] In one embodiment of the methods described herein, an anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule is administered parenterally to a subject. Parenterical administration includes intraperitoneal, intramuscular, intravenous, intradermal, and subcutaneous administration. In a preferred embodiment, a pharmaceutical composition comprising a therapeutically effective amount of the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule is administered subcutaneously to a subject. In these and other embodiments of administration of the pharmaceutical composition via parenterical injection, the pharmaceutical composition may be administered to the subject using a syringe. In one embodiment, the syringe is pre-filled with the pharmaceutical composition. In other embodiments of administration of the pharmaceutical composition to a subject via parenterical injection (e.g., subcutaneous injection), the pharmaceutical composition is administered using an injection device (including devices for self-administration). Such devices are commercially available and include, but are not limited to, autoinjectors, pens, microinfusion pumps, and pre-filled syringes. Exemplary devices for administering a pharmaceutical composition comprising a therapeutically effective amount of an anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule according to the method of the present invention include auto-injectors (e.g., SureClick®, EverGentle®, Avanti®, DosePro®, Molly®, and Leva®) and pen-injection devices (e.g., Madie® pen injector, DCP). TM Pen-type injector, BD Vystra TM Disposable pen, BD TM Reusable pen) and pre-filled syringe (BD Sterifill from Baxter) TM BD Hypak TM(Pre-filled syringe). In one embodiment, a pharmaceutical composition comprising a therapeutically effective amount of an anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule is administered to a subject using a pre-filled syringe. In another embodiment, a pharmaceutical composition comprising a therapeutically effective amount of an anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule is administered to a subject using an autoinjector. In one embodiment, the injection volume is about 3 mL or less, about 2 mL or less, or about 1 mL or less.

[0268] In one embodiment, the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule as disclosed herein is administered to the subject during a defined treatment period. The “treatment period” begins with the administration of the first dose of the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule and ends with the administration of the final dose of the conjugate molecule. The treatment period can comprise approximately 1 month to approximately 36 months, such as approximately 2 months, approximately 3 months, approximately 4 months, approximately 5 months, approximately 6 months, approximately 7 months, approximately 8 months, approximately 9 months, approximately 10 months, approximately 11 months, approximately 12 months, approximately 13 months, approximately 14 months, approximately 15 months, approximately 18 months, approximately 21 months, approximately 24 months, approximately 27 months, approximately 30 months, or approximately 33 months. In one embodiment, the treatment period is approximately 6 months. In one embodiment, the treatment period is approximately 7 months. In one embodiment, the treatment period is approximately 12 months. In one embodiment, the treatment period can be longer than 36 months, such as 48, 60, or 64 months or longer.

[0269] Administration of the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule according to the methods disclosed herein preferably causes few or no adverse side effects in treated subjects. As used herein, the term "adverse side effect" means any abnormality, defect, mutation, lesion, degeneration, harmful or undesirable reaction, symptom, or injury that may be caused by taking the drug. In one embodiment, administration of the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule substantially does not cause one or more adverse side effects associated with other obesity treatments. Side effects associated with other weight loss treatments include, but are not limited to, fatigue, nausea, dizziness, insomnia, depression, decreased exercise tolerance, tremor, paresthesia, teratogenicity, and cognitive difficulties. In one embodiment, administration of the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule is associated with a lower incidence or number of adverse side effects compared to the ratio or number of adverse side effects associated with other obesity treatments. In one embodiment, administration of the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule is associated with a lower discontinuation rate due to adverse side effects compared to the discontinuation rate due to adverse side effects associated with other weight loss treatments. In one embodiment, there was no statistically significant difference in the number and type of adverse side effects associated with administration of the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule compared with the number and type of adverse side effects associated with administration of placebo.

[0270] Example Example 1 is a human glucagon-like peptide-1 (GLP-1) receptor agonist polypeptide containing H[Aib]EGTFTSDYSSYLEEX 17 AAX 20 EFIX 24 WLX 27 X 28 The amino acid sequence of GGG (SEQ ID NO: 1575), where X 17 It is Q, K, E, or R; X 20 It is K, R, Q or high in arginine (hArg); X 24 It is A, E, Q, D, d-Ala, G, N, K, (1S,2S)-2-aminocyclopentanecarboxylic acid (ACPC), (3S,4R)-4-amino-3-pyrrolidinecarboxylic acid (APCA), T, S, or Y; X 27 It is V, K, Aib, N, S, T, Y, Q, or R; and X 28 It is K, E, R, Q, D, N, G, S, or T; and wherein the GLP-1 receptor agonist polypeptide does not contain the amino acid sequence of SEQ ID NO:1574 (H[Aib]EGTFTSDYSSYLEEQAAKEFIAWLVKGGG).

[0271] Example 2 is a GLP-1 receptor agonist peptide as described in Example 1, wherein the GLP-1 receptor agonist peptide comprises H[Aib]EGTFTSDYSSYLEEX 17 AAX 20 EFIX 24 WLX 27 X 28 The amino acid sequence of GGG (SEQ ID NO: 1576), where X 17 Is it Q or K; X 20 It is K or R; X 24 It is A, E, or Q; X 27 It is V or K; and X 28 It is K, E, or R.

[0272] Example 3 is a GLP-1 receptor agonist polypeptide as described in Example 1, wherein the GLP-1 receptor agonist polypeptide contains H[Aib]EGTFTSDYSSYLEEX 17 AAREFIX 24 WLX 27 X 28 The amino acid sequence of GGG (SEQ ID NO: 1577), where X 17 Is it Q or K; X 24 It is A, E, or Q; X 27 It is V or K; and X 28 It is K, E, or R.

[0273] Example 4 is a GLP-1 receptor agonist polypeptide as described in Example 1, wherein the GLP-1 receptor agonist polypeptide contains H[Aib]EGTFTSDYSSYLEEX 17 AAX 20 EFIX 24 WLKX 28 The amino acid sequence of GGG (SEQ ID NO: 1578), where X 17 Is it Q or K; X 20 It is K or R; X 24 It is A, E, or Q; and X 28 It is K, E, or R.

[0274] Example 5 is a GLP-1 receptor agonist polypeptide as described in any one of Examples 1-4, wherein the GLP-1 receptor agonist polypeptide comprises the amino acid sequence of any one of SEQ ID NO: 1579, SEQ ID NO: 1580, SEQ ID NO: 1581, SEQ ID NO: 1582 or SEQ ID NO: 1583.

[0275] Example 6 is a human glucagon-like peptide-1 (GLP-1) receptor agonist polypeptide, wherein: the polypeptide contains 31 amino acids, and contains an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 1580; and wherein the polypeptide contains α-amino-isobutyric acid (Aib) at position 2; tyrosine at position 10; glutamic acid at positions 16, 24 and 28; arginine at position 20; lysine at positions 17 and 27; and glycine at position 31.

[0276] Example 7 is a human glucagon-like peptide-1 (GLP-1) receptor agonist polypeptide, wherein: the GLP-1 receptor agonist polypeptide comprises 31 amino acids, and includes an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 1579; and wherein the GLP-1 receptor agonist polypeptide includes Aib at position 2; tyrosine at position 10; glutamic acid at positions 16 and 24; arginine at position 20; lysine at position 27; and glycine at position 30.

[0277] Example 8 is a human glucagon-like peptide-1 (GLP-1) receptor agonist polypeptide, wherein: the GLP-1 receptor agonist polypeptide comprises 31 amino acids, and includes an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 1581; and wherein the GLP-1 receptor agonist polypeptide includes Aib at position 2; tyrosine at position 10; glutamic acid at positions 16 and 24; arginine at position 20; lysine at positions 17 and 27; and glycine at position 30.

[0278] Example 9 is a human glucagon-like peptide-1 (GLP-1) receptor agonist polypeptide, wherein: the GLP-1 receptor agonist polypeptide comprises 31 amino acids, and includes an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 1583; and wherein the GLP-1 receptor agonist polypeptide includes Aib at position 2; tyrosine at position 10; glutamic acid at positions 16 and 28; arginine at position 20; lysine at positions 17 and 27; glutamine at position 24; and glycine at position 30.

[0279] Example 10 is a human glucagon-like peptide-1 (GLP-1) receptor agonist polypeptide, wherein: the GLP-1 receptor agonist polypeptide comprises 31 amino acids, and includes an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 1582; ​​and wherein the GLP-1 receptor agonist polypeptide includes Aib at position 2; tyrosine at position 10; glutamic acid at positions 16 and 24; arginine at positions 20 and 28; lysine at position 27; and glycine at position 30.

[0280] Example 11 is a molecule comprising: a first human glucagon-like peptide-1 (GLP-1) receptor agonist polypeptide containing H[Aib]EGTFTSDYSSYLEEX 17 AAX 20 EFIX 24 WLX 27 X 28 The amino acid sequence of GGG (SEQ ID NO: 1575), where X 17 It is Q, K, E, or R; X 20 It is K, R, Q or high in arginine (hArg); X 24 It is A, E, Q, D, d-Ala, G, N, K, (1S,2S)-2-aminocyclopentanecarboxylic acid (ACPC), (3S,4R)-4-amino-3-pyrrolidinecarboxylic acid (APCA), T, S, or Y; X 27 It is V, K, Aib, N, S, T, Y, Q, or R; and X 28 It is K, E, R, Q, D, N, G, S, or T, and wherein the GLP-1 receptor agonist polypeptide does not contain the amino acid sequence of SEQ ID NO: 1574; and a half-life extension portion.

[0281] Example 12 is a molecule as described in Example 11, wherein the first GLP-1 receptor agonist polypeptide comprises H[Aib]EGTFTSDYSSYLEEX 17 AAX 20 EFIX 24 WLX 27 X 28 The amino acid sequence of GGG (SEQ ID NO: 1576), where X 17 Is it Q or K; X 20 It is K or R; X 24 It is A, E, or Q; X 27 It is V or K; and X 28 It is K, E, or R.

[0282] Example 13 is a molecule as described in Example 11, wherein the first GLP-1 receptor agonist polypeptide comprises H[Aib]EGTFTSDYSSYLEEX 17 AAR 20 EFIX 24 WLX 27 X 28 The amino acid sequence of GGG (SEQ ID NO: 1577), where X 17 Is it Q or K; X 24 It is A, E, or Q; X 27 It is V or K; and X 28 It is K, E, or R.

[0283] Example 14 is a molecule as described in Example 11, wherein the first GLP-1 receptor agonist polypeptide comprises H[Aib]EGTFTSDYSSYLEEX 17 AAX 20 EFIX 24 WLK 27 X 28 The amino acid sequence of GGG (SEQ ID NO: 1578), where X 17 Is it Q or K; X 20 It is K or R; X 24 It is A, E, or Q; and X 28 It is K, E, or R.

[0284] Example 15 is a molecule as described in Example 11, wherein the first GLP-1 receptor agonist polypeptide comprises the amino acid sequence of any one of SEQ ID NO: 1579, SEQ ID NO: 1580, SEQ ID NO: 1581, SEQ ID NO: 1582 or SEQ ID NO: 1583.

[0285] Example 16 is a molecule as described in any one of Examples 11-15, wherein the extended half-life portion is an antibody.

[0286] Example 17 is a conjugate molecule comprising: (i) a first human glucagon-like peptide-1 (GLP-1) receptor agonist polypeptide comprising H[Aib]EGTFTSDYSSYLEEX 17 AAX 20 EFIX 24 WLX 27 X 28 The amino acid sequence of GGG (SEQ ID NO: 1575), where X 17 It is Q, K, E, or R; X 20 It is K, R, Q or high in arginine (hArg); X24 It is A, E, Q, D, d-Ala, G, N, K, (1S,2S)-2-aminocyclopentanecarboxylic acid (ACPC), (3S,4R)-4-amino-3-pyrrolidinecarboxylic acid (APCA), T, S, or Y; X 27 It is V, K, Aib, N, S, T, Y, Q, or R; and X 28 It is K, E, R, Q, D, N, G, S or T, and wherein the GLP-1 receptor agonist polypeptide does not contain the amino acid sequence of SEQ ID NO: 1574; and (ii) an antagonist anti-glucose-dependent insulinotropic peptide receptor (GIPR) human antibody.

[0287] Example 18 is a conjugate molecule as described in Example 17, wherein the anti-GIPR antibody antagonizes human GIPR.

[0288] Example 19 is a conjugate molecule as described in Example 17 or 18, wherein the first GLP-1 receptor agonist polypeptide comprises the amino acid sequence of SEQ ID NO: 1575.

[0289] Example 20 is a conjugate molecule as described in Example 17 or 18, wherein the first GLP-1 receptor agonist polypeptide comprises the amino acid sequence of SEQ ID NO: 1576.

[0290] Example 21 is a conjugate molecule as described in Example 17 or 18, wherein the first GLP-1 receptor agonist polypeptide comprises the amino acid sequence of SEQ ID NO: 1577.

[0291] Example 22 is a conjugate molecule as described in Example 17 or 18, wherein the first GLP-1 receptor agonist polypeptide comprises the amino acid sequence of SEQ ID NO: 1578.

[0292] Example 23 is a conjugate molecule as described in Example 17 or 18, wherein the first GLP-1 receptor agonist polypeptide comprises the amino acid sequence of any one of SEQ ID NO: 1579, SEQ ID NO: 1580, SEQ ID NO: 1581, SEQ ID NO: 1582 or SEQ ID NO: 1583.

[0293] Example 24 is a conjugate molecule as described in Example 17 or 18, wherein the anti-GIPR antibody contains a first cysteine ​​conjugate site located within the light or heavy chain of the antibody, and wherein the first GLP-1 receptor agonist polypeptide is conjugated at its C-terminus to the first cysteine ​​conjugate site of the anti-GIPR antibody.

[0294] Example 25 is a conjugate molecule as described in Example 24, wherein the first GLP-1 receptor agonist polypeptide is conjugated at its C-terminus to the first cysteine ​​conjugate site of the anti-GIPR antibody via a first linker portion.

[0295] Example 26 is a conjugate molecule as described in Example 25, wherein the first linker portion is a peptide linker and the peptide linker contains an amino acid sequence of any one of SEQ ID NO: 1585-1593.

[0296] Example 27 is a conjugate molecule as described in Example 25, wherein the first connector portion is a PEG connector.

[0297] Example 28 is a conjugate molecule as described in any one of Examples 24 to 27, wherein the first cysteine ​​conjugate site of the anti-GIPR antibody is located at position 88 of the light chain, position 384 of the heavy chain, or position 487 of the heavy chain according to the AHo number.

[0298] Example 29 is a conjugate molecule as described in any one of Examples 17 to 28, wherein the molecule further comprises: a second GLP-1 receptor agonist polypeptide, wherein the second GLP-1 receptor agonist polypeptide is conjugated at its C-terminus to the second cysteine ​​conjugate site of the anti-GIPR antibody.

[0299] Example 30 is a conjugate molecule as described in Example 29, wherein the second GLP-1 receptor agonist polypeptide comprises the amino acid sequence of SEQ ID NO: 1575.

[0300] Example 31 is a conjugate molecule as described in Example 29, wherein the second GLP-1 receptor agonist polypeptide comprises the amino acid sequence of SEQ ID NO: 1576.

[0301] Example 32 is a conjugate molecule as described in Example 29, wherein the second GLP-1 receptor agonist polypeptide comprises the amino acid sequence of SEQ ID NO: 1577.

[0302] Example 33 is a conjugate molecule as described in Example 29, wherein the second GLP-1 receptor agonist polypeptide contains the amino acid sequence of SEQ ID NO: 1578.

[0303] Example 34 is a conjugate molecule as described in Example 29, wherein the second GLP-1 receptor agonist polypeptide comprises the amino acid sequence of any one of SEQ ID NO: 1579, SEQ ID NO: 1580, SEQ ID NO: 1581, SEQ ID NO: 1582 or SEQ ID NO: 1583.

[0304] Example 35 is a conjugate molecule as described in Example 29, wherein the second GLP-1 receptor agonist polypeptide contains the same amino acid sequence as the first GLP-1 receptor agonist polypeptide.

[0305] Example 36 is a conjugate molecule as described in any one of Examples 29 to 35, wherein the second GLP-1 receptor agonist polypeptide is conjugated at its C-terminus to the second cysteine ​​conjugate site of the anti-GIPR antibody via a second linker portion.

[0306] Example 37 is a conjugate molecule as described in Example 36, wherein the second linker portion is a peptide linker and the peptide linker contains an amino acid sequence of any one of SEQ ID NO: 1585-1593.

[0307] Example 38 is a conjugate molecule as described in Example 36, wherein the second connector portion is a PEG connector.

[0308] Example 39 is a conjugate molecule as described in Example 29, wherein the first and second conjugate sites of the anti-GIPR antibody are located at position 88 of each light chain, position 384 of each heavy chain, or position 487 of each heavy chain according to the AHo number.

[0309] Example 40 is a conjugate molecule as described in any one of Examples 17 to 39, wherein the anti-GIPR antibody comprises light chain complementarity-determining region 1 (CDRL1), CDRL2, CDRL3, heavy chain complementarity-determining region 1 (CDRH1), CDRH2, and CDRH3, wherein CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3 comprise an amino acid sequence selected from the following: i. These are SEQ ID NO: 629, SEQ ID NO: 786, SEQ ID NO: 943, SEQ ID NO: 1100, SEQ ID NO: 1257 and SEQ ID NO: 1414, respectively; ii. These are SEQ ID NO: 630, SEQ ID NO: 787, SEQ ID NO: 944, SEQ ID NO: 1101, SEQ ID NO: 1258 and SEQ ID NO: 1415, respectively; iii. These are SEQ ID NO: 631, SEQ ID NO: 788, SEQ ID NO: 945, SEQ ID NO: 1102, SEQ ID NO: 1259 and SEQ ID NO: 1416, respectively; iv. These are SEQ ID NO: 632, SEQ ID NO: 789, SEQ ID NO: 946, SEQ ID NO: 1103, SEQ ID NO: 1260 and SEQ ID NO: 1417, respectively; v. are SEQ ID NO: 633, SEQ ID NO: 790, SEQ ID NO: 947, SEQ ID NO: 1104, SEQ ID NO: 1261 and SEQ ID NO: 1418 respectively; vi. These are SEQ ID NO: 634, SEQ ID NO: 791, SEQ ID NO: 948, SEQ ID NO: 1105, SEQ ID NO: 1262 and SEQ ID NO: 1419, respectively; vii. These are SEQ ID NO: 635, SEQ ID NO: 792, SEQ ID NO: 949, SEQ ID NO: 1106, SEQ ID NO: 1263 and SEQ ID NO: 1420, respectively; viii. These are SEQ ID NO: 636, SEQ ID NO: 793, SEQ ID NO: 950, SEQ ID NO: 1107, SEQ ID NO: 1264 and SEQ ID NO: 1421, respectively; ix. are SEQ ID NO: 637, SEQ ID NO: 794, SEQ ID NO: 951, SEQ ID NO: 1108, SEQ ID NO: 1265 and SEQ ID NO: 1422 respectively; x. are SEQ ID NO: 638, SEQ ID NO: 795, SEQ ID NO: 952, SEQ ID NO: 1109, SEQ ID NO: 1266 and SEQ ID NO: 1423 respectively; xi. are SEQ ID NO: 639, SEQ ID NO: 796, SEQ ID NO: 953, SEQ ID NO: 1110, SEQ ID NO: 1267 and SEQ ID NO: 1424 respectively; xii. These are SEQ ID NO: 640, SEQ ID NO: 797, SEQ ID NO: 954, SEQ ID NO: 1111, SEQ ID NO: 1268 and SEQ ID NO: 1425, respectively; xiii. These are SEQ ID NO: 641, SEQ ID NO: 798, SEQ ID NO: 955, SEQ ID NO: 1112, SEQ ID NO: 1269 and SEQ ID NO: 1426, respectively; xiv. are SEQ ID NO: 642, SEQ ID NO: 799, SEQ ID NO: 956, SEQ ID NO: 1113, SEQ ID NO: 1270 and SEQ ID NO: 1427 respectively; xv. are SEQ ID NO: 643, SEQ ID NO: 800, SEQ ID NO: 957, SEQ ID NO: 1114, SEQ ID NO: 1271 and SEQ ID NO: 1428 respectively; xvi. are SEQ ID NO: 644, SEQ ID NO: 801, SEQ ID NO: 958, SEQ ID NO: 1115, SEQ ID NO: 1272 and SEQ ID NO: 1429 respectively; xvii. are SEQ ID NO: 645, SEQ ID NO: 802, SEQ ID NO: 959, SEQ ID NO: 1116, SEQ ID NO: 1273 and SEQ ID NO: 1430 respectively; xviii. are SEQ ID NO: 646, SEQ ID NO: 803, SEQ ID NO: 960, SEQ ID NO: 1117, SEQ ID NO: 1274 and SEQ ID NO: 1431, respectively; xix. are SEQ ID NO: 647, SEQ ID NO: 804, SEQ ID NO: 961, SEQ ID NO: 1118, SEQ ID NO: 1275 and SEQ ID NO: 1432 respectively; xx. are SEQ ID NO: 648, SEQ ID NO: 805, SEQ ID NO: 962, SEQ ID NO: 1119, SEQ ID NO: 1276 and SEQ ID NO: 1433 respectively; xxi. are SEQ ID NO: 649, SEQ ID NO: 806, SEQ ID NO: 963, SEQ ID NO: 1120, SEQ ID NO: 1277 and SEQ ID NO: 1434 respectively; xxii. are SEQ ID NO: 650, SEQ ID NO: 807, SEQ ID NO: 964, SEQ ID NO: 1121, SEQ ID NO: 1278 and SEQ ID NO: 1435 respectively; xxiii. These are SEQ ID NO: 651, SEQ ID NO: 808, SEQ ID NO: 965, SEQ ID NO: 1122, SEQ ID NO: 1279 and SEQ ID NO: 1436, respectively; xxiv. are SEQ ID NO: 652, SEQ ID NO: 809, SEQ ID NO: 966, SEQ ID NO: 1123, SEQ ID NO: 1280 and SEQ ID NO: 1437 respectively; The xxv. are SEQ ID NO: 653, SEQ ID NO: 810, SEQ ID NO: 967, SEQ ID NO: 1124, SEQ ID NO: 1281 and SEQ ID NO: 1438, respectively; xxvi. are SEQ ID NO: 654, SEQ ID NO: 811, SEQ ID NO: 968, SEQ ID NO: 1125, SEQ ID NO: 1282 and SEQ ID NO: 1439 respectively; xxvii. are SEQ ID NO: 655, SEQ ID NO: 812, SEQ ID NO: 969, SEQ ID NO: 1126, SEQ ID NO: 1283 and SEQ ID NO: 1440 respectively; xxviii. are SEQ ID NO: 656, SEQ ID NO: 813, SEQ ID NO: 970, SEQ ID NO: 1127, SEQ ID NO: 1284 and SEQ ID NO: 1441, respectively; xxix. are SEQ ID NO: 657, SEQ ID NO: 814, SEQ ID NO: 971, SEQ ID NO: 1128, SEQ ID NO: 1285 and SEQ ID NO: 1442 respectively; The numbers xxx are SEQ ID NO: 658, SEQ ID NO: 815, SEQ ID NO: 972, SEQ ID NO: 1129, SEQ ID NO: 1286 and SEQ ID NO: 1443, respectively. xxxi are SEQ ID NO: 659, SEQ ID NO: 816, SEQ ID NO: 973, SEQ ID NO: 1130, SEQ ID NO: 1287 and SEQ ID NO: 1444 respectively; xxxii. are SEQ ID NO: 660, SEQ ID NO: 817, SEQ ID NO: 974, SEQ ID NO: 1131, SEQ ID NO: 1288 and SEQ ID NO: 1445 respectively; xxxiii. are SEQ ID NO: 661, SEQ ID NO: 818, SEQ ID NO: 975, SEQ ID NO: 1132, SEQ ID NO: 1289 and SEQ ID NO: 1446 respectively; xxxiv. are SEQ ID NO: 662, SEQ ID NO: 819, SEQ ID NO: 976, SEQ ID NO: 1133, SEQ ID NO: 1290 and SEQ ID NO: 1447 respectively; xxxv. are SEQ ID NO: 663, SEQ ID NO: 820, SEQ ID NO: 977, SEQ ID NO: 1134, SEQ ID NO: 1291 and SEQ ID NO: 1448 respectively; xxxvi. are SEQ ID NO: 664, SEQ ID NO: 821, SEQ ID NO: 978, SEQ ID NO: 1135, SEQ ID NO: 1292 and SEQ ID NO: 1449 respectively; xxxvii. are SEQ ID NO: 665, SEQ ID NO: 822, SEQ ID NO: 979, SEQ ID NO: 1136, SEQ ID NO: 1293 and SEQ ID NO: 1450 respectively; xxxviii. are SEQ ID NO: 666, SEQ ID NO: 823, SEQ ID NO: 980, SEQ ID NO: 1137, SEQ ID NO: 1294 and SEQ ID NO: 1451 respectively; xxxix. are SEQ ID NO: 667, SEQ ID NO: 824, SEQ ID NO: 981, SEQ ID NO: 1138, SEQ ID NO: 1295 and SEQ ID NO: 1452 respectively; xl. are SEQ ID NO: 668, SEQ ID NO: 825, SEQ ID NO: 982, SEQ ID NO: 1139, SEQ ID NO: 1296 and SEQ ID NO: 1453 respectively; xli. are SEQ ID NO: 669, SEQ ID NO: 826, SEQ ID NO: 983, SEQ ID NO: 1140, SEQ ID NO: 1297 and SEQ ID NO: 1454 respectively; xlii. are SEQ ID NO: 670, SEQ ID NO: 827, SEQ ID NO: 984, SEQ ID NO: 1141, SEQ ID NO: 1298 and SEQ ID NO: 1455 respectively; xliii. are SEQ ID NO: 671, SEQ ID NO: 828, SEQ ID NO: 985, SEQ ID NO: 1142, SEQ ID NO: 1299 and SEQ ID NO: 1456 respectively; xliv. are SEQ ID NO: 672, SEQ ID NO: 829, SEQ ID NO: 986, SEQ ID NO: 1143, SEQ ID NO: 1300 and SEQ ID NO: 1457 respectively; The xlv. are SEQ ID NO: 673, SEQ ID NO: 830, SEQ ID NO: 987, SEQ ID NO: 1144, SEQ ID NO: 1301 and SEQ ID NO: 1458, respectively; xlvi. are SEQ ID NO: 674, SEQ ID NO: 831, SEQ ID NO: 988, SEQ ID NO: 1145, SEQ ID NO: 1302 and SEQ ID NO: 1459 respectively; xlvii. are SEQ ID NO: 675, SEQ ID NO: 832, SEQ ID NO: 989, SEQ ID NO: 1146, SEQ ID NO: 1303 and SEQ ID NO: 1460 respectively; xlviii. are SEQ ID NO: 676, SEQ ID NO: 833, SEQ ID NO: 990, SEQ ID NO: 1147, SEQ ID NO: 1304 and SEQ ID NO: 1461, respectively; xlix. are SEQ ID NO: 677, SEQ ID NO: 834, SEQ ID NO: 991, SEQ ID NO: 1148, SEQ ID NO: 1305 and SEQ ID NO: 1462 respectively; l. These are SEQ ID NO: 678, SEQ ID NO: 835, SEQ ID NO: 992, SEQ ID NO: 1149, SEQ ID NO: 1306 and SEQ ID NO: 1463, respectively; The li are SEQ ID NO: 679, SEQ ID NO: 836, SEQ ID NO: 993, SEQ ID NO: 1150, SEQ ID NO: 1307 and SEQ ID NO: 1464 respectively; The lii. are SEQ ID NO: 680, SEQ ID NO: 837, SEQ ID NO: 994, SEQ ID NO: 1151, SEQ ID NO: 1308 and SEQ ID NO: 1465 respectively; liii. are SEQ ID NO: 681, SEQ ID NO: 838, SEQ ID NO: 995, SEQ ID NO: 1152, SEQ ID NO: 1309 and SEQ ID NO: 1466 respectively; The liv. are SEQ ID NO: 682, SEQ ID NO: 839, SEQ ID NO: 996, SEQ ID NO: 1153, SEQ ID NO: 1310 and SEQ ID NO: 1467 respectively; The lv. are SEQ ID NO: 683, SEQ ID NO: 840, SEQ ID NO: 997, SEQ ID NO: 1154, SEQ ID NO: 1311 and SEQ ID NO: 1468 respectively; lvi. are SEQ ID NO: 684, SEQ ID NO: 841, SEQ ID NO: 998, SEQ ID NO: 1155, SEQ ID NO: 1312 and SEQ ID NO: 1469 respectively; lvii. are SEQ ID NO: 685, SEQ ID NO: 842, SEQ ID NO: 999, SEQ ID NO: 1156, SEQ ID NO: 1313 and SEQ ID NO: 1470 respectively; lviii. are SEQ ID NO: 686, SEQ ID NO: 843, SEQ ID NO: 1000, SEQ ID NO: 1157, SEQ ID NO: 1314 and SEQ ID NO: 1471, respectively; The lix. are SEQ ID NO: 687, SEQ ID NO: 844, SEQ ID NO: 1001, SEQ ID NO: 1158, SEQ ID NO: 1315 and SEQ ID NO: 1472 respectively; lx. are SEQ ID NO: 688, SEQ ID NO: 845, SEQ ID NO: 1002, SEQ ID NO: 1159, SEQ ID NO: 1316 and SEQ ID NO: 1473 respectively; lxi. are SEQ ID NO: 689, SEQ ID NO: 846, SEQ ID NO: 1003, SEQ ID NO: 1160, SEQ ID NO: 1317 and SEQ ID NO: 1474 respectively; lxii. are SEQ ID NO: 690, SEQ ID NO: 847, SEQ ID NO: 1004, SEQ ID NO: 1161, SEQ ID NO: 1318 and SEQ ID NO: 1475 respectively; lxiii. are SEQ ID NO: 691, SEQ ID NO: 848, SEQ ID NO: 1005, SEQ ID NO: 1162, SEQ ID NO: 1319 and SEQ ID NO: 1476 respectively; The lxiv. are SEQ ID NO: 692, SEQ ID NO: 849, SEQ ID NO: 1006, SEQ ID NO: 1163, SEQ ID NO: 1320 and SEQ ID NO: 1477, respectively; lxv. are SEQ ID NO: 693, SEQ ID NO: 850, SEQ ID NO: 1007, SEQ ID NO: 1164, SEQ ID NO: 1321 and SEQ ID NO: 1478 respectively; lxvi. are SEQ ID NO: 694, SEQ ID NO: 851, SEQ ID NO: 1008, SEQ ID NO: 1165, SEQ ID NO: 1322 and SEQ ID NO: 1479 respectively; lxvii. are SEQ ID NO: 695, SEQ ID NO: 852, SEQ ID NO: 1009, SEQ ID NO: 1166, SEQ ID NO: 1323 and SEQ ID NO: 1480 respectively; lxviii. are SEQ ID NO: 696, SEQ ID NO: 853, SEQ ID NO: 1010, SEQ ID NO: 1167, SEQ ID NO: 1324 and SEQ ID NO: 1481, respectively; lxix. are SEQ ID NO: 697, SEQ ID NO: 854, SEQ ID NO: 1011, SEQ ID NO: 1168, SEQ ID NO: 1325 and SEQ ID NO: 1482 respectively; lxx. are SEQ ID NO: 698, SEQ ID NO: 855, SEQ ID NO: 1012, SEQ ID NO: 1169, SEQ ID NO: 1326 and SEQ ID NO: 1483 respectively; lxxi. are SEQ ID NO: 699, SEQ ID NO: 856, SEQ ID NO: 1013, SEQ ID NO: 1170, SEQ ID NO: 1327 and SEQ ID NO: 1484 respectively; lxxii. are SEQ ID NO: 700, SEQ ID NO: 857, SEQ ID NO: 1014, SEQ ID NO: 1171, SEQ ID NO: 1328 and SEQ ID NO: 1485 respectively; lxxiii. are SEQ ID NO: 701, SEQ ID NO: 858, SEQ ID NO: 1015, SEQ ID NO: 1172, SEQ ID NO: 1329 and SEQ ID NO: 1486 respectively; lxxiv. are 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 respectively; lxxv. are SEQ ID NO: 703, SEQ ID NO: 860, SEQ ID NO: 1017, SEQ ID NO: 1174, SEQ ID NO: 1331 and SEQ ID NO: 1488 respectively; lxxvi. are SEQ ID NO: 704, SEQ ID NO: 861, SEQ ID NO: 1018, SEQ ID NO: 1175, SEQ ID NO: 1332 and SEQ ID NO: 1489 respectively; lxxvii. are SEQ ID NO: 705, SEQ ID NO: 862, SEQ ID NO: 1019, SEQ ID NO: 1176, SEQ ID NO: 1333 and SEQ ID NO: 1490 respectively; lxxviii. are SEQ ID NO: 706, SEQ ID NO: 863, SEQ ID NO: 1020, SEQ ID NO: 1177, SEQ ID NO: 1334 and SEQ ID NO: 1491, respectively; lxxix. are SEQ ID NO: 707, SEQ ID NO: 864, SEQ ID NO: 1021, SEQ ID NO: 1178, SEQ ID NO: 1335 and SEQ ID NO: 1492 respectively; lxxx. are SEQ ID NO: 708, SEQ ID NO: 865, SEQ ID NO: 1022, SEQ ID NO: 1179, SEQ ID NO: 1336 and SEQ ID NO: 1493 respectively; lxxxi. are SEQ ID NO: 709, SEQ ID NO: 866, SEQ ID NO: 1023, SEQ ID NO: 1180, SEQ ID NO: 1337 and SEQ ID NO: 1494 respectively; lxxxii. are SEQ ID NO: 710, SEQ ID NO: 867, SEQ ID NO: 1024, SEQ ID NO: 1181, SEQ ID NO: 1338 and SEQ ID NO: 1495 respectively; lxxxiii. are SEQ ID NO: 711, SEQ ID NO: 868, SEQ ID NO: 1025, SEQ ID NO: 1182, SEQ ID NO: 1339 and SEQ ID NO: 1496 respectively; lxxxiv. are SEQ ID NO: 712, SEQ ID NO: 869, SEQ ID NO: 1026, SEQ ID NO: 1183, SEQ ID NO: 1340 and SEQ ID NO: 1497 respectively; lxxxv. are SEQ ID NO: 713, SEQ ID NO: 870, SEQ ID NO: 1027, SEQ ID NO: 1184, SEQ ID NO: 1341 and SEQ ID NO: 1498 respectively; lxxxvi. are SEQ ID NO: 714, SEQ ID NO: 871, SEQ ID NO: 1028, SEQ ID NO: 1185, SEQ ID NO: 1342 and SEQ ID NO: 1499 respectively; lxxxvii. are SEQ ID NO: 715, SEQ ID NO: 872, SEQ ID NO: 1029, SEQ ID NO: 1186, SEQ ID NO: 1343 and SEQ ID NO: 1500 respectively; lxxxviii. are SEQ ID NO: 716, SEQ ID NO: 873, SEQ ID NO: 1030, SEQ ID NO: 1187, SEQ ID NO: 1344 and SEQ ID NO: 1501, respectively; lxxxix. are SEQ ID NO: 717, SEQ ID NO: 874, SEQ ID NO: 1031, SEQ ID NO: 1188, SEQ ID NO: 1345 and SEQ ID NO: 1502 respectively; xc. are SEQ ID NO: 718, SEQ ID NO: 875, SEQ ID NO: 1032, SEQ ID NO: 1189, SEQ ID NO: 1346 and SEQ ID NO: 1503 respectively; xci. are SEQ ID NO: 719, SEQ ID NO: 876, SEQ ID NO: 1033, SEQ ID NO: 1190, SEQ ID NO: 1347 and SEQ ID NO: 1504 respectively; xcii. are SEQ ID NO: 720, SEQ ID NO: 877, SEQ ID NO: 1034, SEQ ID NO: 1191, SEQ ID NO: 1348 and SEQ ID NO: 1505 respectively; xciii. are SEQ ID NO: 721, SEQ ID NO: 878, SEQ ID NO: 1035, SEQ ID NO: 1192, SEQ ID NO: 1349 and SEQ ID NO: 1506 respectively; xciv. are SEQ ID NO: 722, SEQ ID NO: 879, SEQ ID NO: 1036, SEQ ID NO: 1193, SEQ ID NO: 1350 and SEQ ID NO: 1507 respectively; xcv. are SEQ ID NO: 723, SEQ ID NO: 880, SEQ ID NO: 1037, SEQ ID NO: 1194, SEQ ID NO: 1351 and SEQ ID NO: 1508 respectively; xcvi. are SEQ ID NO: 724, SEQ ID NO: 881, SEQ ID NO: 1038, SEQ ID NO: 1195, SEQ ID NO: 1352 and SEQ ID NO: 1509 respectively; xcvii. are SEQ ID NO: 725, SEQ ID NO: 882, SEQ ID NO: 1039, SEQ ID NO: 1196, SEQ ID NO: 1353 and SEQ ID NO: 1510 respectively; xcviii. are SEQ ID NO: 726, SEQ ID NO: 883, SEQ ID NO: 1040, SEQ ID NO: 1197, SEQ ID NO: 1354 and SEQ ID NO: 1511, respectively; xcix. are SEQ ID NO: 727, SEQ ID NO: 884, SEQ ID NO: 1041, SEQ ID NO: 1198, SEQ ID NO: 1355 and SEQ ID NO: 1512 respectively; c. These are SEQ ID NO: 728, SEQ ID NO: 885, SEQ ID NO: 1042, SEQ ID NO: 1199, SEQ ID NO: 1356 and SEQ ID NO: 1513, respectively; Ci. are SEQ ID NO: 729, SEQ ID NO: 886, SEQ ID NO: 1043, SEQ ID NO: 1200, SEQ ID NO: 1357 and SEQ ID NO: 1514 respectively; cii. are SEQ ID NO: 730, SEQ ID NO: 887, SEQ ID NO: 1044, SEQ ID NO: 1201, SEQ ID NO: 1358 and SEQ ID NO: 1515 respectively; ciii. are SEQ ID NO: 731, SEQ ID NO: 888, SEQ ID NO: 1045, SEQ ID NO: 1202, SEQ ID NO: 1359 and SEQ ID NO: 1516 respectively; civ. are SEQ ID NO: 732, SEQ ID NO: 889, SEQ ID NO: 1046, SEQ ID NO: 1203, SEQ ID NO: 1360 and SEQ ID NO: 1517 respectively; cv. are SEQ ID NO: 733, SEQ ID NO: 890, SEQ ID NO: 1047, SEQ ID NO: 1204, SEQ ID NO: 1361 and SEQ ID NO: 1518 respectively; cvi. are SEQ ID NO: 734, SEQ ID NO: 891, SEQ ID NO: 1048, SEQ ID NO: 1205, SEQ ID NO: 1362 and SEQ ID NO: 1519 respectively; cvii. are SEQ ID NO: 735, SEQ ID NO: 892, SEQ ID NO: 1049, SEQ ID NO: 1206, SEQ ID NO: 1363 and SEQ ID NO: 1520 respectively; cviii. are SEQ ID NO: 736, SEQ ID NO: 893, SEQ ID NO: 1050, SEQ ID NO: 1207, SEQ ID NO: 1364 and SEQ ID NO: 1521, respectively; cix. are SEQ ID NO: 737, SEQ ID NO: 894, SEQ ID NO: 1051, SEQ ID NO: 1208, SEQ ID NO: 1365 and SEQ ID NO: 1522 respectively; cx. are SEQ ID NO: 738, SEQ ID NO: 895, SEQ ID NO: 1052, SEQ ID NO: 1209, SEQ ID NO: 1366 and SEQ ID NO: 1523 respectively; cxi. are SEQ ID NO: 739, SEQ ID NO: 896, SEQ ID NO: 1053, SEQ ID NO: 1210, SEQ ID NO: 1367 and SEQ ID NO: 1524 respectively; cxii. are SEQ ID NO: 740, SEQ ID NO: 897, SEQ ID NO: 1054, SEQ ID NO: 1211, SEQ ID NO: 1368 and SEQ ID NO: 1525 respectively; cxiii. are SEQ ID NO: 741, SEQ ID NO: 898, SEQ ID NO: 1055, SEQ ID NO: 1212, SEQ ID NO: 1369 and SEQ ID NO: 1526 respectively; cxiv. are SEQ ID NO: 742, SEQ ID NO: 899, SEQ ID NO: 1056, SEQ ID NO: 1213, SEQ ID NO: 1370 and SEQ ID NO: 1527 respectively; cxv. are SEQ ID NO: 743, SEQ ID NO: 900, SEQ ID NO: 1057, SEQ ID NO: 1214, SEQ ID NO: 1371 and SEQ ID NO: 1528 respectively; cxvi. are SEQ ID NO: 744, SEQ ID NO: 901, SEQ ID NO: 1058, SEQ ID NO: 1215, SEQ ID NO: 1372 and SEQ ID NO: 1529 respectively; cxvii. are SEQ ID NO: 745, SEQ ID NO: 902, SEQ ID NO: 1059, SEQ ID NO: 1216, SEQ ID NO: 1373 and SEQ ID NO: 1530 respectively; cxviii. are SEQ ID NO: 746, SEQ ID NO: 903, SEQ ID NO: 1060, SEQ ID NO: 1217, SEQ ID NO: 1374 and SEQ ID NO: 1531, respectively; cxix. are SEQ ID NO: 747, SEQ ID NO: 904, SEQ ID NO: 1061, SEQ ID NO: 1218, SEQ ID NO: 1375 and SEQ ID NO: 1532 respectively; cxx. are SEQ ID NO: 748, SEQ ID NO: 905, SEQ ID NO: 1062, SEQ ID NO: 1219, SEQ ID NO: 1376 and SEQ ID NO: 1533 respectively; cxxi. are SEQ ID NO: 749, SEQ ID NO: 906, SEQ ID NO: 1063, SEQ ID NO: 1220, SEQ ID NO: 1377 and SEQ ID NO: 1534 respectively; cxxii. are SEQ ID NO: 750, SEQ ID NO: 907, SEQ ID NO: 1064, SEQ ID NO: 1221, SEQ ID NO: 1378 and SEQ ID NO: 1535 respectively; cxxiii. are SEQ ID NO: 751, SEQ ID NO: 908, SEQ ID NO: 1065, SEQ ID NO: 1222, SEQ ID NO: 1379 and SEQ ID NO: 1536 respectively; cxxiv. are SEQ ID NO: 752, SEQ ID NO: 909, SEQ ID NO: 1066, SEQ ID NO: 1223, SEQ ID NO: 1380 and SEQ ID NO: 1537 respectively; cxxv. are SEQ ID NO: 753, SEQ ID NO: 910, SEQ ID NO: 1067, SEQ ID NO: 1224, SEQ ID NO: 1381 and SEQ ID NO: 1538 respectively; cxxvi. are SEQ ID NO: 754, SEQ ID NO: 911, SEQ ID NO: 1068, SEQ ID NO: 1225, SEQ ID NO: 1382 and SEQ ID NO: 1539 respectively; cxxvii. are SEQ ID NO: 755, SEQ ID NO: 912, SEQ ID NO: 1069, SEQ ID NO: 1226, SEQ ID NO: 1383 and SEQ ID NO: 1540 respectively; cxxviii. are SEQ ID NO: 756, SEQ ID NO: 913, SEQ ID NO: 1070, SEQ ID NO: 1227, SEQ ID NO: 1384 and SEQ ID NO: 1541, respectively; cxxix. are SEQ ID NO: 757, SEQ ID NO: 914, SEQ ID NO: 1071, SEQ ID NO: 1228, SEQ ID NO: 1385 and SEQ ID NO: 1542 respectively; cxxx. are SEQ ID NO: 758, SEQ ID NO: 915, SEQ ID NO: 1072, SEQ ID NO: 1229, SEQ ID NO: 1386 and SEQ ID NO: 1543 respectively; cxxxi. are SEQ ID NO: 759, SEQ ID NO: 916, SEQ ID NO: 1073, SEQ ID NO: 1230, SEQ ID NO: 1387 and SEQ ID NO: 1544 respectively; cxxxii. are SEQ ID NO: 760, SEQ ID NO: 917, SEQ ID NO: 1074, SEQ ID NO: 1231, SEQ ID NO: 1388 and SEQ ID NO: 1545 respectively; cxxxiii. are SEQ ID NO: 761, SEQ ID NO: 918, SEQ ID NO: 1075, SEQ ID NO: 1232, SEQ ID NO: 1389 and SEQ ID NO: 1546 respectively; cxxxiv. are SEQ ID NO: 762, SEQ ID NO: 919, SEQ ID NO: 1076, SEQ ID NO: 1233, SEQ ID NO: 1390 and SEQ ID NO: 1547 respectively; cxxxv. are SEQ ID NO: 763, SEQ ID NO: 920, SEQ ID NO: 1077, SEQ ID NO: 1234, SEQ ID NO: 1391 and SEQ ID NO: 1548 respectively; cxxxvi. are SEQ ID NO: 764, SEQ ID NO: 921, SEQ ID NO: 1078, SEQ ID NO: 1235, SEQ ID NO: 1392 and SEQ ID NO: 1549 respectively; cxxxvii. are SEQ ID NO: 765, SEQ ID NO: 922, SEQ ID NO: 1079, SEQ ID NO: 1236, SEQ ID NO: 1393 and SEQ ID NO: 1550 respectively; cxxxviii. are SEQ ID NO: 766, SEQ ID NO: 923, SEQ ID NO: 1080, SEQ ID NO: 1237, SEQ ID NO: 1394 and SEQ ID NO: 1551, respectively; cxxxix. are SEQ ID NO: 767, SEQ ID NO: 924, SEQ ID NO: 1081, SEQ ID NO: 1238, SEQ ID NO: 1395 and SEQ ID NO: 1552 respectively; cxl. are SEQ ID NO: 768, SEQ ID NO: 925, SEQ ID NO: 1082, SEQ ID NO: 1239, SEQ ID NO: 1396 and SEQ ID NO: 1553 respectively; cxli. are SEQ ID NO: 769, SEQ ID NO: 926, SEQ ID NO: 1083, SEQ ID NO: 1240, SEQ ID NO: 1397 and SEQ ID NO: 1554 respectively; cxlii. are SEQ ID NO: 770, SEQ ID NO: 927, SEQ ID NO: 1084, SEQ ID NO: 1241, SEQ ID NO: 1398 and SEQ ID NO: 1555 respectively; cxliii. are SEQ ID NO: 771, SEQ ID NO: 928, SEQ ID NO: 1085, SEQ ID NO: 1242, SEQ ID NO: 1399 and SEQ ID NO: 1556 respectively; cxliv. are SEQ ID NO: 772, SEQ ID NO: 929, SEQ ID NO: 1086, SEQ ID NO: 1243, SEQ ID NO: 1400 and SEQ ID NO: 1557 respectively; cxlv. are SEQ ID NO: 773, SEQ ID NO: 930, SEQ ID NO: 1087, SEQ ID NO: 1244, SEQ ID NO: 1401 and SEQ ID NO: 1558 respectively; cxlvi. are SEQ ID NO: 774, SEQ ID NO: 931, SEQ ID NO: 1088, SEQ ID NO: 1245, SEQ ID NO: 1402 and SEQ ID NO: 1559 respectively; cxlvii. are SEQ ID NO: 775, SEQ ID NO: 932, SEQ ID NO: 1089, SEQ ID NO: 1246, SEQ ID NO: 1403 and SEQ ID NO: 1560 respectively; cxlviii. are SEQ ID NO: 776, SEQ ID NO: 933, SEQ ID NO: 1090, SEQ ID NO: 1247, SEQ ID NO: 1404 and SEQ ID NO: 1561, respectively; cxlix. are SEQ ID NO: 777, SEQ ID NO: 934, SEQ ID NO: 1091, SEQ ID NO: 1248, SEQ ID NO: 1405 and SEQ ID NO: 1562 respectively; Cl. are SEQ ID NO: 778, SEQ ID NO: 935, SEQ ID NO: 1092, SEQ ID NO: 1249, SEQ ID NO: 1406 and SEQ ID NO: 1563 respectively; The cli. are SEQ ID NO: 779, SEQ ID NO: 936, SEQ ID NO: 1093, SEQ ID NO: 1250, SEQ ID NO: 1407 and SEQ ID NO: 1564 respectively; The clii are SEQ ID NO: 780, SEQ ID NO: 937, SEQ ID NO: 1094, SEQ ID NO: 1251, SEQ ID NO: 1408 and SEQ ID NO: 1565, respectively; cliii. are SEQ ID NO: 781, SEQ ID NO: 938, SEQ ID NO: 1095, SEQ ID NO: 1252, SEQ ID NO: 1409 and SEQ ID NO: 1566 respectively; cliv. are SEQ ID NO: 782, SEQ ID NO: 939, SEQ ID NO: 1096, SEQ ID NO: 1253, SEQ ID NO: 1410 and SEQ ID NO: 1567 respectively; The clv. are SEQ ID NO: 783, SEQ ID NO: 940, SEQ ID NO: 1097, SEQ ID NO: 1254, SEQ ID NO: 1411 and SEQ ID NO: 1568 respectively; Clvi. are SEQ ID NO: 784, SEQ ID NO: 941, SEQ ID NO: 1098, SEQ ID NO: 1255, SEQ ID NO: 1412 and SEQ ID NO: 1569 respectively; and clvii. are SEQ ID NO: 785, SEQ ID NO: 942, SEQ ID NO: 1099, SEQ ID NO: 1256, SEQ ID NO: 1413 and SEQ ID NO: 1570 respectively.

[0310] Example 41 is a conjugate molecule as described in Example 40, wherein the anti-GIPR antibody comprises CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3 of 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, respectively.

[0311] Example 42 is a conjugate molecule as described in any one of Examples 17 to 39, wherein the anti-GIPR antibody comprises a light chain variable region (V... L ) and heavy chain variable region (V H ), where the V L and the V H It contains an amino acid sequence selected from the following: i. These are SEQ ID NO: 1 and SEQ ID NO: 158, respectively; ii. These are SEQ ID NO: 2 and SEQ ID NO: 159, respectively; iii. These are SEQ ID NO: 3 and SEQ ID NO: 160, respectively; iv. These are SEQ ID NO: 4 and SEQ ID NO: 161, respectively; v. are SEQ ID NO: 5 and SEQ ID NO: 162, respectively; vi. These are SEQ ID NO: 6 and SEQ ID NO: 163, respectively; vii. These are SEQ ID NO: 7 and SEQ ID NO: 164, respectively; viii. These are SEQ ID NO: 8 and SEQ ID NO: 165, respectively; ix. These are SEQ ID NO: 9 and SEQ ID NO: 166, respectively; x. are SEQ ID NO: 10 and SEQ ID NO: 167, respectively; xi. are SEQ ID NO: 11 and SEQ ID NO: 168 respectively; xii. These are SEQ ID NO: 12 and SEQ ID NO: 169, respectively; xiii. These are SEQ ID NO: 13 and SEQ ID NO: 170, respectively; xiv. These are SEQ ID NO: 14 and SEQ ID NO: 171, respectively; xv. are SEQ ID NO: 15 and SEQ ID NO: 172, respectively; xvi. are SEQ ID NO: 16 and SEQ ID NO: 173, respectively; xvii. are SEQ ID NO: 17 and SEQ ID NO: 174, respectively; xviii. These are SEQ ID NO: 18 and SEQ ID NO: 175, respectively; xix. are SEQ ID NO: 19 and SEQ ID NO: 176, respectively; xx. are SEQ ID NO: 20 and SEQ ID NO: 177 respectively; xxi. are SEQ ID NO: 21 and SEQ ID NO: 178, respectively; xxii. are SEQ ID NO: 22 and SEQ ID NO: 179, respectively; xxiii. These are SEQ ID NO: 23 and SEQ ID NO: 180, respectively; xxiv. are SEQ ID NO: 24 and SEQ ID NO: 181, respectively; xxv. are SEQ ID NO: 25 and SEQ ID NO: 182, respectively; xxvi. are SEQ ID NO: 26 and SEQ ID NO: 183, respectively; xxvii. are SEQ ID NO: 27 and SEQ ID NO: 184, respectively; xxviii. are SEQ ID NO: 28 and SEQ ID NO: 185, respectively; xxix. are SEQ ID NO: 29 and SEQ ID NO: 186, respectively; xxx. are SEQ ID NO: 30 and SEQ ID NO: 187 respectively; xxxi. are SEQ ID NO: 31 and SEQ ID NO: 188, respectively; xxxii. are SEQ ID NO: 32 and SEQ ID NO: 189, respectively; xxxiii. These are SEQ ID NO: 33 and SEQ ID NO: 190, respectively; xxxiv. are SEQ ID NO: 34 and SEQ ID NO: 191, respectively; xxxv. are SEQ ID NO: 35 and SEQ ID NO: 192, respectively; xxxvi. are SEQ ID NO: 36 and SEQ ID NO: 193, respectively; xxxvii. are SEQ ID NO: 37 and SEQ ID NO: 194, respectively; xxxviii. are SEQ ID NO: 38 and SEQ ID NO: 195 respectively; xxxix. are SEQ ID NO: 39 and SEQ ID NO: 196, respectively; xl. are SEQ ID NO: 40 and SEQ ID NO: 197, respectively; xli. are SEQ ID NO: 41 and SEQ ID NO: 198, respectively; xlii. are SEQ ID NO: 42 and SEQ ID NO: 199, respectively; xliii. are SEQ ID NO: 43 and SEQ ID NO: 200 respectively; xliv. are SEQ ID NO: 44 and SEQ ID NO: 201, respectively; xlv. are SEQ ID NO: 45 and SEQ ID NO: 202, respectively; xlvi. are SEQ ID NO: 46 and SEQ ID NO: 203, respectively; xlvii. are SEQ ID NO: 47 and SEQ ID NO: 204, respectively; xlviii. are SEQ ID NO: 48 and SEQ ID NO: 205, respectively; xlix. are SEQ ID NO: 49 and SEQ ID NO: 206 respectively; l. These are SEQ ID NO: 50 and SEQ ID NO: 207, respectively; li. are SEQ ID NO: 51 and SEQ ID NO: 208 respectively; lii. are SEQ ID NO: 52 and SEQ ID NO: 209 respectively; liii. are SEQ ID NO: 53 and SEQ ID NO: 210 respectively; The liv. are SEQ ID NO: 54 and SEQ ID NO: 211, respectively; The lv. are SEQ ID NO: 55 and SEQ ID NO: 212 respectively; lvi. are SEQ ID NO: 56 and SEQ ID NO: 213 respectively; lvii. are SEQ ID NO: 57 and SEQ ID NO: 214 respectively; lviii. are SEQ ID NO: 58 and SEQ ID NO: 215, respectively; The lix numbers are SEQ ID NO: 59 and SEQ ID NO: 216, respectively. lx. are SEQ ID NO: 60 and SEQ ID NO: 217 respectively; lxi. are SEQ ID NO: 61 and SEQ ID NO: 218 respectively; lxii. are SEQ ID NO: 62 and SEQ ID NO: 219, respectively; lxiii. are SEQ ID NO: 63 and SEQ ID NO: 220, respectively; The lxiv files are SEQ ID NO: 64 and SEQ ID NO: 221, respectively. lxv. are SEQ ID NO: 65 and SEQ ID NO: 222, respectively; lxvi. are SEQ ID NO: 66 and SEQ ID NO: 223, respectively; lxvii. are SEQ ID NO: 67 and SEQ ID NO: 224, respectively; lxviii. are SEQ ID NO: 68 and SEQ ID NO: 225, respectively; lxix. are SEQ ID NO: 69 and SEQ ID NO: 226 respectively; lxx. are SEQ ID NO: 70 and SEQ ID NO: 227 respectively; lxxi. are SEQ ID NO: 71 and SEQ ID NO: 228 respectively; lxxii. are SEQ ID NO: 72 and SEQ ID NO: 229, respectively; lxxiii. are SEQ ID NO: 73 and SEQ ID NO: 230, respectively; lxxiv. are SEQ ID NO: 74 and SEQ ID NO: 231, respectively; lxxv. are SEQ ID NO: 75 and SEQ ID NO: 232, respectively; lxxvi. are SEQ ID NO: 76 and SEQ ID NO: 233, respectively; lxxvii. are SEQ ID NO: 77 and SEQ ID NO: 234, respectively; lxxviii. are SEQ ID NO: 78 and SEQ ID NO: 235, respectively; lxxix. are SEQ ID NO: 79 and SEQ ID NO: 236, respectively; lxxx. are SEQ ID NO: 80 and SEQ ID NO: 237 respectively; lxxxi. are SEQ ID NO: 81 and SEQ ID NO: 238 respectively; lxxxii. are SEQ ID NO: 82 and SEQ ID NO: 239, respectively; lxxxiii. are SEQ ID NO: 83 and SEQ ID NO: 240 respectively; lxxxiv. are SEQ ID NO: 84 and SEQ ID NO: 241, respectively; lxxxv. are SEQ ID NO: 85 and SEQ ID NO: 242, respectively; lxxxvi. are SEQ ID NO: 86 and SEQ ID NO: 243, respectively; lxxxvii. are SEQ ID NO: 87 and SEQ ID NO: 244, respectively; lxxxviii. are SEQ ID NO: 88 and SEQ ID NO: 245 respectively; lxxxix. are SEQ ID NO: 89 and SEQ ID NO: 246, respectively; xc. are SEQ ID NO: 90 and SEQ ID NO: 247, respectively; xci. are SEQ ID NO: 91 and SEQ ID NO: 248, respectively; xcii. are SEQ ID NO: 92 and SEQ ID NO: 249, respectively; xciii. are SEQ ID NO: 93 and SEQ ID NO: 250, respectively; xciv. are SEQ ID NO: 94 and SEQ ID NO: 251, respectively; xcv. are SEQ ID NO: 95 and SEQ ID NO: 252, respectively; xcvi. are SEQ ID NO: 96 and SEQ ID NO: 253, respectively; xcvii. are SEQ ID NO: 97 and SEQ ID NO: 254, respectively; xcviii. are SEQ ID NO: 98 and SEQ ID NO: 255, respectively; xcix. are SEQ ID NO: 99 and SEQ ID NO: 256, respectively; c. These are SEQ ID NO: 100 and SEQ ID NO: 257, respectively; ci. are SEQ ID NO: 101 and SEQ ID NO: 258, respectively; cii. are SEQ ID NO: 102 and SEQ ID NO: 259, respectively; ciii. These are SEQ ID NO: 103 and SEQ ID NO: 260, respectively; civ. are SEQ ID NO: 104 and SEQ ID NO: 261, respectively; cv. are SEQ ID NO: 105 and SEQ ID NO: 262, respectively; cvi. are SEQ ID NO: 106 and SEQ ID NO: 263, respectively; cvii. are SEQ ID NO: 107 and SEQ ID NO: 264, respectively; cviii. are SEQ ID NO: 108 and SEQ ID NO: 265, respectively; cix. are SEQ ID NO: 109 and SEQ ID NO: 266, respectively; cx. are SEQ ID NO: 110 and SEQ ID NO: 267, respectively; cxi. are SEQ ID NO: 111 and SEQ ID NO: 268, respectively; cxii. are SEQ ID NO: 112 and SEQ ID NO: 269, respectively; cxiii. are SEQ ID NO: 113 and SEQ ID NO: 270, respectively; cxiv. are SEQ ID NO: 114 and SEQ ID NO: 271, respectively; cxv. are SEQ ID NO: 115 and SEQ ID NO: 272, respectively; cxvi. are SEQ ID NO: 116 and SEQ ID NO: 273, respectively; cxvii. are SEQ ID NO: 117 and SEQ ID NO: 274, respectively; cxviii. are SEQ ID NO: 118 and SEQ ID NO: 275, respectively; cxix. are SEQ ID NO: 119 and SEQ ID NO: 276, respectively; cxx. are SEQ ID NO: 120 and SEQ ID NO: 277, respectively; cxxi. are SEQ ID NO: 121 and SEQ ID NO: 278 respectively; cxxii. are SEQ ID NO: 122 and SEQ ID NO: 279, respectively; cxxiii. are SEQ ID NO: 123 and SEQ ID NO: 280, respectively; cxxiv. are SEQ ID NO: 124 and SEQ ID NO: 281, respectively; cxxv. are SEQ ID NO: 125 and SEQ ID NO: 282, respectively; cxxvi. are SEQ ID NO: 126 and SEQ ID NO: 283, respectively; cxxvii. are SEQ ID NO: 127 and SEQ ID NO: 284, respectively; cxxviii. are SEQ ID NO: 128 and SEQ ID NO: 285, respectively; cxxix. are SEQ ID NO: 129 and SEQ ID NO: 286, respectively; cxxx. are SEQ ID NO: 130 and SEQ ID NO: 287 respectively; cxxxi. are SEQ ID NO: 131 and SEQ ID NO: 288, respectively; cxxxii. are SEQ ID NO: 132 and SEQ ID NO: 289, respectively; cxxxiii. are SEQ ID NO: 133 and SEQ ID NO: 290, respectively; cxxxiv. are SEQ ID NO: 134 and SEQ ID NO: 291, respectively; cxxxv. are SEQ ID NO: 135 and SEQ ID NO: 292, respectively; cxxxvi. are SEQ ID NO: 136 and SEQ ID NO: 293, respectively; cxxxvii. are SEQ ID NO: 137 and SEQ ID NO: 294, respectively; cxxxviii. are SEQ ID NO: 138 and SEQ ID NO: 295, respectively; cxxxix. are SEQ ID NO: 139 and SEQ ID NO: 296, respectively; cxl. are SEQ ID NO: 140 and SEQ ID NO: 297 respectively; cxli. are SEQ ID NO: 141 and SEQ ID NO: 298, respectively; cxlii. are SEQ ID NO: 142 and SEQ ID NO: 299, respectively; cxliii. are SEQ ID NO: 143 and SEQ ID NO: 300 respectively; cxliv. are SEQ ID NO: 144 and SEQ ID NO: 301, respectively; cxlv. are SEQ ID NO: 145 and SEQ ID NO: 302, respectively; cxlvi. are SEQ ID NO: 146 and SEQ ID NO: 303, respectively; cxlvii. are SEQ ID NO: 147 and SEQ ID NO: 304, respectively; cxlviii. are SEQ ID NO: 148 and SEQ ID NO: 305, respectively; cxlix. are SEQ ID NO: 149 and SEQ ID NO: 306 respectively; cl. are SEQ ID NO: 150 and SEQ ID NO: 307, respectively; The cli. are SEQ ID NO: 151 and SEQ ID NO: 308, respectively; The clii are SEQ ID NO: 152 and SEQ ID NO: 309, respectively; cliii. are SEQ ID NO: 153 and SEQ ID NO: 310, respectively; cliv. are SEQ ID NO: 154 and SEQ ID NO: 311, respectively; clv. are SEQ ID NO: 155 and SEQ ID NO: 312 respectively; clvi. are SEQ ID NO: 156 and SEQ ID NO: 313 respectively; and clvii. are SEQ ID NO: 157 and SEQ ID NO: 314, respectively.

[0312] Example 43 is a conjugate molecule as described in Example 42, wherein the anti-GIPR antibody comprises the V of SEQ ID NO: 74 and SEQ ID NO: 231, respectively. L and V H .

[0313] Example 44 is a conjugate molecule as described in any one of Examples 17 to 39, wherein the anti-GIPR antibody comprises a light chain and a heavy chain, wherein the light chain and the heavy chain comprise an amino acid sequence selected from: i. These are SEQ ID NO: 315 and SEQ ID NO: 472, respectively; ii. These are SEQ ID NO: 316 and SEQ ID NO: 473, respectively; iii. These are SEQ ID NO: 317 and SEQ ID NO: 474, respectively; iv. These are SEQ ID NO: 318 and SEQ ID NO: 475, respectively; v. are SEQ ID NO: 319 and SEQ ID NO: 476, respectively; vi. These are SEQ ID NO: 320 and SEQ ID NO: 477, respectively; vii. These are SEQ ID NO: 321 and SEQ ID NO: 478, respectively; viii. These are SEQ ID NO: 322 and SEQ ID NO: 479, respectively; ix. These are SEQ ID NO: 323 and SEQ ID NO: 480, respectively; x. are SEQ ID NO: 324 and SEQ ID NO: 481, respectively; xi. are SEQ ID NO: 325 and SEQ ID NO: 482, respectively; xii. These are SEQ ID NO: 326 and SEQ ID NO: 483, respectively; xiii. These are SEQ ID NO: 327 and SEQ ID NO: 484, respectively; xiv. These are SEQ ID NO: 328 and SEQ ID NO: 485, respectively; xv. are SEQ ID NO: 329 and SEQ ID NO: 486, respectively; xvi. are SEQ ID NO: 330 and SEQ ID NO: 487, respectively; xvii. are SEQ ID NO: 331 and SEQ ID NO: 488, respectively; xviii. These are SEQ ID NO: 332 and SEQ ID NO: 489, respectively; xix. are SEQ ID NO: 333 and SEQ ID NO: 490, respectively; xx. are SEQ ID NO: 334 and SEQ ID NO: 491, respectively; xxi. are SEQ ID NO: 335 and SEQ ID NO: 492, respectively; xxii. are SEQ ID NO: 336 and SEQ ID NO: 493, respectively; xxiii. These are SEQ ID NO: 337 and SEQ ID NO: 494, respectively; xxiv. are SEQ ID NO: 338 and SEQ ID NO: 495, respectively; xxv. are SEQ ID NO: 339 and SEQ ID NO: 496, respectively; xxvi. are SEQ ID NO: 340 and SEQ ID NO: 497, respectively; xxvii. are SEQ ID NO: 341 and SEQ ID NO: 498, respectively; xxviii. are SEQ ID NO: 342 and SEQ ID NO: 499, respectively; xxix. are SEQ ID NO: 343 and SEQ ID NO: 500, respectively; xxx. are SEQ ID NO: 344 and SEQ ID NO: 501, respectively; xxxi. are SEQ ID NO: 345 and SEQ ID NO: 502, respectively; xxxii. are SEQ ID NO: 346 and SEQ ID NO: 503, respectively; xxxiii. These are SEQ ID NO: 347 and SEQ ID NO: 504, respectively; xxxiv. are SEQ ID NO: 348 and SEQ ID NO: 505, respectively; xxxv. are SEQ ID NO: 349 and SEQ ID NO: 506, respectively; xxxvi. are SEQ ID NO: 350 and SEQ ID NO: 507, respectively; xxxvii. are SEQ ID NO: 351 and SEQ ID NO: 508, respectively; xxxviii. are SEQ ID NO: 352 and SEQ ID NO: 509, respectively; xxxix. are SEQ ID NO: 353 and SEQ ID NO: 510, respectively; xl. are SEQ ID NO: 354 and SEQ ID NO: 511, respectively; xli. are SEQ ID NO: 355 and SEQ ID NO: 512, respectively; xlii. are SEQ ID NO: 356 and SEQ ID NO: 513 respectively; xliii. are SEQ ID NO: 357 and SEQ ID NO: 514 respectively; xliv. are SEQ ID NO: 358 and SEQ ID NO: 515, respectively; xlv. are SEQ ID NO: 359 and SEQ ID NO: 516, respectively; xlvi. are SEQ ID NO: 360 and SEQ ID NO: 517, respectively; xlvii. are SEQ ID NO: 361 and SEQ ID NO: 518 respectively; xlviii. are SEQ ID NO: 362 and SEQ ID NO: 519, respectively; xlix. are SEQ ID NO: 363 and SEQ ID NO: 520 respectively; l. These are SEQ ID NO: 364 and SEQ ID NO: 521, respectively; li. are SEQ ID NO: 365 and SEQ ID NO: 522 respectively; lii. are SEQ ID NO: 366 and SEQ ID NO: 523 respectively; liii. are SEQ ID NO: 367 and SEQ ID NO: 524 respectively; The liv. are SEQ ID NO: 368 and SEQ ID NO: 525 respectively; The lv. are SEQ ID NO: 369 and SEQ ID NO: 526 respectively; lvi. are SEQ ID NO: 370 and SEQ ID NO: 527 respectively; lvii. are SEQ ID NO: 371 and SEQ ID NO: 528 respectively; lviii. are SEQ ID NO: 372 and SEQ ID NO: 529, respectively; The lix. are SEQ ID NO: 373 and SEQ ID NO: 530, respectively; lx. are SEQ ID NO: 374 and SEQ ID NO: 531, respectively; lxi. are SEQ ID NO: 375 and SEQ ID NO: 532, respectively; lxii. are SEQ ID NO: 376 and SEQ ID NO: 533, respectively; lxiii. are SEQ ID NO: 377 and SEQ ID NO: 534, respectively; The lxiv files are SEQ ID NO: 378 and SEQ ID NO: 535, respectively. lxv. are SEQ ID NO: 379 and SEQ ID NO: 536, respectively; lxvi. are SEQ ID NO: 380 and SEQ ID NO: 537, respectively; lxvii. are SEQ ID NO: 381 and SEQ ID NO: 538, respectively; lxviii. are SEQ ID NO: 382 and SEQ ID NO: 539, respectively; lxix. are SEQ ID NO: 383 and SEQ ID NO: 540, respectively; lxx. are SEQ ID NO: 384 and SEQ ID NO: 541, respectively; lxxi. are SEQ ID NO: 385 and SEQ ID NO: 542 respectively; lxxii. are SEQ ID NO: 386 and SEQ ID NO: 543, respectively; lxxiii. are SEQ ID NO: 387 and SEQ ID NO: 544, respectively; lxxiv. are SEQ ID NO: 388 and SEQ ID NO: 545, respectively; lxxv. are SEQ ID NO: 389 and SEQ ID NO: 546, respectively; lxxvi. are SEQ ID NO: 390 and SEQ ID NO: 547, respectively; lxxvii. are SEQ ID NO: 391 and SEQ ID NO: 548, respectively; lxxviii. are SEQ ID NO: 392 and SEQ ID NO: 549, respectively; lxxix. are SEQ ID NO: 393 and SEQ ID NO: 550, respectively; lxxx. are SEQ ID NO: 394 and SEQ ID NO: 551, respectively; lxxxi. are SEQ ID NO: 395 and SEQ ID NO: 552, respectively; lxxxii. are SEQ ID NO: 396 and SEQ ID NO: 553, respectively; lxxxiii. are SEQ ID NO: 397 and SEQ ID NO: 554, respectively; lxxxiv. are SEQ ID NO: 398 and SEQ ID NO: 555, respectively; lxxxv. are SEQ ID NO: 399 and SEQ ID NO: 556, respectively; lxxxvi. are SEQ ID NO: 400 and SEQ ID NO: 557 respectively; lxxxvii. are SEQ ID NO: 401 and SEQ ID NO: 558, respectively; lxxxviii. are SEQ ID NO: 402 and SEQ ID NO: 559, respectively; lxxxix. are SEQ ID NO: 403 and SEQ ID NO: 560, respectively; xc. are SEQ ID NO: 404 and SEQ ID NO: 561, respectively; xci. are SEQ ID NO: 405 and SEQ ID NO: 562, respectively; xcii. are SEQ ID NO: 406 and SEQ ID NO: 563, respectively; xciii. are SEQ ID NO: 407 and SEQ ID NO: 564, respectively; xciv. are SEQ ID NO: 408 and SEQ ID NO: 565, respectively; xcv. are SEQ ID NO: 409 and SEQ ID NO: 566, respectively; xcvi. are SEQ ID NO: 410 and SEQ ID NO: 567, respectively; xcvii. are SEQ ID NO: 411 and SEQ ID NO: 568, respectively; xcviii. are SEQ ID NO: 412 and SEQ ID NO: 569, respectively; xcix. are SEQ ID NO: 413 and SEQ ID NO: 570, respectively; c. These are SEQ ID NO: 414 and SEQ ID NO: 571, respectively; ci. are SEQ ID NO: 415 and SEQ ID NO: 572, respectively; cii. are SEQ ID NO: 416 and SEQ ID NO: 573, respectively; ciii. These are SEQ ID NO: 417 and SEQ ID NO: 574, respectively; civ. are SEQ ID NO: 418 and SEQ ID NO: 575, respectively; cv. are SEQ ID NO: 419 and SEQ ID NO: 576 respectively; cvi. are SEQ ID NO: 420 and SEQ ID NO: 577, respectively; cvii. are SEQ ID NO: 421 and SEQ ID NO: 578, respectively; cviii. are SEQ ID NO: 422 and SEQ ID NO: 579, respectively; cix. are SEQ ID NO: 423 and SEQ ID NO: 580, respectively; cx. are SEQ ID NO: 424 and SEQ ID NO: 581, respectively; cxi. are SEQ ID NO: 425 and SEQ ID NO: 582, respectively; cxii. are SEQ ID NO: 426 and SEQ ID NO: 583, respectively; cxiii. are SEQ ID NO: 427 and SEQ ID NO: 584, respectively; cxiv. are SEQ ID NO: 428 and SEQ ID NO: 585 respectively; cxv. are SEQ ID NO: 429 and SEQ ID NO: 586, respectively; cxvi. are SEQ ID NO: 430 and SEQ ID NO: 587, respectively; cxvii. are SEQ ID NO: 431 and SEQ ID NO: 588, respectively; cxviii. are SEQ ID NO: 432 and SEQ ID NO: 589, respectively; cxix. are SEQ ID NO: 433 and SEQ ID NO: 590, respectively; cxx. are SEQ ID NO: 434 and SEQ ID NO: 591, respectively; cxxi. are SEQ ID NO: 435 and SEQ ID NO: 592 respectively; cxxii. are SEQ ID NO: 436 and SEQ ID NO: 593, respectively; cxxiii. are SEQ ID NO: 437 and SEQ ID NO: 594, respectively; cxxiv. are SEQ ID NO: 438 and SEQ ID NO: 595, respectively; cxxv. are SEQ ID NO: 439 and SEQ ID NO: 596, respectively; cxxvi. are SEQ ID NO: 440 and SEQ ID NO: 597, respectively; cxxvii. are SEQ ID NO: 441 and SEQ ID NO: 598, respectively; cxxviii. are SEQ ID NO: 442 and SEQ ID NO: 599, respectively; cxxix. are SEQ ID NO: 443 and SEQ ID NO: 600, respectively; cxxx. are SEQ ID NO: 444 and SEQ ID NO: 601, respectively; cxxxi. are SEQ ID NO: 445 and SEQ ID NO: 602, respectively; cxxxii. are SEQ ID NO: 446 and SEQ ID NO: 603, respectively; cxxxiii. are SEQ ID NO: 447 and SEQ ID NO: 604, respectively; cxxxiv. are SEQ ID NO: 448 and SEQ ID NO: 605, respectively; cxxxv. are SEQ ID NO: 449 and SEQ ID NO: 606, respectively; cxxxvi. are SEQ ID NO: 450 and SEQ ID NO: 607, respectively; cxxxvii. are SEQ ID NO: 451 and SEQ ID NO: 608, respectively; cxxxviii. are SEQ ID NO: 452 and SEQ ID NO: 609, respectively; cxxxix. are SEQ ID NO: 453 and SEQ ID NO: 610, respectively; cxl. are SEQ ID NO: 454 and SEQ ID NO: 611, respectively; cxli. are SEQ ID NO: 455 and SEQ ID NO: 612, respectively; cxlii. are SEQ ID NO: 456 and SEQ ID NO: 613 respectively; cxliii. are SEQ ID NO: 457 and SEQ ID NO: 614 respectively; cxliv. are SEQ ID NO: 458 and SEQ ID NO: 615 respectively; cxlv. are SEQ ID NO: 459 and SEQ ID NO: 616, respectively; cxlvi. are SEQ ID NO: 460 and SEQ ID NO: 617, respectively; cxlvii. are SEQ ID NO: 461 and SEQ ID NO: 618 respectively; cxlviii. are SEQ ID NO: 462 and SEQ ID NO: 619, respectively; cxlix. are SEQ ID NO: 463 and SEQ ID NO: 620 respectively; cl. are SEQ ID NO: 464 and SEQ ID NO: 621, respectively; The cli. are SEQ ID NO: 465 and SEQ ID NO: 622, respectively; clii. are SEQ ID NO: 466 and SEQ ID NO: 623, respectively; cliii. are SEQ ID NO: 467 and SEQ ID NO: 624, respectively; cliv. are SEQ ID NO: 468 and SEQ ID NO: 625 respectively; clv. are SEQ ID NO: 469 and SEQ ID NO: 626 respectively; clvi. are SEQ ID NO: 470 and SEQ ID NO: 627 respectively; and clvii. are SEQ ID NO: 471 and SEQ ID NO: 628, respectively. The antibody contains one or more cysteine ​​amino acid substitutions at one or more of the following positions selected according to AHo number: position 88 of the light chain, position 384 of the heavy chain, or position 487 of the heavy chain.

[0314] Example 45 is a conjugate molecule as described in Example 44, wherein the anti-GIPR antibody comprises the light chain and heavy chain of SEQ ID NO: 388 and SEQ ID NO: 545, respectively.

[0315] Example 46 is a conjugate molecule comprising: (i) an antagonist anti-glucose-dependent insulinotropic peptide receptor (GIPR) antibody, wherein the anti-GIPR antibody comprises: a first light chain and a second light chain, each light chain comprising CDRL1, CDRL2, and CDRL3 of SEQ ID NO: 702, SEQ ID NO: 859, and SEQ ID NO: 1016, respectively; and a first heavy chain and a second heavy chain, each heavy chain comprising CDRH1, CDRH2, and CDRH3 of SEQ ID NO: 1173, SEQ ID NO: 1330, and SEQ ID NO: 1487, respectively; (ii) a first GLP-1 receptor agonist peptide and a second GLP-1 receptor agonist peptide, wherein each GLP-1 receptor agonist peptide comprises the amino acid sequence of SEQ ID NO: 1579; and (iii) a first peptide linker and a second peptide linker, wherein each peptide linker comprises the amino acid sequence of SEQ ID NO: 1579. The amino acid sequence is 1592; wherein the first GLP-1 receptor agonist polypeptide is conjugated at its C-terminus to the first heavy chain of the anti-GIPR antibody via the first linker at a cysteine ​​residue at position 384 of the first heavy chain according to AHo number, and wherein the second GLP-1 receptor agonist polypeptide is conjugated at its C-terminus to the second heavy chain of the anti-GIPR antibody via the second linker at a cysteine ​​residue at position 384 of the second heavy chain according to AHo number.

[0316] Example 47 is a conjugate molecule as described in Example 46, wherein each light chain contains VL of SEQ ID NO: 74 and each heavy chain contains VH of SEQ ID NO: 231.

[0317] Example 48 is a conjugate molecule as described in Example 46, wherein each light chain contains the amino acid sequence of SEQ ID NO: 388 and each heavy chain contains the amino acid sequence of SEQ ID NO: 1571.

[0318] Example 49 is a conjugate molecule comprising: (i) an antagonist anti-glucose-dependent insulinotropic peptide receptor (GIPR) antibody, wherein the anti-GIPR antibody comprises: a first light chain and a second light chain, each light chain comprising CDRL1, CDRL2, and CDRL3 of SEQ ID NO: 702, SEQ ID NO: 859, and SEQ ID NO: 1016, respectively; and a first heavy chain and a second heavy chain, each heavy chain comprising CDRH1, CDRH2, and CDRH3 of SEQ ID NO: 1173, SEQ ID NO: 1330, and SEQ ID NO: 1487, respectively; a first GLP-1 receptor agonist peptide and a second GLP-1 receptor agonist peptide, wherein each GLP-1 receptor agonist peptide comprises the amino acid sequence of SEQ ID NO: 1580; and (ii) a first peptide linker and a second peptide linker, wherein each peptide linker comprises the amino acid sequence of SEQ ID NO: 1580. The amino acid sequence is 1591; wherein the first GLP-1 receptor agonist polypeptide is conjugated at its C-terminus to the first heavy chain of the anti-GIPR antibody via the first linker at a cysteine ​​residue at position 384 of the first heavy chain according to AHo number, and wherein the second GLP-1 receptor agonist polypeptide is conjugated at its C-terminus to the second heavy chain of the anti-GIPR antibody via the second linker at a cysteine ​​residue at position 384 of the second heavy chain according to AHo number.

[0319] Example 50 is a conjugate molecu...

Claims

1. A human glucagon-like peptide-1 (GLP-1) receptor agonist polypeptide comprising H[Aib]EGTFTSDYSSYLEEX17AAX 20 EFIX 24 WLX 27 X 28 The amino acid sequence of GGG (SEQ ID NO: 1575), Where X 17 It is Q, K, E, or R; X 20 It is K, R, Q or high in arginine (hArg); X 24 It is A, E, Q, D, d-Ala, G, N, K, (1S,2S)-2-aminocyclopentanecarboxylic acid (ACPC), (3S,4R)-4-amino-3-pyrrolidinecarboxylic acid (APCA), T, S, or Y; X 27 It is V, K, Aib, N, S, T, Y, Q, or R; and X 28 It is K, E, R, Q, D, N, G, S, or T; and The GLP-1 receptor agonist peptide does not contain the amino acid sequence of SEQ ID NO: 1574 (H[Aib]EGTFTSDYSSYLEEQAAKEFIAWLVKGGG).

2. The GLP-1 receptor agonist peptide of claim 1, wherein the GLP-1 receptor agonist peptide comprises H[Aib]EGTFTSDYSSYLEEX 17 AAX 20 EFIX 24 WLX 27 X 28 The amino acid sequence of GGG (SEQ ID NO: 1576), where X 17 Is it Q or K; X 20 It is K or R; X 24 It is A, E, or Q; X 27 It is V or K; and X 28 It is K, E, or R.

3. The GLP-1 receptor agonist peptide of claim 1, wherein the GLP-1 receptor agonist peptide comprises H[Aib]EGTFTSDYSSYLEEX 17 AAREFIX 24 WLX 27 X 28 The amino acid sequence of GGG (SEQ ID NO: 1577), where X 17 Is it Q or K; X 24 It is A, E, or Q; X 27 It is V or K; and X 28 It is K, E, or R.

4. The GLP-1 receptor agonist peptide of claim 1, wherein the GLP-1 receptor agonist peptide comprises H[Aib]EGTFTSDYSSYLEEX 17 AAX 20 EFIX 24 WLKX 28 The amino acid sequence of GGG (SEQ ID NO: 1578), where X 17 Is it Q or K; X 20 It is K or R; X 24 It is A, E, or Q; and X 28 It is K, E, or R.

5. The GLP-1 receptor agonist polypeptide of claim 1, wherein the GLP-1 receptor agonist polypeptide comprises the amino acid sequence of any one of SEQ ID NO: 1579, SEQ ID NO: 1580, SEQ ID NO: 1581, SEQ ID NO: 1582 or SEQ ID NO: 1583.

6. A human glucagon-like peptide-1 (GLP-1) receptor agonist polypeptide, wherein: The polypeptide contains 31 amino acids, and includes an amino acid sequence that has at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 1580; and The polypeptide contains α-aminoisobutyric acid (Aib) at position 2; tyrosine at position 10; glutamic acid at positions 16, 24 and 28; arginine at position 20; and lysine at positions 17 and 27. And glycine at position 31.

7. A human glucagon-like peptide-1 (GLP-1) receptor agonist polypeptide, wherein: This GLP-1 receptor agonist peptide contains 31 amino acids, and includes an amino acid sequence that has at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 1579; and The GLP-1 receptor agonist peptide contains Aib at position 2; tyrosine at position 10; glutamic acid at positions 16 and 24; arginine at position 20; lysine at position 27; and glycine at position 30.

8. A human glucagon-like peptide-1 (GLP-1) receptor agonist polypeptide, wherein: This GLP-1 receptor agonist peptide comprises 31 amino acids, and includes an amino acid sequence that has at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 1581; and The GLP-1 receptor agonist peptide contains Aib at position 2; tyrosine at position 10; glutamic acid at positions 16 and 24; arginine at position 20; lysine at positions 17 and 27; and glycine at position 30.

9. A human glucagon-like peptide-1 (GLP-1) receptor agonist polypeptide, wherein: This GLP-1 receptor agonist peptide contains 31 amino acids, and includes an amino acid sequence that has at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 1583; and The GLP-1 receptor agonist peptide contains Aib at position 2; tyrosine at position 10; glutamic acid at positions 16 and 28; arginine at position 20; lysine at positions 17 and 27; glutamine at position 24; and glycine at position 30.

10. A human glucagon-like peptide-1 (GLP-1) receptor agonist polypeptide, wherein: This GLP-1 receptor agonist peptide contains 31 amino acids, and includes an amino acid sequence that has at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 1582; ​​and The GLP-1 receptor agonist peptide contains Aib at position 2; tyrosine at position 10; glutamic acid at positions 16 and 24; arginine at positions 20 and 28; lysine at position 27; and glycine at position 30.

11. A molecule comprising: The first human glucagon-like peptide-1 (GLP-1) receptor agonist polypeptide, containing H[Aib]EGTFTSDYSSYLEEX 17 AAX 20 EFIX 24 WLX 27 X 28 The amino acid sequence of GGG (SEQ ID NO: 1575), Where X 17 It is Q, K, E, or R; X 20 It is K, R, Q or high in arginine (hArg); X 24 It is A, E, Q, D, d-Ala, G, N, K, (1S,2S)-2-aminocyclopentanecarboxylic acid (ACPC), (3S,4R)-4-amino-3-pyrrolidinecarboxylic acid (APCA), T, S, or Y; X 27 It is V, K, Aib, N, S, T, Y, Q, or R; and X 28 It is K, E, R, Q, D, N, G, S, or T, and The GLP-1 receptor agonist peptide does not contain the amino acid sequence of SEQ ID NO: 1574; and The portion with extended half-life.

12. The molecule of claim 11, wherein the first GLP-1 receptor agonist polypeptide comprises H[Aib]EGTFTSDYSSYLEEX 17 AAX 20 EFIX 24 WLX 27 X 28 The amino acid sequence of GGG (SEQ ID NO: 1576), where X 17 Is it Q or K; X 20 It is K or R; X 24 It is A, E, or Q; X 27 It is V or K; and X 28 It is K, E, or R.

13. The molecule of claim 11, wherein the first GLP-1 receptor agonist polypeptide comprises H[Aib]EGTFTSDYSSYLEEX 17 AAR 20 EFIX 24 WLX 27 X 28 The amino acid sequence of GGG (SEQ ID NO: 1577), where X 17 Is it Q or K; X 24 It is A, E, or Q; X 27 It is V or K; and X 28 It is K, E, or R.

14. The molecule of claim 11, wherein the first GLP-1 receptor agonist polypeptide comprises H[Aib]EGTFTSDYSSYLEEX 17 AAX 20 EFIX 24 WLK 27 X 28 The amino acid sequence of GGG (SEQ ID NO: 1578), where X 17 Is it Q or K; X 20 It is K or R; X 24 It is A, E, or Q; and X 28 It is K, E, or R.

15. The molecule of claim 11, wherein the first GLP-1 receptor agonist polypeptide comprises the amino acid sequence of any one of SEQ ID NO: 1579, SEQ ID NO: 1580, SEQ ID NO: 1581, SEQ ID NO: 1582 or SEQ ID NO: 1583.

16. The molecule of any one of claims 11-15, wherein the extended half-life portion is an antibody.

17. A conjugate molecule comprising: The first human glucagon-like peptide-1 (GLP-1) receptor agonist polypeptide, containing H[Aib]EGTFTSDYSSYLEEX 17 AAX 20 EFIX 24 WLX 27 X 28 The amino acid sequence of GGG (SEQ ID NO: 1575), Where X 17 It is Q, K, E, or R; X 20 It is K, R, Q or high in arginine (hArg); X 24 It is A, E, Q, D, d-Ala, G, N, K, (1S,2S)-2-aminocyclopentanecarboxylic acid (ACPC), (3S,4R)-4-amino-3-pyrrolidinecarboxylic acid (APCA), T, S, or Y; X 27 It is V, K, Aib, N, S, T, Y, Q, or R; and X 28 It is K, E, R, Q, D, N, G, S, or T, and The GLP-1 receptor agonist peptide does not contain the amino acid sequence of SEQ ID NO: 1574; and Antagonist anti-glucose-dependent insulinotropic peptide receptor (GIPR) human antibody.

18. The conjugate molecule of claim 17, wherein the anti-GIPR antibody antagonizes human GIPR.

19. The conjugate molecule of claim 17, wherein the first GLP-1 receptor agonist polypeptide comprises the amino acid sequence of SEQ ID NO: 1575.

20. The conjugate molecule of claim 17, wherein the first GLP-1 receptor agonist polypeptide comprises the amino acid sequence of SEQ ID NO: 1576.

21. The conjugate molecule of claim 17, wherein the first GLP-1 receptor agonist polypeptide comprises the amino acid sequence of SEQ ID NO: 1577.

22. The conjugate molecule of claim 17, wherein the first GLP-1 receptor agonist polypeptide comprises the amino acid sequence of SEQ ID NO: 1578.

23. The conjugate molecule of claim 17, wherein the first GLP-1 receptor agonist polypeptide comprises the amino acid sequence of any one of SEQ ID NO: 1579, SEQ ID NO: 1580, SEQ ID NO: 1581, SEQ ID NO: 1582 or SEQ ID NO: 1583.

24. The conjugate molecule of claim 17 or claim 18, wherein the anti-GIPR antibody comprises a first cysteine ​​conjugate site in the light or heavy chain of the antibody, and The first GLP-1 receptor agonist peptide is conjugated at its C-terminus to the first cysteine ​​conjugate site of the anti-GIPR antibody.

25. The conjugate molecule of claim 24, wherein the first GLP-1 receptor agonist polypeptide is conjugated at its C-terminus to the first cysteine ​​conjugate site of the anti-GIPR antibody via a first linker portion.

26. The conjugate molecule of claim 25, wherein the first linker portion is a peptide linker, and the peptide linker comprises an amino acid sequence of any one of SEQ ID NO: 1585-1593.

27. The conjugate molecule of claim 25, wherein the first connector portion is a PEG connector.

28. The conjugate molecule of any one of claims 24 to 27, wherein the first cysteine ​​conjugate site of the anti-GIPR antibody is located at position 88 of the light chain, position 384 of the heavy chain, or position 487 of the heavy chain according to the AHo number.

29. The conjugate molecule of any one of claims 17 to 28, wherein the molecule further comprises: The second GLP-1 receptor agonist polypeptide is conjugated at its C-terminus to the second cysteine ​​conjugate site of the anti-GIPR antibody.

30. The conjugate molecule of claim 29, wherein the second GLP-1 receptor agonist polypeptide comprises the amino acid sequence of SEQ ID NO: 1575.

31. The conjugate molecule of claim 29, wherein the second GLP-1 receptor agonist polypeptide comprises the amino acid sequence of SEQ ID NO: 1576.

32. The conjugate molecule of claim 29, wherein the second GLP-1 receptor agonist polypeptide comprises the amino acid sequence of SEQ ID NO: 1577.

33. The conjugate molecule of claim 29, wherein the second GLP-1 receptor agonist polypeptide comprises the amino acid sequence of SEQ ID NO: 1578.

34. The conjugate molecule of claim 29, wherein the second GLP-1 receptor agonist polypeptide comprises the amino acid sequence of any one of SEQ ID NO: 1579, SEQ ID NO: 1580, SEQ ID NO: 1581, SEQ ID NO: 1582 or SEQ ID NO: 1583.

35. The conjugate molecule of claim 29, wherein the second GLP-1 receptor agonist polypeptide comprises the same amino acid sequence as the first GLP-1 receptor agonist polypeptide.

36. The conjugate molecule of any one of claims 29 to 35, wherein the second GLP-1 receptor agonist polypeptide is conjugated at its C-terminus to the second cysteine ​​conjugate site of the anti-GIPR antibody via a second linker portion.

37. The conjugate molecule of claim 36, wherein the second linker portion is a peptide linker, and the peptide linker comprises an amino acid sequence of any one of SEQ ID NO: 1585-1593.

38. The conjugate molecule of claim 36, wherein the second connector portion is a PEG connector.

39. The conjugate molecule of claim 29, wherein the first and second conjugate sites of the anti-GIPR antibody are located at position 88 of each light chain, position 384 of each heavy chain, or position 487 of each heavy chain according to the AHo number.

40. The conjugate molecule as described in any one of Examples 17 to 39, wherein the anti-GIPR antibody comprises light chain complementarity-determining region 1 (CDRL1), CDRL2, CDRL3, heavy chain complementarity-determining region 1 (CDRH1), CDRH2, and CDRH3, wherein CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3 comprise an amino acid sequence selected from: i. These are SEQ ID NO: 629, SEQ ID NO: 786, SEQ ID NO: 943, SEQ ID NO: 1100, SEQ ID NO: 1257 and SEQ ID NO: 1414, respectively; ii. These are SEQ ID NO: 630, SEQ ID NO: 787, SEQ ID NO: 944, SEQ ID NO: 1101, SEQ ID NO: 1258 and SEQ ID NO: 1415, respectively; iii. These are SEQ ID NO: 631, SEQ ID NO: 788, SEQ ID NO: 945, SEQ ID NO: 1102, SEQ ID NO: 1259 and SEQ ID NO: 1416, respectively; iv. These are SEQ ID NO: 632, SEQ ID NO: 789, SEQ ID NO: 946, SEQ ID NO: 1103, SEQ ID NO: 1260 and SEQ ID NO: 1417, respectively; v. are SEQ ID NO: 633, SEQ ID NO: 790, SEQ ID NO: 947, SEQ ID NO: 1104, SEQ ID NO: 1261 and SEQ ID NO: 1418 respectively; vi. These are SEQ ID NO: 634, SEQ ID NO: 791, SEQ ID NO: 948, SEQ ID NO: 1105, SEQ ID NO: 1262 and SEQ ID NO: 1419, respectively; vii. These are SEQ ID NO: 635, SEQ ID NO: 792, SEQ ID NO: 949, SEQ ID NO: 1106, SEQ ID NO: 1263 and SEQ ID NO: 1420, respectively; viii. These are SEQ ID NO: 636, SEQ ID NO: 793, SEQ ID NO: 950, SEQ ID NO: 1107, SEQ ID NO: 1264 and SEQ ID NO: 1421, respectively; ix. are SEQ ID NO: 637, SEQ ID NO: 794, SEQ ID NO: 951, SEQ ID NO: 1108, SEQ ID NO: 1265 and SEQ ID NO: 1422 respectively; x. are SEQ ID NO: 638, SEQ ID NO: 795, SEQ ID NO: 952, SEQ ID NO: 1109, SEQ ID NO: 1266 and SEQ ID NO: 1423 respectively; xi. are SEQ ID NO: 639, SEQ ID NO: 796, SEQ ID NO: 953, SEQ ID NO: 1110, SEQ ID NO: 1267 and SEQ ID NO: 1424 respectively; xii. These are SEQ ID NO: 640, SEQ ID NO: 797, SEQ ID NO: 954, SEQ ID NO: 1111, SEQ ID NO: 1268 and SEQ ID NO: 1425, respectively; xiii. These are SEQ ID NO: 641, SEQ ID NO: 798, SEQ ID NO: 955, SEQ ID NO: 1112, SEQ ID NO: 1269 and SEQ ID NO: 1426, respectively; xiv. are SEQ ID NO: 642, SEQ ID NO: 799, SEQ ID NO: 956, SEQ ID NO: 1113, SEQ ID NO: 1270 and SEQ ID NO: 1427 respectively; xv. are SEQ ID NO: 643, SEQ ID NO: 800, SEQ ID NO: 957, SEQ ID NO: 1114, SEQ ID NO: 1271 and SEQ ID NO: 1428 respectively; xvi. are SEQ ID NO: 644, SEQ ID NO: 801, SEQ ID NO: 958, SEQ ID NO: 1115, SEQ ID NO: 1272 and SEQ ID NO: 1429 respectively; xvii. are SEQ ID NO: 645, SEQ ID NO: 802, SEQ ID NO: 959, SEQ ID NO: 1116, SEQ ID NO: 1273 and SEQ ID NO: 1430 respectively; xviii. are SEQ ID NO: 646, SEQ ID NO: 803, SEQ ID NO: 960, SEQ ID NO: 1117, SEQ ID NO: 1274 and SEQ ID NO: 1431, respectively; xix. are SEQ ID NO: 647, SEQ ID NO: 804, SEQ ID NO: 961, SEQ ID NO: 1118, SEQ ID NO: 1275 and SEQ ID NO: 1432 respectively; xx. are SEQ ID NO: 648, SEQ ID NO: 805, SEQ ID NO: 962, SEQ ID NO: 1119, SEQ ID NO: 1276 and SEQ ID NO: 1433 respectively; xxi. are SEQ ID NO: 649, SEQ ID NO: 806, SEQ ID NO: 963, SEQ ID NO: 1120, SEQ ID NO: 1277 and SEQ ID NO: 1434 respectively; xxii. are SEQ ID NO: 650, SEQ ID NO: 807, SEQ ID NO: 964, SEQ ID NO: 1121, SEQ ID NO: 1278 and SEQ ID NO: 1435 respectively; xxiii. These are SEQ ID NO: 651, SEQ ID NO: 808, SEQ ID NO: 965, SEQ ID NO: 1122, SEQ ID NO: 1279 and SEQ ID NO: 1436, respectively; xxiv. are SEQ ID NO: 652, SEQ ID NO: 809, SEQ ID NO: 966, SEQ ID NO: 1123, SEQ ID NO: 1280 and SEQ ID NO: 1437 respectively; xxv. are SEQ ID NO: 653, SEQ ID NO: 810, SEQ ID NO: 967, SEQ ID NO: 1124, SEQ ID NO: 1281 and SEQ ID NO: 1438 respectively; xxvi. are SEQ ID NO: 654, SEQ ID NO: 811, SEQ ID NO: 968, SEQ ID NO: 1125, SEQ ID NO: 1282 and SEQ ID NO: 1439 respectively; xxvii. are SEQ ID NO: 655, SEQ ID NO: 812, SEQ ID NO: 969, SEQ ID NO: 1126, SEQ ID NO: 1283 and SEQ ID NO: 1440 respectively; xxviii. are SEQ ID NO: 656, SEQ ID NO: 813, SEQ ID NO: 970, SEQ ID NO: 1127, SEQ ID NO: 1284 and SEQ ID NO: 1441, respectively; xxix. are SEQ ID NO: 657, SEQ ID NO: 814, SEQ ID NO: 971, SEQ ID NO: 1128, SEQ ID NO: 1285 and SEQ ID NO: 1442 respectively; The numbers xxx are SEQ ID NO: 658, SEQ ID NO: 815, SEQ ID NO: 972, SEQ ID NO: 1129, SEQ ID NO: 1286 and SEQ ID NO: 1443, respectively. xxxi are SEQ ID NO: 659, SEQ ID NO: 816, SEQ ID NO: 973, SEQ ID NO: 1130, SEQ ID NO: 1287 and SEQ ID NO: 1444 respectively; xxxii. are SEQ ID NO: 660, SEQ ID NO: 817, SEQ ID NO: 974, SEQ ID NO: 1131, SEQ ID NO: 1288 and SEQ ID NO: 1445 respectively; xxxiii. are SEQ ID NO: 661, SEQ ID NO: 818, SEQ ID NO: 975, SEQ ID NO: 1132, SEQ ID NO: 1289 and SEQ ID NO: 1446 respectively; xxxiv. are SEQ ID NO: 662, SEQ ID NO: 819, SEQ ID NO: 976, SEQ ID NO: 1133, SEQ ID NO: 1290 and SEQ ID NO: 1447 respectively; xxxv. are SEQ ID NO: 663, SEQ ID NO: 820, SEQ ID NO: 977, SEQ ID NO: 1134, SEQ ID NO: 1291 and SEQ ID NO: 1448 respectively; xxxvi. are SEQ ID NO: 664, SEQ ID NO: 821, SEQ ID NO: 978, SEQ ID NO: 1135, SEQ ID NO: 1292 and SEQ ID NO: 1449 respectively; xxxvii. are SEQ ID NO: 665, SEQ ID NO: 822, SEQ ID NO: 979, SEQ ID NO: 1136, SEQ ID NO: 1293 and SEQ ID NO: 1450 respectively; xxxviii. are SEQ ID NO: 666, SEQ ID NO: 823, SEQ ID NO: 980, SEQ ID NO: 1137, SEQ ID NO: 1294 and SEQ ID NO: 1451 respectively; xxxix. are SEQ ID NO: 667, SEQ ID NO: 824, SEQ ID NO: 981, SEQ ID NO: 1138, SEQ ID NO: 1295 and SEQ ID NO: 1452 respectively; xl. are SEQ ID NO: 668, SEQ ID NO: 825, SEQ ID NO: 982, SEQ ID NO: 1139, SEQ ID NO: 1296 and SEQ ID NO: 1453 respectively; xli. are SEQ ID NO: 669, SEQ ID NO: 826, SEQ ID NO: 983, SEQ ID NO: 1140, SEQ ID NO: 1297 and SEQ ID NO: 1454 respectively; xlii. are SEQ ID NO: 670, SEQ ID NO: 827, SEQ ID NO: 984, SEQ ID NO: 1141, SEQ ID NO: 1298 and SEQ ID NO: 1455 respectively; xliii. are SEQ ID NO: 671, SEQ ID NO: 828, SEQ ID NO: 985, SEQ ID NO: 1142, SEQ ID NO: 1299 and SEQ ID NO: 1456 respectively; xliv. are SEQ ID NO: 672, SEQ ID NO: 829, SEQ ID NO: 986, SEQ ID NO: 1143, SEQ ID NO: 1300 and SEQ ID NO: 1457 respectively; The xlv. are SEQ ID NO: 673, SEQ ID NO: 830, SEQ ID NO: 987, SEQ ID NO: 1144, SEQ ID NO: 1301 and SEQ ID NO: 1458, respectively; xlvi. are SEQ ID NO: 674, SEQ ID NO: 831, SEQ ID NO: 988, SEQ ID NO: 1145, SEQ ID NO: 1302 and SEQ ID NO: 1459 respectively; xlvii. are SEQ ID NO: 675, SEQ ID NO: 832, SEQ ID NO: 989, SEQ ID NO: 1146, SEQ ID NO: 1303 and SEQ ID NO: 1460 respectively; xlviii. are SEQ ID NO: 676, SEQ ID NO: 833, SEQ ID NO: 990, SEQ ID NO: 1147, SEQ ID NO: 1304 and SEQ ID NO: 1461, respectively; xlix. are SEQ ID NO: 677, SEQ ID NO: 834, SEQ ID NO: 991, SEQ ID NO: 1148, SEQ ID NO: 1305 and SEQ ID NO: 1462 respectively; l. These are SEQ ID NO: 678, SEQ ID NO: 835, SEQ ID NO: 992, SEQ ID NO: 1149, SEQ ID NO: 1306 and SEQ ID NO: 1463, respectively; The li are SEQ ID NO: 679, SEQ ID NO: 836, SEQ ID NO: 993, SEQ ID NO: 1150, SEQ ID NO: 1307 and SEQ ID NO: 1464 respectively; The lii. are SEQ ID NO: 680, SEQ ID NO: 837, SEQ ID NO: 994, SEQ ID NO: 1151, SEQ ID NO: 1308 and SEQ ID NO: 1465 respectively; liii. are SEQ ID NO: 681, SEQ ID NO: 838, SEQ ID NO: 995, SEQ ID NO: 1152, SEQ ID NO: 1309 and SEQ ID NO: 1466 respectively; The liv. are SEQ ID NO: 682, SEQ ID NO: 839, SEQ ID NO: 996, SEQ ID NO: 1153, SEQ ID NO: 1310 and SEQ ID NO: 1467 respectively; The lv. are SEQ ID NO: 683, SEQ ID NO: 840, SEQ ID NO: 997, SEQ ID NO: 1154, SEQ ID NO: 1311 and SEQ ID NO: 1468 respectively; lvi. are SEQ ID NO: 684, SEQ ID NO: 841, SEQ ID NO: 998, SEQ ID NO: 1155, SEQ ID NO: 1312 and SEQ ID NO: 1469 respectively; lvii. are SEQ ID NO: 685, SEQ ID NO: 842, SEQ ID NO: 999, SEQ ID NO: 1156, SEQ ID NO: 1313 and SEQ ID NO: 1470 respectively; lviii. are SEQ ID NO: 686, SEQ ID NO: 843, SEQ ID NO: 1000, SEQ ID NO: 1157, SEQ ID NO: 1314 and SEQ ID NO: 1471, respectively; The lix numbers are SEQ ID NO: 687, SEQ ID NO: 844, SEQ ID NO: 1001, SEQ ID NO: 1158, SEQ ID NO: 1315 and SEQ ID NO: 1472, respectively. lx. are SEQ ID NO: 688, SEQ ID NO: 845, SEQ ID NO: 1002, SEQ ID NO: 1159, SEQ ID NO: 1316 and SEQ ID NO: 1473 respectively; lxi. are SEQ ID NO: 689, SEQ ID NO: 846, SEQ ID NO: 1003, SEQ ID NO: 1160, SEQ ID NO: 1317 and SEQ ID NO: 1474 respectively; lxii. are SEQ ID NO: 690, SEQ ID NO: 847, SEQ ID NO: 1004, SEQ ID NO: 1161, SEQ ID NO: 1318 and SEQ ID NO: 1475 respectively; lxiii. are SEQ ID NO: 691, SEQ ID NO: 848, SEQ ID NO: 1005, SEQ ID NO: 1162, SEQ ID NO: 1319 and SEQ ID NO: 1476 respectively; The lxiv. are SEQ ID NO: 692, SEQ ID NO: 849, SEQ ID NO: 1006, SEQ ID NO: 1163, SEQ ID NO: 1320 and SEQ ID NO: 1477, respectively. lxv. are SEQ ID NO: 693, SEQ ID NO: 850, SEQ ID NO: 1007, SEQ ID NO: 1164, SEQ ID NO: 1321 and SEQ ID NO: 1478 respectively; lxvi. are SEQ ID NO: 694, SEQ ID NO: 851, SEQ ID NO: 1008, SEQ ID NO: 1165, SEQ ID NO: 1322 and SEQ ID NO: 1479 respectively; lxvii. are SEQ ID NO: 695, SEQ ID NO: 852, SEQ ID NO: 1009, SEQ ID NO: 1166, SEQ ID NO: 1323 and SEQ ID NO: 1480 respectively; lxviii. are SEQ ID NO: 696, SEQ ID NO: 853, SEQ ID NO: 1010, SEQ ID NO: 1167, SEQ ID NO: 1324 and SEQ ID NO: 1481, respectively; lxix. are SEQ ID NO: 697, SEQ ID NO: 854, SEQ ID NO: 1011, SEQ ID NO: 1168, SEQ ID NO: 1325 and SEQ ID NO: 1482 respectively; lxx. are SEQ ID NO: 698, SEQ ID NO: 855, SEQ ID NO: 1012, SEQ ID NO: 1169, SEQ ID NO: 1326 and SEQ ID NO: 1483 respectively; lxxi. are SEQ ID NO: 699, SEQ ID NO: 856, SEQ ID NO: 1013, SEQ ID NO: 1170, SEQ ID NO: 1327 and SEQ ID NO: 1484 respectively; lxxii. are SEQ ID NO: 700, SEQ ID NO: 857, SEQ ID NO: 1014, SEQ ID NO: 1171, SEQ ID NO: 1328 and SEQ ID NO: 1485 respectively; lxxiii. are SEQ ID NO: 701, SEQ ID NO: 858, SEQ ID NO: 1015, SEQ ID NO: 1172, SEQ ID NO: 1329 and SEQ ID NO: 1486 respectively; lxxiv. are 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 respectively; lxxv. are SEQ ID NO: 703, SEQ ID NO: 860, SEQ ID NO: 1017, SEQ ID NO: 1174, SEQ ID NO: 1331 and SEQ ID NO: 1488 respectively; lxxvi. are SEQ ID NO: 704, SEQ ID NO: 861, SEQ ID NO: 1018, SEQ ID NO: 1175, SEQ ID NO: 1332 and SEQ ID NO: 1489 respectively; lxxvii. are SEQ ID NO: 705, SEQ ID NO: 862, SEQ ID NO: 1019, SEQ ID NO: 1176, SEQ ID NO: 1333 and SEQ ID NO: 1490 respectively; lxxviii. are SEQ ID NO: 706, SEQ ID NO: 863, SEQ ID NO: 1020, SEQ ID NO: 1177, SEQ ID NO: 1334 and SEQ ID NO: 1491, respectively; lxxix. are SEQ ID NO: 707, SEQ ID NO: 864, SEQ ID NO: 1021, SEQ ID NO: 1178, SEQ ID NO: 1335 and SEQ ID NO: 1492 respectively; lxxx. are SEQ ID NO: 708, SEQ ID NO: 865, SEQ ID NO: 1022, SEQ ID NO: 1179, SEQ ID NO: 1336 and SEQ ID NO: 1493 respectively; lxxxi. are SEQ ID NO: 709, SEQ ID NO: 866, SEQ ID NO: 1023, SEQ ID NO: 1180, SEQ ID NO: 1337 and SEQ ID NO: 1494 respectively; lxxxii. are SEQ ID NO: 710, SEQ ID NO: 867, SEQ ID NO: 1024, SEQ ID NO: 1181, SEQ ID NO: 1338 and SEQ ID NO: 1495 respectively; lxxxiii. are SEQ ID NO: 711, SEQ ID NO: 868, SEQ ID NO: 1025, SEQ ID NO: 1182, SEQ ID NO: 1339 and SEQ ID NO: 1496 respectively; lxxxiv. are SEQ ID NO: 712, SEQ ID NO: 869, SEQ ID NO: 1026, SEQ ID NO: 1183, SEQ ID NO: 1340 and SEQ ID NO: 1497 respectively; lxxxv. are SEQ ID NO: 713, SEQ ID NO: 870, SEQ ID NO: 1027, SEQ ID NO: 1184, SEQ ID NO: 1341 and SEQ ID NO: 1498 respectively; lxxxvi. are SEQ ID NO: 714, SEQ ID NO: 871, SEQ ID NO: 1028, SEQ ID NO: 1185, SEQ ID NO: 1342 and SEQ ID NO: 1499 respectively; lxxxvii. are SEQ ID NO: 715, SEQ ID NO: 872, SEQ ID NO: 1029, SEQ ID NO: 1186, SEQ ID NO: 1343 and SEQ ID NO: 1500 respectively; lxxxviii. are SEQ ID NO: 716, SEQ ID NO: 873, SEQ ID NO: 1030, SEQ ID NO: 1187, SEQ ID NO: 1344 and SEQ ID NO: 1501, respectively; lxxxix. are SEQ ID NO: 717, SEQ ID NO: 874, SEQ ID NO: 1031, SEQ ID NO: 1188, SEQ ID NO: 1345 and SEQ ID NO: 1502 respectively; xc. are SEQ ID NO: 718, SEQ ID NO: 875, SEQ ID NO: 1032, SEQ ID NO: 1189, SEQ ID NO: 1346 and SEQ ID NO: 1503 respectively; xci. are SEQ ID NO: 719, SEQ ID NO: 876, SEQ ID NO: 1033, SEQ ID NO: 1190, SEQ ID NO: 1347 and SEQ ID NO: 1504 respectively; xcii. are SEQ ID NO: 720, SEQ ID NO: 877, SEQ ID NO: 1034, SEQ ID NO: 1191, SEQ ID NO: 1348 and SEQ ID NO: 1505 respectively; xciii. are SEQ ID NO: 721, SEQ ID NO: 878, SEQ ID NO: 1035, SEQ ID NO: 1192, SEQ ID NO: 1349 and SEQ ID NO: 1506 respectively; xciv. are SEQ ID NO: 722, SEQ ID NO: 879, SEQ ID NO: 1036, SEQ ID NO: 1193, SEQ ID NO: 1350 and SEQ ID NO: 1507 respectively; xcv. are SEQ ID NO: 723, SEQ ID NO: 880, SEQ ID NO: 1037, SEQ ID NO: 1194, SEQ ID NO: 1351 and SEQ ID NO: 1508 respectively; xcvi. are SEQ ID NO: 724, SEQ ID NO: 881, SEQ ID NO: 1038, SEQ ID NO: 1195, SEQ ID NO: 1352 and SEQ ID NO: 1509 respectively; xcvii. are SEQ ID NO: 725, SEQ ID NO: 882, SEQ ID NO: 1039, SEQ ID NO: 1196, SEQ ID NO: 1353 and SEQ ID NO: 1510 respectively; xcviii. are SEQ ID NO: 726, SEQ ID NO: 883, SEQ ID NO: 1040, SEQ ID NO: 1197, SEQ ID NO: 1354 and SEQ ID NO: 1511, respectively; xcix. are SEQ ID NO: 727, SEQ ID NO: 884, SEQ ID NO: 1041, SEQ ID NO: 1198, SEQ ID NO: 1355 and SEQ ID NO: 1512 respectively; c. These are SEQ ID NO: 728, SEQ ID NO: 885, SEQ ID NO: 1042, SEQ ID NO: 1199, SEQ ID NO: 1356 and SEQ ID NO: 1513, respectively; Ci. are SEQ ID NO: 729, SEQ ID NO: 886, SEQ ID NO: 1043, SEQ ID NO: 1200, SEQ ID NO: 1357 and SEQ ID NO: 1514 respectively; cii. are SEQ ID NO: 730, SEQ ID NO: 887, SEQ ID NO: 1044, SEQ ID NO: 1201, SEQ ID NO: 1358 and SEQ ID NO: 1515 respectively; ciii. are SEQ ID NO: 731, SEQ ID NO: 888, SEQ ID NO: 1045, SEQ ID NO: 1202, SEQ ID NO: 1359 and SEQ ID NO: 1516 respectively; civ. are SEQ ID NO: 732, SEQ ID NO: 889, SEQ ID NO: 1046, SEQ ID NO: 1203, SEQ ID NO: 1360 and SEQ ID NO: 1517 respectively; cv. are SEQ ID NO: 733, SEQ ID NO: 890, SEQ ID NO: 1047, SEQ ID NO: 1204, SEQ ID NO: 1361 and SEQ ID NO: 1518 respectively; cvi. are SEQ ID NO: 734, SEQ ID NO: 891, SEQ ID NO: 1048, SEQ ID NO: 1205, SEQ ID NO: 1362 and SEQ ID NO: 1519 respectively; cvii. are SEQ ID NO: 735, SEQ ID NO: 892, SEQ ID NO: 1049, SEQ ID NO: 1206, SEQ ID NO: 1363 and SEQ ID NO: 1520 respectively; cviii. are SEQ ID NO: 736, SEQ ID NO: 893, SEQ ID NO: 1050, SEQ ID NO: 1207, SEQ ID NO: 1364 and SEQ ID NO: 1521, respectively; cix. are SEQ ID NO: 737, SEQ ID NO: 894, SEQ ID NO: 1051, SEQ ID NO: 1208, SEQ ID NO: 1365 and SEQ ID NO: 1522 respectively; cx. are SEQ ID NO: 738, SEQ ID NO: 895, SEQ ID NO: 1052, SEQ ID NO: 1209, SEQ ID NO: 1366 and SEQ ID NO: 1523 respectively; cxi. are SEQ ID NO: 739, SEQ ID NO: 896, SEQ ID NO: 1053, SEQ ID NO: 1210, SEQ ID NO: 1367 and SEQ ID NO: 1524 respectively; cxii. are SEQ ID NO: 740, SEQ ID NO: 897, SEQ ID NO: 1054, SEQ ID NO: 1211, SEQ ID NO: 1368 and SEQ ID NO: 1525 respectively; cxiii. are SEQ ID NO: 741, SEQ ID NO: 898, SEQ ID NO: 1055, SEQ ID NO: 1212, SEQ ID NO: 1369 and SEQ ID NO: 1526 respectively; cxiv. are SEQ ID NO: 742, SEQ ID NO: 899, SEQ ID NO: 1056, SEQ ID NO: 1213, SEQ ID NO: 1370 and SEQ ID NO: 1527 respectively; cxv. are SEQ ID NO: 743, SEQ ID NO: 900, SEQ ID NO: 1057, SEQ ID NO: 1214, SEQ ID NO: 1371 and SEQ ID NO: 1528 respectively; cxvi. are SEQ ID NO: 744, SEQ ID NO: 901, SEQ ID NO: 1058, SEQ ID NO: 1215, SEQ ID NO: 1372 and SEQ ID NO: 1529 respectively; cxvii. are SEQ ID NO: 745, SEQ ID NO: 902, SEQ ID NO: 1059, SEQ ID NO: 1216, SEQ ID NO: 1373 and SEQ ID NO: 1530 respectively; cxviii. are SEQ ID NO: 746, SEQ ID NO: 903, SEQ ID NO: 1060, SEQ ID NO: 1217, SEQ ID NO: 1374 and SEQ ID NO: 1531, respectively; cxix. are SEQ ID NO: 747, SEQ ID NO: 904, SEQ ID NO: 1061, SEQ ID NO: 1218, SEQ ID NO: 1375 and SEQ ID NO: 1532 respectively; cxx. are SEQ ID NO: 748, SEQ ID NO: 905, SEQ ID NO: 1062, SEQ ID NO: 1219, SEQ ID NO: 1376 and SEQ ID NO: 1533 respectively; cxxi. are SEQ ID NO: 749, SEQ ID NO: 906, SEQ ID NO: 1063, SEQ ID NO: 1220, SEQ ID NO: 1377 and SEQ ID NO: 1534 respectively; cxxii. are SEQ ID NO: 750, SEQ ID NO: 907, SEQ ID NO: 1064, SEQ ID NO: 1221, SEQ ID NO: 1378 and SEQ ID NO: 1535 respectively; cxxiii. are SEQ ID NO: 751, SEQ ID NO: 908, SEQ ID NO: 1065, SEQ ID NO: 1222, SEQ ID NO: 1379 and SEQ ID NO: 1536 respectively; cxxiv. are SEQ ID NO: 752, SEQ ID NO: 909, SEQ ID NO: 1066, SEQ ID NO: 1223, SEQ ID NO: 1380 and SEQ ID NO: 1537 respectively; cxxv. are SEQ ID NO: 753, SEQ ID NO: 910, SEQ ID NO: 1067, SEQ ID NO: 1224, SEQ ID NO: 1381 and SEQ ID NO: 1538 respectively; cxxvi. are SEQ ID NO: 754, SEQ ID NO: 911, SEQ ID NO: 1068, SEQ ID NO: 1225, SEQ ID NO: 1382 and SEQ ID NO: 1539 respectively; cxxvii. are SEQ ID NO: 755, SEQ ID NO: 912, SEQ ID NO: 1069, SEQ ID NO: 1226, SEQ ID NO: 1383 and SEQ ID NO: 1540 respectively; cxxviii. are SEQ ID NO: 756, SEQ ID NO: 913, SEQ ID NO: 1070, SEQ ID NO: 1227, SEQ ID NO: 1384 and SEQ ID NO: 1541, respectively; cxxix. are SEQ ID NO: 757, SEQ ID NO: 914, SEQ ID NO: 1071, SEQ ID NO: 1228, SEQ ID NO: 1385 and SEQ ID NO: 1542 respectively; cxxx. are SEQ ID NO: 758, SEQ ID NO: 915, SEQ ID NO: 1072, SEQ ID NO: 1229, SEQ ID NO: 1386 and SEQ ID NO: 1543 respectively; cxxxi. are SEQ ID NO: 759, SEQ ID NO: 916, SEQ ID NO: 1073, SEQ ID NO: 1230, SEQ ID NO: 1387 and SEQ ID NO: 1544 respectively; cxxxii. are SEQ ID NO: 760, SEQ ID NO: 917, SEQ ID NO: 1074, SEQ ID NO: 1231, SEQ ID NO: 1388 and SEQ ID NO: 1545 respectively; cxxxiii. are SEQ ID NO: 761, SEQ ID NO: 918, SEQ ID NO: 1075, SEQ ID NO: 1232, SEQ ID NO: 1389 and SEQ ID NO: 1546 respectively; cxxxiv. are SEQ ID NO: 762, SEQ ID NO: 919, SEQ ID NO: 1076, SEQ ID NO: 1233, SEQ ID NO: 1390 and SEQ ID NO: 1547 respectively; cxxxv. are SEQ ID NO: 763, SEQ ID NO: 920, SEQ ID NO: 1077, SEQ ID NO: 1234, SEQ ID NO: 1391 and SEQ ID NO: 1548 respectively; cxxxvi. are SEQ ID NO: 764, SEQ ID NO: 921, SEQ ID NO: 1078, SEQ ID NO: 1235, SEQ ID NO: 1392 and SEQ ID NO: 1549 respectively; cxxxvii. are SEQ ID NO: 765, SEQ ID NO: 922, SEQ ID NO: 1079, SEQ ID NO: 1236, SEQ ID NO: 1393 and SEQ ID NO: 1550 respectively; cxxxviii. are SEQ ID NO: 766, SEQ ID NO: 923, SEQ ID NO: 1080, SEQ ID NO: 1237, SEQ ID NO: 1394 and SEQ ID NO: 1551, respectively; cxxxix. are SEQ ID NO: 767, SEQ ID NO: 924, SEQ ID NO: 1081, SEQ ID NO: 1238, SEQ ID NO: 1395 and SEQ ID NO: 1552 respectively; cxl. are SEQ ID NO: 768, SEQ ID NO: 925, SEQ ID NO: 1082, SEQ ID NO: 1239, SEQ ID NO: 1396 and SEQ ID NO: 1553 respectively; cxli. are SEQ ID NO: 769, SEQ ID NO: 926, SEQ ID NO: 1083, SEQ ID NO: 1240, SEQ ID NO: 1397 and SEQ ID NO: 1554 respectively; cxlii. are SEQ ID NO: 770, SEQ ID NO: 927, SEQ ID NO: 1084, SEQ ID NO: 1241, SEQ ID NO: 1398 and SEQ ID NO: 1555 respectively; cxliii. are SEQ ID NO: 771, SEQ ID NO: 928, SEQ ID NO: 1085, SEQ ID NO: 1242, SEQ ID NO: 1399 and SEQ ID NO: 1556 respectively; cxliv. are SEQ ID NO: 772, SEQ ID NO: 929, SEQ ID NO: 1086, SEQ ID NO: 1243, SEQ ID NO: 1400 and SEQ ID NO: 1557 respectively; cxlv. are SEQ ID NO: 773, SEQ ID NO: 930, SEQ ID NO: 1087, SEQ ID NO: 1244, SEQ ID NO: 1401 and SEQ ID NO: 1558 respectively; cxlvi. are SEQ ID NO: 774, SEQ ID NO: 931, SEQ ID NO: 1088, SEQ ID NO: 1245, SEQ ID NO: 1402 and SEQ ID NO: 1559 respectively; cxlvii. are SEQ ID NO: 775, SEQ ID NO: 932, SEQ ID NO: 1089, SEQ ID NO: 1246, SEQ ID NO: 1403 and SEQ ID NO: 1560 respectively; cxlviii. are SEQ ID NO: 776, SEQ ID NO: 933, SEQ ID NO: 1090, SEQ ID NO: 1247, SEQ ID NO: 1404 and SEQ ID NO: 1561, respectively; cxlix. are SEQ ID NO: 777, SEQ ID NO: 934, SEQ ID NO: 1091, SEQ ID NO: 1248, SEQ ID NO: 1405 and SEQ ID NO: 1562 respectively; Cl. are SEQ ID NO: 778, SEQ ID NO: 935, SEQ ID NO: 1092, SEQ ID NO: 1249, SEQ ID NO: 1406 and SEQ ID NO: 1563 respectively; The cli. are SEQ ID NO: 779, SEQ ID NO: 936, SEQ ID NO: 1093, SEQ ID NO: 1250, SEQ ID NO: 1407 and SEQ ID NO: 1564, respectively; The clii are SEQ ID NO: 780, SEQ ID NO: 937, SEQ ID NO: 1094, SEQ ID NO: 1251, SEQ ID NO: 1408 and SEQ ID NO: 1565, respectively; cliii. are SEQ ID NO: 781, SEQ ID NO: 938, SEQ ID NO: 1095, SEQ ID NO: 1252, SEQ ID NO: 1409 and SEQ ID NO: 1566 respectively; cliv. are SEQ ID NO: 782, SEQ ID NO: 939, SEQ ID NO: 1096, SEQ ID NO: 1253, SEQ ID NO: 1410 and SEQ ID NO: 1567 respectively; The clv. are SEQ ID NO: 783, SEQ ID NO: 940, SEQ ID NO: 1097, SEQ ID NO: 1254, SEQ ID NO: 1411 and SEQ ID NO: 1568 respectively; Clvi. are SEQ ID NO: 784, SEQ ID NO: 941, SEQ ID NO: 1098, SEQ ID NO: 1255, SEQ ID NO: 1412 and SEQ ID NO: 1569 respectively; and clvii. are SEQ ID NO: 785, SEQ ID NO: 942, SEQ ID NO: 1099, SEQ ID NO: 1256, SEQ ID NO: 1413 and SEQ ID NO: 1570 respectively.

41. The conjugate molecule of claim 40, wherein the anti-GIPR antibody comprises CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3 of 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, respectively.

42. The conjugate molecule of any one of claims 17 to 39, wherein the anti-GIPR antibody comprises a light chain variable region (V... L ) and heavy chain variable region (V H ), where the V L and the V H It contains an amino acid sequence selected from the following: i. These are SEQ ID NO: 1 and SEQ ID NO: 158, respectively; ii. These are SEQ ID NO: 2 and SEQ ID NO: 159, respectively; iii. These are SEQ ID NO: 3 and SEQ ID NO: 160, respectively; iv. These are SEQ ID NO: 4 and SEQ ID NO: 161, respectively; v. are SEQ ID NO: 5 and SEQ ID NO: 162, respectively; vi. These are SEQ ID NO: 6 and SEQ ID NO: 163, respectively; vii. These are SEQ ID NO: 7 and SEQ ID NO: 164, respectively; viii. These are SEQ ID NO: 8 and SEQ ID NO: 165, respectively; ix. These are SEQ ID NO: 9 and SEQ ID NO: 166, respectively; x. are SEQ ID NO: 10 and SEQ ID NO: 167, respectively; xi. are SEQ ID NO: 11 and SEQ ID NO: 168 respectively; xii. These are SEQ ID NO: 12 and SEQ ID NO: 169, respectively; xiii. These are SEQ ID NO: 13 and SEQ ID NO: 170, respectively; xiv. These are SEQ ID NO: 14 and SEQ ID NO: 171, respectively; xv. are SEQ ID NO: 15 and SEQ ID NO: 172, respectively; xvi. are SEQ ID NO: 16 and SEQ ID NO: 173, respectively; xvii. are SEQ ID NO: 17 and SEQ ID NO: 174, respectively; xviii. These are SEQ ID NO: 18 and SEQ ID NO: 175, respectively; xix. are SEQ ID NO: 19 and SEQ ID NO: 176, respectively; xx. are SEQ ID NO: 20 and SEQ ID NO: 177 respectively; xxi. are SEQ ID NO: 21 and SEQ ID NO: 178, respectively; xxii. are SEQ ID NO: 22 and SEQ ID NO: 179, respectively; xxiii. These are SEQ ID NO: 23 and SEQ ID NO: 180, respectively; xxiv. are SEQ ID NO: 24 and SEQ ID NO: 181, respectively; xxv. are SEQ ID NO: 25 and SEQ ID NO: 182, respectively; xxvi. are SEQ ID NO: 26 and SEQ ID NO: 183, respectively; xxvii. are SEQ ID NO: 27 and SEQ ID NO: 184, respectively; xxviii. are SEQ ID NO: 28 and SEQ ID NO: 185, respectively; xxix. are SEQ ID NO: 29 and SEQ ID NO: 186, respectively; xxx. are SEQ ID NO: 30 and SEQ ID NO: 187 respectively; xxxi. are SEQ ID NO: 31 and SEQ ID NO: 188, respectively; xxxii. are SEQ ID NO: 32 and SEQ ID NO: 189, respectively; xxxiii. These are SEQ ID NO: 33 and SEQ ID NO: 190, respectively; xxxiv. are SEQ ID NO: 34 and SEQ ID NO: 191, respectively; xxxv. are SEQ ID NO: 35 and SEQ ID NO: 192, respectively; xxxvi. are SEQ ID NO: 36 and SEQ ID NO: 193, respectively; xxxvii. are SEQ ID NO: 37 and SEQ ID NO: 194, respectively; xxxviii. are SEQ ID NO: 38 and SEQ ID NO: 195 respectively; xxxix. are SEQ ID NO: 39 and SEQ ID NO: 196, respectively; xl. are SEQ ID NO: 40 and SEQ ID NO: 197, respectively; xli. are SEQ ID NO: 41 and SEQ ID NO: 198, respectively; xlii. are SEQ ID NO: 42 and SEQ ID NO: 199, respectively; xliii. are SEQ ID NO: 43 and SEQ ID NO: 200 respectively; xliv. are SEQ ID NO: 44 and SEQ ID NO: 201, respectively; xlv. are SEQ ID NO: 45 and SEQ ID NO: 202, respectively; xlvi. are SEQ ID NO: 46 and SEQ ID NO: 203, respectively; xlvii. are SEQ ID NO: 47 and SEQ ID NO: 204, respectively; xlviii. are SEQ ID NO: 48 and SEQ ID NO: 205, respectively; xlix. are SEQ ID NO: 49 and SEQ ID NO: 206 respectively; l. These are SEQ ID NO: 50 and SEQ ID NO: 207, respectively; li. are SEQ ID NO: 51 and SEQ ID NO: 208 respectively; lii. are SEQ ID NO: 52 and SEQ ID NO: 209 respectively; liii. are SEQ ID NO: 53 and SEQ ID NO: 210 respectively; The liv. are SEQ ID NO: 54 and SEQ ID NO: 211, respectively; The lv. are SEQ ID NO: 55 and SEQ ID NO: 212 respectively; lvi. are SEQ ID NO: 56 and SEQ ID NO: 213 respectively; lvii. are SEQ ID NO: 57 and SEQ ID NO: 214 respectively; lviii. are SEQ ID NO: 58 and SEQ ID NO: 215, respectively; The lix numbers are SEQ ID NO: 59 and SEQ ID NO: 216, respectively. lx. are SEQ ID NO: 60 and SEQ ID NO: 217 respectively; lxi. are SEQ ID NO: 61 and SEQ ID NO: 218 respectively; lxii. are SEQ ID NO: 62 and SEQ ID NO: 219, respectively; lxiii. are SEQ ID NO: 63 and SEQ ID NO: 220, respectively; The lxiv files are SEQ ID NO: 64 and SEQ ID NO: 221, respectively. lxv. are SEQ ID NO: 65 and SEQ ID NO: 222, respectively; lxvi. are SEQ ID NO: 66 and SEQ ID NO: 223, respectively; lxvii. are SEQ ID NO: 67 and SEQ ID NO: 224, respectively; lxviii. are SEQ ID NO: 68 and SEQ ID NO: 225, respectively; lxix. are SEQ ID NO: 69 and SEQ ID NO: 226 respectively; lxx. are SEQ ID NO: 70 and SEQ ID NO: 227 respectively; lxxi. are SEQ ID NO: 71 and SEQ ID NO: 228 respectively; lxxii. are SEQ ID NO: 72 and SEQ ID NO: 229, respectively; lxxiii. are SEQ ID NO: 73 and SEQ ID NO: 230, respectively; lxxiv. are SEQ ID NO: 74 and SEQ ID NO: 231, respectively; lxxv. are SEQ ID NO: 75 and SEQ ID NO: 232, respectively; lxxvi. are SEQ ID NO: 76 and SEQ ID NO: 233, respectively; lxxvii. are SEQ ID NO: 77 and SEQ ID NO: 234, respectively; lxxviii. are SEQ ID NO: 78 and SEQ ID NO: 235, respectively; lxxix. are SEQ ID NO: 79 and SEQ ID NO: 236, respectively; lxxx. are SEQ ID NO: 80 and SEQ ID NO: 237 respectively; lxxxi. are SEQ ID NO: 81 and SEQ ID NO: 238 respectively; lxxxii. are SEQ ID NO: 82 and SEQ ID NO: 239, respectively; lxxxiii. are SEQ ID NO: 83 and SEQ ID NO: 240 respectively; lxxxiv. are SEQ ID NO: 84 and SEQ ID NO: 241, respectively; lxxxv. are SEQ ID NO: 85 and SEQ ID NO: 242, respectively; lxxxvi. are SEQ ID NO: 86 and SEQ ID NO: 243, respectively; lxxxvii. are SEQ ID NO: 87 and SEQ ID NO: 244, respectively; lxxxviii. are SEQ ID NO: 88 and SEQ ID NO: 245 respectively; lxxxix. are SEQ ID NO: 89 and SEQ ID NO: 246, respectively; xc. are SEQ ID NO: 90 and SEQ ID NO: 247, respectively; xci. are SEQ ID NO: 91 and SEQ ID NO: 248, respectively; xcii. are SEQ ID NO: 92 and SEQ ID NO: 249, respectively; xciii. are SEQ ID NO: 93 and SEQ ID NO: 250, respectively; xciv. are SEQ ID NO: 94 and SEQ ID NO: 251, respectively; xcv. are SEQ ID NO: 95 and SEQ ID NO: 252, respectively; xcvi. are SEQ ID NO: 96 and SEQ ID NO: 253, respectively; xcvii. are SEQ ID NO: 97 and SEQ ID NO: 254, respectively; xcviii. are SEQ ID NO: 98 and SEQ ID NO: 255, respectively; xcix. are SEQ ID NO: 99 and SEQ ID NO: 256, respectively; c. These are SEQ ID NO: 100 and SEQ ID NO: 257, respectively; ci. are SEQ ID NO: 101 and SEQ ID NO: 258, respectively; cii. are SEQ ID NO: 102 and SEQ ID NO: 259, respectively; ciii. These are SEQ ID NO: 103 and SEQ ID NO: 260, respectively; civ. are SEQ ID NO: 104 and SEQ ID NO: 261, respectively; cv. are SEQ ID NO: 105 and SEQ ID NO: 262, respectively; cvi. are SEQ ID NO: 106 and SEQ ID NO: 263, respectively; cvii. are SEQ ID NO: 107 and SEQ ID NO: 264, respectively; cviii. are SEQ ID NO: 108 and SEQ ID NO: 265, respectively; cix. are SEQ ID NO: 109 and SEQ ID NO: 266, respectively; cx. are SEQ ID NO: 110 and SEQ ID NO: 267, respectively; cxi. are SEQ ID NO: 111 and SEQ ID NO: 268, respectively; cxii. are SEQ ID NO: 112 and SEQ ID NO: 269, respectively; cxiii. are SEQ ID NO: 113 and SEQ ID NO: 270, respectively; cxiv. are SEQ ID NO: 114 and SEQ ID NO: 271, respectively; cxv. are SEQ ID NO: 115 and SEQ ID NO: 272, respectively; cxvi. are SEQ ID NO: 116 and SEQ ID NO: 273, respectively; cxvii. are SEQ ID NO: 117 and SEQ ID NO: 274, respectively; cxviii. are SEQ ID NO: 118 and SEQ ID NO: 275, respectively; cxix. are SEQ ID NO: 119 and SEQ ID NO: 276, respectively; cxx. are SEQ ID NO: 120 and SEQ ID NO: 277, respectively; cxxi. are SEQ ID NO: 121 and SEQ ID NO: 278 respectively; cxxii. are SEQ ID NO: 122 and SEQ ID NO: 279, respectively; cxxiii. are SEQ ID NO: 123 and SEQ ID NO: 280, respectively; cxxiv. are SEQ ID NO: 124 and SEQ ID NO: 281, respectively; cxxv. are SEQ ID NO: 125 and SEQ ID NO: 282, respectively; cxxvi. are SEQ ID NO: 126 and SEQ ID NO: 283, respectively; cxxvii. are SEQ ID NO: 127 and SEQ ID NO: 284, respectively; cxxviii. are SEQ ID NO: 128 and SEQ ID NO: 285, respectively; cxxix. are SEQ ID NO: 129 and SEQ ID NO: 286, respectively; cxxx. are SEQ ID NO: 130 and SEQ ID NO: 287 respectively; cxxxi. are SEQ ID NO: 131 and SEQ ID NO: 288, respectively; cxxxii. are SEQ ID NO: 132 and SEQ ID NO: 289, respectively; cxxxiii. are SEQ ID NO: 133 and SEQ ID NO: 290, respectively; cxxxiv. are SEQ ID NO: 134 and SEQ ID NO: 291, respectively; cxxxv. are SEQ ID NO: 135 and SEQ ID NO: 292, respectively; cxxxvi. are SEQ ID NO: 136 and SEQ ID NO: 293, respectively; cxxxvii. are SEQ ID NO: 137 and SEQ ID NO: 294, respectively; cxxxviii. are SEQ ID NO: 138 and SEQ ID NO: 295, respectively; cxxxix. are SEQ ID NO: 139 and SEQ ID NO: 296, respectively; cxl. are SEQ ID NO: 140 and SEQ ID NO: 297 respectively; cxli. are SEQ ID NO: 141 and SEQ ID NO: 298, respectively; cxlii. are SEQ ID NO: 142 and SEQ ID NO: 299, respectively; cxliii. are SEQ ID NO: 143 and SEQ ID NO: 300 respectively; cxliv. are SEQ ID NO: 144 and SEQ ID NO: 301, respectively; cxlv. are SEQ ID NO: 145 and SEQ ID NO: 302, respectively; cxlvi. are SEQ ID NO: 146 and SEQ ID NO: 303, respectively; cxlvii. are SEQ ID NO: 147 and SEQ ID NO: 304, respectively; cxlviii. are SEQ ID NO: 148 and SEQ ID NO: 305, respectively; cxlix. are SEQ ID NO: 149 and SEQ ID NO: 306 respectively; cl. are SEQ ID NO: 150 and SEQ ID NO: 307, respectively; The cli. are SEQ ID NO: 151 and SEQ ID NO: 308, respectively; The clii are SEQ ID NO: 152 and SEQ ID NO: 309, respectively; cliii. are SEQ ID NO: 153 and SEQ ID NO: 310, respectively; cliv. are SEQ ID NO: 154 and SEQ ID NO: 311, respectively; clv. are SEQ ID NO: 155 and SEQ ID NO: 312 respectively; clvi. are SEQ ID NO: 156 and SEQ ID NO: 313 respectively; and clvii. are SEQ ID NO: 157 and SEQ ID NO: 314, respectively.

43. The conjugate molecule of claim 42, wherein the anti-GIPR antibody comprises the V of SEQ ID NO: 74 and SEQ ID NO: 231, respectively. L and V H .

44. The conjugate molecule of any one of claims 17 to 39, wherein the anti-GIPR antibody comprises a light chain and a heavy chain, wherein the light chain and the heavy chain comprise an amino acid sequence selected from: i. These are SEQ ID NO: 315 and SEQ ID NO: 472, respectively; ii. These are SEQ ID NO: 316 and SEQ ID NO: 473, respectively; iii. These are SEQ ID NO: 317 and SEQ ID NO: 474, respectively; iv. These are SEQ ID NO: 318 and SEQ ID NO: 475, respectively; v. are SEQ ID NO: 319 and SEQ ID NO: 476, respectively; vi. These are SEQ ID NO: 320 and SEQ ID NO: 477, respectively; vii. These are SEQ ID NO: 321 and SEQ ID NO: 478, respectively; viii. These are SEQ ID NO: 322 and SEQ ID NO: 479, respectively; ix. These are SEQ ID NO: 323 and SEQ ID NO: 480, respectively; x. are SEQ ID NO: 324 and SEQ ID NO: 481, respectively; xi. are SEQ ID NO: 325 and SEQ ID NO: 482, respectively; xii. These are SEQ ID NO: 326 and SEQ ID NO: 483, respectively; xiii. These are SEQ ID NO: 327 and SEQ ID NO: 484, respectively; xiv. These are SEQ ID NO: 328 and SEQ ID NO: 485, respectively; xv. are SEQ ID NO: 329 and SEQ ID NO: 486, respectively; xvi. are SEQ ID NO: 330 and SEQ ID NO: 487, respectively; xvii. are SEQ ID NO: 331 and SEQ ID NO: 488, respectively; xviii. These are SEQ ID NO: 332 and SEQ ID NO: 489, respectively; xix. are SEQ ID NO: 333 and SEQ ID NO: 490, respectively; xx. are SEQ ID NO: 334 and SEQ ID NO: 491, respectively; xxi. are SEQ ID NO: 335 and SEQ ID NO: 492, respectively; xxii. are SEQ ID NO: 336 and SEQ ID NO: 493, respectively; xxiii. These are SEQ ID NO: 337 and SEQ ID NO: 494, respectively; xxiv. are SEQ ID NO: 338 and SEQ ID NO: 495, respectively; xxv. are SEQ ID NO: 339 and SEQ ID NO: 496, respectively; xxvi. are SEQ ID NO: 340 and SEQ ID NO: 497, respectively; xxvii. are SEQ ID NO: 341 and SEQ ID NO: 498, respectively; xxviii. are SEQ ID NO: 342 and SEQ ID NO: 499, respectively; xxix. are SEQ ID NO: 343 and SEQ ID NO: 500, respectively; xxx. are SEQ ID NO: 344 and SEQ ID NO: 501, respectively; xxxi. are SEQ ID NO: 345 and SEQ ID NO: 502, respectively; xxxii. are SEQ ID NO: 346 and SEQ ID NO: 503, respectively; xxxiii. These are SEQ ID NO: 347 and SEQ ID NO: 504, respectively; xxxiv. are SEQ ID NO: 348 and SEQ ID NO: 505, respectively; xxxv. are SEQ ID NO: 349 and SEQ ID NO: 506, respectively; xxxvi. are SEQ ID NO: 350 and SEQ ID NO: 507, respectively; xxxvii. are SEQ ID NO: 351 and SEQ ID NO: 508, respectively; xxxviii. are SEQ ID NO: 352 and SEQ ID NO: 509, respectively; xxxix. are SEQ ID NO: 353 and SEQ ID NO: 510, respectively; xl. are SEQ ID NO: 354 and SEQ ID NO: 511, respectively; xli. are SEQ ID NO: 355 and SEQ ID NO: 512, respectively; xlii. are SEQ ID NO: 356 and SEQ ID NO: 513 respectively; xliii. are SEQ ID NO: 357 and SEQ ID NO: 514 respectively; xliv. are SEQ ID NO: 358 and SEQ ID NO: 515, respectively; xlv. are SEQ ID NO: 359 and SEQ ID NO: 516, respectively; xlvi. are SEQ ID NO: 360 and SEQ ID NO: 517, respectively; xlvii. are SEQ ID NO: 361 and SEQ ID NO: 518 respectively; xlviii. are SEQ ID NO: 362 and SEQ ID NO: 519, respectively; xlix. are SEQ ID NO: 363 and SEQ ID NO: 520 respectively; l. These are SEQ ID NO: 364 and SEQ ID NO: 521, respectively; li. are SEQ ID NO: 365 and SEQ ID NO: 522 respectively; lii. are SEQ ID NO: 366 and SEQ ID NO: 523 respectively; liii. are SEQ ID NO: 367 and SEQ ID NO: 524 respectively; The liv. are SEQ ID NO: 368 and SEQ ID NO: 525 respectively; The lv. are SEQ ID NO: 369 and SEQ ID NO: 526 respectively; lvi. are SEQ ID NO: 370 and SEQ ID NO: 527 respectively; lvii. are SEQ ID NO: 371 and SEQ ID NO: 528 respectively; lviii. are SEQ ID NO: 372 and SEQ ID NO: 529, respectively; The lix. are SEQ ID NO: 373 and SEQ ID NO: 530, respectively; lx. are SEQ ID NO: 374 and SEQ ID NO: 531, respectively; lxi. are SEQ ID NO: 375 and SEQ ID NO: 532, respectively; lxii. are SEQ ID NO: 376 and SEQ ID NO: 533, respectively; lxiii. are SEQ ID NO: 377 and SEQ ID NO: 534, respectively; The lxiv files are SEQ ID NO: 378 and SEQ ID NO: 535, respectively. lxv. are SEQ ID NO: 379 and SEQ ID NO: 536, respectively; lxvi. are SEQ ID NO: 380 and SEQ ID NO: 537, respectively; lxvii. are SEQ ID NO: 381 and SEQ ID NO: 538, respectively; lxviii. are SEQ ID NO: 382 and SEQ ID NO: 539, respectively; lxix. are SEQ ID NO: 383 and SEQ ID NO: 540, respectively; lxx. are SEQ ID NO: 384 and SEQ ID NO: 541, respectively; lxxi. are SEQ ID NO: 385 and SEQ ID NO: 542 respectively; lxxii. are SEQ ID NO: 386 and SEQ ID NO: 543, respectively; lxxiii. are SEQ ID NO: 387 and SEQ ID NO: 544, respectively; lxxiv. are SEQ ID NO: 388 and SEQ ID NO: 545, respectively; lxxv. are SEQ ID NO: 389 and SEQ ID NO: 546, respectively; lxxvi. are SEQ ID NO: 390 and SEQ ID NO: 547, respectively; lxxvii. are SEQ ID NO: 391 and SEQ ID NO: 548, respectively; lxxviii. are SEQ ID NO: 392 and SEQ ID NO: 549, respectively; lxxix. are SEQ ID NO: 393 and SEQ ID NO: 550, respectively; lxxx. are SEQ ID NO: 394 and SEQ ID NO: 551, respectively; lxxxi. are SEQ ID NO: 395 and SEQ ID NO: 552, respectively; lxxxii. are SEQ ID NO: 396 and SEQ ID NO: 553, respectively; lxxxiii. are SEQ ID NO: 397 and SEQ ID NO: 554, respectively; lxxxiv. are SEQ ID NO: 398 and SEQ ID NO: 555, respectively; lxxxv. are SEQ ID NO: 399 and SEQ ID NO: 556, respectively; lxxxvi. are SEQ ID NO: 400 and SEQ ID NO: 557 respectively; lxxxvii. are SEQ ID NO: 401 and SEQ ID NO: 558, respectively; lxxxviii. are SEQ ID NO: 402 and SEQ ID NO: 559, respectively; lxxxix. are SEQ ID NO: 403 and SEQ ID NO: 560, respectively; xc. are SEQ ID NO: 404 and SEQ ID NO: 561, respectively; xci. are SEQ ID NO: 405 and SEQ ID NO: 562, respectively; xcii. are SEQ ID NO: 406 and SEQ ID NO: 563, respectively; xciii. are SEQ ID NO: 407 and SEQ ID NO: 564, respectively; xciv. are SEQ ID NO: 408 and SEQ ID NO: 565, respectively; xcv. are SEQ ID NO: 409 and SEQ ID NO: 566, respectively; xcvi. are SEQ ID NO: 410 and SEQ ID NO: 567, respectively; xcvii. are SEQ ID NO: 411 and SEQ ID NO: 568, respectively; xcviii. are SEQ ID NO: 412 and SEQ ID NO: 569, respectively; xcix. are SEQ ID NO: 413 and SEQ ID NO: 570, respectively; c. These are SEQ ID NO: 414 and SEQ ID NO: 571, respectively; ci. are SEQ ID NO: 415 and SEQ ID NO: 572, respectively; cii. are SEQ ID NO: 416 and SEQ ID NO: 573, respectively; ciii. These are SEQ ID NO: 417 and SEQ ID NO: 574, respectively; civ. are SEQ ID NO: 418 and SEQ ID NO: 575, respectively; cv. are SEQ ID NO: 419 and SEQ ID NO: 576 respectively; cvi. are SEQ ID NO: 420 and SEQ ID NO: 577, respectively; cvii. are SEQ ID NO: 421 and SEQ ID NO: 578, respectively; cviii. are SEQ ID NO: 422 and SEQ ID NO: 579, respectively; cix. are SEQ ID NO: 423 and SEQ ID NO: 580, respectively; cx. are SEQ ID NO: 424 and SEQ ID NO: 581, respectively; cxi. are SEQ ID NO: 425 and SEQ ID NO: 582, respectively; cxii. are SEQ ID NO: 426 and SEQ ID NO: 583, respectively; cxiii. are SEQ ID NO: 427 and SEQ ID NO: 584, respectively; cxiv. are SEQ ID NO: 428 and SEQ ID NO: 585 respectively; cxv. are SEQ ID NO: 429 and SEQ ID NO: 586, respectively; cxvi. are SEQ ID NO: 430 and SEQ ID NO: 587, respectively; cxvii. are SEQ ID NO: 431 and SEQ ID NO: 588, respectively; cxviii. are SEQ ID NO: 432 and SEQ ID NO: 589, respectively; cxix. are SEQ ID NO: 433 and SEQ ID NO: 590, respectively; cxx. are SEQ ID NO: 434 and SEQ ID NO: 591, respectively; cxxi. are SEQ ID NO: 435 and SEQ ID NO: 592 respectively; cxxii. are SEQ ID NO: 436 and SEQ ID NO: 593, respectively; cxxiii. are SEQ ID NO: 437 and SEQ ID NO: 594, respectively; cxxiv. are SEQ ID NO: 438 and SEQ ID NO: 595, respectively; cxxv. are SEQ ID NO: 439 and SEQ ID NO: 596, respectively; cxxvi. are SEQ ID NO: 440 and SEQ ID NO: 597, respectively; cxxvii. are SEQ ID NO: 441 and SEQ ID NO: 598, respectively; cxxviii. are SEQ ID NO: 442 and SEQ ID NO: 599, respectively; cxxix. are SEQ ID NO: 443 and SEQ ID NO: 600, respectively; cxxx. are SEQ ID NO: 444 and SEQ ID NO: 601, respectively; cxxxi. are SEQ ID NO: 445 and SEQ ID NO: 602, respectively; cxxxii. are SEQ ID NO: 446 and SEQ ID NO: 603, respectively; cxxxiii. are SEQ ID NO: 447 and SEQ ID NO: 604, respectively; cxxxiv. are SEQ ID NO: 448 and SEQ ID NO: 605, respectively; cxxxv. are SEQ ID NO: 449 and SEQ ID NO: 606, respectively; cxxxvi. are SEQ ID NO: 450 and SEQ ID NO: 607, respectively; cxxxvii. are SEQ ID NO: 451 and SEQ ID NO: 608, respectively; cxxxviii. are SEQ ID NO: 452 and SEQ ID NO: 609, respectively; cxxxix. are SEQ ID NO: 453 and SEQ ID NO: 610, respectively; cxl. are SEQ ID NO: 454 and SEQ ID NO: 611, respectively; cxli. are SEQ ID NO: 455 and SEQ ID NO: 612, respectively; cxlii. are SEQ ID NO: 456 and SEQ ID NO: 613 respectively; cxliii. are SEQ ID NO: 457 and SEQ ID NO: 614 respectively; cxliv. are SEQ ID NO: 458 and SEQ ID NO: 615 respectively; cxlv. are SEQ ID NO: 459 and SEQ ID NO: 616, respectively; cxlvi. are SEQ ID NO: 460 and SEQ ID NO: 617, respectively; cxlvii. are SEQ ID NO: 461 and SEQ ID NO: 618 respectively; cxlviii. are SEQ ID NO: 462 and SEQ ID NO: 619, respectively; cxlix. are SEQ ID NO: 463 and SEQ ID NO: 620 respectively; cl. are SEQ ID NO: 464 and SEQ ID NO: 621, respectively; The cli. are SEQ ID NO: 465 and SEQ ID NO: 622, respectively; clii. are SEQ ID NO: 466 and SEQ ID NO: 623, respectively; cliii. are SEQ ID NO: 467 and SEQ ID NO: 624, respectively; cliv. are SEQ ID NO: 468 and SEQ ID NO: 625 respectively; clv. are SEQ ID NO: 469 and SEQ ID NO: 626 respectively; clvi. are SEQ ID NO: 470 and SEQ ID NO: 627 respectively; and clvii. are SEQ ID NO: 471 and SEQ ID NO: 628, respectively. The antibody contains one or more cysteine ​​amino acid substitutions at one or more of the following positions selected according to AHo number: position 88 of the light chain, position 384 of the heavy chain, or position 487 of the heavy chain.

45. The conjugate molecule of claim 44, wherein the anti-GIPR antibody comprises the light chain and heavy chain of SEQ ID NO: 388 and SEQ ID NO: 545, respectively.

46. ​​A conjugate molecule comprising: Antagonistic anti-glucose-dependent insulinotropic peptide receptor (GIPR) antibody, wherein the anti-GIPR antibody comprises: A first light chain and a second light chain, each light chain comprising CDRL1, CDRL2, and CDRL3 of SEQ ID NO: 702, SEQ ID NO: 859, and SEQ ID NO: 1016, respectively; and The first heavy chain and the second heavy chain, each heavy chain containing CDRH1, CDRH2 and CDRH3 of SEQ ID NO: 1173, SEQ ID NO: 1330 and SEQ ID NO: 1487 respectively; A first GLP-1 receptor agonist peptide and a second GLP-1 receptor agonist peptide, wherein each GLP-1 receptor agonist peptide comprises the amino acid sequence of SEQ ID NO: 1579; and First peptide linker and second peptide linker, wherein each peptide linker contains the amino acid sequence of SEQ ID NO: 1592; The first GLP-1 receptor agonist peptide is coupled at its C-terminus to the first heavy chain of the anti-GIPR antibody via the first linker at position 384 of the first heavy chain according to AHo number, and The second GLP-1 receptor agonist peptide is coupled at its C-terminus to the second heavy chain of the anti-GIPR antibody via the second linker at position 384 of the second heavy chain according to the AHo number.

47. The conjugate molecule of claim 46, wherein each light chain comprises VL of SEQ ID NO: 74 and each heavy chain comprises VH of SEQ ID NO:

231.

48. The conjugate molecule of claim 46, wherein each light chain comprises the amino acid sequence of SEQ ID NO: 388, and each heavy chain comprises the amino acid sequence of SEQ ID NO: 1571.

49. A conjugate molecule comprising: Antagonistic anti-glucose-dependent insulinotropic peptide receptor (GIPR) antibody, wherein the anti-GIPR antibody comprises: A first light chain and a second light chain, each light chain comprising CDRL1, CDRL2, and CDRL3 of SEQ ID NO: 702, SEQ ID NO: 859, and SEQ ID NO: 1016, respectively; and The first heavy chain and the second heavy chain, each heavy chain containing CDRH1, CDRH2 and CDRH3 of SEQ ID NO: 1173, SEQ ID NO: 1330 and SEQ ID NO: 1487 respectively; A first GLP-1 receptor agonist peptide and a second GLP-1 receptor agonist peptide, wherein each GLP-1 receptor agonist peptide comprises the amino acid sequence of SEQ ID NO: 1580; and First peptide linker and second peptide linker, wherein each peptide linker contains the amino acid sequence of SEQ ID NO: 1591; The first GLP-1 receptor agonist peptide is coupled at its C-terminus to the first heavy chain of the anti-GIPR antibody via the first linker at position 384 of the first heavy chain according to AHo number, and The second GLP-1 receptor agonist peptide is coupled at its C-terminus to the second heavy chain of the anti-GIPR antibody via the second linker at position 384 of the second heavy chain according to the AHo number.

50. The conjugate molecule of claim 49, wherein each light chain comprises VL of SEQ ID NO: 74 and each heavy chain comprises VH of SEQ ID NO:

231.

51. The conjugate molecule of claim 49, wherein each light chain comprises the amino acid sequence of SEQ ID NO: 388, and each heavy chain comprises the amino acid sequence of SEQ ID NO: 1571.

52. A conjugate molecule comprising: Antagonistic anti-glucose-dependent insulinotropic peptide receptor (GIPR) antibody, wherein the anti-GIPR antibody comprises: A first light chain and a second light chain, each light chain comprising CDRL1, CDRL2, and CDRL3 of SEQ ID NO: 702, SEQ ID NO: 859, and SEQ ID NO: 1016, respectively; and The first heavy chain and the second heavy chain, each heavy chain containing CDRH1, CDRH2 and CDRH3 of SEQ ID NO: 1173, SEQ ID NO: 1330 and SEQ ID NO: 1487 respectively; A first GLP-1 receptor agonist peptide and a second GLP-1 receptor agonist peptide, wherein each GLP-1 receptor agonist peptide comprises the amino acid sequence of SEQ ID NO: 1581; and First peptide linker and second peptide linker, wherein each peptide linker contains the amino acid sequence of SEQ ID NO: 1586; The first GLP-1 receptor agonist peptide is coupled at its C-terminus to the first heavy chain of the anti-GIPR antibody via the first linker at position 384 of the first heavy chain according to AHo number, and The second GLP-1 receptor agonist peptide is coupled at its C-terminus to the second heavy chain of the anti-GIPR antibody via the second linker at position 384 of the second heavy chain according to the AHo number.

53. The conjugate molecule of claim 52, wherein each light chain comprises VL of SEQ ID NO: 74, and each heavy chain comprises VH of SEQ ID NO:

231.

54. The conjugate molecule of claim 52, wherein each light chain comprises the amino acid sequence of SEQ ID NO: 388, and each heavy chain comprises the amino acid sequence of SEQ ID NO: 1571.

55. A conjugate molecule comprising: Antagonistic anti-glucose-dependent insulinotropic peptide receptor (GIPR) antibody, wherein the anti-GIPR antibody comprises: A first light chain and a second light chain, each light chain comprising CDRL1, CDRL2, and CDRL3 of SEQ ID NO: 702, SEQ ID NO: 859, and SEQ ID NO: 1016, respectively; and The first heavy chain and the second heavy chain, each heavy chain containing CDRH1, CDRH2 and CDRH3 of SEQ ID NO: 1173, SEQ ID NO: 1330 and SEQ ID NO: 1487 respectively; A first GLP-1 receptor agonist peptide and a second GLP-1 receptor agonist peptide, wherein each GLP-1 receptor agonist peptide comprises the amino acid sequence of SEQ ID NO: 1581; and First peptide linker and second peptide linker, wherein each peptide linker contains the amino acid sequence of SEQ ID NO: 1585; The first GLP-1 receptor agonist peptide is coupled at its C-terminus to the first heavy chain of the anti-GIPR antibody via the first linker at position 275 of the first heavy chain, and The second GLP-1 receptor agonist peptide is coupled at its C-terminus to the second heavy chain of the anti-GIPR antibody via the second linker at position 275 of the second heavy chain.

56. The conjugate molecule of claim 55, wherein each light chain comprises VL of SEQ ID NO: 74, and each heavy chain comprises VH of SEQ ID NO:

231.

57. The conjugate molecule of claim 55, wherein each light chain comprises the amino acid sequence of SEQ ID NO: 388, and each heavy chain comprises the amino acid sequence of SEQ ID NO: 1571.

58. A pharmaceutical composition comprising: The GLP-1 receptor agonist peptide as described in any one of claims 1 to 10, the molecule as described in any one of claims 11 to 16, or the conjugate molecule as described in any one of claims 17 to 57; and Pharmaceutically acceptable excipients.

59. A method for reducing the weight and / or food intake of a subject in need, the method comprising: The subject is administered a GLP-1 receptor agonist polypeptide as described in any one of claims 1 to 10, a molecule as described in any one of claims 11 to 16, a conjugate molecule as described in any one of claims 17 to 57, or a pharmaceutical composition as described in claim 58.

60. A method for treating obesity or obesity-related conditions in a subject of need, the method comprising: The subject is administered a GLP-1 receptor agonist polypeptide as described in any one of claims 1 to 10, a molecule as described in any one of claims 11 to 16, a conjugate molecule as described in any one of claims 17 to 57, or a pharmaceutical composition as described in claim 58.

61. The method of claim 60, wherein the obesity-related condition is selected from the group consisting of: sleep apnea, dyslipidemia, atherosclerotic cardiovascular disease, heart failure, hypertension, chronic renal failure, and metabolic dysfunction-related steatohepatitis.

62. A method for treating type 2 diabetes or type 2 diabetes-related conditions in a subject of need, the method comprising: The subject is administered a GLP-1 receptor agonist polypeptide as described in any one of claims 1 to 10, a molecule as described in any one of claims 11 to 17, a conjugate molecule as described in any one of claims 17 to 57, or a pharmaceutical composition as described in claim 58.

63. The method of claim 62, wherein the type 2 diabetes-related condition is selected from the group consisting of: hypertension, hyperglycemia, diabetic nephropathy, and diabetic renal failure.

64. The GLP-1 receptor agonist polypeptide of any one of claims 1 to 10, the molecule of any one of claims 11 to 16, or the conjugate molecule of any one of claims 17 to 57, for use as a medicine.

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