WO2007047489A2 - Compositions et procedes utilises dans le traitement du cancer - Google Patents

Compositions et procedes utilises dans le traitement du cancer Download PDF

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Publication number
WO2007047489A2
WO2007047489A2 PCT/US2006/040183 US2006040183W WO2007047489A2 WO 2007047489 A2 WO2007047489 A2 WO 2007047489A2 US 2006040183 W US2006040183 W US 2006040183W WO 2007047489 A2 WO2007047489 A2 WO 2007047489A2
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egfr
rtk
ligand
inhibitor
dosage form
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PCT/US2006/040183
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English (en)
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WO2007047489A3 (fr
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Mark Brann
Hans Schiffer
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Acadia Pharmaceuticals Inc.
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Publication of WO2007047489A3 publication Critical patent/WO2007047489A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1808—Epidermal growth factor [EGF] urogastrone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1841—Transforming growth factor [TGF]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/185—Nerve growth factor [NGF]; Brain derived neurotrophic factor [BDNF]; Ciliary neurotrophic factor [CNTF]; Glial derived neurotrophic factor [GDNF]; Neurotrophins, e.g. NT-3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present invention relates to the field of medicine.
  • it relates to pharmaceutical compositions and methods for ameliorating one or more adverse effects associated with administering a chemotherapeutic agent.
  • EGFR epidermal growth factor receptor
  • RTK receptor tyrosine kinase
  • quinazoline EGFR inhibitors represent a convenient treatment option for patients that show a response to these compounds because they can be orally, self administered according to a once-daily treatment regimen.
  • the amount of quinazoline EGFR inhibitor that can be administered, and thus the inhibitory effect is limited by the high incidence of adverse side effects.
  • both gefitinib and erlotinib produce adverse gastrointestinal effects and skin disorders in a large portion of the patient population receiving either of these treatments. Accordingly, there is a need to ameliorate the adverse gastrointestinal effects and skin disorders associated with the oral administration of quinazoline therapeutics. More generally, there is a need to reduce adverse effects associated with administering any RTK inhibitor to patients in need of RTK inhibitor therapy.
  • compositions for increasing receptor tyrosine kinase (RTK) function in noncancerous tissues of patients that are treated with RTK inhibitors comprise a first dosage form comprising an RTK inhibitor and a second dosage form comprising an RTK ligand.
  • RTK ligand interacts with an RTK that is inhibited by the supplied RTK inhibitor.
  • Pharmaceutical compositions described herein can be for any type of administration including, but not limited to, oral, parenteral and topical administration.
  • the method comprises co-administering an RTK inhibitor and an RTK ligand.
  • the RTK ligand interacts with an RTK that is inhibited by the supplied RTK inhibitor.
  • RTK inhibitors and RTK ligands can be co-administered by various routes of administrations including, but not limited to, oral, parenteral and topical administration.
  • Still other aspects of the present invention relate to methods of using an RTK ligand to ameliorate adverse effects associated with administration of an RTK inhibitor in a human.
  • the method comprises informing the human that co-administering RTK ligand with an RTK inhibitor ameliorates at least one adverse effect associated with the administration of the RTK inhibitor.
  • the RTK ligand interacts with an RTK that is inhibited by the supplied RTK inhibitor.
  • aspects of the invention also relate to methods of manufacturing a pharmaceutical composition, wherein the method comprises obtaining a first oral dosage form comprising an RTK inhibitor, obtaining a second oral dosage form comprising an RTK ligand, and packaging together the first oral dosage form and the second oral dosage form.
  • the RTK ligand interacts with an RTK that is inhibited by the supplied RTK inhibitor.
  • One aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a first dosage form, which comprises epidermal growth factor receptor (EGRF) inhibitor and a second dosage form, which comprises an EGFR ligand.
  • EGRF epidermal growth factor receptor
  • the first and second dosage forms are combined into a single dosage form.
  • Another aspect of the present invention relates to methods of ameliorating adverse effects associated with administration of an EGFR inhibitor.
  • the methods comprise co-administering to a patient an EGFR inhibitor and an EGFR ligand.
  • a further aspect of the present invention relates to methods of using an EGFR ligand to ameliorate adverse effects associated with administration of an EGFR inhibitor in a human.
  • the method comprises informing the human that co-administering an EGFR ligand with an EGFR inhibitor ameliorates at least one adverse effect associated with the administration of an EGFR inhibitor.
  • Another aspect of the present invention relates to methods of manufacturing a pharmaceutical composition, wherein the method comprises obtaining a first oral dosage form comprising an EGFR inhibitor, obtaining a second oral dosage form comprising an EGFR ligand, and packaging together the first oral dosage form and the second oral dosage form.
  • the EGFR ligand comprises EGF.
  • the EGFR inhibitor comprises gef ⁇ tinib and/or erlotinib.
  • Still other aspects of the present invention relate to a pharmaceutical composition produced by the above-described manufacturing methods.
  • Another aspect of the invention involves promoting the use of an
  • EGFR ligand to ameliorate the adverse effects associated with administration of an EGFR inhibitor in humans.
  • One embodiment disclosed herein relates to a pharmaceutical composition that includes a first dosage form which can include an epidermal growth factor receptor (EGFR) inhibitor and a second dosage form which can include an EGFR ligand.
  • the pharmaceutical composition can include a first dosage form and a second dosage form each having an oral dosage form.
  • the EGFR inhibitor can be selected from the group consisting of reversible inhibitors and irreversible inhibitors.
  • the EGFR inhibitor can be a small molecule. In one embodiment when the EGFR inhibitor is a small molecule, the small molecule can include a quinazoline compound.
  • the quinazoline compound when the molecule is a quinazoline compound, can be selected from the group consisting of erlotinib, gefitinib and 4-(4-benzyloxyanilino)-6,7- dimethoxyquinazoline. In another aspect of this embodiment, the quinazoline compound can be present in an amount from about 50 mg/dose to about 50 g/dose. In another aspect of this embodiment, the quinazoline compound can be present in an amount from about 500 mg/dose to about 20 g/dose. hi another aspect of this embodiment, the quinazoline compound can be present in an amount of about 10 g/dose.
  • the small molecule can include a carbohydrate or carbohydrate analog.
  • the carbohydrate or carbohydrate analog can be selected from the group consisting of lacto-N-neotetraose, 3'-sialyllactose and 6'- sialyllactose.
  • the EGFR ligand can include a proteinaceous EGFR ligand.
  • the proteinaceous EGFR ligand can be selected from the group consisting of epidermal growth factor (EGF), transforming growth factor- ⁇ (TGF- ⁇ ), amphiregulin (AR), betacellulin (BTC), heparin-binding EGF (HB-EGF), epiregulin (EPR), neuregulins (NRGs) and mucin 4 (MUC4).
  • EGF epidermal growth factor
  • TGF- ⁇ transforming growth factor- ⁇
  • AR amphiregulin
  • BTC betacellulin
  • HB-EGF heparin-binding EGF
  • EPR epiregulin
  • NGFs neuregulins
  • MUC4 mucin 4
  • the EGF can be selected from the group consisting of the 53 amino acid form, the 52 amino acid form, the 51 amino acid form, the 48 amino acid form and homologs having at least 30% amino acid identity with any one of the aforementioned EGF forms.
  • the proteinaceous EGFR ligand can be present in an amount from about 1 mg/dose to about 50 g/dose. In another aspect of this embodiment, the proteinaceous EGFR ligand can be present in an amount from about 10 mg/dose to about 10 g/dose. hi another aspect of this embodiment, the proteinaceous EGFR ligand can be present in an amount of about 1 g/dose. In another aspect of this embodiment, the first dosage form and the second dosage form can further include a pharmaceutically acceptable carrier, hi another aspect of this embodiment, the first dosage form and the second dosage form can be selected from the group consisting of a tablet, a capsule, a solution, a suspension, a cream, an ointment and a gel.
  • the first dosage form and the second dosage form can be merged, thereby forming a combined dosage form, hi one embodiment when the dosages are merged, the combined dosage form can further include a pharmaceutically acceptable carrier, hi another aspect of this embodiment, the combined dosage form can be selected from the group consisting of a tablet, a capsule, a solution, a suspension, a cream, an ointment and a gel.
  • the EGFR inhibitor can be gefitinib and said EGFR ligand can be EGF.
  • the EGFR inhibitor can be erlotinib and said EGFR ligand can be EGF.
  • the EGFR inhibitor can be Panitumumab and said EGFR ligand can be EGF.
  • the EGFR ligand can be capable of activating EGFR.
  • Another embodiment disclosed herein relates to a method of ameliorating adverse effects associated with the administration of an EGFR inhibitor, the method can include co-administering to a patient an EGFR inhibitor and a therapeutically effective amount of an EGFR ligand.
  • the EGFR inhibitor and the EGFR ligand can be orally co-administered to the patient.
  • co-administering the EGFR inhibitor and the EGFR ligand can include administering the EGFR ligand at least about 1 hour prior to the administration of the EGFR inhibitor.
  • co-administering the EGFR inhibitor and the EGFR ligand can include administering the EGFR ligand at least about 1 hour subsequent to the administration of the EGFR inhibitor. In another aspect of this embodiment, coadministering the EGFR inhibitor and the EGFR ligand can include administering the EGFR ligand at about the same time as administering the EGFR inhibitor. In another aspect of this embodiment, the EGFR ligand and the EGFR inhibitor can be administered at the same time. In another aspect of this embodiment, the EGFR ligand and the EGFR inhibitor can be administered together in a single dosage form.
  • the EGFR inhibitor can be selected from the group consisting of reversible inhibitors and irreversible inhibitors.
  • the EGFR inhibitor can be a small molecule.
  • the small molecule can include a quinazoline compound.
  • the quinazoline compound can be selected from the group consisting of erlotinib, gefitinib and 4-(4- benzyloxyanilino)-6,7-dimethoxyquinazoline.
  • the quinazoline compound can be administered in a range from about 1 mg/kg/day to about 1 g/kg/day.
  • the quinazoline compound can be administered in a range from about 10 mg/kg/day to about 400 mg/kg/day. In another aspect of this embodiment, the quinazoline compound can be administered at about 200 mg/kg/day.
  • the small molecule can include a carbohydrate or carbohydrate analog, hi one aspect of this embodiment, the carbohydrate or carbohydrate analog can be selected from the group consisting of lacto-N-neotetraose, 3'-sialyllactose and 6'-sialyllactose.
  • the EGFR ligand can be a proteinaceous EGFR ligand.
  • the proteinaceous EGFR ligand may not be substantially absorbed into the bloodstream, hi another aspect of this embodiment, the proteinaceous EGFR ligand may not substantially alter the activity of EGFRs outside of the gut. hi another aspect of this embodiment, the proteinaceous EGFR ligand may not substantially alter the activity of EGFRs in a cancerous tissue, hi another aspect of this embodiment, the cancerous tissue can be lung tissue, hi another embodiment, the proteinaceous EGFR ligand can be selected from the group consisting of epidermal growth factor (EGF), transforming growth factor- ⁇ (TGF- ⁇ ), amphiregulin (AR), betacellulin (BTC), heparin-binding EGF (HB-EGF), epiregulin (EPR), neuregulins (NRGs) and mucin 4 (MUC4).
  • EGF epidermal growth factor
  • TGF- ⁇ transforming growth factor- ⁇
  • AR amphiregulin
  • BTC betacellulin
  • HB-EGF he
  • the EGF can be selected from the group consisting of the 53 amino acid form, the 52 amino acid form, the 51 amino acid form, the 48 amino acid form and homologs having at least 30% amino acid identity with any one of the aforementioned EGF forms.
  • the proteinaceous EGFR ligand can be administered in a range from about 20 ⁇ g/kg/day to about 1 g/kg/day. In another embodiment the proteinaceous EGFR ligand can be administered in a range from about 200 ⁇ g/kg/day to about 200 mg/kg/day. hi another embodiment, the proteinaceous EGFR ligand can be administered at about 20 mg/kg/day. hi another embodiment, the adverse effects can include adverse gastrointestinal effects.
  • the adverse gastrointestinal effects can be selected from the group consisting of diarrhea, nausea, vomiting, anorexia and weight loss, hi another aspect of this embodiment, the patient can be identified as suffering adverse gastrointestinal effects or at risk of suffering adverse gastrointestinal effects due to the administration of the EGFR inhibitor, hi another aspect of this embodiment, the patient can have condition associated with a mutant EGFR which can be substantially unresponsive to EGF. hi another embodiment, the adverse effects can include adverse skin effects. In one aspect of this embodiment, the adverse skin effects can be selected from the group consisting of rash, acne, dry skin, pruritus, vesiculobullous rash and mouth ulcerations.
  • the patient can be identified as suffering adverse skin effects or at risk of suffering adverse skin effects due to the administration of the EGFR inhibitor.
  • the patient can have a condition associated with a mutant EGFR that is substantially unresponsive to EGF.
  • the EGFR inhibitor can be gefitinib and the EGFR ligand can be EGF.
  • the EGFR inhibitor can be erlotinib and the EGFR ligand can be EGF.
  • the EGFR ligand can be capable of activating EGFR.
  • Another embodiment disclosed herein relates to a method of using an EGFR ligand to ameliorate adverse effects associated with the administration of an EGFR inhibitor in a human subject, the method can include informing the human subject that coadministering the EGFR ligand with the EGFR inhibitor ameliorates at least one adverse effect associated with the administration of the EGFR inhibitor.
  • the EGFR ligand can be capable of activating EGFR.
  • the administration of the EGFR inhibitor can be oral administration.
  • at least one adverse effect can be an adverse gastrointestinal effect.
  • the adverse gastrointestinal effect can be selected from the group consisting of diarrhea, nausea, vomiting, anorexia and weight loss.
  • At least one adverse effect can be an adverse skin effect.
  • the adverse gastrointestinal effect can be selected from the group consisting of rash, acne, dry skin, pruritus, vesiculobullous rash and mouth ulcerations.
  • the method of informing the human subject can include providing printed matter that advises that co-administering the EGFR ligand with the EGFR inhibitor ameliorates at least one adverse effect associated with the administration of the EGFR inhibitor.
  • the printed matter can be a label.
  • Another embodiment disclosed herein relates to a method of manufacturing a pharmaceutical composition
  • the method can include obtaining a first dosage form comprising an EGFR inhibitor, obtaining a second dosage form comprising an EGFR ligand, and packaging together the first dosage form and the second dosage form.
  • the first dosage form and the second dosage form can each include an oral dosage form.
  • the EGFR ligand can be capable of activating EGFR.
  • the EGFR ligand can be EGF.
  • the EGFR inhibitor can be gefitinib.
  • the EGFR ligand can be EGF.
  • the EGFR inhibitor can be erlotinib.
  • the EGFR ligand can be EGF.
  • the first dosage form and the second dosage form can be merged together, thereby forming a combined dosage form.
  • Another embodiment disclosed herein relates to a pharmaceutical composition made by the methods disclosed herein.
  • a pharmaceutical composition comprising a first dosage form which can include a receptor tyrosine kinase (RTK) inhibitor and a second dosage form which can include an RTK ligand.
  • the first dosage form and the second dosage form can each include an oral dosage form.
  • the RTK inhibitor can be selected from the group consisting of reversible inhibitors and irreversible inhibitors.
  • the RTK inhibitor can include a small molecule.
  • the small molecule can be selected from the group consisting of erlotinib, gefitinib, 4-(4-benzyloxyanilino)-6,7- dimethoxyquinazoline, imatinib, PKC412, MLN518, CEP-701, SU5402, SU5416, PD0173074 and SMS-354825.
  • the small molecule can be present in an amount from about 50 mg/dose to about 50 g/dose.
  • the small molecule can be present in an amount from about 500 mg/dose to about 20 g/dose.
  • the small molecule can be present in an amount of about 10 g/dose.
  • the RTK ligand can include a proteinaceous RTK ligand.
  • the proteinaceous RTK ligand can be selected from the group consisting of epidermal growth factor (EGF), transforming growth factor- ⁇ (TGF- ⁇ ), amphiregulin (AR), betacellulin (BTC), heparin-binding EGF (HB-EGF), epiregulin (EPR), neuregulins (NRGs), mucin 4 (MUC4), fibroblast growth factor- 1 (FGFl), fibroblast growth factor 2 (FGF2), fins- related tyrosine kinase 3 ligand (FMS-TK3), colony stimulating factor-1 (CSF-I), platelet- derived growth factor (PDGF), growth hormone (GH), prolactin (PL), erythropoietin (EP), leptin (LP), stem cell factor (SFC), nerve growth factor (NGF), neutrophin 3 (NTF3) and vegetative growth factor (VEGF
  • EGF epi
  • the proteinaceous RTK ligand can be present in an amount from about 1 mg/dose to about 50 g/dose. In another embodiment, the proteinaceous RTK ligand can be present in an amount from about 10 mg/dose to about 10 g/dose. In another embodiment, the proteinaceous RTK ligand can be present in an amount of about 1 g/dose. In another embodiment, the first dosage form and the second dosage form can further include a pharmaceutically acceptable carrier. In another embodiment, the first dosage form and the second dosage form can be selected from the group consisting of a tablet, a capsule, a solution, a suspension, a cream, an ointment and a gel.
  • the first dosage form and the second dosage form can be merged, thereby forming a combined dosage form.
  • the combined dosage form can further include a pharmaceutically acceptable carrier.
  • the combined dosage form can be selected from the group consisting of a tablet, a capsule, a solution, a suspension, a cream, an ointment and a gel.
  • the RTK ligand can interact with an RTK that is inhibited by the RTK inhibitor.
  • the RTK ligand can be capable of activating an RTK.
  • Another embodiment disclosed herein relates to a method of ameliorating adverse effects associated with the administration of an RTK inhibitor, the method can include co-administering to a patient an RTK inhibitor and a therapeutically effective amount of an RTK ligand.
  • the RTK inhibitor and the RTK ligand can be orally co-administered to the patient, hi another embodiment, co-administering the RTK inhibitor and the RTK ligand can include administering the RTK ligand at least about 1 hour prior to the administration of the RTK inhibitor.
  • co-administering the RTK inhibitor and the RTK ligand can include administering the RTK ligand at least about 1 hour subsequent to the administration of the RTK inhibitor.
  • coadministering the RTK inhibitor and the RTK ligand can include administering the RTK ligand at about the same time as administering the RTK inhibitor.
  • the RTK ligand and the RTK inhibitor can be administered at the same time, hi another embodiment, the RTK ligand and the RTK inhibitor can be administered together in a single dosage form, hi another embodiment, the RTK inhibitor can be selected from the group consisting of reversible inhibitors and irreversible inhibitors.
  • the RTK inhibitor can be a small molecule
  • the small molecule can be selected from the group consisting of erlotinib, gefitinib, 4-(4-benzyloxyanilino)-6,7- dimethoxyquinazoline, imatinib, PKC412, MLN518, CEP-701, SU5402, SU5416, PD0173074 and SMS-354825.
  • the small molecule can be administered in a range from about 1 mg/kg/day to about 1 g/kg/day.
  • the small molecule can be administered in a range from about 10 mg/kg/day to about 400 mg/kg/day.
  • the small molecule can be administered at about 200 mg/kg/day.
  • the RTK ligand can include a proteinaceous RTK ligand.
  • the proteinaceous RTK ligand may not be substantially absorbed into the bloodstream.
  • the proteinaceous RTK ligand may not substantially alter the activity of RTKs outside of the gut.
  • the proteinaceous RTK ligand may not substantially alter the activity of RTKs in a cancerous tissue.
  • the proteinaceous RTK ligand can be selected from the group consisting of epidermal growth factor (EGF), transforming growth factor- ⁇ (TGF- ⁇ ), amphiregulin (AR), betacellulin (BTC), heparin-binding EGF (HB-EGF), epiregulin (EPR), neuregulins (NRGs), mucin 4 (MUC4), fibroblast growth factor-1 (FGFl), fibroblast growth factor 2 (FGF2), fins-related tyrosine kinase 3 ligand (FMS-TK3), colony stimulating factor-1 (CSF-I), platelet-derived growth factor (PDGF), growth hormone (GH), prolactin (PL), erythropoietin (EP), leptin (LP), stem cell factor (SFC), nerve growth factor (NGF), neutrophin 3 (NTF3) and vegetative growth factor (VEGF).
  • EGF epidermal growth factor
  • TGF- ⁇ transforming growth factor- ⁇
  • AR amphire
  • the proteinaceous RTK ligand can be administered in a range from about 20 ⁇ g/kg/day to about 1 g/kg/day. In another embodiment, the proteinaceous RTK ligand can be administered in a range from about 200 ⁇ g/kg/day to about 200 mg/kg/day. In another embodiment, the proteinaceous RTK ligand can be administered at about 20 mg/kg/day.
  • the patient can be identified as suffering adverse effects or at risk of suffering adverse effects due to the administration of the RTK inhibitor. In another embodiment, the patient can have a condition associated with a mutant RTK which is substantially unresponsive to an RTK ligand. In another embodiment, the adverse effects can include adverse gastrointestinal effects. In another embodiment, the adverse effects can include adverse skin effects.
  • the RTK ligand can interact with an RTK that is inhibited by the RTK inhibitor. In another embodiment, the RTK ligand can be capable of activating an RTK.
  • Another embodiment disclosed herein relates to a method of using an RTK ligand to ameliorate adverse effects associated with the administration of an RTK inhibitor in a human subject, the method can include informing the human subject that co-administering the RTK ligand with the RTK inhibitor ameliorates at least one adverse effect associated with the administration of the RTK inhibitor.
  • the administration of the RTK inhibitor can include oral administration.
  • the RTK ligand can be capable of activating an RTK.
  • the method of informing the human subject can include providing printed matter that advises that co-administering the RTK ligand with the RTK inhibitor ameliorates at least one adverse effect associated with the administration of the RTK inhibitor.
  • the printed matter can be a label.
  • the RTK ligand can interact with an RTK that is inhibited by the RTK inhibitor.
  • Another embodiment disclosed herein relates to a method of manufacturing a pharmaceutical composition
  • the method can include obtaining a first dosage form comprising an RTK inhibitor, obtaining a second dosage form comprising an RTK ligand, and packaging together the first dosage form and the second dosage form, hi one embodiment, the first dosage form and the second dosage form can each include an oral dosage form, hi another embodiment, the first dosage form and the second dosage form can be merged 1 together, thereby forming a combined dosage form, hi another embodiment, the RTK ligand can interact with an RTK that is inhibited by the RTK inhibitor, hi another embodiment, the RTK ligand can be capable of activating an RTK.
  • Another embodiment disclosed herein relates to a pharmaceutical composition made by the methods disclosed herein.
  • Figs. IA-E are line graphs displaying BRET-2 signal as a function of ligand concentration.
  • Dose-responses for the epidermal growth factor (EGF) agonist (filled symbols) response are compared with dose responses for the inhibition of constitutive receptor activity with the small molecule inhibitor gefitinib (open symbols).
  • Cells were starved for 24 hours in 0.1% FBS before testing (A) EGFR wild type (WT), (B) EGFR G719C, (C) EGFR L858R, (D) EGFR ⁇ 752-759 and (E) EGFR ⁇ 747-749 A750P.
  • the BRET-2 signal is calculated as the ratio between the Renilla luciferase emission and the GFP2 emission corrected by the background emissions of non-transfected cells.
  • Figs. 2A-E are bar charts showing the differential effects of somatic EGFR mutations on constitutive EGFR signaling and EGF-induced signaling.
  • the indicated wild type or mutant EGFR isoforms were co-expressed with (A) GFP2-Grb2, (B) Stat5A- GFP2, (C and E) GFP2-p85 or (D) GFP2-PLC ⁇ l, in HEK293T cells and analyzed by BRET- 2.
  • the BRET-2 signal of the mutant EGFR isoforms was expressed as percent of wild type EGFR responses and derived from ratios between the Renilla luciferase emission and the GFP2 emission corrected by the background emissions of non-transfected cells.
  • Figs. 3A-C are line graphs displaying BRET-2 signal as a function of ligand concentration. Dose responses for the inhibition of constitutive receptor activity with the small molecule inhibitor gefitinib and erlotinib are compared. Cells were starved for 24 hours in 0.1% FBS before testing (A) EGFR T790M, (B) EGFR L858R T790M and (C) EGFR ⁇ 747-749 A750P. The BRET-2 signal was calculated as the ratio between the Renilla luciferase emission and the GFP2 emission corrected by the background emissions of non- transfected cells.
  • RTKs receptor tyrosine kinases
  • RTKs having such mutations are often associated with abnormal cell proliferation diseases, such as cancers.
  • the present disclosure involves the discovery that the activation of certain mutant RTKs does not substantially increase in the presence of their activator ligand.
  • an appropriate RTK ligand can be supplied to patients suffering from RTK-associated cancers without exacerbating the already heightened activity of the mutant receptors.
  • Administration of the RTK ligand to a patient suffering from an RTK-associated cancer is beneficial in cases where the patient is being administered one or more RTK inhibitors in their chemotherapeutic regimen.
  • RTK inhibitors are capable of inhibiting the activity of certain mutant RTKs, thereby reducing, and in some cases, even eliminating the aberrant proliferation response in cancerous tissues.
  • RTK inhibitors also affect the RTKs in noncancerous cells, which can lead to unpleasant and even severe adverse effects. Because the frequency, severity, and/or duration of the adverse effects are often directly correlated with the dose of the inhibitor, the maximum tolerable dose of RTK inhibitor is often well below the dose necessary to bring the blood concentration of the inhibitor to a level high enough to eradicate the cells having the mutant RTKs.
  • Embodiments of the present invention relate to pharmaceutical compositions and methods for co-administering an RTK ligand and an RTK inhibitor.
  • the RTK ligand interacts with and activates non-mutant RTKs so as to reduce, and in some cases even, reverse inhibitory effects due to the RTK inhibitor. Because the mutant RTKs are not further substantially activated by RTK ligand, these receptors will be inhibited by the RTK inhibitor.
  • the dose of the RTK inhibitor can be substantially increased in the presence of an RTK ligand, for example, from about 2-fold to about 1000-fold above its highest normally-prescribed, therapeutic dose.
  • co-administration of and RTK ligand and an RTK inhibitor results in the reduction of one or more of the adverse effects associated with the administration of the RTK inhibitor.
  • an appropriate RTK ligand is administered to a patient suffering from a cell proliferation disorder associated with a mutant RTK.
  • the cell proliferation disorder is cancer.
  • Cancers resulting from the constitutive or otherwise abnormal activation of RTKs are well known and have been described in Krause et al. (2005). N. Engl. J. Med. 353:172-87, the disclosure of which is incorporated herein by reference in its entirety.
  • RTKs having mutations resulting in constitutive or otherwise abnormal activation include, but are not limited to, EGFR, FGFRl, FGFR3, FLT3, c-FMS, ⁇ TRK3, PDGF ⁇ , PDGF ⁇ and VEGF.
  • Mutations in EGFR include, among other things, deletions and specific point mutations which result in receptor activation, and which are associated with, but not limited to, breast cancer, glioblastoma and lung cancer, including non-small cell lung cancer (NSCLC).
  • NSCLC non-small cell lung cancer
  • some mutant EGFRs have a deletion of amino acids 747 to 750.
  • Others carry point mutations, such as G719C/S (GIy to Cys or Ser at position 719), L858R (Leu to Arg at position 858) and/or L861Q (Leu to GIn at position 861).
  • Mutations in FGFRl which are typically associated with myeloproliferative syndrome and atypical chronic myeloid leukemia, predominantly include translocations, which result in activation.
  • translocations include, for example, translocations between chromosomes 8 and 13 (t8;13), 6 and 8 (t6;8), 8 and 9 (t8;9), 8 and 19 (t8;19) as well as 8 and 22 (t8;22).
  • Mutations in FGFR3, which are associated with multiple myeloma include point mutations, such as K650E (Lys to Ser at position 650) and translocations, such as between chromosomes 4 and 12 (t4;12).
  • the FLT3 mutants, which are associated with acute myeloid leukemia can include, for example, internal tandem duplications and point mutations, such as D835X (Asp to any amino acid at position 835).
  • the RTK, c-FMS is activated by the point mutations L301F/S (Leu to Phe or Ser at position 301) and Y969C (Tyr to Cys at position 969). Such activation is typically associated with myelodysplastic syndrome and acute myeloid leukemia. Translocations in NTRK3 result in activation, which can lead to acute myeloid leukemia.
  • NTRK3 is activated by a translocation between chromosomes 12 and 15 (tl2;15).
  • Activating mutations in PDGF ⁇ can include interstitial deletions as well as translocations, for example, the joining of chromosomes 4 and 22 (t4;22).
  • Such activation is typically associated with hypereosinophilic syndrome, systemic mastocytosis, atypical chronic myeloid leukemia.
  • Activating mutations in PDGF ⁇ primarily include translocations, such as between chromosomes 5 and 12 (t5;12), 5 and 7 (t5;7), 5 and 17 (t5;17), 5 and 10 (t5;10) as well as 5 and 14 (t5;14).
  • Such activation is typically associated with chronic myelomonocytic leukemia and acute myeloid leukemia.
  • Mutations in JAK2 that cause activation include, among others things, point mutations and translocations.
  • JAK2 can be activated by the point mutation V617F (VaI to Phe at position 617) and translocations, such as the joining of chromosomes 9 and 12 (t9;12) or 9 and 22 (t9;22).
  • Such mutations are associated with diseases, such as polycythemia vera, essential thrombocythemia openia, idiopathic myelofibrosis, acute myeloid leukemia, acute lymphoblastic leukemia and atypical chronic myeloid leukemia.
  • Mutations in c-KIT that cause activation primarily include point mutations, such as D419X (Asp to any amino acid at position 419), V560X (VaI to any amino acid at position 560) and D816X (Asp to any amino acid at position 816). Such mutations are associated with acute myeloid leukemia and systemic mastocytosis. It will be appreciated that the above description of activating mutations for RTKs is an exemplary listing of such mutations. Patients having RTKs that include activating mutations other than those appearing in the above description can be also be treated using the pharmaceutical compositions and methods described herein.
  • RTK inhibitors can be used in the treatment of cell proliferation disorders that are associated with increased activation of RTKs. Some inhibitors include specifically developed monoclonal antibodies targeted to specific RTKs. Other inhibitors include small molecules, such as erlotinib, gef ⁇ tinib, 4-(4-benzyloxyanilino)- 6,7-dimethoxyquinazoline, imatinib, PKC412, MLN518, CEP-701, SU5402, SU5416, PD0173074 and SMS-354825. Some small molecule RTK inhibitors can act to inhibit a wide range of RTKs (broad spectrum inhibitors), whereas others specifically inhibit only one or a few RTKs. Given the wide ranging inhibitory effects of some RTK inhibitors, certain embodiments of the present invention comprise pharmaceutical compositions and coadministration methods that include a plurality of different RTK ligands.
  • RTKs have more than one known ligand. Natural ligands for RTKs are commonly polypeptides. Many of these polypeptides are endogenously generated by cleavage of a precursor protein to produce the active form, hi addition to polypeptide ligands, RTKs can bind to and/or be activated by other macromolecules as well as small molecules. In some embodiments, RTK ligands can include molecules that are previously unknown to bind to and/or activate an RTK. Detailed methods for the identification of such ligands are described below in connection with EGFR ligands.
  • Endogenous polypeptide ligands for RTKs include growth factors and other polypeptides that typically bind to the extracellular ligand binding domain of an RTK, thereby causing activation.
  • RTK ligands activate RTKs through mechanisms other than binding at the extracellular ligand binding domain, for example, anti-RTK antibodies that facilitate receptor dimerization.
  • RTK ligands bind to the receptor activation domain but do not activate the RTK.
  • RTK ligands for various receptors include, but are not limited to, epidermal growth factor (EGF), transforming growth factor- ⁇ (TGF- ⁇ ), amphiregulin (AR), betacellulin (BTC), heparin-binding EGF (HB-EGF), epiregulin (EPR), neuregulins (NRGs), mucin 4 (MUC4), fibroblast growth factor- 1 (FGFl) 5 fibroblast growth factor 2 (FGF2), fins- related tyrosine kinase 3 ligand (FMS-TK3), colony stimulating factor- 1 (CSF-I), platelet- derived growth factor (PDGF), growth hormone (GH), prolactin (PL), erythropoietin (EP), leptin (LP), stem cell factor (SFC), nerve growth factor (NGF), neutrophin 3 (NTF3) and vegetative growth factor (VEGF).
  • EGF epidermal growth factor
  • TGF- ⁇ transforming growth factor- ⁇
  • fibroblast growth factor-1 FGFl
  • aFGF acidic FGF
  • Homologs may have at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or greater than at least 99% amino acid identity with a full-length or truncated wild type FGFl.
  • the FGFl is selected from any of SEQ ID NOs: 1-5, homologs thereof, active fragments of SEQ ID NOs: 1-5 or active fragments of homologs of SEQ ID NOs: 1-5.
  • fibroblast growth factor-2 or “basic FGF (bFGF)” means any full-length or truncated FGF2 protein or FGF2 homolog that can act as a ligand for an FGFR. In some, but not all embodiments of the present invention, the FGF2 will function so as to activate wild type FGFRs.
  • FGF2 includes, but is not limited to, wild type and other truncated forms that continue to act as a ligand for an FGFR. Additionally, the term “FGF2” includes homologs of the full-length and truncated forms that have the ability to function as a ligand of an FGFR.
  • Homologs may have at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or greater than at least 99% amino acid identity with a full-length or truncated wild type FGF2.
  • the FGF2 is selected from any of SEQ ED NOs: 6-10, homologs thereof, active fragments of SEQ ID NOs: 6-10 or active fragments of homologs of SEQ ED NOs: 6-10.
  • FMS-TK3 farnesoid tyrosine kinase 3 ligand
  • FMS-TK3 any full-length or truncated FMS-TK3 protein or FMS-TK3 homolog that can act as a ligand for a FLT3. In some, but not all embodiments of the present invention, the FMS-TK3 will function so as to activate wild type FLT3.
  • FMS-TK3 includes, but is not limited to, wild type and other truncated forms that continue to act as a ligand for a FLT3.
  • FMS-TK3 includes homologs of the full-length and truncated forms that have the ability to function as a ligand of a FLT3. Homologs may have at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or greater than at least 99% amino acid identity with a full-length or truncated wild type FMS-TK3.
  • the FMS-TK3 is selected from any of SEQ ID NOs: 11-18, homologs thereof, active fragments of SEQ IDNOs: 11-18 or active fragments of homologs of SEQ ED NOs: 11-18.
  • colony stimulating factor-1 or “macrophage colony stimulating factor (M-CSF)” means any full-length or truncated CSF-I protein or CSF-I homolog that can act as a ligand for a c-FMS. In some, but not all embodiments of the present invention, the CSF-I will function so as to activate wild type c-FMS.
  • CSF-I includes, but is not limited to, wild type and other truncated forms that continue to act as a ligand for a c-FMS.
  • CSF-I includes homologs of the full- length and truncated forms that have the ability to function as a ligand of a c-FMS. Homologs may have at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or greater than at least 99% amino acid identity with a full-length or truncated wild type CSF-I.
  • the CSF-I is selected from any of SEQ ED NOs: 19- 23, homologs thereof, active fragments of SEQ ID NOs: 19-23 or active fragments of homologs of SEQ ID NOs: 19-23.
  • platelet derived growth factor means any full- length or truncated PDGF ⁇ or PDGF ⁇ protein or PDGF ⁇ or PDGF ⁇ homolog that can act as a ligand for a PDGFR ⁇ and/or PDGFR ⁇ .
  • the PDGF will function so as to activate wild type PDGFR ⁇ and/or PDGFR ⁇ .
  • PDGF includes, but is not limited to, wild type and other truncated forms that continue to act as a ligand for a PDGFR ⁇ and/or PDGFR ⁇ . Additionally, the term “PDGF” includes homologs of the full-length and truncated forms that have the ability to function as a ligand of a PDGFR ⁇ and/or PDGFR ⁇ .
  • Homologs may have at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or greater than at least 99% amino acid identity with a full-length or truncated wild type PDGF.
  • the PDGF is selected from any of SEQ ID NOs: 24-34, homologs thereof, active fragments of SEQ ID NOs: 24-34 or active fragments of homologs of SEQ IDNOs: 24-34.
  • growth hormone means any full-length or truncated GH protein or GH homolog that can act as a ligand for a JAK2. In some, but not all embodiments of the present invention, the GH will function so as to activate wild type JAK2.
  • the term “GH” includes, but is not limited to, wild type and other truncated forms that continue to act as a ligand for a JAK2. Additionally, the term “GH” includes homologs of the full-length and truncated forms that have the ability to function as a ligand of a JAK2.
  • Homologs may have at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or greater than at least 99% amino acid identity with a full-length or truncated wild type GH.
  • the GH is selected from any of SEQ ID NOs; 35-42, homologs thereof, active fragments of SEQ ID NOs: 35-42 or active fragments of homologs of SEQ ID NOs: 35-42.
  • prolactin (PL) means any full-length or truncated PL protein or PL homolog that can act as a ligand for a JAK2. hi some, but not all embodiments of the present invention, the PL will function so as to activate wild type JAK2.
  • GH includes, but is not limited to, wild type and other truncated forms that continue to act as a ligand for a JAK2.
  • PL includes homologs of the full-length and truncated forms that have the ability to function as a ligand of a JAK2.
  • Homologs may have at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or greater than at least 99% amino acid identity with a full-length or truncated wild type PL.
  • the PL is selected from any of SEQ E) NOs: 43-47, homologs thereof, active fragments of SEQ ID NOs: 43-47 or active fragments of homologs of SEQ ID NOs: 43-47.
  • EP erythropoietin
  • EP means any full-length or truncated EP protein or EP homolog that can act as a ligand for a JAK2. In some, but not all embodiments of the present invention, the EP will function so as to activate wild type JAK2.
  • the term "EP” includes, but is not limited to, wild type and other truncated forms that continue to act as a ligand for a JAK2. Additionally, the term “EP” includes homologs of the full-length and truncated forms that have the ability to function as a ligand of a JAK2.
  • Homologs may have at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or greater than at least 99% amino acid identity with a full-length or truncated wild type EP.
  • the EP is selected from any of SEQ DD NOs: 48-52, homologs thereof, active fragments of SEQ ID NOs: 48-52 or active fragments of homologs of SEQ ID NOs: 48-52.
  • LP means any full-length or truncated LP protein or LP homolog that can act as a ligand for a JAK2. In some, but not all embodiments of the present invention, the LP will function so as to activate wild type JAK2.
  • the term "LP” includes, but is not limited to, wild type and other truncated forms that continue to act as a ligand for a JAK2. Additionally, the term “LP” includes homologs of the full-length and truncated forms that have the ability to function as a ligand of a JAK2.
  • Homologs may have at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or greater than at least 99% amino acid identity with a full-length or truncated wild type LP.
  • the LP is selected from any of SEQ ED NOs: 53-56, homologs thereof, active fragments of SEQ ID NOs: 53-56 or active fragments of homologs of SEQ ID NOs: 53-56.
  • SCF stem cell factor
  • SCF steel factor
  • MCGF massive cell growth factor
  • KL kit ligand
  • SCF includes homologs of the full-length and truncated forms that have the ability to function as a ligand of a c-KIT. Homologs may have at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or greater than at least 99% amino acid identity with a full-length or truncated wild type SCF.
  • the SCF is selected from any of SEQ ID NOs: 57-63, homologs thereof, active fragments of SEQ DD NOs: 57-63 or active fragments of homologs of SEQ DD NOs: 57-63.
  • NGF nerve growth factor
  • NGF nerve growth factor
  • the term “NGF” includes, but is not limited to, wild type and other truncated forms that continue to act as a ligand for an NTRKl. Additionally, the term “NGF” includes homologs of the full-length and truncated forms that have the ability to function as a ligand of an NTRKl.
  • Homologs may have at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or greater than at least 99% amino acid identity with a full-length or truncated wild type NGF.
  • the NGF is ( selected from any of SEQ DD NOs: 64-68, homologs thereof, active fragments of SEQ ID NOs: 64-68 or active fragments of homologs of SEQ ID NOs: 64-68.
  • NTF3 neurotrophin 3
  • NTF3 means any full-length or truncated NTF3 protein or NTF3 homolog that can act as a ligand for an NTRK3. In some, but not all embodiments of the present invention, the NTF3 will function so as to activate wild type NTRK3.
  • the term “NTF3” includes, but is not limited to, wild type and other truncated forms that continue to act as a ligand for an NTRK3. Additionally, the term “NTF3” includes homologs of the full-length and truncated forms that have the ability to function as a ligand of an NTRK3.
  • Homologs may have at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or greater than at least 99% amino acid identity with a full-length or truncated wild type NTF3.
  • the NTF3 is selected from any of SEQ ID NOs: 69-73, homologs thereof, active fragments of SEQ ID NOs: 69-73 or active fragments of homologs of SEQ ID NOs: 69-73.
  • VEGFR ligands which include, but are not limited to, VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E and PIGF and homologs of any of these growth factors that can act as a ligand for a VEGFR.
  • VEGFs include, but is not limited to, truncated VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E and PIGF or any of their homologs that can act as a ligand for a VEGFR.
  • Homologs of the full-length and truncated VEGFs that have the ability to function as a ligand of a VEGFR may have at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or greater than at least 99% amino acid identity with a full-length or truncated wild type VEGF.
  • the VEGF is selected from any of SEQ ID NOs: 74-91, homologs thereof, active fragments of SEQ ID NOs: 74-91 or active fragments of homologs of SEQ ID NOs: 74-91.
  • VEGFR includes, but is not limited to VEGFRl (also known as FLTl), VEGFR2 (also known as FLK-1/KDR) and VEGGR3 (also known as FLT-4).
  • Embodiments of the present invention relate to pharmaceutical compositions for the co-administration of an RTK inhibitor and an RTK ligand.
  • a pharmaceutical composition comprising a first dosage form, which comprises an RTK inhibitor, and a second dosage form, which comprises an RTK ligand.
  • the first dosage form and/or the second dosage form further comprises a pharmaceutically acceptable carrier.
  • the first dosage form and the second dosage form are separate. In other embodiments, the first dosage form and second the dosage form are merged together to form a single combined dosage form.
  • the RTK ligand is responsible for activating a receptor that has been inhibited by, or that is subject to inhibition by, an RTK inhibitor.
  • the RTK ligand binds to or otherwise interacts with an RTK that is inhibited by, or that is subject to inhibition by, the RTK inhibitor, m certain embodiments where a broad spectrum RTK inhibitor, such as imatinib, is present in the first dosage form, a plurality of RTK ligands can be present in the second dosage form.
  • the plurality RTK ligands are provided in a plurality of separate dosage forms each comprising one to a few RTK ligands.
  • compositions of the present invention are used to ameliorate adverse effects due to the administration of the RTK inhibitor. By reducing such adverse effects, the pharmaceutical compositions of the present invention permit the RTK inhibitors to be administered at a dose up to 1000-fold above the currently maximum prescribed dose.
  • Some embodiments of the pharmaceutical compositions described herein comprise an RTK inhibitor in an amount ranging from about 50 mg/dose to about 50 g/dose.
  • the pharmaceutical compositions described herein comprise an RTK inhibitor in an amount ranging from about 500 mg/dose to about 20 g/dose.
  • the pharmaceutical compositions described herein comprise an RTK inhibitor in an amount of about 5 g/dose.
  • RTK ligands for use in the pharmaceutical compositions described herein can be selected from small molecule ligands or macromolecule ligands.
  • Such ligands can include, but are not limited to, epidermal growth factor (EGF), transforming growth factor- ⁇ (TGF- ⁇ ), amphiregulin (AR), betacellulin (BTC), heparin-binding EGF (HB-EGF), epiregulin (EPR), neuregulins (NRGs), mucin 4 (MUC4), fibroblast growth factor- 1 (FGFl), fibroblast growth factor 2 (FGF2), fms-related tyrosine kinase 3 ligand (FMS-TK3), colony stimulating factor- 1 (CSF-I), platelet-derived growth factor (PDGF), growth hormone (GH), prolactin (PL), erythropoietin (EP), leptin (LP), stem cell factor (SFC), nerve growth factor (NGF), neutroph
  • EGF epi
  • RTK ligand that is present in the pharmaceutical compositions described herein will depend on, among other things, the affinity of the ligand for the RTK.
  • RTK ligand is present in the pharmaceutical compositions described herein in an amount ranging from about 1 mg/dose to about 50 g/dose.
  • the RTK ligand is present in an amount ranging from about 10 mg/dose to about 10 g/dose.
  • the RTK ligand is present at about 1 g/dose. It will be appreciated that an appropriate amount of RTK ligand for inclusion in the pharmaceutical compositions described herein can be determined using methods well known to those or ordinary skill in the art.
  • Typical dosage forms comprising RTK inhibitors and/or RTK ligands include, but are not limited to, conventional tablets, capsules (softgel or hard gel), caplets, gelcaps, pills, liquids (e.g., solutions, suspensions or elixirs), powders, lozenges, micronized particles or osmotic delivery systems and any other oral dosage forms known in the pharmaceutical arts.
  • Dosage forms for parenteral administration are also contemplated. Such dosage forms are well within the ordinary skill in the art and include, but are not limited to intravenous and/or subcutaneous injectables, suppositories and aerosols. Also contemplated are dosage forms for topical administration, such as creams, salves ointments and gels.
  • Embodiments of the present invention relate to methods of ameliorating adverse effects associated with the administration of an RTK inhibitor in a patient in need of RTK inhibitor administration.
  • patients in need of RTK inhibitor administration are individuals who suffer from one or more cell proliferation disorders that are amenable to treatment with an RTK inhibitor, such as cancers and cell proliferative syndromes.
  • Administration of the RTK inhibitor causes dose-dependent adverse effects in the majority of the patient population receiving such treatment.
  • inhibitors such as gef ⁇ tinib and erlotinib
  • adverse skin effects and adverse gastrointestinal effects are the most common.
  • Such adverse skin, gastrointestinal and/or other effects typically increase in frequency, severity and/or duration as the dose of the RTK inhibitor increases.
  • Embodiments of the present invention which relate to the coadministration of an RTK ligand with the RTK inhibitor, permit an increased dosing of RTK inhibitor, thereby expanding the therapeutic efficacy of such compounds.
  • the RTK inhibitor dose is increase to levels that would be lethal in the absence of RTK ligand.
  • an RTK inhibitor can be administered in a range from about 1 mg/kg/day to about 1 g/kg/day. In a preferred embodiment, the RTK inhibitor is administered in a range from about 10 mg/kg/day to about 100 mg/kg/day. In another preferred embodiment, the RTK inhibitor is administered at about 50 mg/kg/day. In yet another preferred embodiments, the RTK inhibitor is administered at about 20 mg/kg/day.
  • RTK ligands for use in methods of ameliorating adverse effects associated with the administration of an RTK inhibitor can be selected from small molecule ligands or macromolecule ligands.
  • the RTK ligands are administered parenterally, whereas in other embodiments, the RTK ligands are administered orally, m certain embodiments, wherein administration is oral, RTK ligands are not substantially absorbed from the gut into the bloodstream. In such embodiments, RTK ligands do not substantially come into contact with RTKs outside the gut, and thus, do not cause activation of RTKs outside of the gut.
  • RTK ligands are, at least in part, absorbed from the gut into the bloodstream; however, such ligands do not substantially activate RTKs outside of the gut. In preferred embodiments, RTK ligands do not substantially activate RTKs associated with cancerous tissue or other abnormal tissues.
  • the RTK ligands that are co-administered with the RTK inhibitors include, but are not limited to, epidermal growth factor (EGF), transforming growth factor- ⁇ (TGF- ⁇ ), amphiregulin (AR), betacellulin (BTC), heparin-binding EGF (HB-EGF), epiregulin (EPR), neuregulins (NRGs), mucin 4 (MUC4), fibroblast growth factor- 1 (FGFl), fibroblast growth factor 2 (FGF2), fms-related tyrosine kinase 3 ligand (FMS-TK3), colony stimulating factor-1 (CSF-I), platelet-derived growth factor (PDGF), growth hormone (GH), prolactin (PL), erythropoietin (EP), leptin (LP), stem cell factor (SFC), nerve growth factor (NGF), neutrophin 3 (NTF3) and vegetative growth factor (VEGF)
  • EGF epidermal growth factor
  • the effective dose of RTK ligand that is used for co-administration will depend on, among other things, the route of administration and the affinity of the ligand for the RTK.
  • the RTK ligand is orally coadministered with the RTK inhibitors.
  • the RTK ligand is administered in a range from about 20 ⁇ g/kg/day to about 1 g/kg/day.
  • the RTK ligand is administered in a range from about 200 ⁇ g/kg/day to about 200 mg/kg/day.
  • the RTK ligand is administered at about 20 mg/kg/day.
  • the RTK ligand is administered at about 2 mg/kg/day. It will be appreciated that an appropriate dose of RTK ligand for co-administration can be determined in view of the dose of RTK inhibitor to be administered, using methods well known to those or ordinary skill in the art.
  • a plurality of different RTK ligands are co-administered with the RTK inhibitor. Such embodiments are particularly preferred when the administered RTK inhibitor is a broad spectrum RTK inhibitor, such as imatinib, or when a plurality of RTK inhibitors are administered.
  • the RTK ligand interacts with one or more different RTKs that are inhibited by the RTK inhibitor.
  • Additional embodiments of the present invention relate to the timing of the administration of the RTK ligand and RTK inhibitor.
  • the RTK ligand is administered prior to the administration of the RTK inhibitor.
  • administration of the RTK ligand occurs about 1 hour, about 2 hours, about 3 hours or about 4 hours prior to the administration of the RTK inhibitor.
  • the RTK ligand in administered after the administration of the RTK inhibitor.
  • administration of the RTK ligand occurs about 1 hour, about 2 hours, about 3 hours or about 4 hours after the administration of the RTK inhibitor.
  • administration of the RTK ligand occurs at about the same time as the administration of the RTK inhibitor.
  • the RTK ligand and RTK inhibitor can be administered in separate dosage forms or together in a single combined dosage form, hi other embodiments, the RTK ligand is administered at anytime that allows it to reduce or eliminate one or more adverse effects of the RTK inhibitor.
  • Embodiments of the present invention relate to co-administering an RTK ligand and an RTK inhibitor to ameliorate adverse effects due to administration of the RTK inhibitor. All of the above-described embodiments are based on the discovery that mutant receptors involved in certain cell proliferative disorders are not substantially activated by the binding of ligand.
  • the RTK ligand can be administered by a parenteral route, such as intravenously, rectally, subcutaneously, sublingually, or intranasally.
  • the RTK ligand can be administered either orally or topically.
  • Additional embodiments of the present invention include methods of using an RTK ligand to ameliorate adverse effects associated with the administration of an RTK inhibitor in a human subject.
  • Such methods comprise informing a human subject that coadministering an RTK ligand with an RTK inhibitor ameliorates at least one adverse effect associated with the administration of the RTK inhibitor.
  • the subject is a patient in need of administration of an RTK inhibitor.
  • the patient may be suffering from one or more adverse effects associated with the administration of the RTK inhibitor or the patient may one who is not suffering from an adverse effect associated with the administration of an RTK inhibitor but who is at risk of suffering from one or more adverse effects if the amount of RTK inhibitor that is administered is increased.
  • the methods comprise informing the subject that orally co-administering an RTK ligand and an RTK inhibitor ameliorates at least one adverse effect associated with the administration of the RTK inhibitor.
  • compositions and co-administration methods utilizing RTK ligands and RTK inhibitors have been generally described. Provided below is a detailed description of such pharmaceutical compositions and co-administration methods as relates' to EGFR inhibitors and EGFR ligands. It will be appreciated that the methods of making pharmaceutical compositions and methods of co-administration, as related to EGFR inhibitors and EGFR ligands, which are described below, can be applied with any RTK inhibitors and RTK ligands, including those previously described. For example, a skilled artisan will appreciate that RTK inhibitors and RTK ligand combinations can be used to ameliorate side effects associated with the administration of the RTK inhibitor as well as to increase the maximum tolerable dose of RTK inhibitor.
  • EGFR epidermal growth factor receptor
  • NSCLC non-small-cell lung cancer
  • the heightened activity of mutant EGFRs in NSCLC patients can often be inhibited by quinazoline drugs, such as gefitinib and erlotinib.
  • quinazoline drugs such as gefitinib and erlotinib.
  • administration of these inhibitors causes an extremely high incidence of adverse effects, such as adverse effects to the skin, eyes, respiratory system and gastrointestinal system.
  • adverse effects increase as the dose of the inhibitor is increased.
  • the dose of quinazoline inhibitor that can be administered to a patient suffering from NSCLC is limited by such adverse effects. It is thought that these adverse effects are due to the inhibition of the tyrosine kinase activity of non-mutant EGFRs that are present in affected areas of the body.
  • adverse gastrointestinal effects are due to the inhibition of tyrosine kinase activity of non-mutant EGFRs that are present throughout the gastrointestinal system.
  • One embodiment of the present invention provides a method for ameliorating adverse effects due to the administration of an EGFR inhibitor by coadministering to a patient the EGFR inhibitor and a therapeutically effective amount of an EGFR ligand.
  • the patient is one who is identified as suffering adverse effects due to the administration of an EGFR inhibitor or one who is identified as at risk of suffering adverse effects if their normal dose of EGFR inhibitor is increased.
  • Other embodiments relate to co-administering an EGFR ligand in an amount sufficient to counteract the potentially toxic effects of the administration of a substantial overdose of EGFR inhibitor.
  • a preferred embodiment of the present invention provides a method for ameliorating adverse effects due to the oral administration of an EGFR inhibitor by orally coadministering to a patient the EGFR inhibitor and a therapeutically effective amount of an EGFR ligand.
  • the patient is one who is identified as suffering adverse gastrointestinal effects due to the administration of an EGFR inhibitor or one who is identified as at risk of suffering adverse gastrointestinal effects if their normal dose of EGFR inhibitor is increased.
  • an EGFR ligand may act to ameliorate the adverse effects resulting from the administration of an EGFR inhibitor.
  • oral administration of an EGFR ligand will sufficiently activate non-mutant EGFR receptors present in the gastrointestinal tract so as to ameliorate adverse gastrointestinal effects that are due to the EGFR inhibitor-mediated inhibition of these receptors.
  • much of the orally administered EGFR activator ligand is not absorbed from the gastrointestinal environment in an active form, and thus, it is not significantly available to EGFRs at the site of the tumor.
  • any active EGFR ligand that becomes localized to the site of the tumor does not substantially activate the mutant receptors because these receptors are not substantially responsive to the EGFR activator ligand.
  • the EGFR ligand may act to ameliorate adverse gastrointestinal effects by competing with an EGFR inhibitor for binding to the ligand-binding domain of EGFR receptors in the gut.
  • much of the orally administered EGFR activator ligand is not absorbed from the gastrointestinal environment in an active form, and thus, it is not be available to EGFRs at the site of the tumor.
  • the EGFR does not substantially activate the mutant receptors.
  • EGFRI Epidermal growth factor receptor
  • Subclass I of the receptor tyrosine kinase (RTK) superfamily consists epidermal growth factor receptors (EGFR), which are also known as the ERBB receptors. This group of receptors comprises four members: EGFR/ERBBl, ERBB2, ERBB3 and ERBB4. All members have an extracellular ligand-binding region, a single membrane- spanning region and a cytoplasmic tyrosine-kinase-containing domain. The ERBB receptors are expressed in various tissues of epithelial, mesenchymal and neuronal origin.
  • ERBB receptors Under normal physiological conditions, activation of the ERBB receptors is controlled by the spatial and temporal expression of their ligands, which are members of the EGF family of growth factors. Ligand binding to ERBB receptors induces the formation of receptor homodimers and heterodimers and activation of the intrinsic kinase domain, resulting in phosphorylation on specific tyrosine residues within the cytoplasmic tail. These phosphorylated residues serve as docking sites for a range of proteins, the recruitment of which leads to the activation of intracellular signaling pathways.
  • EGFR epidermal growth factor receptor
  • EGFR epidermal growth factor receptor
  • the term “EGFR” also refers to mutant forms of EGFR, ERBB2, ERBB3 or ERBB4, including those mutant forms which have altered activities as compared to their wild type counterparts, such as mutant EGFR, ERBB2, ERBB3 or ERBB4 forms that are involved in cancer.
  • mutant EGFR EGFR roles in cancer, see Hynes, et al. (2005). Nature Reviews Cancer 5: 341-54, the disclosure of which is incorporated herein by reference in its entirety.
  • Embodiments of the present invention relate to methods and pharmaceutical compositions for the co-administration of an EGFR ligand with one or more molecules that inhibit the tyrosine kinase activity of an EGFR (EGFR inhibitor) so as to ameliorate side effects resulting from the administration of the EGFR inhibitor.
  • EGFR inhibitors can be utilized with such methods and compositions.
  • the inhibitors can be reversible or irreversible and can mediate their inhibitory effects through a variety of mechanisms. The following non-limiting examples describe mechanisms by which EGFR inhibitors may act.
  • an EGRF inhibitor may inhibit EGFR tyrosine kinase activity by binding to the intracellular tyrosine kinase domain or may act as a receptor antagonist by binding at the extracellular ligand binding domain.
  • the EGFR inhibitor may prevent dimerization of EGFRs.
  • EGFR inhibitors that are contemplated for use with the present invention can be selected from any administrable inhibitor molecules.
  • the EGFR inhibitors are orally administrable.
  • a common class of EGFR inhibitors comprises •quinazoline drugs and derivatives thereof (hereinafter "quinazoline compounds").
  • quinazoline compounds •quinazoline drugs and derivatives thereof.
  • Methods of synthesizing quinazoline compounds are well known in the art. Such methods are described in, for example, United States Patent Nos. 5,814,630; 5,814,631; 5,866,572; 6,291,455; 6,849,625; 6,897,214 and 6,939,866, the disclosures of which are incorporated herein by reference in their entireties.
  • Preferred quinazoline inhibitors include gefitinib (Astrazenica, Wilmington, DE), erlotinib (OSI Pharmaceuticals, Melville, NY) and 4- 4(benzyloxyanilino)-6,7-dimethoxyquinazoline (Calbiochem, San Diego, CA).
  • carbohydrate and carbohydrate analogs are known to be inhibitors of EGFR activity.
  • exemplary compounds include, but are not limited to, lacto-N-neotetraose, 3'-sialyllactose and 6'-sialyllactose. Methods for making and using such compounds in the treatment of cancer are described in United States Patent No. 6,281,202, the disclosure of which is incorporated herein by reference in its entirety.
  • EGFR ligands can be used in connection with the methods and pharmaceutical compositions described herein.
  • EGFR ligands can include any molecules that bind to the extracellular, ligand-binding domain of an EGFR or molecules which function to activate EGFR tyrosine kinase activity.
  • An EGFR ligand can act as an agonist of the EGFR or may have no effect on the activity of the EGFR.
  • EGFR ligands bind to and activate the tyrosine kinase activity of EGFRs present in the gut.
  • Activation can occur by binding of the EGFR ligand at the extracellular binding domain of the EGFR, or alternatively, activation can occur by binding of the EGFR ligand at a domain other than the extracellular ligand binding domain.
  • the EGFR ligand need not function to activate EGFR tyrosine kinase activity (competitive mechanism).
  • an EGFR ligand can bind either reversibly or irreversibly to the EGFR.
  • Another aspect of the invention is the use of agents that result in stimulation of a naturally occurring RTK ligand. Examples of such agents include, without limitation, idebenone, and propentofylline.
  • Some embodiments of the present invention relate to methods and/or compositions in which the EGFR ligand is provided either as a small molecule or as a macromolecule.
  • the term "small molecule” refers to a chemical compound that has a molecular weight of less than about 10,000 amu. In some embodiments, the small molecule is a previously unknown ligand for an EGFR.
  • Previously unknown small molecule ligands of EGFR can be identified from combinatorial libraries of small molecules by screening such compounds in bioluminescence resonance energy transfer assays (BRET) assays using an EGFR-luminesce ⁇ t protein fusion in conjunction with a protein fusion comprising a luminescent protein fused to a signaling protein that interacts with the EGFR.
  • BRET bioluminescence resonance energy transfer assays
  • Exemplary signaling proteins that interact with EGFRs include, but are not limited to, PLC ⁇ , CBL, GRB2, SHC, SHPl, CRKH, DOK-R, p85 and GRB7.
  • Exemplary methods of conducting BRET assays using the above-described constructs are provided in the Examples below.
  • a small molecule EGFR inhibitor is formulated so that it is not substantially absorbed from the gut into the bloodstream.
  • the degree to which a small molecule is absorbed through the gut into the bloodstream can be controlled using methods established in the art. For example, small molecule absorbance in the gut can be delayed or even inhibited by providing the small molecule in a controlled release formulation, providing the small molecule with and appropriate carrier or by attaching the small molecule to a non-absorbing macromolecule. Any other known methods of delaying and/or inhibiting the absorbance of small molecule from the gut into the bloodstream are also contemplated herein.
  • the EGFR ligand is provided as a macromolecule.
  • the EGFR ligand is a proteinaceous macromolecule.
  • proteinaceous is meant comprised, at least in part, of protein.
  • Proteinaceous material can consist entirely of protein or primarily of protein.
  • Proteinaceous material also includes material that is primarily of a substance other than protein but which also includes a protein component.
  • proteinaceous EGFR ligands include, but are not limited to, EGF-family ligands and homologs thereof that have the ability to bind to the extracellular binding domain of an EGFR.
  • proteinaceous EGFR ligands include members of the mucin-family and homologs thereof that have the ability to activate EGFR tyrosine kinase activity. Additionally, proteinaceous EGFR ligands can include anti-EGFR antibodies and fragments thereof that bind to the extracellular binding domain of an EGFR or which otherwise activate the tyrosine kinase activity of an EGFR.
  • EGF-family ligands are typically short polypeptides that bind to an EGFR at the extracellular ligand binding domain, thereby activating the EGFR tyrosine kinase activity.
  • EGF-family ligands include, but are not limited to, epidermal growth factor (EGF), transforming growth factor- ⁇ (TGF- ⁇ ), amphiregulin (AR), betacellulin (BTC), heparin-binding EGF (HB-EGF), epiregulin (EPR) and neuregulins (NRGs).
  • EGF epidermal growth factor
  • EGF epidermal growth factor
  • the term “EGF” includes, but is not limited to, wild type 53 amino acid form, the 52 amino acid form, the 51 amino acid form (EGF-2), the 48 amino acid form (EGF-5) and any other truncated forms that continue to act as a ligand for an EGFR.
  • EGF includes homologs of the full-length and truncated forms that have the ability to function as a ligand of an EGFR. Homologs may have at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or greater than at least 99% amino acid identity with a full-length or truncated wild type EGF.
  • the EGF is selected from any of SEQ ID NOs: 92-96, homologs thereof, active fragments of SEQ ID NOs: 92-96 or active fragments of homologs of SEQ ED NOs: 92-96.
  • TGF- ⁇ transforming growth factor- ⁇
  • EGFR ligands which include, but are not limited to, wild type TGF- ⁇ and homologs thereof as well as truncated TGF- ⁇ and homologs thereof, wherein these molecule retain the ability to act as a ligand for an EGFR.
  • Homologs of the full-length and truncated TGF- ⁇ that have the ability to function as a ligand of an EGFR may have at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or greater than at least 99% amino acid identity with a full-length or truncated wild type TGF- ⁇ .
  • the TGF ⁇ is selected from any of SEQ ID NOs: 97-103, homologs thereof, active fragments of SEQ ID NOs: 97-103 or active fragments of homologs of SEQ ID NOs: 97-103.
  • AR immunodegulin
  • EGFR ligands which include, but are not limited to, wild type AR and homologs thereof as well as truncated AR and homologs thereof, wherein these molecule retain the ability to act as a ligand for an EGFR.
  • Homologs of the full-length and truncated AR that have the ability to function as a ligand of an EGFR may have at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or greater than at least 99% amino acid identity with a full-length or truncated wild type AR.
  • the AR is selected from any of SEQ ID NOs: 104-107, homologs thereof, active fragments of SEQ ID NOs: 104-107 or active fragments of homologs of SEQ ID NOs: 104-107.
  • BTC betacellulin
  • Homologs of the full-length and truncated BTC that have the ability to function as a ligand of an EGFR may have at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or greater than at least 99% amino acid identity with a full-length or truncated wild type iBJTC.
  • the BTC is selected from any of SEQ ID NOs: 108-111, homologs thereof, active fragments of SEQ ID NOs: 108-111 or active fragments of homologs of SEQ ID NOs: 108-111.
  • heparin-binding EGF refers to EGFR ligands which include, but are not limited to, wild type HB-EGF and homologs thereof as well as truncated HB-RGF and homologs thereof, wherein these molecule retain the ability to act as a ligand for an EGFR.
  • Homologs of the full-length and truncated HB-EGF that have the ability to function as a ligand of an EGFR may have at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or greater than at least 99% amino acid identity with a full-length or truncated wild type HB-EGF.
  • the HB-EGF is selected from any of SEQ ED NOs: 112-117, homologs thereof, active fragments of SEQ ID NOs: 112-117 or active fragments ofhomologs of SEQ ID NOs: 112-117.
  • EPR epiregulin
  • Homologs of the full-length and truncated EPR that have the ability to function as a ligand of an EGFR may have at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or greater than at least 99% amino acid identity with a full-length or truncated wild type EPR.
  • the EPR is selected from any of SEQ ID NOs: 118-120, homologs thereof, active fragments of SEQ ID NOs: 118-120 or active fragments of homologs ofSEQ ID NOs: 118-120.
  • NRGs neuroregulins
  • EGFR ligands which include, but are not limited to, NRGl, NRG2, NRG3, NRG4 and homologs of any of these neuregulins that can act as a ligand for an EGFR.
  • NRGs include, but is not limited to, truncated NRGl, NRG2, NRG3, NRG4 or any of their homologs that can act as a ligand for an EGFR.
  • Homologs of the full-length and truncated NRGs that have the ability to function as a ligand of an EGFR may have at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or greater than at least 99% amino acid identity with a full-length or truncated wild type NRG.
  • the NGR is selected from any of SEQ ID NOs: 121-124, homologs thereof, active fragments of SEQ ID NOs: 121-124 or active fragments of homologs of SEQ ID NOs: 121-124.
  • the protein mucin 4 can be supplied so as to activate the tyrosine kinase activity of EGFRs in the presence of an EGFR inhibitor.
  • the term “mucin 4 (MUC4)” refers to EGFR ligands which include, but are not limited to, wild type MUC4 and homologs thereof as well as truncated MUC4 and homologs thereof, wherein these molecule retain the ability to activate the tyrosine kinase activity of an EGFR.
  • Homologs of the full-length and truncated MUC4 that have the ability to activate the tyrosine kinase activity of an EGFR may have at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or greater than at least 99% amino acid identity with a full-length or truncated wild type MUC4.
  • the MUC4 is selected from any of SEQ ED NOs: 125-134, homologs thereof, active fragments of SEQ ED NOs: 125-134 or active fragments of homologs of SEQ ID NOs: 125-134.
  • an anti-EGFR antibody can be supplied as an EGFR ligand.
  • the anti-EGFR antibody binds to or facilitates dimerization of EGFRs so as to activate the receptor tyrosine kinase activity.
  • the anti-EGFR antibody binds to or facilitates dimerization of EGFRs present in the gut, thereby activating the receptor tyrosine kinase activity.
  • the anti-EGFR antibody competes with EGFR inhibitor binding.
  • a preferred embodiment of the present invention relates to the coadministration of an EGFR inhibitor and EGF.
  • commercially available preparations of recombinant EGF can be used.
  • recombinantly produced EGF can be obtained from Chiron Corporation (Emeryville, CA), Austral Biological (San Ramon, CA) or other manufactures and/or distributors.
  • recombinant EGF and homologs thereof can be produced using methodology that is known in the art. Exemplary methods are described in United States Patent No. 5,004,686, the disclosure of which is incorporated herein by reference in its entirety. Methods for large scale production of recombinantly-expressed EGF and homologs thereof are also known in the art.
  • United States Patent No. 5,102,789 describes the large-scale production of EGF in the yeast Pichia pastoris.
  • Recombinant EGF can be stored in solution or as a crystalline solid.
  • Methods of producing stabile, crystalline EGF by forming a complex between EGF and a pharmaceutically acceptable metal ion, such as zinc, are described in United States Patent No. 5,130,298, the disclosure of which is incorporated by reference in its entirety.
  • Embodiments of the present invention relate to methods of ameliorating adverse effects associated with the administration of an EGFR inhibitor.
  • Preferred embodiments relate to methods of ameliorating adverse gastrointestinal effects associated with the oral administration of an EGFR inhibitor.
  • an EGFR inhibitor is orally administered to a patient in need of EGFR inhibitor therapy.
  • patients in need of EGFR inhibitor therapy are individuals who suffer from one or more cancers that are amenable to treatment with an EGFR inhibitor, such as non-small-cell lung cancer (NSCLC).
  • NSCLC non-small-cell lung cancer
  • Administration of the EGFR inhibitor causes dose-dependent adverse effects in the majority of the patient population receiving such treatment. Adverse skin effects and adverse gastrointestinal effects are the most common.
  • Adverse skin effects can include, but are not limited to, rash, acne, dry skin, pruritus, vesiculobullous rash and mouth ulcerations.
  • Adverse gastrointestinal effects can include, but are not limited to, diarrhea, nausea, vomiting, weight loss and anorexia.
  • Other adverse effects can include, but are not limited to, asthenia, peripheral edema, amblyopia, conjunctivitis and dyspnea.
  • Such adverse skin, gastrointestinal and/or other effects typically increase in frequency, severity and/or duration as the dose of the EGFR inhibitor increases. Because these adverse effects increase with dose, there is a limit on the amount of EGFR inhibitor that can be administered. As a result, certain tumors may not be treatable at the maximum tolerable EGFR inhibitor dose.
  • Embodiments of the present invention which relate to the co-administration of an EGFR ligand with the EGFR inhibitor, permit an increased dosing of EGFR inhibitor, thereby expanding the therapeutic efficacy of such compounds.
  • the EGFR inhibitor dose is increase to levels that would be lethal in the absence of EGFR ligand.
  • Some preferred embodiments of the methods described herein relate to orally co-administering an EGFR inhibitor and an EGFR ligand to a patient who is suffering from adverse gastrointestinal effects due to the administration of an EGFR inhibitor or who is at risk of suffering adverse gastrointestinal effects due to the administration of an increased dose of an EGFR inhibitor.
  • to "co-administer” means to provide two or more substances to a subject within a time frame that allows therapeutically effective amounts of each substance to be present in the subject at the same time.
  • to “coadminister” refers to administering two or more substances within about 4 hours of each other. For example, consider the co-administration of substance A and substance B. If substance A is administered at 4:00 PM, then substance B can be administered as early as about 12:00 PM or as late as about 8:00 PM.
  • “therapeutically effective amount” means an amount of EGFR ligand that is sufficient to ameliorate the frequency, severity and/or duration of adverse gastrointestinal effects that result from the oral administration of an EGFR inhibitor.
  • an EGFR inhibitor that can be utilized in connection with the methods described herein can be any molecule for oral administration that is capable of inhibiting the tyrosine kinase activity of an EGFR. Such inhibitors can be reversible or irreversible.
  • the methods described herein contemplate the administration of an EGFR inhibitor comprising a small molecule.
  • the small molecule EGFR inhibitor is a quinazoline compound. Especially preferred quinazoline inhibitors are selected from the group consisting of gefitinib, erlotinib and 4-(4-benzyloxyanilino)-6,7-dimethoxyquinazoline.
  • quinazoline compounds are typically orally administered in a range from about 3.5 mg/kg/day to about 7 mg/kg/day.
  • a quinazoline inhibitor can be administered in a range from about 1 mg/kg/day to about 1 g/kg/day.
  • the quinazoline inhibitor is administered in a range from about 10 mg/kg/day to about 100 mg/kg/day.
  • the quinazoline inhibitor is administered at about 50 mg/kg/day.
  • the quinazoline inhibitor is administered at about 20 mg/kg/day.
  • the quinazoline inhibitor is orally administered.
  • the EGFR inhibitor that is administered is a carbohydrate or carbohydrate analog.
  • carbohydrate or carbohydrate analogs include, but are not limited to, lacto-N-neotetraose, 3'-sialyllactose and 6'- sialyllactose.
  • EGFR ligands for use in methods of ameliorating adverse effects associated with the oral administration of an EGFR inhibitor can be selected from small molecule ligands or macromolecule ligands.
  • the EGFR ligands are administered parenterally, whereas in other embodiments, the EGFR ligands are administered orally.
  • EGFR ligands are not substantially absorbed from the gut into the bloodstream. In such embodiments, EGFR ligands do not substantially come into contact with EGFRs outside the gut, and thus, do not cause activation of EGFRs outside of the gut.
  • EGFR ligands are, at least in part, absorbed from the gut into the bloodstream; however, as described in the Examples below, such ligands do not substantially activate EGFRs outside of the gut. In preferred embodiments, EGFR ligands do not substantially activate EGFRs associated with cancerous tissue, such as EGFRs associated with NSCLC.
  • the EGFR ligands that are co-administered with the EGFR inhibitors comprise proteinaceous ligands.
  • proteinaceous EGFR ligands include, but are not limited to, EGF, TGF- ⁇ , AR, BTC, HB- EGF, EPR, NRGs, MUC4 and anti-EGFR antibodies.
  • the effective dose of EGFR ligand that is used for co-administration will depend on, among other things, the route of administration and the affinity of the ligand for the EGFR.
  • the proteinaceous EGFR ligand is orally co-administered with the EGFR inhibitors.
  • the proteinaceous EGFR ligand is administered in a range from about 20 ⁇ g/kg/day to about 1 g/kg/day. In other embodiments, the proteinaceous EGFR ligand is administered in a range from about 200 ⁇ g/kg/day to about 200 mg/kg/day. In still other embodiments, the proteinaceous EGFR ligand is administered at about 20 mg/kg/day. In yet other embodiments, the proteinaceous EGFR ligand is administered at about 2 mg/kg/day. It will be appreciated that an appropriate dose of EGFR ligand for coadministration can be determined in view of the dose of EGFR inhibitor to be administered, using methods well known to those or ordinary skill in the art.
  • Preferred embodiments of the present invention relate to the oral coadministration of an EGFR inhibitor and an EGF-family ligand, such as EGF.
  • EGF EGF-family ligand
  • the EGF that is administered is selected from the group consisting of the 53 amino acid form, the 52 amino acid form, the 51 amino acid form, the 48 amino acid form and homologs having at least 30% amino acid identity with any one of the aforementioned EGF forms.
  • Additional embodiments of the present invention relate to the timing of the administration of the EGFR ligand and EGFR inhibitor.
  • the EGFR ligand in administered prior to the administration of the EGFR inhibitor.
  • administration of the EGFR ligand occurs about 1 hour, about 2 hours, about 3 hours or about 4 hours prior to the administration of the EGFR inhibitor, hi other embodiments, the EGFR ligand in administered after the administration of the EGFR inhibitor.
  • administration of the EGFR ligand occurs about 1 hour, about 2 hours, about 3 hours or about 4 hours after the administration of the EGFR inhibitor.
  • administration of the EGFR ligand occurs at about the same time as the administration of the EGFR inhibitor.
  • the EGFR ligand and EGFR inhibitor can be administered in separate dosage forms or together in a single combined dosage form.
  • the EGFR ligand and EGFR inhibitor can be administered in separate oral dosage forms or together in a single combined oral dosage form.
  • the EGFR ligand can be administered by a parenteral route, such as intravenously, rectally, subcutaneously, sublingually, or intranasally.
  • the EGFR ligand can be administered topically.
  • compositions for co-administering EGFR ligands and EGFR inhibitors are provided.
  • Embodiments of the present invention relate to pharmaceutical compositions for the co-administration of an EGFR inhibitor and an EGFR ligand.
  • the pharmaceutical composition comprises a first oral dosage form which comprises an EGFR inhibitor and a second oral dosage form which comprises an EGFR ligand.
  • the first oral dosage form and/or the second oral dosage form further comprises a pharmaceutically acceptable carrier.
  • the first oral dosage form and the second oral dosage form are separate.
  • the first oral dosage form and second the oral dosage form are merged together to form a single combined oral dosage form.
  • the combined oral dosage form further comprises a pharmaceutically acceptable carrier.
  • Typical oral dosage forms comprising EGFR inhibitors and/or EGFR ligands include, but are not limited to, conventional tablets, capsules (softgel or hard gel), caplets, gelcaps, pills, liquids (e.g., solutions, suspensions or elixirs), powders, lozenges, micronized particles or osmotic delivery systems and any other oral dosage forms known in the pharmaceutical arts.
  • Each dosage form includes an EGFR inhibitor and/or an effective amount of an EGFR ligand along with pharmaceutically inert ingredients, e.g., conventional excipients, vehicles, fillers, binders, disentegrants, solvents, solubilizing agents, sweeteners, coloring agents and any other inactive ingredients which are regularly included in pharmaceutical dosage forms for oral administration.
  • pharmaceutically inert ingredients e.g., conventional excipients, vehicles, fillers, binders, disentegrants, solvents, solubilizing agents, sweeteners, coloring agents and any other inactive ingredients which are regularly included in pharmaceutical dosage forms for oral administration.
  • pharmaceutically inert ingredients e.g., conventional excipients, vehicles, fillers, binders, disentegrants, solvents, solubilizing agents, sweeteners, coloring agents and any other inactive ingredients which are regularly included in pharmaceutical dosage forms for oral administration.
  • Many such dosage forms and oral vehicles immediately after listings of inactive ingredients therefore are set forth in Remington's Pharmaceutical
  • the EGFR inhibitor used in the pharmaceutical compositions described herein can be any molecule for oral administration that is capable of inhibiting the tyrosine kinase activity of an EGFR. Such inhibitors can be reversible or irreversible.
  • the pharmaceutical compositions described herein comprise a small molecule EGFR inhibitor.
  • the small molecule EGFR inhibitor is a quinazoline compound. Especially preferred quinazoline inhibitors are selected from the group consisting of gefitinib, erlotinib and 4-(4-benzyloxyanilino)-6,7-dimethoxyquinazoline.
  • compositions described herein comprise a quinazoline compound in an amount ranging from about 50 mg/dose to about 50 g/dose.
  • the pharmaceutical compositions described herein comprise a quinazoline compound in an amount ranging from about 500 mg/dose to about 20 g/dose.
  • the pharmaceutical compositions described herein comprise a quinazoline compound in an amount of about 10 g/dose.
  • the EGFR inhibitor present in the pharmaceutical compositions described herein is a carbohydrate or carbohydrate analog.
  • Such carbohydrate or carbohydrate analogs include, but are not limited to, lacto-N- neotetraose, 3'-sialyllactose and 6'-sialyllactose.
  • EGFR ligands for use in the pharmaceutical compositions described herein can be selected from small molecule ligands or macromolecule ligands.
  • the EGFR ligands comprise proteinaceous ligands.
  • proteinaceous EGFR ligands include, but are not limited to, EGF, TGF- ⁇ , AR, BTC, HB-EGF, EPR, NRGs, MUC4 and anti-EGFR antibodies.
  • the effective amount of EGFR ligand that is present in the pharmaceutical compositions described herein will depend on, among other things, the affinity of the ligand for the EGFR.
  • the proteinaceous EGFR ligand is present in the pharmaceutical compositions described herein in an amount ranging from about 1 mg/dose to about 50 g/dose. In other embodiments, the proteinaceous EGFR ligand is present in an amount ranging from about 10 mg/dose to about 10 g/dose. In still other embodiments, proteinaceous EGFR ligand is present at about 1 g/dose. It will be appreciated that an appropriate amount of EGFR ligand for inclusion in the pharmaceutical compositions described herein can be determined using methods well known to those or ordinary skill in the art.
  • [0106] ' Preferred embodiments of the present invention relate to pharmaceutical compositions comprising a first oral dosage form that comprise an EGFR inhibitor and a second oral dosage form that comprises an EGF-family ligand, such as EGF.
  • EGF EGF-family ligand
  • the EGF present in the second oral dosage form is selected from the group consisting of the 53 amino acid form, the 52 amino acid form, the 51 amino acid form, the 48 amino acid form and homologs having at least 30% amino acid identity with any one of the aforementioned EGF forms.
  • the first oral dosage form is separate from the second oral dosage form.
  • the first oral dosage form is merged with the second oral dosage form, thereby forming a combined oral dosage form comprising EGF and an EGFR inhibitor.
  • the EGF inhibitor is selected from the group consisting of gefitinib and erlotinib.
  • dosage forms are preferred, other pharmaceutical dosage forms for the co-administration of an EGFR inhibitor and an EGFR ligand can be made.
  • dosage forms are well within the ordinary skill in the art and include, but are not limited to, dosage forms for parenteral administration, such as intravenous and/or subcutaneous injectables, suppositories and aerosols, and dosage forms for topical administration, such as creams, salves ointments and gels.
  • composition refers to a mixture of a compound disclosed herein with other chemical components, such as diluents or carriers.
  • the pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to, oral, intramuscular, intraocular, intranasal, intravenous, injection, aerosol, parenteral, and topical administration.
  • compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid and the like.
  • inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid and the like.
  • physiologically acceptable defines a carrier or diluent that does not abrogate the biological activity and properties of the compound.
  • compositions described herein can be administered to a human patient per se, . or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or suitable carriers or excipient(s).
  • suitable carriers or excipient(s) include but are not limited to, butyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N
  • Suitable routes of administration may, for example, include oral, rectal, transmucosal, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intranasal, intraocular injections or as an aerosol inhalant.
  • compositions disclosed herein may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes.
  • compositions for use in accordance with the present disclosure thus may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compounds into preparations, which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients maybe used as suitable and as understood in the art; e.g., as disclosed in Remington's Pharmaceutical Sciences, cited above.
  • the agents disclosed herein may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the compounds disclosed herein to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipient with pharmaceutical combination disclosed herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions which can be used orally, include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added.
  • AU formulations for oral administration should be in dosages suitable for such administration.
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds for use according to the present disclosure are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or
  • the compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents, which increase the solubility of the compounds to allow for the preparation of highly, concentrated solutions. [0123] Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • An exemplary pharmaceutical carrier for the hydrophobic compounds disclosed herein is a co-solvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase.
  • a common co-solvent system used is the VPD co-solvent system, which is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80TM, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
  • VPD co-solvent system which is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80TM, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
  • the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics.
  • co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of Polysorbate 80TM; the fraction size of polyethylene glycol may be varied; and other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone.
  • other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity.
  • the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
  • sustained-release materials have been established and are well known by those skilled in the art.
  • Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days.
  • additional strategies for protein stabilization may be employed.
  • salts may be provided as salts with pharmaceutically compatible counterions.
  • Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free acids or base forms.
  • compositions suitable for use in the methods disclosed herein include compositions where the active ingredients are contained in an amount effective to achieve its intended purpose. More specifically, a therapeutically effective amount means an amount of compound effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
  • the dose range of the composition administered to the patient can be from about 0.5 to 1000 mg/kg of the patient's body weight, or 1 to 500 mg/kg, or 10 to 500 mg/kg, or 50 to 100 mg/kg of the patient's body weight.
  • the dosage may be a single one or a series of two or more given in the course of one or more days, as is needed by the patient. Where no human dosage is established, a suitable human dosage can be inferred from ED 50 or ID 50 values, or other appropriate values derived from in vitro or in vivo studies, as qualified by toxicity studies and efficacy studies in animals. '
  • the daily dosage regimen for an adult human patient may be, for example, an oral dose of between 0.1 mg and 500 mg of each ingredient, preferably between 1 mg and 250 mg, e.g. 5 to 200 mg or an intravenous, subcutaneous, or intramuscular dose of each ingredient between 0.01 mg and 100 mg, preferably between 0.1 mg and 60 mg, e.g. 1 to 40 mg of each ingredient of the pharmaceutical compositions disclosed herein or a pharmaceutically acceptable salt thereof calculated as the free base, the composition being administered 1 to 4 times per day.
  • compositions disclosed herein may be administered by continuous intravenous infusion, preferably at a dose of each ingredient up to 400 mg per day.
  • the total daily dosage by oral administration of each ingredient will typically be in the range 1 to 2000 mg and the total daily dosage by parenteral administration will typically be in the range 0.1 to 400 mg.
  • the compounds will be administered for a period of continuous therapy, for example for a week or more, or for months or years.
  • Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety, which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC).
  • MEC minimal effective concentration
  • the MEC will vary for each compound but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations.
  • Dosage intervals can also be determined using MEC value.
  • Compositions should be administered using a regimen, which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%.
  • the effective local concentration of the drug may not be related to plasma concentration.
  • composition administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.
  • compositions may, if desired, be presented in a pack or dispenser device, which may contain one or more unit dosage forms containing the active ingredient.
  • the pack may for example comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • the pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert.
  • Compositions comprising a compound disclosed herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • Additional embodiments of the present invention include methods of using an EGFR ligand to ameliorate adverse effects associated with the administration of an EGFR inhibitor in a human subject. Such methods comprise informing a human subject that coadministering an EGFR ligand with an EGFR inhibitor ameliorates at least one adverse effect associated with the administration of the EGFR inhibitor.
  • the subject is a patient in need of administration of an EGFR inhibitor.
  • the patient may be suffering from one or more adverse effects associated with the administration of the EGFR inhibitor or the patient may one who is not suffering from an adverse effect associated with the administration of an EGFR inhibitor but who is at risk of suffering from one or more adverse effects if the amount of EGFR inhibitor that is administered is increased.
  • the adverse effects are adverse gastrointestinal effects due to oral administration of the EGFR inhibitor.
  • the methods comprise informing the subject that orally co-administering an EGFR ligand and an EGFR inhibitor ameliorates at least one adverse gastrointestinal effect associated with the administration of the EGFR inhibitor.
  • informing refers to providing information relating to the pharmacodynamic activities of an EGFR ligand co-administered with an EGFR inhibitor.
  • the act of informing can be performed, for example, by providing a verbal description or by providing printed matter.
  • the printed matter may provide, for example, information relating to effects of co-administering an EGFR ligand and an EGFR inhibitor.
  • the printed matter may further provide information relating to the amelioration of specific adverse effects as a result of this co-administration.
  • informing does not require any more than the mere act of providing the information. It is not required that intended recipients of the information accept, acknowledge receipt of or understand the information.
  • Some embodiment of the present invention relate to a method of using an EGFR ligand to ameliorate adverse effects in a human patient who is suffering from adverse effects associated with the administration of an EGFR inhibitor or who is at risk of suffering from adverse effects associated with increasing the amount of administered EGFR inhibitor.
  • the method comprises informing the human patient that co-administering the EGFR ligand and the EGFR inhibitor ameliorates the frequency, severity and/or duration of at least one adverse effect associated with the administration of the EGFR inhibitor.
  • the adverse effect is selected from the group consisting of rash, acne, dry skin, pruritus, vesiculobullous rash, mouth ulcerations, asthenia, peripheral edema, amblyopia, conjunctivitis, dyspnea, diarrhea, nausea, vomiting, weight loss and anorexia.
  • a preferred embodiment of the present invention relates to a method of using an EGFR ligand to ameliorate adverse gastrointestinal effects in a human patient who is suffering from adverse gastrointestinal effects associated with the oral administration of an EGFR inhibitor or who is at risk of suffering from adverse gastrointestinal effects associated with increasing the amount of administered EGFR inhibitor.
  • the method comprises informing the human patient that orally co-administering the EGFR ligand and the EGFR inhibitor ameliorates the frequency, severity and/or duration of at least one adverse gastrointestinal effect associated with the oral administration of the EGFR inhibitor.
  • the adverse gastrointestinal effect is selected from the group consisting of diarrhea, nausea, vomiting, weight loss and anorexia.
  • the informing step comprises providing printed matter that advises that co-administering said EGFR ligand with said EGFR inhibitor ameliorates at least one adverse effect associated with the oral administration of said EGFR inhibitor.
  • the printed matter comprises a label.
  • label refers to printed matter that is associated with a container for holding a pharmaceutical composition.
  • the label and container can be placed together in a box or shrink wrap.
  • the label can be attached directly to the container.
  • the label need not be physically associated with or in physical proximity with the container, however, the label should be provided at the same time or at a time reasonably near to the time of providing the container.
  • RTKs receptor tyrosine kinases
  • the rapid ligand-stimulated autophosphorylation of specific tyrosine residues in the intracellular carboxy-terminus of receptor tyrosine kinases (RTKs) is an obligatory event in how RTKs transduce growth factor signals across the cell membrane.
  • the phosphorylated tyrosine residues serve as docking sites for a diverse set of proteins, which are involved in building, shaping and directing the specific RTK downstream signaling pathways.
  • RTK pharmacology and signaling have been quantitatively studied using methods that detect RTK phosphorylation or downstream effects on proliferation. Western blotting, immunoprecipitation or ELISA have been the most frequently applied methods to quantitate RTK autophosphorylation.
  • RTKs are good candidates for setting up a quantitative proximity assay due to the ligand-stimulated autophosphorylation of tyrosine residues and subsequent the recruitment of specific signaling proteins to these residues. No additional proteins are required in this initial step in the RTK signaling cascades, reducing the likelihood of interference through other proteins or signaling pathways.
  • the BRET technology was applied to quantitatively monitor in living cells the recruitment of various EGFR signaling proteins, which directly or indirectly interacted with EGFR to link the receptor to the four-major RTK signaling pathways.
  • the adapter proteins Grb2 and She were used as signaling molecules of the MAP-kinase (MAPK) proliferation pathway.
  • STAT5A as a signaling protein of the STAT pathway
  • phospholipase C ⁇ l as a key protein in the phospholipase C ⁇ l - calcium pathway
  • PBK phosphatidyl-inositol-3-kinase
  • the human EGFR protein was in frame carboxy-terminal tagged with Renilla luciferase, which neither affected the expression levels nor the downstream signaling properties.
  • EGF stimulated recruitment of the GFP2-tagged signaling proteins to EGFR-Luc was effectively inhibited through the application of various commercially available EGFR inhibitors (IC 50 AG1478 5 nM, IC5 0 PD 168393 6.3 nM).
  • This EGFR BRET assay was used as new tool to study the pharmacology and signaling properties of somatic EGFR mutations in lung cancer and in particular compared the activities of gefitinib and erlotinib.
  • Human cDNA's encoding EGFR, Grb2, p85, PLCyI, STAT5A were obtained by standard RT-PCR on poly- A-RNA isolated from various human tissues or tumor cell lines. Identities of all cDNA's were confirmed by completely sequencing the open reading frames.
  • EGFR isoforms containing somatic mutations were generated by standard mutagenesis methods. EGFR and isoforms were in-frame subcloned into the vector pRluc-N (Perkin-Elmer, USA) to generate a chimeric cDNA expressing the EGFR-(i?e«z7/ ⁇ )-luciferase fusion protein (EGFR-Luc).
  • the cDNA's encoding the EGFR signaling molecules (GRB2, STAT5A, PLCyI and p85) were subcloned into the vector pGFP2-N or pGFP2-C (Perkin- Elmer, USA) to generate chimeric cDNA's expressing the corresponding fusion proteins: GFP2-Grb2, GFP2-p85, GFP2-PLCyl, STAT5A-GFP2.
  • HEK293T cells were cultured in DMEM (with 4500 mg/I D-glucose and glutamine, with out sodium pyruvate) (Invitrogen - GIBCO, Carlsbad, CA, USA), 10% fetal bovine serum (FBS) (Hyclone, Logan, UT) supplemented with penicillin-streptomycin- glutamine solution (Invitrogen - GIBCO, Carlsbad, CA, USA). Two days before transfection, 2 million cells were plated in 10 cm cell culture dishes. The cells reached 70-80% confluency at the day of transfection.
  • DMEM with 4500 mg/I D-glucose and glutamine, with out sodium pyruvate
  • FBS fetal bovine serum
  • FBS penicillin-streptomycin- glutamine solution
  • Plasmid-DNA's were transient transfected using the lipid based Polyfect transfection reagent (Qiagen, Valencia, CA, USA) as instructed by the manufacturer. Transfection efficiencies reached 50-75%, verified by control transfection with beta- galactosidase.
  • One day after transfection cells were serum starved for 24 hours in DMEM with 0.1% FBS and supplemented with penicillin-streptomycin-glutamine solution. Experiments were performed two days after transfection. Cells were cultured at 37 0 C in a humidified 5% CO 2 incubator.
  • Small molecule EGFR inhibitors used in bioluminescence energy transfer assays were obtained as by direct synthesis (gefitinib and erlotinib) or purchased from Calbiochem, USA (CL-387,785).
  • EGFR bioluminescence resonance energy transfer assays were performed according to the following protocol.
  • HEK293T cells cultured in 10 cm plates were transiently transfected with plasmid DNAs expressing a bioluminescence donor (1 ⁇ g plasmid DNA expressing EGFR-Luc isoform) and a fluorescence acceptor (40 ⁇ g plasmid DNA expressing GFP2 tagged RTK signaling molecule).
  • Transfection was performed with Polyfect (Qiagen) as described by manufacturer.
  • One day after transfection cells were serum starved for 24 hours in DMEM, 0.1 % FBS supplemented with penicillin-streptomycin- glutamine solution.
  • Somatic EGFR mutations have been identified in NSCLC, which activate EGFR signaling.
  • Four somatic EGFR mutations were studied in the EGFR BRET-2 assay described herein: L858R, the most frequent in NSCLC identified point mutation (exon 21) was localized in the activation loop of the EGFR TK domain; G719C (exon 18); localized in the nucleotide phosphate binding loop (P-loop), and the two deletion mutations ⁇ 752-759 and ⁇ 747-749 A750P (exon 19), localized close to the ATP binding region.
  • EGFR-Luc isoforms carrying these mutations were co-transfected with GFP2-Grb2 to evaluate the effects of these somatic mutations on the MAP-kinase pathway signaling.
  • GFP2-Grb2 GFP2-Grb2
  • significant constitutive activity was observed for all 4 mutations tested (no ligand in Figs. IA-E), which was reflected by the higher BRET-2 signal of the mutants compared to the wild type EGFR.
  • wild type EGFR exhibited a BRET-2 signal of 0.21 in the absence of EGF, the L858R mutant receptor showed the highest constitutive activity with a BRET-2 signal of 0.33.
  • EGF was a very potent agonist for wild type EGFR (Table 1, EC 50 about 0.1 nM) in the EGFR/Grb2 BRET-2 assay, demonstrating the sensitivity of the EGFR BRET assay. All mutant EGFR isoforms were only slightly less potent in responding to EGF, but showed more dramatic differences in efficacy (Figs. IA-E and Table 1). For the wild type receptor, the BRET-2 signal increased to 0.55 in the presence of EGF (Fig. IA).
  • the signal with EGF increased to only 0.50 for G719C and 0.45 for L858R (Figs. IB and 1C, respectively).
  • the EGF signal was further impaired in the deletion mutants, which showed only a slight ligand induced increase in the BRET-2 signal to 0.35 (Figs. ID and IE), indicating a strong impairment in transducing EGF signals into the MAP-kinase pathway signaling. Therefore, none of the tested constitutively active EGFR mutants reached wild type EGFR activity level after EGF stimulation. This reduced EGFR response to EGF has previously not been recognized.
  • EGFRWT 10.14 +/- 0.01 32 6.59 +/- 0.08 15 6.83 +/- 0.08 15 EGFR L858R 9.63 +/- 0.03* 8 7.59 +/- 0.05* 4 8.04 +/- 0.04* 4
  • EGFR ⁇ 747-749A750P 9.69 +/- 0.08* 7 7.64 +/- 0.03* 3 8.00 +/- 0.06* 4
  • EGFR G719C 9.78 +/- 0.04* 8 7.41 +/- 0.10* 4 8.05 +/- 0.06* 4
  • Gefitinib and erlotinib effectively inhibit constitutive activity of EGFR isoforms
  • the constitutive activity displayed by the wild type and mutant EGFR isoforms in the EGFR/Grb2 BRET-2 assay was effectively inhibited by gefitinib (Figs. IA-E) and erlotinib (Table 1).
  • the BRET-2 signals were reduced to around 0.19 for wild type and all mutants at the highest concentrations of these EGFR inhibitors, which was likely to be the baseline BRET-2 signal for the EGFR/Grb2 BRET-2 assay.
  • Quantification of the pharmacological dose-responses obtained in the EGFR/Grb2 BRET-2 assays determined a log IC 50 for gefitinib and erlotinib acting at the wild type EGFR as -6.59 +/- 0.32 (257 nM) and -6.86 +/- 0.3 (138 nM), respectively.
  • the wild type EGFR also showed a low level of constitutive activity in the MAP -kinase pathway, indicated through the small inhibition with gefitinib or erlotinib in the EGFR/Grb2 BRET-2 assay (Fig. IA and Table 1).
  • the constitutive activity of the wild type EGFR could not be neutralized by anti-human EGF antibodies in contrast to EGF stimulated EGFR activity.
  • the BRET-2 signals obtained for the wild type EGFR in the presence of EGF plus the constitutive activity determined by gefitinib inhibition was normalized to 100% and the signals obtained for the other receptor isoforms were compared to the activated wild type EGFR responses.
  • the results showed that both mutant EGFR variants were constitutively active (in the absence of EGF) in all pathways tested (Figs. 2A-E open bars), but with quantitative differences.
  • all EGFR mutants tested predominantly signaled through the PI3K/Akt survival pathway.
  • the constitutive activity Fig. 2C, L858R open bar
  • the corresponding constitutive signaling activity of the L858R mutant through the MAP-kinase, STAT and PLC ⁇ l-calcium signaling pathways ranged only between 28% and 40% of the total wild type responses (Figs. 2A, 2B and 2D, L858R open bars).
  • the deletion mutant EGFR ⁇ 752-759 showed a similar profile for constitutive activity and coupling to the different signaling pathways, with 54% activity in the PI3K/Akt pathway (Figs. 2C, ⁇ 752-759, open bar) and lower levels of activity 30-35% in the other pathways (Figs. 2A, 2B, and 2D, ⁇ 752-759 open bar).
  • EGF responsiveness differs between the somatic EGFR L858R and ⁇ 752-759 mutant EGFR isoforms
  • L858R and ⁇ 752-759 EGFR isoforms were treated with EGF in BRET assays monitoring STAT, PBK/Akt or PLC ⁇ l -calcium signaling
  • a reduced EGF responsiveness for both mutants compared to EGFR wild type Figs. 2B-D, filled bars
  • Figs. IA-E filled symbols and Figs. 2A filled bars
  • the L858R mutant showed a response to EGF for all signaling pathways (Figs. 2A-D, compare open bars with filled bars).
  • the ⁇ 752-759 mutant isoform showed a dramatic quantitative difference in signaling between the different pathways.
  • EGF stimulated signaling for this mutant was induced for the STAT, PBK/Akt and PLC ⁇ l pathways (Figs. 2B-D, compare open and filled bars) but not for the Grb2/MAP- kinase pathway (Fig. 2A). This finding may be due to the difference in the pattern of autophosphorylated tyrosine residues required for Grb2 or Stat5a recruitment to EGFR.
  • Table 1 shows that with respect to each other, the different mutants did not display significant quantitative differences in the increase in drug sensitivity when comparing results obtained for gefitinib with erlotinib for different mutants or different signaling pathways.
  • the EGFR isoforms were more sensitive to gefitinib and erlotinib treatment compared to wild type EGFR. This was consistent with the increase in drug sensitivity seen in cancer cell lines that harbor these mutations.
  • Constitutive activity was not detected in the wild type EGFR with the EGFR/Stat5a or EGFR/PLCyl BRET-2 assays, which prevented us from quantitating the increase of drug sensitivity.
  • the T790M mutation has only been found in the presence of an activating EGFR mutation in tumor samples, although only in a small fraction of the total tumor cells number. The mutation has also been found in patients that did not undergo treatment with gefitinib and erlotinib. Blencke, et al introduced T790M into the EGFR receptor and found in an in- vitro kinase assay that the mutated receptor had a 100 fold reduced sensitivity to inhibition by the 4-anilino-quinazoline inhibitor PD153035.
  • a mutant EGFR variant was analyzed bearing the T790M mutation alone and mutant EGFRs that carry T790M in combination with the mutation L858R or ⁇ 747-749 A750P in the BRET/p85 BRET-2 assay, which monitored signaling through the PDK/Akt survival pathway.
  • the results showed that the T790M mutation alone generates a highly constititutively active EGFR receptor (Fig. 2E open bar and Fig. 3A).
  • erlotinib was not effective in inhibiting the constitutive activity of the EGFR T790M isoform (Fig. 3A, circles).
  • Gefitinib which has a similar structure as erlotinib, was expected to behave similarly to erlotinib; however, despite similarities with erlotinib in structure and mode of action, gefitinib inhibited the constitutive activity of the T790M isoform (85% inhibition with 33 ⁇ M high dose), but with a lower potency compared to the other somatic mutants (pICso - 5.3 +/- 0.033) (Fig. 3A triangles). Additionally, the double mutant EGFRs L858R T790M and ⁇ 747-749 A750P T790M, reported to occur in patients that developed drug resistance in NSCLC was analyzed.
  • patients having NSCLC are randomly divided into four groups.
  • a tumor biopsy is obtained from each patient and used for EGFR genotyping analysis.
  • the first group is given 500 mg of gefitinib and 50 mg of placebo in a single, oral administration daily for 14 days.
  • the second group is given 500 mg of gefitinib and 50 mg of EGF in a single, oral administration daily for 14 days.
  • the third and fourth groups are identical to the first and second groups except that gefitinib is replaced with erlotinib.
  • patients are evaluated for frequency and severity of adverse gastrointestinal effects.
  • patients are asked to record any instance of an adverse gastrointestinal event including a description of the event and the duration.
  • patients are asked to rank the severity of the adverse event on a scale of 1-5.
  • Somatic mutations in RTKs cause constitutive activity and affect responsiveness to activator ligands
  • This Example shows that mutations associated with the constitutive activation of various RTKs also diminish the responsiveness of these receptors to activator ligand.
  • RTK-luc isoforms carrying point, insertion, deletion or translocation mutations are co-transfected with an appropriate GFP2-signaling protein fusion to evaluate the effects of these somatic mutations on the downstream pathway signaling.
  • the mutant isoforms of FGFl, FGF3, FLT-3, c-FMS, PDGF ⁇ , PDGF ⁇ , JAK2, c-KTT, NTRKl, NTRK3 and VEGFR that have been previously described are tested.
  • the various mutant RTK isoforms are then treated with an appropriate RTK ligand.
  • FGFl and FGF2 are agonists for wild type FGFRl and FGFR3 the BRET-2 assay, thus demonstrating the sensitivity of the FGFR BRET assay.
  • FMS-TK3, CSF-I, PDGF, GH, SFC, NGF, NTF3 and VEGF are agonists for wild type FLT- 3, c-FMS, PDGF ⁇ , PDGF ⁇ , JAK2, c-KIT, NTRKl, NTRK3 and VEGFR, respectively. All mutant RTK isoforms are less potent in responding to their "activator" ligands and show a reduction in efficacy, which is shown by a lack of increase in BRET-2 signal in the presence of the appropriate activator ligand.
  • patients are evaluated for frequency and severity of adverse effects.
  • patients are asked to record any instance of an adverse event including a description of the event and the duration.
  • patients are asked to rank the severity of the adverse event on a scale of 1-5.
  • Appropriate statistical methods such as a two-way analysis of variance, are used to determine whether co-administration of the RTK inhibitor and RTK ligand resulted in a statistically significant difference in the incidence, severity or duration of any of the recorded classes of adverse effects. A statistically significant difference is observed between patients who received the RTK inhibitor and the RTK ligand and those who received RTK inhibitor alone.

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Abstract

L'invention concerne des compositions destinées à coadministrer un inhibiteur RTK et un ligand RTK. L'invention concerne également des procédés destinés à réduire un effet indésirable dû à l'administration d'un inhibiteur RTK par coadministration d'un inhibiteur RTK et d'un ligand RTK. L'invention concerne enfin des procédés destinés à informer un sujet que la coadministration d'un inhibiteur RTK et d'un ligand RTK réduit un effet indésirable dû à l'administration d'un inhibiteur RTK.
PCT/US2006/040183 2005-10-18 2006-10-16 Compositions et procedes utilises dans le traitement du cancer WO2007047489A2 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011054359A3 (fr) * 2009-11-06 2011-10-06 University Of Copenhagen Méthode de détection précoce du cancer
KR101116868B1 (ko) * 2008-10-20 2012-02-29 성균관대학교산학협력단 안질환의 예방 또는 치료용 조성물
WO2015000921A1 (fr) * 2013-07-01 2015-01-08 Fondazione Centro San Raffaele Activateurs de la voie ptgds et utilisation dans des pathologies caractérisées par une altération de la myélinisation dans le snc
CN106659768A (zh) * 2014-05-29 2017-05-10 株式会社大熊制药 用于预防或治疗皮疹的药物组合物

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
No further relevant documents disclosed *

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101116868B1 (ko) * 2008-10-20 2012-02-29 성균관대학교산학협력단 안질환의 예방 또는 치료용 조성물
WO2011054359A3 (fr) * 2009-11-06 2011-10-06 University Of Copenhagen Méthode de détection précoce du cancer
US9588121B2 (en) 2009-11-06 2017-03-07 Go Therapeutics, Inc. Method for early detection of cancer
US10139414B2 (en) 2009-11-06 2018-11-27 Go Therapeutics, Inc. Tn-MUC4 binding polypeptides and uses thereof
US11067578B2 (en) 2009-11-06 2021-07-20 Go Therapeutics, Inc. Tn-MUC4 binding polypeptides and uses thereof
US11860165B2 (en) 2009-11-06 2024-01-02 Go Therapeutics, Inc. CORE3-MUC1 binding polypeptides and uses thereof
WO2015000921A1 (fr) * 2013-07-01 2015-01-08 Fondazione Centro San Raffaele Activateurs de la voie ptgds et utilisation dans des pathologies caractérisées par une altération de la myélinisation dans le snc
CN106659768A (zh) * 2014-05-29 2017-05-10 株式会社大熊制药 用于预防或治疗皮疹的药物组合物
US20170202917A1 (en) * 2014-05-29 2017-07-20 Daewoong Pharmaceutical Co., Ltd. Pharmaceutical composition for preventing or treating skin rash
EP3148570A4 (fr) * 2014-05-29 2018-02-14 Daewoong Pharmaceutical Co., Ltd. Composition pharmaceutique destinée à la prévention ou au traitement d'éruptions cutanées

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