WO2010066125A1 - Peptide court, sa préparation et ses utilisations - Google Patents

Peptide court, sa préparation et ses utilisations Download PDF

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Publication number
WO2010066125A1
WO2010066125A1 PCT/CN2009/071610 CN2009071610W WO2010066125A1 WO 2010066125 A1 WO2010066125 A1 WO 2010066125A1 CN 2009071610 W CN2009071610 W CN 2009071610W WO 2010066125 A1 WO2010066125 A1 WO 2010066125A1
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pacap
peptide
cyclic heptapeptide
cysteine
cycloheptapeptide
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PCT/CN2009/071610
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English (en)
Chinese (zh)
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余榕捷
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Yu Rongjie
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/64—Cyclic peptides containing only normal peptide links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to a polypeptide having pharmacological action, in particular to a short peptide and preparation thereof
  • PACAP is fairly conserved during animal evolution, and the vertebrate frog and human PACAP differ only by 2 amino acids, indicating that PACAP performs key physiological functions. PACAP and its receptors (PAC1, VPAC1 and VPAC2)
  • non-neural tissues such as brain, testis, ovary, respiratory tract, lung, pancreas, adipose tissue, etc.
  • PACAP has been shown to have neurotransmitters I
  • PACAP27 is PACAP27 is PACAP38
  • PACAP38 The N-terminus of PACAP38 is 27 amino acids. In vivo, PACAP loses its N-terminal five amino acids, His-Ser-Asp-Gly-Ile, under the action of dipeptidylpeptidase (IVDPP IV).
  • PACAP (6-27) and PACAP (6-38) are antagonists of PACAP. Therefore, the short peptide of the N-terminal five amino acids of PACAP (His-Ser-Asp-Gly-Ile) is maintained for PACAP.
  • Vasoactive intestinal peptide with high homology to PACAP vasoactive intestinal peptide, VIP
  • His-Ser-Asp-Gly-Ile also has an effect of regulating VIP activity in vivo.
  • the linear pentapeptide is very unstable in vivo.
  • the main chain of the cyclic peptide has a cyclic structure and has a certain conformational constraint. Its conformation has a certain stability relative to the linear peptide, and its anti-enzymatic ability is better than the linear type.
  • Peptide is strong, so consider His-Ser-Asp-Gly-Ile
  • His-Ser-Asp-Gly-Ile reports on PACAP and VIP activity after cyclization.
  • the purpose of the present invention is to provide an effective intervention for PACAP in vivo, in view of the deficiencies of the prior art.
  • Antagonistic function to assist the body in PACAP, VIP
  • Another object of the present invention is to provide a cyclic heptapeptide which is stable in the above short peptide.
  • Another object of the present invention is to provide a process for producing the above cyclic heptapeptide.
  • a further object of the present invention is to provide the above short peptide or cyclic heptapeptide in diagnosis or treatment with PACAP,
  • the present invention has been extensively studied to find that the short peptide histidine-serine-aspartate-glycine-isoleucine (His-Ser-Asp-Gly-Ile) maintains APCAP, VIP
  • the activity and function are very important, however, the linear structure of this pentapeptide makes it very unstable in vivo.
  • the present invention not only regulates by designing some amino acids or groups (such as cysteine or methyl group) at both ends of the pentapeptide, so that the resulting peptide chain is a cyclic peptide structure.
  • APCAP, VIP amino acids or groups
  • the action of the activity ensures the conformational stability of the peptide chain in the body and the strong anti-enzymatic ability.
  • the cysteine of the invention cyclizes the pentapeptide to effect conversion from a linear polypeptide to a cyclic peptide structure. Add cysteine Cys to both ends of His-Ser-Asp-Gly-Ile
  • the thiol group of the two cysteines at the beginning and the end forms an intramolecular disulfide bond, thereby producing a cyclic heptapeptide which is conformationally stable and can effectively resist the enzymatic hydrolysis of aminopeptidase and carboxypeptidase.
  • Its structural formula is ring-(cysteine-histidine-serine
  • each peptide bond needs to undergo functional steps such as functional group protection, condensation, deprotection, etc., plus the separation and purification of each step of the product, the operation is quite complicated and expensive, so now it is more effective.
  • the synthesis of polypeptides is carried out by phase synthesis.
  • the synthesis of the cyclic heptapeptide of the present invention is carried out by solid phase synthesis, preferably by the Fmoc method.
  • the method for synthesizing the cyclic heptapeptide of the present invention comprises the following steps:
  • the crude product is obtained by cutting off the resin with a cutting reagent, and purified by reverse-phase high performance liquid chromatography to obtain a cyclic heptapeptide.
  • the condensing agent used in the solid phase synthesis method is TBTU/HOBT/DIEA
  • TBTU 0-(7-azobenzotriazole-1-oxo)- ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethylurea hexafluorophosphate
  • ⁇ ⁇ -hydroxybenzo Triazole
  • DIEA ⁇ , ⁇ '-diisopropylethylamine
  • the TBTU/HOBT/DIEA complex condensing agent is Fmoc
  • step (2) the cyclization of the linear peptide is carried out on the resin before shearing, such as a linear chain.
  • the protected sulfhydryl group is oxidized on the resin to convert the linear pentapeptide into a cyclic heptapeptide structure;
  • the oxidizing agent may be any oxidizing agent such as I 2 , H 2 0 2 , Hg 2 + salt, K 3 Fe(CN) 6 , bismuth trifluoroacetate (tfa) 3 , chlorosilicon sulfonium sulfone oxidant or dimethyl sulfoxide DMSO.
  • PACAP-mediated biological function can also complement the natural antagonists PACAP (6-27) or PACAP (6-38), reverse its antagonism, promote agonism, and enhance PACAP in vivo.
  • vasoactive intestinal peptide VIP is highly homologous to PACAP and has a similar N
  • the cyclic heptapeptide of the present invention also has an effect of regulating VIP activity in vivo.
  • the cycloheptapeptide of the present invention can be used for diagnosis and treatment with PACAP, VIP
  • the diseases which the cycloheptapeptide of the present invention may treat cover the nervous system, the endocrine system, digestion and energy metabolism, the cardiovascular cycle, the reproductive system and the immune system, such as diabetes. (including type I, II
  • obesity obesity-related diseases, metabolic disorders, metabolic-related syndromes, brain damage, cerebral ischemia, prevention of nerve cell death, damaged nerve cell protection and regeneration, anti-inflammatory, male impotence, sexual indifference, infertility , female sexual dysfunction, neuralgia, neuropathy, neurological disorders, anxiety, psychosis, memory impairment, dementia, cognitive confusion, central nervous system disorders, migraine, nervous contracture, myocardial ischemia, myocardial infarction /
  • Fibrosis arteriosclerosis, muscle contracture, gastric ulcer, hypertension, endotoxic shock, thrombosis, retinopathy, cardiovascular disease, renal failure, heart failure, tumor cell apoptosis, tumor cell proliferation, etc.
  • the cyclic heptapeptide of the present invention can specifically regulate the activity of PACAP and VIP in vivo, and can also reverse the PACAP (6-38) in vivo and
  • the antagonistic effect of PACAP (6-27) has broad application prospects and high application value;
  • Adding amino acids or groups at both ends of the sequence such as adding cysteine at both ends, and forming a cyclic structure by using the intermolecular disulfide bond of cysteine, thereby ensuring the stability of the entire loop heptapeptide in vivo conformation, as well as Effective anti-enzymatic ability, also guarantees His-Ser-Asp-Gly-Ile
  • the active peptide stably functions in the body to regulate the activity of PACAP and VIP;
  • the cyclic heptapeptide of the present invention is solid phase synthesis, and the initial reactants and products are all attached to a solid phase carrier, so that all reactions can be carried out in one reaction vessel, which is convenient for automation, and an excessive amount of reactants can be added. High yield of product, the same product is easily separated;
  • the cyclic heptapeptide of the present invention is capable of effectively compensating and reversing the pair of PACAP (6-38) and PACAP (6-27)
  • PACAP antagonism
  • the cyclic heptapeptide of the present invention can be used for diagnosis and treatment of diseases associated with PACAP and VIP, in view of PACAP, VIP
  • cycloheptapeptide It is very conservative in the process of biological evolution, and has a wide range of important biological functions. Therefore, the medical value of cycloheptapeptide is high, and the cyclic heptapeptide can be obtained by a simple solid phase synthesis method, and thus has a broad market prospect.
  • Figure 1 is a mass spectrum of the cyclic heptapeptide CHC
  • Figure 2 is a HPLC detection diagram of cycloheptapeptide CHC
  • Figure 3 is a graph showing the effect of cyclic heptapeptide CHC on blood glucose transients
  • Figure 4 is a graph of blood glucose concentration of the cyclic heptapeptide CHC intervention in the glucose tolerance test
  • Figure 5 is a blood glucose concentration integral map of the cyclic heptapeptide CHC intervention in the glucose tolerance test
  • Figure 6 is a histogram of the effect of cycloheptapeptide CHC on STZ-induced diabetes
  • A is Buffer+ saline
  • B is STZ+ saline
  • C is STZ+PACAP38
  • D is STZ+HSDGI
  • E is STZ+cycloheptapeptide CHC
  • ⁇ means ⁇ 0 ⁇ 01 ( ⁇ group vs. group A)
  • * means ⁇ 0 ⁇ 01 (group D vs. group B, group v vs. B) Group);
  • Figure 7 is a bar graph of the reversal of PACAP (6-38) antagonistic nerve growth by cycloheptide CHC;
  • A is a blank control
  • B is PACAP38
  • C is PACAP (6-38)
  • D is CHC ten.
  • E is PACAP (6-38) + PACAP38
  • F is CHC+ PACAP (6-38) + PACAP38
  • ⁇ means ⁇ 0 ⁇ 01 (group B vs. E group)
  • * means ⁇ 0 ⁇ 01 (Group D vs. Group C)
  • ** means ⁇ 0 ⁇ 01 (Group F vs. E).
  • the cyclic heptapeptide of the present example is prepared by solid phase synthesis, and the specific steps are as follows:
  • the cyclization solution containing an oxidizing agent is added. 1 and 2 (weighed 2.6 gl 2 was dissolved in 85 mL of methanol and 15 mL of dimethylformamide DMF mixture, dubbed 0.1 mol / L 1 2 solution),
  • a cleavage reagent for phenol preparation which is cleaved from the resin to obtain a crude product, and the crude product is purified by RP-HPLC to obtain a cycloheptapeptide [cyclo-(Cy-His-Ser-Asp-Gly-Ile-Cys)].
  • CHC cycloheptapeptide
  • the cyclic heptapeptide of the present embodiment is solid phase synthesis, which avoids the production of liquid phase cyclized dimers or multimers, and has a high reaction concentration and low cost.
  • the molecular weight of the cyclic heptapeptide of this example is 732.3.
  • the yield can reach 19%, and the purity after purification is over 96%.
  • the mass spectrometry and HPLC detection of the synthesized cyclic heptapeptide are shown in Fig. 1 and Fig. 2.
  • the blood glucose was measured, and the results are shown in Fig. 3.
  • the CHC cycloheptapeptide has an activity of regulating blood sugar transiently, which is consistent with the activity of PACAP.
  • the cycloheptapeptide can effectively improve the body's ability to remove high glucose (P ⁇ 0.01).
  • Tail vein blood sampling is used to measure fasting blood glucose with a blood glucose meter.
  • the blood glucose level is less than 6 mol/L.
  • mice entered the trial. Randomly divided into 5 groups according to body weight, 10 mice in each group, fasted for 16h
  • Group A citric acid buffer (Buffer) ten physiological saline (0.9% by mass NaCl);
  • Group B 50 mg/kg streptozotocin (STZ) ten normal saline (0.9 mass% NaCl); group C: 50 mg/kg STZ ten 500 ⁇ g/kg PACAP38;
  • Group D 50 mg/kg STZ ten 500 ⁇ g/kg HSDGI linear pentapeptide (HSDGI linear pentapeptide is His-Ser-Asp-Gly-Ile linear peptide);
  • Group E 50 mg/kg STZ ten 500 ⁇ g/kg CHC cycloheptapeptide.
  • the blood glucose level in the 10 saline group was significantly increased (P ⁇ 0.01), indicating that the STZ induced diabetes model was successful; the blood glucose rise in the STZ ten PACAP38 group was slightly inhibited, but not statistically significant; STZ ten CHC Both the cycloheptapeptide and the STZ-10 HSDGI group were effective (P ⁇ 0.01), which inhibited the rise of blood glucose, indicating that CHC cycloheptapeptide and HSDGI linear peptide are resistant to STZ damage to islet cells, and CHC loop heptapeptide ratio
  • HSDGI linear peptides work better.
  • PC 12 cells are a commonly used nerve cell line, commercially available), and the culture medium contains
  • the volume fraction is 0.05 C0 2 in the incubator.
  • PACAP (6-38) itself inhibits the action of PACAP38 on neurite outgrowth ( ⁇ p ⁇ 0.01

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Abstract

La présente invention concerne un peptide court constitué de la séquence d'acides aminés His-Ser-Asp-Gly-Ile et son analogue cyclique cyclo-(Cys-His-Ser-Asp-Gly-Ile-Cys). L'invention concerne également un procédé de préparation du cycloheptapeptide par synthèse en phase solide et des utilisations du peptide court et du cycloheptapeptide pour le diagnostic ou le traitement des maladies impliquant le polypeptide activateur de l'adénylcyclase hypophysaire (PACAP) et le peptide intestinal vasoactif (VIP).
PCT/CN2009/071610 2008-12-12 2009-04-30 Peptide court, sa préparation et ses utilisations WO2010066125A1 (fr)

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CN2008102198844A CN101434649B (zh) 2008-12-12 2008-12-12 一种环七肽及其制备方法和应用
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9365653B2 (en) 2013-03-15 2016-06-14 Amgen Inc. Human PAC1 antibodies
US10738110B2 (en) 2018-01-12 2020-08-11 Amgen Inc. PAC1 antibodies and uses thereof
US10822408B2 (en) 2015-12-15 2020-11-03 Amgen Inc. PACAP antibodies and uses thereof
US10934362B2 (en) 2014-09-15 2021-03-02 Amgen Inc. Bi-specific anti-CGRP receptor/PAC1 receptor antigen binding proteins and uses thereof

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CN106279362B (zh) * 2015-06-23 2019-07-12 首都医科大学 Arg-Leu-Val-Cys-Val，其合成，药理活性和应用
CN110012897A (zh) * 2019-03-11 2019-07-16 广州赛莱拉干细胞科技股份有限公司 干细胞制剂及其在制备治疗骨关节炎的药物中的应用
CN111110830B (zh) * 2020-02-18 2023-05-26 暨南大学 生物活性多肽pacap在制备提高肥胖男性生育力的药物中的应用

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JASIONOWSKI M. ET AL: "Conformational studies of PACAP(1-27) and its fragments", LETTERS IN PEPTIDE SCIENCE, vol. 5, no. 5-6, October 1998 (1998-10-01), pages 371 - 374 *
KOWALIK-JANKOWSKA T. ET AL: "Copper(II) complexation by pituitary adenylate cyclase activating polypeptide fragments", JOURNAL OF INORGANIC BIOCHEMISTRY, vol. 76, no. 1, 30 July 1999 (1999-07-30), pages 63 - 70 *

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10793631B2 (en) 2013-03-15 2020-10-06 Amgen Inc. Human PAC1 antibodies
US9676851B2 (en) 2013-03-15 2017-06-13 Amgen Inc. Human PAC1 antibodies
US9822178B2 (en) 2013-03-15 2017-11-21 Amgen Inc. Human PAC1 antibodies
US10053507B2 (en) 2013-03-15 2018-08-21 Amgen Inc. Human PAC1 antibodies
US10294298B2 (en) 2013-03-15 2019-05-21 Amgen Inc. Human PAC1 antibodies
US10472417B2 (en) 2013-03-15 2019-11-12 Amgen Inc. Human PAC1 antibodies
US9365653B2 (en) 2013-03-15 2016-06-14 Amgen Inc. Human PAC1 antibodies
US10934362B2 (en) 2014-09-15 2021-03-02 Amgen Inc. Bi-specific anti-CGRP receptor/PAC1 receptor antigen binding proteins and uses thereof
US11919964B2 (en) 2014-09-15 2024-03-05 Amgen Inc. Bi-specific anti-CGRP receptor/PAC1 receptor antigen binding proteins and uses thereof
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