US20030223991A1 - Methods of modulating CD200 receptors - Google Patents

Methods of modulating CD200 receptors Download PDF

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US20030223991A1
US20030223991A1 US10/389,231 US38923103A US2003223991A1 US 20030223991 A1 US20030223991 A1 US 20030223991A1 US 38923103 A US38923103 A US 38923103A US 2003223991 A1 US2003223991 A1 US 2003223991A1
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Holly Cherwinski
Michael Bigler
Jonathon Sedgwick
Joseph Phillips
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Merck Sharp and Dohme LLC
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Publication of US20030223991A1 publication Critical patent/US20030223991A1/en
Priority to US11/478,778 priority patent/US20060240010A1/en
Priority to US12/045,153 priority patent/US8263070B2/en
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Definitions

  • the present invention relates to methods and compositions for modulating mammalian physiology, including immune system function. In particular, it provides methods for modulating the metabolism and activity of mast cells. Diagnostic and therapeutic uses are disclosed.
  • the immune system composed of cells of the bone marrow, spleen, and hematopoietic cells, including but not limited to lymphoid and myeloid lineage cells, is responsible for defending against bacteria, viruses, and foreign multicellular organisms, as well as cancer cells. Improper regulation of the immune system can result in a number of disorders or pathological conditions, e.g., chronic inflammation, autoimmune diseases and disorders, and undesired allergic reactions to foreign particles or foreign tissues.
  • disorders or pathological conditions e.g., chronic inflammation, autoimmune diseases and disorders, and undesired allergic reactions to foreign particles or foreign tissues.
  • mast cells a myeloid lineage immune cell
  • cytokines and enzymes that result in inflammation.
  • rapid degranulation by mast cells contributes to the pathology of asthma, anaphylaxis, and other allergic responses, while slower degranulation by mast cells contributes to arthritis and other types of chronic inflammation.
  • the release of inflammatory cytokines and enzymes by mast cells can result in tissue damage, further attraction of mast cells, resulting in further tissue damage.
  • Cells of the immune system possess many types of membrane-bound proteins that can serve as receptors.
  • the ligands for these receptors can be small molecules, proteins, e.g., cytokines or chemokines, or membrane-bound proteins residing on a separate cell. Changes in the activity of a cell or tissue can result from occupation of a receptor by its physiological ligand, by an analogue of the physiological ligand, by an antibody, by agents that cross-link like-receptors to each other, and by agents that cross-link non-identical receptors to each other.
  • Mast cells contain a number of receptors that relay an inhibitory signal to the cell. These include CD200 receptor a (a.k.a. CD200Ra; OX2Ra), as well as various Ig-ITIM-bearing receptors, e.g., low affinity IgG receptor Fc ⁇ RIIB, transmembrane glycoprotein receptor gp49B1, signal regulatory protein (SIRP), mast cell function-associated Ag, and platelet endothelial cell adhesion molecule-1 (PECAM-1)/(CD31) (Wong, et al. (2002) J. Immunol. 168:6455-6462).
  • CD200 receptor a a.k.a. CD200Ra; OX2Ra
  • Ig-ITIM-bearing receptors e.g., low affinity IgG receptor Fc ⁇ RIIB, transmembrane glycoprotein receptor gp49B1, signal regulatory protein (SIRP), mast cell function-associated Ag, and platelet endothelial cell adh
  • CD200 (a.k.a. OX2) is a widely distributed membrane-bound protein occurring on lymphoid, neuronal, endothelial, dendritic cells, and B cells (Wright, et al. (2000) Immunity 13, 233-242; Wright, et al. (2001) Immunology 102:173-179; Hoek, et al. (2000) Science 290:1768-1771; Barclay, et al. (2001) Immunol. 102:173-179; McCaughan, et al. (1987) Immunogenetics 25:329-335).
  • CD200 the ligand of CD200R, can bind to CD200R, which is expressed on a separate cell.
  • CD200Ra occurs, e.g., on macrophages, dendritic cells, and microglia, of the rat (Wright, et al. (2000) supra; Preston, et al. (1997) Eur. J. Immunol. 27:1911-1918.
  • the present invention fulfills this need by providing methods of diagnosis and treatment of mast cell disorders by targeting mast cell receptor molecules, e.g., CD200Rs.
  • FIG. 1 shows secretion of ⁇ -hexosaminidase versus concentration of degranulation signal.
  • FIG. 2 shows cytokine release versus concentration of degranulation signal.
  • the invention is based, in part, upon the discovery that binding of an antibody to an inhibiting receptor, e.g., CD200Ra, inactivates a cell.
  • an inhibiting receptor e.g., CD200Ra
  • the invention provides a method of modulating the activity of a cell comprising contacting the cell with a binding composition derived from the antigen binding site of an antibody that specifically binds to CD200Ra (SEQ ID NOs:2 or 6), or an antigenic fragment thereof. Also provided is the above method wherein the cell is a mast cell; wherein the modulating inhibits cell activity or stimulates cell activity; wherein the modulating inhibits cell activity and the binding composition comprises an agonist of CD200Ra (SEQ ID NOs:2 or 6); or wherein the modulating increases cell activity and the binding composition comprises an antagonist of CD200Ra (SEQ ID NOs:2 or 6).
  • the invention provides the above method wherein the binding composition comprises a humanized antibody; a monoclonal antibody; a polyclonal antibody; an Fab fragment; an F(ab′) 2 fragment; a peptide mimetic of an antibody; or a detectable label.
  • the binding composition comprises a humanized antibody; a monoclonal antibody; a polyclonal antibody; an Fab fragment; an F(ab′) 2 fragment; a peptide mimetic of an antibody; or a detectable label.
  • Yet another aspect of the invention is the above method, further comprising contacting the cell with an agent that specifically enhances expression of CD200Ra (SEQ ID NOs:2 or 6).
  • Also encompassed is a method of treating a subject suffering from an immune condition comprising treating with or administering the binding composition derived from the antigen binding site of an antibody that specifically binds to CD200Ra (SEQ ID NOs:2 or 6), or an antigenic fragment thereof.
  • the binding composition comprises an agonist or antagonist of CD200Ra (SEQ ID NOs:2 or 6); wherein the immune condition is an inflammatory condition or an autoimmune condition.
  • the immune condition is rheumatoid arthritis; endotoxemia; psoriasis; or allergy; or where the immune condition is an infection or a cancerous condition.
  • the binding composition is administered in conjunction with an agent that specifically enhances expression CD200Ra (SEQ ID NOs:2 or 6), or an antigenic fragment thereof.
  • “Activity” of a molecule may describe or refer to binding of the molecule to a ligand or to a receptor, to catalytic activity, to the ability to stimulate gene expression, to antigenic activity, to the modulation of activities of other molecules, and the like. “Activity” of a molecule may also refer to activity in modulating or maintaining cell-to-cell interactions, e.g., adhesion, or activity in maintaining a structure of a cell, e.g., cell membranes or cytoskeleton. “Activity” may also mean specific activity, e.g., [catalytic activity]/[mg protein], or [immunological activity]/[mg protein], or the like.
  • amino acid refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids.
  • Naturally occurring amino acids are those encoded by the genetic code, including selenomethionine, as well as those amino acids that are modified after incorporation into a polypeptide, e.g., hydroxyproline, O-phosphoserine, O-phosphotyrosine, ⁇ -carboxyglutamate, and cystine.
  • Amino acid analogs refers to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an ⁇ -carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid.
  • Amino acid mimetic refers to a chemical compound that has a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally occurring amino acid. Amino acids may be referred to herein by either their commonly known three letter symbols or by their one-letter symbols.
  • Binding composition encompasses, e.g., an antibody, polyclonal antibody, monoclonal antibody, engineered antibody, recombinant antibody, humanized antibody, binding fragment derived from an antibody, peptide mimetic of an antibody, a bifunctional, or multifunctional reagent.
  • the binding composition may further comprise, e.g., a linker, oligosaccharide, or label.
  • “Derived from an antibody” refers, e.g., to treatment or manipulation of an antibody to produce a fragment or complex, e.g., an antigen-binding site of the antibody, or use of genetically engineering to produce a molecule or complex that mimics predetermined features of the antibody, e.g., the antigen-binding site.
  • Bispecific antibody generally refers to a covalent complex, but may refer to a stable non-covalent complex of binding fragments from two different antibodies, humanized binding fragments from two different antibodies, or peptide mimetics of binding fragments from two different antibodies. Each binding fragment recognizes a different target or epitope, e.g., a different receptor, e.g., an inhibiting receptor and an activating receptor. Bispecific antibodies normally exhibit specific binding to two different antigens.
  • Constantly modified variants applies to both amino acid and nucleic acid sequences. With respect to particular nucleic acid sequences, conservatively modified variant refers to those nucleic acids that encode identical or essentially identical amino acid sequences. An example of a conservative substitution is the exchange of an amino acid in one of the following groups for another amino acid of the same group (U.S. Pat. No. 5,767,063 issued to Lee, et al.; Kyte and Doolittle (1982) J. Mol. Biol. 157:105-132).
  • ITIM and ITAM are two motifs found on some inhibiting and activating receptors, respectively.
  • the ITIM motif is defined by the consensus sequence I/V/LxYxxL/V in the cytoplasmic domain where (Y) can be phosphorylated, resulting in the ability of the polypeptide bearing the ITIM motif to recruit various enzymes, where the enzymes aid in relaying an inhibitory signal to the cell (Sathish, et al., (2001) J. Immunol. 166:1763-1770).
  • the consensus ITAM sequence is YxxL/Ix 6-8 YxxL/I, where (Y) may be phosphorylated resulting in a change in signaling properties of the activating receptor or an accessory protein.
  • the ITAM motif may occur within an activating receptor itself, or within an accessory protein that binds to the activating receptor, thus conferring activating properties to the activating receptor.
  • “Monofunctional reagent” refers, e.g., to an antibody, binding composition derived from the binding site of an antibody, an antibody mimetic, a soluble receptor, engineered, recombinant, or chemically modified derivatives thereof, that specifically binds to a single type of target.
  • a monofunctional reagent may contain one or more functioning binding sites for an CD200 receptor.
  • “Monofunctional reagent” also refers to a polypeptide, antibody, or other reagent that contains one or more functioning binding sites for, e.g., CD200 receptor and one or more non-functioning binding sites for Fc receptor.
  • a monofunctional reagent may comprise an antibody binding site for CD200 receptor plus an Fc fragment that has been engineered so that the Fe fragment does not specifically bind to Fc receptor.
  • Bifunctional reagent refers, e.g., to an antibody, binding composition derived from the binding site of an antibody, an antibody mimetic, a soluble receptor, engineered, recombinant, or chemically modified derivatives thereof, that specifically binds to two different targets, e.g., to an inhibiting CD200 receptor and an activating receptor.
  • the bifunctional reagent will comprise binding sites from, e.g., two different antibodies, two different soluble receptors, or an antibody and a soluble receptor.
  • Nucleic acid refers to deoxyribonucleotides or ribonucleotides and polymers thereof in either single stranded or double-stranded form.
  • the term nucleic acid may be used interchangeably with gene, cDNA, mRNA, oligonucleotide, and polynucleotide.
  • a particular nucleic acid sequence also implicitly encompasses “allelic variants” and “splice variants.”
  • Specific binding of a binding composition means that the binding composition binds to a specific antigen, e.g., CD200Ra (SEQ ID NO:2), with a binding constant ordinarily about 2-fold greater than to another antigen, typically about 4-fold greater than to another antigen, more typically at least about 10-fold greater than to another antigen, frequently at least about 40-fold greater than to another antigen; and most frequently at least about 100-fold greater than to another antigen.
  • a specific antigen e.g., CD200Ra (SEQ ID NO:2)
  • Ligand refers to small molecules, peptides, polypeptides, and membrane associated or membrane-bound molecules that act as agonists or antagonists of a receptor, as well as to soluble versions of the above membrane-associated or membrane-bound molecules.
  • the receptor usually occurs on a second cell.
  • the second cell may have the same or a different identity as the first cell.
  • a ligand or receptor may be entirely intracellular, that is, it may reside in the cytosol, nucleus, or some other intracellular compartment.
  • the ligand or receptor may change its location, e.g., from an intracellular compartment to the outer face of the plasma membrane.
  • the complex of a ligand and receptor is termed a “ligand receptor complex.” Where a ligand and receptor are involved in a signaling pathway, the ligand occurs at an upstream position and the receptor occurs at a downstream position of the signaling pathway.
  • Humanized antibody means an antibody comprising an antigen-binding region of nonhuman origin, e.g., rodent, and at least a portion of an immunoglobin of human origin, e.g., a human framework region, a human constant region, or portion thereof. See, e.g., U.S. Pat. No. 6,352,832.
  • Immunoser condition means, e.g., pathological inflammation, an inflammatory disorder, an inflammatory disease or disorder, or an autoimmune disorder or disease. “Immune condition” also refers to infections and cancerous conditions, e.g., pathological states where the immune system attempts to reduce the infection or reduce the cancerous condition. “Cancerous condition” includes, e.g., cancer, cancer cells, tumors, angiogenesis, and precancerous conditions such as dysplasia.
  • sample refers to a sample from a human, animal, or to a research sample, e.g., a cell, tissue, organ, fluid, gas, aerosol, slurry, colloid, or coagulated material.
  • the “sample” may be tested in vivo, e.g., without removal from the human or animal, or it may be tested in vitro. The sample may be tested after processing, e.g., by histological methods.
  • sample also refers, e.g., to a cell comprising a fluid or tissue sample or a cell separated from a fluid or tissue sample.
  • sample may also refer to a cell, tissue, organ, or fluid that is freshly taken from a human or animal, or to a cell, tissue, organ, or fluid that is processed or stored.
  • “Therapeutically effective amount” of a therapeutic agent is defined as an amount of each active component of the pharmaceutical formulation that is sufficient to show a meaningful patient benefit, i.e., to cause a decrease in or amelioration of the symptoms of the condition being treated.
  • “a therapeutically effective amount” is defined as an amount that is sufficient to produce a signal, image, or other diagnostic parameter. Effective amounts of the pharmaceutical formulation will vary according to factors such as the degree of susceptibility of the individual, the age, gender, and weight of the individual, and idiosyncratic responses of the individual. See, e.g., U.S. Pat. No. 5,888,530.
  • the invention provides methods for the treatment and diagnosis of immune conditions, inflammatory conditions, and autoimmune disorders involving cells bearing CD200R, e.g., mast cells, antigen presenting cells (APCs), dendritic cells, neutrophils, T cells, monocytes, and macrophages.
  • Dendritic cells are professional APCs. These conditions include, e.g., rheumatoid arthritis, bronchial hyperreactivity, asthma, allergic conditions, psoriasis, inflammatory bowel disease, multiple sclerosis, and pathological innate response, e.g., endotoxemia, sepsis, and septic shock.
  • the invention contemplates methods of modulating a CD200R using, e.g., an agonist or an antagonist of CD200Ra or CD200Rb.
  • the invention contemplates use of binding compositions to CD200Ra, e.g., for inhibiting mast cells in the treatment of mast cell-dependent pathological conditions.
  • Mast cells are implicated in the initiation and prolongation of rheumatoid arthritis (RA) (Lee, et al. (2002) Science 297:1689-1692; Vastag (2002) J. Am. Med. Assoc. 288:1457-1458; Woolley and Tetlow (2000) Arthritis Res. 2:65-74; Olsson, et al. (2001) Ann. Rheum. Dis. 60:187-193).
  • Collagen-induced arthritis CIA is an experimental animal model for RA.
  • RA and CIA involve, e.g., fibrin deposition, hyperplasia of synovial cells, periosteal bone formation, mononuclear infiltrates, pannus formation, and ankylosis of the joints (Luross and Willians (2001) Immunology 103:407-416). Immune cells, such as T cells and B cells, infiltrate the joints and induce pathology, e.g., inflammation, edema, or destruction of bone and cartilage.
  • RA is, in part, an autoimmune disorder, wherein autoimmunity occurs against various proteins, including cartilage structural proteins (Griffiths and Remmers (2001) Immunol. Revs. 184:172-183).
  • CIA encompasses many features common to several human autoimmune diseases, e.g., RA, diabetes, multiple sclerosis, and autoimmune thyroiditis (Griffiths and Remmers, supra).
  • Mast cells also contribute to endotoxemia, which can be induced by administration of LPS to mice and related conditions (Tuncel, et al. (2000) Peptides 21:81-89; Muchamuel, et al. (1997) J. Immunol. 158:2898-2903; Howard, et al. (1993) J. Exp. Med. 177:1205-1208).
  • Endotoxemia correlates with sepsis, septic shock, infection with Gram negative and other bacteria, and adverse reactions in innate immunity (Cohen (2000) Intensive Care Med., 26 Suppl. 1: S51-56; Freise, et al. (2001) J. Invest. Surg. 14:195-212).
  • Psoriasis occurs in over 4% of the population of Western countries. Psoriasis, which may be life threatening in some instances, is characterized by frequent relapses. It has also been associated with a form of arthritis known as psoriatic arthritis (Ackermann and Harvima (1998) Arch. Dermatol. Res. 290:353-359; Yamamoto, et al. (2000) J. Dermatol. Sci. 24:171-176; Ackerman, et al. (1999) Br. J. Dermatol.
  • Asthma is another disorder involving mast cells, APCs, and other immune cells (Black (2002) New Engl. J. Med. 346:1742-1743; Brightling, et al. (2002) New Engl. J. Med. 346:1699-1705; Carroll, et al. (2002) Eur. Respir. J. 19:1-7; Xiang and Nilsson (2000) Clin. Exp. Allergy 30:1379-1386; Woodruff and Fahy (2001) J. Am. Med. Assoc. 286:395-398).
  • Asthma is a chronic disorder characterized by bronchial hyperreactivity, which is the manifestation of pulmonary inflammatory disorders, including asthma, chronic obstructive pulmonary disease (a.k.a. COPD; chronic obstructive pulmonary disorder), chronic bronchitis, eosinophilic bronchitis, bronchiolitis, and viral bronchiolitis (Riffo-Vasquez and Spina (2002) Pharmacol. Therapeutics 94:185-211). Asthma is the result of a cascade of immune events, including the release of IgE. (See, e.g., Marone (1998) Immunol. Today 19:5-9; Barnes and Lemanske (2001) New Engl. J. Med. 344:350-362).
  • Mast cells contribute to the pathology of inflammatory bowel disease, e.g., Crohn's disease and colitis (Raithel, et al. (2001) Scand. J. Gastroenterol. 36:174-179; Nishida, et al. (2002) Hepatogastroenterol. 49:678-682; Gelbmann, et al. (1999) Gut 45:210-217; Nolte, et al. (1990) Gut 31:791-794; Jeziorska, et al. (2001) J. Pathol. 194:484-492).
  • IgE activates mast cells resulting in constriction of the airways and damage by eosinophils to the airways.
  • Mast cells also contribute to the pathology of inflammatory conditions of the nervous system, e.g., multiple sclerosis (Robbie-Ryan, et al. (2003) J. Immunol. 170:1630-1634; Dines and Powell (1997) J. Neuropathol. Exp. Neurol. 56:627-640). These cells also play a role in allograft rejection, e.g., of the liver, kidney, and lung and graft versus host disease (GVHD), and glomerulonephritis (O'Keefe, et al. (2002) Liver Transpl. 8:50-57; Lajoie, et al. (1996) Mod. Pathol.
  • GVHD graft versus host disease
  • APCs have also been implicated in the mechanisms of disorders, such as, rheumatoid arthritis, allergies, asthma, endotoxemia, septic shock, and skin conditions, e.g., psoriasis (Santiago-Schwarz, et al. (2001) J. Immunol. 167:1758-1768; Lambrecht and Hammad (2003) Curr. Opin. Pulm. Med. 9:34-41; Eigenmann (2002) Pediatr. Allergy Immunol. 13:162-167; Curry, et al. (2003) Arch. Pathol. Lab. Med. 127:178-186; Supajatura, et al. (2002) J. Clin. Invest. 109:1351-1359; Koga, et al. (2002) Dermatol. 204:100-103).
  • the invention also contemplates a method of modulating a CD200R using, e.g., an antagonist of CD200Ra or an agonist of CD200Rb, in the treatment of infections or proliferative conditions, such as cancer and tumors.
  • Mast cells, APCs, and other cells of the immune system play a role in preventing or combatting infections, e.g., bacterial, viral, and protozoal infections. See, e.g., Marshall, et al. (2003) Curr. Pharm. Dis. 9:11-24; Malaviya and Georges (2002) Clin. Rev. Allergy Immunol. 22:189-204; Mekori and Metcalfe (2000) Immunol. Rev.
  • Murine CD200Ra (a.k.a. muCD200Ra; SEQ ID NO:6) has a relatively long cytoplasmic tail. From in vivo studies, muCD200Ra is believed to be an inhibitory receptor, although it lacks a classical ITIM sequence. MuCD200Rb (SEQ ID NO:8), muCD200Rc (SEQ ID NO:10) and muCD200Rd (SEQ ID NO:12) have short cytoplasmic tails, charged amino acids in their transmembrane regions, and have been shown to pair with a cellular activating adaptor molecule, Dap12 (Lanier and Bakker (2000) Immunol. Today 21:611-614). Human CD200Ra is homologous to murine CD200Ra. Human CD200Rb (SEQ ID NO:4) is most homologous to muCD200Rb/d and is also a pairing partner with Dap12.
  • Polypeptides e.g., antigens, antibodies, and antibody fragments, for use in the contemplated method can be purified by methods that are established in the art. Purification may involve homogenization of cells or tissues, immunoprecipitation, and chromatography. Stability during purification or storage can be enhanced, e.g., by anti-protease agents, anti-oxidants, ionic and non-ionic detergents, and solvents, such as glycerol or dimethylsulfoxide.
  • Modification to proteins and peptides include epitope tags, fluorescent or radioactive groups, monosaccharides or oligosaccharides, sulfate or phosphate groups, C-terminal amides, acetylated and esterified N-groups, acylation, e.g., fatty acid, intrachain cleaved peptide bonds, and deamidation products (Johnson, et al. (1989) J. Biol. Chem. 264:14262-14271; Young, et al. (2001) J. Biol. Chem. 276:37161-37165).
  • Glycosylation depends upon the nature of the recombinant host organism employed or physiological state (Jefferis (2001) BioPharm 14:19-27; Mimura, et al. (2001) J. Biol. Chem. 276:45539-45547; Axford (1999) Biochim. Biophys. Acta 1:219-229; Malhotra, et al. (1995) Nature Medicine 1:237-243).
  • Derivatives of polypeptides also include modification by a fusion protein partner (Ausubel, et al. (2001) Current Protocols in Molecular Biology, Vol. 3, John Wiley and Sons, Inc., NY, N.Y., pp. 16.0.5-16.22.17; Sigma-Aldrich, Co. (2001) Products for Life Science Research, St. Louis, Mo.; pp. 45-89; Amersham Pharmacia Biotech (2001) BioDirectory, Piscataway, N.J., pp. 384-391).
  • a fusion protein partner Ausubel, et al. (2001) Current Protocols in Molecular Biology, Vol. 3, John Wiley and Sons, Inc., NY, N.Y., pp. 16.0.5-16.22.17; Sigma-Aldrich, Co. (2001) Products for Life Science Research, St. Louis, Mo.; pp. 45-89; Amersham Pharmacia Biotech (2001) BioDirectory, Piscataway, N.J., pp
  • Antibodies can be derived from human or non-human sources. Intact protein, denatured protein, or a peptide fragment of the protein, may be used for immunization (Harlow and Lane, supra, pp. 139-243). Regions of increased antigenicity may be used for peptide fragment immunization.
  • Human CD200Ra (SEQ ID NO:2) has regions of increased antigenicity, e.g., at amino acids 43-47, 62-66, 109-114, 165-174, 187-199, 210-214, 239-244, 260-267, and 293-300 of SEQ ID NO:2 (Vector NTI® Suite, InforMax, Inc., Bethesda, Md.).
  • Human CD200Rb (SEQ ID NO:4) is unusually antigenic at amino acids 55-75 of SEQ ID NO:4.
  • Mouse CD200Ra (SEQ ID NO:6) has regions of increased antigenicity at amino acids 25-40 and amino acids 85-95 of SEQ ID NO:6.
  • Mouse CD200Rb (SEQ ID NO:8) has regions of increased antigenicity at amino acids 10-22, 85-90, and 105-120 of SEQ ID NO:8.
  • Mouse CD200Rc (SEQ ID NO:10) has regions of increased antigenicity at amino acids 20-40, 115-130, and 190-220 of SEQ ID NO:10.
  • Mouse CD200Rd has regions of increased antigenicity at amino acids 20-50, 90-120, 155-175, and 180-200 of SEQ ID NO:12 (MacVector 6.5®, Accelrys, San Diego, Calif.). This list of antigenic fragments and regions is not intended to limit the regions of the polypeptides that can be used to raise antibodies or that can be bound by antibodies.
  • Binding compositions comprising an extracellular domain of CD200, or antigenic fragments thereof, are contemplated, e.g., in mono- and bifunctional agents.
  • the extracellular domain of human, mouse, and rat CD200 is described (Chen, et al. (1997) Biochim. Biophys. Acta 1362:6-10).
  • Antibodies derived from murine or other non-human sources can provoke an immune response, provide weak recruitment of effector function, or show rapid clearance from the bloodstream (Baca, et al. (1997) J. Biol. Chem. 272:10678-10684). For these reasons, it may be desired to prepare therapeutic antibodies by humanization.
  • a humanized antibody contains the amino acid sequences from six complementarity determining regions (CDRs) of the parent mouse antibody, that are grafted on a human antibody framework.
  • the content of non-human sequence in humanized antibodies is preferably low, i.e., about 5% (Baca, et al. (1997) J. Biol. Chem. 272:10678-10684).
  • the humanized antibody may need fine-tuning, by changing certain framework amino acids, usually involved in supporting the conformation of the CDRs, back to the corresponding amino acid found in the parent mouse antibody.
  • the framework amino acids that are generally changed back to those of the parent are those involved in supporting the conformation of the CDR loops (Chothia, et al. (1989) Nature 342:877-883; Foote and Winter (1992) J. Mol. Biol. 224:487-499).
  • the framework residues that most often influence antigen binding is relatively small, and may be a small as eleven residues (Baca, et al. (1997) J. Biol. Chem. 272:10678-10684).
  • Humanized antibodies include antibodies having all types of constant regions, including IgM, IgG, IgD, IgA and IgE, and any isotype, including IgG1, IgG2, IgG3 and IgG4.
  • the constant domain is usually a complement-fixing constant domain and the class is typically IgG1.
  • the constant domain can be of the IgG2 class.
  • the humanized antibody may comprise sequences from more than one class or isotype (U.S. Pat. No. 6,329,511 issued to Vasquez, et al.).
  • An alternative to humanization is to use human antibody libraries displayed on phage or human antibody libraries in transgenic mice (Vaughan, et al. (1996) Nature Biotechnol. 14:309-314; Barbas (1995) Nature Medicine 1:837-839; Mendez, et al. (1997) Nature Genetics 15:146-156; Hoogenboom and Chames (2000) Immunol. Today 21:371-377; Barbas, et al. (2001) Phage Display:A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.; Kay, et al. (1996) Phage Display of Peptides and Proteins:A Laboratory Manual, Academic Press, San Diego, Calif.; de Bruin, et al. (1999) Nature Biotechnol. 17:397-399).
  • Bifunctional antibodies are provided. See, e.g., Mack, et al. (1995) Proc. Natl. Acad. Sci. USA 92:7021-7025; Carter (2001) J. Immunol. Methods 248:7-15; Volkel, et al. (2001) Protein Engineering 14:815-823; Segal, et al. (2001) J. Immunol. Methods 248:1-6; Brennan, et al (1985) Science 229:81; Raso, et al. (1997) J. Biol. Chem. 272:27623; Morrison (1985) Science 229:1202; Traunecker, et al. (1991) EMBO J. 10:3655; and U.S.
  • Therapeutic antibodies may be conjugated, e.g., to small drug molecules, enzymes, liposomes, polyethylene glycol (PEG), or fusion protein antibodies. See, e.g., van Oosterhout, et al. (2001) Int. J. Pharm. 221:175-186; Marsh and Klinman (1990) 144:1046-1051; Kreitman (2001) Curr. Pharm. Biotechnol. 2:313-325; Dinndorf, et al. (2001). J. Immunother. 24:511-516; Wahl, et al. (2001) Int. J. Cancer 93:540-600; Garber (2000) J. Nat. Cancer Instit.
  • PEG polyethylene glycol
  • Antibodies are useful for diagnostic or kit purposes, and include antibodies coupled, e.g., to dyes, radioisotopes, enzymes, or metals, e.g., colloidal gold (Le Doussal, et al. (1991) J. Immunol. 146:169-175; Gibellini, et al. (1998) J. Immunol. 160:3891-3898; Hsing and Bishop (1999) J. Immunol. 162:2804-2811; Everts, et al. (2002) J. Immunol. 168:883-889).
  • antibodies coupled, e.g., to dyes, radioisotopes, enzymes, or metals, e.g., colloidal gold (Le Doussal, et al. (1991) J. Immunol. 146:169-175; Gibellini, et al. (1998) J. Immunol. 160:3891-3898; Hsing and Bishop (1999) J. Immunol
  • the invention provides methods for cross-linking two different receptors, e.g., an inhibiting receptor and an activating receptor, for modulating cell activity.
  • Examples of inhibiting receptors include, e.g., Fc ⁇ RIIB, LAIR, FDF03, KIR, gp49B, ILT25, PIR-B, Ly49, CTLA-4, CD200Ra (SEQ ID NO:2), CD94/NKG2A, NKG2BE, PECAM-1, CD5, CD22, CD72, PIR1, SIRP ⁇ , HM18, LRC, ILT, KIR, LIR, MIR, and MAFA. See, e.g., Long (1999) Ann. Rev. Immunol. 17:875-904; Lanier (1997) Immunity 6:371-378; Sinclair (1999) Scan. J. Immunol. 50:10-13; Pan, et al.
  • Inhibiting receptors also include DNAX Surface Protein-1 (a.k.a. DSP-1) (Cantoni, et al. (1999) Eur. J. Immunol. 29:3148-3159.
  • Activating receptors include, e.g., CD3, CD2, CD10, CD161, Dap12, KAR, KARAP, Fc ⁇ RI, Fc ⁇ RII, Fc ⁇ RIIA, Fc ⁇ RIIC, Fc ⁇ RIII/CD16, Trem-1, Trem-2, CD28, p44, p46, B cell receptor, LMP2A, STAM, STAM-2, GPVI, and CD40.
  • Activating receptors include, e.g., CD3, CD2, CD10, CD161, Dap12, KAR, KARAP, Fc ⁇ RI, Fc ⁇ RII, Fc ⁇ RIIA, Fc ⁇ RIIC, Fc ⁇ RIII/CD16, Trem-1, Trem-2, CD28, p44, p46, B cell receptor, LMP2A, STAM, STAM-2, GPVI, and CD40.
  • Azzoni et al. (1998) J. Immunol. 161:3493-3500; Kita, et
  • the invention provides methods for inhibiting, e.g., lymphoid cells, myeloid cells, and endothelial cells.
  • Cell inhibition is accomplished, e.g., by treating a cell, tissue, organ, extracellular fluid, animal, human subject, or cells or tissues ex vivo, with a mono-, bi-, or multifunctional reagent or binding composition.
  • the invention encompasses using an agent to increase expression of an inhibiting receptor, such as CD200Ra (SEQ ID NO:2), in order to increase efficiency of interaction of a binding composition specific for CD200Ra with CD200Ra, e.g., associated with mast cells, APCs, neutrophils, T cells, B cells, basophils, eosinophils, or epithelial cells.
  • an agent to increase expression of an activating receptor such as CD200Rb (SEQ ID NO:4).
  • the agent may comprise, e.g., a cytokine such as interferon or IL-10, a growth factor, a bifunctional reagent, an enzyme, or a small molecule such as adenosine.
  • the agent may comprise a factor that promotes maturation of, e.g., mast cells, dendritic cells, or other APCs, or neutrophils, such as, stem cell factor, granulocyte-macrophage colony-stimulating factor, tumor necrosis factor, or IL-6 (Hjertson, et al. (1999) Brit. J. Haematol. 104:516-522; Austen and Boyce (2001) Leuk. Res. 25:511-518; Vandenabeele and Wu (1999) Immunol. Cell Biol. 77:411-419; Santiago-Schwarz (1999) J. Leuk. Biol. 66:209-216; Liu, et al. (2001) Nat. Immunol. 2:585-589; Kondo, et al. (2003 Ann. Rev. Immunol.; Dumortier, et al. (2003) Blood 101:2219-2226).
  • a factor that promotes maturation of e.g.
  • Assays comprising animals, cells, or reagents such as beads or wells, are contemplated for screening for CD200, CD200R, and for agents that modulate interactions between CD200 and CD200R. See, e.g., Steinitz (2000) Analyt. Biochem. 232-238; Gast, et al. (1999) Analyt. Biochem. 276:227-241; Kaiser, et al. (2000) Analyt. Biochem. 282:173-185; and U.S. Pat. Nos. 6,176,962 and 6,517,234.
  • Cells or animals can be engineered, e.g., to express a CD200R, in order to facilitate their use in screening. Expression can be measured by, e.g., by hybridization-based techniques (Ausubel, et al. (2001) Curr. Protocols Mol. Biol., Vol. 4, John Wiley and Sons, New York, N.Y., pp. 25.0.1-25B.2.20; Ausubel, et al. (2001) Curr. Protocols Mol. Biol., Vol. 3, John Wiley and Sons, New York, N.Y., pp. 14.0.1-14.14.8; Liu, et al. (2002) Analyt. Biochem. 300:40-45; Huang, et al.
  • Polypeptides can be detected, e.g., by antibody-based techniques. See, e.g., Harlow and Lane, supra, pp. 553-612; Sims, et al. (2000) Analyt. Biochem. 281:230-232.
  • Formulations of, e.g., binding compositions, binding compounds, or antibodies are prepared by mixing, e.g., the antibody having the desired degree of purity with optional physiologically acceptable carriers, excipients, or stabilizers in the form of lyophilized cake or aqueous solutions.
  • optional physiologically acceptable carriers, excipients, or stabilizers in the form of lyophilized cake or aqueous solutions.
  • compositions comprising: Parenteral Medications, Marcel Dekker, NY; Lieberman, et al. (eds.) (1990) Pharmaceutical Dosage Forms: Tablets, Marcel Dekker, NY; and Lieberman, et al. (eds.) (1990) Pharmaceutical Dosage Forms: Disperse Systems Dekker, NY.
  • the therapeutic or pharmaceutical of this invention may be combined with or used in association with, e.g., anti-inflammatory, chemotherapeutic or chemopreventive agents.
  • Therapeutic antibody compositions generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.
  • the route of antibody administration is, e.g. injection or infusion by intravenous, intraperitoneal, intracerebral, intramuscular, intraocular, intraarterial, intracerebrospinal, intralesional, or pulmonary routes, or by sustained release systems. Sustained release systems are described. See, e.g.; Sidman et al. (1983) Biopolymers, 22:547-556; Langer et al. (1981) J. Biomed. Mater. Res.
  • an “effective amount” of antibody to be employed therapeutically will depend, e.g., upon the therapeutic objectives, the route of administration, the type of antibody employed, and the condition of the patient. Accordingly, it will be necessary for the therapist to titer the dosage and modify the route of administration as required to obtain the optimal therapeutic effect. Typically, the clinician will administer the antibody until a dosage is reached that achieves the desired effect. The progress of this therapy is easily monitored by conventional assays.
  • the binding composition will be formulated, dosed, and administered in a fashion consistent with good medical practice.
  • Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the antibody, the particular type of antibody, the method of administration, the scheduling of administration, and other factors known to medical practitioners.
  • the “therapeutically effective amount” of antibody to be administered will be governed by such considerations, and is the minimum amount necessary to prevent, ameliorate, or treat the proliferative disorder. Such amount is preferably below the amount that is toxic to the host.
  • the initial pharmaceutically effective amount of the antibody administered parenterally will be in the range of about 0.1 ⁇ g/kg to 10 mg/kg of the patient's body weight per day, ordinarily 0.1 ⁇ g/kg/day to 1.0 mg/kg/day, preferably 0.1 ⁇ g/kg/day to 0.1 mg/kg/day, more preferably 0.1 ⁇ g/kg/day to 0.01 mg/kg/day, and most preferably 0.1 ⁇ g/kg/day, or less.
  • the desired dosage can be delivered by a single bolus administration, by multiple bolus administrations, or by continuous infusion administration of antibody, depending on the pattern of pharmacokinetics that the practitioner wishes to achieve. As noted above, however, these suggested amounts of antibody are subject to a fair amount of therapeutic discretion. The key factor in selecting an appropriate dose and scheduling is the result obtained.
  • the invention contemplates use of combinations of an agonist or antagonist of CD200R with a second agent, e.g., an anti-inflammatory, immunosuppressive, or anti-neoplastic agent.
  • Anti-inflammatory agents include, e.g., steroids and non-steroidal anti-inflammatories (U.S. Pat. No. 6,294,170 issued to Boone, et al.; U.S. Pat. No. 6,096,728 issued to Collins, et al.; Hardman, et al. (2001) Goodman and Gilman's the Pharmacological Basis of Therapeutics, McGraw-Hill, New York, N.Y.).
  • Immunosuppressive agents include, e.g., azothioprine, mercaptopurine, and methotrexate.
  • Anti-neoplastic agents include, e.g., 5-fluorouracil, methotrexate, cis-platin, and doxorubicin (U.S. Pat. No. 6,066,668 issued Hausheer, et al.).
  • the contemplated method is adapted for use in kits, i.e., for screening or diagnostic purposes.
  • the kit may be adapted for use in detecting or quantitating a binding composition to CD200R, e.g., in a pharmaceutical composition or in a biological sample.
  • the contemplated kit is adapted for use with, e.g., mast cells from a subject or patient.
  • the kit will have a compartment, a reagent, or directions for use or disposal, or any combination thereof. Kits adapted to binding assays are described, e.g., U.S. Pat. Nos. 6,306,608; 6,150,122; 6,083,760; and 5,863,739.
  • the present invention contemplates methods for using a binding composition specific for a CD200R to modulate disorders associated with improper function of cells of the immune system, e.g., mast cells, APCs, such as dendritic cells, T cells, neutrophils, monocytes, or macrophages.
  • the binding composition may comprise an agonist or antagonist of a CD200R.
  • Agonists of an inhibiting receptor, e.g., CD200Ra (SEQ ID NOs:2 or 6) will be useful in inhibiting activity of mast cells, APCs, such as dendritic cells, T cells, neutrophils, monocytes, or macrophages.
  • Antagonists of an activating receptor e.g., CD200Rb (SEQ ID NOs:4, 6, 10, or 12) will also be useful in inhibiting activity of, e.g., mast cells, APCs, such as dendritic cells, T cells, neutrophils, monocytes, or macrophages.
  • Antagonists of CD200Ra and agonists of CD200Rb will be useful for stimulating, e.g., mast cells and APCs, such as dendritic cells, T cells, neutrophils, monocytes, or macrophages, for the treatment of infections and proliferative conditions.
  • the methods of the present invention contemplate use of, e.g., peptides, small molecules, antibodies, and binding compositions derived from the antigen binding site of an antibody, to treat or diagnose a variety of immune disorders, e.g., bronchial hyperreactivity, allergic rhinitis, asthma, bronchitis, and anaphylaxis. See, e.g., Woodruff and Fahy, supra; Plaut (2001) J. Am. Med. Assoc. 286:3005-3006; and Marshall and Bienenstock (1994) Curr. Op. Immunol. 6:853-859; Luskin and Luskin (1996) Am. J. Ther. 3:515-520.
  • immune disorders e.g., Woodruff and Fahy, supra; Plaut (2001) J. Am. Med. Assoc. 286:3005-3006; and Marshall and Bienenstock (1994) Curr. Op. Immunol. 6:853-859; Luskin and
  • the methods of the present invention can also be used to treat or diagnose rheumatoid arthritis, and skin disorders including psoriasis and atopic dermatitis. See, e.g., Mican and Metcalfe (1990) J. Allergy Clin. Immunol. 86:677-683; Malone, et al. (1987) Arthritis Rheum. 30:130-137; Malfait, et al. (1999) J. Immunol. 162:6278-6280; Ackermann and Harvima (1998) Arch. Dermatol. Res. 290:353-359; Ackermann, et al. (1999) Brit. J. Dermatol.
  • the method also contemplates treatment or diagnosis of inflammatory diseases of the gastrointestinal tract, e.g., Crohn's disease, ulcerative colitis, and irritable bowel syndrome. See, e.g., Malaviya, et al. (1995) Am. J. Ther. 2:787-792; Jeziorska, et al. (2001) J. Pathol. 194:484-492; Sullivan, et al (2000) Neurogastroenterol. Motility 12:449; Nolte, et al.
  • the invention also encompasses methods of treatment or diagnosis of demyelination or neurodegeneration, e.g., multiple sclerosis, Guillain-Barre syndrome, Alzheimer's disease, Parkinson's disease, and epilepsy (Purcell and Atterwill (1995) Neurochem. Res. 20:521-532; Secor, et al. (2000) J. Exp. Med. 191:813-822; Dines and Powell (1997) J. Neuropathol. Exp. Neurol. 56:627-640; Purcell and Atterwill (1995) Neurochem. Res. 20:521-532; Dietsch and Hinrichs (1989) J. Immunol. 142:1476-1481).
  • demyelination or neurodegeneration e.g., multiple sclerosis, Guillain-Barre syndrome, Alzheimer's disease, Parkinson's disease, and epilepsy (Purcell and Atterwill (1995) Neurochem. Res. 20:521-532; Secor, et al. (2000)
  • the invention encompasses a method of treating or diagnosing Sjogren's syndrome, transplant and graft rejection, graft-versus-host disease (GVHD), mastocytosis, and methods for preventing angiogenesis (Pedersen and Nauntofte (2001) Expert Opin. Pharmacother. 2:1415-1436; Konttinen, et al. (2000) Rheumatol. Int. 19:141-147; Moutsopoulos and Youinou (1991) Curr. Opin. Rheumatol. 3:815-822, Gorczynski, et al. (2000) Clin. Immunol. 95:182-189; Koskinen, et al.
  • Yet another aspect of the invention provides methods of modulating activity of a CD200R, e.g., SEQ ID NO:2, for the treatment or prevention of cardiovascular disease, e.g., atherosclerosis.
  • Immune cells e.g., mast cells, dendritic cells, neutrophils, monocytes, and macrophages, contribute to the pathology of atherosclerosis. See, e.g., Huang, et al. (2002) Cardiovasc. Res. 55:150-160; Kelley, et al. (2000) Mol. Med. Today 3:18; Aicher, et al. (2003) Circulation 107:604-611; Ozmen, et al. (2002) Histol. Histopathol. 17:223-237; Wanders, et al. (1994) Transpl. Int. 7 Suppl. 1:S371-S375.
  • Murine mast cell cultures were established from 2-3 week old C57BL/6 mice. Bone marrow was flushed from the femurs of 2-3 mice and subsequently washed three times with phosphate buffered saline (PBS). Cells were resuspended in 15 ml Dulbecco's minimal essential media (MEM) supplemented with sodium pyruvate, non-essential amino acids, 2-mercaptoethanol, N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid (HEPES), glutamine, 10-15% fetal calf serum (Hyclone, Inc., Logan, Utah), 100 ng/mg rSCF, and 100 ng/ml of rIL-3.
  • MEM Dulbecco's minimal essential media
  • HEPES N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid
  • glutamine 10-15% fetal calf serum (Hyclone, Inc
  • CD200 receptors were introduced by retrovirus vectors into Baf cell lines that had previously been transfected with one of the following FLAG-tagged molecules: Dap12, Dap10, Fc ⁇ R ⁇ , or CD3- ⁇ .
  • the FLAG-tagged molecules are only expressed on the cell surface when stably associated with appropriate pairing partner molecule.
  • murine CD200Rc SEQ ID NO:10
  • murine CD200Rd SEQ ID NO:12
  • CD200R molecules were stably introduced into normal mouse mast cells. These CD200Rs were then directly engaged with monoclonal antibodies specific for various epitope tags. Mast cell degranulation, cytokine secretion, and proliferation were monitored with and without subsequent cross-linking of the anti-tag antibodies. Triggering CD200Ra had no effects on resting mast cells, however, triggering the CD200 receptors that pair with Dap12, i.e., activating CD200Rs, caused significant mast cell degranulation, cytokine secretion, and autocrine-dependent proliferation.
  • CD200Ra was stably introduced into normal mast cells.
  • CD200Ra (SEQ ID NO:6) further comprising an epitope tag was engaged by a CD200 Ig-fusion protein or by monoclonal antibodies against the epitope tags while simultaneously activating the Fc ⁇ RI with IgE antibodies. Mast cells were then monitored for degranulation, cytokine secretion, and proliferative responses.
  • CD200Ra and Fc ⁇ RI were co-ligated by a secondary antibody. The results demonstrated that CD200Ra is an inhibitory receptor capable of inhibiting Fc ⁇ RI-dependent responses in mast cells.
  • Monoclonal antibodies specific for human CD200Ra were tested for agonist activity using activated mast cells.
  • Anti-huCD200Ra antibodies i.e., DX136 (rIgG2a) and DX139 (rIgM), were found to be agonists of CD200Ra as measured by assessing changes in degranulation and secretion, using murine mast cells expressing human CD200Ra. Agonist activity is expressed by IC50.
  • Fusion proteins comprising two CD200 extracellular domains fused to an Fc region, were also tested for agonist activity (huCD200-Ig; muCD200-Ig). These fusion proteins contained a mutation (D265A in the constant regions of the Fc used to create both huCD200-Ig and muCD200-Ig) to prevent binding to Fc receptor (FcR) and to complement (Idusogie, et al. (2000) J. Immunol. 164:4178-4184). These fusion proteins also delivered a signal that inhibited mast cell degranulation and cytokine secretion.
  • Mouse mast cells expressing the human CD200Ra molecule were stimulated with 25 ⁇ g/ml monoclonal antibody to trigger the Dap12-linked activating receptor of mouse CD200Rd, followed by measurement of secreted ⁇ -hexosaminidase at 1.0 hours (Table 2).
  • Agonist activity of anti-CD200Ra antibody or CD200-Ig fusion protein was assessed by adding anti-CD200Ra antibody or CD200-Ig fusion protein to the cell incubation mixtures and determining inhibition of secretion.
  • Incubations were conducted with antibodies or CD200-Ig fusion protein at concentrations of 0, 0.01, 0.03, 0.1, 0.3, 1.0, 3.0, and 9.0 ⁇ g/ml. Control cell incubations were conducted with the rat isotype control mAb.
  • Mouse mast cells were stimulated with IgE anti-TNP with antigen (TNP-keyhole limpet hemocyanin; KLH), followed by assay of released ⁇ -hexosaminidase (degranulation; Abs 405-650 ) and cytokine (secretion) (FIGS. 1 - 2 )
  • the degranulation signal, IgE anti-TNP was used at the indicated concentrations.
  • DX109 monoclonal anti-CD200R antibody (mAb) and control rat IgG1 mAb were tested for their effect on inhibiting mast cell activity.
  • DX109 mAb or rat IgG1 mAb were added at a constant concentration of 13 nM.
  • the cytokines assayed were IL-13 and tumor necrosis factor (TNF) (FIGS. 1 - 2 ).
  • the results demonstrate that anti-CD200R antibody is effective in inhibiting degranulation and cytokine secretion.
  • Tryptase assays were performed with the substrate N-alpha-benzyl-DL-arginine p-nitroanilide hydrochloride (BAPNA) with color measurement at 405-570 nm.
  • BAPNA N-alpha-benzyl-DL-arginine p-nitroanilide hydrochloride
  • PCA passive cutaneous anaphylaxis
  • mice One hour later, the backs of all ten mice were shaved and mouse IgE anti-DNP mAb was injected intradermally (i.d.) in a volume of 20 ⁇ l at 3 sites per mouse, respectively 10, 20 or 40 ng IgE per site. Twenty four hours later, all mice received i.v. a mixture of antigen (DNP-HSA) and the dye Evans's blue. Where the injected antigen binds to, and cross-links the IgE bound to skin mast cells, degranulation occurs, leading to release of mediators such as histamine that cause vascular edema, enabling the movement of the blue dye from the blood into the skin and appearance of blue spots on the skin.
  • DNP-HSA antigen-HSA
  • the size of the blue spot is proportional to the amount of IgE injected into the skin at that site.
  • the PCA reaction proceeded and blue spots appeared in all five mice, the largest size spot at the site where 40 ng IgE was injected, the smallest blue spot where 10 ng IgE was injected.
  • the DX109 anti-CD200Ra mAb no blue spots appeared at any concentration of injected IgE.
  • the DX109 mAb delivered an inhibitory signal to the skin mast cells in vivo, preventing degranulation.
  • CIA was induced in mice followed by treatment with anti-CD200Ra antibody (DX109 mAb) or with control IgG antibody.
  • DX109 mAb anti-CD200Ra antibody
  • Female B10.RIII mice 8-10 weeks old, were treated with bovine type II collagen in complete Freund's adjuvant (CFA) (Jirholt, et al. (1998) Eur. J. Immunol. 28:3321-3328). At day 0, mice were treated with one dose of bovine Type II collagen in CFA. Starting at day 7, antibody was administered at weekly intervals.
  • DX109 antibody and control IgG doses were 1 mg, i.p. at days 7 and 14, and 1 mg, s.c. at days 21 and 28. Disease scoring commenced at day 14 and was continued to day 45.
  • Experimental mice received DX109, while control mice received control IgG.
  • CIA was scored by cumulative incidence in units of percent.
  • CIA was also scored by Mean Clinical Score (MCS) (Hoek, et al, supra).
  • MCS Mean Clinical Score
  • Endotoxaemia was induced in mice by LPS-treatment followed by treatment with anti-CD200R antibody (DX109) or control antibody and assessment of survival rate.
  • the LPS dose was adjusted to provide sufficient toxicity to provoke toxicity and death of the mice, while avoiding saturating levels that would prevent the antibody from enhancing survival.
  • the mice were of the C57BL/6 strain.
  • Mice received 0.5 mg antibody (i.p.) at two time points, i.e., 1 hour prior to as well as simultaneously with the LPS.
  • the anti-CD200R antibody treated mice showed a higher survival rate at various time points when compared to the control group. The results demonstrated that anti-CD200R antibody protects mice from LPS-induced toxicity.
  • CD200Ra was visualized in green by rat anti-CD200Ra and tagging with goat anti-rat containing Alexa Fluor®-488 (Molecular Probes, Eugene, Oreg.). Mast cells were visualized in red with mouse anti-CD117 (a marker for mast cells) and tagging with goat anti-mouse containing Alexa Fluor®-594 (Molecular Probes, Eugene, Oreg.). Staining with anti-CD117 revealed an array of discrete red spots. Staining with both antibodies indicated that about one third of CD200Ra-bearing cells were mast cells.
  • CD200Ra SEQ ID NO:2
  • CD200Ra was localized by staining with anti-CD200Ra tagged with green. Macrophages were located with anti-CD11b antibody tagged with red. Staining with either antibody alone or with both antibodies together demonstrated that a majority of macrophages expressed CD200Ra.
  • SEQ ID NO:1 is human CD200Ra nucleic acid.
  • SEQ ID NO:2 is human CD200Ra polypeptide.
  • SEQ ID NO:3 is human CD200Rb nucleic acid.
  • SEQ ID NO:4 is human CD200Rb polypeptide.
  • SEQ ID NO:5 is murine CD200Ra nucleic acid.
  • SEQ ID NO:6 is murine CD200Ra polypeptide.
  • SEQ ID NO:7 is murine CD200Rb nucleic acid.
  • SEQ ID NO:8 is murine CD200Rb polypeptide.
  • SEQ ID NO:9 is murine CD200Rc nucleic acid.
  • SEQ ID NO:10 is murine CD200Rc polypeptide.
  • SEQ ID NO:11 is murine CD200Rd nucleic acid.
  • SEQ ID NO:12 is murine CD200Rd polypeptide.
  • SEQ ID NO:13 is rat CD200R nucleic acid.
  • SEQ ID NO:14 is rat CD200R polypeptide.

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030077282A1 (en) * 2001-10-12 2003-04-24 Bigler Michael Eric Use of bispecific antibodies to regulate immune responses
US20050169870A1 (en) * 2004-02-02 2005-08-04 Schering Corporation Methods of modulating CD200
US20050287603A1 (en) * 2002-06-07 2005-12-29 Gorczynski Reginald M Modulation of bone development
US20060084121A1 (en) * 1999-05-13 2006-04-20 Barclay A N OX2 receptor homologs
WO2009004339A3 (en) * 2007-07-03 2009-10-22 Imperial Innovations Limited Modulation of reactive oxygen species in the treatment of respiratory infection
US20100178296A1 (en) * 2006-12-22 2010-07-15 Schering Corporation Antibodies to cd200r
WO2011019423A2 (en) 2009-05-20 2011-02-17 Schering Corporation Modulation of pilr receptors to treat microbial infections
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ570998A (en) * 2002-03-15 2010-08-27 Schering Corp Method of diagnosising allergy or asthma by using a CD200Ra antibody
WO2004060295A2 (en) * 2002-12-27 2004-07-22 Schering Corporation Methods of inducing and maintaining immune tolerance
JP4919453B2 (ja) * 2005-04-07 2012-04-18 独立行政法人理化学研究所 炎症性疾患の予防又は治療剤
DK2037967T3 (en) 2006-06-16 2017-03-13 Univ Pennsylvania PROSTAGLANDIN-D2 RECEPTOR ANTAGONISTS FOR TREATMENT OF ANDROGENETIC ALOPECI
AU2008206502A1 (en) * 2007-01-11 2008-07-24 Boehringer Ingelheim International Gmbh CD200 and its receptor, CD200R, modulate bone mass via the differentiation of osteoclasts
US20120121588A1 (en) * 2009-05-20 2012-05-17 Schering Corporation Modulation of pilr receptors to treat sepsis
US20150231215A1 (en) 2012-06-22 2015-08-20 Randolph J. Noelle VISTA Antagonist and Methods of Use
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US9890215B2 (en) 2012-06-22 2018-02-13 King's College London Vista modulators for diagnosis and treatment of cancer
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JP5854432B2 (ja) * 2012-09-28 2016-02-09 森永乳業株式会社 アレルギー反応検出法
PL3712174T3 (pl) 2013-12-24 2022-07-04 Janssen Pharmaceutica Nv Przeciwciała i fragmenty anty-vista
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MX2017007136A (es) 2014-12-05 2017-12-04 Immunext Inc Identificacion de vsig8 como el receptor vista putativo y su uso para producir moduladores vista/vsig8.
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JP7277047B2 (ja) 2016-04-15 2023-05-18 イミュネクスト インコーポレイテッド 抗ヒトｖｉｓｔａ抗体およびその使用
AR116668A1 (es) * 2018-09-14 2021-06-02 Lilly Co Eli Anticuerpos agonistas contra cd200r y sus usos

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6476195B1 (en) * 1998-07-30 2002-11-05 Human Genome Sciences, Inc. Secreted protein HNFGF20
US20030077282A1 (en) * 2001-10-12 2003-04-24 Bigler Michael Eric Use of bispecific antibodies to regulate immune responses
US20040126777A1 (en) * 2002-01-28 2004-07-01 Bhatt Ramesh Rajani Lp mammalian proteins; related reagents
US20040214187A1 (en) * 2001-04-26 2004-10-28 Anne-Renee Van Der Vuurst De Vries Human ox2 receptors

Family Cites Families (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4946778A (en) 1987-09-21 1990-08-07 Genex Corporation Single polypeptide chain binding molecules
US5202267A (en) 1988-04-04 1993-04-13 Hygeia Sciences, Inc. Sol capture immunoassay kit and procedure
US5468468A (en) 1989-02-09 1995-11-21 The United States Of America, As Represented By The Secretary Of The Department Of Health & Human Services Method for making a monoclonal antibody, monoclonal antibodies to α PD
US6176962B1 (en) 1990-02-28 2001-01-23 Aclara Biosciences, Inc. Methods for fabricating enclosed microchannel structures
DK0469477T3 (da) * 1990-08-02 1995-12-27 Hoffmann La Roche Antiallergisk kombination
US5440021A (en) 1991-03-29 1995-08-08 Chuntharapai; Anan Antibodies to human IL-8 type B receptor
US5571702A (en) 1991-03-29 1996-11-05 Genentech, Inc. Amplification method for detection of human PF4A receptors
US5932448A (en) 1991-11-29 1999-08-03 Protein Design Labs., Inc. Bispecific antibody heterodimers
US6129914A (en) 1992-03-27 2000-10-10 Protein Design Labs, Inc. Bispecific antibody effective to treat B-cell lymphoma and cell line
US5532210A (en) 1994-06-08 1996-07-02 E. I. Du Pont De Nemours And Company High temperature superconductor dielectric slow wave structures for accelerators and traveling wave tubes
US6132764A (en) 1994-08-05 2000-10-17 Targesome, Inc. Targeted polymerized liposome diagnostic and treatment agents
US5919816A (en) 1994-11-14 1999-07-06 Bionumerik Pharmaceuticals, Inc. Formulations and methods of reducing toxicity of antineoplastic agents
AU6501296A (en) 1995-07-21 1997-02-18 General Hospital Corporation, The Method and apparatus of enhancing the delivery of a pharmaceutical formulation
US6096728A (en) 1996-02-09 2000-08-01 Amgen Inc. Composition and method for treating inflammatory diseases
DE69735760T2 (de) 1996-05-27 2007-05-10 Medical & Biological Laboratories Co., Ltd., Nagayo Antikörper gegen menschliches lect2, zellen die diesen produzieren und verfahren und kit zu dessen bestimmung
US6056973A (en) 1996-10-11 2000-05-02 Sequus Pharmaceuticals, Inc. Therapeutic liposome composition and method of preparation
JPH10212242A (ja) * 1996-11-27 1998-08-11 Tosoh Corp 新規血小板増多剤
US6294170B1 (en) 1997-08-08 2001-09-25 Amgen Inc. Composition and method for treating inflammatory diseases
US5948627A (en) 1997-05-30 1999-09-07 One Lambda Immunobead flow cytometric detection of anti-HLA panel-reactive antibody
US6342220B1 (en) 1997-08-25 2002-01-29 Genentech, Inc. Agonist antibodies
US6989435B2 (en) * 1997-09-11 2006-01-24 Cambridge University Technical Services Ltd. Compounds and methods to inhibit or augment an inflammatory response
US5842787A (en) 1997-10-09 1998-12-01 Caliper Technologies Corporation Microfluidic systems incorporating varied channel dimensions
JPH11246435A (ja) * 1997-10-29 1999-09-14 Ajinomoto Co Inc 免疫調整剤
US6312689B1 (en) 1998-07-23 2001-11-06 Millennium Pharmaceuticals, Inc. Anti-CCR2 antibodies and methods of use therefor
JP2002531466A (ja) 1998-12-01 2002-09-24 プロテイン デザイン ラブス， インコーポレイテッド γ−インターフェロンに対するヒト化抗体
HK1044023A1 (zh) * 1999-05-13 2002-10-04 Medical Research Council Ox2受体同系物
CA2417874C (en) * 2000-08-03 2012-10-02 Transplantation Technologies Inc. Use of ox-2 inhibitors for the treatment of cancer
CA2448668A1 (en) * 2001-05-24 2002-11-28 Trillium Therapeutics Inc. Modulation of cd200 receptors
NZ570998A (en) * 2002-03-15 2010-08-27 Schering Corp Method of diagnosising allergy or asthma by using a CD200Ra antibody

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6476195B1 (en) * 1998-07-30 2002-11-05 Human Genome Sciences, Inc. Secreted protein HNFGF20
US20040214187A1 (en) * 2001-04-26 2004-10-28 Anne-Renee Van Der Vuurst De Vries Human ox2 receptors
US20030077282A1 (en) * 2001-10-12 2003-04-24 Bigler Michael Eric Use of bispecific antibodies to regulate immune responses
US20040126777A1 (en) * 2002-01-28 2004-07-01 Bhatt Ramesh Rajani Lp mammalian proteins; related reagents

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060084121A1 (en) * 1999-05-13 2006-04-20 Barclay A N OX2 receptor homologs
US20100330034A1 (en) * 2001-10-12 2010-12-30 Schering Corporation Use of bispecific antibodies to regulate immune responses
US8236309B2 (en) 2001-10-12 2012-08-07 Schering Corporation Use of bispecific antibodies to regulate immune responses
US20030077282A1 (en) * 2001-10-12 2003-04-24 Bigler Michael Eric Use of bispecific antibodies to regulate immune responses
US20050287603A1 (en) * 2002-06-07 2005-12-29 Gorczynski Reginald M Modulation of bone development
US20090214573A1 (en) * 2002-06-07 2009-08-27 Reginald Gorczynski Modulation of bne development
US20050169870A1 (en) * 2004-02-02 2005-08-04 Schering Corporation Methods of modulating CD200
US20100178296A1 (en) * 2006-12-22 2010-07-15 Schering Corporation Antibodies to cd200r
US8212008B2 (en) * 2006-12-22 2012-07-03 Schering Corporation Antibodies to CD200R
WO2009004339A3 (en) * 2007-07-03 2009-10-22 Imperial Innovations Limited Modulation of reactive oxygen species in the treatment of respiratory infection
WO2011019423A2 (en) 2009-05-20 2011-02-17 Schering Corporation Modulation of pilr receptors to treat microbial infections
WO2011084357A1 (en) 2009-12-17 2011-07-14 Schering Corporation Modulation of pilr to treat immune disorders
US8691227B2 (en) 2009-12-17 2014-04-08 Merck Sharp & Dohme Corp. Methods of treating multiple sclerosis, rheumatoid arthritis and inflammatory bowel disease using agonists antibodies to PILR-α

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