Compositions and methods for treating postural orthostatic tachycardia syndrome

Abstract

The present invention provides compositions and methods for treating postural orthostatic tachycardia syndrome (POTS). In some embodiments, POTS is associated with hypermobility spectrum disorder / hypermobility Ehlers-Danlos syndrome (HSD / hEDS). In various embodiments, the invention relates to administering to a patient in need thereof a composition comprising an effective amount of a molecular antagonist of glucose-dependent insulinotropic polypeptide (GIP). In various embodiments, the molecular antagonist can be provided in a convenient self-administered form or, in other embodiments, administered at a predetermined frequency to prevent or reduce POTS symptoms at the onset of symptoms or after meals.

Description

【Technical Field】 【0001】 The present disclosure provides compositions and methods for treating postural orthostatic tachycardia syndrome (POTS) and related symptoms. 【0002】 Cross - Reference to Related Applications This application claims the benefit of U.S. Provisional Application No. 63 / 349,630, filed on June 7, 2022, the entire content of which is incorporated herein by reference. 【0003】 Description of Electronically Submitted Text File This application contains an XML - formatted sequence listing that is submitted electronically herewith through Patent Center. The content of the XML copy, created on May 30, 2023, is named "NMT - 039PC_116031 - 5039.xml" and is 21,646 bytes in size. This sequence listing is hereby incorporated by reference in its entirety into this specification. 【Background Art】 【0004】 Postural orthostatic tachycardia syndrome (POTS) refers to a condition that affects blood flow and affects approximately 3 million young men and women in the United States. POTS is a form of autonomic neuropathy - a disorder of the autonomic nervous system that controls and regulates important body functions. POTS is characterized by various symptoms including dizziness, fainting, and a sudden increase in heart rate upon standing. POTS is also associated with various gastrointestinal symptoms, and a carbohydrate - rich diet may exacerbate the symptoms. POTS is sometimes treated or controlled by medications such as salt tablets, fludrocortisone, pyridostigmine, midodrine, and / or beta - blockers, but in other cases, disease management tools include thigh - high compression stockings and close management of diet and health status. 【0005】 There is a need for pharmaceutical compositions and methods for treating POTS and related conditions, including treatments that reduce or prevent the symptoms of the condition. 【BRIEF DESCRIPTION OF THE INVENTION】 【0006】 The present invention provides compositions and methods for treating postural orthostatic tachycardia syndrome (POTS), including mild, moderate, or severe POTS. In some embodiments, POTS is associated with hypermobility spectrum disorder / hypermobile Ehlers-Danlos syndrome (HSD / hEDS). In various embodiments, the present invention relates to administering to a patient in need thereof a composition comprising an effective amount of a molecular antagonist of glucose-dependent insulinotropic polypeptide (GIP). In various embodiments, the molecular antagonist can be provided in a convenient form for self-administration at the onset of symptoms, or to prevent or reduce postprandial POTS symptoms, or in other embodiments, provided for administration at a predetermined frequency (e.g., approximately once a day or once a week). Further, in some embodiments, the compositions described herein reduce pre-syncopal symptoms associated with POTS. 【0007】 According to the present disclosure, a composition comprising a molecular antagonist of GIP is administered to prevent or reduce symptoms associated with POTS. For example, in some embodiments, the compositions and methods reduce chronic pre-syncopal symptoms associated with POTS, such as those selected from dizziness, orthostatic tachycardia, mental confusion, blurred vision, shortness of breath, tachycardia, tremors, chest discomfort, headache, nausea, and dizziness. In some embodiments, administering the composition can result in control and / or increase of stroke volume upon standing, and / or decrease of norepinephrine and / or epinephrine levels upon standing, and / or control of visceral circulation. In some embodiments, administering or using the compositions described herein can result in control and / or reduction of plasma levels of GIP. 【0008】 POTS is a circulatory disorder characterized by two factors: (1) a specific group of symptoms that frequently occur when standing upright, and (2) an increase in heart rate from lying down to standing up, measured during the first 10 minutes of standing, of at least 30 beats per minute in adults or at least 40 beats per minute in adolescents. Symptoms of POTS include, but are not limited to, dizziness, orthostatic tachycardia, mental confusion, blurred vision, shortness of breath, tachycardia, tremors, chest discomfort, headache, nausea, and dizziness. 【0009】 In people with POTS, the blood vessels do not respond efficiently to signals of constriction. As a result, the longer the individual stands upright, the more blood pools in the lower body. This can cause, for example, insufficient blood to return to the brain, resulting in dizziness (fainting), brain fog, and / or fatigue. The nervous system continues to release epinephrine and norepinephrine, constricting the blood vessels, which can further increase the heart rate and cause tremors, strong heartbeats or palpitations, and chest pain. Some individuals with POTS develop low blood pressure when standing for an extended period. Other individuals develop an increase in blood pressure when standing. The symptoms of POTS can sometimes worsen when the subject is in a warm environment, or in situations involving many standing positions, or when fluid and salt intake are insufficient. 【0010】 According to an embodiment, a patient may exhibit mild and / or rare or sporadic POTS symptoms, or may exhibit moderate POTS symptoms, or the patient may exhibit severe and incomplete symptoms. 【0011】 In various embodiments, the subject may have one or more of neuropathic POTS, hyperadrenergic POTS, hypovolemic POTS, and secondary POTS. Neuropathic POTS is associated with damage to small fiber nerves (small fiber neuropathy). These nerves control the constriction of blood vessels in the limbs and abdomen. Hyperadrenergic POTS is associated with increased levels of the stress hormone norepinephrine. Hypovolemic POTS is associated with an abnormally low amount of blood (hypovolemia). Secondary POTS is associated with another condition known to potentially cause an autonomic disorder such as diabetes, Lyme disease, or an autoimmune disease (such as lupus (SLE) or Sjogren's syndrome). 【0012】 In embodiments, a patient with POTS may have an associated condition such as Ehlers-Danlos syndrome. Ehlers-Danlos syndrome is a group of hereditary disorders that affect connective tissue - mainly the skin, joints, and blood vessel walls. A more severe form of the disorder, called vascular Ehlers-Danlos syndrome, can cause rupture of the blood vessels, intestine, or uterine wall. In some embodiments, the subject may be a subject having hypermobility spectrum disorder / hypermobile Ehlers-Danlos syndrome (HSD / hED) (e.g., type III) and may have an associated functional gastrointestinal disorder. For example, the subject may have gastrointestinal symptoms such as dysphagia, reflux, nausea, abdominal pain, and abdominal distension. 【0013】 GIP is an insulinotropic peptide released from intestinal K cells during the postprandial period. As an incretin, GIP stimulates pancreatic beta cells in response to feeding, thereby stimulating insulin secretion. GIP, also designated GIP(1-42) (SEQ ID NO: 1), circulates primarily as a 42-amino acid polypeptide, but also exists as a form lacking the first two N-terminal amino acids (GIP(3-42)). GIP functions by binding to its cognate receptor (GIPR) found on the surface of target cells. GIPR is a member of the glucagon-secretin family of G protein-coupled receptors (GPCRs) with seven transmembrane domains. Endogenous GIP(1-42) and derivatives bind to GIPR with high affinity and possess agonist properties. GIP receptors are described, for example, in Pujadas G. and Drucker DJ, Vascular Biology of Glucagon Receptor Superfamily Peptides: Mechanistic and Clinical Relevance, Endocrine Reviews, Volume 37, Issue 6, (2016). 【0014】 In embodiments, to prevent or reduce postprandial POTS symptoms, administration of the molecular antagonist occurs before, or simultaneously with, food intake and may in some cases occur immediately prior to food intake. For example, in these embodiments, administration of the molecular antagonist occurs within about 10 minutes, or within about 20 minutes, or within about 30 minutes, or within about 1 hour before food intake (e.g., commencement). In other embodiments, the molecular antagonist is administered during or after food intake and may in some cases be administered immediately after food intake. In some embodiments, administration of the molecular antagonist occurs within about 15 minutes, within about 30 minutes, or within about 1 hour after food intake, or in other cases, at the onset of symptoms. In other embodiments, the molecular antagonist is administered at a predetermined frequency, for example, once or twice a day, once a week, once every two weeks, or once a month. In some embodiments, the molecular antagonist of GIP is administered parenterally, such as intramuscularly, subcutaneously, intradermally, or intravenously. In certain embodiments, the GIP antagonist is administered by subcutaneous injection. 【0015】 In various embodiments, the molecular antagonist binds to GIP and / or the GIP receptor (GIPR). In embodiments, the molecular antagonist is an antibody, antigen-binding fragment, peptide, aptamer, adnectin, single domain antibody, recombinant heavy chain only antibody (VHH), single chain antibody (scFv), shark heavy chain only antibody (VNAR), microprotein (cysteine knot protein, knottin), DARPin, tenectin, affibody, transbody, anticalin, adnectin, affilin, microbody, peptide aptamer, filomer, stradbody, maxibody, evibody, finomer, armadillo repeat protein, Kunitz domain, avimer, atrimer, probody, immunobody, triomab, troibody, pepbody, waxibody, unibody, duoibody, Fv, Fab, Fab’, F(ab’)2, peptidomimetic molecule, or synthetic molecule, or as described in U.S. Patent or Patent Publication Nos. US7,417,130, US2004 / 132094, US5,831,012, US2004 / 023334, US7,250,297, US6,818,418, US2004 / 209243, US7,838,629, US7,186,524, US6,004,746, US5,475,096, US2004 / 146938, US2004 / 157209, US6,994,982, US6,794,144, US2010 / 239633, US7,803,907, US2010 / 119446, and / or US7,166,697, the entire contents of all of which are incorporated herein by reference. See also Storz MAbs. 2011 May-Jun;3(3):310-317, which is incorporated herein by reference in its entirety. Exemplary targeting agents include, but are not limited to, antigen-binding antibody fragments such as F(ab’)2 or Fab, single chain antibodies, bispecific antibodies, or single domain antibodies. 【0016】 The binding of monoclonal antibodies to GIP is described, for example, in U.S. Patent Nos. 9,771,422, 10,196,441, and 10,538,586, which are hereby incorporated by reference in their entirety and can be used in accordance with the embodiments of the present disclosure. Other antagonists include peptide antagonists of GIPR such as GIP(3-30)NH2, which can be used in some embodiments. See Gasbjerg LS, et al., GIP(3-30)NH2 is an efficacious GIP receptor antagonist in humans: a randomised, double-blinded, placebo-controlled, crossover study, Diabetologia volume 61 (2018). In general, peptide antagonists can be prepared by derivatizing the GIP sequence or a fragment thereof by including one or more non-natural amino acids and / or (d)-amino acids. 【0017】 In some embodiments, the GIP antagonist has a size of less than about 40 kDa, or less than about 30 kDa, and in these embodiments, the GIP antagonist has a short half-life suitable for preventing or inhibiting the onset of symptoms (e.g., postprandial symptoms), but does not affect the important physiological role of GIP when symptoms do not appear (or after symptoms are controlled). In such embodiments, the GIP antagonist can be an scFv or Fab, or can be a peptide antagonist of GIPR. In other embodiments, the antagonist is a full monoclonal antibody, which is suitable for once-daily or once-weekly administration, for example, to control GIP levels. 【0018】 In an embodiment, the molecular antagonist is a monoclonal antibody or an antigen-binding fragment thereof that binds to GIP and neutralizes the binding of GIP to GIPR. An exemplary monoclonal antibody comprises the light chain sequence of SEQ ID NO: 2 and the heavy chain variable domain of SEQ ID NO: 14. In various embodiments, the monoclonal antibody has a light chain sequence having at least 80%, at least 90%, at least 95%, or at least 98% identity to the amino acid sequence of SEQ ID NO: 2. In various embodiments, the monoclonal antibody has a heavy chain variable domain having at least 80%, at least 90%, at least 95%, or at least 98% identity to the amino acid sequence of SEQ ID NO: 14. In such embodiments, the light chain sequence may have CDR1 of SEQ ID NO: 3, CDR2 of SEQ ID NO: 4, and CDR3 of SEQ ID NO: 5. Alternatively, each of such light chain CDRs may have one or two modifications (i.e., amino acid substitutions). In such embodiments, the heavy chain variable region may have CDR1 of SEQ ID NO: 15, CDR2 of SEQ ID NO: 16, and CDR3 of SEQ ID NO: 17. Alternatively, each of such heavy chain CDRs may have one or two modifications (i.e., amino acid substitutions). 【0019】 In certain embodiments, the molecular antagonist is a humanized monoclonal antibody or an antigen-binding fragment thereof. Exemplary monoclonal antibodies include a humanized light chain sequence of SEQ ID NO: 6 or SEQ ID NO: 7 and / or a humanized heavy chain variable domain of SEQ ID NO: 18, SEQ ID NO: 19, or SEQ ID NO: 20. In various embodiments, the monoclonal antibody has a humanized light chain sequence having at least 80%, at least 90%, at least 95%, or at least 98% identity to the amino acid sequence of SEQ ID NO: 6 or SEQ ID NO: 7. In various embodiments, the monoclonal antibody has a humanized heavy chain variable domain having at least 80%, at least 90%, at least 95%, or at least 98% identity to the amino acid sequence of SEQ ID NO: 18, SEQ ID NO: 19, or SEQ ID NO: 20. In such embodiments, the humanized light chain may have CDR1 of SEQ ID NO: 9, CDR2 of SEQ ID NO: 10, SEQ ID NO: 12, or SEQ ID NO: 13, and CDR3 of SEQ ID NO: 11. Alternatively, each of such light chain CDRs may have one or two modifications (i.e., amino acid substitutions). In such embodiments, the humanized heavy chain variable domain may have CDR1 of SEQ ID NO: 15, CDR2 of SEQ ID NO: 16, and CDR3 of SEQ ID NO: 17. Alternatively, each of such heavy chain CDRs may have one or two modifications (i.e., amino acid substitutions). 【0020】 In some embodiments, the molecular antagonist is a single-chain variable fragment (scFv), F(ab’)2 fragment, Fab or Fab’ fragment, diabody, triabody, or tetrabody derived from the monoclonal antibodies described herein. 【0021】 In an embodiment, the molecular antagonist is a monoclonal antibody that includes a human constant region. In an embodiment, the molecular antagonist is a monoclonal antibody formed from a light chain and a heavy chain having a variable region or domain, combined with a human constant region. The constant region of the heavy chain can be any human isotype including IgA1, IgA2, IgD, IgE, IgG1, IgG2, IgG3, IgG4, or IgM. The human constant region of the light chain can be a kappa or lambda isotype. In certain embodiments, the heavy chain constant region is an IgG1 isotype and the light chain constant region is a kappa isotype. In some embodiments, the monoclonal antibody has one or more amino acid substitutions for pharmacodynamic enhancement. Such amino acid modifications include, but are not limited to, mutations in the crystallizable fragment (Fc) domain selected from one or more of M252Y, S254T, T256E, M428L, and N434S. For example, the monoclonal antibody can have a YTE modification (M252Y, S254T, T256E) for half-life extension. 【0022】 In some embodiments, the monoclonal antibody antagonist of GIP (regardless of whether it is a full antibody or an antigen-binding fragment) has a binding affinity for GIP characterized by a K D of less than about 50 nM, or less than about 20 nM, or less than about 10 nM, or less than about 5 nM, or less than about 1 nM. 【0023】 In some embodiments, the composition is formulated as a composition suitable for parenteral administration. Dosage forms suitable for parenteral administration (e.g., intravenous, intramuscular, i.v. infusion, and subcutaneous) include, for example, solutions, suspensions, dispersions, emulsions, and the like. These can also be manufactured in the form of sterile solid compositions (e.g., lyophilized compositions) that can be dissolved or suspended in a sterile injectable medium immediately prior to use. These can contain, for example, a suspending or dispersing agent. In yet other embodiments, one or more unit doses are provided as a convenient self-administering injection pen. 【0024】 In some embodiments, the composition may further comprise a pharmaceutically acceptable excipient or carrier. Specific excipients include buffers, surfactants, preservatives, bulking agents, polymers, and stabilizers useful with these molecular antagonists. Buffers are used to control the pH of the composition. Surfactants are used to stabilize proteins, inhibit protein aggregation, inhibit protein adsorption to surfaces, and aid in protein refolding. Exemplary surfactants include Tween 80, Tween 20, Brij 35, Triton X-10, Pluronic F127, and sodium dodecyl sulfate. Preservatives are used to prevent microbial growth. Examples of preservatives include benzyl alcohol, m-cresol, and phenol. Bulking agents are used to add bulk during lyophilization. Hydrophilic polymers such as dextran, hydroxyethyl starch, polyethylene glycol, and gelatin can be used to stabilize proteins. Polymers with nonpolar moieties, such as polyethylene glycol, can also be used as surfactants. Protein stabilizers can include polyols, sugars, amino acids, amines, and salts. Suitable sugars include sucrose and trehalose. Amino acids include histidine, arginine, glycine, methionine, proline, lysine, glutamic acid, and mixtures thereof. Proteins such as human serum albumin can also competitively adsorb to surfaces and reduce aggregation of active agents. Certain formulation components can serve multiple purposes. For example, histidine can function as a buffer and antioxidant. Glycine can be used as a buffer and bulking agent. 【0025】 In certain aspects and embodiments, a composition comprising a GIP molecule antagonist is contained within a convenient self - administration injection pen. The injection pen can accommodate unit doses of from 1 to 100 units, such as unit doses of 10 to 60 units. In some embodiments, the injection pen contains and delivers a unit dose of the molecular antagonist in an amount of from about 10 mg to about 500 mg. In some embodiments, the injection pen contains and delivers a unit dose of the molecular antagonist in an amount of from about 50 mg to about 200 mg, or from about 10 to about 100 mg. In embodiments, the unit dose is a volume of about 1.5 mL or less, or about 1 mL or less. In some embodiments, the unit dose is a volume of 0.8 mL or less, or about 0.50 mL or less. 【0026】 The singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise. 【0027】 As used in the specification and claims, the open - ended transitional phrases "comprise(s)", "include(s)", "having", "contain(s)", and variations thereof are to be construed to mean the inclusion of the stated feature / step(s) without precluding the presence of other feature(s) / step(s). These phrases are also to be interpreted as disclosing the closed - ended phrases "consisting of" or "consisting essentially of", which admit only the stated feature(s) / step(s) and inevitable impurities and exclude other feature(s) / step(s). 【0028】 As used herein, the term "about" means ± 10% of a numerical value unless otherwise required by the context. 【0029】 The term "identity" means the similarity between a pair of sequences (nucleotides or amino acids). Identity is measured by dividing the number of identical residues by the total number of residues and multiplying the product by 100 to obtain a percentage. Thus, two copies of an exactly identical sequence have 100% identity, while sequences that are not highly conserved and have deletions, additions, or substitutions may have a lower degree of identity. Those skilled in the art will recognize that several computer programs, such as those using algorithms like BLAST, are available for measuring sequence identity. The BLAST nucleotide search is performed with the NBLAST program, and the BLAST protein search is performed with the BLASTP program, using the default parameters of each program. 【0030】 The term "CDR" means complementarity-determining region. CDRs are part of the variable chains of immunoglobulins (antibodies). A series of CDRs constitutes the paratope. 【0031】 Sequence SEQ ID NO:1 - Human GIP YAEGTFISDYSIAMDKIHQQDFVNWLLAQKGKKNDWKHNITQ SEQ ID NO:2 - 10g10 light chain DIQLTQSPSTMAASPGEKITITCSASSSISSNSLHWYQQKPGFSPKLLIYRTSNLASGVPGRFSGSGSGTSYSLTIGTMETEDVATYYCQQGSSFPRMLTFGTGTKLEIKR SEQ ID NO:3 - 10g10 light chain CDR1 SASSSISSNSLH SEQ ID NO:4 - 10g10 light chain CDR2 RTSNLAS SEQ ID NO:5 - 10g10 light chain CDR3 QQGSSFPRMLT SEQ ID NO:6 - Humanized light chain (LC1) DIQMTQSPSSVSASVGDRVTITCRASSSISSNSLHWYQQKPGKAPKLLIYRTSSLQSGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGSSFPRMLTFGQGTKLEIKR Sequence number 7 - Humanized light chain (LC2) DIQLTQSPSSVSASVGDRVTITCRASSSISSNSLHWYQQKPGKAPKLLIYRTSNLQSGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGSSFPRMLTFGQGTKLEIKR Sequence number 8 - Humanized light chain (LC3) DIQMTQSPGTLSLSPGERATLSCRASSSISSNSLHWYQQKPGQAPRLLIYRTSNRATGIPARFSGSGSGTDYTLTISSLEPEDFAVYYCQQGSSFPRMLTFGGGTKVEIKR Sequence number 9 - Light chain CDR1 RASSSISSNSLH Sequence number 10 - Light chain CDR2 RTSNLQS Sequence number 11 - Light chain CDR3 QQGSSFPRMLT Sequence number 12 - Light chain CDR2 RTSSLQS Sequence number 13 - Light chain CDR2 RTSNRAT Sequence number 14 - 10g10 heavy chain variable domain QVQLQESGAELVRSGASVKLSCTASGFNIRDYYLHWIKQRPEQGLEWIGWIDPENGDTEYAPKFQDKATVTADTSSNTAYLQLNSLTSEDTAVYYCNVYGIYFMDYWGQGTTVTVSS Sequence number 15 - 10g10 heavy chain CDR1 GFNIRDYYLH Sequence number 16 - 10g10 heavy chain CDR2 APKFQDK Sequence number 17 - 10g10 heavy chain CDR3 NVYGIYFMDY Accession No. 18 - Humanized heavy chain (HC1) QVQLVQSGAEVKKPGATVKISCKVSGFNIRDYYLHWVQQAPGKGLEWMGWIDPENGDTEYAPKFQGRVTITADTSTDTAYMELSSLRSEDTAVYYCNVYGIYFMDYWGQGTMVTVSS Accession No. 19 - Humanized heavy chain (HC2) QVQLVQSGAEVKKPGATVKISCKASGFNIRDYYLHWVQQAPGKGLEWMGWIDPENGDTEYAPKFQGRVTITADTSTNTAYMELSSLRSEDTAVYYCNVYGIYFMDYWGQGTMVTVSS Accession No. 20 - Humanized heavy chain (HC3) QVQLQESGAEVKKPGASVKVSCKASGFNIRDYYLHWVRQAPGQGLEWMGWIDPENGDTEYAPKFQGRVTTTADTSISTAYMELSRLRSDDTAVYYCNVYGIYFMDYWGQGTLVTVSS Accession No. 21 - Humanized heavy chain CDR1 GFNIRDYYLH Accession No. 22 - Humanized heavy chain CDR2 APKFQGR Accession No. 23 - Humanized heavy chain CDR1 NVYGIYFMDY

Claims

[Claim 1] A molecular antagonist of glucose-dependent insulin-secreting polypeptide (GIP) for use in a method of treating postural orthostatic tachycardia syndrome (POTS) in a patient requiring treatment for POTS, wherein the method comprises administering to the patient a composition comprising an effective amount of the GIP molecular antagonist. [Claim 2] i) The patient presents with mild symptoms of POTS; ii) The patient presents with moderate symptoms of POTS; and / or iii) The patient has a severe form of POTS, and the patient may present with incomplete symptoms. A molecular antagonist of GIP for use according to claim 1. [Claim 3] The patient has one or more of the following conditions: neuropathic POTS, hyperadrenergic POTS, hypovolemic POTS, and secondary POTS, and optionally, the patient has hypermobile spectrum disorder / hypermobile Ehlers-Danlos syndrome (HSD / hEDS), a molecular antagonist of GIP for use according to claim 1. [Claim 4] The patient exhibits presyncope symptoms, which are optionally selected from unsteadiness, orthostatic tachycardia, mental confusion, blurred vision, shortness of breath, tachycardia, tremor, chest discomfort, headache, nausea, and / or dizziness, a molecular antagonist of GIP for use according to claim 1. [Claim 5] The molecular antagonist of GIP for use according to claim 1, wherein the molecular antagonist of GIP is administered parenterally, and the parenteral administration route is optionally selected from intramuscular, subcutaneous, intradermal, or intravenous (IV) administration. [Claim 6] The aforementioned administration is i) Before eating, such as within about an hour before a meal; ii) During or after eating; iii) Within approximately one hour after eating A molecular antagonist of GIP for use according to claim 1, which is produced in the following: [Claim 7] The aforementioned administration is i) When symptoms begin; ii) Approximately once or twice a day; iii) About once a week; iv) Approximately once every two weeks; or v) About once a month A molecular antagonist of GIP for use according to claim 1. [Claim 8] i) The molecular antagonist of GIP binds to GIP or the GIP receptor (GIPR); ii) The molecular antagonist of the GIP is a peptide; and / or iii) The molecular antagonist of the GIP is an antibody or its antigen-binding portion, and optionally, the antibody or its antigen-binding portion is a single-stranded variable fragment (scFv), Fab, or Fab' fragment. A molecular antagonist of GIP for use according to any one of claims 1 to 7. [Claim 9] The light chain variable domains include LCDR1, LCDR2, and LCDR3, and the heavy chain variable domains include HCDR1, HCDR2, and HCDR3. i) LCDR1 contains the amino acid sequence of SEQ ID NO: 3, LCDR2 contains the amino acid sequence of SEQ ID NO: 4, LCDR3 contains the amino acid sequence of SEQ ID NO: 5, HCDR1 contains the amino acid sequence of SEQ ID NO: 15, HCDR2 contains the amino acid sequence of SEQ ID NO: 16, HCDR3 contains the amino acid sequence of SEQ ID NO: 17, each light chain CDR may optionally have one or two amino acid substitutions relative to SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5, and each heavy chain CDR may optionally have one or two amino acid substitutions relative to SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17; ii) LCDR1 contains the amino acid sequence of SEQ ID NO: 9, LCDR2 contains the amino acid sequence of SEQ ID NO: 10, SEQ ID NO: 12, or SEQ ID NO: 13, LCDR3 contains the amino acid sequence of SEQ ID NO: 11, HCDR1 contains the amino acid sequence of SEQ ID NO: 15, HCDR2 contains the amino acid sequence of SEQ ID NO: 16, HCDR3 contains the amino acid sequence of SEQ ID NO: 17, each light chain CDR may optionally have one or two amino acid substitutions relative to SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, or SEQ ID NO: 13, and each heavy chain CDR may optionally have one or two amino acid substitutions relative to SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17; iii) LCDR1 contains the amino acid sequence of SEQ ID NO: 9, LCDR2 contains the amino acid sequence of SEQ ID NO: 10, LCDR3 contains the amino acid sequence of SEQ ID NO: 11, HCDR1 contains the amino acid sequence of SEQ ID NO: 15, HCDR2 contains the amino acid sequence of SEQ ID NO: 16, HCDR3 contains the amino acid sequence of SEQ ID NO: 17, each light chain CDR may optionally have one or two amino acid substitutions relative to SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11, and each heavy chain CDR may optionally have one or two amino acid substitutions relative to SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17; iv) LCDR1 contains the amino acid sequence of SEQ ID NO: 9, LCDR2 contains the amino acid sequence of SEQ ID NO: 12, LCDR3 contains the amino acid sequence of SEQ ID NO: 11, HCDR1 contains the amino acid sequence of SEQ ID NO: 15, HCDR2 contains the amino acid sequence of SEQ ID NO: 16, HCDR3 contains the amino acid sequence of SEQ ID NO: 17, each light chain CDR may optionally have one or two amino acid substitutions relative to SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11, and each heavy chain CDR may optionally have one or two amino acid substitutions relative to SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17; or v) LCDR1 contains the amino acid sequence of SEQ ID NO: 9, LCDR2 contains the amino acid sequence of SEQ ID NO: 13, LCDR3 contains the amino acid sequence of SEQ ID NO: 11, and HCDR1 contains the sequence number The light chain CDR contains the amino acid sequence of sequence number 15, HCDR2 contains the amino acid sequence of sequence number 16, HCDR3 contains the amino acid sequence of sequence number 17, each light chain CDR may optionally have one or two amino acid substitutions relative to sequence number 9, sequence number 10, or sequence number 11, and each heavy chain CDR may optionally have one or two amino acid substitutions relative to sequence number 15, sequence number 16, or sequence number 17. A molecular antagonist of GIP for use according to claim 8. [Claim 10] The antibody or its antigen-binding site is i) A light chain variable domain containing the amino acid sequence of SEQ ID NO: 2 or a derivative thereof, and a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 14 or a derivative thereof; or ii) Light chain variable domains containing the amino acid sequence of SEQ ID NO: 6, SEQ ID NO: 7, or SEQ ID NO: 8, or derivatives thereof, and heavy chain variable domains containing the amino acid sequence of SEQ ID NO: 18, SEQ ID NO: 19, or SEQ ID NO: 20, or derivatives thereof. A molecular antagonist of GIP for use according to claim 9, comprising: [Claim 11] i) The light chain variable domain includes an amino acid sequence having at least 80%, at least 90%, at least 95%, at least 98%, or 100% identity with the amino acid sequence of SEQ ID NO: 2, and the heavy chain variable domain includes an amino acid sequence having at least 80%, at least 90%, at least 95%, at least 98%, or 100% identity with the amino acid sequence of SEQ ID NO: 14; ii) The light chain variable domain includes an amino acid sequence having at least 80%, at least 90%, at least 95%, at least 98%, or 100% identity with the amino acid sequence of SEQ ID NO: 6, SEQ ID NO: 7, or SEQ ID NO: 8, and the heavy chain variable domain includes an amino acid sequence having at least 80%, at least 90%, at least 95%, at least 98%, or 100% identity with the amino acid sequence of SEQ ID NO: 18, SEQ ID NO: 19, or SEQ ID NO: 20; iii) The light chain variable domain includes an amino acid sequence having at least 80%, at least 90%, at least 95%, at least 98%, or 100% identity with the amino acid sequence of SEQ ID NO: 7, and the heavy chain variable domain includes an amino acid sequence having at least 80%, at least 90%, at least 95%, at least 98%, or 100% identity with the amino acid sequence of SEQ ID NO: 19; iv) The light chain variable domain includes an amino acid sequence having at least 80%, at least 90%, at least 95%, at least 98%, or 100% identity with the amino acid sequence of SEQ ID NO: 6, and the heavy chain variable domain includes an amino acid sequence having at least 80%, at least 90%, at least 95%, at least 98%, or 100% identity with the amino acid sequence of SEQ ID NO: 18; or v) The light chain variable domain contains an amino acid sequence having at least 80%, at least 90%, at least 95%, at least 98%, or 100% identity with the amino acid sequence of SEQ ID NO: 8, and the heavy chain variable domain contains an amino acid sequence having at least 80%, at least 90%, at least 95%, at least 98%, or 100% identity with the amino acid sequence of SEQ ID NO:

20. A molecular antagonist of GIP for use according to claim 10. [Claim 12] The light chain variable domain includes LCDR1 containing the amino acid sequence of SEQ ID NO: 9, LCDR2 containing the amino acid sequence of SEQ ID NO: 10, and LCDR3 containing the amino acid sequence of SEQ ID NO: 11, and the heavy chain variable domain includes HCDR1 containing the amino acid sequence of SEQ ID NO: 15, HCDR2 containing the amino acid sequence of SEQ ID NO: 16, and HCDR3 containing the amino acid sequence of SEQ ID NO:

17. Optionally, the light chain variable domain contains an amino acid sequence having at least 80%, at least 90%, at least 95%, at least 98%, or 100% identity with the amino acid sequence of SEQ ID NO: 7, and the heavy chain variable domain has at least the same amino acid sequence as the amino acid sequence of SEQ ID NO:

19. A molecular antagonist of GIP for use according to claim 11, comprising an amino acid sequence having 80%, at least 90%, at least 95%, at least 98%, or 100% identity. [Claim 13] The molecular antagonist of the aforementioned GIP is KM less than approximately 50 nM, less than approximately 20 nM, less than approximately 10 nM, less than approximately 5 nM, or less than approximately 1 nM. D A molecular antagonist of GIP for use according to claim 1, characterized by having binding affinity to GIP. [Claim 14] The aforementioned composition is contained in an injection pen, optionally, i) The injection pen contains and delivers a unit dose of a GIP molecular antagonist ranging from approximately 10 mg to approximately 500 mg; ii) The injection pen contains and delivers a unit dose of a GIP molecular antagonist in an amount of approximately 50 mg to approximately 200 mg; and / or The unit dose of iii)i) or ii) is approximately 1.5 mL or less, or approximately 1 mL or less in volume. A molecular antagonist of GIP for use according to claim 1. [Claim 15] Administration of the aforementioned GIP molecular antagonist resulted in the following: i) Decreased plasma levels of GIP; ii) Reduction of one or more chronic presyncope symptoms selected from dizziness, orthostatic tachycardia, mental confusion, blurred vision, shortness of breath, tachycardia, tremor, chest discomfort, headache, nausea, and dizziness; iii) Controlling and / or increasing stroke volume in an upright position; and / or iv) Reduction of norepinephrine and / or epinephrine levels in the upright position A molecular antagonist of GIP for use according to claim 1, which brings about the results described in claim 1.