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WO2001051084A1 - Diagnostic et traitement de troubles hepatiques inflammatoires par inhibition de la liaison de lfa-1 a icam-1 - Google Patents

Diagnostic et traitement de troubles hepatiques inflammatoires par inhibition de la liaison de lfa-1 a icam-1 Download PDF

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Publication number
WO2001051084A1
WO2001051084A1 PCT/US2001/001050 US0101050W WO0151084A1 WO 2001051084 A1 WO2001051084 A1 WO 2001051084A1 US 0101050 W US0101050 W US 0101050W WO 0151084 A1 WO0151084 A1 WO 0151084A1
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WIPO (PCT)
Prior art keywords
icam
disorder
agent
antibody
hepatic
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PCT/US2001/001050
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English (en)
Inventor
Sherman Fong
Kenneth J. Hillan
Wyne Pun Lee
Daniel B. Tumas
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Genentech, Inc.
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Publication date
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Priority to AU2001230920A priority Critical patent/AU2001230920A1/en
Publication of WO2001051084A1 publication Critical patent/WO2001051084A1/fr

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    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies

Definitions

  • This invention relates to methods and compositions which can be employ ed in the prophylaxis, treatment and management of liver disorders especially those characterized by inflammation Also disclosed are methods and reagents useful in the prognosis and diagnosis of inflammatory liver disorders
  • Lymphocyte function-associated antigen 1 (LFA-1 , CD 1 1 a/CD 18) is involved in leukocyte adhesion during cellular interactions essential for immunologic responses and inflammation (Larson et al Immunol Rev 1 14 181-217 ( 1990))
  • LFA- 1 is a member of the ⁇ 2 integral family and consists of a unique ⁇ subunit, CD1 la, and a ⁇ subunit CD 18, common to other ⁇ 2 integrin receptors Mac-1 and pi 50,95
  • the ligands of LFA-1 include intercellular adhesion molecule- 1 , ICAM- 1 , expressed on leukocytes, endothe um, and dermal fibroblasts (Dustin et al J Immunol 137 245-254 (1986)), ICAM- 2 expressed on resting endothehum and lymphocytes (de Fougerolles et al J Exp Med 174 253-267 (1991)), and ICAM-3 expressed on monocytes and resting lymphocytes (de Fouge
  • T cell-dependent immune functions Monoclonal antibodies (MAbs) against LFA-1 and the ICAMs have been shown, in v ro, to inhibit several T cell-dependent immune functions including T cell activation (Kuypers et al Res Immunol 140 461( 1989)), T cell-dependent B cell proliferation (Fischer et al J Immunol 136 3198- 3203 (1986)), target cell lysis (Krensky e.
  • the present invention encompasses methods and compositions useful in the diagnosis, prognosis and treatment of hepatic disorders
  • the methods and compositions of the invention can be employed in the diagnosis, prognosis and treatment of a variety of hepatic disorders, especially those characterized by ICAM associated leukocyte recruitment to the liver
  • Hepatic disorders within the present invention include any disease or disorder characterized by ICAM expression including infections, especially viral infections, autoimmune disorders, iatrogenic disorders, hereditary disorders, cholestatic disorders, sarcoidosis, liver injury as a result of organ transplantation, I e , in graft rejection or graft versus host disease such as after bone marrow transplant
  • the invention is preferably used to treat hepatitis, especially viral hepatitis, drug induced hepatitis and autoimmune hepatitis, cholestatic disorders such as primary biliary cirrhosis and primary sclerosing cholangitis and allograft rejection
  • the methods of treatment encompassed within the present invention comprise administration to a host in need thereof of an agent which prevents the interaction of ICAM with a ICAM binding partner or hgand such as LFA-1 or which inhibits the expression of ICAM in the liver
  • Hepatic leukocytes for example, lymphocytes
  • the methods are useful in preventing ICAM associated leukocyte recruitment to the liver as well as inhibiting a primary event in the inflammatory response such as blocking interactions between intercellular adhesion molecules and their hgands They are also useful in preventing ICAM associated activation of resident leukocytes within the liver
  • the methods of the present invention are employed to reduce or prevent the infiltration of LFA- 1 bearing leukocytes into liver thereby decreasing the severity of inflammation and the degree of tissue injury in the hepatic disease or disorder treated Severity of inflammation and degree of tissue damage will also be blocked or reduced by preventing ICAM associated activation of resident hepatic leukocytes
  • Another aspect is a method of inhibiting the binding between a first cell expressing a hgand for ICAM and a second cell expressing ICAM, wherein the second cell is present in a liver, comprising contacting one or both of the cells in vivo or in vitro with an agent which prevents the interaction of
  • the hgand for ICAM is LFA-1 and the agent used to block the interaction is an ant ⁇ -LFA-1 antibody, preferably an anti-CDl l a antibody, preferably a human or humanized form of the antibody
  • the invention includes compositions, including pharmaceutical compositions comprising agents such as antibodies for the treatment of hepatic disorders as well as kits and articles of manufacture Kits and articles of manufacture preferably include (a) a container, (b) a label on said container, and
  • kits optionally include accessory components such as a second container comprising a pharmaceutically-acceptable buffer and instructions for using the composition to treat a hepatic disorder
  • the diseases or disorders for prognosis or diagnosis under the present invention include those diseases and disorders treatable within the context of the present invention
  • the diagnostic methods can be employed to detect the presence of ICAM in a sample, especially a liver biopsy or the presence of infiltrating leukocytes bearing a hgand for ICAM in the sample
  • the methods can be employed to detect the disorder or to monitor, stage or predict the course of the disease or the therapy used to treat the disorder
  • Figure 1 shows that treatment with anti-CDl l a significantly reduces the degree of portal inflammation, when compared with isotype treated controls Statistical analysis was with Scheffe's test and graphs show means ⁇ 1 S E
  • Figure 2 shows that treatment with anti-CDl l a significantly reduces the severity of the total hepatitis score, when compared with isotype treated controls Statistical analysis was with Scheffe's test and graphs show means ⁇ 1 S E
  • ICAM in the context of the present invention refers to the protein intercellular adhesion molecules, ICAM-1 expressed on leukocytes, endothehum, and dermal fibroblasts (Dustin et al J Immunol 137 245-254 (1986)), ICAM-2 expressed on resting endothehum and lymphocytes (de Fougerolles et al J Exp Med 174 253-267 (1991)), and ICAM-3 expressed on monocytes and resting lymphocytes (de Fougerolles et al , J Exp Med 179 619-629 (1994))
  • ICAM-binding partner or hgand it is meant a molecule that interacts with ICAM The molecule may be naturally occurring and may be soluble or localized to the surface of a cell
  • ICAM hgand is the lymphocyte lnteg ⁇ n LFA-1 ( ⁇ L ⁇ 2 or CD1 la/CD 18), a heterodime ⁇ c structure consisting of an ⁇ and a ⁇ subunit
  • a “conditioning dose” is a dose which attenuates or reduces the frequency or the severity of first dose adverse side effects associated with administration of a therapeutic compound The conditioning dose may be a therapeutic dose, a sub-therapeutic dose, a symptomatic dose or a sub-symptomatic dose
  • a therapeutic dose is a dose which exhibits a therapeutic effect on the patient and a sub-therapeutic dose is a dose which dose not exhibit a therapeutic effect on the patient treated
  • a symptomatic dose is a dose which induces at least one adverse effect on administration and a sub-symptomatic dose is a dose which does not induce
  • a “therapeutically effective amount” refers to the minimum concentration (amount) of an agent herein administered to a mammal that is effective in at least attenuating a pathological symptom (e g causing, inducing or resulting in a detectable / measurable improvement, lessen the severity, extent or duration of symptoms) which occurs as a result of a hepatic disorder
  • Treatment is an intervention performed with the intention of preventing the development or altering the pathology of a disorder
  • treatment refers to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent, slow down or lessen the seventy, extent or duration of symptoms, or delay the onset of (e g , in subjects predisposed to develop a hepatic disorder due to genetic make-up or other risk factors, e g , in cirrhosis) a targeted pathological condition or disorder
  • the term treatment includes the administration of an agent prior to or following the onset of a disease or disorder or after clinical manifestation of the disease thereby preventing or removing all signs of the disease or disorder
  • Treating a disease, disorder, condition or cell population includes therapy and prophylactic treatment on an acute short term basis and on a chronic long-term basis Treatment is successful if it results in a detectable or measurable improvement in at least one symptom of the disorder being treated (consistent with the definition of "therapeutically effective amount
  • Those "in need of treatment” include mammals, such as humans, already having the disease or disorder, including those in which the disease or disorder is to be prevented
  • agent used within the scope of the present invention interchangeably and are meant to include any molecule or substance which prevents the interaction between ICAM and a ICAM hgand or binding partner, such as LFA-1
  • molecules include small bioorganic molecules, e g peptidomimetics, antibodies, immunoadhesins, proteins, peptides, glycoproteins, glycopeptides, glycohpids, polysaccha ⁇ des.
  • a specific defense system reaction is a specific immune system reaction to an antigen.
  • specific defense system reactions include T cell and antibody response to antigens, such as viruses, and delayed-type hypersensitivity.
  • a non-specific defense system reaction is an inflammatory response mediated by leukocytes generally incapable of immunological memory. Such cells include macrophages, eosinophils and neutrophils. Examples of non-specific reactions include the immediate swelling after a bee sting, and the collection of PMN leukocytes at sites of bacterial infection, e.g., pulmonary infiltrates in bacterial pneumonias and pus formation in abscesses.
  • iatrogenic disorder refers to those disorders induced by exposure to a therapeutic compound or surgical treatment intended to treat some other disorder.
  • drug induced liver diseases or disorders include, for example chronic active hepatitis associated with administration of Amineptine, Clometacine, Dantrolene, Diclofenac, Fenofibrate, Triglitazone, Piaglitazone, to name but a few; chronic cholestasis associated with the administration of Aceprometazine, Ajmaline and related drugs, Amitryptyline, and Ampicillin to name but a few; or hepatic granulomas associated with administration of Allopurinal, Aspirin, and Diazepam to name but a few.
  • antibody is used in the broadest sense and specifically covers single monoclonal antibodies (including agonist and antagonist antibodies) and antibody compositions with poly ⁇ pitopic specificity.
  • mAb monoclonal antibody
  • monoclonal antibody refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts.
  • Monoclonal antibodies are highly specific, being directed against a single antigenic site.
  • polyclonal antibody preparations which typically include different antibodies directed against different determinants (epitopes)
  • each mAb is directed against a single determinant on the antigen.
  • the monoclonal antibodies are advantageous in that they can be synthesized by hybridoma culture, uncontaminated by other immunoglobulins.
  • the monoclonal antibodies herein include hybrid and recombinant antibodies produced by splicing a variable (including hypervariable) domain of one antibody with a constant domain of another antibody, or a light chain with a heavy chain, or a chain from one species with a chain from another species, or fusions with heterologous proteins, regardless of species of origin or immunoglobulin class or subclass designation, as well as antibody fragments (e.g.. Fab, F(ab') , and Fv), so long as they exhibit the desired biological activity.
  • Fab, F(ab') , and Fv antibody fragments
  • the modifier "monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method
  • the monoclonal antibodies to be used in accordance with the present invention can be made by the hyb ⁇ doma method first described by Kohler and Milstein, Nature 256 495 (1975), or can be made by recombinant DNA methods (Cabilly et al supra)
  • the monoclonal antibodies herein specifically include "chime ⁇ c" antibodies in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass while the remainder of the cha ⁇ n(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (U S Patent No 4,816,567, and Morrison et al Proc Natl Acad Set USA, 81 6851 -6855 (1984))
  • Chime ⁇ c antibodies of interest herein include "p ⁇ matized" antibodies comprising variable domain antigen-bindmg sequences derived from a non-human primate (e g Old World Monkey, Ape etc) and human constant region sequences
  • humanized forms of non-human (e g , mu ⁇ ne) antibodies are specific chime ⁇ c immunoglobuhns, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab', F(ab') , or other antigen-bindmg subsequences of antibodies) which contain minimal sequence derived from non-human immunoglobulin
  • humanized antibodies are human immunoglobuhns (recipient antibody) in which residues from a complementary-determining region (CDR) of the recipient are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat, or rabbit having the desired specificity, affinity, and capacity
  • donor antibody such as mouse, rat, or rabbit having the desired specificity, affinity, and capacity
  • framework residues of the human immunoglobulin are replaced by corresponding non-human residues
  • humanized antibodies can comprise residues which are found neither in the recipient antibody nor in the imported CDR or framework sequences of the donor antibody
  • Isolated antibody includes the antibody in situ within recombinant cells since at least one component of the antibody's natural environment will not be present Ordinarily, however, isolated antibody will be prepared by at least one purification step
  • the term “lmmunoadhesin” designates antibody-like molecules which combine the "binding domain" of a heterologous protein, for example ICAM (an “adhesin", for example, a receptor, gand or enzyme) with the effector functions of immunoglobulin constant domains Structurally, the immunoadhesins comprise a fusion of the adhesin amino acid sequence with the desired binding specificity which is other than the antigen recognition and binding site (antigen combining site) of an antibody (l e is "heterologous") and an immunoglobulin constant domain sequence
  • the immunoglobulin constant domain sequence in the lmmunoadhesin may be obtained from any immunoglobulin, such as IgG, IgM, IgE, IgA, and any subclass or isotype thereof
  • the term "ant ⁇ -LFA-1 antibody” or “ant ⁇ -LFA-1 MAb” refers to an antibody directed against either CD1 l a or CD 18 or both The anti-
  • Examples of ant ⁇ -CD18 antibodies include MHM23 [Hildreth et al , supra], M l 8/2 (IgG2a) [Sanches-Mad ⁇ d et al , J Exp Med , 158 586 (1983)], H52 [Fekete et al , J Chn Lab Immunol , 3J 145-149 (1990)], Masl 91c [Vermot Desroches et al , supra], IOT18 [Vermot Desroches et al , supra], 60 3 [Taylor et al , Chn Exp Immunol .
  • LFA-1 antagonists including antibodies
  • WO 91/1801 1 published Nov 28. 1991 WO 91/16928 published Nov 14. 1991
  • WO 91/16927 published Nov 14, 1991 Can Pat Appln 2,008,368 published June 13, 1991.
  • WO 90/15076 published Dec. 13, 1990 WO 90/10652 published Sept. 20, 1990, EP 387,668 published Sept. 19. 1990, EP 379,904 published Aug. 1 , 1990, EP 346,078 published Dec. 13, 1989
  • ICAM-1 antibodies include YN/1.7.4; RR1/1 (Rothlein, R. et al., J. Immunol.
  • ICAM-2 antibodies are described in U.S. 5,565,550. Soluble fragments of human ICAM- 1 are described, e.g., in U.S. 5,831,036. These references describe how to prepare ICAM antibodies.
  • a hepatic disorder or disease is any liver disease or disorder accompanied by the expression of ICAM in the liver and surrounding vasculature.
  • the methods of the invention are useful in the diagnosis, prognosis and treatment of variety of hepatic disorders including those resulting from infection, iatrogenic disorders, hereditary disorders, autoimmmune disorders, cholestatic syndromes, sarcoidosis, organ transplantation, and the like so long as the disorder is characterized by the presence of ICAM bearing cell types.
  • Diseases or disorders within the scope of the present invention include but are not limited to the diseases and disorders detailed in Table I.
  • liver e g portal, lobular, pe ⁇ venular
  • inflammation of the liver e g portal, lobular, pe ⁇ venular
  • liver inflammation including for example, chronic active hepatitis, cholestasis or granuloma formation
  • Any inflammation associated with gene-linked trait for example cirrhotic changes in the liver associated with hepatolenticular degeneration, a) Wilson's disease b) ⁇ - 1 -antitrypsin deficiency c) other inherited metabolic disorders for example, galactosemia B Cholestatic Syndromes
  • any inflammation of the intrahepatic bile ducts including those resulting in hepatic dysfunction and cirrhosis as for example in primary biliary cirrhosis primary sclerosing cholangitis and adult ldiopathic ductopenia
  • Any inflammation of the liver or hepatic ducts including that associated with hepatic transplantation, liver injury in graft versus host disease and recipients of renal and other allografts, for example hyperacute allograft rejection, and xenograft rejection
  • Particularly preferred disorders within the context of the invention are chronic hepatitis particularly hepatitis resulting from infection, particularly viral infection
  • chronic hepatitis particularly hepatitis resulting from infection, particularly viral infection
  • include this category are the established serological categories of chronic hepatitis, including viral (HBV, HDV, HCV), autoimmune hepatitis (classic lupoid type and subtypes), autoimmune overlap syndromes drug induced (any hepatitis inducing compound, for example, nitrofurantoin, alpha methyldopa, isoniazid) and so- called "cryptogenic" hepatitis
  • the skilled artisan will make reference to chapter 9, and especially Tables 9 2 and 9 3 in Pathology of the Liver, 3rd Edition, (MacSween, Anthony, Scheuer, Burt and Portman, eds ) Churchill Livingstone ( 1994) the disclosure of which is incorporated in its entirety herein by reference
  • HCV hepatitis C virus
  • HCV hepatitis C virus
  • Current therapies include ⁇ -interferon, emphasize B and ⁇ bivi ⁇ n, each of which have limited efficacy and serious side effects
  • Current therapy also includes transplantation, however, since the infected individual remains infected with the virus, post-transplant immunosuppressed patients exhibit increased viral RNA levels and often rapidly progress to liver disease with the new liver Chronic cholestatic syndromes are characterized by progressive inflammatory destruction of intrahepatic bile ducts resulting in hepatic dysfunction, fibrosis and cirrhosis Examples of this type of disorder include primary
  • Hereditary disorders treatable by the methods disclosed herein include those inflammatory disorders associated with a gene-linked trait Examples include Wilson's disease ⁇ - 1 -ant ⁇ tryps ⁇ n deficiency and inherited metabolic disorders such as galactosemia and tyrosineanemia Diagnosing and Prognosing a Hepatic Disorder
  • Hepatic disorders for prognosis and diagnosis within the context of the present invention are described above and are characterized by the presence of ICAM in a sample, for example a sample of hepatic tissue or surprisingly, in a cell free sample such as serum. Therefore, one embodiment of the present invention is directed to the detection and/or measurement of ICAM in a sample and the use of such detection or measurement in the diagnosis, staging, determination of severity, and prognosis in general of the hepatic disease or disorder. Further, since the expression of ICAM has been shown to correlate with the presence of lymphocytes bearing the LFA-1 integrin, prognosis and diagnosis of hepatic disorders within the context of the present invention encompass the measurement or detection of the presence of lymphocytes bearing LFA-1 integrin.
  • the present invention includes a method for diagnosis and prognosis of diseases and disorders not limited to hepatic diseases and disorders but appropriately used therefor, based upon the discovery that ICAM can be detected in the serum of a subject. Therefore the present invention includes methods of diagnosis and prognosis of diseases or disorders characterized by the expression of ICAM bearing cell types in general and which include but are not limited to the hepatic diseases or disorders listed above.
  • a sample which is subjected to testing is a sample derived from a subject such as a human and includes, but is not limited to, any biological fluid, preferably a bodily fluid.
  • a sample derived from a subject such as a human and includes, but is not limited to, any biological fluid, preferably a bodily fluid.
  • cell-free samples the term cell-free being used herein to indicate that the sample is substantially devoid of cells or that the sample is substantially free of cell types bearing ICAM.
  • bodily fluids include, but are not limited to, whole blood, serum, plasma, urine, synovial fluid, cranial or spinal fluid, saliva, tissue infiltrate, cervical or vaginal exudate, tissue infiltrate, pleural effusions, bronchoalveolar lavage fluid, gastric lavage fluid, small or large bowel contents, fecal preparations, and the like.
  • the biological fluid may be a cell culture medium or supernatant of cultured cells.
  • the sample is a blood sample and especially a serum sample.
  • the methods provided by the present invention overcome many of the limitations of prior art methods of measuring or detecting ICAM, which heretofore required samples comprising cells followed by immunohistochemical techniques or direct or indirect immunofluorescence analysis by microscopy or flow cytometry.
  • Limitations of the prior art procedures include the requirement for: (1) fairly rare tissue samples comprising a large number of cells, (2) extensive preparation time, and (3) expensive equipment, such as a flow cytometer.
  • the methods provided herein overcome these limitations.
  • any procedure known in the art for the measurement of analytes can be used in the practice of the measurement of ICAM in a sample.
  • Such procedures include but are not limited to competitive and non-competitive assay systems using techniques such as radioimmunoassays, enzyme immunoassays (EIA), preferably the enzyme linked immunosorbent assay (ELISA), "sandwich” immunoassays, precipitin reactions, gel diffusion reactions, immunodiffusion assays, agglutination assays, complement-fixation assays, immunoradiometric assays, fluorescent immunoassays, protein A immunoassays, and lmmunoelectrophoresis assays, to name but a few
  • EIA enzyme immunoassays
  • ELISA enzyme linked immunosorbent assay
  • an ICAM binding partner typically an antibody will be labeled with a detectable moiety and used to detect ICAM in a sample as described above
  • a detectable moiety typically an antibody
  • Numerous labels are available which can be preferably grouped into the following categories
  • Radioisotopes such as J S, C, I, H, and J I
  • the ICAM binding partner such as an antibody can be labeled with the radioisotope using the techniques described in Current Protocols in Immunology, Volumes 1 and 2, Cohgen et al , Ed , Wiley-Interscience, New York, New York, Pubs , (1991 ) for example and radioactivity can be measured using scintillation counting
  • Fluorescent labels such as rare earth chelates (europium chelates) or fluorescein and its derivatives rhodamine and its derivatives, dansyl, Lissamine, phycoerythrin and Texas Red are available
  • the fluorescent labels can be conjugated to the ICAM binding partner such as an antibody using the techniques disclosed in Current Protocols in Immunology, supra, for example Fluorescence can be quantified using a fluo ⁇ meter
  • Various enzyme-substrate labels are available and U S Patent No 4.275, 149 provides a review of some of these The enzyme preferably
  • enzyme-substrate combinations include for example
  • ⁇ -D-galactosidase ( ) ⁇ -D-galactosidase ( ⁇ -D-Gal) with a chromogenic substrate (e g p-nitrophenyl- ⁇ -D- galactosidase) or fluoroge c substrate 4-methylumbelhferyl- ⁇ -D-galactos ⁇ dase
  • a chromogenic substrate e g p-nitrophenyl- ⁇ -D- galactosidase
  • fluoroge c substrate 4-methylumbelhferyl- ⁇ -D-galactos ⁇ dase
  • an ICAM binding partner such as an antibody is preferably bound to a solid phase support or carrier
  • solid phase support or carrier any support capable of binding an antigen or antibodies
  • supports, or carriers include glass, polystyrene, polypropylene, polyethylene, dextran, nylon, amyloses, natural and modified celluloses polyacrylamides, agaroses, and magnetite
  • the nature of the carrier can be either soluble to some extent or insoluble for the purposes of the present invention
  • the support material may have virtually any possible structural configuration so long as the coupled molecule is capable of binding to an antigen or antibody
  • the support configuration may be spherical, as in a bead, or cylindrical, as in the inside surface of a test tube, or the external surface of a rod Alternatively, the surface may be flat such as
  • an antibody-ICAM-antibody sandwich immunoassay is done ; e , ICAM is detected or measured by a method comprising binding of a first antibody to the ICAM antigen, and binding of a second antibody to the ICAM, and detecting or measuring ICAM immunospecifically bound by both the first and second antibody
  • the first and second antibodies are monoclonal antibodies
  • the second monoclonal antibody preferably binds to a site different from that of the first antibody (as reflected e g , by the lack of competitive inhibition between the two antibodies for binding to the antigen)
  • the first or second antibody is a polyclonal antibody
  • both the first and second antibodies are polyclonal antibodies
  • a "forward" sandwich enzyme immunoassay is used, as described schematically below
  • An antibody (capture antibody, Abl ) directed against the ICAM is attached to a solid phase matrix, preferably a microplate
  • the sample is brought in contact with the Abl-coated matrix and such that any ICAM in the sample to which Abl is specific binds to the solid-phase Abl Unbound sample components are removed by washing
  • An enzyme-conjugated second antibody (detection antibody, Ab2) directed against a second epitope of the ICAM binds to the antigen captured by Abl and completes the sandwich
  • a chromogenic substrate for the enzyme is added, and a colored product is formed in proportion to the amount of enzyme present in the sandwich, which reflects the amount of ICAM in the sample
  • the reaction is terminated by addition of stop solution
  • the color is measured as absorbance at an appropriate wavelength using a spectrophotometer
  • a standard curve is prepared from known concentrations of the ICAM, from which unknown sample values can be determined
  • the methods of the present invention can be used alone or in conjunction with other diagnostic tests for the diagnosis and detection of a hepatic disorder
  • Viral infections can be detected using techniques known in the art Hepatitis C infection, for example, can be detected using commercially available serologic assays which detect anti-HCV antibodies or molecular assays which detect HCV RNA genomes within an infected patient
  • the methods of present invention can be used alone or in conjunction with these routine tests as an aid in diagnosis
  • the specific cause of a liver disorder is identified on the basis of elevated liver function tests or an enlarged liver
  • the diagnostic methods of the present invention can be used alone or in conjunction with these tests to diagnose a disease or disorder within the context of the present invention
  • blood tests and a liver biopsy are routinely used to diagnose or confirm a diagnosis and as well to determine the amount, extent and severity of damage to the liver
  • the diagnostic methods of the present invention can be used alone or m conjunction with these tests in determining the amount, extent, or seventy of damage to the liver
  • a diagnostic test performed on for example a serum sample, an in vivo sample or a liver biopsy can, with the present invention, be extended to the detection of ICAM or LFA-1 expression in the sample Further, the detection of ICAM or LFA-1 in the sample can be used to monitor the course or progression of the disease as well as the course of or effectiveness of a therapeutic treatment
  • the diagnostic techniques described can be used to follow the progress of therapy
  • the amount of lymphocyte trafficking may serve as a useful measure for the success or failure of the treatment
  • the present invention provides a method for monitoring the effect of a therapeutic treatment in a subject which comprises measuring at suitable time intervals the amount of ICAM expressed in a sample of liver tissue or conversely the amount or number of lymphocytes in the sample
  • the total amount of ICAM or LFA-1 is compared to a "baseline" or "control" value which depending on the disease, and the treatment, may be the amount of ICAM in a similar sample from a normal subject, from the patient prior to disease onset or during remission of disease, or from the patient prior to the initiation of therapy
  • a preferred subject for the methods of the present invention is a vertebrate, including but not limited to a mammal, fish, amphibian, reptile, bird, marsupial, and most preferably, a human either fetal or adult human liver
  • the methods and kits of this invention are applicable to human clinical and veterinary uses
  • a sample for example a liver biopsy sample is derived from a subject by methods routine to those skilled in the art
  • the most common way a liver sample is obtained is by liver biopsy, a procedure used to obtain a small amount of liver tissue which can be subsequently examined employing routine immunohistochemical techniques in conjunction with the methods of the present invention
  • liver sample can be obtained by needle biopsy directly into the liver of subject, or for example by guiding a needle into the liver of the subject through the abdomen or chest using various imaging techniques known to the skilled artisan
  • samples are obtained using techniques such as laproscopy, transvenous or transjugular liver biopsy and surgical liver biopsy
  • any procedure known in the art for the measurement of analytes can be used in the practice of the instant invention to detect the presence of ICAM or a hgand therefor, such as LFA- 1
  • Such procedures include but are not limited to immunohistochemical techniques known to those skilled in the art, competitive and noncompetitive assay systems using techniques such as radioimmunoassays, enzyme immunoassays (EIA), preferably the enzyme linked lmmunosorbent assay (ELISA), "sandwich” immunoassays, precipitin reactions, gel diffusion teactions, immunodiffusion assays, agglutination assays, complement fixation assays, lmmunoradiomet ⁇ c assays, fluorescent immunoassays, protein A immunoassays, and lmmunoelectrophoresis assays, to name but a few Kits comprising one or more containers or vials containing components for carrying out the assays of the present invention are also within the scope of the invention
  • compositions useful in the therapeutic and the diagnostic methods of the present invention are available to the skilled artisan and can be identified based upon their ability to prevent, block or suppress ICAM mediated cell adhesion
  • the compositions are useful in the treatment and diagnosis of hepatic disorders associated with that adhesion, such as inflammation and immune reactions
  • appropriate agents able to prevent, block or suppress ICAM mediated cell adhesion may accomplish this effect in various ways
  • one class of agents will bind to ICAM with sufficient affinity and specificity to prevent interaction with lymphocytes expressing a naturally occurring hgand for ICAM. such as the lymphocyte integrin LFA- 1
  • Another class of agents will bind to a naturally occurring leukocyte hgand for ICAM, such as the lymphocyte integrin LFA-1 and thereby prevent its interaction with ICAM
  • Exemplary agents are antibodies preferably a monoclonal, chime ⁇ c and or humanized antibody or an antigen binding fragment thereof which inhibits adhesion of leukocytes to ICAM
  • a further exemplary agent is a soluble ICAM molecule or a molecule based upon ICAM such as a soluble form of ICAM comprising the integrin binding site of ICAM or an ICAM lmmunoadhesin comprising, for example, the extracellular domain of ICAM fused to an immunoglobulin constant domain
  • a peptide or a molecule based upon a peptide sequence present in ICAM and required for integrin binding can be used as an agent within the context of the present invention
  • integ ⁇ ns can selectively bind a variety of Arg-Gly-Asp ⁇ RGD) containing hgands RGD-based peptide inhibitors with different structures can be prepared which are effective agents within the context of the present invention
  • a further agent is an antisense nucleic add, which is complementary in whole or in part, to a target molecule comprising a sense strand, and can hybridize to the target molecule
  • antisense nucleic acid When introduced into a cell antisense nucleic acid can inhibit the expression of the gene encoded by the sense strand
  • Antisense nucleic acid in whole or in part complimentary to the nucleic acid sequence of ICAM can be produced for this purpose
  • the agent is an antibody, which antibody has the desirable properties of binding to ICAM and preventing its interaction with the leukocyte associated gand or binding to LFA-1 and preventing the interaction of LFA-1 with ICAM
  • Useful antibodies are available to the skilled artisan such as those described herein or those described in the references identified above in the definitions of ant ⁇ -LFA- 1 antibodies, anti-CDl la antibodies, and ant ⁇ -CD18 antibodies
  • the following techniques can, without limitation, be employed in identifying and isolating appropriate agents useful in blocking or preventing the interaction between ICAM and an ICAM binding partner
  • the compositions of the invention can be assayed by techniques known in the art in order to demonstrate their activity Such assays include, but are not limited to, the following in vitro tests for the ability to interact with
  • ICAM proteins to inhibit ICAM related activity, or to selectively inhibit the generation of ICAM derived peptides
  • purified LFA- 1 is immobilized on a solid support such as a glass slide or a plastic plate pre-incubated with an antibody to the ⁇ subunit that does not block interaction of the integrin with ICAM
  • a solid support such as a glass slide or a plastic plate pre-incubated with an antibody to the ⁇ subunit that does not block interaction of the integrin with ICAM
  • ICAM or preferably a ICAM-immunoglobuhn chimera is incubated with the immobilized integrin in the presence or absence of a suspected agent
  • the binding or absence of binding of ICAM in the presence of the agent being tested can then be measured with a detecting agent such as an anti-ICAM or anti-Ig antibody
  • a cell based assay employing a cell transfected with the LFA- 1 integrin subunits and which expresses the intact integrin can be used in a cell based assay for identification of appropriate agents
  • the ability of a monoclonal antibody to inhibit adhesion of the natural cellular hgands to the cells expressing ICAM or the LFA-1 integrin can be used
  • the agent of the invention is incubated with the ICAM/LFA-1 bearing cells in the presence of the natural receptor/ gand- bea ⁇ ng cells, wherein the ICAM-bea ⁇ ng cells have been immobilized on a solid support
  • Inhibition of the cellular adhesion is then assessed by either calculating the amount of the bound mAb or assessing the displaced cells
  • the specificity or discrimination between two or more competing substrates is determined by the ratios of bound to unbound
  • radiolabeled or flourescent labeled LFA-1 is incubated with immobilized ICAM receptor- lmmunoglobuhn chimeras in varying concentration of unlabeled candidate compound Increasing concentrations of successful candidate molecule effectively prevent binding of labeled LFA-1 to immobilized receptor chimeras
  • concentration of unlabeled agent at which 50% maximal LFA-1 is displaced is referred to as the EC50 and reflects the receptor binding affinity Therefore a candidate compound with an EC50 of 100 nM displays a substantially weaker interaction with a receptor than candidate agent with an EC50 of 10 nM
  • This discrimination in substrate specificity indicates that the preferred agent or antagonist has utility in, for example, preventing or blocking the interaction of ICAM with leukocyte surface antigens and especially LFA- 1 in a setting where both the natural hgand and the so-called agent or
  • An exemplary agent is a monoclonal antibody reactive with LFA-1 or ICAM Antibodies are assessed by affinity constants
  • Affinity constants are a measure of the interaction between a particular hgand and its cognate receptor
  • the "binding affinity" or the measure of the strength of association between a particular receptor gand interaction is generally measured by affinity constants for the equilibrium concentrations of associated and dissociated configurations of the hgand and its receptor
  • the present invention contemplates such an interaction between an agent or composition and the endothehal cell adhesion molecule ICAM
  • the dissociation constants of hgand/integnn interactions in solution are relatively weak and range from low micromolar to high nanomolar Additivity of multiple adhesive interactions at a cell surface, or the "avidity,” provides the necessary binding energy to anchor leukocytes to the vascular endothehum Therefore, in general, a useful composition or agent has a higher affinity for the integrin receptor than its native hgand Such an antagonist blocks or prevents a high
  • those forms of the molecule that are readily absorbed by tissues, that are protected from rapid metabolism and/or that provide for prolonged half life, are preferentially selected in producing the compositions of the invention
  • modifications of the protein formulation include, but are not limited to, use of a pro-drug and chemical modification of the primary structure (Wearley, L L , 1991 , C ⁇ t Rev in Ther Drug Carrier Systems, 8(4) 333)
  • modifications include but are not limited to chemical modifications and covalent attachment to a polymer (Wearley, L L , 1991 , supra)
  • leukocyte traffic across the vessel walls to extravascular tissue is necessary for host defense against microbial organisms or foreign antigens and repair of tissue damage
  • leukocyte-endothehal interactions may have deleterious consequences for the host
  • leukocytes may release products such as oxidants, proteases, or cytokines that directly damage endothehum or cause endothehal damage by releasing a variety of inflammatory mediators
  • the interaction of ICAM with leukocyte surface molecules, such as LFA- 1 facilitates leukocyte migration and activation and contributes to the destructive effects of the inflammatory process
  • agents that prevent the interaction between hepatically expressed ICAM and hgands such as LFA-1 can be employed to treat these types of disorders in the liver
  • the pharmaceutical compositions of the present invention can be used to eliminate or block the injury occurring in transplanted livers
  • agent is suitably administered to the patient at one time or over a series of treatments
  • the agents may be administered to a mammal, preferably a patient, in a pharmaceutically acceptable dosage form, including those that may be administered to a patient intravenously as a bolus or by continuous infusion over a period of minutes, hours, days, weeks. or months, intramuscularly, subcutaneously, mtra-articularly, intrasynovially, intrathecaliy, or periostally, or by oral, topical, or inhalation routes
  • a dose of agent may be administered to the patient in one or more single administrations, continuous infusion, or bolus injection
  • an initial dose of the agent is administered to the patient by injection or infusion
  • the treatment is repeated until a desired suppression of disease symptoms occurs
  • other dosage regimens may be useful
  • the effectiveness of the agent may be improved by administering the agent serially or in combination with another agent that is effective for this purpose (for example, interferon)
  • compositions of the present invention may be part of a delivery system such as posomes Delivery systems involving hposomes are discussed in International Patent Publication No WO
  • compositions of the invention can be administered to a subject in need thereof to treat the subject by either prophylactically preventing a disease state or relieving it after it has begun
  • the pharmaceutical compositions of the invention may be administered in any suitable manner, including parental, topical, oral, or local (such as aerosol or transdermal) or any combination thereof
  • the compositions are preferably administered with a pharmaceutically acceptable carrier, the nature of the carrier differing with the mode of administration, for example, oral administration, usually using a solid carrier and I V administration a liquid salt solution carrier
  • compositions of the present invention include pharmaceutically acceptable components that are compatible with the patient and the protein and carbohydrate moieties of the compositions of the invention
  • These generally include suspensions, solutions and elixirs, and most especially biological buffers, such as phosphate buffered saline, saline, Dulbecco's Media, and the like Aerosols may also be used, or carriers such as starches, sugars, microcrystal ne cellulose, diluents, granulating agents lubricants, binders, disintegrating agents, and the like (in the case of oral solid preparations, such as powders, capsules, and tablets)
  • the term "pharmaceutically acceptable” preferably means approved by a regulatory agency of the Federal or a state government or listed in the U S Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans
  • the formulation of choice can be accomplished using a variety of the aforementioned buffers, or even excipients including, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin cellulose, magnesium carbonate, and the like
  • "Peglation" of the compositions may be achieved using techniques known to the art (see for example International Patent Publication No W092/16555, U S Patent No 5,122,614 to Enzon, and International Patent Publication No
  • Oral compositions may be taken in the form of solutions, suspensions, tablets, pills, capsules, sustained release formulations, or powders
  • compositions of the invention should be administered to the patient to ensure that a substantial amount of the interaction between ICAM and a binding partner is inhibited In this way, hepatic inflammation can either be prevented or ameliorated
  • the selection of compositions, frequency of administration, and amount of composition so administered will be in accordance with the particular disease being treated and its severity, the type of agent employed, the method of administration, the overall condition of the patient, and the judgment of the treating physician Typical dosing regions will be analogous to treatment of these disease states by the use of antibodies and other biologicals
  • the compositions of the instant invention will contain from about 1% to about 95% of the active ingredient, preferably about 10% to about 50%
  • the dosing will be between about 0 25- 100 mg kg About 1 mg to about 50 mg will be administered to a child, and between about 25 mg and about 1000 mg will be administered to an adult
  • An LFA-1 antagonist, humanized anti-CDl la antibody hu l 124 can be administered at a dosage range of between 0 25 mg/kg to
  • compositions to be administered it must be kept in mind that one may not wish to completely block all of the ICAM molecules, or may wish to completely block such receptors for only a limited amount of time
  • the dose of the composition administered as a blocking agent is adjusted based on the particular needs of the patient while taking into consideration a variety of factors such as the type of disease that is being treated
  • an effective amount of a composition in accordance with the present invention is an amount effective to inhibit the interaction between ICAM and a ICAM-binding partner
  • Humanized antibodies were prepared as described in WO 98/23761 and U S 6,037,454
  • Con A induced a mild to moderate hepatitis, characterized by a lymphoblastic ' lymphocytic infiltrate in portal tracts (portal tnaditis), within the liver parenchyma proper (lobular hepatitis) and around terminal hepatic venules
  • the inflammatory infiltrate was accompanied in one animal by parenchymal necrosis
  • Hepatitis was scored using a modified version of the histological activity index (HAI), a semi-quantitative scoring system
  • Figure 1 is a graph showing the effect of treatment on portal tract inflammation which is graded on a scale of 0-4
  • Figure 2 shows the overall grade or hepatitis score on a scale of 0- 16.
  • the cell mean on the y-axis indicates the grade of inflammation.
  • the tables showing the statistical analysis below demonstrated the statistical significance of the results. These experiments were repeated and the results were reproducible with the same statistical significance.
  • Group Info for Portal Tract Inflammation (0-4) Grouping Variable: Group Label
  • Group Info for Overall Grade (0-16) Grouping Variable: Group Label

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Abstract

La présente invention se rapporte à des méthodes et à des compositions permettant de diagnostiquer et de traiter des troubles hépatiques, notamment ceux caractérisés par une inflammation. Une telle méthode consiste à administrer un agent qui prévient l'interaction de la molécule d'adhésion intercellulaire ICAM-1 avec un partenaire de liaison ou un ligand de ICAM. Ces compositions s'avèrent utiles s'agissant de traiter des maladies ou des troubles impliquant un blocage de l'antigène associé à la fonction lymphocytaire (LFA-1) et/ou de la molécule ICAM, et s'agissant d'inhiber un événement primaire de la réaction inflammatoire tel que le blocage des interactions entre les molécules d'adhésion cellulaires et leur ligands. Lesdites méthodes permettent de traiter des troubles tels que des inflammations, et notamment les infections virales, des troubles iatrogènes, des troubles cholestatiques, des troubles héréditaires, la sarcoïdose, les troubles liés à la transplantation d'organes et analogues. Les méthodes diagnostiques de cette invention peuvent permettre de détecter l'existence d'un trouble ou de surveiller le cours d'une thérapie mise en oeuvre pour traiter ce trouble.
PCT/US2001/001050 2000-01-14 2001-01-12 Diagnostic et traitement de troubles hepatiques inflammatoires par inhibition de la liaison de lfa-1 a icam-1 WO2001051084A1 (fr)

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Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0289949A2 (fr) * 1987-05-04 1988-11-09 Dana Farber Cancer Institute Molécules d'adhésion intercellulaire et leurs ligands de liaison
WO1990010652A1 (fr) * 1989-03-09 1990-09-20 Dana Farber Cancer Institute Procede de traitement d'infections virales a l'aide de lfa-1
WO1990015076A2 (fr) * 1989-06-02 1990-12-13 The Johns Hopkins University School Of Medicine ANTICORPS MONOCLONAUX CONTRE LA CHAINE β DE RECEPTEURS D'ADHESION DE LEUCOCYTES, PROCEDE DE PRODUCTION DE CES ANTICORPS ET UTILISATION
EP0512301A1 (fr) * 1991-05-03 1992-11-11 Boehringer Ingelheim Pharmaceuticals Inc. Procédé pour détecter des inflammations
WO1993006864A1 (fr) * 1991-10-01 1993-04-15 The General Hospital Corporation Prevention du rejet d'une allogreffe a l'aide d'anticorps contre des molecules d'adhesion
US5284931A (en) * 1987-05-04 1994-02-08 Dana Farber Cancer Institute Intercellular adhesion molecules, and their binding ligands
WO1994004188A1 (fr) * 1992-08-21 1994-03-03 Genentech, Inc. Procede pour traiter une affection ayant pour origine l'antigene 1 associe a la fonction lymphocytaire
FR2700471A1 (fr) * 1993-01-21 1994-07-22 Pasteur Merieux Serums Vacc Utilisation d'anticorps monoclonaux anti-LFA-1 pour la préparation d'un médicament destiné à prévenir le rejet des greffes d'organes solides et médicaments obtenus.
WO1995028170A1 (fr) * 1994-04-19 1995-10-26 The University Of Kansas Peptides a chaine courte a base d'icam-1/lfa-1 et leur methode d'utilisation
US5747035A (en) * 1995-04-14 1998-05-05 Genentech, Inc. Polypeptides with increased half-life for use in treating disorders involving the LFA-1 receptor
WO1998023761A1 (fr) * 1996-11-27 1998-06-04 Genentech, Inc. ANTICORPS ANTI-CD11a HUMANISES
US6037454A (en) * 1996-11-27 2000-03-14 Genentech, Inc. Humanized anti-CD11a antibodies
WO2000059880A1 (fr) * 1999-04-02 2000-10-12 Abbott Laboratories Composes inhibiteur de l'adhesion cellulaire, anti-inflammatoires et immunosuppresseurs

Patent Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0289949A2 (fr) * 1987-05-04 1988-11-09 Dana Farber Cancer Institute Molécules d'adhésion intercellulaire et leurs ligands de liaison
US5284931A (en) * 1987-05-04 1994-02-08 Dana Farber Cancer Institute Intercellular adhesion molecules, and their binding ligands
WO1990010652A1 (fr) * 1989-03-09 1990-09-20 Dana Farber Cancer Institute Procede de traitement d'infections virales a l'aide de lfa-1
WO1990015076A2 (fr) * 1989-06-02 1990-12-13 The Johns Hopkins University School Of Medicine ANTICORPS MONOCLONAUX CONTRE LA CHAINE β DE RECEPTEURS D'ADHESION DE LEUCOCYTES, PROCEDE DE PRODUCTION DE CES ANTICORPS ET UTILISATION
EP0512301A1 (fr) * 1991-05-03 1992-11-11 Boehringer Ingelheim Pharmaceuticals Inc. Procédé pour détecter des inflammations
WO1993006864A1 (fr) * 1991-10-01 1993-04-15 The General Hospital Corporation Prevention du rejet d'une allogreffe a l'aide d'anticorps contre des molecules d'adhesion
WO1994004188A1 (fr) * 1992-08-21 1994-03-03 Genentech, Inc. Procede pour traiter une affection ayant pour origine l'antigene 1 associe a la fonction lymphocytaire
FR2700471A1 (fr) * 1993-01-21 1994-07-22 Pasteur Merieux Serums Vacc Utilisation d'anticorps monoclonaux anti-LFA-1 pour la préparation d'un médicament destiné à prévenir le rejet des greffes d'organes solides et médicaments obtenus.
WO1995028170A1 (fr) * 1994-04-19 1995-10-26 The University Of Kansas Peptides a chaine courte a base d'icam-1/lfa-1 et leur methode d'utilisation
US5747035A (en) * 1995-04-14 1998-05-05 Genentech, Inc. Polypeptides with increased half-life for use in treating disorders involving the LFA-1 receptor
WO1998023761A1 (fr) * 1996-11-27 1998-06-04 Genentech, Inc. ANTICORPS ANTI-CD11a HUMANISES
US6037454A (en) * 1996-11-27 2000-03-14 Genentech, Inc. Humanized anti-CD11a antibodies
WO2000059880A1 (fr) * 1999-04-02 2000-10-12 Abbott Laboratories Composes inhibiteur de l'adhesion cellulaire, anti-inflammatoires et immunosuppresseurs

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
HOWELL C D ET AL: "ROLE OF INTERCELLULAR ADHESION MOLECULE-1 AND LYMPHOCYTE FUNCTION-ASSOCIATED ANTIGEN-1 DURING NONSUPPURATIVE DESTRUCTIVE CHOLANGITIS IN A MOUSE GRAFT-VERSUS-HOST DISEASE MODEL", HEPATOLOGY,WILLIAMS AND WILKINS, BALTIMORE, MD,US, vol. 29, no. 3, March 1999 (1999-03-01), pages 766 - 776, XP000996023, ISSN: 0270-9139 *
NAKANO ET AL: "Efficacy of intraportal injection of ICAM-1 monoclonal antibody against liver cell injury following warm ischemia in the rat", THE AMERICAN JOURNAL OF SURGERY, vol. 170, 1995, XP000995588 *
SAKAMOTO ET AL: "Intercellular Adhesion Molecule-1 and CD18 are involved in Neutrophil Adhesion and its cytotoxicity to cultured sinusoidal endothelial cells in rats", HEPATOLOGY, vol. 26, no. 3, 1997, pages 658 - 663, XP000996027 *
TANAKA ET AL: "Inhibition of inflammatory liver injury by a monoclonal antibody against lymphocyte function-associated antigen-1", JOURNAL OF IMMUNOLOGY, vol. 151, no. 9, 1993, pages 5088 - 5095, XP002078020, ISSN: 0022-1767 *

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