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WO1998036763A9 - Traitement de l'infertilite au moyen de ligands des recepteurs de leptine - Google Patents

Traitement de l'infertilite au moyen de ligands des recepteurs de leptine

Info

Publication number
WO1998036763A9
WO1998036763A9 PCT/US1998/002909 US9802909W WO9836763A9 WO 1998036763 A9 WO1998036763 A9 WO 1998036763A9 US 9802909 W US9802909 W US 9802909W WO 9836763 A9 WO9836763 A9 WO 9836763A9
Authority
WO
WIPO (PCT)
Prior art keywords
leptin receptor
leptin
puberty
treating
treatment
Prior art date
Application number
PCT/US1998/002909
Other languages
English (en)
Other versions
WO1998036763A1 (fr
Filing date
Publication date
Application filed filed Critical
Priority to JP53675198A priority Critical patent/JP2001512483A/ja
Priority to AU66560/98A priority patent/AU6656098A/en
Priority to CA002281888A priority patent/CA2281888A1/fr
Priority to EP98908555A priority patent/EP0991419A1/fr
Publication of WO1998036763A1 publication Critical patent/WO1998036763A1/fr
Publication of WO1998036763A9 publication Critical patent/WO1998036763A9/fr

Links

Definitions

  • This invention relates generally to a method for treating the infertility associated with improper nutrition in a mammal in need of such treatment by administration of a therapeutically effective amount of a leptin receptor agonist.
  • Improper nutrition can lead to fertility problems: delay in onset of puberty, abnormal menstrual cycles, and sterility in females. In obese males, fertility is also greatly reduced. It has been reported that leptin levels in obese patients are higher than in lean patients and that starvation reduces leptin levels in blood.
  • F. Chehab (Chehab, F.F. et al. (1996) Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin. Nature Genetics, 12:318-320) showed that the sterility in ob/ob mice can be corrected by treatment with human leptin.
  • Leptin administration to starved mice tends to reverse the effects of starvation on testosterone and LH levels (Ahima, R.S. et al. (1996) Leptin is a major mediator of the neuroendocrine response to fasting. Submitted). Additional evidence for a role of leptin in the hypothalamic- pituitary-gonadal axis (HPG) derives from the distribution of the long form of OB-R that is abundant in the gonads as well as the hypothalamus (Lee, G.H. et al. (1996) Abnormal splicing of the leptin receptor in diabetic mice. Nature 379:632-635).
  • HPG hypothalamic- pituitary-gonadal axis
  • NPY neuropeptide Y
  • a major object of the present invention is to provide a method of treating the infertility associated with improper nutrition.
  • Leptin used as an adjunct in weight loss programs would not only aid the weight loss itself but could prevent fertility problems that were induced by a rapid drop in leptin levels.
  • leptin receptor ligands represent an opportunity for therapy in conditions associated with either abnormally low or high adiposity, or relative leptin deficiency.
  • infertility in subjects with low adiposity may be restored by exogenous leptin administration.
  • Delayed puberty may be treated with a leptin regimen.
  • This invention discloses the utility of leptin, leptin mimetics, or novel leptin analogs to treat fertility disorders and delayed puberty in either obese or lean subjects.
  • leptin antagonists or neutralizing antileptin antibodies may be used to treat precocious puberty.
  • This invention arose from a desire of the inventors to provide a safe, effective treatment for infertility, in particular a treatment which would prevent or inhibit the infertility associated with improper nutrition in a mammal in need of such treatment.
  • Base pair (bp) -- refers to DNA or RNA.
  • the abbreviations A,C,G, and T correspond to the 5'-monophosphate forms of the nucleotides (deoxy)adenine, (deoxy)cytidine, (deoxy)guanine, and (deoxy)thymine, respectively, when they occur in DNA molecules.
  • the abbreviations U,C,G, and T correspond to the 5'-monophosphate forms of the nucleosides uracil, cytidine, guanine, and thymine, respectively when they occur in RNA molecules.
  • base pair may refer to a partnership of A with T or C with G.
  • base pair may refer to a partnership of T with U or C with G.
  • Chelating Peptide An amino acid sequence capable of complexing with a multivalent metal ion.
  • DNA Deoxyribonucleic acid.
  • HPAAA Hypothalamic-Pituitary-Adrenal-Adipose Axis
  • CRH released by the hypothalamus stimulates pituitary secretion of ACTH, that in turn stimulates adrenal secretion of glucocorticoids, which in turn modulates adipose tissue leptin release, that finally acts back on the hypothalamus.
  • Immunoreactive Protein(s) a term used to collectively describe antibodies, fragments of antibodies capable of binding antigens of a similar nature as the parent antibody molecule from which they are derived, and single chain polypeptide binding molecules as described in PCT Application No. PCT/US 87/02208, International Publication No. WO 88/01649.
  • mRNA messenger RNA.
  • MWCO an abbreviation for molecular weight cut-off.
  • Modulating - stimulation, potentiation, or inhibition of the activity of a receptor or system Modulating - stimulation, potentiation, or inhibition of the activity of a receptor or system.
  • Plasmid an extrachromosomal self-replicating genetic element.
  • PMSF an abbreviation for phenylmethylsulfonyl fluoride.
  • Reading frame the nucleotide sequence from which translation occurs "read” in triplets by the translational apparatus of tRNA, ribosomes and associated factors, each triplet corresponding to a particular amino acid. Because each triplet is distinct and of the same length, the coding sequence must be a multiple of three. A base pair insertion or deletion (termed a frameshift mutation) may result in two different proteins being coded for by the same DNA segment.
  • the triplet codons corresponding to the desired polypeptide must be aligned in multiples of three from the initiation codon, i.e. the correct "reading frame" must be maintained.
  • the reading frame of the DNA sequence encoding the structural protein must be maintained in the DNA sequence encoding the chelating peptide.
  • Receptor agonist any compound that binds to a receptor and triggers the action of the receptor (usually an intracellular signalling event or, in the case of receptors that form transmembrane channel, the opening or closing of the channel).
  • Receptor antagonist any compound that binds to a receptor and blocks the action of the receptor (usually by out-competing the endogenous agonist for binding sites on the receptor).
  • Receptor ligand any compound that binds to a receptor.
  • Recombinant DNA Cloning Vector any autonomously replicating agent including, but not limited to, plasmids and phages, comprising a DNA molecule to which one or more additional DNA segments can or have been added.
  • Recombinant DNA Expression Vector any recombinant DNA cloning vector in which a promoter has been incorporated.
  • Replicon - A DNA sequence that controls and allows for autonomous replication of a plasmid or other vector.
  • RNA - ribonucleic acid A DNA sequence that controls and allows for autonomous replication of a plasmid or other vector.
  • Transcription the process whereby information contained in a nucleotide sequence of DNA is transferred to a complementary RNA sequence.
  • Tris - an abbreviation for tris-(hydroxymethyl)aminomethane.
  • Treating - describes the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of a leptin receptor ligand of the present invention to prevent the onset of the symptoms or complications, alleviating the symptoms or complications, or eliminating the disease, condition, or disorder.
  • Treating obesity for example, includes the inhibition of food intake, the inhibition of weight gain, and inducing weight loss in patients in need thereof.
  • Vector - a replicon used for the transformation of cells in gene manipulation bearing polynucleotide sequences corresponding to appropriate protein molecules which, when combined with appropriate control sequences, confer specific properties on the host cell to be transformed.
  • Plasmids, viruses, and bacteriophage are suitable vectors, since they are replicons in their own right.
  • Artificial vectors are constructed by cutting and joining DNA molecules from different sources using restriction enzymes and ligases. vectors include Recombinant DNA cloning vectors and Recombinant DNA expression vectors.
  • X-gal - an abbreviation for 5-bromo-4-chloro-3-idolyl beta-D- galactoside.
  • Leptin receptor agonists may be used to treat fertility disorders and delayed puberty.
  • leptin antagonists alone or combined with specific antibodies to leptin, may be used to treat precocious puberty.
  • proteins include a leader sequence such as Met-Asp or Met-Arg, or altered primary sequence to achieve higher physical stability.
  • leptin receptor ligands in particular leptin receptor agonists or leptin receptor antagonists
  • receptor ligands in particular leptin receptor agonists or leptin receptor antagonists
  • receptor antagonists used herein are understood to refer to pharmacologically active compounds, and to salts thereof.
  • Preferred leptin receptor agonists for use in the present invention include endogenous leptin (i.e., endogenous OB protein - the protein produced from the obesity gene following transcription and translation and deletion of introns, translation to a protein and processing to the mature protein with secretory signal peptide removed, e.g., from the N-terminal valine-proline to the C- terminal cysteine of the mature protein).
  • endogenous leptin i.e., endogenous OB protein - the protein produced from the obesity gene following transcription and translation and deletion of introns, translation to a protein and processing to the mature protein with secretory signal peptide removed, e.g., from the N-terminal valine-proline to the C- terminal cysteine of the mature protein.
  • the mouse OB protein and human OB protein are published in Zhang et al., Nature 372:425-432 (1994).
  • the rat OB protein is published in Murakami et al., Biochem
  • the porcine and bovine OB genes and proteins are disclosed in EP 0 743 321 , the contents of which are incorporated by reference.
  • Various primate OB genes and proteins are disclosed in U.S. Application Serial No.08/710,483, the contents of which are incorporated by reference.
  • Also preferred for use in the present invention are leptin analogs, preferably leptin analogs having one or more amino acid substitution, more preferably less than five and most preferably less than three substitutions.
  • Particularly preferred leptin analogs for use in the present invention include proteins disclosed by Basinski et al., in WO 96/23515 and WO 96/23517 (the contents of which are incorporated by reference), of the Formula (I):
  • Xaa at position 28 is Gin or absent; said protein having at least one of the following substitutions:
  • Gin at position 4 is replaced with Glu
  • Thr at position 27 is replaced with Ala
  • Xaa at position 28 is replaced with Glu
  • Gin at position 34 is replaced with Glu
  • Met at position 54 is replaced with methionine sulfoxide, Leu, lie, Val, Ala, or Gly;
  • Gin at position 56 is replaced with Glu
  • Gin at position 62 is replaced with Glu
  • Gin at position 63 is replaced with Glu
  • Met at position 68 is replaced with methionine sulfoxide, Leu, lie, Val, Ala, or Gly;
  • Asn at position 72 is replaced with Gin, Glu, or Asp;
  • Gin at position 75 is replaced with Glu
  • His at position 97 is replaced with Gin, Asn, Ala, Gly, Ser, or Pro;
  • Trp at position 100 is replaced with Ala, Glu, Asp, Asn, Met, lie, Phe, Tyr, Ser, Thr, Gly, Gin, Val, or Leu;
  • Ala at position 101 is replaced with Ser, Asn, Gly, His, Pro, Thr, or Val;
  • Ser at position 102 is replaced with Arg; Gly at position 103 is replaced with Ala;
  • Glu at position 105 is replaced with Gin
  • Thr at position 106 is replaced with Lys or Ser;
  • Leu at position 107 is replaced with Pro; Asp at position 108 is replaced with Glu;
  • Gly at position 111 is replaced with Asp
  • Gin at position 130 is replaced with Glu
  • Gin at position 134 is replaced with Glu; Met at position 136 is replaced with methionine sulfoxide, Leu, lie,
  • Trp at position 138 is replaced with Ala, Glu, Asp, Asn, Met, lie, Phe, Tyr, Ser, Thr, Gly, Gin, Val, or Leu; or
  • the leptin receptor ligands of the present invention are optionally substituted with a functional group. Any art-recognized functional group which does not eliminate or significantly reduce the compound's ability to bind to leptin receptors are contemplated, including, but not limited to, ester, amide, acid, amine, alcohol, ether, thioether, etc. Solvates, e.g., hydrates of the compounds useful in the methods of the present invention, are also included within the scope of the present invention. Methods of solvation to produce such solvates are generally known in the art.
  • compositions of the leptin receptor agonists and antagonists suitable for administration by a variety of routes are known in the art and need not be described herein in detail.
  • pharmaceutically acceptable salts of the leptin receptor ligands and derivatives thereof according to the invention include base salts, e.g., derived from an appropriate base.
  • Pharmaceutically acceptable salts of an acid group or an amino group include, but are not limited to, salts of organic carboxylic acids such as acetic, lactic, tartaric, malic, isothionic, and lactobionic acids; organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-tolylsuifonic acids, and inorganic acids such as hydrochloric, sulfuric, phosphoric and sulfamic acids.
  • Pharmaceutically- acceptable salts of a compound with a hydroxy group include, but are not limited to, the anion of the compound in combination with a suitable cation such as Na + .
  • a further embodiment of the present invention comprises a method for treating the infertility associated with improper nutrition by administration of antibodies to endogenous leptin receptor agonists to a mammal in need of such treatment.
  • Such antibodies may be monoclonal or polyclonal antibodies to leptin receptor agonists, or to antigenic parts thereof.
  • Both polyclonal and monoclonal antibodies to leptin receptor agonists are obtainable by immunization of an animal with purified leptin receptor agonists, purified recombinant leptin receptor agonists, fragments of these proteins, or purified fusion proteins of leptin receptor agonists, with another protein.
  • partially purified proteins or fragments may serve as immunogens.
  • the methods of obtaining both types of antibodies are well known in the art with excellent protocols for antibody production being found in Harlow et al. (1988) Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 726 pp.
  • Polyclonal sera are relatively easily prepared by injection of a suitable laboratory animal with an effective amount of purified leptin receptor agonists, or parts thereof, collecting serum from the animal, and isolating specific sera by any of the known immunoadsorbent techniques.
  • Monoclonal antibodies are particularly useful because they can be produced in large quantities and with a high degree of homogeneity.
  • Hybridoma cell lines which produce monoclonal antibodies are prepared by fusing an immortal cell line with lymphocytes sensitized against the immunogenic preparation and is done by techniques which are well known to those who are skilled in the art. (See, for example, Douillard, I.Y. and Hoffman, T., "Basic Facts About Hybridomas", in Compendium of Immunology, Vol. II, L.
  • a still further part of this invention is a pharmaceutical composition of matter for treating the infertility associated with improper nutrition that comprises at least one of the leptin receptor agonists or antagonists described above, mixtures thereof, and/or pharmaceutical salts thereof, and a pharmaceutically-acceptable carrier therefor.
  • Such compositions are prepared in accordance with accepted pharmaceutical procedures, for example, as described in Remington's Pharmaceutical Sciences, seventeenth edition, ed. Alfonso R. Gennaro, Mack Publishing Company, Easton, PA (1985).
  • a leptin receptor agonist or antagonist, or its salt can be conveniently administered in the form of a pharmaceutical composition containing one or more leptin receptor agonists or . antagonists, or salts thereof, and a pharmaceutically acceptable carrier therefor.
  • Suitable carriers are well known in the art and vary with the desired form and mode of administration of the pharmaceutical composition. For example, they may include diluents or excipients such as fillers, binders, wetting agents, disintegrators, surface-active agents, lubricants, and the like.
  • the carrier may be a solid, liquid, or vaporizable carrier, or combinations thereof.
  • the composition is a therapeutic composition and the carrier is a pharmaceutically acceptable carrier.
  • the leptin receptor ligands for use in the present invention, or salts thereof, may be formulated together with the carrier into any desired unit dosage form.
  • Typical unit dosage forms include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories; injectable solutions and suspensions are particularly preferred.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients in the formulation and not injurious to the patient.
  • the carrier must be biologically acceptable and inert, i.e., it must permit the cell to conduct its metabolic reactions so that the leptin receptor ligands suitable for use in the method of the present invention may effect its inhibitory activity.
  • Formulations include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, and transdermal) administration, with topical ointment formulations, and formulations appropriate for oral administration, being preferred.
  • solutions and suspensions are sterilized and are preferably isotonic to blood.
  • carriers which are commonly used in this field can also be used, for example, water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitate esters.
  • isotonicity adjusters such as sodium chloride, glucose or glycerin can be added to make the preparations isotonic.
  • the aqueous sterile injection solutions may further contain anti-oxidants, buffers, bacteriostats, and like additions acceptable for parenteral formulations.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any method known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which may encompass one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product. Various unit dose and multidose containers, e.g., sealed ampules and vials, may be used, as is well known in the art. In addition to the ingredients particularly mentioned above, the formulations of this invention may also include other agents conventional in the art for this type of pharmaceutical formulation.
  • the leptin receptor ligands suitable for use in the present invention may be present in the composition in an broad proportion to the carrier.
  • the leptin receptor ligands may be present in the amount of 0.01 to 99.9 wt%, and more preferably in about 0.1 to 99 wt%. Still more preferably, the leptin receptor ligand may be present in an amount of about 1 to 70 wt% of the composition.
  • the dosage of the leptin receptor agonists or antagonists, pharmaceutically acceptable salts thereof, or mixtures thereof administered to a patient according to the present invention will vary depending on several factors, including, but not limited to, the age, weight, and species of the patient, the general health of the patient, the severity of the symptoms, whether the composition is being administered alone or in combination with other therapeutic agents, the incidence of side effects and the like.
  • a dose suitable for application in treating the infertility associated with improper nutrition is about 0.001 to 100 mg/kg body weight/dose, preferably about 0.01 to 60 mg/kg body weight/dose, and still more preferably about 0.1 to 40 mg/kg body weight/dose per day.
  • the desired dose may be administered as 1 to 6 or more subdoses administered at appropriate intervals throughout the day.
  • the leptin receptor ligands may be administered repeatedly over a period of months or years, or it may be slowly and constantly infused to the patient. Higher and lower doses may also be administered.
  • the daily dose may be adjusted taking into account, for example, the above-identified variety of parameters.
  • the present compositions may be administered in an amount of about 0.001 to 100 mg/kg body weight/day. However, other amounts may also be administered.
  • leptin receptor ligands suitable for use in the present invention may be administered, for instance, by intravenous injection of an approximate 0.1 to 1% solution of the active ingredient, optionally in saline, or orally administered as a bolus.
  • the active ingredient may be administered for therapy by any suitable routes, including topical, oral, rectal, nasal, vaginal and parenteral (including intraperitoneal, subcutaneous, intramuscular, intravenous, intradermal, and transdermal) routes. It will be appreciated that the preferred route will vary with the condition and age of the patient, the nature of the disorder and the chosen active ingredient including other therapeutic agents. Preferred is the oral route. Also preferred is the topical route. However, other routes may also be utilized depending on the conditions of the patient and how long-lasting the treatment is.
  • the active ingredient While it is possible for the active ingredient to be administered alone, it is preferably present as a pharmaceutical formulation.
  • the formulations of the present invention comprise at least one active ingredient, as defined above, together with one or more acceptable carriers thereof and optionally other therapeutic agents.
  • the above method may be practiced by administration of leptin receptor ligands by themselves or in a combination with other active ingredients, including therapeutic agents in a pharmaceutical composition.
  • Other therapeutic agents suitable for use herein are any compatible drugs that are effective by the same or other mechanisms for the intended purpose, or drugs that are complementary to those of the present agents. These include agents that are effective for the treatment of infertility and/or associated conditions in humans.
  • the compounds utilized in combination therapy may be administered simultaneously, in either separate or combined formulations, or at different times than the present compounds, e.g., sequentially, such that a combined effect is achieved.
  • the amounts and regime of administration will be adjusted by the practitioner, by preferably initially lowering their standard doses and then titrating the results obtained.
  • the therapeutic method of the invention may be used in conjunction with other therapies as determined by the practitioner. While the invention has been described and illustrated herein by references to various specific material, procedures and examples, it is understood that the invention is not restricted to the particular material, combinations of material, and procedures selected for that purpose. Numerous variations of such details can be implied and will be appreciated by those skilled in the art.

Abstract

Cette invention se rapporte de manière générale à un procédé de traitement de l'infertilité associée à une alimentation déséquilibrée, ledit procédé consistant à administrer à un mammifère justiciable d'un tel traitement, une quantité thérapeutiquement efficace d'un agoniste de récepteur de leptine.
PCT/US1998/002909 1997-02-25 1998-02-24 Traitement de l'infertilite au moyen de ligands des recepteurs de leptine WO1998036763A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP53675198A JP2001512483A (ja) 1997-02-25 1998-02-24 レプチンレセプターリガンドによる不妊症の治療
AU66560/98A AU6656098A (en) 1997-02-25 1998-02-24 Treatment of infertility with leptin receptor ligands
CA002281888A CA2281888A1 (fr) 1997-02-25 1998-02-24 Traitement de l'infertilite au moyen de ligands des recepteurs de leptine
EP98908555A EP0991419A1 (fr) 1997-02-25 1998-02-24 Traitement de l'infertilite au moyen de ligands des recepteurs de leptine

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US80610497A 1997-02-25 1997-02-25
US08/806,104 1997-02-25

Publications (2)

Publication Number Publication Date
WO1998036763A1 WO1998036763A1 (fr) 1998-08-27
WO1998036763A9 true WO1998036763A9 (fr) 1999-02-11

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EP (1) EP0991419A1 (fr)
JP (1) JP2001512483A (fr)
AU (1) AU6656098A (fr)
CA (1) CA2281888A1 (fr)
WO (1) WO1998036763A1 (fr)

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JP4468488B2 (ja) 1996-05-29 2010-05-26 コーネル・リサーチ・ファンデーション・インコーポレイテッド 組み合せたリガーゼ検出およびポリメラーゼ連鎖反応を用いる核酸配列相違の検出
US6777388B1 (en) 1998-08-21 2004-08-17 Clf Medical Technology Acceleration Program, Inc. Leptin-related peptides
US7208572B2 (en) 1998-08-21 2007-04-24 Albany Medical College Leptin-related peptides
US20050272652A1 (en) 1999-03-29 2005-12-08 Gault Victor A Peptide analogues of GIP for treatment of diabetes, insulin resistance and obesity
IL146655A0 (en) * 2001-11-21 2002-07-25 Yeda Res & Dev The use of leptin in fertility
US8076288B2 (en) 2004-02-11 2011-12-13 Amylin Pharmaceuticals, Inc. Hybrid polypeptides having glucose lowering activity
KR101427024B1 (ko) 2004-02-11 2014-08-05 아스트라제네카 파마수티컬스 엘피 선택가능한 특성을 갖는 하이브리드 폴리펩티드
WO2007022123A2 (fr) 2005-08-11 2007-02-22 Amylin Pharmaceuticals, Inc. Polypeptides hybrides presentant des proprietes selectionnables
EP2392595A1 (fr) 2005-02-11 2011-12-07 Amylin Pharmaceuticals Inc. Analogues de GIP et polypeptides hybrides de GIP aux propriétés sélectionnables
US8263545B2 (en) 2005-02-11 2012-09-11 Amylin Pharmaceuticals, Inc. GIP analog and hybrid polypeptides with selectable properties
EP2330125A3 (fr) 2005-08-11 2012-12-12 Amylin Pharmaceuticals, Inc. Polypeptides hybrides ayant des propriétés sélectionnables
WO2007025349A1 (fr) * 2005-09-01 2007-03-08 The University Of New England Modulation de l’ovulation et des taux de croissance
US8497240B2 (en) 2006-08-17 2013-07-30 Amylin Pharmaceuticals, Llc DPP-IV resistant GIP hybrid polypeptides with selectable properties
CN104360086B (zh) * 2014-12-05 2016-06-15 重庆中元生物技术有限公司 一种可溶性瘦素受体的胶乳增强免疫比浊检测试剂盒

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WO1996023815A1 (fr) * 1995-01-31 1996-08-08 Eli Lilly And Company Anticorps contre les produits du gene ob
GB9509164D0 (en) * 1995-05-05 1995-06-28 Smithkline Beecham Plc Novel compounds
WO1996035787A1 (fr) * 1995-05-08 1996-11-14 Chiron Corporation Acides nucleiques pour traiter l'obesite
EP0832220A1 (fr) * 1995-06-07 1998-04-01 Amgen Inc. Compositions renfermant la proteine ob et procedes associes
GB9511935D0 (en) * 1995-06-13 1995-08-09 Smithkline Beecham Plc Novel compound

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