How to Treat Obesity

Abstract

The present invention relates to a method for treating obesity or type II diabetes using an antagonistic anti-GIPR antibody conjugated to a GLP-1R agonist. Specifically, a method for treating obesity or type II diabetes in a patient in need thereof is disclosed, comprising administering to the patient an antagonistic anti-GIPR antibody conjugated to a GLP-1R agonist according to a specific dosing regimen. Pharmaceutical compositions and administration devices comprising the antagonistic anti-GIPR antibody conjugated to a GLP-1R agonist for use in the method are also described.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 382,700, filed November 7, 2022, and U.S. Provisional Patent Application No. 63 / 387,837, filed December 16, 2022, which are incorporated by reference herein in their entireties.

[0002] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in XML format, which is incorporated herein by reference in its entirety. A copy of said XML, created on November 7, 2023, is named 10304-WO01-SEC_Seqlisting.XML and is 16,012 bytes in size.

[0003] The present invention relates to the treatment of obesity with antibody-peptide conjugates that selectively inhibit the glucose-dependent insulinotropic polypeptide receptor (GIPR) while agonizing the glucagon-like peptide-1 receptor (GLP-1R). [Background technology]

[0004] As a multifactorial chronic disease, obesity is an increasingly prevalent health problem worldwide (World Health Organisation. 2016. Obesity and overweight: fact sheet 311). Obesity-related comorbidities further burden healthcare systems (Apovian CM, 2016). The current unmet expectations of anti-obesity therapeutics support the need to develop novel safe and effective agents (Wright SM, Aronne LJ. 2011; Valsamakis et al., 2017).

[0005] Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are gut-derived incretin hormones well known for their ability to enhance glucose-stimulated insulin secretion. In addition to its incretin effects, GLP-1 promotes satiety through the GLP-1 receptor (GLP-1R) (Turton et al., 1996), whereas GIP promotes adiposity through the GIP receptor (GIPR) (Yip et al., 1998; Beck and Max, 1987; Hauner et al., 1988; Knapper et al., 1995). Several GLP-1 receptor agonists have been approved to treat type 2 diabetes and have demonstrated benefit in controlling obesity (Prasad-Reddy and Isaacs, 2015). Genome-wide association studies in humans and mice indicate that the GIPR locus contributes to body weight and that GIPR knockout mice are protected from diet-induced obesity (Berndt et al., 2013; Saxena et al., 2010; Speliotes et al., 2010; Althage et al., 2013). 2008; Miyawaki et al., 2002; Nasteska et al., 2014). Pharmacological inhibition of GIPR with anti-GIPR antibodies prevented weight gain in diet-induced obese (DIO) mice and obese cynomolgus monkeys (Killion et al., 2018). Furthermore, GIPR antagonism combined with GLP-1R agonism synergistically reduced body weight in DIO mice and obese cynomolgus monkeys (Killion et al., 2018), suggesting the potential of GIPR / GLP-1R bispecific molecules for the treatment of obesity.

[0006] As an anti-GIPR / GLP-1R bispecific molecule, maridevat cafraglutide (also known as "AMG-133") was engineered by conjugating a fully human monoclonal anti-human GIPR antagonist antibody with a GLP-1 analog agonist peptide using a natural amino acid linker. Herein, the inventors report their discovery, preclinical development in DIO mice and obese cynomolgus monkeys, and a clinical proof-of-concept study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of maridevat cafraglutide in obese patients. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] World Health Organ. 2016. Obesity and overweight:fact sheet 311 [Non-patent document 2] Apovian CM, 2016 [Non-patent document 3] Wright SM, Aronne LJ. 2011 [Non-patent document 4] Valsamakis et al., 2017 [Non-Patent Document 5] Turton et al., 1996 [Non-patent document 6] Yip et al., 1998 [Non-Patent Document 7] Beck and Max, 1987 [Non-patent document 8] Hauner et al., 1988 [Non-Patent Document 9] Knapper et al., 1995 [Non-Patent Document 10] Prasad-Reddy and Isaacs, 2015 [Non-Patent Document 11] Berndt et al., 2013 [Non-Patent Document 12] Saxena et al., 2010 [Non-Patent Document 13] Speliotes et al., 2010 [Non-Patent Document 14] Althage et al., 2008 [Non-Patent Document 15] Miyawaki et al., 2002 [Non-Patent Document 16] Nasteska et al., 2014 [Non-Patent Document 17] Killion et al., 2018 Summary of the Invention [Means for solving the problem]

[0008] The present invention is based, in part, on the identification of treatment regimens for effectively treating obesity or type II diabetes in a patient. Accordingly, in one aspect, the present invention provides a method of treating obesity or type II diabetes in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising an antagonistic anti-GIPR antibody conjugated to a GLP-1R agonist at a dose of about 21 mg to about 840 mg every 4 weeks, about 21 mg to about 840 mg every 6 weeks, about 21 mg to about 840 mg every 8 weeks, or about 21 mg to about 840 mg every 12 weeks.

[0009] In another aspect, the invention relates to the use of an antagonistic anti-GIPR antibody conjugated to a GLP-1R agonist for the preparation of a medicament for treating obesity or type II diabetes in a patient in need thereof, wherein the medicament is formulated for administration at a dose of about 21 mg to about 840 mg every 4 weeks, at a dose of about 21 mg to about 840 mg every 6 weeks, at a dose of about 21 mg to about 840 mg every 8 weeks, or at a dose of about 21 mg to about 840 mg every 12 weeks.

[0010] In certain embodiments, the dosage is about 21 mg, about 70 mg, about 140 mg, about 280 mg, about 420 mg, about 560 mg, or about 840 mg every 4 weeks; about 21 mg, about 70 mg, about 140 mg, about 280 mg, about 420 mg, about 560 mg, or about 840 mg every 6 weeks; about 21 mg, about 70 mg, about 140 mg, about 280 mg, about 420 mg, about 560 mg, or about 840 mg every 8 weeks, or about 21 mg, about 70 mg, about 140 mg, about 280 mg, about 420 mg, about 560 mg, or about 840 mg every 12 weeks.

[0011] In particular embodiments, the dosage is about 280 mg every 4 weeks; about 280 mg every 6 weeks, about 280 mg every 8 weeks, or about 280 mg every 12 weeks.

[0012] In a particular embodiment, the dosage is about 280 mg every four weeks.

[0013] In certain embodiments, the dosage is about 420 mg every 4 weeks; about 420 mg every 6 weeks, about 420 mg every 8 weeks, or about 420 mg every 12 weeks.

[0014] In certain embodiments, the pharmaceutical composition is administered once every four weeks.

[0015] In another aspect, the invention provides a method of treating obesity or type II diabetes in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising an antagonistic anti-GIPR antibody conjugated to a GLP-1R agonist at a dose of about 21 mg to about 840 mg monthly, at a dose of about 21 mg to about 840 mg every 1.5 months, at a dose of about 21 mg to about 840 mg every 2 months, or at a dose of about 21 mg to about 840 mg every 3 months.

[0016] In another aspect, the invention is directed to the use of an antagonistic anti-GIPR antibody conjugated to a GLP-1R agonist for the preparation of a medicament for treating obesity or type II diabetes in a patient in need thereof, wherein the medicament is formulated for administration at a dose of about 21 mg to about 840 mg monthly, at a dose of about 21 mg to about 840 mg every 1.5 months, at a dose of about 21 mg to about 840 mg every 2 months, or at a dose of about 21 mg to about 840 mg every 3 months.

[0017] In certain embodiments, the dosage is about 21 mg, about 70 mg, about 140 mg, about 280 mg, about 420 mg, about 560 mg, or about 840 mg monthly; about 21 mg, about 70 mg, about 140 mg, about 280 mg, about 420 mg, about 560 mg, or about 840 mg every one and a half months; about 21 mg, about 70 mg, about 140 mg, about 280 mg, about 420 mg, about 560 mg, or about 840 mg every two months, or about 21 mg, about 70 mg, about 140 mg, about 280 mg, about 420 mg, about 560 mg, or about 840 mg every three months.

[0018] In certain embodiments, the dosage is about 280 mg monthly; about 280 mg every one and a half months, about 280 mg every two months, or about 280 mg every three months.

[0019] In a particular embodiment, the dosage is about 280 mg monthly.

[0020] In certain embodiments, the dosage is about 420 mg monthly; about 420 mg every one and a half months, about 420 mg every two months, or about 420 mg every three months.

[0021] In certain embodiments, the pharmaceutical composition is administered once a month.

[0022] In certain embodiments, the pharmaceutical composition is administered parenterally.

[0023] In certain embodiments, the parenteral administration is subcutaneous administration.

[0024] In certain embodiments, the pharmaceutical composition is administered to the patient using a syringe pre-filled with the pharmaceutical composition.

[0025] In certain embodiments, the pharmaceutical composition is administered to the patient by an autoinjector.

[0026] In certain embodiments, administration of the pharmaceutical composition causes substantially no adverse side effects in the patient.

[0027] In certain embodiments, the patient has a body mass index ("BMI") greater than 30 kg / m2, 35 kg / m2, or 40 kg / m2.

[0028] In certain embodiments, the patient has an HbA1c of 7% or greater and 10% or less (53-86 mmol / mol).

[0029] In certain embodiments, the patient was treated with metformin, a sulfonylurea, or a sodium-glucose cotransporter 2 (SGLT2) inhibitor, either as monotherapy or in combination therapy.

[0030] In certain embodiments, the patient has or has been diagnosed with type 2 diabetes, hi other embodiments, the patient is obese but does not have type 2 diabetes.

[0031] In certain embodiments, the patient has not previously undergone therapy for obesity.

[0032] In certain embodiments, the anti-GIPR antibody comprises a CDRH1 comprising the amino acid sequence of SEQ ID NO: 5, a CDRH2 comprising the amino acid sequence of SEQ ID NO: 6, a CDRH3 comprising the amino acid sequence of SEQ ID NO: 7, a CDRL1 comprising the amino acid sequence of SEQ ID NO: 8, a CDRL2 comprising the amino acid sequence of SEQ ID NO: 9, and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 10.

[0033] In certain embodiments, the antagonistic anti-GIPR antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:1 and a light chain comprising the amino acid sequence of SEQ ID NO:2.

[0034] In certain embodiments, the GLP-1R agonist comprises the amino acid sequence of SEQ ID NO:3.

[0035] In certain embodiments, the antagonistic anti-GIPR antibody is linked to the GLP-1R agonist via a peptide linker comprising SEQ ID NO:4.

[0036] In one embodiment, the antagonistic anti-GIPR antibody conjugated to a GLP-1R agonist is maridevert caffraglutide.

[0037] In certain embodiments, the pharmaceutical composition further comprises a buffering agent.

[0038] In certain embodiments, the buffer is an acetate buffer.

[0039] In certain embodiments, the pharmaceutical composition further comprises a surfactant.

[0040] In certain embodiments, the surfactant is polysorbate 20 or polysorbate 80.

[0041] In certain embodiments, the pharmaceutical composition further comprises a stabilizer.

[0042] In certain embodiments, the stabilizer is sucrose. [Brief explanation of the drawings]

[0043] [Figure 1] 1 shows physical parameters after single and repeated administration of AMG 133. [Figure 2] Table 1A: Baseline characteristics by treatment group for subjects receiving single ascending doses of AMG 133 or placebo. [Figure 3] 1 shows changes in metabolic and inflammatory parameters in subjects in a multiple ascending dose study with AMG 133. [Figure 4]Table 1B: Baseline characteristics by treatment group in subjects receiving multiple ascending doses of AMG 133 or placebo. [Figure 5] Table 3A: Treatment-emergent adverse events after single doses of placebo and AMG 133. [Figure 6] Table 3B: Treatment-emergent adverse events after multiple doses of placebo and AMG 133. [Figure 7] Table 4A: Vital sign measurements in subjects after a single dose of placebo or AMG 133. [Figure 8] Table 4B: Vital sign measurements in subjects after repeated administration of placebo or AMG 133. [Figure 9] 1 shows the Phase 2 study scheme (Cohort A)—Part 1 (subjects without type 1 or type 2 diabetes mellitus). [Figure 10] 1 shows the Phase 2 study scheme (Cohort B)—Part 1 (subjects with diabetes mellitus). [Figure 11] Phase 2 study scheme - Part 2 is shown. [Figure 12] Phase 2 investigational drug. [Figure 13A] 1 shows the Phase 2 Part 1 study groups for Cohort A (subjects without type 1 or type 2 diabetes mellitus). [Figure 13B] 1 shows the Phase 2 Part 1 study groups for Cohort B (subjects with a diagnosis of type 2 diabetes mellitus). [Figure 14] Phase 2 Part 2 study arms are shown. DETAILED DESCRIPTION OF THE INVENTION

[0044] The present disclosure provides methods for treating metabolic disorders such as disorders of glucose metabolism (e.g., type 2 diabetes, elevated blood glucose levels, elevated insulin levels, dyslipidemia, metabolic syndrome (syndrome X or insulin resistance syndrome), glycosuria, metabolic acidosis, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, type 1 diabetes, obesity, and conditions exacerbated by obesity) by blocking or interfering with the biological activity of GIP. In one embodiment, a therapeutically effective amount of an isolated human GIPR binding protein conjugated to a GLP-1 receptor agonist is administered to a subject in need thereof. Methods of administration and delivery are also provided.

[0045] In one embodiment, the human GIPR has a sequence comprising a sequence selected from the group consisting of SEQ ID NO:11, SEQ ID NO:12 and SEQ ID NO:13.

[0046] The 466 amino acid sequence of human GIPR is (Volz et al., FEBS Lett. 373:23-29 (1995); NCBI reference sequence NP_0001555): [ka]

[0047] The 430 amino acid isoform of human GIPR (isoform X1) predicted by automated computer analysis has the sequence (NCBI reference sequence XP_005258790): [ka]

[0048] A 493 amino acid isoform of human GIPR produced by alternative splicing has the sequence (Gremlich et al., Diabetes 44:1202-8 (1995); UniProtKB sequence identification number P48546-2): [ka]

[0049] The recombinant polypeptide and nucleic acid methods used herein, including the Examples, are generally those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (Cold Spring Harbor Laboratory Press, 1989) or Current Protocols in Molecular Biology (Ausubel et al., eds., Green Publishers Inc. and Wiley and Sons 1994), both of which are incorporated herein by reference for all purposes.

[0050] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0051] Unless otherwise defined herein, scientific and technical terms used in connection with this application shall have the meanings commonly understood by those of ordinary skill in the art. Further, unless the context otherwise requires, singular terms shall include the plural and plural terms shall include the singular.

[0052] Generally, the nomenclatures and techniques used in connection with the cell and tissue culture, molecular biology, immunology, microbiology, genetics, and protein and nucleic acid chemistry, and hybridization techniques described herein are those well known and commonly used in the art. Unless otherwise specified, the methods and techniques herein are generally performed according to conventional methods well known in the art and as described in various general and more specific references cited and discussed throughout this specification. See, for example, Sambrook et al., Molecular Cloning: A Laboratory Manual, 3rd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY (2001), Ausubel et al., Current Protocols in Molecular Biology, Greene Publishing Associates (1992), and Harlow and Lane Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY (1990), which are incorporated herein by reference. Enzymatic reactions and purification techniques are performed according to manufacturer's instructions, as commonly accomplished in the art, or as described herein. The nomenclature used in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well known and commonly used in the art. Standard techniques may be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation and delivery, and treatment of patients.

[0053] It is to be understood that this invention is not limited to the particular methodology, protocols, and reagents, etc., described herein and as such may vary. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the disclosure, which is defined solely by the claims.

[0054] Except as otherwise noted in the examples, all numbers indicating quantities of ingredients or reaction conditions used herein should be understood to be modified in all instances by the term "about." When used in connection with percentages, the term "about" can mean ±1%.

[0055] Unless otherwise specified, as used herein, "a" and "an" are used conventionally to mean "one or more."

[0056] As used herein, the terms "amino acid" and "residue" are used interchangeably and, when used in connection with a peptide or polypeptide, refer to both naturally occurring and synthetic amino acids, as well as amino acid analogs, amino acid mimetics, and non-naturally occurring amino acids that are chemically similar to the naturally occurring amino acids.

[0057] "Naturally occurring amino acids" are those amino acids encoded by the genetic code, as well as amino acids encoded by the genetic code that are modified after synthesis, e.g., hydroxyproline, γ-carboxyglutamate, and O-phosphoserine. Amino acid analogs are compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an alpha carbon bonded to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methylmethionine sulfonium. Such analogs may have modified R groups (e.g., norleucine) or modified peptide backbones, but will retain the same basic chemical structure as a naturally occurring amino acid.

[0058] "Amino acid mimetics" are chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally occurring amino acid. Examples include methacryloyl or acryloyl derivatives of amides, β-imino acids, γ-imino acids, δ-imino acids (such as piperidine-4-carboxylic acid), and the like.

[0059] A "non-naturally occurring amino acid" is a compound that has the same basic chemical structure as a naturally occurring amino acid, but is not incorporated into a growing polypeptide chain by the translation complex. "Non-naturally occurring amino acids" also include, but are not limited to, amino acids that arise by modification (e.g., post-translational modification) of a naturally encoded amino acid (including, but not limited to, the 20 common amino acids), but that are not themselves naturally incorporated into a growing polypeptide chain by the translation complex. A non-limiting list of examples of non-naturally occurring amino acids that can be inserted into or substitute for wild-type residues in a polypeptide sequence includes β-amino acids, homoamino acids, cyclic amino acids, and side-chain derivatized amino acids. Examples include (in either L- or D-form);Abbreviated as in parentheses): citrulline (Cit), homocitrulline (hCit), Nα-methylcitrulline (NMeCit), Nα-methylhomocitrulline (Nα-MeHoCit), ornithine (Orn), Nα-methylornithine (Nα-MeOrn or NMeOrn), sarcosine (Sar), homolysine (hLys or hK), homoarginine (hArg or hR), homoglutamine (hQ), Nα-methylarginine (NMeR), Nα-methylleucine (Nα-MeL or NMeL), N-methylhomolysine (NMeH oK), Nα-methylglutamine (NMeQ), norleucine (Nle), norvaline (Nva), 1,2,3,4-tetrahydroisoquinoline (Tic), octahydroindole-2-carboxylic acid (Oic), 3-(1-naphthyl)alanine (1-Nal), 3-(2-naphthyl)alanine (2-Nal), 1,2,3,4-tetrahydroisoquinoline (Tic), 2-indanylglycine (IgI), para-iodophenylalanine (pI-Phe), para-aminophenylalanine (4AmP or 4-amino-Phe), 4-guaialine (4-guanidinium-2-phosphate dehydrogenase), 4-amino-2-methyl-3-(4-amino-2-methyl-3-methyl-4-methyl-2 ... Nitrophenylalanine (Guf), glycyrrhizin (abbreviated as "K(Nε-glycyl)" or "K(glycyl)" or "K(gly)"), nitrophenylalanine (nitrophe), aminophenylalanine (aminophe or amino-Phe), benzylphenylalanine (benzylphe), gamma-carboxyglutamic acid (gamma-carboxyglu), hydroxyproline (hydroxypro), p-carboxyl-phenylalanine (Cpa), alpha-aminoadipic acid (Aad), Nα-methylvaline (NMeVal), N-α- Methylleucine (NMeLeu), Nα-methylnorleucine (NMeNle), cyclopentylglycine (Cpg), cyclohexylglycine (Chg), acetylarginine (acetylarg), α,β-diaminopropionic acid (Dpr), α,γ-diaminobutyric acid (Dab), diaminopropionic acid (Dap), cyclohexylalanine (Cha), 4-methyl-phenylalanine (MePhe), β,β-diphenyl-alanine (BiPhA), aminobutyric acid (Abu), 4-phenyl-phenylalanine (or biphenylalanine;4Bip), α-amino-isobutyric acid (Aib), beta-alanine, beta-aminopropionic acid, piperidinic acid, aminocaproic acid, aminoheptanoic acid, aminopimelic acid, desmosine, diaminopimelic acid, N-ethylglycine, N-ethylasparagine, hydroxylysine, allo-hydroxylysine, isodesmosine, allo-isoleucine, N-methylglycine, N-methylisoleucine, N-methylvaline, 4-hydroxyproline (Hyp), γ-carboxyglutamate, ε-N,N,N-trimethyllysine, ε-N-acetyllysine, O-phosphoserine, N-acetylserine, N-formylmethionine, 3-methylhistidine, 5-hydroxylysine, ω-methylarginine, 4-amino-O-phthalic acid (4APA) and other similar amino acids and derivatized forms of any of those specifically listed;

[0060] The term "isolated nucleic acid molecule" refers to a single- or double-stranded polymer of deoxyribonucleotide or ribonucleotide bases, read from the 5' to the 3' end (e.g., a GIPR nucleic acid sequence provided herein), or an analog thereof, that is separated from at least about 50 percent of the polypeptides, peptides, lipids, carbohydrates, polynucleotides, or other materials that are naturally found with the nucleic acid when the total nucleic acid is isolated from a source cell. Preferably, an isolated nucleic acid molecule is substantially free of any other contaminating nucleic acid molecules or other molecules found in the nucleic acid's natural environment that would interfere with its use in polypeptide production or its therapeutic, diagnostic, prophylactic, or research uses.

[0061] The term "isolated polypeptide" refers to a polypeptide (e.g., a GIPR polypeptide sequence provided herein or an antigen binding protein of the invention) that has been separated from at least about 50 percent of the polypeptides, peptides, lipids, carbohydrates, polynucleotides, or other materials that are naturally found with the polypeptide when it is isolated from a source cell. Preferably, an isolated polypeptide is substantially free of any other contaminating polypeptides or other contaminants found in its natural environment that would interfere with its therapeutic, diagnostic, prophylactic, or research uses.

[0062] The compositions of the invention are "conjugates" or "conjugated" molecules, whether they comprise a GLP-1 receptor agonist of the invention covalently linked, attached or bound to an antagonistic anti-GIPR antibody of the invention, either directly or indirectly via a linker moiety, or conjugated by chemical means (e.g., post-translationally or post-synthetically).

[0063] The term "encoding" refers to a polynucleotide sequence that encodes one or more amino acids. This term does not require a start or stop codon.

[0064] In certain embodiments, the invention is directed to a method of treating obesity or type II diabetes in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising an antagonistic anti-GIPR antibody conjugated to a GLP-1R agonist at a dose of about 21 mg to about 840 mg every four weeks, about 21 mg to about 840 mg every six weeks, or about 21 mg to about 840 mg every eight weeks. In another aspect, the invention is directed to the use of an antagonistic anti-GIPR antibody conjugated to a GLP-1R agonist for the preparation of a medicament for treating obesity or type II diabetes in a patient in need thereof, wherein the medicament is formulated for administration at a dose of about 21 mg to about 840 mg every four weeks, about 21 mg to about 840 mg every six weeks, or about 21 mg to about 840 mg every eight weeks. In certain embodiments, the dosage is about 21 mg, about 70 mg, about 140 mg, about 280 mg, about 560 mg, or about 840 mg every 4 weeks; about 21 mg, about 70 mg, about 140 mg, about 280 mg, about 560 mg, or about 840 mg every 6 weeks; or about 21 mg, about 70 mg, about 140 mg, about 280 mg, about 560 mg, or about 840 mg every 8 weeks. In certain embodiments, the dosage is about 280 mg every 4 weeks; about 280 mg every 6 weeks, or about 280 mg every 8 weeks.

[0065] The weekly and monthly administration schedules of antagonistic anti-GIPR antibodies conjugated to GLP-1R agonists are similar between patients regardless of body weight.In other words, in these embodiments, the dose of antagonistic anti-GIPR antibodies conjugated to GLP-1R agonists is a total dose and is not adjusted for patient body weight.In one embodiment, the antagonistic anti-GIPR antibodies conjugated to GLP-1R agonists are administered to patients monthly at a total dose of about 280 mg.

[0066] In certain embodiments, the monthly dosage of an antagonistic anti-GIPR antibody conjugated to a GLP-1R agonist may be based on the patient's body weight. For example, in some embodiments, the monthly dosage of an antagonistic anti-GIPR antibody conjugated to a GLP-1R agonist may range from about 0.3 mg / kg to about 3.5 mg / kg of body weight, from about 0.5 mg / kg to about 3 mg / kg of body weight, or from about 1 mg / kg to about 2.5 mg / kg of body weight. For example, the monthly dosage of an antagonistic anti-GIPR antibody conjugated to a GLP-1R agonist may be about 0.3 mg / kg of body weight, about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, about 0.8 mg / kg, about 0.9 mg / kg, about 1 mg / kg, about 1.1 mg / kg, about 1.2 mg / kg, about 1.3 mg / kg, about 1.4 mg / kg, about 1.5 mg / kg, about 1.6 mg / kg The monthly dose of the antagonistic anti-GIPR antibody conjugated to a GLP-1R agonist can be about 0.8 mg / kg to about 1.2 mg / kg of body weight. In another embodiment, the monthly dose of the antagonistic anti-GIPR antibody conjugated to a GLP-1R agonist can be about 1.6 mg / kg to about 2.2 mg / kg of body weight.

[0067] The dose of an antagonistic anti-GIPR antibody conjugated to a GLP-1R agonist can be administered as a single dose or divided into multiple doses over a dosing frequency period. For example, in certain embodiments, a therapeutically effective dose of an antagonistic anti-GIPR antibody conjugated to a GLP-1R agonist is administered as a single dose at each frequency period. Thus, in some embodiments, any of the doses of an antagonistic anti-GIPR antibody conjugated to a GLP-1R agonist described herein can be administered to a patient once a month (QM dosing). Patients receiving a QM dosing regimen typically receive an antagonistic anti-GIPR antibody conjugated to a GLP-1R agonist every 24 to 36 days, preferably every 28 to 35 days, more preferably every 28 to 31 days, or even more preferably every 28 days or every 30 days. In these and other embodiments, the monthly dose is administered to the patient as a bolus injection, e.g., using an autoinjection device as described herein. For example, a monthly dose of 280 mg can be administered to a patient as a single bolus injection of 280 mg, optionally using an autoinjector, pen injector or pre-filled syringe that contains 280 mg dose.In certain embodiments, a monthly dose is given by two or more consecutive injections.For example, a monthly dose of 280 mg can be administered to a patient as two consecutive injections of 140 mg, optionally using two injection devices (for example, an autoinjector, pen injector or pre-filled syringe) that contain 140 mg dose.

[0068] In an alternative embodiment, the dose of the antagonistic anti-GIPR antibody conjugated to a GLP-1R agonist is divided into two or more administrations over a dosing frequency period. For example, for a one-month dosing frequency period, the monthly dose can be divided into four doses and administered weekly, or divided into two doses and administered every two weeks. Any of the doses of the antagonistic anti-GIPR antibody conjugated to a GLP-1R agonist described herein can be divided into two or more administrations. The number of administrations and the interval between interventions can be adjusted for a particular patient depending on the severity of obesity, the patient's age, the patient's physical health, concurrent treatment with other drugs, and / or the presence of other conditions.

[0069] In certain embodiments, the administration frequency period of the dosage of the antagonistic anti-GIPR antibody conjugated with GLP-1R agonist described herein is monthly.In other words, the dosage of the antagonistic anti-GIPR antibody conjugated with GLP-1R agonist is monthly dosage (monthly dosage is equivalent to once every 4 weeks), but can be administered in one administration (monthly; QM administration) or repeated administration throughout the month (for example, half of the monthly dosage is administered every 2 weeks).

[0070] In certain embodiments, the patient has a body mass index ("BMI") greater than 30 kg / m, 35 kg / m, or 40 kg / m. In certain embodiments, the patient has a BMI greater than 30 kg / m and less than 40 kg / m. In certain embodiments, the patient has a BMI greater than 35 kg / m and less than 40 kg / m. In certain embodiments, the patient has a BMI greater than 30 kg / m and less than 35 kg / m. Measurements can also be converted to lbs / in.

[0071] Body mass index (BMI) is a person's weight in kilograms (or pounds) divided by the square of their height in meters (or feet). A high BMI can indicate high body fatness.

[0072] In certain embodiments, treating obesity comprises promoting weight loss in a patient. Accordingly, the present invention is directed to methods of treating obesity in which a patient loses about 5% of their body weight in 52 weeks, about 10% of their body weight in 52 weeks, about 15% of their body weight in 52 weeks, about 20% of their body weight in 52 weeks, about 25% of their body weight in 52 weeks, or about 30% of their body weight in 52 weeks. "Weight" refers to the patient's weight prior to the first administration of the pharmaceutical composition.

[0073] In certain embodiments, treating obesity includes maintaining body weight by administering a maintenance dose to a patient. Accordingly, the present invention is directed to methods of treating obesity in which the patient's body weight does not fluctuate by more than ±0.5% of the target body weight, ±1.0% of the target body weight, ±1.5% of the target body weight, ±2.0% of the target body weight, ±2.5% of the target body weight, ±3.0% of the target body weight, ±3.5% of the target body weight, ±4.0% of the target body weight, ±4.5% of the target body weight, or ±5.0% of the target body weight. "Target body weight" refers to the body weight that the patient wishes to maintain. The maintenance dose can be the same amount and frequency as the weight-loss-promoting dose. Alternatively, the maintenance dose can be 1) an amount less than the weight-loss-promoting dose, 2) administered less frequently than the weight-loss-promoting dose, or 3) both less than the weight-loss-promoting dose and less frequently than the weight-loss-promoting dose.

[0074] In certain embodiments, the patient has been diagnosed with type 2 diabetes. In certain embodiments, the patient has an HbA1c of 7% or more and 10% or less (53-86 mmol / mol).

[0075] In certain embodiments, the patient is being treated with metformin, a sulfonylurea, or a sodium-glucose cotransporter 2 (SGLT2) inhibitor as monotherapy or combination therapy.

[0076] In some embodiments of the methods of the present invention, an antagonistic anti-GIPR antibody conjugated to a GLP-1R agonist is administered to a patient over a set treatment period. The "treatment period" begins with the administration of the first dose of the antagonistic anti-GIPR antibody conjugated to a GLP-1R agonist and ends with the administration of the final dose of the anti-GIPR antibody or binding fragment. The treatment period can range from about 1 month to about 36 months, e.g., about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 18 months, about 21 months, about 24 months, about 27 months, about 30 months, or about 33 months. In some embodiments, the treatment period is about 6 months. In other embodiments, the treatment period is about 7 months. In yet other embodiments, the treatment period is about 12 months. In certain embodiments, the treatment period may be longer than 36 months, such as 48 months or 60 months or 64 months or more.

[0077] Administration of an antagonistic anti-GIPR antibody conjugated to a GLP-1R agonist according to the methods of the present invention preferably causes few or no adverse side effects in patients. As used herein, the term "adverse side effects" refers to any abnormalities, defects, mutations, lesions, alterations, adverse or undesirable reactions, symptoms, or damage that may be caused by medication. In some embodiments, administration of an antagonistic anti-GIPR antibody conjugated to a GLP-1R agonist does not substantially cause one or more adverse side effects associated with other obesity treatments. Side effects associated with other weight loss treatments include fatigue, nausea, dizziness, insomnia, depression, decreased exercise tolerance, tremor, dysesthesias, teratogenicity, and cognitive impairment. In other embodiments, administration of an antagonistic anti-GIPR antibody conjugated to a GLP-1R agonist is associated with a lower rate or number of adverse side effects compared to the rate or number of adverse side effects associated with other obesity treatments. In yet other embodiments, administration of an antagonistic anti-GIPR antibody conjugated to a GLP-1R agonist is associated with a lower rate of discontinuation due to adverse side effects compared to discontinuation rates due to adverse side effects associated with other weight loss treatments, hi certain embodiments, the number and type of adverse side effects associated with administration of an antagonistic anti-GIPR antibody conjugated to a GLP-1R agonist are not statistically different from the number and type of adverse side effects associated with administration of a placebo.

[0078] The methods described herein involve administering to a patient an antagonistic anti-GIPR antibody conjugated to a GLP-1R agonist. As used herein, the term "antibody" refers to an intact immunoglobulin of any isotype that can compete with an intact antibody for specific binding to a target antigen, including, for example, chimeric, humanized, or fully human. The structural unit of an antibody typically comprises one or more tetramers, each composed of two identical couplets of polypeptide chains, although some mammalian species also produce antibodies with only a single heavy chain. In a typical antibody, each pair or couplet comprises one full-length "light" chain (approximately 25 kDa in certain embodiments) and one full-length "heavy" chain (approximately 50-70 kDa in certain embodiments). Each individual immunoglobulin chain is composed of several "immunoglobulin domains," each of which consists of approximately 90-110 amino acids and exhibits a characteristic folding pattern. These domains are the basic units from which antibody polypeptides are constructed. The amino-terminal portion of each chain typically contains a variable domain responsible for antigen recognition. The carboxy-terminal portion is evolutionarily more conserved than the other end of the chain and is called the "constant region" or "C region." Human light chains are generally classified as kappa and lambda light chains, each of which contains one variable domain and one constant domain. Heavy chains are typically classified as mu, delta, gamma, alpha, or epsilon, which define the antibody isotype as IgM, IgD, IgG, IgA, and IgE, respectively. IgG has several subtypes, including, but not limited to, IgG1, IgG2, IgG3, and IgG4. IgM subtypes include IgM1 and IgM2. IgA subtypes include IgA1 and IgA2. In humans, IgA and IgD isotypes contain four heavy chains and four light chains, IgG and IgE isotypes contain two heavy chains and two light chains, and IgM isotypes contain five heavy chains and five light chains. The C region of the heavy chain typically contains one or more domains that may be responsible for effector function. The number of heavy chain constant region domains depends on the isotype.The heavy chain of IgG, for example, contains three C-region domains known as CH1, CH2, and CH3. Antibodies that can be used in the methods of the present invention may have any of these isotypes and subtypes. In certain embodiments, the anti-GIPR antibody is of the IgG1, IgG2, or IgG4 subtype. In one particular embodiment, the anti-GIPR antibody is an IgG2 antibody (e.g., comprises a human IgG2 constant domain). In another particular embodiment, the anti-GIPR antibody is an IgG1 antibody (e.g., comprises a human IgG1 constant domain).

[0079] In full-length light and heavy chains, the variable and constant regions are connected by a "J" region of about 12 or more amino acids, and heavy chains also include a "D" region of about 10 or more amino acids. See, e.g., Fundamental Immunology, 2nd ed., Ch. 7 (Paul, W., ed.) 1989, New York: Raven Press (incorporated herein by reference in its entirety for all purposes). The variable regions of each light / heavy chain pair typically form the antigen-binding site. The variable regions of immunoglobulin chains generally exhibit the same overall structure, comprising relatively conserved framework regions (FRs) joined by three hypervariable regions (more often referred to as "complementarity-determining regions" or CDRs). The CDRs from the two chains of each heavy / light chain pair are typically aligned by the framework regions to form a structure that specifically binds to a particular epitope of a target protein (e.g., GIPR). From N- to C-terminus, naturally occurring light and heavy chain variable regions typically have the following order of these elements: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. A numbering system has been devised to assign numbers to the amino acids that occupy positions in each of these domains. This numbering system is defined in Kabat Sequences of Proteins of Immunological Interest (1987 and 1991, NIH, Bethesda, MD), or in Chothia & Lesk, 1987, J. Mol. Biol. 196:901-917; Chothia et al., 1989, Nature 342:878-883.

[0080] The term "binding fragment" is used interchangeably herein with the term "antigen-binding fragment" and refers to a portion of an antibody (regardless of how the portion is obtained or synthesized) that lacks at least some of the amino acids present in a full-length heavy and / or light chain, but is capable of specifically binding to an antigen. Such fragments are biologically active in that they specifically bind to a target antigen and can compete with other antigen-binding proteins, including intact antibodies, for specific binding to a given epitope. In one aspect, such a fragment retains at least one CDR present in a full-length light or heavy chain, and in some embodiments will comprise a single heavy and / or light chain or portion thereof. These biologically active fragments can be produced by recombinant DNA techniques or by enzymatic or chemical cleavage of antigen-binding proteins, including intact antibodies. Immunologically functional immunoglobulin fragments include, but are not limited to, Fab, Fab', F(ab')2, Fv, domain antibodies, and single-chain antibodies, and may be derived from any mammalian source, including, but not limited to, human, mouse, rat, camel, or rabbit.

[0081] Antibody-binding fragments may be synthetic proteins or genetically engineered proteins. For example, antigen-binding fragments include isolated fragments consisting of a light-chain variable region, "Fv" fragments consisting of heavy- and light-chain variable regions, and recombinant single-chain polypeptide molecules (scFv proteins) in which the light- and heavy-chain variable regions are linked by a peptide linker. Another form of antigen-binding fragment is a peptide containing one or more complementarity-determining regions (CDRs) of an antibody. CDRs (also called "minimal recognition units" or "hypervariable regions") can be obtained by constructing polynucleotides encoding the desired CDRs. Such polynucleotides are prepared, for example, by using the polymerase chain reaction to synthesize the variable region using mRNA from antibody-producing cells as a template (see, for example, Larrick et al., Methods: A Companion to Methods in Enzymology, 2:106 (1991); Courtenay-Luck, "Genetic Manipulation of Monoclonal Antibodies," in Monoclonal Antibodies Production, Engineering and Clinical Application, Ritter et al. (eds.), page 166, Cambridge University Press (1995); and Ward et al., "Genetic Manipulation and Expression of Antibodies," in Monoclonal Antibodies: Principles and Applications, Birch et al., (eds.), page 137, Wiley-Liss, Inc. (1995)).

[0082] An antibody or binding fragment is said to "specifically bind" to its target antigen when the dissociation constant (KD) is ≦10 M. An antibody or binding fragment specifically binds to a target antigen with "high affinity" when the KD is ≦1×10 M. In one embodiment, the antibody binds to human GIPR with a KD ≦5×10 M. In another embodiment, the antibody or binding fragment binds to human GIPR with a KD ≦1×10 M. In yet another embodiment, the antibody or binding fragment binds to human GIPR with a KD ≦5×10 M. In another embodiment, the antibody or binding fragment binds to human GIPR with a KD ≦1×10 M. In another embodiment, the antibody or binding fragment binds to human GIPR with a KD ≦5×10 M. In a particular embodiment, the antibody or binding fragment binds to human GIPR with a KD ≦1×10 M. In other embodiments, the antibody or binding fragment binds to human GIPR with a KD ≦5×10 M. In yet other embodiments, the antibody or binding fragment binds to human GIPR with a KD≦1×10 M. Affinity is determined using a variety of techniques, examples of which are affinity ELISA assays. In various embodiments, affinity is determined by a BIAcore assay. In some embodiments, affinity is determined by a kinetic method. In other embodiments, affinity is determined by an equilibrium / solution method. In certain embodiments, affinity is determined by a FACS binding assay. WO 2010 / 075238, incorporated herein by reference in its entirety, describes suitable affinity assays for determining affinity for anti-GIPR antibodies.

[0083] An antibody or antigen-binding fragment thereof "selectively inhibits" a specific receptor compared to other receptors if the IC50 of the antibody or antigen-binding fragment thereof in an inhibition assay of the specific receptor is at least 50-fold lower than the IC50 in an inhibition assay of another "reference" receptor. "IC50" is the amount of a drug or substance required to inhibit half of a given biological process. The IC50 of any particular substance or antagonist can be determined by constructing a dose-response curve and testing the effect of different concentrations of the drug or antagonist on reversing agonist activity in a specific functional assay. By determining the concentration required to inhibit half of the maximal biological response of the agonist, the IC50 value can be calculated for a given antagonist or substance. Thus, for example, the IC50 value of any anti-GIPR antibody or binding fragment can be calculated by determining the concentration of the antibody or binding fragment required to inhibit half of the maximal biological response of a GIP ligand in activating GIPR in any functional assay.

[0084] Anti-GIPR antibodies and binding fragments thereof for use in the methods disclosed herein may comprise one heavy chain CDR1 ("CDRH1"), and / or one heavy chain CDR2 ("CDRH2"), and / or one heavy chain CDR3 ("CDRH3"), and / or one light chain CDR1 ("CDRL1"), and / or one light chain CDR2 ("CDRL2"), and / or one light chain CDR3 ("CDRL3"). In some embodiments, an antagonistic anti-GIPR antibody conjugated to a GLP-1R agonist comprises at least one heavy chain variable region comprising CDRH1, CDRH2, and CDRH3, and at least one light chain variable region comprising CDRL1, CDRL2, and CDRL3.

[0085] The complementarity determining regions (CDRs) and framework regions (FRs) of a given antibody can be identified using the system described by Kabat et al. in Sequences of Proteins of Immunological Interest, 5th Ed., US Dept. of Health and Human Services, PHS, NIH, NIH Publication no. 91-3242, 1991.

[0086] In certain embodiments, the anti-GIPR antibody comprises a CDRH1 comprising the amino acid sequence of SEQ ID NO: 5, a CDRH2 comprising the amino acid sequence of SEQ ID NO: 6, a CDRH3 comprising the amino acid sequence of SEQ ID NO: 7, a CDRL1 comprising the amino acid sequence of SEQ ID NO: 8, a CDRL2 comprising the amino acid sequence of SEQ ID NO: 9, and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 10. SEQ ID NO: 5 NYGMH Sequence number 6 AIWFDASDKYYADAVKG SEQ ID NO: 7 DQAIFGVVPDY SEQ ID NO: 8 RASQSVSSNLA SEQ ID NO: 9 GAATRAT SEQ ID NO: 10 QQYNNWPLT

[0087] In certain embodiments, the antagonistic anti-GIPR antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:1 and a light chain comprising the amino acid sequence of SEQ ID NO:2. [ka] [ka]

[0088] In certain embodiments, the GLP-1R agonist comprises the amino acid sequence of SEQ ID NO:3. SEQ ID NO: 3 H[Aib]EGTFTSDYSSYLEEQAAKEFIAWLVKGGG

[0089] In certain embodiments, the antagonistic anti-GIPR antibody is linked to the GLP-1R agonist via a peptide linker comprising SEQ ID NO:4. SEQ ID NO: 4 GGGGSGGGGSGGGGSK

[0090] Malidevatcafraglutide (also known as "AMG-133," "AMG133," and "AMG 133") is engineered by conjugating a fully human monoclonal anti-human GIPR antagonist antibody to a GLP-1 analog agonist peptide using a natural amino acid linker. The heavy chain of AMG 133 consists of SEQ ID NO: 1. The light chain of AMG 133 consists of SEQ ID NO: 2. AMG 133 comprises a linker (SEQ ID NO: 4) linked to cysteine ​​275 of SEQ ID NO: 1 via the C-terminal lysine of SEQ ID NO: 4. AMG 133 further comprises the C-terminus of SEQ ID NO: 3 linked to the N-terminus of SEQ ID NO: 4. Thus, the C-terminal lysine of the peptide H[Aib]EGTFTSDYSSYLEEQAAKEFIAWLVKGGG GGGGSGGGGSGGGGSK (SEQ ID NO: 14) is linked to cysteine ​​275 of SEQ ID NO: 1 in the AMG 133 molecule.

[0091] The anti-GIPR antibody used in the methods described herein may be a monoclonal antibody, a polyclonal antibody, a recombinant antibody, a human antibody, a humanized antibody, or a chimeric antibody. In certain embodiments, the anti-GIPR antibody is a monoclonal antibody. In such embodiments, the anti-GIPR antibody may be a human monoclonal antibody. In some embodiments, the anti-GIPR antibody is a human antibody and may be of the IgG1, IgG2, IgG3, or IgG4 type. Thus, the anti-GIPR antibody may have a human IgG1 or IgG2 constant domain in some embodiments. In one embodiment, the anti-GIPR antibody is a monoclonal IgG1 antibody. In another embodiment, the anti-GIPR antibody is a monoclonal IgG2 antibody.

[0092] Monoclonal antibodies can be produced using any technique known in the art, for example, by immortalizing spleen cells harvested from transgenic animals after the completion of the immunization schedule. The spleen cells can be immortalized using any technique known in the art, for example, by fusing them with myeloma cells to produce hybridomas. Myeloma cells for use in the fusion procedure to produce hybridomas are preferably non-antibody-producing cells, have high fusion efficiency, and possess enzyme deficiencies that prevent them from growing in certain selective media that support the growth of only the desired fused cells (hybridomas). Examples of cell lines suitable for use in mouse fusions include Sp-20, P3-X63 / Ag8, P3-X63-Ag8.653, NS1 / 1.Ag 4 1, Sp210-Ag14, FO, NSO / U, MPC-11, MPC11-X45-GTG 1.7, and S194 / 5XXO Bul, while examples of cell lines used in rat fusions include R210.RCY3, Y3-Ag 1.2.3, IR983F, and 4B210. Other cell lines useful for cell fusions are U-266, GM1500-GRG2, LICR-LON-HMy2, and UC729-6.

[0093] The antagonistic anti-GIPR antibody conjugated to a GLP-1R agonist is generally administered to a patient in a pharmaceutical composition that may contain a pharmaceutically acceptable carrier, excipient, or diluent. "Pharmaceutically acceptable" refers to molecules, compounds, and compositions that are non-toxic to human recipients at the dosages and concentrations used and / or do not cause allergic or adverse reactions when administered to humans. In certain embodiments, pharmaceutical compositions may contain formulation materials to modify, maintain, or preserve, for example, the pH, osmolality, viscosity, transparency, color, isotonicity, odor, sterility, stability, dissolution rate or release rate, absorption, or permeability of the composition. Methods and suitable materials for formulating molecules for therapeutic use are known in the pharmaceutical art and are described, for example, in REMINGTON'S PHARMACEUTICAL SCIENCES, 18th Edition, (AR Genrmo, ed.), 1990, Mack Publishing Company.

[0094] In some embodiments, the selection of carriers and excipients for incorporation into pharmaceutical compositions affects the physical state, stability, in vivo release rate, and in vivo clearance rate of the anti-GIPR antibody or binding fragment thereof. In certain embodiments, the primary vehicle or carrier in a pharmaceutical composition may be aqueous or non-aqueous in nature. For example, a suitable vehicle or carrier may be water for injection, saline solution, or artificial cerebrospinal fluid, optionally supplemented with other materials common in compositions for parenteral administration.

[0095] In certain embodiments of the methods described herein, an antagonistic anti-GIPR antibody conjugated to a GLP-1R agonist is administered parenterally to a patient. Parenteral administration includes intraperitoneal, intramuscular, intravenous, intraarterial, intradermal, subcutaneous, intracerebral, intracerebroventricular, and intrathecal administration. In a particular embodiment, a pharmaceutical composition comprising a therapeutically effective amount of an antagonistic anti-GIPR antibody conjugated to a GLP-1R agonist is administered subcutaneously to a patient. In these and other embodiments in which the pharmaceutical composition is administered by parenteral injection, the pharmaceutical composition can be administered to a patient using a syringe. In some embodiments, the syringe is pre-filled with the pharmaceutical composition. In other embodiments in which the pharmaceutical composition is administered to a patient by parenteral injection, such as subcutaneous injection, the pharmaceutical composition is administered using an injection device, such as a device for self-administration. Such devices are commercially available and include, but are not limited to, autoinjectors, administration pens, microinjection pumps, and pre-filled syringes. Exemplary devices for administering a pharmaceutical composition comprising a therapeutically effective amount of an antagonistic anti-GIPR antibody conjugated to a GLP-1R agonist according to the methods of the invention include autoinjectors (e.g., SureClick®, EverGentle®, Avanti®, DosePro®, Molly®, and Leva®), pen injection devices (e.g., Madie® pen injector, DCP™ pen injector, BD Vystra™ disposable pen, BD™ reusable pen), and pre-filled syringes (BD Sterifill™, BD Hypak™, Baxter pre-filled syringes). In some embodiments, a pharmaceutical composition comprising a therapeutically effective amount of an antagonistic anti-GIPR antibody conjugated to a GLP-1R agonist is administered to a patient via a pre-filled syringe. In other embodiments, a pharmaceutical composition comprising a therapeutically effective amount of an antagonistic anti-GIPR antibody conjugated to a GLP-1R agonist is administered to a patient by autoinjector. In certain related embodiments, the injection volume is about 1 mL or less.

[0096] In one embodiment, the antagonistic anti-GIPR antibody conjugated with GLP-1R agonist is administered to patients at a monthly dose of about 280 mg to promote patient weight loss, and the dose is delivered by a single subcutaneous injection.In a related embodiment, the single subcutaneous injection is delivered by a pre-filled syringe.In another related embodiment, the single subcutaneous injection is delivered by an autoinjector.

[0097] In another embodiment, a GLP-1R agonist-conjugated antagonistic anti-GIPR antibody is administered to a patient at a monthly dose of about 280 mg to promote weight loss in the patient, and the dose is delivered by a single subcutaneous injection. In such an embodiment, the single injection can be delivered by a pre-filled syringe or an auto-injector. In one embodiment, the monthly 280 mg dose of a GLP-1R agonist-conjugated antagonistic anti-GIPR antibody is administered to a patient by two consecutive injections, each containing a 140 mg dose. In such an embodiment, the two consecutive injections can be delivered using two pre-filled syringes or two auto-injectors, each containing a 140 mg dose.

[0098] Typical pharmaceutical forms suitable for parenteral injection include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. Preferably, the pharmaceutical forms are sterile and sufficiently fluid to allow delivery by syringe (i.e., the formulation is not excessively viscous so as to prevent passage through a syringe). Sterilization can be achieved by filtration through sterile filtration membranes. If the composition is lyophilized, sterilization using this method can be performed either before or after lyophilization and reconstitution. Compositions for parenteral administration can be stored in lyophilized form or as a solution. Parenteral formulations can be placed in a container having a sterile access port, such as an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle. Parenteral formulations can also be stored in a syringe, automatic injection device, or pen injection device, or a cartridge adapted for use with such an injection device.

[0099] In certain embodiments, a pharmaceutical composition useful for treating obesity or type II diabetes mellitus using the methods described herein comprises about 21 mg / ml to about 840 mg / ml of an antagonistic anti-GIPR antibody conjugated to its GLP-1R agonist, about 8 mM to about 20 mM sodium acetate, about 0.002% to about 0.015% weight / volume (w / v) polysorbate, and about 7% to about 10% w / v sucrose. In other embodiments, the pharmaceutical composition comprises about 70 mg / ml to about 280 mg / ml of an antagonistic anti-GIPR antibody conjugated to its GLP-1R agonist, about 10 mM to about 15 mM sodium acetate, about 0.008% to about 0.012% w / v polysorbate, and about 8% to about 9% w / v sucrose. The pH of these formulations ranges from about 4.8 to about 5.5 (eg, a pH of about 4.8, about 5.0, about 5.2, or about 5.4).

[0100] In one embodiment, the pharmaceutical composition administered in accordance with the methods of the invention comprises 280 mg / ml of an antagonistic anti-GIPR antibody conjugated to its GLP-1R agonist, about 10 mM sodium acetate, about 0.004% w / v polysorbate 20, and about 9% w / v sucrose at a pH of 5.2±0.2. In another embodiment, the pharmaceutical composition comprises about 280 mg / ml of an antagonistic anti-GIPR antibody conjugated to its GLP-1R agonist, about 10 mM sodium acetate, about 0.004% w / v polysorbate 80, and about 9% w / v sucrose at a pH of 5.2±0.2. In another embodiment, the pharmaceutical composition comprises about 140 mg / ml of an antagonistic anti-GIPR antibody conjugated to its GLP-1R agonist, about 10 mM sodium acetate, about 0.004% w / v polysorbate 20, and about 9% w / v sucrose at a pH of 5.2±0.2. In yet another embodiment, the pharmaceutical composition comprises about 140 mg / ml of an antagonistic anti-GIPR antibody conjugated to its GLP-1R agonist, about 10 mM sodium acetate, about 0.004% w / v polysorbate 80, and about 9% w / v sucrose at a pH of 5.2±0.2. In another embodiment, the pharmaceutical composition comprises about 420 mg / ml of an antagonistic anti-GIPR antibody conjugated to its GLP-1R agonist, about 10 mM sodium acetate, about 0.010% w / v polysorbate 20, and about 9% w / v sucrose at a pH of 5.2±0.2. In yet another embodiment, the pharmaceutical composition comprises about 420 mg / ml of an antagonistic anti-GIPR antibody conjugated to its GLP-1R agonist, about 10 mM sodium acetate, about 0.010% w / v polysorbate 80, and about 9% w / v sucrose at a pH of 5.2±0.2.

[0101] The present invention also includes kits for treating obesity or type II diabetes in patients in need thereof. In one embodiment, the kit includes a pharmaceutical composition of an antagonistic anti-GIPR antibody conjugated to a GLP-1R agonist described herein and packaging material providing instructions for use of the pharmaceutical composition. The pharmaceutical composition of the kit may be present in a container such as a vial or syringe. The pharmaceutical composition may be provided as a solution, suspension, gel, emulsion, solid, crystal, or dehydrated or lyophilized powder. In embodiments in which the pharmaceutical composition is provided as a powder, the kit may also include a diluent (e.g., water, saline, phosphate-buffered saline) necessary to reconstitute the pharmaceutical composition and instructions for preparing the composition for administration. In some embodiments, the kit includes a self-administration injection device (e.g., a pre-filled syringe or auto-injector) pre-filled with the pharmaceutical composition described herein. Either the pre-filled syringe or auto-injector described above may be included in the kit.

[0102] The following examples, including the experiments conducted and results achieved, are provided for illustrative purposes only and are not to be construed as limiting the scope of the appended claims. [Example]

[0103] Example 1: material: cell line CHOK1-expressing hGLP-1R cells or mouse GLP-1R cells stably expressing CHOK1 were cultured in Ham's F12 medium (Thermo Fisher, Waltham, MA) supplemented with 1% penicillin / streptomycin / L-glutamine (PSG, Thermo Fisher), 10% fetal bovine serum (FBS, Thermo Fisher), and 250 μg / ml Zeocin (Thermo Fisher). CHO AMID cells stably expressing monkey or rat GLP-1R were cultured in Dulbecco's modified Eagle's medium (DMEM, Thermo Fisher) supplemented with 1% PSG, 10% dialyzed FBS, 1% non-essential amino acids (NEAA, Thermo Fisher), 1 mM sodium pyruvate, 1% hypoxanthine sodium and thymidine supplement (HT supplement, Thermo Fisher), and 400 μg / ml hygromycin (Thermo Fisher). HEK293T hGIPR cells were cultured in DMEM supplemented with 1% PSG, 10% FBS, and 5 μg / ml puromycin. CHO AMID mouse or rat GIPR cells were cultured in DMEM supplemented with 1% PSG, 10% dialyzed FBS, 1% NEAA, 1 mM sodium pyruvate, 1% HT supplement, and 400 μg / ml hygromycin. 293T monkey GIPR cells were cultured in DMEM supplemented with 1% PSG, 10% FBS, and 2 μg / ml puromycin. All cells were cultured in a humidified incubator maintained at 37°C and 5% CO2.

[0104] Normal mouse Pharmacokinetic evaluation in normal mice was performed at Amgen, Inc. (Thousand Oaks, CA). All study procedures were approved by the Amgen, Inc. Animal Care and Use Committee and conducted in accordance with the Guide for the Care and Use of Laboratory Animals, 8th Edition. Animals used in the study were male CD-1 mice, approximately 8-12 weeks old and weighing approximately 30 g (Charles River Laboratories, CA). After 1 week of acclimation, mice (n=3) received a single IV bolus dose of 5 mg / kg AMG 133 via a lateral tail vein. Blood samples were collected by submandibular venipuncture at predetermined time points up to 14 days post-dose. Whole blood was placed into Microvette® 500 μl K3 EDTA plasma separator tubes (20.1341.102, Sarstedt, Newton, NC), gently mixed by manual inversion 8-10 times, and centrifuged at 11,500 × g for 5 minutes at 4°C. The resulting plasma was stored at −70°C (±10°C) until analysis.

[0105] DIO Mouse Normal cynomolgus monkey PK studies in normal monkeys were conducted at MPI Research (Mattawan, MI). Animal care followed the Guide for the Care and Use of Laboratory Animals, 8th Edition, and studies were conducted in accordance with protocols approved by the Animal Care and Use Committee at MPI Research. Animals used in the study were female (young adult) monkeys weighing 2–3 kg from the MPI Research stock colony of naive cynomolgus monkeys (Macaca fascicularis). Prior to study assignment, monkeys were isolated and acclimated according to MPI Research procedures. Monkeys were housed individually in stainless steel cages and provided with environmental enrichment during the study. Light was provided by an automatic timer for approximately 12 hours per day. Food was provided twice daily (Lab Diet® Certified Primate Diet #5048, PMI Nutrition International), and water was available ad libitum. Temperature and humidity were maintained within the range of 64°F–79°F and 30%–70%, respectively. After an 8-hour fasting period before dosing, monkeys (n=3) received a single SC bolus dose of 3 mg / kg AMG 133 in the scapular region of each animal's back. Blood samples (approximately 1 mL) were collected from the femoral vein / artery at predetermined time points up to 35 days post-dose. Blood samples were processed to K2 EDTA plasma and stored at -70°C (±10°C) until analysis.

[0106] Obese cynomolgus monkeys Details of how: Peptide synthesis: Linker-containing peptides were prepared by standard fluorenylmethoxycarbonyl (Fmoc)-based solid-state peptide synthesis using Rink Amide MBHA resin (Petide International) on an Intavis MultiPep Rsi synthesizer. 20% 4-methylpiperidine in N,N-dimethylformamide (DMF) was used for Fmoc removal, and 1,3-diisopropylcarbodiimide (DIC) / ethyl cyanohydroxyiminoacetate (Oxyma) was used for amino acid coupling. Boc-Tyr(OtBu)-OH was utilized for the final coupling in the sequence. Each residue was coupled with an excess of coupling solution (5.0 equivalents), and each coupling reaction was performed twice at each position. Lysine residues were protected with 4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)-3-methylbutyl (ivDde), and the ivDde group was selectively removed with 2% hydrazine in DMF. The bromoacetyl group was introduced by DIC (10 equiv.) / bromoacetic acid (20 equiv.) in a mixture of methylene chloride and DMF.

[0107] In vitro cAMP assay For GLP-1R agonist activity, peptide- or bispecific molecule-induced cAMP production was measured using a homogeneous time-resolved fluorescence (HTRF) assay (Cisbio, Bedford, MA, catalog number 62AM4PEJ) using CHO cells stably expressing human, mouse, rat, and monkey GLP-1R. Serially diluted peptides or bispecific molecules were incubated with 40,000 cells in assay buffer (0.1% bovine serum albumin, 500 μM 3-isobutyl-1-methylxanthine in F12 medium) at 37°C for 15 minutes. Cells were then lysed with lysis buffer (Cisbio, Bedford, MA) containing cAMP-d2 and cAMP cryptate, and incubated at room temperature for 1 hour before measurement using an Envision plate reader (PerkinElmer, Waltham, MA). cAMP levels were expressed as the fluorescence ratio at 665 / 620 nm.

[0108] For GIPR antagonist activity, cAMP production induced by peptides or bispecific molecules was measured in an HTRF assay using HEK293T cells stably expressing human or monkey GIPR and CHO AMID cells stably expressing mouse GIPR. Serially diluted molecules were incubated with 30,000 cells in assay buffer (0.1% BSA, 500 μM IBMX in F12 medium) for 30 minutes at 37°C before treatment with GIP at a final concentration of 0.05 nM. Cells were incubated for 30 minutes at 37°C and then lysed for 1 hour at room temperature in lysis buffer (Cisbio) containing cAMP-d2 and cAMP cryptate. Fluorescence was measured using an Envision plate reader (PerkinElmer), and cAMP levels are expressed as a 665 / 620 nm ratio.

[0109] Graphs were generated by plotting the concentration of GLP-1, GIP, AMG 133, or AMG 133 surrogate on the x-axis against the mean of duplicate cAMP values ​​with the standard error of the mean on the y-axis. Dose-response curves were then analyzed using a logarithmic, variable slope (4-parameter) GraphPad Prism fit of the agonist or antagonist to the response to calculate both EC50 and IC50 values.

[0110] Bioanalysis and Pharmacokinetics AMG 133 concentrations in mouse and cynomolgus monkey plasma were determined by ELISA methods developed to monitor intact AMG 133 (anti-GIPR Ab bound to the GLP-1 analog peptide) and total AMG 133 (anti-GIPR Ab with or without the GLP-1 analog peptide). The analytical range for both assays was 30 to 2000 ng / mL. Pharmacokinetic parameters were estimated from individual plasma concentration-nominal time data using standard noncompartmental analysis in Phoenix® WinNonlin® (v6.4; Certara, Princeton, NJ).

[0111] Intact AMG 133 ELISA Microtiter plates were passively coated overnight at 4°C with a mouse mAb against human IgG Fc (clone no. 1.35, Amgen Inc.) in phosphate-buffered saline. The coated plates were blocked overnight at 4°C with blocking buffer. Calibration standards were prepared in mouse or monkey plasma (BioIVT, Westbury, NY) at concentrations ranging from 30 to 2,000 ng / mL. After dilution with blocking buffer, standards, controls, and unknown samples were added and incubated at room temperature for approximately 2 hours. After washing, a biotin-conjugated mouse mAb against the free N-terminus of GLP-1 (clone no. 4, Thermo Fisher Scientific) was added and incubated at room temperature for approximately 1 hour. Following an additional wash step, streptavidin-horseradish peroxidase (SAV-HRP) conjugate (R&D Systems, Inc., Minneapolis, MN) was added and incubated at room temperature for approximately 30 minutes. After a final wash step, tetramethylbenzidine peroxidase substrate solution (SeraCare, Milford, MA) was added and incubated at room temperature for approximately 10 minutes. The color reaction was stopped by adding H2SO4, and absorbance values ​​were determined at 450 nm with a reference at 650 nm using a SpectraMax microtiter plate reader (Molecular Devices, San Jose, CA). Sample concentrations were interpolated from a standard curve fit to a four-parameter logistic model using Watson LIMS (v7.4; Thermo Fisher Scientific).

[0112] Total AMG 133 ELISA The total assay followed the same procedure as the intact assay, except for the detection reagent: Detection of AMG 133 in the total assay was achieved using an HRP-conjugated mouse monoclonal antibody against human IgG Fc (clone no. 21.1, Amgen, Inc., CA).

[0113] Example 2 Phase 1 Clinical Trial Details: Clinical Trial Design and Randomization This was a first-in-human, double-blind, randomized, placebo-controlled study in obese participants, consisting of two parts: a single ascending dose (SAD) and a multiple ascending dose (MAD). Three clinical sites in the United States have been conducting this ongoing trial since August 2020. The study (ClinicalTrials.gov, NCT04478708) was conducted in full compliance with the Declaration of Helsinki and the International Council on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICPHA). The study protocol, all amendments, and informed consent forms were reviewed and approved by each site's institutional review board. Written informed consent was obtained by eligible participants prior to any study-related procedures.

[0114] Eligible participants were non-reproductive women and men aged 18 to 65 years with a body mass index (BMI) of 30.0 kg / m² to 40.0 kg / m², an HbA1c of 6.5% or less, and / or a fasting blood glucose level of 125 mg / dL or more. Participants had normal vital signs, 12-lead electrocardiogram results, and laboratory tests at the time of randomization.

[0115] Participants were randomly assigned to receive AMG 133 or placebo in a 3:1 ratio. The SAD evaluated AMG 133 doses ranging from 21 to 840 mg in six cohorts. The MAD evaluated three doses administered every four weeks on days 1, 29, and 57. Sentinel pairs were observed for at least 48 hours before being dosed to the remaining participants if no safety or tolerability concerns were identified by the investigator. Enrollment into the SAD and MAD cohorts was sequential. Subsequent cohorts were dosed after the dosing regimen in the preceding cohort was recommended by the Dose Level Review Team (DLRT) as safe and well-tolerated based on safety and clinical data through at least day 15. Participants received AMG 133 in vials containing 70 mg / ml AMG 133. Placebo was provided as saline in a volume matching the study drug at each dose level. AMG 133 or matching placebo was administered by subcutaneous injection into the abdomen of participants in the morning (fasting state).

[0116] Clinical outcomes Primary endpoints were participant incidence of treatment-emergent adverse events, changes in clinical laboratory safety tests, vital signs, and 12-lead electrocardiograms. Secondary endpoints were AMG 133 pharmacokinetic parameters, including but not limited to, maximum observed drug concentration (Cmax), time to maximum observed concentration (tmax), and area under the concentration-time curve (AUC) during the dosing interval. Exploratory endpoints were pharmacodynamic parameters, including but not limited to, fasting blood glucose concentration, insulin, c-peptide, glucagon, hemoglobin A1c, change in weight, waist circumference, and BMI.

[0117] Statistical analysis of phase 1 trials The sample size of this trial was not based on statistical inference. Because this was an exploratory, first-in-human study with a small sample size, all pharmacokinetic, pharmacodynamic, and safety parameters were analyzed descriptively. Participants who discontinued the study before Day 15 at the SAD or Day 36 at the MAD were replaced to achieve the target number of participants for safety review and data collection; the replaced participant was assigned to receive the same treatment as the discontinued participant. The full analysis set consisted of all randomized participants who received at least one dose of AMG 133. The safety analysis set was the same as the full analysis set. The pharmacokinetic analysis set consisted of all participants who received at least one dose of AMG 133 for whom at least one pharmacokinetic parameter or endpoint could be adequately estimated. Missing data were not entered.

[0118] Inclusion criteria Subjects are eligible for inclusion in the study only if all of the following criteria apply: Subjects provided informed consent prior to the initiation of any study-specific actions / procedures. Age 18 years or older and 65 years or younger at the time of signing informed consent Except for obesity, they are otherwise healthy based on a medical evaluation including medical history, physical examination, laboratory tests, and ECG. BMI is 30.0kg / m2 or more and 40.0kg / m2 or less Had a stable weight (self-reported change of less than 5 kg in the last 8 weeks) before screening Willingness to maintain current general dietary and physical activity regimens, with the exception of physical activity which should not be strenuous for 72 hours prior to each blood sample collection for clinical laboratory analysis. Women are not reproductive Postmenopausal status is defined as being 55 years of age or older and having had no menstrual periods for at least 12 months, or being under 55 years of age and having had no menstrual periods for at least 12 months and having a follicle-stimulating hormone level greater than 40 IU / L. History of hysterectomy History of bilateral oophorectomy

[0119] Exclusion criteria Participants will be excluded from the study if any of the following criteria apply: History or clinical evidence of diabetes mellitus, including HbA1c greater than 6.5% and / or fasting blood glucose greater than or equal to 125 mg (6.9 mmol / L) at screening Triglycerides ≥ 5.65 mmol / L (i.e., 500 mg / dL) at screening Screening calcitonin 50ng / L or higher Liver enzyme aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, or total bilirubin levels greater than 1.5 times the upper limit of normal (ULN) at screening History or clinical evidence of bleeding tendency or any coagulation disorder, including prothrombin time (PT), activated partial thromboplastin time (PTT), international normalized ratio (INR), or platelet count outside the normal reference range of laboratory tests at screening. History of gastrointestinal abnormalities that may affect gastrointestinal motility (including small intestinal or colonic resection, inflammatory bowel disease, irritable bowel disease, and colon or gastrointestinal cancer) Family or personal history of medullary thyroid cancer or multiple endocrine neoplasia type 2, or personal history of non-familial medullary thyroid cancer History of confirmed chronic pancreatitis or idiopathic acute pancreatitis History of gallbladder disease (i.e., cholelithiasis or cholecystitis) not treated with cholecystectomy Untreated or uncontrolled hypothyroidism / hyperthyroidism defined as thyroid-stimulating hormone >6mIU / L or <0.4mIU / L Corrected QT interval (QTc) at screening >450 msec in men or >470 msec in women or a history of long QT syndrome Renal dysfunction or history of renal disease and / or estimated glomerular filtration rate ≤ 60 mL / min / 1.73 m2 Obesity induced by other endocrine disorders (e.g., Cushing's syndrome) Subjects with previous bariatric surgical procedures (excluding liposuction if performed more than one year prior to study enrollment) and / or recent (within six months) or planned bariatric endoscopic procedures History of major depressive disorder, severe mental disorder, or any suicidal behavior Positive results for human immunodeficiency virus antibody, hepatitis B surface antigen, hepatitis B core antibody, or hepatitis C virus RNA Systolic blood pressure ≥ 150mmHg or diastolic blood pressure ≥ 90mmHg at screening Surgery, excluding minor surgical procedures, is scheduled during the study duration History of any type of malignancy other than cervical intraepithelial neoplasia or surgically excised non-melanoma skin cancer occurring more than 5 years prior to randomization

[0120] result PK and PD of AMG 133 in humans A phase 1, randomized, double-blind, placebo-controlled study was conducted to evaluate the safety, tolerability, PK, and PD of single ascending doses (SAD) and multiple ascending doses (MAD) of AMG 133 (NCT04478708). A total of 75 obese adults were enrolled in the study. 49 participants participated in the SAD portion (6 cohorts) and 26 participants participated in the MAD portion (3 cohorts). They received AMG 133 every 4 weeks for 12 weeks (85 days of treatment) and were followed up until Day 207. One participant in the 140 mg SAD cohort and three participants in the 420 mg MAD cohort withdrew consent within the first 29 days of the study (Figure 1). Baseline demographic characteristics are summarized in Table 1. The mean age ranged from 45.7 to 50.2 years in the SAD cohort and from 40.3 to 51.6 years in the MAD cohort. The mean BMI ranged from 32.5 to 34.8 kg / m² in the SAD cohort and from 32.5 to 34.2 kg / m² in the MAD cohort. Participants had no history of diabetes mellitus, and the mean HbA1c ranged from 5.38% to 5.61% in the SAD cohort and from 5.50 to 5.58% in the MAD cohort.

[0121] The pharmacokinetics of AMG 133 appeared dose-proportional across the evaluated dose range of 21 mg to 840 mg. The mean half-life was approximately 14 to 25 days, therefore supporting the administration of AMG 133 every 4 weeks. Treatment with AMG 133 at all dose levels (SAD and MAD) resulted in a mean body weight reduction from baseline (Figure 1). Weight reduction was greatest at the highest dose levels of 840 mg SAD and 420 mg MAD. At the lowest single dose of 21 mg, the mean percent change in body weight from baseline ranged from -1.59% on Day 6 to a maximum reduction of 2.39% on Day 29 after dosing. The highest single dose of 840 mg resulted in a -2.85% change on Day 6 and a maximum reduction of 8.24% on Day 92, suggesting a long-term weight-reducing effect after a single dose of AMG 133. Weight reduction was maintained through Day 150 after all SADs except the lowest dose of 21 mg. The lowest MAD dose of 140 mg reduced body weight from baseline by 1.97% at day 7 after dosing, reaching a maximum reduction of 7.44% after three doses on day 78. The highest MAD dose of 420 mg resulted in a reduction of body weight of 4.86% by day 7 and 14.5% by day 85. Weight loss after repeated doses of AMG 133 was maintained through the end of the study on day 207 in the MAD cohort. Changes in BMI from baseline followed a similar pattern to changes in body weight (Figure 1). Dose-dependent reductions in waist circumference were observed with MAD 140 mg and 420 mg, while MAD 280 mg showed variable changes in waist circumference.

[0122] Changes in pharmacodynamic markers in the MAD cohort are shown in Figure 3. After treatment with 140 and 420 mg AMG 133, fasting blood glucose levels decreased in a dose-responsive manner on days 29 and 85. Lower blood glucose levels were maintained throughout the safety follow-up period (day 127) at the 420 mg dose, while blood glucose levels returned to levels above baseline at the 140 and 280 mg doses. The greatest reduction in glucagon was observed at day 85 with the 280 mg dose but returned by day 127. HbA1c levels, which were within the normal (nondiabetic) range at baseline, decreased in all three dose groups but trended toward baseline at day 127. There was a dose-responsive decrease in hs-CRP from baseline among the MAD cohort. The reduction in hs-CRP levels persisted through day 127 at the 280 and 420 mg doses but returned to baseline at the 140 mg dose.

[0123] Participants tolerated AMG 133 well. No serious TEAEs, TEAEs leading to permanent discontinuation, or serious TEAEs were reported during the study (Tables 3A and 3B). In the SAD cohort, all GI-related TEAEs were mild, except for one participant in the 140 mg cohort who experienced moderate GI symptoms. Reports of dyspepsia were more frequent with treatment at lower doses (70 mg and 140 mg), while nausea and vomiting were reported in participants treated with 70 mg or more of AMG 133. In the MAD cohort, all participants receiving AMG 133 experienced mild nausea and vomiting. No significant changes in blood pressure were observed after either single or multiple doses of AMG 133 (Tables 4A and 4B). Heart rate increased with a single dose of 280, 560, or 840 mg of AMG 133, but not in a dose-dependent manner. In the MAD cohort, the 280 mg cohort had a higher heart rate than the 140 mg or 420 mg cohorts, suggesting that the heart rate changes were not dose-dependent.

[0124] Test Design overall design Part A (Cohorts 1-6 and Cohort 11) is a Phase 1, randomized, double-blind, placebo-controlled SAD study in obese adult subjects. AMG 133 will be administered SC in Cohorts 1-5 and Cohort 11 and IV in Cohort 6. Part A consists of a total of 7 cohorts.

[0125] Subjects will remain in the Clinical Research Unit from check-in (morning of Day -2) until the morning of Day 8 for Cohorts 1-5 and Cohort 11, and until Day 6 for Cohort 6.

[0126] Approximately 56 subjects will be enrolled in one of seven cohorts. In each cohort, eight subjects will be randomized in a 3:1 ratio as described in Table 1 to receive AMG 133 or placebo either SC (Cohorts 1-5 and Cohort 11) or IV (Cohort 6). In Cohort 1, the first two subjects (sentinel pair) will be randomized to receive one AMG 133 and one placebo. The sentinel pair will be observed for at least 48 hours before the remaining subjects in the cohort receive treatment, provided there are no safety or tolerability concerns as assessed by the investigator. Enrollment into the SAD cohorts will be sequential. Subsequent cohorts will be dosed after the dosing regimen in the preceding cohort is recommended as safe and well-tolerated by the Dose Ranking Review Team (DLRT) based on safety and clinical laboratory data through at least Day 15 for at least seven of the eight dosed subjects. Subjects in Cohorts 1-5 and Cohort 11 will also participate in gastric emptying studies on Days -1 and 7.

[0127] Part B (Cohorts 7-10) is a randomized, placebo-controlled, double-blind MAD study in adult subjects with obesity. In each cohort, subjects will be randomized 3:1 to receive AMG 133 or placebo SC, as described in Table 1. Approximately 24 subjects will be enrolled in Cohorts 7-9. Cohorts 7-9 will include assessment of food intake using the Remote Food Photography Method (RFPM). Enrollment in Part B Cohort 7 will occur at a starting MAD dose that is at least two SAD dose steps below that recommended by the DLRT as safe and reasonably tolerated in Part A. Enrollment in MAD Cohorts 8 and 9 will be sequential.

[0128] Subjects in Cohorts 8 and 9 will be dosed after the dosing regimen of the preceding MAD cohort has been recommended by the DLRT as safe and reasonably tolerated based on safety and laboratory data through at least Study Day 36 for six of the eight dosed subjects. The DLRT for SAD Cohort 11 will also make dosing recommendations for Cohort 9. In summary, if the DLRT agrees that the Cohort 11 dose did not raise any safety or tolerability concerns, the recommended dose for Cohort 9 will be 560 mg or less SC Q4W (every 4 weeks). However, if there are safety and tolerability concerns, the DLRM for Cohort 11 may recommend a dose of 420 mg or less SC Q4W for Cohort 9. All subjects in each Part B (MAD) cohort may be dosed on the same day.

[0129] Cohort 10 will enroll up to 20 subjects and will include the use of digital health tools for exploratory assessments of sleep, activity, and weight. The purpose of Cohort 10 is to evaluate whether the digital tools influence subject behavior and have an additional effect on weight beyond IP. Therefore, the recommended dose for Cohort 10 should be the same as the dose tested in previous cohorts.

[0130] The dose recommended for Cohort 10 will depend on the final dose recommended for Cohort 9 and the safety and tolerability profiles of MAD Cohorts 7 and 8. If DLRT in Cohort 7 (≦140 mg SC Q4W) demonstrates an acceptable safety and tolerability profile, the DLTR may recommend an escalating dose for Cohort 8 (≦280 mg SC Q4W). However, if DLRT in Cohort 7 demonstrates safety and tolerability concerns, the DLTR may recommend the dose for Cohort 10 (≦140 mg SC Q4W). In this case, Cohort 10 would be enrolled following Cohort 8. If DLRT in Cohort 8 demonstrates an acceptable safety and tolerability profile, it may be recommended to proceed to Cohort 9. If the dose recommended by the DLRT for Cohort 9 is ≤420 mg SC Q4W, the dose for Cohort 10 will be recommended in the DLRM for Cohort 8, and Cohort 10 will be enrolled in parallel with Cohort 9. If the dose selected for Cohort 9 is ≤560 mg SC Q4W, the DLRT for Cohort 8 can recommend that dose for Cohort 10, and Cohort 10 can be enrolled in parallel with Cohort 9.

[0131] MAD Cohorts 7-9: Study drug will be administered every 4 weeks for a total of three SC doses. Dose levels will be defined after evaluation of available PK and PD data from the preceding cohorts in the SAD phase (Part A). Three different dose levels will be evaluated, with the lowest dose administered to Cohort 7 and two higher escalating doses administered to Cohorts 8 and 9. The dose level for Cohorts 7-9 will not exceed the highest dose evaluated in Cohorts 1-6 and Cohort 11 (Part A). Subjects enrolled in Cohorts 7-9 will also be asked to record their food intake using the RFPM.

[0132] MAD Cohort 10: Up to 20 subjects will be randomized in a 3:1 ratio to receive AMG 133 or placebo SC. All subjects will be asked to use digital health tools, such as a digital scale and activity / sleep tracker (provided by Amgen). Dose tiers will be defined after evaluation of available PK and PD data from the prior MAD cohort. Dose tiers will not exceed the maximum dose evaluated in Cohorts 7 through 9 (Part B).

[0133] Part C (Cohorts 12-13) is an open-label, modified dose-escalation MAD study in subjects with obesity. Approximately 12 subjects (maximum 6 subjects per cohort) will be enrolled in Part C and receive AMG 133 (see Table 1). The doses selected for these cohorts are known to have acceptable safety and tolerability profiles based on DLRT-reviewed data from previous cohorts in Parts A and B and do not exceed the dose levels previously tested in MAD Cohorts 7-9. Cohort 12 will receive 70 mg SC on Days 1 and 8, followed by 420 mg SC on Days 15 and 43. Cohort 13 will receive 70 mg SC on Days 1, 8, 15, and 22, followed by 420 mg SC on Days 29 and 57. Cohorts 12 and 13 will be enrolled in parallel. The DLRT will review safety and laboratory data through at least Day 36.

[0134] [Table 1]

[0135] The overall study design is described by the study scheme in section Error! Reference not found. The assessment items are defined in section Error! Reference not found.

[0136] Number of targets A total of approximately 112 subjects will be enrolled in the study. Approximately 56 subjects will be enrolled in Part A of the study, with 8 subjects in each of 7 cohorts. Approximately 44 subjects will be enrolled in Part B of the study, with 8 subjects in Cohorts 7-9 and up to 20 subjects in Cohort 10. Part C Cohorts 12-13 will enroll up to 12 subjects. Additional subjects may be enrolled if DLRT recommendations are made to expand, replicate, or add cohorts to the study, or if replacement subjects are needed.

[0137] The subject of this clinical study shall be referred to as the "subject."

[0138] Target Swap Subjects who discontinue the study or prematurely discontinue study medication may be replaced at Amgen's discretion in consultation with the investigator. Replacement subjects will be assigned to receive the same treatment as the replaced subject.

[0139] Number of facilities Approximately 1-3 investigational sites in the U.S. will be included in the trial. Sites that do not enroll subjects within one month of site opening may be closed.

[0140] Rationale for investigational drug dosage The planned cohorts in this extension of the study consist of repeat-dose cohorts following a dose-adjustment scheme.

[0141] Previously, subjects in Part A received single doses of 21, 70, 140, 280, 560, and 840 mg of AMG 133 administered SC. This part also consisted of an IV cohort (Cohort 6) at the 70 mg dose administered IV; all SADs were completed. The starting dose and exposure multiple for the doses evaluated in the SAD were calculated based on the NOAEL determined in a 13-week good laboratory practice repeated-dose mouse and cynomolgus monkey non-human primate toxicity study (dosing every 2 weeks; Section Error! Reference source not found) and the weight loss observed in a chronic efficacy study in obese cynomolgus monkeys.

[0142] Part B consisted of evaluation of AMG 133 after repeated doses of 140, 280, and 420 mg administered Q4W for a total of 3 doses per cohort. Preliminary review of PK data in the FIH SAD and MAD parts of the study demonstrated that AMG 133 pharmacokinetics followed linear, dose-proportional kinetics based on Cmax (area under the curve [AUC] data pending), with a half-life of approximately 15 to 20 days.

[0143] No serious adverse events or deaths were reported in SAD cohorts 1-6 and 11, and the majority of reported adverse events were mild, related to nausea, vomiting, and dyspepsia. One subject in cohort 3 (140 mg dose) had a moderate adverse event related to IP-associated gastroenteritis. Approximately 90% of subjects enrolled in MAD cohorts 7-10 reported mild GI-related adverse events (primarily nausea, vomiting, and diarrhea) after the first dose of AMG 133, and fewer than 5% experienced GI-related adverse events after the second dose. No serious adverse events or deaths were reported after either dose. Approximately 26% of subjects in the MAD study discontinued the study before receiving the second dose, raising concerns about the tolerability of the first dose; 50% of subjects in cohort 9 withdrew consent after receiving the 420 mg dose on Day 1 due to GI-related adverse events. Dosages were selected to allow for an overall integer injection volume to avoid any possible dosing errors.

[0144] Part C consists of two cohorts (Cohorts 12 and 13), both open-label, evaluating dose escalation from 70 mg to 420 mg. The objective of Part C is to evaluate the effect of the first dose of AMG 133 on GI-related adverse events using an escalation method. Cohort 12 will start with a lower dose (70 mg) of AMG 133 given weekly in two doses to build exposure levels before receiving repeat doses of 420 mg on days 15 and 43.

[0145] Cohort 13 will start on a lower dose (70 mg) of AMG 133 given weekly for four doses to build exposure levels before receiving repeat doses of 420 mg on days 29 and 57.

[0146] The rationale for dose selection in Part C is based on available PK data from Cohorts 1-11 (Parts A and B) of this ongoing FIH study and the NOAEL exposure established based on a 13-week GLP repeat-dose study in mice and cynomolgus monkeys.

[0147] Similarly, in Cohort 12, the predicted human exposure fold of intact AMG 133 after the second dose of 420 mg on Day 43 is approximately 40.5-fold and 45-fold for Cmax and AUCss, respectively, based on the NOAEL established in cynomolgus monkeys, and 43-fold and 42.4-fold for Cmax and AUCss, respectively, based on the NOAEL established in mice. The predicted human exposure fold of total AMG 133 after the second dose of 420 mg on Day 43 is approximately 45-fold and 49-fold for Cmax and AUCss, respectively, based on the NOAEL established in cynomolgus monkeys, and 54-fold and 42-fold for Cmax and AUCss, respectively, based on the NOAEL established in mice (Tables 2 and 3).

[0148] In Cohort 13, the predicted human exposure fold of intact AMG 133 after the second dose of 420 mg on Day 57 is approximately 39-fold and 43.2-fold for Cmax and AUCss, respectively, based on the NOAEL established in cynomolgus monkeys, and 41.3-fold and 40.6-fold for Cmax and AUCss, respectively, based on the NOAEL established in mice. The predicted human exposure fold of total AMG 133 after the second dose of 420 mg on Day 57 is approximately 42.2-fold and 45.5-fold for Cmax and AUCss, respectively, based on the NOAEL established in cynomolgus monkeys, and 50.9-fold and 47.5-fold for Cmax and AUCss, respectively, based on the NOAEL established in mice (Tables 2 and 3).

[0149] [Table 2]

[0150] AUC = area under the concentration-time curve; AUClast = area under the concentration-time curve during the last dosing interval; AUC0-28 = area under the concentration-time curve during the dosing interval defined herein from time 0 to 28 days after the second dose; Cmax = maximum observed drug concentration during the dosing interval defined herein after the second dose; FIH = first-in-human dose; NOAEL = no-observed-adverse-effect level; PK = pharmacokinetics; SC = subcutaneous; Q4W = every 4 weeks.

[0151] aPK data from the AMG 133 FIH study will be used for PK prediction. b After the last dose after 13 weeks of treatment (total of 7 doses) at the NOAEL dose of 150 mg / kg in mice (Study 150238); the mean AUClast (AUC0~68hrs) of intact AMG 133 is 188 000 μg hr / mL, and the mean Cmax is 1590 mg / mL. c After the last dose after 13 weeks of treatment (7 doses total) at the NOAEL dose of 120 mg / kg in cynomolgus monkeys (Study 150239); the mean AUClast (AUC0~168 hrs) of intact AMG 133 was 200 000 μg hr / mL, and the mean Cmax was 1500 mg / mL. d AUC exposure fold = AUClast × 4 after 13 weeks (7 doses) of AMG 133 administration in mice or monkeys / ratio of predicted AUC0–28 in humans after the second dose. e Cmax fold = ratio of Cmax after the last dose after 13 weeks (7 doses) of AMG 133 in mice or monkeys to the predicted Cmax of each single human dose. fActual dose tiering will be based on available data from previous cohorts. Source:Report 153788

[0152] [Table 3]

[0153] AUC = area under the concentration-time curve; AUC0-28 = area under the concentration-time curve during the dosing interval defined herein from 0 to 28 days after the second dose; Cmax = maximum observed drug concentration during the dosing interval defined herein after the second dose; FIH = first-in-human dose; NOAEL = no-observed-adverse-effect level; PK = pharmacokinetics; SC = subcutaneous; Q4W = every 4 weeks. a PK data from the AMG133 FIH study will be used for PK prediction b After the last dose after 13 weeks of treatment (total of 7 doses) at the NOAEL dose of 150 mg / kg in mice (Study 150238); total AMG 133 had a mean AUClast (AUC0~168hrs) of 291000 μg hr / mL and a mean Cmax of 2360 mg / mL. c After the last dose after 13 weeks of treatment (7 doses total) at the NOAEL dose of 120 mg / kg in cynomolgus monkeys (Study 150239); total AMG 133 had a mean AUClast (AUC0~168 hrs) of 279000 μg hr / mL and a mean Cmax of 1960 mg / mL. d AUC exposure fold = ratio of AUClast × 4 after 13 weeks (7 doses) of AMG 133 administration in mice or monkeys / predicted (AUC0–28 days) after the second dose in humans. e Cmax fold = ratio of Cmax after the last dose after 13 weeks (7 doses) of AMG 133 in mice or monkeys to the predicted Cmax for each single human dose. fActual dose tiering will be based on available data from previous cohorts.

[0154] Definition of Exam Completion Primary End: The primary end date is defined as the date the last subject was evaluated or received the intervention for the final collection of data on the primary endpoint.

[0155] If the study is completed before the primary completion date originally planned in the protocol (i.e., early termination of the study), primary completion will be the date on which the last subject is evaluated or receives the intervention for evaluation in the study (i.e., the last subject's final visit).

[0156] End of Study: The end of study (EOS) is defined as the date the last subject across all centers was evaluated or received the intervention for evaluation in the study (i.e., last subject's final visit), if applicable, after any additional parts of the study (e.g., long-term follow-up, additional antibody testing).

[0157] Example 3 Phase 2 trial overall design This is a Phase 2, randomized, double-blind, dose-ranging, placebo-controlled study to evaluate the efficacy, safety, and tolerability of AMG 133 in adult subjects with overweight or obesity, with or without diabetes mellitus. Cohort A consists of subjects without a diagnosis of type 1 or type 2 diabetes mellitus, and Cohort B consists of subjects with a diagnosis of type 2 diabetes mellitus. Potential subjects will be screened within approximately 28 days prior to Day 1 to assess their eligibility for enrollment in the study. The study will include two parts:

[0158] Part 1 All subjects randomized into the study (Cohort A and Cohort B) will begin the Part 1 portion of the study.

[0159] Subjects in Cohort A will be randomized on Day 1 in a 3:3:3:2:2:2:3 ratio to receive AMG 133 140, 280, or 420 mg every 4 weeks (Q4W), or 420 mg every 8 weeks (Q8W) (all without dose escalation), 420 mg Q4W with 4- or 12-week dose escalation, or placebo, respectively.

[0160] Cohort B subjects will be randomized in a 1:1:1:1 ratio on Day 1 to receive AMG 133 140, 280, or 420 mg Q4W (all without dose escalation), or placebo, respectively.

[0161] Subjects will be stratified by sex. In Cohort A, women will be capped at 70%. For both Cohorts A and B, the study will attempt to enroll approximately 10% of subjects who have previously been treated with glucagon-like peptide 1 (GLP-1) receptor agonists for weight management and who have discontinued such treatment at least 90 days prior to screening.

[0162] The treatment period in Part 1 continues through Week 52, with the final dose of AMG 133 / placebo administered at the Week 48 visit. At the Week 52 visit, subjects have the option to begin Part 2 if they meet the entry criteria. Subjects who do not meet the entry criteria for Part 2 will proceed to the Safety Follow-Up / End-of-Study visit 16 weeks (+7 days) after the last dose of AMG 133 / placebo or 12 weeks (+7 days) after the Week 52 visit.

[0163] Part 2 Part 2 is optional, and subjects must provide informed consent before beginning any Part 2 study-specific activities / procedures. Subjects may enter Part 2 only if they have completed dosing through Week 48 of Part 1 and have lost at least 15% of their body weight from baseline (Day 1) to Week 52, using the same units (either kg or lb) for both measures using the following formula: % weight loss = ([baseline weight - week 52 weight] / baseline weight) x 100

[0164] In Part 2, subjects will be re-randomized in a double-blind manner to a new Part 2 treatment arm based on their treatment assignment in Part 1. Arm 1 subjects will receive placebo in Part 2. Arm 2 subjects will be re-randomized in a 1:1 allocation ratio to either placebo or AMG 133 70 mg Q4W. Arm 3 subjects will be re-randomized in a 2:3:3:2 ratio to receive placebo, AMG 133 140 mg Q4W, 420 mg Q4W, or AMG 133 420 mg Q12W, respectively.

[0165] For subjects entering Part 2 of the study, treatment with AMG 133 / placebo at the newly assigned Part 2 dose will continue from Week 52 through Week 104, with a safety follow-up / end-of-study visit 12 weeks (+7 days) after the Week 104 visit.

[0166] The primary analysis will be performed at week 52, with a management interim analysis planned at week 24. Management interim analyses may be performed throughout the study to inform strategic considerations, but the study team will remain blinded to treatment assignment for analyses performed before the primary analysis.

[0167] Phase 2 Treatment Overview: Part 1 Subjects in the non-escalation treatment group in Cohort A will receive AMG 133 140, 280, or 420 mg or placebo administered subcutaneously (SC) Q4W, or AMG 133 420 mg Q8W for 52 weeks (last dose at Week 48). In addition, two separate dose escalation regimens will be evaluated at the 420 mg dose in Cohort A only.

[0168] Subjects in the 420 mg 4-week dose-escalation arm will receive AMG 133 70 mg SC on Days 1 and 2 and 420 mg Q4W from Weeks 4 through 48. Subjects in the 420 mg 12-week dose-escalation arm will receive 70 mg SC on Day 1, 140 mg on Week 4, 280 mg on Week 8, and 420 mg Q4W from Weeks 12 through 48. To ensure blinding, subjects in Cohort A assigned to the AMG 133 arm who are by design not to receive AMG 133 at the administration visits in the Schedule of Activities (Section 1.3) will receive placebo at those visits. Subjects in Cohort B will receive AMG 133 140, 280, or 420 mg SC Q4W or placebo for 52 weeks (last dose at Week 48).

[0169] Part 2 Subjects in group 1 will receive placebo administered SC Q4W, subjects in group 2 will receive either placebo or AMG 133 70 mg administered SC Q4W, and subjects in group 3 will receive either placebo administered SC Q4W, AMG 133 140 or 420 mg administered SC Q4W, or AMG 133 420 mg administered SC Q12W.

Claims

1. 1. A method of treating obesity in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising an antagonistic anti-GIPR antibody conjugated to a GLP-1R agonist at a dose of about 21 mg to about 840 mg every 4 weeks, at a dose of about 21 mg to about 840 mg every 6 weeks, at a dose of about 21 mg to about 840 mg every 8 weeks, or at a dose of about 21 mg to about 840 mg every 12 weeks.

2. 10. The method of claim 1, wherein the dosage is about 21 mg, about 70 mg, about 140 mg, about 280 mg, about 420 mg, about 560 mg, or about 840 mg every 4 weeks; about 21 mg, about 70 mg, about 140 mg, about 280 mg, about 420 mg, about 560 mg, or about 840 mg every 6 weeks; about 21 mg, about 70 mg, about 140 mg, about 280 mg, about 420 mg, about 560 mg, or about 840 mg every 8 weeks, or about 21 mg, about 70 mg, about 140 mg, about 280 mg, about 420 mg, about 560 mg, or about 840 mg every 12 weeks.

3. 10. The method of claim 1, wherein the dosage is about 280 mg every 4 weeks; about 280 mg every 6 weeks, about 280 mg every 8 weeks, or about 280 mg every 12 weeks.

4. 10. The method of claim 1, wherein the dosage is about 280 mg every four weeks.

5. 10. The method of claim 1, wherein the dosage is about 420 mg every 4 weeks; about 420 mg every 6 weeks, about 420 mg every 8 weeks, or about 420 mg every 12 weeks.

6. 10. The method of claim 1, wherein the dosage is about 420 mg every four weeks.

7. The method of any one of claims 1 to 6, wherein the pharmaceutical composition is administered once every four weeks.

8. The method of any one of claims 1 to 7, wherein the composition is administered parenterally.

9. 9. The method of claim 8, wherein the parenteral administration is subcutaneous administration.

10. The method of any one of claims 1 to 9, wherein the pharmaceutical composition is administered to the patient by a syringe pre-filled with the pharmaceutical composition.

11. The method of any one of claims 1 to 9, wherein the pharmaceutical composition is administered to the patient by autoinjector.

12. The method of any one of claims 1 to 9, wherein administration of the pharmaceutical composition causes substantially no adverse side effects in the patient.

13. 13. The method of any one of claims 1 to 12, wherein the patient has a body mass index ("BMI") greater than 30 kg / m2, 35 kg / m2, or 40 kg / m2.

14. The method of any one of claims 1 to 13, wherein the subject has or has been diagnosed with diabetes.

15. The method of any one of claims 1 to 14, wherein the patient has not previously undergone therapy for obesity.

16. The method of any one of claims 1 to 15, wherein the anti-GIPR antibody comprises a CDRH1 comprising the amino acid sequence of SEQ ID NO: 5, a CDRH2 comprising the amino acid sequence of SEQ ID NO: 6, a CDRH3 comprising the amino acid sequence of SEQ ID NO: 7, a CDRL1 comprising the amino acid sequence of SEQ ID NO: 8, a CDRL2 comprising the amino acid sequence of SEQ ID NO: 9, and a CDRL3 comprising the amino acid sequence of SEQ ID NO:

10.

17. The method of any one of claims 1 to 16, wherein the antagonistic anti-GIPR antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 1 and a light chain comprising the amino acid sequence of SEQ ID NO:

2.

18. The method of any one of claims 1 to 17, wherein the GLP-1R agonist comprises the amino acid sequence of SEQ ID NO:

3.

19. The method of any one of claims 1 to 18, wherein the antagonistic anti-GIPR antibody is linked to the GLP-1R agonist via a peptide linker comprising SEQ ID NO:

4.

20. The method of any one of claims 1 to 19, wherein the pharmaceutical composition further comprises a buffering agent.

21. 21. The method of claim 20, wherein the buffer is an acetate buffer.

22. The method of any one of claims 1 to 21, wherein the pharmaceutical composition further comprises a surfactant.

23. 23. The method of claim 22, wherein the surfactant is polysorbate 20 or polysorbate 80.

24. The method of any one of claims 1 to 23, wherein the pharmaceutical composition further comprises a stabilizer.

25. 25. The method of claim 24, wherein the stabilizer is sucrose.

26. 1. Use of an antagonistic anti-GIPR antibody conjugated to a GLP-1R agonist for the preparation of a medicament for treating obesity in a patient in need thereof, wherein the medicament is formulated for administration at a dose of about 21 mg to about 840 mg every 4 weeks, about 21 mg to about 840 mg every 6 weeks, about 21 mg to about 840 mg every 8 weeks, or about 21 mg to about 840 mg every 12 weeks.

27. 1. Use of an antagonistic anti-GIPR antibody conjugated to a GLP-1R agonist for the preparation of a medicament for the treatment of obesity in a patient in need thereof, wherein the medicament is formulated for administration at a dosage of about 21 mg, about 70 mg, about 140 mg, about 280 mg, about 420 mg, about 560 mg, or about 840 mg every 4 weeks; about 21 mg, about 70 mg, about 140 mg, about 280 mg, about 420 mg, about 560 mg, or about 840 mg every 6 weeks; about 21 mg, about 70 mg, about 140 mg, about 280 mg, about 420 mg, about 560 mg, or about 840 mg every 8 weeks, or about 21 mg, about 70 mg, about 140 mg, about 280 mg, about 420 mg, about 560 mg, or about 840 mg every 12 weeks.

28. 28. The use of claim 26 or 27, wherein the dosage is about 280 mg every 4 weeks; about 280 mg every 6 weeks, about 280 mg every 8 weeks, or about 280 mg every 12 weeks.

29. The use according to any one of claims 26 to 28, wherein the medicament is formulated for administration once every four weeks.

30. 28. The use of claim 26 or 27, wherein the dosage is about 420 mg every 4 weeks; about 420 mg every 6 weeks, about 420 mg every 8 weeks, or about 420 mg every 12 weeks.

31. 31. The use of any one of claims 26, 27 or 30, wherein the medicament is formulated for administration once every four weeks.

32. The use according to any one of claims 26 to 31, wherein the medicament is formulated for parenteral administration.

33. 33. The use according to claim 32, wherein the parenteral administration is subcutaneous administration.

34. The use according to any one of claims 26 to 33, wherein the medicament is formulated for administration by syringe.

35. The use according to any one of claims 26 to 34, wherein the medicament is formulated for administration by autoinjector.

36. 36. The use of any one of claims 26 to 35, wherein the patient has a body mass index ("BMI") of greater than 30 kg / m2, 35 kg / m2, or 40 kg / m2.

37. 37. The use according to any one of claims 26 to 36, wherein the medicament causes substantially no adverse side effects in the patient.

38. The use according to any one of claims 26 to 37, wherein the patient has or has been diagnosed with diabetes.

39. The use of any one of claims 26 to 38, wherein the patient has not previously undergone therapy for obesity.

40. The use of any one of claims 26 to 39, wherein the anti-GIPR antibody comprises a CDRH1 comprising the amino acid sequence of SEQ ID NO: 5, a CDRH2 comprising the amino acid sequence of SEQ ID NO: 6, a CDRH3 comprising the amino acid sequence of SEQ ID NO: 7, a CDRL1 comprising the amino acid sequence of SEQ ID NO: 8, a CDRL2 comprising the amino acid sequence of SEQ ID NO: 9, and a CDRL3 comprising the amino acid sequence of SEQ ID NO:

10.

41. The use according to any one of claims 26 to 40, wherein the antagonistic anti-GIPR antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 1 and a light chain comprising the amino acid sequence of SEQ ID NO:

2.

42. The use according to any one of claims 26 to 41, wherein the GLP-1R agonist comprises the amino acid sequence of SEQ ID NO:

3.

43. The use according to any one of claims 26 to 42, wherein the antagonistic anti-GIPR antibody is linked to the GLP-1R agonist via a peptide linker comprising SEQ ID NO:

4.

44. The use according to any one of claims 26 to 43, wherein the pharmaceutical composition further comprises a buffering agent.

45. 45. The use of claim 44, wherein the buffer is an acetate buffer.

46. The use according to any one of claims 26 to 45, wherein the pharmaceutical composition further comprises a surfactant.

47. 47. The use of claim 46, wherein the surfactant is polysorbate 20 or polysorbate 80.

48. The use according to any one of claims 26 to 47, wherein the pharmaceutical composition further comprises a stabilizer.

49. 49. The use of claim 48, wherein the stabilizer is sucrose.

50. 1. A method of treating obesity in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising an antagonistic anti-GIPR antibody conjugated to a GLP-1R agonist at a dose of about 21 mg, about 70 mg, about 140 mg, about 280 mg, about 420 mg, about 560 mg, or about 840 mg every 4 weeks; about 21 mg, about 70 mg, about 140 mg, about 280 mg, about 420 mg, about 560 mg, or about 840 mg every 6 weeks; about 21 mg, about 70 mg, about 140 mg, about 280 mg, about 420 mg, about 560 mg, or about 840 mg every 8 weeks, or about 21 mg, about 70 mg, about 140 mg, about 280 mg, about 420 mg, about 560 mg, or about 840 mg every 12 weeks, the anti-GIPR antibody comprises a CDRH1 comprising the amino acid sequence of SEQ ID NO:5, a CDRH2 comprising the amino acid sequence of SEQ ID NO:6, a CDRH3 comprising the amino acid sequence of SEQ ID NO:7, a CDRL1 comprising the amino acid sequence of SEQ ID NO:8, a CDRL2 comprising the amino acid sequence of SEQ ID NO:9, and a CDRL3 comprising the amino acid sequence of SEQ ID NO:10; and The method, wherein the GLP-1R agonist comprises the amino acid sequence of SEQ ID NO:

3.

51. 51. The method of claim 50, wherein the dosage is about 280 mg every 4 weeks, about 280 mg every 6 weeks, about 280 mg every 8 weeks, or about 280 mg every 12 weeks.

52. 51. The method of claim 50, wherein the dosage is about 280 mg every four weeks.

53. 51. The method of claim 50, wherein the dosage is about 420 mg every 4 weeks, about 420 mg every 6 weeks, about 420 mg every 8 weeks, or about 420 mg every 12 weeks.

54. 51. The method of claim 50, wherein the dosage is about 420 mg every four weeks.

55. 55. The method of any one of claims 50 to 54, wherein the pharmaceutical composition is administered once every four weeks.

56. 56. The method of any one of claims 50 to 55, wherein the pharmaceutical composition is administered parenterally.

57. 58. The method of claim 57, wherein the parenteral administration is subcutaneous administration.

58. 58. The method of any one of claims 50 to 57, wherein the pharmaceutical composition is administered to the patient by a syringe pre-filled with the pharmaceutical composition.

59. 58. The method of any one of claims 50 to 57, wherein the pharmaceutical composition is administered to the patient by autoinjector.

60. 58. The method of any one of claims 50 to 57, wherein administration of the pharmaceutical composition causes substantially no adverse side effects in the patient.

61. 61. The method of any one of claims 50-60, wherein the patient has a body mass index ("BMI") greater than 30 kg / m2, 35 kg / m2, or 40 kg / m2.

62. 62. The method of any one of claims 50 to 61, wherein the patient has or has been diagnosed with diabetes.

63. 63. The method of any one of claims 50 to 62, wherein the patient has not previously undergone therapy for obesity.

64. The method of any one of claims 50 to 63, wherein the antagonistic anti-GIPR antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 1 and a light chain comprising the amino acid sequence of SEQ ID NO:

2.

65. 65. The method of any one of claims 50 to 64, wherein the antagonistic anti-GIPR antibody is linked to the GLP-1R agonist via a peptide linker comprising SEQ ID NO:

4.

66. 66. The method of any one of claims 50 to 65, wherein the pharmaceutical composition further comprises a buffering agent.

67. 67. The method of claim 66, wherein the buffer is an acetate buffer.

68. 68. The method of any one of claims 50 to 67, wherein the pharmaceutical composition further comprises a surfactant.

69. 69. The method of claim 68, wherein the surfactant is polysorbate 20 or polysorbate 80.

70. 70. The method of any one of claims 1 to 69, wherein the pharmaceutical composition further comprises a stabilizer.

71. 71. The method of claim 70, wherein the stabilizer is sucrose.

72. 1. Use of an antagonistic anti-GIPR antibody conjugated to a GLP-1R agonist for the preparation of a medicament for treating obesity in a patient in need thereof, wherein the medicament is formulated for administration at a dosage of about 21 mg, about 70 mg, about 140 mg, about 280 mg, about 420 mg, about 560 mg, or about 840 mg every 4 weeks; about 21 mg, about 70 mg, about 140 mg, about 280 mg, about 420 mg, about 560 mg, or about 840 mg every 6 weeks; about 21 mg, about 70 mg, about 140 mg, about 280 mg, about 420 mg, about 560 mg, or about 840 mg every 8 weeks; or about 21 mg, about 70 mg, about 140 mg, about 280 mg, about 420 mg, about 560 mg, or about 840 mg every 12 weeks, the anti-GIPR antibody comprises a CDRH1 comprising the amino acid sequence of SEQ ID NO:5, a CDRH2 comprising the amino acid sequence of SEQ ID NO:6, a CDRH3 comprising the amino acid sequence of SEQ ID NO:7, a CDRL1 comprising the amino acid sequence of SEQ ID NO:8, a CDRL2 comprising the amino acid sequence of SEQ ID NO:9, and a CDRL3 comprising the amino acid sequence of SEQ ID NO:10; and The GLP-1R agonist comprises the amino acid sequence of SEQ ID NO:

3.

73. 73. The use of claim 72, wherein the dosage is about 280 mg every 4 weeks, about 280 mg every 6 weeks, about 280 mg every 8 weeks, or about 280 mg every 12 weeks.

74. 74. The use of claim 72 or 73, wherein the medicament is formulated for administration once every four weeks.

75. 74. The use of claim 72 or 73, wherein the dosage is about 420 mg every 4 weeks, about 420 mg every 6 weeks, about 420 mg every 8 weeks, or about 420 mg every 12 weeks.

76. 76. The use of claim 75, wherein the medicament is formulated for administration once every four weeks.

77. 77. The use according to any one of claims 72 to 76, wherein the medicament is formulated for parenteral administration.

78. 78. The use of claim 77, wherein the parenteral administration is subcutaneous administration.

79. 79. The use according to any one of claims 72 to 78, wherein the medicament is formulated for administration by syringe.

80. 80. The use of any one of claims 72 to 79, wherein the medicament is formulated for administration by autoinjector.

81. 81. The use of any one of claims 72 to 80, wherein the patient has a body mass index ("BMI") of greater than 30 kg / m2, 35 kg / m2, or 40 kg / m2.

82. 82. The use of any one of claims 72 to 81, wherein the medicament causes substantially no adverse side effects in the patient.

83. 83. The use of any one of claims 72 to 82, wherein the patient has or has been diagnosed with diabetes.

84. 84. The use of any one of claims 72 to 83, wherein the patient has not previously undergone therapy for obesity.

85. The method of any one of claims 72 to 84, wherein the antagonistic anti-GIPR antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 1 and a light chain comprising the amino acid sequence of SEQ ID NO:

2.

86. 86. The method of any one of claims 72 to 85, wherein the antagonistic anti-GIPR antibody is linked to the GLP-1R agonist via a peptide linker comprising SEQ ID NO:

4.

87. 87. The method of any one of claims 72 to 86, wherein the pharmaceutical composition further comprises a buffering agent.

88. 88. The method of claim 87, wherein the buffer is an acetate buffer.

89. 89. The method of any one of claims 72 to 88, wherein the pharmaceutical composition further comprises a surfactant.

90. 90. The method of claim 89, wherein the surfactant is polysorbate 20 or polysorbate 80.

91. 91. The method of any one of claims 72 to 90, wherein the pharmaceutical composition further comprises a stabilizer.

92. 92. The method of claim 91, wherein the stabilizer is sucrose.

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