WO1999000143A1 - Therapie de blocage par cd154 pour maladies auto-immunes - Google Patents

Therapie de blocage par cd154 pour maladies auto-immunes Download PDF

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Publication number
WO1999000143A1
WO1999000143A1 PCT/US1998/013284 US9813284W WO9900143A1 WO 1999000143 A1 WO1999000143 A1 WO 1999000143A1 US 9813284 W US9813284 W US 9813284W WO 9900143 A1 WO9900143 A1 WO 9900143A1
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autoimmune disease
subject
disease
effective amount
binding
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PCT/US1998/013284
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English (en)
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David W. Thomas
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Biogen, Inc.
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Priority to AU82667/98A priority Critical patent/AU8266798A/en
Publication of WO1999000143A1 publication Critical patent/WO1999000143A1/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 generally to the suppression of unwanted immune responses, particularly of counter-adaptive T-lymphocyte mediated immune responses.
  • the invention relates in particular to the prevention, treatment, suppression or reversal of counter- adaptive T-lymphocyte mediated responses to self- or autoantigens, especially autoantigens implicated in autoimmune diseases.
  • Autoimmunity arises when the immune system recognition of the distinction between “self and “non-self determinants is impaired, e.g., by exposure to a pathogen or other environmental element, by a congenital or hereditary defect, or by any other means.
  • Autoimmune tissue destruction can be mediated predominantly by autoantibody responses, or by autoreactive T helper (T H ) cell responses, although both processes can contribute to the observed pathology of any given disease.
  • Autoimmune lesions sites of inflammatory or other immune response mediated tissue destruction
  • ITP idiopathic thrombocytopenia
  • Other representative autoantibody mediated disease include lupus, hemolytic anemia (HA), diabetes mellitus (DM), Myasthenia gravis (MG), and rheumatoid arthritis (RA).
  • ITP defined as a low platelet count (less than 100,000 per microliter [100 K/ ⁇ L]) that cannot be explained by other causes, including drug effects or viral infections. Indeed, the majority of symptomatic and asymptomatic cases of thrombocytopenia usually turn out to be "idiopathic.” Over 80% of patients with ITP have anti-platelet antibodies, with various platelet binding specificities, coating their platelets and/or circulating free in their serum.
  • These antibodies are of the IgG class and generally fix complement and bind to macrophages and other cells through the Fc ⁇ receptor. Such antibodies enhance macrophage-mediated clearance of the platelets from circulation, leading to a reduction in the platelet count.
  • the platelet count drops below 30-50 K/ ⁇ L, bruising, gum bleeding, hematuria, and other symptoms can develop.
  • the risk of intracranial hemorrhage increases substantially.
  • Approximately 20,000 adults are treated annually for ITP in the United States. The majority of these cases are new presentations. Most physicians agree that all patients with platelet counts ⁇ 30 K/ ⁇ L should be offered therapy. George et al. (1994), 331 N. End. J. Med.
  • glucocorticoids intravenous immunoglobulin
  • ITP intravenous immunoglobulin
  • These doses of glucocorticoids are effective in raising platelet counts in nearly all cases within 1-2 weeks. As the glucocorticoid doses are lowered, platelet counts fall again.
  • Azathioprine is occasionally used, mainly as a "steroid-sparing" agent, but its efficacy is questionable and it can cause pancreatitis, hepatitis, nausea, vomiting, bone marrow suppression, and other problems.
  • Combination chemotherapies have been used, but the risks of such therapies generally outweigh the risk of severe bleeding with platelet counts ⁇ 10 K/ ⁇ L.
  • George et al. (1997), Ann. Intern. Med. 319-326.
  • Autologous stem cell transplantation following high dose chemotherapy has been used in a limited number of patients with some success. Lim et al. (1997), 349 Lancet 475.
  • IVIg (2-3 g/kg/dose) is often effective in acutely elevating platelet counts, but the duration of response following each course of therapy is typically ⁇ 4 weeks, often only about 2 weeks, and responses often decline over time with repeated courses.
  • the cost of this therapy currently ranges from $8,000US to $15,000US per treatment course.
  • lupus an autoimmune collagen vascular disease. Lupus is also described in commonly owned PCT/US97/23482, filed 31 December 1997, the teachings of which are incorporated herein by reference.
  • ITP in which the autoantibody pathology is relatively specific to blood tissue, lupus is characterized by systemic inflammatory lesions of varying severity. These lesions can affect the kidneys, endocardium, lungs, joints, spleen, central nervous system (CNS), peripheral nervous system (PNS), vasculature, or any combination of the foregoing.
  • CNS central nervous system
  • PNS peripheral nervous system
  • lupus is commonly manifested as photosensitivity, fatigue, malaise, anorexia, weight loss, fever and/or inflammation of the skin, joints cardiovascular or pulmonary systems.
  • Additional manifestations of systemic lupus erythematosus are diverse and include polyarthritis, nephritis, proteinurea, hematological arthritis, peripheral neuropathy, neuropsychiatric abnormalities, thrombocytopenia, anemia, leukopenia, thrombocytopenia, endocarditis and pericarditis. Tan et al. (1982), 25 Arthritis Rheum. 1271-1277.
  • Autoantibodies of various specificities have been isolated from lupus patients, including antinuclear antibodies (ANA); anti-DNA (single-stranded or double-stranded), anti-RNA, anti-ribonucleoprotein antibodies, anti-histone antibodies; anti-Ro antibodies; antibodies specific for cardiolipin and other phospholipids and/or phosphoproteins; anti- erythrocyte, anti-platelet, anti-lymphocyte and anti-neuronal antibodies.
  • SLE affects approximately 140,000 people in the United States and 105,000 in western Europe, predominantly women of childbearing age. About 10-20% of patients with lupus nephritis, a common manifestation of SLE, also have lupus- associated disorders of the central nervous system. These often manifest as psychological changes, but also can include vasculitis, stroke, meningitis, and meningioencephalitis. There is no cure for lupus.
  • MS multiple sclerosis
  • MS is a chronic demyelinating disease, which affects some 350,000 individuals in the United States.
  • MS is the second most frequent cause of neurologic disability in early to middle adulthood (the most frequent being trauma).
  • the causes of MS are unclear, but appear to include both genetic and environmental contributory factors, the latter of which may include viral infection.
  • MS produces plaques, or inflammatory lesions, in the CNS, with the periphery being largely spared.
  • MS lesions Histopathologic analysis of MS lesions reveal CNS infiltration by mononuclear cells, predominantly T lymphocytes and macrophages, as well as demyelination and gliosis (scarring).
  • Autoreactive T cells in MS plaques are known to have specificity for myelin basic protein (MBP) or myelin proteolipid protein (PLP), and to mediate CNS inflammatory destruction.
  • MBP myelin basic protein
  • PGP myelin proteolipid protein
  • Neuronal axons with compromised myelin sheathing may display a number of functional abnormalities, such as impaired or enhanced conduction and/or crosstalk with other affected axons.
  • MS symptoms often include weakness in one or more limbs, visual blurring due to optic neuritis, sensory disturbance (e.g., parasthesia or "pins and needles" sensation, or hypesthesia or numbness), diplopia or other gaze disruption, ataxia, vertigo, incontinence.
  • Cognitive dysfunction predominates later on, in advanced MS, and can be manifested as memory loss, depression, impaired judgement, inappropriate bouts of laughter or crying.
  • the disease generally can be categorized either as chronic, progressive MS or relapsing/remitting MS.
  • an object of this invention to provide an immunomodulatory agent that mitigates counter-adaptive T cell responses without the need for pan-T cell immunosuppression or chronic glucocorticoid use. Another object is to provide an immunomodulatory agent that inhibits or suppresses autoantibody production. Thus, a further object is to provide an immunomodulatory agent that interrupts delivery of a costimulatory signal to activated T cells. Another object is to provide an immunomodulatory agent that inhibits, prevents or delays onset of an autoimmune disease, particularly an autoantibody driven disease. Still another object is to provide an immunomodulatory agent that delays progression of an autoimmune disease, mitigates the disease, treats it or suppresses its effects or manifestations.
  • a particular object is to provide a CD40:CD154 binding interruptor, such as a CD 154 blocking agent, for use in therapy, particularly for use in therapy to mitigate, delay or reverse autoimmune diseases, including ITP, all forms of lupus including SLE, HA, DM, MG, RA, MS, APS, Crohn's disease, IBD, and the like.
  • a CD40:CD154 binding interruptor such as a CD 154 blocking agent
  • the present invention rests on the discovery that use of a CD40:CD154 binding interruptor, such as a CD 154 blocking agent, prevents, delays, attenuates, mitigates, suppresses, treats or reverses counter-adaptive immune system responses to self- components, such as autoantigens, without the need for pan-suppression of a subject's immune system. More precisely, the present invention rests on the discovery that a CD 154 blocking agent beneficially blocks or interferes with counter-adaptive, self-destructive effects of numerous human autoimmune diseases, regardless of whether the disease is associated with exposure to a pathogen, is congenital or acquired, or is associated with a hereditary risk factor.
  • a CD40:CD154 binding interruptor such as a CD 154 blocking agent
  • the invention accordingly provides methods and compositions for immunomodulatory therapy for blockade or inhibition of an inappropriate, self-directed immune response, irrespective of whether the response is an autoantibody response or an autoreactive T cell response.
  • a first method prevents development of an autoimmune disease.
  • a second method delays onset of the disease.
  • a third method delays progression of the disease.
  • a fourth method attenuates (detectably downmodulates) severity of the disease.
  • a fifth method suppresses one or more effects or manifestations of the disease.
  • a sixth method mitigates or abrogates the disease.
  • a seventh method treats (improves clinical status or stage of) the disease.
  • CD40:CD154 binding interruptor any agent that interrupts the binding of CD40 Ligand (CD40L, also known as CD 154 or the 5c8 antigen, and sometimes referred to in the art as gp39 or TRAP) to its counter or cognate receptor (CD40).
  • CD40L CD40 Ligand
  • the binding interruptor is a CD 154 (CD40L) blocking agent, by which is meant any agent that binds to CD 154 and prevents or interferes with its binding to its counter receptor(s).
  • An exemplary CD 154 blocking agent is a monoclonal antibody (MAb), particularly one having the antigen-specific binding characteristics of the 5c8 MAb disclosed in U.S. Patent 5,474,771, the teachings of which are incorporated herein by reference.
  • MAb monoclonal antibody
  • the present methods are suitable for human or animal (e.g., primate) therapy.
  • the present invention accordingly provides means for treating autoimmune disease manifestations (e.g., lesions) affecting any body tissue, solid organ or organ system.
  • autoimmune disease manifestations e.g., lesions
  • the present methods can be used for treatment of lesions affecting cutaneous, cardiac, pericardial, endocardial, vascular lining or wall, blood (e.g., erythrocytes, platelets), blood-forming (e.g., marrow, spleen), endocrine (e.g., pancreatic, thyroid), gastrointestinal tract (e.g., bowel), respiratory tract (e.g., nasopharyngeal, sinus, bronchial, lung), renal, central nervous system (CNS), peripheral nervous system (PNS), muscular or skeletal joint (e.g., articular cartilage; synovial lining or fluid) tissue.
  • CNS central nervous system
  • PNS peripheral nervous system
  • muscular or skeletal joint e.g., articular cartilage; synovi
  • the present methods can be used for treatment of any autoimmune disease, including atopic dermatitis, any form of lupus (including cutaneous lupus (discoid lupus erythematosis), and any extracutaneous type of lupus, including systemic lupus erythrematosus (SLE) acute lupus, lupus annularis, lupus discretus, lupus lymphaticus, lupus papollomatis, lupus psoriasis, lupus vulgaris, lupus sclerosis, neonatal lupus erythematosus and drug-induced lupus), anti-phospholipid syndrome (APS), hemolytic anemia (HA), idiopathic thromocytopenia (ITP), thyroiditis, diabetes mellitus (DM), thyroiditis, inflammatory bowel disease (IBD), Crohn's disease, rhinitis, demyelinating diseases such as multiple l
  • T cell activation, and immunological processes dependent thereon, requires both T cell receptor (TCR) mediated signals and concurrently delivered costimulatory signals.
  • An important costimulatory signal is delivered by the ligation of CD40 on an antigen- presenting cell (APC), such as a dendritic cell, B cell, or macrophage, by CD40L (CD 154) on a T cell.
  • APC antigen-presenting cell
  • CD40L CD 154
  • Grewal et al. (1996), 273 Science 1864-1867.
  • Human CD40 is a 50 kD cell surface protein expressed on APCs, including mature B cells, as well as on macrophages, activated endothelial cells and activated smooth muscle cells.
  • CD40 belongs to a class of receptors involved in programmed cell death, including Fas/CD95 and the tumor necrosis factor alpha (TNF ⁇ ) receptor.
  • Human CD154 (CD40L) is a 32 kD type II membrane glycoprotein with homology to TNF ⁇ that is expressed, transiently, primarily on activated T cells (CD154 also can be expressed on other activating cell types).
  • CD40:CD154 binding has been shown to be required for mounting T helper cell (T H ) immune responses, including all T cell-dependent antibody responses.
  • T H T helper cell
  • CD40:CD154 binding provides anti-apoptotic and/or lymphokine stimulatory signals.
  • X-linked hyper-IgM syndrome (X-HIGM) in humans is the phenotype resulting from genetic lack of functional CD 154.
  • Affected individuals have normal or high IgM levels, but fail to produce IgG, IgA or IgE antibodies, and suffer from recurrent, sometimes severe, bacterial and parasitic infections, as well as an increased incidence of lymphomas and abdominal cancers.
  • anti-CD154 antibodies can block the induction of anti-collagen antibodies in collagen-induced arthritis. Durie et al. (1993), 261 Science 1328-1330. Anti- CD 154 antibodies can reduce anti-dsDNA and anti-nucleosomal autoantibodies in mice with spontaneous lupus. Mohan et al. (1995), 154 J. Immunol. 1470-1480; Gerritse et al. (1996), 93 Proc. Natl. Acad. Sci. USA 2499-2504. In addition, anti-CD154 antibodies can reduce symptoms in mice with experimental autoimmune encephalomyelitis (EAE), a model of MS.
  • EAE experimental autoimmune encephalomyelitis
  • CD40:CD154 blockade thus may provide potentially powerful therapies for attenuating or ameliorating unwanted, self-reactive immune responses, particularly in the context of autoimmune diseases.
  • a preferred CD 154 blocking agent a humanized MAb having the antigen-specific binding properties of MAb 5c8 (Lederman et al. (1992), 175 J. Exp. Med. 1091-1101), in human clinical trials for idiopathic thrombocytopenia (ITP), an exemplary autoimmune disease for which no well- established preclinical model system is available.
  • ITP idiopathic thrombocytopenia
  • the disclosed protocols are expected to yield results strongly suggesting that CD 154 blockade therapy is not limited to effectiveness for ITP, but will also effectively suppress or attenuate manifestations of many other autoimmune diseases, particularly autoantibody-driven diseases.
  • the following discussion illustrates and exemplifies the variety of contexts and circumstances in which the invention can be practiced, as well as providing proof-of- principle studies involving specific embodiments of the invention.
  • the invention can be used for treatment or prophylaxis of any mammalian subject in need of, or already receiving, immunosuppressive therapy for unwanted immune system responses to self-components, such as autoantigens or autoreactive T cells.
  • the subject mammal is a primate, more preferably a higher primate, most preferably a human.
  • the subject may be another mammal in need of immunomodulatory therapy, particularly a mammal of commercial importance, or a companion animal or other animal of value, such as a member of an endangered species.
  • subjects also include, but are not limited to, sheep, horses, cattle, goats, pigs, dogs, cats, rabbits, guinea pigs, hamsters, gerbils, rats and mice.
  • Subjects are afflicted with, or at risk of, an autoimmune disease.
  • Subjects may have autoimmune pathology affecting any body tissue or organ, including skin, heart, pericardium, endocardium, vasculature, any blood component (e.g., erythrocytes, platelets), blood-forming tissue (e.g., marrow, spleen), endocrine tissue or organs (e.g., pancreas, thyroid), gastrointestinal tract (e.g., bowel), respiratory tract (e.g., lung), kidney, central nervous system (CNS), peripheral nervous system (PNS), muscle and skeletal joints.
  • any blood component e.g., erythrocytes, platelets
  • blood-forming tissue e.g., marrow, spleen
  • endocrine tissue or organs e.g., pancreas, thyroid
  • gastrointestinal tract e.g., bowel
  • respiratory tract e.g., lung
  • kidney central nervous system
  • PNS peripheral nervous system
  • the invention can be practiced on any patient who presents with symptoms, manifestations or significant risk factors for atopic dermatitis, any form of lupus (including cutaneous lupus (discoid lupus erythematosis), and any extracutaneous type of lupus, including systemic lupus erythrematosus (SLE) acute lupus, lupus annularis, lupus discretus, lupus lymphaticus, lupus papollomatis, lupus psoriasis, lupus vulgaris, lupus sclerosis, neonatal lupus erythematosus and drug-induced lupus), anti-phospholipid syndrome (APS), hemolytic anemia (HA), idiopathic thromocytopenia (ITP), thyroiditis, diabetes mellitus (DM), thyroiditis, inflammatory bowel disease (IBD), Crohn's disease, rhinitis, myasth
  • Therapeutic compounds useful for practice of the invention include any compound that blocks the interaction of cell surface CD40 (e.g., on B cells) with CD40L (CD 154) expressed, e.g., on the surface of activated T cells.
  • CD40:CD154 binding interruptor compounds, such as CD154 blocking agents, that are 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 has substantially the same antigen-specific binding characteristics as MAb 5c8, as described in U.S. Patent 5,474,771, the disclosure of which is hereby incorporated by reference.
  • the antibody is a humanized 5c8 (hu5c8).
  • Other known antibodies against CD 154 include antibodies Im ⁇ M90, ImxM91 and ImxM92 (disclosed by Immunex Corp., Seattle WA), an anti-CD40L MAb commercially available from Ancell (clone 24-31 , catalog # 353-020, Bayport, MN), and an anti-CD 154 MAb commercially available from Genzyme (Cambridge, MA, catalog # 80-3703-01). Also commercially available is an anti-CD 154 MAb from PharMingen (San Diego, catalog #33580D). Numerous additional anti-CD 154 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 use of CD 154 blocking agents that are derived from, or engineered from the above-mentioned and equivalent MAbs, such as complete Fab fragments, F(ab') 2 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. (1995), 188 J. Immunol. Meth.1-7. which is hereby incorporated by reference), and small molecule compounds such as small semi-peptidic compounds or non-peptide compounds, all capable of blocking or interrupting CD40:CD154 binding. Procedures for designing, screening and optimizing small molecules are provided in PCT/US96/10664, filed June 21, 1996, the specification of which is hereby incorporated by reference.
  • CD154 blocking agents created using standard recombinant DNA techniques (Winter and Milstein (1991), 349 Nature 293-99).
  • One class of such CD154 blocking agents includes chimeric antibodies, or fusion proteins constructed by joining nucleic acid encoding the antigen binding domain of a non-human mammalian antibody (e.g., a mouse or rat antibody) of desired specificity to nucleic acid encoding a human immunoglobulin (Ig) constant region.
  • a non-human mammalian antibody e.g., a mouse or rat antibody
  • Ig human immunoglobulin
  • Chimeric antibody polypeptides expressed from such constructs generally have lower immunogenicity, when used for human therapy or prophylaxis, than the non-human antibody from which the chimera was derived.
  • a second class of such CD 154 blocking agents includes recombinant "humanized” or “primatized”antibodies.
  • Humanized or primatized antibodies are antibodies are genetically engineered from non-human mammalian antibodies having the desired specificity, by replacing some or all of the codons for amino acids not required for antigen binding with codons for amino acids from corresponding regions of a human or primate Ig light or heavy chain gene.
  • chimeras comprising mostly human immunoglobulin sequences into which the regions responsible for antigen specific binding have been genetically inserted (see, e.g., PCT patent application WO 94/04679).
  • Humanized antibodies generally have even lower immunogenicity in vivo than chimeric antibodies.
  • a humanized MAb having substantially the same antigen specificity as MAb 5c8 (herein, hu5c8) is preferred for practice of the invention.
  • MAb-derived CD 154 blocking agents useful in the invention includes human antibodies, which can be produced in transgenic nonhuman mammals, into whom one or more human immunoglobulin transgenes have been integrated. Such animals may be used as a source for splenocytes for producing human hybridomas, as described in U.S. 5,569,825.
  • any antigen-specific binding fragment of one of the foregoing MAbs or MAb derived therapeutic agent can be used in the present invention, provided that the fragment is sufficiently large to sterically impede CD 154 binding to its counter-receptor.
  • MAb fragments and univalent MAbs can be used.
  • 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 CD 154, 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.
  • the CD40:CD154 binding interruptors, including CD 154 blocking agents, used in the invention can be administered in any manner which is medically acceptable. Depending on the specific circumstances, local or systemic administration may be desirable.
  • the agent is administered via a parenteral route such as by an intravenous, intraarterial, subcutaneous, intramuscular, intraorbital, intraventricular, intraperitoneal, subcapsular, intracranial, intraspinal, or intranasal injection, infusion or inhalation.
  • intravenous, intramuscular and subcutaneous routes are preferred.
  • the agent also can be administered by implantation of an infusion pump, or a biocompatible or bioerodable sustained release implant, into the recipient host, either before or after implantation of donor tissue.
  • certain compounds of the invention, or formulations thereof may be appropriate for oral or enteral administration. Still other compounds of the invention will be suitable for topical administration.
  • the CD40:CD154 binding interruptor is provided indirectly to the recipient, by administration of a vector or other expressible genetic material encoding the interruptor.
  • the genetic material is internalized and expressed in cells or tissue of the recipient, thereby producing the interruptor in situ.
  • a suitable nucleic acid construct would comprise sequence encoding one or more of the MAb 5c8 immunoglobulin (Ig) chains as disclosed in U.S. Pat. 5,474,771.
  • Other suitable constructs would comprise sequences encoding chimeric or humanized versions of the MAb 5c8 Ig chains or antigen-binding fragments thereof.
  • Still other suitable constructs would comprise sequences encoding part or all of other CD154-specific MAbs.
  • the construct is delivered systemically or locally, e.g., by local injection, infusion or implantation to a desired site.
  • the vector or other genetic material encoding the interruptor is internalized within a suitable population of isolated cells to generate interuptor-producing host cells. These host cells then are implanted or infused into the subject, either locally or systemically, to provide in situ production of the CD40:CD154 binding interruptor.
  • Appropriate host cells include cultured cells, such as immortalized cells, as well as cells obtained from the recipient (e.g., peripheral blood or lymph node cells, such as natural killer (NK) cells).
  • an exemplary carrier comprises normal physiologic saline (0.15M NaCl, pH 7.0 to 7.4).
  • Another exemplary carrier comprises 50 mM sodium phosphate, 100 mM sodium chloride.
  • Acceptable carriers can include biocompatible, inert or bioabsorbable salts, buffering agents, oligo- or polysaccharides, polymers, viscosity- improving agents, preservatives, and the like.
  • any CD40:CD154 binding interruptor such as a CD 154 blocking agent, that is used in practice of the invention is formulated to deliver a pharmaceutically-effective or therapeutically-effective amount or dose, which is an amount sufficient to produce a detectable, preferably medically beneficial effect on the subject.
  • Medically beneficial effects would include preventing, delaying or attenuating deterioration of, or detectably improving, the subject's medical condition.
  • a medically beneficial effect on a subject afflicted with ITP would include an increase in platelet count, preferably to a level between about 50,000 and 150,000 per cubic milliliter.
  • an effective amount of a therapeutic compound of the invention, such as a CD 154 blocking agent is any amount which produces a detectable, preferably sustained, increase in platelet count.
  • An optimal effective amount is one which returns the platelet count to normal levels.
  • an effective amount is any which detectably eases or prevents worsening of erythema, edema or other skin irritation.
  • an effective amount is any which detectably eases or prevents worsening of nephritis, pericarditis, endocarditis, vasculitis, sclerosis, or any other lupus-associated pathology, including neurological pathologies and abdominal inflammation, particularly splenic inflammation or fibrosis.
  • an effective amount is any which detectably eases or prevents worsening of valvular disease, pericarditis, endocarditis or vasculitis.
  • an effective amount is any which detectably eases or prevents worsening of anemia.
  • an effective amount is any which detectably eases or prevents worsening of bleeding events.
  • an effective amount is any which detectably eases or prevents worsening of dependence on insulin to maintain glucose homeostasis.
  • an effective amount is any which detectably eases or prevents worsening of bowel stenosis, anorexia, malabsorbtion or other associated pathology.
  • an effective amount is any which detectably eases or prevents worsening of any associated CNS pathology.
  • an MG subject an effective amount is any which detectably eases or prevents worsening of neuromuscular pathology.
  • an effective amount is any which detectably eases or prevents worsening of joint swelling, pain or degradation.
  • the amount of and frequency of dosing for any particular compound to be used in practice of the invention is within the skills and clinical judgement of ordinary practitioners of the medical arts, such as physicians.
  • the dosage amount and timecourse of should be sufficient to produce a clinically beneficial change in one or more indicia of the subject's health status. For some subjects, a single dose may be sufficient to produce the desired response, while in others, daily, biweekly, weekly, bimonthly or monthly doses may be required. Exemplary timecourse and dosage regimes are set forth in the Examples included herein.
  • an anti-CD 154 MAb To further exemplify dosing considerations for an anti-CD 154 compound, the following examples of administration strategies are given for an anti-CD 154 MAb. The dosing amounts could easily be adjusted for other types of CD 154 blocker compounds. In general, single dosages of between about 0.05 and about 50 mg/kg subject body weight are contemplated, with dosages most frequently in the 1-20 mg/kg range.
  • an effective dose of MAb ranges from about 1 mg/kg body weight to about 20 mg/kg body weight, administered daily or at intervals ranging from two to five days, for a period of up to about three weeks.
  • the interdose interval may range from about one week up to about three months. At present, a one-month (four week) interdose interval is preferred.
  • an initial dose of MAb contains between about 1.0 mg and 30 mg MAb for a 70 kg subject.
  • doses can be administered on successive days, every two to six days, once weekly, once every two or three weeks, or once monthly, until the desired effect on the subject's health status is achieved.
  • Therapy can be suspended until disease manifestations are again observed, or if deemed prudent, can be maintained, e.g., by administering MAb every three weeks, on a monthly basis, a bimonthly basis, quarterly, semiannually or annually.
  • Reappearance of disease manifestations can be treated by repeating the initial dosage series, or by a bolus administration of MAb (e.g., 100 mg).
  • CD 154 blockade therapy can be practiced, if desired, serially or in combination with conventional immunosuppression therapy.
  • a conventional immunosuppressant agent e.g., a corticosteroid or calcineurin inhibitor
  • CD 154 blocking MAb 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 should be avoided.
  • CD 154 blocking MAbs can be used together with other agents targeted at B cells, such as anti-CD 19, anti- CD28 or anti-CD20 antibody (unconjugated or radiolabeled), EL- 14 antagonists, LJP394 (LaJolla Pharmaceuticals receptor blocker), JR-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), EL- 14 antagonists, LJP394 (LaJolla Pharmaceuticals receptor blocker), JR-1116 (Takeda small molecule) and anti-Ig idiotype monoclonal antibodies.
  • the combinations may include T cell B cell targeted agents, such as CTLA4Ig, BL-2 antagonists, IL-4 antagonists, IL-6 antagonists, receptor antagonists, anti-CD80/CD86 monoclonal antibodies, TNF, LFA1/ICAM antagonists, VLA4/VCAM antagonists, brequinar and IL-2 toxin conjugates (e.g., DAB), prednisone, anti-CD3 MAb (OKT3), mycophenolate mofetil (MMF), cyclophosphamide, and other immunosuppressants such as calcineurin signal blockers, including without limitation, tacrolimus (FK506).
  • T cell targeted agents such as CD4 antagonists, CD2 antagonists and IL-12.
  • a CD40:CD154 interrupting compound e.g., an anti-CD40L compound or a CD154 blocking agent, such as a MAb having the specificity of MAb 5c8
  • routine modifications or adaptations can be made, to tailor the techniques as needed to assess the effects of any desired CD40:CD154 interrupting compound on the status of autoimmune disease.
  • Some exemplary modifications are mentioned below; however, many other appropriate modifications will be apparent to the skilled practitioner and are contemplated herein.
  • the protocol can be routinely adapted for testing efficacy of a CD154 blocking agent in any other autoimmune disease, e.g., by substituting appropriate subject inclusion criteria, evaluations, analyses, and therapeutic endpoints.
  • an appropriate therapeutic endpoint could be a measurable effect on hematuria, proteinuria, glomerular filtration rate (GFR), serum creatinine, serum complement level, or serum titer of an autoantibody (e.g., an anti-DNA antibody).
  • an appropriate therapeutic endpoint could be a measurable effect on frequency of insulin use, circulating glucose level, performance in a glucose tolerance test, or serum titer of an autoantibody reactive with pancreatic islet beta ( ⁇ ) cells.
  • Each randomized 12 subject cohort will receive a humanized 5c8 MAb (hu5c8) at a dose of 0 mg/kg, 3 mg/kg or 10 mg/kg.
  • Subjects will receive 6 doses given every four weeks, not to exceed a 24 week study period.
  • the primary endpoint established for this study is to determine the number of subjects achieving and maintaining platelet counts >30 K/ ⁇ L.
  • Female subjects must be post-menopausal or surgically sterile, or using contraception. In particular, all female subjects must have a negative pregnancy test on predosing evaluation.
  • hematocrit white blood count (WBC) and differential, serum blood urea nitrogen (BUN), creatinine, bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatine kinase (CK), prothrombin time (PT), activated partial thromboplastin time (aPTT).
  • WBC white blood count
  • BUN serum blood urea nitrogen
  • ALT alanine aminotransferase
  • AST aspartate aminotransferase
  • CK creatine kinase
  • PT prothrombin time
  • aPTT activated partial thromboplastin time
  • influenza (within the previous 2 years), pneumococcus (within the previous 10 years), and tetanus toxoid (within the previous 10 years).
  • the primary analysis for subjects who complete the full 24 weeks of dosing, will be of the proportion of subjects maintaining platelet counts >30 K/ ⁇ L. This proportion will be analyzed by logistic regression, and a component due to dose response will be isolated from the" between treatment" variation. Each hu5c8 dose level will be compared with control.

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Abstract

L'invention concerne des procédés et des compositions permettant de prévenir le développement d'une maladie auto-immune, d'en retarder l'installation, d'en retarder la progression, d'en atténuer la gravité, d'en atténuer les effets ou de traiter cette maladie. Les procédés de l'invention font intervenir un interrupteur de liaison CD40:CD154, de préférence un inhibiteur de CD154, tel qu'un anticorps monoclonal anti-CD154. Ces procédés peuvent être utilisés pour la thérapie de toute maladie auto-immune, que cette maladie soit liée à une réponse due à des autoanticorps, à une réponse d'autoréaction des lymphocytes T, ou aux deux. Ces procédés sont utiles pour les maladies associées à une exposition aux agents pathogènes, pour les maladies congénitales, les maladies héréditaires, et les maladies acquises. Ces procédés se prêtent tout particulièrement au traitement de la thrombopénie idiopathique chez l'homme.
PCT/US1998/013284 1997-06-27 1998-06-26 Therapie de blocage par cd154 pour maladies auto-immunes WO1999000143A1 (fr)

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US5107297P 1997-06-27 1997-06-27
US60/051,072 1997-06-27
US5148497P 1997-07-01 1997-07-01
US5148397P 1997-07-01 1997-07-01
US5148197P 1997-07-01 1997-07-01
US60/051,481 1997-07-01
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Cited By (13)

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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
EP1101495A1 (fr) * 1999-06-01 2001-05-23 Eisai Co., Ltd. Agents prophylactiques du purpura thrombocytopenique idiopathique
WO2001066141A1 (fr) * 2000-03-06 2001-09-13 Eisai Co., Ltd. Agents therapeutiques et prophylactiques diriges contre le syndrome des antiphospholipides
JP2002118894A (ja) * 2000-08-04 2002-04-19 Yamaha Corp 線状加振装置及び該加振装置を備えたスピーカ
EP1289554A1 (fr) * 2000-06-02 2003-03-12 Regents Of The University Of Minnesota Procede immunotherapeutique permettant de prevenir le rejet de cellules insulaires
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
US6797263B2 (en) 2000-05-12 2004-09-28 Beth Israel Deaconess Medical Center, Inc. Compositions and methods for achieving immune suppression
WO2006030220A1 (fr) * 2004-09-17 2006-03-23 Domantis Limited Compositions monovalentes pour la liaison au cd40l et procedes d'utilisation
EP1649282A2 (fr) * 2003-07-07 2006-04-26 David H. Wagner Methodes de prediction du developpement de maladies auto-immunes et traitement associe
US7445781B2 (en) 1992-02-14 2008-11-04 Trustees Of Dartmouth College Anti-CD40CR MR1 antibody
EP2583678A2 (fr) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Immunopotentiateurs de petites molécules et dosages pour leur détection
EP2283861A3 (fr) * 2000-11-20 2013-05-29 Canadian Blood Services Procédé de traitement de la thrombocytopénie avec l'immunoglobuline intraveineuse monoclonale
US9528088B2 (en) 2002-06-28 2016-12-27 Life Technologies Corporation Methods for eliminating at least a substantial portion of a clonal antigen-specific memory T cell subpopulation

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Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7445781B2 (en) 1992-02-14 2008-11-04 Trustees Of Dartmouth College Anti-CD40CR MR1 antibody
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
EP1067954A4 (fr) * 1998-04-03 2004-08-18 Dartmouth College Utilisation d'anticorps anti-gp39 pour traiter et/ou faire regresser un lupus et une maladie renale associee
EP1101495A1 (fr) * 1999-06-01 2001-05-23 Eisai Co., Ltd. Agents prophylactiques du purpura thrombocytopenique idiopathique
EP1101495A4 (fr) * 1999-06-01 2003-05-07 Eisai Co Ltd Agents prophylactiques du purpura thrombocytopenique idiopathique
WO2001066141A1 (fr) * 2000-03-06 2001-09-13 Eisai Co., Ltd. Agents therapeutiques et prophylactiques diriges contre le syndrome des antiphospholipides
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
US7347995B2 (en) 2000-05-12 2008-03-25 Beth Israel Deaconess Medical Center, Inc. Compositions and methods for achieving immune suppression
US6797263B2 (en) 2000-05-12 2004-09-28 Beth Israel Deaconess Medical Center, Inc. Compositions and methods for achieving immune suppression
EP1289554A1 (fr) * 2000-06-02 2003-03-12 Regents Of The University Of Minnesota Procede immunotherapeutique permettant de prevenir le rejet de cellules insulaires
EP1289554A4 (fr) * 2000-06-02 2004-05-26 Univ Minnesota Procede immunotherapeutique permettant de prevenir le rejet de cellules insulaires
JP4683367B2 (ja) * 2000-08-04 2011-05-18 ヤマハ株式会社 線状加振装置及び該加振装置を備えたスピーカ
JP2002118894A (ja) * 2000-08-04 2002-04-19 Yamaha Corp 線状加振装置及び該加振装置を備えたスピーカ
EP2283861A3 (fr) * 2000-11-20 2013-05-29 Canadian Blood Services Procédé de traitement de la thrombocytopénie avec l'immunoglobuline intraveineuse monoclonale
US9528088B2 (en) 2002-06-28 2016-12-27 Life Technologies Corporation Methods for eliminating at least a substantial portion of a clonal antigen-specific memory T cell subpopulation
EP1649282A4 (fr) * 2003-07-07 2007-08-29 Webb Waring Inst Methodes de prediction du developpement de maladies auto-immunes et traitement associe
EP1649282A2 (fr) * 2003-07-07 2006-04-26 David H. Wagner Methodes de prediction du developpement de maladies auto-immunes et traitement associe
EP2583678A2 (fr) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Immunopotentiateurs de petites molécules et dosages pour leur détection
WO2006030220A1 (fr) * 2004-09-17 2006-03-23 Domantis Limited Compositions monovalentes pour la liaison au cd40l et procedes d'utilisation
US7563443B2 (en) 2004-09-17 2009-07-21 Domantis Limited Monovalent anti-CD40L antibody polypeptides and compositions thereof
US7829096B2 (en) 2004-09-17 2010-11-09 Domantis Ltd. CD40L-specific monovalent polypeptides
US7927596B2 (en) 2004-09-17 2011-04-19 Domantis Limited Methods of antagonizing binding of CD40 to CD40L with CD40L-specific monovalent polypeptides
EP2371862A3 (fr) * 2004-09-17 2012-10-24 Domantis Limited Compositions monovalentes pour la liaison au CD40L et procédés d'utilisation
US8524236B2 (en) 2004-09-17 2013-09-03 Domantis Limited Methods of antagonizing the binding of CD40 to CD40L with CD40L-specific monovalent polypeptides in autoimmune individuals

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