JP6612860B2 - コンジュゲート及びコンジュゲート試薬 - Google Patents

コンジュゲート及びコンジュゲート試薬 Download PDF

Info

Publication number
JP6612860B2
JP6612860B2 JP2017519672A JP2017519672A JP6612860B2 JP 6612860 B2 JP6612860 B2 JP 6612860B2 JP 2017519672 A JP2017519672 A JP 2017519672A JP 2017519672 A JP2017519672 A JP 2017519672A JP 6612860 B2 JP6612860 B2 JP 6612860B2
Authority
JP
Japan
Prior art keywords
group
conjugate
reagent
polyethylene glycol
formula
Prior art date
Legal status (The legal status 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 status listed.)
Active
Application number
JP2017519672A
Other languages
English (en)
Japanese (ja)
Other versions
JP2017537062A5 (cg-RX-API-DMAC7.html
JP2017537062A (ja
Inventor
アントニー・ゴドウィン
マーク・フリゲリオ
Original Assignee
ポリセリックス・リミテッド
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
Priority claimed from GBGB1418989.8A external-priority patent/GB201418989D0/en
Priority claimed from GBGB1418986.4A external-priority patent/GB201418986D0/en
Priority claimed from GB1418984.9A external-priority patent/GB2531715A/en
Application filed by ポリセリックス・リミテッド filed Critical ポリセリックス・リミテッド
Publication of JP2017537062A publication Critical patent/JP2017537062A/ja
Publication of JP2017537062A5 publication Critical patent/JP2017537062A5/ja
Application granted granted Critical
Publication of JP6612860B2 publication Critical patent/JP6612860B2/ja
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Cell Biology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicinal Preparation (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
JP2017519672A 2014-10-24 2015-10-08 コンジュゲート及びコンジュゲート試薬 Active JP6612860B2 (ja)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
GB1418989.8 2014-10-24
GBGB1418989.8A GB201418989D0 (en) 2014-10-24 2014-10-24 Novel conjugation process and reagents
GB1418986.4 2014-10-24
GBGB1418986.4A GB201418986D0 (en) 2014-10-24 2014-10-24 Novel conjugates and novel conjugating reagents
GB1418984.9A GB2531715A (en) 2014-10-24 2014-10-24 Novel drug conjugates
GB1418984.9 2014-10-24
PCT/GB2015/052953 WO2016063006A1 (en) 2014-10-24 2015-10-08 Conjugates and conjugating reagents

Publications (3)

Publication Number Publication Date
JP2017537062A JP2017537062A (ja) 2017-12-14
JP2017537062A5 JP2017537062A5 (cg-RX-API-DMAC7.html) 2018-11-22
JP6612860B2 true JP6612860B2 (ja) 2019-11-27

Family

ID=54337308

Family Applications (1)

Application Number Title Priority Date Filing Date
JP2017519672A Active JP6612860B2 (ja) 2014-10-24 2015-10-08 コンジュゲート及びコンジュゲート試薬

Country Status (15)

Country Link
US (3) US20170290925A1 (cg-RX-API-DMAC7.html)
EP (1) EP3220956B1 (cg-RX-API-DMAC7.html)
JP (1) JP6612860B2 (cg-RX-API-DMAC7.html)
KR (1) KR102513926B1 (cg-RX-API-DMAC7.html)
CN (1) CN107073131B (cg-RX-API-DMAC7.html)
AU (1) AU2015334717B2 (cg-RX-API-DMAC7.html)
BR (1) BR112017005760A2 (cg-RX-API-DMAC7.html)
CA (1) CA2963043A1 (cg-RX-API-DMAC7.html)
ES (1) ES2960741T3 (cg-RX-API-DMAC7.html)
IL (1) IL250644B (cg-RX-API-DMAC7.html)
MX (1) MX2017005199A (cg-RX-API-DMAC7.html)
RU (1) RU2017108448A (cg-RX-API-DMAC7.html)
SG (1) SG11201701342XA (cg-RX-API-DMAC7.html)
WO (1) WO2016063006A1 (cg-RX-API-DMAC7.html)
ZA (1) ZA201701337B (cg-RX-API-DMAC7.html)

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10098960B2 (en) 2015-04-03 2018-10-16 Ucl Business Plc Polymer conjugate
JP2019506155A (ja) 2016-01-12 2019-03-07 クレッシェンド、バイオロジックス、リミテッドＣｒｅｓｃｅｎｄｏ Ｂｉｏｌｏｇｉｃｓ Ｌｉｍｉｔｅｄ 治療分子
WO2017161206A1 (en) 2016-03-16 2017-09-21 Halozyme, Inc. Conjugates containing conditionally active antibodies or antigen-binding fragments thereof, and methods of use
EP3442595A1 (en) * 2016-04-14 2019-02-20 Polytherics Limited Conjugates and conjugating reagents comprising a linker that includes at least two (-ch2-ch2-0-) units in a ring
GB201608936D0 (en) * 2016-05-20 2016-07-06 Polytherics Ltd Novel conjugates and novel conjugating reagents
EP4282434A3 (en) 2016-06-06 2024-03-06 Abzena (UK) Limited Antibodies, uses thereof and conjugates thereof
GB201614162D0 (en) 2016-08-18 2016-10-05 Polytherics Ltd Antibodies, uses thereof and conjugates thereof
GB201615725D0 (en) 2016-09-15 2016-11-02 Polytherics Ltd Novel cytotoxic agents and conjugates thereof
WO2018181059A1 (ja) 2017-03-30 2018-10-04 日油株式会社 ヘテロ二官能性単分散ポリエチレングリコール及びそれを用いた複合体
GB201711068D0 (en) 2017-07-10 2017-08-23 Crescendo Biologics Ltd Therapeutic molecules binding PSMA
CN111836846B (zh) 2018-03-13 2023-06-13 日油株式会社 在主链和侧链具有单分散聚乙二醇的异双官能性化合物
EP3789401A1 (en) 2019-09-03 2021-03-10 Gamamabs Pharma Amhrii-binding antibody drug conjugates and their use thereof in the treatment of cancers
EP4145134A1 (en) * 2020-04-29 2023-03-08 Araclón Biotech, S. L. Methods for quantification of amyloid beta peptides in plasma by mass spectrometry
GB2594753B (en) 2020-05-27 2022-05-18 Spirea Ltd Antibody-drug conjugates
EP4404974A1 (en) 2021-09-21 2024-07-31 Spirea Limited Antibody-drug conjugates

Family Cites Families (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5446090A (en) * 1993-11-12 1995-08-29 Shearwater Polymers, Inc. Isolatable, water soluble, and hydrolytically stable active sulfones of poly(ethylene glycol) and related polymers for modification of surfaces and molecules
EP1061954B1 (en) * 1998-03-12 2004-06-09 Nektar Therapeutics Al, Corporation Poly(ethylene glycol) derivatives with proximal reactive groups
KR100511749B1 (ko) * 2001-11-06 2005-09-02 선바이오(주) 변형된 인터페론-베타, 및 이의 화학적으로 변형된 배합체
KR101520209B1 (ko) * 2003-11-06 2015-05-13 시애틀 지네틱스, 인크. 리간드에 접합될 수 있는 모노메틸발린 화합물
WO2007018431A2 (en) * 2005-08-05 2007-02-15 Syntarga B.V. Triazole-containing releasable linkers and conjugates comprising the same
US20070141134A1 (en) * 2005-12-16 2007-06-21 Kosak Matthew K Shielded micelles for polynucleotide delivery
MX2009002855A (es) * 2006-09-15 2009-03-30 Enzon Pharmaceuticals Inc Profarmacos polimericos dirigidos que contienen enlazadores multifuncionales.
US8575397B2 (en) * 2007-02-14 2013-11-05 Biocompatibles Uk Limited Derivatisation of biological molecules
GB0922354D0 (en) * 2009-12-21 2010-02-03 Polytherics Ltd Novel polymer conjugates
WO2012113847A1 (en) * 2011-02-25 2012-08-30 Lonza Ltd Branched linker for protein drug conjugates
CN104906592B (zh) * 2011-02-25 2017-11-03 广州南沙龙沙有限公司 用于蛋白质药物偶联物的支链联接体
GB201210770D0 (en) * 2012-06-18 2012-08-01 Polytherics Ltd Novel conjugation reagents
US9650331B2 (en) * 2012-06-18 2017-05-16 Polytherics Limited Conjugation reagents
IN2014DN10428A (cg-RX-API-DMAC7.html) * 2012-06-19 2015-08-21 Polytherics Ltd
IN2015DN02349A (cg-RX-API-DMAC7.html) * 2012-10-24 2015-08-28 Polytherics Ltd
NO2789793T3 (cg-RX-API-DMAC7.html) * 2012-10-24 2018-01-27
KR102356814B1 (ko) * 2013-10-15 2022-01-28 씨젠 인크. 개선된 리간드-약물 컨쥬게이트 약물동력학을 위한 peg화된 약물-링커

Also Published As

Publication number Publication date
SG11201701342XA (en) 2017-03-30
CA2963043A1 (en) 2016-04-28
EP3220956A1 (en) 2017-09-27
US20170290925A1 (en) 2017-10-12
CN107073131B (zh) 2021-05-25
MX2017005199A (es) 2017-07-26
IL250644B (en) 2020-10-29
KR102513926B1 (ko) 2023-03-23
ES2960741T3 (es) 2024-03-06
IL250644A0 (en) 2017-06-29
AU2015334717B2 (en) 2021-02-25
US20240293549A1 (en) 2024-09-05
EP3220956B1 (en) 2023-08-09
ZA201701337B (en) 2018-05-30
WO2016063006A1 (en) 2016-04-28
AU2015334717A1 (en) 2017-04-13
US20200268885A1 (en) 2020-08-27
KR20170075724A (ko) 2017-07-03
BR112017005760A2 (pt) 2017-12-12
CN107073131A (zh) 2017-08-18
RU2017108448A (ru) 2018-11-27
JP2017537062A (ja) 2017-12-14

Similar Documents

Publication Publication Date Title
JP6612860B2 (ja) コンジュゲート及びコンジュゲート試薬
EP1534334B1 (en) Releasable polymeric conjugates based on aliphatic biodegradable linkers
JP4824404B2 (ja) 脂肪族生物分解性リンカーに基づく放出可能なポリマー複合体
US20040192769A1 (en) Heterobifunctional polymeric bioconjugates
JP7069043B2 (ja) コンジュゲート及びコンジュゲート試薬
JP2017534612A (ja) Ｐｅｇの部分を含めた脱離基を含む試薬を用いるペプチド又はタンパク質のコンジュゲーションのための方法
JP5405746B2 (ja) 脂肪族生物分解性リンカーに基づく放出可能なポリマー複合体
US11865183B2 (en) Conjugates and conjugating reagents comprising a linker that includes at least two (−CH2—CH2—O—) units in a ring
JP4999226B2 (ja) クマリン及び関連芳香族系ポリマープロドラッグ

Legal Events

Date Code Title Description
A521 Request for written amendment filed

Free format text: JAPANESE INTERMEDIATE CODE: A523

Effective date: 20181009

A621 Written request for application examination

Free format text: JAPANESE INTERMEDIATE CODE: A621

Effective date: 20181009

A977 Report on retrieval

Free format text: JAPANESE INTERMEDIATE CODE: A971007

Effective date: 20190606

A131 Notification of reasons for refusal

Free format text: JAPANESE INTERMEDIATE CODE: A131

Effective date: 20190617

A521 Request for written amendment filed

Free format text: JAPANESE INTERMEDIATE CODE: A523

Effective date: 20190917

TRDD Decision of grant or rejection written
A01 Written decision to grant a patent or to grant a registration (utility model)

Free format text: JAPANESE INTERMEDIATE CODE: A01

Effective date: 20191007

A61 First payment of annual fees (during grant procedure)

Free format text: JAPANESE INTERMEDIATE CODE: A61

Effective date: 20191031

R150 Certificate of patent or registration of utility model

Ref document number: 6612860

Country of ref document: JP

Free format text: JAPANESE INTERMEDIATE CODE: R150

R250 Receipt of annual fees

Free format text: JAPANESE INTERMEDIATE CODE: R250

R250 Receipt of annual fees

Free format text: JAPANESE INTERMEDIATE CODE: R250

R250 Receipt of annual fees

Free format text: JAPANESE INTERMEDIATE CODE: R250

S533 Written request for registration of change of name

Free format text: JAPANESE INTERMEDIATE CODE: R313533

R350 Written notification of registration of transfer

Free format text: JAPANESE INTERMEDIATE CODE: R350

R250 Receipt of annual fees

Free format text: JAPANESE INTERMEDIATE CODE: R250