WO2011109280A1 - Procédés et compositions permettant de traiter les troubles d'origines immunes - Google Patents

Procédés et compositions permettant de traiter les troubles d'origines immunes Download PDF

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WO2011109280A1
WO2011109280A1 PCT/US2011/026445 US2011026445W WO2011109280A1 WO 2011109280 A1 WO2011109280 A1 WO 2011109280A1 US 2011026445 W US2011026445 W US 2011026445W WO 2011109280 A1 WO2011109280 A1 WO 2011109280A1
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antagonist
taci
april
blys
seq
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PCT/US2011/026445
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English (en)
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Sumantha S. Bhatt
Anna Valujskikh
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Lerner Research Institute
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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
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39541—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against normal tissues, cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the present invention relates to methods and compositions for modulating an immune response.
  • ASCII Code for Information Interchange
  • Immunosuppressive drugs were developed to inhibit or attenuate transplant rejection.
  • An example is cyclosporine A (US Patent 4,117,118) produced from Tolypocladium inflatum, a soil fungus.
  • FK-506 has also been discovered to be an immunosuppressant and has been commercialized, as has the calcineurin inhibitors-cyclosporine, which has become the mainstay of immunosuppressive therapy in solid organ transplantation.
  • each of these drugs produces severe adverse drug effects (ADEs) such as nephrotoxicity, posttransplantation diabetes mellitus, and hypertension.
  • ADs severe adverse drug effects
  • the methods of the invention comprise administering to a subject a therapeutically effective amount of a BLyS/APRIL antagonist in combination with an antagonist of the CD40 pathway.
  • the combination of the BLyS/APRIL antagonist and the CD40 pathway antagonist promotes a desired therapeutic response.
  • the BLyS/APRIL antagonist and the CD40 pathway antagonist may be administered simultaneously or sequentially as a single pharmaceutical composition or as separate pharmaceutical compositions, each pharmaceutical composition comprising a
  • Methods of the invention find use in treating or preventing or delaying the development of a variety of immune-mediated conditions including, for example, treating or preventing or delaying the development of transplant rejections, graft-versus-host disease, reducing or delaying anti-graft responses in a subject, reducing the level of an immune response or reducing the level of immunoglobulins, including alloantibodies or xenoantibodies, in a subject in need thereof.
  • Figure 1 shows donor reactive IgG alloantibody serum titers on day 10 post transplantation.
  • Figure 2 shows donor reactive IgG alloantibody serum titers on day 14 post transplantation.
  • Figure 3 shows allograft survival post transplantation following BAFF and APRIL neutralization.
  • B-cell activating factor of the TNF (Tumor Necrosis Factor) family (BAFF), and A PRoliferation-Inducing Ligand (APRIL) signaling is required for memory CD4+ T cell induced alloantibody production when the CD40-CD154 pathway is compromised.
  • the BLyS/APRIL antagonist and the antagonist of the CD40 pathway promotes a desired therapeutic response comprising a reduction in serum immunoglobulin levels.
  • the therapeutic response comprises a reduction in donor-reactive immunoglobulins.
  • Such reductions in an immune response find use in reducing an anti- graft response, promoting immune tolerance, and reducing an immune response in a subject in need thereof.
  • the methods for treating or preventing various immune-mediated disorders are provided, including but not limited to, transplant rejections and graft- vs. -host disease.
  • a “reduction in serum immunoglobulin levels” comprises any statistically significant decrease in the level of serum antibody titers of any one or all of the immunoglobulin classes (i.e. IgE, IgG, IgM, IgD and/or IgA) in a subject.
  • Such a reduction can comprise a decrease in serum IgE, IgM, IgD, or IgA antibody titers of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or greater in the serum of a subject following the administration of the combination therapy.
  • such a reduction comprises a decrease in serum IgG antibody titers of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or greater in the serum of a subject following the administration of the therapy.
  • the reduction in serum immunoglobulin levels can comprises a statistically significant reduction in the level of any one of the subtypes of IgG, including a decrease of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or greater in the serum of any one or any combination of IgGl, IgG2, IgG3 or IgG4.
  • the reduction in serum immunoglobulin levels can comprise any statistically significant decrease in the level of donor-reactive
  • a "donor-reactive immunoglobulin(s)” include and “xenoantibody (ies)” and “alloantibody(ies)”.
  • Donor-reactive immunoglobulins refer to antibodies that are generated in a subject against non-self (alio or xeno) antigens.
  • the alloantibodies or the xenoantibodies can further include subject- host reactive antibodies that arise from a graft transplant (e.g., heart allograft) or GVHD.
  • an alloantibody or a xenoantibody can arise from a response in either direction (graft-vs-host or host-vs-graft).
  • immunoglobulins comprises any statistically significant decrease in antibody titers of any one or all donor-reactive immunoglobulin classes (i.e. IgE, IgG, IgM, IgD and/or IgA) in a subject.
  • a reduction can comprise a decrease in donor-reactive IgE, IgM, IgD, or IgA antibody titers in the serum of a subject of at least 10%, 20%>, 30%>, 40%>, 50%, 60%, 70%, 80%, 90%, 95% or greater in a subject following the administration of the combination therapy.
  • such a reduction in donor-reactive immunoglobulins comprise a decrease in serum donor-reactive IgG antibody titers of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or greater in a subject following the administration of the therapy.
  • the reduction in donor-reactive immunoglobulin levels in the serum can comprise a statistically significant reduction in the level of any one of the subtypes of donor-reactive IgG, including a decrease of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or greater in the serum of any one or any combination of donor-reactive IgGl, IgG2, IgG3 or IgG4.
  • the methods employed herein do not require that the biological sample from the subject be analyzed for an elevated level of BLyS/APRIL heterotrimer (HT), APRIL, or BCMA prior to administration of the combination therapy.
  • a biological sample from the subject is not analyzed for an elevated level of BLyS/APRIL heterotrimer (HT), APRIL, or BCMA prior to administration of the combination therapy.
  • the methods employed herein do not require that the biological sample from the subject be analyzed for an elevated level of BLyS/APRIL heterotrimer (HT), APRIL, BCMA, TACI, BAFF-R, and/or BLyS prior to administration of the combination therapy.
  • a biological sample from the subject is not analyzed for an elevated level of BLyS/APRIL heterotrimer (HT), APRIL, BCMA, TACI, BAFF-R, and/or BLyS prior to administration of the combination therapy.
  • the elevated level of APRIL or BLyS can be detected by either detecting the homotrimer of each protein form, or alternatively, by detecting the level of the individual subunit of each
  • BLyS or “BLyS polypeptide,” “TALL-1 “ or “TALL-1 polypeptide,” or “BAFF” or “BAFF polypeptide” when used herein encompass native BLyS polypeptides and BLyS variants.
  • “BLyS” is a designation given to those polypeptides which are encoded by the human BLyS sequence (SEQ ID NO: 1) or the mouse BLyS sequence (SEQ ID NO: 2). Variants or fragments of the BLyS polypeptides which show BLyS biological activity are encompassed within this designation as well.
  • a biologically active BLyS polypeptide can bind three members of the TNF receptor family, namely the transmembrane activator and calcium modulator cyclophilin ligand interactor (TACI), B-cell maturation antigen (BCMA), and B-cell activation factor of the TNF family receptor (BAFF-R) and thereby activate downstream pathway signaling in these pathways.
  • TNF transmembrane activator and calcium modulator cyclophilin ligand interactor
  • BCMA B-cell maturation antigen
  • BAFF-R B-cell activation factor of the TNF family receptor
  • a biologically active BLyS potentiates any one or combination of the following events in vitro or in vivo: an increased survival of B cells, an increased level of IgG and/or IgM, an increased numbers of plasma cells, and processing of NF- KB2/100 to p52NF-KB in splenic B cells (e.g., Batten et al. (2000) J. Exp. Med. 192: 1453-1465; Moore et al. (1999) Science 285: 260-263; Kayagaki et al.
  • APRIL APRIL polypeptide
  • a PRoliferation-Inducing Ligand A PRoliferation-Inducing Ligand
  • TNSF13A A PRoliferation-Inducing Ligand
  • Tall-2 Tall-2
  • TRDL-1 TRDL-1
  • transmembrane activator and calcium modulator cyclophilin ligand interactor TACI
  • BCMA B-cell maturation antigen
  • TACI transmembrane activator and calcium modulator cyclophilin ligand interactor
  • BCMA B-cell maturation antigen
  • TACI transmembrane activator and calcium modulator cyclophilin ligand interactor
  • BCMA B-cell maturation antigen
  • heparin sulfate proteoglycans and thereby activate downstream pathway signaling in these pathways.
  • TACI transmembrane activator and calcium modulator cyclophilin ligand interactor
  • BCMA B-cell maturation antigen
  • APRIL APRIL has also been shown to have an anti-apoptotic effect (Kimberley et al. (2009) Results Probl Cell Differ. 49: 161-82 and Kimberley et al. (2009) J Cell Physiol. 218: 1-8).
  • active variants and fragments of APRIL are further described in Hahne et al. (1998) J. Exp. Med.
  • BLyS/APRIL refers to a compound or a combination of compounds, including for example, an antibody, a synthetic or native sequence peptide and/or a small molecule antagonist, that can function in a direct or indirect manner to partially or fully block, inhibit or neutralize BLyS and APRIL signaling in vitro or in vivo.
  • a BLyS/APRIL antagonist can comprises a single antagonistic compound or can comprise multiple, distinct compounds, one acting as a BLyS antagonist and one acting as an APRIL antagonist.
  • Antagonism using a BLyS/APRIL antagonist does not necessarily indicate a total elimination of BLyS/APRIL activity. Instead, the activity of both BLyS and APRIL signaling could decrease by a physiologically relevant amount including, for example, a decrease in both BLyS signaling and APRIL signaling of at least about 5%, 10%, 15%,
  • the BLyS/APRIL antagonist directly binds BLyS and/or APRIL and thereby blocks/inhibits their activity or, alternatively, the BLyS/APRIL antagonist binds to the BLyS and/or APRIL receptors (i.e., BAFF-R, BCMA, and TACI) and thereby block the activity of BLyS and APRIL.
  • the BLyS/APRIL antagonist directly binds BLyS and/or APRIL and thereby blocks/inhibits their activity or, alternatively, the BLyS/APRIL antagonist binds to the BLyS and/or APRIL receptors (i.e., BAFF-R, BCMA, and TACI) and thereby block the activity of BLyS and APRIL.
  • the BLyS/APRIL antagonist directly binds BLyS and/or APRIL and thereby blocks/inhibits their activity or, alternatively, the BLyS/
  • BLyS/APRIL antagonist comprise an soluble form of a BAFF-R, BCMA and/or TACI receptor.
  • an antagonist that directly binds BLyS and APRIL comprises, for example, a polypeptide comprising the extracellular domain (ECD) of
  • TACI TACI.
  • extracellular domains of TACI or active variants and fragments thereof are disclosed in further detail elsewhere herein.
  • the TACI active variants and fragments thereof are disclosed in further detail elsewhere herein.
  • BLyS/APRIL antagonist can comprise multiple, distinct compounds, one acting as a BLyS antagonist and one acting as an APRIL antagonist.
  • the BLyS/APRIL antagonist can comprise an effective combination of any of the
  • the extracellular domains of the BLyS and APRIL receptors i.e. TACI, BCMA, or BAFF-R
  • the activity of both BLyS and APRIL is disrupted in the presence of the combination.
  • APRIL/BLyS antagonist comprises an antagonistic antibody or other peptide or small molecule, wherein the antibody or small molecule blocks activity of both APRIL and BLyS.
  • a combination of antagonistic antibodies and/or small molecules and/or peptides wherein one compound antagonizes APRIL and the other compound antagonizes BLyS can be used.
  • assays useful for testing BLyS and/or APRIL antagonists such as the B cell proliferation assay described in WO 00/40716 among others are well known to one of ordinary skill in the art. i. Extracellular Domains of BLyS and APRIL Receptors
  • the BLyS/APRIL antagonist comprises at least the extracellular domain of a BLyS or an APRIL receptor (i.e., TACI, BAFF-R, and/or
  • the BLyS/APRIL antagonist comprises at least the extracellular domain of the TACI polypeptide or an active fragment or variant thereof.
  • the general term "TACI” includes the TACI polypeptides described in WO 98/39361, WO 00/40716, WO 01/85782, WO 01/87979, WO 01/81417, and WO 02/094852, each of which is herein incorporated by reference.
  • One form of the TACI polypeptide is set forth herein and comprises or consists of amino acids 1-246 of SEQ ID NO: 4.
  • TACI polypeptides or fragments and variants thereof that can be employed as BLyS/APRIL antagonists can be isolated from a variety of sources, such as from human tissue types or from another source, or prepared by recombinant and/or synthetic methods.
  • the BLyS/APRIL antagonist comprises an extracellular domain of the BCMA polypeptide or an active fragment or active variant thereof.
  • the general term "BCMA” includes the BCMA polypeptides described in Laabi et al. (1992) EMBO J. 11 : 3897-3904; Laabi et al. (1994) Nucleic Acids Res. 22: 1147-1154; Gras et al. (1995) Int. Immunology 7: 1093-1106; and Madry et al. (1998) Int. Immunology 10: 1693-1702, each of which is herein incorporated by reference.
  • One form of the BCMA polypeptide is set forth herein and comprises or consists of amino acid residues 1-184 of SEQ ID NO:5.
  • the BCMA polypeptides of the invention can be isolated from a variety of sources, such as from human tissue types or from another source, or prepared by recombinant and/or synthetic methods.
  • a BLyS antagonist can comprise an extracellular domain of the BAFF-R polypeptide or an active fragments or variants thereof.
  • BAFF-R includes the BAFF-R polypeptides described in WO 02/24909 and WO 03/14294, each of which are herein incorporated by reference.
  • One form of the BAFF-R polypeptide is set forth herein and comprises or consists of amino acid residues 1 to 184 of SEQ ID NO:6.
  • the BAFF-R polypeptides of the invention can be isolated from a variety of sources, such as from human tissue types or from another source, or prepared by recombinant and/or synthetic methods.
  • the extracellular domain of these various receptors comprises a polypeptide essentially free of the transmembrane or cytoplasmic domains and retains the ability to bind and inhibit BLyS and/or APRIL.
  • the extracellular domain of TACI can comprise amino acids 1 to 154 of the TACI polypeptide sequence (SEQ ID NO:4) or active variants and fragments thereof.
  • Exemplary, but non-limiting extracellular domains of TACI that can be employed as a BLyS/APRIL antagonist are described in von Bulow et ah, supra, WO
  • Extracellular domains of TACI and variants and fragment thereof will continue to bind at least one of ZTNF2 (APRIL) or ZTNF4 (BLyS).
  • the extracellular domains can comprise amino acids 1-106 of SEQ ID NO:4, amino acids 1-142 of SEQ ID NO:4, amino acids 30-154 of SEQ ID NO:4, amino acids 30-106 of SEQ ID NO:4, amino acids 30-110 of SEQ ID NO:4, amino acids 30-119 of SEQ ID NO:4, amino acids 1-166 of SEQ ID NO:4, amino acids 1-165 of SEQ ID NO:4, amino acids 1-114 of SEQ ID NO: 4, amino acids 1-119 of SEQ ID NO:4, amino acids 1-120 of SEQ ID NO:4, and amino acids 1-126 of SEQ ID NO:4.
  • the BLyS/APRIL antagonist comprise amino acid residues 34-66 and 71-104 of SEQ ID NO:4 or amino acids 30-110 of SEQ ID NO:4.
  • the TACI extracellular domain can comprise those molecules having only one cysteine rich domain, i.e., comprising either amino acid residues 34-66 or amino acid residues 71-104 of SEQ ID NO: 4.
  • Extracellular domains of BAFF-R include polypeptides comprising amino acids
  • BAFF-R polypeptide sequence SEQ ID NO:6
  • active fragments and variants thereof which have the ability to act as BLyS/APRIL antagonists.
  • variants and fragments of the extracellular domain of BAFF-R are described in WO 02/24909, WO 03/14294, and WO 02/38766, each of which is herein incorporated by reference.
  • these extracellular domains can comprise amino acids 1-77 of SEQ ID NO: 6, amino acids 7-77 of SEQ ID NO:6, amino acids 1- 69 of SEQ ID NO:6, amino acids 7-69 of SEQ ID NO:6, amino acids 2-62 of SEQ ID NO:6, amino acids 2-71 of SEQ ID NO:6, amino acids 1-61 of SEQ ID NO:6, amino acids 2-63 of SEQ ID NO:6, amino acids 1-45 of SEQ ID NO:6, amino acids 1-39 of SEQ ID NO:6, amino acids 7-39 of SEQ ID NO:6, amino acids 1-17 of SEQ ID NO:6, amino acids 39-64 of SEQ ID NO:6, amino acids 19-35 of SEQ ID NO:6, and amino acids 17-42 of SEQ ID NO:6.
  • BAFF-R extracellular domain polypeptide can comprise those molecules having a cysteine rich domain, for example, amino acids 1-35 of SEQ ID NO:6. See, Thompson et al. (2001) Science 293:2108-211 1, herein incorporated by reference.
  • Extracellular domains of BCMA include polypeptides comprising amino acids 1- 48 of the BCMA polypeptide sequence (SEQ ID NO:5). Additionally, the extracellular domain can be fragments or variants of this sequence, such as extracellular domains as described in WO 00/40716 and WO 05/075511 , each of which is herein incorporated by reference.
  • these extracellular domains of BCMA can comprise amino acids 1-150 of SEQ ID NO:5, amino acids 1-48 of SEQ ID NO:5, amino acids 1-41 of SEQ ID NO:5, amino acids 8-41 of SEQ ID NO:5, amino acids 8-37 of SEQ ID NO:5, amino acids 8-88 of SEQ ID NO:5, amino acids 41-88 of SEQ ID NO:5, amino acids 1-54 of SEQ ID NO:5, amino acids 4-55 of SEQ ID NO:5, amino acids 4-51 of SEQ ID NO:5, and amino acids 21-53 of SEQ ID NO:5.
  • the BCMA extracellular domain can comprise those molecules having only a partial cysteine rich domain, including for example, amino acids 6-45 of SEQ ID NO:5. See, also U.S. Patent No. 7,507,580, herein incorporated by reference. ii. Immunoglobulin Fusion Proteins
  • the various extracellular domains or active fragments and variants thereof of the various APRIL and BLyS receptors discussed above can further be employed as fusion proteins comprising the extracellular domain or active fragment or variant thereof operably linked to a region of a constant region domain of an immunoglobulin.
  • the term "operably linked" is intended to indicate that the two heterologous proteins are fused in-frame to allow for the expression of a single polypeptide.
  • a region of the APRIL or BLyS receptor can be fused in- frame to at least one constant region domain of an immunoglobulin. Any such fusion protein is referred to herein as Ig-fusion proteins.
  • immunoglobulin-fusion protein refers to a fusion protein comprising a first polypeptide having a desired antagonist activity (i.e., a BLyS/APRIL antagonist or CD40 pathway antagonist) operably linked to at least one constant region domain of an immunoglobulin.
  • an immunoglobulin heavy chain comprises a variable region and a constant region.
  • the constant region is comprised of distinct domains including, for example, the C H 1 domain, the C H 2 domain, and the C H 3 domain.
  • an Fc fragment of an immunoglobulin heavy chain comprises the disulfide heavy chain hinge region, a C R 2 domain and a C R 3 domain.
  • Fc fragments of an immunoglobulin heavy chain include, with or without a hinge region, an Fc fragment comprising a C H 3 domain, or an Fc fragment comprising a C H 3 domain and a C H 2 domain.
  • the various domains of the heavy chain constant region can be obtained from any immunoglobulin, such as IgGi, IgG 2 , IgG 3 , or IgG 4 subtypes, IgA (includinglgAi and IgA 2 ), IgE, IgD or IgM.
  • useful Fc-fusion proteins are polypeptides that comprise the BLyS/APRIL binding portions of a BLyS/APRIL receptor (i.e., TACI, BAFF-R, or BCMA) without the transmembrane or cytoplasmic sequences of the BLyS/APRIL receptor.
  • a BLyS/APRIL receptor i.e., TACI, BAFF-R, or BCMA
  • the extracellular domain of BAFF-R, TACI or BCMA or active variant or fragment thereof is fused to the Fc fragment of an immunoglobulin.
  • Fcyl, Fc4, Fc5, and Fc6 contain mutations in human IgGi Fc to reduce effector functions mediated by the Fc by reducing FcyRI binding and complement Clq binding.
  • sequences of these modified Fc regions are set forth in US Patent No. 7,501,497 which is herein incorporated by reference.
  • the BLyS/APRIL antagonist comprises a TACI-Ig fusion protein.
  • a non-limiting example of a TACI-Ig fusion protein comprises the following components: 1) a polypeptide that comprises the extracellular domain of TACI or a active variant and/or fragment thereof; and 2) at least one immunoglobulin constant region domain.
  • the methods of the invention utilize a fusion protein comprising at least one human immunoglobulin constant region domain and any polypeptide with at least 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to the TACI extracellular domain or an active fragment or variant thereof.
  • U.S. Patent Nos. 5,969,102, 6,316,222 and 6,500,428 and U.S. patent applications 091569,245 and 091627,206 disclose sequences for the extracellular domain of TACI as well as specific fragments of the TACI extracellular domain that interact with BLyS and APRIL.
  • the TACI-Ig fusion protein can comprise, for example, any of the following regions of TACI operably linked to at least one immunoglobulin constant region domain: amino acids 1-106 of SEQ ID NO:4, amino acids 1-142 of SEQ ID NO:4, amino acids 30-154 of SEQ ID NO:4, amino acids 30-106 of SEQ ID NO:4, amino acids 30-110 of SEQ ID NO:4, amino acids 30-119 of SEQ ID NO:4, amino acids 1-166 of SEQ ID NO:4, amino acids 1-165 of SEQ ID NO:4, amino acids 1-114 of SEQ ID NO: 4, amino acids 1-119 of SEQ ID NO:4, amino acids 1-120 of SEQ ID NO:4, amino acids 1-126 of SEQ ID NO:4, or amino acid residues 34- 66 and 71-104 of SEQ ID NO:4.
  • the BLyS/APRIL antagonist comprising the TACI-Ig fusion protein comprises TACI-Fcyl, TACI-Fc4, or TACI- Fc6.
  • the BLyS/APRIL antagonist comprising the TACI-Ig fusion protein comprises TACI-Fcyl, TACI-Fc4, or TACI- Fc6.
  • TACI-Fc5 is employed and comprises a recombinant fusion polypeptide comprising the extracellular domain of TACI or active variant or fragment thereof fused in- frame to Fc5.
  • the amino acid sequence of Fc5 is set forth in SEQ ID NO: 7. Any of the various extracellular domains of TACI described herein can be operably linked to Fc5.
  • the TACI-Fc5 polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 8 or an active fragment or variant thereof.
  • a variant of TACI-Fc5 can comprise at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 8.
  • the BLyS/APRIL antagonist comprises a BAFF-R-Ig fusion protein.
  • a non-limiting example of a BAFF-R-Ig fusion protein comprises the following components: 1) a polypeptide that comprises the extracellular domain of BAFF-R or a active variant and/or fragment thereof; and 2) at least one immunoglobulin constant region domain.
  • the methods of the invention utilize a fusion protein comprising at least one human immunoglobulin constant region domain and any polypeptide with at least 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%,
  • BAFF-R extracellular domain 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to the BAFF-R extracellular domain or an active fragment or variant thereof.
  • variants and fragments of the extracellular domain of BAFF-R are described in WO 02/24909, WO 03/14294, and WO 02/38766, each of which is herein incorporated by reference.
  • the BAFF-R-Ig fusion protein can comprise, for example, any of the following regions of BAFF-R operably linked to at least one immunoglobulin constant region domain: amino acids 1-77 of SEQ ID NO: 6, amino acids 7-77 of SEQ ID NO:6, amino acids 1-69 of SEQ ID NO:6, amino acids 7-69 of SEQ ID NO:6, amino acids 2-62 of SEQ ID NO:6, amino acids 2-71 of SEQ ID NO:6, amino acids 1-61 of SEQ ID NO:6, amino acids 2-63 of SEQ ID NO:6, amino acids 1-45 of SEQ ID NO:6, amino acids 1-39 of SEQ ID NO:6, amino acids 7-39 of SEQ ID NO:6, amino acids 1-17 of SEQ ID NO:6, amino acids 39-64 of SEQ ID NO:6, amino acids 19-35 of SEQ ID NO:6, and amino acids 17-42 of SEQ ID NO:6.
  • the BAFF-R extracellular domain polypeptide can comprise those molecules having a cysteine rich domain, for example, amino acids 1-35 of SEQ ID NO:6. See, Thompson et al. (2001) Science 293:2108-211 1, herein incorporated by reference.
  • the BLyS/APRIL antagonist comprising the TACI-Ig fusion protein comprises BAFF-R-Fcyl, BAFF-R-Fc4, BAFF-R-Fc5, or BAFF-R- Fc6.
  • the BLyS/APRIL antagonist comprises a BCMA-Ig fusion protein.
  • a non-limiting example of a BCMA-Ig fusion protein comprises the following components: 1) a polypeptide that comprises the extracellular domain of BCMA or a active variant and/or fragment thereof; and 2) at least one immunoglobulin constant region domain.
  • the methods of the invention utilize a fusion protein comprising at least one human immunoglobulin constant region domain and any polypeptide with at least 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to the BCMA
  • Extracellular domains of BCMA include polypeptides comprising amino acids 1-48 of the BCMA polypeptide sequence (SEQ ID NO:5). Additionally, the extracellular domain can be fragments or variants of this sequence, such as extracellular domains as described in WO 00/40716 and WO 05/075511 , each of which is herein incorporated by reference.
  • the BCMA-Ig fusion protein can comprise, for example, any of the following regions of BCMA operably linked to at least one immunoglobulin constant region domain:
  • these extracellular domains of BCMA can comprise amino acids 1-150 of SEQ ID NO:5, amino acids 1-48 of SEQ ID NO:5, amino acids 1-41 of SEQ ID NO:5, amino acids 8-41 of SEQ ID NO:5, amino acids 8-37 of SEQ ID NO:5, amino acids 8-88 of SEQ ID NO:5, amino acids 41-88 of SEQ ID NO:5, amino acids 1-54 of SEQ ID NO:5, amino acids 4-55 of SEQ ID NO:5, amino acids 4-51 of SEQ ID NO:5, and amino acids 21-53 of SEQ ID NO:5.
  • the BCMA extracellular domain can comprise those molecules having only a partial cysteine rich domain as disclosed elsewhere herein.
  • the BLyS/APRIL antagonist comprising the BCMA-Ig fusion protein comprises BCMA-Fcyl, BCMA-Fc4, BCMA-Fc5 or BCMA- Fc6.
  • the APRIL/BLyS antagonist comprises an antagonistic antibody.
  • the antagonistic antibody can block the activity of both APRIL and BLyS or alternatively, the antagonist antibody can comprise a combination of antagonistic antibodies wherein one antibody antagonizes APRIL and the other antibody antagonizes BLyS.
  • the antagonist antibody is specific for BLyS and binds within a region of human BLyS (SEQ ID NO: 1) comprising residues 162-275 of SEQ ID NO: l and/or a neighboring amino acid or amino acids selected from the group consisting of 162, 163, 206, 211, 231, 233, 264 and 265 of human BLyS.
  • the binding of the antibody is such that the antibody sterically hinders BLyS binding to one or more of its receptors.
  • Such antibodies are described in WO 02/02641 and WO 03/055979.
  • a particularly preferred antibody is the one described as Lymphostat-BTM (belimumab) (Baker et al. (2003) Arthritis Rheum 48, 3253-3265).
  • the antagonist antibody is specific for APRIL and bind within a region of human APRIL (SEQ ID NO: 3).
  • the binding of the antibody is such that the antibody sterically hinders APRIL binding to one or more of its receptors.
  • BLyS/APRIL antagonistic antibodies include, for example, indirect antagonists which interact with TACI, BCMA, and BAFF-R and thereby prevent BLyS and APRIL from activating their receptors.
  • antagonistic antibodies include a TACI antibody that binds in a region of TACI (SEQ ID NO:4) such that the binding of BLyS is sterically hindered. For example, binding at amino acids 72-109 of SEQ ID NO:4 or a neighboring region of TACI is believed to block BLyS binding.
  • APRIL binding to TACI is believed to occur in the region of amino acids 82-222 of SEQ ID NO:4. Thus, binding of APRIL to this region of TACI can also be blocked.
  • Another BLyS/APRIL antagonist is a BAFF-R antibody that binds in a region of BAFF-R such that binding of human BAFF-R (SEQ ID NO: 6) to BLyS is sterically hindered. For example, binding at amino acids 23-38 or amino acids 17-42 of SEQ ID NO:6 or a neighboring region of BAFF-R is believed to block BLyS binding.
  • a further indirect antagonist would be a BCMA antibody that binds in a region of BCMA (SEQ ID NO:5) such that the binding of BLyS is sterically hindered. For example, binding at amino acids 5-43 of SEQ ID NO: 5 or a neighboring region of BCMA is believed to block BLyS (or APRIL) binding.
  • APRIL and BLyS receptors a combination of antibodies which block activation of all receptors (BAFF-R, TACI and BCMA) is preferred. iv. Other BLyS/ 'APRIL Antagonists
  • a BLyS/APRIL antagonist can include BLyS or
  • APRIL binding polypeptides that are not native sequences or variants of BLyS or APRIL.
  • BLyS antagonistic polypeptides are those having the sequence of Formula I, Formula II, Formula III as described in WO 05/000351.
  • some binding polypeptides include ECFDLLVRAWVPCSVLK (SEQ ID NO:9), ECFDLLVRHWVPCGLLR (SEQ ID NO: 10), ECFDLLVRRWVPCEMLG
  • BLyS/APRIL antagonistic peptides or small molecules include, for example, indirect antagonists which interact with TACI, BCMA, and BAFF-R and thereby prevent BLyS and APRIL from activating their receptors.
  • Such antagonistic peptides or small molecules can bind TACI in a region such that the binding of BLyS and/or APRIL is sterically hindered. For example, binding at amino acids 72-109 of SEQ ID NO:4 or a neighboring region of TACI is believed to block BLyS binding.
  • Another BLyS/APRIL antagonist is an antagonist peptide or small molecule that binds in a region of BAFF-R such that binding of human BAFF-R to BLyS is sterically hindered. For example, binding at amino acids 23-38 or amino acids 17-42 of SEQ ID NO: 6 or a neighboring region of BAFF-R is believed to block BLyS binding.
  • a further indirect antagonist would be an antagonistic peptide that binds in a region of BCMA such that the binding of BLyS and APRIL is sterically hindered. For example, binding at amino acids 5-43 of SEQ ID NO: 5 or a neighboring region of BCMA is believed to block BLyS (or APRIL) binding. It is recognized when employing an antagonistic peptide or small molecule that directly interacts with the various APRIL and BLyS receptors, a combination of molecules which block activation of all receptors (BAFF-R, TACI and BCMA) is preferred.
  • CD40 is a member of the tumor necrosis factor receptor superfamily and is broadly expressed by immune, hematopoietic, vascular, epithelial, and other cell types.
  • CD40 pathway refers to a compound, including for example, an antibody, a synthetic or native sequence peptide and/or a small molecule antagonist, that functions in a direct or indirect manner to partially or fully block, inhibit or neutralize CD40 signaling in vitro or in vivo.
  • Antagonism using the CD40 pathway antagonist does not necessarily result in the total elimination of CD40 signaling activity. Instead, the activity of the CD40 pathway could decrease by a physiological relevant amount including, for example, a decrease of at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 95% or 100% of the activity of CD40 signaling compared to an appropriate control.
  • the CD40 pathway antagonist comprises a "CD40 antagonist".
  • CD40 comprises a member of the TNF-receptor superfamily and is a co-stimulatory protein found on antigen presenting cells and is required for their activation.
  • the binding of CD 154 (CD40L) on T R cells to CD40 activates antigen presenting cells and induces a variety of downstream effects.
  • the CD40 receptor has been found to be essential in mediating a broad variety of immune and inflammatory responses including T cell-dependent immunoglobulin class switching, memory B cell development, and germinal center formation.
  • a CD40 antagonist inhibits/reduces, directly or indirectly, CD40 activity, interactions of CD40 with the CD40 ligands, or the functional responses mediated through CD40 signaling.
  • a CD40 antagonist will inhibit or reduce such activities by a physiologically relevant amount, including, at least by about 10%> or 20%>, more preferably by at least about 30%> or 40%>, still more preferably by at least about 50% or 60%, yet more preferably by at least about 70% or 80%) and most preferably by at least about 90%>.
  • Such antagonists can be identified by a number of art recognized APC- and/or T-cell functional assays, such as T cell proliferation and/or effector function, antibody production, cytokine production, and phagocyctosis.
  • the biological activity of the CD40 antagonist is determined, for example, by competition for binding to the ligand binding domain of CD40 (i.e. competitive binding assays). Both murine CD 154 and human CD 154 bind to human CD40.
  • CD40 antagonist will disrupt the CD40/CD154 interaction.
  • the CD40 pathway antagonist comprises an antagonist antibody that binds directly to CD40.
  • CD40 antagonistic antibodies include, but are not limited to, F33 (Ellmark et al. (2002) Immunology 106: 456-463), 4D11 (Aoyagi et al. (2009) Am J Transplant. 9(8): 1732-41), HCD122 (Luqman et al. (2008) Blood 112(3):711-20), 15B8 (US Patent 7445780), and 5D12 (US Patent 7361345).
  • Additional antagonistic antibodies that bind to CD40 and block/inhibit its function include, but are not limited to, Mab5D12 and variant thereof as disclosed in
  • the CD40 pathway antagonist comprises a "CD 154" or "CD40L” antagonist.
  • CD40L or sCD40L is interchangeable with
  • CD 154 represents a ligand for CD40 and the mammalian form of CD 154 and various variants thereof are characterized in US Publication 2003/0091564, which is herein incorporated by reference.
  • Such an antagonist inhibits/reduces, directly or indirectly, the ability of CD 154 from binding to the CD40 receptor or inhibits/reduces, directly or indirectly, the ability of CD 154 to activate CD40.
  • a CD 154 antagonist will inhibit or reduce the production, secretion, release, binding, uptake or biological activity of CD 154 by a physiological relevant amount, for example, by at least about 10% or 20%, by at least about 30% or 40%, by at least about 50% or 60%, by at least about 70% or 80%, or by at least about 90%.
  • the CD40 pathway antagonist comprises an antagonist antibody that binds directly to CD 154.
  • CD 154 antagonistic antibodies include BG9588 (Boumpas et al. (2003) Arthritis Rheum 48(3):719-27), hu5C8 (Huang et al. (2002) Arthritis Rheum 46(6): 1554-62), IDEC-131 (Brams et al. (2001) Int Immunopharmacol l(2):277-94), MR-1 (Stein (1998) Gene Ther 5(4):431-9), each of these references is herein incorporated by reference.
  • Small molecule antagonists of CD40/CD154 are also known. See, for example, Margolles-Clark et al. (2009) Journal of Molecular Medicine 87:1133-1143.
  • the CD40 pathway antagonist comprises an immunoglobulin fusion protein which comprises a first polypeptide having an antagonistic activity for the CD40 pathway operably linked to at least one constant region domain of an immunoglobulin.
  • the CD40 antagonist comprises a CD40 pathway antagonist polypeptide-Ig fusion protein.
  • the CD40 pathway antagonist polypeptide comprises at least the extracellular domain or active variant or fragment thereof of receptors found in the CD40 pathway, including, the extracellular domain from CD40 or from CD 154.
  • constant region domains of immunoglobulins that can be employed in these CD40 pathway antagonist-Ig fusion proteins and can comprise, for example, a C H I domain, a C H 2 domain, or a C H 3 domain, or an Fc fragment of an immunoglobulin heavy chain.
  • Exemplary Fc fragments of an immunoglobulin heavy chain include, with or without a hinge region, an Fc fragment comprising a C R 3 domain, or a C R 3 domain and a C H 2 domain.
  • the various domains of the heavy chain constant region can be obtained from any immunoglobulin, such as IgGi, IgG 2 , IgG 3 , or IgG 4 subtypes, IgA (including IgAi and IgA 2 ), IgE, IgD or IgM.
  • immunoglobulin such as IgGi, IgG 2 , IgG 3 , or IgG 4 subtypes, IgA (including IgAi and IgA 2 ), IgE, IgD or IgM.
  • Modified version of human IgGi Fc can also be used, such as, Fcyl, Fc4, Fc5, and Fc6, which are described elsewhere herein.
  • a CD40 pathway antagonist-Ig fusion protein can be produced by recombinant methods according to standard techniques (e.g., see Current Protocols in Molecular
  • the CD40 antagonistic polypeptide comprises of a portion of the CD40 polypeptide (e.g., a portion after cleavage of the signal sequence) that is sufficient to continue to bind the ligand, CD 154.
  • the second peptide can include an immunoglobulin constant region domain (see, for example, U.S. Pat. Nos. 5,116,964; 5,580,756; 5,844,095); a GST peptide, or an influenza hemagglutinin epitope tag (HA) (e.g. Herrsher et al. (1995) Genes Dev.
  • Such fusion proteins can be monovalent or bivalent as is recognized in the art.
  • the immunoglobulin constant region may contain genetic modifications which reduce or eliminate effector activity inherent in the immunoglobulin structure. See, for example, WO 97/28267. III. Antibodies and Antibody Fragments
  • the BLyS/APRIL antagonist and/or the CD40 pathway antagonist comprises an antagonist antibody.
  • these antagonist antibodies are collectively referred to as “antagonistic BLyS/APRIL antibodies” and “antagonistic CD40 pathway antibodies”. All of these antibodies are encompassed by the discussion herein.
  • the respective antibodies can be used alone or in combination in the methods of the invention.
  • the term "antibody” is used in the broadest sense and specifically covers, for example, monoclonal antibodies, polyclonal antibodies, antibodies with polyepitopic specificity, single chain antibodies, and fragments of antibodies.
  • Antibodies also include fragments of the above (e.g., CDR's, CDR3, single-chain antibodies, FAV, and the like which confer the binding specificity of the antibody to the target.
  • the antibody employed herein can be chimeric, humanized, or human antibody.
  • antibodies that specifically bind is intended that the antibodies will not substantially cross-react with another polypeptide.
  • not substantially cross react is intended that the antibody or fragment has a binding affinity for a non-homologous protein which is less than 10%, more preferably less than 5%, and even more preferably less than 1%, of the binding affinity for its given target.
  • polyclonal sera may be prepared by conventional methods.
  • a solution containing the desired antigen is first used to immunize a suitable animal, preferably a mouse, rat, rabbit, or goat.
  • Rabbits or goats are preferred for the preparation of polyclonal sera due to the volume of serum obtainable, and the availability of labeled anti-rabbit and anti-goat antibodies.
  • Polyclonal sera can be prepared in a transgenic animal, preferably a mouse bearing human immunoglobulin loci. Immunization can also be performed by mixing or emulsifying the antigen-containing solution in saline, preferably in an adjuvant such as Freund's complete adjuvant, and injecting the mixture or emulsion parenterally
  • Immunization is generally boosted 2-6 weeks later with one or more injections of the protein in saline, preferably using Freund's incomplete adjuvant.
  • Polyclonal antisera are obtained by bleeding the immunized animal into a glass or plastic container, incubating the blood at 25°C for one hour, followed by incubating at 4°C for 2-18 hours. The serum is recovered by centrifugation ⁇ e.g., 1,000 x g for 10 minutes). About 20-50 ml per bleed may be obtained from rabbits.
  • the term "monoclonal antibody” as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that can be present in minor amounts.
  • Monoclonal antibodies are highly specific, being directed against a single antigenic site. Furthermore, in contrast to conventional (polyclonal) antibody
  • each monoclonal antibody is directed against a single determinant on the antigen.
  • the monoclonal antibodies are advantageous in that they are synthesized by the hybridoma culture, uncontaminated by other immunoglobulins.
  • the modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.
  • the monoclonal antibodies to be used in accordance with the present invention may be made by the hybridoma method first described by Kohler et al.
  • the "monoclonal antibodies” may also be isolated from phage antibody libraries using the techniques described in Clackson et al. (1991) Nature 352: 624-628 and Marks et al. (1991) J. Mol. Biol. 222: 581-597, for example.
  • the monoclonal antibodies herein specifically include "chimeric" antibodies (immunoglobulins) in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain (s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (U.S. Patent No. 4,816, 567; Morrison et al. (1984) Proc. Natl. Acad. Sci. USA, 81 : 6851- 6855). Methods of making chimeric antibodies are known in the art.
  • “Humanized” forms of non-human (e.g., murine) antibodies are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab', F (ab') 2 or other antigen-binding subsequences of antibodies) which contain minimal sequence derived from non-human immunoglobulin.
  • humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a complementarity-determining region (CDR) of the recipient are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat or rabbit having the desired specificity, affinity, and capacity.
  • CDR complementarity-determining region
  • donor antibody non-human species
  • Fv framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues.
  • humanized antibodies may comprise residues which are found neither in the recipient antibody nor in the imported CDR or framework sequences. These modifications are made to further refine and maximize antibody performance.
  • the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin sequence although the FR regions may include one or more amino acid substitutions that improve binding affinity. The number of these amino acid
  • the humanized antibody optimally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin.
  • Fc immunoglobulin constant region
  • the humanized antibody includes a PRIMATIZED antibody wherein the antigen-binding region of the antibody is derived from an antibody produced by, e.g., immunizing macaque monkeys with the antigen of interest. Methods of making humanized antibodies are known in the art.
  • Human antibodies can also be produced using various techniques known in the art, including phage-display libraries. Hoogenboom and Winter (1991) J. Mol.Biol. 227: 381; Marks et al. (1991) J. Mol. Biol. 222: 581. The techniques of Cole et al. and
  • Boerner et al. are also available for the preparation of human monoclonal antibodies.
  • fragment refers to a portion of the amino acid sequence of a polypeptide or protein, or polynucleotide encoding a portion of the amino acid sequence of a polypeptide or protein. Fragments may retain the activity of the original protein and hence, such "active" fragments include, for example, fragments of an extracellular domain of TACI, BCMA, BAFF-R, CD40 or CD 154 which continue to bind their ligand, and thereby act as BLyS/APRIL antagonists.
  • active fragments of an extracellular domain of TACI, BCMA, BAFF-R, CD40 or CD 154 can encode at least 15, 25, 30, 50, 100, 150, 200, or 250 contiguous amino acids, or up to the total number of amino acids present in a full-length extracellular domain.
  • active fragments of a nucleotide sequence can range from at least 20 nucleotides, 50 nucleotides, 100 nucleotides, and up to the full-length polynucleotide encoding an active extracellular domain of TACI, BCMA, BAFF-R, CD40 or CD 154.
  • Variant protein is intended to mean a protein derived from a native and/or original protein by deletion (so-called truncation) of one or more amino acids at the N- terminal and/or C-terminal end of the protein; deletion and/or addition of one or more amino acids at one or more internal sites in the protein; or substitution of one or more amino acids at one or more sites in the protein.
  • Variant proteins encompassed by the present invention are active. Active variants continue to possess the desired activity, i.e., having antagonistic activity against BLyS and/or APRIL.
  • active variants of an antagonistic polypeptide of the invention will have at least 40%, 45%, 50%>, 55%>, 60%>, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to the amino acid sequence for the native protein as determined by sequence alignment programs and parameters described elsewhere herein.
  • An active variant of a polypeptide may differ from that polypeptide by as few as 1-15 amino acid residues, as few as 1-10, such as 6-10, as few as 5, as few as 4, 3, 2, or even 1 amino acid residue.
  • the extracellular domain of TACI, BCMA, BAFF-R, CD40 or CD 154 may be altered in various ways including amino acid substitutions, deletions, truncations, and insertions. Methods for such manipulations are generally known in the art.
  • active amino acid sequence variants and fragments of the extracellular domains of the TACI, BCMA and BAFF-R, CD40 or CD 154 can be prepared by mutations in the encoding polynucleotide. Methods for mutagenesis and polynucleotide alterations are well known in the art. See, for example, Kunkel (1985) Proc. Natl. Acad. Sci. USA 82: 488-492; Kunkel et al. (1987) Methods in Enzymol. 154: 367-382; U.S. Patent No.
  • a "native sequence" polypeptide comprises a polypeptide having the same amino acid sequence as the corresponding polypeptide derived from nature. Such native sequence polypeptides can be isolated from nature or can be produced by recombinant and/or synthetic means.
  • the term "native sequence” specifically encompasses naturally-occurring truncated, soluble or secreted forms (e. g., an extracellular domain sequence), naturally-occurring variant forms (e. g., alternatively spliced forms) and naturally-occurring allelic variants of the polypeptide.
  • sequence identity or “identity” in the context of two
  • polynucleotides or polypeptide sequences makes reference to the residues in the two sequences that are the same when aligned for maximum correspondence over a specified comparison window.
  • residue positions which are not identical often differ by conservative amino acid substitutions, where amino acid residues are substituted for other amino acid residues with similar chemical properties (e.g., charge or
  • sequences differ in conservative substitutions the percent sequence identity may be adjusted upwards to correct for the conservative nature of the substitution. Sequences that differ by such conservative substitutions are said to have "sequence similarity" or “similarity”. Means for making this adjustment are well known to those of skill in the art. Typically this involves scoring a conservative substitution as a partial rather than a full mismatch, thereby increasing the percentage sequence identity. Thus, for example, where an identical amino acid is given a score of 1 and a non-conservative substitution is given a score of zero, a conservative substitution is given a score between zero and 1. The scoring of conservative substitutions is calculated, e.g., as implemented in the program PC/GENE (Intelligenetics, Mountain View, California).
  • percentage of sequence identity means the value determined by comparing two optimally aligned sequences over a comparison window, wherein the portion of the polynucleotide sequence in the comparison window may comprise additions or deletions (i.e., gaps) as compared to the reference sequence (which does not comprise additions or deletions) for optimal alignment of the two sequences. The percentage is calculated by determining the number of positions at which the identical nucleic acid base or amino acid residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison, and multiplying the result by 100 to yield the percentage of sequence identity.
  • sequence identity/similarity values provided herein refer to the value obtained using GAP Version 10 using the following parameters: % identity and % similarity for a nucleotide sequence using GAP Weight of 50 and Length Weight of 3, and the nwsgapdna.cmp scoring matrix; % identity and % similarity for an amino acid sequence using GAP Weight of 8 and Length Weight of 2, and the BLOSUM62 scoring matrix; or any equivalent program thereof.
  • equivalent program is intended any sequence comparison program that, for any two sequences in question, generates an alignment having identical nucleotide or amino acid residue matches and an identical percent sequence identity when compared to the corresponding alignment generated by GAP Version 10.
  • the BLyS/APRIL antagonist and the CD40 pathway antagonist can be incorporated into pharmaceutical compositions suitable for administration.
  • the BLyS/APRIL antagonist and the CD40 pathway antagonist can be formulated in separate pharmaceutical compositions or can be formulated within a single pharmaceutical composition for simultaneous administration.
  • Such compositions typically comprise each antagonist separately or in combination and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration.
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions.
  • a pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration.
  • routes of administration include parenteral, e.g., intravenous, intradermal, or subcutaneous administration.
  • This can be achieved by, for example, local or regional infusion or perfusion during surgery, injection, catheter, or implant (for example, implants formed from porous, non-porous, or gelatinous materials, including membranes, such as sialastic membranes or fibers), and the like.
  • administration can be by direct injection at the site (or former site) of a graft transplant.
  • the therapeutically effective amount of the pharmaceutical composition is delivered in a vesicle, such as liposomes (see, e.g., Langer, Science 249:1527-33, 1990 and Treat et al., in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez Berestein and Fidler (eds.), Liss, N.Y., pp. 353-65, 1989).
  • the therapeutically effective amount of the pharmaceutical composition can be delivered in a controlled release system.
  • a pump can be used (see, e.g., Langer, Science 249: 1527-33, 1990; Sefton, Crit. Rev. Biomed. Eng. 14:201-40, 1987; Buchwald et al, Surgery 88:507-16, 1980; Saudek et al., N. Engl. J. Med. 321 :574-79, 1989).
  • polymeric materials can be used (see, e.g., Levy et al., Science 228:190-92, 1985; During et al., Ann. Neurol. 25:351-56, 1989; Howard et al, J. Neurosurg. 71 : 105-12, 1989).
  • Other controlled release systems such as those discussed by Langer (Science 249: 1527-33, 1990), can also be used.
  • Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
  • the parenteral preparation can be enclosed in ampoules, disposable syringes, or multiple dose vials made of glass or plastic.
  • compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the
  • suitable carriers include physiological saline, bacteriostatic water, Cremophor ELO (BASF; Parsippany, NJ), or phosphate buffered saline (PBS).
  • the composition must be sterile and should be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants.
  • Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride, in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and freeze-drying, which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the subject to be treated with each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.
  • compositions can be included in a container, pack, or dispenser together with instructions for administration.
  • NSAIDS nonsteroidal anti-inflammatory drugs
  • diclofenac sodium, indomethacin diflunisal and nabumetone anti-malarials
  • hydroxychloroquine sulfate and chloroquine corticosteroids such as prednisone, hydrocortisone, and methylprednisolone
  • immunosuppressives such as azathioprine, cyclophosphamide, methotrexate, cyclosporine, and mycophenolate mofetil, and IVIg
  • a pharmaceutical composition comprises a therapeutically effective amount of a combination therapy comprising the polypeptide set forth in SEQ ID NO: 8 or an active variant or fragment thereof and the MR1 antibody.
  • Methods that promote immune tolerance and act to reduce an immune response in a subject in need thereof.
  • the methods comprise administering to the subject a therapeutically effective amount of a combination therapy comprising a
  • BLyS/APRIL antagonist e.g., TACI-Ig fusion protein, including for example, the TACI- Ig fusion protein set forth in SEQ ID NO : 8 or an active variant or fragment thereof
  • CD40 pathway antagonist e.g., CD40-Ig fusion protein, including for example, the TACI- Ig fusion protein set forth in SEQ ID NO : 8 or an active variant or fragment thereof
  • TACI-Ig fusion protein including for example, the TACI- Ig fusion protein set forth in SEQ ID NO : 8 or an active variant or fragment thereof
  • CD40 pathway antagonist e.g., CD40 pathway antagonist.
  • the immunoglobulins in the serum of the subject can be employed to reduce an immune response to a foreign antigen (i.e., a decrease in alloantibody levels or xenoantibody levels) and/or in treating a subject having an immune-mediated disorder, such as an autoimmune disorder or an inflammatory disorder.
  • a foreign antigen i.e., a decrease in alloantibody levels or xenoantibody levels
  • an immune-mediated disorder such as an autoimmune disorder or an inflammatory disorder.
  • the combination therapy comprising a BLyS/APRIL antagonist and a CD40 pathway antagonist prevents or treats graft transplant rejection, reduces anti-graft responses in a subject in need thereof, prolongs graft transplant survival and/or treats or prevents graft-vs.-host disease.
  • autoimmune diseases include arthritis (rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, psoriatic arthritis), psoriasis, dermatitis including atopic dermatitis; chronic autoimmune urticaria,
  • polymyositis/dermatomyositis polymyositis/dermatomyositis, toxic epidermal necrolysis, systemic scleroderma and sclerosis, responses associated with inflammatory bowel disease (IBD) (Crohn's disease, ulcerative colitis), respiratory distress syndrome, adult respiratory distress syndrome (ARDS), meningitis, allergic rhinitis, encephalitis, uveitis, colitis, glomerulonephritis, allergic conditions, eczema, asthma, conditions involving infiltration of T cells and chronic inflammatory responses, atherosclerosis, autoimmune myocarditis, leukocyte adhesion deficiency, systemic lupus erythematosus (SLE), lupus (including nephritis, non-renal, discoid, alopecia), juvenile onset diabetes, multiple sclerosis, allergic encephalomyelitis, immune responses associated with acute and delayed hypersensitivity mediated by cytok
  • Glomerulonephritis Primary biliary cirrhosis, Celiac sprue (gluten enteropathy),
  • methods to reduce antibody levels in a mammal in need thereof; method to reduce alloantibody levels (including IgG alloantibody levels), method to reduce xenoantibody levels (including IgG xenoantibody levels), method to reduce donor-reactive antibody levels (including
  • the methods comprise administering to the mammal a therapeutically effective amount of a combination therapy comprising (a) a TACI-immunoglobulin fusion protein comprising the extracellular domain of TACI or an active fragment thereof; and, (b) an antagonist of the CD40 pathway.
  • a combination therapy comprising (a) a TACI-immunoglobulin fusion protein comprising the extracellular domain of TACI or an active fragment thereof; and, (b) an antagonist of the CD40 pathway.
  • the TACI-Ig fusion protein comprises the sequence set forth in SEQ ID NO: 8 or an active variant or fragment thereof.
  • the combination therapy comprises the TACI-Ig fusion protein and the MR1 anti-CD 154 antibody.
  • the combination therapy can decrease antibody titers (including IgG antibody titers, or other combination of antibody classes as discussed herein) in the serum of the mammal by a statistically significant amount including a reduction of about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%,
  • the combination therapy can decrease alloantibody titers (including IgG alloantibody titers, or other combination of alloantibody classes as discussed herein) in the serum of the mammal by a statistically significant amount including a reduction of about 5%, 10%>, 15%, 20%>, 30%>, 40%>, 50%>, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100%.
  • the combination therapy can decrease xenoantibody titers (including IgG xenoantibody titers, or other combination of xenoantibody classes as discussed herein) in the serum of the mammal by a statistically significant amount including a reduction of about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100%.
  • a biological sample from the subject is not analyzed for an elevated level of BLyS/APRIL heterotrimer (HT), APRIL, or BCMA prior to administration of the combination therapy.
  • HT BLyS/APRIL heterotrimer
  • APRIL APRIL
  • BCMA BCMA
  • a biological sample from the subject need not be analyzed for an elevated level of BLyS/APRIL heterotrimer (HT), APRIL, or BCMA prior to administration of said combination therapy.
  • the methods employed herein do not require that the biological sample from the subject be analyzed for an elevated level of BLyS/APRIL heterotrimer (HT), APRIL, BCMA, TACI, BAFF-R, and/or BLyS prior to administration of the combination therapy.
  • a biological sample from the subject is not analyzed for an elevated level of BLyS/APRIL heterotrimer (HT), APRIL, BCMA, TACI, BAFF-R, and/or BLyS prior to administration of the combination therapy.
  • the elevated level of APRIL or BLyS can be detected by either detecting the homotrimer of each protein form, or alternatively, by detecting the level of the individual subunit of each homotrimer.
  • Treatment is herein defined as curing, healing, alleviating, relieving, altering, remedying, ameliorating, improving, or affecting the condition or the symptoms of a subject with an immune-mediated disorder, including for example, transplant rejections or graft-vs-host disease.
  • the subject to be treated can be suffering from or at risk of developing an immune-mediated disorder, including, for example, be in need of a reduction in immunoglobulin levels, being prepared for a graft transplantation procedure, has undergone a graft transplantation procedure, or is suffering from or is at risk of suffering from host-vs-graft disease.
  • treatment is also intended that the
  • combination of the BLyS/APRIL antagonist and the CD40 pathway antagonist is administered to the subject as part of a single pharmaceutical composition, or
  • each comprising either the BLyS/APRIL antagonist or the CD40 pathway antagonist.
  • Administration of the BLyS/APRIL antagonist in combination with the CD40 pathway antagonist can be for either a prophylactic or therapeutic purpose.
  • preventing is intended that the combination of agents is provided prophylactically, i.e., the combination is provided in advance of any symptom.
  • administration of the combination of agents serves to prevent or attenuate any
  • the substance When provided therapeutically, the substance is provided at (or shortly after) the onset of a symptom.
  • the therapeutic administration of the substance serves to attenuate any actual symptom.
  • methods are provided to treat or prevent or prolong the development of graft transplantation rejection or host-vs-graft disease in a subject.
  • a "graft” as used herein refers to biological material derived from a donor for
  • Grafts include such diverse material as, for example, isolated cells such as islet cells; tissue such as the amniotic membrane of a newborn, bone marrow, hematopoietic precursor cells, stem cells, neuronal or embryonic cells, and ocular tissue, such as corneal, macular or retinal, tissue; and organs such as heart, skin, liver, spleen, pancreas, thyroid lobe, lung, kidney, tubular organs (e.g., intestine, blood vessels, or esophagus), etc.
  • the tubular organs can be used to replace damaged portions of esophagus, blood vessels, or bile duct.
  • the skin grafts can be used not only for burns, but also as a dressing to damaged intestine or to close certain defects such as
  • the graft is derived from any mammalian source, including human, whether from cadavers or living donors.
  • the graft is bone marrow or an organ such as heart and the donor of the graft and the host are matched for HLA class II antigens.
  • a "donor" as used herein refers to the mammalian species, dead or alive, from which the graft is derived.
  • subject is intended mammals, e.g., primates, humans, agricultural and domesticated animals such as, but not limited to, dogs, cats, cattle, horses, pigs, sheep, and the like.
  • the subject undergoing treatment with the pharmaceutical formulations of the invention is a human.
  • the subjects of the invention may be suffering from the symptoms of transplant rejection or graft- vs-host disease or may be at risk for transplant rejection or graft-vs-host disease (e.g. a subject that will undergo transplantation procedures).
  • a “mammalian subject host” refers to any compatible transplant recipient.
  • compatible is meant a mammalian subject host that will accept the donated graft (e.g., heart allograft). If both the donor of the graft and the host are human, they are preferably matched for HLA class II antigens so as to improve histocompatibility.
  • transplant or “transplantation” and variations thereof refers to the insertion of a graft into a host, whether the transplantation is syngeneic (where the donor and recipient are genetically identical), allogeneic (where the donor and recipient are of different genetic origins but of the same species), or xenogeneic (where the donor and recipient are from different species).
  • the host is human and the graft is an allograft, derived from a human of the same or different genetic origins.
  • the host is human and the graft is a heart allograft, derived from a human of the same or different genetic origins.
  • the graft is derived from a species different from that into which it is transplanted, such as a baboon heart transplanted into a human recipient host, and including animals from phylogenically widely separated species, for example, a pig heart valve, or animal beta islet cells or neuronal cells transplanted into a human host.
  • the methods of the invention can be used to treat or prevent various forms of graft rejections.
  • the methods can be used to treat or prevent acute rejection, hyperacute rejection and/or chronic rejection.
  • acute rejection refers to onset of a primary immune response to a graft, generally within days or weeks, and up to about
  • the immune response is caused by T cell recognition of the transplanted tissue associated with e.g., prominent local cytokine production, widespread pro-inflammatory activation of vascular endothelia, intense leukocyte infiltration, and development of graft-reactive, cytolytic T cells (CTL) that has traditionally been associated with the acute loss of graft function.
  • CTL cytolytic T cells
  • the methods of the invention treat or prevent hyperacute rejection.
  • a "hyperacute rejection” is a type of rejection that occurs very rapidly, resulting in necrosis of the transplanted tissue within minutes or a few hours of contact, and is caused by reactivity of the donor cells with pre-existing antibody.
  • chronic rejection refers to indolent, progressive immune responses that often occur one or more years after transplantation. Chronic rejection usually manifests in vascularized solid organ allografts as obliterative arteriopathy or graft vascular disease (GVD), infiltration of immunocytes, interstitial and tubularatrophy, graft arteriosclerosis, and a marked fibrosis.
  • VLD graft vascular disease
  • graft-versus-host reaction or disease refers to the pathologic consequences of a response initiated by transplanted immunocompetent T lymphocytes into an allogeneic or xenogeneic, immunologically incompetent host.
  • the host is unable to reject the grafted T cells and the transplanted T lymphocytes attack the tissues of the recipient due to recognition of recipient's antigens on recipient's MHC molecules (not necessarily by recipient's tissues).
  • the administration of the BLyS/APRIL antagonist in combination with the CD40 pathway antagonist results in a statistically significant decrease in an anti-graft response of the subject having undergone treatment (e.g., a heart allograft transplantation) compared to a subject not having undergone the treatment.
  • undergone treatment e.g., a heart allograft transplantation
  • a decreased anti-graft response can be measured by a number of clinical symptoms known to those of skill in the art and can be reflected in a reduction in the level of immunoglobulins in the serum of the patient, including, for example, a reduction in the level of alloantibody or xenoantibody production against the graft tissue (e.g., heart allograft) or a reduction in the level of donor-reactive antibody production against the graft tissue, including a reduction in any of the antibody or alloantibody or xenoantibody classes or combinations thereof as described elsewhere herein.
  • the decrease in the anti-graft response can occur for at least at least about 1 week, 1 month, 6 months, 1 year or more.
  • the therapy disclosed herein can be used to achieve at least 2, 3, 4, 5, 6, 7,
  • the decrease in the anti-graft response can be achieved through repeated administration of the therapy over this time period or it can be achieved after the termination of the treatment.
  • the phrase "long-term decrease or prevention of an anti-graft response" refers to a significant decrease in the anti-graft response in a subject for an extensive period of time, such as one or more years, preferably several years, and more preferably life.
  • the methods disclosed here provide for delaying the onset of an anit-graft response by a statistically significant amount when compared to an appropriate control.
  • the delayed onset can about a 5%, 10%, 15%, 20%, 25%, 30%, 50%, 60%, 70%, 80%,
  • the graft survival time can be increased employing the methods disclosed herein by at least 5%, 10%, 15%, 20%, 25%, 30%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200% or greater increase in time compared to an appropriate control (i.e., a patient not receiving the combination therapy disclosed herein).
  • the combination therapy when the combination therapy is administered to treat or prevent transplantation rejection or graft- vs. -host disease, the combination therapy can result in a decrease in serum antibody titers or a decrease in serum alloantibody titers or a decrease in serum xenoantibody titers, including serum IgG antibody and/or IgG alloantibody and/or IgG xenoantibody titers, within at least 30 days, 25 days, 20 days, 15 days, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 day post-graft transplantation.
  • the methods disclosed herein provide for delaying the onset of transplantation rejection or graft-vs.-host disease by a statistically significant amount when compared to an appropriate control.
  • the delayed onset can be by about
  • the methods provided herein find use in delaying memory CD4 T cell induced alloantibody responses in heart allograft recipients. This delay may attenuate antibody-mediated allograft injury, but, in some embodiments, may also hinders the kinetics of T cell priming and/or impairs T cell trafficking into the graft, thus leading to prolonged allograft survival.
  • the methods of the invention comprise using a combination therapy.
  • combination is used in its broadest sense and means that a subject is treated with at least two therapeutic agents, more particularly a BLyS/APRIL antagonist and a CD40 pathway.
  • the timing of administration of the BLyS/APRIL antagonist and the CD40 pathway antagonist can be varied so long as the beneficial effects of the combination of these agents are achieved.
  • in combination with refers to the administration of a BLyS/APRIL antagonist with a CD40 pathway antagonist either simultaneously, sequentially, or a combination thereof.
  • a subject undergoing a combination therapy of the invention can receive the BLyS/APRIL antagonist and the CD40 pathway antagonist at the same time (i.e., simultaneously) or at different times (i.e., sequentially, in either order, on the same day or on different days), so long as the therapeutic effect of the combination of both agents is achieved in the subject undergoing therapy.
  • BLyS/APRIL antagonist and the CD40 pathway antagonist are administered
  • compositions each comprising either a BLyS/APRIL antagonist or a CD40 pathway antagonist, or can be administered as a single pharmaceutical composition comprising both agents.
  • the methods of the invention comprise administering to a subject a
  • a BLyS/APRIL antagonist in combination with a CD40 pathway antagonist.
  • Any method for administering the BLyS/APRIL antagonist and/or the CD40 pathway antagonist to a subject may be used in the practice of the invention.
  • routes of administration include parenteral, (e.g., intravenous (IV), intramuscular (IM), intradermal, subcutaneous (SC), or infusion) administration.
  • terapéuticaally effective dose By “therapeutically effective dose,” “therapeutically effective amount,” or “effective amount” is intended an amount of the BLyS/APRIL antagonist that, when administered in combination with an amount of a CD40 pathway antagonist, brings about a positive therapeutic response with respect to treatment or prevention.
  • “Positive therapeutic response” refers to, for example, improving the condition of at least one of the symptoms of an immune mediated disorder.
  • the administration may be by continuous infusion or by single or multiple boluses.
  • one or both of the agents is infused over a period of less than about 4 hours, 3 hours, 2 hours or 1 hour.
  • the infusion occurs slowly at first and then is increased over time.
  • the dosage of the combination of agents will vary depending upon such factors as the patient's age, weight, height, sex, general medical condition and previous medical history.
  • the range of administration can be from about 1 to 20 mg/kg, 5 to 10 mg/kg, 2 to 10 mg/kg, 10 to 20 mg/kg, 5 to 15 mg/kg, 1 to 10 mg/kg, 0.1 to 5 mg/kg, 1 to 5 mg/kg, 1 to 3 mg/kg, 2 to 5 mg/kg or any range in between 1 and 20 mg/kg.
  • the CD40 pathway antagonist in the range of from about 1 to 100 mg/kg, 20 to 30mg/kg, 30 to 40 mg/kg, 40 to 50 mg/kg, 50 to 60 mg/kg, 60 to 70 mg/kg, 70 to 80 mg/kg, 80 to lOOmg/kg, 1 to 20 mg/kg, 5 to 10 mg/kg, 2 to 10 mg/kg, 10 to 20 mg/kg, 5 to 15 mg/kg, 1 to 10 mg/kg, 1 to 5 mg/kg, 2 to 5 mg/kg or any range in between 1 and 20 mg/kg.
  • the range of administration can be from about 1 to 100 mg/kg, 20 to 30mg/kg, 30 to 40 mg/kg, 40 to 50 mg/kg, 50 to 60 mg/kg, 60 to 70 mg/kg, 70 to 80 mg/kg, 80 to lOOmg/kg, 5 to 10 mg/kg, 2 to 10 mg/kg, 10 to 20 mg/kg, 5 to 15 mg/kg, 1 to 10 mg/kg, 1 to 5 mg/kg, 2 to 5 mg/kg or any range in between 1 and 100 mg/kg.
  • the timing of administration of the BLyS/APRIL antagonist and the CD40 pathway antagonist can vary.
  • Each agent can be administered simultaneously or separately pre or post-graft transplantation.
  • both agents can be
  • the agents can be administered consecutively but prior to graft transplantation, during the graft transplantation procedure, following graft
  • the antagonist of the CD40 pathway is administered prior to transplantation and the TACI immunoglobulin fusion protein is administered following transplantation.
  • Administration of the BLyS/APRIL antagonist and/or CD40 pathway antagonist prior to the graft transplantation procedure can act to "desensitize" a mammal awaiting transplantation and thereby reduce or abolish allergic sensitivity or reactivity to a graft transplant, prior to administration of the transplant to the mammal.
  • one or both of the BLyS/APRIL antagonist and CD40 pathway antagonist are administered prior to graft transplantation.
  • the method comprises administration of multiple doses of a BLyS/APRIL antagonist in combination with multiple doses of a CD40 pathway antagonist.
  • the method may comprise administration of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, or more therapeutically effective doses of a pharmaceutical composition comprising either a BLyS/APRIL antagonist or a CD40 pathway antagonist, or both.
  • the frequency and duration of administration of multiple doses of the pharmaceutical compositions is such as to reduce an immune response and thereby treat or prevent immune-mediated disorders (e.g., transplant rejection or graft-vs- host disease) or decrease the level of immunoglobulins in a subject in need thereof.
  • combination of a BLyS/APRIL antagonist and a CD40 pathway antagonist can include a single treatment or can include a series of treatments. It will also be appreciated that the effective dosage of a BLyS/APRIL antagonist or CD40 pathway antagonist used for treatment may increase or decrease over the course of a particular treatment. Changes in dosage may result and become apparent from the results of diagnostic assays known in the art.
  • the BLyS/APRIL antagonist and/or the CD40 antagonist can be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection can be presented in unit dosage form, e.g., in ampoules or in multidose containers, with an added preservative.
  • the compositions can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing, and/or dispersing agents.
  • the exact formulation, route of administration, and dosage of the BLyS/APRIL antagonist and the CD40 pathway antagonist can be chosen by the individual physician in view of the patient's condition. Dosage amount and dosing intervals can be adjusted individually to provide plasma levels of the BLyS/APRIL antagonist and the CD40 pathway antagonist that are sufficient to maintain positive therapeutic effects.
  • Such therapies include but are not limited to therapies employed to treat or prevent various immune-mediated disorders, including, transplant rejection or graft- vs-host disease including for example, inhaled cyclosporine, corticosteroids, calcineurin inhibitors, anti-proliferative agents, and/or mTOR inhibitors.
  • a physician of ordinary skill in the art can determine when treatment of an immune-mediated disorder should be initiated and for how long the treatment should continue. Such treatment decisions may be supported by standard clinical laboratory results which monitor the clinical manifestations of an immune mediated disorder.
  • the methods of the invention may be practiced by continuously or intermittently
  • BLyS/APRIL antagonist in combination with a CD40 pathway antagonist for as long as deemed efficacious.
  • the decision to end therapy by the method of the invention may also be supported by standard clinical laboratory results indicating the disappearance of at least one of the clinical symptoms associated with transplant rejection or host-vs-graft disease.
  • a physician may choose to initiate the therapeutic methods described herein for a patient at risk of developing prior to the appearance of clinical symptoms associated with transplant rejection.
  • Factors influencing the mode of administration and the respective amount of the combination of agents disclosed herein include, but are not limited to, the severity of the disease, the history of the disease, and the age, height, weight, health, medical history
  • combination of therapeutic agents disclosed herein to be administered will be dependent upon the mode of administration and whether the subject will undergo a single dose or multiple doses of these recited APRIL/BLyS antagonist and CD40 pathway antagonist. Generally, a higher dosage of is preferred with increasing weight of the patient undergoing therapy.
  • Treatment regimens will be based on doses and dosing schedules that maximize therapeutic effects.
  • BLyS/APRIL antagonist and a CD40 pathway antagonist can be determined.
  • BLyS/APRIL antagonist and the CD40 pathway antagonist may comprise doses of the individual agents that, when administered alone, would not be therapeutically effective or would be less therapeutically effective than when administered in combination with each other.
  • a synergistic therapeutic effect may be observed when a BLyS/APRIL antagonist and the CD40 pathway antagonist are administered in combination.
  • “Synergistic therapeutic effect” refers to a therapeutic effect observed with a
  • the therapeutic effect (as measured by any of a number of parameters including a synergistic decrease in the level of the serum immunoglobulins, including any one or combination of IgE, IgG, IgM, IgD, and/or IgA or as measured by a synergistic decrease in the level of the donor-reactive
  • immunoglobulins including any one or combination of donor-reactive IgE, IgG, IgM, IgD, and/or IgA) is greater than the sum of the respective individual therapeutic effects observed with the respective individual therapies.
  • the combination of a BLyS/APRIL and the CD40 pathway antagonist may produce a synergistic effect that permits a reduction in the dosages of these agents and an improvement of the clinical outcome of the subject being treated.
  • a reduced dose of the BLyS/APRIL antagonist and the CD40 pathway antagonist may in turn reduce unwanted side effects associated with each agent.
  • the present invention also provides for the use of a BLyS/APRIL antagonist in the manufacture of a medicament for treating, decreasing an anti-graft response, preventing an immune mediated disorder such as graft-vs-host-disease and/or transplant rejection or reducing the level of serum immunoglobulins or donor-reactive
  • immunoglobulins in a subject in need thereof, wherein the medicament is coordinated with treatment using a CD40 pathway antagonist.
  • coordinated is intended that the medicament comprising the BLyS/APRIL antagonist is to be used either prior to, during, or after treatment of the subject using a CD40 pathway antagonist.
  • the combination of agents is a synergistic combination that produces a synergistic therapeutic effect.
  • helper CD4 T cells specific for the same set of donor antigens.
  • this help is delivered by activated helper CD4+ T cells in germinal centers within secondary lymphoid organs and is largely dependent on the CD40/CD154 co- stimulatory pathway.
  • primary T cells responses are efficiently controlled by current graft-prolonging therapies, the T cell repertoire of many human transplant recipients contains alloreactive memory CD4+ T cells. Due to their enhanced survival, activation and trafficking properties, memory T cells precipitate allograft rejection despite immunosuppression or conventional costimulatory blockade.
  • BLyS BLyS
  • APRIL proliferation-inducing ligand
  • mice were transplanted with cardiac allografts from male C3H (H-2 k ) donors.
  • transferred MAR T cells recognize donor male antigen through the indirect pathway and behave similarly to polyclonal memory CD4 T cells providing help for donor-specific alloAb production (1 , 2).
  • All recipients were treated with anti-CD 154 antibody (clone MRl , BioXCell, West Riverside NH) at 0.5 mg/mouse intravenously 1 day prior to transplantation.
  • mBAFFR-Fc blocks only BLyS
  • mTACI-Fc blocks both BAFF and APRIL
  • control mFc4 all produced by ZymoGenetics, Seattle WA. Fusion proteins were administered
  • Heart allograft recipients containing memory CD4+ T cells and treated with anti-CD154 antibody were divided into 4 groups of 3-4 mice: 1) no further treatment; 2) control mFc4; 3) mBAFFR-Fc and 4) mTACI-Fc.
  • MCF mean channel fluorescence
  • mice that received no treatment of mFc4 had high titers of all anti-donor IgG isotypes despite treatment with anti-CD 154 antibody (Tables 2 and 3).
  • the combination of anti-CD 154 antibody and mTACI-Fc treatment resulted in complete abrogation of anti-donor IgG antibody production.
  • mice treated with MR1 and mBAFF-R-Fc had high titers of IgG 1, intermediate titers of IgG 2 c and low titers of IgG 2 b and IgG 3 on d. 10 post-transplant.
  • the titers of IgG 2c , IgG 2 b and IgG 3 tended to decline in group by d. 14 post-transplant, but the decrease did not reach statistical significance.
  • the temporal analyses of donor-reactive IgG production and B cell numbers suggest that the decline in anti-donor Ab caused by anti-CD 154/mTACI-Fc treatment can be attributed to a disruption in BAFF- and APRIL-mediated B cell activation and/or generation and function of antibody-secreting cells rather than to B cell depletion.
  • Table 1 Percentage of CD45 B220 cells in peripheral blood.
  • Donor-reactive antibodies initiate acute rejection and may lead to chronic pathology of transplanted organs.
  • Alloreactive memory CD4 T cells can use pathways other than CD40/CD154 to induce anti-donor IgG alloantibodies (alloAb) and accelerate rejection.
  • the combination of anti-CD 154 antibody MRl and reagents neutralizing B- cell activating factor (BAFF, aka BLyS) and a proliferation inducing ligand (APRIL) inhibits alloantibody production induced by donor-reactive memory CD4 T cells in murine cardiac allograft recipients.
  • BAFF B- cell activating factor
  • APRIL proliferation inducing ligand
  • MAR cells are specific for male HYo by peptide presented by I-A b .
  • spleen cells from MAR mice were cultured with 3 ⁇ HYn by peptide for 5 days followed by an adoptive transfer into naive female C57BL/6 (H-2 b ) mice.
  • mice were transplanted with cardiac allografts from male BALB/c (H-2 d ) donors.
  • transferred MAR T cells recognize donor male antigen through the indirect pathway and behave similarly to polyclonal memory CD4 T cells providing help for
  • CD8 T cells are the main mechanism of heart allograft rejection 1 .
  • all recipients were depleted of CD8 T cells.
  • fusion proteins containing effector function negative Fc derived from C57BL/6 mice mBAFFR-Fc (blocks only BAFF), mTACI-Fc (blocks both BAFF and APRIL) and control mFc4 (all provided by
  • grafts For morphology examination, portions of the grafts were fixed with 10% formalin, paraffin embedded sections were prepared and stained with hematoxyline and eosin (H&E). To assess antibody-mediated injury to the graft tissue, immunohistochemistry staining for C4d complement component was performed on paraffin embedded sections.
  • the survival fractions were calculated using Kaplan-Meier method and compared by the log-rank test.
  • the results of ELISPOT assays were analyzed using one-way ANOVA, followed by Bonferroni's multiple comparison post- test. A value of p ⁇ 0.05 was considered statistically significant. The data are presented as mean ⁇ SEM.
  • the priming of anti-donor IFNy producing spleen CD4 T cells was comparable between groups at the time of rejection and at d. 90 post transplant in non-rejecting mice. Cardiac allografts rejected by mFc4- treated recipients were heavily infiltrated with mononuclear cells and had high intensity diffuse C4d deposition.
  • the rejection by mTACI-Fc or mBAFFR-Fc treated recipients was characterized by moderate cellular infiltrate and focal C4d staining. The levels of C4d deposition and leukocyte infiltrate directly correlated with the time after
  • a - all recipients contained donor-reactive memory CD4 T cells, were treated with anti- CD 154 antibody and depleted of CD8 T cells.

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Abstract

La présente invention a trait à des procédés et à des compositions permettant de traiter ou de prévenir les conditions d'origines immunes. Les procédés selon la présente invention comprennent une étape consistant à administrer à un sujet une quantité thérapeutiquement efficace d'un antagoniste BLyS/APRIL (par exemple, TACI-lg) en association avec un antagoniste du mécanisme d'action CD40 (par exemple, un anticorps anti-CD40 ou un anticorps anti-CD154). L'association de l'antagoniste BLyS/APRIL et de l'antagoniste du mécanisme d'action CD40 favorise une réponse thérapeutique souhaitée. L'antagoniste BLySAPRIL et l'antagoniste du mécanisme d'action CD40 peuvent être administrés simultanément ou de façon séquentielle en tant que composition pharmaceutique unique ou en tant que compositions pharmaceutiques distinctes, chacune comprenant un antagoniste BLySAPRIL et un antagoniste du mécanisme d'action CD40. Les procédés selon la présente invention sont utiles dans le cadre du traitement ou de la prévention d'une variété de conditions d'origines immunes y compris, par exemple, le traitement ou la prévention des rejets de greffe ou la réaction de greffe contre hôte ou la réduction du niveau de la réponse immune ou la réduction du niveau des immunoglobulines chez un sujet qui en a besoin.
PCT/US2011/026445 2010-03-05 2011-02-28 Procédés et compositions permettant de traiter les troubles d'origines immunes WO2011109280A1 (fr)

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WO2021226551A1 (fr) * 2020-05-08 2021-11-11 Alpine Immune Sciences, Inc. Protéines immunomodulatrices inhibitrices d'april et de baff et leurs procédés d'utilisation

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