WO2001037870A1 - Traitement de maladies auto-immunes par une proteine liant le cd40 agonistique - Google Patents

Traitement de maladies auto-immunes par une proteine liant le cd40 agonistique Download PDF

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WO2001037870A1
WO2001037870A1 PCT/GB2000/004511 GB0004511W WO0137870A1 WO 2001037870 A1 WO2001037870 A1 WO 2001037870A1 GB 0004511 W GB0004511 W GB 0004511W WO 0137870 A1 WO0137870 A1 WO 0137870A1
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cell
agonistic
antibody
mab
mice
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PCT/GB2000/004511
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Marco Londei
Claudia Mauri
Leonaredus Theodorus Mars
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Kennedy Rheumatology Inst
Claudia Mauri
Leonaredus Theodorus Mars
Marco Londei
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Priority to JP2001539484A priority Critical patent/JP2003514873A/ja
Priority to AU15376/01A priority patent/AU1537601A/en
Priority to EP00977741A priority patent/EP1146902A1/fr
Publication of WO2001037870A1 publication Critical patent/WO2001037870A1/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
    • C07K16/2878—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-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/564—Immunoassay; Biospecific binding assay; Materials therefor for pre-existing immune complex or autoimmune disease, i.e. systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, rheumatoid factors or complement components C1-C9
    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • G01N2333/70596—Molecules with a "CD"-designation not provided for elsewhere in G01N2333/705

Definitions

  • the invention relates to the treatment of autoimmune diseases such as rheumatoid arthritis, with CD40 binding proteins such as anti-CD40 antibodies.
  • T lymphocytes drive immuno-mediated pathologies, such as autoimmune diseases and transplant rejection, consequentially much effort has been focused in recent years on devising successful strategies able to treat these pathologies by controlling the expansion of pathogenic T cells.
  • the increasing knowledge of the basic mechanisms governing T cell activation has allowed the emergence of a novel generation of compounds able to modulate T cell function and to induce a state of immunological tolerance permitting transplant acceptance and amelioration of autoimmune diseases.
  • the abogration of T cell co-stimulation by blocking CD28 engagement one of the essential second signals involved in T cell activation 1 , with CTLA4-Ig has been successful in many models 2"4 .
  • CTLA4Ig has been recently shown to provide very promising results when used in long term bone marrow allograft acceptance 5 .
  • CD40L Another surface molecule CD 154, formerly called CD40L, has been extensively targeted for immunotherapeutic purposes due to the key role that this molecule plays in modulating immune responses principally via the engagement of CD40 on B lymphocytes on dendritic cells (DC) 6 .
  • DC dendritic cells
  • Many studies have indicated the great therapeutic potential of targeting CD 154.
  • anti-CD 154 monoclonal antibody (mAb) prevents the induction of autoimmune disorders in many animal models 7"10 , and also ameliorates established diseases (R-EAE)".
  • agonistic anti-CD40 mAb can have a key role in promoting protective immune responses against B cell lymphomas 14 , as well as promoting antigen specific immunotherapy for cancer 15 16 .
  • the inventors have also identified the surprising ability of agonistic anti-C40 mAb to control arthritis when administered during disease induction.
  • agonistic anti-CD40 mAb Puzzled by the apparent contrast between the widely described in vivo adjuvant action of agonistic anti-CD40 mAb and the inventor's preliminary findings, the inventors have explored the therapeutic potential and the possible mechanisms of action of agonistic anti-CD40 mAb in a model for CCIA (Chronic Collagen Induced Arthritis) 17 . They have reported that agonistic anti-CD40 mAb have a remarkable therapeutic effect on the development of arthritis, thus indicating their potential clinical use to control chronic inflammatory conditions of autoimmune origin.
  • First aspect of the invention provides use of an agonistic CD40 binding proteins, such as anti-CD40 antibody, in the manufacture of a medicament to treat an autoimmune disease.
  • the CD40 binding protein may also be a CD40 ligand.
  • ligands are known in the art and are shown, for example, in WO 96/26735. Such ligands are expected to behave in a similar manner to the agonistic anti-CD40 antibodies.
  • Agonistic anti-CD40 antibodies are able to induce activation of CD40. For example, they mimic the action of natural CD40 ligands by activating CD40.
  • pharmaceutically effective dose means an amount of anti-CD40 antibody sufficient to ameriolate the autoimmune diseased state in an animal or patient.
  • the dose required can be assessed using routine clinical trials.
  • the typical dose of antibody will be in the range of about l ⁇ g ⁇ kg ⁇ day to 10 mg ⁇ kg ⁇ day of patient or animal body weight. Preferably, this dose is at least 0.01 mg ⁇ kg ⁇ day.
  • the animal or patient is a mammal, especially a human.
  • the anti-CD40 antibody may be introduced into a patient by any methods known in the art.
  • the antibody may be delivered intramuscularly, intravenously or parenterally.
  • the anti-CD40 antibody may be a polyclonal antibody or a monoclonal antibody. Techniques for the production of polyclonal antibodies or monoclonal antibodies are well known in the art.
  • the term "antibody” refers to intact molecules as well as fragments thereof, such as Fa,F(ab') 2 , and Fv which are capable of binding the CD40 protein.
  • Intact CD40 polypeptide or fragments of CD40 may be used as the immunising antigen.
  • a natural ligand for CD40 such as CD 154 (cD40L) may be used.
  • the anti-CD40 antibodies may be humanized, that is how amino acids replaced in the non-antigen binding regions in order to more closely resemble a human antibody, whilst still remaining the original binding ability.
  • Methods for humanizing antibodies are well known in the art.
  • the antibody is a monoclonal antibody with functional characteristics when implemented in man of FGK45 or 3 ⁇ 23, or soluble CD 154.
  • the autoimmune disease is preferably selected from rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus and diabetes myllitus.
  • Antibodies are preferably administered after disease onset. That is, the antibody is used to treat the diseased state, rather than helping to prevent the disease.
  • a second aspect of the invention provides a method of studying an autoimmune disease comprising administering a pharmaceutically effective dose of an agonistic anti-CD40 antibody to an animal, sample of tissue or cell and observing a physiological change to the animal, sample of tissue or cell. Preferably such a method is carried out in vitro on an isolated cell, cultured cell or an isolated sample of tissue. This allows the effect of anti-CD40 antibodies on the cells to be studied.
  • the cell, tissue, or antibody is diseased, that is it has characteristics of an autoimmune disease.
  • the antibodies and autoimmune diseases may be as defined above.
  • Another aspect of the invention provides an anti-CD40 antibody for use to treat an autoimmune disease.
  • the anti-CD40 antibody and autoimmune disease may be as defined above.
  • an anti-CD40 antibody in combination with a pharmaceutically effective carrier.
  • Pharmaceutically effective carriers for antibodies are well known in the art.
  • Figure 2
  • Agonistic anti-CD40 mAb treatment induces B cell expansion.
  • Sex-matched TcR- ⁇ Tg mice 8-12 weeks old, were immunised with 200 ⁇ g/ml. of bovine collagen type II in CFA. Mice were treated from the day of immunisation for 8 days with daily injections of 300 ⁇ l PBS (a), 300 ⁇ g AFRC-MAC-1 (b), 300 ⁇ g 3 ⁇ 23 (c), 300 ⁇ g FGK45 (d). Spleens removed from the animals were snap-frozen 8 days after immunisation, 5 ⁇ m sections were stained with anti-B220 mAb. Isotype matched control mAb gave negative staining.
  • Therapeutic administration of agonistic anti-CD40 mAb preferentially induces CII specific IgGl over IgG2a immunoglobulin isotypes.
  • mice were treated daily from disease onset with FGK45 ( ), 3 ⁇ 23 (D), AFRC-MAC-1 or PBS, the latter two combined as control (M), for a total of 10 days.
  • Peripheral blood serum was collected 12 days after disease onset.
  • CII specific IgG2a and IgGl titers were detected by ELISA. The results are represented as the mean fold increase of the CII specific IgG titer of FGK45 and 3 ⁇ 23 relative to the control CII specific IgG titer ⁇ SEM.
  • Agonistic anti-CD40 mAb therapy alters the cytokine profile of antigen specific activated T cells.
  • Results represent the mean cytokine expression of n independent splenocyte cultures obtained from individual mice ⁇ SEM (*p ⁇ 0.05, **p ⁇ 0.001).
  • Statistics in graphs d, e and f are relative to the values represented in graphs a, b and c respectively.
  • Figure 8 shows the effect of AFRC Mac-1 monoclonal antibodies and anti-CD40 antibodies on anti-CII Ig G2a and anti CII Ig Gl production.
  • Figure 9 shows the effect of anti-CD40 on IL-12 expression on pathogenic/arthritogenic splenocytes from mice in vivo.
  • TcR- ⁇ Tg SWR J mice TcR- ⁇ Tg was backcrossed into DBA/1 in order to derive the Chronic Collagen Induced Arthritis model 36 , subsequent transgenic offspring was consistently backcrossed against DBA/1.
  • the treatment antibodies used were FGK45, rat IgG anti-mouse CD40 37 (kindly provided by Dr A. Rolink, Basel Institute for Immunology); 3 ⁇ 23 (kindly provided by Dr D. Gray,
  • rat IgG2a anti-mouse CD40 38 rat IgG2a anti-mouse CD40 38 ; AFRC MAC-1 (isotype control), rat IgG2a anti-dog chlamydomonas cell wall glycoprotein (European Collection of Animal Cell Culture, Salisbury, UK).
  • the mAbs were purified from culture supernatants by affinity chromatography, using a staphylococcal protein G column (Bioprocessing, Durham, UK) and filter sterilised.
  • the mAbs used for FACS -analysis were against mouse CD3 FITC, mouse v ⁇ l2 TcR biotinylated (screening), mouse B220 PE, and streptavidin-PE, all obtained from Pharmingen (San Diego, CA). Finally, the primary antibodies used for immunocytochemistry were anti-mouse B220 biotinylated and an isotype control rat IgG2a biotinylated. both obtained from Pharmingen (San Diego, CA).
  • IL-2 JES6- 1A12/JES6-5H4 (Pharmingen, San Diego, CA); IL-4: idl l/BVD6-24G2 (ATCC and Pharmingen, San Diego, CA, respectively); IL-5: HB9897/HB 10647 and IFN- ⁇ (R4- 6A2/XG1.2), ATCC, courtesy of Dr J. Abrams at DNAX (Palo Alto, CA). Preparation of Collagen.
  • Bovine CII was purified and prepared as previously described Bovine CII was solubilized by stirring overnight at 4°C in 0.1 M acetic acid, to be used for immunisation, or 0.05 mM Tris-HCL, 0.2 M NaCl pH 7.4 for in vitro stimulation of splenocyte cultures (SPC).
  • TcR- ⁇ Tg mice were i.p. treated, from the day of CII in CFA immunisation, with either FGK45, 3 ⁇ 23, AFRC MAC-1 or with PBS, with 14 daily doses over a period of 18 days.
  • TcR- ⁇ Tg were treated i.p. with FGK45, 3 ⁇ 23, AFRC or with PBS from the day of disease onset with a total of 14 i.p. injections over 18 days.
  • the pre-immunisation treatment was performed by 5 daily i.p. injections with FGK45, 3 ⁇ 23 or AFRC MAC-1 initiated 5 days prior to CII in CFA immunization. All antibodies were administered at 300 ⁇ g/mouse. Histological evaluation.
  • Hind paws were removed post mortem and fixed in 10% (w/v) buffered formalin and decalcified in 5% EDTA. The paws were subsequently embedded in paraffin, sectioned and stained with haematoxylin and eosin or safranin O. Arthritic changes in the ankle, the metatarsophalangeal joints, the proximal interphalangeal and the distal interphalangeal joints were scored blindly as normal (unaffected), mild (mild synovial hyperplasia), moderate (pannus formation and limited erosion), or severe (extended bone and cartilage erosion with loss of joint architecture).
  • Spleen were teased apart to make a single cells suspension and red blood cells were depleted with a red cell lysis buffer (Sigma Aldrich, Dorset, UK), washed and cultured in RPM1 1640 containing 10% (v/v) heat-inactivated FCS, 100 U/ml. penicillin, 100 ⁇ g/ml. streptomycin, 2 x 10" 5 M 2-mercaptoethanol, and 20 mM L-glutamine. SP were cultured in 96-well plates (Nunc, Uxbridge, UK) at the density of 5 x 10 6 cells/ml. (200 ⁇ l/wells) in medium alone or with 50 ⁇ g/ml. of CII for 24 h. for IL-4 and IL-5 detection or for 72 hr. for IFN- ⁇ . Supematants were collected and analysed for cytokines were quantified by a sandwich ELISA as previously described .
  • Anti-CII antibodies were quantified as previously described . Briefly, microtiter plates
  • TcR- ⁇ Tg mice were treated from the day of immunisation with 8 daily intraperitoneal injections of the indicated mAbs at 300 ⁇ g/mouse.
  • Spleens were excised post mortem 8 days after immunisation, embedded in OCT compound (Raymond A. Lamb, London, UK) and 'snap-frozen' in liquid nitrogen/ isopentane bath. Sections were obtained of 5 ⁇ m and adhered to microscope slides (Merck Ltd, Leicester, UK). Wax-encircled sections were blocked with rat serum before being incubated for 1 hr. with the biotinylated primary antibodies followed by streptavidin labelled alkaline phosphatase (Vector, Burlingane, Ca). Enzyme localisation was visualised with the substrate fast-red according to the manufacturers' recommendations (DAKO, Carpinteria, Ca) and fixed in 2% formaldehyde for 20'. Finally, slides were washed in water and coverslipped with glycerol gelatin (Sigma Aldrich, Dorset, UK). Slides were washed at least 3 times in PBS at each step.
  • anti-CD40 mAb treated mice like the anti-CD4 mAb treated animals, showed a significant reduction in disease severity.
  • two groups of TcR- ⁇ Tg mice were treated, from the day of immunisation, with two different agonistic anti-CD40 mAbs (FGK45 or 3 ⁇ 23) which have been previously used by several groups for in vivo upregulation of immune responses 14 ' 16 ' 18 .
  • PBS were administrated 14 times over an 18 day period from the day of immunisation.
  • Figure 1 shows the suppressive effects of the anti-CD40 mAb treatment on the evolution of the most severe (onset of the disease 13-14 as opposed to the usual day 19-20) form of CCIA, which we have observed in 1 out of 3 independent experiments. Even when administered in these experimental conditions both agonistic anti-CD40 mAb exerted their ability to control onset and to significantly reduce the severity of disease when compared with the results obtained from the control treated group ( Figure 1 and Table 1).
  • B lymphocytes (Table 1) were observed in response to in vivo administration of either agonistic anti-CD40 mAbs.
  • the increase of the splenic B cell population was also confirmed, by immuno-histochemistry, in a parallel experiment 8 days after immunisation in the 3 ⁇ 23 and FGK45 treated mice.
  • Figure 2 a clear increase in number of B220 + B cells was observed in the marginal zone of both anti-CD40 mAbs (2 d and e) treated animals compared to control group (2 a and B). Aspecific crossreactions were carefully excluded in each analysed sample by using an appropriate isotype control mAb (data not shown).
  • Anti-CD40 mAb therapy ameliorates established CCIA.
  • mice were treated from the day of clinical onset with 10 daily injections (300 ⁇ g/mouse) of FGK45, 3 ⁇ 23, AFRC-MAC-1 or 300 ⁇ l/mouse of PBS, the latter two refereed as control groups.
  • both anti-CD40 mAbs showed a strong suppressive effect on the progression of disease, which was apparent within one day of the first administration.
  • the amelioration of arthritis was also supported by the significant inhibition of paw swelling measured in mice treated with either FGK45 (pO.OOOl) or 3 ⁇ 23 (p ⁇ 0.0001) compared to the results obtained in the control group ( Figure 3b).
  • Anti-CII antibodies are a trademark of CIA (collagen-induced arthritis), and have been reported to play a pathogenic role in the evolution of arthritis 19.
  • CIA collagen-induced arthritis
  • a Thl self-antigen specific response drives the immune response . Therefore, upon CII in CFA immunisation high levels of CII specific IgG2a
  • Thl dependent subclass 21 antibodies, a Thl dependent subclass 21 , are produced.
  • the isotype subclasses are an accepted indicator of whether a dominant Thl or Th2 response is mounted against CII in CIA.
  • Thl IgG2a
  • Th2 IgGl
  • Thl pathogenic Thl (IgG2a) to a potentially protective Th2 (IgGl) response ' .
  • Peripheral blood serum CII specific IgGl and IgG2a levels were quantified 12 days after disease onset ( Figure 5). Both agonistic anti-CD40 mAbs upregulated the CII specific IgG2a (Thl) levels by 29 (FGK45) and 72 (3 ⁇ 23) fold, relative to control treated mice. Critically, the levels of IgGl (Th2) were amplified up to 46 fold for FGK45 and 260 fold in 3 ⁇ 23 treated mice. These data suggest that anti-CD40 mAb therapy would preferentially redirect the IgG2a/IgGl CII specific antibody ratio in favour of the Th2 controlled IgGl isotype.
  • Anti-CD40 mAb therapy alters the antigen specific T cell cytokine profile.
  • Agonistic anti-CD40 administration before immunisation does not prevent CCIA.
  • mice treated mice with 5 daily injections (300 ⁇ g/mouse) of FGK45, 3 ⁇ 23, AFRC-MAC-1 or PBS (300 ⁇ l/mouse) prior to CII in CFA immunisation.
  • 5 daily injections 300 ⁇ g/mouse
  • FGK45, 3 ⁇ 23, AFRC-MAC-1 or PBS 300 ⁇ l/mouse
  • PBS 300 ⁇ l/mouse
  • Figure 8 shows that anti-CD40 antibodies reduce Ig G2a (THl pathogenic) levels in favour of Ig Gl (TH2) in splenocyte.
  • Cells were treated with AFRC macl isotype monoclonal antibody or anti-CD40 monoclonal antibodies. The cells were then placed in SCID mice for one month before assaying for Ig G2a or Ig Gl .
  • Figure 9 shows the effect of injecting anti-CD40 antibodies into mice on IL-12 productions in pathogenic/arthrlitogenic splenocytes.
  • CD40-CD154 axis Disruption of the CD40-CD154 axis has recently gained central stage as one of the ideal approaches to control unwanted immune responses , more interestingly even other therapeutic strategies, such as the use of non depleting anti-CD4 mAb, seem to be based on down-modulation of CD 154 expression (unpublished results).
  • agonistic mAbs provides the opposite effect of boosting the immune response, a property widely used to enhance the immune system when required " ' .
  • the inventors paradoxically observed that agonistic anti-CD40 mAb could successfully prevent CCIA (unpublished results).
  • B cells act as APC they induce the activation of T cells expressing IL-4 with a Th2 compatible cytokine profile .
  • the induction of these Th2 responses have been well
  • MBP Myelin Basic protein
  • agonistic anti-CD40 mAbs can successfully control chronic autoimmune inflammatory processes opening their potential use for patients suffering from autoimmune disorders for whom to date no satisfactory therapy is available.
  • agonistic anti-CD40 antibodies are effective in controlling immune responses when there is already an immune response in place. For example, in immune-inflammatory responses in rheumatoid arthritis and other chronic autoimmune diseases.
  • Th2 clones secrete a factor that inhibits cytokine production by Thl clones. J Exp. Med.

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Abstract

L'invention concerne des procédés de traitement de maladies auto-immunes, par exemple la polyarthrite rhumatoïde, le lupus érythémateux disséminé, les diabètes sucrés ou la sclérose en plaques, qui consistent à administrer une protéine liant le CD40 agonistique comme anticorps anti-CD40. De préférence, l'anticorps anti-CD40 est FGK45 ou 3/23.
PCT/GB2000/004511 1999-11-25 2000-11-27 Traitement de maladies auto-immunes par une proteine liant le cd40 agonistique WO2001037870A1 (fr)

Priority Applications (3)

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JP2001539484A JP2003514873A (ja) 1999-11-25 2000-11-27 作用性ｃｄ４０結合タンパク質による自己免疫疾患の治療
AU15376/01A AU1537601A (en) 1999-11-25 2000-11-27 Treatment of autoimmune diseases by an agonistic CD40-binding protein
EP00977741A EP1146902A1 (fr) 1999-11-25 2000-11-27 Traitement de maladies auto-immunes par une proteine liant le cd40 agonistique

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GBGB9927757.6A GB9927757D0 (en) 1999-11-25 1999-11-25 Treatment of autoimmune diseases
GB9927757.6 1999-11-25

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WO2003011324A1 (fr) * 2001-07-31 2003-02-13 Genset S.A. Agonistes et d'antagonistes du moxifin pour le traitement de troubles metaboliques
EP1455812A2 (fr) * 2001-11-26 2004-09-15 Chiron Corporation Traitement aux anticorps monoclonaux anti-cd40 antagonistes utilise pour traiter la sclerose en plaques
JP2005508176A (ja) * 2001-11-09 2005-03-31 ファイザー・プロダクツ・インク Ｃｄ４０に対する抗体
JP2005527553A (ja) * 2002-03-29 2005-09-15 ザ ボード オブ トラスティーズ オブ ザ レランド スタンフォード ジュニア ユニバーシティー 自己免疫疾患の治療におけるスタチン類および他の自己免疫調節剤の利用
EP1649282A2 (fr) * 2003-07-07 2006-04-26 David H. Wagner Methodes de prediction du developpement de maladies auto-immunes et traitement associe
WO2017009842A2 (fr) 2015-07-16 2017-01-19 Biokine Therapeutics Ltd. Compositions et méthodes pour le traitement du cancer
WO2017220990A1 (fr) 2016-06-20 2017-12-28 Kymab Limited Anticorps anti-pd-l1
WO2021048595A1 (fr) * 2019-09-11 2021-03-18 Novartis Ag Procédé de prévention de troubles associés au virus humain chez des patients
US11179417B2 (en) 2014-07-03 2021-11-23 Transimmune Ag Method for obtaining globally activated monocytes

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GB201006096D0 (en) * 2010-04-13 2010-05-26 Alligator Bioscience Ab Novel compositions and uses thereof

Citations (2)

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EP1649282A4 (fr) * 2003-07-07 2007-08-29 Webb Waring Inst Methodes de prediction du developpement de maladies auto-immunes et traitement associe
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