WO2013017494A1 - Pharmaceutical composition of oxidised avidin suitable for inhalation - Google Patents
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- WO2013017494A1 WO2013017494A1 PCT/EP2012/064576 EP2012064576W WO2013017494A1 WO 2013017494 A1 WO2013017494 A1 WO 2013017494A1 EP 2012064576 W EP2012064576 W EP 2012064576W WO 2013017494 A1 WO2013017494 A1 WO 2013017494A1
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- oxidized avidin
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
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- 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
- A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/66—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid the modifying agent being a pre-targeting system involving a peptide or protein for targeting specific cells
- A61K47/665—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid the modifying agent being a pre-targeting system involving a peptide or protein for targeting specific cells the pre-targeting system, clearing therapy or rescue therapy involving biotin-(strept) avidin systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/041—Heterocyclic compounds
- A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
- A61K51/0453—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
Definitions
- composition of oxidised avidin suitable for inhalation
- the invention described herein relates to a new pharmaceutical formulation of an oxidized avidin or biotinylated therapeutic agent/oxidized avidin complex for use by inhalation. It further relates to biotinylated therapeutics for targeting preconditioned lungs of mammals affected by inoperable and/or diffuse diseases. BACKGROUND OF THE INVENTION
- nebulised therapeutics have become a frequent drug delivery method for the treatment of lung diseases such as asthma or lung infections and other respiratory diseases.
- lung diseases such as asthma or lung infections and other respiratory diseases.
- mode of administration usually requires repeating the treatment several times per day, which however, may not be always compliant with patient's health conditions depending on the disease he suffers from or the grade of severity of the disease itself.
- Frequent inhalations of therapeutic agents also constitutes a severe life-limiting stress.
- Continuous nebulisation therapy of ⁇ 2 agonists has proved to be a useful alternative therapy for patients suffering from severe asthma (Raabe O.G., et ah, Ann. Allergy Asthma Immunol., 1998, 80, 499).
- the therapy is very time consuming and renders the patient's life uncomfortable.
- Lung's anatomy and physiology are well adapted to process exogenous nebulised substances for clearance in order to protect the organ. It is also recognized that also in the case of volunteer treatment exposure through inhalation of therapeutic agents, the latter are fast cleared therefore influencing negatively and thereby limiting the benefit of inhalation therapy.
- AKR AKR and short-chain dehydrogenases/reductases
- SDRs short-chain dehydrogenases/reductases
- CBRs carbonyl reductases
- a dry powder formulation for inhalation of temozolomide has recently been reported.
- the latter required a particle size reduction to enable a 51% release of the administered dose (Wauthoz N., et al., Pharm. Res., 2011, 28, 762), and also the presence of biocompatible and biodegradable phospholipids as surfactants to stabilise the aqueous temozolomide suspension (Wauthoz N., et al., Eur. J. Pharm. Sci., 2010, 39, 402).
- Nebulisation of 5-fluorouracil in dogs demonstrated that the drug could reach very high concentrations mainly in the trachea, to a less extent but still important into bronchi and oesophagus and a reduced concentration (i.e., one fiftieth of the one encountered in the trachea) into the lymph nodes at the bronchial level (Tatsumura T., et al., Br. J. Cancer, 1993, 68, 1146).
- Aerosol gene delivery is another application long pursued for the targeted therapy of lung diseases.
- cystic fibrosis gene there was great interest in the non-invasive delivery of genes directly to the pulmonary surfaces by aerosol.
- This approach could have application to inoperable pulmonary cancers as well and most early efforts focused mainly on the use of nonviral vectors, primarily cationic lipids and other formulation excipients (Densmore C.L., et al., J. Gene Med., 1999, 1, 4, 251; Densmore C.L., et al, Mol. Ther., 2000, 1, 2, 180).
- a polymer-based nanoparticle delivery system for inhalation has been disclosed recently (WO2009121631), wherein particles were administered by endotracheal instillation to mice.
- S a targeting agent such as an antibody, a low molecular weight compound or a protein (preferably covalently linked to the linker),
- Such nanoparticles had a mean size of 150 to 180 nm.
- delivery system took advantage of the molecular linker having a lipophilic portion which non-covalently anchors to the particle's polymeric matrix and a second portion comprising a maleimide compound to which it is possible to bind a targeting agent.
- the targeting agent could be a member of a binding couple such as avidin-biotin.
- avidin-biotin the specific embodiment involving avidin-biotin was not described in an enabling manner in this document.
- Ethanol based formulations have been previously reported to be suitable for nebulisation of proteins with biological activity including enzymes (Choi W.S., et al., Proc. Natl. Acad. Sci., 2001, 98, 20, 11103).
- very limited exposure to inhaled ethanol is disclosed (i.e. 10 minutes) since longer inhalation period can provoke inflammatory side effects.
- o oral delivery e.g., drug permeability issues, first-pass effect
- o other systemic drug delivery routes which can be correlated to severe if not compromising toxic side effects and/or high clearance issues; and/or o instability of the therapeutic according to its administration route and/or metabolic process; and/or
- the oxidized avidin administered by inhalation, link to the surface of lung epithelial cells uniformly down to the alveoli, and that it does not surprisingly bind to the respiratory upper track (e.g., trachea).
- the oxidized avidin did not bind to tissue surfaces like skin, eye or bladder unless a damage was procured to said surfaces. It was also surprising that such mode of administration preserves the chemical integrity of the protein.
- the present invention regards a pharmaceutical inhalable composition
- a pharmaceutical inhalable composition comprising an oxidized avidin or a biotinylated therapeutic agent/oxidized avidin complex, for targeted delivery of biotinylated therapeutics by inhalation to the lung. It further deals with the aerosol delivery of an oxidized avidin as a tool for conditioning the lung to accept a stable linkage of biotinylated therapeutics useful for the treatment of lung cancer, asthma, tuberculosis, Chronic Obstructive Pulmonary Disease (COPD), lung alveolitis, cystic fibrosis and alpha- 1-antitrypsin deficiency.
- COPD Chronic Obstructive Pulmonary Disease
- Biotinylation of proteins, cells and nucleic acid is a biochemical procedure well known in the art. It can be performed by a number of different commercially available reagents reacting with different groups (i.e. primary and second amines, sulphydryl and carboxyl groups, etc). Biotinylation reagents are designed to be very flexible (long spacers to reduce steric hindrance) or to be releasable (to free active moieties) and have been extensively used for targeting functional biotinylated moieties to proteins of the avidin family. In particular, protein biotinylation has been extensively applied to monoclonal antibodies and other functional proteins (Bayer E.A., et al., Methods Enzymol, 1990b, 184, 138).
- biotinylated anti-cancer therapeutics are for example chosen from the group comprising IgGl monoclonal antibody that binds specifically to the epidermal growth factor receptor (EGFR) such as biotinylated cetuximab (Hama Y., et al., Cancer Res., 2007, 67, 3809).
- EGFR epidermal growth factor receptor
- biotinylated cetuximab Hama Y., et al., Cancer Res., 2007, 67, 3809
- Further biotinylated anti-cancer therapeutics are for example biotinylated adducts of anti c-Met antibody (Stella G.M., et al., Expert. Opin. Investig. Drugs, 2010, 19, 11, 1381); anti-HGF (Okamoto W., et al., Mol.
- the present invention also deals with nebulised oxidized avidin for use in lung targeting of biotinylated anti-cancer effector cells, viral or plasmid vectors (D'Atri S., et al., Immunopharmacol., 1991, 21, 3, 199; Densmore C.L., Curr. Cancer Drug Targets, 2003, 3, 4, 275).
- the present invention further deals with the aerosol delivery of oxidized avidin as a useful tool for conditioning the lung to accept a stable linkage of anti-inflammatory biotinylated therapeutics.
- Suitable anti-inflammatory biotinylated therapeutics includes for example biotinylated adducts of anti-TNF, anti-Tweak, anti-IL-6, anti- IL-23, anti IL-17 monoclonal antibodies; IL-10 or other anti-inflammatory cytokines (Marchi E., et al., Chest, 2011) or chemokines (Farberman M.M., et al., Am. J. Respir. Cell Mol. Biol., 2010; Tauler J., et al., Curr. Opin.
- CFTCR Cystic Fibrosis Transmembrane Conductance Regulator
- the avidin-biotin system has been known for many years as an exceptional tool for qualitative and quantitative studies in interactions between small molecules and biological receptors (Wilchek, M., Methods Enzymol., 1990, 184, 14).
- Avidin is a glycoprotein of about 68 kDa present in the poultry egg white and showing high affinity for the vitamin H biotin. Its dissociation constant (Kd ⁇ 10 15 M) is the lowest known in nature (Green, N.M., Adv. Protein Chem., 1975, 29, 85; Hytonen V.P., et al, Biochem. J., 2003, 372, Ptl, 219). It is composed of four subunits of identical amino acid sequence, each of which can potentially bind one molecule of biotin. Glycosylation accounts for about 10% of its molecular weight with an average of four to five mannose and three N-acetylglucosamine residues per subunit (Bruch R.C., et al, Biochemistry, 1982, 21, 21, 5334).
- oxidized avidin In WO2009016031 in the name of the Applicant, was reported for the first time a chemically oxidized avidin named OXavidinHABA, (herein named oxidized avidin), that had higher permanence in injected tissues compared to wild type avidin as a consequence of the formation of chemical linkages between the oxidized avidin aldehyde groups and the tissue protein amino groups. Said oxidized avidin could be administered directly into the diseased tissue either alone, in which case a second step for delivering the biotinylated active therapeutic agent was necessary, or as a complex with the therapeutic agent. It is important to note that in said document the oxidized avidin was administered locally by means of injection rendering impractical a homogeneous whole lung conditioning.
- bronchioloalveolar cancer also known as lepidic lung cancer is a form of neoplasia affecting the surface of bronchus and alveoli that might benefit from a topical therapy delivered by aerosol (Anami Y., et al., J. Thorac. Oncol., 2009, 4, 8, 951).
- oxidized avidin can efficiently reach and link to the lung tissue through aerosol administration. This result was not predictable based on the data of WO2009016031 and further investigation showed that the intra-tissue injection was a requirement for the oxidized avidin linkage to the tissues. In fact, deposition of oxidized avidin on intact skin or eye was not sufficient to observe a linkage ( Figure 1). Linkage of the oxidized avidin was confirmed to occur only on tissue proteins exposed by surgery also in the pig bladder ( Figure 2). Moreover, nebulised oxidized avidin was found bound to the lung but not to the trachea thus indicating a specific and unpredictable linkage event in this organ (Table 1).
- oxidized avidin refers to a chemically oxidized avidin as claimed in WO2009016031 (i.e., an oxidized avidin in which at least one mannose residue per avidin molecule is replaced by a residue of the following formula
- oxidized avidin contains about 8 to 15 aldehyde moieties and has a thermal stability equal or greater than 78°C.
- oxidized avidin also refers to a compound that was obtained by oxidation of avidin in the presence of the ligand HABA in order to prevent from oxidation tryptophan residues that are involved in the biotin-binding site.
- anticancer agent means an agent capable of fighting tumours.
- a non-exhaustive list of anticancer agents consists of chemotherapeutic drugs, monoclonal antibodies, radiolabeled compounds, effector cells, toxins, cytokines, viral and plasmid vectors, RNA inhibitors and anticancer cells.
- the terms “aerosol”, “aerosolised”, “inhalable” and “nebulised” all refer to the same concept of breaking into small aerosol droplets, medical solutions/suspensions to enable them to be directly and efficiently inhaled from the mouth.
- lung conditioning agent for conditioning the lung
- preconditioned lungs refer to the concept of enabling lung cells to interact with biotinylated therapeutic agents through oxidized avidin interaction that would have been inhaled in beforehand.
- the expression "for substantially wholly conditioning the lung” means that once administered, the oxidized avidin can be detected in at least 95% of the lung.
- an object of the present invention resides in a pharmaceutical inhalable composition
- a pharmaceutical inhalable composition comprising:
- a sterile buffer solution at acidic pH wherein said buffer is preferably sodium acetate, and optionally
- a non-ionic agent selected from the group comprising mannitol, glycerol, glucose, lactose, trehalose, sucrose, propylene-glycol, sorbitol, xylitol, polyethylene- lycol, ethanol and isopropanol;
- said pharmaceutical composition is delivered through inhalation after nebulization.
- acidic pH means that the pH is comprised between 5.0 and 6.9.
- acidic pH means that the pH is comprised between 5.0 and 6.0.
- acidic pH means that the pH is comprised between 5.0 and 5.5.
- the pharmaceutical inhalable composition is freeze- dried.
- the oxidized avidin is useful as a lung conditioning agent through inhalation.
- said oxidized avidin is useful for substantially wholly conditions the lung through inhalation.
- the pharmaceutical inhalable composition of the invention is useful for the treatment of the following diseases: tuberculosis, Chronic Obstructive Pulmonary Disease (COPD), lung cancer in general and with particular interest on bronchioloalveolar (BAC) cancer, asthma, lung alveolitis, lung inflammatory diseases, cystic fibrosis and alpha-l-antitrypsin deficiency.
- COPD Chronic Obstructive Pulmonary Disease
- BAC bronchioloalveolar
- the pharmaceutical inhalable composition of the invention is useful for the treatment of primary lung cancer in multi-focal or metastatic form.
- the biotinylated therapeutic agent is a biotinylated adduct of an anticancer agent.
- the biotinylated anticancer agent is a biotinylated adduct of well-known anti-cancer drugs selected from the group comprising anti-EGFR, anti-CEA, anti-MUCl, anti-EpCAM, anti-cMET, anti-CTL4 monoclonal antibodies, TNF, TRAIL, Tweak, gamma interferon, G-CSF, GM-CSF, IL-2, IL-12 or chemotherapeutics.
- said anticancer agent is radioactive derivative selected from the group comprising of radiolabeled biotin-DOTA (ST2210). The latter was described in the patent application WO2002066075.
- the radioisotope used to label biotin-DOTA is selected from the group comprising 52 Fe, 62m Mn, 55 Co, 64 Cu, 67 Cu, 67 Ga, 68 Ga, 99m Tc, min, i23 L i25 I; m L 3 2 p 5 47 Sc5 9o Y; niAg, i49Pm, 186 Re, 188 Re, 211 At, 212 Pb, 212 Bi and 177 Lu.
- said anticancer agent is a biotinylated adduct of well-known anti-cancer drugs selected from the group consisting of viral or plasmid vectors, RNA inhibitors or anti-cancer effector cells.
- the biotinylated agent is an agent useful for the treatment of lung inflammatory diseases and is a biotinylated adduct of well-known anti-inflammatory drugs anti-inflammatory agent selected from the group comprising anti-TNF, anti-Tweak, anti-IL-17, anti-IL-23, anti-IL-6, anti-IL-1 monoclonal antibodies, IL-10 or chemokines.
- a therapeutic agent is a biotinylated adduct of known deficient protein like CFTCR in cystic fibrosis alpha-l- antitrypsin.
- a further preferred embodiment consists in a kit comprising the pharmaceutical inhalable composition mentioned herein-above, wherein the latter is either freeze- dried or dissolved in a sterile buffer solution.
- kit comprises the pharmaceutical inhalable composition mentioned herein-above and a nebulizer.
- oxidized avidin which is required to achieve a therapeutic effect will, of course, vary with the subject under treatment, and the particular disorder or disease to be treated. It will further depend on the efficiency of the nebulizer used and the deposition of the aerosol droplets in the lung. Suitable concentrations of oxidized avidin within the solution for nebulisation can be in the range of 0.005% to 0.5% (w/v) (i.e. 0.05 mg/ml to 5mg/ml).
- Non-ionic agent can be used for adjusting the osmolality of the solution for nebulisation.
- non-ionic agents for adjusting the osmolality which can be used in the present invention are selected from the group comprising mannitol, glycerol, glucose, lactose, trehalose, sucrose, propylene-glycol, sorbitol, xylitol, polyethylene- lycol, ethanol and isopropanol.
- the invention may contain one ore more additional suitable excipients.
- suitable excipients which can be mentioned include agents for modifying the pH of the solution and optionally preservatives.
- the formulation of the invention may be distributed in suitable containers such as multidose vials or, preferably, unit dose vials for single dosage administration.
- suitable containers such as multidose vials or, preferably, unit dose vials for single dosage administration.
- the solution for nebulisation of the present invention can be obtained as follows: oxidized avidin of a first vial can be dissolved by addition of sterile sodium acetate solution at pH 5.5 of a second vial.
- the formulations of the invention are intended for administration by nebulisation using suitable apparatus instrument that is capable of generating very fine liquid droplets for inhalation into the lungs.
- suitable instruments are for example jet nebulisers or ultrasonic nebulisers.
- EGFR+ A431 cells incubated with biotinylated cetuximab at the dose of 5 ⁇ g, 0.05 ⁇ g, 0.05 ng and 0.05 pg/ml for 1 hour in PBS without (a) or with (b) pre-treatment with oxidized avidin.
- mice of about 20 g were treated in the indicated sites with a solution of avidin or oxidized avidin as obtained following the procedure described at example 1 of WO2009016031 (3.0 mg/ml dissolved in 100 mM sodium acetate, pH 5.5) pre- complexed with m In-ST2210. Twenty four hours after injection/deposition, the mice were sacrificed by CO2 asphyxia and the treated sites analysed by means of a gamma counter. Data are reported in Figure 1, and are expressed as the % of injected dose/100 mg of tissue (%ID/100 mg).
- Results show a statistically significant higher amount of oxidized avidin/ m In-ST2210 complex in injected tongue, limb muscle and on the topically treated scraped skin compared to the Avidin/ m In- ST2210 complex.
- deposition of the oxidized avidin/ m In-ST2210 or Avidin/ m In-ST2210 complex on normal skin or in the eye did not lead to similar results, indicating that the complex does not bind to external tissue surfaces and consequently that a surgical operation is required to take advantage of the binding properties of oxidized avidin either as single agent when complexed with a biotinylated agent.
- Anesthetised female pig of about 40 kg was subjected to surgery to generate two 2 cm superficial lesions on the bladder wall. Then, 30 ml of oxidized avidin solution (3.0 mg/ml dissolved in 100 mM sodium acetate, pH 5.5) were instilled via a catheter and let interact for 1 hour. Bladder was then washed with saline and 0.5 ⁇ g 68-Ga-ST2210 was i.v. administered. After 4 hours the pig was subjected to PET.
- a 100 mM sodium acetate solution at pH 5.5 containing oxidized avidin at the concentration of 3.0 mg/ml was nebulised by means of a the Nose-Only inExpose System (Scireq-EMKA technologies) for 1 hour at room temperature.
- the particle size of the protein solution midst was 5 ⁇ .
- the nebulised solution was recovered in a falcon tube and analyzed by HPLC. Data in Figure 3 show the same elution profile for the oxidized avidin solution pre and post nebulisation indicating perfect stability of the protein.
- Biological activity and biostribution of nebulised oxidized avidin were evaluated in rat by measuring the uptake of 5 ⁇ g of m Indium radiolabeled biotinDOTA (i.e., ul In-ST2210) intravenously injected, 24 hours after oxidized avidin, avidin (3.0 mg/ml solution, 0.8ml/min, 1 hour nebulisation) or vehicle inhalation exposure, in the lung and non target organs.
- m Indium radiolabeled biotinDOTA i.e., ul In-ST2210
- nebulised vehicle only i.e., 100 mM sodium acetate solution at pH 5.5
- the rats received a 5 ⁇ g i.v. dose of m In-ST2210 in 0.5 ml of saline
- the second group (made of 8 rats) was exposed to nebulised avidin (about 10 mg/kg) in a 100 mM sodium acetate solution at pH 5.5 and 24 hours later the rats received a 5 ⁇ i.v. dose of m In-ST2210 in 0.5 ml of saline,
- the third group (made of 8 rats) was exposed to nebulised oxidized avidin (about 10 mg/kg) in a 100 mM sodium acetate solution at pH 5.5 and 24 hours later the rats received a 5 ⁇ g i.v. dose of m In-ST2210 in 0.5 ml of saline.
- mice of about 20 g were exposed to nebulised (i.e., by means of Nose-Only inExpose System -Scireq- EMKA technologies) oxidized avidin (3 mg/ml solution) or vehicle (3 ml) for 1 hour; 1 hour exposition corresponding to about a 90 mg/kg dose.
- the lung and non target organs were collected weighed and counted in a gamma counter. Data were expressed as the % of injected dose/gram of tissue.
- mice of about 20 g were exposed to nebulised oxidized avidin according to the protocol described at example 3, and were sacrificed by asphyxia 24 hours after.
- the lungs were removed and fixed in formalin and paraffin embedded.
- Serial sections obtained by means of a microtome were processed and incubated with a HRP- conjugated rabbit anti-avidin antibody (GeneTex, USA) and then with DAB substrate.
- Figure 5 shows the presence of oxidized avidin at broncho/epithelial level down to terminal bronchioles. This distribution was found to be homogenous in all lung compartments.
- mice of about 20 g were exposed to nebulised oxidized avidin or vehicle according to the protocol described at example 5. After 24 hours, they received an intravenous 1 ⁇ g dose of 64 Cu-ST2210. 64 Cu-ST2210 distribution was examined by PET imaging 4 hours after.
- Figure 6 shows the presence of a radioactive signal in the lungs of the mouse pre-treated with nebulised oxidized avidin but not in the lungs of a vehicle treated mouse. Kidneys, bladder are visible in both groups of mice. This observation is consistent with the physiological elimination of ST2210 at that time point. A radioactive signal in one limb is also visible in both groups of mice since they had been i.m. pre-treated with oxidized avidin at the time of aerosol in order to have an internal positive control in the experiment.
- Human EGFR + , epidermoid carcinoma cells A431 were incubated in PBS for 1 hour with 1 ml of an anti-EGFR monoclonal biotinylated antibody (i.e., biotinylated cetuximab) in the dose range of 0.05 pg/ml to 5 ⁇ g ml.
- biotinylated cetuximab an anti-EGFR monoclonal biotinylated antibody
- the cells were previously incubated with oxidized avidin meanwhile in the first experiment, cells were only treated with biotinylated cetuximab.
- biotinylated cetuximab binding was detected by cytofluorimetry after incubation with a mouse anti-human antibody conjugated with phycoerythrin (PE).
- PE phycoerythrin
- Data in Figure 9 indicate that the pro-apoptotic effect of biotinylated cetuximab is increased at least 3 times when AvidinOX is anchored on the membrane of the EGFR + cells but not of the EGFR- cells thus indicating the specificity of pro-apoptotic activity of the AvidinOX-anchored biotinylated cetuximab.
- biotinylated cetuximab were added, in triplicates, in the range of 0.05 pg/ml to 5 ⁇ g ml, in DMEM 1% FCS.
- the cells were washed after 15 minutes and cultivated for 48 hours in DMEM 1% FCS. Cell viability was detected by CellTiter-Glow® (Promega).
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KR1020147001707A KR101966630B1 (en) | 2011-08-02 | 2012-07-25 | Pharmaceutical composition of oxidised avidin suitable for inhalation |
ES12740137T ES2729549T3 (en) | 2011-08-02 | 2012-07-25 | Pharmaceutical composition of oxidized avidin suitable for inhalation |
US14/236,445 US9872831B2 (en) | 2011-08-02 | 2012-07-25 | Pharmaceutical composition of oxidised avidin suitable for inhalation |
EA201490401A EA026453B1 (en) | 2011-08-02 | 2012-07-25 | Use of oxidised avidin for inhalation |
JP2014523289A JP6019118B2 (en) | 2011-08-02 | 2012-07-25 | Pharmaceutical composition of oxidized avidin suitable for inhalation |
MX2014001176A MX355177B (en) | 2011-08-02 | 2012-07-25 | Pharmaceutical composition of oxidised avidin suitable for inhalation. |
PL12740137T PL2739314T3 (en) | 2011-08-02 | 2012-07-25 | Pharmaceutical composition of oxidised avidin suitable for inhalation |
AU2012292229A AU2012292229B2 (en) | 2011-08-02 | 2012-07-25 | Pharmaceutical composition of oxidised avidin suitable for inhalation |
NZ620202A NZ620202B2 (en) | 2011-08-02 | 2012-07-25 | Pharmaceutical composition of oxidised avidin suitable for inhalation |
CA2842276A CA2842276C (en) | 2011-08-02 | 2012-07-25 | Pharmaceutical composition of oxidised avidin suitable for inhalation |
EP12740137.0A EP2739314B1 (en) | 2011-08-02 | 2012-07-25 | Pharmaceutical composition of oxidised avidin suitable for inhalation |
BR112014002593-2A BR112014002593B1 (en) | 2011-08-02 | 2012-07-25 | PHARMACEUTICAL COMPOSITION OF OXIDIZED AVIDIN SUITABLE FOR INHALATION AND RELATED KITS |
CN201280037217.9A CN103717239B (en) | 2011-08-02 | 2012-07-25 | It is suitable for the pharmaceutical composition of the Oxavidin of suction |
UAA201402021A UA114482C2 (en) | 2011-08-02 | 2012-07-25 | Pharmaceutical composition of oxidised avidin suitable for inhalation |
DK12740137.0T DK2739314T3 (en) | 2011-08-02 | 2012-07-25 | PHARMACEUTICAL COMPOSITION OF OXIDATED AVIDIN SUITABLE FOR INHALATION |
IL230597A IL230597A0 (en) | 2011-08-02 | 2014-01-22 | Pharmaceutical composition of oxidised avidin suitable for inhalation |
ZA2014/01921A ZA201401921B (en) | 2011-08-02 | 2014-02-27 | Pharmaceutical composition of oxidised avidin suitable for inhalation |
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WO2006064283A1 (en) * | 2004-12-17 | 2006-06-22 | Cipla Limited | Pharmaceutical compounds and compositions |
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AU2012292229B2 (en) | 2017-08-03 |
MX2014001176A (en) | 2014-07-14 |
MX355177B (en) | 2018-04-09 |
BR112014002593A2 (en) | 2017-03-01 |
UA114482C2 (en) | 2017-06-26 |
BR112014002593B1 (en) | 2022-11-29 |
NZ620202A (en) | 2016-05-27 |
ZA201401921B (en) | 2015-05-27 |
KR20140047668A (en) | 2014-04-22 |
CN103717239A (en) | 2014-04-09 |
PL2739314T3 (en) | 2019-09-30 |
IL230597A0 (en) | 2014-03-31 |
EP2739314B1 (en) | 2019-05-22 |
EP2739314A1 (en) | 2014-06-11 |
ES2729549T3 (en) | 2019-11-04 |
DK2739314T3 (en) | 2019-06-24 |
EA201490401A1 (en) | 2014-05-30 |
PT2739314T (en) | 2019-06-21 |
AU2012292229A1 (en) | 2014-02-13 |
US9872831B2 (en) | 2018-01-23 |
JP2014521675A (en) | 2014-08-28 |
JP6019118B2 (en) | 2016-11-02 |
US20140134106A1 (en) | 2014-05-15 |
CA2842276C (en) | 2020-11-24 |
EA026453B1 (en) | 2017-04-28 |
CA2842276A1 (en) | 2013-02-07 |
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