GLP-1 receptor agonists and their medical use

Abstract

The present disclosure relates to improved GLP-1 receptor agonist polypeptides and molecules comprising these improved GLP-1 receptor agonist polypeptides, such as molecules comprising one or more GLP-1 receptor agonist polypeptides conjugated to an anti- gastric inhibitory peptide receptor (GIPR) antibody. The present disclosure is also directed to the use of these improved GLP-1 receptor agonist polypeptides and conjugate molecules comprising these polypeptides for treating or preventing obesity, an obesity related condition, type 2 diabetes, and / or a type 2 diabetes related condition.

Description

COMPOSITIONS AND METHODS OF TREATING OR AMELIORATING METABOLIC DISORDERS

[0001] This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 63 / 566,857, filed March 18, 2024.INCORPORATION BY REFERENCE OF MATERIAL SUBMITTED ELECTRONICALLY

[0002] Incorporated by reference in its entirety is a computer-readable nucleotide / amino acid sequence listing submitted concurrently herewith and identified as follows: 1.51 MB (XML) file named “10889-W001-SEC_Sequence_Listing.xml”; created on March 13, 2025.FIELD OF THE INVENTION

[0003] The present disclosure relates to improved Glucagon-like peptide- 1 (GLP-1) receptor agonist polypeptides and molecules comprising these improved GLP-1 receptor agonist polypeptides, such as conjugate molecules comprising one or more GLP-1 receptor agonist polypeptides conjugated to an anti-gastric inhibitory peptide receptor (GIPR) antibody. The present disclosure is also directed to the use of these improved GLP-1 receptor agonist polypeptides and conjugate molecules comprising these polypeptides for treating or ameliorating a metabolic disorder, such as obesity and type 2 diabetes. These improved GLP-1 receptor agonist polypeptides and conjugate molecules comprising these polypeptides are also useful for treating or ameliorating obesity related conditions and type 2 diabetes related conditions.BACKGROUND OF THE INVENTION

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

[0005] GIP secretion is induced by food ingestion. GIP has a number of physiological effects in tissues, including promotion of fat storage in adipocytes and promotion of pancreatic islet 0-cell function and glucose-dependent insulin secretion. GIP and glucagon like polypeptide- 1 (GLP-1) are known insulinotropic factors (“incretins”). Intact GIP is rapidly degraded by DPPIV to an inactive form. The insulinotropic effect of GIP is lost in type 2 diabetic subjects while GLP-l’s incretin effect remains intact (Nauck et al. J. Cline. Invest. 1993; 91:301-307).

[0006] The GIP receptor (GIPR) is a member of the secretin-glucagon family of G- protein coupled receptors (GPCRs) having an extracellular N-terminus, seven transmembrane domains and an intracellular C-terminus. The N-terminal extracellular domains of this family of receptors are usually glycosylated and form the recognition and binding domain of the receptor. GIPR is highly expressed in a number of tissues, including the pancreas, gut, adipose tissue, heart, pituitary, adrenal cortex, and brain (Usdin et al., Endocrinology 1993, 133:2861-2870). Human GIPR comprises 466 amino acids and is encoded by a gene located on chromosome 19ql3.3 (Gremhch et al., Diabetes 1995; 44: 1202-8; Volz et al., FEBSLett. 1995, 373:23-29). Studies have suggested that alternative mRNA splicing results in the production of GIP receptor variants of differing lengths in human, rat and mouse.

[0007] GIPR knockout mice (GIPR' ') are resistant to high fat diet-induced weight gain and have improved insulin sensitivity and lipid profiles (Yamada et al., Diabetes. 2006, 55:S86; Miyawaki et al. Nature Med. 2002, 8:738-742). In addition, a novel small molecule GIPR antagonist SKL-14959 prevents obesity and insulin resistance (Diabetologia 2008, 51:S373, 44th EASD Annual meeting poster).

[0008] Collectively, these links to obesity and insulin resistance imply GIPR inhibition is a useful approach for therapeutic intervention.

[0009] Glucagon-like peptide- 1 is a 31 -amino acid peptide derived from the proglucagon gene. It is secreted by intestinal L-cells and released in response to food ingestion to induce insulin secretion from pancreatic 0-cells (Diabetes 2004, 53:S3, 205-214). In addition to the incretin effects, GLP-1 also decreases glucagon secretion, delays gastric emptying and reduces caloric intake (Diabetes Care, 2003, 26(10): 2929-2940). GLP-1 exerts its effects by activation of the GLP-1 receptor, which belongs to a class B G- protein-coupled receptor (Endocrinology 1993, 133(4): 1907- 10). The function of GLP-1 is limited by rapid degradation by the DPP-IV enzyme, resulting in a half-life of approximately 2 minutes. Recently, long-lasting GLP-1receptor agonists (GLP-1 RAs) such as exenatide, liraglutide, dulaglutide have been developed and are now being used clinically to improve glycemic control in subjects with type 2 diabetes. Furthermore, GLP-1 receptor agonists also promote body weight reduction as well as reduction in blood pressure and plasma cholesterol levels in subjects (Bioorg. Med. Chem.Lett 2013, 23:4011-4018).SUMMARY OF THE INVENTION

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

[0011] Accordingly, a first aspect of the present disclosure is directed to a human glucagon-like peptide 1 (GLP-1) receptor agonist polypeptide comprising the amino acid sequence of H[Aib]EGTFTSDYSSYLEEXi7AAX2oEFIX24WLX27X28GGG (SEQ ID NO: 1575), wherein Aib at position 2 is a-amino-isobutyric acid (also referred to as 2-amino-isobutyric acid), X17 is Q, K, E, or R; X20 is K, R, Q, or homoarginine (hArg); X24 is A, E, Q, D, d-Ala, G, N, K, (lS,2S)-2-Aminocyclopentanecarboxylic acid (ACPC), (3S,4R)-4-Amino-3- pyrrolidinecarboxylic acid (APCA), T, S, or Y; X27 is V, K, Aib, N, S, T, Y, Q, or R; and X28 is K, E, R, Q, D, N, G, S, or T; and wherein the GLP-1 receptor agonist polypeptide does not comprise the amino acid sequence of H[Aib]EGTFTSDYSSYLEEQAAKEFIAWLVKGGG (SEQ ID NO: 1574).

[0012] In one embodiment, the GLP-1 receptor agonist polypeptide of the present disclosure comprises the amino acid sequence of H[Aib]EGTFTSDYSSYLEEXi7AAX2oEFIX24WLX27X28GGG (SEQ ID NO: 1576), wherein X17 is Q or K; X20 is K or R; X24 is A, E, or Q; X27 is V or K; and X28 is K, E, or R, wherein the GLP-1 receptor agonist polypeptide does not comprise the amino acid sequence of H[Aib]EGTFTSDYSSYLEEQAAKEFIAWLVKGGG (SEQ ID NO: 1574).

[0013] In one embodiment, the GLP-1 receptor agonist polypeptide of the present disclosure comprises the amino acid sequence ofH[Aib]EGTFTSDYSSYLEEXi7AAREFIX24WLX27X28GGG (SEQ ID NO: 1577) wherein X17 is Q or K; X24 is A, E, or Q; X27 is V or K; and X28 is K, E, or R.

[0014] In one embodiment, the GLP-1 receptor agonist polypeptide of the present disclosure comprises the amino acid sequence of H[Aib]EGTFTSDYSSYLEEXi7AAX2oEFIX24WLKX28GGG (SEQ ID NO: 1578), wherein X17 is Q or K; X20 is K or R; X24 is A, E, or Q; and X28 is K, E, or R.

[0015] In one embodiment, the GLP-1 receptor agonist polypeptide of the present disclosure 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] In another aspect, the GLP-1 receptor agonist polypeptide of the present disclosure comprises 31 amino acids, comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 1580, and comprises an Aib at position 2; a tyrosine at position 10; a glutamic acid at positions 16, 24, and 28; an arginine at position 20; a lysine at positions 17 and 27; and a glycine at position 30.

[0017] In another aspect, the GLP-1 receptor agonist polypeptide of the present disclosure comprises 31 amino acids, comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 1579, and comprises an Aib at position 2; a tyrosine at position 10; a glutamic acid at positions 16 and 24; an arginine at position 20; a lysine at positions 27; and a glycine at position 30.

[0018] In another aspect, the GLP-1 receptor agonist polypeptide of the present disclosure comprises 31 amino acids, comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 1581, and comprises an Aib at position 2; a tyrosine at position 10; a glutamic acid at positions 16 and 24; an arginine at position 20; a lysine at positions 17, 27; and a glycine at position 30.

[0019] In another aspect, the GLP-1 receptor agonist polypeptide of the present disclosure comprises 31 amino acids, comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 1583, and comprises an Aib at position 2; a tyrosine at position 10; a glutamic acid at positions 16 and 28; an arginine at position 20; a lysine at positions 17, 27; a glutamine at position 24; and a glycine at position 30.

[0020] In another aspect, the GLP-1 receptor agonist polypeptide of the present disclosure comprises 31 amino acids, comprises an amino acid sequence having at least 90%sequence identity to the amino acid sequence of SEQ ID NO: 1582, and comprises an Aib at position 2; a tyrosine at position 10; a glutamic acid at positions 16 and 24; an arginine at positions 20 and 28; a lysine at positions 27; and a glycine at position 30.

[0021] Another aspect of the present disclosure is directed to a molecule comprising a first human glucagon-like peptide 1 (GLP-1) receptor agonist polypeptide as described herein and a half-life extending moiety.

[0022] In one embodiment, the first GLP-1 receptor agonist polypeptide of the molecule comprises the amino acid sequence of H[Aib]EGTFTSDYSSYLEEXi7AAX2oEFIX24WLX27X28GGG (SEQ ID NO: 1575), wherein X17 is Q, K, E, or R; X20 is K, R, Q, or homoarginine (hArg); X24 is A, E, Q, D, d-Ala, G, N, K, (lS,2S)-2-Aminocyclopentanecarboxylic acid (ACPC), (3S,4R)-4-Amino-3- pyrrolidinecarboxylic acid (APCA), T, S, or Y; X27 is V, K, Aib, N, S, T, Y, Q, or R; and X28 is K, E, R, Q, D, N, G, S, or T; and wherein the GLP-1 receptor agonist polypeptide does not comprise the amino acid sequence of SEQ ID NO: 1574.

[0023] In one embodiment, the first GLP-1 receptor agonist polypeptide of the molecule comprises the amino acid sequence of H[Aib]EGTFTSDYSSYLEEXi7AAX2oEFIX24WLX27X28GGG (SEQ ID NO: 1576), wherein X17 is Q or K; X20 is K or R; X24 is A, E, or Q; X27 is V or K; and X28 is K, E, or R, wherein the GLP-1 receptor agonist polypeptide does not comprise the amino acid sequence of SEQ ID NO: 1574.

[0024] In one embodiment, the first GLP-1 receptor agonist polypeptide of the molecule comprises the amino acid sequence of H[Aib]EGTFTSDYSSYLEEXi7AAREFIX24WLX27X28GGG (SEQ ID NO: 1577) wherein X17 is Q or K; X24 is A, E, or Q; X27 is V or K; and X28 is K, E, or R.

[0025] In one embodiment, the first GLP-1 receptor agonist polypeptide of the molecule comprises the amino acid sequence of H[Aib]EGTFTSDYSSYLEEXi7AAX2oEFIX24WLKX28GGG (SEQ ID NO: 1578), wherein X17 is Q or K; X20 is K or R; X24 is A, E, or Q; and X28 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 half-life extending moiety of the molecule is an antibody.

[0028] Another aspect of the present disclosure is directed to a conjugate molecule comprising a first human glucagon-like peptide 1 (GLP-1) receptor agonist polypeptide as described herein conjugated to an antagonist anti-glucose-dependent insulinotropic polypeptide receptor (GIPR) antibody.

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

[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 conjugation site of the anti-GIPR antibody via a first linker moiety. In one embodiment, the first linker moiety is a peptide linker and the peptide linker comprises the amino acid sequence of any one of SEQ ID NOs: 1585- 1593. In one embodiment, the first linker moiety is a PEG linker.

[0031] In one embodiment, the 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 conjugation site of the anti-GIPR antibody.

[0032] In one embodiment, the second GLP-1 receptor agonist polypeptide comprises any of the GLP-1 receptor agonist polypeptides disclosed herein. In one embodiment, the second GLP-1 receptor agonist polypeptide comprises an 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 polypeptide of the conjugate molecule is conjugated, at its C-terminus, to the second cysteine conjugation site of the anti-GIPR antibody via a second linker moiety. In one embodiment, the second linker moiety is a peptide linker and the peptide linker comprises the amino acid sequence of any one of SEQ ID NOs: 1585-1593. In one embodiment, the secondpeptide linker comprises the same amino acid sequence as the first peptide linker. In one embodiment, the second linker moiety is a PEG linker.

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

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

[0036] In one embodiment, the anti-GIPR antibody of the conjugate molecule comprises a VL and VH comprising the amino acid sequence 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 comprising the amino acid sequence of SEQ ID NO: 388 and SEQ ID NO: 545, respectively, with a cysteine substitution at position 88 of each light chain, position 384 of each heavy chain, or position 487 of each heavy chain according to AHo numbering.

[0038] Another aspect of the present disclosure is directed to a molecule, where the molecule comprises an antagonist anti-glucose-dependent insulinotropic polypeptide receptor (GIPR) antibody, wherein said antibody comprises: a first and second light chain, each light chain comprising a CDRL1, a CDRL2, and a CDRL3 of SEQ ID NO: 702, SEQ ID NO: 859, and SEQ ID NO: 1016, respectively, and a first and second heavy chain, each heavy chain comprising a CDRH1, a CDRH2, and a CDRH3 of SEQ ID NO: 1173, SEQ ID NO: 1330, and SEQ ID NO: 1487, respectively. The molecule further comprises a first and second GLP-1 receptor agonist polypeptide, wherein each GLP-1 receptor agonist polypeptide comprises the amino acid sequence of SEQ ID NO: 1579; and a first and 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, via the first linker, to the first heavy chain of the anti-GIPR antibody at a cysteine residue at position 384 of the first heavy chain according to AHo numbering (which corresponds to position 275 of SEQ ID NO:1571), and the second GLP-1 receptor agonist polypeptide is conjugated, at its C-terminus via the second linker, to the second heavy chain of the anti-GIPR antibody at a cysteine residue at position 384 of the second heavy chain according to AHo numbering (which corresponds to position 275 of SEQ ID NO: 1571). In one embodiment, each light chain of the antibody comprises a VL of SEQ ID NO: 74, and each heavy chain of the antibody comprises a VH of SEQ ID NO: 231. In one 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 the present disclosure is directed to a molecule, where the molecule comprises an antagonist anti-glucose-dependent insulinotropic polypeptide receptor (GIPR) antibody, wherein said antibody comprises: a first and second light chain, each light chain comprising a CDRL1, a CDRL2, and a CDRL3 of SEQ ID NO: 702, SEQ ID NO: 859, and SEQ ID NO: 1016, respectively, and a first and second heavy chain, each heavy chain comprising a CDRH1, a CDRH2, and a CDRH3 of SEQ ID NO: 1173, SEQ ID NO: 1330, and SEQ ID NO: 1487, respectively. The molecule further comprises a first and second GLP-1 receptor agonist polypeptide, wherein each GLP-1 receptor agonist polypeptide comprises the amino acid sequence of SEQ ID NO: 1580; and a first and 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 via the first linker, to the first heavy chain of the anti-GIPR antibody at a cysteine residue at position 384 of the first heavy chain according to AHo numbering (which corresponds to position 275 of SEQ ID NO: 1571), and the second GLP-1 receptor agonist polypeptide is conjugated, at its C-terminus via the second linker, to the second heavy chain of the anti-GIPR antibody at a cysteine residue at position 384 of the second heavy chain according to AHo numbering (which corresponds to position 275 of SEQ ID NO: 1571). In one embodiment, each light chain of the antibody comprises a VL of SEQ ID NO: 74, and each heavy chain of the antibody comprises a VH of SEQ ID NO: 231. In one 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 the present disclosure is directed to a molecule, where the molecule comprises an antagonist anti-glucose-dependent insulinotropic polypeptide receptor(GIPR) antibody, wherein said antibody comprises: a first and second light chain, each light chain comprising a CDRL1, a CDRL2, and a CDRL3 of SEQ ID NO: 702, SEQ ID NO: 859, and SEQ ID NO: 1016, respectively, and a first and second heavy chain, each heavy chain comprising a CDRH1, a CDRH2, and a CDRH3 of SEQ ID NO: 1173, SEQ ID NO: 1330, and SEQ ID NO: 1487, respectively. The molecule further comprises a first and second GLP-1 receptor agonist polypeptide, wherein each GLP-1 receptor agonist polypeptide comprises the amino acid sequence of SEQ ID NO: 1581; and a first and 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 via the first linker, to the first heavy chain of the anti-GIPR antibody at a cysteine residue at position 384 of the first heavy chain according to AHo numbering (which corresponds to position 275 of SEQ ID NO: 1571), and the second GLP-1 receptor agonist polypeptide is conjugated, at its C-terminus via the second linker, to the second heavy chain of the anti-GIPR antibody at a cysteine residue at position 384 of the second heavy chain according to AHo numbering (which corresponds to position 275 of SEQ ID NO: 1571). In one embodiment, each light chain of the antibody comprises a VL of SEQ ID NO: 74, and each heavy chain of the antibody comprises a VH of SEQ ID NO: 231. In one 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 the present disclosure is directed to a molecule, where the molecule comprises an antagonist anti-glucose-dependent insulinotropic polypeptide receptor (GIPR) antibody, wherein said antibody comprises: a first and second light chain, each light chain comprising a CDRL1, a CDRL2, and a CDRL3 of SEQ ID NO: 702, SEQ ID NO: 859, and SEQ ID NO: 1016, respectively, and a first and second heavy chain, each heavy chain comprising a CDRH1, a CDRH2, and a CDRH3 of SEQ ID NO: 1173, SEQ ID NO: 1330, and SEQ ID NO: 1487, respectively. The molecule further comprises a first and second GLP-1 receptor agonist polypeptide, wherein each GLP-1 receptor agonist polypeptide comprises the amino acid sequence of SEQ ID NO: 1581; and a first and 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 via the first linker, to the first heavy chain of the anti-GIPR antibody at a cysteine residue at position 384 of the firstheavy chain according to AHo numbering (which corresponds to position 275 of SEQ ID NO: 1571), and the second GLP-1 receptor agonist polypeptide is conjugated, at its C-terminus via the second linker, to the second heavy chain of the anti-GIPR antibody at a cysteine residue at position 384 of the second heavy chain according to AHo numbering (which corresponds to position 275 of SEQ ID NO: 1571). In one embodiment, each light chain of the antibody comprises a VL of SEQ ID NO: 74, and each heavy chain of the antibody comprises a VH of SEQ ID NO: 231. In one 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 the present disclosure is directed to a pharmaceutical composition comprising a GLP-1 receptor agonist polypeptide as disclosed herein, or a GLP-1 receptor agonist polypeptide containing molecule as disclosed herein, and a pharmaceutically acceptable excipient.

[0043] Another aspect of the present disclosure is directed to a method of reducing body weight and / or food intake in a subject in need thereof. This method comprises administering, to the subject in need thereof, a GLP-1 receptor agonist polypeptide as disclosed herein, a GLP-1 receptor agonist polypeptide containing molecule as disclosed herein, or a pharmaceutical composition as disclosed herein.

[0044] Another aspect of the present disclosure is directed to a method of treating obesity or an obesity related condition in a subject in need thereof. This method comprises administering, to the subject in need thereof, a GLP-1 receptor agonist polypeptide as disclosed herein, a GLP-1 receptor agonist polypeptide containing molecule as disclosed herein, or a pharmaceutical composition as disclosed herein.

[0045] Another aspect of the present disclosure is directed to a method of treating type 2 diabetes or type 2 related condition in a subject in need thereof. This method comprises administering, to the subject in need thereof, a GLP-1 receptor agonist polypeptide as disclosed herein, a GLP-1 receptor agonist polypeptide containing molecule as disclosed herein, or a pharmaceutical composition as disclosed herein.

[0046] Described herein are novel GLP-1 receptor agonist polypeptides and molecules comprising an antagonist anti-GIPR antibody conjugated to one or more of the novel GLP-1 receptor agonist polypeptides. The GLP-receptor agonist polypeptides described hereincomprise one or more defined amino acid substitutions that enhance stability and / or efficacy of the agonist polypeptides and molecules containing the peptides.BRIEF DESCRIPTION OF THE DRAWINGS

[0047] FIG. 1 shows the reaction scheme for the generation of an anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule of the present disclosure.

[0048] FIG. 2 shows the structure of a GLP-1 receptor agonist polypeptide of the present disclosure covalently linked to a peptide linker. The GLP-1 receptor agonist polypeptide comprises the amino acid sequence of SEQ ID NO: 1579. The C-terminal amino acid residue of the GLP-1 receptor agonist polypeptide is covalently linked to the N-terminal amino acid residue of the linker peptide of SEQ ID NO: 1592. The C-terminus of the polypeptide linker has been bromoacetylated (at the s-amino group on the side chain of the lysine residue) to permit further conjugation to an anti-GIPR antibody via a bromoacetyl-thiol reaction with a thiol group of a cysteine residue.

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

[0050] FIG. 4 shows the structure of a GLP-1 receptor agonist polypeptide of the present disclosure covalently linked to a peptide linker. The GLP-1 receptor agonist polypeptide comprises the amino acid sequence of SEQ ID NO: 1581. As shown, the C-terminal amino acid residue of the GLP-1 receptor agonist polypeptide 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 polypeptide linker has been bromoacetylated (at the s-amino group on the side chain of the lysine residue) to permit further conjugation to an anti-GIPR antibody via a bromoacetyl-thiol reaction with a thiol group of a cysteine residue

[0051] FIG. 5 shows the structure of a GLP-1 receptor agonist polypeptide of the present disclosure covalently linked to a peptide linker. The GLP-1 receptor agonist polypeptidecomprises the amino acid sequence of SEQ ID NO: 1581. As shown, the C-terminal amino acid residue of the GLP-1 receptor agonist polypeptide 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 polypeptide linker has been bromoacetylated (at the s-amino group on the side chain of the lysine residue) to permit further conjugation to an anti-GIPR antibody via a bromoacetyl-thiol reaction with a thiol group of a cysteine residue

[0052] FIG. 6 shows the structure of a GLP-1 receptor agonist polypeptide of the present disclosure covalently linked to a peptide linker. The GLP-1 receptor agonist polypeptide comprises the amino acid sequence of SEQ ID NO: 1581. As shown, the C-terminal amino acid residue of the GLP-1 receptor agonist polypeptide 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 polypeptide linker has been bromoacetylated (at the s-amino group on the side chain of the lysine residue) to permit further conjugation to an anti-GIPR antibody via a bromoacetyl-thiol reaction with a thiol group of a cysteine residue.

[0053] FIG. 7 shows the structure of a GLP-1 receptor agonist polypeptide of the present disclosure covalently linked to a PEG linker. The GLP-1 receptor agonist polypeptide comprises the amino acid sequence of SEQ ID NO: 1581. As shown, the C-terminal amino acid residue of the GLP-1 receptor agonist polypeptide is covalently linked to the PEG20 linker via the a-amino group of the lysine residue of the PEG20 linker. The PEG20 is covalently linked to the s-amino group on the side chain of the lysine. The glycine residue at the opposing terminal end of the PEG linker has been bromoacetylated to permit further conjugation to an anti-GIPR antibody via a bromoacetyl-thiol reaction with a thiol group of a cysteine residue.

[0054] FIG. 8 shows the structure of a GLP-1 receptor agonist polypeptide of the present disclosure covalently linked to a PEG linker. The GLP-1 receptor agonist polypeptide comprises the amino acid sequence of SEQ ID NO: 1582. As shown, the C-terminal amino acid residue of the GLP-1 receptor agonist polypeptide is covalently linked to the PEG20 linker via the a-amino group of the lysine residue of the PEG20 linker. The PEG20 is covalently linked to the s-amino group on the side chain of the lysine. The glycine residue at the opposing terminal end of the PEG linker has been bromoacetylated to permit further conjugation to an anti-GIPR antibody via a bromoacetyl-thiol reaction with a thiol group of a cysteine residue.

[0055] FIG. 9 shows the structure of a GLP-1 receptor agonist polypeptide of the present disclosure covalently linked to a PEG linker. The GLP-1 receptor agonist polypeptide comprises the amino acid sequence of SEQ ID NO: 1583. As shown, the C-terminal amino acid residue of the GLP-1 receptor agonist polypeptide is covalently linked to the PEG20 linker via the a-amino group of the lysine residue of the PEG20 linker. The PEG20 is covalently linked to the s-amino group on the side chain of the lysine. The glycine residue at the opposing terminal end of the PEG linker has been bromoacetylated to permit further conjugation to an anti-GIPR antibody via a bromoacetyl-thiol reaction with a thiol group of a cysteine residue.

[0056] FIG. 10 shows body weight loss over a 12-day period in diet- induced obese C57BL6 mice administered, on day 0, a single dose of 0.5 mg / kg surrogate anti-GIPR / GLP-1 agonist conjugates, i.e., reference conjugate molecule 1238 and conjugate molecule 62207 of the present disclosure, or vehicle (A52Su).

[0057] FIG. 11 shows body weight loss over an 18-day period in diet-induced obese C57BL6 mice administered, on day 0, a single dose of 0.5 mg / kg surrogate anti-GIPR / GLP-1 agonist conjugates, i.e., reference conjugate molecule 1238 and conjugate molecule 65296 of the present disclosure, or vehicle (A52Su).

[0058] FIG. 12 shows body weight loss over an 18-day period in diet-induced obese C57BL6 mice administered, on day 0, a single dose of 0.5 mg / kg surrogate anti-GIPR / GLP-1 agonist conjugates, i.e., reference conjugate molecule 1238 and conjugate molecules 69730 and 69850 of the present disclosure, or vehicle (A52Su).

[0059] FIG. 13 shows body weight loss over a 16-day period in diet- induced obese C57BL6 mice administered, on day 0, a single dose of 0.5 mg / kg surrogate anti-GIPR / GLP-1 agonist conjugates, i.e., reference conjugate molecule 1238 and conjugate molecules 59112 and 59117 of the present disclosure, or vehicle (A52Su).

[0060] FIG. 14 shows body weight loss over a 20-day period in diet- induced obese C57BL6 mice administered, on day 0, a single dose of 0.5 mg / kg surrogate anti-GIPR / GLP-1 agonist conjugates, i.e., reference conjugate molecule 1238 and conjugate molecule 65300 of the present disclosure, or vehicle (A52Su).

[0061] FIG. 15 shows body weight loss over a 24-day period in diet- induced obese C57BL6 mice administered, on day 0 and day 10, 0.5 mg / kg surrogate anti-GIPR / GLP-1 agonistconjugates, i.e., reference conjugate molecule 1238 and conjugate molecule 59112 of the present disclosure, or vehicle.

[0062] FIG. 16 shows body weight loss over a 24-day period in diet- induced obese C57BL6 mice administered, on day 0 and day 10, 0.5 mg / kg surrogate anti-GIPR / GLP-1 agonist conjugates, i.e., reference conjugate molecule 1238 and conjugate molecules 62207, 65296, 65300 of the present disclosure, or vehicle.

[0063] FIG. 17 shows body weight loss over a 24-day period in diet- induced obese C57BL6 mice administered, on day 0 and day 10, 0.5 mg / kg surrogate anti-GIPR / GLP-1 agonist conjugates, i.e., reference conjugate molecule 1238 and conjugate molecules 59117, 69730, 69850, 73313 of the present disclosure, or vehicle.DETAILED DESCRIPTION OF THE INVENTION

[0064] The present disclosure relates to improved GLP-1 receptor agonists and molecules comprising the improved GLP-1 receptor agonists. The present disclosure further relates to the utility of these improved protein therapeutics for treating or ameliorating metabolic disorders, such as obesity, type 2 diabetes, elevated glucose levels, elevated insulin levels, nonalcoholic fatty liver disease, cardiovascular diseases, and diabetic nephropathy. land type 2 diabetes related conditions as described herein. The present disclosure also relates to the utility of these improved protein therapeutics for treating or ameliorating obesity related conditions and type 2 diabetes related conditions.

[0065] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0066] Unless otherwise defined herein, scientific and technical terms used in connection with the present application shall have the meanings that are commonly understood by those of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

[0067] Other than in the operating examples, or where otherwise indicated, all numbers expressing quantities of ingredients or reaction conditions used herein should be understood as modified in all instances by the term “about.” The term “about” when used in connection with percentages means ±1%.

[0068] Following convention, as used herein “a” and “an” mean “one or more” unless specifically indicated otherwise.

[0069] As used herein, the terms “amino acid” and “residue” are interchangeable 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 mimetics and non-naturally occurring amino acids that are chemically similar to the naturally occurring amino acids.

[0070] A “naturally occurring amino acid” is an amino acid that is encoded by the human genetic code, as well as those amino acids that are encoded by the genetic code that are modified after synthesis, e.g., hydroxyproline, y-carboxyglutamate, and O-phosphoserine. An amino acid analog is a compound that has the same basic chemical structure as a naturally occurring amino acid, i.e., an a carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs can have modified R groups (e.g., norleucine) or modified peptide backbones, but will retain the same basic chemical structure as a naturally occurring amino acid.

[0071] An “amino acid mimetic” is a chemical compound that has a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally occurring amino acid. Examples include a methacryloyl or acryloyl derivative of an amide, 0-, y-, 8-imino acids (such as piperidine-4-carboxylic acid) and the like.

[0072] A “non-naturally occurring amino acid” is a compound that has the same basic chemical structure as a naturally occurring amino acid, but is not incorporated into a growing polypeptide chain by the translation complex. A non-naturally occurring amino acid also includes, but is not limited to, amino acids that occur by modification (e.g., posttranslational modifications) of a naturally encoded amino acid (including but not limited to, the 20 common amino acids) but are not themselves naturally incorporated into a growing polypeptide chain by the translation complex. A non-limiting list of examples of non-naturally occurring amino acids that can be inserted into a polypeptide sequence or substituted for a wild-type residue in polypeptide sequence include 0-amino acids, homoamino acids, cyclic amino acids and amino acids with derivatized side chains. Examples include (in the L-form or D-form; abbreviated as in parentheses): citrulline (Cit), homocitrulline (hCit), Na- methylcitrulline (NMeCit), Na-methylhomocitrulline (Na-MeHoCit), ornithine (Orn), Na-Methylornithine (Na-MeOrn or NMeOrn), sarcosine (Sar), homolysine (hLys or hK), homoarginine (hArg or hR),homoglutamine (hQ), Na-methylarginine (NMeR), Na-methylleucine (Na-MeL or NMeL), N- methylhomolysine (NMeHoK), Na-methylglutamine (NMeQ), norleucine (Nle), norvaline (Nva), 1,2,3,4-tetrahydroisoquinoline (Tic), Octahydroindole-2-carboxylic acid (Oic), 3-(l- naphthyl)alanine (1-Nal), 3-(2-naphthyl)alanine (2-Nal), 1,2,3,4-tetrahydroisoquinoline (Tic), 2- indanylglycine (Igl), para-iodophenylalanine (pl-Phe), para-aminophenylalanine (4AmP or 4- Amino-Phe), 4-guanidino phenylalanine (Guf), glycyllysine (abbreviated “K(Ns-glycyl)” or “K(glycyl)” or “K(gly)”), nitrophenylalanine (nitrophe), aminophenylalanine (aminophe or Amino-Phe), benzylphenylalanine (benzylphe), y-carboxyglutamic acid (y-carboxyglu), hydroxyproline (hydroxypro), p-carboxyl-phenylalanine (Cpa), a-aminoadipic acid (Aad), Na- methyl valine (NMeVal), N-a-methyl leucine (NMeLeu), Na-methylnorleucine (NMeNle), cyclopentylglycine (Cpg), cyclohexylglycine (Chg), acetylarginine (acetylarg), a, 0- diaminopropionoic acid (Dpr), a, y-diaminobutyric acid (Dab), diaminopropionic acid (Dap), cyclohexylalanine (Cha), 4-methyl-phenylalanine (MePhe), 0, 0-diphenyl-alanine (BiPhA), aminobutyric acid (Abu), 4-phenyl-phenylalanine (or biphenylalanine; 4Bip), a-amino-isobutyric acid (Aib), beta-alanine, beta-aminopropionic acid, piperidinic acid, aminocaprioic acid, aminoheptanoic acid, aminopimelic acid, desmosine, diaminopimelic acid, N-ethylglycine, N-ethylaspargine, hydroxylysine, allo-hydroxylysine, isodesmosine, allo-isoleucine, N-methylglycine, N-methylisoleucine, N-methylvaline, 4-hydroxyproline (Hyp), y- carboxyglutamate, s-N,N,N-trimethyllysine, s-N-acetyllysine, O-phosphoserine, N-acetylserine, N-formylmethionine, 3 -methylhistidine, 5-hydroxylysine, co-methylarginine, 4-Amino-O- Phthalic Acid (4APA), and other similar amino acids, and derivatized forms of any of those specifically listed.

[0073] As used herein, the term “polypeptide” refers to a polymer of amino acid residues. Polypeptides comprising between two and fifty amino acids may also be referred to as “peptides” herein. “Polypeptide” further encompasses an amino acid polymer in which one or more amino acid residue is an analog or mimetic of a corresponding naturally occurring amino acid, as well as naturally occurring amino acid polymers. The term can also encompass an amino acid polymer that has been modified, e.g., by the addition of carbohydrate residues to form a glycoprotein, or by the addition of a phosphate group to form a phosphorylated polypeptide. Polypeptides can be produced by a naturally-occurring and non-recombinant cell, or polypeptides can be produced by a genetically-engineered or recombinant cell, and comprisemolecules having the amino acid sequence of a native protein, or molecules having deletions from, additions to, and / or substitutions of one or more amino acids of a native sequence. Polypeptide can also be produced synthetically.

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

[0075] As used herein, a “derivative” of a polypeptide is a polypeptide that has been chemically modified in some manner distinct from insertion, deletion, or substitution variants, such as, e.g., via conjugation to another chemical moiety.

[0076] A composition of the present invention that includes a GLP-1 receptor agonist polypeptide as described herein covalently linked, attached, or bound either directly or indirectly through a linker moiety, to an anti-GIPR antibody of the invention is referred to herein as a “conjugate”, conjugate molecule”, “conjugate protein”, or “antibody conjugate”.

[0077] As used herein, the term “linker moiety” refers to a biologically acceptable (i.e., safe and non-toxic) peptidyl or non-peptidyl organic group that is covalently bound to a first molecule (e.g., a first polypeptide) and covalently joins or conjugates the molecule to a second molecule (e.g., a second polypeptide). Where the linker moiety consists of a polypeptide or a polypeptide derivative (e.g., a polypeptide that has been chemically modified at one or both of the N-terminus and C-terminus to incorporate a functional group that permits conjugation to the first or second molecule), it may be referred to as a “linker polypeptide” herein. For example, in one embodiment, a linker polypeptide may comprise an acetylated terminus (e.g., when a thiolbromoacetyl reaction is used to conjugate the derivatized terminus of the linker polypeptide to a cysteine residue of a polypeptide by forming a thioether linkage that comprises a sulfur atom of the cysteine residue).

[0078] The phrase “percent sequence identity,” in the context of two or more polypeptide sequences, refers to the ratio of the number of identical amino acid residues between two or more aligned amino acid (polypeptide or protein) sequences over the aligned length of the sequences, expressed as a percentage. To calculate the percent sequence identity of two sequences, the sequences are aligned along their length. A sequence alignment algorithm, e.g., BLAST (Myers et al., J. Mol. Biol. 215(3):403- 10 (1990)), can be utilized to align two sequences to ensure the corresponding amino acids are positioned correctly against each other. The number of identicalamino acids at each position in the alignment is divided by the number of total number of aligned positions and multiplied by 100.

[0079] The terms “GIPR polypeptide” and “GIPR protein” are used interchangeably to refer to the naturally-occurring glucose-dependent insulinotropic polypeptide receptor protein that is expressed in a mammal, such as a human or a mouse, and includes naturally occurring alleles (e.g., naturally occurring allelic forms of human GIPR protein). For purposes of this disclosure, the term “GIPR polypeptide” can be used interchangeably to refer to any full-length GIPR polypeptide (UniProt Accession No. P48546-1), e.g., SEQ ID NO: 1572, which consists of 466 amino acid residues and which is encoded by the nucleotide sequence SEQ ID NO: 1573. The term also encompasses known isoforms of the GIPR protein (see e.g., UniProt Accession Nos. P48546-2 and P48546-3).

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

[0081] The terms “GIP”, “Gastric inhibitory polypeptide”, “glucose-dependent insulinotropic peptide” and “GIP ligand” are used interchangeably and mean a naturally- occurring wild-type polypeptide expressed in a mammal, such as a human or a mouse, and includes naturally occurring alleles (e.g., naturally occurring allelic forms of human GIP protein). GIP is a natural ligand for GIPR. For purposes of this disclosure, the term “GIP” can be used interchangeably to refer to any mature GIP polypeptide.

[0082] As used herein, the term “antibody” refers to an intact immunoglobulin. An antibody comprises two full-length heavy chains and two full-length light chains. Antibodiesmay be derived solely from a single source, or may be “chimeric,” that is, different portions of the antibody may be derived from two different antibodies as described further below.

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

[0084] As used herein, the term “heavy chain” or “immunoglobulin heavy chain” refers to a polypeptide comprising, from amino terminus (N-terminus) to carboxyl terminus (C- terminus), a single immunoglobulin heavy chain variable region (VH), an immunoglobulin heavy chain constant domain 1 (CHI), an immunoglobulin hinge region, an immunoglobulin heavy chain constant domain 2 (CH2), an immunoglobulin heavy chain constant domain 3 (CH3), and optionally an immunoglobulin heavy chain constant domain 4 (CH4). Heavy chains are classified as mu (p), delta (A), gamma (y), alpha (a), and epsilon (s), and define the antibody's isotype as IgM, IgD, IgG, IgA, and IgE, respectively. In accordance with the present disclosure, an antibody is of the IgG isotype. IgG has several subclasses, including, but not limited to IgGl, IgG2, IgG3, and IgG4.

[0085] Variable regions of immunoglobulin chains generally exhibit the same overall structure, comprising relatively conserved framework regions (FR) joined by three hypervariable regions, more often called “complementarity determining regions” or CDRs. The CDRs from the two chains of each heavy chain and light chain pair typically are aligned by the framework regions to form a structure that binds specifically to a specific epitope on the target antigen or protein. From N-terminus to C-terminus, naturally-occurring light and heavy chain variable regions of an antibody both typically conform with the following order of these elements: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. Numbering systems have been devised for assigning numbers to amino acids that occupy positions in each of these domains. Exemplary numbering systems are defined in Kabat Sequences of Proteins of Immunological Interest (1987 and 1991, NIH, Bethesda, MD), and Chothia & Lesk, J. Mol. Biol. 196:901-917 (1987); Chothia et al., Nature 342:878-883 (1989). Other numbering systems for identifying amino acids in immunoglobulin chains include IMGT® (the international ImMunoGeneTics informationsystem; 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, an “antagonist anti-GIPR antibody” and “anti-GIPR antibody” refer to an intact immunoglobulin of the IgG isotype that partially or fully blocks, inhibits, or neutralizes a biological activity of the GIPR protein. Antagonist activity of the anti-GIPR antibody of the present disclosure is determined using the GIPR activity assay and GIPR binding assay defined herein.

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

[0088] As used herein, a “Fc domain” refers to the portion of an antibody comprising the second and third constant domains of the heavy chain (i.e., CH2 and CH3), and can optionally comprise the CH4 domain. The Fc domain may be an Fc domain from an IgGl, IgG2, IgG3, or IgG4 immunoglobulin. In some embodiments, the Fc region comprises CH2 and CH3 domains from a human IgGl or human IgG2 immunoglobulin. The Fc region may retain effector function, such as Clq binding, complement dependent cytotoxicity (CDC), Fc receptor binding, antibodydependent cell-mediated cytotoxicity (ADCC), and phagocytosis. In other embodiments, the Fc region may be modified to reduce or eliminate effector function. A “Fc-containing polypeptide” refers to a polypeptide comprising an Fc domain as defined herein.

[0089] As used herein, the terms “GLP-1 receptor agonist” and “GLP-1 receptor agonist polypeptide” are used interchangeably and refer to a molecule that mimics a biological activity of the naturally occurring glucagon-like peptide (GLP-1) molecule with respect to a GLP-1 receptor.

[0090] As used herein, the term “pharmaceutically acceptable” refers to a species or component that is generally safe, non-toxic, and neither biologically nor otherwise undesirable for use in a subject.

[0091] As used herein, the term “pharmaceutically acceptable excipient” refers to a broad range of ingredients that may be combined with a polypeptide or conjugate molecule disclosed herein to prepare a pharmaceutically acceptable composition or formulation. Excipients include,for example, vehicles (e.g., solvents, dispersion media), coatings, isotonic and absorption delaying agents, diluents, colorants, glidants, disintegrants, flavoring agents, coatings, binders, sweeteners, lubricants, sorbents, and preservatives (e.g., antibacterial and antifungal agents).

[0092] As used herein, the term “therapeutically effective amount” refers to that amount of a polypeptide or conjugate molecule disclosed herein that elicits a desired biological or medical response in a cell, a tissue, a system, or a subject. The desired biological or medical response does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations.

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

[0094] It should be understood that this invention is not limited to the particular methodology, protocols, and reagents, etc., described herein and as such may vary. The terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the disclosed, which is defined solely by the claims.GLP-1 RECEPTOR AGONIST POLYPEPTIDES

[0095] The present disclosure is directed to GLP-1 receptor agonist polypeptides and molecules, e.g., protein conjugates, comprising these GLP-1 receptor agonist polypeptides. These GLP-1 receptor agonist polypeptides, which are also referred to herein as GLP-1 receptor agonists and GLP-1 R agonist polypeptides, encompass molecules that mimic one or more biological activities of the native human GLP-1 polypeptide with respect to its binding to the human GLP-1 receptor. In addition, these GLP-1 receptor agonist polypeptides possess one or more advantageous properties relative to the native GLP-1 protein and / or other GLP-1 receptor agonist polypeptides known in the art.

[0096] The native human GLP-1 polypeptide is produced from post-translational processing of proglucagon within intestinal cells. Proglucagon cleavage by PCSK1 / PC1 generates a peptide comprising the proglucagon residues 71-108 or a C-terminally amidated form comprising residues 71-107 amide. Additional N-terminal truncation of this proglucagonderived peptide fragment within the intestinal cells is required to form the active GLP-1 peptide. Thus, the active human GLP-1 peptide, which is referred to as GLP-l(7-37), comprises the ammo acid sequence of HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG (SEQ ID NO: 1584). A C-terminally amidated version of this peptide is known as GLP-1 (7-36)amide.

[0097] In one embodiment of the present disclosure, the GLP-1 receptor agonist polypeptide is an analog of the native human GLP-1 (7-37) peptide, i.e., an analog of the amino acid sequence of SEQ ID NO: 1584. As used herein, a “GLP-1 analog” refers to a molecule which possesses improved biological activity, e.g., improved stability or agonist potency, relative to the corresponding biological activity of GLP-l(7-37), when evaluated by the GLP-1 receptor agonist activity assay as described in Example 3 herein or using other art-known measures such as receptor binding assays or in vivo blood glucose assays as described, e.g., by Hargrove et al., Regulatory Peptides, 141 :113-119 (2007), the disclosure of which is incorporated by reference herein. In one embodiment, a GLP-1 analog refers to a peptide comprising an amino acid sequence with at least 4, at least 5, at least 6, at least 7, at least 8, or at least 9 amino acid substitutions, insertions, deletions (or a combination of two or more of substitutions, insertions, deletions), when compared to the amino acid sequence of a GLP-l(7-37). In one embodiment, the GLP-1 analog of the present disclosure comprises an amino acid sequence with 5, 6, 7, 8, or 9 amino acid substitutions, insertions, deletions (or a combination of two or more of substitutions, insertions, deletions), when compared to the amino acid sequence of a GLP-1 (7- 37) (SEQ ID NO: 1584). In one embodiment, the GLP-1 analog of the present disclosure comprises an amino acid sequence with 5, 6, 7, 8, or 9 amino acid substitutions in the amino acid sequence of the GLP-l(7-37) polypeptide of SEQ ID NO: 1584. In one embodiment, these 5, 6, 7, 8, or 9 amino acid substitutions comprise a substitution at any 5 or more positions selected from A2, V10, G16, Q17, K20, A24, V27, K28, and R30 of the GLP-l(7-37) peptide of SEQ ID NO: 1584. In one embodiment, the GLP-1 analog comprises substitutions at A2, V10, G16, and R30, plus one or more additional amino acid substitutions at residues selected from QI 7, 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, plus two additional amino acid substitutions as 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, VI 0, G16, and R30, plus three additional amino acid substitutions as residues selected from QI 7, K20, A24, V27, and K28 of SEQ ID NO: 1584.In one embodiment, the GLP-1 analog comprises substitutions at A2, VI 0, G16, and R30, plus four additional amino acid substitutions as residues selected from QI 7, K20, A24, V27, and K28 of SEQ ID NO: 1584. In one embodiment, the GLP-1 analog comprises substitutions at A2, V10, G16, R30, Q17, K20, A24, V27, and K28 of the GLP-l(7-37) peptide of SEQ ID NO: 1584. GLP-1 analogs of the present disclosure include any of the aforementioned analogs in an amidated form, acid form, pharmaceutically acceptable salt form, and any other physiologically active forms of the molecule.

[0098] In one embodiment, the GLP-1 receptor agonist polypeptide of the present disclosure comprises the amino acid sequence of H[Aib]EGTFTSDYSSYLEEXi7AAX2oELIX24WLX27X28GGG (SEQ ID NO: 1575), where Aib at position 2 is a-amino-isobutyric acid; X17 is selected from glutamine (Q), lysine (K), glutamic acid (E), or arginine (R), X20 is selected from K, R, Q, or homoarginine (hArg), X24 is selected from alanine (A), E, Q, aspartic acid (D), d-Ala, glycine (G), asparagine (N), K, (lS,2S)-2- Aminocyclopentanecarboxylic acid (ACPC), (3S,4R)-4-Amino-3-pyrrolidinecarboxylic acid (APCA), threonine (T), serine (S), or tyrosine (Y); X27 is selected from valine (V), K, a-amino- isobutyric acid (Aib), N, S, T, Y, Q, or R; and X28 is selected from K, E, R, Q, D, N, G, S, orT. In accordance with this, and all embodiments of the present disclosure, the GLP-1 receptor agonist of the present disclosure does not comprise the amino acid sequence of SEQ ID NO: 1574 (H[Aib]EGTFTSDYSSYLEEQAAKEFIAWLVKGGG).

[0099] In one embodiment, the GLP-1 receptor agonist polypeptide of the present disclosure comprises the amino acid sequence of H[Aib]EGTFTSDYSSYLEEXi7AAX2oEFIX24WLX27X28GGG (SEQ ID NO: 1576), where X17 is Q or K; X20 is K or R; X24 is A, E, or Q; X27 is V or K; and X28 is K, E, or R. As noted above, the GLP-1 receptor agonist of the present disclosure does not comprise the amino acid sequence of SEQ ID NO: 1574.

[0100] In one embodiment, the GLP-1 receptor agonist polypeptide of the present disclosure comprises the amino acid sequence H[Aib]EGTFTSDYSSYLEEXi7AAREFIX24WLX27X28GGG (SEQ ID NO: 1577), where X17 is Q or K; X24 is A, E, or Q; X27 is V or K; and X28 is K, E, or R. Alternatively, the GLP-1 receptor agonist of the present disclosure comprises the amino acid sequence of(H[Aib]EGTFTSDYSSYLEEXi7AAX2oEFIX24WLKX28GGG (SEQ ID NO: 1578), where X17 is Q or K; X20 is K or R; X24 is A, E, or Q; and X28 is K, E, or R.

[0101] Non-limiting examples of GLP-1 receptor agonists of the present disclosure are presented in the Table 1 below. The description column of Table 1 provides the amino acid substitution (relative to GLP-1 (7-37)) that are present at the identified position in the particular GLP-1 receptor agonist polypeptide sequence.Table 1. GLP-1 Receptor Agonist Polypeptide SequencesAib is a-amino-isobutyric acid

[0102] In one embodiment, the human glucagon-like peptide 1 (GLP-1) receptor agonist polypeptide of the present disclosure comprises 31 amino acids and comprises 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 to the amino acid sequence of SEQ ID NO: 1580. This GLP-1 receptor agonist polypeptide also comprises an a-amino-isobutyric acid (Aib) at position 2; a tyrosine at position 10; a glutamic acid at positions 16, 24, and 28; an arginine at position 20; a lysine at positions 17 and 27; and a glycine at position 30. In one embodiment, this GLP-1 receptor agonist polypeptide comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 1580. In one embodiment, this GLP-1 receptor agonist polypeptide comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1580. In one embodiment, this GLP-1 receptor agonist polypeptide 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 of the present disclosure comprises 31 amino acids and comprises an amino acidsequence 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 to the amino acid sequence of SEQ ID NO: 1579. This GLP-1 receptor agonist polypeptide also comprises an Aib at position 2; a tyrosine at position 10; a glutamic acid at positions 16 and 24; an arginine at position 20; a lysine at positions 27; and a glycine at position 30. In one embodiment, this GLP-1 receptor agonist polypeptide comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 1579. In one embodiment, this GLP-1 receptor agonist polypeptide comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1579. In one embodiment, this 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 of the present disclosure comprises 31 amino acids and comprises 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 to the amino acid sequence of SEQ ID NO: 1581. This GLP-1 receptor agonist polypeptide also comprises an Aib at position 2; a tyrosine at position 10; a glutamic acid at positions 16 and 24; an arginine at position 20; a lysine at positions 17, 27; and a glycine at position 30. In one embodiment, this GLP-1 receptor agonist polypeptide comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 1581. In one embodiment, this GLP-1 receptor agonist polypeptide comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1581. In one embodiment, this 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 of the present disclosure comprises 31 amino acids and comprises 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 to the amino acid sequence of SEQ ID NO: 1583. This GLP-1 receptor agonist polypeptide also comprises an Aib at position 2; a tyrosine at position 10; a glutamic acid at positions 16 and 28; an arginine at position 20; a lysine at positions 17, 27; a glutamine at position 24; and a glycine at position 30. In one embodiment, this GLP-1 receptor agonist polypeptide comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 1583. In one embodiment, this GLP-1 receptor agonistpolypeptide comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1583. In one embodiment, this GLP-1 receptor agonist polypeptide 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 of the present disclosure comprises 31 amino acids and comprises 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 to the amino acid sequence of SEQ ID NO: 1582. This GLP-1 receptor agonist polypeptide also comprises an Aib at position 2; a tyrosine at position 10; a glutamic acid at positions 16 and 24; an arginine at positions 20 and 28; a lysine at positions 27; and a glycine at position 30. In one embodiment, this GLP-1 receptor agonist polypeptide comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 1582. In one embodiment, this GLP-1 receptor agonist polypeptide comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1582. In one embodiment, this GLP-1 receptor agonist polypeptide comprises the amino acid sequence of SEQ ID NO: 1582.

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

[0108] In one embodiment, the GLP-1 receptor agonist agonizes the human GLP-1 receptor. In one embodiment, the GLP-1 receptor agonist polypeptide has an ECso of less than or equal to 50 pM for agonizing the human GLP-1 receptor as measured using the GLP-1 receptor agonist activity assay described herein in Example 3. Lor example, the GLP-1 receptor agonist polypeptide has an ECso of 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, the GLP-1 ECso is measured in the GLP-1 receptor agonist activity assay described in Example 3 herein.

[0109] In one embodiment, the GLP-1 receptor agonist polypeptide has an ECso of about 10 pM for agonizing the human GLP-1 receptor as measured using the GLP-1 receptor agonistactivity assay described herein in Example 3. In one embodiment, the GLP-1 receptor agonist polypeptide has an ECso of about 15 pM, about 20 pM, about 25 pM, about 30 pM, about 35 pM, about 40 pM, about 45 pM, about 50 pM, about 55 pM, about 60 pM, about 65 pM, about 70 pM, about 75 pM for agonizing the human GLP-1 receptor as measured using the GLP-1 receptor agonist activity assay described herein in Example 3.

[0110] In one embodiment, the GLP-1 receptor agonists disclosed herein are chemically derivatized at one or more amino acid residues by known organic chemistry techniques. In accordance with this and all embodiments of the disclosure “chemical derivative” or “chemically derivatized” refers to a peptide (e.g., peptide linker as described herein), polypeptide (e.g., GLP- 1 receptor agonist polypeptide), or other protein (e.g., anti-GIPR antibody as described herein) having one or more residues chemically derivatized by reaction of a functional side group. Such derivatized molecules include, for example, those molecules in which free amino groups have been derivatized to form amine hydrochlorides, p-toluene sulfonyl groups, carbobenzoxy groups, t-butyloxycarbonyl groups, chloroacetyl groups or formyl groups. Free carboxyl groups may be derivatized to form salts, methyl and ethyl esters or other types of esters or hydrazides. Free hydroxyl groups may be derivatized to form O-acyl or O-alkyl derivatives. The imidazole nitrogen of histidine may be derivatized to form N-im-benzylhistidine. Also included as chemical derivatives are those polypeptides which contain one or more naturally occurring amino acid derivatives of the twenty canonical amino acids, whether in L- or D-form. For example, 4-hydroxyproline may be substituted for proline; 5-hydroxylysine may be substituted for lysine; 3 -methylhistidine may be substituted for histidine; homoserine may be substituted for serine; and ornithine may be substituted for lysine.

[0111] Useful derivatizations include, in one embodiment, those in which the amino terminal of the polypeptide is chemically blocked so that conjugation to an Fc-containing peptide or an antibody will be prevented from taking place at an N-terminal free amino group of the GLP-1 receptor agonist polypeptide. There may be other beneficial effects of such as modification, for example, a reduction in the polypeptide agonist’s susceptibility to enzymatic proteolysis. The N-terminus can be acylated or modified to a substituted amine, or derivatized with another functional group, such as an aromatic moiety (e.g., an indole 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, such as, but not limited to, a formyl,acetyl (Ac), propanoyl, butanyl, heptanyl, hexanoyl, octanoyl, or nonanoyl, are covalently linked to the N-terminal end of the peptide, which can prevent undesired side reactions during conjugation of the peptide to an Fc-containing peptide or antibody. Other exemplary N-terminal derivative groups include — NRRI (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 lower alkyl and wherein the phenyl ring may be substituted with 1 to 3 substituents selected from C1-C4 alkyl, C1-C4 alkoxy, chloro, and bromo.

[0112] In one embodiment, one or more individual amino acid residues of the GLP-1 receptor agonist polypeptide as described herein is derivatized. Various derivatizing agents are known to react specifically with selected sidechains or terminal residues, as described in detail below by way of example.

[0113] Lysinyl residues and amino terminal residues of the GLP-1 receptor agonist polypeptides described herein may be reacted with succinic or other carboxylic acid anhydrides, which reverse the charge of the lysinyl residues. Other suitable reagents for derivatizing alpha- amino-containing residues include imidoesters such as methyl picolinimidate; pyridoxal phosphate; pyridoxal; chloroborohydride; trinitrobenzenesulfonic acid; O-methylisourea; 2,4 pentanedione; and transaminase-catalyzed reaction with glyoxylate.

[0114] Arginyl residues may be modified by reaction with any one or combination of several conventional reagents, including phenylglyoxal, 2,3-butanedione, 1 ,2-cyclohexanedione, and ninhydrin. Derivatization of arginyl residues requires that the reaction be performed in alkaline conditions because of the high pKa of the guanidine functional group. Furthermore, these reagents may react with the groups of lysine as well as the arginine epsilon-amino group

[0115] Specific modification of tyrosyl residues has been studied extensively, with particular interest in introducing spectral labels into tyrosyl residues by reaction with aromatic diazonium compounds or tetranitromethane. Most commonly, N-acetylimidizole and tetranitromethane are used to form O-acetyl tyrosyl species and 3 -nitro derivatives, respectively.

[0116] Carboxyl sidechain groups (aspartyl or glutamyl) of the GLP-1 receptor agonist polypeptides described herein may be selectively modified by reaction with carbodiimides (R' — N=C=N — R') such as l-cyclohexyl-3-(2-morpholinyl-(4-ethyl) carbodiimide or l-ethyl-3-(4- azonia-4,4-dimethylpentyl) carbodiimide. Furthermore, aspartyl and glutamyl residues may be converted to asparaginyl and glutaminyl residues by reaction with ammonium ions.

[0117] Glutaminyl and asparaginyl residues may be deamidated to the corresponding glutamyl and aspartyl residues. Alternatively, these residues are deamidated under mildly acidic conditions.

[0118] Cysteinyl residues can be replaced by amino acid residues or other moieties either to eliminate disulfide bonding or, conversely, to stabilize cross-linking.

[0119] In one embodiment, one or more peptidyl [ — C(O)NR — ] linkages (bonds) between amino acid residues of the GLP-1 receptor agonist polypeptide are replaced by a non- peptidyl linkage. Exemplary non-peptidyl linkages 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 — wherein R6 is lower alkyl],

[0120] Other possible modifications to the GLP-1 receptor agonist polypeptide include hydroxylation of proline and lysine, phosphorylation of hydroxyl groups of seryl or threonyl residues, oxidation of the sulfur atom in Cys, methylation of the alpha-amino groups of lysine, arginine, and histidine side chains.CONJUGATE MOLECULES COMPRISING THE GLP-1 RECEPTOR AGONIST POLYPEPTIDES

[0121] Another aspect of the present disclosure is directed to molecules comprising aGLP-1 receptor agonist polypeptide as described supra.

[0122] In one embodiment, the molecule comprises a first GLP-1 receptor agonist polypeptide, where the first GLP-1 receptor agonist polypeptide is conjugated to a half-life extending domain. The half-life extending domain may be conjugated directly or via a linker moiety to the GLP-1 receptor agonist polypeptide.

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

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

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

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

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

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

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

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

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

[0132] Another aspect of the disclosure is directed to a conjugate molecule comprising a GLP-1 receptor agonist polypeptide as disclosed herein and an antagonist anti-glucose-dependent insulinotropic polypeptide receptor (GIPR) antibody. In one embodiment, the conjugate molecule comprises a first GLP-1 receptor agonist polypeptide comprising the amino acid sequence of H[Aib]EGTFTSDYSSYLEEXi7AAX2oEFIX24WLX27X28GGG (SEQ ID NO: 1575), wherein X17 is Q, K, E, or R; X20 is K, R, Q, or homoarginine (hArg); X24 is A, E, Q, D, d-Ala, G, N, K, (lS,2S)-2-Aminocyclopentanecarboxylic acid (ACPC), (3S,4R)-4-Amino-3- pyrrolidinecarboxylic acid (APCA), T, S, or Y; X27 is V, K, Aib, N, S, T, Y, Q, or R; and X28 is K, E, R, Q, D, N, G, S, or T, and wherein the GLP-1 receptor agonist polypeptide does not comprise the amino acid sequence of SEQ ID NO: 1574; and an antagonist anti-GIPR human antibody.

[0133] An exemplary molecule of the present disclosure comprises a first GLP-1 receptor agonist polypeptide conjugated to an antagonist anti-GIPR human antibody. This molecule is referred to herein as an “anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule”, a “conjugate molecule”, or an “anti-GIPR / GLP-1 conjugate molecule”. Exemplary antagonist anti-GIPR antibodies are disclosed infra.

[0134] According to this embodiment of the disclosure, the antagonist anti-GIPR antibody of this anti-GIPR / GLP-1 conjugate molecule comprises a first cysteine conjugation site within a light chain or a 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 conjugation site of the anti-GIPR antibody.

[0135] In one embodiment, this 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 conjugation site of the anti-GIPR antibody. The second cysteine conjugation site of the anti-GIPR antibody is also located within a light chain or heavy chain of the anti-GIPR antibody. Preferably the first and second cysteine conjugations sites of the anti-GIPR antibody are located at corresponding positions within each light chain or within each heavy chain.

[0136] In one embodiment, the first and second GLP-1 receptor agonist polypeptides of this conjugate molecule that are conjugated to the anti-GIPR antibody comprise the same amino acid sequence. In one embodiment, the first and second GLP-1 receptor agonist polypeptides of the conjugate molecule comprise different amino acid sequences.

[0137] In one embodiment, the first and / or second GLP-1 receptor agonist polypeptides of this anti-GIPR / GLP-1 receptor agonist conjugate molecule (or any conjugate molecule of the present disclosure) comprise the amino acid sequence of H[Aib]EGTFTSDYSSYLEEXi7AAX2oEFIX24WLX27X28GGG (SEQ ID NO: 1575), where Aib at position 2 is a-amino-isobutyric acid; X17 is selected from glutamine (Q), lysine (K), glutamic acid (E), or arginine (R), X20 is selected from K, R, Q, or homoarginine (hArg), X24 is selected from alanine (A), E, Q, aspartic acid (D), d-Ala, glycine (G), asparagine (N), K, (lS,2S)-2- Aminocyclopentanecarboxylic acid (ACPC), (3S,4R)-4-Amino-3-pyrrolidinecarboxylic acid (APCA), threonine (T), serine (S), or tyrosine (Y); X27 is selected from valine (V), K, a-amino- isobutyric acid (Aib), N, S, T, Y, Q, R; and X28 is selected from K, E, R, Q, D, N, G, S, T. In accordance with this, and all embodiments of the present disclosure, the GLP-1 receptor agonist of the anti-GIPR / GLP-1 conjugate molecule of the present disclosure does not comprise the ammo acid sequence of H[Aib]EGTFTSDYSSYLEEQAAKEFIAWLVKGGG (SEQ ID NO: 1574).

[0138] In one embodiment, incorporation of the amino acid substitutions at the identified positions, in particular at residues 17, 20, 24, 27, and 28 (SEQ ID NO: 1575), improves in vivo stability of the conjugate molecule. For example, the identified amino acid substitutions render the GLP-1 polypeptide resistant to in vivo clipping from the conjugate as measured by a high ratio (> 0.65) of intact to total GIPR-GLP-1 molecule AUCo-t (see Example 5). In one embodiment, the incorporation of the amino acid substitutions at the identified positions of the GLP-1 receptor agonist polypeptide, in particular at positions 17, 20, 24, 27, and 28, improves the potency of the conjugate molecule. For example, the identified amino acid substitutions render the conjugate molecule more therapeutically potent as measured by body weight loss following in vivo administration (see Example 4).

[0139] In one embodiment, the first and / or second GLP-1 receptor agonist polypeptides of the anti-GIPR / GLP-1 receptor agonist conjugate molecule comprises the amino acid sequence of H[Aib]EGTFTSDYSSYLEEXi7AAX2oEFIX24WLX27X28GGG (SEQ ID NO: 1576), where X17 is Q or K; X20 is K or R; X24 is A, E, or Q; X27 is V or K; and X28 is K, E, or R. As noted above, the GLP-1 receptor agonist of the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule does not comprise the amino acid sequence of SEQ ID NO: 1574.

[0140] In one embodiment, the first and / or second GLP-1 receptor agonist polypeptides of the anti-GIPR / GLP-1 receptor agonist conjugate molecule comprises the amino acid sequence of H[Aib]EGTFTSDYSSYLEEXi7AAREFIX24WLX27X28GGG (SEQ ID NO: 1577), where X17 is Q or K; X24 is A, E, or Q; X27 is V or K; and X28 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 comprises the amino acid sequence of H[Aib]EGTFTSDYSSYLEEXi7AAX2oEFIX24WLKX28GGG (SEQ ID NO: 1578), where X17 is Q or K; X20 is K or R; X24 is A, E, or Q; and X28 is K, E, or R.

[0141] In one embodiment, the first and / or second GLP-1 receptor agonist polypeptides of the conjugate molecule comprise 31 amino acids and comprise 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 to the amino acid sequence of SEQ ID NO: 1580. This GLP-1 receptor agonist polypeptide also comprises an Aib at position 2; a tyrosine at position 10; a glutamic acid at positions 16, 24, and 28; an arginine at position 20; a lysine at positions 17 and 27; and a glycine at position 30. In one embodiment, the first and / or second GLP-1 receptor agonist polypeptidecomprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 1580. In one embodiment, the first and / or second GLP-1 receptor agonist polypeptide of the conjugate molecule comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1580. In one embodiment, the first and / or 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 and / or second GLP-1 receptor agonist polypeptides of the conjugate molecule comprise 31 amino acids and comprise 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 to the amino acid sequence of SEQ ID NO: 1579. This GLP-1 receptor agonist polypeptide also comprises an Aib at position 2; a tyrosine at position 10; a glutamic acid at positions 16 and 24; an arginine at position 20; a lysine at positions 27; and a glycine at position 30. In one embodiment, the first and / or second GLP-1 receptor agonist polypeptide comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 1579. In one embodiment, the first and / or second GLP-1 receptor agonist polypeptide comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1579. In one embodiment, the first and / or 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 and / or second GLP-1 receptor agonist polypeptides of the conjugate molecule comprise 31 amino acids and comprise 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 to the amino acid sequence of SEQ ID NO: 1581. The first and / or second GLP-1 receptor agonist polypeptide also comprises an Aib at position 2; a tyrosine at position 10; a glutamic acid at positions 16 and 24; an arginine at position 20; a lysine at positions 17, 27; and a glycine at position 30. In one embodiment, first and / or second GLP-1 receptor agonist polypeptide comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 1581. In one embodiment, the first and / or second GLP-1 receptor agonist polypeptide comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1581. In one embodiment, the first and / orsecond 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 and / or second GLP-1 receptor agonist polypeptides of the conjugate molecule comprise 31 amino acids and comprise 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 to the amino acid sequence of SEQ ID NO: 1583. This GLP-1 receptor agonist polypeptide also comprises an Aib at position 2; a tyrosine at position 10; a glutamic acid at positions 16 and 28; an arginine at position 20; a lysine at positions 17, 27; a glutamine at position 24; and a glycine at position 30. In one embodiment, the first and / or second GLP-1 receptor agonist polypeptide comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 1583. In one embodiment, the first and / or second GLP-1 receptor agonist polypeptide comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1583. In one embodiment, the first and / or 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 and / or second GLP-1 receptor agonist polypeptides of the conjugate molecule comprise 31 amino acids and comprise 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 to the amino acid sequence of SEQ ID NO: 1582. This GLP-1 receptor agonist polypeptide also comprises an Aib at position 2; a tyrosine at position 10; a glutamic acid at positions 16 and 24; an arginine at positions 20 and 28; a lysine at positions 27; and a glycine at position 30. In one embodiment, the first and / or second GLP-1 receptor agonist polypeptide comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 1582. In one embodiment, the first and / or second GLP-1 receptor agonist polypeptide comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1582. In one embodiment, the first and / or 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 polypeptide of the conjugate molecule is directly conjugated, at its C-terminus, to the first cysteine conjugation site of the anti-GIPR antibody. In one embodiment, each of the first and second GLP-1 receptor agonistpolypeptides of the molecule is directly conjugated, at its C-terminus, to the first and second cysteine conjugations sites of the anti-GIPR antibody, respectively. The position of the first and second cysteine conjugation sites within the anti-GIPR antibody are described in more detail infra.

[0147] In one embodiment, the first GLP-1 receptor agonist polypeptide of the conjugate molecule is conjugated, at its C-terminus, to the first cysteine conjugation site of the anti-GIPR antibody via a linker moiety. In one embodiment, each of the first and second GLP-1 receptor agonist polypeptides of the conjugate molecule are conjugated, at their C-terminus, to the first and second cysteine conjugation sites of the anti-GIPR antibody, respectively, via first and second linker moieties, respectively.

[0148] In one embodiment a linker moiety couples the C-terminal end of a GLP-1 receptor agonist polypeptide to a conjugation site on an anti-GIPR antibody. The presence of any linker moiety in the GLP-1 receptor agonist conjugate molecules as described herein is optional. In one embodiment, the linker moiety serves primarily as a spacer to position, join, connect, or optimize presentation or position of the functional moieties of the molecule (e.g., the GLP-1 receptor agonist polypeptide and / or the anti-GIPR antibody). In another embodiment, a linker moiety is utilized to optimize pharmacological activity or stability of the GLP-1 receptor agonist containing molecules disclosed herein. In a preferred embodiment, the linker moiety of the anti-GIPR antibody / GLP-1 receptor agonist polypeptide conjugate molecule described herein contributes to the enhanced the stability of the molecule in terms of resistance to cleavage upon in vivo administration.

[0149] In one embodiment, the linker moiety is a peptide linker moiety. Peptide linkers are made up of amino acids that are typically linked together by peptide bonds and are a length of from 1 to about 40 amino acid residues, preferably, a length of from 10 to about 30 amino acid residues, and more preferably, a length of from 10 to about 20 amino acid residues. In some embodiments, the peptide linker may comprise amino acid residues where one or more of the amino acid residues are not linked via a peptide bond (i.e., The amino acid residues of the linker are chosen from among the twenty canonical amino acids. More preferably, the amino acid residues of the linker are chosen from among glycine, alanine, proline, asparagine, glutamine, and / or serine. Even more preferably, a peptidyl linker is made up of a majority of amino acids that are sterically unhindered, such as glycine, serine, and alanine linked by a peptide bond. It isalso desirable that, if present, the peptidyl linker is one that is not subject to rapid proteolytic turnover in circulation.

[0150] Exemplary linker moieties of the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecules described herein include the linker peptide of SEQ ID NO: 1585, the linker peptide of SEQ ID NO: 1586, the linker peptide of SEQ ID NO: 1587, the linker peptide of SEQ ID NO: 1588, the linker peptide of SEQ ID NO: 1589, the linker peptide of SEQ ID NO: 1590, the linker peptide of SEQ ID NO: 1591, the linker peptide of SEQ ID NO: 1592, and the linker peptide of 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 linkage between a GLP-1 receptor polypeptide and a peptide linker is a peptide bond between the C-terminal amino acid residue of the GLP-1 agonist polypeptide and N-terminal amino acid residue of the peptide linker. In one embodiment, the linkage between a GLP-1 receptor polypeptide and a peptide linker is an amide bond between the C-terminal amino acid residue of the GLP-1 agonist polypeptide and the side chain of a lysine residue (i.e., at the £ amino group of the lysine) on the peptide linker. In one embodiment, the linkage between a GLP-1 receptor polypeptide and a peptide linker is an amide bond between the C-terminal amino acid residue of the GLP-1 agonist polypeptide and the a amino group of a C-terminal lysine residue on the peptide linker.

[0152] In one embodiment, exemplary linker peptides comprise a sequence of amino acid residues coupled via standard peptide bonds (e.g., the peptide linkers of SEQ ID NOs: 1585- 1587 and 1592-1654). In one embodiment, exemplary linker peptides comprise at least on nonstandard peptide bond. In this embodiment, the linker peptide comprises a sequence of amino acid residues coupled via standard peptide bonds, where the C-terminal residue of this sequence is coupled, via an amide bond, to the epsilon amino group of a lysine residue. For example, the exemplary linker peptides of SEQ ID NOs: 1588-1591 comprise a non-standard amino acid linkage at the lysine residue. In particular, for the linker peptides of SEQ ID NOs: 1588 and 1590, the glutamine residue at position 15 of these peptides is linked via an amide bond to the epsilon amino group of the adjacent lysine. This unique linkage is represented in the linker peptide as provided in Table 2 by the lysine residue outside the parenthesis enclosing the remainder of the linker sequence. Similarly, for the linker peptides of SEQ ID NOs: 1589 and1591, the serine residue at position 15 of these peptides is linked via an amide bond to the epsilon amino group of the adjacent lysine residue. The linkage between a GLP-1 receptor polypeptide and a peptide linker 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 polypeptide and the a 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 the cysteine conjugation site on the anti-GIPR antibody residue. The N-terminal amino acid residue of the linker peptide may be modified, e.g., bromoacetylated, to facility the coupling to the cysteine conjugation site on the anti-GIPR antibody.

[0153] In one embodiment, the molecule disclosed herein comprises a GLP-1 receptor agonist polypeptide of SEQ ID NO: 1579 covalently linked to the linker peptide of SEQ ID NO: 1585, the linker peptide of SEQ ID NO: 1586, the linker peptide of SEQ ID NO: 1587, the linker peptide of SEQ ID NO: 1588, the linker peptide of SEQ ID NO: 1589, the linker peptide of SEQ ID NO: 1590, the linker peptide of SEQ ID NO: 1591, the linker peptide of SEQ ID NO: 1592, or the linker peptide of SEQ ID NO: 1593. In one embodiment, the molecule disclosed herein comprises a GLP-1 receptor agonist polypeptide of SEQ ID NO: 1579, where the C-terminal amino acid residue of the polypeptide is covalently linked to the N-terminal amino acid residue of the linker peptide of SEQ ID NO: 1592 as depicted in FIG. 2. In one embodiment, the C- terminal lysine of the linker peptide is modified, e.g., bromoacetylated, for coupling to the cysteine residue of the conjugation site on the anti-GIPR antibody.

[0154] In one embodiment, the molecule disclosed herein comprises a GLP-1 receptor agonist polypeptide of SEQ ID NO: 1580 covalently linked to the linker peptide of SEQ ID NO: 1585, the linker peptide of SEQ ID NO: 1586, the linker peptide of SEQ ID NO: 1587, the linker peptide of SEQ ID NO: 1588, the linker peptide of SEQ ID NO: 1589, the linker peptide of SEQ ID NO: 1590, the linker peptide of SEQ ID NO: 1591, the linker peptide of SEQ ID NO: 1592, or the linker peptide of SEQ ID NO: 1593. In one embodiment, the molecule disclosed herein comprises a GLP-1 receptor agonist polypeptide of SEQ ID NO: 1580, where the C-terminal amino acid residue of the polypeptide is covalently linked to the a-amino group of the lysine residue of the linker peptide of SEQ ID NO: 1591 as depicted in FIG. 3. As noted above, the adjacent serine residue of the linker, i.e., the serine at position 15 of the linker peptide of SEQ ID NO: 1591, is linked via an amide bond to the epsilon amino group of the lysine residue as shownin FIG. 3. In this embodiment, the N-terminal glycine residue of the linker peptide is modified, i.e., bromoacetylated, for coupling to the cysteine residue of the conjugation site on the anti- GIPR antibody.

[0155] In one embodiment, the molecule disclosed herein comprise a GLP-1 receptor agonist polypeptide of SEQ ID NO: 1581 covalently linked to the linker peptide of SEQ ID NO: 1585, the linker peptide of SEQ ID NO: 1586, the linker peptide of SEQ ID NO: 1587, the linker peptide of SEQ ID NO: 1588, the linker peptide of SEQ ID NO: 1589, the linker peptide of SEQ ID NO: 1590, the linker peptide of SEQ ID NO: 1591, the linker peptide of SEQ ID NO: 1592, or the linker peptide of SEQ ID NO: 1593. In one embodiment, the molecule disclosed here comprises a GLP-1 receptor agonist polypeptide of SEQ ID NO: 1581, where the C-terminal amino acid residue of the polypeptide is covalently linked to the N-terminal amino acid residue of the linker peptide of SEQ ID NO: 1585 as depicted in FIG. 4. In one embodiment, the C- terminal lysine of the linker peptide is modified, e.g., bromoacetylated as shown in FIG. 4, for coupling to the cysteine residue of the conjugation site on the anti-GIPR antibody.

[0156] In one embodiment, the molecule disclosed here comprises a GLP-1 receptor agonist polypeptide of SEQ ID NO: 1581, where the C-terminal amino acid residue of the polypeptide is covalently linked to the N-terminal amino acid residue of the linker peptide of SEQ ID NO: 1586 as depicted in FIG. 5. In one embodiment, the C-terminal lysine of the linker peptide is modified, e.g., bromoacetylated as shown in FIG. 5, for coupling to the cysteine residue of the conjugation site on the anti-GIPR antibody.

[0157] In one embodiment, the molecule disclosed here comprises a GLP-1 receptor agonist polypeptide of SEQ ID NO: 1581, where the C-terminal amino acid residue of the polypeptide is covalently linked to N-terminal amino acid residue of the linker peptide of SEQ ID NO: 1593 as depicted in FIG. 6. In one embodiment, the C-terminal lysine of the linker peptide is modified, e.g., bromoacetylated on the sidechain, as shown in FIG. 6, for coupling to the cysteine residue of the conjugation site on the anti-GIPR antibody.

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

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

[0160] Other peptide linkers that are suitable for inclusion in the molecules as described herein are provided in Table 2.Table 2. Linker Peptide Sequences

[0161] In one embodiment, the linker moiety, if present, is a non-peptidyl linker moiety.One non-limiting example class of suitable non-peptidyl linkers is polyethylene glycol (PEG) linkers, such as, e.g.,wherein n is such that the linker has a molecular weight of about 100 Daltons (Da) to about 5000 Da, preferably about 100 Da to about 500 Da. Additional non-peptidyl linker moieties that are suitable for incorporation into the GLP-1 agonist polypeptide containing molecules are disclosedinfra. 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 comprise a GLP-1 receptor agonist polypeptide of SEQ ID NO: 1581 covalently linked to the a-amino group of the lysine residue of the PEG20 linker (G-PEG20)-K as shown in FIG. 7. At the opposite end of the PEG20 molecule is a bromoacetylated glycine residue that facilitates conjugation to the cysteine conjugation site on the anti-GIPR antibody.

[0163] In one embodiment, the molecule disclosed herein comprise a GLP-1 receptor agonist polypeptide of SEQ ID NO: 1582 covalently linked to the a-amino group of the lysine residue of the PEG20 linker (G-PEG20)-K as shown in FIG. 8. At the opposite end of the PEG20 molecule is a bromoacetylated glycine residue that facilitates conjugation to the cysteine conjugation site on the anti-GIPR antibody.

[0164] In one embodiment, the molecule disclosed herein comprise a GLP-1 receptor agonist polypeptide of SEQ ID NO: 1583 covalently linked to the a-amino group of the lysine residue of the PEG20 linker (G-PEG20)-K as shown in FIG. 9. At the opposite end of the PEG20 molecule is a bromoacetylated glycine residue that facilitates conjugation to the cysteine conjugation site on the anti-GIPR antibody.

[0165] Additional non-peptidyl linker moieties that are suitable for incorporation into the GLP-1 agonist polypeptide containing molecules include alkyl linkers such as -NH-(CH2)s-C(O), wherein s = 2-20. These alkyl linkers may further be substituted by any non-sterically hindering group such as lower alkyl (e.g., Ci-Ce) lower acyl, halogen (e.g., Cl, Br), CN, NEE, phenyl, etc.

[0166] Other suitable non-peptidyl linkers comprise a rigid polyheterocyclic core of controlled length. Such linkers may be chemically differentiated on either end to accommodate orthogonal coupling chemistries (i.e., azide “click”, amide coupling, thioether formation by alkylation with maleimide or haloacetamide, oxime formation, reductive amination, etc.).

[0167] Non-peptidyl linkers can be synthesized by conventional organic chemistry reactions.

[0168] The above is merely illustrative and not an exhaustive treatment of the kinds of non-peptidyl linkers that can optionally be employed in accordance with the present disclosure.

[0169] In one embodiment, the antagonist anti-GIPR antibodies of the conjugate molecules disclosed herein comprise at least one conjugation site. In one embodiment, the anti-GIPR antibodies of the conjugate molecule disclosed herein comprise at least two conjugation sites (e.g., a first and second conjugation site). The one or more conjugation sites of the anti- GIPR antibody are amenable to conjugation of the GLP-1 receptor agonist polypeptides as disclosed herein by a defined conjugation chemistry through the side chain of an amino acid residue at the conjugation site. GLP-1 receptor agonist polypeptides can be conjugated or coupled to the selected conjugation site of the anti-GIPR antibody through an assortment of different conjugation chemistries known in the art. For example, in one embodiment, a maleimide-activated conjugation partner targeting an accessible cysteine thiol on the anti-GIPR antibody can be used. In one embodiment, conjugation or coupling chemistries targeting the side chains of either canonical or non-canonical, e.g., unnatural, amino acids in the anti-GIPR antibody sequence can be used.

[0170] Chemistries for chemoselective conjugation of the anti-GIPR antibody to the GLP-1 receptor agonist polypeptide include, but are not limited to, copper(I)-catalyzed azidealkyne [3+2] dipolar cycloadditions, Staudinger ligation, other acyl transfers processes, oximations, hydrazone bonding formation, and other suitable organic chemistry reactions such as cross-couplings using water-soluble palladium catalysts (see e.g., Bong et al., Organic Letters 3(16):2509-l 1 (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 1(1); 13-21 (2005)).

[0171] In one embodiment, conjugation (or covalent binding) to the anti-GIPR antibody is through the side chain of an amino acid residue at the conjugation site, for example, but not limited to, a cysteinyl residue. The amino acid residue, for example, a cysteinyl residue, at the internal conjugation site that is selected can be one that occupies the same amino acid residue position in a native Fc domain sequence, or the amino acid residue can be engineered into the Fc domain sequence by substitution or insertion.

[0172] Non-limiting examples of unnatural amino acid residues that can be useful as a conjugation site include: azido-containing amino acid residues, e.g., azidohomoalanine, p-azido- phenylalanine; keto-containing amino acid residues, e.g., p-acetyl-phenylalanine; alkyne- containing amino acid residues, e.g., p-ethynylphenylalanine, homopropargylglycine, p-(prop-2- ynyl)-tyrosine; alkene-containing amino acid residues e.g., homoallylglycine; aryl halide-containing amino acid residues e.g. p-iodophenylalanine, p-bromophenylalanine; and 1,2- aminothiol containing amino acid residues.

[0173] Non-canonical amino acid residues (e.g., unnatural amino acid residues) can be incorporated into an anti-GIPR antibody by amino acid substitution or insertion. Non-canonical amino acid residues can be incorporated into the antibody by chemical peptide synthesis rather than by synthesis in biological systems, such as recombinantly expressing cells, or alternatively the skilled artisan can employ known techniques of protein engineering that use recombinantly expressing cells (see, e.g., Link et al., Current Opinion in Biotechnology, 14(6):603-609 (2003); U.S. Patent No. 7,045,337 to Schultz).

[0174] Any of the exposed amino acid residues on the anti-GIPR antibody can be potentially useful conjugation sites. Such sites may naturally contain cysteine or another reactive amino acid for site-selective coupling. Other sites can be mutated to a 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 (CHI), CH2 or CH3 region of the anti-GIPR antibody.

[0175] In one embodiment, the anti-GIPR antibody comprises a cysteine amino acid at one or more conjugation site(s). In one embodiment, the one or more conjugation site(s) is located within the CL, CHI, CH2 or CH3 region of the anti-GIPR antibody. In one embodiment, the one or more conjugation site(s) are at positions independently selected from the group consisting of 88 (e.g., D88) of the light chain, 384 (e.g., E384) of the heavy chain, and 487 (e.g., T487) of the heavy chain, according to AHo numbering. For sake of clarity position 88 of the light chain according to Aho number corresponds to position 70 according to Kabat Numbering. Position 88 of the light chain according to 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 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 of the heavy chain according to AHo numbering is another suitable conjugation site within the anti-GIPR antibody. Position 384 of the heavy chain according to AHo numbering corresponds to position 272 according to EU Numbering. Position 384 of the heavy chain according to AHo numbering corresponds to position 276 in the reference heavychain antibody sequence of SEQ ID NO: 612 (heavy chain of anti-GIPR antibody 5G12.006) and to 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 of the heavy chain according to AHo numbering is another suitable conjugation site within the anti-GIPR antibody. Position 487 of the antibody heavy chain according to AHo numbering corresponds to position 359 according to EU numbering. Position 487 according to AHo numbering 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 and antagonize GIPR, including human GIPR (hGIPR), for inclusion in the conjugate molecules as described herein are provided infra 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, antagonist anti-GIPR antibody inhibits 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 one embodiment, the antagonist anti-GIPR antibody inhibits binding of GIP to the N-terminal extracellular domain of human GIPR. In one embodiment, the human GIPR has the amino acid sequence of 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 binding of GIP to the amino acids at positions 1-139 of human GIPR. In one embodiment, the 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 of the present disclosure prevents or reduces binding of GIP to GIPR, where the level of prevention or reduction can be measured, for example, by a GIPR binding assay (e.g., a radioactive- or fluorescence-labeled GIP ligand binding study). A GIPR binding assay can be anassay using FMAT or FACS that measures fluorescence-labeled GIP binding to GIPR expressing cells, and the antagonistic activity of an anti-GIPR antibody is measured by its ability to displace fluorescence-labeled GIP binding to GIPR expressing cells. Alternatively, a GIPR binding assay can measure radioactive- labeled GIP binding to GIPR expressing cells, and the antagonist activity of an anti-GIPR antibody is measured by its ability to displace radioactive labeled GIP binding to GIPR expressing cells (see e.g., Biochimica et Biophysica Acta (2001) 1547:143-155). The reduction in GIP binding can be at least 10%, 25%, 50%, 100% or more relative treatment with a non-GIPR control antibody under comparable conditions.

[0183] In one embodiment, the antagonist anti-GIPR antibody of the conjugate molecule of the present disclosure prevents or reduces binding of GIP to GIPR, where the level of prevention or reduction is measured using a GIPR activity assay that measures GIP binding protein activity in a cellular setting. In one embodiment, the GIPR activity assay is a cAMP assay in GIPR expressing cells, in which GIP induces cAMP signal, and the antagonist activity of an anti-GIPR antibody is measured in the presence / absence of GIP ligand, in which IC50 / EC50 and degree of inhibition / activation can be obtained (see e.g., Gault et al., Biochem. Biophys. Res. Commun. (2002) 290:1420-1426). In another embodiment, the GIPR activity assay is an insulin secretion assay in pancreatic beta cells. GIP induces glucose-dependent insulin secretion, and the antagonist activity of an anti-GIPR antibody is measured in the presence / absence of GIP ligand and the IC50 / EC50 and degree of GIP inhibition can be obtained (see e.g, Gault et al., Biochem. Biophys. Res. Commun. (2002) 290:1420-1426).

[0184] The prevention or reduction of GIP binding to GIPR achieved using the anti- GIPR antibody-GLP-1 conjugate molecule of the present disclosure results in one or more of the following pharmacodynamic effects following in vivo administration: an increase in glucose tolerance; an increase in insulin sensitivity; a decrease in body weight or a reduction in body weight gain; a decrease in fat mass or a decrease in inflammation in fat tissue; a decrease in circulating cholesterol levels; a decrease in circulating triglyceride levels; a decrease in liver steatosis or reduction of the liver triglyceride level; a decrease one or more liver enzymes, e.g., aspartate aminotransferase (AST), alanine aminotransferase (ALT), and / or alkaline phosphatase (ALP) levels. Methods for assaying and determining the preceding characteristics are known in the art and 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 antibodies disclosed herein are characterized by their binding affinity for GIPR. In one embodiment, the anti-GIPR antibodies disclosed herein that are suitable for conjugation to a GLP-1 receptor agonist disclosed herein binds human GIPR with an equilibrium dissociation constant (KD) of <200 nM, a KD of <150 nM, a KD of <100 nM, a KD of <50 nM, a KD of <10 nM, a KD of <5 nM, a KD of <2 nM, or a KD of <1 nM, e.g., as measured via a surface plasma resonance or kinetic exclusion assay technique. In one embodiment, the anti-GIPR antibody has a KD for human GIPR of 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, 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 antibodies disclosed herein have a slow dissociation rate or off-rate. For example, in one embodiment, the antagonist anti-GIPR antibody has a kd (off-rate) of lx 10'2s'1, or lx 10'3s'1, or lx 10'4s'1, or lx 10'5s'1.

[0187] In one embodiment, the antagonist anti-GIPR antibody is a monoclonal antibody, a recombinant antibody, a human antibody, or a multi-specific 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 is of the IgG isotype. In one embodiment, the antagonist anti-GIPR antibody is of the IgGl-, IgG2- IgG3- or IgG4-subclass. In one embodiment, the antibody is of the IgGl-, IgG2-, or IgG4- subclass. In one embodiment, the antibody is of the IgGl- or IgG2- subclass. In one embodiment, the antibody is of the IgGl- subclass.

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

[0190] SEQ ID NOs have been assigned to variable light chain, variable heavy chain, light chain, heavy chain, CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3 sequences ofthe exemplary antagonist anti-GIPR antibodies provided in Tables 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 Tables 3-11 below can be grouped into families based on construct name. For example, the “4B1 family” includes the constructs 4B1, 4B1.010, 4B1.011, 4B1.012, 4B1.013, 4B1.014, 4B1.015, and 4B1.016.

[0191] The various light chain and heavy chain variable regions provided herein are depicted in Tables 4 and 5, respectively. Each of these variable regions may be attached to a heavy or light chain constant regions to form a complete antibody heavy and light chain, respectively. Furthermore, each of the so generated heavy and light chain sequences may be combined to form a complete antibody structure.Table 4. Variable Light (VL) Region Amino Acid Sequences of Exemplary Anti-GIPR AntibodiesTable 5. Variable Heavy (VH) Region Amino Acid Sequences of Exemplary Anti-GIPR AntibodiesTable 6. CDRL1, CDRL2, and CDRL3 Amino Acid Sequences of Exemplary Anti-GIPR AntibodiesTable 7. CDRH1, CDRH2, and CDRH3 Amino Acid Sequences of Exemplary Anti-GIPR AntibodiesTable 8. Light Chain (LC) Amino Acid Sequences of Exemplary Anti-GIPR AntibodiesTable 9. Heavy Chain (HC) Amino Acid Sequences of Exemplary Anti- GIPR AntibodiesTable 10. Light Chain (LC) Amino Acid Sequences of Example Anti-GIPR Antibodies with Cysteine ModificationsTable 11. Heavy Chain (HC) Amino Acid Sequences of Example Anti-GIPR Antibodies with Cysteine Modifications

[0192] In one embodiment, the antagonist anti-GIPR antibody of the conjugate molecule comprises a light chain variable region, where the light chain variable region comprises light chain complementarity determining region 1 (CDRL1), a CDRL2, a CDRL3. In one embodiment, the CDRL1 of the antibody comprises an amino acid sequence of any one of SEQ ID NOs: 629-785 of Table 6; the CDRL2 comprises an amino acid sequence of any one of SEQ ID NOs: 786-942 of Table 6; and the CDRL3 comprises an amino acid sequence of any one of SEQ ID NOs: 943-1099 of Table 6. In one embodiment, the antagonist anti-GIPR antibody of the conjugate molecule comprises a heavy chain variable region, where the heavy chain variable region comprises a heavy chain complementarity determining region 1 (CDRH1), a CDRH2, a CDRH3. In one embodiment, the CDRH1 of the antibody comprises an amino acid sequence of any one of SEQ ID NOs: 1100-1256 as disclosed in Table 7; the CDRH2 comprises an amino acid sequence of any one of SEQ ID NOs: 1257-1413 of Table 7; and the CDRH3 comprises an amino acid sequence of any one of SEQ ID NOs: 1414-1570 of Table 7.

[0193] In one embodiment, the anti-GIPR antibody of the conjugate molecule comprises a light chain variable region comprising CDRL1, CDRL2, CDRL3 amino acid sequences as listed in one of the rows for one of the antibodies listed in Table 3. In one embodiment, the anti- GIPR antibody of the conjugate molecule comprises a heavy chain variable region comprising CDRH1, CDRH2, CDRH3 amino acid sequences as listed in one of the rows for one of the antibodies listed in Table 3.

[0194] In one embodiment, the anti-GIPR antibody of the conjugate molecule described herein comprises a combination of CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3 sequences as listed in one of the rows for one of the antibodies listed in Table 3. In one embodiment, the CDRL1, the CDRL2, the CDRL3, the CDRH1, the CDRH2, and the CDRH3 of the antagonist anti-GIPR antibody comprise the amino acid sequences selected from: i. 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. 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; in. SEQ ID NO: 631, SEQ ID NO: 788, SEQ ID NO: 945, SEQ ID NO: 1102, SEQID NO: 1259, and SEQ ID NO: 1416, respectively;iv. 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. 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. 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; vn. 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; vin. 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. 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. 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. 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; xn. 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; xin. 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. 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. 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. 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; xvn. 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; xvin. 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. 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. 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. 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; xxn. 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; xxin. 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. 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. 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. 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; xxvn. 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; xxvin. 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. 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; xxx. 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. 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; xxxn. 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; xxxm. 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. 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. 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. 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. 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. 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. 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. 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; xh. 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; xln. 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; xlm. 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; xhv. 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; xlv. 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. 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; xlvn. 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; xlvm. 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. 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;1. 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; li. 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;In. 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;Im. 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; liv. 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;Iv. 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;Ivi. 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;Ivn. 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;Ivm. 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; lix. 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. 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;Ixi. 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;Ixn. 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;Ixin. 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;Ixiv. 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;Ixv. 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;Ixvi. 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;Ixvn. 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;Ixviii. 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;Ixix. 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;Ixx. 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;Ixxi. 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;Ixxn. 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;Ixxm. 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;Ixxiv. 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;Ixxv. 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;Ixxvi. 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;Ixxvn. 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;Ixxviii. 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;Ixxix. 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;Ixxx. 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;Ixxxi. 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;Ixxxn. 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;Ixxxm. 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;Ixxxiv. 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;Ixxxv. 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;Ixxxvi. 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;Ixxxvii. 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;Ixxxviii. 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;Ixxxix. 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. 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. 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; xcn. 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; xcm. 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. 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. 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. 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; xcvn. 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; xcvm. 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. 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. 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. 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; cn. 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; cm. 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. 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. 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. 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; cvn. 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; cvm. 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. 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; ex. 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. 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; cxn. 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; cxin. 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. 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. 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. 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; exvn. 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; cxvin. 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. 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. 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. 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; exxn. 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; exxm. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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; cxxxm. 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. 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. 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. 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. 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. 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. 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. 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; exh. 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; cxln. 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; cxlm. 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. 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. 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. 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; cxlvn. 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; cxlvm. 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. 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. 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; ch. 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; cln. 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; elm. 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. 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; civ. 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. 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 clvn. 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 as described herein comprises light chain CDRL1, CDRL2, and CDRL3 comprising the amino acid sequences of SEQ ID NOs: 702, 859, 1016, respectively and heavy chain HCDR1, HCDR2, and HCDR3 comprising the amino acid sequences of SEQ ID NOs: 1173, 1330, and 1487, respectively. An exemplary antibody disclosed herein comprising these light and heavy chain CDRs is referred to as the 2G10 LC 1.006 anti-GIPR antibody.

[0196] In one embodiment, the anti-GIPR antibody of the conjugate molecule comprises a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-157 and a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 158-314.

[0197] In one embodiment, the antagonist anti-GIPR antibody of the conjugate molecule comprises a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-157 and a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 158-314, wherein the antibody comprises at least one cysteine conjugation site at a position selected from the group consisting of 88 (e.g., D88) of the light chain, 384 (e.g., E384) of the heavy chain, and 487 (e.g., T487) of the heavy chain, all according to AHo numbering.

[0198] In one embodiment, the anti-GIPR antibody of the conjugate molecule comprises a light chain variable region and a heavy chain variable region as listed in one of the rows for one of the antibodies listed in Table 3. In one embodiment, the anti-GIPR antibody comprises a light chain variable region and a heavy chain variable region as listed in one of the rows for one of the antibodies listed in Table 3, except that one or both of the light chain variable region andthe heavy chain variable region differs from the sequence specified in Table 4 (VL) or Table 5 (VH) at 1, 2, 3, 4, or 5 amino acid residues (combined), wherein each such sequence difference is independently either a single amino acid deletion, insertion, or substitution, with the deletions, insertions and / or substitutions resulting in no more than 1, 2, 3, 4, or 5 amino acid changes (combined) 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 light chain variable regions and heavy chain variable regions as listed in one of the rows for one of the antibodies listed in Tables 3, except that one or both of the variable regions differs 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 a sequence of amino acids that has at least 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequences of the heavy chain variable region or light chain variable domain region as specified in Table 5 or Table 4, respectively.

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

[0201] In one embodiment, the antagonist anti-GIPR antibody of the conjugate molecule as described herein comprises the light chain variable region amino acid sequence of SEQ ID NO: 74 and the heavy chain variable region amino acid sequence of SEQ ID NO: 231. An exemplary antibody disclosed herein comprising these light and heavy chain variable regions is referred to as the 2G10 LC 1.006 anti-GIPR antibody.

[0202] In one embodiment the antagonist anti-GIPR of the conjugate molecule described herein comprises a light chain comprising a sequence selected from the group consisting of SEQ ID NOs: 315-471 and a heavy chain comprising a sequence selected from the group consisting of SEQ ID NOs: 472-628, wherein the antibody or functional fragment thereof comprises a cysteine or non-canonical amino acid amino acid substitution at one or more conjugation site(s) selected from the group consisting of 88 in the antibody light chain according to AHo numbering, position 384 of the antibody heavy chain according to AHo numbering, and position 487 of the antibody heavy chain according to AHo numbering.

[0203] Antagonist anti-GIPR antibodies suitable for incorporation in the conjugate molecules described herein, i.e., molecules comprising a GLP-1 receptor agonist polypeptide conjugated to an anti-GIPR antibody, may comprise a full length light chain and a full length heavy chain as listed in one of the rows for one of the antibodies listed in Table 3. Some antibodies that are provided comprise a full length light chain and a full length heavy chain aslisted in one of the rows for one of the antibodies listed in Table 3, except that one or both of the chains differs 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 either a single amino acid deletion, insertion or substitution, with the deletions, insertions and / or substitutions resulting in no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid changes relative to the full length sequences specified in Tables 8 and 9. In one embodiment the anti-GIPR antibody comprises a full length light chain from Table 8 and / or a full length heavy chain from Table 9 with the N- terminal methionine, if present, deleted. In one embodiment the anti-GIPR antibody comprises a full length light chain from Table 8 and / or a full length heavy chain from Table 9 with the C- terminal lysine, if present, deleted. Other anti-GIPR antibodies also comprise a full length light chain and a full length heavy chain as listed in one of the rows for one of the antibodies listed in Table 3, except that one or both of the chains differs from the sequence specified in the table in that the light chain and / or heavy chain comprises or consists of a sequence of amino acids that has at least 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequences of the light chain or heavy chain sequences as specified in Table 3.

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

[0205] In one embodiment, the antagonist anti-GIPR antibody of the conjugate molecule as 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 comprises one or more cysteine amino acid substitution(s) at one or more position(s) selected from 88 of the light chain, 384 of the heavy chain, or 487 of the heavy chain, according to AHo numbering. An exemplary antibody disclosed herein comprising these light and heavy chains is referred to as the 2G10 LC1.006 anti-GIPR antibody.

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

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

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

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

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

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

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

[0213] In one embodiment, the antagonist anti-GIPR antibodies of the conjugate molecules herein are monoclonal antibodies that bind to GIPR. Monoclonal antibodies may 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 completion of the immunization schedule. The spleen cells can be immortalized using any technique known in the art, e.g., by fusing them with myeloma cells to produce hybridomas. Myeloma cells for use in hybridoma-producing fusion procedures preferably are non-antibody-producing, have high fusion efficiency, and enzyme deficiencies that render them incapable of growing in certain selective media which support the growth of only the desired fused cells (hybridomas). Examples of suitable cell lines for use in mouse fusions include Sp-20, P3- X63 / Ag8, P3-X63-Ag8.653, NSl / l.Ag 4 1, Sp210-Agl4, FO, NSO / U, MPC-11, MPC11-X45- GTG 1.7 and S194 / 5XXO Bui; examples of cell lines used in rat fusions include R210.RCY3, Y3-Ag 1.2.3, IR983F and 4B210. Other cell lines useful for cell fusions are U-266, GM1500- GRG2, LICR-L0N-HMy2 and UC729-6.

[0214] In some instances, a hybridoma cell line is produced 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 to a myeloma cell line, thereby generating hybridoma cells; establishing hybridoma cell lines from the hybridoma cells, and identifying a hybridoma cell line that produces an antibody that binds a GIPR polypeptide. 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 a hybridoma cell line can be purified using any technique known in the art. Hybridomas or mAbs may be further screened to identify mAbs with particular properties, such as the ability to antagonize GIPR activity.

[0216] Anti-GIPR chimeric and humanized antibodies are also suitable for use in the conjugate molecules described herein. The anti-GIPR antibody sequences disclosed herein may 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 that are covalently joined to produce functional immunoglobulin light or heavy chains or immunologically functional portions thereof. Generally, a portion of the heavy chain and / or light chain is identical with or homologous to a corresponding sequence in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is / are identical with or homologous to a corresponding sequence in antibodies derived from another species or belonging to another antibody class or subclass. For methods relating to chimeric antibodies, see, for example, United States Patent No. 4,816,567; and Morrison et al., 1985, Proc. Natl. Acad. Set. USA 81:6851-6855. which are hereby incorporated by reference. CDR grafting is described, for example, in United States Patent No. 6,180,370, No. 5,693,762, No. 5,693,761, No. 5,585,089, and No. 5,530,101.

[0217] Generally, the goal of making a chimeric antibody is to create a chimera in which the number of amino acids from the intended subject species is maximized. One example is the “CDR-grafted” antibody, in which the antibody comprises one or more complementarity determining regions (CDRs) from a particular species or belonging to a particular antibody class or subclass, while the remainder of the antibody chain(s) is / are identical with or homologous to a corresponding sequence in antibodies derived from another species or belonging to another antibody class or subclass. For use in humans, the variable region or selected CDRs from a rodent antibody often are grafted into a human antibody, replacing the naturally-occurring variable regions or CDRs of the human antibody.

[0218] In one aspect, the CDRs of the light and heavy chain variable regions of the antibodies provided herein are grafted to framework regions (FRs) from antibodies from the same, or a different, phylogenetic species. For example, the CDRs of the heavy and light chain variable regions VHI, VH2, VH3, VH4, VH5, VH6, VH7, VH8, VH9, VHIO, VHI 1, VH12 and / or VLI , and VL2 can be grafted to consensus human FRs. To create consensus human FRs, FRs from several human heavy chain or light chain amino acid sequences may be aligned to identify a consensus amino acid sequence. In other embodiments, the FRs of a heavy chain or light chain disclosed herein are replaced with the FRs from a different heavy chain or light chain. In one aspect, rare amino acids in the FRs of the heavy and light chains of GIPR antibodies are not replaced, while the rest of the FR amino acids are replaced. A "rare amino acid" is a specific amino acid that is in a position in which this particular amino acid is not usually found in an FR. Alternatively, the grafted variable regions from the one heavy or light chain may be used with a constant region that is different from the constant region of that particular heavy or light chain as disclosed herein.

[0219] Human antagonist anti-GIPR antibodies are also provided. Methods are available for making human antibodies specific for a given antigen without exposing human beings to the antigen. One specific means provided for implementing the production of human antibodies is the "humanization" of the mouse humoral immune system. Introduction of human immunoglobulin (Ig) loci into mice in which the endogenous Ig genes have been inactivated is one means of producing human monoclonal antibodies (mAbs) in mouse, an animal that can be immunized with any desirable antigen. Using human antibodies can minimize the immunogenicand allergic responses that can sometimes be caused by administering mouse or mouse-derived mAbs to humans as therapeutic agents.

[0220] Human antibodies can be produced by immunizing transgenic animals (usually mice) that are capable of producing a repertoire of human antibodies in the absence of endogenous immunoglobulin production. Antigens for this purpose typically have six or more contiguous amino acids, and optionally are conjugated to a carrier, such as a hapten. See, e.g., Jakobovits et al., 1993, Proc. Natl. Acad. Sci. USA 90:2551-2555; Jakobovits et al., 1993, Nature 362:255-258; and Bruggermann et al., 1993, Year in Immunol. T. . In one example of such a method, transgenic animals are produced by incapacitating the endogenous mouse immunoglobulin loci encoding the mouse heavy and light immunoglobulin chains therein, and inserting into the mouse genome large fragments of human genome DNA containing loci that encode human heavy and light chain proteins. Partially modified animals, which have less than the full complement of human immunoglobulin loci, are then cross-bred to obtain an animal having all of the desired immune system modifications. When administered an immunogen, these transgenic animals produce antibodies that are immunospecific for the immunogen but have human rather than murine amino acid sequences, including the variable regions. For further details of such methods, see, for example, WO96 / 33735 and W094 / 02602. Additional methods relating to transgenic mice for making human antibodies are described in United States Patent No. 5,545,807; No. 6,713,610; No. 6,673,986; No. 6,162,963; No. 5,545,807; No. 6,300,129;No. 6,255,458; No. 5,877,397; No. 5,874,299 and No. 5,545,806; in PCT publications WO91 / 10741, W090 / 04036, and in EP 546073B1 and EP 546073 Al.

[0221] Suitable human antibodies can alternatively be derived from phage-display libraries (as disclosed in Hoogenboom et al., 1991, J. Mol. Biol. 227:381; and Marks et al., 1991, J. Mol. Biol. 222:581). Phage display techniques mimic immune selection through the display of antibody repertoires on the surface of filamentous bacteriophage, and subsequent selection of phage by their binding to an antigen of choice. One such technique is described in PCT Publication No. WO 99 / 10494 (hereby incorporated by reference).

[0222] The anti-GIPR antibody used in the molecules described herein may be prepared by any of a number of conventional techniques. For example, antibodies can be produced by recombinant expression systems. See, e.g., Monoclonal Antibodies, Hybridomas: A New Dimension in Biological Analyses, Kennet et al. (eds.) Plenum Press, New York (1980); andAntibodies: A Laboratory Manual, Harlow and Lane (eds.), Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1988).

[0223] In one embodiment, the anti-GIPR antibodies provided herein are expressed in hybridoma cell lines or in cell lines other than hybridomas. Expression constructs encoding the anti-GIPR antibodies can be used to transform a mammalian, insect or microbial host cell. Transformation can be performed using any known method for introducing polynucleotides into a host cell, including, for example, packaging the polynucleotide in a virus or bacteriophage and transducing a host cell with the construct by transfection procedures known in the art, as exemplified by United States Patent No. 4,399,216; No. 4,912,040; No. 4,740,461;No. 4,959,455. The choice of transformation procedure used will depend upon which type of host cell is being transformed. Methods for introduction of heterologous polynucleotides into mammalian cells are 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 the polynucleotide(s) in liposomes, mixing nucleic acid with positively-charged lipids, and direct microinjection of the DNA into nuclei.

[0224] Recombinant expression constructs typically comprise a nucleic acid molecule encoding a polypeptide comprising 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., CHI, CH2 and / or CH3); and a heavy chain variable region of an anti-GIPR antibody. These nucleic acid sequences are inserted into an appropriate expression vector using standard ligation techniques. In one embodiment, the heavy or light chain constant region is appended to the C-terminus of the anti-GIPR specific heavy or light chain variable region and is ligated into an expression vector. The vector is typically selected to be functional in the particular host cell employed (i.e., the vector is compatible with the host cell machinery, permitting amplification, and / or expression of the gene can occur).

[0225] Typically, expression vectors used in any of the host cells will contain sequences for plasmid maintenance and for cloning and expression of exogenous nucleotide sequences. Such sequences, collectively referred to as “flanking sequences,” can include one or more of the following nucleotide sequences: a promoter, one or more enhancer sequences, an origin of replication, a transcriptional termination sequence, a complete intron sequence containing a donor and acceptor splice site, a sequence encoding a leader sequence for polypeptide secretion,a ribosome binding site, a polyadenylation sequence, a polylinker region for inserting the nucleic acid encoding the polypeptide to be expressed, and a selectable marker element.

[0226] Flanking sequences may be homologous (i.e., from the same species and / or strain as the host cell), heterologous (i.e., from a species other than the host cell species or strain), hybrid (i.e., a combination of flanking sequences from more than one source), synthetic, or native. As such, the source of a flanking sequence may be any prokaryotic or eukaryotic organism, any vertebrate or invertebrate organism, or any plant, provided that the flanking sequence is functional in, and can be activated by, the host cell machinery.

[0227] Flanking sequences useful in the vectors can be obtained by methods known in the art. Typically, flanking sequences will have been previously identified by mapping and / or by restriction endonuclease digestion and can thus be isolated from the proper tissue source using the appropriate restriction endonucleases. In some cases, the full nucleotide sequence of a flanking sequence may be known. The flanking sequence may be synthesized using conventional methods for nucleic acid synthesis or cloning.

[0228] An origin of replication is typically a part of commercially available prokaryotic expression vectors; the origin of replication aids in the amplification of the vector in a host cell. If the vector of choice does not contain an origin of replication site, one may be chemically synthesized based on a known sequence and ligated into the vector. For example, the origin of replication from the plasmid pBR322 (New England Biolabs, Beverly, MA) is suitable for most gram-negative bacteria and various viral origins (e.g., SV40, polyoma, adenovirus, vesicular stomatitus virus (VSV), or papillomaviruses, such as, e.g., HPV or BPV). Generally, the origin of replication component is not needed for mammalian expression vectors (for example, the SV40 origin is often used only because it also contains the virus early promoter).

[0229] A transcription termination sequence is typically located 3' to the end of a polypeptide coding region and serves to terminate transcription. Usually, a transcription termination sequence in prokaryotic cells is a G-C rich fragment followed by a poly-T sequence. While the sequence is easily cloned from a library or even purchased commercially as part of a vector, it can also be readily synthesized using conventional methods for nucleic acid synthesis.

[0230] A selectable marker gene encodes a protein necessary for the survival and growth of a host cell grown in a selective culture medium. Typical selection marker genes encode proteins that (a) confer resistance to antibiotics or other toxins, e.g., ampicillin, tetracycline, orkanamycin for prokaryotic host cells; (b) complement auxotrophic deficiencies of the cell; or (c) supply critical nutrients not available from complex or defined media. Specific selectable markers are the kanamycin resistance gene, the ampicillin resistance gene, and the tetracycline resistance gene. Advantageously, a neomycin resistance gene may also be used for selection in both prokaryotic and eukaryotic host cells.

[0231] Other selectable genes may be used to amplify the gene that will be expressed. Amplification is the process wherein genes that are required for production of a protein critical for growth or cell survival are reiterated in tandem within the chromosomes of successive generations of recombinant cells. Examples of suitable selectable markers for mammalian cells include dihydrofolate reductase (DHFR) and promoter-less thymidine kinase genes. Mammalian cell transformants are placed under selection pressure wherein only the transformants are uniquely adapted to survive by virtue of the selectable gene present in the vector. Selection pressure is imposed by culturing the transformed cells under conditions in which the concentration of selection agent in the medium is successively increased, thereby leading to the amplification of both the selectable gene and the DNA that encodes another gene, such as an antibody that binds GIPR polypeptide. As a result, increased quantities of a polypeptide such as an anti-GIPR antibody are synthesized from the amplified DNA.

[0232] A ribosome-binding site is usually necessary for translation initiation of mRNA and is characterized by a Shine-Dalgarno sequence (prokaryotes) or a Kozak sequence (eukaryotes). The element is typically located 3' to the promoter and 5' to the coding sequence of the polypeptide to be expressed.

[0233] In some cases, such as where glycosylation is desired in a eukaryotic host cell expression system, one may manipulate the various pre- or pro-sequences to improve glycosylation or yield. For example, one may alter the peptidase cleavage site of a particular signal peptide, or add prosequences, which also may affect glycosylation. The final protein product may have, in the -1 position (relative to the first amino acid of the mature protein), one or more additional amino acids incident to expression, which may not have been totally removed. For example, the final protein product may have one or two amino acid residues found in the peptidase cleavage site, attached to the amino-terminus. Alternatively, use of some enzyme cleavage sites may result in a slightly truncated form of the desired polypeptide, if the enzyme cuts at such area within the mature polypeptide.

[0234] Expression and cloning will typically contain a promoter that is recognized by the host organism and operably linked to the molecule encoding the anti-GIPR antibody. Promoters are untranscribed sequences located upstream (i.e., 5') to the start codon of a structural gene (generally within about 100 to 1000 bp) that control transcription of the structural gene. Promoters are conventionally grouped into one of two classes: inducible promoters and constitutive promoters. Inducible promoters initiate increased levels of transcription from DNA under their control in response to some change in culture conditions, such as the presence or absence of a nutrient or a change in temperature. Constitutive promoters, on the other hand, uniformly transcribe a gene to which they are operably linked, that is, with little or no control over gene expression. A large number of promoters, recognized by a variety of potential host cells, are known. A suitable promoter is operably linked to the DNA encoding heavy chain or light chain comprising a GIPR antibody by removing the promoter from the source DNA by restriction enzyme digestion and inserting the desired promoter sequence into the vector.

[0235] Suitable promoters for use with yeast hosts are also known in the art. Yeast enhancers are advantageously used with yeast promoters. Suitable promoters for use with mammalian host cells are known and include, but are not limited to, those obtained from the genomes of viruses such as polyoma virus, fowlpox virus, adenovirus (such as, e.g., Adenovirus 2), bovine papilloma virus, avian sarcoma virus, cytomegalovirus, retroviruses, hepatitis-B virus, and Simian Virus 40 (SV40). Other suitable mammalian promoters include, but are not limited to, heterologous mammalian promoters, for example, heat-shock promoters and the actin promoter.

[0236] An enhancer sequence may be inserted into the vector to increase transcription of DNA encoding the light chain or heavy chain of an anti-GIPR antibody by higher eukaryotes. Enhancers are cis-acting elements of DNA, usually about 10-300 bp in length, which act on the promoter to increase transcription. Enhancers are relatively orientation and position independent, having been found at positions both 5' and 3' to the transcription unit. Several enhancer sequences available from mammalian genes are known (e.g., globin, elastase, albumin, alpha- feto-protein and insulin). Alternatively, an enhancer from a virus can be used. The SV40 enhancer, the cytomegalovirus early promoter enhancer, the polyoma enhancer, and adenovirus enhancers known in the art are non-limiting examples of enhancing elements for the activation of eukaryotic promoters. While an enhancer may be positioned in the vector either 5' or 3' to acoding sequence, it is typically located at a site 5' from the promoter. A sequence encoding an appropriate native or heterologous signal sequence (leader sequence or signal peptide) can be incorporated into an expression vector, e.g., to promote extracellular secretion of the antibody. The choice of signal peptide or leader depends on the type of host cells in which the antibody is to be produced, and a heterologous signal sequence can replace the native signal sequence. Non-limiting examples of signal peptides that are functional in mammalian host cells include the following: the signal sequence for interleukin-7 (IL-7) described in US Patent No. 4,965,195; the signal sequence for interleukin-2 receptor described in Cosman etNature 312:768; the interleukin-4 receptor signal peptide described in EP Patent No. 0367 566; the type I interleukin- 1 receptor signal peptide described in U.S. Patent No. 4,968,607; the type II interleukin-1 receptor signal peptide described in EP 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 may be constructed from a starting vector such as a commercially available vector. Such vectors may or may not contain all of the desired flanking sequences. Where one or more of the flanking sequences described herein are not already present in the vector, they may be individually obtained and ligated into the vector. Methods used for obtaining each of the flanking sequences are known to one 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 coding sequence; the oligonucleotide sequence encodes polyHis (such as hexaHis), or another “tag” such as FLAG®, HA (hemagglutinin influenza virus), or myc, for which commercially available antibodies exist. This tag is typically fused to the polypeptide upon expression of the polypeptide, and can serve as a means for affinity purification or detection of the antibody from the host cell. Affinity purification can be accomplished, for example, by column chromatography using antibodies against the tag as an affinity matrix. Optionally, the tag can subsequently be removed from the purified antibody by various means such as using certain peptidases for cleavage.

[0240] After the vector has been constructed and a nucleic acid molecule encoding a light chain, a heavy chain, or a light chain and a heavy chain has been inserted into the proper site of the vector, the completed vector may be inserted into a suitable host cell for amplification and / orpolypeptide expression. The transformation of an expression vector encoding an antibody into a selected host cell may be accomplished by conventional methods including, but not limited to, transfection, infection, calcium phosphate co-precipitation, electroporation, microinjection, lipofection, DEAE-dextran mediated transfection, or other known techniques. The method selected will in part be a function of the type of host cell to be used.

[0241] A host cell, when cultured under appropriate conditions, synthesizes an anti-GIPR antibody that can subsequently be collected from the culture medium (if the host cell secretes it into the medium) or directly from the host cell producing it (if it is not secreted). The selection of an appropriate host cell will depend upon various factors, such as, e.g., desired expression levels, polypeptide modifications that are desirable or necessary for activity (such as, e.g., glycosylation or phosphorylation), and ease of folding into a biologically active molecule.

[0242] Mammalian cell lines available as hosts for expression are 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, baby hamster kidney (BHK) cells, monkey kidney cells (COS), human hepatocellular carcinoma cells (e.g., Hep G2), and a number of other cell lines. In one embodiment, a host cell line can be selected by determining which cell lines have high expression levels and constitutively produce the desired anti-GIPR antibody. In one embodiment, a cell line from the B cell lineage that does not make its own antibody but has a capacity to make and secrete a heterologous antibody can be selected.

[0243] Additionally, in one embodiment, a mammalian cell line modified to provide for reduced cleavage of peptides that will be conjugated to polypeptides expressed by the cells (e.g., a cathepsin D knock-out cell line) can be used. In one embodiment, a mammalian cell line (e.g., a CHO cell line) in which both alleles of cathepsin D are knocked out (e.g., using CRISPR or zinc-finger technology) can be used. An example of a cathepsin D knock-out cell that can be used to produce an antibody-peptide conjugate of the disclosure is described in WO 2023 / 086790, which is incorporated by reference herein.PHARMACEUTICAL COMPOSITIONS

[0244] While it may be possible to administer a GLP-1 receptor agonist polypeptide or anti-GIPR / GLP-1 conjugate molecule disclosed herein alone in the uses described herein, theGLP-1 receptor agonist polypeptide or conjugate molecule will normally be administered as an active ingredient in a pharmaceutical composition. Thus, further provided herein is a pharmaceutical composition comprising a GLP-1 receptor agonist polypeptide or anti- GIPR / GLP-1 conjugate molecule disclosed herein and a pharmaceutically acceptable excipient. Non-limiting examples of pharmaceutically acceptable excipients include calcium carbonate, calcium phosphate, sugars (e.g., lactose, glucose, or sucrose), starches, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols, and physiologically compatible solvents. See, e.g., Remington: The Science and Practice of Pharmacy, Volume I and Volume II, twenty-second edition, edited by Loyd V. Allen Jr., Philadelphia, PA, Pharmaceutical Press, 2012;Pharmaceutical Dosage Forms (Vol. 1-3), Liberman et al., Eds., Marcel Dekker, New York, 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), first edition, edited by GD Tovey, Royal Society of Chemistry, 2018.

[0245] In some cases, the pharmaceutical composition described herein comprises a therapeutically effective amount of a GLP-1 receptor agonist polypeptide or anti-GIPR / GLP-1 conjugate molecule disclosed herein. In one embodiment, the pharmaceutical composition is made in the form of a dosage unit containing a particular amount of the active ingredient.

[0246] The GLP-1 receptor agonist polypeptides or anti-GIPR / GLP-1 conjugate molecules disclosed herein may be administered by any suitable route in the form of a pharmaceutical composition adapted to such a route and in a dose effective for the treatment intended. The polypeptides, molecules, and compositions presented herein may, for example, be administered orally, mucosally, transdermally, parentally, intravenously, intraperitoneally, subcutaneously, intramuscularly, by infusion techniques, in dosage unit formulations containing conventional pharmaceutically acceptable excipients. For example, in one embodiment, a pharmaceutical composition disclosed herein may be provided for peripheral administration, such as parenteral (e.g., subcutaneous, intravenous, intramuscular), continuous infusion (e.g., intravenous drip, intravenous bolus, intravenous infusion), topical, nasal, or oral administration.

[0247] Pharmaceutical compositions disclosed herein may be sterilized by conventional sterilization techniques or may be sterile-filtered. In one embodiment, such compositions comprise sterile water. In one embodiment, such compositions can contain pharmaceuticallyacceptable auxiliary substances as required to approximate physiological conditions, such as, e.g., pH buffering agents (e.g., an acetic acid 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 one 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 at a pH in the range of 3.0 to 8.0 (such as, 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 form of repository or “depot” slow release preparation may be used so that therapeutically effective amounts of the preparation are delivered into the bloodstream over many hours or days following subcutaneous injection, transdermal injection, or other delivery method. The desired isotonicity may be accomplished using sodium chloride or other pharmaceutically acceptable excipients, such as, e.g., dextrose, boric acid, sodium tartrate, propylene glycol, polyols (such as, e.g., mannitol and sorbitol), or other inorganic or organic solutes.METHODS OF TREATMENT

[0252] The GLP-1 receptor agonist polypeptides and conjugate molecules comprising these GLP-1 receptor agonist polypeptides, e.g., the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecules, as disclosed herein are useful for reducing body weight of a subject in need thereof. The GLP-1 receptor agonist polypeptides and conjugate molecules comprising these GLP-1 receptor agonist polypeptides as disclosed herein are also useful for reducing food intake in a subject in need thereof. The GLP-1 receptor agonist polypeptides and conjugate molecules comprising these GLP-1 receptor agonist polypeptides as disclosed herein are also useful for reducing hypertension and / or blood sugar levels in a subject in need thereof. The GLP-1 receptor agonist polypeptides and conjugate molecules comprising these GLP-1 receptor agonist polypeptides are also useful for treating obesity in a subject in need thereof, and for treating andpreventing obesity-related conditions in a subject in need thereof. Obesity-related conditions include, without limitation, cardiovascular disease, in particular hypertension, heart failure, and atherosclerotic cardiovascular (ASCVD); sleep apnea; dyslipidemia; chronic kidney disease; and metabolic dysfunction-associated steatohepatitis (MASH). The GLP-1 receptor agonist polypeptides and conjugate molecules comprising these GLP-1 receptor agonist polypeptides are also useful for treating type 2 diabetes in a subject in need thereof, and for treating and preventing conditions associated with type 2 diabetes in a subject in need thereof. Conditions associated with type 2 diabetes include, without limitation, hypertension, high blood sugar, cardiovascular disease, diabetic kidney disease, and diabetic kidney failure.

[0253] Accordingly, in one aspect, the present disclosure provides a method for preventing or treating obesity, obesity-related conditions, type 2 diabetes, and / or type 2 diabetes related conditions in a subject in need thereof. In one embodiment, this method involves administering, to the subject, the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule disclosed herein, or a pharmaceutical composition comprising the same, 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 pharmaceutical composition comprising the same, 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 pharmaceutical composition comprising the same, is administered to the subject at a dose of about 21 mg to about 840 mg every month, at a dose of about 21 mg to about 840 mg every one and a half months, 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 obesity. In one embodiment, the subject has 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 or is at risk of having a cardiovascular disease. In one embodiment, the subject has 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 kidney failure. In one embodiment, the subject has MASH. In one embodiment, the subject has type 2 diabetes. In one embodiment, the subject a type 2 diabetes related condition. In one embodiment, the subject has hypertensionand / or high blood sugar. In one embodiment, the subject has diabetic kidney disease or diabetic kidney failure. In one embodiment, the subject has cardiovascular disease.

[0254] In another aspect, the present disclosure provides a method for reducing body weight or reducing food intake in a subject in need thereof. This method involves administering, to the subject, the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule disclosed herein, or pharmaceutical composition comprising the same, 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 pharmaceutical composition comprising the same, 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 pharmaceutical composition comprising the same, is administered to the subject at a dose of about 21 mg to about 840 mg every month, at a dose of about 21 mg to about 840 mg every one and a half months, 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 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 or is at risk of having a cardiovascular disease. In one embodiment, the subject has 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 kidney failure. In one embodiment, the subject has MASH. In one embodiment, the subject has type 2 diabetes. In one embodiment, the subject a type 2 diabetes related condition. In one embodiment, the subject has hypertension and / or high blood sugar. In one embodiment, the subject has diabetic kidney disease or diabetic kidney failure. In one embodiment, the subject has cardiovascular disease.

[0255] In another aspect, the present disclosure provides a method for reducing blood pressure and / or reducing blood sugar levels in a subject in need thereof. This method involves administering, to the subject, the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule disclosed herein, or pharmaceutical composition comprising the same, 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 pharmaceutical composition comprising the same, is administered to the subject at adose 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 pharmaceutical composition comprising the same, is administered to the subject at a dose of about 21 mg to about 840 mg every month, at a dose of about 21 mg to about 840 mg every one and a half months, 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 obesity. In one embodiment, the subject has 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 or is at risk of having a cardiovascular disease. In one embodiment, the subject has 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 kidney failure. In one embodiment, the subject has MASH. In one embodiment, the subject has type 2 diabetes. In one embodiment, the subject a type 2 diabetes related condition. In one embodiment, the subject has hypertension and / or high blood sugar. In one embodiment, the subject has diabetic kidney disease or diabetic kidney failure. In one embodiment, the subject has cardiovascular disease.

[0256] In another aspect, the present disclosure provides the use of the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule disclosed herein for preparation of a medicament for preventing or treating obesity, an obesity related condition, type 2 diabetes, or a type 2 diabetes related condition in a subject in need thereof. 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 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 every month, every one and a half months, every two months, or every three month. In one embodiment, the subject has obesity. In one embodiment, the subject has or is at risk of having an obesity related condition. In one embodiment, the subject has from sleep apnea. In one embodiment, the subject has dyslipidemia. In one embodiment, the subject has or is at risk of having a cardiovascular disease. In one embodiment, the subject has or is at risk of having ASCVD. In one embodiment, thesubject has heart failure. In one embodiment, the subject has hypertension. In one embodiment, the subject has chronic kidney failure. In one embodiment, the subject has MASH. In one embodiment, the subject has type 2 diabetes. In one embodiment, the subject a type 2 diabetes related condition. In one embodiment, the subject has hypertension and / or high blood sugar. In one embodiment, the subject has diabetic kidney disease or diabetic kidney failure. In one embodiment, the subject has cardiovascular disease.

[0257] In another aspect, the present disclosure is directed to the use of the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule disclosed herein for preparation of a medicament for reducing body weight or reducing food intake in a subject in need thereof. 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 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 every month, every one and a half months, every two months, or every three month. In one embodiment, the subject has obesity. In one embodiment, the subject has 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 or is at risk of having a cardiovascular disease. In one embodiment, the subject has 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 kidney failure. In one embodiment, the subject has MASH. In one embodiment, the subject has type 2 diabetes. In one embodiment, the subject a type 2 diabetes related condition. In one embodiment, the subject has hypertension and / or high blood sugar. In one embodiment, the subject has diabetic kidney disease or diabetic kidney failure. In one embodiment, the subject has cardiovascular disease.

[0258] In another aspect, the present disclosure is directed to the use of the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule disclosed herein for preparation of a medicament for reducing blood pressure and / or reducing blood sugar levels in a subject in need thereof. 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 every four weeks, every six weeks, every eight weeks, or everytwelve weeks. In one embodiment, the medicament, formulated at a dose of about 21 mg to about 840 mg, is administered to the subject every month, every one and a half months, every two months, or every three month. In one embodiment, the subject has obesity. In one embodiment, the subject has 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 or is at risk of having a cardiovascular disease. In one embodiment, the subject has 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 kidney failure. In one embodiment, the subject has MASH. In one embodiment, the subject has type 2 diabetes. In one embodiment, the subject a type 2 diabetes related condition. In one embodiment, the subject has hypertension and / or high blood sugar. In one embodiment, the subject has diabetic kidney disease or diabetic kidney failure. In one embodiment, the subject has cardiovascular disease.

[0259] In one embodiment, the weekly and monthly dosing schedules of the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule is similar among subjects regardless of body weight. Alternatively, the monthly dose of the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule may be based upon a subject’s body weight.

[0260] The dose of the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule described herein can be administered in a single administration or divided among multiple administrations over the course of the dosing frequency period. For example, in one embodiment, the therapeutically effective dose of anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule is administered in a single administration each frequency period. Thus, in one embodiment, any of the doses of anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule described herein can be administered to the subject once a month (QM dosing). Subjects on a QM dosing regimen are typically administered 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 as a bolus injection, for example, using a self-injection device as described herein.

[0261] In alternative embodiments, the doses of the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule are divided among two or more administrations over the course ofthe dosing frequency period. For example, for a dosing frequency period of one month, the monthly dose may be divided into four doses and administered on a weekly basis or divided into two doses and administered every two weeks. Any of the doses of anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule described herein can be divided among two or more administrations. The number of administrations and intervening interval can be adjusted for a particular subject depending on the severity of the condition (e.g., obesity, type 2 diabetes, or an obesity or type 2 diabetes related condition), the age of the subject, the physical health of the subject, concomitant treatment with other medications, and / or the presence of other conditions

[0262] In one embodiment, a subject suitable for treatment in accordance with the methods and compositions described herein is a subject who has or is diagnosed with type 2 diabetes. In one embodiment, the subject having type 2 diabetes is a subject having a hemoglobin A1C (HbAlc) level of > 6.5% and < 10% (48 to 86 mmol / mol), where administration of the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule at the dose and frequency disclosed herein lowers the subject’s HbAlc level. In one embodiment, administration of the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule at the dose and frequency disclosed herein lowers the subject’s HbAlc level by about 0.5%, about 1%, about 1.5%, about 2%, or >2%. In one embodiment, a subject suitable for treatment in accordance with the methods and compositions described herein is a subject having type 2 diabetes who has been treated with metformin, a sulfonylurea, or a sodium-glucose cotransporter 2 (SGLT2) inhibitor as monotherapy or combination therapy.

[0263] In one embodiment, the subject has obesity, but does not have type 2 diabetes. In one embodiment, the subject has not previously received therapy for obesity.

[0264] In one embodiment, a subject suitable for treatment in accordance with the method and compositions described herein is a subject having a body mass index (“BMI”) of > 25 kg / m2In one embodiment, the subject has a BMI of > 27 kg / m2In one embodiment, the subject has a BMI of > 30 kg / m2. Body Mass Index (BMI) is a person’s weight in kilograms (or pounds) divided by the square of height in meters (or feet). A high BMI can indicate high body fatness. In one embodiment, the subject has a BMI of > 35 kg / m2. In one embodiment, the subject has a BMI of > 40 kg / m2. In one embodiment, the subject has a BMI greater than 25 kg / m2 and less than 40 kg / m2. In one embodiment, the subject has a BMI greater than 27 kg / m2 and less than 40 kg / m2. In one embodiment, the subject has a BMI greater than 30 kg / m2 andless than 35 kg / m2. The measurements can also be converted to lbs / in2. In one embodiment, the subject having a BMI of > 25 kg / m2, > 27 kg / m2, or > 30 kg / m2further comprises one or more obesity associated conditions, e.g., hypertension, dyslipidemia, sleep apnea, or cardiovascular disease.

[0265] In one embodiment, treating obesity comprises promoting weight loss in a subject. Accordingly, the present disclosure is directed to a method of treating obesity wherein the subject loses about 5% of body weight over 52 weeks, about 10% of body weight over 52 weeks, about 15% of body weight over 52 weeks, about 20% of body weight over 52 weeks, about 25% of body weight over 52 weeks, or about 30% of body weight over 52 weeks. “Body weight” as used in the forgoing context is referring to a subject’s weight before the first administration of the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule disclosed herein, or a pharmaceutical composition comprising the same.

[0266] In one embodiment, treating obesity comprises maintaining a subject’s body weight by administering a maintenance dose of the anti-GIPR antibody / GLP-1 receptor agonist to subject. Accordingly, the present disclosure is directed to a method of maintaining a subject’s body weight wherein the subject’s body weight does not fluctuate more than ±0.5% of goal body weight, ±1.0% of goal body weight, ±1.5% of goal body weight, ±2.0% of goal body weight, ±2.5% of goal body weight, ±3.0% of goal body weight, ±3.5% of goal body weight, ±4.0% of goal body weight, ±4.5% of goal body weight, or ±5.0% of goal body weight. “Goal body weight” as used in the foregoing context refers to the body weight a subject means to maintain. A maintenance dose can be the same amount and frequency as a dose that promotes weight loss. Alternatively, a maintenance dose can be 1) a lower amount of the anti-GIPR antibody / GLP-1 receptor agonist conjugate than a dose that promotes weight loss, 2) a dose administered less frequently than a dose that promotes weight loss, or 3) a dose that is both a lower amount than a dose that promotes weight loss and administered less frequently than a dose that promotes weight loss.

[0267] In one embodiment of the methods described herein, the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule is administered to the subject parenterally. Parenteral administration includes intraperitoneal, intramuscular, intravenous, intradermal, and subcutaneous administration. In a preferred embodiment, the pharmaceutical composition comprising a therapeutically effective amount of an anti-GIPR antibody / GLP-1 receptor agonistconjugate molecule is administered to the subject subcutaneously. In these and other embodiments in which the pharmaceutical composition is administered by parenteral injection, the pharmaceutical composition can be administered to the subject with a syringe. In one embodiment, the syringe is pre-filled with the pharmaceutical composition. In other embodiments in which the pharmaceutical composition is administered to the subject by parenteral injection, such as subcutaneous injection, the pharmaceutical composition is administered with an injection device, including devices for self-administration. Such devices are commercially available and include, but are not limited to, autoinjectors, dosing 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 methods of the invention include autoinjectors (e.g., SureClick®, EverGentle®, Avanti®, DosePro®, Molly®, and Leva®), pen injection devices (e.g., Madie® pen injector, DCPTMpen injector, BD Vystra™ disposable pen, BD™ reusable pen), and pre-filled syringes (BD Sterifill™, BD Hypak™, prefilled syringes from Baxter). In one embodiment, the pharmaceutical composition comprising a therapeutically effective amount of an anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule is administered to the subject with a pre- filled syringe. In one embodiment, the pharmaceutical composition comprising a therapeutically effective amount of an anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule is administered to the subject with an autoinjector. In one embodiment, the injection volume is about 3mL or less, about 2mL 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 over the course of a set treatment period. A “treatment period” begins upon administration of a first dose of the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule and ends upon administration of a final dose of the conjugate molecule. The treatment period may comprise from about 1 month to about 36 months, such as about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 18 months, about 21 months, about 24 months, about 27 months, about 30 months, or about 33 months. In one embodiment, the treatment period is about 6 months. In one embodiment, thetreatment period is about 7 months. In one embodiment, the treatment period is about 12 months. In one embodiment, the treatment period can be longer than 36 months, such as 48 or 60 or 64 months or more.

[0269] Administration of an anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule according to the methods disclosed herein preferably causes few or no adverse side effects in the subject being treated. As used herein, the term “adverse side effect” refers to any abnormality, defect, mutation, lesion, degeneration, harmful or undesirable reaction, symptom, or injury, which may be caused by taking the drug. In one embodiment, administration of the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule does not substantially 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, reduced exercise tolerance, tremor, paresthesia, teratogenicity, and cognitive difficulty. In one embodiment, administration of the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule is associated with a lower rate or number of adverse side effects as compared to the rate 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 rate of discontinuation due to adverse side effects as compared to the rate of discontinuation due to adverse side effects associated with other weight loss treatments. In one embodiment, the number and type of adverse side effects associated with administration of the anti-GIPR antibody / GLP-1 receptor agonist conjugate molecule is not statistically different than the number and type of adverse side effects associated with administration of placebo.EMBODIMENTS

[0270] Embodiment 1 is a human glucagon-like peptide 1 (GLP-1) receptor agonist polypeptide comprising the amino acid sequence of H[Aib]EGTFTSDYSSYLEEXi7AAX2oEFIX24WLX27X28GGG (SEQ ID NO: 1575), wherein Xnis Q, K, E, or R; X20 is K, R, Q, or homoarginine (hArg); X24 is A, E, Q, D, d-Ala, G, N, K, (lS,2S)-2-Aminocyclopentanecarboxylic acid (ACPC), (3S,4R)-4-Amino-3- pyrrolidinecarboxylic acid (APCA), T, S, or Y; X27 is V, K, Aib, N, S, T, Y, Q, or R; and X28 is K, E, R, Q, D, N, G, S, or T; and wherein the GLP-1 receptor agonist polypeptide does not comprise the amino acid sequence of SEQ ID NO: 1574 (H[Aib]EGTFTSDYSSYLEEQAAKEFIAWLVKGGG).

[0271] Embodiment 2 is the GLP-1 receptor agonist polypeptide of embodiment 1, wherein the GLP-1 receptor agonist polypeptide comprises the amino acid sequence of H[Aib]EGTFTSD¥SS¥LEEXi7AAX2oEFIX24WLX27X28GGG (SEQ ID NO: 1576), wherein Xi7is Q or K; X20 is K or R; X24 is A, E, or Q; X27 is V or K; and X28 is K, E, or R.

[0272] Embodiment 3 is the GLP-1 receptor agonist polypeptide of embodiment 1, wherein the GLP-1 receptor agonist polypeptide comprises the amino acid sequence of H[Aib]EGTFTSDYSSYLEEXi7AAREFIX24WLX27X28GGG (SEQ ID NO: 1577) wherein Xj7is Q or K; X24 is A, E, or Q; X27 is V or K; and X28is K, E, or R.

[0273] Embodiment 4 is the GLP-1 receptor agonist polypeptide of embodiment 1, wherein the GLP-1 receptor agonist polypeptide comprises the amino acid sequence of H[Aib]EGTFTSDYSSYLEEXi7AAX2oEFIX24WLKX28GGG (SEQ ID NO: 1578), wherein Xi7is Q or K; X20 is K or R; X24 is A, E, or Q; and X28is K, E, or R.

[0274] Embodiment 5 is the GLP-1 receptor agonist polypeptide of any one of embodiments 1-4, where 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] Embodiment 6 is a human glucagon-like peptide 1 (GLP-1) receptor agonist polypeptide, wherein: the polypeptide comprises 31 amino acids and comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 1580; and wherein the polypeptide comprises an a-amino-isobutyric acid (Aib) at position 2; a tyrosine at position 10; a glutamic acid at positions 16, 24, and 28; an arginine at position 20; a lysine at positions 17 and 27; and a glycine at position 31.

[0276] Embodiment 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 comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 1579; and wherein the GLP-1 receptor agonist polypeptide comprises an Aib at position 2; a tyrosine at position 10; a glutamic acid at positions 16 and 24; an arginine at position 20; a lysine at positions IT, and a glycine at position 30.

[0277] Embodiment 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 comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 1581; and wherein the GLP-1 receptor agonist polypeptide comprises an Aib at position 2; a tyrosine at position 10;a glutamic acid at positions 16 and 24; an arginine at position 20; a lysine at positions 17, 27; and a glycine at position 30.

[0278] Embodiment 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 comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 1583; and wherein the GLP-1 receptor agonist polypeptide comprises an Aib at position 2; a tyrosine at position 10; a glutamic acid at positions 16 and 28; an arginine at position 20; a lysine at positions 17, 27; a glutamine at position 24; and a glycine at position 30.

[0279] Embodiment 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 comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 1582; and wherein the GLP-1 receptor agonist polypeptide comprises an Aib at position 2; a tyrosine at position 10; a glutamic acid at positions 16 and 24; an arginine at positions 20 and 28; a lysine at positions IT, and a glycine at position 30.

[0280] Embodiment 11 is a molecule comprising: a first human glucagon-like peptide 1 (GLP-1) receptor agonist polypeptide comprising the amino acid sequence of H[Aib]EGTFTSD¥SS¥LEEXi7AAX2oEFIX24WLX27X28GGG (SEQ ID NO: 1575), wherein Xi7is Q, K, E, or R; X20 is K, R, Q, or homoarginine (hArg); X24 is A, E, Q, D, d-Ala, G, N, K, (lS,2S)-2- Aminocyclopentanecarboxylic acid (ACPC), (3S,4R)-4-Amino-3-pyrrolidinecarboxylic acid (APCA), T, S, or Y; X27 is V, K, Aib, N, S, T, Y, Q, or R; and X28 is K, E, R, Q, D, N, G, S, or T, and wherein the GLP-1 receptor agonist polypeptide does not comprise the amino acid sequence of SEQ ID NO: 1574; and a half-life extending moiety.

[0281] Embodiment 12 is the molecule of embodiment 11, wherein the first GLP-1 receptor agonist polypeptide comprises the amino acid sequence of H[Aib]EGTFTSDYSSYLEEXi7AAX2oEFIX24WLX27X28GGG (SEQ ID NO: 1576), wherein Xi7is Q or K; X20 is K or R; X24 is A, E, or Q; X27 is V or K; and X28is K, E, or R.

[0282] Embodiment 13 is the molecule of embodiment 11, wherein the first GLP-1 receptor agonist polypeptide comprises the amino acid sequence of H[Aib]EGTFTSDYSSYLEEXi7AAR2oEFIX24WLX27X28GGG (SEQ ID NO: 1577) wherein Xi7is Q or K; X24 is A, E, or Q; X27 is V or K; and X28is K, E, or R.

[0283] Embodiment 14 is the molecule of embodiment 11, wherein the first GLP-1 receptor agonist polypeptide comprises the amino acid sequence ofH[Aib]EGTFTSD¥SS¥LEEXi7AAX2oEFIX24WLK27X28GGG (SEQ ID NO: 1578), wherein Xi7is Q or K; X2o is K or R; X24 is A, E, or Q; and X28is K, E, or R.

[0284] Embodiment 15 is the molecule of embodiment 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] Embodiment 16 is the molecule of any one of embodiments 11-15, wherein the half-life extending moiety is an antibody.

[0286] Embodiment 17 is a conjugate molecule comprising: (i) a first human glucagon-like peptide 1 (GLP-1) receptor agonist polypeptide comprising the amino acid sequence of H[Aib]EGTFTSDYSSYLEEXi7AAX2oEFIX24WLX27X28GGG (SEQ ID NO: 1575), wherein Xi7is Q, K, E, or R; X20 is K, R, Q, or homoarginine (hArg); X24 is A, E, Q, D, d-Ala, G, N, K, (1 S,2S)-2- Aminocyclopentanecarboxylic acid (ACPC), (3S,4R)-4-Amino-3-pyrrolidinecarboxylic acid (APCA), T, S, or Y; X27 is V, K, Aib, N, S, T, Y, Q, or R; and X28is K, E, R, Q, D, N, G, S, or T, and wherein the GLP-1 receptor agonist polypeptide does not comprise the amino acid sequence of SEQ ID NO: 1574; and (ii) an antagonist anti-glucose-dependent insulinotropic polypeptide receptor (GIPR) human antibody.

[0287] Embodiment 18 is the conjugate molecule of embodiment 17, wherein the anti-GIPR antibody antagonizes human GIPR.

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

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

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

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

[0292] Embodiment 23 is the conjugate molecule of embodiment 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] Embodiment 24 is the conjugate molecule of embodiment 17 or 18, wherein the anti- GIPR antibody comprises a first cysteine conjugation site within a light chain or heavy chain of theantibody, and wherein the first GLP-1 receptor agonist polypeptide is conjugated, at its C-terminus, to the first cysteine conjugation site of the anti-GIPR antibody.

[0294] Embodiment 25 is the conjugate molecule of embodiment 24, wherein the first GLP-1 receptor agonist polypeptide is conjugated, at its C-terminus, to the first cysteine conjugation site of the anti-GIPR antibody via a first linker moiety.

[0295] Embodiment 26 is the conjugate molecule of embodiment 25, wherein the first linker moiety is a peptide linker and the peptide linker comprises the amino acid sequence of any one of SEQ ID NOs: 1585-1593.

[0296] Embodiment 27 is the conjugate molecule of embodiment 25, wherein the first linker moiety is a PEG linker.

[0297] Embodiment 28 is the conjugate molecule of any one of embodiments 24 to 27, wherein the first cysteine conjugation site of the anti-GIPR antibody is at position 88 of the light chain, position 384 of the heavy chain, or position 487 of the heavy chain according to AHo numbering.

[0298] Embodiment 29 is the conjugate molecule of anyone of embodiments 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 a second cysteine conjugation site of the anti-GIPR antibody.

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

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

[0301] Embodiment 32 is the conjugate molecule of embodiment 29 wherein the second GLP-1 receptor agonist polypeptide comprises the amino acid sequence of SEQ ID NO: 1577.

[0302] Embodiment 33 is the conjugate molecule of embodiment 29, wherein the second GLP-1 receptor agonist polypeptide comprises the amino acid sequence of SEQ ID NO: 1578.

[0303] Embodiment 34 is the conjugate molecule of embodiment 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] Embodiment 35 is the conjugate molecule of embodiment 29, wherein the second GLP-1 receptor agonist polypeptide comprises the same amino acid sequence as the first GLP-1 receptor agonist polypeptide.

[0305] Embodiment 36 is the conjugate molecule of any one of embodiments 29 to 35, wherein the second GLP-1 receptor agonist polypeptide is conjugated, at its C-terminus, to the second cysteine conjugation site of the anti-GIPR antibody via a second linker moiety.

[0306] Embodiment 37 is the conjugate molecule of embodiment 36, wherein the second linker moiety is a peptide linker and the peptide linker comprises the amino acid sequence of any one of SEQ ID NOs: 1585-1593.

[0307] Embodiment 38 is the conjugate molecule of embodiment 36, wherein the second linker moiety is a PEG linker.

[0308] Embodiment 39 is the conjugate molecule of embodiment 29, wherein the first and second conjugation sites of the anti-GIPR antibody are at position 88 of each light chain, position 384 of each heavy chain, or position 487 of each heavy chain according to AHo numbering.

[0309] Embodiment 40 is the conjugate molecule of any one of embodiments 17 to 39, wherein the anti-GIPR antibody comprises a light chain complementarity determining region 1 (CDRL1), a CDRL2, a CDRL3, a heavy chain complementarity determining region 1 (CDRH1), a CDRH2, and a CDRH3, wherein the CDRL1, the CDRL2, the CDRL3, the CDRH1, the CDRH2, and the CDRH3 comprise the amino acid sequences selected from: i. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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; xxx. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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; xlv. 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. 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. 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. 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. 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;1. 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; li. 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; lii. 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. 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; liv. 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;Iv. 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;Ivi. 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;Ivii. 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;Iviii. 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; lix. 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. 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;Ixi. 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;Ixii. 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;Ixiii. 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;Ixiv. 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;Ixv. 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;Ixvi. 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;Ixvii. 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;Ixviii. 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;Ixix. 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;Ixx. 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;Ixxi. 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;Ixxii. 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;Ixxiii. 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;Ixxiv. 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;Ixxv. 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;Ixxvi. 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;Ixxvii. 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;Ixxviii. 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;Ixxix. 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;Ixxx. 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;Ixxxi. 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;Ixxxii. 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;Ixxxiii. 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;Ixxxiv. 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;Ixxxv. 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;Ixxxvi. 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;Ixxxvii. 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;Ixxxviii. 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;Ixxxix. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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; ex. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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; exxi. 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; exxii. 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. 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; exxiv. 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; exxv. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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; cli. 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; clii. 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. 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. 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; civ. 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. 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. 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] Embodiment 41 is the conjugate molecule of embodiment 40, wherein the anti-GIPR antibody comprises the CDRL1, the CDRL2, the CDRL3, the CDRH1, the CDRH2, and the 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] Embodiment 42 is the conjugate molecule of any one of embodiments 17 to 39, wherein the anti-GIPR antibody comprises a light chain variable region (VL) and a heavy chain variable region (VH), wherein the VL and the VH comprise amino acid sequences selected from: i. SEQ ID NO: 1 and SEQ ID NO: 158, respectively; ii. SEQ ID NO: 2 and SEQ ID NO: 159, respectively; iii. SEQ ID NO: 3 and SEQ ID NO: 160, respectively; iv. SEQ ID NO: 4 and SEQ ID NO: 161, respectively; v. SEQ ID NO: 5 and SEQ ID NO: 162, respectively; vi. SEQ ID NO: 6 and SEQ ID NO: 163, respectively; vii. SEQ ID NO: 7 and SEQ ID NO: 164, respectively; viii. SEQ ID NO: 8 and SEQ ID NO: 165, respectively; ix. SEQ ID NO: 9 and SEQ ID NO: 166, respectively; x. SEQ ID NO: 10 and SEQ ID NO: 167, respectively xi. SEQ ID NO: 11 and SEQ ID NO: 168, respectively; xii. SEQ ID NO: 12 and SEQ ID NO: 169, respectively; xiii. SEQ ID NO: 13 and SEQ ID NO: 170, respectively; xiv. SEQ ID NO: 14 and SEQ ID NO: 171, respectively; xv. SEQ ID NO: 15 and SEQ ID NO: 172, respectively; xvi. SEQ ID NO: 16 and SEQ ID NO: 173, respectively; xvii. SEQ ID NO: 17 and SEQ ID NO: 174, respectively; xviii. SEQ ID NO: 18 and SEQ ID NO: 175, respectively; xix. SEQ ID NO: 19 and SEQ ID NO: 176, respectively; xx. SEQ ID NO: 20 and SEQ ID NO: 177, respectively; xxi. SEQ ID NO: 21 and SEQ ID NO: 178, respectively; xxii. SEQ ID NO: 22 and SEQ ID NO: 179, respectively; xxiii. SEQ ID NO: 23 and SEQ ID NO: 180, respectively; xxiv. SEQ ID NO: 24 and SEQ ID NO: 181 , respectively; xxv. SEQ ID NO: 25 and SEQ ID NO: 182, respectively; xxvi. SEQ ID NO: 26 and SEQ ID NO: 183, respectively; xxvii. SEQ ID NO: 27 and SEQ ID NO: 184, respectively; xxviii. SEQ ID NO: 28 and SEQ ID NO: 185, respectively; xxix. SEQ ID NO: 29 and SEQ ID NO: 186, respectively; xxx. SEQ ID NO: 30 and SEQ ID NO: 187, respectively; xxxi. SEQ ID NO: 31 and SEQ ID NO: 188, respectively;xxxii. SEQ ID NO: 32 and SEQ ID NO: 189, respectively; xxxiii. SEQ ID NO: 33 and SEQ ID NO: 190, respectively; xxxiv. SEQ ID NO: 34 and SEQ ID NO: 191, respectively; xxxv. SEQ ID NO: 35 and SEQ ID NO: 192, respectively; xxxvi. SEQ ID NO: 36 and SEQ ID NO: 193, respectively; xxxvii. SEQ ID NO: 37 and SEQ ID NO: 194, respectively; xxxviii. SEQ ID NO: 38 and SEQ ID NO: 195, respectively; xxxix. SEQ ID NO: 39 and SEQ ID NO: 196, respectively; xl. SEQ ID NO: 40 and SEQ ID NO: 197, respectively; xli. SEQ ID NO: 41 and SEQ ID NO: 198, respectively; xlii. SEQ ID NO: 42 and SEQ ID NO: 199, respectively; xliii. SEQ ID NO: 43 and SEQ ID NO: 200, respectively; xliv. SEQ ID NO: 44 and SEQ ID NO: 201, respectively; xlv. SEQ ID NO: 45 and SEQ ID NO: 202, respectively; xlvi. SEQ ID NO: 46 and SEQ ID NO: 203, respectively; xlvii. SEQ ID NO: 47 and SEQ ID NO: 204, respectively; xlviii. SEQ ID NO: 48 and SEQ ID NO: 205, respectively; xlix. SEQ ID NO: 49 and SEQ ID NO: 206, respectively;1. SEQ ID NO: 50 and SEQ ID NO: 207, respectively; li. SEQ ID NO: 51 and SEQ ID NO: 208, respectively; lii. SEQ ID NO: 52 and SEQ ID NO: 209, respectively; liii. SEQ ID NO: 53 and SEQ ID NO: 210, respectively; liv. SEQ ID NO: 54 and SEQ ID NO: 211, respectively; Iv. SEQ ID NO: 55 and SEQ ID NO: 212, respectively; Ivi. SEQ ID NO: 56 and SEQ ID NO: 213, respectively; Ivii. SEQ ID NO: 57 and SEQ ID NO: 214, respectively; Iviii. SEQ ID NO: 58 and SEQ ID NO: 215, respectively; lix. SEQ ID NO: 59 and SEQ ID NO: 216, respectively; lx. SEQ ID NO: 60 and SEQ ID NO: 217, respectively; Ixi. SEQ ID NO: 61 and SEQ ID NO: 218, respectively; Ixii. SEQ ID NO: 62 and SEQ ID NO: 219, respectively; Ixiii. SEQ ID NO: 63 and SEQ ID NO: 220, respectively; Ixiv. SEQ ID NO: 64 and SEQ ID NO: 221, respectively; Ixv. SEQ ID NO: 65 and SEQ ID NO: 222, respectively;Ixvi. SEQ ID NO: 66 and SEQ ID NO: 223, respectively;Ixvii. SEQ ID NO: 67 and SEQ ID NO: 224, respectively;Ixviii. SEQ ID NO: 68 and SEQ ID NO: 225, respectively;Ixix. SEQ ID NO: 69 and SEQ ID NO: 226, respectively;Ixx. SEQ ID NO: 70 and SEQ ID NO: 227 , respectively;Ixxi. SEQ ID NO: 71 and SEQ ID NO: 228, respectively;Ixxii. SEQ ID NO: 72 and SEQ ID NO: 229, respectively;Ixxiii. SEQ ID NO: 73 and SEQ ID NO: 230, respectively;Ixxiv. SEQ ID NO: 74 and SEQ ID NO: 231, respectively;Ixxv. SEQ ID NO: 75 and SEQ ID NO: 232, respectively;Ixxvi. SEQ ID NO: 76 and SEQ ID NO: 233, respectively;Ixxvii. SEQ ID NO: 77 and SEQ ID NO: 234, respectively;Ixxviii. SEQ ID NO: 78 and SEQ ID NO: 235, respectively;Ixxix. SEQ ID NO: 79 and SEQ ID NO: 236, respectively;Ixxx. SEQ ID NO: 80 and SEQ ID NO: 237, respectively;Ixxxi. SEQ ID NO: 81 and SEQ ID NO: 238, respectively;Ixxxii. SEQ ID NO: 82 and SEQ ID NO: 239, respectively;Ixxxiii. SEQ ID NO: 83 and SEQ ID NO: 240, respectively;Ixxxiv. SEQ ID NO: 84 and SEQ ID NO: 241, respectively;Ixxxv. SEQ ID NO: 85 and SEQ ID NO: 242, respectively;Ixxxvi. SEQ ID NO: 86 and SEQ ID NO: 243, respectively;Ixxxvii. SEQ ID NO: 87 and SEQ ID NO: 244, respectively;Ixxxviii. SEQ ID NO: 88 and SEQ ID NO: 245, respectively;Ixxxix. SEQ ID NO: 89 and SEQ ID NO: 246, respectively; xc. SEQ ID NO: 90 and SEQ ID NO: 247, respectively; xci. SEQ ID NO: 91 and SEQ ID NO: 248, respectively; xcii. SEQ ID NO: 92 and SEQ ID NO: 249, respectively; xciii. SEQ ID NO: 93 and SEQ ID NO: 250, respectively; xciv. SEQ ID NO: 94 and SEQ ID NO: 251, respectively; xcv. SEQ ID NO: 95 and SEQ ID NO: 252, respectively; xcvi. SEQ ID NO: 96 and SEQ ID NO: 253, respectively; xcvii. SEQ ID NO: 97 and SEQ ID NO: 254, respectively; xcviii. SEQ ID NO: 98 and SEQ ID NO: 255, respectively; xcix. SEQ ID NO: 99 and SEQ ID NO: 256, respectively;c. SEQ ID NO: 100 and SEQ ID NO: 257, respectively; ci. SEQ ID NO: 101 and SEQ ID NO: 258, respectively; cii. SEQ ID NO: 102 and SEQ ID NO: 259, respectively; ciii. SEQ ID NO: 103 and SEQ ID NO: 260, respectively; civ. SEQ ID NO: 104 and SEQ ID NO: 261, respectively; cv. SEQ ID NO: 105 and SEQ ID NO: 262, respectively; cvi. SEQ ID NO: 106 and SEQ ID NO: 263, respectively; cvii. SEQ ID NO: 107 and SEQ ID NO: 264, respectively; cviii. SEQ ID NO: 108 and SEQ ID NO: 265, respectively; cix. SEQ ID NO: 109 and SEQ ID NO: 266, respectively; ex. SEQ ID NO: 110 and SEQ ID NO: 267, respectively; cxi. SEQ ID NO: 111 and SEQ ID NO: 268, respectively; cxii. SEQ ID NO: 112 and SEQ ID NO: 269, respectively; cxiii. SEQ ID NO: 113 and SEQ ID NO: 270, respectively; cxiv. SEQ ID NO: 114 and SEQ ID NO: 271, respectively; cxv. SEQ ID NO: 115 and SEQ ID NO: 272, respectively; cxvi. SEQ ID NO: 116 and SEQ ID NO: 273, respectively; cxvii. SEQ ID NO: 117 and SEQ ID NO: 274, respectively; cxviii. SEQ ID NO: 118 and SEQ ID NO: 275, respectively; cxix. SEQ ID NO: 119 and SEQ ID NO: 276, respectively; cxx. SEQ ID NO: 120 and SEQ ID NO: 277, respectively; exxi. SEQ ID NO: 121 and SEQ ID NO: 278, respectively; exxii. SEQ ID NO: 122 and SEQ ID NO: 279, respectively; cxxiii. SEQ ID NO: 123 and SEQ ID NO: 280, respectively; exxiv. SEQ ID NO: 124 and SEQ ID NO: 281, respectively; exxv. SEQ ID NO: 125 and SEQ ID NO: 282, respectively; exxvi. SEQ ID NO: 126 and SEQ ID NO: 283, respectively; cxxvii. SEQ ID NO: 127 and SEQ ID NO: 284, respectively; cxxviii. SEQ ID NO: 128 and SEQ ID NO: 285, respectively; cxxix. SEQ ID NO: 129 and SEQ ID NO: 286, respectively; exxx. SEQ ID NO: 130 and SEQ ID NO: 287, respectively; cxxxi. SEQ ID NO: 131 and SEQ ID NO: 288, respectively; cxxxii. SEQ ID NO: 132 and SEQ ID NO: 289, respectively; cxxxiii. SEQ ID NO: 133 and SEQ ID NO: 290, respectively;cxxxiv. SEQ ID NO: 134 and SEQ ID NO: 291, respectively; cxxxv. SEQ ID NO: 135 and SEQ ID NO: 292, respectively; cxxxvi. SEQ ID NO: 136 and SEQ ID NO: 293, respectively; cxxxvii. SEQ ID NO: 137 and SEQ ID NO: 294, respectively; cxxxviii. SEQ ID NO: 138 and SEQ ID NO: 295, respectively; cxxxix. SEQ ID NO: 139 and SEQ ID NO: 296, respectively; cxl. SEQ ID NO: 140 and SEQ ID NO: 297, respectively; cxli. SEQ ID NO: 141 and SEQ ID NO: 298, respectively; cxlii. SEQ ID NO: 142 and SEQ ID NO: 299, respectively; cxliii. SEQ ID NO: 143 and SEQ ID NO: 300, respectively; cxliv. SEQ ID NO: 144 and SEQ ID NO: 301, respectively; cxlv. SEQ ID NO: 145 and SEQ ID NO: 302, respectively; cxlvi. SEQ ID NO: 146 and SEQ ID NO: 303, respectively; cxlvii. SEQ ID NO: 147 and SEQ ID NO: 304, respectively; cxlviii. SEQ ID NO: 148 and SEQ ID NO: 305, respectively; cxlix. SEQ ID NO: 149 and SEQ ID NO: 306, respectively; cl. SEQ ID NO : 150 and SEQ ID NO : 307, respectively; cli. SEQ ID NO: 151 and SEQ ID NO: 308, respectively; clii. SEQ ID NO: 152 and SEQ ID NO: 309, respectively; cliii. SEQ ID NO: 153 and SEQ ID NO: 310, respectively; cliv. SEQ ID NO: 154 and SEQ ID NO: 311, respectively; civ. SEQ ID NO: 155 and SEQ ID NO: 312, respectively; clvi. SEQ ID NO: 156 and SEQ ID NO: 313, respectively; and clvii. SEQ ID NO: 157 and SEQ ID NO: 314, respectively.

[0312] Embodiment 43 is the conjugate molecule of embodiment 42, wherein the anti-GIPR antibody comprises the VL and VH of SEQ ID NO: 74 and SEQ ID NO: 231, respectively.

[0313] Embodiment 44 is the conjugate molecule of any one of embodiments 17 to 39, wherein the anti-GIPR antibody comprises a light chain and a heavy chain, wherein the light chain and heavy chain comprise amino acid sequences selected from: i. SEQ ID NO: 315 and SEQ ID NO: 472, respectively; ii. SEQ ID NO: 316 and SEQ ID NO: 473, respectively; iii. SEQ ID NO: 317 and SEQ ID NO: 474, respectively; iv. SEQ ID NO: 318 and SEQ ID NO: 475, respectively;v. SEQ ID NO: 319 and SEQ ID NO: 476, respectively; vi. SEQ ID NO: 320 and SEQ ID NO: 477, respectively; vii. SEQ ID NO: 321 and SEQ ID NO: 478, respectively; viii. SEQ ID NO: 322 and SEQ ID NO: 479, respectively; ix. SEQ ID NO: 323 and SEQ ID NO: 480, respectively; x. SEQ ID NO: 324 and SEQ ID NO: 481, respectively; xi. SEQ ID NO: 325 and SEQ ID NO: 482, respectively; xii. SEQ ID NO: 326 and SEQ ID NO: 483, respectively; xiii. SEQ ID NO: 327 and SEQ ID NO: 484, respectively; xiv. SEQ ID NO: 328 and SEQ ID NO: 485, respectively; xv. SEQ ID NO: 329 and SEQ ID NO: 486, respectively; xvi. SEQ ID NO: 330 and SEQ ID NO: 487, respectively; xvii. SEQ ID NO: 331 and SEQ ID NO: 488, respectively; xviii. SEQ ID NO: 332 and SEQ ID NO: 489, respectively; xix. SEQ ID NO: 333 and SEQ ID NO: 490, respectively;XX. SEQ ID NO: 334 and SEQ ID NO: 491, respectively; xxi. SEQ ID NO: 335 and SEQ ID NO: 492, respectively; xxii. SEQ ID NO: 336 and SEQ ID NO: 493, respectively; xxiii. SEQ ID NO: 337 and SEQ ID NO: 494, respectively; xxiv. SEQ ID NO: 338 and SEQ ID NO: 495, respectively; xxv. SEQ ID NO: 339 and SEQ ID NO: 496, respectively; xxvi. SEQ ID NO: 340 and SEQ ID NO: 497, respectively; xxvii. SEQ ID NO: 341 and SEQ ID NO: 498, respectively; xxviii. SEQ ID NO: 342 and SEQ ID NO: 499, respectively; xxix. SEQ ID NO: 343 and SEQ ID NO: 500, respectively; xxx. SEQ ID NO: 344 and SEQ ID NO: 501, respectively; xxxi. SEQ ID NO: 345 and SEQ ID NO: 502, respectively; xxxii. SEQ ID NO: 346 and SEQ ID NO: 503, respectively; xxxiii. SEQ ID NO: 347 and SEQ ID NO: 504, respectively; xxxiv. SEQ ID NO: 348 and SEQ ID NO: 505, respectively; xxxv. SEQ ID NO: 349 and SEQ ID NO: 506, respectively; xxxvi. SEQ ID NO: 350 and SEQ ID NO: 507, respectively; xxxvii. SEQ ID NO: 351 and SEQ ID NO: 508, respectively; xxxviii. SEQ ID NO: 352 and SEQ ID NO: 509, respectively;xxxix. SEQ ID NO: 353 and SEQ ID NO: 510, respectively; xl. SEQ ID NO: 354 and SEQ ID NO: 511, respectively; xli. SEQ ID NO: 355 and SEQ ID NO: 512, respectively; xlii. SEQ ID NO: 356 and SEQ ID NO: 513, respectively; xliii. SEQ ID NO: 357 and SEQ ID NO: 514, respectively; xliv. SEQ ID NO: 358 and SEQ ID NO: 515, respectively; xlv. SEQ ID NO: 359 and SEQ ID NO: 516, respectively; xlvi. SEQ ID NO: 360 and SEQ ID NO: 517, respectively; xlvii. SEQ ID NO: 361 and SEQ ID NO: 518, respectively; xlviii. SEQ ID NO: 362 and SEQ ID NO: 519, respectively; xlix. SEQ ID NO: 363 and SEQ ID NO: 520, respectively;1. SEQ ID NO: 364 and SEQ ID NO: 521, respectively; li. SEQ ID NO: 365 and SEQ ID NO: 522, respectively; lii. SEQ ID NO: 366 and SEQ ID NO: 523, respectively; liii. SEQ ID NO: 367 and SEQ ID NO: 524, respectively; liv. SEQ ID NO: 368 and SEQ ID NO: 525, respectively;Iv. SEQ ID NO: 369 and SEQ ID NO: 526, respectively;Ivi. SEQ ID NO: 370 and SEQ ID NO: 527, respectively;Ivii. SEQ ID NO: 371 and SEQ ID NO: 528, respectively;Iviii. SEQ ID NO: 372 and SEQ ID NO: 529, respectively; lix. SEQ ID NO: 373 and SEQ ID NO: 530, respectively; lx. SEQ ID NO: 374 and SEQ ID NO: 531, respectively;Ixi. SEQ ID NO: 375 and SEQ ID NO: 532, respectively;Ixii. SEQ ID NO: 376 and SEQ ID NO: 533, respectively;Ixiii. SEQ ID NO: 377 and SEQ ID NO: 534, respectively;Ixiv. SEQ ID NO: 378 and SEQ ID NO: 535, respectively;Ixv. SEQ ID NO: 379 and SEQ ID NO: 536, respectively;Ixvi. SEQ ID NO: 380 and SEQ ID NO: 537, respectively;Ixvii. SEQ ID NO: 381 and SEQ ID NO: 538, respectively;Ixviii. SEQ ID NO: 382 and SEQ ID NO: 539, respectively;Ixix. SEQ ID NO: 383 and SEQ ID NO: 540, respectively;Ixx. SEQ ID NO: 384 and SEQ ID NO: 541, respectively;Ixxi. SEQ ID NO: 385 and SEQ ID NO: 542, respectively;Ixxii. SEQ ID NO: 386 and SEQ ID NO: 543, respectively;Ixxiii. SEQ ID NO: 387 and SEQ ID NO: 544, respectively;Ixxiv. SEQ ID NO: 388 and SEQ ID NO: 545, respectively;Ixxv. SEQ ID NO: 389 and SEQ ID NO: 546, respectively;Ixxvi. SEQ ID NO: 390 and SEQ ID NO: 547, respectively;Ixxvii. SEQ ID NO: 391 and SEQ ID NO: 548, respectively;Ixxviii. SEQ ID NO: 392 and SEQ ID NO: 549, respectively;Ixxix. SEQ ID NO: 393 and SEQ ID NO: 550, respectively;Ixxx. SEQ ID NO: 394 and SEQ ID NO: 551, respectively;Ixxxi. SEQ ID NO: 395 and SEQ ID NO: 552, respectively;Ixxxii. SEQ ID NO: 396 and SEQ ID NO: 553, respectively;Ixxxiii. SEQ ID NO: 397 and SEQ ID NO: 554, respectively;Ixxxiv. SEQ ID NO: 398 and SEQ ID NO: 555, respectively;Ixxxv. SEQ ID NO: 399 and SEQ ID NO: 556, respectively;Ixxxvi. SEQ ID NO: 400 and SEQ ID NO: 557, respectively;Ixxxvii. SEQ ID NO: 401 and SEQ ID NO: 558, respectively;Ixxxviii. SEQ ID NO: 402 and SEQ ID NO: 559, respectively;Ixxxix. SEQ ID NO: 403 and SEQ ID NO: 560, respectively; xc. SEQ ID NO: 404 and SEQ ID NO: 561, respectively; xci. SEQ ID NO: 405 and SEQ ID NO: 562, respectively; xcii. SEQ ID NO: 406 and SEQ ID NO: 563, respectively; xciii. SEQ ID NO: 407 and SEQ ID NO: 564, respectively; xciv. SEQ ID NO: 408 and SEQ ID NO: 565, respectively; xcv. SEQ ID NO: 409 and SEQ ID NO: 566, respectively; xcvi. SEQ ID NO: 410 and SEQ ID NO: 567, respectively; xcvii. SEQ ID NO: 411 and SEQ ID NO: 568, respectively; xcviii. SEQ ID NO: 412 and SEQ ID NO: 569, respectively; xcix. SEQ ID NO: 413 and SEQ ID NO: 570, respectively; c. SEQ ID NO: 414 and SEQ ID NO: 571, respectively; ci. SEQ ID NO: 415 and SEQ ID NO: 572, respectively; cii. SEQ ID NO: 416 and SEQ ID NO: 573, respectively; ciii. SEQ ID NO: 417 and SEQ ID NO: 574, respectively; civ. SEQ ID NO: 418 and SEQ ID NO: 575, respectively; cv. SEQ ID NO: 419 and SEQ ID NO: 576, respectively; cvi. SEQ ID NO: 420 and SEQ ID NO: 577, respectively;cvii. SEQ ID NO: 421 and SEQ ID NO: 578, respectively; cviii. SEQ ID NO: 422 and SEQ ID NO: 579, respectively; cix. SEQ ID NO: 423 and SEQ ID NO: 580, respectively; ex. SEQ ID NO: 424 and SEQ ID NO: 581, respectively; cxi. SEQ ID NO: 425 and SEQ ID NO: 582, respectively; cxii. SEQ ID NO: 426 and SEQ ID NO: 583, respectively; cxiii. SEQ ID NO: 427 and SEQ ID NO: 584, respectively; cxiv. SEQ ID NO: 428 and SEQ ID NO: 585, respectively; cxv. SEQ ID NO: 429 and SEQ ID NO: 586, respectively; cxvi. SEQ ID NO: 430 and SEQ ID NO: 587, respectively; cxvii. SEQ ID NO: 431 and SEQ ID NO: 588, respectively; cxviii. SEQ ID NO: 432 and SEQ ID NO: 589, respectively; cxix. SEQ ID NO: 433 and SEQ ID NO: 590, respectively; cxx. SEQ ID NO: 434 and SEQ ID NO: 591, respectively; exxi. SEQ ID NO: 435 and SEQ ID NO: 592, respectively; exxii. SEQ ID NO: 436 and SEQ ID NO: 593, respectively; cxxiii. SEQ ID NO: 437 and SEQ ID NO: 594, respectively; exxiv. SEQ ID NO: 438 and SEQ ID NO: 595, respectively; exxv. SEQ ID NO: 439 and SEQ ID NO: 596, respectively; exxvi. SEQ ID NO: 440 and SEQ ID NO: 597, respectively; cxxvii. SEQ ID NO: 441 and SEQ ID NO: 598, respectively; cxxviii. SEQ ID NO: 442 and SEQ ID NO: 599, respectively; cxxix. SEQ ID NO: 443 and SEQ ID NO: 600, respectively; exxx. SEQ ID NO: 444 and SEQ ID NO: 601, respectively; cxxxi. SEQ ID NO: 445 and SEQ ID NO: 602, respectively; cxxxii. SEQ ID NO: 446 and SEQ ID NO: 603, respectively; cxxxiii. SEQ ID NO: 447 and SEQ ID NO: 604, respectively; cxxxi v. SEQ ID NO: 448 and SEQ ID NO: 605, respectively; cxxxv. SEQ ID NO: 449 and SEQ ID NO: 606, respectively; cxxxvi. SEQ ID NO: 450 and SEQ ID NO: 607, respectively; cxxxvii. SEQ ID NO: 451 and SEQ ID NO: 608, respectively; cxxxviii. SEQ ID NO: 452 and SEQ ID NO: 609, respectively; cxxxix. SEQ ID NO: 453 and SEQ ID NO: 610, respectively; cxl. SEQ ID NO: 454 and SEQ ID NO: 611, respectively;cxli. SEQ ID NO: 455 and SEQ ID NO: 612, respectively; cxlii. SEQ ID NO: 456 and SEQ ID NO: 613, respectively; cxliii. SEQ ID NO: 457 and SEQ ID NO: 614, respectively; cxliv. SEQ ID NO: 458 and SEQ ID NO: 615, respectively; cxlv. SEQ ID NO: 459 and SEQ ID NO: 616, respectively; cxlvi. SEQ ID NO: 460 and SEQ ID NO: 617, respectively; cxlvii. SEQ ID NO: 461 and SEQ ID NO: 618, respectively; cxlviii. SEQ ID NO: 462 and SEQ ID NO: 619, respectively; cxlix. SEQ ID NO: 463 and SEQ ID NO: 620, respectively; cl. SEQ ID NO: 464 and SEQ ID NO: 621, respectively; cli. SEQ ID NO: 465 and SEQ ID NO: 622, respectively; clii. SEQ ID NO: 466 and SEQ ID NO: 623, respectively; cliii. SEQ ID NO: 467 and SEQ ID NO: 624, respectively; cliv. SEQ ID NO: 468 and SEQ ID NO: 625, respectively; civ. SEQ ID NO: 469 and SEQ ID NO: 626, respectively; clvi. SEQ ID NO: 470 and SEQ ID NO: 627, respectively; and clvii. SEQ ID NO: 471 and SEQ ID NO: 628, respectively, wherein the antibody comprises one or more cysteine amino acid substitution(s) at one or more position(s) selected from 88 of the light chain, 384 of the heavy chain, or 487 of the heavy chain, according to AHo numbering.

[0314] Embodiment 45 is the conjugate molecule of embodiment 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] Embodiment 46 is a conjugate molecule comprising: (i) an antagonist anti-glucose- dependent insulinotropic polypeptide receptor (GIPR) antibody, wherein the anti-GIPR antibody comprises: a first and second light chain, each light chain comprising a CDRL1, a CDRL2, and a CDRL3 of SEQ ID NO: 702, SEQ ID NO: 859, and SEQ ID NO: 1016, respectively, and a first and second heavy chain, each heavy chain comprising a CDRH1, a CDRH2, and a CDRH3 of SEQ ID NO: 1173, SEQ ID NO: 1330, and SEQ ID NO: 1487, respectively; (ii) a first and second GLP-1 receptor agonist polypeptide, wherein each GLP-1 receptor agonist polypeptide comprises the amino acid sequence of SEQ ID NO: 1579; and (in) a first and second peptide linker, wherein each peptide linker comprises the amino acid sequence of SEQ ID NO: 1592; wherein the first GLP-1 receptor agonist polypeptide is conjugated, at its C-terminus via the first linker, to the first heavy chain of the anti-GIPR antibody at acysteine residue at position 384 of the first heavy chain according to AHo numbering, and wherein the second GLP-1 receptor agonist polypeptide is conjugated, at its C-terminus via the second linker, to the second heavy chain of the anti-GIPR antibody at a cysteine residue at position 384 of the second heavy chain according to AHo numbering.

[0316] Embodiment 47 is the conjugate molecule of embodiment 46, wherein each light chain comprises a VL of SEQ ID NO: 74, and each heavy chain comprises a VH of SEQ ID NO: 231.

[0317] Embodiment 48 is the conjugate molecule of embodiment 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.

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

[0319] Embodiment 50 is the conjugate molecule of embodiment 49, wherein each light chain comprises a VL of SEQ ID NO: 74, and each heavy chain comprises a VH of SEQ ID NO: 231.

[0320] Embodiment 51 is the conjugate molecule of embodiment 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.

[0321] Embodiment 52 is a conjugate molecule comprising: (i) an antagonist anti-glucose- dependent insulinotropic polypeptide receptor (GIPR) antibody, wherein the anti-GIPR antibody comprises: a first and second light chain, each light chain comprising a CDRL1, a CDRL2, and a CDRL3 of SEQ ID NO: 702, SEQ ID NO: 859, and SEQ ID NO: 1016, respectively, and a first and second heavychain, each heavy chain comprising a CDRH1, a CDRH2, and a CDRH3 of SEQ ID NO: 1173, SEQ ID NO: 1330, and SEQ ID NO: 1487, respectively; (ii) a first and second GLP-1 receptor agonist polypeptide, wherein each GLP-1 receptor agonist polypeptide comprises the amino acid sequence of SEQ ID NO: 1581; and (in) a first and second peptide linker, wherein each peptide linker comprises the amino acid sequence of SEQ ID NO: 1586; wherein the first GLP-1 receptor agonist polypeptide is conjugated, at its C-terminus via the first linker, to the first heavy chain of the anti-GIPR antibody at a cysteine residue at position 384 of the first heavy chain according to AHo numbering, and wherein the second GLP-1 receptor agonist polypeptide is conjugated, at its C-terminus via the second linker, to the second heavy chain of the anti-GIPR antibody at a cysteine residue at position 384 of the second heavy chain according to AHo numbering.

[0322] Embodiment 53 is the conjugate molecule of embodiment 52, wherein each light chain comprises a VL of SEQ ID NO: 74, and each heavy chain comprises a VH of SEQ ID NO: 231.

[0323] Embodiment 54 is the conjugate molecule of embodiment 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.

[0324] Embodiment 55 is a conjugate molecule comprising: (i) an antagonist anti-glucose- dependent insulinotropic polypeptide receptor (GIPR) antibody, wherein the anti-GIPR antibody comprises: a first and second light chain, each light chain comprising a CDRL1, a CDRL2, and a CDRL3 of SEQ ID NO: 702, SEQ ID NO: 859, and SEQ ID NO: 1016, respectively, and a first and second heavy chain, each heavy chain comprising a CDRH1, a CDRH2, and a CDRH3 of SEQ ID NO: 1173, SEQ ID NO: 1330, and SEQ ID NO: 1487, respectively; (ii) a first and second GLP-1 receptor agonist polypeptide, wherein each GLP-1 receptor agonist polypeptide comprises the amino acid sequence of SEQ ID NO: 1581; and (in) a first and second peptide linker, wherein each peptide linker comprises the amino acid sequence of SEQ ID NO: 1585; wherein the first GLP-1 receptor agonist polypeptide is conjugated, at its C-terminus via the first linker, to the first heavy chain of the anti-GIPR antibody at a cysteine residue at position 275 of the first heavy chain, and wherein the second GLP-1 receptor agonist polypeptide is conjugated, at its C-terminus via the second linker, to the second heavy chain of the anti- GIPR antibody at a cysteine residue at position 275 of the second heavy chain.

[0325] Embodiment 56 is the conjugate molecule of embodiment 55, wherein each light chain comprises a VL of SEQ ID NO: 74, and each heavy chain comprises a VH of SEQ ID NO: 231.

[0326] Embodiment 57 is the conjugate molecule of embodiment 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.

[0327] Embodiment 58 is a pharmaceutical composition comprising: a GLP-1 receptor agonist polypeptide of any one of embodiments 1 to 10, the molecule of any one of embodiments 11 to 16, or the conjugate molecule of any one of embodiments 17 to 57; and a pharmaceutically acceptable excipient.

[0328] Embodiment 59 is a method of reducing body weight and / or food intake in a subject in need thereof, the method comprising: administering the GLP-1 receptor agonist polypeptide of any one of embodiments 1 to 10, the molecule of any one of embodiments 11 to 16, the conjugate molecule of any one of embodiments 17 to 57, or the pharmaceutical composition of embodiment 58 to the subject.

[0329] Embodiment 60 is a method of treating obesity or an obesity related condition in a subject in need thereof, the method comprising: administering, to the subject, the GLP-1 receptor agonist polypeptide of any one of embodiments 1 to 10, the molecule of any one of embodiments 11 to 16, the conjugate molecule of any one of embodiments 17 to 57, or the pharmaceutical composition of embodiment 58.

[0330] Embodiment 61 is the method of embodiment 60, wherein the obesity related condition is selected from the group consisting of sleep apnea, dyslipidemia, atherosclerotic cardiovascular disease, heart failure, hypertension, chronic kidney failure, and metabolic dysfunction-associated steatohepatitis.

[0331] Embodiment 62 is a method of treating type 2 diabetes or a type 2 diabetes related condition in a subject in need thereof, the method comprising: administering, to the subject, the GLP-1 receptor agonist polypeptide of any one of embodiments 1 to 10, the molecule of any one of embodiments 11 to 17, the conjugate molecule of any one of embodiments 17 to 57, or the pharmaceutical composition of embodiment 58.

[0332] Embodiment 63 is the method of embodiment 62, wherein the type 2 diabetes related conditions is selected from the group consisting of hypertension, high blood sugar, diabetic kidney disease, and diabetic kidney failure.

[0333] Embodiment 64 is the GLP-1 receptor agonist polypeptide of any one of embodiments 1 to 10, the molecule of any one of embodiments 11 to 16, or the conjugate molecule of any one of embodiments 17 to 57 for use as a medicament.EXAMPLESExample 1: Generation of Bis-Cysteamin e-Capped Anti-GIPR cys mAb (2 g Scale)

[0334] Anti-GIPR monoclonal antibodies with a specific cysteine mutation (anti-GIPR cys mAb, 2 g) were incubated with 800 mL solution of 2.5 rnM cystamine and 1 mM cysteamine in 40 mM HEPES buffer, pH 7.5-8.5 for 15-20 h. The reaction mixture was filtered using 0.22 pm filter, and diluted in 1200 mL of 100 mM sodium acetate buffer pH 5. Cation exchange chromatography was used to purify the bis-cysteamine-capped anti-GIPR cys mAb from the reaction mixture. First, 2 L of reaction mixture diluted in 100 mM sodium acetate buffer pH 5 was loaded onto 240 mL SP HP column at 20 mL / min. The column was washed with 2 column volumes of 100 mM sodium acetate pH 5, followed by a 0-20% gradient of 100 mM sodium acetate with 1 M NaCl pH 5. The main peak containing bis-cysteamine-capped anti-GIPR cys mAb was collected and buffer exchanged to 10 mM sodium acetate with 9% sucrose pH 5.2 using tangential flow filtration.Example 2: Generation of Anti-GIPR / GLP-1 Peptide Conjugates

[0335] The reaction scheme for the generation of anti-GIPR / GLP-1 peptide conjugates is shown in FIG. 1. Bis-cysteamine-capped anti-GIPR cys mAb (6 mg / mL in 10 mM sodium acetate with 9% sucrose) was partially reduced using 3-4 equivalents of triphenylphosphine- 3,3',3"-trisulfonic acid trisodium salt (TPPTS) at RT for 60-90 min. TPPTS was removed, and partially reduced cys mAb was buffer exchanged to 50 mM sodium phosphate buffer containing 2 mM ethylenediaminetetraacetic acid (EDTA) pH 7.5. To the partially reduced cys mAb was added 6-10 equivalents of dehydroascorbic acid (DHAA), and oxidation was carried out until only trace amount of partially reduced mAb species were observed (30-120 min). Without removing DHAA, 3-8 equivalents of bromoacetyl-GLP- 1 peptide was added to the reaction mixture and incubated for 12-16 hrs. Either cation exchange chromatography or hydrophobic interaction chromatography were used to purify the conjugates. For cation exchange, first the reaction was diluted in 100 mM sodium acetate buffer pH 5 and loaded on a 5 mL SPHP column at 5 mL / min. The column was then washed with 2 column volumes of 20 mM sodium acetate pH 5, followed by a 0-20% gradient of 20 mM sodium acetate with 1 M NaCl pH5. For hydrophobic interaction chromatography, first the reaction was diluted in a buffer containing 1 M ammonium sulfate and 20 mM sodium acetate pH 5. The sample was then loaded on a 5 mL Butyl HPcolumn at 5 mL / min. The column was washed with 2 column volumes of a buffer containing 1 M ammonium sulfate and 20 mM sodium acetate pH 5, followed by a 0-100% gradient of a buffer containing 20 mM sodium acetate and 10% acetonitrile pH5. The main peak containing the anti-GIPR / GLP-1 conjugates comprising a drug-to-antibody ratio of 2: 1 (DAR2) was collected and buffer exchanged into 10 mM sodium acetate with 9% sucrose pH5.2 using spin concentration.Example 3: GLP-1 Receptor A...

Claims

What is Claimed:

1. A human glucagon-like peptide 1 (GLP-1) receptor agonist polypeptide comprising the amino acid sequence of H[Aib]EGTFTSDYSSYLEEXi7AAX2oEFIX24WLX27X28GGG (SEQ ID NO: 1575), wherein X17 is Q, K, E, or R; X20 is K, R, Q, or homoarginine (hArg); X24 is A, E, Q, D, d-Ala, G, N, K, (lS,2S)-2-Aminocyclopentanecarboxylic acid (ACPC), (3S,4R)-4-Amino-3- pyrrolidinecarboxylic acid (APCA), T, S, or Y; X27 is V, K, Aib, N, S, T, Y, Q, or R; and X28 is K, E, R, Q, D, N, G, S, or T; and wherein the GLP-1 receptor agonist polypeptide does not comprise the amino acid sequence of SEQ ID NO: 1574 (H[Aib]EGTFTSDYSSYLEEQAAKEFIAWLVKGGG).

2. The GLP-1 receptor agonist polypeptide of claim 1, wherein the GLP-1 receptor agonist polypeptide comprises the amino acid sequence of H[Aib]EGTFTSDYSSYLEEXi7AAX2oEFIX24WLX27X28GGG (SEQ ID NO: 1576), wherein Xi7is Q or K; X2o is K or R; X24 is A, E, or Q; X27 is V or K; and X28is K, E, or R.

3. The GLP-1 receptor agonist polypeptide of claim 1, wherein the GLP-1 receptor agonist polypeptide comprises the amino acid sequence of H[Aib]EGTFTSDYSSYLEEXi7AAREFIX24WLX27X28GGG (SEQ ID NO: 1577) wherein Xi7is Q or K; X24 is A, E, or Q; X27 is V or K; and X28is K, E, or R.

4. The GLP-1 receptor agonist polypeptide of claim 1, wherein the GLP-1 receptor agonist polypeptide comprises the amino acid sequence of H[Aib]EGTFTSDYSSYLEEXi7AAX2oEFIX24WLKX28GGG (SEQ ID NO: 1578), wherein Xi7is Q or K; X20 is K or R; X24 is A, E, or Q; and X28is K, E, or R.

5. The GLP-1 receptor agonist polypeptide of claim 1, where 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 comprises 31 amino acids and comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 1580; and wherein the polypeptide comprises an a-amino-isobutyric acid (Aib) at position 2; a tyrosine at position 10; a glutamic acid at positions 16, 24, and 28; an arginine at position 20; a lysine at positions 17 and IT, and a glycine at position 31.

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

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

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

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

11. A molecule comprising:a first human glucagon-like peptide 1 (GLP-1) receptor agonist polypeptide comprising the amino acid sequence of H[Aib]EGTFTSD¥SS¥LEEXi7AAX2oEFIX24WLX27X28GGG (SEQ ID NO: 1575), wherein Xi7is Q, K, E, or R; X20 is K, R, Q, or homoarginine (hArg); X24 is A, E, Q, D, d-Ala, G, N, K, (lS,2S)-2-Aminocyclopentanecarboxylic acid (ACPC), (3S,4R)-4-Amino-3- pyrrolidinecarboxylic acid (APCA), T, S, or Y; X27 is V, K, Aib, N, S, T, Y, Q, or R; and X28 is K, E, R, Q, D, N, G, S, or T, and wherein the GLP-1 receptor agonist polypeptide does not comprise the amino acid sequence of SEQ ID NO: 1574; and a half-life extending moiety.

12. The molecule of claim 11, wherein the first GLP-1 receptor agonist polypeptide comprises the amino acid sequence of H[Aib]EGTFTSDYSSYLEEXi7AAX2oEFIX24WLX27X2sGGG (SEQ ID NO: 1576), wherein Xnis Q or K; X20 is K or R; X24 is A, E, or Q; X2? is V or K; and X28 is K, E, or R.

13. The molecule of claim 11, wherein the first GLP-1 receptor agonist polypeptide comprises the amino acid sequence of H[Aib]EGTFTSDYSSYLEEXi7AAR2oEFIX24WLX27X28GGG (SEQ ID NO: 1577) wherein Xnis Q or K; X24 is A, E, or Q; X2? is V or K; and X28is K, E, or R.

14. The molecule of claim 11, wherein the first GLP-1 receptor agonist polypeptide comprises the amino acid sequence of H[Aib]EGTFTSDYSSYLEEXi7AAX2oEFIX24WLK27X2sGGG (SEQ ID NO: 1578), wherein Xnis Q or K; X20 is K or R; X24 is A, E, or Q; and X28is 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 half-life extending moiety is an antibody.

17. A conjugate molecule comprising: a first human glucagon-like peptide 1 (GLP-1) receptor agonist polypeptide comprising the amino acid sequence of H[Aib]EGTFTSDYSSYLEEXi7AAX2oEFIX24WLX27X28GGG (SEQ ID NO: 1575),wherein X17 is Q, K, E, or R; X20 is K, R, Q, or homoarginine (hArg); X24 is A, E, Q, D, d-Ala, G, N, K, (lS,2S)-2-Aminocyclopentanecarboxylic acid (ACPC), (3S,4R)-4-Amino-3- pyrrolidinecarboxylic acid (APCA), T, S, or Y; X27 is V, K, Aib, N, S, T, Y, Q, or R; and X28 is K, E, R, Q, D, N, G, S, or T, and wherein the GLP-1 receptor agonist polypeptide does not comprise the amino acid sequence of SEQ ID NO: 1574; and an antagonist anti-glucose-dependent insulinotropic polypeptide 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 conjugation site within a light chain 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 conjugation 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 conjugation site of the anti-GIPR antibody via a first linker moiety.

26. The conjugate molecule of claim 25, wherein the first linker moiety is a peptide linker and the peptide linker comprises the amino acid sequence of any one of SEQ ID NOs: 1585-1593.

27. The conjugate molecule of claim 25, wherein the first linker moiety is a PEG linker.

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

29. The conjugate molecule of anyone of claims 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 a second cysteine conjugation 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 conjugation site of the anti-GIPR antibody via a second linker moiety.

37. The conjugate molecule of claim 36, wherein the second linker moiety is a peptide linker and the peptide linker comprises the amino acid sequence of any one of SEQ ID NOs:1585-1593.

38. The conjugate molecule of claim 36, wherein the second linker moiety is a PEG linker.

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

40. The conjugate molecule of any one of embodiments 17 to 39, wherein the anti- GIPR antibody comprises a light chain complementarity determining region 1 (CDRL1), a CDRL2, a CDRL3, a heavy chain complementarity determining region 1 (CDRH1), a CDRH2, and a CDRH3, wherein the CDRL1, the CDRL2, the CDRL3, the CDRH1, the CDRH2, and the CDRH3 comprise the amino acid sequences selected from: i. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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; xxx. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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; xlv. 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. 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. 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. 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. 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;1. 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; li. 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; lii. 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. 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; liv. 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;Iv. 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;Ivi. 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;Ivii. 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;Iviii. 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; lix. 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. 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;Ixi. 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;Ixii. 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;Ixiii. 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;Ixiv. 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;Ixv. 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;Ixvi. 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;Ixvii. 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;Ixviii. 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;Ixix. 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;Ixx. 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;Ixxi. 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;Ixxii. 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;Ixxiii. 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;Ixxiv. 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;Ixxv. 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;Ixxvi. 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;Ixxvii. 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;Ixxviii. 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;Ixxix. 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;Ixxx. 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;Ixxxi. 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;Ixxxii. 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;Ixxxiii. 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;Ixxxiv. 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;Ixxxv. 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;Ixxxvi. 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;Ixxxvii. 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;Ixxxviii. 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;Ixxxix. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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; ex. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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; cli. 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; clii. 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. 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. 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; civ. 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. 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. 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 the CDRL1, the CDRL2, the CDRL3, the CDRH1, the CDRH2, and the 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 (VL) and a heavy chain variable region (VH), wherein the VL and the VH comprise amino acid sequences selected from: i. SEQ ID NO: 1 and SEQ ID NO: 158, respectively;n. SEQ ID NO: 2 and SEQ ID NO: 159, respectively; iii. SEQ ID NO: 3 and SEQ ID NO: 160, respectively; iv. SEQ ID NO: 4 and SEQ ID NO: 161, respectively; v. SEQ ID NO: 5 and SEQ ID NO: 162, respectively; vi. SEQ ID NO: 6 and SEQ ID NO: 163, respectively; vii. SEQ ID NO: 7 and SEQ ID NO: 164, respectively; viii. SEQ ID NO: 8 and SEQ ID NO: 165, respectively; ix. SEQ ID NO: 9 and SEQ ID NO: 166, respectively; x. SEQ ID NO: 10 and SEQ ID NO: 167, respectively xi. SEQ ID NO: 11 and SEQ ID NO: 168, respectively; xii. SEQ ID NO: 12 and SEQ ID NO: 169, respectively; xiii. SEQ ID NO: 13 and SEQ ID NO: 170, respectively; xiv. SEQ ID NO: 14 and SEQ ID NO: 171, respectively; xv. SEQ ID NO: 15 and SEQ ID NO: 172, respectively; xvi. SEQ ID NO: 16 and SEQ ID NO: 173, respectively; xvii. SEQ ID NO: 17 and SEQ ID NO: 174, respectively; xviii. SEQ ID NO: 18 and SEQ ID NO: 175, respectively; xix. SEQ ID NO: 19 and SEQ ID NO: 176, respectively; xx. SEQ ID NO: 20 and SEQ ID NO: 177, respectively; xxi. SEQ ID NO: 21 and SEQ ID NO: 178, respectively; xxii. SEQ ID NO: 22 and SEQ ID NO: 179, respectively; xxiii. SEQ ID NO: 23 and SEQ ID NO: 180, respectively; xxiv. SEQ ID NO: 24 and SEQ ID NO: 181, respectively; xxv. SEQ ID NO: 25 and SEQ ID NO: 182, respectively; xxvi. SEQ ID NO: 26 and SEQ ID NO: 183, respectively; xxvii. SEQ ID NO: 27 and SEQ ID NO: 184, respectively; xxviii. SEQ ID NO: 28 and SEQ ID NO: 185, respectively; xxix. SEQ ID NO: 29 and SEQ ID NO: 186, respectively; xxx. SEQ ID NO: 30 and SEQ ID NO: 187, respectively; xxxi. SEQ ID NO: 31 and SEQ ID NO: 188, respectively; xxxii. SEQ ID NO: 32 and SEQ ID NO: 189, respectively; xxxiii. SEQ ID NO: 33 and SEQ ID NO: 190, respectively; xxxiv. SEQ ID NO: 34 and SEQ ID NO: 191, respectively; xxxv. SEQ ID NO: 35 and SEQ ID NO: 192, respectively;xxxvi. SEQ ID NO: 36 and SEQ ID NO: 193, respectively; xxxvii. SEQ ID NO: 37 and SEQ ID NO: 194, respectively; xxxviii. SEQ ID NO: 38 and SEQ ID NO: 195, respectively; xxxix. SEQ ID NO: 39 and SEQ ID NO: 196, respectively; xl. SEQ ID NO: 40 and SEQ ID NO: 197, respectively; xli. SEQ ID NO: 41 and SEQ ID NO: 198, respectively; xlii. SEQ ID NO: 42 and SEQ ID NO: 199, respectively; xliii. SEQ ID NO: 43 and SEQ ID NO: 200, respectively; xliv. SEQ ID NO: 44 and SEQ ID NO: 201, respectively; xlv. SEQ ID NO: 45 and SEQ ID NO: 202, respectively; xlvi. SEQ ID NO: 46 and SEQ ID NO: 203, respectively; xlvii. SEQ ID NO: 47 and SEQ ID NO: 204, respectively; xlviii. SEQ ID NO: 48 and SEQ ID NO: 205, respectively; xlix. SEQ ID NO: 49 and SEQ ID NO: 206, respectively; 1. SEQ ID NO: 50 and SEQ ID NO: 207, respectively; li. SEQ ID NO: 51 and SEQ ID NO: 208, respectively; lii. SEQ ID NO: 52 and SEQ ID NO: 209, respectively; liii. SEQ ID NO: 53 and SEQ ID NO: 210, respectively; liv. SEQ ID NO: 54 and SEQ ID NO: 211, respectively; Iv. SEQ ID NO: 55 and SEQ ID NO: 212, respectively; Ivi. SEQ ID NO: 56 and SEQ ID NO: 213, respectively; Ivii. SEQ ID NO: 57 and SEQ ID NO: 214, respectively; Iviii. SEQ ID NO: 58 and SEQ ID NO: 215, respectively; lix. SEQ ID NO: 59 and SEQ ID NO: 216, respectively; lx. SEQ ID NO: 60 and SEQ ID NO: 217, respectively; Ixi. SEQ ID NO: 61 and SEQ ID NO: 218, respectively; Ixii. SEQ ID NO: 62 and SEQ ID NO: 219, respectively; Ixiii. SEQ ID NO: 63 and SEQ ID NO: 220, respectively; Ixiv. SEQ ID NO: 64 and SEQ ID NO: 221, respectively; Ixv. SEQ ID NO: 65 and SEQ ID NO: 222, respectively; Ixvi. SEQ ID NO: 66 and SEQ ID NO: 223, respectively; Ixvii. SEQ ID NO: 67 and SEQ ID NO: 224, respectively; Ixviii. SEQ ID NO: 68 and SEQ ID NO: 225, respectively; Ixix. SEQ ID NO: 69 and SEQ ID NO: 226, respectively;Ixx. SEQ ID NO: 70 and SEQ ID NO: 227, respectively;Ixxi. SEQ ID NO: 71 and SEQ ID NO: 228, respectively;Ixxii. SEQ ID NO: 72 and SEQ ID NO: 229, respectively;Ixxiii. SEQ ID NO: 73 and SEQ ID NO: 230, respectively;Ixxiv. SEQ ID NO: 74 and SEQ ID NO: 231, respectively;Ixxv. SEQ ID NO: 75 and SEQ ID NO: 232, respectively;Ixxvi. SEQ ID NO: 76 and SEQ ID NO: 233, respectively;Ixxvii. SEQ ID NO: 77 and SEQ ID NO: 234, respectively;Ixxviii. SEQ ID NO: 78 and SEQ ID NO: 235, respectively;Ixxix. SEQ ID NO: 79 and SEQ ID NO: 236, respectively;Ixxx. SEQ ID NO: 80 and SEQ ID NO: 237, respectively;Ixxxi. SEQ ID NO: 81 and SEQ ID NO: 238, respectively;Ixxxii. SEQ ID NO: 82 and SEQ ID NO: 239, respectively;Ixxxiii. SEQ ID NO: 83 and SEQ ID NO: 240, respectively;Ixxxiv. SEQ ID NO: 84 and SEQ ID NO: 241, respectively;Ixxxv. SEQ ID NO: 85 and SEQ ID NO: 242, respectively;Ixxxvi. SEQ ID NO: 86 and SEQ ID NO: 243, respectively;Ixxxvii. SEQ ID NO: 87 and SEQ ID NO: 244, respectively;Ixxxviii. SEQ ID NO: 88 and SEQ ID NO: 245, respectively;Ixxxix. SEQ ID NO: 89 and SEQ ID NO: 246, respectively; xc. SEQ ID NO: 90 and SEQ ID NO: 247, respectively; xci. SEQ ID NO: 91 and SEQ ID NO: 248, respectively; xcii. SEQ ID NO: 92 and SEQ ID NO: 249, respectively; xciii. SEQ ID NO: 93 and SEQ ID NO: 250, respectively; xciv. SEQ ID NO: 94 and SEQ ID NO: 251, respectively; xcv. SEQ ID NO: 95 and SEQ ID NO: 252, respectively; xcvi. SEQ ID NO: 96 and SEQ ID NO: 253, respectively; xcvii. SEQ ID NO: 97 and SEQ ID NO: 254, respectively; xcviii. SEQ ID NO: 98 and SEQ ID NO: 255, respectively; xcix. SEQ ID NO: 99 and SEQ ID NO: 256, respectively; c. SEQ ID NO: 100 and SEQ ID NO: 257, respectively; ci. SEQ ID NO: 101 and SEQ ID NO: 258, respectively; cii. SEQ ID NO: 102 and SEQ ID NO: 259, respectively; ciii. SEQ ID NO: 103 and SEQ ID NO: 260, respectively;civ. SEQ ID NO: 104 and SEQ ID NO: 261, respectively; cv. SEQ ID NO: 105 and SEQ ID NO: 262, respectively; cvi. SEQ ID NO: 106 and SEQ ID NO: 263, respectively; cvii. SEQ ID NO: 107 and SEQ ID NO: 264, respectively; cviii. SEQ ID NO: 108 and SEQ ID NO: 265, respectively; cix. SEQ ID NO: 109 and SEQ ID NO: 266, respectively; ex. SEQ ID NO: 110 and SEQ ID NO: 267, respectively; cxi. SEQ ID NO: 111 and SEQ ID NO: 268, respectively; cxii. SEQ ID NO: 112 and SEQ ID NO: 269, respectively; cxiii. SEQ ID NO: 113 and SEQ ID NO: 270, respectively; cxiv. SEQ ID NO: 114 and SEQ ID NO: 271, respectively; cxv. SEQ ID NO: 115 and SEQ ID NO: 272, respectively; cxvi. SEQ ID NO: 116 and SEQ ID NO: 273, respectively; cxvii. SEQ ID NO: 117 and SEQ ID NO: 274, respectively; cxviii. SEQ ID NO: 118 and SEQ ID NO: 275, respectively; cxix. SEQ ID NO: 119 and SEQ ID NO: 276, respectively; cxx. SEQ ID NO: 120 and SEQ ID NO: 277, respectively; exxi. SEQ ID NO: 121 and SEQ ID NO: 278, respectively; exxii. SEQ ID NO: 122 and SEQ ID NO: 279, respectively; cxxiii. SEQ ID NO: 123 and SEQ ID NO: 280, respectively; exxiv. SEQ ID NO: 124 and SEQ ID NO: 281, respectively; exxv. SEQ ID NO: 125 and SEQ ID NO: 282, respectively; exxvi. SEQ ID NO: 126 and SEQ ID NO: 283, respectively; cxxvii. SEQ ID NO: 127 and SEQ ID NO: 284, respectively; cxxviii. SEQ ID NO: 128 and SEQ ID NO: 285, respectively; cxxix. SEQ ID NO: 129 and SEQ ID NO: 286, respectively; exxx. SEQ ID NO: 130 and SEQ ID NO: 287, respectively; cxxxi. SEQ ID NO: 131 and SEQ ID NO: 288, respectively; cxxxii. SEQ ID NO: 132 and SEQ ID NO: 289, respectively; cxxxiii. SEQ ID NO: 133 and SEQ ID NO: 290, respectively; cxxxi v. SEQ ID NO: 134 and SEQ ID NO: 291, respectively; cxxxv. SEQ ID NO: 135 and SEQ ID NO: 292, respectively; cxxxvi. SEQ ID NO: 136 and SEQ ID NO: 293, respectively; cxxxvii. SEQ ID NO: 137 and SEQ ID NO: 294, respectively;cxxxviii. SEQ ID NO: 138 and SEQ ID NO: 295, respectively; cxxxix. SEQ ID NO: 139 and SEQ ID NO: 296, respectively; cxl. SEQ ID NO: 140 and SEQ ID NO: 297, respectively; cxli. SEQ ID NO: 141 and SEQ ID NO: 298, respectively; cxlii. SEQ ID NO: 142 and SEQ ID NO: 299, respectively; cxliii. SEQ ID NO: 143 and SEQ ID NO: 300, respectively; cxliv. SEQ ID NO: 144 and SEQ ID NO: 301, respectively; cxlv. SEQ ID NO: 145 and SEQ ID NO: 302, respectively; cxlvi. SEQ ID NO: 146 and SEQ ID NO: 303, respectively; cxlvii. SEQ ID NO: 147 and SEQ ID NO: 304, respectively; cxlviii. SEQ ID NO: 148 and SEQ ID NO: 305, respectively; cxlix. SEQ ID NO: 149 and SEQ ID NO: 306, respectively; cl. SEQ ID NO: 150 and SEQ ID NO: 307, respectively; cli. SEQ ID NO: 151 and SEQ ID NO: 308, respectively; clii. SEQ ID NO: 152 and SEQ ID NO: 309, respectively; cliii. SEQ ID NO: 153 and SEQ ID NO: 310, respectively; cliv. SEQ ID NO: 154 and SEQ ID NO: 311, respectively; civ. SEQ ID NO: 155 and SEQ ID NO: 312, respectively; clvi. SEQ ID NO: 156 and SEQ ID NO: 313, respectively; and clvii. SEQ ID NO: 157 and SEQ ID NO: 314, respectively.

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

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 heavy chain comprise amino acid sequences selected from: i. SEQ ID NO: 315 and SEQ ID NO: 472, respectively; ii. SEQ ID NO: 316 and SEQ ID NO: 473, respectively; iii. SEQ ID NO: 317 and SEQ ID NO: 474, respectively; iv. SEQ ID NO: 318 and SEQ ID NO: 475, respectively; v. SEQ ID NO: 319 and SEQ ID NO: 476, respectively; vi. SEQ ID NO: 320 and SEQ ID NO: 477, respectively; vii. SEQ ID NO: 321 and SEQ ID NO: 478, respectively;viii. SEQ ID NO: 322 and SEQ ID NO: 479, respectively; ix. SEQ ID NO: 323 and SEQ ID NO: 480, respectively; x. SEQ ID NO: 324 and SEQ ID NO: 481, respectively; xi. SEQ ID NO: 325 and SEQ ID NO: 482, respectively; xii. SEQ ID NO: 326 and SEQ ID NO: 483, respectively; xiii. SEQ ID NO: 327 and SEQ ID NO: 484, respectively; xiv. SEQ ID NO: 328 and SEQ ID NO: 485, respectively; xv. SEQ ID NO: 329 and SEQ ID NO: 486, respectively; xvi. SEQ ID NO: 330 and SEQ ID NO: 487, respectively; xvii. SEQ ID NO: 331 and SEQ ID NO: 488, respectively; xviii. SEQ ID NO: 332 and SEQ ID NO: 489, respectively; xix. SEQ ID NO: 333 and SEQ ID NO: 490, respectively;XX. SEQ ID NO: 334 and SEQ ID NO: 491, respectively; xxi. SEQ ID NO: 335 and SEQ ID NO: 492, respectively; xxii. SEQ ID NO: 336 and SEQ ID NO: 493, respectively; xxiii. SEQ ID NO: 337 and SEQ ID NO: 494, respectively; xxiv. SEQ ID NO: 338 and SEQ ID NO: 495, respectively; xxv. SEQ ID NO: 339 and SEQ ID NO: 496, respectively; xxvi. SEQ ID NO: 340 and SEQ ID NO: 497, respectively; xxvii. SEQ ID NO: 341 and SEQ ID NO: 498, respectively; xxviii. SEQ ID NO: 342 and SEQ ID NO: 499, respectively; xxix. SEQ ID NO: 343 and SEQ ID NO: 500, respectively; xxx. SEQ ID NO: 344 and SEQ ID NO: 501, respectively; xxxi. SEQ ID NO: 345 and SEQ ID NO: 502, respectively; xxxii. SEQ ID NO: 346 and SEQ ID NO: 503, respectively; xxxiii. SEQ ID NO: 347 and SEQ ID NO: 504, respectively; xxxiv. SEQ ID NO: 348 and SEQ ID NO: 505, respectively; xxxv. SEQ ID NO: 349 and SEQ ID NO: 506, respectively; xxxvi. SEQ ID NO: 350 and SEQ ID NO: 507, respectively; xxxvii. SEQ ID NO: 351 and SEQ ID NO: 508, respectively; xxxviii. SEQ ID NO: 352 and SEQ ID NO: 509, respectively; xxxix. SEQ ID NO: 353 and SEQ ID NO: 510, respectively; xl. SEQ ID NO: 354 and SEQ ID NO: 511, respectively; xli. SEQ ID NO: 355 and SEQ ID NO: 512, respectively;xlii. SEQ ID NO: 356 and SEQ ID NO: 513, respectively; xliii. SEQ ID NO: 357 and SEQ ID NO: 514, respectively; xliv. SEQ ID NO: 358 and SEQ ID NO: 515, respectively; xlv. SEQ ID NO: 359 and SEQ ID NO: 516, respectively; xlvi. SEQ ID NO: 360 and SEQ ID NO: 517, respectively; xlvii. SEQ ID NO: 361 and SEQ ID NO: 518, respectively; xlviii. SEQ ID NO: 362 and SEQ ID NO: 519, respectively; xlix. SEQ ID NO: 363 and SEQ ID NO: 520, respectively;1. SEQ ID NO: 364 and SEQ ID NO: 521, respectively; li. SEQ ID NO: 365 and SEQ ID NO: 522, respectively; lii. SEQ ID NO: 366 and SEQ ID NO: 523, respectively; liii. SEQ ID NO: 367 and SEQ ID NO: 524, respectively; liv. SEQ ID NO: 368 and SEQ ID NO: 525, respectively;Iv. SEQ ID NO: 369 and SEQ ID NO: 526, respectively;Ivi. SEQ ID NO: 370 and SEQ ID NO: 527, respectively;Ivii. SEQ ID NO: 371 and SEQ ID NO: 528, respectively;Iviii. SEQ ID NO: 372 and SEQ ID NO: 529, respectively; lix. SEQ ID NO: 373 and SEQ ID NO: 530, respectively; lx. SEQ ID NO: 374 and SEQ ID NO: 531, respectively;Ixi. SEQ ID NO: 375 and SEQ ID NO: 532, respectively;Ixii. SEQ ID NO: 376 and SEQ ID NO: 533, respectively;Ixiii. SEQ ID NO: 377 and SEQ ID NO: 534, respectively;Ixiv. SEQ ID NO: 378 and SEQ ID NO: 535, respectively;Ixv. SEQ ID NO: 379 and SEQ ID NO: 536, respectively;Ixvi. SEQ ID NO: 380 and SEQ ID NO: 537, respectively;Ixvii. SEQ ID NO: 381 and SEQ ID NO: 538, respectively;Ixviii. SEQ ID NO: 382 and SEQ ID NO: 539, respectively;Ixix. SEQ ID NO: 383 and SEQ ID NO: 540, respectively;Ixx. SEQ ID NO: 384 and SEQ ID NO: 541, respectively;Ixxi. SEQ ID NO: 385 and SEQ ID NO: 542, respectively;Ixxii. SEQ ID NO: 386 and SEQ ID NO: 543, respectively;Ixxiii. SEQ ID NO: 387 and SEQ ID NO: 544, respectively;Ixxiv. SEQ ID NO: 388 and SEQ ID NO: 545, respectively;Ixxv. SEQ ID NO: 389 and SEQ ID NO: 546, respectively;Ixxvi. SEQ ID NO: 390 and SEQ ID NO: 547, respectively;Ixxvii. SEQ ID NO: 391 and SEQ ID NO: 548, respectively;Ixxviii. SEQ ID NO: 392 and SEQ ID NO: 549, respectively;Ixxix. SEQ ID NO: 393 and SEQ ID NO: 550, respectively;Ixxx. SEQ ID NO: 394 and SEQ ID NO: 551, respectively;Ixxxi. SEQ ID NO: 395 and SEQ ID NO: 552, respectively;Ixxxii. SEQ ID NO: 396 and SEQ ID NO: 553, respectively;Ixxxiii. SEQ ID NO: 397 and SEQ ID NO: 554, respectively;Ixxxiv. SEQ ID NO: 398 and SEQ ID NO: 555, respectively;Ixxxv. SEQ ID NO: 399 and SEQ ID NO: 556, respectively;Ixxxvi. SEQ ID NO: 400 and SEQ ID NO: 557, respectively;Ixxxvii. SEQ ID NO: 401 and SEQ ID NO: 558, respectively;Ixxxviii. SEQ ID NO: 402 and SEQ ID NO: 559, respectively;Ixxxix. SEQ ID NO: 403 and SEQ ID NO: 560, respectively; xc. SEQ ID NO: 404 and SEQ ID NO: 561, respectively; xci. SEQ ID NO: 405 and SEQ ID NO: 562, respectively; xcii. SEQ ID NO: 406 and SEQ ID NO: 563, respectively; xciii. SEQ ID NO: 407 and SEQ ID NO: 564, respectively; xciv. SEQ ID NO: 408 and SEQ ID NO: 565, respectively; xcv. SEQ ID NO: 409 and SEQ ID NO: 566, respectively; xcvi. SEQ ID NO: 410 and SEQ ID NO: 567, respectively; xcvii. SEQ ID NO: 411 and SEQ ID NO: 568, respectively; xcviii. SEQ ID NO: 412 and SEQ ID NO: 569, respectively; xcix. SEQ ID NO: 413 and SEQ ID NO: 570, respectively; c. SEQ ID NO: 414 and SEQ ID NO: 571, respectively; ci. SEQ ID NO: 415 and SEQ ID NO: 572, respectively; cii. SEQ ID NO: 416 and SEQ ID NO: 573, respectively; ciii. SEQ ID NO: 417 and SEQ ID NO: 574, respectively; civ. SEQ ID NO: 418 and SEQ ID NO: 575, respectively; cv. SEQ ID NO: 419 and SEQ ID NO: 576, respectively; cvi. SEQ ID NO: 420 and SEQ ID NO: 577, respectively; cvii. SEQ ID NO: 421 and SEQ ID NO: 578, respectively; cviii. SEQ ID NO: 422 and SEQ ID NO: 579, respectively; cix. SEQ ID NO: 423 and SEQ ID NO: 580, respectively;ex. SEQ ID NO: 424 and SEQ ID NO: 581, respectively; cxi. SEQ ID NO: 425 and SEQ ID NO: 582, respectively; cxii. SEQ ID NO: 426 and SEQ ID NO: 583, respectively; cxiii. SEQ ID NO: 427 and SEQ ID NO: 584, respectively; cxiv. SEQ ID NO: 428 and SEQ ID NO: 585, respectively; cxv. SEQ ID NO: 429 and SEQ ID NO: 586, respectively; cxvi. SEQ ID NO: 430 and SEQ ID NO: 587, respectively; cxvii. SEQ ID NO: 431 and SEQ ID NO: 588, respectively; cxviii. SEQ ID NO: 432 and SEQ ID NO: 589, respectively; cxix. SEQ ID NO: 433 and SEQ ID NO: 590, respectively; cxx. SEQ ID NO: 434 and SEQ ID NO: 591, respectively; exxi. SEQ ID NO: 435 and SEQ ID NO: 592, respectively; exxii. SEQ ID NO: 436 and SEQ ID NO: 593, respectively; cxxiii. SEQ ID NO: 437 and SEQ ID NO: 594, respectively; exxiv. SEQ ID NO: 438 and SEQ ID NO: 595, respectively; exxv. SEQ ID NO: 439 and SEQ ID NO: 596, respectively; exxvi. SEQ ID NO: 440 and SEQ ID NO: 597, respectively; cxxvii. SEQ ID NO: 441 and SEQ ID NO: 598, respectively; cxxviii. SEQ ID NO: 442 and SEQ ID NO: 599, respectively; cxxix. SEQ ID NO: 443 and SEQ ID NO: 600, respectively; exxx. SEQ ID NO: 444 and SEQ ID NO: 601, respectively; cxxxi. SEQ ID NO: 445 and SEQ ID NO: 602, respectively; cxxxii. SEQ ID NO: 446 and SEQ ID NO: 603, respectively; cxxxiii. SEQ ID NO: 447 and SEQ ID NO: 604, respectively; cxxxiv. SEQ ID NO: 448 and SEQ ID NO: 605, respectively; cxxxv. SEQ ID NO: 449 and SEQ ID NO: 606, respectively; cxxxvi. SEQ ID NO: 450 and SEQ ID NO: 607, respectively; cxxxvii. SEQ ID NO: 451 and SEQ ID NO: 608, respectively; cxxxviii. SEQ ID NO: 452 and SEQ ID NO: 609, respectively; cxxxix. SEQ ID NO: 453 and SEQ ID NO: 610, respectively; cxl. SEQ ID NO: 454 and SEQ ID NO: 611, respectively; cxli. SEQ ID NO: 455 and SEQ ID NO: 612, respectively; cxiii. SEQ ID NO: 456 and SEQ ID NO: 613, respectively; exliii. SEQ ID NO: 457 and SEQ ID NO: 614, respectively;cxliv. SEQ ID NO: 458 and SEQ ID NO: 615, respectively; cxlv. SEQ ID NO: 459 and SEQ ID NO: 616, respectively; cxlvi. SEQ ID NO: 460 and SEQ ID NO: 617, respectively; cxlvii. SEQ ID NO: 461 and SEQ ID NO: 618, respectively; cxlviii. SEQ ID NO: 462 and SEQ ID NO: 619, respectively; cxlix. SEQ ID NO: 463 and SEQ ID NO: 620, respectively; cl. SEQ ID NO: 464 and SEQ ID NO: 621, respectively; cli. SEQ ID NO: 465 and SEQ ID NO: 622, respectively; clii. SEQ ID NO: 466 and SEQ ID NO: 623, respectively; cliii. SEQ ID NO: 467 and SEQ ID NO: 624, respectively; cliv. SEQ ID NO: 468 and SEQ ID NO: 625, respectively; civ. SEQ ID NO: 469 and SEQ ID NO: 626, respectively; clvi. SEQ ID NO: 470 and SEQ ID NO: 627, respectively; and clvii. SEQ ID NO: 471 and SEQ ID NO: 628, respectively, wherein the antibody comprises one or more cysteine amino acid substitution(s) at one or more position(s) selected from 88 of the light chain, 384 of the heavy chain, or 487 of the heavy chain, according to AHo numbering.

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

47. The conjugate molecule of claim 46, wherein each light chain comprises a VL of SEQ ID NO: 74, and each heavy chain comprises a 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: an antagonist anti-glucose-dependent insulinotropic polypeptide receptor (GIPR) antibody, wherein the anti-GIPR antibody comprises: a first and second light chain, each light chain comprising a CDRL1, a CDRL2, and a CDRL3 of SEQ ID NO: 702, SEQ ID NO: 859, and SEQ ID NO: 1016, respectively, and a first and second heavy chain, each heavy chain comprising a CDRH1, a CDRH2, and a CDRH3 of SEQ ID NO: 1173, SEQ ID NO: 1330, and SEQ ID NO: 1487, respectively; a first and second GLP-1 receptor agonist polypeptide, wherein each GLP-1 receptor agonist polypeptide comprises the amino acid sequence of SEQ ID NO: 1580; and a first and second peptide linker, wherein each peptide linker comprises the amino acid sequence of SEQ ID NO: 1591; wherein the first GLP-1 receptor agonist polypeptide is conjugated, at its C- terminus via the first linker, to the first heavy chain of the anti-GIPR antibody at a cysteine residue at position 384 of the first heavy chain according to AHo numbering, and wherein the second GLP-1 receptor agonist polypeptide is conjugated, at its C- terminus via the second linker, to the second heavy chain of the anti-GIPR antibody at a cysteine residue at position 384 of the second heavy chain according to AHo numbering.

50. The conjugate molecule of claim 49, wherein each light chain comprises a VL of SEQ ID NO: 74, and each heavy chain comprises a 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: an antagonist anti-glucose-dependent insulinotropic polypeptide receptor (GIPR) antibody, wherein the anti-GIPR antibody comprises: a first and second light chain, each light chain comprising a CDRL1, a CDRL2, and a CDRL3 of SEQ ID NO: 702, SEQ ID NO: 859, and SEQ ID NO: 1016, respectively, and a first and second heavy chain, each heavy chain comprising a CDRH1, a CDRH2, and a CDRH3 of SEQ ID NO: 1173, SEQ ID NO: 1330, and SEQ ID NO: 1487, respectively; a first and second GLP-1 receptor agonist polypeptide, wherein each GLP-1 receptor agonist polypeptide comprises the amino acid sequence of SEQ ID NO: 1581; and a first and second peptide linker, wherein each peptide linker comprises the amino acid sequence of SEQ ID NO: 1586; wherein the first GLP-1 receptor agonist polypeptide is conjugated, at its C- terminus via the first linker, to the first heavy chain of the anti-GIPR antibody at a cysteine residue at position 384 of the first heavy chain according to AHo numbering, and wherein the second GLP-1 receptor agonist polypeptide is conjugated, at its C- terminus via the second linker, to the second heavy chain of the anti-GIPR antibody at a cysteine residue at position 384 of the second heavy chain according to AHo numbering.

53. The conjugate molecule of claim 52, wherein each light chain comprises a VL of SEQ ID NO: 74, and each heavy chain comprises a 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: an antagonist anti-glucose-dependent insulinotropic polypeptide receptor (GIPR) antibody, wherein the anti-GIPR antibody comprises: a first and second light chain, each light chain comprising a CDRL1, a CDRL2, and a CDRL3 of SEQ ID NO: 702, SEQ ID NO: 859, and SEQ ID NO: 1016, respectively, anda first and second heavy chain, each heavy chain comprising a CDRH1, a CDRH2, and a CDRH3 of SEQ ID NO: 1173, SEQ ID NO: 1330, and SEQ ID NO: 1487, respectively; a first and second GLP-1 receptor agonist polypeptide, wherein each GLP-1 receptor agonist polypeptide comprises the amino acid sequence of SEQ ID NO: 1581; and a first and second peptide linker, wherein each peptide linker comprises the amino acid sequence of SEQ ID NO: 1585; wherein the first GLP-1 receptor agonist polypeptide is conjugated, at its C- terminus via the first linker, to the first heavy chain of the anti-GIPR antibody at a cysteine residue at position 275 of the first heavy chain, and wherein the second GLP-1 receptor agonist polypeptide is conjugated, at its C- terminus via the second linker, to the second heavy chain of the anti-GIPR antibody at a cysteine residue at position 275 of the second heavy chain.

56. The conjugate molecule of claim 55, wherein each light chain comprises a VL of SEQ ID NO: 74, and each heavy chain comprises a 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: a 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; and a pharmaceutically acceptable excipient.

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

60. A method of treating obesity or an obesity related condition in a subject in need thereof, the method comprising:administering, to the subject, the GLP-1 receptor agonist polypeptide of any one of claims 1 to 10, the molecule of any one of claims 11 to 16, the conjugate molecule of any one of claims 17 to 57, or the pharmaceutical composition of 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 kidney failure, and metabolic dysfunction-associated steatohepatitis.

62. A method of treating type 2 diabetes or a type 2 diabetes related condition in a subject in need thereof, the method comprising: administering, to the subject, the GLP-1 receptor agonist polypeptide of any one of claims 1 to 10, the molecule of any one of claims 11 to 17, the conjugate molecule of any one of claims 17 to 57, or the pharmaceutical composition of claim 58.

63. The method of claim 62, wherein the type 2 diabetes related conditions is selected from the group consisting of hypertension, high blood sugar, diabetic kidney disease, and diabetic kidney 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 medicament.

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