US20070264277A1 - Compositions and Methods of Use for Mgd-Csf in Disease Treatment - Google Patents

Compositions and Methods of Use for Mgd-Csf in Disease Treatment Download PDF

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US20070264277A1
US20070264277A1 US11/632,319 US63231905A US2007264277A1 US 20070264277 A1 US20070264277 A1 US 20070264277A1 US 63231905 A US63231905 A US 63231905A US 2007264277 A1 US2007264277 A1 US 2007264277A1
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polypeptide
csf
mgd
cells
seq
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Dirk Behrens
Elizabeth Bosch
Stephen Doberstein
Robert Halenbeck
Kevin Hestir
Min Huang
Ernestine Lee
Haishan Lin
Thomas Linnemann
Shannon Marshall
Justin Wong
Ge Wu
Aileen Zhou
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Five Prime Therapeutics Inc
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Assigned to FIVE PRIME THERAPEUTICS, INC. reassignment FIVE PRIME THERAPEUTICS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BOSCH, ELIZABETH, HESTIR, KEVIN, WU, GE, BEHRENS, DIRK, LEE, ERNESTINE, LINNEMANN, THOMAS, MARSHALL, SHANNON, DOBERSTEIN, STEPHEN K., HALENBACK, ROBERT FORGAN, HUANG, MIN MEI, LEO, CINDY, LIN, HAISHAN, WILLIAMS, LEWIS T., WONG, JUSTIN G.P., ZHOU, AILEEN
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    • C07—ORGANIC CHEMISTRY
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    • 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
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/243—Colony Stimulating Factors
    • 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
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/53—Colony-stimulating factor [CSF]
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    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the first nucleotide sequence is SEQ. ID. NO.:3.
  • This embodiment may further comprise a second polynucleotide.
  • This second polynucleotide may comprise a second nucleotide sequence encoding a homologous or heterologous secretory leader.
  • the secretory leader may be chosen from SEQ. ID. NOS.:14-211.
  • the invention additionally provides a method of stimulating an immune response in a subject comprising providing a composition comprising a substantially pure polynucleotide encoding a polypeptide chosen from SEQ. ID. NOS.:7-12 and active fragments of any of these; and administering the composition to the subject.
  • the polypeptide may be encoded by a nucleic acid molecule comprising a nucleotide sequence chosen from SEQ. ID. NOS.:1-6.
  • the polypeptide may be administered locally or systemically. It may be administered intravenously, by enema, intraperitoneally, subcutaneously, topically, or transdermally.
  • the invention further provides a method for inhibiting tumor growth in a subject comprising providing a composition comprising a substantially pure polypeptide chosen from SEQ. ID. NOS.:7-12 and active fragments of any of these; and administering the composition to the subject.
  • the tumor may comprise human tumor cells, for example, solid tumor cells or leukemic tumor cells.
  • the invention yet further provides a method of increasing the number of NK cells in a subject comprising providing a polypeptide chosen from SEQ. ID. NOS.:7-12 and active fragments of any of these; and administering the polypeptide to the subject.
  • Transfected means possessing introduced DNA or RNA, with or without the use of any accompanying facilitating agents such as lipofectamine. Methods for transfection that are known in the art include calcium phosphate transfection, DEAE dextran transfection, protoplast fusion, electroporation, and lipofection.
  • polypeptide and “protein” are used interchangeably to refer to a polymer of amino acid residues, and are not limited to a minimum length. Thus, peptides, oligopeptides, dimers, multimers, and the like, are included within the definition. Both full-length proteins and fragments thereof are encompassed by the definition.
  • the terms also include post-expression modifications of the polypeptide, for example, glycosylation, acetylation, phosphorylation, and the like.
  • a “polypeptide” refers to a protein which includes modifications, such as deletions, additions, and substitutions (generally conservative in nature), to the native sequence, as long as the protein maintains the desired activity. These modifications may be deliberate, as through site-directed mutagenesis, or may be accidental, such as through mutations of hosts which produce the proteins or errors due to PCR amplification.
  • an “isolated,” “purified,” “substantially isolated,” or “substantially pure” molecule is one that has been manipulated to exist in a higher concentration than in nature.
  • a subject antibody is isolated, purified, substantially isolated, or substantially purified when at least 10%, or 20%, or 40%, or 50%, or 70%, or 90% of non-subject-antibody materials with which it is associated in nature have been removed.
  • an “isolated,” “purified,” “substantially isolated,” or “substantially purified” molecule includes recombinant molecules.
  • an antibody that binds specifically to one epitope (a “first epitope”) and not to another (a “second epitope”) is a “specific antibody.”
  • An antibody specific to a first epitope may cross react with and bind to a second epitope if the two epitopes share homology or other similarity.
  • the term “binds specifically,” in the context of a polynucleotide refers to hybridization under stringent conditions. Conditions that increase stringency of both DNA/DNA and DNA/RNA hybridization reactions are widely known and published in the art ( Curr. Prot. Molec. Biol., John Wiley & Sons (2001)).
  • MGC34647 is predicted to encode a protein with an open reading frame of 242 amino acids, with a nucleic acid coding sequence 729 nucleotides in length.
  • the proprotein is predicted to weigh 27,479 daltons and have an isoelectric point of 7.72.
  • the mature protein is predicted to weigh 25,229 daltons and have an isoelectric point of 6.74.
  • This mature protein is predicted to be 222 amino acids long, encoded by a nucleic acid molecule of 669 nucleotides.
  • MGC34647 has six exons. It maps to the genome on chromosome 16q22.1 from the start position of 70456649 to the stop position of 70470765.
  • the invention provides a DNA molecule that contains a promoter of a liver-expressed gene operably linked to a gene encoding MGD-CSF or NP — 688669, and that can be expressed in vivo to produce a protein that is functionally active.
  • Non-limiting embodiments of nucleic acid molecules include genes or gene fragments, exons, introns, mRNA, tRNA, rRNA, siRNA, ribozymes, antisense cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes, and primers.
  • Nucleic acid molecules include splice variants of an mRNA.
  • Nucleic acids can be naturally occurring, for example DNA or RNA, or can be synthetic analogs, as known in the art. Such analogs demonstrate stability under assay conditions, thus they are suitable as probes.
  • a nucleic acid molecule can also comprise modified nucleic acid molecules, such as methylated nucleic acid molecules and nucleic acid molecule analogs. Analogs of purines and pyrimidines are known in the art.
  • nucleic acid molecule is at least 70%, 80%, 90%, or 95% identical to, for instance, the nucleotide sequences set forth in the Sequence Listing can be determined conventionally using known computer programs such as the Bestfit program (Wisconsin Sequence Analysis Package, Version 8 for Unix, Genetics Computer Group, Madison, Wis.). Bestfit uses the local homology algorithm of Smith and Waterman, Advances in Applied Mathematics 2:482-489 (1981), to find the best segment of homology between two sequences.
  • Bestfit program Wiconsin Sequence Analysis Package, Version 8 for Unix, Genetics Computer Group, Madison, Wis.
  • the present invention also relates to vectors which include the isolated nucleic acid molecules of the present invention, host cells which are genetically engineered with the recombinant vectors, and the production of MGD-CSF polypeptides or fragments thereof by recombinant techniques. It provides recombinant vectors that contain, for example, nucleic acid constructs that encode secretory leader sequences (see, for example, the Sequence Listing; the secretory leader may be a collagen secretory leader), and a selected heterologous polypeptide of interest, and host cells that are genetically engineered with the recombinant vectors.
  • the vector may be, for example, a phage, plasmid, or viral vector. Retroviral vectors may be replication competent or replication defective.
  • a polypeptide having an amino acid sequence at least, for example, 95% identical to a reference amino acid sequence of a MGD-CSF polypeptide is one in which the amino acid sequence of the polypeptide is identical to the reference sequence except that the polypeptide sequence may include up to five amino acid alterations per each 100 amino acids of the reference polypeptide.
  • up to 5% of the amino acid residues in the reference sequence may be deleted or substituted with another amino acid, or a number of amino acids, up to 5% of the total amino acid residues in the reference sequence, may be inserted into the reference sequence.
  • These alterations of the reference sequence may occur at the amino or carboxy terminal positions of the reference amino acid sequence or anywhere between those terminal positions, interspersed either individually among residues in the reference sequence, or in one or more contiguous groups within the reference sequence.
  • polypeptides bearing an antigenic epitope that is, those which contain a region of a protein molecule to which an antibody can bind
  • relatively short synthetic peptides that mimic part of a protein sequence are routinely capable of eliciting an antiserum that reacts with the partially mimicked protein.
  • Peptides capable of eliciting protein-reactive sera are frequently represented in the primary sequence of a protein, can be characterized by a set of simple chemical rules, and are confined neither to immunodominant regions of intact proteins (that is, to immunogenic epitopes) nor to the amino or carboxyl terminals.
  • Antigenic epitope-bearing peptides and polypeptides of the invention are therefore useful for raising antibodies, including monoclonal antibodies, that bind specifically to a polypeptide of the invention. See, for instance, Wilson et al., Cell, 37:767-778 (1984).
  • the epitope-bearing peptides and polypeptides of the invention may be produced by any conventional means. See, for example, Houghten, Proc. Natl. Acad. Sci. 82:5131-5135 (1985), and U.S. Pat. No. 4,631,211 (1986).
  • Fusion proteins that have a disulfide-linked dimeric structure due to the IgG portion can also be more efficient in binding and neutralizing other molecules than the monomeric MGD-CSF protein or protein fragment alone, for example, as described by Fountoulakis et al., J. Biochem., 270:3958-3964 (1995).
  • Suitable, clinically acceptable, water soluble polymers include, but are not limited to, polyethylene glycol (PEG), polyethylene glycol propionaldehyde, copolymers of ethylene glycol/propylene glycol, monomethoxy-polyethylene glycol, carboxymethylcellulose, dextran, polyvinyl alcohol (PVA), polyvinyl pyrrolidone, poly-1,3-dioxolane, poly-1,3,6-trioxane, ethylene/maleic anhydride copolymer, poly ( ⁇ -amino acids) (either homopolymers or random copolymers), poly(n-vinyl pyrrolidone) polyethylene glycol, polypropylene glycol homopolymers (PPG) and other polyakylene oxides, polypropylene oxide/ethylene oxide copolymers, polyoxyethylated polyols (POG) (e.g., glycerol) and other polyoxyethylated polyols, polyoxye
  • a modified heterologous polypeptide of the invention may be prepared by attaching polyaminoacids or branch point amino acids to the polypeptide.
  • the polyaminoacid may be a carrier protein that serves to increase the circulation half life of the polypeptide (in addition to the advantages achieved via a fusion molecule).
  • such polyaminoacids should ideally be those that have or do not create neutralizing antigenic response, or other adverse responses.
  • heterologous polypeptides of the present invention and the epitope-bearing fragments thereof described herein can be combined with parts of the constant domain of immunoglobulins (IgG), resulting in chimeric polypeptides.
  • IgG immunoglobulins
  • These particular fusion molecules facilitate purification and show an increased half-life in vivo. This has been shown, for example, in chimeric proteins consisting of the first two domains of the human CD4-polypeptide and various domains of the constant regions of the heavy or light chains of mammalian immunoglobulins, such as EP 0 394 827; Traunecker et al., Nature, 331:84-86 (1988).
  • chemically modified derivatives of the polypeptides of the invention which may provide additional advantages such as increased solubility, stability, and circulating time of the polypeptide, or decreased immunogenicity (see U.S. Pat. No. 4,179,337).
  • the chemical moieties for derivitization may be chosen from water soluble polymers such as polyethylene glycol, ethylene glycol/propylene glycol copolymers, carboxymethylcellulose, dextran, polyvinyl alcohol and the like.
  • the polypeptides may be modified at random positions within the molecule, or at predetermined positions within the molecule and may include one, two, three, or more attached chemical moieties.
  • a cDNA herein disclosed is used to clone the genomic nucleic acid of MGD-CSF. This can be accomplished using a variety of well known techniques and libraries, which generally are commercially available.
  • the genomic DNA then is used for in situ chromosome mapping using techniques well known for this purpose. Therefore, the nucleic acid molecules of the present invention are also valuable for chromosome identification.
  • the sequence is specifically targeted to and can hybridize with a particular location on an individual human chromosome.
  • the mapping of DNAs to chromosomes according to the present invention is an important first step in correlating those sequences with genes associated with disease.
  • compositions can be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, enemas, injections, inhalants and aerosols.
  • the following methods and excipients are merely exemplary and are in no way limiting.
  • the agents, polynucleotides, and polypeptides can be formulated into preparations for injection by dissolving, suspending, or emulsifying them in an aqueous or nonaqueous solvent, such as vegetable or other similar oils, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol; and if desired, with conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives.
  • an aqueous or nonaqueous solvent such as vegetable or other similar oils, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol
  • solubilizers isotonic agents
  • suspending agents emulsifying agents
  • stabilizers and preservatives emulsifying agents
  • the invention also provides a method of screening compounds to identify those which modulate the biological activity of a polypeptide of the present invention. Examples of the biological activities of the polypeptides of the invention are described in greater detail herein, for example in the Examples and the Figures.
  • Antisense technology can be used to control gene expression through triple-helix formation or antisense DNA or RNA; both methods are based on the binding of a polynucleotide to DNA or RNA.
  • a 5′ coding portion of the polynucleotide sequence which encodes mature polypeptides of the present invention, can be used to design an antisense RNA oligonucleotide of from about 10 to about 40 base pairs in length.
  • a DNA oligonucleotide is designed to be complementary to a region of the gene involved in transcription, for example, a triple helix; see Lee et al., Nucl.
  • Molecules of the invention and fragments and variants thereof may be used in diagnosing, prognosing, preventing, treating, and developing treatments for any disorder mediated, either directly or indirectly, by defective or insufficient amounts of MGD-CSF.
  • MGD-CSF polypeptides, agonists, or antagonists may be administered to a patient afflicted with such a disorder.
  • a gene therapy approach may be applied to treat such disorders. Disclosure herein of sequences of the invention permits the detection of defective MGD-CSF related genes, and the replacement thereof with normal or corrective genes. Defective genes may be detected in in vitro diagnostic assays, and by comparison of the sequences of the invention with that of a gene derived from a patient suspected of harboring a defect.
  • the molecules of the invention are useful for treating cancer, immune diseases, such as an autoimmune disease or an inflammatory disease, ischemic diseases, infectious diseases, bone diseases, and neural diseases.
  • the molecules of the invention are useful for inhibiting the multiplication of a tumor cell or cancer cell, and for treating cancer.
  • the molecules of the invention can be used accordingly in a variety of settings for the treatment of animal cancers.
  • Other particular types of cancers that can be treated with molecules of the invention include, but are not limited to, those disclosed below.
  • the molecules of the invention are useful for killing or inhibiting the replication of a cell that produces an autoimmune disease or an inflammatory disease or for treating an autoimmune disease or an inflammatory disease. They can be used accordingly in a variety of settings for the treatment of an autoimmune disease or an inflammatory disease in an animal.
  • Molecules of the invention may be used to diagnose, determine a prognosis for, treat, or prevent one or more of the following diseases, disorders, or conditions associated therewith: primary immuodeficiencies, immune-mediated thrombocytopenia, Kawasaki syndrome, bone marrow transplant (for example, recent bone marrow transplant in adults or children), chronic B cell lymphocytic leukemia, HIV infection (for example, adult or pediatric HIV infection), chronic inflammatory demyelinating polyneuropathy, and post-transfusion purpura.
  • diseases, disorders, or conditions associated therewith include primary immuodeficiencies, immune-mediated thrombocytopenia, Kawasaki syndrome, bone marrow transplant (for example, recent bone marrow transplant in adults or children), chronic B cell lymphocytic leukemia, HIV infection (for example, adult or pediatric HIV infection), chronic inflammatory demyelinating polyneuropathy, and post-transfusion purpura.
  • autoimmune disorders and conditions associated with these disorders include, but are not limited to, autoimmune hemolytic anemia, autoimmune neonatal thrombocytopenia, idiopathic thrombocytopenia purpura, autoimmunocytopenia, hemolytic anemia, antiphospholipid syndrome, dermatitis, allergic encephalomyelitis, myocarditis, relapsing polychondritis, rheumatic heart disease, glomerulonephritis (for example, IgA nephropathy), multiple sclerosis, neuritis, uveitis ophthalmia, polyendocrinopathies, purpura (for example, Henloch-Scoenlein purpura), Reiter's disease, stiff-man syndrome, autoimmune pulmonary inflammation, Guillain-Barre Syndrome, insulin dependent diabetes mellitis, and autoimmune inflammatory eye disease.
  • autoimmune hemolytic anemia autoimmune neonatal thrombocytopenia, idiopathic thrombocytopenia purpur
  • the molecules of the invention are used to treat or prevent SLE and/or associated diseases, disorders, or conditions.
  • Lupus-associated diseases, disorders, and conditions which may be treated or prevented with molecules of the invention include, but are not limited to, hematologic disorders, for example, hemolytic anemia, leukopenia, lymphopenia, and thrombocytopenia; immunologic disorders, for example, anti-DNA antibodies, and anti-Sm antibodies, rashes, photosensitivity, oral ulcers, arthritis, fever, fatigue, weight loss, serositis, for example, pleuritus (pleurisy); renal disorders, for example, nephritis; neurological disorders, for example, seizures, peripheral neuropathy and CNS related disorders; gastroinstestinal disorders; Raynaud's phenomenon; and pericarditis.
  • Another embodiment of the present invention is directed to the use of MGD-CSF polynucleotides, polypeptides, or antagonists to reduce MGD-CSF or NP — 689669 mediated death of T cells in HIV-infected patients.
  • MGD-CSF polynucleotides, polypeptides, or antagonists to reduce MGD-CSF or NP — 689669 mediated death of T cells in HIV-infected patients.
  • the role of T cell apoptosis in the development of AIDS has been the subject of a number of studies (see, for example, Meyaard et al., Science, 257:217-219 (1992); Groux et al., J. Exp. Med., 175:331 (1992); and Oyaizu et al., in Cell Activation and Apoptosis in HIV Infection, Andrieu and Lu, eds., Plenum Press, New York, pp. 101-114 (1995)).
  • Suitable agents for blocking binding of Fas-ligand to Fas include, but are not limited to, soluble Fas polypeptides; multimeric forms of soluble Fas polypeptides (for example, dimers of sFas/Fc); anti-Fas antibodies that bind Fas without transducing the biological signal that results in apoptosis; anti-Fas-ligand antibodies that block binding of Fas-ligand to Fas; and muteins of Fas-ligand that bind Fas but do not transduce the biological signal that results in apoptosis.
  • Monoclonal antibodies may be employed according to this method. Examples of suitable agents for blocking Fas-ligand/Fas interactions, including blocking anti-Fas monoclonal antibodies, are described in WO 95/10540.
  • Molecules of the invention may also be employed to regulate hematopoeisis, including erythropoiesis.
  • Hematopoeisis is a multi-step cell proliferation and differentiation process which begins with a pool of multipotent stem cells. These cells can proliferate and differentiate into hematopoietic progenitors in reply to different stimuli.
  • the molecules of the invention may be used to either stimulate or inhibit development of hematopoietic cells, for example, erythropoietic precursor cells.
  • the molecules of the invention are used to treat or prevent cardiovascular disorders, including peripheral artery disease, such as limb ischemia.
  • cardiovascular disorders include cardiovascular abnormalities, such as arterio-arterial fistula, arteriovenous fistula, cerebral arteriovenous malformations, congenital heart defects, pulmonary atresia, and scimitar syndrome.
  • Arrhythmias that can be treated with molecules of the invention include sinus arrhythmia, atrial fibrillation, atrial flutter, bradycardia, extrasystole, Adams-Stokes syndrome, bundle-branch block, sinoatrial block, long QT syndrome, parasystole, Lown-Ganong-Levine syndrome, Mahaim-type pre-excitation syndrome, Wolff-Parkinson-White syndrome, sick sinus syndrome, tachycardias, and ventricular fibrillation.
  • Tachycardias that can be treated with molecules of the invention include paroxysmal tachycardia, supraventricular tachycardia, accelerated idioventricular rhythm, atrioventricular nodal reentry tachycardia, ectopic atrial tachycardia, ectopic junctional tachycardia, sinoatrial nodal reentry tachycardia, sinus tachycardia, Torsades de Pointes, and ventricular tachycardia.
  • Heart valve diseases include aortic valve insufficiency, aortic valve stenosis, heart murmurs, aortic valve prolapse, mitral valve prolapse, tricuspid valve prolapse, mitral valve insufficiency, mitral valve stenosis, pulmonary atresia, pulmonary valve insufficiency, pulmonary valve stenosis, tricuspid atresia, tricuspid valve insufficiency, and tricuspid valve stenosis.
  • nephritis bone disease (for example, osteoporosis), atherosclerosis, pain, cardiovascular disorders (for example, neovascularization, hypovascularization), and reduced circulation (for example, ischemic diseases, such as myocardial infarction, stroke, etc., AIDS, allergy, inflammation, neurodegenerative disease (for example, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, pigmentary retinitis, cerebellar degeneration, etc., graft rejection (acute and chronic), graft vs.
  • ischemic diseases such as myocardial infarction, stroke, etc.
  • AIDS allergy, inflammation
  • neurodegenerative disease for example, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, pigmentary retinitis, cerebellar degeneration, etc.
  • graft rejection acute and chronic
  • graft vs graft vs.
  • Molecules of the invention are useful in promoting angiogenesis and wound healing (for example, wounds, bums, and bone fractures). They are also useful as an adjuvant to enhance immune responsiveness to specific antigen and/or anti-viral immune responses.
  • Antibodies of the invention include polyclonal and monoclonal antibody preparations, as well as preparations including hybrid antibodies, altered antibodies, chimeric antibodies and, humanized antibodies, as well as hybrid (chimeric) antibody molecules (see, for example, Winter et al., Nature 349:293-299 (1991)); and U.S. Pat. No. 4,816,567); F(ab′) 2 and F(ab) fragments; Fv molecules (noncovalent heterodimers, see, for example, Inbar et al., Proc. Natl. Acad. Sci. 69:2659-2662 (1972)); and Ehrlich et al.
  • the invention also includes humanized antibodies, i.e., those with mostly human immunoglobulin sequences.
  • Humanized antibodies of the invention generally refer to non-human immunoglobulins that have been modified to incorporate portions of human sequences.
  • a humanized antibody may include a human antibody that contains entirely human immunoglobulin sequences.
  • Antibodies of the invention specifically bind to their respective antigen(s); they may display high avidity and/or high affinity to a specific polypeptide, or more accurately, to an epitope of an antigen. Antibodies of the invention may bind to one epitope, or to more than one epitope. They may display different affinities and/or avidities to different epitopes on one or more molecules. When an antibody binds more strongly to one epitope than to another, adjusting the binding conditions can, in some instances, result in antibody binding almost exclusively to the specific epitope and not to any other epitopes on the same polypeptide, and not to a polypeptide that does not comprise the epitope.
  • the invention provides a method for prophylactic or therapeutic treatment of a subject needing or desiring such treatment by providing a vaccine, that can be administered to the subject. It also provides a method for enhancing immune response to a subject by providing a substantially purified polypeptide from SEQ. ID. NOS.:7-12 or an active fragment; providing a vaccine composition, and administering the polypeptide and vaccine compositions to the subject.
  • the vaccine may comprise one or more of a polynucleotide, polypeptide, or modulator of the invention, for example an antibody vaccine composition, a polypeptide vaccine composition, or a polynucleotide vaccine composition, useful for treating cancer, proliferative, inflammatory, immune, metabolic, bacterial, or viral disorders.
  • the vaccine comprises a polynucleotide encoding one or more such fragments, administered for the treatment, for example, of proliferative disorders, such as cancer. Further, the vaccine can be administered with or without an adjuvant.
  • the vaccine can be administered with polypeptides shown in the Tables and Sequence Listing; it may be administered prior to, substantially contemporaneously with, or after administering the polypeptides.
  • the molecules of the invention find use in immunotherapy of hyperproliferative disorders, including cancer, neoplastic, and paraneoplastic disorders. That is, the subject molecules can correspond to tumor antigens, of which over 1770 have been identified to date (Yu and Restifo, J. Clin. Invest. 110:289-294, 2002). hnmunotherapeutic approaches include passive immunotherapy and vaccine therapy and can accomplish both generic and antigen-specific cancer immunotherapy.
  • the expression of the recombinant gene may be assayed using standard techniques. Initial screening may be accomplished by Southern blot analysis or PCR techniques to analyze animal tissues to verify that integration of the transgene has taken place. The level of mRNA expression of the transgene in the tissues of the transgenic animals may also be assessed using techniques which include, but are not limited to, Northern blot analysis of tissue samples obtained from the animal, in situ hybridization analysis, and reverse transcriptase-PCR (RT-PCR). Samples of transgenic gene-expressing tissue may also be evaluated immunocytochemically or immunohistochemically using antibodies specific for the transgene product.
  • RT-PCR reverse transcriptase-PCR
  • the amino acid sequence of MGD-CSF differs from the amino acid sequence of NP — 689669 (MCG34647).
  • the latter sequence has a glutamine (Q) residue at amino acid 81.
  • the five flanking amino acid residues adjacent to and on either side of amino acid 81 in the NCBI sequence of MCG34647 are NVTRLQRAQVS (SEQ ID NO.:279).
  • CLN00816424 was designated MGD-CSF collagen SP(1-23aa)_MGD-CSF(21 to 241aa)_TEV_V5_Streptag II_H8, and is C-tagged in vector pTT5-G.
  • a third such construct was generated with a TEV site engineered between the N-terminal tag and the protein.
  • CLN00816425 was designated MGD-CSF collagenSP(1-23aa)_H8_Streptag II_V5_TEV_MGD-CSF(21 to 241aa), and is N-tagged in vector pTT5-H.
  • CLN00848185 has 28 C-terminal amino acids and 20 N-terminal amino acids (signal peptide) deleted; it was designated MGD-CSF collagenSP(1-23aa)_MGD-CSF(21 to 213aa), and is untagged in vector pTT5.
  • CLN00848220 has 25 N-terminal amino acids and 10 C-terminal amino acids deleted; it was designated MGD-CSF collagenSP(1-23aa)_MGD-CSF(26 to 231aa), and is untagged in vector pTT5.
  • Cell suspensions (1 ml) were pelleted then mixed with four parts XT sample buffer (Bio-Rad, Hercules Calif.). Following denaturation at 99° C. for 3 minutes, samples were either loaded onto a Criterion XT SDS-PAGE gel (Bio-Rad, Hercules Calif.) or stored at ⁇ 20° C. Cell pellets were lysed by resuspension in 100 ⁇ l lysis buffer (1% NP-40; 50 mM Tris-HCl, pH 8.0; 150 mM NaCl; and one tablet complete protease inhibitors (Roche, Indianapolis Ind.)).
  • the protein loads of the cells and supernatants were matched so that the gel loads of the left and middle panels reflect comparable cell numbers.
  • the amount of MGD-CSF shown in the middle panels reflects the cells' secretory efficiency.
  • Tagged protein detected in the supernatant had a molecular weight of approximately 40 kD, whereas the intracellular protein had a molecular weight of approximately 37 kD, presumably due to incomplete glycosylation. Yields of the secreted protein differed depending on the construct design. CLN00732663 was expressed intracellularly at a low yield.
  • 293-6E cells transiently transfected with CLN00816424 continued to proliferate from days 3 through 6 post-transfection.
  • the density of the cells in suspension culture was monitored by counting cells that excluded trypan blue using a hemocytometer from day 3 through day 6 following transfection with CLN00542945 (black), CLN00732663 (light grey), CLN00821867 (diagonal stripe), and CLN00816424 (cross-hatch), and compared to a control gene encoding secreted alkaline phosphatase (SEAP) (dark grey).
  • SEAP secreted alkaline phosphatase
  • CLN00542945 untagged MGD-CSF
  • CLN00732663 V5H8-tagged MGD-CSF
  • CLN00821867 streptagged MGD-CSF
  • the Western blot of the nonreducing gel was analyzed for changes in apparent molecular weight, as determined by the relative migration of the MGD-CSF species compared with protein standards.
  • apparent size of the protein will typically increase under the denaturing conditions of SDS-PAGE, and the magnitude of this increase will typically be correlated with the distance between the two cysteine residues in the primary sequence of the protein.
  • the disruption of a disulfide bond may lead to the formation of higher molecular weight aggregated species.
  • C167S is observed to have the same migration time as wild type MGD-CSF, while all of the other muteins have altered migration behavior.
  • C167 is likely the only unpaired cysteine in native MGD-CSF.
  • C179S and C190S both primarily form higher molecular weight species. These muteins have the same changes in protein yield and migration, suggesting that they are paired with one another in native MGD-CSF.
  • C176S and C178S show the same slight decrease in migration, suggesting that they may be paired with each other in native MGD-CSF.
  • C198S has a larger change in migration, suggesting that its partner may be C35, which is located further away in the protein sequence.
  • MGD-CSF increased their growth in a dose dependent manner from 20 ng/ml to 500 ng/ml. MGD-CSF induced stem cell proliferation to a greater extent than M-CSF and to a similar extent as G-CSF and GM-CSF.
  • Human primary monocytes were purified from PBMC using a protocol modified from a previously-described method (de Almeida, et al., Mem. Inst Oswaldo Cruz 95:221-223, 2000).
  • the buffy coat was diluted in a six-fold volume of PBS, then overlain onto 20-ml Ficoll in a 50 ml tube.
  • the tubes were centrifuged at 2,000 rpm at 22° C. for 20 minutes without the use of the centrifuge brake.
  • the PMBC cells were collected from the interface, washed with PBS twice then resuspended in RPMI 5% FBS and filtered through a BD Falcon cell strainer.
  • the monocyte assay was performed by incubating approximately 30,000 purified monocytes with MGD-CSF purified as described above. After four days of incubation in RPMI with 5% FBS, monocyte proliferation was determined using the CellTiter-Glo Luminescent Cell Viability Assay Kit (Promega # G7571).
  • the stimulatory effect of MGD-CSF CM on monocyte proliferation was dose-dependent over a 10,000-fold range.
  • Increasing the dose 10-fold to 0.1 ⁇ l MGD-CSF CM induced cell proliferation to a significant level compared to controls.
  • Further increasing the dose to 1 ⁇ l MGD-CSF CM and 10 ⁇ l MGD-CSF CM further increased monocyte proliferation in a dose-dependent manner. No dose dependency was observed with the empty vector or the negative controls CLN003732 or FPT026.
  • the effect of a single dose of 10 ng/ml GM-CSF, a stimulatory positive control, is shown, as well as the effect of the negative control IL-10, and of unconditioned medium.
  • both purified GM-CSF and conditioned media from cells transfected with MGD-CSF stimulated human monycyte proliferation.
  • MGD-CSF functions as an agonist of monocyte proliferation, in addition to its role in the differentiation and growth of myeloid cells and granulocytes. It may be used as a hematopoietic factor to enhance the recovery of hematopoietic cells following chemotherapy or radiation treatment and bone marrow transplantation in cancer patients.
  • MGD-CSF stimulated the differentiation of granulocytes from undifferentiated cells to differentiated granulocytes possessing the differentiation markers CD67 + and CD24 + .
  • the baseline level of granulocyte differentiation in the presence of empty vector and the absence of cytokine was measured to be 12%.
  • the positive control, G-CSF stimulated 55% of the granulocytes to differentiate.
  • MGD-CSF CM stimulated 41% of the granulocytes to differentiate (arrow). The effect of MGD-CSF was synergistic with that of G-CSF, in the presence of both, 64% of the granulocytes were stimulated to differentiate.
  • CD24 and CD15 antibodies were used to monitor granulocyte differentiation.
  • the CD24 antibody reacted with a 35-45 kDa two-chain glycoprotein expressed on the surface of B cells and granulocytes.
  • the CD15 antibody reacted with 3-fucosyl-N-acetyllactosamine (3-FAL), a 220 kDa carbohydrate structure, also known as X-hapten.
  • 3-FAL was expressed on 95% of the granulocytes examined, including neutrophils and eosinophils, and to a varying degree on monocytes, but not on lymphocytes or basophils.
  • CD15 plays a role in mediating phagocytosis, bactericidal activity and chemotaxis. Cells positive for both CD24 and CD15 represent granulocytes which have differentiated from the BM CD34 + hematopoietic progenitor cells.
  • MGD-CSF stimulated the differentiation of dendritic cells from undifferentiated cells to differentiated dendritic cells possessing the CD86 and CD1 markers.
  • the baseline level of dendritic cell differentiation in the presence of empty vector was measured to be 4%.
  • MGD-CSF stimulated 22% of the undifferentiated cells to differentiate into dendritic cells.
  • MGD-CSF promoted formation of CFU-G, CFU-M, CFU-GM, and total colony formation.
  • MGD-CSF promoted large CFU-M colonies distinct from those promoted by G-CSF or GM-CSF.
  • Human bone marrow CD34 + cells (Cambrex, Inc., Baltimore Md.) were plated on 24-well cell culture plates in serum-free X-vivo 20 medium (Cambrex, Inc., Baltimore Md.), and treated with vector control conditioned medium (CM) or MGD-CSF CM. The cells were examined and photographed with an Axiovert 25 microscope and AxioCam HRc (both from Carl Zeiss, Gottingen, Germany) using a 40 ⁇ lens. Cells were visualized with a Zeiss KS300 3.0 digital imaging system.
  • NP_000945 HMM_SP leader sequence NO.: 96 NM_000954_1-23 HG1018373 SEQ. ID. NP_000945: leader sequence NO.: 97 NM_000954_1-22 HG1018374 SEQ. ID. NP_000945: leader sequence NO.: 98 NM_000954_1-18 HG1018376 SEQ. ID. NP_001176: leader sequence NO.: 99 NM_001185_1-18 HG1018377 SEQ. ID. NP_001176: leader sequence NO.: 100 NM_001185_1-20 HG1018378 SEQ. ID. NP_001176: leader sequence NO.: 101 NM_001185_1-21 HG1018379 SEQ.
  • NP_002893 leader sequence NO.: 142 NM_002902_1-21 HG1018430 SEQ. ID. NP_002893: leader sequence NO.: 143 NM_002902_1-23 HG1018432 SEQ. ID. NP_005133: HMM_SP leader sequence NO.: 144 NM_005142_1-19 HG1018433 SEQ. ID. NP_005133: leader sequence NO.: 145 NM_005142_1-18 HG1018434 SEQ. ID. NP_005133: leader sequence NO.: 146 NM_005142_1-20 HG1018435 SEQ. ID.
  • MGD-CSF Promotes Myelocytic Cell Proliferation In Vitro Clone ID Description Potency Expression CLN00542945 MGD-CSF (1-241 aa) +++ +++ CLN00848149 CSP-025 (20 to 241aa) ++ ++ CLN00848160 CSP-025 (25 to 241aa) + + CLN00848173 CSP-025 (30 to 241aa) ++ ++ CLN00848185 CSP-025 (20 to 213 aa) +++ ++ CLN00848197 CSP-025 (20 to 231aa) ++ +++ CLN00848209 CSP-025 (20 to 236 aa) + + CLN00848220 CSP-025 (25 to 231aa) ++ ++ Vector Control ⁇

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