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WO1998039026A2 - Procedes d'administration therapeutiques de composes anti-cd40l - Google Patents

Procedes d'administration therapeutiques de composes anti-cd40l Download PDF

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Publication number
WO1998039026A2
WO1998039026A2 PCT/US1997/024133 US9724133W WO9839026A2 WO 1998039026 A2 WO1998039026 A2 WO 1998039026A2 US 9724133 W US9724133 W US 9724133W WO 9839026 A2 WO9839026 A2 WO 9839026A2
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WIPO (PCT)
Prior art keywords
day
patient
weeks
cd40l
effective amount
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PCT/US1997/024133
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English (en)
Inventor
Susan L. Kalled
David W. Thomas
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Biogen, Inc.
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Publication date
Application filed by Biogen, Inc. filed Critical Biogen, Inc.
Priority to AU56233/98A priority Critical patent/AU5623398A/en
Publication of WO1998039026A2 publication Critical patent/WO1998039026A2/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
    • C07K16/2875—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 NGF/TNF superfamily, e.g. CD70, CD95L, CD153, CD154
    • 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 invention relates to regimens for therapeutically administering anti-CD40L compounds to patients.
  • CD40L CD40 ligand
  • the inventors have demonstrated that administering an anti-CD40L compound at intervals of three weeks or more is effective in treatment of disorders with antibody-related pathogenesis.
  • the invention provides a method of treating a patient with an antibody-related disease, which includes administering a therapeutically effective amount of an anti-CD40L compound to the patient on a first day and again on a second day, with at least about 3 weeks between the first day and the second day. Similar amounts of an anti-CD40L compound may subsequently be given to the patient, with at least about 3 weeks between successive doses. In one embodiment, the interval between doses is at least about 4 weeks.
  • a method for treating a patient with an antibody-related disease comprising administering a therapeutically effective amount of an anti-CD40L compound to the patient for a first therapeutic period at intervals of less than about 3 weeks, then administering a therapeutically effective amount of an anti-CD40L compound to the patient for a second therapeutic period at intervals of at least about 3 weeks or at least about 4 weeks.
  • a further application for the above-described administration regimens is for treating a patient with a chronic immune system disorder, such as psoriasis, allergic conditions, arthritis or multiple sclerosis.
  • a chronic immune system disorder such as psoriasis, allergic conditions, arthritis or multiple sclerosis.
  • the methods of the invention are useful for treating a chronic autoimmune disease, such as systemic lupus erythematosis, myasthenia gravis, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, or anti-phospholipid syndrome.
  • a chronic autoimmune disease such as systemic lupus erythematosis, myasthenia gravis, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, or anti-phospholipid syndrome.
  • Yet another aspect of the invention provides a method of inhibiting rejection of transplanted tissue within a patient; this method includes administering a therapeutically effective amount of an anti-CD40L compound to the patient on a first day and again on a second day, with at least about 3 weeks between the first day and the second day.
  • the compound may be given subsequently at varying intervals, but in one embodiment, it is given subsequent to the second dose at intervals of at least about 3 weeks or at least about 4 weeks.
  • transplants of skin, kidney, liver, heart, bone marrow, or eye tissue are particularly intended for inclusion.
  • the graft may be an allograft or a xenograft.
  • an anti-CD40L compound is administered to the patient for a first therapeutic period at intervals of less than about 3 weeks, then administering for a second therapeutic period at intervals of at least about 3 weeks.
  • the anti-CD40L compound may be any compound that binds to CD40L on the surface of CD40L-expressing cells, such as activated T cells.
  • the compound is an anti-CD40L antibody, preferably a monoclonal antibody.
  • the monoclonal antibody may be 5c8 (ATCC Accession No. HB 10916).
  • the anti-CD40L compound may be formulated in a therapeutic composition which includes a therapeutically-effective amount of the anti-CD40L compound and a pharmaceutically acceptable carrier.
  • the therapeutic composition may also include a second therapeutically effective compound.
  • Fig. 1 is a chart of the changes with time in several measured characteristics of blood and urine from control and treated (SWR X NZB) Fi mice in Experiment II.
  • the anti-CD40L mAb MR1 at 500 ug/animal i.p., was administered once when the mice were 4 months old, again at 7 months of age, again at 9 months, and then at monthly intervals.
  • Each of the upper five rows of the chart, marked AR-BN contains data from a single control animal, and each of the lower six rows, marked CL-CR , contains data from a single treated animal. This study began when the animals were 4 months of age, in February 1996.
  • the vertical double lines separate 4 groups of data, each data group providing the measurements for urine and blood samples collected on the date listed above the data.
  • Proteinuria (PU) levels are indicated from trace to level 4.
  • Level 1 correlates with urine albumin of 30 mg/dl albumin, level 2 with 100 mg/dl, level 3 with 300 mg/dl, and level 4 with over 2000 mg/dl.
  • Levels of anti-MRl antibodies (provided in column labeled "anti-MRl"), anti-ssDNA antibodies and anti-dsDNA antibodies are given in ⁇ g/ml blood. Where appropriate, values are given as mean and standard deviation of several samples, in the form mean(S.D.). A dash indicates that a sample was not collected, typically because the animal had died. ND refers to "not done.”
  • Fig. 2 is a chart of proteinuria measurements of the Experiment II animals over time. The first column provides the animal numbers as in Fig. 1. The columns are headed with the dates of sample collection. NC means "not collected.”
  • Fig. 3 is a chart of blood and urine characteristics with time in Experiment V control and untreated mice, which started treatment at 4.5 months of age.
  • MR1 was administered to treated animals once at 500 ug/animal i.p. when the mice were 4.5 months old, and then as monthly injections of 500 ug, i.p.
  • This study began when the animals were 4.5 months of age, in May 1996. Other descriptions of the figure are the same as those of Fig. 1.
  • Fig. 4 is a chart of proteinuria measurements of the Experiment V animals over time. Animal numbers are as described for Fig. 3. Other descriptions of the figure are the same as those of Fig. 2.
  • Fig. 5 is a chart of chart of blood and urine characteristics with time in Experiment VII control and untreated mice, which started treatment at 5.5 months of age.
  • MR1 was administered to treated animals once weekly at 500 ug/animal i.p. for six weeks, followed by monthly injections of 500 ug, i.p.
  • This study began when the animals were 5.5 months of age, in June 1996. Other descriptions of the figure are the same as those of Fig. 1.
  • Fig. 6 is a chart of proteinuria measurements of the Experiment VII animals over time.
  • Each of the upper seven rows of the chart, marked AR-BN contains data from a single control animal, and each of the lower seven rows, marked CR-DN , contains data from a single treated animal.
  • Fig. 7 is a chart of blood and urine characteristics with time in Experiment X control and untreated mice, which started treatment at 5.5 months of age.
  • MR1 was administered to treated animals once weekly at 500 ug/animal i.p. for four weeks, followed by monthly injections of 200 ug, i.p.
  • Each of the upper eight rows of the chart, marked AR-BLR, contains data from a single control animal
  • each of the lower eight rows, marked CR-DLR contains data from a single treated animal. This study began when the animals were 5.5 months of age, in October 1996. Other descriptions of the figure are the same as those of Fig. 1.
  • Fig. 8 is a chart of proteinuria measurements of the Experiment X animals over time. The first column provides the animal numbers as in Fig. 7. Other descriptions of the figure are the same as those of Fig. 2.
  • Fig. 9 is a chart of blood and urine characteristics with time in Experiment VI control and untreated mice, which started treatment at 7 months of age.
  • MR1 was administered to 4 treated animals once weekly at 500 ug/animal i.p. for six weeks, followed by monthly injections of 500 ug, i.p.
  • Each of the lower four rows, marked DN-EN contains data from a single treated animal.
  • Fig. 10 This study began when the animals were 7 months of age, in June 1996. Other descriptions of the figure are the same as those of Fig. 1.
  • Fig. 10 is a chart of proteinuria measurements of the Experiment VI animals over time.
  • Other descriptions of the figure are the same as those of Fig. 2.
  • the method of the invention involves treating, preventing, reversing or stabilizing a patient with an antibody-related disease, by treating the patient with an anti-CD40L compound at intervals of more than two weeks.
  • the compound blocks the interaction of CD40L on T cells with CD40 on B cells, which is thought to inhibit the production of pathologic antibodies responsible for many of the pathologic effects of various autoimmune diseases and chronic immune disorders.
  • Therapeutic compounds useful for the methods of the invention include any compound that blocks the interaction of CD40 on B cells with CD40L expressed on the surface of activated T cells.
  • Anti-CD40L compounds specifically contemplated include polyclonal antibodies and monoclonal antibodies (mAbs), as well as antibody derivatives such as chimeric molecules, humanized molecules, molecules with reduced effector functions, bispecific molecules, and conjugates of antibodies.
  • the antibody is 5c8, as described in U.S. Patent 5,474,771, the specification of which is hereby incorporated by reference.
  • antibodies against 5c8 antigen include antibodies ImxM90, ImxM91 and ImxM92 (obtained from Immunex), an anti-CD40L mAb commercially available from Ancell (clone 24-31, catalog # 353-020, Bayport, MN), and an anti-CD40L mAb commercially available from Genzyme (Cambridge, MA, catalog # 80-3703-01). Also commercially available is an anti-CD40L mAb from PharMingen (San Diego, catalog #33580D). Numerous additional anti-CD40L antibodies have been produced and characterized (see, e.g., WO 96/23071 of Bristol-Myers Squibb, the specification of which is hereby incorporated by reference).
  • the invention also includes anti-CD40L molecules of other types, such as complete Fab fragments, F(ab' ⁇ compounds, V H regions, Fy regions, single chain antibodies (see, e.g., WO 96/23071), polypeptides, fusion constructs of polypeptides, fusions of CD40 (such as CD40Ig, as in Hollenbaugh et al., J. Immunol. Meth. 188: 1-7, 1995, which is hereby incorporated by reference), and small molecule compounds such as small semi-peptidic compounds or non-peptide compounds, all capable of blocking the CD40-CD40L interaction.
  • anti-CD40L molecules of other types such as complete Fab fragments, F(ab' ⁇ compounds, V H regions, Fy regions, single chain antibodies (see, e.g., WO 96/23071), polypeptides, fusion constructs of polypeptides, fusions of CD40 (such as CD40Ig, as in Hollenbaugh et al
  • chimeric antibodies may be constructed, in which the antigen binding domain from an animal antibody is linked to a human constant domain (an antibody derived initially from a nonhuman mammal in which recombinant DNA technology has been used to replace all or part of the hinge and constant regions of the heavy chain and/or the constant region of the light chain, with corresponding regions from a human immunoglobin light chain or heavy chain) (see, e.g., Cabilly et al., United States patent 4,816,567; Morrison et al., Proc. Natl. Acad. Sci. 81: 6851-55, 1984). Chimeric antibodies reduce the immunogenic responses elicited by animal antibodies when used in human clinical treatments.
  • a human constant domain an antibody derived initially from a nonhuman mammal in which recombinant DNA technology has been used to replace all or part of the hinge and constant regions of the heavy chain and/or the constant region of the light chain, with corresponding regions from a human immunoglobin light chain or heavy chain
  • Humanized antibodies are antibodies initially derived from a nonhuman mammal in which recombinant DNA technology has been used to substitute some or all of the amino acids not required for antigen binding with amino acids from corresponding regions of a human immunoglobin light or heavy chain (chimeras comprising mostly human IgG sequences into which the regions responsible for specific antigen-binding have been inserted)(see, e.g., PCT patent application WO 94/04679). Animals are immunized with the desired antigen, the corresponding antibodies are isolated and the portion of the variable region sequences responsible for specific antigen binding are removed.
  • the animal-derived antigen binding regions are then cloned into the appropriate position of the human antibody genes in which the antigen binding regions have been deleted.
  • Humanized antibodies minimize the use of heterologous (inter- species) sequences in human antibodies and are less likely to elicit immune responses in the treated subject.
  • Also useful in the methods and compositions of this invention are primate or primatized antibodies.
  • Antibody fragments and univalent antibodies may also be used in the methods and compositions of this invention.
  • Univalent antibodies comprise a heavy chain/light chain dimer bound to the Fc (or stem) region of a second heavy chain.
  • Fab region refers to those portions of the chains which are roughly equivalent, or analogous, to the sequences which comprise the Y branch portions of the heavy chain and to the light chain in its entirety, and which collectively (in aggregates) have been shown to exhibit antibody activity.
  • a Fab protein includes aggregates of one heavy and one light chain (commonly known as Fab'), as well as tetramers which correspond to the two branch segments of the antibody Y, (commonly known as F(ab) 2 ), whether any of the above are covalently or non-covalently aggregated, so long as the aggregation is capable of selectively reacting with a particular antigen or antigen family.
  • standard recombinant DNA techniques can be used to alter the binding affinities of recombinant antibodies with their antigens by altering amino acid residues in the vicinity of the antigen binding sites.
  • the antigen binding affinity of a humanized antibody may be increased by mutagenesis based on molecular modeling (Queen et al., Proc. Natl. Acad. Sci. 86: 10029-33, 1989; PCT patent application WO 94/04679). It may be desirable to increase or to decrease the affinity of the antibodies for CD40L, depending on the targeted tissue type or the particular treatment schedule envisioned. This may be done utilizing phage display technology (see, e.g., Winter et al., Ann. Rev. Immunol.
  • patient is taken to mean any mammalian patient to which anti-CD40L compounds may be administered.
  • Patients specifically intended for treatment with the method of the invention include humans, as well as nonhuman primates, sheep, horses, cattle, goats, pigs, dogs, cats, rabbits, guinea pigs, hamsters, gerbils, rats and mice, as well as the organs, tumors, and cells derived or originating from these hosts.
  • the subjects for which the methods of the invention are intended have disease related to antibody production.
  • the compounds of the invention may be administered in any manner which is medically acceptable. This may include injections, by parenteral routes such as intravenous, intravascular, intraarterial, subcutaneous, intramuscular, intratumor, intraperitoneal, intraventricular, intraepidural, or others as well as oral, nasal, ophthalmic, rectal, or topical. Sustained release administration is also specifically included in the invention, by such means as depot injections. Some forms of anti-CD40L compounds may be suitable for oral administration, and could be formulated as suspensions or pills.
  • Dosages and Frequency of Treatment The amount of and frequency of dosing for any particular compound to be administered to a patient for a given immune complex disease is a judgment made by the patient's physician, based on a number of factors.
  • the general dosage is established by preclinical and clinical trials, which involve extensive experiments to determine the beneficial and deleterious effects on the patient of different dosages of the compound. Even after such recommendations are made, the physician will often vary these dosages for different patients based on a variety of considerations, such as a patient's age, medical status, weight, sex, and concurrent treatment with other pharmaceuticals. Determining the optimal dosage for each anti-CD40L compound used to treat lupus nephritis is a routine matter for those of skill in the pharmaceutical and medical arts.
  • Various regimens may be used for treatment of lupus or other immune complex diseases according to this invention.
  • the frequency of dosing would be determined by the attending physician, and might include periods of greater dosing frequency, such as at daily or weekly intervals, alternating with periods of less frequent dosing, such as at monthly or longer intervals.
  • dosing considerations for an anti-CD40L compound the following examples of administration strategies are given for an anti-CD40L mAb.
  • the dosing amounts could easily be adjusted for other types of anti-CD40L compounds.
  • single dosages of between about 0.05 and about 50 mg/kg patient body weight are contemplated, with dosages most frequently in the 1-20 mg/kg range.
  • an effective dose of antibodies ranges from about 1 mg/kg body weight to about 20 mg/kg body weight, administered daily for a period of about 1 to 5 days, preferably by bolus intravenous administration.
  • the same dosage and dosing schedule may be used in the load phase of a load-maintenance regimen, with the maintenance phase involving intravenous or intramuscular administration of antibodies in a range of about 0.1 mg/kg body weight to about 20 mg/kg body weight, for a treatment period of anywhere from weekly to 3 month intervals.
  • Chronic treatment may also be carried out by a maintenance regimen, in which antibodies are administered by intravenous or intramuscular route, in a range of about 0.1 mg kg body weight to about 20 mg/kg body weight, with interdose intervals being anywhere between about 1 week and about to 3 months.
  • chronic treatment may be effected by an intermittent bolus intravenous regimen, in which between about 1.0 mg/kg body weight and about 100 mg/kg body weight of antibodies are administered, with the interval between successive treatments being from 1 to 6 months.
  • administration may also be by oral, pulmonary, nasal or subcutaneous routes.
  • therapy is commenced with low doses of antibodies.
  • an initial dose of antibodies is administered to the patient by, for example, injection or infusion.
  • That initial dose should contain between about 1.0 mg and 30 mg of antibodies per day for a 70 kg patient.
  • dosages may be administered on successive days, every two to six days, once a week, every two to four weeks or once a month, until a desired suppression of disease symptoms is observed.
  • other dosage regimens are also useful.
  • treatment may cease. Patients may, however, require intermittent treatment on a long term basis upon recurrence of disease symptoms.
  • the effectiveness of the antibodies may be increased by administration serially or in combination with conventional anti-lupus therapeutic agents or drugs such as, for example, salicylates, corticosteroids or immunosuppressants.
  • the antibodies may be conjugated to a conventional agent. This advantageously permits the administration of the conventional agent in an amount less than the conventional dosage, for example, less than about 50% of the conventional dosage, when the agent is administered as monotherapy. Accordingly, the occurrence of many side effects associated with that agent might be avoided.
  • Combination therapies according to this invention for treatment of lupus include the use of anti-CD40L antibodies together with agents targeted at B cells, such as anti-CD 19, anti- CD28 or anti-CD20 antibody (unconjugated or radiolabeled), IL-14 antagonists, LJP394 (LaJolla Pharmaceuticals receptor blocker), IR-1116 (Takeda small molecule) and anti-Ig idiotype monoclonal antibodies.
  • agents targeted at B cells such as anti-CD 19, anti- CD28 or anti-CD20 antibody (unconjugated or radiolabeled), IL-14 antagonists, LJP394 (LaJolla Pharmaceuticals receptor blocker), IR-1116 (Takeda small molecule) and anti-Ig idiotype monoclonal antibodies.
  • the combinations may include T cell/B cell targeted agents, such as CTLA4Ig, IL-2 antagonists, EL-4 antagonists, IL-6 antagonists, receptor antagonists, anti-B7 monoclonal antibodies, TNF, LFAl/ICAM antagonists, VLA4/VCAM antagonists, brequinar and IL-2 toxin conjugates (e.g., DAB), prednisone, cyclophosphamide, and other immunosuppressants.
  • T cell targeted agents such as CD4 antagonists, CD2 antagonists and IL-12.
  • Combination therapies for treatment of a patient with a non-lupus immune complex disease might involve administration of an anti-CD40L compound as well as an agent which would typically be administered for the particular immune complex disease in question.
  • a maintenance dose of anti- CD40L antibodies is administered, if necessary. Subsequently, the dosage or the frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained. When the symptoms have been alleviated to the desired level, treatment might cease. In other instances, as determined by a patient's physician, occasional treatment might be administered, for example at intervals of four weeks or more. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
  • An anti-CD40L compound used in the methods of the invention is administered in a pharmaceutically-effective amount, which is an amount which produces a medically beneficial effect on a patient with an antibody-related disease, an immune-associated disorder, or a patient with a transplant or a transgene for which suppression of rejection is desirable.
  • Medically beneficial effects would include preventing deterioration or causing improvement in the patient's medical condition.
  • an organ that is often damaged by pathologic antibodies is the kidney in SLE patients.
  • renal function and health may be monitored with one or more laboratory tests which measure the concentrations of relevant substances in blood or urine, other urine characteristics, or the rate of clearance of various substances from the blood into the urine.
  • the parameters measured by these tests can be used by a physician to assess renal function or damage.
  • parameters include the blood concentration of urea, creatinine or protein; the urine concentration of protein or of various blood cells such as erythrocytes or leucocytes; urine specific gravity; amount of urine; the clearance rates of inulin, creatinine, urea or p-aminohippuric acid; and the presence of hypertension or edema.
  • Medically beneficial effects would also include the diminution of autoantibodies, such as anti-dsDNA antibodies in the serum of lupus patients.
  • An anti-CD40L compound of the invention is administered to a patient in a pharmaceutically acceptable composition, which may include a pharmaceutically-acceptable carrier.
  • Such a carrier is relatively non-toxic and innocuous to a patient at concentrations consistent with effective activity of the anti-CD40L compound or other active ingredients, so that any side effects ascribable to the carrier do not vitiate the beneficial effects of the active ingredients of the composition.
  • the composition may include other compatible substances; compatible, as used herein, means that the components of the pharmaceutical composition are capable of being commingled with the anti-CD40L compound, and with each other, in a manner such that there is no interaction which would substantially reduce the therapeutic efficacy of the pharmaceutical.
  • Nasal spray formulations comprise purified aqueous solutions of the active compound with preservative agents and isotonic agents. Such formulations are preferably adjusted to a pH and isotonic state compatible with the nasal mucous membranes.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets, pills or lozenges, each containing a predetermined amount of the potentiating anti-CD40L compound as a powder or granules; as liposomes; or as a suspension in an aqueous liquor or non-aqueous liquid such as a syrup, an elixir, an emulsion or a draught.
  • Use of Anti-CD40L Compounds Administered at Wide Intervals to Treat Lupus Nephritis in Nonhuman Subjects
  • SLE Systemic lupus erythematosus
  • Proteinuria levels are indicated from trace to level 4.
  • Level 1 correlates with urine albumin of 30 mg/dl albumin, level 2 with 100 mg/dl, level 3 with 300 mg/dl, and level 4 with over 2000 mg/dl.
  • a level of 2 was considered to indicate moderate nephritis, with 2.5 and greater indicating severe nephritis.
  • mice If untreated, or if treated with the nonspecific hamster immunoglobulins administered to control animals, the mice normally die by 12 months of age. While the onset of proteinuria in untreated animals is variable, most have mild to moderate proteinuria by 3 months of age; the proteinuria tends to increase with age. By about 5 months of age, all control animals typically have detectable anti-dsDNA antibodies, and most have detectable anti-ssDNA antibodies; this contrasts with the complete lack of detectable levels of these antibodies in normal mice, such as the female SWR parents of the (SWR X NZB) Fi mice.
  • MR1 treatment was initiated when the mice were 4 months of age.
  • MR1 was administered to treated animals once at 500 ug/animal i.p. when the mice were 4 months old, once at 7 months of age, and once at 9 months followed by once-monthly injections.
  • 4 months of treatment 4 of the 5 control animals had died, but four of the six treated animals were yet alive.
  • nephritis (2+ proteinuria) from ages 8 to 13 months, which has decreased to only trace levels of proteinuria for the last two months. This is the first demonstration of a functional reversal of nephritis in a mouse of this strain.
  • MR1 treatment was initiated when the mice were 4.5 months of age. MR1 was administered to treated animals once at 500 ug/animal i.p. when the mice were 4.5 months old, and then as monthly injections of 500 ug, i.p. After 4.5 months, 6 of the 7 control animals had died, but six of the seven treated animals survived. After 8 months of treatment, all controls were dead, but only three of the seven treated mice had died. As shown in Fig. 4, four of the seven MR 1 -treated animals had their nephritis reversed as shown by sustained lowered proteinuria levels. These four animals are still alive at age 12.5 months.
  • MR1 treatment was initiated when the mice were 5.5 months of age. MR1 at 500 ⁇ g/animal i.p. was administered to treated animals once weekly for six weeks, followed by monthly injections. After 5 months of treatment, at age 10.5 months, 6 of the 7 control animals had died; all of the 7 treated animals are still alive at age 12 months. The following values were measured in the animals which still survived at 8.5 months, after 3.5 months of treatment:
  • MRl treatment was initiated when the mice were seven months of age. MRl was administered to 4 treated animals once weekly at 500 ug/animal i.p. for six weeks, followed by monthly injections of 500 ug, i.p. By age 10 months, all 4 control animals had died. While 2 of the treated mice died at age 11 months, and a third at 13 months, one of the four treated animals remains alive currently at 14 months of age, after 7 months of treatment. The surviving treated animal (number VI:ER) currently has level 1 proteinuria, and detectable anti- dsDNA and anti-ssDNA antibodies.

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Abstract

On peut traiter efficacement des troubles de type immunologique en administrant des composés anti-CD40L à des intervalles de trois semaines ou davantage.
PCT/US1997/024133 1997-03-07 1997-12-31 Procedes d'administration therapeutiques de composes anti-cd40l WO1998039026A2 (fr)

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EP1067954A1 (fr) * 1998-04-03 2001-01-17 The Trustees Of Dartmouth College Utilisation d'anticorps anti-gp39 pour traiter et/ou faire regresser un lupus et une maladie renale associee
WO2001024823A1 (fr) * 1999-10-04 2001-04-12 Chiron Corporation Antagonistes de cd40 permettant de traiter le psoriasis
WO2001034194A1 (fr) * 1999-11-08 2001-05-17 Idec Pharmaceuticals Corporation Traitement de tumeurs malignes des cellules b a l'aide d'anticorps anti-cd40l associes a des anticorps anti-cd20, et/ou chimiotherapie et radiotherapie
WO2001066141A1 (fr) * 2000-03-06 2001-09-13 Eisai Co., Ltd. Agents therapeutiques et prophylactiques diriges contre le syndrome des antiphospholipides
WO2001087310A1 (fr) * 2000-05-18 2001-11-22 Biotransplant, Inc. Procede de reduction de la reponse anticorps contre des xenogreffes
WO2002022212A3 (fr) * 2000-09-18 2003-02-27 Idec Pharma Corp Polytherapie pour le traitement de maladies auto-immunes utilisant une combinaison d'anticorps d'immunoregulation/de depletion de cellules b
US6534277B1 (en) 2000-04-14 2003-03-18 Millennium Pharmaceuticals, Inc. Method for identifying a compound to be tested for an ability to reduce immune rejection by determining Stat4 and Stat6 proteins
WO2002018445A3 (fr) * 2000-09-01 2003-04-17 Biogen Inc Structure co-cristalline de l'anticorps monoclonal 5c8 et cd154, et utilisation de cette structure dans la mise au point de medicaments
WO2004047826A1 (fr) * 2002-11-21 2004-06-10 Genzyme Corporation Combinaison de derives de diamide et agents immunosuppresseurs pour l'induction de la tolerance immunitaire
EP1839674A1 (fr) * 1999-10-04 2007-10-03 Novartis Vaccines and Diagnostics, Inc. Antagoniste CD40 pour le traitement du psoriasis
US7445781B2 (en) 1992-02-14 2008-11-04 Trustees Of Dartmouth College Anti-CD40CR MR1 antibody
US7687530B2 (en) 2002-11-21 2010-03-30 Genzyme Corporation Inhibition of chronic tissue transplant rejection
US8518999B2 (en) 2000-05-12 2013-08-27 Genzyme Corporation Modulators of TNF-αsignaling

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