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WO2003103717A1 - Conjugue therapeutique compose d'un inhibiteur de la mek et d'un agent de ciblage - Google Patents

Conjugue therapeutique compose d'un inhibiteur de la mek et d'un agent de ciblage Download PDF

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Publication number
WO2003103717A1
WO2003103717A1 PCT/GB2003/002501 GB0302501W WO03103717A1 WO 2003103717 A1 WO2003103717 A1 WO 2003103717A1 GB 0302501 W GB0302501 W GB 0302501W WO 03103717 A1 WO03103717 A1 WO 03103717A1
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WO
WIPO (PCT)
Prior art keywords
targeting agent
mek inhibitor
conjugate according
pain
conjugate
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.)
Ceased
Application number
PCT/GB2003/002501
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English (en)
Inventor
Kevin Lee
Michael Ting Bong Ho
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cambridge Biotechnology Ltd
Original Assignee
Cambridge Biotechnology 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 Cambridge Biotechnology Ltd filed Critical Cambridge Biotechnology Ltd
Priority to AU2003240080A priority Critical patent/AU2003240080A1/en
Publication of WO2003103717A1 publication Critical patent/WO2003103717A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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

Definitions

  • This invention relates to a conjugate for use in therapy, and in particular for use in the treatment of pain.
  • MEK inhibitors One class of compounds that can be used for the treatment of pain comprises MEK inhibitors.
  • MEK enzymes are dual- specificity kinases involved in, for example, immunomodulation, inflammation and proliferative diseases such as cancer and restenosis .
  • MEK inhibitors may reduce chronic pain as the MEK pathway is 'upregulated in dorsal horn neurons in persistent pain (Journal of Neuroscience, January 15, 2002, 22(2): 478-485).
  • MEK inhibitors and their uses are described in, for example, WO 01/05390, WO 01/05391, WO 01/05392 and WO 01/05393 (these publications, and also publications identified therein, are incorporated herein by reference) .
  • the present invention is based on the realisation that the utility of MEK inhibitors as agents for the treatment of a condition such as arthritis, cancer or pain can be enhanced by conjugation with a suitable targeting agent.
  • the targeting agent should be capable of delivering the MEK inhibitor to the locus of the condition.
  • the MEK inhibitor may be targeted to those neurons actually malfunctioning in neuropathic pain, i.e. c-fibres and dorsal horn neurons .
  • MEK inhibitors are known.
  • therapeutic endpoints, including pain that may be treated with MEK inhibitors are known.
  • a conjugate of the MEK inhibitor and a targeting agent is provided.
  • conjugate for use in the treatment of a condition such as arthritis, cancer or pain, comprising a MEK inhibitor and a targeting agent, wherein the targeting agent can deliver the MEK inhibitor to the locus of a condition.
  • the MEK inhibitor may be any compound that reduces or blocks MEK activity, particularly the ability of MEK to activate MAP kinase, specifically the ERK kinase.
  • Known MEK inhibitors are described in WO 01/05390, WO 01/05391, WO 01/05392, and WO 01/05393, and the publications cited therein.
  • Preferred MEK inhibitors include U0126 (MEKl/2 inhibitor from Cell Signaling Technology) : and PD98059 (MEK1 inhibitor from Cell Signaling Technology) :
  • the targeting agent may also be known.
  • suitable targeting agents include monoclonal antibodies and axonal transport facilitators .
  • Compounds such as NGF receptor and the IB4 lectin binding site can be used as c- fibre recognition structures.
  • Such compounds, their preparation and means for their conjugation to drugs, are known.
  • a hydrolysable linker may be used.
  • the targeting agent should be capable of binding to the locus of the condition to allow- the MEK inhibitor to act.
  • the locus of the condition includes any site- at which delivery of a MEK inhibitor will allow the MEK inhibitor to exert a beneficial therapeutic effect in relation to the condition.
  • the targeting agent may comprise any binding partner of a component at the locus .
  • the targeting agent may comprise an antibody (or fragment or derivative thereof) , . preferably a monoclonal antibody.
  • the antibody, fragment, or derivative is directed to a cell surface molecule.
  • the targeting agent can bind to sensory neurons .
  • Targeting of a MEK inhibitor to sensory neurons is expected to provide relief against pain, particularly ' chronic pain such as neuropathic or inflammatory pain.
  • the chronic pain may be associated with cancer or arthritis .
  • the targeting agent can bind to c-fibres or A fibres (in particular A ⁇ fibres) .
  • the targeting agent may comprise an antibody (or fragment or derivative thereof) , NGF (or a derivative thereof which binds the NGF receptor) , lectin (or a derivative thereof which binds the IB4 lectin binding site) , or any ligand that binds to receptors expressed on c-fibres.
  • MEK inhibitors are also known to have anti-cancer activity.
  • a conjugate can be used in the treatment of cancer.
  • the targeting agent can bind to a tumour cell.
  • the targeting agent may be an antibody (preferably a monoclonal antibody) against a tumour cell.
  • MEK inhibitors are also known to have anti-inflammatory activity in arthritis.
  • a conjugate can be used in the treatment of arthritis .
  • the targeting agent can bind to a site of inflammation in arthritis.
  • the targeting agent may be covalently or non-covalently conjugated to the MEK inhibitor.
  • the conjugate binds to a cell, it is thought that the conjugate is internalised, and the MEK inhibitor released from the targeting agent so that it can inhibit MEK.
  • Preferred covalent linkages comprise bonds that are likely to be broken in vivo after the conjugate has been delivered to the cell and internalised. Suitable covalent linkages comprise an ester, peptide, or disulphide bond.
  • a method of making a conjugate of the invention which comprises conjugating a MEK inhibitor to a targeting agent which can deliver the MEK inhibitor to the locus of a condition.
  • a method of preventing, treating or ameliorating arthritis, cancer or pain which comprises administering a conjugate of the invention to a subject in need of such prevention, treatment, or amelioration.
  • Preferred methods of the invention are for the prevention, treatment, or amelioration of chronic pain, such as neuropathic or inflammatory pain.
  • a conjugate may be formulated with any suitable carrier, excipient or diluent.
  • a composition of the invention may be in any suitable form, of which examples are tablets, capsules, sachets, vials, powders, granules, lozenges, suppositories and liquid preparations such as oral and/or sterile . parenteral solutions or suspensions .
  • the compound may be formulated for administration by any suitable route, depending on the site of the condition to be treated. Suitable routes of administration are oral, rectal, topical, parenteral and pulmonary. Parenteral administration may be by subcutaneous, intravenous, intramuscular or intrasternal injection.
  • the amount of • the active agent to be administered can be determined depending on the usual factors, such as the potency of the active agent, the nature and severity of the condition to be treated, and the condition, age and other characteristics of the patient .
  • a suitable dosage can be determined by one skilled in the art, or can be based on existing data for MEK inhibitors, allowing for the fact that targeted administration will generally require less of the active agent to be administered.
  • Coupling of drugs to specific carriers e.g. antibodies, NGF, lectins or other specific recognition processes enables the drug to be selectively administered to c- fibres which may also transport the said drug and deliver it to the dorsal horn neurons . This may dramatically reduce the dose required and avoid (or reduce) the side- effects seen with most MEK inhibitors.
  • Figure 1 shows Western blot analysis of ERKl/2 and pERKl/2 activity in rat DRGs (L4-L6) following carrageenan injection into the hind paw;
  • Figure 2 shows the effect of MEK inhibitor on paw withdrawal latency (PWL) in carrageenan induced thermal hyperalgesia (CITH) .
  • MEK activity was assessed in the dorsal root ganglion (DRG) by measuring the phosphorylation of ERK1 and ERK2 using Western blotting.
  • Figure 1 shows Western blot analysis of ⁇ RKl/2 and pERKl/2 activity in rat dorsal root ganglions (DRGs) (L4-L6) following carrageenan injection into the hind paw.
  • the intensity of the bands is proportional to the level of protein.
  • Administration of carrageenan into the right paw (Ipsi) produced an increase in the level of pERKl/2 but not ERKl/2 when compared with the control paw (Con) .
  • the increase in staining intensity indicates an increase in MEK activity on the treated side but not the untreated side.
  • the MEK inhibitor U0126 (2mg/kg, i.p.) was administered 30 minutes prior to injection of carrageenan into the hind paw

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des conjugués utilisés pour le traitement de la douleur, notamment des douleurs chroniques. Ces conjugués contiennent un inhibiteur de la MEK et un agent de ciblage. L'agent de ciblage cible l'inhibiteur de la MEK pour détecter les neurones, ce qui permet de réduire le dosage d'inhibiteur de la MEK requis dans le traitement des douleurs chroniques. L'invention concerne également des procédés de traitement des douleurs chroniques utilisant des conjugués.
PCT/GB2003/002501 2002-06-11 2003-06-11 Conjugue therapeutique compose d'un inhibiteur de la mek et d'un agent de ciblage Ceased WO2003103717A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003240080A AU2003240080A1 (en) 2002-06-11 2003-06-11 Therapeutic conjugate consisting of a mek inhibitor and a targeting agent

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB0213383.3A GB0213383D0 (en) 2002-06-11 2002-06-11 Therapeutic conditions
GB0213383.3 2002-06-11

Publications (1)

Publication Number Publication Date
WO2003103717A1 true WO2003103717A1 (fr) 2003-12-18

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2003/002501 Ceased WO2003103717A1 (fr) 2002-06-11 2003-06-11 Conjugue therapeutique compose d'un inhibiteur de la mek et d'un agent de ciblage

Country Status (3)

Country Link
AU (1) AU2003240080A1 (fr)
GB (1) GB0213383D0 (fr)
WO (1) WO2003103717A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114788867A (zh) * 2022-04-24 2022-07-26 天津医科大学总医院 Map2k1作为化疗后神经痛的治疗靶点的应用

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994023752A1 (fr) * 1993-04-16 1994-10-27 University Of Portsmouth Enterprise Limited Systeme d'apport en medicament
WO1999017806A1 (fr) * 1997-10-08 1999-04-15 The Speywood Laboratory Limited Conjugues de lectines fixatrices de galactose et de neurotoxines clostridiales, utilises comme analgesiques
WO2000056725A1 (fr) * 1999-03-19 2000-09-28 Du Pont Pharmaceuticals Company N-adamant-1-yl-n'-[4-chlorobenzothiazol-2-yl] uree utilisee dans le traitement des inflammations et comme agent de radiosensibilisation anticancereux
WO2000056706A1 (fr) * 1999-03-19 2000-09-28 Du Pont Pharmaceuticals Company Amino-thio-acrylonitriles utilises comme inhibiteurs des kinases mek
WO2000057897A1 (fr) * 1999-03-31 2000-10-05 Microbiological Research Authority Utilisation de la lectine ou de conjugues pour moduler l'activite de la fibre c
WO2001005390A2 (fr) * 1999-07-16 2001-01-25 Warner-Lambert Company Methode de traitement de la douleur chronique au moyen d'inhibiteurs de mek
WO2002017952A2 (fr) * 2000-09-01 2002-03-07 Van Andel Institute Inhibition de la voie de la proteine mapkkk: une strategie therapeutique selective contre les melanomes

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994023752A1 (fr) * 1993-04-16 1994-10-27 University Of Portsmouth Enterprise Limited Systeme d'apport en medicament
WO1999017806A1 (fr) * 1997-10-08 1999-04-15 The Speywood Laboratory Limited Conjugues de lectines fixatrices de galactose et de neurotoxines clostridiales, utilises comme analgesiques
WO2000056725A1 (fr) * 1999-03-19 2000-09-28 Du Pont Pharmaceuticals Company N-adamant-1-yl-n'-[4-chlorobenzothiazol-2-yl] uree utilisee dans le traitement des inflammations et comme agent de radiosensibilisation anticancereux
WO2000056706A1 (fr) * 1999-03-19 2000-09-28 Du Pont Pharmaceuticals Company Amino-thio-acrylonitriles utilises comme inhibiteurs des kinases mek
WO2000057897A1 (fr) * 1999-03-31 2000-10-05 Microbiological Research Authority Utilisation de la lectine ou de conjugues pour moduler l'activite de la fibre c
WO2001005390A2 (fr) * 1999-07-16 2001-01-25 Warner-Lambert Company Methode de traitement de la douleur chronique au moyen d'inhibiteurs de mek
WO2002017952A2 (fr) * 2000-09-01 2002-03-07 Van Andel Institute Inhibition de la voie de la proteine mapkkk: une strategie therapeutique selective contre les melanomes
US20020054869A1 (en) * 2000-09-01 2002-05-09 Han-Mo Koo Inhibition of mitogen-activated protein kinase (MAPK) pathway: a selective therapeutic strategy against melanoma

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
DUNCIA J V ET AL: "MEK inhibitors: the chemistry and biological activity of U0126, its analogs, and cyclization products", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, OXFORD, GB, vol. 8, no. 20, 20 October 1998 (1998-10-20), pages 2839 - 2844, XP004139571, ISSN: 0960-894X *
RU-RONG JI ET AL: "NOCICEPTIVE-SPECIFIC ACTIVATION OF ERK IN SPINAL NEURONS CONTRIBUTES TO PAIN HYPERSENSITIVITY", NATURE NEUROSCIENCE, NATURE AMERICA, INC, US, vol. 2, no. 12, December 1999 (1999-12-01), pages 1114 - 1119, XP000978586, ISSN: 1097-6256 *
SEBOLT-LEOPOLD J.S.: "Development of anticancer drugs targeting the MAP kinase pathway", ONCOGENE, vol. 19, no. 56, 27 December 2000 (2000-12-27), pages 6594 - 6599, XP002250479 *
SEZAKI H ET AL: "MACROMOLECULE-DRUG CONJUGATES IN TARGETED CANCER CHEMOTHERAPY", CRITICAL REVIEWS IN THERAPEUTIC DRUG CARRIER SYSTEMS, XX, XX, vol. 1, 1984, pages 1 - 38, XP002037405, ISSN: 0743-4863 *
TAKAKURA Y ET AL: "MACROMOLECULAR CARRIER SYSTEMS FOR TARGETED DRUG DELIVERY: PHARMACOKINETIC CONSIDERATIONS ON BIODISTRIBUTION", PHARMACEUTICAL RESEARCH, NEW YORK, NY, US, vol. 13, no. 6, June 1996 (1996-06-01), pages 820 - 831, XP001006101, ISSN: 0724-8741 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114788867A (zh) * 2022-04-24 2022-07-26 天津医科大学总医院 Map2k1作为化疗后神经痛的治疗靶点的应用

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AU2003240080A1 (en) 2003-12-22
GB0213383D0 (en) 2002-07-24

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