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WO2025037259A1 - Méthodes et compositions pour la prévention ou le traitement de l'asthme sévère - Google Patents

Méthodes et compositions pour la prévention ou le traitement de l'asthme sévère Download PDF

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Publication number
WO2025037259A1
WO2025037259A1 PCT/IB2024/057907 IB2024057907W WO2025037259A1 WO 2025037259 A1 WO2025037259 A1 WO 2025037259A1 IB 2024057907 W IB2024057907 W IB 2024057907W WO 2025037259 A1 WO2025037259 A1 WO 2025037259A1
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WO
WIPO (PCT)
Prior art keywords
asthma
hdm
acid
seq
severe asthma
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PCT/IB2024/057907
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English (en)
Inventor
Jorge DEALBA
Roly FOULKES
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Revolo Biotherapeutics Limited
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Publication date
Application filed by Revolo Biotherapeutics Limited filed Critical Revolo Biotherapeutics Limited
Publication of WO2025037259A1 publication Critical patent/WO2025037259A1/fr

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • 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
    • A61K38/164—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria

Definitions

  • the embodiments of the present invention relate to compositions and methods for the prevention or treatment of severe asthma with peptides related to Chaperonin 60.1 (Cpn60.1).
  • Asthma is a chronic and heterogeneous respiratory condition characterized by airflow obstruction, airway inflammation and AHR (airway hyperresponsiveness) with symptoms of wheeze, cough, chest tightness and shortness of breath. 1 It affects approximately 300 million people worldwide. 2 The majority of asthma patients with asthma can be treated effectively with the currently available medications. However, a significant proportion of patients, labelled as “severe refractory asthma” or “severe asthma,” remain a challenge for the treating clinician. Severe asthma encompasses a variety of subphenotypes of asthma that do not respond to current standard therapy, i.e., high doses of corticosteroid (ICS) in combination with long-acting P2-agonists.
  • ICS corticosteroid
  • the embodiments of the present invention provide a method for treating or preventing severe asthma in a subject that is resistant to one or more corticosteroid drug, the method comprising administering to the subject, a therapeutically-effective amount of a peptide related to Chaperonin 60.1 (Cpn60.1).
  • the Cpn60.1 -related peptide is selected from: DGSVVVNKVSELPAGHGLNVNTLSYGDLAAD (SEQ ID NO: 1) (PIN201104); DGSVVVNKVSELPAGH (SEQ ID NO: 2); GLNVNTLSYGDLAAD (SEQ ID NO: 3);
  • the Cpn60.1 -related peptide is SEQ ID NO:1.
  • the method further comprises the step of diagnosing the subject as having, or likely to develop, severe asthma prior to administration, or receiving the results of an assay that diagnoses the subject as having, or likely to develop, severe asthma.
  • the Cpn60.1 -related peptide is administered prior to the first symptom of severe asthma. In alternative embodiments, the Cpn60.1 -related peptide is administered upon clinical signs of severe asthma.
  • the embodiments of the present invention provide a method for treating severe asthma in a subject resistant to one or more corticosteroid drug, the method comprising the steps of: (i) administering a peptide related to Cpn60.1)to the subject upon clinical signs of severe asthma, and (ii) stopping the administration of the peptide related to Cpn60.1 upon remission of the clinical signs of severe asthma. wherein the severe asthma in the subject is resistant to one or more corticosteroid drug.
  • the Cpn60.1 -related peptide is selected from: DGSVVVNKVSELPAGHGLNVNTLSYGDLAAD (SEQ ID NO: 1) (PIN201104);
  • DGSVVVNKVSELPAGH (SEQ ID NO: 2); GLNVNTLSYGDLAAD (SEQ ID NO: 3);
  • the Cpn60.1 -related peptide is SEQ ID NO:1.
  • the method further comprises the step of diagnosing the subject as having, or likely to develop, severe asthma prior to administration, or receiving the results of an assay that diagnoses the subject as having, or likely to develop, severe asthma.
  • the Cpn60.1 -related peptide is administered prior to the first symptom of severe asthma. In alternative embodiments, the Cpn60.1 -related peptide is administered upon clinical signs of severe asthma.
  • FIG. 1A-B shows bar graphs representing the total cell count in the bronchoalveolar lavage fluid following treatment with vehicle (5 ml_/kg, IV), IRL201104 (20 or 80 pg/kg, IV) or dexamethasone (1 mg/kg, IP) 1 hour before HDM challenge on day 14 in HDM (100 pg, s.c., day 0) sensitized mice and challenged (days 14) with PBS or HDM (25 pg, IN). See FIG. 1A.
  • vehicle 5 ml_/kg, IV
  • IRL201104 20 or 80 pg/kg, IV
  • dexamethasone (1 mg/kg, IP
  • FIG. 4A-B shows bar graphs representing the number of macrophages in the bronchoalveolar lavage fluid following treatment with vehicle (5 mL/kg, IV), IRL201104 (20 or 80 pg/kg, IV) or dexamethasone (1 mg/kg, IP) 1 hour before HDM challenge on day 14 in HDM (100 pg, s.c., day 0) sensitized mice and challenged (days 14) with PBS or HDM (25 pg, IN). See FIG. 4A.
  • Vehicle + HDM or Vehicle + polylC + HDM was compared to all other groups using ANOVA followed by Dunnett’s test. **P ⁇ 0.01, ***P ⁇ 0.001.
  • FIG. 5A-B shows bar graphs representing the number of lymphocytes in the bronchoalveolar lavage fluid following treatment with vehicle (5 mL/kg, IV), IRL201104 (20 or 80 pg/kg, IV) or dexamethasone (1 mg/kg, IP) 1 hour before HDM challenge on day 14 in HDM (100 pg, s.c., day 0) sensitized mice and challenged (days 14) with PBS or HDM (25 pg, IN). See FIG. 5A.
  • mice were also challenged with polylC on day 13, 24 hours before HDM challenge.
  • FIG. 6A-B provides line graphs showing the change in total resistance (Rl) following 20 sec methacholine (MCh, 1-30 pg/mL) aerosol following treatment with vehicle (5 mL/kg, IV), IRL201104 (20 or 80 pg/Kg, IV) or dexamethasone (1 mg/Kg, IP) 1 hour before HDM challenge on day 14 in HDM (100 pg, s.c., day 0) sensitized mice and challenged (days 14) with PBS or HDM (25 pg, IN). See FIG. 6A.
  • FIG. 7A-B provides line graphs showing the change in dynamic compliance (Cdyn) following 20 sec methacholine (MCh, 1-30 pg/mL) aerosol following treatment with vehicle (5 mL/kg, IV), IRL201104 (20 or 80 pg/Kg, IV) or dexamethasone (1 mg/Kg, IP) 1 hour before HDM challenge on day 14 in HDM (100 pg, s.c., day 0) sensitized mice and challenged (days 14) with PBS or HDM (25 pg, IN). See FIG. 7A. In FIG. 7B, mice were also challenged with polylC on day 13, 24 hours before HDM challenge.
  • FIG. 8A-D provides bar graphs showing the effects of treatment on HDM- induced cellular infiltration on eosinophils (FIG. 8A), neutrophils (FIG. 8B), macrophages (FIG. 8C), and lymphocytes (FIG. 8D) lung infiltrate.
  • FIG. 9A-D provides bar graphs showing the effects of treatment on HDM- induced cellular infiltration exacerbated by Poly l:C exposure on eosinophils (FIG. 9A), neutrophils (FIG. 9B), macrophages (FIG. 9C), and lymphocytes (FIG. 9D) lung infiltrate.
  • Data are expressed as cells per mL of BALF, mean ⁇ SEM.
  • Groups were compared to HDM/Poly I :C/ vehicle group using a one-way ANOVA, followed by a Dunnett’s test;*P ⁇ 0.05,***P ⁇ 0.001.
  • AUC area under the curve
  • the term “approximately” or “about” in reference to a value or parameter are generally taken to include numbers that fall within a range of 5%, 10%, 15%, or 20% in either direction (greater than or less than) of the number unless otherwise stated or otherwise evident from the context (except where such number would be less than 0% or exceed 100% of a possible value).
  • reference to “approximately” or “about” a value or parameter includes (and describes) embodiments that are directed to that value or parameter. For example, description referring to "about X” includes description of "X”.
  • the term “or” means “and/or.”
  • the term “and/or” as used in a phrase such as "A and/or B” herein is intended to include both A and B; A or B; A (alone); and B (alone).
  • the term “and/or” as used in a phrase such as "A, B, and/or C” is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).
  • compositions, methods, and respective components thereof as described herein, which are exclusive of any element not recited in that description of the embodiment.
  • the term "consisting essentially of” refers to those elements required for a given embodiment. The term permits the presence of additional elements that do not materially affect the basic and novel or functional characteristic(s) of that embodiment of the invention.
  • statically significant or “significantly” refers to statistical significance and generally means a two-standard deviation (2SD) or greater difference.
  • the term "subject” refers to a mammal, including but not limited to a dog, cat, horse, cow, pig, sheep, goat, chicken, rodent, or primate.
  • Subjects can be house pets (e.g., dogs, cats), agricultural stock animals (e.g., cows, horses, pigs, chickens, etc.), laboratory animals (e.g., mice, rats, rabbits, etc.), but are not so limited.
  • Subjects include human subjects.
  • the human subject may be a pediatric, adult, or a geriatric subject.
  • the human subject may be of either sex.
  • the terms "effective amount” and “therapeutically-effective amount” include an amount sufficient to prevent or ameliorate a manifestation of severe asthma. It will be appreciated that there will be many ways known in the art to determine the effective amount for a given application. For example, the pharmacological methods for dosage determination may be used in the therapeutic context. In the context of therapeutic or prophylactic applications, the amount of a composition administered to the subject will depend on the type and severity of the disease and on the characteristics of the individual, such as general health, age, sex, body weight and tolerance to drugs. It will also depend on the degree, severity and type of disease. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. The compositions can also be administered in combination with one or more additional therapeutic compounds.
  • treating or “treatment” or “to treat” or “alleviating” or “to alleviate” refer to both (1) therapeutic measures that cure, slow down, lessen symptoms of, and/or halt progression of a diagnosed disease or infection and (2) prophylactic or preventative measures that prevent or slow the development of a disease or infection.
  • the terms “treat,” “treatment,” “treating,” or “amelioration” when used in reference to a disease, disorder or medical condition refer to therapeutic treatments for a condition, wherein the object is to reverse, alleviate, ameliorate, inhibit, slow down or stop the progression or severity of a symptom or condition.
  • the term “treating” includes reducing or alleviating at least one adverse effect or symptom of a condition.
  • Treatment is generally “effective” if one or more symptoms or clinical markers are reduced. Alternatively, treatment is “effective” if the progression of a condition is reduced or halted.
  • treatment includes not just the improvement of symptoms or markers, but also a cessation or at least slowing of progress or worsening of symptoms that would be expected in the absence of treatment.
  • Beneficial or desired clinical results include, but are not limited to, alleviation of one or more symptom(s), diminishment of extent of the deficit, stabilized (/.e., not worsening) state of an immune disorder, delay or slowing of an immune disorder, and an increased lifespan as compared to that expected in the absence of treatment.
  • Signs and symptoms of an asthma attack include, but are not limited to, severe shortness of breath, chest tightness or pain, coughing or wheezing, and low peak expiratory flow (PEF) readings, using a peak flow meter.
  • PEF peak expiratory flow
  • Severe asthma is present when adequate control of asthma cannot be achieved by high-dose treatment with inhaled corticosteroids and additional controllers (long-acting inhaled beta 2 agonists, montelukast, and/or theophylline) or by oral corticosteroid treatment (for at least six months per year) or is lost when the treatment is reduced.
  • the term “acute treatment” is used to mean that the peptide is administered at the onset of or during a period of relapse of the condition, but that it is not necessary for the peptide to be continuously administered. In particular, it may not be necessary for the peptide to be administered during periods of remission of the condition.
  • the “acute treatment” according to the present invention can be distinguished from known methods for the treatment of relapsing-remitting conditions which provide chronic therapy requiring continuous, long-term administration of the pharmaceutical without any breaks in treatment.
  • the provision of an acute treatment provides significant advantages to the patient. Since the peptides of the invention only need to be administered over a short period of time, side effects, for example injection site reactions are reduced.
  • a single dose of the peptide molecule is administered to the subject.
  • two or more doses are administered over a short period of time, for example over a period of one day, three days, 28 days, 56 days or 112 days.
  • the time between dose administration to the subject may be three hours, one day, 14 days, 28 days or 56 days after the previous dose.
  • Remission usually comprises the reduction, alleviation or elimination of one or more symptoms of the condition.
  • remission or clinical remission comprises a period with no symptoms associated with the relapsing-remitting disease or a period during which the symptoms associated with the disease have decreased in severity and/or in number.
  • a symptom associated with a condition, disease or disorder includes any clinical or laboratory manifestation associated with the disease or disorder.
  • Clinical remission may therefore be measured according to the relevant scale or remission indicators, and well known in the medical field by for example, clinicians and researchers.
  • relapse of the condition may be defined as the increase or appearance of one or more symptoms of the condition.
  • symptoms of asthma may be shortness of breath, difficulty breathing, chest tightness, coughing, reduced lung capacity, trouble sleeping caused by shortness of breath, coughing or wheezing, a whistling or wheezing sound when inhaling, coughing or wheezing attacks that are worsened by a respiratory virus such as cold or flu.
  • symptoms may include hospitalization or loss of work/school attendance.
  • a reduction or elimination of one or more symptoms is typically a significant reduction or elimination of one or more symptoms as identified by a physician.
  • Symptoms of the relapsing-remitting conditions can be measured and quantified using well-known diagnostic tests. For example, lung function tests such as spirometry and methacholine challenge tests can be used to quantify the symptoms of asthma, using ACQ scores.
  • the ACQ is a simple questionnaire to measure the adequacy of asthma control and change in asthma control which occurs either spontaneously or as a result of treatment.
  • ACQ has a multidimensional construct assessing symptoms (5 items-self-administered) and rescue bronchodilator use (1 item-self- administered) and forced expiratory volume in 1 minute (FEV1) (1 item) completed by clinic staff. 13
  • the condition is associated with eosinophilia and/or neutrophilia.
  • remission comprises a significant reduction in the number of neutrophils and/or the number of eosinophils trafficking to a site of inflammation in the human or animal subject relative to a control subject who has not been administered the peptide molecule.
  • the condition is a pulmonary condition, remission comprises a significant reduction in the number of neutrophils and/or the number of eosinophils recruited to the lungs or found within the circulatory system.
  • Remission may also be associated with a significant reduction in the number of lymphocytes or a significant increase in the number of macrophages in the human subject relative to a control subject.
  • Remission may further be associated with a significant change in the amount of one or more inflammatory markers such as cytokines, for example IL-4, IL-5, IL-10, or IL-13 in the human subject relative to a control subject.
  • Remission may comprise a significant increase in the amount of IL-10 in the human subject relative to a control subject.
  • Remission may comprise a significant reduction in the amount of IL-4, IL-5 or IL-13 in the human subject relative to a control subject.
  • a relapsing-remitting condition is any condition which has one or more periods of relapse, wherein each relapse is followed by a period of remission. During these symptom free periods or periods of remission, patients do not require quantifiable circulating levels of the therapeutic peptide. In a preferred embodiment remission is maintained when the plasma peptide concentration is below the lower limit of quantification. This limit of quantification may vary depending on the detection method employed. Typically, the plasma peptide concentration is undetectable at circulating levels of less than 40 ng/mL, for example less than 30 ng/mL or 20 ng/mL. A typical method for determining the plasma peptide concentration is high resolution accurate mass (HRAM) LC-MS/MS.
  • HRAM high resolution accurate mass
  • remission of the condition is for a period of at least 7 days, for example 14 days, at least 28 days, more preferably at least 6 months after the concentration of the peptide molecule in the plasma of the subject is undetectable.
  • remission of the condition is for a period of at least 7 days, optionally at least 14 days, optionally at least 28 days, optionally at least 6 months after administration of the final dose of the peptide.
  • long-term administration means that the therapeutic agent or drug is administered for a period of at least 12 weeks. This includes that the therapeutic agent or drug is administered such that it is effective over, or for, a period of at least 12 weeks and does not necessarily imply that the administration itself takes place for 12 weeks, e.g., if sustained release compositions or long-acting therapeutic agent or drug is used. Thus, the subject is treated for a period of at least 12 weeks. In many cases, long-term administration is for at least 4, 5, 6, 7, 8, 9 months or more, or for at least 1 , 2, 3, 5, 7 or 10 years, or more.
  • compositions contemplated herein may be carried out in any convenient manner, including by aerosol inhalation, injection, ingestion, transfusion, implantation or transplantation.
  • compositions are administered parenterally.
  • parenteral administration and “administered parenterally” as used herein refers to modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravascular, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intratumoral, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion.
  • the compositions contemplated herein are administered to a subject by direct injection into a tumor, lymph node, or site of infection.
  • “decrease,” “reduced,” “reduction,” or “inhibit” are all used herein to mean a decrease by a statistically significant amount.
  • “reduce,” “reduction” or “decrease” or “inhibit” typically means a decrease by at least 10% as compared to a reference level (e.g., the absence of a given treatment or agent) and can include, for example, a decrease by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99% , or more.
  • “reduction” or “inhibition” does not encompass a complete inhibition or reduction as compared to a reference level. “Complete inhibition” is a 100% inhibition as compared to a reference level. A decrease can be preferably down to a level accepted as within the range of normal for an individual without a given disorder.
  • the terms “increased”, “increase”, “enhance”, or “activate” are all used herein to mean an increase by a statically significant amount.
  • the terms “increased”, “increase”, “enhance”, or “activate” can mean an increase of at least 10% as compared to a reference level, for example an increase of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% increase or any increase between 10-100% as compared to a reference level, or at least about a 2-fold, or at least about a 3-fold, or at least about a 4-fold, or at least about a 5-fold or at least about a 10-fold increase, or any increase between 2-fold and 10-fold or greater as compared to a reference level.
  • a “increase” is a statistically significant increase in such level.
  • protein and “polypeptide” are used interchangeably herein to designate a series of amino acid residues, connected to each other by peptide bonds between the alpha-amino and carboxy groups of adjacent residues.
  • protein and “polypeptide” refer to a polymer of amino acids, including modified amino acids (e.g., phosphorylated, glycated, glycosylated, etc.) and amino acid analogs, regardless of its size or function.
  • modified amino acids e.g., phosphorylated, glycated, glycosylated, etc.
  • amino acid analogs regardless of its size or function.
  • Protein and “polypeptide” are often used in reference to relatively large polypeptides, whereas the term “peptide” is often used in reference to small polypeptides, but usage of these terms in the art overlaps.
  • polypeptide proteins and “polypeptide” are used interchangeably herein when referring to a gene product and fragments thereof.
  • exemplary polypeptides or proteins include gene products, naturally occurring proteins, homologs, orthologs, paralogs, fragments and other equivalents, variants, fragments, and analogs of the foregoing.
  • variants naturally occurring or otherwise
  • alleles homologs
  • conservatively modified variants conservative substitution variants of any of the particular polypeptides described are encompassed.
  • amino acid sequences one of skill will recognize that individual substitutions, deletions or additions to a nucleic acid, peptide, polypeptide, or protein sequence which alters a single amino acid or a small percentage of amino acids in the encoded sequence is a “conservatively modified variant” where the alteration results in the substitution of an amino acid with a chemically similar amino acid and retains the desired activity of the polypeptide.
  • conservatively modified variants are in addition to and do not exclude polymorphic variants, interspecies homologs, and alleles consistent with the disclosure.
  • the polypeptide described herein can be a functional fragment of one of the amino acid sequences described herein.
  • a “functional fragment” is a fragment or segment of a peptide which retains at least 50% of the wildtype reference polypeptide’s activity according to the assays described below herein.
  • a functional fragment can comprise conservative substitutions of the sequences disclosed herein.
  • the polypeptide described herein can be a variant of a sequence described herein.
  • the variant is a conservatively modified variant.
  • Conservative substitution variants can be obtained by mutations of native nucleotide sequences, for example.
  • a “variant,” as referred to herein, is a polypeptide substantially homologous to a native or reference polypeptide, but which has an amino acid sequence different from that of the native or reference polypeptide because of one or a plurality of deletions, insertions or substitutions.
  • Variant polypeptide-encoding DNA sequences encompass sequences that comprise one or more additions, deletions, or substitutions of nucleotides when compared to a native or reference DNA sequence, but that encode a variant protein or fragment thereof that retains activity.
  • a wide variety of PCR-based site-specific mutagenesis approaches are known in the art and can be applied by the ordinarily skilled artisan.
  • nucleic acid or “nucleic acid sequence” refers to any molecule, preferably a polymeric molecule, incorporating units of ribonucleic acid, deoxyribonucleic acid or an analog thereof.
  • the nucleic acid can be either single-stranded or double-stranded.
  • a single-stranded nucleic acid can be one nucleic acid strand of a denatured double- stranded DNA. Alternatively, it can be a single-stranded nucleic acid not derived from any double-stranded DNA.
  • the nucleic acid can be DNA.
  • nucleic acid can be RNA.
  • Suitable DNA can include, e.g., genomic DNA or cDNA.
  • Suitable RNA can include, e.g., mRNA.
  • a polypeptide, nucleic acid, or cell as described herein can be engineered.
  • engineered refers to the aspect of having been manipulated by the hand of man.
  • a polypeptide is considered to be “engineered” when at least one aspect of the polypeptide, e.g., its sequence, has been manipulated by the hand of man to differ from the aspect as it exists in nature.
  • progeny of an engineered cell are typically still referred to as “engineered” even though the actual manipulation was performed on a prior entity.
  • a nucleic acid encoding a polypeptide as described herein is comprised by a vector.
  • a nucleic acid sequence encoding a given polypeptide as described herein, or any module thereof is operably linked to a vector.
  • a vector can include, but is not limited to, a cloning vector, an expression vector, a plasmid, phage, transposon, cosmid, chromosome, virus, virion, etc.
  • expression vector refers to a vector that directs expression of an RNA or polypeptide from sequences linked to transcriptional regulatory sequences on the vector.
  • the sequences expressed will often, but not necessarily, be heterologous to the cell.
  • An expression vector may comprise additional elements, for example, the expression vector may have two replication systems, thus allowing it to be maintained in two organisms, for example in human cells for expression and in a prokaryotic host for cloning and amplification.
  • expression refers to the cellular processes involved in producing RNA and proteins and as appropriate, secreting proteins, including where applicable, but not limited to, for example, transcription, transcript processing, translation and protein folding, modification and processing.
  • “Expression products” include RNA transcribed from a gene, and polypeptides obtained by translation of mRNA transcribed from a gene.
  • the term “gene” means the nucleic acid sequence which is transcribed (DNA) to RNA in vitro or in vivo when operably linked to appropriate regulatory sequences.
  • the gene may or may not include regions preceding and following the coding region, e.g., 5’ untranslated (5’UTR) or “leader” sequences and 3’ UTR or “trailer” sequences, as well as intervening sequences (introns) between individual coding segments (exons).
  • isolated refers, in the case of a nucleic acid or polypeptide, to a nucleic acid or polypeptide separated from at least one other component (e.g., nucleic acid or polypeptide) that is present with the nucleic acid or polypeptide as found in its natural source and/or that would be present with the nucleic acid or polypeptide when expressed by a cell, or secreted in the case of secreted polypeptides.
  • component e.g., nucleic acid or polypeptide
  • a chemically synthesized nucleic acid or polypeptide or one synthesized using in vitro transcription/translation is considered “isolated.”
  • the terms “purified” or “substantially purified” refer to an isolated nucleic acid or polypeptide that is at least 95% by weight the subject nucleic acid or polypeptide, including, for example, at least 96%, at least 97%, at least 98%, at least 99% or more.
  • the antibody, antigen-binding portion thereof, or chimeric antigen receptor (CAR) described herein is isolated.
  • the antibody, antibody reagent, antigen-binding portion thereof, or CAR described herein is purified.
  • engineered refers to the aspect of having been manipulated by the hand of man.
  • an antibody, antibody reagent, antigen-binding portion thereof, CAR or bispecific antibody is considered to be “engineered” when the sequence of the antibody, antibody reagent, antigen-binding portion thereof, CAR or bispecific antibody is manipulated by the hand of man to differ from the sequence of an antibody as it exists in nature.
  • progeny and copies of an engineered polynucleotide and/or polypeptide are typically still referred to as “engineered” even though the actual manipulation was performed on a prior entity.
  • compositions and methods of the present invention may be utilized to treat an individual in need thereof.
  • the individual is a mammal such as a human, or a non-human mammal.
  • the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the invention and a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters.
  • the aqueous solution is pyrogen-free, or substantially pyrogen-free.
  • the excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs.
  • the pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like.
  • the composition can also be present in a transdermal delivery system, e.g., a skin patch.
  • the composition can also be present in a solution suitable for topical administration, such as a lotion, cream, or ointment.
  • a pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a compound of the invention.
  • physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients.
  • the choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent depends, for example, on the route of administration of the composition.
  • the preparation or pharmaceutical composition can be a self-emulsifying drug delivery system or a self-micro emulsifying drug delivery system.
  • the pharmaceutical composition also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention.
  • Liposomes for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable carrier means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc;
  • excipients such as cocoa butter and suppository waxes
  • oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil
  • glycols such as propylene glycol
  • polyols such as glycerin, sorbitol, mannitol and polyethylene glycol
  • esters such as ethyl oleate and ethyl laurate
  • agar such as agar
  • buffering agents such as magnesium hydroxide and aluminum hydroxide
  • alginic acid such as pyrogen-free water
  • a pharmaceutical composition can be administered to a subject by any of a number of routes of administration including, for example, orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually); subcutaneously; transdermally (for example as a patch applied to the skin); and topically (for example, as a cream, ointment or spray applied to the skin).
  • routes of administration including, for example, orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually); subcutaneously; transdermally (for example
  • the compound may also be formulated for inhalation.
  • a compound may be simply dissolved or suspended in sterile water. Details of appropriate routes of administration and compositions suitable for same can be found in, for example, U.S. Patent Nos. 6,110,973, 5,763,493, 5,731 ,000, 5,541 ,231 , 5,427,798, 5,358,970 and 4,172,896, as well as in patents cited therein.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
  • Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the invention, with the carrier and, optionally, one or more accessory ingredients.
  • an active compound such as a compound of the invention
  • the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations of the invention suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), lyophile, powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
  • Compositions or compounds may also be administered as a bolus, electuary or paste.
  • the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate;
  • pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose,
  • solution retarding agents such as paraffin
  • absorption accelerators such as quaternary ammonium compounds
  • wetting agents such as, for example, cetyl alcohol and glycerol monostearate
  • absorbents such as kaolin and bentonite clay
  • lubricants such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof
  • complexing agents such as, modified and unmodified cyclodextrins
  • (11) coloring agents in the case of capsules (including sprinkle capsules and gelatin capsules), tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropyl methyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surfaceactive or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropyl methyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions that can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophiles for reconstitution, micro-emulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Dosage forms for the topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to an active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body.
  • dosage forms can be made by dissolving or dispersing the active compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intraocular (such as intravitreal), intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion.
  • intravenous, intraocular such as intravitreal
  • intramuscular intraarterial
  • intrathecal intracapsular
  • intraorbital intracardiac
  • intradermal intraperitoneal
  • transtracheal subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion.
  • compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • suitable aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.
  • adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and
  • Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.
  • biodegradable polymers such as polylactide-polyglycolide.
  • Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.
  • active compounds can be given perse or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • Methods of introduction may also be provided by rechargeable or biodegradable devices.
  • Various slow-release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinaceous biopharmaceuticals.
  • a variety of biocompatible polymers including hydrogels, including both biodegradable and non-degradable polymers, can be used to form an implant for the sustained release of a compound at a particular target site.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the pharmaceutical composition or compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • therapeutically effective amount is meant the concentration of a compound that is sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the weight, sex, age, and medical history of the subject. Other factors which influence the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent being administered with the compound of the invention. A larger total dose can be delivered by multiple administrations of the agent. Methods to determine efficacy and dosage are known to those skilled in the art. See, e.g., Isselbacher et al. (1996). 14
  • a suitable daily dose of an active compound used in the compositions and methods of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
  • the effective daily dose of the active compound may be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
  • the active compound may be administered two or three times daily. In other embodiments, the active compound will be administered once daily.
  • the patient receiving this treatment is any animal in need, including primates, in particular humans; and other mammals such as equines bovine, porcine, sheep, feline, and canine; poultry; and pets in general.
  • compounds of the invention may be used alone or conjointly administered with another type of therapeutic agent.
  • contemplated salts of the invention include, but are not limited to, alkyl, dialkyl, trialkyl or tetra-alkyl ammonium salts.
  • contemplated salts of the invention include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1 H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2- hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts.
  • contemplated salts of the invention include, but are not limited to, Na, Ca, K, Mg, Zn or other metal salts.
  • contemplated salts of the invention include, but are not limited to, 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2- hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, l-ascorbic acid, l-aspartic acid, benzenesulfonic acid, benzoic acid, (+)- camphoric acid, (+)-camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid,
  • the pharmaceutically acceptable acid addition salts can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared.
  • the source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal-chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), le
  • Asthma is a complex, respiratory disease characterized by airway inflammation and bronchoconstriction, which make it difficult to breathe. Asthma affects approximately 300 million people worldwide. 27 There are heterogeneous clinical symptoms with varying degrees of response to therapy in asthma. Inhaled corticosteroid (ICS) is a common therapy for asthma, to which controllers such as a long-acting [32 agonist are added if required, and if these fail oral corticosteroids are also added. 28,29 Approximately 10% of asthma patients do not respond to available steroid treatments.
  • ICS Inhaled corticosteroid
  • severe asthma This condition is referred to as “severe asthma,’’ “severe refractory asthma,’’ “corticosteroid refractory asthma” or “severe corticosteroid refractory asthma.”
  • a task force of ERS/ATS defined severe asthma as “asthma which requires treatment with high dose inhaled corticosteroids (ICS) plus a second controller (and/or systemic corticosteroids) to prevent it from becoming ‘uncontrolled,’ or which remains ‘uncontrolled’ despite this therapy.”
  • Asthma is among the most common chronic diseases in the developed and developing world, but its diagnosis can be difficult. Although symptoms including wheeze, chest tightness and shortness of breath are often considered essential features of asthma in humans, the adage ‘all that is asthma does not wheeze and all that wheezes is not asthma’ holds true. Epidemiological studies that rely on ‘doctor diagnosis’ of asthma overestimate the true disease prevalence owing to misclassification. 37 A diagnosis of asthma usually begins when a child or adult presents with a range of spontaneous respiratory symptoms including recurrent cough and nocturnal awakening, along with symptoms triggered by external stimuli, such as allergens, viral infections, exercise and cold air.
  • Physiologically determined abnormalities such as reduced spirometry, are also of value in establishing an asthma diagnosis early in the course of the condition. Patients should be tested on a spirometer that is equipped with population normal values and, ideally, one that generates a flow-volume loop that can be evaluated for both inspiratory and expiratory effort. FEV1, forced vital capacity (FVC) and the FEV1/FVC ratio should be reported alongside reversibility of lung function with an inhaled SABA. Symptomatic asthma is often associated with a predicted FEV1 of ⁇ 80% and an age- adjusted FEV1/FVC of ⁇ 75%.
  • bronchodilator reversibility and peak expiratory flow (PEF) variability have poor sensitivity and specificity for the diagnosis of asthma.
  • PEF peak expiratory flow
  • a diagnosis of asthma requires at least a 12% improvement in FEV1 over baseline and a total improvement of at least 200 mL.
  • Additional diagnostic aids include repeat testing over time and diurnal PEF monitoring using a portable PEF meter.
  • bronchial provocation testing with inhaled methacholine or mannitol should be considered to establish if airway hyper-responsiveness exists as another characteristic feature of asthma, although some variability in responses can be seen.
  • the patient inhales increasing concentrations of the challenge substance until there is a >20% fall in the FEV1 from the saline control value.
  • Each challenge agent has a threshold concentration for the fall that identifies asthma.
  • Exercise testing or, as an alternative, eucapnic hyperventilation, which mimics the volume of air exchanged during exercise, is another method for uncovering hyperresponsiveness and is especially useful in diagnosing asthma in children.
  • ICS treatment monitored by sputum eosinophil testing is highly effective, 4647 and both sputum and blood eosinophil counts are being used to effectively identify patients who might be responsive to biologic therapies that target IL-4, IL-13 and IL-5. 48 ’ 49 Measurement of sputum and blood eosinophilia is, unfortunately, not widely implemented. 50
  • periostin an extracellular matrix protein, is induced by IL-4 and IL-13 in airway epithelial cells and lung fibroblasts, 56 and periostin is secreted as a soluble peptide from the basolateral surface from which it gains access to the circulation.
  • Periostin functions as a ligand for aV[33 and aV[35 integrins to promote adhesion and migration of epithelial cells and aids in the crosslink-age of submucosal collagen.
  • biomarkers Perhaps the most crucial use of these biomarkers will be to identify various molecular phenotypes of asthma, in particular severe asthma, where biologic agents are likely to be targeted. To date, the biomarkers identified are all linked to T2-type inflammatory phenotypes, which might either predict or be responsive to these T2-type-targeted therapies. Blood eosinophil counts of ⁇ 150 per .L seem to both predict responses to IL-5-targeted therapies and fall in response to these treatments. 62 At present, it is unclear which biomarker will best predict response to I L-4— I L-13 pathway-targeted therapies, as all have shown some predictive ability.
  • IL-4 IL- 3 blockade caused an increase in TH17 cells and neutrophilic inflammation
  • neutralization of IL-13 and IL-17 protected mice from eosinophilia, mucus metaplasia and airway hyper-responsiveness as well as causing an attenuation of neutrophilic inflammation. It was concluded that combination therapy targeting both pathways may maximize therapeutic efficacy across a patient population comprising both TH2 and TH17 endotypes.
  • compositions useful in the methods of the present invention include, but are not limited to:
  • DGSVVVNKVSELPAGHGLNVNTLSYGDLAAD (SEQ ID NO: 1) (PIN201104); DGSVVVNKVSELPAGH (SEQ ID NO: 2); GLNVNTLSYGDLAAD (SEQ ID NO: 3); SELPAGHGLNVNLTS (SEQ ID NO: 4); DGSVVVNKVS (SEQ ID NO: 5); ELPAGHGLNV (SEQ ID NO: 6); NTLSYGDLAAD (SEQ ID NO: 7); or a functionally equivalent fragment or variant thereof.
  • compositions useful in the methods of the present invention include, but are not limited to, Cpn60.1 -related peptides disclosed in United States Published Patent Application No. 20040132163 6S and United States Patent Nos. 11 ,098,090; 67 9,320,791 ; 68 9, 085, 632. 69 [0110]
  • a Cpn60.1 -related peptide is composed of amino acid residues.
  • amino acid residue is used interchangeably with the terms “amino acid” or “aa” to refer to an amino acid which is part of a peptide or protein.
  • an agonist or ligand of the present invention is composed of amino acids with the standard structure NH2 — C(H)(R) — COOH, where R represents an individual amino acid side chain.
  • an agonist or ligand is composed of amino acid residues which are naturally occurring amino acids.
  • a naturally occurring amino acid includes one of the twenty standard amino acids found in naturally occurring peptides and proteins.
  • an agonist or ligand of the present invention is about 50 aa in length; 49 aa in length; 48 aa in length; 47 aa in length; 46 aa in length; 45 aa in length; 44 aa in length; 43 aa in length; 42 aa in length; 41 aa in length; 40 aa in length; 39 aa in length; 39 aa in length; 38 aa in length; 37 aa in length; 36 aa in length; 35 aa in length; 34 aa in length;
  • a Cpn60.1 -related peptide used in the methods of the present invention and/or pharmaceutical compositions thereof may be administered via portal vein catheter.
  • the invention encompasses the delivery of a Cpn60.1 -related peptide used in the methods of the present invention and/or pharmaceutical compositions thereof by any appropriate route taking into consideration likely advances in the art of drug delivery.
  • a Cpn60.1 -related peptide used in the methods of the present invention and/or pharmaceutical compositions thereof may be administered at dosage levels sufficient to deliver from about 0.001 mg/kg to 100 mg/kg, from about 0.01 mg/kg to 50 mg/kg, from about 0.1 mg/kg to 40 mg/kg, from about 0.5 mg/kg to 30 mg/kg, from about 0.01 mg/kg to 10 mg/kg, from about 0.1 mg/kg to 10 mg/kg, or from about 1 mg/kg to 25 mg/kg of patient body weight per day to obtain the desired therapeutic effect.
  • a Cpn60.1 -related peptide used in the methods of the present invention may be utilized for prophylactic applications.
  • prophylactic applications involve systems and methods for preventing, inhibiting progression of, and/or delaying the onset of severe asthma, in individuals susceptible to and/or displaying symptoms of severe asthma.
  • a Cpn60.1-related peptide used in the methods of the present invention is administered to a target cell in vivo.
  • a Cpn60.1 -related peptide used in the methods of the present invention is administered to a target cell ex vivo.
  • a Cpn60.1 -related peptide used in the methods of the present invention is administered to a target cell ex vivo, then the target cell is re-introduced into an organism.
  • the target cell is cultured into multiple progeny cells ex vivo before being re-introduced in an organism.
  • the organism is a human.
  • the organism is a human patient.
  • the target cell was originally derived from the organism to which it is re-introduced.
  • the target cell was originally derived from a different organism to which it is re-introduced.
  • a Cpn60.1-related peptide used in the methods of the present invention and/or pharmaceutical compositions thereof are employed in combination therapies for treating or reducing the risk of severe asthma.
  • administration can be in combination with one or more additional therapeutic agents.
  • the phrases “combination therapy,” “combined with,” “in combination,” and the like refer to the use of more than one medication or treatment simultaneously to increase the response.
  • a Cpn60.1 -related peptide used in the methods of the present invention and/or pharmaceutical compositions thereof are administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures.
  • a Cpn60.1 -related peptide used in the methods of the present invention and/or pharmaceutical compositions thereof are administered in combination together in a single composition or administered separately in different compositions.
  • the particular combination of therapies to employ in a combination regimen will generally consider the compatibility of the desired therapeutics and/or procedures, and the desired therapeutic effect to be achieved.
  • the therapies employed may achieve a desired effect for the same purpose (e.g., a Cpn60.1 -related peptide used in the methods of the present invention which is useful for treating, preventing, and/or delaying the onset of severe asthma may be administered concurrently with another therapeutic agent which is also useful for treating, preventing, and/or delaying the onset of severe asthma symptoms), or they may achieve different effects.
  • the combination of therapies employed may achieve the same or a substantially similar desired effect for the same disease, condition or disorder; may achieve the same or a substantially similar desired effect for one or more different diseases, conditions or disorders; may achieve different desired effects for the same disease, condition or disorder; or may achieve different desired effects for one or more different diseases, conditions or disorders.
  • the delivery of a Cpn60.1 -related peptide used in the methods of the present invention as a pharmaceutical composition is in combination with one or more additional components that may improve the bioavailability of the Cpn60.1 -related peptide used in the methods of the present invention, reduce and/or modify its metabolism, inhibit its excretion, and/or modify its distribution in the body.
  • combination therapy may involve administrations of a plurality of Cpn60.1 -related peptides in accordance with the present invention.
  • combination therapy may involve administrations of a plurality of a Cpn60.1 -related peptides that treat, prevent, improve, achieve remission of, and/or reduce the risk of severe asthma.
  • combination therapy can be a plurality of Cpn60.1 -related peptides that treat, prevent, improve, achieve remission of, and/or reduce the risk of severe asthma.
  • a Cpn60.1-related peptide used in the methods of the present invention is combined with at least one pharmaceutically acceptable excipient, in the form of a pharmaceutical composition.
  • pharmaceutical composition refers to a formulation containing an active ingredient, and optionally a pharmaceutically acceptable carrier, diluent or excipient.
  • active ingredient can interchangeably refer to an “effective ingredient,” and is meant to refer to any agent that is capable of inducing a sought- after effect upon administration. Examples of active ingredient include, but are not limited to, chemical compound, drug, therapeutic agent, small molecule, and the like.
  • the active ingredient is a Cpn60.1 -related peptide as disclosed herein.
  • the active ingredient is PIN201104, or a derivative thereof.
  • the active ingredient is PIN201360, PIN201361 , PIN201362, PIN201116, PI N201105 or a derivative thereof.
  • the active ingredient is a peptide described in W02009/106819, or a derivative thereof.
  • the pharmaceutical compositions are useful in medicine or the manufacture of medicaments.
  • the pharmaceutical compositions are useful in one or more of the therapeutic applications disclosed herein, for example, in an individual suffering from an autoimmune disorder.
  • the pharmaceutical compositions are formulated for administration to a human patient.
  • the pharmaceutical composition is in a sterile injectable form (e.g., a form that is suitable for subcutaneous injection or intravenous infusion).
  • the pharmaceutical composition is in a liquid dosage form that is suitable for injection.
  • the pharmaceutical composition is in a powder (e.g., lyophilized and/or sterilized), optionally under vacuum, which is reconstituted with an aqueous diluent (e.g., water; buffer; salt solution, and the like) prior to injection.
  • an aqueous diluent e.g., water; buffer; salt solution, and the like
  • the pharmaceutical composition is diluted and/or reconstituted in an aqueous diluent (e.g., water, sodium chloride solution, sodium acetate solution, benzyl alcohol solution, phosphate buffered saline, and the like).
  • an aqueous diluent e.g., water, sodium chloride solution, sodium acetate solution, benzyl alcohol solution, phosphate buffered saline, and the like.
  • the pharmaceutical composition is in a form that can be refrigerated and/or frozen.
  • the pharmaceutical composition is in a form that cannot be refrigerated and/or frozen.
  • the pharmaceutical composition is a reconstituted solution and/or liquid dosage form which can be stored for a certain period of time after reconstitution (e.g., 2 hours, 12 hours, 24 hours, 2 days, 5 days, 7 days, 10 days, 2 weeks, a month, two months, or longer).
  • preparatory methods for pharmaceutical compositions include the step of bringing the active ingredient (e.g., a Cpn60.1 -related peptide used in the methods of the present invention) into association with one or more pharmaceutically acceptable excipients and then shaping and/or packaging the product into a desired single- or multi-dose unit.
  • a pharmaceutical composition in accordance with the invention may be prepared, packaged in bulk, packaged as a single unit dose, and/or packaged as a plurality of single unit doses.
  • a “unit dose” refers to a discrete amount of the pharmaceutical composition including a predetermined amount of the active ingredient.
  • the amount of the active ingredient is generally equal to a dose that would be administered to a subject and/or a convenient fraction of such a dose such as, for example, one-half or one-third of such a dose.
  • the relative amounts of active ingredient, pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition in accordance with the invention may vary, depending upon the identity, size, and/or condition of the subject treated and/or depending upon the route by which the composition is to be administered. In certain aspects, for example, the composition may include between about 0.1 % to 100% (w/w) of an active ingredient.
  • the present invention includes kits that are useful for carrying out the methods of the present invention.
  • the components contained in the kit depend on a number of factors, including the particular application (e.g., the particular route of administration to be employed, or the particular disease, condition or disorder to be treated).
  • the present invention provides a kit for administering a Cpn60.1 -related peptide in accordance with the present invention to treat a disease, condition or disorder disclosed herein.
  • the kit further includes instructions for administration.
  • the kit is for administering a Cpn60.1 -related peptide to treat a patient with severe asthma.
  • the kits contain one or more a Cpn60.1 -related peptides.
  • kits for use in accordance with the present invention include instructions (e.g., for administration, for storage, and the like), buffers and/or other reagents.
  • the kit includes (i) at least one Cpn60.1 -related peptide, (ii) a syringe, needle, applicator, or the like for administration of the at least one Cpn60.1 -related peptide to a patient, and (iii) instructions for use.
  • the kit includes a treatment schedule designating when the unit dosages are to be administered.
  • kits include one or more containers so that certain of the individual components or reagents may be separately housed.
  • kits may include a means for enclosing the individual containers in relatively close confinement for commercial sale, e.g., a plastic box, in which instructions, packaging materials such as Styrofoam, and the like, may be enclosed.
  • Acute exacerbations are significant events in severe asthma and have enormous implications for patients, their caregivers and healthcare providers.
  • 70 Asthma exacerbations are characterized by progressive shortness of breath, chest tightness, cough and wheezing, or a combination of these, and increased airflow obstruction that is manifested by reductions in lung function. Exacerbations accelerate disease progression, impair quality of life, cause significant morbidity and are a major cause of mortality. Preventing exacerbations is a major therapeutic goal not achieved with currently available treatments.
  • Viral infections are major triggers for asthma exacerbations in both adults and children.
  • Most viruses including those that cause respiratory infections (rhinovirus, influenza, respiratory syncytial virus), produce dsRNA at some point during their replication.
  • poly(l:C) polyinosinic:polycytidylic acid
  • poly(l:C) polyinosinic:polycytidylic acid
  • poly(l:C) polyinosinic:polycytidylic acid
  • poly(l:C) polyinosinic:polycytidylic acid
  • poly(l:C) polyinosinic:polycytidylic acid
  • Cpn60.1 -related peptides have already been shown to be effective for the treatment of asthma induced by house dust mite. 75 However, the effectiveness of Cpn60.1- related peptides have never been assessed in an animal model of severe asthma. Accordingly, present study assessed the anti-inflammatory and pulmonary functional effect of IRL201104 (20 and 80 pg/kg, i.v.) in a mouse model of asthma induced by house dust mite, as well as in a mouse model of severe asthma induced by house dust mite exacerbated by poly-IC.
  • mice Male BalbC mice (20-30 g on arrival, Charles Rivers, UK) were used in the present study.
  • mice On arrival from the supplier, animals were acclimatized for period of 7 days before start of experimental procedures. Mice were housed in cages of four on arrival based on weight (equal distribution of animal weights amongst each of the cages by the animal technician) with a 12 hour light dark cycle. Room temperature and humidity were maintained between 17-24°C and 40-70%, respectively. Environmental enrichment was provided in all cages. Mice had access to standard chow ad libitum and Water was available from bottles ad libitum.
  • HDM sensitization and challenge Mice were actively sensitized with house dust mite (HDM, 100 pg, s.c.) in FCA (Sigma Aldrich) on days 0. In order to elicit a local inflammatory response in the lungs, mice were intranasally challenged on day 14 with an HDM (25 pg) or saline under isoflurane (5% in 02) anesthesia. The HDM or saline was instilled into each nostril in a drop wise fashion alternating between the two until a volume of 50pL had been delivered.
  • HDM house dust mite
  • FCA Sigma Aldrich
  • Non-fasted mice were weighed and placed into a hotbox for 5 min before being placed in a whole body restrainer to receive an intravenous administration (5 mL/kg) via the tail vein of either I RL201104 or vehicle (15 min before HDM challenge on day 14).
  • Dexamethasone (1 mg/kg) treatment was administered orally (10 mL/kg) 1 hour before HDM challenge.
  • Airway hyperresponsiveness is the predisposition of a patient’s airways to narrow excessively in response to stimuli that would produce little or no effect in healthy subjects. 24 hours after HDM challenge, mice were anaesthetized with 100mg/kg ketamine, 10 mg/kg xylazine and 3mg/kg acepromazine. Mice were laid supine, and a tracheotomy was performed with a cannula (17 gauge) inserted into the trachea.
  • mice were placed in a whole body plethysmograph and the tracheotomy tube connected to a mechanical ventilator set at a rate of 150 breaths per minute with a tidal volume of 0.15 - 0.2 mL.
  • the flow signal was recorded using the plethysmograph and the pressure signal was recorded from a sidearm of the tracheal catheter.
  • the flow and pressure signals were processed together to determine lung resistance (RL) and dynamic compliance (Cdyn) using a software analyzer provided in the FinePointe resistance-compliance software (DSI Inc.).
  • Dynamic compliance is the continuous measurement of pulmonary compliance calculated at each point representing schematic changes during rhythmic breathing. 76 It monitors both elastic and airway resistance. Airway resistance depends on the air viscosity, density, and length, and radius of airways.
  • Blood sample collection A terminal blood sample was collected via cardiac puncture and placed into a serum tube. Each serum sample were kept at room temperature for 45 minutes to allow coagulation, before being centrifuged (2000g, 15 min at 4°C) from which the resulting supernatant was extracted, aliquoted and stored at -80°C for analysis.
  • Bronchoalveolar Lavage (BAL) and Cell Counts The trachea was cannulated to allow the lungs to be lavaged by aspirating 0.5 mL of phosphate buffered saline into the lungs. This procedure was repeated until the recovered volume was 1 ,6mL. The isolated BALF was then centrifuged at 1500 rpm for 10 mins at 4°C and the supernatant was aliquoted (400 pL) at -80°C for cytokine analysis. The cell pellets were then re-suspended in 1.6 mL of phosphate buffered saline and the BAL cells were then analyzed for total and differential numbers.
  • Cytokine levels (see below for details of cytokines to be evaluated) of BALF supernatant (all groups) were measured using magnetic multiplex assays as per the manufacturer’s instructions. Levels were measured using a Magpix system (Luminex Corp.).
  • Cytokine levels of 13 mouse cytokine/chemokine using a magnetic multiplex panel IFNg, IL-4, IL-5, IL-6, IL-10, IL-12(p40), IL-13, Eotaxin, IL-17, G-CSF, KC, RANTES, and MCP-1.
  • HDM specific IgE ELISA assay Serum supernatant was evaluated for HDM specific IgE concentrations using ELISA kit (Condrex Inc.) as per the manufacturer’s instructions. Optical density was measured at 450 nM using a microplate reader (SpectraMax 340PC). Concentrations of IgE were determined using SoftMax Pro v. 6.4 (Molecular Devices). Data were reported as HDM specific IgE (pg/mL), mean ⁇ S.E.M. (standard error of the mean). [0153] Data Analysis: Inter-group deviations were statistically analyzed by a one-way analysis of variance (ANOVA).
  • Bronchoalveolar Lavage (BAL) and Cell Counts Total cell counts were significantly elevated in mice challenged with HDM (FIG. 1A) and in mice challenged with HDM and poly IC (FIG. 1 B). Cells that were elevated included eosinophils (FIG. 2A-B), neutrophils (FIG. 3A-B), macrophages (FIG. 4A-B), and lymphocytes (FIG. 5A-B). Treatment with IRL201104 was able to significantly reduce HDM-induced elevation in total cell counts (FIG. 1A), eosinophils (FIG. 2A-B), neutrophils (FIG. 3A-B), and lymphocytes (FIG. 5A-B).
  • IRL201104 80 pg/kg was able to significantly reduce HDM-induced elevation in total cell counts (FIG. 1 B), eosinophils (FIG. 2B), and neutrophils (FIG. 3B).
  • AHR airway hyperresponsiveness
  • lung resistance (R ) was significantly increased, and dynamic compliance (Cdyn) was significantly decreased in mice challenged with HDM (FIG. 6A and FIG. 7A, respectively) and in mice challenged with HDM and poly IC (FIG. 6B and FIG. 7B, respectively) compared to the vehicle + saline mice.
  • Both doses of IRL201104 (20 and 80 pg/kg) significantly prevented the increase in lung resistance (RL) and decrease in dynamic compliance (Cdyn) induced by HDM (FIG. 6A and FIG. 7A, respectively) and HDM and poly IC (FIG. 6B and FIG. 7B, respectively).
  • Model Mice were sensitized with HDM (100 pg, s.c., GREER) in FCA (Sigma) at day 1 and then intranasally challenged at day 14 with either HDM (25 pg) or saline. A second group of animals also received high molecular mass Poly l:C (30 pg/animal) or saline administered intranasally 24 hrs before HDM/saline challenge. All endpoints were taken 48h after HDM challenge, other than AHR which was measured 24 hrs after challenge.
  • Dexamethasone (1 mg/kg, po) was administered 1 hour before challenge.
  • BALF collection, differential cell counts and cytokine/chemokine measurements Animals were overdosed with pentobarbitone 48 hrs after HDM challenge, and bronchoalveolar lavage was carried out using phosphate buffered saline. The isolated bronchoalveolar lavage fluid (BALF) was then centrifuged at 1500 rpm for 10 min at 4°C and the supernatant was aliquoted and stored at-80°C for cytokine analysis. Cell pellets were then re-suspended in 0.2% w/v NaCI to induce hemolysis of any erythrocytes. After isotonization with the same volume of 1 .6% w/v NaCI, the BALF cells were analyzed for total and differential cell numbers using a XT-2000iV analyzer (Sysmex).
  • a 14-Plex cytokine/chemokine panel (IFN-y, I L-4, IL-5, IL-6, KC, IL-10, I L-12(p40), IL-13, IL-17, Eotaxin, G-CSF, GM-CSF, RANTES and MCP-1) was run in BALF supernatant using a magnetic multiplex assay as per the manufacturer’s instructions (Biotechne Ltd). Levels were measured using a Magpix system (Luminex Corp).
  • HDM specific IgE ELISA assay A terminal blood sample was collected via cardiac puncture 48 hrs after HDM challenge, and serum separated. HDM specific IgE concentration in serum was determined using an ELISA kit (Condrex Inc.) as per the manufacturer’s instructions. Optical density was measured at 450 nM using a microplate reader (SpectraMax 340PC). Concentrations of IgE were determined using SoftMax Pro v. 6.4 (Molecular Devices).
  • AHR airway hyper-responsiveness
  • HDM challenge elicited an increase in HDM specific IgE in serum with was exacerbated by Poly l:C exposure. See, FIG. 10A-B.
  • Dexamethasone treatment significantly reduced HDM specific IgE in serum in the non-exacerbated model (FIG. 10A) while 1104 was effective in both the exacerbated and nonexacerbated model (FIG. 10B).

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Abstract

L'invention concerne des procédés de prévention ou de traitement de l'asthme sévère par administration de peptides associés à la chaperonine 60,1.
PCT/IB2024/057907 2023-08-15 2024-08-14 Méthodes et compositions pour la prévention ou le traitement de l'asthme sévère WO2025037259A1 (fr)

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Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4172896A (en) 1978-06-05 1979-10-30 Dainippon Pharmaceutical Co., Ltd. Methane-sulfonamide derivatives, the preparation thereof and composition comprising the same
US5358970A (en) 1993-08-12 1994-10-25 Burroughs Wellcome Co. Pharmaceutical composition containing bupropion hydrochloride and a stabilizer
US5427798A (en) 1992-08-14 1995-06-27 Burroughs Wellcome Co. Controlled sustained release tablets containing bupropion
US5541231A (en) 1993-07-30 1996-07-30 Glaxo Wellcome Inc. Stabilized Pharmaceutical
US5731000A (en) 1993-07-30 1998-03-24 Glaxo Wellcome Inc. Stabilized pharmaceutical composition containing bupropion
US6110973A (en) 1998-01-29 2000-08-29 Sepracor Methods for treating obesity and weight gain using optically pure (-)-bupropion
US20040132163A1 (en) 2000-11-17 2004-07-08 Coates Anthony Robert Milnes Biological materials and uses thereof
WO2009106819A2 (fr) 2008-02-25 2009-09-03 Helperby Therapeutics Limited Matériaux biologiques et leurs utilisations
US20140341932A1 (en) * 2011-10-21 2014-11-20 Peptinnovate Limited Novel pepetides
US20190224203A1 (en) * 2018-01-23 2019-07-25 National Jewish Health Methods of Treating Steroid Resistant Diseases and Conditions
US11098090B2 (en) 2017-01-12 2021-08-24 Revolo Biotherapeutics Limited Mycobacteria tuberculosis chaperonin 60.1 peptides and uses thereof
US11479585B2 (en) 2017-01-12 2022-10-25 Revolo Biotherapeutics Limited Method for the treatment of a relapsing-remitting condition
US20230242596A1 (en) * 2017-01-12 2023-08-03 Revolo Biotherapeutics Limited Method for the treatment of a relapsing-remitting condition

Patent Citations (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4172896A (en) 1978-06-05 1979-10-30 Dainippon Pharmaceutical Co., Ltd. Methane-sulfonamide derivatives, the preparation thereof and composition comprising the same
US5427798A (en) 1992-08-14 1995-06-27 Burroughs Wellcome Co. Controlled sustained release tablets containing bupropion
US5541231A (en) 1993-07-30 1996-07-30 Glaxo Wellcome Inc. Stabilized Pharmaceutical
US5731000A (en) 1993-07-30 1998-03-24 Glaxo Wellcome Inc. Stabilized pharmaceutical composition containing bupropion
US5763493A (en) 1993-07-30 1998-06-09 Glaxo Wellcome Inc. Stabilized pharmaceutical
US5358970A (en) 1993-08-12 1994-10-25 Burroughs Wellcome Co. Pharmaceutical composition containing bupropion hydrochloride and a stabilizer
US6110973A (en) 1998-01-29 2000-08-29 Sepracor Methods for treating obesity and weight gain using optically pure (-)-bupropion
US20040132163A1 (en) 2000-11-17 2004-07-08 Coates Anthony Robert Milnes Biological materials and uses thereof
WO2009106819A2 (fr) 2008-02-25 2009-09-03 Helperby Therapeutics Limited Matériaux biologiques et leurs utilisations
US9085632B2 (en) 2008-02-25 2015-07-21 Peptinnovate Limited Biological materials and uses thereof
US20140341932A1 (en) * 2011-10-21 2014-11-20 Peptinnovate Limited Novel pepetides
US9320791B2 (en) 2011-10-21 2016-04-26 Peptinnovate Limited Peptides from chaperonin 60.1
US11098090B2 (en) 2017-01-12 2021-08-24 Revolo Biotherapeutics Limited Mycobacteria tuberculosis chaperonin 60.1 peptides and uses thereof
US11479585B2 (en) 2017-01-12 2022-10-25 Revolo Biotherapeutics Limited Method for the treatment of a relapsing-remitting condition
US20230242596A1 (en) * 2017-01-12 2023-08-03 Revolo Biotherapeutics Limited Method for the treatment of a relapsing-remitting condition
US20190224203A1 (en) * 2018-01-23 2019-07-25 National Jewish Health Methods of Treating Steroid Resistant Diseases and Conditions

Non-Patent Citations (55)

* Cited by examiner, † Cited by third party
Title
"Am. J. Respir. Crit. Care Med", vol. 162, 2000, AMERICAN THORACIC SOCIETY, article "Proceedings of the ATS workshop on refractory asthma: current understanding, recommendations, and unanswered questions", pages: 2341 - 2351
"CURRENT PROTOCOLS IN IMMUNOLOGY (CPI", 2003, JOHN WILEY AND SONS, INC
"CURRENT PROTOCOLS IN PROTEIN SCIENCE (CPPS", 2005, JOHN WILEY AND SONS
"MOLECULAR BIOLOGY AND BIOTECHNOLOGY: COMPREHENSIVE DESK REFERENCE", 1995, VCH PUBLISHERS, INC
"National Institute for Health and Care Excellence", 2015, NICE, article "Asthma: diagnosis and monitoring of asthma in adults, children and young people."
"Statement on standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma.", AM. REV. RESPIR. DIS., vol. 136, 1987, pages 225 - 244
"THE ENCYCLOPEDIA OF MOLECULAR CELL BIOLOGY AND MOLECULAR MEDICINE", 1999, BLACKWELL SCIENCE LTD.,
AARON, S.D ET AL.: "Overdiagnosis of asthma in obese and nonobese adults.", CMAJ, vol. 179, 2008, pages 1121 - 1131
BARNES, P.J.ADCOCK, I.M: "Glucocorticoid resistance in inflammatory diseases.", LANCET, vol. 373, 2009, pages 1905 - 1917, XP026159213, DOI: 10.1016/S0140-6736(09)60326-3
BEL, E.H. ET AL.: "Diagnosis and definition of severe refractory asthma: an international consensus statement from the Innovative Medicine Initiative (IMI).", THORAX, vol. 66, 2011, pages 910 - 917
BEL, E.H.: ""Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma."", N. ENGL. J. MED., vol. 371, 2014, pages 1189 - 1197, XP055317701, DOI: 10.1056/NEJMoa1403291
BELL, M.C. AND BUSSE, W.W: ""Severe asthma: an expanding and mounting clinical challenge."", J. ALLERGY CLIN. IMMUNOL. PRACT, vol. 1, 2013, pages 110 - 121
BUSSE, W.W.: ""Role of viral respiratory infections in asthma and asthma exacerbations."", LANCET, vol. 376, 2010, pages 826 - 834
CHOY, D.F. ET AL.: "TH2 and TH17 inflammatory pathways are reciprocally regulated in asthma.", SCI. TRANSL. MED., vol. 7, 2015, pages 301 - 129
CHUNG, K.F. ET AL.: "CURRENT PROTOCOLS IN MOLECULAR BIOLOGY (CPMB", vol. 43, 2014, JONES & BARTLETT PUBLISHERS, article "International ERSIATS guidelines on definition, evaluation and treatment of severe asthma.", pages: 343 - 373
CHUNG, K.F. ET AL.: "Difficult/therapy-resistant asthma: the need for an integrated approach to define clinical phenotypes, evaluate risk factors, understand pathophysiology and find novel therapies. ERS Task Force on Difficult/Therapy-Resistant Asthma.", EUR. RESPIR. J., vol. 13, 1999, pages 1198 - 1208
CHUNG, K.F. ET AL.: "International ERSIATS guidelines on definition, evaluation and treatment of severe asthma.", EUR. RESPIR. J, vol. 43, 2014, pages 343 - 373
CONWAY, S.J. ET AL.: "The role of periostin in tissue remodeling across health and disease", CELL, vol. 71, 2014, pages 1279 - 1288
CORREN, J. ET AL.: "Lebrikizumab treatment in adults with asthma.", N. ENGL. J. MED., vol. 365, 2011, pages 1088 - 1098, XP009164420, DOI: 10.1056/NEJMoa1106469
DE ALBA J. ET AL: "IRL201104, A Novel Immunomodulatory Peptide, Shows Efficacy on Inflammatory Endpoints and Airway Hyperresponsiveness in a House Dust Mite Driven Model of Allergic Inflammation With or Without Poly I:C Exacerbation", D21. TERMINATOR: CONTROL OF AIRWAY INFLAMMATION AND IMMUNE RESPONSE IN ASTHMA, 30 April 2024 (2024-04-30), pages A6982 - A6982, XP093231669, DOI: 10.1164/ajrccm-conference.2024.209.1_MeetingAbstracts.A6982 *
DE ALBA, J. ET AL.: "Double-stranded RNA evokes exacerbation in a mouse model of corticosteroid refractory asthma.", CLINICAL SCIENCE, vol. 129, 2015, pages 973 - 987
FAHY, J.V: "Type 2 inflammation in asthma - present in most, absent in many", NAT. REV. IMMUNOL, vol. 15, 2015, pages 57 - 65, XP055400625, DOI: 10.1038/nri3786
FRY, D.LHYATT, R.E: "Pulmonary mechanics. A unified analysis of the relationship between pressure, volume and gasflow in the lungs of normal and diseased human subjects.", AM J MED, vol. 29, 1960, pages 672 - 689, XP023211491, DOI: 10.1016/0002-9343(60)90100-5
GREEN, R.H ET AL.: "Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial.", LANCET, vol. 360, 2002, pages 1715 - 1721, XP004764216, DOI: 10.1016/S0140-6736(02)11679-5
GUO, F.H.: ""Interferon y and interleukin 4 stimulate prolonged expression of inducible nitric oxide synthase in human airway epithelium through synthesis of soluble mediators.", INVEST., vol. 100, 1997, pages 829 - 838
HANANIA, N.A. ET AL.: "''Exploring the effects of omalizumab in allergic asthma: an analysis of biomarkers in the EXTRA study.", AM. J. RESPIR. CRIT. CARE MED., vol. 187, 2013, pages 804 - 811, XP055883599, DOI: 10.1164/rccm.201208-1414OC
HOLGATE, S.T: "Asthma: a simple concept but in reality a complex disease.", EUR. J. CLIN. INVEST, vol. 41, 2011, pages 1339 - 1352, XP071217408, DOI: 10.1111/j.1365-2362.2011.02534.x
IVANOVA, J.I. ET AL.: "Effect of asthma exacerbations on health care costs among asthmatic patients with moderate and severe persistent asthma.", J. ALLERGY CLIN. IMMUNOL., vol. 129, 2012, pages 1229 - 1235, XP028421194, DOI: 10.1016/j.jaci.2012.01.039
IZUHARA, K. ET AL.: "Periostin in allergic inflammation.", ALLERGOL. INT., vol. 63, 2014, pages 143 - 151
JACOBS, B.LLANGLAND, J.O: "When two strands are better than one: the mediators and modulators of the cellular responses to double-stranded RNA.", VIROLOGY, vol. 219, 1996, pages 339 - 349, XP055077060, DOI: 10.1006/viro.1996.0259
JAYARAM, L. ET AL.: "Determining asthma treatment by monitoring sputum cell counts: effect on exacerbations.", EUR. RESPIR. J., vol. 27, 2006, pages 483 - 494
JIA, G. ET AL.: "Periostin is a systemic biomarker of eosinophilic airway inflammation in asthmatic patients.", J. ALLERGY CLIN. IMMUNOL., vol. 130, 2012, pages 647 - 654, XP009164752, DOI: 10.1016/j.jaci.2012.06.025
JUNIPER, E.F ET AL.: "Development and validation of a questionnaire to measure asthma control.", EUR. RESPIR. J, vol. 14, no. 4, 1999, pages 902 - 907
MATSUMOTO, KINOUE, H: "Viral infections in asthma and COPD.", RESPIR. INVESTIG., vol. 52, 2014, pages 92 - 100
MODENA, B.D. ET AL.: "Gene expression in relation to exhaled nitric oxide identifies novel asthma phenotypes with unique biomolecular pathways", AM. J. RESPIR. CRIT. CARE MED., vol. 190, 2014, pages 1363 - 1372
NABE, T: "''Steroid-resistant asthma and neutrophils.", BIOL. PHARM. BULL., vol. 43, 2020, pages 31 - 35
NUNES, C. ET AL.: "Asthma costs and social impact.", ASTHMA RES. PRACT, vol. 3, 2017, pages 1
NUNES, C. ET AL.: "Asthma costs and social impact.", ASTHMA RES. PRACT., vol. 3, 2017, pages 1
ORTEGA, H.G.: "Mepolizumab treatment in patients with severe eosinophilic asthma."", N. ENGL. J. MED., vol. 371, 2014, pages 1198 - 1207, XP055317697, DOI: 10.1056/NEJMoa1403290
PAVORD, I.D. ET AL.: "Asthma diagnosis: addressing the challenges.", LANCET RESPIR. MED, vol. 3, 2015, pages 339 - 341
PAVORD, I.D. ET AL.: "Asthma diagnosis: addressing the challenges.", LANCET RESPIR. MED., vol. 3, 2015, pages 339 - 341
PAVORD, I.D. ET AL.: "Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double- blind, placebo-controlled trial", LANCET, vol. 380, 2012, pages 651 - 659, XP002714506, DOI: 10.1016/S0140-6736(12)60988-X
POON, A.H. ET AL.: "Pathogenesis of severe asthma.", CLIN. EXP. ALLERGY, vol. 42, 2012, pages 625 - 637, XP071887615, DOI: 10.1111/j.1365-2222.2012.03983.x
SCHULMAN, E.SPOHLIG, C: "Rationale for specific allergen testing of patients with asthma in the clinical pulmonary office setting.", CHEST, vol. 147, 2015, pages 251 - 258
SENNA, G.: ""Sex differences in severe asthma: results from severe asthma network in", ALLERGY ASTHMA IMMUNOL. RES., vol. 13, pages 219 - 228
SIDHU, S.S ET AL.: "Roles of epithelial cell-derived periostin in TGF β activation, collagen production, and collagen gel elasticity in asthma.", PROC. NATL ACAD. SCI. USA, vol. 107, 2010, pages 14170 - 14175, XP009164761, DOI: 10.1073/pnas.1009426107
SINGANAYAGAM, A. ET AL.: "Viruses exacerbating chronic pulmonary disease: the role of immune modulation.", BMC MED., vol. 10, 2012, pages 27, XP021125326, DOI: 10.1186/1741-7015-10-27
SMITH, A.D ET AL.: "Diagnosing asthma: comparisons between exhaled nitric oxide measurements and conventional tests.", AM. J. RESPIR. CRIT. CARE MED., vol. 169, 2004, pages 473 - 478
TAKAYAMA, G. ET AL.: "Periostin: a novel component of subepithelial fibrosis of bronchial asthma downstream of IL-4 and IL-13 signals.", J. ALLERGY CLIN. IMMUNOL., vol. 118, 2006, pages 98 - 104, XP005610109, DOI: 10.1016/j.jaci.2006.02.046
WANG, E. ET AL.: "Characterization of severe asthma worldwide: data from the international severe asthma registry.", CHEST., vol. 157, 2020, pages 790 - 804
WENZEL, S. ET AL.: "Dupilumab in persistent asthma with elevated eosinophil levels.", N. ENGL. J, vol. 368, 2013, pages 2455 - 2466, XP008165248, DOI: 10.1056/NEJMoa1304048
WENZEL, S.E.: ""Asthma phenotypes: the evolution from clinical to molecular approaches.", MED., vol. 18, 2012, pages 716 - 725
WENZEL, S.E: "Asthma phenotypes: the evolution from clinical to molecular approaches.", NAT, vol. 18, 2012, pages 716 - 725, XP055944372, DOI: 10.1038/nm.2678
WOODRUFF, P.G. ET AL.: "T-helper type 2-driven inflammation defines major subphenotypes of asthma.", AM. J. RESPIR. CRIT. CARE MED., vol. 180, 2009, pages 388 - 395, XP055049862, DOI: 10.1164/rccm.200903-0392OC
YANIRA RIFFO-VASQUEZ ET AL: "Modulation of allergic inflammation in the lung by a peptide derived from Mycobacteria tuberculosis chaperonin 60.1", CLINICAL & EXPERIMENTAL ALLERGY, WILEY INTERSCIENCE, UK, vol. 50, no. 4, 15 January 2020 (2020-01-15), pages 508 - 519, XP071889015, ISSN: 0954-7894, DOI: 10.1111/CEA.13550 *

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