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  • A61K39/39541—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against normal tissues, cells
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• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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• • C—CHEMISTRY; METALLURGY
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  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
  • C07K16/2896—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against molecules with a "CD"-designation, not provided for elsewhere
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
  • A61K2039/577—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2 tolerising response
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  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
  • C07K2317/51—Complete heavy chain or Fd fragment, i.e. VH + CH1
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
  • C07K2317/515—Complete light chain, i.e. VL + CL
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
  • C07K2317/55—Fab or Fab'
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
  • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
  • C07K2317/565—Complementarity determining region [CDR]
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
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  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
  • C07K2317/72—Increased effector function due to an Fc-modification
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
  • C07K2317/75—Agonist effect on antigen
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
  • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Definitions

• the present invention is in the field of medicine. More particularly, the present invention relates to agonistic antibodies directed to CD200 Receptor (CD200R), compositions comprising such CD200R agonistic antibodies, and methods of using such CD200R agonistic antibodies for the treatment of disorders such as autoimmune disease, allergic disease, asthma, or other inflammatory disorders.
• CD200R CD200 Receptor
• Immune checkpoint pathways may modulate both the autoimmune response and the anti -cancer immune response.
• autoimmune disease therapy promoting, /. e. , agonizing, the effect of an immune-inhibitory pathway, such that the immune response is suppressed, is desirable.
• cancer therapy inhibiting, i.e ., antagonizing, the effect of an immune-inhibitory pathway, such that the immune response is derepressed (stimulated), is desirable.
• CD200R is an Ig superfamily member and part of a family of checkpoint receptors that negatively regulate immune cell activation. Activation of the CD200R pathway leads to decreased cellular function, such as reduced cellular proliferation and inhibition of inflammatory cytokines. CD200R is primarily expressed on the surface of cells of the innate system, specifically of the monocytic lineage like macrophages, mast cells, dendritic cells, but also on activated T cell subsets such as T memory cells. The natural ligand for CD200R is CD200, which is more broadly expressed on multiple cell types including lymphocytes.
• CD200R (SEQ ID NO: 15), comprising a heavy chain variable region (HCVR) and a light chain variable region (LCVR), wherein the HCVR comprises a HCDR1, HCDR2, and HCDR3, and the LCVR comprises a LCDR1, LCDR2, and LCDR3, wherein the amino acid sequence of the HCDR1 is given by SEQ ID NO: 1, the amino acid sequence of the HCDR2 is given by SEQ ID NO: 2, and the amino acid sequence of the HCDR3 is given by SEQ ID NO: 3, the amino acid sequence of the LCDR1 is given by SEQ ID NO: 4, the amino acid sequence of the LCDR2 is given by SEQ ID NO: 5, and the amino acid sequence of the LCDR3 is given by SEQ ID NO: 6.
• the present invention provides an antibody that binds human CD200R, comprising a heavy chain (HC) and a light chain (LC), wherein the amino acid sequence of the HC is given by SEQ ID NO: 9 and the amino acid sequence of the LC is given by SEQ ID NO: 10.
• Xaa at position 1 of SEQ ID NO: 9 is glutamine.
• Xaa at position 1 of SEQ ID NO: 9 is pyroglutamic acid.
• Xaa at position 446 of SEQ ID NO: 9 is glycine.
• Xaa at position 446 of SEQ ID NO: 9 is absent.
• the present disclosure provides a process for producing a CD200R antibody, comprising: a) cultivating a mammalian cell capable of expressing the antibody, wherein the antibody comprises: 1) a HCVR having the amino acid sequence of SEQ ID NO: 7; and 2) a LCVR having the amino acid sequence of SEQ ID NO: 8; and b) recovering the antibody.
• the present disclosure provides a process for producing an anti-human CD200R antibody, comprising: a) cultivating a mammalian cell capable of expressing the antibody, wherein the antibody comprises: 1) a heavy chain having the amino acid sequence of SEQ ID NO: 9; and 2) a light chain having the amino acid sequence of SEQ ID NO: 10; and b) recovering the antibody.
• the present disclosure also provides a DNA molecule comprising a polynucleotide having the sequence of SEQ ID NO: 13.
• the present disclosure also provides a DNA molecule comprising a
• the present invention also provides a method of treating a patient having a disease, wherein the disease is an autoimmune disease, allergic disease, asthma, or other inflammatory disorders, comprising administering to a patient in need thereof, an effective amount of an antibody of the present invention.
• the present invention also provides use of an antibody of the present invention for the manufacture of a medicament for the treatment of a disease, wherein the disease is an autoimmune disease, allergic disease, asthma, or other inflammatory disorders.
• the disease is an autoimmune disease.
• the disease is an allergic disease.
• the disease is asthma.
• the disease is chronic idiopathic urticaria (also referred to herein as chronic spontaneous urticaria (CSU)), celiac disease (including, but not limited to, refractory celiac disease type II), allergy, chronic allergic disease, food allergies, eosinophilic esophagitis, macrophage activation syndrome (MAS), asthma, scleroderma, pemphigus, irritable bowel disease (IBD), systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), graft versus host disease (GvHD), psoriasis,
• CSU chronic spontaneous urticaria
• celiac disease including, but not limited to, refractory celiac disease type II
• allergy chronic allergic disease
• food allergies eosinophilic esophagitis
• the disease is allergic contact dermatitis, seasonal allergies, anaphylaxis treatment and prevention, bullous pemphigoid and other autoimmune blistering diseases, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis, idiopathic pulmonary fibrosis, myasthenia gravis, vasculitis, and myositis.
• the chronic allergic disease is hay fever or allergic rhinitis.
• the disease is atopic dermatitis.
• the present invention provides a CD200R agonist antibody, wherein the antibody does not cause significant cytokine release compared to a wild-type IgGl antibody having the same CDRs as the CD200R agonist antibody.
• a significant cytokine release is detected by comparing the amount of cytokine present in blood samples incubated with the antibody and the amount of cytokine present in blood samples without incubation with the antibody and determining the presence of significant cytokine release if the amount of cytokine present in blood sample incubated with the antibody is at least three- fold higher than the amount of cytokine present in blood sample with no antibody.
• the present invention provides an antibody of the present invention that binds at least one, at least two, at least three, at least four, or all of Fey RI, Fey RIIA 131H, Fey RIIA 131R, Fey Rllb, and Fey RIIIA 158V.
• the binding affinities of the antibody to the receptor are about 70 pM to about 500 pM to Fey RI, about 2 pM to about 5 pM to Fey RIIA 131H, about 1 mM to about 5 mM to Fey RIIA 131R, about 1 mM to about 4 mM to Fey Rllb, about 1 mM to about 6 mM to Fey RIIIA 158V, and greater than 9 mM to Fey RIIIA 158F.
• “human CD200R agonist antibody” or“anti-human CD200R agonist antibody” refers to an antibody that binds to human CD200R, and when administered in vitro or in vivo , results in an achieved immunosuppressive response such as at least one significantly lessened desired activity such as a desired reduction in IL-8 production.
• the terms“production” and“secretion,” as they relate to cytokines are used interchangeably.
• Antibodies of the present invention may be an IgGl or IgG4 antibody.
• antibodies of the present invention are IgG4 antibodies.
• An IgG4 antibody may have an S228P mutation within the HC (i.e., IgG4P), which is known to eliminate half-antibody formation common for the human IgG4 subclass.
• the constant region of the heavy chains contains CH1, CH2, and CH3 domains.
• CH1 comes after the HCVR; the CH1 and HCVR form the heavy chain portion of an antigen-binding (Fab) fragment, which is the part of an antibody that binds antigen(s).
• CH2 comes after the hinge region and before CH3.
• CH3 comes after CH2 and is at the carboxy-terminal end of the heavy chain.
• the constant region of the light chains contains one domain, CL.
• CL comes after the LCVR; the CL and LCVR form the light chain portion of a Fab.
• the Chothia CDR definition (Chothia et ak,“Canonical structures for the hypervariable regions of immunoglobulins”, Journal of Molecular Biology, 196, 901-917 (1987); Al-Lazikani et ak,“Standard conformations for the canonical structures of immunoglobulins”, Journal of Molecular Biology, 273, 927-948 (1997)) is based on three-dimensional structures of antibodies and topologies of the CDR loops.
• the Chothia CDR definitions are identical to the Rabat CDR definitions with the exception of HCDR1 and HCDR2.
• a human monocyte cell line U937 (ATCC, CRL1539.2) is transfected with the cDNA for human CD200R. Cytokine production, including IL-8, from these cells can be induced by immune complexes (IC) that bind and activate Fey Receptors.
• IC immune complexes
• human IgGl isotype control antibody is coated to a high-binding plate overnight.
• 4xl0 5 CD200R- expressing U937 cells/well are incubated with different concentrations of Antibody I-4P for 1 hour on ice before added to the pre-coated plate for IC stimulation and incubated at 37°C for 24 hours. After 24 hours the cells are spun down, the supernatant is removed, and the IL-8 concentration measured using MSD kit (Mesoscale Diagnostics).
• Fc block (Miltenyi Biotec) for 20 minutes at room temperature.
• the cells are stained with various concentrations of AF647-labeled Antibody I-4P for one hour at room temperature and cells are then washed and suspended in FACS buffer for analysis by flow cytometry.
• the epitope for Antibody I-4P was determined to be close to the cell membrane on domain 2 of CD200R (data not shown).
• Antibody HCVR of Antibody I-4P and Antibody I- IgGl (SEQ ID NO: 7)
• Xaa at position 1 is either glutamine or pyroglutamic acid
• Antibody LCVR of Antibody I-4P and Antibody I- IgGl (SEQ ID NO: 8)
• XVQLVQSGAEVKKPGAS VKVSCKASGF SF S SGYYMAWVRQAPGQGLEWMGLI GVGSGSLWYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARHFALSDP FNLW GQGTL VTV S S ASTKGP S VFPLAPC SRST SEST AALGCLVKD YFPEP VTV S W NSGALT SGVHTFP AVLQ S SGL Y SLS SWT VP S S SLGTKT YTCNVDHKP SNTKVDK RVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPE VQFNWYVDGVEVHNAKTKPREEQFNSTYRVV S VLTVLHQDWLNGKEYKCKV S NKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQ
• Xaa at position 1 is either glutamine or pyroglutamic acid; and Xaa at position 446 is either glycine or absent.

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