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 PDFInfo
- 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
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- targeting agent
- mek inhibitor
- conjugate according
- pain
- conjugate
- Prior art date
Links
- 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 title claims abstract description 44
- 239000003795 chemical substances by application Substances 0.000 title claims abstract description 34
- 230000008685 targeting Effects 0.000 title claims abstract description 34
- 229940124647 MEK inhibitor Drugs 0.000 title claims abstract description 31
- 230000001225 therapeutic effect Effects 0.000 title description 4
- 208000002193 Pain Diseases 0.000 claims abstract description 26
- 208000000094 Chronic Pain Diseases 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 8
- 210000001044 sensory neuron Anatomy 0.000 claims abstract description 4
- 206010003246 arthritis Diseases 0.000 claims description 11
- 206010028980 Neoplasm Diseases 0.000 claims description 10
- 201000011510 cancer Diseases 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 8
- 208000004296 neuralgia Diseases 0.000 claims description 7
- 102000004856 Lectins Human genes 0.000 claims description 6
- 108090001090 Lectins Proteins 0.000 claims description 6
- 239000002523 lectin Substances 0.000 claims description 6
- 208000021722 neuropathic pain Diseases 0.000 claims description 6
- 206010065390 Inflammatory pain Diseases 0.000 claims description 5
- 230000002265 prevention Effects 0.000 claims description 5
- 230000002981 neuropathic effect Effects 0.000 claims description 4
- 210000004044 posterior horn cell Anatomy 0.000 claims description 4
- 108091008604 NGF receptors Proteins 0.000 claims description 3
- 102000007339 Nerve Growth Factor Receptors Human genes 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 210000002569 neuron Anatomy 0.000 claims description 3
- 230000008335 axon cargo transport Effects 0.000 claims description 2
- 230000001268 conjugating effect Effects 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 238000001727 in vivo Methods 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 description 12
- 102000004232 Mitogen-Activated Protein Kinase Kinases Human genes 0.000 description 8
- 108090000744 Mitogen-Activated Protein Kinase Kinases Proteins 0.000 description 8
- 229940113118 carrageenan Drugs 0.000 description 7
- 235000010418 carrageenan Nutrition 0.000 description 7
- 229920001525 carrageenan Polymers 0.000 description 7
- 239000000679 carrageenan Substances 0.000 description 7
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 7
- 229940079593 drug Drugs 0.000 description 6
- 210000002683 foot Anatomy 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 210000003594 spinal ganglia Anatomy 0.000 description 5
- 210000000548 hind-foot Anatomy 0.000 description 4
- 208000004454 Hyperalgesia Diseases 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 239000012634 fragment Substances 0.000 description 3
- 238000001262 western blot Methods 0.000 description 3
- 208000035154 Hyperesthesia Diseases 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 102100024193 Mitogen-activated protein kinase 1 Human genes 0.000 description 2
- 230000005754 cellular signaling Effects 0.000 description 2
- 230000021615 conjugation Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 101000876610 Dictyostelium discoideum Extracellular signal-regulated kinase 2 Proteins 0.000 description 1
- 108030004793 Dual-specificity kinases Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 108010007457 Extracellular Signal-Regulated MAP Kinases Proteins 0.000 description 1
- 101001052493 Homo sapiens Mitogen-activated protein kinase 1 Proteins 0.000 description 1
- 102000019149 MAP kinase activity proteins Human genes 0.000 description 1
- 108040008097 MAP kinase activity proteins Proteins 0.000 description 1
- 102000043136 MAP kinase family Human genes 0.000 description 1
- 108091054455 MAP kinase family Proteins 0.000 description 1
- 239000012820 MEK1 Inhibitor Substances 0.000 description 1
- 208000001294 Nociceptive Pain Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 208000005298 acute pain Diseases 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003070 anti-hyperalgesia Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000003040 nociceptive effect Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
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)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
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 |
---|---|---|---|
GB0213383.3 | 2002-06-11 | ||
GBGB0213383.3A GB0213383D0 (en) | 2002-06-11 | 2002-06-11 | Therapeutic conditions |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2003103717A1 true WO2003103717A1 (fr) | 2003-12-18 |
Family
ID=9938360
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB2003/002501 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)
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)
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 |
WO2000056706A1 (fr) * | 1999-03-19 | 2000-09-28 | Du Pont Pharmaceuticals Company | Amino-thio-acrylonitriles utilises comme inhibiteurs des kinases mek |
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 |
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 |
-
2002
- 2002-06-11 GB GBGB0213383.3A patent/GB0213383D0/en not_active Ceased
-
2003
- 2003-06-11 WO PCT/GB2003/002501 patent/WO2003103717A1/fr not_active Application Discontinuation
- 2003-06-11 AU AU2003240080A patent/AU2003240080A1/en not_active Abandoned
Patent Citations (8)
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 |
WO2000056706A1 (fr) * | 1999-03-19 | 2000-09-28 | Du Pont Pharmaceuticals Company | Amino-thio-acrylonitriles utilises comme inhibiteurs des kinases mek |
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 |
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)
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)
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 |
Also Published As
Publication number | Publication date |
---|---|
GB0213383D0 (en) | 2002-07-24 |
AU2003240080A1 (en) | 2003-12-22 |
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