Modulators for gipr, glp1r and / or gcgr and uses thereof

Abstract

Disclosed herein are novel modulators of GIPR, GLP-1R, and / or GCGR. In particular, provided herein are antibodies, oxyntomodulin analogue peptides, and antibody-peptide conjugates (APC) that specifically bind to GIPR, the antibody-peptide conjugates comprising an anti-GIPR antibody and an agonist of GLP-1R and / or GCGR (e.g., oxyntomodulin analogue). Also provided are pharmaceutical compositions comprising these modulators disclosed herein, and the use of the pharmaceutical compositions in the treatment of metabolic conditions and disorders, such as diabetes (e.g., type 2 diabetes), NASH, overweight, and obesity.

Description

1. Electronic submission of sequence listing

[0001] The sequence listing incorporated by reference in the present application is an XML file named "sequence listing.xml" which was created on May 29, 2025 and has a size of 125,911 bytes. 2. Related Applications

[0002] This application claims priority to PCT Patent Application No. PCT / CN2024 / 097088, filed June 3, 2024, which is incorporated by reference herein in its entirety. 3. TECHNICAL FIELD

[0003] The present application relates to molecular biology, cell biology, and medicine. In particular, the present application relates to novel biological agents capable of modulating metabolic regulation and useful for treating metabolic disorders. 4. BACKGROUND

[0004] Gastric inhibitory polypeptide receptor (GIPR), glucagon-like peptide-1 receptor (GLP1R), and glucagon receptor (GCGR) are indispensable for the regulation of glucose metabolism, lipid metabolism, and insulin secretion. Incretin-based therapies target GIPR and GLP1R, which enhance insulin release in response to a meal, thereby improving glycemic control in diabetic patients. In particular, GLP1R agonists show great promise not only in managing blood glucose levels, but also in promoting weight loss and reducing cardiovascular risk. Meanwhile, antagonizing GCGR has potential benefits in lowering blood glucose levels at least in part by reducing glucose production in the liver. In contrast, GCGR activation stimulates hepatic fatty acid oxidation. With the rising prevalence of metabolic disorders such as diabetes and obesity worldwide, the continued research and development of drugs targeting these receptors are of particular importance, highlighting the urgent need for more effective therapeutic agents that can address these complex diseases through multiple pathways.

[0005] The compositions and methods disclosed herein address these unmet needs and provide related advantages. 5. SUMMARY

[0006] Provided herein are antibodies or antigen-binding fragments thereof that specifically bind human GIPR, the antibodies or antigen-binding fragments thereof comprising: (a) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from a VL having an amino acid sequence selected from the group consisting of SEQ ID NOs: 24, 26, 28, and 30, or a variant thereof having up to about 5 amino acid substitutions, additions and / or deletions in these VL CDRs; and / or (b) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 from a VH having an amino acid sequence selected from the group consisting of SEQ ID NOs: 25, 27, 29, and 31, or a variant thereof having up to about 5 amino acid substitutions, additions and / or deletions in these VH CDRs.

[0007] In some embodiments, the VL comprises a VL CDR1 having an amino acid sequence of SEQ ID NO: 1 or 8, a VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 9, and 10, and a VL CDR3 having an amino acid sequence of SEQ ID NO: 3 or 11, or a variant thereof having up to about 5 amino acid substitutions, additions and / or deletions in these VL CDRs; and / or (b) the VH comprises a VH CDR1 having an amino acid sequence of SEQ ID NO: 4 or 12, a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 5, 6, and 13, and a VH CDR3 having an amino acid sequence of SEQ ID NO: 7 or 14, or a variant thereof having up to about 5 amino acid substitutions, additions and / or deletions in these VH CDRs.

[0008] In some embodiments, the antibodies or antigen-binding fragments described herein comprise a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having an amino acid sequence selected from the group consisting of: (1) SEQ ID NOs: 1, 2, 3, 4, 5, and 7, respectively; (2) SEQ ID NOs: 1, 2, 3, 4, 6, and 7, respectively; (3) SEQ ID NOs: 8, 9, 11, 12, 13, and 14, respectively; and (4) SEQ ID NOs: 8, 10, 11, 12, 13, and 14, respectively; or a variant thereof having up to about 5 amino acid substitutions, additions and / or deletions in these CDRs.

[0009] In some embodiments, the antibody or antigen-binding fragment described herein comprises (a) a VL having at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 24, and / or a VH having at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 25; (b) a VL having at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 26, and / or a VH having at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 27; (c) a VL having at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 28, and / or a VH having at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 29; or (d) a VL having at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 30, and / or a VH having at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 31. In some embodiments, the antibody or antigen-binding fragment described herein comprises a VL and a VH having the amino acid sequences of: (1) SEQ ID NOs: 24 and 25, respectively; (2) SEQ ID NOs: 26 and 27, respectively; (3) SEQ ID NOs: 28 and 29, respectively; or (4) SEQ ID NOs: 30 and 31, respectively.

[0010] Provided herein are antibodies or antigen-binding fragments that compete with the anti-GIPR antibodies or antigen-binding fragments described herein for binding to human GIPR.

[0011] In some embodiments, the antibody or antigen-binding fragment described herein is selected from the group consisting of a Fab, a Fab', a F(ab')2, a Fv, a scFv, a (scFv)2, a single domain antibody (sdAb), and a heavy chain antibody (HCAb). In some embodiments, the antibody or antigen-binding fragment described herein is an IgGl antibody, an IgG2 antibody, an IgG3 antibody, or an IgG4 antibody.

[0012] In some embodiments, the antibody or antigen-binding fragment described herein further comprises a light chain constant (CL) region and a heavy chain constant (CH) region. In some embodiments, the CL region is kappa CL (CK; SEQ ID NO: 37) or lambda CL (CL; SEQ ID NO: 38), or a variant thereof having up to ten amino acid substitutions, additions and / or deletions. In some embodiments, the CH region is IgGl CH (SEQ ID NO: 39, 43 or 88), IgG2 CH (SEQ ID NO: 40), IgG3 CH (SEQ ID NO: 41), or IgG4 CH (SEQ ID NO: 42), or a variant thereof having up to ten amino acid substitutions, additions and / or deletions.

[0013] In some embodiments, the antibody or antigen-binding fragment described herein is an IgGl antibody. In some embodiments, the IgGl antibody has L234A / L235A substitutions in the Fc region. In some embodiments, the IgGl antibody has E272C substitution in the Fc region. In some embodiments, the IgGl antibody has L234A / L235A / E272C substitutions in the Fc region. In some embodiments, the IgGl antibody has M252Y / S254T / T256E substitutions in the Fc region. In some embodiments, the IgGl antibody has E272C / L234A / L235A / M252Y / S254T / T256E substitutions in the Fc region.

[0014] In some embodiments, the antibody or antigen-binding fragment described herein comprises a light chain (LC) and a heavy chain (HC), wherein (1) the LC is at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 48, and the HC is at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 49; (2) the LC is at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 50, and the HC is at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 51; (3) the LC is at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 48, and the HC is at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 89; or (4) the LC is at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 50, and the HC is at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 90.

[0015] In some embodiments, the antibody or antigen-binding fragment described herein is a monoclonal antibody or antigen-binding fragment.

[0016] In some embodiments, the antibody or antigen-binding fragment inhibits the binding of GIP to the extracellular portion of a human GIPR.

[0017] Also provided herein are polynucleotides encoding a peptide of the antibodies or antigen-binding fragments described herein. Also provided herein are vectors comprising the polynucleotides described herein. Also provided herein are host cells comprising the polynucleotides described herein.

[0018] Also provided herein are methods of producing an antibody or antigen-binding fragment thereof that specifically binds to a human GIPR, the method comprising culturing a cell described herein under conditions suitable for expression of the antibody or antigen-binding fragment. In some embodiments, the methods provided herein comprise isolating the antibody or antigen-binding fragment from the culture.

[0019] Provided herein are peptides comprising an oxyntomodulin analog, wherein the oxyntomodulin analog has the amino acid sequence of SEQ ID NO: 55. Provided herein are peptides comprising an oxyntomodulin analog, wherein the oxyntomodulin analog has the amino acid sequence of SEQ ID NO: 56. In some embodiments of the peptides described herein, the C-terminal amino acid is amidated.

[0020] In some embodiments of the peptides described herein, the Lys at position 20 of the oxyntomodulin analog is chemically modified by conjugation of a C14-C24fatty acid to the epsilon-amino group of the Lys side chain. In some embodiments, the fatty acid is conjugated via ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(y-Glu)1-CO-(CH2)2-CO2H t conjugated to Lys, where t is 1 or 2. In some embodiments, Lys is conjugated to ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(yGlu)1-CO-(CH2)2-CO2H 18 ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(yGlu)1-CO-(CH2)2-CO2H (i.e., [2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(yGlu)1-CO-(CH2)2-CO2H 18 -C(O)OH).

[0021] Also provided herein are antibody-peptide conjugates ("APCs") having a structure represented by the following formula: [P-L]n-Ab, where P is a peptide that is a glucagon-like peptide-1 receptor (GLP-1R) and / or glucagon receptor (GCR) agonist; L is a peptide linker or is absent; Ab is an antibody that specifically binds GIPR, an antibody that specifically binds PCSK9, or an Fc region; and n represents a number in the range of 1 to 8.

[0022] In some embodiments, the APCs provided herein have a structure represented by the following formula: [P-L]n-Ab, where: Ab is an antibody or antigen-binding fragment described herein; L is a peptide linker or is absent; P is a peptide that is a glucagon-like peptide-1 receptor (GLP-1R) and / or glucagon receptor (GCR) agonist; and n represents a number in the range of 1 to 8.

[0023] In some embodiments, P is a GLP-1R agonist. In some embodiments, the GLP-1R agonist is exenatide, liraglutide, dulaglutide, semaglutide, albiglutide, lixisenatide, efpeglenatide, and taspoglutide.

[0024] In some embodiments, P is a GCGR agonist. In some embodiments, the GCGR agonist is REMD-477.

[0025] In some embodiments, P is a dual GLP-1R / GCGR agonist. In some embodiments, P is oxyntomodulin or an oxyntomodulin analog. In some embodiments, P is an oxyntomodulin analog. In some embodiments, the oxyntomodulin analog has the amino acid sequence of SEQ ID NO: 55 or 56, or a variant thereof having up to 5 amino acid substitutions, additions and / or deletions. In some embodiments, the oxyntomodulin analog has the amino acid sequence of SEQ ID NO: 55. In some embodiments, the oxyntomodulin analog has the amino acid sequence of SEQ ID NO: 56.

[0026] In some embodiments, the Lys at position 20 of the oxyntomodulin analog is chemically modified by conjugation of a C14-C24fatty acid to the epsilon-amino group of the Lys side chain. In some embodiments, the fatty acid is conjugated via ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(y-Glu)1-CO-(CH2)2-CO2H t conjugated to Lys, where t is 1 or 2. In some embodiments, Lys is conjugated to ([2-(2-amino- ethoxy)-ethoxy]-acetyl)2-(yGlu)1-CO-(CH2)2-CO2H 18 -CO2H.

[0027] In some embodiments of the APC disclosed herein, L has an amino acid sequence selected from the group consisting of (GGGGS)3(SEQ ID NO: 81), (GGGGS)2(SEQ ID NO: 82), GGGGS (SEQ ID NO: 83), VA, VC, VKG, and GGFG (SEQ ID NO: 84). In some embodiments, P-L has an amino acid sequence selected from the group consisting of SEQ ID NOs: 61-68 and 71-78.

[0028] In some embodiments, P-L is conjugated to Ab via linker (C). In some embodiments, linker (C) has the following structure:

[0029] In some embodiments, provided herein are APCs having a structure represented by the following formula: [P-L]n-Ab, wherein P is a peptide described herein; L is a peptide linker or is absent; Ab is an antibody that specifically binds GIPR, an antibody that specifically binds PCSK9, or an Fc region; and n represents a number in the range of 1 to 8.

[0030] In some embodiments, Ab is an antibody that specifically binds GIPR. In some embodiments, Ab is 2G10.

[0031] In some embodiments, Ab is an antibody that specifically binds PCSK9. In some embodiments, Ab is toriselumab, alirocumab, or evolocumab.

[0032] In some embodiments, Ab is an Fc region.

[0033] In some embodiments, L has an amino acid sequence selected from the group consisting of (GGGGS)3(SEQ ID NO: 81), (GGGGS)2(SEQ ID NO: 82), GGGGS (SEQ ID NO: 83), VA, VC, VKG, and GGFG (SEQ ID NO: 84).

[0034] In some embodiments, P-L is conjugated to Ab via linker (C). In some embodiments, linker (C) has the following structure:

[0035] In some embodiments, the APC described herein has the following structure:

[0036] In some embodiments, Ab comprises one or more Cys, and P-L is conjugated to Ab through the side chain of the Cys at one or more conjugation sites. In some embodiments, Ab comprises an IgGl Fc region with an E272C substitution, and P is conjugated to the side chain of the Cys at position 272.

[0037] Provided herein is an APC having the following structure: wherein: Ab is an antibody that specifically binds GIPR, wherein the antibody comprises a LC and a HC having the amino acid sequences of SEQ ID NOs: 48 and 49, respectively; P is a peptide; L is a peptide linker; P-L has the amino acid sequence of SEQ ID NO: 71; and n represents the number 1 or 2.

[0038] Provided herein is an APC having the following structure: wherein: Ab is an antibody that specifically binds GIPR, wherein the antibody comprises a LC and a HC having the amino acid sequences of SEQ ID NOs: 48 and 49, respectively; P is a peptide; L is a peptide linker; P-L has the amino acid sequence of SEQ ID NO: 61; and n represents the number 1 or 2.

[0039] Provided herein is an APC having the following structure: wherein: Ab is an antibody that specifically binds GIPR, wherein the antibody comprises a LC and a HC having the amino acid sequences of SEQ ID NOs: 48 and 89, respectively; P is a peptide; L is a peptide linker; P-L has the amino acid sequence of SEQ ID NO: 71; and n represents the number 1 or 2.

[0040] Provided herein is an APC having the following structure: wherein: Ab is an antibody that specifically binds GIPR, wherein the antibody comprises a LC and a HC having the amino acid sequences of SEQ ID NOs: 48 and 89, respectively; P is a peptide; L is a peptide linker; P-L has the amino acid sequence of SEQ ID NO: 61; and n represents the number 1 or 2.

[0041] Provided herein is an APC having the following structure: wherein: Ab is an antibody that specifically binds GIPR, wherein the antibody comprises a LC and a HC having the amino acid sequences of SEQ ID NOs: 50 and 51, respectively; P is a peptide; L is a peptide linker; P-L has the amino acid sequence of SEQ ID NO: 71; and n represents the number 1 or 2.

[0042] Provided herein is an APC having the following structure: wherein: Ab is an antibody that specifically binds GIPR, wherein the antibody comprises a LC and a HC having the amino acid sequences of SEQ ID NOs: 50 and 51, respectively; P is a peptide; L is a peptide linker; P-L has the amino acid sequence of SEQ ID NO: 61; and n represents the number 1 or 2.

[0043] Provided herein is an APC having the following structure: wherein: Ab is an antibody that specifically binds GIPR, wherein the antibody comprises a LC and a HC having the amino acid sequences of SEQ ID NOs: 50 and 90, respectively; P is a peptide; L is a peptide linker; P-L has the amino acid sequence of SEQ ID NO: 71; and n represents the number 1 or 2.

[0044] Provided herein is an APC having the following structure: wherein: Ab is an antibody that specifically binds GIPR, wherein the antibody comprises a LC and a HC having the amino acid sequences of SEQ ID NOs: 50 and 90, respectively; P is a peptide; L is a peptide linker; P-L has the amino acid sequence of SEQ ID NO: 61; and n represents the number 1 or 2.

[0045] Also provided herein are methods of producing an APC described herein, the method comprising conjugating P-L to Ab.

[0046] Provided herein are methods for making an APC having the structure shown in the following formula: [P-L]n-Ab, wherein: Ab is an antibody or antigen binding fragment; L is a linker; P is a peptide, comprising a) contacting the antibody or antigen binding fragment with a cysteine blocking agent, wherein the cysteine blocking agent forms a stable mixed disulfide with at least one cysteine residue of the antibody or antigen binding fragment; b) contacting the antibody or antigen binding fragment with a reducing agent to form a reduced antibody or antigen binding fragment; and c) contacting the reduced antibody or antigen binding fragment with a peptide having an activated chemical moiety to form the APC; wherein the method does not use an oxidizing agent.

[0047] In some embodiments, the mixed disulfide is an antibody or antigen binding fragment having a capped free cysteine. In some embodiments, the antibody or antigen binding fragment having a capped free cysteine comprises a cap selected from the group consisting of cysteine, cysteamine, cystamine, and glutathione.

[0048] In some embodiments, the methods provided herein further comprise removing excess cysteine blocking agent. In some embodiments, excess cysteine blocking agent is removed by ultrafiltration or cation exchange chromatography.

[0049] In some embodiments, the reducing agent is selected from the group consisting of triphenylphosphine-3,3',3"-trisulfonate ("TPPTS"), tris(2-carboxyethyl)phosphine ("TCEP"), and triphenylphosphine-3,3'-disulfonate ("TPPDS"). In some embodiments, the molar ratio of reducing agent to antibody or antigen binding fragment is 2: 1 to 4: 1.

[0050] In some embodiments, the methods provided herein further comprise removing excess reducing agent. In some embodiments, excess reducing agent is removed by buffer exchange. In some embodiments, the buffer exchange step is ultrafiltration / diafiltration.

[0051] In some embodiments, the activated chemical moiety comprises a halogen, wherein the halogen is selected from the group consisting of Br, I, and Cl. In some embodiments, the molar ratio of peptide having an activated chemical moiety to antibody or antigen binding fragment is 2: 1 to 6: 1.

[0052] In some embodiments, the methods provided herein further comprise step d) removing excess peptide. In some embodiments, the purification step comprises size exclusion chromatography, hydrophobic interaction chromatography ("HIC"), or ultrafiltration / diafiltration, or any combination thereof.

[0053] Also provided herein are pharmaceutical compositions comprising a therapeutically effective amount of an antibody or antigen binding fragment described herein, a peptide described herein, or an APC described herein, and a pharmaceutically acceptable carrier.

[0054] Also provided herein are methods of treating a metabolic condition or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an antibody or antigen-binding fragment described herein, a peptide described herein, or an APC described herein. In some embodiments, the subject is a human.

[0055] Also provided herein are uses of an antibody or antigen-binding fragment described herein, a peptide described herein, or an APC described herein in the treatment of a metabolic condition or disorder. Also provided herein are uses of an antibody or antigen-binding fragment described herein, a peptide described herein, or an APC described herein for the manufacture of a medicament for the treatment of a metabolic condition or disorder.

[0056] In some embodiments, the metabolic condition or disorder is overweight or obesity. In some embodiments, the metabolic condition or disorder is diabetes. In some embodiments, the metabolic condition or disorder is nonalcoholic steatohepatitis (NASH).

[0057] Also provided herein are kits comprising an antibody or antigen-binding fragment described herein, a peptide described herein, or an APC described herein. 6. BRIEF DESCRIPTION OF DRAWINGS

[0058] Figure 1 It is shown that exemplary humanized antibodies Hz32H1.4 and HzS3-90.1 effectively blocked GIP binding to GIPR in cells, comparable to 2G10.

[0059] Figure 2 It is shown that exemplary humanized antibodies Hz32H1.4 and HzS3-90.1 effectively inhibited cAMP secretion, comparable to 2G10.

[0060] Figure 3 It is shown that exemplary humanized antibodies Hz32H1.4 and HzS3-90.1 were effectively internalized by cells, comparable to 2G10.

[0061] Figure 4 The structure of exemplary peptide-linker p007 is shown.

[0062] Figure 5 Representative LCMS results for exemplary peptide-linker p007 are shown.

[0063] Figure 6 Representative HPLC results for exemplary peptide-linker p007 are shown.

[0064] Figures 7A-7B An exemplary structure of an APC disclosed herein is shown. Among others, Figure 7AExemplary details of the three components of the APC are provided, namely anti-GIPR with IgGl Fc region with LALA substitution and E272C substitution, GLP-1 peptide, and (G4S)3 peptide linker. Figure 7B Exemplary details of the linker (C) that conjugates the peptide-linker (P-L) to the antibody are provided.

[0065] Figure 8 Cation exchange chromatograms of exemplary anti-GIPR antibodies disclosed herein blocked with cysteamine are shown before and after reduction with triphenylphosphine trisulfonic acid sodium salt (TPPTS).

[0066] Figure 9 Representative hydrophobic chromatograms of the APCs obtained are shown.

[0067] Figures 10A-10D Representative results are provided showing that both the peptides and APCs disclosed herein exhibit GLP-1 receptor agonist activity. Figure 10A and Figure 10B It is shown that the oxyntomodulin analogs disclosed herein, connected with different linkers, all effectively promote cAMP production in cells expressing GLP-1R. Figure 10C and Figure 10D It is shown that exemplary APCs F1.4, S1.4, F90.1, and S90.1 all effectively promote cAMP production in cells expressing GLP-1R, indicating that they have strong GLP-1 receptor agonist activity.

[0068] Figures 11A-11C Representative results are provided showing that both the peptides and APCs disclosed herein exhibit GCG receptor agonist activity. Figure 11A It is shown that the oxyntomodulin analog FP236 disclosed herein, connected with different linkers, all effectively promote cAMP production in cells expressing GCGR. Figure 11B and Figure 11C It is shown that exemplary APCs F1.4, S1.4, F90.1, and S90.1 all effectively promote cAMP production in cells expressing GCGR, indicating that they have strong GCG receptor agonist activity.

[0069] Figures 12A-12H Representative results are provided showing efficacy of exemplary APCs disclosed in a high-fat fed DIO mouse model. Figure 12A Body weight changes in DIO mice at day 15 after first dose are shown. As shown, exemplary APCs F1.4 and F90.1 both effectively reduced body weight in DIO mice on high-fat diet. Figure 12B Representative OGTT assay results at day 25 after first dose are shown.Figure 12C The 0 hour to 2 hour AUC of OGTT results are shown. As shown, exemplary APC F1.4 and F90.1 exhibit strong glucose control ability even 13 days after the last dose. Figures 12D-12H Fat content ( Figure 12D ), fat percentage ( Figure 12E ), alanine aminotransferase (ALT) level ( Figure 12F ), aspartate aminotransferase (AST) level ( Figure 12G ), and liver weight ( Figure 12H ) of mice on day 32 after the first dose are shown. As shown, exemplary APC F1.4 and F90.1 both effectively reduced fat content ( Figure 12D ), fat percentage ( Figure 12E ), ALT level ( Figure 12F ), AST level ( Figure 12G ), and liver weight ( Figure 12H ) of DIO mice.

[0070] Figures 13A-13G Additional representative results are provided showing efficacy of the disclosed exemplary APCs in a DIO mouse model on a high fat diet. Figure 13A Body weight change of DIO mice on day 18 after the first dose is shown. As shown, exemplary APC F1.4, S1.4, F90.1, and S90.1 all effectively reduced body weight of DIO mice on a high fat diet. Figures 13B-13C Fat content ( Figure 13B ) and fat percentage ( Figure 13C ) of mice on day 27 after the first dose are shown. As shown, exemplary APC F1.4, S1.4, F90.1, and S90.1 all effectively reduced fat content ( Figure 13B ) and fat percentage ( Figure 13C ) of DIO mice. Figures 13D-13G ALT level ( Figure 13D ), AST level ( Figure 13E ), total cholesterol (TCHOI) level ( Figure 13F ), and liver weight ( Figure 13G ) of mice on day 36 after the first dose are shown. As shown, exemplary APC F1.4, S1.4, F90.1, and S90.1 all effectively reduced ALT level ( Figure 13D ), AST level ( Figure 13E ), TCHOI level ( Figure 13F ), and liver weight ( Figure 13G ) of DIO mice.

[0071] Figures 14A-14ERepresentative results are provided showing efficacy of exemplary APCs disclosed herein in a GIPR knock-in mouse model of human high-fat diet-induced obesity ("GIPR mice"). Figure 14A Body weight change in mice at day 18 post first dose is shown. As shown, exemplary APCs F1.4 and F90.1 both effectively reduced body weight in GIPR mice. Figure 14B Body fat content in mice at day 15 post first dose is shown. Figure 14C Percent body fat in mice at day 15 post first dose is shown. Figure 14D Body fat content in mice at day 36 post first dose is shown. Figure 14E Percent body fat in mice at day 36 post first dose is shown. As shown, exemplary APCs F1.4 and F90.1 both effectively reduced both fat content and percent fat in GIPR mice.

[0072] Figure 15 Additional representative results are provided showing efficacy of exemplary APCs disclosed herein in "GIPR mice with high-fat diet-induced obesity." Figure 15 Body weight change in mice at day 18 post first dose is shown. As shown, exemplary APCs F1.4, S1.4, F90.1, and S90.1 all effectively reduced body weight in GIPR mice.

[0073] Figure 16 Pharmacokinetic (PK) profiles of exemplary APCs disclosed herein in mice are shown. As shown, exemplary APCs are relatively stable in mice and have IgG-like PK behavior.

[0074] Figure 17 Key steps for making APCs disclosed herein are shown.

[0075] Figure 18 It is shown that exemplary APC S90.1-YTE effectively blocked GIP binding to GIPR in cells, a result comparable to APC S90.1 (i.e., S90.1-non YTE, or S90.1-non YTE).

[0076] Figure 19 It is shown that exemplary APC S90.1-YTE effectively inhibited GIP-induced cAMP production, a result comparable to APC S90.1 (i.e., S90.1-non YTE).

[0077] Figure 20 It is shown that exemplary APC S90.1-YTE was effectively internalized by cells, a result comparable to APC S90.1 (i.e., S90.1-non YTE).

[0078] Figure 21 It is shown that the exemplary APC S90.1-YTE effectively promotes cAMP production in cells expressing GLP-1R, indicating that it has strong GLP-1 receptor agonist activity.

[0079] Figure 22 It is shown that the exemplary APC S90.1-YTE effectively promotes cAMP production in cells expressing GCGR, indicating that it has strong GCG receptor agonist activity. 7. DETAILED DESCRIPTION

[0080] Gastric inhibitory polypeptide (GIP) receptor (GIPR) is a key component of the entero- islet axis that plays a key role in glucose homeostasis and lipid metabolism. GIP (also known as glucose-dependent insulinotropic polypeptide) is a single 42 amino acid peptide processed from proGIP, a 153 amino acid precursor. GIP is secreted by K cells in the small intestine (duodenum and jejunum) when induced by food intake. GIP has many physiological roles in tissues, including promoting fat storage in adipocytes and promoting islet beta cell function and glucose-dependent insulin secretion.

[0081] As a member of the glucagon receptor family of G protein-coupled receptors, GIPR is primarily expressed in pancreatic beta cells, adipose tissue, and brain. GIPR promotes insulin secretion in a glucose-dependent manner upon activation by its ligand GIP, thereby modulating postprandial insulin levels and influencing lipid deposition in adipocytes (Holst and Gribble (2018) Endocrinology 159(5): 2724-2732).

[0082] Human GIPR exists in three isoforms (UniProt: P48546). The canonical isoform has a total of 466 amino acids (SEQ ID NO: 21). Further information on human GIPR can be found in the public databases with the following IDs: HGNC: 4271; neXtProt: NX_P48546; MIM: 137241; UniProt: P48546. MTTSPILQLLLRLSLCGLLLQRAETGSKGQTAGELYQRWERYRRECQETLAAAEPPS GLACNGSFDMYVCWDYAAPNATARASCPWYLPWHHHVAAGFVLRQCGSDGQWGLWRD HTQCENPEKNEAFLDQRLILERLQVMYTVGYSLSLATLLLALLILSLFRRLHCTRNY IHINLFTSFMLRAAAILSRDRLLPRPGPYLGDQALALWNQALAACRTAQIVTQYCVG ANYTWLLVEGVYLHSLLVLVGGSEEGHFRYYLLLGWGAPALFVIPWVIVRYLYENTQ CWERNEVKAIWWIIRTPILMTILINFLIFIRILGILLSKLRTRQMRCRDYRLRLARS TLTLVPLLGVHEVVFAPVTEEQARGALRFAKLGFEIFLSSFQGFLVSVLYCFINKEV QSEIRRGWHHCRLRRSLGEEQRQLPERAFRALPSGSGPGEVPTSRGLSSGTLPGPGN EASRELESYC (SEQ ID NO: 21)

[0083] Many peptides derived from proglucagon and analogs thereof have been proposed as therapeutic agents for the treatment of type 2 diabetes and obesity, particularly Gcg, GLP-1 and oxyntomodulin (OXM). Proglucagon is a precursor polypeptide of 158 amino acids that is differentially processed in tissues to form structurally related glucagon-derived peptides, including Gcg, glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2), and oxyntomodulin (OXM). These molecules are involved in a variety of physiological functions, including glucose homeostasis, insulin secretion, gastric emptying and intestinal growth, and regulation of food intake.

[0084] Like GIP, GLP-1 is also a pro-insulin factor or incretin. In patients with type 2 diabetes, the pro-insulin effect of GIP is lost, while the incretin effect of GLP-1 remains intact (Nauck et al., J. Clinc. Invest. 1993; 91 :301-307). GLP-1 is a peptide of 30 amino acids with an amide at the C-terminus, corresponding to amino acids 98 to 127 of preproglucagon. It is secreted by intestinal L cells and released in response to food intake to induce insulin secretion by pancreatic beta cells. Its half-life is short, about 1 to 2 minutes, due to the action of dipeptidyl peptidase-4 (DPP-4). In addition to the incretin effect, GLP-1 also reduces glucagon secretion, delays gastric emptying and reduces caloric intake. GLP-1 exerts its effects by activating the GLP-1 receptor (GLP-1R), a G protein-coupled receptor expressed in the pancreas, heart, kidney, stomach, and brain. This interaction leads to an increase in cyclic AMP (cAMP) levels, which enhances insulin secretion by pancreatic beta cells when glucose levels are high. Long-acting GLP-1R agonists (GLP-1RAs) such as exenatide, liraglutide, lixisenatide, albiglutide, and dulaglutide have been used clinically to improve glycemic control in patients with type 2 diabetes.

[0085] Gcg is a peptide of 29 amino acids, corresponding to amino acids 53 to 81 of preproglucagon. OXM is a peptide of 37 amino acids and consists of the complete Gcg sequence of 29 amino acids with an octapeptide carboxy-terminal extension (amino acids 82 to 89 of preproglucagon and referred to as “interposed peptide 1” or IP-1). Gcg helps maintain glucose levels in the blood by binding to the Gcg receptor (GCGR) on liver cells. GCGR is a member of the class B family of G protein-coupled receptors (GPCRs). Upon Gcg binding, the activated GCGR triggers a cascade of events that raises blood glucose levels, balancing the blood glucose-lowering action of insulin. Specifically, the activated GCGR stimulates cAMP production, which initiates the phosphorylation of enzymes that promote glycogenolysis and inhibit glycogenesis. GCGR activation also enhances gluconeogenesis.

[0086] OXM is released from L cells in the small intestine in proportion to nutrient uptake, along with GLP-1. OXM activates both the Gcg receptor and the GLP-1 receptor, with slightly higher potency for the Gcg receptor than the GLP-1 receptor, but with lower potency for their respective receptors than native Gcg and GLP-1. OXM is involved in the regulation of food intake and body weight, and has been shown to suppress appetite and food intake in humans. Endogenous OXM is rapidly degraded in vivo by dipeptidyl peptidase IV and other peptidases, and is rapidly cleared by the kidney. OXM analog peptides with amino acid substitutions to improve stability and with additional modifications to slow clearance are disclosed in the art, such as Mazdutide.

[0087] Despite recent advances, there remains a pressing need for more effective, long-acting, and / or well-tolerated therapeutics that target GIPR, GLP1R, and / or GCGR. The antibodies, peptides, and antibody-peptide conjugates (APCs) disclosed herein address these needs and provide related advantages.

[0088] Before further description of the disclosure, it should be understood that the disclosure is not limited to the particular embodiments set forth herein and that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. 7.1 Definitions

[0089] Unless otherwise defined herein, scientific and technical terms used in this disclosure have the meanings that are commonly understood by a person of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. Generally, nomenclatures used in connection with, and techniques of, cell and tissue culture, molecular biology, immunology, microbiology, genetics, and protein and nucleic acid chemistry and hybridization described herein are those well-known and commonly used in the art.

[0090] The term "a" or "an" entity refers to one or more than one of that entity; for example, "a antibody" should be understood to mean one or more antibodies.

[0091] The term "and / or" as used herein refers to, and sets forth, each of the two specified features or components individually (with or without the other). Thus, the term "and / or" as used herein in a phrase such as "A and / or B" is intended to cover the aspects of "A and B," "A or B," "A" (alone), and "B" (alone). Likewise, the term "and / or" as used herein in a phrase such as "A, B, and / or C" is intended to cover each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0092] As used herein, the term "about" is used to indicate that a value includes the inherent variation of error for the device, the method being employed to determine the value, or the variation that exists among the study subjects. The term "about" encompasses the exact number. In some embodiments, "about" means ±10% of the given value or range. In some embodiments, "about" means a variation of ±5%, ±4%, ±3%, ±2%, ±1%, ±0.5%, ±0.2%, or ±0.1% of the value that "about" refers to. In some embodiments, "about" means a variation of ±1%, ±0.5%, ±0.2%, or ±0.1% of the value that "about" refers to.

[0093] As used herein, the term "antibody" and grammatical equivalents thereof refer to an immunoglobulin molecule that recognizes and specifically binds to a target, such as a protein, polypeptide, peptide, carbohydrate, polynucleotide, lipid, or combinations of any of the foregoing, through at least one antigen binding site, where the antigen binding site is typically within the variable region of the immunoglobulin molecule. As used herein, the term encompasses intact polyclonal antibodies, intact monoclonal antibodies, single domain antibodies (sdAbs; e.g., camelid antibodies, llama antibodies), single chain Fv (scFv) antibodies, heavy chain antibodies (HCAbs), light chain antibodies (LC Abs), multispecific antibodies, bispecific antibodies, monospecific antibodies, monovalent antibodies, and any other modified immunoglobulin molecule that contains an antigen binding site (e.g., dual variable domain immunoglobulin molecules), so long as the antibodies exhibit the desired biological activity. Antibodies also include, but are not limited to, mouse antibodies, camelid antibodies, chimeric antibodies, humanized antibodies, and human antibodies. Antibodies can be of any of the five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, or subclasses (isotypes) thereof (e.g., IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2), based on the identity of their heavy chain constant domains, which are called alpha, delta, epsilon, gamma, and mu, respectively. The term "antibody" as used herein includes "antigen-binding fragments" of intact antibodies, unless specifically stated to the contrary. As used herein, the term "antigen-binding fragment" refers to a portion or fragment of an intact antibody that is an antigenic determinant variable region of the intact antibody. Examples of antigen-binding fragments include, but are not limited to, Fab, Fab', F(ab')2, Fv, linear antibodies, single-chain antibody molecules (e.g., scFv), heavy chain antibodies (HCAbs), light chain antibodies (LC Abs), disulfide-linked scFv (dsscFv), diabodies, triabodies, tetrabodies, minibodies, dual variable domain antibodies (DVDs), single variable domain antibodies (sdAbs; e.g., camelid antibodies, llama antibodies), and single variable domains of heavy chain antibodies (VHHs), and bispecific or multispecific antibodies formed from antibody fragments. "Bispecific" antibodies are artificial hybrid antibodies formed from a hybridization of two different hybridomas or linking of two Fab' fragments. See, e.g., Songsivilai and Lachmann, Clin. Exp. Immunol. 79:315-321 (1990); Kostelny et al., J. Immunol. 148, 1547-1553 (1992).

[0094] As used herein, the term "humanized antibody" refers to forms of non-human (e.g., murine) antibodies that are specific immunoglobulin chains, chimeric immunoglobulins, or fragments thereof containing minimal non-human sequences. Typically, a humanized antibody is a human immunoglobulin. In some cases, Fv framework region residues of the human immunoglobulin are replaced by corresponding residues from an antibody of a non-human species. In some cases, residues of CDRs are replaced by residues from CDRs of a non-human species (e.g., mouse, rat, hamster, camel) that have the desired specificity, affinity, and / or binding capacity. A humanized antibody can be further modified by the substitution of additional residues either in the Fv framework region and / or elsewhere in the humanized antibody to refine and optimize antibody specificity, affinity, and / or binding capacity. As used herein, the term "human antibody" refers to an antibody produced by a human or an antibody having an amino acid sequence corresponding to that produced by a human, made using any of the techniques known in the art.

[0095] The term "heavy chain," when used to refer to an antibody, refers to a polypeptide chain of about 50 kDa to 70 kDa, where the amino-terminal portion includes a variable region of about 120 to 130 or more amino acids, and the carboxy-terminal portion includes a constant region. Based on the amino acid sequence of the constant region of the heavy chain, the constant region can be one of five different types, called alpha, delta, epsilon, gamma, and mu. The different heavy chains vary in size: alpha, delta, and gamma contain approximately 450 amino acids, while mu and epsilon contain approximately 550 amino acids. When combined with a light chain, these different types of heavy chains give rise to the five well-known classes of antibodies, namely IgA, IgD, IgE, IgG, and IgM, including the four subclasses of IgG, namely IgGl, IgG2, IgG3, and IgG4. The heavy chain can be a human heavy chain.

[0096] The term "light chain," when used to refer to an antibody, refers to a polypeptide chain of about 25 kDa, where the amino-terminal portion includes a variable region of about 100 to about 110 or more amino acids, and the carboxy-terminal portion includes a constant region. The approximate length of a light chain is 211 to 217 amino acids. Based on the amino acid sequence of the constant domain, there are two different types, called kappa or lambda. Light chain amino acid sequences are well known in the art. The light chain can be a human light chain.

[0097] The term "variable domain" or "variable region" refers to the portion of a light or heavy chain of an antibody that is generally located at the amino-terminal of the light or heavy chain and has a length of about 120 to 130 amino acids in the heavy chain and about 100 to 110 amino acids in the light chain and is responsible for binding and specificity of each particular antibody to its particular antigen. The variable domains vary greatly in sequence among different antibodies. The variability in sequence is concentrated in the CDRs, while the less variable parts of the variable domain are called framework regions (FRs). The CDRs of the light and heavy chains are primarily responsible for the interaction of the antibody with antigen. The variable region can be a human variable region.

[0098] CDR refers to one of the three hypervariable regions (H1, H2, or H3) within the non- framework region of an immunoglobulin (Ig or antibody) VH beta-sheet framework, or one of the three hypervariable regions (L1, L2, or L3) within the non-framework region of an antibody VL beta-sheet framework. Thus, CDRs are sequences within the variable region sequences interspersed within the framework region sequences. CDR regions are well known to those skilled in the art and have been defined by a variety of methods / systems. These systems and / or definitions have been developed and refined over the years and include Kabat, Chothia, IMGT, AbM, and Contact. For example, Kabat defines regions within the antibody variable (V) domain that have high variability (Kabat et al., J. Biol. Chem. 252:6609-6616 (1977); Kabat, Adv. Prot. Chem. 32:1-75 (1978)). Chothia defines based on the location of structural loop regions, which define CDR region sequences as those residues that are not part of the conserved beta-sheet framework, thus enabling different conformations (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)). Both terminologies are art-recognized. Additionally, the IMGT system is based on sequence variability and location within the variable region structure. The AbM definition is a compromise between Kabat and Chothia. The Contact definition is based on analysis of available antibody crystal structures. Software programs for analyzing antibody sequences and determining CDRs (e.g., abYsis) are available and known to those skilled in the art. The positions of CDRs within the canonical antibody variable domain have been determined by comparing many structures (Al-Lazikani et al., J. Mol. Biol. 273:927-948 (1997); Morea et al., Methods 20:267-279 (2000)). Because the number of residues within the hypervariable regions varies among different antibodies, additional residues relative to the canonical position are typically numbered with a, b, c, etc. next to the residue number in the canonical variable domain numbering scheme (Al-Lazikani et al., supra, 1997). This nomenclature is also well known to those skilled in the art.

[0099] For example, CDRs according to Kabat (hypervariable), Chothia (structure), and / or AbM designation definitions are listed in the table below. CDR Definitions Kabat Chothia AbM Kabat / AbM* VL CDR1 L24-L34 L26-L32 L24-L34 L24-L34 VL CDR2 L50-L56 L50-L52 L50-L56 L50-L56 VL CDR3 L89-L97 L91-L96 L89-L97 L89-L97 VH CDR1 H31-H35 H26-H32 H26-H35 H26-H35 VH CDR2 H50-H65 H53-H55 H50-H58 H50-H65 VH CDR3 H95-H102 H96-H101 H95-H102 H95-H102 *In the present disclosure, the CDRs of the anti-GIPR antibodies provided herein are defined using this Kabat / AbM combined scheme. That is, the three VL CDRs and VH CDR3 are defined according to both the Kabat and AbM schemes, which yields identical results; while VH CDR1 is defined according to the AbM scheme and VH CDR2 is defined according to the Kabat scheme.

[0100] Unless otherwise indicated, in the present disclosure, numbering of amino acid positions is according to the EU index (Kabat et al., “Sequences of Proteins of Immunological Interest” 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991).

[0101] One or more CDRs can also be covalently or non-covalently incorporated into a molecule, making it an immunoadhesin. The immunoadhesin can incorporate the CDRs as part of a larger polypeptide chain, the CDRs can be covalently linked to another polypeptide chain, or the CDRs can be non-covalently incorporated. The CDRs allow the immunoadhesin to bind to a particular antigen of interest. The CDR regions can be analyzed by, for example, the abysis website (http: / / abysis.org / ).

[0102] As used herein, the term “specifically binds” means that a polypeptide or molecule interacts more frequently, more rapidly, for a longer duration, with higher affinity, or some combination of the above characteristics with an epitope, protein, or target molecule than with alternative substances, including related and unrelated proteins. Binding moieties (e.g., antibodies) that specifically bind to a target molecule (e.g., an antigen) can be identified, for example, by immunoassays, ELISA, biolayer interferometry (“BLI”), SPR (e.g., Biacore), or other techniques known to one of skill in the art. Typically, the particular reaction will be at least twice background or noise, and can be more than 10 times background. For a discussion of antibody specificity, see, e.g., Paul, ed., 1989, “Fundamental Immunology 2nd Edition” (Plenum Press, New York), particularly Chapters 3 and 4. Fundamental Immunology Second Edition), Raven Press, New York, pp. 332-336. A binding moiety that specifically binds to a target molecule can bind to the target molecule with a higher affinity than its affinity for a different molecule. In some embodiments, a binding moiety that specifically binds to a target molecule can bind to the target molecule with at least 20-fold, at least 30-fold, at least 40-fold, at least 50-fold, at least 60-fold, at least 70-fold, at least 80-fold, at least 90-fold, or at least 100-fold greater affinity than its affinity for a different molecule. In some embodiments, a binding moiety that specifically binds to a particular target molecule binds a different molecule with such low affinity that the binding is not detectable using assays described herein or otherwise known in the art. In some embodiments, “specifically binds” means, for example, that a binding moiety has a K D binding to a target molecule. In some embodiments, “specifically binds” means that a polypeptide or molecule has a K D binding to a target molecule. In some embodiments, “specifically binds” means that a polypeptide or molecule has a K D binding to a target molecule. Due to sequence identity between homologous proteins in different species, specific binding can include a polypeptide or molecule that recognizes a protein or target in more than one species. Likewise, due to homology within certain regions of the polypeptide sequences of different proteins, specific binding can include a polypeptide or molecule that recognizes more than one protein or target. It will be appreciated that, in some embodiments, a binding moiety (e.g., an antibody) that specifically binds to a first target can or can not specifically bind to a second target. Thus, “specifically binds” does not necessarily require (although it can include) exclusive binding, i.e., binding to a single target. Thus, in some embodiments, a binding moiety (e.g., an antibody) can specifically bind to more than one target. For example, in certain instances, an antibody can comprise two identical antigen binding sites that each specifically bind to the same epitope on two or more proteins. In certain alternative embodiments, an antibody can be bispecific and comprise at least two antigen binding sites with different specificities.

[0103] As used herein, the term “binding affinity” generally refers to the strength of the sum total of noncovalent interactions between a binding moiety and a target molecule (e.g., an antigen). Binding of a binding moiety to a target molecule is a reversible process, and the affinity of a binding is generally expressed in terms of an equilibrium dissociation constant (K D ). The K D is the ratio of the dissociation rate (k off or k d ) to the association rate (k on or k a ) of the binding pair. The K DThe lower, the higher the affinity. A variety of methods of measuring binding affinity are known in the art, any of which can be used for the purposes of the present disclosure. Particular illustrative embodiments include the following. In some embodiments, the "K D " or "K D value" can be measured by assays known in the art, for example, by binding assays. K D may be measured in a radiolabeled antigen binding assay (RIA) (Chen et al., (1999) J. Mol Biol 293:865-881). K D or K D values can also be measured by using BioLayer Interferometry technology (BLI), using, for example, the Octet® QKe system (ForteBio®) or the Octet® QKe system (ForteBio®). K D or K D values can also be measured by using surface plasmon resonance assays (SPR) by Biacore, using, for example, the BIAcore™-2000 or BIAcore™-3000 (BIAcore, Inc., Piscataway, NJ). Binding affinity can also be quantified by EC 50 , EC 50 is the ligand concentration at which half the target is present in bound state in a binding assay.

[0104] The terms "polypeptide," "peptide," "protein," and their grammatical equivalents are used interchangeably herein to refer to a polymer of amino acids of any length that can be straight or branched. The polymer can comprise unnatural or modified amino acids or be interrupted by non-amino acids. Polypeptides, peptides, or proteins can also be modified, for example, by disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification.

[0105] As used herein, the term "variant" in relation to a protein or peptide having a particular sequence characteristic ("reference protein" or "reference peptide") refers to a different protein or peptide having one or more (e.g., about 1 to about 30, about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1 to about 10, or about 1 to about 5) amino acid substitutions, deletions, and / or additions as compared to the reference protein or reference peptide. The alteration in the amino acid sequence can be an amino acid substitution. The alteration in the amino acid sequence can be a conservative amino acid substitution. The alteration in the amino acid sequence can be an amino acid deletion. The variant can be a fragment of the reference protein or peptide. A functional variant of a protein or peptide retains the essential structural and functional properties of the reference protein or peptide.

[0106] As is known in the art, amino acids can be classified on the basis of common side-chain properties, including 1) hydrophobic: Norleucine, Met, Ala, Val, Leu, He; 2) neutral hydrophilic: Cys, Ser, Thr, Asn, Gin; 3) acidic: Asp, Glu; 4) basic: His, Lys, Arg; 5) residues that influence chain orientation: Gly, Pro; and aromatic: Trp, Tyr, Phe. Conservative amino acid substitutions can involve the exchange of a member of one of these classes for another member of the same class. Conversely, non-conservative substitutions can involve the exchange of a member of one of the above classes for a member from another class. Conservative amino acid substitutions can also encompass non-naturally occurring amino acid residues that are typically incorporated through chemical peptide synthesis rather than synthesis in biological systems. These substitutions include peptidomimetics as well as other reverse or inverted forms of amino acid moieties. Synthetic, rare, or modified amino acid residues with similar known physiochemical properties as the above groupings can be used as “conservative” substitutions for particular amino acid residues in a sequence. For example, a D-Arg residue can be used as a substitute for a typical L-Arg residue. It is also possible that a particular substitution can be described according to two or more of the above classes (e.g., substitution with a small and hydrophobic residue means substitution with a residue that exists in two of the above classes or other synthetic, rare, or modified residues known in the art that have similar physiochemical properties as such residues that satisfy both definitions).

[0107] As used herein, the term “antibody-peptide conjugate” or “APC” refers to a complex or composition formed by the linkage of an antibody to a peptide. Peptides can be conjugated to antibodies using methods well known in the art. Peptides can be conjugated to antibodies with or without a linker. The antibody component of the conjugate provides specificity by recognizing and binding to a particular antigen (e.g., human GIPR), while the peptide component can perform various functions such as drug delivery, imaging, or modulating an immune response, among others. For example, an antibody targeting human GIPR can be conjugated to a peptide targeting GLP-1R and GCGR to form an antibody-peptide conjugate that can simultaneously modulate the signaling pathways of GIPR, GCGR, and GLP-1R to provide potential therapeutic benefits.

[0108] As used herein, the term “drug-antibody ratio” or “DAR” refers to the number of peptide molecules conjugated to an antibody in the case of a single antibody-peptide conjugate molecule, or the average number of peptide molecules conjugated to each antibody molecule in the case of a plurality of antibody-peptide conjugate molecules.

[0109] The terms "polynucleotide," "nucleic acid," and their grammatical equivalents are used interchangeably herein to refer to a polymer or oligomer of nucleotides of any length. The nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases (such as methylated, hydroxymethylated or glycosylated), non-natural nucleotides, non-nucleotide structural units that exhibit structural and / or functional properties similar to naturally occurring nucleotides (i.e., "nucleotide analogs"), and / or any substrate that can be incorporated into a polymer by DNA or RNA polymerase. The nucleic acid or polynucleotide can be heterogenous or homogenous in composition, can be isolated from a naturally occurring source, or can be produced in an artificial or synthetic manner. Furthermore, the nucleic acid can be DNA or RNA, or a mixture thereof, and can exist permanently or transiently in a single-stranded or double-stranded form, including homoduplexes, heteroduplexes, and hybridized states. Nucleic acid structures also include, for example, DNA / RNA hybrids, peptide nucleic acids (PNA), morpholino nucleic acids (see, e.g., Braasch and Corey, Biochemistry, 4(14):4503-4510 (2002) and U.S. Patent 5,034,506), locked nucleic acids (LNA; see Wahlestedt et al., Proc. Natl. Acad. Sci. U.S.A., 97:5633-5638 (2000)), cyclohexenyl nucleic acids (see Wang, Am. Chem. Soc, 122:8595-8602 (2000)), and / or ribozymes.

[0110] In the context of two or more polynucleotides or polypeptides, the terms "identical," "identity," percent identity, and their grammatical equivalents as used herein refer to the sequences being the same, or having a specified percentage of nucleotides or amino acid residues identical, disregarding any conservative amino acid substitutions as part of sequence identity, when the two or more sequences or subsequences are compared and aligned for maximum correspondence, as necessary, introducing gaps. Percent identity can be measured using sequence comparison software or algorithms or by visual inspection. Various algorithms and software are well known in the art for obtaining sequence alignments of amino acid or nucleotide sequences. These algorithms and software include, but are not limited to, BLAST, ALIGN, Megalign, BestFit, the GCG Wisconsin Software Package, and variants thereof. In some embodiments, two polynucleotides or polypeptides provided herein are substantially identical, meaning that when compared and aligned for maximum correspondence, they have at least 70%, at least 75%, at least 80%, at least 85%, at least 90% nucleotide or amino acid residue identity, and in some embodiments, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% nucleotide or amino acid residue identity, as measured using a sequence comparison algorithm or by visual inspection. In some embodiments, identity exists over a sequence region of at least about 10 residues, at least about 20 residues, at least about 40 to 60 residues, at least about 60 to 80 residues, or any integer value therebetween, of an amino acid sequence. In some embodiments, identity exists over a region longer than 60 to 80 residues, such as at least about 80 to 100 residues, and in some embodiments, the sequences are substantially identical over the entire length of the sequences being compared, such as a coding region of a target protein or antibody. In some embodiments, identity exists over a sequence region of at least about 10 bases, at least about 20 bases, at least about 40 to 60 bases, at least about 60 to 80 bases, or any integer value therebetween, of a nucleotide sequence. In some embodiments, identity exists over a region longer than 60 to 80 bases, such as at least about 80 to 100 bases or more, and in some embodiments, the sequences are substantially identical over the entire length of the sequences being compared, such as a nucleotide sequence encoding a protein of interest.

[0111] As used herein, the term "vector" and its grammatical equivalents refers to an agent for carrying genetic material (e.g., a polynucleotide sequence) that can be introduced into a host cell and replicated and / or expressed in that host cell. Suitable vectors include, for example, expression vectors, plasmids, phage vectors, viral vectors, episomes, and artificial chromosomes, which can comprise selection sequences or markers for stable integration into the host cell chromosome. Additionally, a vector can comprise one or more selectable marker genes and appropriate expression control sequences. Selectable marker genes can be included, for example, to provide resistance to antibiotics or toxins, to complement auxotrophic deficiencies, or to supply critical nutrients missing from the culture medium. Expression control sequences can include constitutive and inducible promoters, transcription enhancers, transcription terminators, and the like, which are well known in the art. When co-expression of two or more polynucleotides is desired, the two polynucleotides can be inserted into, for example, a single expression vector or separate expression vectors. For single vector expression, the coding polynucleotides can be operably linked to one common expression control sequence or to different expression control sequences, such as one inducible promoter and one constitutive promoter. Methods well known in the art can be used to confirm that a polynucleotide has been introduced into a host cell. It will be understood by those skilled in the art that the polynucleotide is expressed in an amount sufficient to produce the desired product (e.g., an anti-GIPR antibody or antigen-binding fragment as described herein), and it will further be understood that expression levels can be optimized using methods well known in the art to achieve sufficient expression.

[0112] As used herein, the term "encode" and its grammatical equivalents refer to the inherent property of a specific sequence of nucleotides in a polynucleotide or nucleic acid, such as a gene, cDNA, or mRNA, to serve as a template for synthesis of other polymers and macromolecules having a defined sequence of nucleotides (i.e., rRNA, tRNA, and mRNA) or a defined sequence of amino acids and the biological properties resulting therefrom in a biological process. Thus, if the transcription and translation of mRNA corresponding to a gene produces a protein, the gene encodes the protein. Unless otherwise indicated, a "nucleotide sequence encoding an amino acid sequence" includes all nucleotide sequences which are degenerate versions of each other and which encode the same amino acid sequence. Nucleotide sequences which encode proteins and RNA can include introns.

[0113] An "isolated" polypeptide, peptide, protein, antibody, polynucleotide, vector, cell, or composition is a polypeptide, peptide, protein, antibody, polynucleotide, vector, cell, or composition in a form not found in nature. Isolated polypeptides, peptides, proteins, antibodies, polynucleotides, vectors, cells, or compositions include those that have been purified to the extent that they are no longer in their natural form. In some embodiments, an isolated polypeptide, peptide, protein, antibody, polynucleotide, vector, cell, or composition is substantially pure. As used herein, the term "substantially pure" means that the molecular species is the predominant species present, i.e., the amount of the molecular species is greater than that of any other individual species in the same mixture on a molar basis. In some embodiments, a substantially pure molecule is one in which the subject material constitutes at least 50% (on a molar basis) of all macromolecular species present in the composition. In other embodiments, a substantially pure composition will comprise at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% of all macromolecular species present in the composition. In some embodiments, the subject material is purified to homogeneity, where no contaminating species are detectable in the composition by conventional methods of detection, and thus the composition consists of a single detectable macromolecular species.

[0114] The term "pharmaceutically acceptable" refers to a material (e.g., an active ingredient or an excipient) that is useful in contacting with the tissues or organs of a subject without undue toxicity, allergic reaction, immunological reaction, and with a reasonable benefit / risk ratio, and that is effective for its intended use.

[0115] As used herein, the term "treat" and grammatical equivalents thereof, when used in reference to a disease, disorder, or condition, or a subject having a disease or condition, refers to the act of inhibiting, abrogating, reducing, and / or ameliorating a symptom, severity of symptoms, and / or frequency of symptoms associated with the disease, disorder, or condition being treated.

[0116] As used herein, the term "administering" and grammatical equivalents thereof means the act of delivering or causing the delivery of a therapeutic agent or pharmaceutical composition to a subject by a method described herein or otherwise known in the art. Administering a therapeutic agent or pharmaceutical composition includes prescribing a therapeutic agent or pharmaceutical composition to be delivered to a subject. Exemplary forms of administration include oral dosage forms such as tablets, capsules, syrups, suspensions; injectable dosage forms such as intravenous (IV), intramuscular (IM), or intraperitoneal (IP); transdermal dosage forms including creams, gels, powders, or patches; buccal dosage forms; inhalation powders, sprays, suspensions, and rectal suppositories.

[0117] As used herein, the terms "effective amount," "therapeutically effective amount," and grammatical equivalents thereof mean the amount of an agent, alone or as part of a pharmaceutical composition, and whether administered in a single dose or as part of a series of doses, that is capable of having any detectable positive effect on any symptom, aspect, or feature of a disease, disorder, or condition when administered to a subject. A therapeutically effective amount can be determined by measuring the relevant physiological effect. The precise amount required is dependent on the subject, and will depend on the age, body mass, and general condition of the subject, the severity of the condition being treated, the judgment of the clinician, and the like. Suitable "effective amounts" in any individual case can be determined by one of ordinary skill in the art using routine experimentation.

[0118] As used herein, the term "subject" refers to any animal (e.g., a mammal), including, but not limited to, humans, non-human primates, canids, felines, rodents, and the like, that is the recipient of a particular treatment. A subject can be a human. A subject can have a particular disease or condition.

[0119] The expression "(Br-Ac)" or "(Ac-Br)" as used herein means 2-bromoacetyl. The abbreviation "{Aib}" as used herein means 2-aminoisobutyric acid.

[0120] Ranges: Throughout this disclosure, various aspects of the application can be presented in a range format. The description in range format is merely for convenience and brevity and should not be construed as limiting the scope of the application. Therefore, the description of a range should be considered flexible and also modified in language to apply to individual values within the range, unless the context clearly indicates otherwise. Thus, for example, description of a range such as from 1 to 6 should be considered to have explicitly disclosed sub-ranges such as from 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., as well as individual numbers within that range, for example 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This same principle applies to ranges recited using terminology such as "between," "up to," "at least," "up to," "greater than," "less than," and the like.

[0121] Exemplary genes and polypeptides are described herein with reference to GenBank Accession Numbers, GI Numbers, and / or SEQ ID NOs. It will be appreciated by persons skilled in the art that homologous sequences can be readily identified by reference to the sequence sources, including but not limited to GenBank (ncbi.nlm.nih.gov / genbank / ) and EMBL (embl.org / ). 7.2 Anti-GIPR Antibodies

[0122] Provided herein are antibodies or antigen-binding fragments thereof that specifically bind to GIPR (e.g., human GIPR). In some embodiments, provided herein are anti-GIPR antibodies. In some embodiments, the antibody is an IgA, IgD, IgE, IgG, or IgM antibody. In some embodiments, the antibody is an IgA antibody. In some embodiments, the antibody is an IgD antibody. In some embodiments, the antibody is an IgE antibody. In some embodiments, the antibody is an IgG antibody. In some embodiments, the antibody is an IgM antibody. In some embodiments, the antibody provided herein can be an IgGl antibody, an IgG2 antibody, an IgG3 antibody, or an IgG4 antibody. In some embodiments, the antibody is an IgGl antibody. In some embodiments, the antibody is an IgG2 antibody. In some embodiments, the antibody is an IgG3 antibody. In some embodiments, the antibody is an IgG4 antibody.

[0123] In some embodiments, provided herein are antigen-binding fragments of anti-GIPR antibodies. In some embodiments, the antigen-binding fragment provided herein can be a single domain antibody (sdAb), a heavy chain antibody (HCAb), a Fab, a Fab', a F(ab')2, a Fv, a single chain variable fragment (scFv), or a (scFv)2. In some embodiments, the antigen-binding fragment of anti-GIPR antibodies is a single domain antibody (sdAb). In some embodiments, the antigen-binding fragment of anti-GIPR antibodies is a heavy chain antibody (HCAb). In some embodiments, the antigen-binding fragment of anti-GIPR antibodies is a Fab. In some embodiments, the antigen-binding fragment of anti-GIPR antibodies is a Fab'. In some embodiments, the antigen-binding fragment of anti-GIPR antibodies is a F(ab')2. In some embodiments, the antigen-binding fragment of anti-GIPR antibodies is a Fv. In some embodiments, the antigen-binding fragment of anti-GIPR antibodies is a scFv. In some embodiments, the antigen-binding fragment of anti-GIPR antibodies is a disulfide-linked scFv [(scFv)2]. In some embodiments, the antigen-binding fragment of anti-GIPR antibodies is a diabody (dAb).

[0124] In some embodiments, the anti-GIPR antibodies or antigen-binding fragments provided herein include recombinant antibodies or antigen-binding fragments. In some embodiments, the anti-GIPR antibodies or antigen-binding fragments provided herein include monoclonal antibodies or antigen-binding fragments. In some embodiments, the anti-GIPR antibodies or antigen-binding fragments provided herein include polyclonal antibodies or antigen-binding fragments. In some embodiments, the anti-GIPR antibodies or antigen-binding fragments provided herein include camelid (e.g., camel, dromedary, and llama) antibodies or antigen-binding fragments. In some embodiments, the anti-GIPR antibodies or antigen-binding fragments provided herein include chimeric antibodies or antigen-binding fragments. In some embodiments, the anti-GIPR antibodies or antigen-binding fragments provided herein include humanized antibodies or antigen-binding fragments. In some embodiments, the anti-GIPR antibodies or antigen-binding fragments provided herein include human antibodies or antigen-binding fragments. In some embodiments, anti-GIPR human scFvs are provided herein.

[0125] In some embodiments, the anti-GIPR antibodies or antigen-binding fragments provided herein are isolated. In some embodiments, the anti-GIPR antibodies or antigen-binding fragments provided herein are substantially pure.

[0126] In some embodiments, the anti-GIPR antibodies or antigen-binding fragments provided herein include multispecific antibodies or antigen-binding fragments. In some embodiments, the anti-GIPR antibodies or antigen-binding fragments provided herein include bispecific antibodies or antigen-binding fragments. In some embodiments, the bispecific antibodies or antigen-binding fragments include the anti-GIPR antibodies or antigen-binding fragments provided herein. In some embodiments, the bispecific antibodies or antigen-binding fragments include the anti-GIPR scFvs provided herein.

[0127] In some embodiments, the anti-GIPR antibodies or antigen-binding fragments provided herein comprise monovalent antigen-binding sites. In some embodiments, the anti-GIPR antibodies or antigen-binding fragments comprise monospecific binding sites. In some embodiments, the anti-GIPR antibodies or antigen-binding fragments comprise bivalent binding sites.

[0128] In some embodiments, the anti-GIPR antibodies or antigen-binding fragments are monoclonal antibodies or antigen-binding fragments. Monoclonal antibodies can be prepared by any method known to one of skill in the art.

[0129] In some embodiments, monoclonal antibodies are modified by using recombinant DNA technology to generate alternative antibodies. In some embodiments, the constant domains of the light and heavy chains of a mouse monoclonal antibody are replaced with the constant regions of a human antibody to generate a chimeric antibody. In some embodiments, the constant regions are truncated or removed to generate a desired antibody fragment of the monoclonal antibody. In some embodiments, the variable regions are subjected to site-directed mutagenesis or high-density mutagenesis for optimization of the specificity and / or affinity of the monoclonal antibody.

[0130] In some embodiments, provided herein is an anti-GIPR antibody clone S3-90. Sequence features are described below. The specific CDR sequences defined herein are generally based on the Kabat / AbM combination. However, it should be understood that general references to one or more heavy chain CDRs and / or one or more light chain CDRs of a specific antibody encompass all CDR definitions known to those of skill in the art. In some embodiments, provided herein is an anti-GIPR antibody having the VL CDRs and / or VH CDRs of antibody clone S3-90 disclosed herein, wherein the CDRs are defined by Kabat, Chothia, IMGT, AbM, Contact, or any combination thereof. In some embodiments, the CDRs are defined by Kabat. In some embodiments, the CDRs are defined by Chothia. In some embodiments, the CDRs are defined by IMGT. In some embodiments, the CDRs are defined by AbM. In some embodiments, the CDRs are defined by Contact.

[0131] In some embodiments, an anti-GIPR antibody or antigen-binding fragment thereof provided herein is the antibody designated S3-90 (chimeric S3-90). In some embodiments, an anti-GIPR antibody or antigen-binding fragment thereof provided herein has a VL from S3-90 (SEQ ID NO: 24). In some embodiments, an anti-GIPR antibody or antigen-binding fragment thereof provided herein has a VH from S3-90 (SEQ ID NO: 25). An anti-GIPR antibody or antigen-binding fragment thereof provided herein can have both a VL and a VH from S3-90. In some embodiments, a VL of an anti-GIPR antibody or antigen-binding fragment thereof provided herein comprises a VL CDR1, a VL CDR2, and a VL CDR3 from a VL of S3-90 (SEQ ID NO: 24). In some embodiments, a VH of an anti-GIPR antibody or antigen-binding fragment thereof provided herein comprises a VH CDR1, a VH CDR2, and a VH CDR3 from a VH of S3-90 (SEQ ID NO: 25). An anti-GIPR antibody or antigen-binding fragment thereof provided herein can have: a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from a VL of S3-90; and a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 from a VH of S3-90. CDRs can be defined by any system known in the art. In some embodiments, CDRs are defined by Kabat, Chothia, IMGT, AbM, or Contact. In some embodiments, CDRs are defined by Kabat as detailed herein. In some embodiments, CDRs are defined by Chothia. In some embodiments, CDRs are defined by IMGT. In some embodiments, CDRs are defined by AbM. In some embodiments, CDRs are defined by Contact.

[0132] In some embodiments, an anti-GIPR antibody or antigen-binding fragment thereof provided herein is a variant of S3-90. A S3-90 variant can have a VL that is a variant of the VL of S3-90 having up to about 3, about 5, about 8, about 10, about 12, or about 15 amino acid substitutions, additions and / or deletions in SEQ ID NO: 24. A S3-90 variant can have a VL that is a variant of the VL of S3-90 having up to about 5 amino acid substitutions, additions and / or deletions in SEQ ID NO: 24. A S3-90 variant can have a VH that is a variant of the VH of S3-90 having up to about 3, about 5, about 8, about 10, about 12, or about 15 amino acid substitutions, additions and / or deletions in SEQ ID NO: 25. A S3-90 variant can have a VH that is a variant of the VH of S3-90 having up to about 5 amino acid substitutions, additions and / or deletions in SEQ ID NO: 25. The amino acid substitutions, additions and / or deletions can occur in a VH CDR or a VL CDR. In some embodiments, the amino acid substitutions, additions and / or deletions are not in a CDR region. In some embodiments, a variant of S3-90 has up to about 5 conservative amino acid substitutions. In some embodiments, a variant of S3-90 has up to 3 conservative amino acid substitutions. In some embodiments, an anti-GIPR antibody or antigen-binding fragment thereof provided herein is a humanized antibody or antigen-binding fragment derived from S3-90. In some embodiments, an anti-GIPR antibody or antigen-binding fragment thereof provided herein is a human antibody or antigen-binding fragment derived from S3-90.

[0133] In some embodiments, an anti-GIPR antibody or antigen-binding fragment provided herein comprises one, two, three, four, five, and / or six CDRs of any of the antibodies described herein. In some embodiments, an anti-GIPR antibody or antigen-binding fragment provided herein comprises a light chain variable region (VL) comprising one, two, and / or three light chain CDRs (VL CDRs) from Table 1. In some embodiments, an anti-GIPR antibody or antigen-binding fragment provided herein comprises a heavy chain variable region (VH) comprising one, two, and / or three heavy chain CDRs (VH CDRs) from Table 1. In some embodiments, an anti-GIPR antibody or antigen-binding fragment provided herein comprises one, two, and / or three VL CDRs and one, two, and / or three VH CDRs from Table 1.

[0134] Table 1 CDR sequences of S3-90

[0135] In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind GIPR (e.g., human GIPR), comprising a VL comprising (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 1, (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 2, and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 3, or a variant thereof having up to about 3, about 5, about 8, about 10, about 12, or about 15 amino acid substitutions, additions and / or deletions in these VL CDRs; and / or a VH comprising (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 4, (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 5 or 6, and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 7, or a variant thereof having up to about 3, about 5, about 8, about 10, about 12, or about 15 amino acid substitutions, additions and / or deletions in these VH CDRs.

[0136] In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind GIPR, comprising a VL comprising (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 1, (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 2, or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 3, or a variant thereof having up to about 3, about 5, about 8, about 10, about 12, or about 15 amino acid substitutions, additions and / or deletions in the VL CDRs. In some embodiments, the variant has up to about 5 amino acid substitutions, additions and / or deletions in the VL CDRs. In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind GIPR, comprising a VL comprising (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 1, (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 2, and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 3, or a variant thereof having up to about 3, about 5, about 8, about 10, about 12, or about 15 amino acid substitutions, additions and / or deletions in these VL CDRs. In some embodiments, the variant has up to about 5 amino acid substitutions, additions and / or deletions in these VL CDRs.

[0137] In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind GIPR, the antibodies or antigen-binding fragments thereof comprising a VH comprising (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 4, (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 5 or 6, or (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 7, or a variant of the VH having up to about 3, about 5, about 8, about 10, about 12, or about 15 amino acid substitutions, additions and / or deletions in the VH CDRs. In some embodiments, the variant has up to about 5 amino acid substitutions, additions and / or deletions in the VH CDRs. In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind GIPR, the antibodies or antigen-binding fragments thereof comprising a VH comprising (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 4, (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 5 or 6, and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 7, or a variant of the VH having up to about 3, about 5, about 8, about 10, about 12, or about 15 amino acid substitutions, additions and / or deletions in the VH CDRs. In some embodiments, the variant has up to about 5 amino acid substitutions, additions and / or deletions in the VH CDRs.

[0138] In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind GIPR, the antibodies or antigen-binding fragments thereof comprising: (a) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 of the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, or a variant of the VL having up to about 3, about 5, about 8, about 10, about 12, or about 15 amino acid substitutions, additions and / or deletions in the VL CDRs; and / or (b) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 of the amino acid sequences of SEQ ID NOs: 4, 5, and 7, respectively, or a variant of the VH having up to about 3, about 5, about 8, about 10, about 12, or about 15 amino acid substitutions, additions and / or deletions in the VH CDRs.

[0139] In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind GIPR, comprising: (a) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, or a variant thereof having up to about 3, about 5, about 8, about 10, about 12, or about 15 amino acid substitutions, additions and / or deletions in these VL CDRs; and / or (b) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 4, 6, and 7, respectively, or a variant thereof having up to about 3, about 5, about 8, about 10, about 12, or about 15 amino acid substitutions, additions and / or deletions in these VH CDRs.

[0140] In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind GIPR, comprising a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 7, respectively, or a variant thereof having up to about 3, about 5, about 8, about 10, about 12, or about 15 amino acid substitutions, additions and / or deletions in these CDRs. In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind GIPR, comprising a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 6, and 7, respectively, or a variant thereof having up to about 3, about 5, about 8, about 10, about 12, or about 15 amino acid substitutions, additions and / or deletions in these CDRs.

[0141] Table 2 Amino acid sequences of the light chain variable region (VL) and the heavy chain variable region (VH) of chimeric antibody S3-90 and humanized antibody HzS3-90.1.

[0142] In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind GIPR, the antibodies or antigen-binding fragments thereof comprising a VL having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 24. In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind GIPR, the antibodies or antigen-binding fragments thereof comprising a VH having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 25.

[0143] In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind GIPR, the antibodies or antigen-binding fragments thereof comprising: (a) a VL having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 24; and (b) a VH having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 25. In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind GIPR, the antibodies or antigen-binding fragments thereof comprising a VL and a VH, wherein the VL and VH have the amino acid sequences of SEQ ID NOs: 24 and 25, respectively.

[0144] In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind GIPR, the antibodies or antigen-binding fragments thereof comprising a VL, wherein the VL has at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 24. In some embodiments, the anti-GIPR antibody or antigen-binding fragment thereof has a VL with at least 85% sequence identity to SEQ ID NO: 24. In some embodiments, the anti-GIPR antibody or antigen-binding fragment thereof has a VL with at least 90% sequence identity to SEQ ID NO: 24. In some embodiments, the anti-GIPR antibody or antigen-binding fragment thereof has a VL with at least 95% sequence identity to SEQ ID NO: 24. In some embodiments, the anti-GIPR antibody or antigen-binding fragment thereof has a VL with at least 98% sequence identity to SEQ ID NO: 24. In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind GIPR, the antibodies or antigen-binding fragments thereof comprising a VL having the amino acid sequence of SEQ ID NO: 24.

[0145] In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind GIPR, the antibodies or antigen-binding fragments thereof comprising a VH, wherein the VH has at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 25. In some embodiments, the anti-GIPR antibody or antigen-binding fragment thereof has a VH with at least 85% sequence identity to SEQ ID NO: 25. In some embodiments, the anti-GIPR antibody or antigen-binding fragment thereof has a VH with at least 90% sequence identity to SEQ ID NO: 25. In some embodiments, the anti-GIPR antibody or antigen-binding fragment thereof has a VH with at least 95% sequence identity to SEQ ID NO: 25. In some embodiments, the anti-GIPR antibody or antigen-binding fragment thereof has a VH with at least 98% sequence identity to SEQ ID NO: 25. In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind GIPR, the antibodies or antigen-binding fragments thereof comprising a VH having the amino acid sequence of SEQ ID NO: 25.

[0146] In some embodiments, provided herein is a humanized antibody of S3-90 (i.e., humanized S3-90 or HzS3-90.1). In some embodiments, the humanized anti-GIPR antibody or antigen binding fragment thereof provided herein comprises a VL having the amino acid sequence of SEQ ID NO: 26. In some embodiments, the humanized anti-GIPR antibody or antigen binding fragment thereof provided herein comprises a VH having the amino acid sequence of SEQ ID NO: 27. In some embodiments, the humanized anti-GIPR antibody or antigen binding fragment thereof provided herein comprises a VL having the amino acid sequence of SEQ ID NO: 26 and a VH having the amino acid sequence of SEQ ID NO: 27. In some embodiments, the anti-GIPR antibody or antigen binding fragment thereof provided herein is a variant of the humanized S3-90 provided herein. The variant can have a VL that is a variant of the VL of the humanized S3-90 having up to about 3, about 5, about 8, about 10, about 12, or about 15 amino acid substitutions, additions and / or deletions in the amino acid sequence of SEQ ID NO: 26. The variant can have a VL that is a variant of the VL of the humanized S3-90 having up to about 5 amino acid substitutions, additions and / or deletions in the amino acid sequence of SEQ ID NO: 26. The variant can have a VH that is a variant of the VH of the humanized S3-90 having up to about 3, about 5, about 8, about 10, about 12, or about 15 amino acid substitutions, additions and / or deletions in the amino acid sequence of SEQ ID NO: 27. The variant can have a VH that is a variant of the VH of the humanized S3-90 having up to about 5 amino acid substitutions, additions and / or deletions in the amino acid sequence of SEQ ID NO: 27. In some embodiments, the variant of the humanized S3-90 has up to about 5 conservative amino acid substitutions.

[0147] In some embodiments, provided herein is a humanized antibody or antigen binding fragment thereof that specifically binds GIPR, the humanized antibody or antigen binding fragment thereof comprising: (a) a VL having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 26; and / or (b) a VH having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 27. In some embodiments, provided herein is an antibody or antigen binding fragment thereof that specifically binds GIPR, the antibody or antigen binding fragment thereof comprising a VL and a VH, wherein the VL and the VH can have the amino acid sequences of SEQ ID NOs: 26 and 27, respectively.

[0148] In some embodiments, provided herein is an anti-GIPR antibody or antigen binding fragment thereof comprising a VL CDR from a VL described herein (SEQ ID NO: 24 or 26), and / or a VH CDR from a VH described herein (SEQ ID NO: 25 or 27). Methods of identifying CDRs are well known in the art. For example, it is known to those skilled in the art that software programs on publicly available websites (e.g., abYsis) can be used to analyze antibody sequences and determine CDRs.

[0149] In some embodiments, provided herein is an antibody or antigen binding fragment thereof that specifically binds GIPR, the antibody or antigen binding fragment thereof comprising (a) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from a VL having the amino acid sequence of SEQ ID NO: 24; and / or (b) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 from a VH having the amino acid sequence of SEQ ID NO: 25.

[0150] In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind GIPR, the antibodies or antigen-binding fragments thereof comprising (a) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from a VL having an amino acid sequence of SEQ ID NO: 26; and / or (b) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 from a VH having an amino acid sequence of SEQ ID NO: 27.

[0151] In some embodiments, provided herein are anti-GIPR antibody clone 32H1. Sequence features are described below. The specific CDR sequences defined herein are based on the Kabat / AbM combination. However, it should be understood that general references to one or more heavy chain CDRs and / or one or more light chain CDRs of a specific antibody encompass all CDR definitions known to those of skill in the art. In some embodiments, provided herein are anti-GIPR antibodies having the VL CDRs and / or VH CDRs of antibody clone 32H1 disclosed herein, wherein the CDRs are defined by Kabat, Chothia, IMGT, AbM, Contact, or any combination thereof. In some embodiments, the CDRs are defined by Kabat. In some embodiments, the CDRs are defined by Chothia. In some embodiments, the CDRs are defined by IMGT. In some embodiments, the CDRs are defined by AbM. In some embodiments, the CDRs are defined by Contact.

[0152] In some embodiments, an anti-GIPR antibody or antigen-binding fragment thereof provided herein is a variant of 32H1. A 32H1 variant can have a VL that is a variant of the VL of 32H1 having up to about 3, about 5, about 8, about 10, about 12, or about 15 amino acid substitutions, additions and / or deletions in SEQ ID NO: 28. A 32H1 variant can have a VL that is a variant of the VL of 32H1 having up to about 5 amino acid substitutions, additions and / or deletions in SEQ ID NO: 28. A 32H1 variant can have a VH that is a variant of the VH of 32H1 having up to about 3, about 5, about 8, about 10, about 12, or about 15 amino acid substitutions, additions and / or deletions in SEQ ID NO: 29. A 32H1 variant can have a VH that is a variant of the VH of 32H1 having up to about 5 amino acid substitutions, additions and / or deletions in SEQ ID NO: 29. The amino acid substitutions, additions and / or deletions can occur in a VH CDR or a VL CDR. In some embodiments, the amino acid substitutions, additions and / or deletions are not in a CDR region. In some embodiments, a variant of 32H1 has up to about 5 conservative amino acid substitutions. In some embodiments, a variant of 32H1 has up to 3 conservative amino acid substitutions. In some embodiments, an anti-GIPR antibody or antigen-binding fragment thereof provided herein is a humanized antibody or antigen-binding fragment derived from 32H1. In some embodiments, an anti-GIPR antibody or antigen-binding fragment thereof provided herein is a human antibody or antigen-binding fragment derived from 32H1.

[0153] In some embodiments, an anti-GIPR antibody or antigen-binding fragment provided herein comprises one, two, three, four, five, and / or six CDRs of any of the antibodies described herein. In some embodiments, an anti-GIPR antibody or antigen-binding fragment provided herein comprises a VL comprising one, two, and / or three VL CDRs from Table 3. In some embodiments, an anti-GIPR antibody or antigen-binding fragment provided herein comprises a heavy chain variable region (VH) comprising one, two, and / or three heavy chain CDRs (VH CDRs) from Table 3. In some embodiments, an anti-GIPR antibody or antigen-binding fragment provided herein comprises one, two, and / or three VL CDRs and one, two, and / or three VH CDRs from Table 3.

[0154] Table 3 CDR sequences of 32H1

[0155] In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind GIPR (e.g., human GIPR), comprising a VL comprising (1) a VL CDR1 having the amino acid sequence of SEQ ID NO:8, (2) a VL CDR2 having the amino acid sequence of SEQ ID NO:9 or 10, and / or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 11, or a variant thereof having up to about 3, about 5, about 8, about 10, about 12, or about 15 amino acid substitutions, additions and / or deletions in these VL CDRs; and / or a VH comprising (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 12, (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 13, and / or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 14, or a variant thereof having up to about 3, about 5, about 8, about 10, about 12, or about 15 amino acid substitutions, additions and / or deletions in these VH CDRs.

[0156] In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind GIPR, comprising a VL comprising (1) a VL CDR1 having the amino acid sequence of SEQ ID NO:8, (2) a VL CDR2 having the amino acid sequence of SEQ ID NO:9 or 10, or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 11, or a variant thereof having up to about 3, about 5, about 8, about 10, about 12, or about 15 amino acid substitutions, additions and / or deletions in the VL CDRs. In some embodiments, the variant has up to about 5 amino acid substitutions, additions and / or deletions in the VL CDRs. In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind GIPR, comprising a VL comprising (1) a VL CDR1 having the amino acid sequence of SEQ ID NO:8, (2) a VL CDR2 having the amino acid sequence of SEQ ID NO:9 or 10, and (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 11, or a variant thereof having up to about 3, about 5, about 8, about 10, about 12, or about 15 amino acid substitutions, additions and / or deletions in these VL CDRs. In some embodiments, the variant has up to about 5 amino acid substitutions, additions and / or deletions in these VL CDRs.

[0157] In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind GIPR, the antibodies or antigen-binding fragments thereof comprising a VH comprising (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 12, (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 13, or (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 14, or a variant of the VH having up to about 3, about 5, about 8, about 10, about 12, or about 15 amino acid substitutions, additions and / or deletions in the VH CDRs. In some embodiments, the variant has up to about 5 amino acid substitutions, additions and / or deletions in the VH CDRs. In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind GIPR, the antibodies or antigen-binding fragments thereof comprising a VH comprising (1) a VH CDR1 having an amino acid sequence of SEQ ID NO: 12, (2) a VH CDR2 having an amino acid sequence of SEQ ID NO: 13, and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 14, or a variant of the VH having up to about 3, about 5, about 8, about 10, about 12, or about 15 amino acid substitutions, additions and / or deletions in the VH CDRs. In some embodiments, the variant has up to about 5 amino acid substitutions, additions and / or deletions in the VH CDRs.

[0158] In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind GIPR, the antibodies or antigen-binding fragments thereof comprising: (a) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 of the amino acid sequences of SEQ ID NOs: 8, 9, and 11, respectively, or a variant of the VL having up to about 3, about 5, about 8, about 10, about 12, or about 15 amino acid substitutions, additions and / or deletions in the VL CDRs; and / or (b) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 of the amino acid sequences of SEQ ID NOs: 12, 13, and 14, respectively, or a variant of the VH having up to about 3, about 5, about 8, about 10, about 12, or about 15 amino acid substitutions, additions and / or deletions in the VH CDRs.

[0159] In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind GIPR, comprising: (a) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of SEQ ID NOs: 8, 10, and 11, respectively, or a variant thereof having up to about 3, about 5, about 8, about 10, about 12, or about 15 amino acid substitutions, additions and / or deletions in these VL CDRs; and / or (b) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 12, 13, and 14, respectively, or a variant thereof having up to about 3, about 5, about 8, about 10, about 12, or about 15 amino acid substitutions, additions and / or deletions in these VH CDRs.

[0160] In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind GIPR, comprising a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3, respectively, having the amino acid sequences of SEQ ID NOs: 8, 9, 11, 12, 13, and 14, or variants thereof having up to about 3, about 5, about 8, about 10, about 12, or about 15 amino acid substitutions, additions and / or deletions in these CDRs. In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind GIPR, comprising a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3, respectively, having the amino acid sequences of SEQ ID NOs: 8, 10, 11, 12, 13, and 14, or variants thereof having up to about 3, about 5, about 8, about 10, about 12, or about 15 amino acid substitutions, additions and / or deletions in these CDRs.

[0161] Table 4. VL and VH of chimeric antibody 32H1 and humanized antibody Hz32H1.4.

[0162] In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind GIPR, the antibodies or antigen-binding fragments thereof comprising: (a) a VL having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 28; and (b) a VH having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 29. In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind GIPR, the antibodies or antigen-binding fragments thereof comprising a VL and a VH, wherein the VL and VH have the amino acid sequences of SEQ ID NOs: 28 and 29, respectively.

[0163] In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind GIPR, the antibodies or antigen-binding fragments thereof comprising a VL, wherein the VL has at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 28. In some embodiments, the anti-GIPR antibody or antigen-binding fragment thereof has a VL with at least 85% sequence identity to SEQ ID NO: 28. In some embodiments, the anti-GIPR antibody or antigen-binding fragment thereof has a VL with at least 90% sequence identity to SEQ ID NO: 28. In some embodiments, the anti-GIPR antibody or antigen-binding fragment thereof has a VL with at least 95% sequence identity to SEQ ID NO: 28. In some embodiments, the anti-GIPR antibody or antigen-binding fragment thereof has a VL with at least 98% sequence identity to SEQ ID NO: 28. In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind GIPR, the antibodies or antigen-binding fragments thereof comprising a VL having the amino acid sequence of SEQ ID NO: 28.

[0164] In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind GIPR, the antibodies or antigen-binding fragments thereof comprising a VL, wherein the VL has at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 30. In some embodiments, the anti-GIPR antibody or antigen-binding fragment thereof has a VL with at least 85% sequence identity to SEQ ID NO: 30. In some embodiments, the anti-GIPR antibody or antigen-binding fragment thereof has a VL with at least 90% sequence identity to SEQ ID NO: 30. In some embodiments, the anti-GIPR antibody or antigen-binding fragment thereof has a VL with at least 95% sequence identity to SEQ ID NO: 30. In some embodiments, the anti-GIPR antibody or antigen-binding fragment thereof has a VL with at least 98% sequence identity to SEQ ID NO: 30. In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind GIPR, the antibodies or antigen-binding fragments thereof comprising a VL having the amino acid sequence of SEQ ID NO: 30.

[0165] In some embodiments, provided herein are humanized 30H1 antibodies (i.e., humanized 30H1, Hz30H1.4). In some embodiments, the humanized anti-GIPR antibody or antigen binding fragment thereof provided herein comprises a VL having the amino acid sequence of SEQ ID NO: 30. In some embodiments, the humanized anti-GIPR antibody or antigen binding fragment thereof provided herein comprises a VH having the amino acid sequence of SEQ ID NO: 31. In some embodiments, the humanized anti-GIPR antibody or antigen binding fragment thereof provided herein comprises a VL having the amino acid sequence of SEQ ID NO: 30 and a VH having the amino acid sequence of SEQ ID NO: 31. In some embodiments, the anti-GIPR antibody or antigen binding fragment thereof provided herein is a variant of the humanized 30H1 provided herein. The variant can have a VL that is a variant of the VL of humanized 30H1 having up to about 3, about 5, about 8, about 10, about 12, or about 15 amino acid substitutions, additions and / or deletions in the amino acid sequence of SEQ ID NO: 30. The variant can have a VL that is a variant of the VL of humanized 30H1 having up to about 5 amino acid substitutions, additions and / or deletions in the amino acid sequence of SEQ ID NO: 30. The variant can have a VH that is a variant of the VH of humanized 30H1 having up to about 3, about 5, about 8, about 10, about 12, or about 15 amino acid substitutions, additions and / or deletions in the amino acid sequence of SEQ ID NO: 31. The variant can have a VH that is a variant of the VH of humanized 30H1 having up to about 5 amino acid substitutions, additions and / or deletions in the amino acid sequence of SEQ ID NO: 31. In some embodiments, the variant of humanized 30H1 has up to about 5 conservative amino acid substitutions.

[0166] In some embodiments, provided herein is a humanized antibody or antigen binding fragment thereof that specifically binds GIPR, the humanized antibody or antigen binding fragment thereof comprising: (a) a VL having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 30; and / or (b) a VH having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 31. In some embodiments, provided herein is an antibody or antigen binding fragment thereof that specifically binds GIPR, the antibody or antigen binding fragment thereof comprising a VL and a VH, wherein the VL and the VH can have the amino acid sequences of SEQ ID NOs: 30 and 31, respectively.

[0167] In some embodiments, provided herein is an anti-GIPR antibody or antigen binding fragment thereof comprising a VL CDR from a VL described herein (SEQ ID NO: 28 or 30), and / or a VH CDR from a VH described herein (SEQ ID NO: 29 or 31). Methods of identifying CDRs are well known in the art. For example, it is known to those skilled in the art that software programs on publicly available websites (e.g., abYsis) can be used to analyze antibody sequences and determine CDRs.

[0168] In some embodiments, provided herein is an antibody or antigen binding fragment thereof that specifically binds GIPR, the antibody or antigen binding fragment thereof comprising: (a) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from a VL having the amino acid sequence of SEQ ID NO: 28; and / or (b) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 from a VH having the amino acid sequence of SEQ ID NO: 29.

[0169] In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind GIPR, the antibodies or antigen-binding fragments thereof comprising (a) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from a VL having an amino acid sequence of SEQ ID NO: 30; and / or (b) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 from a VH having an amino acid sequence of SEQ ID NO: 31.

[0170] An anti-GIPR antibody or antigen-binding fragment thereof can comprise any of the VLs disclosed herein and any of the VHs disclosed herein in combination. In some embodiments, the VL and the VH are connected by a linker. The linker can be a flexible linker or a rigid linker. In some embodiments, the linker has an amino acid sequence of (GGGGS)n, n = 1, 2, 3, 4, or 5 (SEQ ID NO: 86). In some embodiments, the linker has an amino acid sequence of (EAAAK)n, n = 1, 2, 3, 4, or 5 (SEQ ID NO: 87).

[0171] In some embodiments, an anti-GIPR antibody provided herein is an IgA, IgD, IgE, IgG, or IgM antibody. In some embodiments, the antibody is an IgA antibody. In some embodiments, the antibody is an IgD antibody. In some embodiments, the antibody is an IgE antibody. In some embodiments, the antibody is an IgG antibody. In some embodiments, the antibody is an IgM antibody. In some embodiments, an antibody provided herein can be an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, or an IgG4 antibody. In some embodiments, the antibody is an IgG1 antibody. In some embodiments, the antibody is an IgG2 antibody. In some embodiments, the antibody is an IgG3 antibody. In some embodiments, the antibody is an IgG4 antibody.

[0172] In some embodiments, an anti-GIPR antibody provided herein comprises a light chain and a heavy chain. The light chain can comprise a light chain constant domain (CL) and a light chain variable domain (VL). The heavy chain can comprise a heavy chain variable domain (VH) and a heavy chain constant domain (CH). The VL / VH can be any VL / VH disclosed herein. In some embodiments, the light chain constant region (CL) is kappa CL (CK; SEQ ID NO: 37). In some embodiments, the light chain constant region (CL) is lambda CL (CL; SEQ ID NO: 38). In some embodiments, the heavy chain can comprise a heavy chain constant domain (CH) from human IgA. In some embodiments, the heavy chain can comprise a heavy chain constant domain (CH) from human IgD. In some embodiments, the heavy chain can comprise a heavy chain constant domain (CH) from human IgE. In some embodiments, the heavy chain can comprise a heavy chain constant domain (CH) from human IgG. In some embodiments, the heavy chain can comprise a heavy chain constant domain (CH) from human IgM. In some embodiments, the heavy chain can comprise a heavy chain constant domain (CH) from human IgGl (e.g., SEQ ID NO: 39). In some embodiments, the heavy chain can comprise a heavy chain constant domain (CH) from human IgG2 (e.g., SEQ ID NO: 40). In some embodiments, the heavy chain can comprise a heavy chain constant domain (CH) from human IgG3 (e.g., SEQ ID NO: 41). In some embodiments, the heavy chain can comprise a heavy chain constant domain (CH) from human IgG4 (e.g., SEQ ID NO: 42). The CH can further comprise a C-terminal lysine (K). Any and all combinations of the VL / VH pairs disclosed herein that specifically bind GIPR (e.g., human GIPR) with the CL / CH disclosed herein or otherwise known in the art are expressly contemplated herein.

[0173] In some embodiments, an antibody provided herein has a light chain constant region (CL) having at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 37. In some embodiments, an antibody provided herein has a CL having the amino acid sequence of SEQ ID NO: 37. In some embodiments, an antibody provided herein has a light chain constant region (CL) having at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 38. In some embodiments, an antibody provided herein has a CL having the amino acid sequence of SEQ ID NO: 38. In some embodiments, an antibody provided herein has a heavy chain constant region (CH) having at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 39. In some embodiments, an antibody provided herein has a CH having the amino acid sequence of SEQ ID NO: 39. In some embodiments, an antibody provided herein has a CH having at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 40. In some embodiments, an antibody provided herein has a CH having the amino acid sequence of SEQ ID NO: 40. In some embodiments, an antibody provided herein has a CH having at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 41. In some embodiments, an antibody provided herein has a CH having the amino acid sequence of SEQ ID NO: 41. In some embodiments, an antibody provided herein has a CH having at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 42. In some embodiments, an antibody provided herein has a CH having the amino acid sequence of SEQ ID NO: 42.

[0174] Table 5. Light and heavy chains of humanized antibody HzS3-90.1.

[0175] In some embodiments, an anti-GIPR antibody provided herein comprises: (1) a light chain comprising, from N-terminus to C-terminus, a VL and a light chain constant (CL) region; and / or (2) a heavy chain comprising, from N-terminus to C-terminus, a VH and a heavy chain constant (CH) region. In some embodiments, an anti-GIPR antibody provided herein comprises a light chain comprising, from N-terminus to C-terminus, a VL and a light chain constant (CL) region, wherein the light chain has an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 48. In some embodiments, an anti-GIPR antibody provided herein comprises a heavy chain comprising, from N-terminus to C-terminus, a VH and a heavy chain constant (CH) region, wherein the heavy chain has an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 49. In some embodiments, an anti-GIPR antibody provided herein comprises a light chain comprising, from N-terminus to C-terminus, a VL and a light chain constant (CL) region, wherein the light chain has the amino acid sequence of SEQ ID NO: 48. In some embodiments, an anti-GIPR antibody provided herein comprises a heavy chain comprising, from N-terminus to C-terminus, a VH and a heavy chain constant (CH) region, wherein the heavy chain has the amino acid sequence of SEQ ID NO: 49. In some embodiments, an anti-GIPR antibody provided herein comprises: (1) a light chain comprising, from N-terminus to C-terminus, a VL and a light chain constant (CL) region; and (2) a heavy chain comprising, from N-terminus to C-terminus, a VH and a heavy chain constant (CH) region; wherein the light chain has an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 48, and the heavy chain has an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 49. In some embodiments, an anti-GIPR antibody provided herein comprises: (1) a light chain comprising, from N-terminus to C-terminus, a VL and a light chain constant (CL) region; and (2) a heavy chain comprising, from N-terminus to C-terminus, a VH and a heavy chain constant (CH) region; wherein the light chain has the amino acid sequence of SEQ ID NO: 48, and the heavy chain has the amino acid sequence of SEQ ID NO: 49.

[0176] Table 6. Light and heavy chains of humanized antibody Hz32H1.4.

[0177] In some embodiments, an anti-GIPR antibody provided herein comprises: (1) a light chain comprising, from N-terminal to C-terminal, a VL and a light chain constant (CL) region; and / or (2) a heavy chain comprising, from N-terminal to C-terminal, a VH and a heavy chain constant (CH) region. In some embodiments, an anti-GIPR antibody provided herein comprises a light chain comprising, from N-terminal to C-terminal, a VL and a light chain constant (CL) region, wherein the light chain has an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 50. In some embodiments, an anti-GIPR antibody provided herein comprises a heavy chain comprising, from N-terminal to C-terminal, a VH and a heavy chain constant (CH) region, wherein the heavy chain has an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 51. In some embodiments, an anti-GIPR antibody provided herein comprises a light chain comprising, from N-terminal to C-terminal, a VL and a light chain constant (CL) region, wherein the light chain has the amino acid sequence of SEQ ID NO: 50. In some embodiments, an anti-GIPR antibody provided herein comprises a heavy chain comprising, from N-terminal to C-terminal, a VH and a heavy chain constant (CH) region, wherein the heavy chain has the amino acid sequence of SEQ ID NO: 51. In some embodiments, an anti-GIPR antibody provided herein comprises: (1) a light chain comprising, from N-terminal to C-terminal, a VL and a light chain constant (CL) region; and (2) a heavy chain comprising, from N-terminal to C-terminal, a VH and a heavy chain constant (CH) region; wherein the light chain has an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 50, and the heavy chain has an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 51. In some embodiments, an anti-GIPR antibody provided herein comprises: (1) a light chain comprising, from N-terminal to C-terminal, a VL and a light chain constant (CL) region; and (2) a heavy chain comprising, from N-terminal to C-terminal, a VH and a heavy chain constant (CH) region; wherein the light chain has the amino acid sequence of SEQ ID NO: 50, and the heavy chain has the amino acid sequence of SEQ ID NO: 51.

[0178] In some embodiments, also provided herein are antibodies or antigen-binding fragments that compete with the antibodies or antigen-binding fragments provided above (e.g., S3-90 or 32H1) for binding to GIPR (e.g., human GIPR). An antibody that "competes with another antibody for binding to a target" is an antibody that (partially or completely) inhibits the binding of the other antibody to the target. Whether two antibodies compete with each other for binding to a target, i.e., whether one antibody inhibits and to what extent it inhibits the binding of the other antibody to the target, can be determined using known competition experiments, e.g. surface plasmon resonance (SPR) analysis or flow cytometry. In some embodiments, an anti-GIPR antibody or antigen-binding fragment competes with and inhibits the binding of another antibody or antigen-binding fragment to GIPR by at least 50%, 60%, 70%, 80%, 90%, or 100%. Competition assays can be performed according to the methods described in, e.g., Ed Harlow and David Lane, Cold Spring Harb Protoc, 2006, doi: 10.1101 / pdb.prot4277, or Ed Harlow and David Lane, Using Antibodies, Chapter 11, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1999.

[0179] In some embodiments, provided herein are antibodies or antigen-binding fragments that compete with the anti-GIPR antibodies or antigen-binding fragments disclosed herein for binding to GIPR (e.g., human GIPR). In some embodiments, provided herein are antibodies or antigen-binding fragments that compete with chimeric S3-90 for binding to GIPR (e.g., human GIPR). In some embodiments, provided herein are antibodies or antigen-binding fragments that compete with the humanized S3-90 disclosed herein for binding to GIPR (e.g., human GIPR). In some embodiments, provided herein are antibodies or antigen-binding fragments that compete with chimeric 32H1 for binding to GIPR (e.g., human GIPR). In some embodiments, provided herein are antibodies or antigen-binding fragments that compete with the humanized 32H1 disclosed herein for binding to GIPR (e.g., human GIPR).

[0180] Epitope mapping is a method of identifying the binding site, region, or epitope on a target protein to which an antibody binds. In the art, a variety of methods are known for mapping epitopes on a target protein. These methods include mutagenesis, including but not limited to, shotgun mutagenesis, site-directed mutagenesis, and alanine scanning; domain or fragment scanning; peptide scanning (e.g., Pepscan technology); display methods (e.g., phage display, microbial display, and ribosome / mRNA display); methods involving proteolysis and mass spectrometry; and structural determination (e.g., X-ray crystallography and NMR). In some embodiments, the anti-GIPR antibodies or antigen-binding fragments described herein are characterized by assays including but not limited to N-terminal sequencing, amino acid analysis, HPLC, mass spectrometry, ion exchange chromatography, and papain digestion.

[0181] The physical, chemical, and / or biological properties of the anti-GIPR antibodies or antigen-binding fragments of the present disclosure can be analyzed by various methods known in the art. In some embodiments, the anti-GIPR antibodies are tested for their ability to bind GIPR (e.g., human GIPR). Binding assays include, but are not limited to, BLI, SPR (e.g., Biacore), ELISA, and FACS. In addition, the solubility, stability, thermal stability, viscosity, expression level, expression quality, and / or purification efficiency of the antibodies can be assessed.

[0182] In some embodiments, the anti-GIPR antibodies or antigen-binding fragments described herein bind human GIPR with high affinity, e.g., with a K -8 M or lower, 10 -8 M or lower, 5 x 10 -9 M or lower, 10 -9 M or lower, 5 x 10 -10 M or lower, or 10 -10 M or lower. In some embodiments, the anti-GIPR antibodies or antigen-binding fragments described herein bind human GIPR with a K D In some embodiments, the anti-GIPR antibodies or antigen-binding fragments described herein bind human GIPR with a K - 9 M or lower. In some embodiments, the anti-GIPR antibodies or antigen-binding fragments described herein bind human GIPR with a K D In some embodiments, the anti-GIPR antibodies or antigen-binding fragments described herein bind human GIPR with high affinity, e.g., with a K -8 M, about 10 -8 M, about 5 x 10 -9 M, about 10 -9 M, about 5 x 10 -10 M, or about 10 -10 M. In some embodiments, the anti-GIPR antibodies or antigen-binding fragments described herein bind human GIPR with a K D In some embodiments, the anti-GIPR antibodies or antigen-binding fragments described herein bind human GIPR with a K -9 M. In some embodiments, the anti-GIPR antibodies or antigen-binding fragments described herein bind human GIPR with a K DBinding to human GIPR. In some embodiments, the anti-GIPR antibody or antigen-binding fragment described herein is in the following range of K D Combined human GIPR: 10 -10 M to 5×10 -8 M, 10 -9 M to 5×10 -8 M, 10 -8 M to 5×10 -8 M, 10 -10 M to 10 -8 M, 10 -9 M to 10 -8 M, 10 -10 M to 5×10 -9 M, 10 -9 M to 5×10 -9 M, or 10 -10 M to 10 -9 M. In some embodiments, the anti-GIPR antibody or antigen-binding fragment described herein binds to human GIPR with high affinity, for example, at 10 -9 M to 5×10 -9 M of K D In some implementations, K D Determined via BLI. In some implementations, K D Assay by SPR. In some embodiments, the anti-GIPR antibody or antigen-binding fragment described herein binds to human GIPR with high affinity, for example, with K, as measured by BLI. D 5×10 -8 M or lower, 10 -8 M or lower, 5×10 -9 M or lower, 10 -9 M or lower, 5×10 -10 M or lower, or 10 -10 M or lower; or about 10 - 7 M, approximately 5×10 -8 M, approximately 10 -8 M, approximately 5×10 -9 M, approximately 10 -9 M, approximately 5×10 -10 M or approximately 10 -10 M; or a range of 10 -10 M to 5×10 -8 M, 10 -9 M to 5×10 -8 M, 10 -8 M to 5×10 -8 M, 10 -10 M to 10 -8 M, 10-9 M to 10 -8 M, 10 -10 M to 5 x 10 -9 M, 10 - 9 M to 5 x 10 -9 M, or 10 -10 M to 10 -9 M.

[0183] In some embodiments, the anti-GIPR antibodies or antigen-binding fragments described herein specifically bind to human GIPR. In some embodiments, the anti-GIPR antibodies or antigen-binding fragments described herein bind to both human GIPR and cynomolgus GIPR. In some embodiments, the anti-GIPR antibodies or antigen-binding fragments described herein also bind to mouse GIPR.

[0184] In some embodiments, the anti-GIPR antibodies or antigen-binding fragments provided herein are capable of blocking GIPR signaling. The terms "block," "inhibit," and "antagonize" are used synonymously herein. No term is intended to indicate that complete blockade is required; partial inhibition - corresponding to a reduction, but not complete abrogation, of a biological effect - is also contemplated.

[0185] In some embodiments, the anti-GIPR antibodies or antigen-binding fragments provided herein can be internalized by cells expressing GIPR.

[0186] In some embodiments, the anti-GIPR antibodies or antigen-binding fragments provided herein are capable of blocking GIPR signaling. In some embodiments, the anti-GIPR antibodies or antigen-binding fragments described herein block the binding of GIP to GIPR. As is known in the art, cAMP is a key downstream component of the GIP / GIPR signaling pathway, and its production is a reliable indicator of pathway activation. In some embodiments, the anti-GIPR antibodies or antigen-binding fragments described herein block GIP-induced cAMP production.

[0187] In some embodiments, the anti-GIPR antibodies or antigen-binding fragments disclosed herein (e.g., S3-90, 32H1, and humanized versions thereof) are capable of antagonizing the biological effects of GIP and have one or more of the following functions when administered to a subject (e.g., a human): (1) lowering blood glucose; (2) increasing glucose tolerance; (3) increasing insulin sensitivity; (4) reducing body weight or decreasing body weight gain; (5) reducing fat mass; (6) reducing inflammation in adipose tissue; (7) lowering fasting insulin levels; (8) lowering circulating triglyceride levels; (9) reducing liver steatosis or lowering triglyceride levels in the liver; or (10) lowering AST, ALT, and / or ALP levels; or any combination of (1) to (10).

[0188] In some embodiments, the anti-GIPR antibodies or antigen-binding fragments described herein (e.g., S3-90, 32H1, and humanized versions thereof) are capable of improving GIP or GIPR-related metabolic disorders, such as overweight, obesity, and diabetes (e.g., type 2 diabetes). In some embodiments, the anti-GIPR antibodies or antigen-binding fragments described herein (e.g., S3-90, 32H1, and humanized versions thereof) are capable of treating overweight. In some embodiments, the anti-GIPR antibodies or antigen-binding fragments described herein (e.g., S3-90, 32H1, and humanized versions thereof) are capable of treating obesity. In some embodiments, the anti-GIPR antibodies or antigen-binding fragments described herein (e.g., S3-90, 32H1, and humanized versions thereof) are capable of treating diabetes (e.g., type 2 diabetes).

[0189] The present disclosure also contemplates additional variants and equivalents of the recombinant, monoclonal, chimeric, or humanized antibodies or antibody fragments thereof described herein that are substantially homologous. In some embodiments, it is desirable to increase the binding affinity of the antibody. In some embodiments, it is desirable to modulate the biological properties of the antibody, including but not limited to specificity, thermal stability, expression level, effector function, glycosylation, immunogenicity, and / or solubility. It will be appreciated by one of skill in the art that amino acid changes can alter the post-translational processing of the antibody, such as changing the number or position of glycosylation sites or changing membrane anchor characteristics.

[0190] The variation can be a substitution, deletion, or insertion of one or more nucleotides encoding the antibody or polypeptide that results in an amino acid sequence that varies from the native antibody or polypeptide sequence. In some embodiments, an amino acid substitution is the result of replacing one amino acid with another amino acid of similar structure and / or chemical properties, such as replacing a leucine with a serine, for example, a conservative amino acid substitution. An insertion or deletion can range from about 1 to 5 amino acids. In some embodiments, the substitution, deletion, or insertion comprises fewer than 25 amino acid substitutions, fewer than 20 amino acid substitutions, fewer than 15 amino acid substitutions, fewer than 10 amino acid substitutions, fewer than 5 amino acid substitutions, fewer than 4 amino acid substitutions, fewer than 3 amino acid substitutions, or fewer than 2 amino acid substitutions relative to the parent molecule. In some embodiments, biologically useful and / or relevant variations of an amino acid sequence can be determined by systematically making insertions, deletions, or substitutions in the sequence and testing the resulting variant proteins for activity compared to the parent protein.

[0191] In some embodiments, for example, single or multiple amino acid substitutions (e.g., conservative amino acid substitutions) can be made in portions of the antibody that are outside of the domains that form intermolecular contacts. In some embodiments, conservative amino acid substitutions that do not substantially alter the structural characteristics of the parent sequence can be used (e.g., one or more replacement amino acids that do not disrupt the secondary structure that characterizes the parent or native antigen binding protein). Examples of polypeptide secondary and tertiary structures that are well-recognized in the art are described in “Proteins, Structures and Molecular Principles” (Creighton, ed.), 1984, W. H. Freeman and Company, New York; “Introduction to Protein Structure” (Branden and Tooze, eds.), 1991, Garland Publishing, New York; and Thornton et al., 1991, Nature 354:105, each of which is incorporated herein by reference.

[0192] In some embodiments, provided herein are variants of the anti-GIPR antibodies or antigen binding fragments described herein. In some embodiments, provided herein are variants of the anti-GIPR antibody clones disclosed herein (e.g., S3-90 or 32H1). In some embodiments, the variants comprise 1 to 30 amino acid substitutions, additions and / or deletions in the parent antibody or antigen binding fragment. In some embodiments, the variants comprise 1 to 25 amino acid substitutions, additions and / or deletions in the parent antibody or antigen binding fragment. In some embodiments, the variants comprise 1 to 20 substitutions, additions and / or deletions in the parent antibody or antigen binding fragment. In some embodiments, the variants comprise 1 to 15 substitutions, additions and / or deletions in the parent antibody or antigen binding fragment. In some embodiments, the variants comprise 1 to 10 substitutions, additions and / or deletions in the parent antibody or antigen binding fragment. In some embodiments, the variants comprise one to five amino acid substitutions, additions and / or deletions in the parent antibody or antigen binding fragment. In some embodiments, the variants comprise one to three amino acid substitutions, additions and / or deletions in the parent antibody or antigen binding fragment. In some embodiments, the amino acid substitutions are in the CDRs of the antibody or antigen binding fragment. In some embodiments, the amino acid substitutions are not in the CDRs of the antibody or antigen binding fragment. In some embodiments, the amino acid substitutions are in the framework regions of the antibody or antigen binding fragment. In some embodiments, the amino acid substitutions, additions and / or deletions are conservative amino acid substitutions.

[0193] The constant regions of antibodies known in the art mediate several effector functions, and these effector functions can vary depending on the isotype of the antibody. For example, the binding of the Cl component of complement to the Fc region of IgG or IgM antibodies (bound to antigen) activates the complement system. Activation of complement is important in the opsonization and lysis of cellular pathogens. Activation of complement also stimulates the inflammatory response, and can participate in autoimmune hypersensitivity reactions. In addition, the Fc region of an antibody can bind to cells that express Fc receptors (FcRs). There are a number of Fc receptors that are specific to the different classes of antibodies, including IgG (gamma receptors), IgE (epsilon receptors), IgA (alpha receptors), and IgM (mu receptors). Binding of antibodies to Fc receptors on the surface of cells triggers a number of important and diverse biological responses, including phagocytosis and destruction of antibody-coated particles, clearance of immune complexes, lysis of antibody-coated target cells by killer cells (a process known as antibody-dependent cellular cytotoxicity or ADCC), release of inflammatory mediators, placental transfer, and control of immunoglobulin production.

[0194] In some embodiments, the anti-GIPR antibodies or antigen-binding fragments described herein comprise a constant region of a human IgA antibody. In some embodiments, the anti-GIPR antibodies or antigen-binding fragments described herein comprise a constant region of a human IgD antibody. In some embodiments, the anti-GIPR antibodies or antigen-binding fragments described herein comprise a constant region of a human IgE antibody. In some embodiments, the anti-GIPR antibodies or antigen-binding fragments described herein comprise a constant region of a human IgG antibody. In some embodiments, the anti-GIPR antibodies or antigen-binding fragments described herein comprise a constant region of a human IgM antibody. In some embodiments, the anti-GIPR antibodies or antigen-binding fragments described herein comprise a constant region of a human IgGl antibody. In some embodiments, the anti-GIPR antibodies or antigen-binding fragments described herein comprise a constant region of a human IgG2 antibody. In some embodiments, the anti-GIPR antibodies or antigen-binding fragments described herein comprise a constant region of a human IgG3 antibody. In some embodiments, the anti-GIPR antibodies or antigen-binding fragments described herein comprise a constant region of a human IgG4 antibody.

[0195] In some embodiments, in the anti-GIPR antibodies or antigen-binding fragments described herein, at least one or more constant regions have been modified or deleted. In some embodiments, the antibody comprises a modification to one or more of the three heavy chain constant regions (CHI, CH2, or CH3) and / or a modification to the light chain constant region (CL).

[0196] In some embodiments, the heavy chain constant region of the modified antibody comprises at least one human constant region. In some embodiments, the heavy chain constant region of the modified antibody comprises more than one human constant region. In some embodiments, the modification to the constant region comprises the addition, deletion, or substitution of one or more amino acids in one or more regions. In some embodiments, one or more regions are partially or completely deleted from the constant region of the modified antibody. In some embodiments, the entire CH2 domain has been removed from the antibody (ACH2 construct). In some embodiments, the deleted constant region is replaced by a short amino acid spacer that provides some of the molecular flexibility normally conferred by the deleted constant region. In some embodiments, the modified antibody comprises a CH3 domain directly fused to the hinge region of the antibody. In some embodiments, the modified antibody comprises a peptide spacer inserted between the hinge region and the modified CH2 and / or CH3 domain.

[0197] In some embodiments, the anti-GIPR antibody or antigen binding fragment comprises an Fc region. In some embodiments, the Fc region is fused via a hinge. The hinge can be an IgGl hinge, an IgG2 hinge, or an IgG3 hinge. The amino acid sequences of the Fc regions of human IgGl, IgG2, IgG3, and IgG4 are known to those of ordinary skill in the art. In some cases, Fc regions with amino acid variations have been identified in natural antibodies. In some embodiments, modified antibodies (e.g., modified Fc regions) provide altered effector functions, which in turn affect the biological characteristics of the antibody. For example, in some embodiments, deletion or inactivation of the constant region (by point mutation or otherwise) reduces Fc receptor binding of the modified antibody when in circulation. In some embodiments, constant region modifications reduce the immunogenicity of the antibody. In some embodiments, constant region modifications prolong the serum half-life of the antibody. In some embodiments, constant region modifications shorten the serum half-life of the antibody. In some embodiments, constant region modifications reduce or eliminate ADCC and / or CDC of the antibody. In some embodiments, specific amino acid substitutions in the human IgGl Fc region with corresponding IgG2 or IgG4 residues reduce the effector functions (e.g., ADCC and CDC) of the modified antibody. In some embodiments, the antibody does not have one or more effector functions (e.g., an "effectorless" antibody). In some embodiments, the antibody does not bind to Fc receptors and / or complement factors. In some embodiments, the antibody does not have effector functions. In some embodiments, the constant region is modified to eliminate disulfide bonds or oligosaccharide moieties. In some embodiments, the constant region is modified to add / substitute one or more amino acids to provide one or more oligosaccharide or carbohydrate attachment sites. In some embodiments, the anti-GIPR antibody or antigen binding fragment comprises a variant Fc region engineered by substitution at specific amino acid positions compared to a native Fc region.

[0198] In some embodiments of the antibodies provided herein, the Fc domain comprises one or more amino acid substitution that reduces binding to an Fc receptor. The Fc receptor can be a human Fc receptor. The Fc receptor can be an Fcy receptor. The Fc receptor can be an activating Fc receptor. The Fc receptor can be an activating human Fcy receptor, such as human FcyRIIIa, FcyRI, or FcyRIIa. In some embodiments of the antibodies provided herein, the Fc domain comprises one or more amino acid substitution that reduces effector function. In some embodiments of the antibodies provided herein, the same one or more amino acid substitution is present in each of the two subunits of the Fc region. In one aspect, the one or more amino acid substitution reduces the binding affinity of the Fc region for an Fc receptor. In one aspect, the one or more amino acid substitution renders the Fc region at least 1 / 2, at least 1 / 5, or at least 1 / 10 as binding-affinitive for an Fc receptor as the original.

[0199] Variants with reduced effector function are known in the art and can be incorporated into the antibodies disclosed herein. For example, amino acid substitutions are known that reduce effector function. The hlgGl L235A / G237A / E318A antibody is unable to bind human cell lines expressing FcyR, resulting in reduced ADCC. hlgGl and hlgG4 antibodies with L234A / L235A Fc domains have no detectable binding to low affinity FcyR and Clq, and ADCC and CDC are significantly reduced. Mutations at specific residues in hlgGl that interact with both FcyR and Clq, such as the amino acid substitutions L234F / L235E / P331S, are known to reduce binding to low affinity FcyR and result in no detectable binding to FcyRI. The G236R / L328R mutation reduces or completely eliminates binding to FcyR. The S267E substitution also reduces binding to all low affinity hFcyR. The S267K substitution was combined with a series of mutations in the lower hinge of hlgG2 (E233P / L234V / L235A mutations and deletion of residue G236) and incorporated into a hlgGl background, resulting in a lack of binding to all hFcyR. The P329G disrupts the interaction between hlgG and hFcyR. The triple mutant L234A / L235A / P329G has no detectable binding to Clq or FcyR, resulting in the elimination of ADCC when introduced into hlgGl. The combination of point mutations N297Q, L234F, L235E, D265A, P331S eliminates Fc function. The combination of L234F / L235E / D265A effectively silences the Fc region, resulting in no detectable binding to FcyRI, reduced binding to low affinity FcyR, and reduced binding to Clq. From a site-saturation mutagenesis library centered on the Fc C' / E loop, the S298G / T299A mutation was found to eliminate or significantly reduce binding to Clq and most FcyR (except FcyRIIA-R131 and FcyRIIB). The E272C substitution can also be introduced into the Fc domain when preparing the anti-GIPR antibodies or antigen-binding fragments disclosed herein as conjugates.

[0200] Additionally, glycoengineering techniques can be used to generate antibodies with reduced effector function. The N297 glycan is central to the binding between hlgGl and FcyR and Clq. Thus, amino acid mutations that remove this glycan at this site, including N297A, N297Q, and N297G, can reduce binding to all FcyR and Clq, resulting in a reduction of ADCC and CDC.

[0201] For hlgG4, which has low affinity for all FcyRs, the serine at position 228 plays a key role in F(ab) arm exchange. The S228P substitution can provide homogenous hlgG4, and this substitution is commonly introduced into therapeutic hlgG4 antibodies. The human gamma 4 constant region can be used in Fc silencing approaches based on its inherent lack of effector function. For example, exchanging the human gamma 1 region with the human gamma 4 region can reduce effector functionality. The murine IgG2b isotype also has low FcyR binding activity, but it differs from hlgG4 at position 235. Incorporating the mouse IgG2b residue (glutamic acid) at this position into hlgG4 antibodies can further minimize Fc effector function, resulting in antibodies with significantly reduced (if any) binding to all FcyRs and Clq and no measurable ADCC (with the S228P / L235E mutations). Additionally, rather than replacing the entire constant region of hlgG1 with hlgG4, it can be preferable to introduce specific amino acids from human gamma 4 into antibodies of other IgG isotypes. For example, after introducing the combination of amino acid mutations— H268Q / V309L / A330S / P331S (IgG2m4) into the hlgG2 backbone, this combination of mutations can result in no detectable binding to hFcyRI, hFcyRIIIA, or Clq, reduced binding to hFcyRIIB, and no change in binding to FcyRIIA-H131 when compared to WT hlgG2 antibodies. As another example, the V234A / G237A / P238S / H268A / V309L / A330S / P331S (IgG2c4d) mutations (in which multiple residues within the hlgG2 constant region are replaced with IgG4 residues) can result in no detectable binding to any FcyR or Clq and no measurable ADCC, ADCP, or CDC when compared to the WT hlgG2 counterpart.

[0202] Accordingly, for illustrative purposes, such variants include: aglycosylation (N297A / Q / G; or “NA”), L235A / G237A / E318A (“AAA”), L234A / L235A (“LALA”), S228P / L235E (“IgG4 PE”), G236R / L328R (“RR”), S298G / T299A (“GA”), L234F / L235E / P331S (“FES”), H268Q / V309L / A330S / P331S (“IgG2m4”), E233P / L234V / L235A / G236 deletion / S267K, L234A / L235A / P329G (“LALAPG”), L234A / L235A / E272C (“LALAEC”), V234A / G237A / P238S / H268A / V309L / A330S / P331S (“IgG2c4d”), and L234F / L235E / D265A (“FEA”). (See Liu et al., Antibodies 9.4 (2020): 64; Delidakis et al., Annual review of biomedical engineering, 24 (2022): 249-274, both of which are incorporated by reference in their entireties). In some embodiments, the anti-GIPR antibodies or antigen binding fragments disclosed herein comprise a NA mutation. In some embodiments, the anti-GIPR antibodies or antigen binding fragments disclosed herein comprise an AAA mutation. In some embodiments, the anti-GIPR antibodies or antigen binding fragments disclosed herein comprise a LALA mutation. In some embodiments, the anti-GIPR antibodies or antigen binding fragments disclosed herein comprise a RR mutation. In some embodiments, the anti-GIPR antibodies or antigen binding fragments disclosed herein comprise a GA mutation. In some embodiments, the anti-GIPR antibodies or antigen binding fragments disclosed herein comprise a FES mutation. In some embodiments, the anti-GIPR antibodies or antigen binding fragments disclosed herein comprise a LALAPG mutation. In some embodiments, the anti-GIPR antibodies or antigen binding fragments disclosed herein comprise a LALAEC mutation. In some embodiments, the anti-GIPR antibodies or antigen binding fragments disclosed herein comprise a FEA mutation. In some embodiments, the anti-GIPR antibodies or antigen binding fragments disclosed herein comprise an IgG2m4 mutation. In some embodiments, the anti-GIPR antibodies or antigen binding fragments disclosed herein comprise an IgG2-PE mutation. In some embodiments, the anti-GIPR antibodies or antigen binding fragments disclosed herein comprise an IgG2c4d mutation.As will be appreciated by one of ordinary skill in the art, the anti-GIPR antibodies or antigen-binding fragments disclosed herein are not limited to specific Fc modifications, and any combination and permutation of the Fc modifications disclosed herein or otherwise known in the art can be used in the anti-GIPR antibodies or antigen-binding fragments, so long as effector function or binding affinity to FcyR is reduced.

[0203] In some embodiments, the anti-GIPR antibodies or antigen-binding fragments described herein comprise an IgG4 heavy chain constant region comprising an amino acid substitution of S228. In some embodiments, the anti-GIPR antibodies or antigen-binding fragments described herein comprise an IgG4 heavy chain constant region comprising at least one amino acid substitution. The IgG4 heavy chain constant region can comprise a substitution of S228.

[0204] In some embodiments, Fc mutations are incorporated to improve serum half-life. Exemplary mutations include, for example, M252Y / S254T / T256E (YTE) substitutions, M428L / N434S (LS) substitutions, T307A / E380A / N434A (TM) substitutions, and H433K / N434F (HS) substitutions. These mutations are specifically designed to enhance the interaction of the antibody with the FcRn receptor, thereby reducing lysosomal degradation and prolonging the circulating time of the antibody in the bloodstream.

[0205] In some embodiments, the anti-GIPR antibodies or antigen-binding fragments disclosed herein are IgGl antibodies with L234A / L235A substitutions in the Fc region. In some embodiments, the anti-GIPR antibodies or antigen-binding fragments disclosed herein are IgGl antibodies with E272C substitutions in the Fc region. In some embodiments, the anti-GIPR antibodies or antigen-binding fragments disclosed herein are IgGl antibodies with L234A / L235A / E272C substitutions in the Fc region. In some embodiments, the anti-GIPR antibodies or antigen-binding fragments disclosed herein are IgGl antibodies with M252Y / S254T / T256E substitutions in the Fc region. In some embodiments, the anti-GIPR antibodies or antigen-binding fragments disclosed herein are IgGl antibodies with L234A / L235A / E272C / M252Y / S254T / T256E substitutions in the Fc region.

[0206] In some embodiments, the anti-GIPR antibodies or antigen binding fragments disclosed herein comprise a heavy chain comprising a CH from a human IgGl with L234A / L235A / E272C substitutions in the Fc region (e.g., SEQ ID NO: 43). In some embodiments, the anti-GIPR antibodies or antigen binding fragments disclosed herein comprise a heavy chain comprising a CH from a human IgGl with E272C / L234A / L235A / M252Y / S254T / T256E substitutions in the Fc region (e.g., SEQ ID NO: 88).

[0207] In some embodiments, the antibodies provided herein have a heavy chain constant region (CH) having at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 43. In some embodiments, the antibodies provided herein have a CH having the amino acid sequence of SEQ ID NO: 43. In some embodiments, the antibodies provided herein have a heavy chain constant region (CH) having at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 88. In some embodiments, the antibodies provided herein have a CH having the amino acid sequence of SEQ ID NO: 88.

[0208] Table 5-1 Light and heavy chains of humanized antibody HzS3-90.1-YTE.

[0209] In some embodiments, an anti-GIPR antibody provided herein comprises: (1) a light chain comprising, from N-terminal to C-terminal, a VL and a light chain constant (CL) region; and / or (2) a heavy chain comprising, from N-terminal to C-terminal, a VH and a heavy chain constant (CH) region. In some embodiments, an anti-GIPR antibody provided herein comprises a light chain comprising, from N-terminal to C-terminal, a VL and a light chain constant (CL) region, wherein the light chain has an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 48. In some embodiments, an anti-GIPR antibody provided herein comprises a heavy chain comprising, from N-terminal to C-terminal, a VH and a heavy chain constant (CH) region, wherein the heavy chain has an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 89. In some embodiments, an anti-GIPR antibody provided herein comprises a light chain comprising, from N-terminal to C-terminal, a VL and a light chain constant (CL) region, wherein the light chain has the amino acid sequence of SEQ ID NO: 48. In some embodiments, an anti-GIPR antibody provided herein comprises a heavy chain comprising, from N-terminal to C-terminal, a VH and a heavy chain constant (CH) region, wherein the heavy chain has the amino acid sequence of SEQ ID NO: 89. In some embodiments, an anti-GIPR antibody provided herein comprises: (1) a light chain comprising, from N-terminal to C-terminal, a VL and a light chain constant (CL) region; and (2) a heavy chain comprising, from N-terminal to C-terminal, a VH and a heavy chain constant (CH) region; wherein the light chain has an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 48, and the heavy chain has an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 89. In some embodiments, an anti-GIPR antibody provided herein comprises: (1) a light chain comprising, from N-terminal to C-terminal, a VL and a light chain constant (CL) region; and (2) a heavy chain comprising, from N-terminal to C-terminal, a VH and a heavy chain constant (CH) region; wherein the light chain has the amino acid sequence of SEQ ID NO: 48, and the heavy chain has the amino acid sequence of SEQ ID NO: 89.

[0210] Table 6-1. Light and heavy chains of humanized antibody Hz32H1.4-YTE.

[0211] In some embodiments, an anti-GIPR antibody provided herein comprises: (1) a light chain comprising, from N-terminal to C-terminal, a VL and a light chain constant (CL) region; and / or (2) a heavy chain comprising, from N-terminal to C-terminal, a VH and a heavy chain constant (CH) region. In some embodiments, an anti-GIPR antibody provided herein comprises a light chain comprising, from N-terminal to C-terminal, a VL and a light chain constant (CL) region, wherein the light chain has an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 50. In some embodiments, an anti-GIPR antibody provided herein comprises a heavy chain comprising, from N-terminal to C-terminal, a VH and a heavy chain constant (CH) region, wherein the heavy chain has an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 90. In some embodiments, an anti-GIPR antibody provided herein comprises a light chain comprising, from N-terminal to C-terminal, a VL and a light chain constant (CL) region, wherein the light chain has the amino acid sequence of SEQ ID NO: 50. In some embodiments, an anti-GIPR antibody provided herein comprises a heavy chain comprising, from N-terminal to C-terminal, a VH and a heavy chain constant (CH) region, wherein the heavy chain has the amino acid sequence of SEQ ID NO: 90. In some embodiments, an anti-GIPR antibody provided herein comprises: (1) a light chain comprising, from N-terminal to C-terminal, a VL and a light chain constant (CL) region; and (2) a heavy chain comprising, from N-terminal to C-terminal, a VH and a heavy chain constant (CH) region; wherein the light chain has an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 50, and the heavy chain has an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 90. In some embodiments, an anti-GIPR antibody provided herein comprises: (1) a light chain comprising, from N-terminal to C-terminal, a VL and a light chain constant (CL) region; and (2) a heavy chain comprising, from N-terminal to C-terminal, a VH and a heavy chain constant (CH) region; wherein the light chain has the amino acid sequence of SEQ ID NO: 50, and the heavy chain has the amino acid sequence of SEQ ID NO: 90.

[0212] In some embodiments, the variants can include amino acid residues added at the amino and / or carboxy terminus of the antibody or polypeptide. The additional amino acid residues can range in length from one residue to one hundred or more. In some embodiments, the variants include an N-terminal methionyl residue. In some embodiments, the variants include additional polypeptides / proteins (e.g., Fc regions) to create fusion proteins. In some embodiments, the variants are engineered to be detectable and can include detectable labels and / or proteins (e.g., fluorescent tags or enzymes).

[0213] Variant antibodies or antigen-binding fragments described herein can be produced using methods known in the art, including but not limited to site-directed mutagenesis, alanine scanning mutagenesis, and PCR mutagenesis. Methods for mutagenesis and nucleotide sequence alteration are well known in the art. See, e.g., Walker and Gaastra, eds. (1983) TECHNIQUES IN MOLECULAR BIOLOGY (MacMillan Publishing Company, New York); Kunkel, Proc. Natl. Acad. Sci. USA 82:488-492 (1985); Kunkel et al., Methods Enzymol. 154:367-382 (1987); Sambrook et al. (1989) MOLECULAR CLONING: A LABORATORY MANUAL (Cold Spring Harbor Laboratory, New York); U.S. Patent No. 4,873,192; and references cited therein; which are incorporated herein by reference. Guidance in appropriate amino acid substitutions not affecting biological activity of a polypeptide of interest can be found using the model set forth by Dayhoff et al. (1978) in the Atlas of Protein Sequence and Structure (Natl. Biomed. Res. Found., Washington, D.C.), pp. 345-352, which is incorporated herein by reference in its entirety. The model of Dayhoff et al. uses the point accepted mutation (PAM) amino acid similarity matrix (PAM 250 matrix) to determine suitable conservative amino acid substitutions. Conservative substitutions such as exchanging one amino acid for another with similar properties can be beneficial. Examples of conservative amino acid substitutions taught by the PAM 250 matrix of the model of Dayhoff et al. include, but are not limited to, Gly→Ala, Val→Ile→Leu, Asp→Glu, Lys→Arg, Asn→Gln, and Phe→Trp→Tyr.

[0214] In constructing variants of anti-GIPR binding molecules (e.g., antibodies or antigen-binding fragments, variants, or derivatives thereof), modifications are made such that the variants continue to have the desired properties, e.g., the ability to specifically bind to GIPR, and in certain embodiments, the ability to block GIPR signaling. Obviously, any mutations made in the DNA encoding the variant polypeptide must not place the sequence out of reading frame. In some embodiments, the mutations that are made in the DNA will not create complementary regions that could produce secondary mRNA structure.

[0215] In some embodiments, variants of the anti-GIPR antibodies or antigen-binding fragments disclosed herein can retain a similar, identical, or higher degree of ability to bind to GIPR as the parent antibody or antigen-binding fragment. In some embodiments, the variants can have at least about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or more identity in the amino acid sequence to the parent antibody or antigen-binding fragment. In certain embodiments, the variants of the anti-GIPR antibodies or antigen-binding fragments comprise the amino acid sequence of the parent anti-GIPR antibody or antigen-binding fragment with one or more conservative amino acid substitutions. Conservative amino acid substitutions are known in the art and include substitutions of one amino acid for another amino acid having certain physical and / or chemical properties.

[0216] In some embodiments, the variants of the anti-GIPR antibodies or antigen-binding fragments comprise the amino acid sequence of the parent antibody or antigen-binding fragment with one or more non-conservative amino acid substitutions. In some embodiments, the variants of the anti-GIPR antibodies or antigen-binding fragments comprise the amino acid sequence of the parent binding antibody or antigen-binding fragment with one or more non-conservative amino acid substitutions, wherein the one or more non-conservative amino acid substitutions do not interfere with or inhibit one or more biological activities of the variant (e.g., GIPR binding). In certain embodiments, the one or more conservative amino acid substitutions and / or the one or more non-conservative amino acid substitutions can enhance the biological activity of the variant such that the biological activity of the functional variant is increased as compared to the parent antibody or antigen-binding fragment.

[0217] In some embodiments, the variants can have 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs (e.g., VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3) of the binding moiety.

[0218] In some embodiments, the anti-GIPR antibodies or antigen-binding fragments described herein are naturally or intentionally chemically modified. In some embodiments, the anti-GIPR antibodies or antigen-binding fragments have been chemically modified by glycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization by known protecting groups / blocking groups, proteolytic cleavage, and / or linkage to a cellular ligand or other protein. Any of a variety of chemical modifications can be made to the anti-GIPR antibodies or antigen-binding fragments by known techniques. The anti-GIPR antibodies or antigen-binding fragments can comprise one or more analogs of an amino acid (including, for example, unnatural amino acids), as well as other modifications known in the art.

[0219] In some embodiments, the anti-GIPR antibodies or antigen-binding fragments disclosed herein can be linked to at least one agent to form an antibody conjugate. The conjugate can be, for example, an antibody conjugated to another protein, carbohydrate, lipid, steroid, immunosuppressant, or a hybrid moiety molecule. Such antibody conjugates include, but are not limited to, modifications that include linking the antibody to one or more polymers. For example, the antibody or antigen-binding fragment can be linked to one or more water-soluble polymers. Linkage to a water-soluble polymer reduces the likelihood that the antibody or antigen-binding fragment will precipitate in an aqueous environment, such as a physiological environment. A person of skill in the art can select a suitable water-soluble polymer based on considerations including, but not limited to, whether the polymer / antibody conjugate will be used to treat a patient, and if so, including the pharmacological profile of the antibody (e.g., half-life, dosage, activity, antigenicity, and / or other factors).

[0220] To increase the efficacy of an antibody molecule as a diagnostic or therapeutic agent, it is conventional to link or covalently bind or complex at least one desired molecule or moiety. Such molecule or moiety can be, but is not limited to, at least one effector or reporter molecule. Non-limiting examples of reporter molecules that have been conjugated to antibodies include enzymes, radiolabels, haptens, fluorescent labels, phosphorescent molecules, chemiluminescent molecules, chromophores, photoaffinity molecules, colored particles or ligands, enzymes (e.g., enzymes that catalyze a colorimetric or fluorescent or bioluminescent reaction), substrates, solid matrices (such as biotin). The antibody can comprise any of one, two, or more of these labels.

[0221] Antibody conjugates are also used as diagnostic agents. In some embodiments, the anti-GIPR antibodies or antigen-binding fragments described herein are conjugated to a detectable substance or molecule that allows the agent to be used for diagnosis and / or detection. The detectable substance can include, but is not limited to, enzymes; prosthetic groups (e.g., biotin and folate); fluorescent materials; bioluminescent materials, such as luciferase; radioactive materials; positron emitting metals; and magnetic metal ions positron emitting metals; and magnetic metal ions.

[0222] Antibody diagnostics generally fall into two categories, one for in vitro diagnosis, such as for a variety of immunoassays, and the other for in vivo diagnostic protocols, often referred to as "antibody-directed imaging." A number of suitable imaging agents are known in the art, as are methods for attaching them to antibodies (see, e.g., U.S. Patents 5,021,236, 4,938,948, and 4,472,509). The imaging moiety used can be a paramagnetic ion, a radioisotope, a fluorescent dye, an NMR detectable substance, an MR hyperpolarized molecule, a targeted ultrasound bubble, and an X-ray imaging agent.

[0223] The anti-GIPR antibodies or antigen-binding fragments described herein can be attached to a solid support. Such solid supports include, but are not limited to, glass, cellulose, polyacrylamide, nylon, polystyrene, polyvinyl chloride, or polypropylene. In some embodiments, the immobilized anti-GIPR antibodies or antigen-binding fragments are used in immunoassays. In some embodiments, the immobilized anti-GIPR antibodies or antigen-binding fragments are used to purify target antigens (e.g., human GIPR).

[0224] Provided herein are anti-GIPR antibodies and antigen-binding fragments thereof, including but not limited to monoclonal antibodies, polyclonal antibodies, chimeric antibodies, human antibodies, humanized antibodies, and antigen-binding fragments thereof. The anti-GIPR antibodies or antigen-binding fragments described herein can be produced by any method known in the art, including chemical synthesis and recombinant expression techniques. Unless otherwise indicated, the practice of the present application employs conventional techniques in molecular biology, microbiology, genetic analysis, recombinant DNA, organic chemistry, biochemistry, PCR, oligonucleotide synthesis and modification, nucleic acid hybridization, and related fields within the skill of the art.

[0225] In some embodiments, monoclonal antibodies are produced using recombinant DNA technology known to those of skill in the art. Also provided herein are methods of producing an antibody or antigen-binding fragment thereof that specifically binds to human GIPR, the method comprising culturing a cell disclosed herein under conditions suitable for expression of the antibody or antigen-binding fragment. In some embodiments, the method further comprises isolating the antibody or antigen-binding fragment from the culture. The polynucleotides of the antibodies or antigen-binding fragments provided herein can be made, manipulated, and / or expressed using any of the well-established techniques known and available in the art. In some embodiments, the polynucleotides of the antibodies or antigen-binding fragments provided herein can be made recombinantly. A number of vectors can be used. Exemplary vectors include, but are not limited to, plasmids, phagemids, cosmids, artificial chromosomes (such as yeast artificial chromosomes (YAC), bacterial artificial chromosomes (BAC), or P1 -derived artificial chromosomes (PAC)), bacteriophages (such as lambda phage or M13 phage), and animal viruses. Examples of categories of animal viruses that can be used as vectors include, but are not limited to, retroviruses (including lentiviruses), adenoviruses, adeno-associated viruses, herpesviruses (e.g., herpes simplex viruses), poxviruses, baculoviruses, papillomaviruses, and papovaviruses (e.g., SV40). Examples of expression vectors are the pClneo vector (Promega) for expression in mammalian cells; the pLenti4 / V5-DEST TM , pLenti6 / V5-DEST TM , and pLenti6.2 / V5-GW / lacZ (Invitrogen) for lentivirus-mediated gene transfer and expression in mammalian cells.

[0226] In some embodiments, recombinant expression vectors are employed to express the polynucleotides encoding the polypeptides described herein. For example, the recombinant expression vector can be a replicable DNA construct that includes a synthetic or cDNA-derived DNA segment encoding a polypeptide operably linked to suitable transcription and / or translation control elements derived from mammalian, microbial, viral, or insect genes. In some embodiments, the coding sequences of the polypeptides disclosed herein can be ligated into such an expression vector so that the former is expressed in a mammalian cell. In some embodiments, viral vectors are used. DNA regions are "operably linked" when they are functionally related to one another. For example, a promoter is operably linked to a coding sequence if the promoter controls the transcription of the coding sequence; or a ribosome binding site is operably linked to the coding sequence if the position of the ribosome binding site allows for translation. In some embodiments, structural elements intended for use in yeast expression systems include a leader sequence enabling host cells to secrete translated protein into the culture medium. In some embodiments, the polypeptides can comprise an N-terminal methionine residue in the absence of a leader or transit sequence when the recombinant protein is expressed without a leader or transit sequence.

[0227] A variety of host / vector combinations can be employed. Suitable host cells for expression include prokaryotes, yeast cells, insect cells, or higher eukaryotic cells under the control of appropriate promoters. Suitable cloning and expression vectors, and methods for use of these, are well known in the art for bacterial, fungal, yeast, and mammalian cells. Expression vectors that can be used in bacterial hosts include known bacterial plasmids, such as plasmids from E. coli, including pCRl, pBR322, pMB9, and their derivatives, and plasmids from other bacterial species, such as M13 and other filamentous single-stranded DNA bacteriophages.

[0228] Expression vectors useful in eukaryotic hosts include, for example, vectors containing expression control sequences from SV40, bovine papilloma virus, adenovirus, and cytomegalovirus. Examples of suitable mammalian host cell lines include, but are not limited to, COS-7 (of monkey kidney origin), L-929 (of murine fibroblast origin), C127 (of murine mammary tumor origin), 3T3 (of murine fibroblast origin), CHO (of Chinese hamster ovary origin), HeLa (of human cervical carcinoma origin), BHK (of hamster kidney fibroblast origin), HEK-293 (of human embryonic kidney origin) cell lines, and variants thereof. Mammalian expression vectors can comprise nontranscribed elements such as an origin of replication, a suitable promoter and enhancer linked to the gene to be expressed, and other 5' or 3' flanking nontranscribed sequences and 5' or 3' nontranslated sequences (such as an necessary ribosome binding site, a polyadenylation site, splice donor and acceptor sites), as well as a transcription termination sequence. Expression of recombinant proteins in insect cell culture systems (e.g., baculovirus) also provides a robust method for producing proteins that are correctly folded and biologically functional. Baculovirus systems for producing heterologous proteins in insect cells are well known to those skilled in the art.

[0229] Peptides can also be synthesized, in whole or in part, using chemical methods (see, e.g., Caruthers (1980) Nucleic Acids Res. Symp. Ser. 215; Horn (1980); and Banga, A. K., THERAPEUTIC PEPTIDES AND PROTEINS, FORMULATION, PROCESSING AND DELIVERY SYSTEMS (1995) Technomic Publishing Co., Lancaster, PA). Peptide synthesis can be performed using a variety of solid phase techniques (see, e.g., Roberge, Science 269:202 (1995); Merrifield, Methods Enzymol. 289:3 (1997)), and automated synthesis can be achieved, e.g., using an ABI 431 A Peptide Synthesizer (Perkin Elmer) according to the manufacturer's instructions. Peptides can also be synthesized using combinatorial methods. Synthetic residues and polypeptides can be synthesized using a variety of procedures and methods known in the art (see, e.g., ORGANIC SYNTHESES COLLECTIVE VOLUMES, Gilman et al. (eds.), John Wiley & Sons, Inc., NY). Modified peptides can be produced by chemical modification methods (see, e.g., Belousov, Nucleic Acids Res. 25:3440 (1997); Frenkel, Free Radic. Biol. Med. 19:373 (1995); and Blommers, Biochemistry 33:7886 (1994)). Peptide sequence variants, derivatives, substitutions, and modifications can also be made using methods such as oligonucleotide-directed (site- directed) mutagenesis, alanine scanning, and PCR-based mutagenesis. Site-directed mutagenesis can be performed on cloned DNA (Carter et al., Nucl. Acids Res., 13:4331 (1986); Zoller et al., Nucl. Acids Res. 10:6487 (1987)), cassette mutagenesis (Wells et al., Gene 34:315 (1985)), restriction selection mutagenesis (Wells et al., Philos. Trans. R. Soc. London Ser A 317:415 (1986)), and other techniques, to produce the peptide sequences, variants, fusions, and chimeras of the application, as well as variants, derivatives, substitutions, and modifications thereof.

[0230] For use in humans, human or humanized antibodies can be preferred. Human antibodies can be produced by a variety of methods known in the art including phage display methods using antibody libraries derived from human immunoglobulin sequences, including improvements to these techniques. See also U.S. Patent Nos. 4,444,887 and 4,716,111 ; and PCT publications WO 98 / 46645, WO 98 / 50433, WO 98 / 24893, WO 98 / 16654, WO 96 / 34096, WO 96 / 33735, and WO 91 / 10741 ; each of these documents is incorporated herein by reference in its entirety. Human antibodies can also be antibodies in which the heavy and light chains are encoded by nucleotide sequences derived from one or more human DNA sources. In some embodiments, the anti-GIPR antibodies or antigen binding fragments are human antibodies or antigen binding fragments. Human antibodies can be produced using a variety of techniques known in the art.

[0231] Alternatively, in some embodiments, the non-human antibody is humanized, in which specific sequences or regions of the antibody are modified to increase similarity to antibodies naturally produced in the human body. In some embodiments, the antigen binding domain portion is humanized. Various methods of generating humanized antibodies are known in the art, including but not limited to CDR grafting (see, e.g., European Patent No. EP 239,400; International Publication No. WO 91 / 09967; and U.S. Patent Nos. 5,225,539, 5,530,101, and 5,585,089, each of which is incorporated by reference herein in its entirety), veneering or resurfacing (see, e.g., European Patent Nos. EP 592,106 and EP 519,596; Padlan, 1991, Molecular Immunology, 28(4 / 5): 489-498; Studnicka et al., 1994, Protein Engineering, 7(6): 805-814; and Roguska et al., 1994, PNAS, 91: 969-973, each of which is incorporated by reference herein in its entirety), chain shuffling (see, e.g., U.S. Patent No. 5,565,332, which is incorporated by reference herein in its entirety), and techniques disclosed in, e.g., U.S. Patent Application Publication No. US 2005 / 0042664, U.S. Patent Application Publication No. US 2005 / 0048617, U.S. Patent No. 6,407,213, U.S. Patent No. 5,766,886, International Publication No. WO 93 / 17105; Tan et al., J. Immunol., 169: 1119-25 (2002); Caldas et al., Protein Eng., 13(5): 353-60 (2000); Morea et al., Methods, 20(3): 267-79 (2000); Baca et al., J. Biol. Chem., 272(16): 10678-84 (1997); Roguska et al., Protein Eng., 9(10): 895-904 (1996); Couto et al., Cancer Res., 55(23 Supp): 5973s-5977s (1995); Couto et al., Cancer Res., 55(8): 1717-22 (1995); Sandhu JS, Gene, 150(2): 409-10 (1994); and Pedersen et al., J. Mol. Biol., 235(3): 959-73 (1994), each of which is incorporated by reference herein in its entirety. Generally, framework residues in the framework regions can be substituted with corresponding residues from a CDR donor antibody to alter, preferably improve, antigen binding.These frameworks can be identified by methods well known in the art, e.g., by modeling the interactions of CDR and framework residues to identify framework residues important for antigen binding, and by sequence comparison to identify unusual framework residues at particular positions. (See, e.g., Queen et al., U.S. Patent No. 5,585,089; and Riechmann et al., 1988, Nature, 332:323, the contents of which are incorporated herein by reference in their entireties.)

[0232] A humanized antibody has one or more amino acid residues introduced into it from a source which is non-human. These non-human amino acid residues are often referred to as "import" residues, which are typically taken from an "import" variable domain. Thus, a humanized antibody will comprise typically one or more CDRs from a non-human immunoglobulin molecule and framework regions from human. Humanization of antibodies is well-known in the art and can be performed essentially according to the method of Winter and co-workers (Jones et al., Nature, 321 :522-525 (1986); Riechmann et al., Nature, 332:323-327 (1988); Verhoeyen et al., Science, 239:1534-1536 (1988)), by substituting one or more non-human CDRs or CDR sequences for the corresponding sequences in the human antibody, i.e., CDR grafting (EP 239,400; PCT Publication No. WO 91 / 09967; and U.S. Patent Nos. 4,816,567; 6,331,415; 5,225,539; 5,530,101; 5,585,089; 6,548,640, the contents of which are incorporated by reference herein in their entireties). In these

[0233] The selection of human variable domains (both light and heavy chains) for making humanized antibodies is directed toward reducing antigenicity. According to the so-called "best-fit" method, the sequence of the variable domain of a rodent antibody is screened against the entire library of known human variable-domain sequences. The human sequence that is closest to that of the rodent is then selected as the human framework (FR) for the humanized antibody (Sims et al., J. Immunol., 151 :2296 (1993); Chothia et al., J. Mol. Biol., 196:901 (1987), the contents of which are incorporated herein by reference in their entireties). Another method uses a particular framework derived from the consensus sequence of all human antibodies of a particular subgroup of light or heavy chains. The same framework can be used for several different humanized antibodies (Carter et al., Proc. Natl. Acad. Sci. USA, 89:4285 (1992); Presta et al., J. Immunol., 151 :2623 (1993), the contents of which are incorporated herein by reference in their entireties).

[0234] Antibodies can be humanized while retaining high affinity for the target antigen and other favorable biological properties. For example, humanized antibodies can be made by a process of analysis of the parental sequences and various conceptual humanized products using three-dimensional models of the parental sequences and humanized sequences. Three-dimensional immunoglobulin models are publicly available and are familiar to those skilled in the art. Computer programs are available which illustrate and display probable three-dimensional conformational structures of selected candidate immunoglobulin sequences. Inspection of these displays permits analysis of the likely role of the residues in the functioning of the candidate immunoglobulin sequence, i.e., the analysis of residues that influence the ability of the candidate immunoglobulin to bind its target antigen. In this way, FR residues can be selected and combined from the recipient and import sequences so as to achieve a desired antibody characteristic, such as increased affinity for the target antigen. Generally, the CDR residues will directly and most substantially affect antigen binding.

[0235] Humanized antibodies retain similar antigenic specificity as the original antibody, e.g., the ability to bind the human GIPR antigen. However, using certain humanization methods, a "directed evolution" approach can be used to increase the affinity and / or specificity of the antibody for a particular antigen, as described in Wu et al., J. Mol. Biol., 294:151 (1999), the contents of which are incorporated herein by reference in their entirety.

[0236] Various methods for purifying anti-GIPR antibodies are known in the art, such as affinity chromatography. Eluted IgG can be checked by gel electrophoresis and high performance liquid chromatography to ensure purity. Buffer solutions can be exchanged, and concentrations can be determined. Monoclonal antibodies can be aliquoted and stored.

[0237] Methods for analyzing the binding affinity, cross-reactivity, and binding kinetics of various anti-GIPR antibodies include standard assays known in the art, such as Western blots, ELISA, and flow cytometry. Other methods available in the art include biolayer interferometry (BLI) using, for example, the Gator system (Probe Life) or the Octet-96 system (Sartorius AG), or using BIACORE TM BIACORE 2000 SPR instrument (Biacore AB, Uppsala, Sweden) TM Surface plasmon resonance (SPR) analysis.

[0238] A GIPR activity assay or GIPR function assay refers to an assay that can be used to measure GIPR activity in a cellular environment. In some embodiments, the assay can be a cAMP assay on cells expressing GIPR, where GIP can induce a cAMP signal, and the activity of a modulator (e.g., an anti-GIPR antibody disclosed herein) can be measured in the presence / absence of GIP, where IC50 / EC50 and the degree of inhibition / activation can be obtained (Gault et al., Biochemical and Biophysical Research Communications (2002) 290: 1420-1426). In some embodiments, the assay can be an insulin secretion assay on pancreatic beta cells, where GIP can induce glucose-dependent insulin secretion, and the activity of a modulator (e.g., an anti-GIPR antibody disclosed herein) can be measured in the presence / absence of GIP, where IC50 / EC50 and the degree of inhibition / activation can be obtained (Gault 2002, supra). 7.3 Oxyntomodulin analogs

[0239] Provided herein are peptides comprising an oxyntomodulin analog. By "oxyntomodulin analog" is meant a peptide that elicits the biological activity of oxyntomodulin (CAS No. 62340-29-8). An oxyntomodulin analog can have potency equal to or superior to oxyntomodulin, or within five orders of magnitude (plus or minus) of oxyntomodulin when assessed by measurement methods known in the art, such as receptor binding and / or competition studies, as described, for example, in Hargrove et al., Regulatory Peptides, 141 : 113-119 (2007), the disclosure of which is incorporated herein by reference. In some embodiments, an oxyntomodulin analog will bind in such assays with an affinity of less than 1 mM, less than 3 nM, less than 1 nM, or less than 0.1 nM. In some embodiments, provided herein is an oxyntomodulin analog having an amino acid sequence selected from the group consisting of SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, and SEQ ID NO: 58, or a variant of the oxyntomodulin analog having up to 1, 2, 3, 4, or 5 amino acid substitutions, additions, or deletions. In some embodiments, provided herein is an oxyntomodulin analog having an amino acid sequence of SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, and SEQ ID NO: 58. In some embodiments, provided herein is an oxyntomodulin analog having an amino acid sequence of SEQ ID NO: 55, or a variant of the oxyntomodulin analog having up to 1, 2, 3, 4, or 5 amino acid substitutions, additions, or deletions. In some embodiments, provided herein is an oxyntomodulin analog having an amino acid sequence of SEQ ID NO: 55. In some embodiments, provided herein is an oxyntomodulin analog having an amino acid sequence of SEQ ID NO: 56, or a variant of the oxyntomodulin analog having up to 1, 2, 3, 4, or 5 amino acid substitutions, additions, or deletions. In some embodiments, provided herein is an oxyntomodulin analog having an amino acid sequence of SEQ ID NO: 56. In some embodiments, provided herein is an oxyntomodulin analog having an amino acid sequence of SEQ ID NO: 57, or a variant of the oxyntomodulin analog having up to 1, 2, 3, 4, or 5 amino acid substitutions, additions, or deletions. In some embodiments, provided herein is an oxyntomodulin analog having an amino acid sequence of SEQ ID NO: 57. In some embodiments, provided herein is an oxyntomodulin analog having an amino acid sequence of SEQ ID NO: 58, or a variant of the oxyntomodulin analog having up to 1, 2, 3, 4, or 5 amino acid substitutions, additions, or deletions.In some embodiments, provided herein are oxyntomodulin analogs having the amino acid sequence of SEQ ID NO: 58. In some embodiments, a variant of an oxyntomodulin analog provided herein has 1 amino acid substitution in the amino acid sequence of an oxyntomodulin analog (e.g., an oxyntomodulin analog of SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, or SEQ ID NO: 58). In some embodiments, a variant of an oxyntomodulin analog provided herein has 2 amino acid substitutions in the amino acid sequence of an oxyntomodulin analog (e.g., an oxyntomodulin analog of SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, or SEQ ID NO: 58). In some embodiments, a variant of an oxyntomodulin analog provided herein has 3 amino acid substitutions in the amino acid sequence of an oxyntomodulin analog (e.g., an oxyntomodulin analog of SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, or SEQ ID NO: 58). In some embodiments, a variant of an oxyntomodulin analog provided herein has 4 amino acid substitutions in the amino acid sequence of an oxyntomodulin analog (e.g., an oxyntomodulin analog of SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, or SEQ ID NO: 58). In some embodiments, a variant of an oxyntomodulin analog provided herein has 5 amino acid substitutions in the amino acid sequence of an oxyntomodulin analog (e.g., an oxyntomodulin analog of SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, or SEQ ID NO: 58).

[0240] The oxyntomodulin analog peptides disclosed herein can be chemically derivatized or altered, for example, peptides with non-natural amino acid residues (e.g., taurine, beta-amino acid residues, gamma-amino acid residues, and D-amino acid residues), C-terminal functional group modifications (such as amide, ester, and C-terminal ketone modifications), and N-terminal functional group modifications (such as acylated amides, Schiff bases, or cyclization) as found, for example, in the amino acid pyroglutamic acid. In some embodiments, the C-terminal amino acid of an oxyntomodulin analog peptide disclosed herein is amidated. In some embodiments, the carboxyl group of the C-terminal amino acid of an oxyntomodulin analog peptide disclosed herein (e.g., the carboxyl group of the C-terminal Gly of SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, or SEQ ID NO: 58) is amidated as a C-terminal primary amide.

[0241] The oxyntomodulin analogs disclosed herein can also contain other chemical moieties, such as a peptide mimetic, a fatty acid (e.g., a C14-C24 fatty acid), etc. In some embodiments, the chemical moiety is a C14-C24 fatty acid. The C14-C24 fatty acid can be a saturated monoacid or a saturated diacid. In some embodiments, the fatty acid is a saturated monoacid or a saturated diacid selected from the group consisting of myristic acid (tetradecanoic acid) (C14 monoacid), tetradecanedioic acid (C14 diacid), palmitic acid (hexadecanoic acid) (C16 monoacid), hexadecanedioic acid (C16 diacid), margaric acid (heptadecanoic acid) (C17 monoacid), heptadecanedioic acid (C17 diacid), stearic acid (octadecanoic acid) (C18 monoacid), octadecanedioic acid (C18 diacid), nonadecanoic acid (nonadecanoic acid) (C19 monoacid), nonadecanedioic acid (C19 diacid), arachidic acid (eicosanoic acid) (C20 monoacid), eicosanedioic acid (C20 diacid), heneicosanoic acid (heneicosanoic acid) (C21 monoacid), heneicosanedioic acid (C21 diacid), behenic acid (docosanoic acid) (C22), docosanedioic acid (C22 diacid), lignoceric acid (tetracosanoic acid) (C24 monoacid), and tetracosanedioic acid (C24 diacid). In some embodiments, the C14-C24 fatty acid is myristic acid. In some embodiments, the C14-C24 fatty acid is tetradecanedioic acid. In some embodiments, the C14-C24 fatty acid is palmitic acid. In some embodiments, the C14-C24 fatty acid is hexadecanedioic acid. In some embodiments, the C14-C24 fatty acid is stearic acid. In some embodiments, the C14-C24 fatty acid is octadecanedioic acid. In some embodiments, the C14-C24 fatty acid is nonadecanedioic acid. In some embodiments, the C14-C24 fatty acid is arachidic acid. In some embodiments, the C14-C24 fatty acid is eicosanedioic acid. In some embodiments, the C14-C24 fatty acid is docosanedioic acid.

[0242] The other chemical moiety (e.g., C14-C24 fatty acid) can be conjugated to the oxyntomodulin analog peptide via (i) a direct bond or (ii) a linker. The direct bond can be formed between an amino acid residue of the oxyntomodulin analog peptide and the chemical moiety. In some embodiments, the direct bond is formed between a Lys of the oxyntomodulin analog peptide and the chemical moiety. In some embodiments, the direct bond is formed between the epsilon-amino group of the Lys side chain of the oxyntomodulin analog peptide and the chemical moiety.

[0243] In some embodiments, the linker is selected from the group consisting of: (a) an aminopol yethylene glycol carboxylate of Formula I: H-{NH-CH2-CH2-[O-CH2-CH2} m -O-(CH2) p -CO}n -OH(I), wherein m is any integer from 1 to 12, n is any integer from 1 to 12, and p is 1 or 2; (b) an amino acid selected from arginine (Arg), asparagine (Asn), aspartic acid (Asp), glutamine (Gin), glutamic acid (Glu), histidine (His), lysine (Lys), serine (Ser), threonine (Thr), citrulline (Cit), ornithine (Orn), sarcosine (Sar), glycine (Gly), gamma-aminobutyric acid (γ-Abu), and gamma-glutamic acid (γ-Glu); (c) a dipeptide selected from Ala-Ala, β-Ala-β-Ala, Glu-Glu, Gly-Gly, Leu-Leu, Ser-Ser, Thr-Thr, γ-Glu-γ-Glu, Glu-γ-Glu, γ-Glu-Glu, γ-Abu-γ-Abu, 6-aminohexanoic acid-6-aminohexanoic acid, 5-aminopentanoic acid-5-aminopentanoic acid, 7-aminoheptanoic acid-7-aminoheptanoic acid, and 8-aminooctanoic acid-8-aminooctanoic acid; (d) a tripeptide selected from Ala-Ala-Ala, β-Ala-β-Ala-β-Ala, Glu-Glu-Glu, γ-Glu-γ-Glu-γ-Glu, Glu-γ-Glu-γ-Glu, γ-Glu-γ-Glu-Glu, γ-Glu-Glu-γ-Glu, Gly-Gly-Gly, Gly-Gly-Ser, Ser-Gly-Gly, Gly-Ser-Gly, Gly-Gly-Glu, Glu-Gly-Gly, Gly-Glu-Gly, Gly-Gly-γ-Glu, γ-Glu-Gly-Gly, Gly-γ-Glu-Gly, Leu-Leu-Leu, and γ-Abu-γ-Abu-γ-Abu; (e) a tetrapeptide selected from (Gly-Gly-Ser) q (Gly-Gly-Gly-Ser) r and (Gly-Gly-Gly-Gly-Ser) r , (6-aminohexanoic acid) s , (5-aminopentanoic acid) s , (7-aminoheptanoic acid) s and (8-aminooctanoic acid) spolypeptides of the formula (Gly-Gly-Ser)q(Gly-Gly-Gly-Ser)r(Gly-Gly-Gly-Gly-Ser)s, wherein q is any integer from 2 to 5, r is any integer from 1 to 3, and s is any integer from 4 to 15; and (f) a conjugate linker, wherein the aminopolyethylene glycol carboxylate of Formula I defined in (a) is conjugated to (i) an amino acid selected from the group consisting of Arg, Asn, Asp, Gin, Glu, His, Lys, Ser, Thr, Cit, Orn, Sar, Gly, γ-Abu, and γ-Glu; (ii) a dipeptide selected from the group consisting of Ala-Ala, β-Ala-β-Ala, Glu-Glu, Gly-Gly, Leu-Leu, Ser-Ser, Thr-Thr, γ-Glu-γ-Glu, Glu-γ-Glu, γ-Glu-Glu, γ-Abu-γ-Abu, 6-aminohexanoic acid-6-aminohexanoic acid, 5-aminopentanoic acid-5-aminopentanoic acid, 7-aminoheptanoic acid-7-aminoheptanoic acid, and 8-aminooctanoic acid-8-aminooctanoic acid; (iii) a tripeptide selected from the group consisting of Ala-Ala-Ala, β-Ala-β-Ala-β-Ala, Glu-Glu-Glu, γ-Glu-γ-Glu-γ-Glu, Glu-γ-Glu-γ-Glu, γ-Glu-γ-Glu-Glu, γ-Glu-Glu-γ-Glu, Gly-Gly-Gly, Gly-Gly-Ser, Ser-Gly-Gly, Gly-Ser-Gly, Gly-Gly-Glu, Glu-Gly-Gly, Gly-Glu-Gly, Gly-Gly-γ-Glu, γ-Glu-Gly-Gly, Gly-γ-Glu-Gly, Leu-Leu-Leu, and γ-Abu-γ-Abu-γ-Abu; or (iv) a polypeptide selected from the group consisting of (Gly-Gly-Ser) q (Gly-Gly-Gly-Ser) r and (Gly-Gly-Gly-Giy-Ser) r , (6-aminohexanoic acid) s , (5-aminopentanoic acid) s , (7-aminoheptanoic acid) s and (8-aminooctanoic acid) s , wherein q is any integer from 2 to 5, r is any integer from 1 to 3, and s is any integer from 4 to 15. In some embodiments, the linker is ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(γ-Glu) or ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(γ-Glu)2. In some embodiments, the linker is ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(γ-Glu). In some embodiments, the linker is ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(γ-Glu)2.

[0244] The linker can be conjugated to an amino acid residue of the oxyntomodulin analog peptide. In some embodiments, the linker is conjugated to a Lys of the oxyntomodulin analog peptide (e.g., a Lys at position 20 of an oxyntomodulin analog having an amino acid sequence selected from the group consisting of SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, and SEQ ID NO: 58). In some embodiments, the linker is conjugated to an ε-amino group of a Lys side chain of the oxyntomodulin analog peptide (e.g., a Lys at position 20 of an oxyntomodulin analog having an amino acid sequence selected from the group consisting of SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, and SEQ ID NO: 58).

[0245] In some embodiments, provided herein is an oxyntomodulin analog having an amino acid sequence selected from the group consisting of SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, and SEQ ID NO: 58, wherein a Lys at position 20 of the oxyntomodulin analog is chemically modified by conjugation to an ε-amino group of a Lys side chain with ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2) 16 CO2H or ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2) 18 In some embodiments, provided herein is an oxyntomodulin analog having the amino acid sequence of SEQ ID NO: 55, wherein a Lys at position 20 of the oxyntomodulin analog is chemically modified by conjugation to an ε-amino group of a Lys side chain with ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2) 16 In some embodiments, provided herein is an oxyntomodulin analog having the amino acid sequence of SEQ ID NO: 56, wherein a Lys at position 20 of the oxyntomodulin analog is chemically modified by conjugation to an ε-amino group of a Lys side chain with ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2) 16 In some embodiments, provided herein is an oxyntomodulin analog having the amino acid sequence of SEQ ID NO: 57, wherein a Lys at position 20 of the oxyntomodulin analog is chemically modified by conjugation to an ε-amino group of a Lys side chain with ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2) 16CO2H conjugation. In some embodiments, provided herein is a oxyntomodulin analog having the amino acid sequence of SEQ ID NO: 58, wherein the Lys at position 20 of the oxyntomodulin analog is chemically modified by conjugation to ([2-(2-aminoethoxy)- ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)2-CO2H through the ε-amino group of the Lys side chain. 16 CO2H conjugation. In some embodiments, provided herein is a oxyntomodulin analog having the amino acid sequence of SEQ ID NO: 55, wherein the Lys at position 20 of the oxyntomodulin analog is chemically modified by conjugation to ([2-(2-aminoethoxy)- ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)2-CO2H through the ε-amino group of the Lys side chain. 18 CO2H conjugation. In some embodiments, provided herein is a oxyntomodulin analog having the amino acid sequence of SEQ ID NO: 56, wherein the Lys at position 20 of the oxyntomodulin analog is chemically modified by conjugation to ([2-(2-aminoethoxy)- ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)2-CO2H through the ε-amino group of the Lys side chain. 18 CO2H conjugation. In some embodiments, provided herein is a oxyntomodulin analog having the amino acid sequence of SEQ ID NO: 57, wherein the Lys at position 20 of the oxyntomodulin analog is chemically modified by conjugation to ([2-(2-aminoethoxy)- ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)2-CO2H through the ε-amino group of the Lys side chain. 18 CO2H conjugation. In some embodiments, provided herein is a oxyntomodulin analog having the amino acid sequence of SEQ ID NO: 58, wherein the Lys at position 20 of the oxyntomodulin analog is chemically modified by conjugation to ([2-(2-aminoethoxy)- ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)2-CO2H through the ε-amino group of the Lys side chain. 18 CO2H conjugation. In some embodiments, the carboxyl group of the C-terminal amino acid of an oxyntomodulin analog peptide disclosed herein (e.g., the carboxyl group of the C-terminal Gly of SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, or SEQ ID NO: 58) is amidated to a C-terminal primary amide.

[0246] Table 7a contains exemplary peptides of oxyntomodulin analogs Aib: isobutyric acid

[0247] In some embodiments, the peptides disclosed herein (e.g., peptides having the amino acid sequence of SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58) are chemically derivatized (e.g., amidated at the C-terminus) according to the methods disclosed herein. In some embodiments, the peptides disclosed herein comprise other chemical moieties conjugated to the Lys at position 20 of the peptide (e.g., ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2) 16 CO2H, ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2) 18CO2H). The chemical moiety can be any chemical moiety disclosed above, such as a peptide mimetic disclosed above, a fatty acid (e.g., a C14-C24 fatty acid). In some embodiments, the chemical moiety is a C14-C24 fatty acid. The C14-C24 fatty acid can be a saturated monoacid or a saturated diacid. In some embodiments, the fatty acid is a saturated monoacid or a saturated diacid selected from the group consisting of myristic acid (tetradecanoic acid) (C14 monoacid), tetradecanedioic acid (C14 diacid), palmitic acid (hexadecanoic acid) (C16 monoacid), hexadecanedioic acid (C16 diacid), margaric acid (heptadecanoic acid) (C17 monoacid), heptadecanedioic acid (C17 diacid), stearic acid (octadecanoic acid) (C18 monoacid), octadecanedioic acid (C18 diacid), nonadecylic acid (nonadecanoic acid) (C19 monoacid), nonadecanedioic acid (C19 diacid), arachidic acid (eicosanoic acid) (C20 monoacid), eicosanedioic acid (C20 diacid), heneicosylic acid (heneicosanoic acid) (C21 monoacid), heneicosanedioic acid (C21 diacid), behenic acid (docosanoic acid) (C22), docosanedioic acid (C22 diacid), lignoceric acid (tetracosanoic acid) (C24 monoacid), and tetracosanedioic acid (C24 diacid). Other chemical moieties (e.g., C14-C24 fatty acids) can be conjugated to Lys at position 20 of the peptide via (i) a direct bond or (ii) a linker. In some embodiments, the chemical moiety is conjugated to Lys at position 20 of the peptide via a direct bond. In some embodiments, the direct bond is formed between the epsilon-amino group of the Lys side chain of the peptide and the chemical moiety. In some embodiments, the chemical moiety is conjugated to Lys at position 20 of the peptide via a linker. The linker can be any linker disclosed above. In some embodiments, the linker is ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(y-Glu) or ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(y-Glu)2. In some embodiments, the linker is ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(y-Glu). In some embodiments, the linker is ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(y-Glu)2. In some embodiments, the ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2) 16 CO2H or ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2) 18 CO2H) is conjugated to Lys at position 20 of the peptide. In some embodiments, the ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2) 16the chemical moiety of CO2H is conjugated to Lys at position 20 of the peptide. In some embodiments, the chemical moiety of ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2) 18 the chemical moiety of CO2H is conjugated to Lys at position 20 of the peptide. In some embodiments, the carboxyl group of the C-terminal amino acid of a peptide disclosed herein is amidated to a C-terminal primary amide.

[0248] In some embodiments, a peptide disclosed herein (e.g., a peptide having an amino acid sequence of SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58) or a derivative thereof has GLP1 (e.g., human GLP1) agonist activity and / or GCGR (e.g., human GCGR) agonist activity. In some embodiments, a peptide disclosed herein has GLP1 (e.g., human GLP1) agonist activity and GCGR (e.g., human GCGR) agonist activity. In some embodiments, the linker does not affect the GLP1 (e.g., human GLP1) agonist activity of a peptide disclosed herein. In some embodiments, the linker does not affect the GCGR (e.g., human GCGR) agonist activity of a peptide disclosed herein. In some embodiments, the linker does not affect both the GLP1 (e.g., human GLP1) agonist activity and the GCGR (e.g., human GCGR) agonist activity of a peptide disclosed herein. A derivative refers to any peptide that is further derivatized (e.g., chemically derivatized, i.e., conjugated to other chemical moieties) via the methods disclosed above. For illustrative purposes, in some embodiments, a derivative comprises modifications known in the art, such as C-terminal functional group modifications, such as amide, ester, and C-terminal ketone modifications, and N-terminal functional group modifications, such as acylated amide, Schiff base, or cyclization. In some embodiments, the C-terminal amino acid (e.g., C-terminal Lys) of a derivative is amidated. In some embodiments, the carboxyl group of the C-terminal amino acid (e.g., C-terminal Lys) is amidated to a C-terminal primary amide. In some embodiments, the peptide (e.g., the epsilon-amino group of the C-terminal Lys side chain of the peptide) is amidated by bromoacetic acid. In some embodiments, a derivative further comprises other chemical moieties disclosed above, such as a peptidomimetic, a fatty acid (e.g., a C14-C24 fatty acid). In some embodiments, a derivative includes ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2) 16 CO2H or ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2) 18CO2H). In some embodiments, the derivative includes ([2-(2-aminoethoxy)-ethoxy]- acetyl)2-(y-Glu)-CO-(CH2) 16 CO2H. In some embodiments, the derivative includes ([2-(2-aminoethoxy)-ethoxy]- acetyl)2-(y-Glu)-CO-(CH2) 18 CO2H).

[0249] In some embodiments, a peptide disclosed herein (e.g., a peptide having an amino acid sequence of SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58) or a derivative thereof is capable of activating the biological effects of GLP1 and / or GCGR when administered to a subject (e.g., a human) and has one or more of the following functions: (1) lowering blood glucose; (2) increasing glucose tolerance; (3) increasing insulin sensitivity; (4) reducing body weight or decreasing body weight gain; (5) reducing fat mass; (6) reducing inflammation in adipose tissue; (7) reducing fasting insulin levels; (8) reducing circulating triglyceride levels; (9) reducing liver steatosis or reducing triglyceride levels in the liver; or (10) reducing AST, ALT, and / or ALP levels; or any combination of (1) to (10). Derivative refers to any peptide that is further derivatized (e.g., chemically derivatized, i.e., conjugated to other chemical moieties) via the methods disclosed above. For illustrative purposes, in some embodiments, the derivative includes modifications known in the art, e.g., C-terminal functional group modifications such as amide, ester, and C-terminal ketone modifications, and N-terminal functional group modifications such as acylated amide, Schiff base, or cyclization. In some embodiments, the C-terminal amino acid (e.g., C-terminal Lys) of the derivative is amidated. In some embodiments, the carboxyl group of the C-terminal amino acid (e.g., C-terminal Lys) is amidated to a C-terminal primary amide. In some embodiments, the peptide (e.g., the epsilon-amino group of the C-terminal Lys side chain of the peptide) is amidated by bromoacetic acid. In some embodiments, the derivative further includes other chemical moieties disclosed above, such as a peptidomimetic, a fatty acid (e.g., a C14-C24 fatty acid). In some embodiments, the derivative includes ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2) 16 CO2H or ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2) 18 CO2H). In some embodiments, the derivative includes ([2-(2-aminoethoxy)-ethoxy]- acetyl)2-(y-Glu)-CO-(CH2) 16CO2H. In some embodiments, the derivative includes ([2-(2-aminoethoxy)-ethoxy]- acetyl)2-(y-Glu)-CO-(CH2) 18 CO2H.

[0250] In some embodiments, the peptides disclosed herein (e.g., peptides having the amino acid sequence of SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58) or derivatives thereof can be used to treat a metabolic disease. In some embodiments, the metabolic disease is overweight or obesity. In some embodiments, the metabolic disease is overweight. In some embodiments, the metabolic disease is obesity. In some embodiments, the metabolic disease is diabetes (e.g., type 2 diabetes). Derivatives refer to any peptide that is further derivatized (e.g., chemically derivatized, i.e., conjugated to other chemical moieties) via the methods disclosed above. For illustrative purposes, in some embodiments, the derivative includes modifications known in the art, e.g., C-terminal functional group modifications, such as amide, ester, and C-terminal ketone modifications, and N-terminal functional group modifications, such as acylated amide, Schiff base, or cyclization. In some embodiments, the C-terminal amino acid (e.g., C-terminal Lys) of the derivative is amidated. In some embodiments, the carboxyl group of the C-terminal amino acid (e.g., C-terminal Lys) is amidated to a C-terminal primary amide. In some embodiments, the derivative further includes other chemical moieties disclosed above, such as a peptidomimetic, a fatty acid (e.g., a C14-C24 fatty acid). In some embodiments, the derivative includes ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2) 16 CO2H or ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2) 18 CO2H. In some embodiments, the derivative includes ([2-(2-aminoethoxy)-ethoxy]- acetyl)2-(y-Glu)-CO-(CH2) 16 CO2H. In some embodiments, the derivative includes ([2-(2-aminoethoxy)-ethoxy]- acetyl)2-(y-Glu)-CO-(CH2) 18CO2H). In some embodiments, a peptide having the amino acid sequence of SEQ ID NO: 55 can be used to treat metabolic diseases (e.g., overweight, obesity, diabetes). In some embodiments, a peptide having the amino acid sequence of SEQ ID NO: 56 can be used to treat metabolic diseases (e.g., overweight, obesity, diabetes). In some embodiments, a peptide having the amino acid sequence of SEQ ID NO: 57 can be used to treat metabolic diseases (e.g., overweight, obesity, diabetes). In some embodiments, a peptide having the amino acid sequence of SEQ ID NO: 58 can be used to treat metabolic diseases (e.g., overweight, obesity, diabetes).

[0251] The peptides disclosed herein can be prepared by methods well known in the art, for example, peptide purification as described in Eng et al., J. Biol. Chem., 265:20259-62 (1990); standard solid-phase peptide synthesis techniques as described in Raufman et al. J. Biol. Chem., 267:21432-37 (1992); recombinant DNA techniques as described in Sambrook et al., “Molecular Cloning: A Laboratory Manual,” 2nd Ed., Cold Spring Harbor Laboratory (1989); and combinations of these methods with conventional organic chemistry reactions. For illustrative purposes, in some embodiments, standard Fmoc chemistry synthesis methods can be used to prepare the peptides disclosed herein. Generally, standard Fmoc chemistry synthesis methods can include the following steps: (a) Activation: coupling of the first amino acid in the peptide chain to a solid support, such as a resin, using an activating agent (such as DIC or HBTU) and a base (such as DIEA). This step is critical for anchoring the peptide to the solid support; (b) Fmoc Deprotection: selective removal of the Fmoc group on the amino acid using a base such as piperidine. This exposes the amino group for use in the next coupling step; (c) Coupling: addition of a new Fmoc-protected amino acid to the growing peptide chain by coupling the new Fmoc-protected amino acid to the deprotected amino group on the peptide bound to the resin. This step is typically catalyzed by a coupling reagent (such as HCTU or HBTU) and a base (such as DIEA); (d) Washing: after each coupling step, the resin is washed to remove any unreacted reagents and byproducts. The resin can be further neutralized in preparation for the next Fmoc deprotection step; (e) Repeat: steps b-d are repeated sequentially for each amino acid in the desired peptide sequence; (f) Final Deprotection and Cleavage: once the peptide chain is complete, the peptide is cleaved from the resin and side chain protecting groups are removed using a cleavage cocktail (such as NH2NH2·H2O). This step produces a crude peptide, which can be further purified and characterized. In some embodiments, the synthesized peptide can be further modified for various purposes (e.g., improved properties, to facilitate further modification, etc.). In some embodiments, the synthesized peptide is further amidated by an amidation reagent. The amidation reagent can be well known in the art. In some embodiments, the amidation reagent is a carboxylic acid. In some embodiments, the carboxylic acid is a halo (e.g., fluoro, chloro, bromo, or iodo) carboxylic acid. In some embodiments, the synthesized peptide is further coupled to 2-bromoacetic acid. In some embodiments, the synthesized peptide is coupled to 2-bromoacetic acid on an amino acid side chain of the peptide. In some embodiments, the epsilon-amino group of a Lys side chain is coupled to 2-bromoacetic acid. In some embodiments, the synthesis methods disclosed herein allow for assembly of peptides with high purity and high yield in an efficient and controllable manner. 7.4 Antibody-peptide conjugates (APC)

[0252] Provided herein are antibody-peptide conjugates ("APC") comprising (1) an antibody or antigen binding fragment that specifically binds to GIPR (e.g., human GIPR), an antibody or antigen binding fragment that specifically binds to PCSK9 (e.g., human PCSK9), or an Fc region; and (2) a peptide that is a GLP-1R and / or GCGR agonist. In some embodiments, a oxyntomodulin analog peptide is tethered to an antibody or Fc region, with the advantage of prolonging the half-life of the peptide and also enhancing localization of the molecule to the pancreas.

[0253] In some embodiments, provided herein are APCs having a structure represented by the following formula: [P-L]n-Ab, wherein: Ab is an antibody or antigen binding fragment that specifically binds to GIPR (e.g., human GIPR), an antibody or antigen binding fragment that specifically binds to PCSK9 (e.g., human PCSK9), or an Fc region; L is a peptide linker or is absent; P is a peptide that is a glucagon-like peptide-1 receptor (GLP-1R) and / or glucagon receptor (GCGR) agonist; and n represents a number in the range of 1 to 8. In some embodiments, provided herein are APCs comprising an antibody or antigen binding fragment that specifically binds to GIPR (e.g., human GIPR) and a peptide that is a GLP-1R and / or GCGR agonist. In some embodiments, provided herein are APCs comprising an antibody or antigen binding fragment that specifically binds to PCKS9 (e.g., human PCSK9) and a peptide that is a GLP-1R and / or GCGR agonist. In some embodiments, provided herein are APCs comprising an Fc region and a peptide that is a GLP-1R and / or GCGR agonist. In some embodiments, the dual agonist is an oxyntomodulin analog disclosed herein.

[0254] When referring to an individual APC molecule, "n" in the drug-antibody ratio (DAR) of the above formula can vary between 1 to about 2, preferably about 1 to about 2, more preferably about 1.5 to about 2. In some embodiments, the DAR is 1. In some embodiments, the DAR is 2. In some embodiments, the DAR is 3. In some embodiments, the DAR is 4. In some embodiments, the DAR is 5. In some embodiments, the DAR is 6. In some embodiments, the DAR is 7. In some embodiments, the DAR is 8. In some embodiments, the DAR is 9. In some embodiments, the DAR is 10. In some embodiments, the DAR is 11. In some embodiments, the DAR is 12. In some embodiments, the DAR is 13. In some embodiments, the DAR is 14. In some embodiments, the DAR is 15. In some embodiments, the DAR is 16. When referring to a composition comprising a population of ADC compounds, the average DAR can vary between 1 to about 16, preferably about 1 to about 14, more preferably about 1 to about 10. In some embodiments, the average DAR is about 0.5, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, about 8.5, about 9, about 9.5, about 10, about 10.5, about 11, about 11.5, or about 12. In some embodiments, the average DAR can be about 4. In some embodiments, the average DAR can be about 2. In some embodiments, the average DAR can be about 1.5. In some embodiments, the average DAR can be about 1. In some embodiments, the average DAR can be about 0.5. In some embodiments, the specific DAR is achieved via site-specific conjugation techniques (e.g., introducing an engineered cysteine into the antibody, including position 272 according to the EU index numbering system at the IgGl Fc). For example, a higher DAR can be achieved if a peptide is conjugated to an introduced cysteine residue in addition to the interchain disulfide bond, such as an introduced cysteine residue at position 239 according to the EU index numbering system.

[0255] The APCs provided herein can comprise any suitable anti-GIPR antibody or antigen binding fragment thereof disclosed herein or otherwise known in the art. For example, the APCs provided herein can comprise anti-GIPR antibody 2G10 (US20210087286A1). In some embodiments, the APCs provided herein can comprise anti-GIPR antibody Gipg013 (Ravn P et al., J Biol Chem. 2013; 288(27): 19760-19772.). In some embodiments, the APCs provided herein can comprise an anti-GIPR antibody or antigen binding fragment thereof disclosed in U.S. Patent No. 10,905,775.

[0256] The APCs provided herein can comprise any suitable anti-PCSK9 antibody or antigen binding fragment thereof disclosed herein or otherwise known in the art. For example, the APCs provided herein can comprise the anti-PCSK9 antibody tafolecimab (e.g., CN107876669B). In some embodiments, the APCs provided herein can comprise the anti-PCSK9 antibody alirocumab (e.g., US8853288B2). In some embodiments, the APCs provided herein can comprise the anti-PCSK9 antibody Evolocumab (e.g., US9724502B2).

[0257] In some embodiments, the APC provided herein comprises an anti-GIPR antibody or antigen-binding fragment thereof disclosed in Section 5.2 herein. In some embodiments, the APC provided herein can comprise an anti-GIPR antibody having (a) a light chain variable region (VL) comprising a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 1, 8, and 15, a VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 9, 10, and 16, a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 3, 11, and 17, or a variant thereof having up to about 5 amino acid substitutions, additions and / or deletions in the VL CDRs; and / or (b) a heavy chain variable region (VH) comprising a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 4, 12, and 18, a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 5, 6, 13, and 20, a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 7, 14, and 20, or a variant thereof having up to about 5 amino acid substitutions, additions and / or deletions in the VH CDRs.In some embodiments, the APC provided herein can comprise an anti-GIPR antibody having (a) a VL having at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 24, and / or a VH having at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 25; (b) a VL having at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 26, and / or a VH having at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 27; (c) a VL having at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 28, and / or a VH having at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 29; (d) a VL having at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 30, and / or a VH having at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 31; or (e) a VL having at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 32, and / or a VH having at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 33.In some embodiments, the APC provided herein can comprise an anti-GIPR antibody having (a) a LC having at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 48, and / or a HC having at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 49; (b) a LC having at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 50, and / or a HC having at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 51; (c) a LC having at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 48, and / or a HC having at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 89; (d) a LC having at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 50, and / or a HC having at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 90; or (e) a LC having at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 52, and / or a HC having at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 53.

[0258] The anti-GIPR antibody or antigen-binding fragment thereof for use in an APC disclosed herein must comprise at least one conjugation site. The conjugation site is suitable for conjugation of an additional functional moiety (e.g., a dual GLP-1R / GCGR agonist peptide) via the side chain of an amino acid residue at the conjugation site according to a defined conjugation chemistry. To achieve a high degree of selectivity for the anti-GIPR antibody or antigen-binding fragment thereof, site-specific conjugation requires consideration of a variety of design criteria. First, a preferred conjugation or coupling chemistry must be defined or predetermined. The functional moiety, such as a dual GLP-1R / GCGR agonist peptide, can be conjugated or coupled to the selected conjugation site of the anti-GIPR antibody or antigen-binding fragment thereof by a variety of different conjugation chemistries known in the art. For example, one embodiment is to employ a maleimide-activated conjugation partner that targets accessible cysteine thiols on the anti-GIPR antibody or antigen-binding fragment thereof, although a variety of conjugation or coupling chemistries that target classic or non-classic amino acid (e.g., non-natural amino acids) side chains in the sequence of the anti-GIPR antibody or antigen-binding fragment thereof can also be employed.

[0259] Chemical methods of chemoselective conjugation include: copper(I)-catalyzed azide alkyne [3+2] dipolar cycloaddition, Staudinger ligation, other acyl transfer processes (S→N; X→N), oxime formation reactions, hydrazone bond formation reactions, and other suitable organic chemistry reactions such as cross-coupling reactions using water-soluble palladium catalysts. (e.g., Bong et al., "Chemoselective Pd(0)-catalyzed peptide coupling in water," Organic Letters 3(16): 2509-11 (2001); Dibowski et al., "Bioconjugation of peptides by palladium-catalyzed C—C cross-coupling in water," Angew. Chem. Int. Ed. 37(4): 476-78 (1998); DeVasher et al., "Aqueous-phase, palladium-catalyzed cross-coupling of aryl bromides under mild conditions, using water-soluble, sterically demanding alkylphosphines," J. Org. Chem. 69: 7919-27 (2004); Shaugnessy et al., J. Org. Chem, 2003, 68, 6767-6774; Prescher, J A and Bertozzi, C R, "Chemistry in living system," Nature Chemical Biology 1(1); 13-21 (2005)).

[0260] As described above, conjugation (e.g., covalent binding) to an anti-GIPR antibody or antigen-binding fragment thereof can be performed through the side chain of an amino acid residue at the conjugation site, such as, but not limited to, a cysteinyl residue. The amino acid residue at the selected internal conjugation site (e.g., a cysteinyl residue) can be an amino acid residue occupying the same amino acid residue position in a native Fc domain sequence, or can be engineered into the Fc domain sequence by substitution or insertion. In some embodiments, conjugation can be performed through C272 of an IgG Fc domain (e.g., an IgG1 Fc domain).

[0261] In some embodiments of the methods and compositions of matter disclosed herein, other examples of non-natural amino acid residues that can be particularly useful as conjugation sites include: azido-containing amino acid residues, such as azidohomoalanine, p-azido-phenylalanine; keto-containing amino acid residues, such as p-acetyl-phenylalanine; alkyne-containing amino acid residues, such as p-ethynylphenylalanine, homopropargylglycine, p(prop-2-ynyl)-tyrosine; alkene-containing amino acid residues, such as homoallylglycine; aryl halide-containing amino acid residues, such as p-iodophenylalanine, p-bromophenylalanine; and 1,2-aminothiol-containing amino acid residues.

[0262] Non-canonical amino acid residues can be incorporated into a peptide by amino acid substitution or insertion. Non-canonical amino acid residues can be incorporated into a peptide by chemical peptide synthesis, rather than by synthesis in a biological system, such as a recombinantly-expressing cell, or, alternatively, a skilled artisan can employ known protein engineering techniques using recombinantly-expressing cells. (See, e.g., Link et al., “Non-canonical amino acids in protein engineering,” Current Opinion in Biotechnology, 14(6):603-609 (2003); Schultz et al., “In vivo incorporation of unnatural amino acids,” U.S. Patent No. 7,045,337).

[0263] The location of the conjugation site selected throughout the anti-GIPR antibody or antigen-binding fragment thereof is another important aspect of selecting an internal conjugation site according to the present application. Any exposed amino acid residue on the anti-GIPR antibody or antigen-binding fragment thereof can be a potentially useful conjugation site, and if a cysteine or some other reactive amino acid does not originally exist at the selected conjugation site of the anti-GIPR antibody or antigen-binding fragment thereof sequence, that amino acid residue can be mutated to a cysteine or some other reactive amino acid for site-selective coupling. The skilled artisan can employ common sense (e.g., potential steric limitations) to determine suitable conjugation sites.

[0264] The amount of conjugation sites can be determined based on the desired DAR. In some embodiments, the anti-GIPR antibody or antigen-binding fragment thereof for use in an APC disclosed herein comprises one conjugation site. In some embodiments, the anti-GIPR antibody or antigen-binding fragment thereof for use in an APC disclosed herein comprises more than one conjugation site, such as two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or sixteen conjugation sites.

[0265] In some embodiments, the anti-GIPR antibody or antigen-binding fragment thereof comprises a cysteine or non-canonical amino acid substitution at one or more conjugation sites. The conjugation site can be located substantially on any residue of the anti-GIPR antibody or antigen-binding fragment thereof. In some embodiments, the conjugation site is located within the CL, CHI, CH2, or CH3 region of the anti-GIPR antibody or antigen-binding fragment thereof. In some embodiments, the anti-GIPR antibody or antigen-binding fragment thereof comprises a conjugation site at C272, engineered by an E272C substitution.

[0266] The APCs provided herein can comprise any suitable peptide that is a GLP-1R and / or GCGR agonist disclosed herein or otherwise known in the art. In some embodiments, the peptide is a GLP-1R agonist. In some embodiments, the peptide comprises exenatide, liraglutide, dulaglutide, semaglutide, albiglutide, lixisenatide, exenatide-139, or taspoglutide. In some embodiments, the peptide comprises exenatide. In some embodiments, the peptide comprises liraglutide. In some embodiments, the peptide comprises dulaglutide. In some embodiments, the peptide comprises semaglutide. In some embodiments, the peptide comprises albiglutide. In some embodiments, the peptide comprises lixisenatide. In some embodiments, the peptide comprises exenatide-139. In some embodiments, the peptide comprises taspoglutide. In some embodiments, the peptide is a GCGR agonist. In some embodiments, the peptide comprises REMD-477. In some embodiments, the peptide is a dual GLP-1R / GCGR agonist. In some embodiments, the peptide comprises oxyntomodulin or an oxyntomodulin analog. In some embodiments, the peptide comprises an oxyntomodulin analog.

[0267] In some embodiments, provided herein are APCs having a structure represented by the following formula: [P-L]n-Ab, wherein: Ab is an antibody or antigen-binding fragment that specifically binds GIPR (e.g., human GIPR), an antibody or antigen-binding fragment that specifically binds PCSK9 (e.g., human PCSK9), or an Fc region; L is a peptide linker or is absent; P is an oxyntomodulin analog having an amino acid sequence selected from the group consisting of SEQ ID NOs: 55, 56, 57, and 58, or a variant of the oxyntomodulin analog having up to 1, 2, 3, 4, or 5 amino acid substitutions, additions, or deletions; and n represents a number in the range of 1 to 8.

[0268] In some embodiments, the obestatin analog has the amino acid sequence of SEQ ID NO: 55, or a variant of the obestatin analog having up to 1, 2, 3, 4, or 5 amino acid substitutions, additions, or deletions. In some embodiments, the obestatin analog has the amino acid sequence of SEQ ID NO: 55. In some embodiments, the obestatin analog has the amino acid sequence of SEQ ID NO: 56, or a variant of the obestatin analog having up to 1, 2, 3, 4, or 5 amino acid substitutions, additions, or deletions. In some embodiments, the obestatin analog has the amino acid sequence of SEQ ID NO: 56. In some embodiments, the obestatin analog has the amino acid sequence of SEQ ID NO: 57, or a variant of the obestatin analog having up to 1, 2, 3, 4, or 5 amino acid substitutions, additions, or deletions. In some embodiments, the obestatin analog has the amino acid sequence of SEQ ID NO: 57. In some embodiments, the obestatin analog has the amino acid sequence of SEQ ID NO: 58, or a variant of the obestatin analog having up to 1, 2, 3, 4, or 5 amino acid substitutions, additions, or deletions. In some embodiments, the obestatin analog has the amino acid sequence of SEQ ID NO: 58.

[0269] The peptides of the APCs disclosed herein can be chemically derivatized or altered according to the methods disclosed in Section 5.3 herein. In some embodiments, the C-terminal amino acid of the peptides disclosed herein is amidated. In some embodiments, the carboxyl group of the C-terminal amino acid is amidated to a C-terminal primary amide. The peptides of the APCs disclosed herein can also contain other chemical moieties disclosed in Section 5.3 herein. In some embodiments, the chemical moiety is ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2) 16 CO2H or ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2) 18 CO2H. In some embodiments, the chemical moiety is ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2) 16 CO2H. In some embodiments, the chemical moiety is ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2) 18CO2H. This chemical moiety can be conjugated to a peptide via a direct bond. In some embodiments, this chemical moiety can be conjugated to a peptide via ([2-(2- aminoethoxy)-ethoxy]-acetyl)2-(y-Glu) or ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(y-Glu)2. In some embodiments, this chemical moiety can be conjugated to a peptide via ([2-(2- aminoethoxy)-ethoxy]-acetyl)2-(y-Glu). In some embodiments, this chemical moiety can be conjugated to a peptide via ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(y-Glu)2.

[0270] The APCs provided herein comprise a linker connecting the peptide and the antibody. The linker can be any suitable linker known in the art. The linker can be a peptide linker (i.e., composed of amino acids linked together by peptide bonds), and in some embodiments, the length of the linker consists of from 1 to about 40 amino acid residues, in some embodiments, from 1 to about 20 amino acid residues, or in some embodiments, from 1 to about 10 amino acid residues. In some embodiments, the amino acid residues in the linker are from the twenty classical amino acids. In some embodiments, the amino acid residues in the linker are from cysteine, glycine, alanine, proline, asparagine, glutamine, and / or serine. In some embodiments, the peptide-based linker consists of mostly sterically unobstructed amino acids, such as glycine, serine, and alanine linked by peptide bonds. It is also desirable to select a peptide-based linker that avoids rapid proteolytic turnover in circulation in vivo. As is well known to those skilled in the art, some of these amino acids can be glycosylated. In some embodiments, 1 to 40 amino acids, 1 to 20 amino acids, or 1 to 10 amino acids of the peptide-based linker portion are selected from glycine, alanine, serine, proline, asparagine, glutamine, valine, cysteine, phenylalanine, and lysine.

[0271] The linker can be further chemically derivatized or altered, for example, linkers with non-natural amino acid residues (e.g., taurine, beta-amino acid residues, gamma-amino acid residues, and D-amino acid residues), C-terminal functional group modifications (such as amide, ester, and C-terminal ketone modifications), and N-terminal functional group modifications (such as acylated amide, Schiff base, or cyclization), as found, for example, in the amino acid pyroglutamic acid.

[0272] In some embodiments, the linker is (GGGGS)3(SEQ ID NO: 81), (GGGGS)2(SEQ ID NO: 82), GGGGS (SEQ ID NO: 83), VA, VC, VKG, or GGFG (SEQ ID NO: 84). In some embodiments, the linker is (GGGGS)3(SEQ ID NO: 81). In some embodiments, the linker is (GGGGS)2(SEQ ID NO: 82). In some embodiments, the linker is GGGGS (SEQ ID NO: 83). In some embodiments, the linker is VA. In some embodiments, the linker is VC. In some embodiments, the linker is VKG. In some embodiments, the linker is GGFG (SEQ ID NO: 84). In some embodiments, the linker does not affect the activity of a peptide of an APC disclosed herein (e.g., GLP1 agonist activity, GCGR agonist activity). In some embodiments, the linker does not affect the activity of an antibody of an APC disclosed herein (e.g., GIPR binding affinity). In some embodiments, the linker does not affect the activity of a peptide of an APC disclosed herein (e.g., GLP1 agonist activity, GCGR agonist activity) nor the activity of an antibody of an APC disclosed herein (e.g., GIPR binding affinity). The linker can be further modified by some modifications known in the art such that the resulting P-L can have desirable or improved properties (e.g., better stability). Modifications known in the art, for example, C-terminal functional group modifications, such as amide, ester, C-terminal ketone modification, and N-terminal functional group modifications, such as acylated amide, Schiff base, or cyclization.

[0273] Table 7b Exemplary Peptide-Linker (P-L) Note: Linker is underlined; Aib: isobutyric acid

[0274] In some embodiments, the APC disclosed herein comprises a peptide-linker (P-L) having an amino acid sequence selected from the group consisting of SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, and SEQ ID NO: 78, or a variant thereof having up to 1, 2, 3, 4, or 5 amino acid substitutions, additions, or deletions. In some embodiments, the APC disclosed herein comprises a peptide-linker (P-L) having an amino acid sequence selected from the group consisting of SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, and SEQ ID NO: 78.

[0275] In some embodiments, the APC disclosed herein comprises a peptide-linker (P-L) having the amino acid sequence of SEQ ID NO: 61, or a variant thereof having up to 1, 2, 3, 4, or 5 amino acid substitutions, additions, or deletions. In some embodiments, the APC disclosed herein comprises a peptide-linker (P-L) having the amino acid sequence of SEQ ID NO: 61. In some embodiments, the APC disclosed herein comprises a peptide-linker (P-L) having the amino acid sequence of SEQ ID NO: 62, or a variant thereof having up to 1, 2, 3, 4, or 5 amino acid substitutions, additions, or deletions. In some embodiments, the APC disclosed herein comprises a peptide-linker (P-L) having the amino acid sequence of SEQ ID NO: 62. In some embodiments, the APC disclosed herein comprises a peptide-linker (P-L) having the amino acid sequence of SEQ ID NO: 63, or a variant thereof having up to 1, 2, 3, 4, or 5 amino acid substitutions, additions, or deletions. In some embodiments, the APC disclosed herein comprises a peptide-linker (P-L) having the amino acid sequence of SEQ ID NO: 63. In some embodiments, the APC disclosed herein comprises a peptide-linker (P-L) having the amino acid sequence of SEQ ID NO: 64, or a variant thereof having up to 1, 2, 3, 4, or 5 amino acid substitutions, additions, or deletions. In some embodiments, the APC disclosed herein comprises a peptide-linker (P-L) having the amino acid sequence of SEQ ID NO: 64. In some embodiments, the APC disclosed herein comprises a peptide-linker (P-L) having the amino acid sequence of SEQ ID NO: 65, or a variant thereof having up to 1, 2, 3, 4, or 5 amino acid substitutions, additions, or deletions. In some embodiments, the APC disclosed herein comprises a peptide-linker (P-L) having the amino acid sequence of SEQ ID NO: 65. In some embodiments, the APC disclosed herein comprises a peptide-linker (P-L) having the amino acid sequence of SEQ ID NO: 66, or a variant thereof having up to 1, 2, 3, 4, or 5 amino acid substitutions, additions, or deletions. In some embodiments, the APC disclosed herein comprises a peptide-linker (P-L) having the amino acid sequence of SEQ ID NO: 66. In some embodiments, the APC disclosed herein comprises a peptide-linker (P-L) having the amino acid sequence of SEQ ID NO: 67, or a variant thereof having up to 1, 2, 3, 4, or 5 amino acid substitutions, additions, or deletions. In some embodiments, the APC disclosed herein comprises a peptide-linker (P-L) having the amino acid sequence of SEQ ID NO: 67.In some embodiments, the APC disclosed herein comprises a peptide-linker (P-L) having the amino acid sequence of SEQ ID NO: 68, or a variant thereof having up to 1, 2, 3, 4, or 5 amino acid substitutions, additions, or deletions. In some embodiments, the APC disclosed herein comprises a peptide-linker (P-L) having the amino acid sequence of SEQ ID NO: 68. In some embodiments, the APC disclosed herein comprises a peptide-linker (P-L) having the amino acid sequence of SEQ ID NO: 71, or a variant thereof having up to 1, 2, 3, 4, or 5 amino acid substitutions, additions, or deletions. In some embodiments, the APC disclosed herein comprises a peptide-linker (P-L) having the amino acid sequence of SEQ ID NO: 71. In some embodiments, the APC disclosed herein comprises a peptide-linker (P-L) having the amino acid sequence of SEQ ID NO: 72, or a variant thereof having up to 1, 2, 3, 4, or 5 amino acid substitutions, additions, or deletions. In some embodiments, the APC disclosed herein comprises a peptide-linker (P-L) having the amino acid sequence of SEQ ID NO: 72. In some embodiments, the APC disclosed herein comprises a peptide-linker (P-L) having the amino acid sequence of SEQ ID NO: 73, or a variant thereof having up to 1, 2, 3, 4, or 5 amino acid substitutions, additions, or deletions. In some embodiments, the APC disclosed herein comprises a peptide-linker (P-L) having the amino acid sequence of SEQ ID NO: 73. In some embodiments, the APC disclosed herein comprises a peptide-linker (P-L) having the amino acid sequence of SEQ ID NO: 74, or a variant thereof having up to 1, 2, 3, 4, or 5 amino acid substitutions, additions, or deletions. In some embodiments, the APC disclosed herein comprises a peptide-linker (P-L) having the amino acid sequence of SEQ ID NO: 74. In some embodiments, the APC disclosed herein comprises a peptide-linker (P-L) having the amino acid sequence of SEQ ID NO: 75, or a variant thereof having up to 1, 2, 3, 4, or 5 amino acid substitutions, additions, or deletions. In some embodiments, the APC disclosed herein comprises a peptide-linker (P-L) having the amino acid sequence of SEQ ID NO: 75. In some embodiments, the APC disclosed herein comprises a peptide-linker (P-L) having the amino acid sequence of SEQ ID NO: 76, or a variant thereof having up to 1, 2, 3, 4, or 5 amino acid substitutions, additions, or deletions. In some embodiments, the APC disclosed herein comprises a peptide-linker (P-L) having the amino acid sequence of SEQ ID NO: 76.In some embodiments, the APC disclosed herein comprises a peptide-linker (P-L) having the amino acid sequence of SEQ ID NO: 77, or a variant thereof having up to 1, 2, 3, 4, or 5 amino acid substitutions, additions, or deletions. In some embodiments, the APC disclosed herein comprises a peptide-linker (P-L) having the amino acid sequence of SEQ ID NO: 77. In some embodiments, the APC disclosed herein comprises a peptide-linker (P-L) having the amino acid sequence of SEQ ID NO: 78, or a variant thereof having up to 1, 2, 3, 4, or 5 amino acid substitutions, additions, or deletions. In some embodiments, the APC disclosed herein comprises a peptide-linker (P-L) having the amino acid sequence of SEQ ID NO: 78.

[0276] In some embodiments, a variant of a peptide-linker (P-L) provided herein has 1 amino acid substitution in the amino acid sequence of the peptide-linker (P-L) (e.g., the peptide-linker (P-L) of SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, or SEQ ID NO: 68). In some embodiments, a variant of a peptide-linker (P-L) provided herein has 2 amino acid substitutions in the amino acid sequence of the peptide-linker (P-L) (e.g., the peptide-linker (P-L) of SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, or SEQ ID NO: 68). In some embodiments, a variant of a peptide-linker (P-L) provided herein has 3 amino acid substitutions in the amino acid sequence of the peptide-linker (P-L) (e.g., the peptide-linker (P-L) of SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, or SEQ ID NO: 68). In some embodiments, a variant of a peptide-linker (P-L) provided herein has 4 amino acid substitutions in the amino acid sequence of the peptide-linker (P-L) (e.g., the peptide-linker (P-L) of SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, or SEQ ID NO: 68). In some embodiments, a variant of a peptide-linker (P-L) provided herein has 5 amino acid substitutions in the amino acid sequence of the peptide-linker (P-L) (e.g., the peptide-linker (P-L) of SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, or SEQ ID NO: 68). In some embodiments, the amino acid substitutions are conservative substitutions.

[0277] In some embodiments, a variant of a peptide-linker (P-L) provided herein has 1 amino acid substitution in the amino acid sequence of the peptide-linker (P-L) (e.g., the peptide-linker (P-L) of SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, or SEQ ID NO: 78). In some embodiments, a variant of a peptide-linker (P-L) provided herein has 2 amino acid substitutions in the amino acid sequence of the peptide-linker (P-L) (e.g., the peptide-linker (P-L) of SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, or SEQ ID NO: 78). In some embodiments, a variant of a peptide-linker (P-L) provided herein has 3 amino acid substitutions in the amino acid sequence of the peptide-linker (P-L) (e.g., the peptide-linker (P-L) of SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, or SEQ ID NO: 78). In some embodiments, a variant of a peptide-linker (P-L) provided herein has 4 amino acid substitutions in the amino acid sequence of the peptide-linker (P-L) (e.g., the peptide-linker (P-L) of SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, or SEQ ID NO: 78). In some embodiments, a variant of a peptide-linker (P-L) provided herein has 5 amino acid substitutions in the amino acid sequence of the peptide-linker (P-L) (e.g., the peptide-linker (P-L) of SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, or SEQ ID NO: 78). In some embodiments, the amino acid substitution is a conservative substitution.

[0278] In some embodiments, an APC provided herein further comprises a linker connecting the peptide-linker (P-L) to the Ab. In some embodiments, the linker has the following structure:

[0279] In some embodiments, the linker is a maleimide linker. In some embodiments, the linker has the following structure: In some embodiments, the linker has the following structure: wherein X2is selected from wherein each u is independently an integer of 1, 2, 3, 4, 5, 6, 7, or 8.

[0280] In some embodiments, the linker can be, for example, an alkyl linker, such as -NH- (CH2) s -C(O)-, wherein s = 2 to 20 can be used. These alkyl linkers can be further substituted with any non-space hindering groups, such as lower alkyl (e.g., C1-C6), lower acyl, halogen (e.g., CI, Br), CN, NH2, phenyl, etc. An exemplary non-peptidyl linker is PEG (e.g., as follows): 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. In some embodiments, the linker is an aryl group. The linker can be altered in the same manner as described herein to form derivatives. An "aryl" is a phenyl group, or a phenyl group ortho-fused to a saturated, partially saturated, or unsaturated 3-, 4-, or 5-membered carbon bridge, which phenyl group or bridge is substituted with 0, 1, 2, or 3 substituents selected from C 1-8 alkyl, C 1-4 haloalkyl, or halogen. A "heteroaryl" is an unsaturated 5-, 6-, or 7-membered monocyclic ring, or a partially saturated or unsaturated 6-, 7-, 8-, 9-, 10-, or 11-membered bicyclic ring, wherein at least one ring is unsaturated, which monocyclic and bicyclic rings contain 1, 2, 3, or 4 atoms selected from N, O, and S, wherein the ring is substituted with 0, 1, 2, or 3 substituents selected from C 1-8 alkyl, C 1-4 haloalkyl, and halogen.

[0281] Some other exemplary linkers include Val-Cit-PAB, Fmoc-Val-Cit-PAB, Fmoc-Val-Cit-PAB-PNP, MC-Val-Cit-PAB-PNP, Fmoc-Phe-Lys(Trt)-PAB, Fmoc-Phe-Lys(Trt)-PAB-PNP, Ala-Ala-Asn-PAB TFA salt, Lys(Trt)-PAB TFA salt, Fmoc-Ala-Ala-Asn-PAB-PNP, Fmoc-Gly3-Val-Cit-PAB, Fmoc-Gly3-Val-Cit-PAB-PNP, SMCC, Py-ds-Prp-OSu, Py-ds-dmBut-OPFP, Py-ds-Prp-OPFP, MAL-HA-OSu, MAL-di-EG-OPFP, MAL-tri-EG-OPFP, MAL-tetra-EG-OPFP, N3-di-EG-OPFP, N3-tri-EG-OPFP, N3-tetra-EG-OPFP, ALD-BZ-OSu, ALD-di-EG-OSu, ALD-tetra-EG-OSu, ALD-di-EG-OPFP, ALD-tetra-EG-OPFP, PHA-di-EG-OPFP, and PHA-tetra-EG-OPFP.

[0282] Linkers can be synthesized by conventional organic chemistry reactions. Other embodiments of multivalent linkers include rigid polyheterocyclic cores with controllable length. Linkers have chemical dissimilarity at both ends to accommodate orthogonal coupling chemistry (i.e., azide “click” reactions, amide coupling reactions, formation of thioethers by alkylation with maleimides or haloacetamides, oxime formation reactions, reductive amination reactions, etc.).

[0283] A skilled artisan can employ common sense (e.g., potential steric limitations) and art to conjugate the peptide-linker (P-L) disclosed herein to an antibody to form an APC. Any exposed amino acid residue on the peptide can be a potentially useful conjugation site, provided that conjugation at the amino acid residue does not substantially affect the activity of the peptide (e.g., GLP1 agonist activity, GCGR agonist activity). In some embodiments, the peptide-linker (P-L) is conjugated to an antibody via a C-terminal linker. In some embodiments, the linker is

[0284] Table 7c Exemplary Peptide-Linker-Linker (P-L-C) Note: Linker is underlined; Aib: isobutyric acid

[0285] In some embodiments, the APC disclosed herein comprises a structure represented by the following formula: [P-L]n-Ab, wherein: Ab is an anti-GIPR antibody or antigen binding fragment thereof; L is a peptide linker or is absent; P is a peptide that is a GLP-1R and / or GCGR agonist; and n represents a number in the range of 1 to 8. In some embodiments, Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having an amino acid sequence selected from the group consisting of: (1) SEQ ID NOs: 1, 2, 3, 4, 5, and 7, respectively, (2) SEQ ID NOs: 1, 2, 3, 4, 6, and 7, respectively, (3) SEQ ID NOs: 8, 9, 11, 12, 13, and 14, respectively, (4) SEQ ID NOs: 8, 10, 11, 12, 13, and 14, respectively, and (5) SEQ ID NOs: 15, 16, 17, 18, 19, and 20, respectively; and P-L has an amino acid sequence selected from the group consisting of: SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, and SEQ ID NO: 78.

[0286] In some embodiments, P-L is conjugated to Ab via a linker (C). In some embodiments, the linker is

[0287] In some embodiments, the APC has the following structure: wherein n represents a number in the range of 1 to 8.

[0288] In some embodiments, the APC disclosed herein comprises a structure represented by the following formula: [P-L]n-Ab, wherein: Ab is an anti-GIPR antibody or antigen binding fragment thereof; L is a peptide linker or is absent; P is a peptide that is a GLP-1R and / or GCGR agonist; and n represents a number in the range of 1 to 8. In some embodiments, Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 7, respectively; and P-L has an amino acid sequence selected from the group consisting of SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, and SEQ ID NO: 78. In some embodiments, Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 7, respectively; and P-L has the amino acid sequence of SEQ ID NO: 55. In some embodiments, Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 7, respectively; and P-L has the amino acid sequence of SEQ ID NO: 56. In some embodiments, Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 7, respectively; and P-L has the amino acid sequence of SEQ ID NO: 57. In some embodiments, Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 7, respectively; and P-L has the amino acid sequence of SEQ ID NO: 58.In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 7, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 61. In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 7, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 62. In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 7, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 63. In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 7, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 64. In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 7, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 65. In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 7, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 66. In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 7, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 67. In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 7, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 68.In some embodiments, the Ab comprises a VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 7, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 71. In some embodiments, the Ab comprises a VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 7, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 72. In some embodiments, the Ab comprises a VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 7, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 73. In some embodiments, the Ab comprises a VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 7, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 74. In some embodiments, the Ab comprises a VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 7, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 75. In some embodiments, the Ab comprises a VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 7, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 76. In some embodiments, the Ab comprises a VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 7, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 77. In some embodiments, the Ab comprises a VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 7, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 78. In some embodiments, the Ab comprises a VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 7, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 79. In some embodiments, the Ab comprises a VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 7, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 80. In some embodiments, the Ab comprises a VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 7, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 81. In some embodiments, the Ab comprises a VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 7, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 82. In some embodiments, the Ab comprises a VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 7, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 83. In some embodiments, the Ab comprises a VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 7, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 84. In some embodiments, the Ab comprises a VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 7, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 85. In some embodiments, the Ab comprises a VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 7, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 86. In some embodiments, the Ab comprises a VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 7, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 87. In some embodiments, the Ab comprises a VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 7, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 88. In some embodiments, the Ab comprises a VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 7, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 89. In some embodiments, the Ab comprises a VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 7, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 90. In some embodiments, the Ab comprises a VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 7, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 91. In some embodiments, the Ab comprises a VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 7, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 92. In some embodiments, the Ab comprises a VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 7, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 93. In some embodiments, the Ab comprises a VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO16 the chemical moiety of CO2H is conjugated to P via ([2-(2-aminoethoxy)-ethoxy]- acetyl)2-(y-Glu)2. In some embodiments, P-L can be conjugated to Ab via a linker (C). In some embodiments, the linker is 18 the chemical moiety of CO2H is conjugated to P via ([2-(2-aminoethoxy)-ethoxy]- acetyl)2-(y-Glu)2. In some embodiments, P-L can be conjugated to Ab via a linker (C). In some embodiments, the linker is In some embodiments, the linker is a maleimide linker. In some embodiments, the APC has the following structure: wherein n represents a number in the range of 1 to 8. In some embodiments, the DAR of the APC is 1 or 2. In some embodiments, n is 1 or 2.

[0289] In some embodiments, the APC disclosed herein comprises a structure represented by the following formula: [P-L]n-Ab, wherein: Ab is an anti-GIPR antibody or antigen binding fragment thereof; L is a peptide linker or is absent; P is a peptide that is a GLP-1R and / or GCGR agonist; and n represents a number in the range of 1 to 8. In some embodiments, Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 6, and 7, respectively; and P-L has an amino acid sequence selected from the group consisting of SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, and SEQ ID NO: 78. In some embodiments, Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 6, and 7, respectively; and P-L has an amino acid sequence of SEQ ID NO: 55. In some embodiments, Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 6, and 7, respectively; and P-L has an amino acid sequence of SEQ ID NO: 56. In some embodiments, Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 6, and 7, respectively; and P-L has an amino acid sequence of SEQ ID NO: 57. In some embodiments, Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 6, and 7, respectively; and P-L has an amino acid sequence of SEQ ID NO: 58.In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 6, and 7, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 61. In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 6, and 7, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 62. In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 6, and 7, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 63. In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 6, and 7, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 64. In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 6, and 7, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 65. In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 6, and 7, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 66. In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 6, and 7, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 67. In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 6, and 7, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 68.In some embodiments, Ab comprises VL CDR1, VL CDR2, VL CDR3, VHCDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 1, 2, 3, 4, 6, and 7, respectively; and PL has the amino acid sequence of SEQ ID NO: 71. In some embodiments, Ab comprises VL CDR1, VL CDR2, VL CDR3, VHCDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 1, 2, 3, 4, 6, and 7, respectively; and PL has the amino acid sequence of SEQ ID NO: 72. In some embodiments, Ab comprises VL CDR1, VL CDR2, VL CDR3, VHCDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 1, 2, 3, 4, 6, and 7, respectively; and PL has the amino acid sequence of SEQ ID NO: 73. In some embodiments, Ab comprises VL CDR1, VL CDR2, VL CDR3, VHCDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 1, 2, 3, 4, 6, and 7, respectively; and PL has the amino acid sequence of SEQ ID NO: 74. In some embodiments, Ab comprises VL CDR1, VL CDR2, VL CDR3, VHCDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 1, 2, 3, 4, 6, and 7, respectively; and PL has the amino acid sequence of SEQ ID NO: 75. In some embodiments, Ab comprises VL CDR1, VL CDR2, VL CDR3, VHCDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 1, 2, 3, 4, 6, and 7, respectively; and PL has the amino acid sequence of SEQ ID NO: 76. In some embodiments, Ab comprises VL CDR1, VL CDR2, VL CDR3, VHCDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 1, 2, 3, 4, 6, and 7, respectively; and PL has the amino acid sequence of SEQ ID NO: 77. In some embodiments, Ab comprises VL CDR1, VL CDR2, VL CDR3, VHCDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 1, 2, 3, 4, 6, and 7, respectively; and PL has the amino acid sequence of SEQ ID NO: 78. In some embodiments, ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2).16 the chemical moiety of CO2H is conjugated to P via ([2-(2-aminoethoxy)-ethoxy]- acetyl)2-(y-Glu)2. In some embodiments, P-L can be conjugated to Ab via a linker (C). In some embodiments, the linker is 18 the chemical moiety of CO2H is conjugated to P via ([2-(2-aminoethoxy)-ethoxy]- acetyl)2-(y-Glu)2. In some embodiments, P-L can be conjugated to Ab via a linker (C). In some embodiments, the linker is In some embodiments, the linker is a maleimide linker. In some embodiments, the APC has the following structure: wherein n represents a number in the range of 1 to 8. In some embodiments, the DAR of the APC is 1 or 2. In some embodiments, n is 1 or 2.

[0290] In some embodiments, the APC disclosed herein comprises a structure represented by the following formula: [P-L]n-Ab, wherein: Ab is an anti-GIPR antibody or antigen binding fragment thereof; L is a peptide linker or is absent; P is a peptide that is a GLP-1R and / or GCGR agonist; and n represents a number in the range of 1 to 8. In some embodiments, Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 8, 9, 11, 12, 13, and 14, respectively; and P-L has an amino acid sequence selected from the group consisting of SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, and SEQ ID NO: 78. In some embodiments, Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 8, 9, 11, 12, 13, and 14, respectively; and P-L has an amino acid sequence of SEQ ID NO: 55. In some embodiments, Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 8, 9, 11, 12, 13, and 14, respectively; and P-L has an amino acid sequence of SEQ ID NO: 56. In some embodiments, Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 8, 9, 11, 12, 13, and 14, respectively; and P-L has an amino acid sequence of SEQ ID NO: 57. In some embodiments, Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 8, 9, 11, 12, 13, and 14, respectively; and P-L has an amino acid sequence of SEQ ID NO: 58.In some embodiments, the Ab comprises a VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 8, 9, 11, 12, 13, and 14, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 61. In some embodiments, the Ab comprises a VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 8, 9, 11, 12, 13, and 14, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 62. In some embodiments, the Ab comprises a VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 8, 9, 11, 12, 13, and 14, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 63. In some embodiments, the Ab comprises a VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 8, 9, 11, 12, 13, and 14, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 64. In some embodiments, the Ab comprises a VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 8, 9, 11, 12, 13, and 14, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 65. In some embodiments, the Ab comprises a VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 8, 9, 11, 12, 13, and 14, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 66. In some embodiments, the Ab comprises a VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 8, 9, 11, 12, 13, and 14, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 67. In some embodiments, the Ab comprises a VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 8, 9, 11, 12, 13, and 14, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 68.In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 8, 9, 11, 12, 13, and 14, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 71. In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 8, 9, 11, 12, 13, and 14, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 72. In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 8, 9, 11, 12, 13, and 14, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 73. In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 8, 9, 11, 12, 13, and 14, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 74. In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 8, 9, 11, 12, 13, and 14, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 75. In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 8, 9, 11, 12, 13, and 14, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 76. In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 8, 9, 11, 12, 13, and 14, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 77. In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 8, 9, 11, 12, 13, and 14, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 78.In some embodiments, the chemical moiety of CO2H is conjugated to P via ([2-(2- aminoethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2). 16 In some embodiments, the chemical moiety of CO2H is conjugated to P via ([2-(2- aminoethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2) 18 In some embodiments, the chemical moiety of CO2H is conjugated to P via ([2-(2- aminoethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2) In some embodiments, the linker is a maleimide linker. In some embodiments, the APC has the following structure: wherein n represents a number in the range of 1 to 8. In some embodiments, the DAR of the APC is 1 or 2. In some embodiments, n is 1 or 2.

[0291] In some embodiments, the APC disclosed herein comprises a structure represented by the following formula: [P-L]n-Ab, wherein: Ab is an anti-GIPR antibody or antigen binding fragment thereof; L is a peptide linker or is absent; P is a peptide that is a GLP-1R and / or GCGR agonist; and n represents a number in the range of 1 to 8. In some embodiments, Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 8, 10, 11, 12, 13, and 14, respectively; and P-L has an amino acid sequence selected from the group consisting of SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, and SEQ ID NO: 78. In some embodiments, Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 8, 10, 11, 12, 13, and 14, respectively; and P-L has an amino acid sequence of SEQ ID NO: 55. In some embodiments, Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 8, 10, 11, 12, 13, and 14, respectively; and P-L has an amino acid sequence of SEQ ID NO: 56. In some embodiments, Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 8, 10, 11, 12, 13, and 14, respectively; and P-L has an amino acid sequence of SEQ ID NO: 57. In some embodiments, Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 8, 10, 11, 12, 13, and 14, respectively; and P-L has an amino acid sequence of SEQ ID NO: 58.In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 8, 10, 11, 12, 13, and 14, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 61. In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 8, 10, 11, 12, 13, and 14, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 62. In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 8, 10, 11, 12, 13, and 14, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 63. In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 8, 10, 11, 12, 13, and 14, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 64. In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 8, 10, 11, 12, 13, and 14, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 65. In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 8, 10, 11, 12, 13, and 14, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 66. In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 8, 10, 11, 12, 13, and 14, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 67. In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 8, 10, 11, 12, 13, and 14, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 68.In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 8, 10, 11, 12, 13, and 14, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 71. In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 8, 10, 11, 12, 13, and 14, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 72. In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 8, 10, 11, 12, 13, and 14, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 73. In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 8, 10, 11, 12, 13, and 14, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 74. In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 8, 10, 11, 12, 13, and 14, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 75. In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 8, 10, 11, 12, 13, and 14, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 76. In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 8, 10, 11, 12, 13, and 14, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 77. In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 8, 10, 11, 12, 13, and 14, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 78.In some embodiments, the chemical moiety of CO2H is conjugated to P via ([2-(2- aminoethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2). 16 In some embodiments, the chemical moiety of CO2H is conjugated to P via ([2-(2- aminoethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2) 18 In some embodiments, the chemical moiety of CO2H is conjugated to P via ([2-(2- aminoethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2) In some embodiments, the linker is a maleimide linker. In some embodiments, the APC has the following structure: where n represents a number in the range of 1 to 8. In some embodiments, the DAR of the APC is 1 or 2. In some embodiments, n is 1 or 2.

[0292] In some embodiments, the APC disclosed herein comprises a structure represented by the following formula: [P-L]n-Ab, wherein: Ab is an anti-GIPR antibody or antigen binding fragment thereof; L is a peptide linker or is absent; P is a peptide that is a GLP-1R and / or GCGR agonist; and n represents a number in the range of 1 to 8. In some embodiments, Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 15, 16, 17, 18, 19, and 20, respectively; and P-L has an amino acid sequence selected from the group consisting of SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, and SEQ ID NO: 78. In some embodiments, Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 15, 16, 17, 18, 19, and 20, respectively; and P-L has the amino acid sequence of SEQ ID NO: 55. In some embodiments, Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 15, 16, 17, 18, 19, and 20, respectively; and P-L has the amino acid sequence of SEQ ID NO: 56. In some embodiments, Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 15, 16, 17, 18, 19, and 20, respectively; and P-L has the amino acid sequence of SEQ ID NO: 57. In some embodiments, Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 15, 16, 17, 18, 19, and 20, respectively; and P-L has the amino acid sequence of SEQ ID NO: 58.In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 15, 16, 17, 18, 19, and 20, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 61. In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 15, 16, 17, 18, 19, and 20, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 62. In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 15, 16, 17, 18, 19, and 20, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 63. In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 15, 16, 17, 18, 19, and 20, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 64. In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 15, 16, 17, 18, 19, and 20, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 65. In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 15, 16, 17, 18, 19, and 20, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 66. In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 15, 16, 17, 18, 19, and 20, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 67. In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 15, 16, 17, 18, 19, and 20, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 68.In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 15, 16, 17, 18, 19, and 20, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 71. In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 15, 16, 17, 18, 19, and 20, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 72. In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 15, 16, 17, 18, 19, and 20, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 73. In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 15, 16, 17, 18, 19, and 20, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 74. In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 15, 16, 17, 18, 19, and 20, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 75. In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 15, 16, 17, 18, 19, and 20, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 76. In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 15, 16, 17, 18, 19, and 20, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 77. In some embodiments, the Ab comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 15, 16, 17, 18, 19, and 20, respectively; and the P-L has the amino acid sequence of SEQ ID NO: 78.In some embodiments, the chemical moiety of CO2H is conjugated to P via ([2-(2- aminoethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2). 16 In some embodiments, the chemical moiety of CO2H is conjugated to P via ([2-(2- aminoethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2) 18 In some embodiments, the chemical moiety of CO2H is conjugated to P via ([2-(2- aminoethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2) In some embodiments, the linker is a maleimide linker. In some embodiments, the APC has the following structure: wherein n represents a number in the range of 1 to 8. In some embodiments, the DAR of the APC is 1 or 2. In some embodiments, n is 1 or 2.

[0293] In some embodiments, the APC disclosed herein comprises a structure represented by the following formula: [P-L]n-Ab, wherein: Ab is an anti-GIPR antibody or antigen binding fragment thereof; L is a peptide linker or is absent; P is a peptide that is a GLP-1R and / or GCGR agonist; and n represents a number in the range of 1 to 8. In some embodiments, Ab comprises (a) a VL having the amino acid sequence of SEQ ID NO: 24, and / or a VH having the amino acid sequence of SEQ ID NO: 25; (b) a VL having the amino acid sequence of SEQ ID NO: 26, and / or a VH having the amino acid sequence of SEQ ID NO: 27; (c) a VL having the amino acid sequence of SEQ ID NO: 28, and / or a VH having the amino acid sequence of SEQ ID NO: 29; (d) a VL having the amino acid sequence of SEQ ID NO: 30, and / or a VH having the amino acid sequence of SEQ ID NO: 31; or (e) a VL having the amino acid sequence of SEQ ID NO: 32, and / or a VH having the amino acid sequence of SEQ ID NO: 33; and the peptide has an amino acid sequence selected from the group consisting of SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, and SEQ ID NO: 78.

[0294] In some embodiments, the APC disclosed herein comprises a structure represented by the following formula: [P-L]n-Ab, wherein: Ab is an anti-GIPR antibody or antigen binding fragment thereof; L is a peptide linker or is absent; P is a peptide that is a GLP-1R and / or GCGR agonist; and n represents a number in the range of 1 to 8. In some embodiments, Ab has: a VL having the amino acid sequence of SEQ ID NO: 24 and / or a VH having the amino acid sequence of SEQ ID NO: 25; and P-L has an amino acid sequence selected from the group consisting of SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, and SEQ ID NO: 78. In some embodiments, Ab has: a VL and a VH having the amino acid sequences of SEQ ID NO: 24 and 25, respectively; and P-L has the amino acid sequence of SEQ ID NO: 55. In some embodiments, Ab has: a VL and a VH having the amino acid sequences of SEQ ID NO: 24 and 25, respectively; and P-L has the amino acid sequence of SEQ ID NO: 56. In some embodiments, Ab has: a VL and a VH having the amino acid sequences of SEQ ID NO: 24 and 25, respectively; and P-L has the amino acid sequence of SEQ ID NO: 57. In some embodiments, Ab has: a VL and a VH having the amino acid sequences of SEQ ID NO: 24 and 25, respectively; and P-L has the amino acid sequence of SEQ ID NO: 58. In some embodiments, Ab has: a VL and a VH having the amino acid sequences of SEQ ID NO: 24 and 25, respectively; and P-L has the amino acid sequence of SEQ ID NO: 61. In some embodiments, Ab has: a VL and a VH having the amino acid sequences of SEQ ID NO: 24 and 25, respectively; and P-L has the amino acid sequence of SEQ ID NO: 62. In some embodiments, Ab has: a VL and a VH having the amino acid sequences of SEQ ID NO: 24 and 25, respectively; and P-L has the amino acid sequence of SEQ ID NO: 63.In some embodiments, Ab has: VL and VH having amino acid sequences of SEQ ID NO:24 and 25 respectively; and PL has the amino acid sequence of SEQ ID NO:64. In some embodiments, Ab has: VL and VH having amino acid sequences of SEQ ID NO:24 and 25 respectively; and PL has the amino acid sequence of SEQ ID NO:65. In some embodiments, Ab has: VL and VH having amino acid sequences of SEQ ID NO:24 and 25 respectively; and PL has the amino acid sequence of SEQ ID NO:66. In some embodiments, Ab has: VL and VH having amino acid sequences of SEQ ID NO:24 and 25 respectively; and PL has the amino acid sequence of SEQ ID NO:67. In some embodiments, Ab has: VL and VH having amino acid sequences of SEQ ID NO:24 and 25 respectively; and PL has the amino acid sequence of SEQ ID NO:68. In some embodiments, Ab has: VL and VH having amino acid sequences of SEQ ID NO:24 and 25 respectively; and PL has the amino acid sequence of SEQ ID NO:71. In some embodiments, Ab has: VL and VH having amino acid sequences of SEQ ID NO:24 and 25 respectively; and PL has the amino acid sequence of SEQ ID NO:72. In some embodiments, Ab has: VL and VH having amino acid sequences of SEQ ID NO:24 and 25 respectively; and PL has the amino acid sequence of SEQ ID NO:73. In some embodiments, Ab has: VL and VH having amino acid sequences of SEQ ID NO:24 and 25 respectively; and PL has the amino acid sequence of SEQ ID NO:74. In some embodiments, Ab has: VL and VH having amino acid sequences of SEQ ID NO:24 and 25 respectively; and PL has the amino acid sequence of SEQ ID NO:75. In some embodiments, Ab has: VL and VH having amino acid sequences of SEQ ID NO:24 and 25 respectively; and PL has the amino acid sequence of SEQ ID NO:76. In some embodiments, Ab has: VL and VH having amino acid sequences of SEQ ID NO:24 and 25 respectively; and PL has the amino acid sequence of SEQ ID NO:77. In some embodiments, Ab has: VL and VH having amino acid sequences of SEQ ID NO:24 and 25, respectively; and PL has amino acid sequence of SEQ ID NO:78. In some embodiments, ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2). 16the chemical moiety of CO2H is conjugated to P via ([2-(2-aminoethoxy)-ethoxy]- acetyl)2-(y-Glu)2. In some embodiments, P-L can be conjugated to Ab via a linker (C). In some embodiments, the linker is 18 the chemical moiety of CO2H is conjugated to P via ([2-(2-aminoethoxy)-ethoxy]- acetyl)2-(y-Glu)2. In some embodiments, P-L can be conjugated to Ab via a linker (C). In some embodiments, the linker is In some embodiments, the linker is a maleimide linker. In some embodiments, the APC has the following structure: where n represents a number in the range of 1 to 8. In some embodiments, the DAR of the APC is 1 or 2. In some embodiments, n is 1 or 2.

[0295] In some embodiments, the APC disclosed herein comprises a structure represented by the following formula: [P-L]n-Ab, wherein: Ab is an anti-GIPR antibody or antigen binding fragment thereof; L is a peptide linker or is absent; P is a peptide that is a GLP-1R and / or GCGR agonist; and n represents a number in the range of 1 to 8. In some embodiments, Ab has a VL having the amino acid sequence of SEQ ID NO: 26, and / or a VH having the amino acid sequence of SEQ ID NO: 27; and P-L has an amino acid sequence selected from the group consisting of SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, and SEQ ID NO: 78. In some embodiments, Ab has a VL and a VH having the amino acid sequences of SEQ ID NO: 26 and 27, respectively; and P-L has the amino acid sequence of SEQ ID NO: 55. In some embodiments, Ab has a VL and a VH having the amino acid sequences of SEQ ID NO: 26 and 27, respectively; and P-L has the amino acid sequence of SEQ ID NO: 56. In some embodiments, Ab has a VL and a VH having the amino acid sequences of SEQ ID NO: 26 and 27, respectively; and P-L has the amino acid sequence of SEQ ID NO: 57. In some embodiments, Ab has a VL and a VH having the amino acid sequences of SEQ ID NO: 26 and 27, respectively; and P-L has the amino acid sequence of SEQ ID NO: 58. In some embodiments, Ab has a VL and a VH having the amino acid sequences of SEQ ID NO: 26 and 27, respectively; and P-L has the amino acid sequence of SEQ ID NO: 61. In some embodiments, Ab has a VL and a VH having the amino acid sequences of SEQ ID NO: 26 and 27, respectively; and P-L has the amino acid sequence of SEQ ID NO: 62. In some embodiments, Ab has a VL and a VH having the amino acid sequences of SEQ ID NO: 26 and 27, respectively; and P-L has the amino acid sequence of SEQ ID NO: 63.In some embodiments, Ab has: VL and VH having amino acid sequences of SEQ ID NO:26 and 27 respectively; and PL has the amino acid sequence of SEQ ID NO:64. In some embodiments, Ab has: VL and VH having amino acid sequences of SEQ ID NO:26 and 27 respectively; and PL has the amino acid sequence of SEQ ID NO:65. In some embodiments, Ab has: VL and VH having amino acid sequences of SEQ ID NO:26 and 27 respectively; and PL has the amino acid sequence of SEQ ID NO:66. In some embodiments, Ab has: VL and VH having amino acid sequences of SEQ ID NO:26 and 27 respectively; and PL has the amino acid sequence of SEQ ID NO:67. In some embodiments, Ab has: VL and VH having amino acid sequences of SEQ ID NO:26 and 27 respectively; and PL has the amino acid sequence of SEQ ID NO:68. In some embodiments, Ab has: VL and VH having amino acid sequences of SEQ ID NO:26 and 27 respectively; and PL has the amino acid sequence of SEQ ID NO:71. In some embodiments, Ab has: VL and VH having amino acid sequences of SEQ ID NO:26 and 27 respectively; and PL has the amino acid sequence of SEQ ID NO:72. In some embodiments, Ab has: VL and VH having amino acid sequences of SEQ ID NO:26 and 27 respectively; and PL has the amino acid sequence of SEQ ID NO:73. In some embodiments, Ab has: VL and VH having amino acid sequences of SEQ ID NO:26 and 27 respectively; and PL has the amino acid sequence of SEQ ID NO:74. In some embodiments, Ab has: VL and VH having amino acid sequences of SEQ ID NO:26 and 27 respectively; and PL has the amino acid sequence of SEQ ID NO:75. In some embodiments, Ab has: VL and VH having amino acid sequences of SEQ ID NO:26 and 27 respectively; and PL has the amino acid sequence of SEQ ID NO:76. In some embodiments, Ab has: VL and VH having amino acid sequences of SEQ ID NO:26 and 27 respectively; and PL has the amino acid sequence of SEQ ID NO:77. In some embodiments, Ab has: VL and VH having amino acid sequences of SEQ ID NO:26 and 27, respectively; and PL has amino acid sequence of SEQ ID NO:78. In some embodiments, ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2). 16the chemical moiety of CO2H is conjugated to P via ([2-(2-aminoethoxy)-ethoxy]- acetyl)2-(y-Glu)2. In some embodiments, P-L can be conjugated to Ab via linker (C). In some embodiments, the linker is 18 the chemical moiety of CO2H is conjugated to P via ([2-(2-aminoethoxy)-ethoxy]- acetyl)2-(y-Glu)2. In some embodiments, P-L can be conjugated to Ab via linker (C). In some embodiments, the linker is In some embodiments, the linker is a maleimide linker. In some embodiments, the APC has the following structure: where n represents a number in the range of 1 to 8. In some embodiments, the DAR of the APC is 1 or 2. In some embodiments, n is 1 or 2.

[0296] In some embodiments, the APC disclosed herein comprises a structure represented by the following formula: [P-L]n-Ab, wherein: Ab is an anti-GIPR antibody or antigen binding fragment thereof; L is a peptide linker or is absent; P is a peptide that is a GLP-1R and / or GCGR agonist; and n represents a number in the range of 1 to 8. In some embodiments, Ab has a VL having the amino acid sequence of SEQ ID NO: 28, and / or a VH having the amino acid sequence of SEQ ID NO: 29; and P-L has an amino acid sequence selected from the group consisting of SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, and SEQ ID NO: 78. In some embodiments, Ab has a VL and a VH having the amino acid sequences of SEQ ID NO: 28 and 29, respectively; and P-L has the amino acid sequence of SEQ ID NO: 55. In some embodiments, Ab has a VL and a VH having the amino acid sequences of SEQ ID NO: 28 and 29, respectively; and P-L has the amino acid sequence of SEQ ID NO: 56. In some embodiments, Ab has a VL and a VH having the amino acid sequences of SEQ ID NO: 28 and 29, respectively; and P-L has the amino acid sequence of SEQ ID NO: 57. In some embodiments, Ab has a VL and a VH having the amino acid sequences of SEQ ID NO: 28 and 29, respectively; and P-L has the amino acid sequence of SEQ ID NO: 58. In some embodiments, Ab has a VL and a VH having the amino acid sequences of SEQ ID NO: 28 and 29, respectively; and P-L has the amino acid sequence of SEQ ID NO: 61. In some embodiments, Ab has a VL and a VH having the amino acid sequences of SEQ ID NO: 28 and 29, respectively; and P-L has the amino acid sequence of SEQ ID NO: 62. In some embodiments, Ab has a VL and a VH having the amino acid sequences of SEQ ID NO: 28 and 29, respectively; and P-L has the amino acid sequence of SEQ ID NO: 63.In some embodiments, Ab has: VL and VH having amino acid sequences of SEQ ID NO:28 and 29 respectively; and PL has the amino acid sequence of SEQ ID NO:64. In some embodiments, Ab has: VL and VH having amino acid sequences of SEQ ID NO:28 and 29 respectively; and PL has the amino acid sequence of SEQ ID NO:65. In some embodiments, Ab has: VL and VH having amino acid sequences of SEQ ID NO:28 and 29 respectively; and PL has the amino acid sequence of SEQ ID NO:66. In some embodiments, Ab has: VL and VH having amino acid sequences of SEQ ID NO:28 and 29 respectively; and PL has the amino acid sequence of SEQ ID NO:67. In some embodiments, Ab has: VL and VH having amino acid sequences of SEQ ID NO:28 and 29 respectively; and PL has the amino acid sequence of SEQ ID NO:68. In some embodiments, Ab has: VL and VH having amino acid sequences of SEQ ID NO:28 and 29 respectively; and PL has the amino acid sequence of SEQ ID NO:71. In some embodiments, Ab has: VL and VH having amino acid sequences of SEQ ID NO:28 and 29 respectively; and PL has the amino acid sequence of SEQ ID NO:72. In some embodiments, Ab has: VL and VH having amino acid sequences of SEQ ID NO:28 and 29 respectively; and PL has the amino acid sequence of SEQ ID NO:73. In some embodiments, Ab has: VL and VH having amino acid sequences of SEQ ID NO:28 and 29 respectively; and PL has the amino acid sequence of SEQ ID NO:74. In some embodiments, Ab has: VL and VH having amino acid sequences of SEQ ID NO:28 and 29 respectively; and PL has the amino acid sequence of SEQ ID NO:75. In some embodiments, Ab has: VL and VH having amino acid sequences of SEQ ID NO:28 and 29 respectively; and PL has the amino acid sequence of SEQ ID NO:76. In some embodiments, Ab has: VL and VH having amino acid sequences of SEQ ID NO:28 and 29 respectively; and PL has the amino acid sequence of SEQ ID NO:77. In some embodiments, Ab has: VL and VH having amino acid sequences of SEQ ID NO:28 and 29, respectively; and PL has amino acid sequence of SEQ ID NO:78. In some embodiments, ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2). 16the chemical moiety of CO2H is conjugated to P via ([2-(2-aminoethoxy)-ethoxy]- acetyl)2-(y-Glu)2. In some embodiments, the chemical moiety of CO2H is conjugated to P via ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2) 18 the chemical moiety of CO2H is conjugated to P via ([2-(2-aminoethoxy)-ethoxy]- acetyl)2-(y-Glu)2. In some embodiments, the chemical moiety of CO2H is conjugated to P via ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)

[0297] In some embodiments, P-L can be conjugated to Ab via a linker (C). In some embodiments, the linker is

[0298] In some embodiments, the linker is a maleimide linker. In some embodiments, the APC has the...

Claims

1. An antibody or antigen-binding fragment thereof that specifically binds human GIPR, the antibody or antigen-binding fragment thereof comprising: (a) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from a VL having an amino acid sequence selected from the group consisting of SEQ ID NOs: 24, 26, 28, and 30, or a variant thereof having up to about 5 amino acid substitutions, additions and / or deletions in the VL CDRs; and / or (b) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 from a VH having an amino acid sequence selected from the group consisting of SEQ ID NOs: 25, 27, 29, and 31, or a variant thereof having up to about 5 amino acid substitutions, additions and / or deletions in the VH CDRs.

2. The antibody or antigen-binding fragment of claim 1, wherein (1) the VL comprises a VL CDR1 having the amino acid sequence of SEQ ID NO: 1 or 8, a VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 9, and 10, and a VL CDR3 having the amino acid sequence of SEQ ID NO: 3 or 11, or a variant thereof having up to about 5 amino acid substitutions, additions and / or deletions in the VL CDRs; and / or (b) the VH comprises a VH CDR1 having the amino acid sequence of SEQ ID NO: 4 or 12, a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 5, 6, and 13, and a VH CDR3 having the amino acid sequence of SEQ ID NO: 7 or 14, or a variant thereof having up to about 5 amino acid substitutions, additions and / or deletions in the VH CDRs.

3. The antibody or antigen-binding fragment of claim 1 or 2, comprising a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2, and a VH CDR3 having an amino acid sequence selected from the group consisting of: (1) SEQ ID NOs: 1, 2, 3, 4, 5, and 7, respectively; (2) SEQ ID NOs: 1, 2, 3, 4, 6, and 7, respectively; (3) SEQ ID NOs: 8, 9, 11, 12, 13, and 14, respectively; and (4) SEQ ID NOs: 8, 10, 11, 12, 13, and 14, respectively; or a variant thereof having up to about 5 amino acid substitutions, additions and / or deletions in the CDRs.

4. The antibody or antigen-binding fragment of any one of claims 1 to 3, comprising: (a) a VL having at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 24, and / or a VH having at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 25; (b) a VL having at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 26, and / or a VH having at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 27; (c) a VL having at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 28, and / or a VH having at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 29; or (d) a VL having at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 30, and / or a VH having at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:

31.

5. The antibody or antigen-binding fragment of any one of claims 1-4, comprising a VL and a VH having the amino acid sequences of: (1) SEQ ID NOs: 24 and 25, respectively; (2) SEQ ID NOs: 26 and 27, respectively; (3) SEQ ID NOs: 28 and 29, respectively; or (4) SEQ ID NOs: 30 and 31, respectively.

6. An antibody or antigen-binding fragment thereof that competes for binding to human GIPR with the antibody or antigen-binding fragment of any one of claims 1-5.

7. The antibody or antigen-binding fragment of any one of claims 1-7, selected from the group consisting of a Fab, Fab', F(ab')2, Fv, scFv, (scFv)2, a single domain antibody (sdAb), and a heavy chain antibody (HCAb).

8. The antibody or antigen-binding fragment of any one of claims 1-6, which is an IgGl antibody, an IgG2 antibody, an IgG3 antibody, or an IgG4 antibody.

9. The antibody or antigen-binding fragment of any one of claims 1-8, further comprising a light chain constant (CL) region and a heavy chain constant (CH) region.

10. The antibody or antigen-binding fragment of claim 9, wherein the CL region is kappa CL (CK; SEQ ID NO: 37) or lambda CL (CL; SEQ ID NO: 38), or a variant thereof having up to ten amino acid substitutions, additions and / or deletions.

11. The antibody or antigen-binding fragment of claim 9 or 10, wherein the CH region is IgGl CH (SEQ ID NO: 39, 43 or 88), IgG2 CH (SEQ ID NO: 40), IgG3 CH (SEQ ID NO: 41) or IgG4 CH (SEQ ID NO: 42), or a variant thereof having up to ten amino acid substitutions, additions and / or deletions.

12. The antibody or antigen-binding fragment of claim 8, wherein the antibody is an IgGl antibody.

13. The antibody or antigen-binding fragment of claim 12, wherein the IgGl antibody (1) has L234A / L235A substitutions in the Fc region, (2) has E272C substitution in the Fc region, (3) has L234A / L235A / E272C substitutions in the Fc region, (4) has M252Y / S254T / T256E substitutions in the Fc region, or (5) has E272C / L234A / L235A / M252Y / S254T / T256E substitutions in the Fc region.

14. The antibody or antigen-binding fragment of claim 12, wherein the antibody comprises a light chain (LC) and a heavy chain (HC), and wherein (1) the LC is at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 48, and the HC is at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 49; (2) the LC is at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 50, and the HC is at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 51; (3) the LC is at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 48, and the HC is at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 89; or (4) the LC is at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 50, and the HC is at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:

90.

15. The antibody or antigen-binding fragment of any one of claims 1-14, which is a monoclonal antibody or antigen-binding fragment.

16. The antibody or antigen-binding fragment of any one of claims 1-15, wherein the antibody or antigen-binding fragment inhibits binding of GIP to the extracellular portion of human GIPR.

17. A polynucleotide encoding a peptide of the antibody or antigen-binding fragment of any one of claims 1-16.

18. A vector comprising the polynucleotide of claim 17.

19. A host cell comprising the polynucleotide of claim 17 or the vector of claim 18.

20. A method of producing an antibody or antigen-binding fragment thereof that specifically binds to human GIPR, the method comprising culturing the cell of claim 19 under conditions suitable for expression of the antibody or antigen-binding fragment; wherein optionally, the method further comprises isolating the antibody or antigen-binding fragment from the culture.

21. A kit comprising the antibody or antigen-binding fragment of any one of claims 1-16.

22. A peptide comprising an oxyntomodulin analog, wherein the oxyntomodulin analog has the amino acid sequence of SEQ ID NO: 55 or SEQ ID NO:

56.

23. The peptide of claim 22, wherein the C-terminal amino acid is amidated.

24. The peptide of claim 22 or 23, wherein the Lys at position 20 of the oxyntomodulin analog is chemically modified by conjugation of a C14-C24 fatty acid to the epsilon- amino group of the Lys side chain.

25. The peptide of claim 24, wherein the fatty acid is conjugated to the Lys via ([2-(2- aminoethoxy)-ethoxy]-acetyl)2-(y-Glu) t wherein t is 1 or 2.

26. The peptide according to claim 24 or 25, wherein the Lys is conjugated with ([2-(2- amino-ethoxy)-ethoxy]-acetyl)2-(yGlu)i-CO-(CH2) 18 -CO2H.

27. A kit comprising the peptide of any one of claims 22-26.

28. An antibody-peptide conjugate ("APC") having the structure shown by the following formula: [P-L]n- Ab, wherein: Ab is the antibody or antigen binding fragment of any one of claims 1-16; L is a peptide linker or is absent; P is a peptide that is a glucagon-like peptide-1 receptor (GLP-1R) and / or glucagon receptor (GCG) agonist; and n represents a number in the range of 1-8.

29. The APC of claim 28, wherein P is a GLP-1R agonist, a GCG agonist, or a dual GLP-1R / GCG agonist.

30. The APC of claim 29, wherein the GLP-1R agonist is exenatide, liraglutide, dulaglutide, semaglutide, albiglutide, lixisenatide, efetogimtide, or taspoglutide; the GCG agonist is REMD-477; or the dual GLP-1R / GCG agonist is oxyntomodulin or an oxyntomodulin analog.

31. The APC of claim 30, wherein the oxyntomodulin analog has the amino acid sequence of SEQ ID NO: 55 or 56, or a variant thereof having up to 5 amino acid substitutions, additions, and / or deletions.

32. The APC of claim 30 or 31, wherein the Lys at position 20 of the oxyntomodulin analog is chemically modified by conjugation of a C14-C24 fatty acid to the epsilon-amino group of the Lys side chain.

34. The APC of any one of claims 28-33, wherein L has an amino acid sequence selected from the group consisting of (GGGGS)3(SEQ ID NO: 81), (GGGGS)2(SEQ ID NO: 82), GGGGS (SEQ ID NO: 83), VA, VC, VKG, and GGFG (SEQ ID NO: 84).

35. The APC of claim 34, wherein the P-L has an amino acid sequence selected from the group consisting of SEQ ID NOs: 61-68 and 71-78.

36. The APC of any one of claims 28-35, wherein the P-L is conjugated to Ab via a linker (C).

37. The APC of claim 36, wherein the linker (C) has the following structure:

38. The APC of any one of claims 28-37, having the following structure:

33. The APC of claim 32, wherein the fatty acid is conjugated to Lys via ([2-(2- aminoethoxy)-ethoxy]-acetyl)2-(y-Glu) t wherein t is 1 or 2, or wherein the Lys is conjugated to ([2-(2-amino-ethoxy)- ethoxy]-acetyl)2-(yGlu)i-CO-(CH2) 18 -CO2H. ​ ​ ​ ​ ​ 39. The APC of any one of claims 28-38, wherein Ab comprises one or more Cys and P-L is conjugated to Ab through the side chain of the Cys at one or more conjugation sites.

40. The APC of any one of claims 28-39, wherein Ab comprises an IgGl Fc region with an E272C substitution and P is conjugated to the side chain of the Cys at position 272.

41. An APC having the structure of the following formula: [P-L]n-Ab, wherein P is a peptide that is a glucagon-like peptide-1 receptor (GLP-1R) and / or a glucagon receptor (GCGR) agonist; L is a peptide linker or is absent; Ab is an antibody that specifically binds GIPR, an antibody that specifically binds PCSK9, or an Fc region; and n represents a number in the range of 1-8.

42. An APC having the structure of the following formula: [P-L]n-Ab, wherein P is the peptide of any one of claims 22-26; L is a peptide linker or is absent; Ab is an antibody that specifically binds GIPR, an antibody that specifically binds PCSK9, or an Fc region; and n represents a number in the range of 1-8.

43. The APC of claim 41 or 42, wherein Ab is 2G10, toriselumab, alirocumab, evolocumab, or an Fc region.

44. The APC of any one of claims 41-43, wherein L has an amino acid sequence selected from the group consisting of (GGGGS)3 (SEQ ID NO: 81), (GGGGS)2 (SEQ ID NO: 82), GGGGS (SEQ ID NO: 83), VA, VC, VKG, and GGFG (SEQ ID NO: 84).

45. The APC of any one of claims 41-44, wherein the P-L is conjugated to Ab via a linker (C).

46. The APC of claim 45, wherein the linker (C) has the following structure:

47. The APC of any one of claims 41-46, having the following structure:

48. The APC of any one of claims 41-47, wherein Ab comprises one or more Cys and the P-L is conjugated to the Ab through the side chain of the Cys at one or more conjugation sites.

49. The APC of any one of claims 41-48, wherein Ab comprises an IgGl Fc region with an E272C substitution and P is conjugated to the side chain of the Cys at position 272.

50. An APC having the following structure: Ab is an antibody that specifically binds GIPR, wherein the antibody comprises LC and HC having the amino acid sequences of SEQ ID NOs: 48 and 49, respectively; P is a peptide; L is a peptide linker; the P-L has the amino acid sequence of SEQ ID NO: 71 or 61; and n represents the number 1 or 2. ​ ​ ​ ​ ​ ​ ​ ​ wherein: ​ 51. An APC, said APC having the following structure: wherein: Ab is an antibody that specifically binds to GIPR, wherein the antibody comprises LC and HC having amino acid sequences of SEQ ID NO:48 and 89, respectively; P is a peptide; L is a peptide linker; PL has an amino acid sequence of SEQ ID NO:71 or 61; and n represents the number 1 or 2.

52. An APC, said APC having the following structure: wherein: Ab is an antibody that specifically binds to GIPR, wherein the antibody comprises LC and HC having amino acid sequences of SEQ ID NO:50 and 51, respectively; P is a peptide; L is a peptide linker; PL has an amino acid sequence of SEQ ID NO:71 or 61; and n represents the number 1 or 2.

53. An APC, said APC having the following structure: wherein: Ab is an antibody that specifically binds to GIPR, wherein the antibody comprises LC and HC having amino acid sequences of SEQ ID NO:50 and 90, respectively; P is a peptide; L is a peptide linker; PL has an amino acid sequence of SEQ ID NO:71 or 61; and n represents the number 1 or 2.

54. A method for generating an APC according to any one of claims 28 to 53, the method comprising attaching a PL to Ab.

55. A pharmaceutical composition comprising a therapeutically effective amount of an antibody or antigen-binding fragment of any one of claims 1 to 16, or a peptide of any one of claims 22 to 26, or an APC of any one of claims 28 to 53, and a pharmaceutically acceptable carrier.

56. Use of the antibody or antigen-binding fragment of any one of claims 1 to 16, or the peptide of any one of claims 22 to 26, or the APC of any one of claims 28 to 53, or the pharmaceutical composition of claim 55 for the preparation of a medicament for treating a metabolic disorder or impairment in a subject in need.

57. The use according to claim 56, wherein the subject is a human.

58. The use according to claim 56 or 57, wherein the metabolic condition or disorder is overweight or obesity, diabetes, or non-alcoholic steatohepatitis (NASH).

59. A kit comprising the APC of any one of claims 28 to 53.

60. A method for preparing an APC having the structure shown in the formula: [P-L]n-Ab, wherein: Ab is an antibody or antigen-binding fragment; L is a linker; P is a peptide, the method comprising a) contacting the antibody or antigen-binding fragment with a cysteine ​​blocker, wherein the cysteine ​​blocker forms a stable mixed disulfide with at least one cysteine ​​residue of the antibody or antigen-binding fragment; b) contacting the antibody or antigen-binding fragment with a reducing agent to form a reduced antibody or antigen-binding fragment; and c) contacting the reduced antibody or antigen-binding fragment with a peptide having an activated chemical moiety to form the APC; wherein the method does not use an oxidizing agent.

61. The method of claim 60, wherein the mixed disulfides are an antibody or antigen binding fragment with a capped free cysteine; wherein optionally, the capped free cysteine comprises a cap selected from cysteine, cysteamine, cystamine, and glutathione.

62. The method of claim 60 or 61, further comprising removing excess cysteine blocking agent; optionally by ultrafiltration or cation exchange chromatography.

63. The method of any one of claims 60-62, wherein the reducing agent is selected from triphenylphosphine-3,3',3"-trisulfonate ("TPPTS"), tris(2-carboxyethyl)phosphine ("TCEP"), and triphenylphosphine-3,3'-disulfonate ("TPPDS").

64. The method of claim 63, wherein the molar ratio of the reducing agent to the antibody or antigen binding fragment is 2: 1 to 4:

1.

65. The method of any one of claims 60-64, comprising removing excess reducing agent.

66. The method of claim 65, wherein excess reducing agent is removed by buffer exchange; wherein optionally, the buffer exchange step is ultrafiltration / diafiltration.

67. The method of any one of claims 60-66, wherein the activated chemical moiety comprises a halogen, wherein the halogen is selected from Br, I, and Cl.

68. The method of claim 67, wherein the molar ratio of the peptide with an activated chemical moiety to the antibody or antigen binding fragment is 2: 1 to 6:

1.

69. The method of any one of claims 60-68, further comprising step d) removing the excess peptide, wherein step d) optionally comprises size exclusion chromatography, hydrophobic interaction chromatography ("HIC"), or ultrafiltration / diafiltration, or any combination thereof.