EP0757697A1 - Utilisation d'agents bloquant l'interaction molecule d'adhesion intercellulaire/recepteur dans le traitement d'une infection respiratoire virale - Google Patents

Utilisation d'agents bloquant l'interaction molecule d'adhesion intercellulaire/recepteur dans le traitement d'une infection respiratoire virale

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Publication number
EP0757697A1
EP0757697A1 EP95916347A EP95916347A EP0757697A1 EP 0757697 A1 EP0757697 A1 EP 0757697A1 EP 95916347 A EP95916347 A EP 95916347A EP 95916347 A EP95916347 A EP 95916347A EP 0757697 A1 EP0757697 A1 EP 0757697A1
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EP
European Patent Office
Prior art keywords
icam
family
antibody
glycoproteins
agent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP95916347A
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German (de)
English (en)
Other versions
EP0757697A4 (fr
Inventor
Craig D. Wegner
Ernest L. Raymond
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Boehringer Ingelheim Pharmaceuticals Inc
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Boehringer Ingelheim Pharmaceuticals Inc
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Publication of EP0757697A1 publication Critical patent/EP0757697A1/fr
Publication of EP0757697A4 publication Critical patent/EP0757697A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/70525—ICAM molecules, e.g. CD50, CD54, CD102
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70546—Integrin superfamily
    • C07K14/70553—Integrin beta2-subunit-containing molecules, e.g. CD11, CD18
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2821—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against ICAM molecules, e.g. CD50, CD54, CD102
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2839—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the integrin superfamily
    • C07K16/2845—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the integrin superfamily against integrin beta2-subunit-containing molecules, e.g. CD11, CD18
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention is directed to the use of agents which block ICAM-1/receptor interactions as a means to increase gas exchange in the lungs of a patient suffering from a viral infection of the respiratory tract.
  • Leukocytes must be able to attach to cellular substrates in order to properly defend the host against foreign invaders such as bacteria or viruses.
  • An excellent review of the defense system is provided by Eisen, H.W., (In: Microbiology, 3rd Ed., Harper & Row, Philadelphia, PA (1980), pp. 290-295 and 381-418).
  • Leukocytes attach to endothelial cells so that they can migrate from circulation to sites of ongoing inflammation.
  • leukocytes attach to antigen-presenting cells so that a normal specific immune response can occur.
  • leukocytes attach to appropriate target cells so that lysis of virally-infected or tumor cells can occur.
  • MAbs monoclonal antibodies directed against human T-cells
  • Mac-1 is found on macrophages, granulocytes and large granular lymphocytes. LFA-1 is found on most lymphocytes (Springer, T.A., et al. Immunol. Rev.
  • leukocyte molecules were found to be structurally similar to one another, and to constitute members of a related family of glycoproteins (Sanchez-Madrid, F. et al., J. Exper. Med. 158:1785-1803 (1983); Keizer, G.D. et al, Eur. J. Immunol. 75:1142-1147 (1985)).
  • This glycoprotein family is composed of heterodimers having one alpha subunit and one beta subunit. Although the alpha subunit of each of the antigens differs from one member to the next, the beta subunit of each member is highly conserved (Sanchez-Madrid, V. etal., J. Exper. Med. 755:1785-1803 (1983)).
  • the beta subunit of the glycoprotein family (referred to as "CD18" family) was found to have a molecular weight of 95 kd whereas the alpha subunits were found to vary from 150 kd to 180 kd (Springer, T., Fed. Proc. 44:2660- 2663 (1985)).
  • CD18 The beta subunit of the glycoprotein family
  • the alpha subunits of the membrane proteins do not share the extensive homology shared by the beta subunits, close analysis of the alpha subunits of the glycoproteins has revealed that there are substantial similarities between them. Reviews of the similarities between the alpha and beta subunits of the LFA-1 related glycoproteins are provided by Sanchez- Madrid, F. et al. (J. Exper. Med. 158:586-602 (1983); J. Exper. Med.
  • LAD individuals present clinically with delayed umbilical cord separation, recurring and progressive soft tissue infections, and impaired pus formation, despite a striking blood leukocytosis. Studies of LAD individuals have revealed that immune reactions are mitigated when leukocytes are unable to adhere in a normal fashion due to the lack of functional adhesion molecules of the CD18 family.
  • ICAM-1 is a single chain glycoprotein varying in mass on different cell types from 76-114 kD, and is a member of the Ig superfamily with five C-like domains (Dustin, M.L. et al., Immunol. Today 9:213-215 (1988); Staunton, D.E. et al., Cell 52:925-933 (1988); Simmons, D. et al., Nature 337:624-627 (1988)). ICAM-1 is highly inducible with cytokines (including IFN- ⁇ , TNF, and IL-1) in a wide range of cell types (Dustin, M.L. et al., Immunol. Today 9:213-215 (1988)).
  • ICAM-1 are provided in U.S. Patent Applications Serial Nos. 07/045,963; 07/115,798; 07/155,943; 07/189,815 and 07/250,446, all of which applications are herein incorporated by reference in their entirety.
  • leukocytes especially lymphocytes to maintain the health and viability of an animal requires that they be capable of adhering to other cells (such as endothelial cells). This adherence has been found to require cell-cell contacts which involve specific receptor molecules present on the cell surface of the lymphocytes. These receptors enable a lymphocyte to adhere to other lymphocytes or to endothelial, and other non-vascular cells.
  • the cell surface receptor molecules have been found to be highly related to one another. Humans whose lymphocytes lack these cell surface receptor molecules exhibit defective antibody responses, chronic and recurring infections, as well as other clinical symptoms. Acute viral respiratory illnesses are among the most common of human diseases, accounting for one-half or more of all acute illnesses.
  • the incidence of acute respiratory disease in the United States is from 3 to 5.6 cases per person per year. The highest rates occur in children under 1 year of age (6.1 to 8.3 cases per year) and remain high until age 6, when a progressive decrease is noted.
  • Adults in the general population have three to four illnesses per person per year. Morbidity from acute respiratory illnesses accounts for 30 to 50 percent of time lost from work by adults and from 60 to 80 percent of time lost from school by children. It has been estimated that two-thirds to three-fourths of cases of acute respiratory illnesses are caused by viruses. More than 200 antigenically distinct viruses from 8 different genera have been reported to cause acute respiratory illness, and it is likely that additional agents will be described in the future. The vast majority of these viral infections involve the upper respiratory tract, but lower respiratory tract disease can also occur, particularly in younger age groups and in certain epidemiologic settings.
  • the illnesses caused by respiratory viruses traditionally have been divided into multiple distinct syndromes, such as the "common cold", pharyngitis, croup (laryngotracheobronchitis) tracheitis, bronchiolitis, bronchitis, and pneumonia. These general categories of illnesses have a certain epidemiologic and clinical utility, e.g., croup occurs exclusively in very young children and has a characteristic clinical course. In addition, some types of respiratory illnesses are more likely to be associated with certain viruses, e.g., the "common cold” with rhinoviruses, while others occupy characteristic epidemiologic niches, such as adenoviruses in military recruits.
  • the syndromes most commonly associated with infection with the major respiratory virus groups are summarized in Table 1.
  • the present invention is based on the observation that agents which block ICAM-1/receptor interactions increase the rate of gas exchange in the lungs of a mammal which is suffering from a reduction in gas exchange as a result of a viral infection of the respiratory tract. Surprisingly, these agents do not affect the airway hyperresponsiveness (e.g., exacerbation of asthma) which also occurs as a result of the viral infection.
  • the present invention provides methods for increasing the rate of oxygen absorption and CO 2 elimination in the lungs of a mammal suffering from a viral infection of the respiratory tract.
  • the rate at which oxygen is absorbed into, and CO 2 eliminated from, the blood in the lungs of a mammal suffering from an infection of the respiratory tract can be increased by providing a therapeutically effective amount of" an agent which is capable of blocking ICAM-1/receptor interactions.
  • Examples of the types of viral pathogens for which the present method can be applied include, but are not limited to, members of the
  • Paramyxoviradae family preferably viruses which are members of the
  • Pneumovirus or Paramyxovirus genus Pneumovirus or Paramyxovirus genus.
  • Specific viral pathogens include the Respiratory Syncytial Virus and Parainfluenza virus.
  • the present methods utilize agents which can be divided into two groups based on the molecule the agent binds to (i.e., interacts with).
  • Group I agents are agents which bind to (interact with) ICAM-1 and block the binding of ICAM-1 to a natural receptor of ICAM-1.
  • Group II agents are agents which bind to a receptor of ICAM-1 and block the binding of the receptor to ICAM-1.
  • agents of the present invention include small molecules, peptides, carbohydrates, proteins and antibodies.
  • a preferred class of agents of the present invention are antibodies, or fragments thereof containing the antigen binding site, which bind to ICAM-1 (Group I agents) or to one or more members of the CD 18 family of glycoproteins (Group II agents).
  • Asterisk (*) signifies significant protection by YNl/1.7 (anti-ICAM-1) compared to RSV alone as well as RSV plus rat IgG treatment (p ⁇ 0.05 by Student's t-test).
  • Figure 2 demonstrates the lung diffusion capacity for carbon monoxide (D L ⁇ ) from naive (normal) mice versus mice six days after inoculation with control media, RSV, RSV and treated with control non-specific rat IgG (3 mg/kg, b.i.d.). Bars represent the mean + S.E. for 4-6 animals per group.
  • D L ⁇ carbon monoxide
  • Asterisk signifies significant protection by YN1/1.7 (anti-ICAM-1) compared to RSV alone as well as RSV plus rat IgG treatment (p ⁇ 0.05 by Student's t-test).
  • Figure 3 demonstrates the inhaled methacholine C m (airway responsiveness) for mice six days after inoculation with control media, RSV,
  • the present invention is based on the observation that agents which block ICAM-l/receptor interaction increase the rate of gas exchange in the lungs of a mammal suffering from a reduction in gas exchange as a result of a viral infection of the respiratory tract. Based on these observations, the present invention provides methods for increasing the rate at which oxygen is absorbed into and CO 2 eliminated from the blood in the lungs of a mammal suffering from a viral infection of the respiratory tract, primarily the lower respiratory tract. Specifically, the rate of oxygen absorption and CO 2 elimination can be increased in a mammal suffering from an infection of the respiratory tract by providing a therapeutically effective amount of an agent which blocks ICAM-l/receptor interactions.
  • an increase in the rate of gas exchange is said to occur if the rate of exchange of gases across the lung membrane is increased.
  • An increase in gas exchange can result in an increase in the rate or extent of oxygen absorption and/or result in an increase in the rate of or extent of carbon dioxide elimination.
  • a skilled artisan can readily adapt known procedures to determine the rate and extent of gas exchange in a particular mammal in response to a particular treatment.
  • a viral infection of the respiratory tract refers to any viral mediated infection of cells which make up and comprise the respiratory tract.
  • Such cells include, but are not limited to epithelial cells, fibroblasts, alveolar macrophages, dendritic cells, and infiltrating leukocytes (for a description of the various cell types which make up the respiratory tract see Plopper et al, Section I in Comparative Biology of the Normal Lung, Vol. 1,
  • the methods of the present invention are intended for use for viruses which infect cells of the respiratory tract and further lead to an increase or induction of ICAM-1 expression. Since the present methods are directed to ameliorating a symptom common to respiratory viral infection and are not directed at treating the specific viral agent, the present methods can be used to augment the treatment of a wide variety of viral pathogens. Examples of such viruses include, but are not limited to, members of the Paramyxoviradae family, more specifically viruses which are members of the Pneumovirus or Paramyxovirus genus.
  • viruses which can be treated using the herein disclosed methods are the Respiratory Syncytial Virus and Parainfluenza virus (for a review of respiratory viruses see Dolin, "Common Viral Respiratory Infections” in Harrison's Principles of Internal Medicine, 11 edition, McGraw-Hill N.Y. (1987) and Table 1).
  • the methods disclosed herein are effective in increasing the rate of gas exchange in the lungs for all viruses which infect cells of the respiratory tract and cause an induction or an increase in ICAM-1 expression on the surfaces of cells of the respiratory tract (e.g., endothelial, epithelial, fibroblasts, alveolar macrophages, lymphocytes, dendritic cells, etc.).
  • a virus is said to induce or increase ICAM-1 expression when a cell produces a higher level of ICAM-1 as a result of the viral infection.
  • a skilled artisan can use known methods to assay for ICAM-1 expression in vivo or in vitro to determine if a particular virus induces ICAM-1 expression (for example, see Wagner et al, Science 247:456-459 (1990)). Such procedures include, but are not limited to, direct assays, methods which use nucleic acid probes or ICAM-1 specific antibodies to directly measure the level of ICAM-1 expression, and indirect assays, methods which detect the presence of cytokines known to induce ICAM-1 expression.
  • interferon gamma interleukin-1
  • tumor-necrosis factor tumor-necrosis factor
  • an agent is said to "block ICAM-l/receptor interactions" if the agent is capable of reducing the rate at which ICAM-1 binds to a receptor.
  • Group I agents are agents which bind to ICAM-1 and block the binding of ICAM-1 to a natural receptor of ICAM-1.
  • Group ⁇ agents are agents which bind to a member of the CD18 family of glycoproteins.
  • Group II agents can be designed to bind to all members of the CD18 family of glycoproteins or can be designed to bind to a specific member of the CD 18 family (Springer T. A. , Nature 346:425-434 (1990)).
  • Assays have been developed to determine if an agent can block ICAM- l/receptor interactions (see Rothlein et al, J. Immunol 737:1270-1274 (1986); Smith et al., J. Clin. Invest. 52:1746-1756 (1986)) for examples). In general, these procedures compare the level of ICAM-1/CD18 interactions in the presence and absence of the agent which is tested.
  • the format of such assays varies and can include the use of isolated ICAM-1 and/or CD18 protein, cells which naturally express ICAM-1 or CD18, or cells which have been altered to express ICAM-1 or CD18. A skilled artisan can readily use these methods, or a combination thereof, to isolate agents for use in the methods herein described.
  • a preferred class of agents of the present invention are antibodies, or fragments thereof containing the antigen binding site, which bind to ICAM-1 (Group I agents) or to a member of the CD 18 family of glycoproteins (Group II agents).
  • ICAM-1 and the members of the CD18 family of molecules are immun ⁇ genic molecules.
  • Group I agents include antibodies, and fragments thereof, which bind to ICAM-1.
  • Group ⁇ agent include antibodies, and fragments thereof, which bind a member of the CD 18 family of glycoproteins.
  • the generation of anti-ICAM-1 and anti-CD 18 antibodies is well known in the art (Harlow et al, Antibodies: A Laboratory Manual, Cold Spring Harbor Press, Cold Spring Harbor, NY (I ?)).
  • the antibody agents of the present invention may be obtained by introducing either a purified protein, or cells which express the desired protein, into an appropriate animal, for example by intraperitoneal injection, etc.
  • the serum of such an animal may be removed and used as a source of polyclonal antibodies capable of binding these molecules.
  • a skilled artisan can remove splenocytes from such animals, fuse these spleen cells with a myeloma cell line to form a hybndoma cell which secretes a monoclonal antibody which binds ICAM-1 or a member of the CD18 family of molecules.
  • the hybridoma cells obtained in the manner described above may be screened using known methods to identify desired hybridoma cells that secrete an antibody which binds to either ICAM-1 or to members of the CD18 family of molecules (either the alpha or beta subunit).
  • Both polyclonal and monoclonal antibodies may be used in the methods of the present invention.
  • antibodies to ICAM-1 or to members of the CD18 family which are produced in humans, or are "humanized” (i.e., non-immunogenic in a human) by recombinant or other technology.
  • Humanized antibodies may be produced, for example by replacing an immunogenic portion of an antibody with a corresponding, but non-immunogenic portion (i.e., chimeric antibodies)
  • Another class of agent which can be used in the present invention are soluble forms of ICAM-1 or members of the CD 18 family of glycoproteins. Because ICAM-1 binds to a CD18 molecule, soluble derivatives of ICAM-1 comprise another type of Group ⁇ agent. Soluble derivatives of ICAM-1 which bind to the CD 18 family member reduce the rate of ICAM-l/receptor binding by competing with the CD 18 found on leukocytic cells, thus attenuating cellular adhesion.
  • ICAM-1 is composed of 5 domains (Staunton, D.E. et al, Immunol. Today 9:213-215 (1988); Staunton, D.E. et al, Cell 52:925-934 (1988); Staunton, D.E. et al, Cell 56:849-854 (1989); Staunton, D.E. et al, Tissue
  • Domains 1 and 2 have been found to be important for the binding of ICAM-1 to its receptor molecule (Staunton, D.E. et al, Tissue Antigens 33:286 (1989); Staunton, D.E. et al, FASEB J. 3:A446 (1989)). Fragments of ICAM-1 from which the transmembrane domain has been deleted, and which possess at least domains 1 and 2, are soluble under physiological conditions and can block ICAM-l/receptor interactions (Becker et al, J. Immunol 747:4398-4401 (1991)).
  • Soluble derivatives of CD18 family members comprise another type of the Group I agents of the present invention.
  • a molecule is a member of the CD18 family of glycoproteins if it contains either an alpha subunit of a member of the CD18 family of glycoproteins (i.e., a CD11 subunit), a beta subunit of a member of the CD18 family of glycoproteins (i.e., a CD18 beta subunit), or both an alpha and a beta subunit of a member of the CD18 family of glycoproteins.
  • a member of the CD 18 family of glycoproteins includes molecules having only one subunit of a CD18 member as well as heterodimers, (molecules having both an alpha and a beta subunit of a member of the CD18 family). Soluble derivatives of members of the CD18 family have been generated by deleting the transmembrane domain (Dana et al, Proc. Natl. Acad. Sci. USA 55:3106- 3110 (1991)). These molecules have been shown to reduce the rate of ICAM- 1/ligand binding by binding to ICAM-1.
  • agents screened in such assays can be, but are not limited to, peptides, carbohydrates, small molecules, or vitamin derivatives.
  • the agents can be selected and screened at random or rationally selected or designed using known protein modeling techniques. For random screening, agents such as peptides or carbohydrates are selected at random and are assayed for the ability to bind to ICAM-1 or a CD 18 family member. Alternatively, agents may be rationally selected or designed.
  • an agent is said to be "rationally selected or designed" when the agent is chosen based on the molecular configuration of the ICAM-1 or a CD 18 family member.
  • an agent is said to be “rationally selected or designed” when the agent is chosen based on the molecular configuration of the ICAM-1 or a CD 18 family member.
  • one skilled in the art can readily adapt currently available procedures to generate peptides capable of binding to a specific peptide sequence in order to generate rationally designed antipeptide peptides (for example, see Hurby et al , "Application of Synthetic Peptides:
  • the agents of the present invention can be used in native form or can be modified to form a chemical derivative.
  • a molecule is said to be a "chemical derivative" of another molecule when it contains additional chemical moieties not normally a part of the molecule. Such moieties may improve the molecule's solubility, absorption, biological half life, etc. The moieties may alternatively decrease the toxicity of the molecule, eliminate or attenuate any undesirable side effect of the molecule, etc. Moieties capable of mediating such effects are disclosed in Remington's Pharmaceutical Sciences (16th ed., Osol, A., Ed., Mack, Easton PA (1980)).
  • a change in the immunological character of the functional derivative is measured by a competitive type immunoassay.
  • Changes in immunomodulation activity are measured by the appropriate assay.
  • Modifications of such protein properties as redox or thermal stability, biological half-life, hydrophobicity, susceptibility to proteolytic degradation or the tendency to aggregate with carriers or into multimers are assayed by methods well known to the ordinarily skilled artisan.
  • the therapeutic effects of the agents of the present invention may be obtained by providing the agent to a patient by any suitable means (i.e., inhalation, intravenously, intramuscularly, subcutaneously, enterally, or parenterally).
  • the agent of the present invention it is preferred to administer the agent of the present invention so as to achieve an effective concentration within the blood or within the lungs.
  • the preferred method is to administer the agent as a nebulized solution by oral inhalation, or via an oral spray or oral aerosol.
  • intra-nasal or intratracheal administration can be employed to achieve an effective lung concentration.
  • the preferred method is to administer the agent by injection.
  • the administration may be by continuous infusion, or by single or multiple injections.
  • the dosage of the administered agent will vary depending upon such factors as the patient's age, weight, height, sex, general medical condition, previous medical history, etc.
  • a dosage of agent which is in the range of from about 1 pg/kg to 10 mg/kg (body weight of patient), although a lower or higher dosage may be administered.
  • the therapeutically effective dose can be lowered by using combinations of the agents of the present invention (such as, for example, if anti-ICAM-1 antibody is additionally administered with an anti-LFA-1 antibody).
  • compositions of the present invention can be administered concurrently with, prior to, or following the administration of other anti- viral or anti-hyperresponsiveness agents.
  • the agents of the present invention are intended to be provided to recipient subjects in an amount sufficient to increase the rate of lung gas exchange and thus attenuate the morbidity (respiratory distress or dyspnea) of an infection of the respiratory tract.
  • the administration of the agent(s) of the invention may be for either a "prophylactic" or "therapeutic" purpose.
  • the agent(s) are provided in advance of any decrease in the rate of gas exchange.
  • the prophylactic administration of the agent(s) serves to prevent or attenuate any subsequent reduction in gas exchange.
  • the agent(s) are provided at (or shortly after) the onset of a reduction in the rate of gas exchange.
  • the therapeutic administration of the compound(s) serves to attenuate any actual reduction in gas exchange.
  • the agents of the present invention may thus be provided after respiratory viral infection and either prior to the onset of a reduction in gas exchange (so as to attenuate the anticipated severity, duration or extent of the reduction) or after the initiation of the reduction.
  • the agents of the present invention are administered to the mammal in a pharmaceutically acceptable form and in a therapeutically effective concentration.
  • a composition is said to be "pharmacologically acceptable” if its administration can be tolerated by a recipient patient.
  • Such an agent is said to be administered in a "therapeutically effective amount” if the amount administered is physiologically significant.
  • An agent is physiologically significant if its presence results in a detectable change in the physiology of a recipient patient.
  • the agents of the present invention can be formulated according to known methods to prepare pharmaceutically useful compositions, whereby these materials, or their functional derivatives, are combined in admixture with a pharmaceutically acceptable carrier vehicle.
  • a pharmaceutically acceptable carrier vehicle e.g., water, alcohol, glycol, and water.
  • suitable vehicles and their formulation, inclusive of other human proteins, e.g., human serum albumin are described, for example, in Remington 's Pharmaceutical Sciences (16th ed. , Osol, A., Ed., Mack, Easton PA (1980)).
  • a pharmaceutically acceptable composition suitable for effective administration such compositions will contain an effective amount of one or more of the agents of the present invention, together with a suitable amount of carrier vehicle.
  • Control release preparations may be achieved through the use of polymers to complex or absorb one or more of the agents of the present invention.
  • the controlled delivery may be exercised by selecting appropriate macromolecules (for example polyesters, polyamino acids, polyvinyl, pyrrolidone, ethylenevinylacetate, methylcellulose, carboxymethylcellulose, or protamine, sulfate) and the concentration of macromolecules as well as the methods of incorporation in order to control release.
  • Another method to control the duration of action by controlled release preparations is to incorporate agents of the present invention into particles of a polymeric material such as polyesters, polyamino acids, hydrogels, poly(lactic acid) or ethylene vinylacetate copolymers.
  • microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization yielding, for example, hydroxymethylcellulose or gelatine-microcapsules and poly (methylmethacy late) microcapsules, respectively, or in colloidal drug delivery systems, for example, liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules or in macroemulsions.
  • colloidal drug delivery systems for example, liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules or in macroemulsions.
  • the objective of the experiments described in this example was to characterize the time course of the immune/inflammatory response (leukocyte influx and cytokine generation) and viral replication induced by RSV, as well as the lung dysfunction and increase in airway responsiveness characteristic of asthma onset and severity (Busse et al, J. Allergy Clin. Immunol. 57:770-775 (1988)) at the peak of the inflammatory response in mice.
  • mice Female Balb/c mice, — 32 weeks of age, were inoculated by intranasal insufflation (inhalation) administration of 10 7 plaque forming units (PFU) of RSV A2 strain or control (HEp-2) media. The mice were sacrificed 1, 3, 6, 15 or 28 days later and (1) lung lavage was performed to assess leukocyte influx (Wegner et al, Lung 170:267-279 (1992)) and cytokine generation (EIA using commercially available kits), (2) lung homogenates were prepared and used in plaque assays on HEp-2 cells to assess viral replication (Graham et al, J. Med. Virol 26:153-162 (1988)), or (3) lungs were fixed for histologic examination.
  • PFU plaque forming units
  • HEp-2 RSV A2 strain or control
  • mice were anesthetized with pentobarbital and their tracheas cannulated with a 18 gauge catheter.
  • Respiratory system resistance (Rrs) and dynamic compliance (Crs) were determined from respiratory system impedance which was measured by discrete frequency (4 to 40 Hz in 11 equal logarithmic steps) sinusoidal-forced oscillations superimposed on tidal breathing (Wegner et al. , Lung 170:267-279
  • Diffusion capacity of the lungs for carbon monoxide was determined by the single breath method. Airway responsiveness was assessed by determining the concentration of nebulized and inhaled methacholine to produce a 100% increase in Rrs (PCir ⁇ ). This was accomplished by administering increasing concentrations of methacholine (diluted with phosphate-buffered saline) in half-logarithmic steps (at ⁇ 10 minute intervals) until a > 100 % increase in Rrs from baseline was obtained. The PC 100 was then calculated by linear regression analysis of the last 2 or 3 points on the logarithmic methacholine concentration versus percent increase in Rrs plot. Results:
  • Viral titers peaked at day 3, leukocyte influx at day 6, TNF , GMCSF and IL-6 generation at day 1, and IFN- ⁇ at day 6 (see Table 2).
  • RSV infection decreased lung diffusion capacity (D LCO : 16 - 6 ⁇ °- 5 t0 14 ° ⁇ °- 6 ⁇ l/min/mmHg, p ⁇ 0.05) and increased airway responsiveness (decreased the methacholine PC 100 : 0.72 ⁇ 0.22 to 0.06 ⁇ 0.02 mg/ml, p ⁇ 0.05) without significantly altering Rrs (797 ⁇ 87 to 799 ⁇ 71 cmH 2 O/l/s) or Crs (35.8 ⁇ 5.7 to 28.3 ⁇ 2.8 ul/cmH 2 O).
  • RSV infection in mice induces a marked lung inflammation and dysfunction.
  • mice Female Balb/c mice, ⁇ 32 weeks of age, were inoculated by intranasal insufflation (inhalation) administration of 10 7 plaque forming units (PFU) of RSV A2 strain or control (HEp-2) media and then sacrificed 6 days later. Lungs were removed, inflated with O.C.T. and then frozen in liquid nitrogen.
  • PFU plaque forming units
  • ICAM-1 The contribution of ICAM-1 to the inflammatory response, attenuated alveolar gas exchange and increase in airway responsiveness induced by RSV infection was evaluated using the rat anti-mouse ICAM-1 monoclonal antibody YN1/1.7.
  • mice Female Balb/c mice were inoculated by intranasal insufflation (inhalation) administration of 10 7 plaque forming units (PFU) of RSV A2 strain or control (HEp-2) media and treated twice daily (b.i.d.) beginning 1 hr prior to RSV inoculation with YNl/1.7 or rat IgG at 3 mg/kg, intraperitoneal.
  • PFU plaque forming units
  • HEp-2 plaque forming units

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Abstract

L'invention concerne l'utilisation de molécules d'adhésion intercellulaire (ICAM-1), leurs dérivés fonctionnels, et des molécules qui se lient à eux, dans des procédés destinés à accroître les échanges gazeux dans les poumons d'un patient souffrant d'une infection respiratoire virale.
EP95916347A 1994-04-12 1995-04-12 Utilisation d'agents bloquant l'interaction molecule d'adhesion intercellulaire/recepteur dans le traitement d'une infection respiratoire virale Withdrawn EP0757697A4 (fr)

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US22599794A 1994-04-12 1994-04-12
US225997 1994-04-12
PCT/US1995/004519 WO1995027736A1 (fr) 1994-04-12 1995-04-12 Utilisation d'agents bloquant l'interaction molecule d'adhesion intercellulaire/recepteur dans le traitement d'une infection respiratoire virale

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US6130202A (en) * 1990-07-20 2000-10-10 Bayer Corporation Antiviral methods
US5817515A (en) * 1993-12-23 1998-10-06 Icos Corporation Human B2 integrin alpha subunit antibodies
US6391452B1 (en) 1997-07-18 2002-05-21 Bayer Corporation Compositions for nasal drug delivery, methods of making same, and methods of removing residual solvent from pharmaceutical preparations
CA2523358A1 (fr) * 2003-04-23 2004-11-04 Hansa Medical Ab Procede et traitement
US20170360815A1 (en) * 2016-02-25 2017-12-21 Applied Biological Laboratories, Inc. Compositions and methods for protecting against airborne pathogens and irritants

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EP0289949A2 (fr) * 1987-05-04 1988-11-09 Dana Farber Cancer Institute Molécules d'adhésion intercellulaire et leurs ligands de liaison
EP0314863A2 (fr) * 1987-11-02 1989-05-10 Baylor College Of Medicine Utilisation du ICAM-1 ou de ses derivés fonctionels pour le traitement des inflammations non spécifiques
EP0391088A2 (fr) * 1989-03-16 1990-10-10 Center For Blood Research Laboratories, Inc. Utilisation de dérivés fonctionnels de la molécule d'adhésion intercellulaire ICAM-1 dans une thérapie anti-virale
WO1993006842A1 (fr) * 1991-10-02 1993-04-15 Boehringer Ingelheim Pharmaceuticals, Inc. Utilisation de molecules d'adhesion intercellulaire et de leurs ligands de liaison dans le traitement de l'asthme
US5235049A (en) * 1989-01-24 1993-08-10 Molecular Therapeutics, Inc. Nucleic acid sequences encoding a soluble molecule (SICAM-1) related to but distinct from ICAM-1

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EP0289949A2 (fr) * 1987-05-04 1988-11-09 Dana Farber Cancer Institute Molécules d'adhésion intercellulaire et leurs ligands de liaison
EP0314863A2 (fr) * 1987-11-02 1989-05-10 Baylor College Of Medicine Utilisation du ICAM-1 ou de ses derivés fonctionels pour le traitement des inflammations non spécifiques
US5235049A (en) * 1989-01-24 1993-08-10 Molecular Therapeutics, Inc. Nucleic acid sequences encoding a soluble molecule (SICAM-1) related to but distinct from ICAM-1
EP0391088A2 (fr) * 1989-03-16 1990-10-10 Center For Blood Research Laboratories, Inc. Utilisation de dérivés fonctionnels de la molécule d'adhésion intercellulaire ICAM-1 dans une thérapie anti-virale
WO1993006842A1 (fr) * 1991-10-02 1993-04-15 Boehringer Ingelheim Pharmaceuticals, Inc. Utilisation de molecules d'adhesion intercellulaire et de leurs ligands de liaison dans le traitement de l'asthme

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ROTHLEIN R ET AL: "TREATMENT OF INFLAMMATION WITH ANTI-ICAM-1" RESEARCH IN IMMUNOLOGY,FR,PARIS, vol. 144, no. 9, 1 January 1993 (1993-01-01), pages 735-739,754-76, XP000575989 *
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WEGNER C D ET AL: "Intercellular adhesion molecule-1 (ICAM-1) in the pathogenesis of asthma." SCIENCE, (1990 JAN 26) 247 (4941) 456-9., XP000872999 *
WEGNER, CRAIG D: "Adhesion molecules in allergy" PROG. ALLERGY CLIN. IMMUNOL., PROC. INT. CONGR. ALLERGOL. CLIN. IMMUNOL., 15TH (1995), MEETING DATE 1994, 13-18. EDITOR(S): JOHANSSON, STIG G. O. PUBLISHER: HOGREFE & HUBER, SEATTLE, WASH., XP000881448 *

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JPH09512252A (ja) 1997-12-09
EP0757697A4 (fr) 2000-05-17
CA2187360A1 (fr) 1995-10-19
WO1995027736A1 (fr) 1995-10-19

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