WO2000021554A1 - Preventives or remedies for cachexia - Google Patents

Preventives or remedies for cachexia Download PDF

Info

Publication number
WO2000021554A1
WO2000021554A1 PCT/JP1999/005570 JP9905570W WO0021554A1 WO 2000021554 A1 WO2000021554 A1 WO 2000021554A1 JP 9905570 W JP9905570 W JP 9905570W WO 0021554 A1 WO0021554 A1 WO 0021554A1
Authority
WO
WIPO (PCT)
Prior art keywords
cachexia
amino acid
ocif
active ingredient
seq
Prior art date
Application number
PCT/JP1999/005570
Other languages
French (fr)
Japanese (ja)
Inventor
Kiyoshi Oizumi
Shinichi Kurakata
Original Assignee
Sankyo Company, Limited
Snow Brand Milk Products Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sankyo Company, Limited, Snow Brand Milk Products Co., Ltd. filed Critical Sankyo Company, Limited
Priority to AU60060/99A priority Critical patent/AU6006099A/en
Publication of WO2000021554A1 publication Critical patent/WO2000021554A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70578—NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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 an agent for preventing or treating cachexia comprising an osteoclast formation inhibitory factor (Ost. Eoclastogenesis Inhibitory Factor; hereinafter, referred to as FOCI Fj) as an active ingredient.
  • an osteoclast formation inhibitory factor Ost. Eoclastogenesis Inhibitory Factor; hereinafter, referred to as FOCI Fj
  • Fluid mainly causes progressive weight loss, anemia, edema, anorexia, etc., which develop in chronic diseases such as malignant tumors, tuberculosis, diabetes, blood diseases, endocrine diseases, infectious diseases and acquired immunodeficiency syndrome. It is a systemic disease that causes symptoms (see J. Parenteral and Enteral Nutrition. Vol. 12, 286-298, (1988): American Journal of Medicine, vol. 85, 289-291. (1988) ).
  • OC.1 F is composed of the amino acid sequences described in Amino Acid Numbers 1 to 380 of SEQ ID NO: 1 and has been found as a protein having an activity of inhibiting osteoclast differentiation or maturation. And bone loss such as osteoporosis, osteoarthritis, multiple myeloma, etc. It is known to be useful as a preventive or therapeutic agent for bone metabolism and dysfunction (WO% / 262 ⁇ 7), however, the protein has a preventive and therapeutic effect on cachexia That isn't true. ' ⁇ ;
  • OCIF or a mutant thereof exerts an excellent preventive or therapeutic effect on cachexia, and completed the present invention.
  • a cachexia comprising, as an active ingredient, an osteoclast formation inhibitory factor (OCIF) comprising an amino acid sequence represented by any one of amino acid numbers 1 to 380 of SEQ ID NO: 1 or a mutant thereof.
  • OCIF osteoclast formation inhibitory factor
  • a preventive or therapeutic agent for cachexia comprising, as an active ingredient, an osteoclast formation inhibitory factor (OCIF) comprising an amino acid sequence represented by amino acid numbers 1 to 380 of SEQ ID NO: 1 in the sequence listing,
  • OCIF osteoclast formation inhibitory factor
  • mutant refers to a protein in which one or more amino acids in the amino acid sequence of OCIF have been substituted, deleted, added or inserted, and the OCIF activity (inhibition of osteoclast formation) is determined. Activity).
  • the OC1 F protein can be produced by the method described in W096 / 26217 ...
  • eukaryotic genes are considered to exhibit polymorphism as is known for interferon genes (eg, Nishi, T. et al. (1985) Biochem. HI, 153- 159), this polymorphism may result in the replacement of one or more amino acids, or the nucleotide sequence may be replaced but the amino acids remain the same.
  • OCIF protein consisting of the amino acid sequences of amino acids 1 to 380 of SEQ ID NO: 1, one or more amino acid residues are substituted or deleted. Lost, added or inserted proteins often also have OCIF activity. In the present invention, these proteins are referred to as OCIF mutants. That is, as long as these naturally occurring or artificially synthesized proteins have OCIF activity, all of those proteins can be used in the present invention.
  • DNA encoding such a protein can be obtained, for example, by the phosphite 'triester method (Nature, ⁇ , 105-111, (1984)! [!
  • the codon for amino acid can be selected arbitrarily, for example, considering the codon usage of ⁇ : 3 ⁇ 4 ⁇ : to be used. (Refer to Nucleic Acid Res. I>, 143-174. (1981).) Further, partial modification of these nucleotide sequence codons can be carried out according to a conventional method. Site-directed mutagenesis / Proc. Natl. Acad. Sci. USA 81, 5662-5666, (] 984) using the primer consisting of the synthetic nucleotide to be used.
  • any -- ⁇ 'or multiple amino acid residues may be deleted.
  • the DNA is trimmed from the end using exonuclease Bal3l (see “Seismological Chemistry Laboratory Lecture 1, Genetic Research Method II”, pages 335-354), cassette mutation (Refer to “Shinogen Chemistry Laboratory Course 2: Nucleic Acid I] I Recombinant DNA Technology”, pp. 242-251.)
  • the codon for the amino acid is known per se, and Selection is optional, and can be determined according to a conventional method, taking into account, for example, the codon usage of the ffj host.
  • the OC [F activity can be measured by the method described in W096 / 26217.
  • the term "cachexia” refers to a progressive weight loss, anemia, which develops in chronic diseases such as malignant tumors, tuberculosis, diabetes, blood diseases, endocrine diseases, infectious diseases and acquired immunodeficiency syndrome. It refers to a systemic disease with edema and anorexia as the main symptoms.
  • OCIF protein represented by amino acid No. 1-No. 3H0 of SEQ ID NO: 1
  • OCIF was 0.0% Tween80 in PBS.
  • Body change ( ⁇ ) body weight on day 12 after cancer transplantation (g) Body weight on day 7 after cancer transplantation
  • Body ® "yl birefringence index (%) Double ( ⁇ Alpha - delta beta) / ( ⁇ c - ⁇ ⁇ ) X 1 0 0
  • Example 1 According to the method described in the above, mouse colon cancer Colon26 cells of about 2 mm square were transplanted under the skin of 10 Balb / c mice (female, 7 weeks old) per group.
  • Life extension activity was evaluated by the survival rate (%) according to the following formula. Life extension (%) ' ⁇ (A /-1) X 1 0 0
  • the cachexia preventive or therapeutic agent containing OC1F of the present invention or a variant thereof as an active ingredient is a water-soluble sterile solution or suspension of adipule dissolved in another pharmacologically acceptable solution. It is also used as a sterile powder formulation (filled in an ampoule with J, preferably a solution of OCIF or a variant thereof, which is preferably dried and dried), and simultaneously diluted with a pharmacologically acceptable solution.
  • the prophylactic or therapeutic agent for serum of the present invention contains OCIF or a mutant thereof as an active ingredient, and can be administered in various forms.
  • the administration form include oral administration by tablets, capsules, granules, powders, and syrups, and parenteral administration by injection, infusion, suppository and the like.
  • the dosage varies depending on symptoms, age, body weight, etc., but in general, for oral administration, it is about 0.1 mg to 1000 mg per day for an adult, and these may be divided into one or several doses. Can be administered. In addition, for parenteral administration, 0.1 mg or 1000 mg can be administered by subcutaneous injection, intramuscular injection or intravenous injection once.

Abstract

Preventives or remedies for cachexia which contain as the active ingredient osteoclastogenesis inhibitory factor (OCIF) or its variant.

Description

明細書 悪液質予防剤又は治療剤 技術分^  Description Cachexia preventive or therapeutic agent
本発明は、 破骨細胞形成抑制因子（Ost.eoclastogenesis Inhibitory Factor:以下、 F OC I Fj という，， ）を有効成分とする悪液質予防剤、 又は治療剤に関する。 背景技術  TECHNICAL FIELD The present invention relates to an agent for preventing or treating cachexia comprising an osteoclast formation inhibitory factor (Ost. Eoclastogenesis Inhibitory Factor; hereinafter, referred to as FOCI Fj) as an active ingredient. Background art
恶:液赏は、 悪性腫瘍、 結核、 糖尿病、 血液疾患、 内分泌疾患、 感染症及び後 天性免疫不全症候群等の慢性病において発症する、 進行性の体重減少、 貧血、 浮 腫、 欲不振などを主症状とする全身性の疾患である（J. Parenteral and Enteral Nutri l ion. vol . 1 2, 286-298, (1988): American Journal of Medicine, vol.85, 289-291 . (1 988)参照）。  恶: Fluid mainly causes progressive weight loss, anemia, edema, anorexia, etc., which develop in chronic diseases such as malignant tumors, tuberculosis, diabetes, blood diseases, endocrine diseases, infectious diseases and acquired immunodeficiency syndrome. It is a systemic disease that causes symptoms (see J. Parenteral and Enteral Nutrition. Vol. 12, 286-298, (1988): American Journal of Medicine, vol. 85, 289-291. (1988) ).
特に恶性腫瘍の患者が悪液質を発症した場合において、 抗腫瘍剤を投与し続 け抗脑瘍効架が現れたと しても、 むしろ抗腫瘍剤による骨髄毒性などの副作用が 加わり、 通常は悪液質の改善は認められない （J. Clinical Oncology, vol.12, 21 3-225. ( )ί )参照）..  In particular, when a patient with a tumor develops cachexia, even if an antitumor agent continues to be administered after the administration of an antitumor agent, side effects such as bone marrow toxicity due to the antitumor agent are added. No improvement in cachexia was observed (see J. Clinical Oncology, vol. 12, 21 3-225. () Ί)).
また、 特に悪性腫瘍患者において悪液質が進行すると、 その患者の体力が著 しく減退するため、 --般的に毒性が強いとされている抗腫瘍剤による治療を続行 することができなくなり、悪性腫瘍の治療に支障をきたすこととなる （J. Clinical Oncology, vol .12, 213-225, (1994)参照）。  In addition, the progression of cachexia, especially in patients with malignant tumors, significantly reduces the patient's physical strength, making it impossible to continue treatment with antitumor drugs, which are generally considered highly toxic. This will hinder the treatment of malignant tumors (see J. Clinical Oncology, vol. 12, 213-225, (1994)).
さらに、 悪液質の症状を改善するために栄養補給を行う ことが多いが、 この ような処置によりかえつて悪性腫瘍の增大をもたらし、 患者の生存期間を短縮す る場合があった (J. Clinical Oncology, vol.12, 213-225, (1994)参照）。  In addition, nutritional supplements are often used to improve cachexia symptoms, but such treatments may instead lead to the growth of malignant tumors and shorten patient survival (J Clinical Oncology, vol. 12, 213-225, (1994)).
以上より、 悪液質の症状を改善する薬剤の開発が望まれている。  Thus, there is a need for the development of a drug that improves the symptoms of cachexia.
一方、 OC.1 Fは配列番号 1 のァミノ酸番号 1乃至 380に記載されるァミノ酸配 列から成り、 破骨細胞の分化ノ又は成熟を抑制する活性を有する蛋白質と して見 出されており、 骨粗鬆症等の骨量減少症や、 変形性関節症又は多発性骨髄腫等の 骨代謝 ·常症の予防又は治療薬と して有用である こ と が知 られている (WO%/262】7 号）， しかしながら、 該蛋白質が悪液質の予防、 治療効果を有す ることは ¾·Πられていなレ、。 の 'ϊ; On the other hand, OC.1 F is composed of the amino acid sequences described in Amino Acid Numbers 1 to 380 of SEQ ID NO: 1 and has been found as a protein having an activity of inhibiting osteoclast differentiation or maturation. And bone loss such as osteoporosis, osteoarthritis, multiple myeloma, etc. It is known to be useful as a preventive or therapeutic agent for bone metabolism and dysfunction (WO% / 262】 7), however, the protein has a preventive and therapeutic effect on cachexia That isn't true. 'Ϊ;
本 ¾明者らは、 OC I F 又はその変異体が悪液質に対し優れた予防又は治療効果 を打することを a出し、 本発明を完成した。  The present inventors have shown that OCIF or a mutant thereof exerts an excellent preventive or therapeutic effect on cachexia, and completed the present invention.
本 ¾明は、  This description is
( 1 ) 配列表の配列番号 1 のァミノ酸番号 1 乃至 380 に示されるァミノ酸配列 を含:むことから成る破骨細胞形成抑制因子 （OCIF) 又はその変異体を有効成分 とする悪液質の予防剤又は治療剤、  (1) A cachexia comprising, as an active ingredient, an osteoclast formation inhibitory factor (OCIF) comprising an amino acid sequence represented by any one of amino acid numbers 1 to 380 of SEQ ID NO: 1 or a mutant thereof. Prophylactic or therapeutic agents,
( ) 配列表の配列番号 1のァミノ酸番号 1 乃至 380に示されるァミノ酸配列 を含むことから成る破骨細胞形成抑制因子 （OCIF) を有効成分とする悪液質の 予防剤又は治療剤、  () A preventive or therapeutic agent for cachexia comprising, as an active ingredient, an osteoclast formation inhibitory factor (OCIF) comprising an amino acid sequence represented by amino acid numbers 1 to 380 of SEQ ID NO: 1 in the sequence listing,
に関する...  About ...
本発明において、 「変異体」 とは、 OCIF の有するアミ ノ酸配列のうち一つ又 は複数のアミ ノ酸が置換、 欠失、 付加又は挿入された蛋白質で OCIF 活性 （破 骨細胞形成抑制活性） を有する蛋白質をいう。  In the present invention, the term “mutant” refers to a protein in which one or more amino acids in the amino acid sequence of OCIF have been substituted, deleted, added or inserted, and the OCIF activity (inhibition of osteoclast formation) is determined. Activity).
OC1 F蛋 質 体は、 W096/26217号に記載された方法により製造することが できる ...  The OC1 F protein can be produced by the method described in W096 / 26217 ...
一般に真核生物の遺伝子は、 インターフヱロン遺伝子などで知られているよ うに多型現象 (polymorphism) を示すと考えられ（例えば、 Nishi, T. et al. (1985) Biochem. HI, 153-159 を参照）、 この多型現象によって、 1個又は複数のアミ ノ酸が置換される場合もあれば、 ヌクレオチド配列の置換はあってもアミノ酸は. 全く変わらない場合もある。  In general, eukaryotic genes are considered to exhibit polymorphism as is known for interferon genes (eg, Nishi, T. et al. (1985) Biochem. HI, 153- 159), this polymorphism may result in the replacement of one or more amino acids, or the nucleotide sequence may be replaced but the amino acids remain the same.
配列番号 1 のァミノ酸番号 1乃至 380に示されるァミノ酸配列から成る OCIF 蛋 質のァミノ酸配列の中の一つ又は複数の部位において、 一つ若しくは複数の アミ ノ酸残基が置換、 欠失、 付加又は挿入されている蛋白質でも OCIF 活性を することが多い.、 本発明においてはこれらの蛋白質を OCIFの変異体と呼ぶ。 すなわち、 それら天然に存在する力 、 あるいは人工合成された蛋白質が、 OCIF 活性を有する限り、 それらの蛋白質はすべて本 明において使用され得る。 At one or more sites in the amino acid sequence of the OCIF protein consisting of the amino acid sequences of amino acids 1 to 380 of SEQ ID NO: 1, one or more amino acid residues are substituted or deleted. Lost, added or inserted proteins often also have OCIF activity. In the present invention, these proteins are referred to as OCIF mutants. That is, as long as these naturally occurring or artificially synthesized proteins have OCIF activity, all of those proteins can be used in the present invention.
このよ うな ¾白質をコー ドする DNAは、 上記の OCIF活性を有する蛋白質の 情報に基づいて、 例えばホスフアイ ト ' ト リエステル法 （Nature, ΰ, 105-111, (1984 ) ![(!) などの常法に従い、 核酸の化学合成により製造することができる。 なお、 所 ァミ ノ酸に対するコ ドンは、 その選択も任意でよく、 例えば利用 する ¾: ί·:のコ ドン使用頻度を考慮して常法に従い決定できる （ Nucleic Acid Res. i>, 143-174. (1981)参照）,， さらにこれらヌクレオチ ド配列のコ ドンの一部改変は、 常法に従い、 所望の改変をコー ドする合成ヌク レオチドからなるプライマ一を利 fflじた、部位特異的変異導入法（site specific mutagenesis/ Proc. Natl. Acad. Sci. USA 81, 5662-5666, (]984)参照） などにより行うことができる。 また、 任意の — ό'若しくは複数のァミ ノ酸残基を欠失させた変異体を作成するためには、 ェキ ソヌク レアーゼ Bal3l 等を用いて DNA を末端から削る方法 （「続生化学実験 講座 1 ， 遺伝子研究法 II」 335-354頁参照）、 カセッ ト変異法 （「新生化学実験講 座 2 ·核酸 I】 I組換え DNA技術」 242-251頁参照） などに従うことができる。 なお、 所 のァ ミ ノ酸に対するコ ドンはそれ自体公知であり、 その選択も任 意でよく、 例えば利 ffjする宿主のコ ドン使用頻度を考慮して常法に従い決定でき る,. DNA encoding such a protein can be obtained, for example, by the phosphite 'triester method (Nature, ΰ, 105-111, (1984)! [! The codon for amino acid can be selected arbitrarily, for example, considering the codon usage of 使用: ¾ ·: to be used. (Refer to Nucleic Acid Res. I>, 143-174. (1981).) Further, partial modification of these nucleotide sequence codons can be carried out according to a conventional method. Site-directed mutagenesis / Proc. Natl. Acad. Sci. USA 81, 5662-5666, (] 984) using the primer consisting of the synthetic nucleotide to be used. In addition, any --ό 'or multiple amino acid residues may be deleted. In order to create a mutant, the DNA is trimmed from the end using exonuclease Bal3l (see “Seismological Chemistry Laboratory Lecture 1, Genetic Research Method II”, pages 335-354), cassette mutation (Refer to “Shinogen Chemistry Laboratory Course 2: Nucleic Acid I] I Recombinant DNA Technology”, pp. 242-251.) The codon for the amino acid is known per se, and Selection is optional, and can be determined according to a conventional method, taking into account, for example, the codon usage of the ffj host.
OC [ F 活性の測定は W096/26217 号に記載された方法により行うことができ る.:.  The OC [F activity can be measured by the method described in W096 / 26217.
本発明において、 「悪液質」 とは、 悪性腫瘍、 結核、 糖尿病、 血液疾患、 内分 泌疾患、 感染症及び後天性免疫不全症候群等の慢性病において発症する、 進行性 の体重減少、 貧血、 浮腫、 食欲不振などを主症状とする全身性の疾患をいう。 発明を実施するための最良の形態  In the present invention, the term "cachexia" refers to a progressive weight loss, anemia, which develops in chronic diseases such as malignant tumors, tuberculosis, diabetes, blood diseases, endocrine diseases, infectious diseases and acquired immunodeficiency syndrome. It refers to a systemic disease with edema and anorexia as the main symptoms. BEST MODE FOR CARRYING OUT THE INVENTION
以下、 実:施例及び製剤例により本発明をさらに詳細に説明するが、 本発明はこ れらに限； 01'さ.れない.,  Hereinafter, the present invention will be described in more detail with reference to Examples and Preparation Examples, but the present invention is not limited thereto;
¾施例 1 . ( ) C 1 Pの抗悪液質効果 ] 群 10匹の Balh/c マウス （雌性、 7週齢） の皮下に、 約 2 mm 角のマウス結 腸癌 Co Ion 26細胞を移植した , Example 1. Anti-cachectic effect of () C 1 P ] A group of 10 Balh / c mice (female, 7 weeks old) were subcutaneously implanted with approximately 2 mm square mouse colon cancer Co Ion 26 cells,
WO 96/26217号記載の方法により製造した OCIF (配列番号 1のァミ ノ酸番号 1 乃 ¾ 3H0 で示される蛋白質） 3mg/kg、 1 0 mg/k 体重を、 1 日 2回、腫瘍細 胞移械 7 II後 1 り速 II静脈内投与した.， OCIF は、 0.0】％Tween80 含有 PBS 3 mg / kg, 10 mg / k body weight of OCIF (protein represented by amino acid No. 1-No. 3H0 of SEQ ID NO: 1) produced by the method described in WO 96/26217 After intracellular transfer 7 II, intravenous injection was performed at a rapid rate II. OCIF was 0.0% Tween80 in PBS.
(Phosphaio Ru Her (Hi Saline ： lOmM りん酸ナト リ ゥム、 0.15M塩化ナト リ ゥム、 （1)117.0)) に溶解したものを使用した。 抗 液質効果は、 以下の式により算定される体重回復率を指標と した。 体童変化 （Δ) =癌移植後 1 2 日 目の体重 （ g ) 一癌移植後 7 日 目の体重、 と して (Phosphaio Ru Her (Hi Saline: lOmM sodium phosphate, 0.15 M sodium chloride, (1) 117.0)). The anti-fluid effect was evaluated using the weight recovery rate calculated by the following formula as an index. Body change (Δ) = body weight on day 12 after cancer transplantation (g) Body weight on day 7 after cancer transplantation
OCTF投 t 担癌マウスの体重変化- (ΔΑ), OCTF injection t Weight change of tumor-bearing mice-(Δ Α ),
OCIF非投^担癌マウスの体重変化 = (ΔΒ) *、 Change in body weight of non-OCIF-bearing mice = (Δ Β ) *,
0 ド非投 -正常マウスの体重変化- (Ac) *、 0 Do not throw-Normal mouse weight change-(A c ) *,
と した場 、 When
体 ®「yl複率 （％) 二 （厶 Α - ΔΒ) / (厶 c— ΔΒ) X 1 0 0 Body ® "yl birefringence index (%) Double (厶Alpha - delta beta) / (厶 c - Δ Β) X 1 0 0
*OCIF非投 >-マゥスには上記 0.01%Tween80含有 PBSのみを投与した。 * Only the above-mentioned PBS containing 0.01% Tween80 was administered to the mouse without OCIF> -mouse.
OCIFを 3mg7kg投与した担癌マウスは 31%の体重回復率、 10 mg/kg投与した 担癌マウスは 50%の体重回復率を示した。 施例 2 , ociFの延命活性 Tumor-bearing mice receiving 3 mg / kg of OCIF showed a 31% body weight recovery rate, and tumor-bearing mice receiving 10 mg / kg showed a 50% body weight recovery rate. Example 2, life-span activity of ociF
実施例〗 記載の方法に従い、 1 群 10 匹の Balb/c マウス （雌性、 7週齢） の皮 下に、 約 2 mm角のマウス結腸癌 Colon26細胞を移植した。  Example 1 According to the method described in the above, mouse colon cancer Colon26 cells of about 2 mm square were transplanted under the skin of 10 Balb / c mice (female, 7 weeks old) per group.
¾施例 】 と同搽の方法で製造した OCIF (配列番号 1 ) 30mg/kg 体重を、 1 日 [Example] 30 mg / kg body weight of OCIF (SEQ ID NO: 1) produced by the same method as in
2回、腫 細胞移植 7 H後より連日腹腔内投与した。 延命活性は、 次式に従い、 延命率 （％) により評価した。 延命率 (%) '■ (A/ - 1 ) X 1 0 0 It was intraperitoneally administered twice daily 7 hours after tumor cell transplantation. The life extension activity was evaluated by the survival rate (%) according to the following formula. Life extension (%) '■ (A /-1) X 1 0 0
Λ ： 0 C fド投 -担癌マウス群生存日数の中央値 Λ: 0 C f de throw-Median days of survival in tumor-bearing mouse group
B： 0 C I F非投 ¥ ft!癌マウス群生存 Θ数の中央値 * B: 0 C I F non-injected ¥ ft!
* OCI I'、非投 -マゥスには上記 0.01%Tween80含有 PBSのみを投与した。 OC1Fを投 したマゥスは 100%の延命率を示した。 製剤例 1 .  * OCI I ', non-cast mice received only PBS containing 0.01% Tween80. The mice that cast OC1F showed a 100% survival rate. Formulation example 1.
本 明の OC1F又はその変異体を有効成分とする悪液質予防剤、 又は治療剤は、 水乂はそれ以外の薬理学的に許容し得る溶液に溶解した無菌性溶液又は懸濁液の アジプルと して使用に供され、 また無菌粉末製剤 （OCIF 又はその変異体の溶液 を^結乾燥するのが望ましい J をアンプルに充填しておき、 同時に薬理学的に 許容し ¾る溶液に希釈してもよい。 産業上の利 fflの可能性  The cachexia preventive or therapeutic agent containing OC1F of the present invention or a variant thereof as an active ingredient is a water-soluble sterile solution or suspension of adipule dissolved in another pharmacologically acceptable solution. It is also used as a sterile powder formulation (filled in an ampoule with J, preferably a solution of OCIF or a variant thereof, which is preferably dried and dried), and simultaneously diluted with a pharmacologically acceptable solution. Industrial profit ffl potential
本発明の恶液質の予防剤又は治療剤は、 OCIF 又はその変異体を有効成分とす るものであるが、 種々の形態で投与することができる。 それらの投与形態と して は、 錠剤、 カプセル剤、 顆粒剤、 散剤、 シロップ剤による経口投与、 又は、 注射 剤、 点滴剤、 座薬などによる非経口投与を挙げることができる。  The prophylactic or therapeutic agent for serum of the present invention contains OCIF or a mutant thereof as an active ingredient, and can be administered in various forms. Examples of the administration form include oral administration by tablets, capsules, granules, powders, and syrups, and parenteral administration by injection, infusion, suppository and the like.
その投与量は、 症状、 年齢、 体重などによって異なるが、 通常、 経口投与で は、 成人に対して、 一日約 0.1m gないし 1000m gであり、 これらを 1 回、 ま たは数回に分けて投与することができる。 また、 非経口投与では 1 回 0.1m gな いし 1000m gを皮下注射、 筋肉注射または静脈注射によって投与することがで きる.:. ' .  The dosage varies depending on symptoms, age, body weight, etc., but in general, for oral administration, it is about 0.1 mg to 1000 mg per day for an adult, and these may be divided into one or several doses. Can be administered. In addition, for parenteral administration, 0.1 mg or 1000 mg can be administered by subcutaneous injection, intramuscular injection or intravenous injection once.
(本頁以下余 ])  (Below this page))

Claims

請求の範囲 The scope of the claims
1 . 配列表の配列番号 1のァミ ノ酸番号 1 乃至 380に示されるァミノ酸配列を 含むことから成る破骨細胞形成抑制因子又はその変異体を有効成分とする悪液質 の ' ) 力剤乂は治療剤.:. 1. The cachexia containing an amino acid sequence represented by amino acid numbers 1 to 380 of SEQ ID NO: 1 in the sequence listing, or a cachexia containing an osteoclast formation inhibitory factor or a mutant thereof as an active ingredient乂 is a therapeutic agent.
2 . 配列 の配列番 - 1 のァミ ノ酸番号 1 乃至 380に示されるァミノ酸配列を 含むことから成る破骨細胞形成抑制因子を有効成分とする悪液質の予防剤又は治 療剤... 2. An agent for preventing or treating cachexia, comprising an osteoclast formation inhibitory factor comprising an amino acid sequence represented by amino acid numbers 1 to 380 of SEQ ID NO: 1 as an active ingredient. .
PCT/JP1999/005570 1998-10-09 1999-10-08 Preventives or remedies for cachexia WO2000021554A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU60060/99A AU6006099A (en) 1998-10-09 1999-10-08 Preventives or remedies for cachexia

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP28773898 1998-10-09
JP10/287738 1998-10-09

Publications (1)

Publication Number Publication Date
WO2000021554A1 true WO2000021554A1 (en) 2000-04-20

Family

ID=17721126

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1999/005570 WO2000021554A1 (en) 1998-10-09 1999-10-08 Preventives or remedies for cachexia

Country Status (2)

Country Link
AU (1) AU6006099A (en)
WO (1) WO2000021554A1 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002097033A2 (en) 2001-05-25 2002-12-05 Human Genome Sciences, Inc. Antibodies that immunospecifically bind to trail receptors
US7749960B2 (en) 2001-04-03 2010-07-06 Nestec S.A. Osteoprotegerin in milk
US8703725B2 (en) 2002-09-20 2014-04-22 Nestec S.A. Nutritional compositions

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0816380A1 (en) * 1995-02-20 1998-01-07 Snow Brand Milk Products Co., Ltd. Novel protein and methods for the production of the same
WO1998012344A1 (en) * 1996-09-18 1998-03-26 Human Genome Sciences, Inc. Human tumor necrosis factor receptor-like genes

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0816380A1 (en) * 1995-02-20 1998-01-07 Snow Brand Milk Products Co., Ltd. Novel protein and methods for the production of the same
WO1998012344A1 (en) * 1996-09-18 1998-03-26 Human Genome Sciences, Inc. Human tumor necrosis factor receptor-like genes

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YASUDA H. ET AL.: "Identity of osteoclastogenesis inhibitory factor (OCIF) and osteoprotegerin (OPG): a mechanism by which OPG/OCIF inhibits osteoclastogenesis", ENDOCRINOLOGY, vol. 139, no. 3, March 1998 (1998-03-01), pages 1329 - 1337 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7749960B2 (en) 2001-04-03 2010-07-06 Nestec S.A. Osteoprotegerin in milk
WO2002097033A2 (en) 2001-05-25 2002-12-05 Human Genome Sciences, Inc. Antibodies that immunospecifically bind to trail receptors
US8703725B2 (en) 2002-09-20 2014-04-22 Nestec S.A. Nutritional compositions

Also Published As

Publication number Publication date
AU6006099A (en) 2000-05-01

Similar Documents

Publication Publication Date Title
JP5357857B2 (en) Anticancer agent and DNA replication inhibitor
CN108026533B (en) Antagonistic PDL1 aptamers and their use in cancer therapy
JP2013543879A (en) Volaceltiv alone or in combination with cytarabine to treat acute myeloid leukemia
KR20040018341A (en) Pharmaceutical combinations for the treatment of cancer
WO1996035430A1 (en) REMEDY AND PREVENTIVE FOR DISEASES CAUSED BY NF-λB
EP1809660B1 (en) A thymus-specific protein
IL272166B2 (en) Combination comprising palbociclib and 6-(2,4-dichlorophenyl)-5-[4-[(3s)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7h-benzo[7]annulene-2-carboxylic acid and its use for the treatment of cancer
JP2009138005A (en) Composition containing ruthenium (iii) complex and containing heterocyclic ring
EP3988175A1 (en) Method for treating malignant tumor
CN111297866B (en) Pharmaceutical composition containing JAK3/JAK1/TBK1 inhibitor and methotrexate and application thereof
TW201122103A (en) Tnf antagonists and tnf inhibitors comprising the same as the active ingredient
EP1894575B1 (en) Therapeutic agent for cancer
EP0758549A1 (en) Medicinal composition as a remedy for nonsmall cell lung cancer
WO2000021554A1 (en) Preventives or remedies for cachexia
CA3059363C (en) Therapeutic agent for blood cancer
EP1208840B1 (en) Combination of fluorouracil and a methylol transfer agent for the treatment of tumor metastases and cancer
TW200306185A (en) Combinations comprising EPOTHILONES and anti-metabolites
EP2117539B1 (en) A method of administering an antitumor compound
JP2002509532A (en) Pharmaceutical compositions of arglabin and arglabin derivatives
CN115243719A (en) CTB006 and Ponatinib combined application
JP2000178200A (en) Cachexia prevention or treatment agent
US20220387475A1 (en) Methods and compositions for treating endometriosis
EP4331614A1 (en) Use of medicament in treatment of tumor disease
JP4395901B2 (en) New drug for gene therapy
US11298366B2 (en) Ibandronate conjugates of nucleoside antimetabolites

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU BR CA CN CZ HU ID IL IN KR MX NO NZ PL RU TR US ZA

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
122 Ep: pct application non-entry in european phase