EP0874637A1 - Therapeutic applications of t-bam (cd40l) technology to treat inflammatory kidney diseases - Google Patents
Therapeutic applications of t-bam (cd40l) technology to treat inflammatory kidney diseasesInfo
- Publication number
- EP0874637A1 EP0874637A1 EP97904780A EP97904780A EP0874637A1 EP 0874637 A1 EP0874637 A1 EP 0874637A1 EP 97904780 A EP97904780 A EP 97904780A EP 97904780 A EP97904780 A EP 97904780A EP 0874637 A1 EP0874637 A1 EP 0874637A1
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- EP
- European Patent Office
- Prior art keywords
- cells
- agent
- antibody
- ligand
- protein
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70575—NGF/TNF-superfamily, e.g. CD70, CD95L, CD153, CD154
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70578—NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2878—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- Immune complex deposition is known to play important roles in mediating the immunopathogenesis of a variety of renal diseases, including the glomerulonephritis associated with systemic lupus erythematosus.
- infiltrating renal interstitial leukocytes predominately T cells and monocytes, are often seen in lupus nephritis and other inflammatory renal diseases.
- the precise role of infiltrating T cells in the inflammatory renal process that ultimately may result in renal scarring and end- organ damage is currently unknown. It is of interest that the extent of mononuclear cell infiltrate correlates with progression to renal failure.
- CD40 is a cell surface molecule expressed on a variety of cells and interacts with a 30-33 kDa activation-induced CD4+ T cell counterreceptor termed CD40L.
- CD40L-CD40 interactions have been extensively studied in T cell-B cell interactions and are essential for T cell dependent B cell differentiation and IgG, IgA and IgE production.
- CD40 is also expressed on monocytes, dendritic cells, epithelial cells, endothelial cells and fibroblasts. CD40 expression on these cells is upregulated in vitro by cytokines, most notably IFN- ⁇ .
- cytokines most notably IFN- ⁇ .
- In vivo studies have demonstrated markedly upregulated CD40 expression in inflammatory sites, such as rheumatoid arthritis synovial membrane or psoriatic plaques.
- In vitro studies utilizing anti-CD40 mAb or CD40L+ cells demonstrate that CD40 is functionally expressed on monocytes, dendritic cells, epit
- idiopathic autoimmune diseases including drug-induced lupus, such as
- CD40 is expressed on the surface of B cells.
- the initiation point of lupus is the deposition of autoantibodies in the kidney, which then attracts cells involved in destruction of kidney tissue.
- the finding, discussed below, that CD40 is expressed on kidney tubule cells provides the basis for treating inflammatory kidney diseases having initiation points other than autoantibody deposition. Bummary of the Invention
- This invention provides a method of inhibiting activation by CD40 ligand of renal cells bearing CD40 on the surface of the cells, comprising contacting the cells with an agent capable of inhibiting interaction between CD40 ligand and CD40 on the cells, the agent being present in an amount effective to inhibit activation of the cells.
- This invention provides a method of inhibiting activation by CD40 ligand of renal cells bearing CD40 on the surface of the cells, in a subject, comprising administering to the subject an agent capable of inhibiting interaction between CD40 ligand and CD40 on the cells, the agent being present in an amount effective to inhibit activation of the cells in the subject.
- This invention provides a method of treating, in a subject, an inflammatory kidney disease, comprising administering to the subject an agent capable of inhibiting interaction between CD40 ligand and CD40 on the cells, the agent being present in an amount effective to inhibit activation of the cells in the subject and thereby treat the inflammatory kidney disease.
- Figures 1A-Y Atomic coordinates of crystal structure of soluble extracellular fragment of human CD40L containing residues Glyll6-Leu261 (in Brookhaven Protein Data Bank format) . (SEQ ID NO:l) .
- Figures 2A-C Expression of CD40 in normal kidney. Shown are frozen sections of normal kidney stained with control mouse IgG ( Figure 2A, magnification 25x) or anti-CD40 mAb G28.5 ( Figures 2B and 2C, magnification 40x) . Distal tubules and interstitial capillaries express CD40 while proximal tubules are CD40 " ( Figure 2B) . Glomerular cells and epithelial cells of Bowmans capsule express CD40 ( Figure 2C) .
- Figures 3A-C Expression of CD40 in diffuse proliferative lupus nephritis. Shown are frozen sections of a kidney biopsy from a patient with Class IV lupus nephritis stained with control mouse IgG ( Figure 3A, magnification 25x) or anti-CD40 mAb G28.5 ( Figures 3B and 3C, magnification 40x) .
- Figure 3B shows intense CD40 staining of distal and proximal tubules.
- Figure 3C shows increased and diffuse CD40 expression in the glomerulus.
- Figure 3C also shows that the epithelial derived crescent is CD40+.
- FIG. 4A CD40L expression on interstitial mononuclear cells in class IV lupus glomerulonephritis. Shown is a frozen section obtained from a renal biopsy specimen stained with anti-CD40L mAb 5c8. Bound antibody was visualized with the Vectastain ABC Elite kit followed by the chromogen 3-amino-9-ethylcarbazole (Vector Laboratories) . The tissue was counterstained with Mayer's hematoxylin (Sigma) . CD40L i munoreactivity is noted as staining of mononuclear cells.
- FIG 4B Isotype control staining of interstitial mononuclear cells in class IV lupus glomerulonephritis. Shown is a frozen section obtained from the same patient studied in Figure 4A and stained with an IgG2a isotype control mAb. Bound antibody was visualized with the Vectastain ABC Elite kit followed by the chromogen 3- amino-9-ethylcarbazole (Vector Laboratories) . The tissue was counterstained with Mayer's hematoxylin (Sigma) . Note the lack of immunoreactivity (staining) .
- FIG. 5 CD40L expression on interstitial mononuclear cells in class IV lupus glomerulonephritis. Shown is a frozen section obtained from a renal biopsy specimen stained with anti-CD40L mAb 5c8. This specimen was obtained from a different patient than shown in Figure 4A. Bound antibody was visualized with the Vectastain ABC Elite kit followed by the chromogen 3-amino-9-ethylcarbazole (Vector Laboratories) . The tissue was counterstained with Mayer's hematoxylin (Sigma) . CD40L immunoreactivity is noted as staining of mononuclear cells. Staining with an isotype control mAb was negative (not shown) .
- FIG. 6 Renal CD40 expression in focal segmental glomerulosclerosis (FSGS) . Shown is a frozen section obtained from a renal biopsy specimen stained with anti-CD40 mAb G28.5. Bound antibody was visualized with the Vectastain ABC Elite kit followed by the chromogen 3-amino-9-ethylcarbazole (Vector Laboratories) . The tissue was counterstained with Mayer's hematoxylin (Sigma) . Note the intense CD40 staining. Staining with an isotype control mAb was negative (not shown) .
- FSGS focal segmental glomerulosclerosis
- FIG. 7 CD40L expression on interstitial mononuclear cells in focal segmental glomerulosclerosis. Shown is a frozen section obtained from the same patient as studied in Figure 6 stained with anti- CD40L mAb 5c8. Bound antibody was visualized with the Vectastain ABC Elite kit followed by the chromogen 3-amino-9- ethylcarbazole (Vector Laboratories) . The tissue was counterstained with Mayer's hematoxylin (Sigma) . CD40L immunoreactivity is noted as staining of mononuclear cells. Staining with an isotype control mAb was negative (not shown) .
- FIG. 8 Renal CD40 expression in IgA nephropathy. Shown is a frozen section obtained from a renal biopsy specimen stained with anti- CD40 mAb G28.5. Bound antibody was visualized with the Vectastain ABC Elite kit followed by the chromogen 3-amino-9- ethylcarbazole (Vector Laboratories) . The tissue was counterstained with Mayer's hematoxylin (Sigma) . Note the intense CD40 staining. Staining with an isotype control mAb was negative (not shown) .
- FIG. 9 CD40L expression on interstitial mononuclear cells in IgA nephropathy. Shown is a frozen section obtained from the same patient as studied in Figure 8 stained with anti-CD40L mAb 5c8. Bound antibody was visualized with the Vectastain ABC Eiite kit followed by the chromogen 3-amino-9-ethylcarbazole (Vector Laboratories) . The tissue was counterstained with Mayer's hematoxylin (Sigma) . CD40L immunoreactivity is noted as staining of mononuclear cells. Staining with as isotype control mAb was negative (not shown) .
- This invention provides a method of inhibiting activation by CD40 ligand of renal cells bearing CD40 on the cell surface, comprising contacting the cells with an agent capable of inhibiting interaction between CD40 ligand and CD40 on the cells, the agent being present in an amount effective to inhibit activation of the cells.
- the agent is capable of inhibiting any interaction between CD40 ligand and CD40.
- Interaction between CD40 ligand and CD40 on the cells refers to one or more aspects, functional or structural, of a CD40-CD40 ligand interrelationship. Therefore, in one embodiment, an agent which inhibits interaction may competitively bind to CD40 ligand in such a way to block or diminish the binding of CD40 ligand to cellular CD40.
- an agent which inhibits interaction may associate with CD40 or CD40 ligand in a manner which does not inhibit binding of CD40 ligand to cellular CD40, but which influences the cellular response to the CD40 ligation, such as by altering the turnover rate of the cellular CD40 or the CD40-agent complex, by altering binding kinetics of CD40 with CD40 ligand, or by altering the rate or extent of cellular activation in response to CD40 ligation.
- the CD40-bearing renal cells are selected from the group consisting of glomerular endothelial cells, mesangial cells, distal tubule cells, proximal tubule cells, parietal epithelial cells, visceral epithelial cells, cells of a Henle loop or limb thereof, and interstitial inflammatory cells.
- the parietal epithelial cells are crescent parietal epithelial cells.
- the agent inhibits binding of CD40 ligand to CD40 on the cells.
- the agent is a protein.
- the agent is a nonprotein.
- nonprotein includes any and all compounds or agents which encompass elements other than simple or conjugated polypeptide chains. This includes elements such as amino acids having non-peptide linkages; nonprotein amino acids such as ⁇ , ⁇ , or ⁇ amino acids, amino acids in D configuration, or other nonprotein amino acids including homocysteine, homoserine, citrulline, ornithine, ⁇ -aminobutyric acid, canavanine, djenkolic acid, or 0-cyanoalanine; monosaccharides, polysaccharides, or carbohydrate moieties; fatty acids or lipid moieties; nucleotide moieties, mineral moieties; or other nonprotein elements.
- the protein comprises an antibody or portion thereof capable of inhibiting interaction between CD40 ligand and CD40 on the cells.
- the antibody is a monoclonal or polyclonal antibody.
- the monoclonal antibody specifically binds to the epitope to which monoclonal antibody 5c8 (ATCC Accession No. HB 10916) specifically binds.
- An example of such a monoclonal antibody is monoclonal antibody 5c8 (ATCC Accession No. HB 10916) .
- the antibody specifically binds to CD40.
- an anti-CD40 antibody is the monoclonal mouse anti-human CD40, available from Genzyme Customer Service (Product 80-3702-01, Cambridge, MA) .
- the monoclonal antibody is a chimeric antibody, a primatized antibody, a humanized antibody, or an antibody which includes a CDR region from a first human and an antibody scaffold from a second human.
- a humanized antibody is an antibody comprising one or more complementarity determining regions (CDRs) of a non-human antibody functionally joined to human framework region segments. Additional residues associated with the non-human antibody can optionally be present.
- CDRs complementarity determining regions
- at least one heavy chain or one light chain comprises non-human CDRs.
- the non-human CDRs are mouse CDRs.
- a primatized antibody i ⁇ an antibody comprising one or more complementarity determining regions (CDRs) of an antibody of a species other than a non-human primate, functionally joined to framework region segments of a non-human primate. Additional residues associated with the species from which the CDR is derived can optionally be present.
- At least one heavy chain or one light chain comprises CDRs of the species which is not a nonhuman primate.
- the CDRs are human CDRs.
- a chimeric antibody is an antibody whose light and/or heavy chains contain regions from different species. For example one or more variable (V) region segments of one species may be joined to one or more constant (C) region segments of another species.
- a chimeric antibody contains variable region segments of a mouse joined to human constant region segments, although other mammalian species may be used.
- Monoclonal antibody 5c8 is produced by a hybridoma cell which was deposited on November 14, 1991 with the American Type Culture Collection (ATCC) , 12301 Parklawn Drive, Rockville, Maryland 20852, U.S.A. under the provisions of the Budapest Treaty for the International Recognition of the Deposit of Microorganisms for the Purposes of Patent Procedure.
- the hybridoma was accorded ATCC Accession Number HB 10916.
- portion of the antibody comprises a complementarity determining region or variable region of a light or heavy chain. In another specific embodiment the portion of the antibody comprises a complementarity determining region or a variable region. In another specific embodiment the portion of the antibody comprises a Fab or a single chain antibody.
- a single chain antibody is made up of variable regions linked by protein spacers in a single protein chain.
- the protein comprises soluble extracellular region of CD40 ligand, or portion thereof, or variant thereof, capable of inhibiting any interaction between CD40 ligand and CD40 on the cells; or soluble extracellular region of CD40, or portion thereof, or variant thereof, capable of inhibiting any interaction between CD40 ligand and CD40 on the cells.
- the soluble extracellular region of CD40 ligand or CD40 is a monomer.
- the soluble extracellular region of CD40 is an oligomer.
- Variants can differ from naturally occurring CD40 or CD40 ligand in amino acid sequence or in ways that do not involve sequence, or both. Variants in amino acid sequence are produced when one or more amino acids in naturally occurring CD40 or CD40 ligand is substituted with a different natural amino acid, an amino acid derivative or non-native amino acid. Particularly preferred variants include naturally occurring CD40 or CD40 ligand, or biologically active fragments of naturally occurring CD40 or CD40 ligand, whose sequences differ from the wild type sequence by one or more conservative amino acid substitutions, which typically have minimal influence on the secondary structure and hydrophobic nature of the protein or peptide.
- Variants may also have sequences which differ by one or more non- conservative amino acid substitutions, deletions or insertions which do not abolish the CD40 or CD40 ligand biological activity.
- Conservative substitutions typically include the substitution of one amino acid for another with similar characteristics such as substitutions within the following groups: valine, glycine; glycine, alanine; valine, isoleucine; aspartic acid,glutamic acid; asparagine,glutamine? serine,threonine;lysine, arginine; and phenyialanine,tyrosine.
- the non-polar (hydrophobic) amino acids include alanine, leucine, isoleucine, valine, proline, phenyialanine, tryptophan and methionine.
- the polar neutral amino acids include glycine, serine, threonine, cysteine, tyrosine, asparagine and glutamine.
- the positively charged (basic) amino acids include arginine, lysine and histidine.
- the negatively charged (acidic) amino acids include aspartic acid and glutamic acid.
- Lysine K D-Lys,Arg, D-Arg, homo-Arg, D- homo-Arg, Met, D-Met, lie, D- Ile, Orn, D-Orn
- Phenyialanine F D-Phe,Tyr, D-Thr,L-Dopa,His,D- Hi ⁇ , Trp, D-Trp, Trans 3,4 or 5-phenylproline, cis 3,4 or 5 phenylproline
- Proline P D-Pro L-I-thioazolidine-4- carboxylic acid, D- or L-l- oxazolidine-4-carboxylic acid Serine S D-Ser, Thr, D-Thr, allo-Thr, Met, D-Met, Met(O), D-Met(0) , Val, D-Val
- variants within the invention are those with modifications which increase peptide stability.
- Such variants may contain, for example, one or more non- peptide bonds (which replace the peptide bonds) in the peptide sequence.
- the peptides of this invention may also be modified by various changes such as insertions, deletions and substitutions, either conservative or nonconservative where such changes might provide for certain advantages in their use.
- variants with amino acid substitutions which are less conservative may also result in desired derivatives, e.g., by causing changes in charge, conformation and other biological properties.
- substitutions would include for example, substitution of hydrophilic residue for a hydrophobic residue, substitution of a cysteine or proline for another residue, substitution of a residue having a small side chain for a residue having a bulky side chain or substitution of a residue having a net positive charge for a residue having a net negative charge.
- the derivatives may be readily assayed according to the methods disclosed herein to determine the presence or absence of the desired characteristics.
- Variants within the scope of the invention include proteins and peptides with amino acid sequences having at least eighty percent homology with the extracellular region of CD40 or the extracellular region of CD40 ligand. More preferably the sequence homology is at least ninety percent, or at least ninety-five percent.
- Non- sequence modifications may include, for example, in vivo or in vitro chemical derivatization of portions of naturally occurring CD40 or CD40 ligand, as well as changes in acetylation, methylation, phosphorylation, carboxylation or glycolsylation.
- the protein including the extracellular region of CD40 ligand and CD40, is modified by chemical modifications in which activity is preserved.
- the proteins may be amidated, sulfated, singly or multiply halogenated, alkylated, carboxylated, or phosphorylated.
- the protein may also be singly or multiply acylated, such as with an acetyl group, with a farnesyl moiety, or with a fatty acid, which may be saturated, monounsaturated or polyunsaturated.
- the fatty acid may also be singly or multiply fluorinated.
- the invention also includes methionine analogs of the protein, for example the methionine sulfone and methionine sulfoxide analogs.
- the invention also includes salts of the proteins, such as ammonium salts, including alkyl or aryl ammonium salts, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, thiosulfate, carbonate, bicarbonate, benzoate, sulfonate, thiosulfonate, mesylate, ethyl sulfonate and benzensulfonate salts.
- ammonium salts including alkyl or aryl ammonium salts, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, thiosulfate, carbonate, bicarbonate, benzoate, sulfonate, thiosulfonate, mesylate, ethyl sulfonate and benzensulfonate salts.
- the soluble, monomeric CD40-L protein can comprise all or part of the extracellular region of CD40-L.
- the extracellular region of CD40-L contains the domain that binds to CD40.
- soluble CD40-L can inhibit the interaction between CD40L and the CD40-bearing cell.
- sCD40-L may constitute the entire extracellular region of CD40-L, or a fragment or derivative containing the domain that binds to CD40.
- Soluble CD40 protein comprises the extracellular region of CD40. sCD40 inhibits the interaction between CD40L and CD40-bearing cells. sCD40 may be in monomeric or oligomeric form.
- the protein comprising soluble extracellular region of CD40 or portion thereof further comprises an Fc region fused to the extracellular region of CD40 or portion thereof.
- the Fc region is capable of binding to protein A or protein G.
- the Fc region comprises IgG, IgG,, IgG 2 , lgG 3 , IgG , IgA, IgA,, IgA 2 , IgM, IgD, or IgE.
- the soluble CD40/FC fusion protein can be prepared using conventional techniques of enzymes cutting and ligation of fragments from desired sequences.
- Suitable Fc regions for the fusion protein are Fc regions that can bind to protein A or protein G, or that are capable of recognition by an antibody that can be used in purification or detection of a fusion protein comprising the Fc region.
- the Fc region may include the Fc region of human IgG, or murine IgG r
- This invention also provides a nucleic acid molecule which encodes the CD40/Fc fusion protein.
- the agent is selected by a screening method.
- the agent is selected by a screening method, which comprises isolating a sample of cells; culturing the sample under conditions permitting activation of CD40-bearing cells; contacting the sample with cells expressing a protein which is specifically recognized by monoclonal antibody 5c8 produced by the hybridoma having ATCC Accession no. HB 10916, or with a protein which is specifically recognized by monoclonal antibody 5c8 produced by the hybridoma having ATCC Accession no.
- the cell sample may be isolated from diverse tissues, including cell lines in culture or cells isolated from an animal, such as dispersed cells from a solid tissue, cells derived from a bone marrow biopsy, or cells isolated from a body fluid such as blood or lymphatic fluid.
- the agent may be selected from a library of known agents, modified from a known agent based on the three-dimensional structure, or designed and synthesized de novo based on the three- dimensional structure.
- the agent (molecule) is designed by structure optimization of a lead inhibitory agent based on a three-dimensional structure of a complex of the soluble extracellular region of CD40 ligand or portion thereof with the lead inhibitory agent.
- a lead inhibitory agent is a molecule which has been identified which, when it is contacted with CD40 ligand, binds to and complexes with the soluble extracellular region of CD40 ligand, CD40, or portion thereof, thereby decreasing the ability of the complexed or bound CD40 ligand or CD40 ligand portion to activate CD40-bearing cells.
- a lead inhibitory agent may act by interacting with either the extracellular region of CD40 ligand, CD40, or in a tertiary complex with both a portion of CD40 ligand and CD40, decreasing the ability of the complexed CD40 ligand-CD40 to activate the CD40-bearing cells.
- the CD40 ligand may be either soluble or bound to cells such as activated T cells, and may be either full length native CD40 ligand or portions thereof. Decreased ability to activate CD40-bearing cells may be measured in different ways. One way it may be measured is by showing that CD40 ligand, in the presence of inhibitor, causes a lesser degree of activation of CD40-bearing cells, as compared to treatment of the cells with a similar amount of CD40 ligand without inhibitor under similar conditions.
- Decreased ability to activate CD40-bearing cells may also be indicated by a higher concentration of inhibitor-CD40 ligand complex being required to produce a similar degree of activation of CD40-bearing cells under similar conditions, as compared to unbound CD40 ligand.
- the inhibitor-contacted CD40 ligand may be unable to activate CD40-bearing cells at concentrations and under conditions which allow activation of these cells by unbound CD40 ligand or a given portion thereof.
- the agent (molecule) can be selected by a computational screening method using the crystal structure of a soluble fragment of the extracellular domain of human CD40L containing residues Glyll6-Leu261 (sCD40L(116-261) ) .
- the crystal structure to be used with the screening method has been determined at 2 A resolution by the method of molecular replacement.
- a soluble fragment of the extracellular domain of human CD40 ligand containing amino acid residues Gly 116 to the c-terminal residue Leu 261 was first produced in soluble form, then purified and crystallized. The crystals were used to collect diffraction data.
- Molecular replacement and refinement were done with the XPLOR program package and QUANTA (Molecular Simulations, Inc.) Software.
- QUANTA Molecular Simulations, Inc.
- a 3-dimensional model of human sCD40L was constructed using the murine CD40L model using QUANTA protein homology modeling software. This model was used as a probe for crystallographic analysis calculations and refined using XPLOR.
- the agent may be an inhibitor selected using computational drug design.
- the SCD40L crystal structure coordinates are used as an input for a computer program, such as DOCK, which outputs a list of molecular structures that are expected to bind to CD40L.
- DOCK computer program
- Use of such computer programs is well-known. See, e.g., Kuntz, "Structure-Based Strategies for drug design and discovery," Science, vol. 257, p. 1078 (1992)-.
- the list of molecular structures can then be screened by biochemical assays for CD40L binding. Competition-type biochemical assays, which are well known, can be used.
- the structures that are found to bind to CD40L can thus be used as agents for the present invention.
- the agent may also be a modified or designed molecule, determined by interactive cycles of structure optimization.
- a small molecule inhibitor of CD40L found using the above computational approach or other approach can be co-crystallized with sCD40L and the crystal structure of the complex solved by molecular replacement.
- the information revealed through molecular replacement can be used to optimize the structure of the inhibitors by clarifying how the molecules interact with CD40L.
- the molecule may be modified to improve its physiochemical properties, including specificity and affinity for CD40L.
- the agent is a small molecule.
- a small molecule is a compound having a molecular weight between 20 Da and 1x10° Da, preferably from 50 Da to 2 kDa.
- This invention also provides a method of inhibiting activation by CD40 ligand of renal cells bearing CD40 on the surface of the cells, in a subject, comprising administering to the subject an agent capable of inhibiting interaction between CD40 ligand and CD40 on the cells, the agent being present in an amount effective to inhibit activation of the cells in the subject.
- the CD40-bearing renal cells are selected from the group consisting of glomerular endothelial cells, mesangial cells, distal tubules, proximal tubules, parietal epithelial cells, visceral epithelial cells, cells of a Henle loop or limb thereof, and interstitial inflammatory cells.
- the parietal epithelial cells are crescent parietal epithelial cells.
- the agent inhibits binding of CD40 ligand to CD40 on the cells.
- the agent i ⁇ a protein. In another embodiment of this invention the agent is a nonprotein.
- the protein comprises an antibody or portion thereof capable of inhibiting any interaction between CD40 ligand and CD40 on the cells.
- the antibody is a monoclonal or polyclonal antibody.
- the monoclonal antibody specifically binds to the epitope to which monoclonal antibody 5c8 (ATCC Accession No. HB 10916) specifically binds.
- An example of such a monoclonal antibody is monoclonal antibody 5c8 (ATCC Accession No. HB 10916) .
- the monoclonal antibody is a chimeric antibody or a humanized antibody.
- portion of the antibody comprises a complementarity determining region or variable region of a light or heavy chain. In another specific embodiment the portion of the antibody comprises a complementarity determining region or a variable region. In another specific embodiment the portion of the antibody comprises a Fab or a single chain antibody.
- the protein comprises soluble extracellular region of CD40 ligand or portion thereof capable of inhibiting any interaction between CD40 ligand and CD40 on the cells; or soluble extracellular region of CD40 or portion thereof capable of inhibiting any interaction between CD40 ligand and CD40 on the cells.
- the soluble extracellular region of CD40 ligand or CD40 is a monomer.
- the soluble extracellular region of CD40 is an oligomer.
- the protein comprising soluble extracellular region of CD40 or portion thereof further comprises an Fc region fused to the extracellular region of CD40 or portion thereof.
- the Fc region is capable of binding to protein A or protein G.
- the Fc region comprises IgG, IgG,, IgG 2 , lgG 3 , IgG 4 , IgA, igA,, IgA 2 , igM, IgD, or IgE.
- the subject which can be treated by the above-described methods is an animal.
- the animal is a mammal.
- mammals which may be treated include, but are not limited to, humans, non-human primates, rodents (including rats, mice, hamster ⁇ and guinea pigs) cow, horse, sheep, goat, pig, dog and cat.
- the agent is ⁇ elected by a screening method.
- the agent is selected by a screening method, which comprises isolating a sample of cells; culturing the sample under conditions permitting activation of CD40-bearing cells; contacting the sample with cells expres ⁇ ing a protein which i ⁇ specifically recognized by monoclonal antibody 5c8 produced by the hybridoma having ATCC Acce ⁇ sion no. HB 10916, or with a protein which is specifically recognized by monoclonal antibody 5c8 produced by the hybridoma having ATCC Accession no.
- the cell sample may be isolated from diverse tissues, including cell lines in culture or cells isolated from an animal, such as dispersed cells from a solid tissue, cells derived from a bone marrow biopsy, or cells isolated from a body fluid such as blood or lymphatic fluid.
- the molecule (agent) i ⁇ selected based on a three-dimensional structure of soluble extracellular region of CD40 ligand or portion thereof capable of inhibiting any interaction between CD40 ligand and CD40 on the cells.
- the molecule may be selected from a library of known molecules, modified from a known molecule based on the three-dimensional structure, or designed and synthesized de novo based on the three-dimensional structure.
- the agent or molecule is designed by structure optimization of a lead inhibitory agent based on a three- dimensional structure of a complex of the soluble extracellular region of CD40 ligand or portion thereof with the lead inhibitory agent.
- This invention provides a method of treating, in a subject, an inflammatory kidney disease, comprising the above-described method of inhibiting activation by CD40 ligand of renal cells bearing CD40 on the surface of the cells, which comprises administering to the subject an agent capable of inhibiting interaction between CD40 ligand and CD40 on the cells, the agent being present in an amount effective to inhibit activation of the cells in the subject, thereby treating the inflammatory kidney disease.
- the inflammatory kidney disease may be one which is initiated by autoantibody deposition in kidney, or one which is not initiated by autoantibody deposition in kidney.
- kidney diseases for which the methods of the invention are useful include ones which have multifactorial etiology.
- the kidney disease i ⁇ selected from the group consisting of: membranous glomerulonephritis, minimal change disease/acute tubular necrosis; pauci-immune glomerulonephritis; focal segmental glomerulosclerosis; interstitial nephritis; antitissue antibody-induced glomerular injury, such as anti-basement membrane antibody disease; circulating immune-complex disease; glomerulopathies associated with multisystem diseases; drug-induced glomerular disease; renal transplant rejection; rapidly progressive glomerulonephritis; and post-streptococcal glomerulonephritis.
- Circulating immune-complex diseases include infective endocarditis, leprosy, syphili ⁇ , hepatitis B, malaria, and disease ⁇ of endogenou ⁇ antigens such as DNA, thyroglobulin, autologous immunoglobulins, erythrocyte stroma, renal tubule antigens, and tumor- specific or tumor-associated antigens.
- Glomerulopathies associated with multisystem diseases include diabetic nephropathy, systemic lupus erythematosus, Goodpasture's disease, vasculitis, multiple myeloma, Waldenstr ⁇ m's macroglobulinemia, and amyloidosis.
- the vasculitis is Henoch-Sch ⁇ nlein purpura, polyarteritis nodosa (sometimes called polyarteritis) , Wegener's granulomatosis, cryoglobulinemia (sometimes called cryoim unoglobulinemia) .
- the kidney disease may also be one which affects the renal tubules, such as toxins, neoplasias, hypersensitivity nephropathy, Sj ⁇ gren's syndrome, and AIDS.
- the pauci-immune glomerulonephritis is ANCA+ pauci-immune glomerulonephritis, or Wegener's granulomatosis.
- the interstitial nephritis is drug-induced interstitial nephritis.
- the compounds of this invention may be administered in any manner which is medically acceptable. This may include injections, by parenteral routes such as intravenous, intravascular, intraarterial, subcutaneous, intramuscular, intratumor, intraperitoneal, intraventricular, intraepidural, or others as well as oral, nasal, ophthalmic, rectal, topical, or inhaled.
- parenteral routes such as intravenous, intravascular, intraarterial, subcutaneous, intramuscular, intratumor, intraperitoneal, intraventricular, intraepidural, or others as well as oral, nasal, ophthalmic, rectal, topical, or inhaled.
- Sustained release administration is also specifically included in the invention, by such means as depot injections of erodible implants directly applied during surgery.
- the compounds are administered at any dose per body weight and any dosage frequency which is medically acceptable.
- Acceptable dosage includes a range of between about 0.01 and 200 mg/kg subject body weight.
- a preferred dosage range is between about 0.1 and 50 mg/kg.
- Particularly preferred is a dose of between about 1 and 30 mg/kg.
- the dosage is repeated at intervals ranging from each day to every other month.
- One preferred do ⁇ ing regimen is to administer a compound of the invention daily for the first three days of treatment, after which the compound is admini ⁇ tered every 3 week ⁇ , with each administration being intravenously at 5 or 10 mg/kg body weight.
- Another preferred regime is to administer a compound of the invention daily intravenously at 5 mg/kg body weight for the first three days of treatment, after which the compound is administered subcutaneously or intramuscularly every week at 10 mg per subject.
- Another preferred regime is to administer a single dose of the compound of the invention parenterally at 20 mg/kg body weight, followed by administration of the compound subcutaneously or intramuscularly every week at 10 mg per subjec .
- the compounds of the invention may be admini ⁇ tered as a single dosage for certain indications such as preventing immune response to an antigen to which a ⁇ ubject i ⁇ exposed for a brief time, ⁇ uch as an exogenous antigen administered on a single day of treatment.
- an antigen would include coadministration of a compound of the invention along with a gene therapy vector, or a therapeutic agent such as an antigenic pharmaceutical or a blood product.
- the compounds of the invention are administered at interval ⁇ for a ⁇ long a time a ⁇ medically indicated, ranging from days or weeks to the life of the subject.
- Inflammatory responses are characterized by redness, swelling, heat and pain, as consequence ⁇ of capillary dilation with edema and migration of phagocytic leukocyte ⁇ . Inflammation i ⁇ further defined by Gallin (Chapter 26, Fundamental Immunology, 2d Ed., Raven Press, New York, 1989, pp. 721-733) , which is herein incorporated by reference.
- Bound antibody was visualized with the Vectastain ABC reagent followed by the chromogen 3-amino- 9-ethylcarbazole (Vector Laboratories) .
- the tissue was counterstained with Mayer's hematoxylin (Sigma) .
- Staining was evaluated visually. In the following tables "0" indicates no staining; 1+ indicates minimal staining; 2+ indicates moderate staining; and 3+ indicates inten ⁇ e ⁇ taining.
- CD40 is normally expressed on endothelial cells in a variety of tissue ⁇ . Con ⁇ i ⁇ tent with this finding, it was found that renal interstitial capillaries and larger vessel ⁇ expre ⁇ s CD40. CD40 was also found to be expressed on other renal parenchymal cells, such as glomerular endothelial cells, glomerular mesangial cells and parietal epithelial cells of Bowman's capsule. Glomerular visceral epithelial cells do not express CD40. Distal tubules are strongly immunoreactive for CD40 and staining was most intense along the basolateral membrane. In contrast, proximal tubules are not immunoreactive with anti-CD40 mAb.
- Renal CD40 expre ⁇ ion in ⁇ ystemic lupus erythematosus was analyzed.
- Patients with Clas ⁇ III and IV lupu ⁇ nephriti ⁇ tended to have increa ⁇ ed CD40 expre ⁇ ion on glomerular endothelial cell ⁇ , mesangial cells and distal tubules.
- proximal tubules are CD40+ in patients with Class III and IV lupu ⁇ nephriti ⁇ .
- CD40 i ⁇ also present on interstitial inflammatory cells.
- the distribution and intensity of renal CD40 expression in patients with pure Class V disease was similar to that seen in normal kidney.
- CD40 upregulation was unique to systemic lupus erythematosus was investigated. To do so, CD40 expression was investigated in patients with the following renal diseases: membranous glomerulonephritis, minimal change disease/acute tubular necrosis, ANCA+ pauci-immune glomerulonephritis, focal segmental glomerulosclerosis and IgA nephropathy. Proximal tubule CD40 expression was upregulated in ANCA+ pauci-immune glomerulonephritis, focal segmental glomerulosclerosis and IgA nephropathy.
- CD40L expression is noted as dim, discrete staining of some infiltrating mononuclear cells. These results provide further evidence that CD40L mediated signals play a role in the im unopathogenesis of inflammatory glomerular or tubulointerstitial diseases by interacting with CD40 * target cells in the kidney.
- MOLECULE TYPE protein
- HYPOTHETICAL NO
- Gly Asp Gin Asn Pro Gin lie Ala Ala His Val lie Ser Glu Ala Ser 1 5 10 15
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Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
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US587334 | 1990-09-24 | ||
US58733496A | 1996-01-16 | 1996-01-16 | |
US64147396A | 1996-05-01 | 1996-05-01 | |
US641473 | 1996-05-01 | ||
PCT/US1997/000668 WO1997026000A1 (en) | 1996-01-16 | 1997-01-16 | Therapeutic applications of t-bam (cd40-l) technology to treat inflammatory kidney diseases______________________________________ |
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EP0874637A1 true EP0874637A1 (en) | 1998-11-04 |
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EP97904780A Withdrawn EP0874637A1 (en) | 1996-01-16 | 1997-01-16 | Therapeutic applications of t-bam (cd40l) technology to treat inflammatory kidney diseases |
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EP (1) | EP0874637A1 (en) |
JP (1) | JP2000503659A (en) |
AU (1) | AU1748897A (en) |
CA (1) | CA2243531A1 (en) |
MX (1) | MX9805724A (en) |
WO (1) | WO1997026000A1 (en) |
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EE9900273A (en) * | 1997-01-10 | 2000-02-15 | Biogen, Incorporated | Treatment of lupus nephritis with anti-CD40L compounds |
WO2001014552A1 (en) * | 1999-08-19 | 2001-03-01 | Kurokawa, Kiyoshi | Meg-1 protein |
CN1441675A (en) | 2000-05-12 | 2003-09-10 | 贝斯以色列护理医疗中心有限公司 | Compositions and methods for achieving immune suppression |
KR102019033B1 (en) * | 2016-11-11 | 2019-09-06 | 다이노나(주) | Antibody specifically binding to CD40 and use thereof |
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US5474771A (en) * | 1991-11-15 | 1995-12-12 | The Trustees Of Columbia University In The City Of New York | Murine monoclonal antibody (5c8) recognizes a human glycoprotein on the surface of T-lymphocytes, compositions containing same |
-
1997
- 1997-01-16 JP JP9526174A patent/JP2000503659A/en active Pending
- 1997-01-16 WO PCT/US1997/000668 patent/WO1997026000A1/en not_active Application Discontinuation
- 1997-01-16 AU AU17488/97A patent/AU1748897A/en not_active Abandoned
- 1997-01-16 EP EP97904780A patent/EP0874637A1/en not_active Withdrawn
- 1997-01-16 CA CA002243531A patent/CA2243531A1/en not_active Abandoned
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1998
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WO1997026000A1 (en) | 1997-07-24 |
MX9805724A (en) | 1998-10-31 |
JP2000503659A (en) | 2000-03-28 |
CA2243531A1 (en) | 1997-07-24 |
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