WO2011057144A2 - Methods for modulating lif activity, treating immune disorders and diseases, and stimulatings immune responses - Google Patents
Methods for modulating lif activity, treating immune disorders and diseases, and stimulatings immune responses Download PDFInfo
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/461—Cellular immunotherapy characterised by the cell type used
- A61K39/4611—T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
- A61K39/4643—Vertebrate antigens
- A61K39/4644—Cancer antigens
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
- C07K16/244—Interleukins [IL]
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0634—Cells from the blood or the immune system
- C12N5/0636—T lymphocytes
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2501/00—Active agents used in cell culture processes, e.g. differentation
- C12N2501/20—Cytokines; Chemokines
- C12N2501/23—Interleukins [IL]
- C12N2501/235—Leukemia inhibitory factor [LIF]
Definitions
- LIF Leukemia inhibitory factor, also known as cholinergic differentiation factor
- Tfh germinal center Tfh
- Tgc germinal center Tfh
- the invention is based, at least in part, on data indicating that expression of LIF (Leukemia inhibitory factor, also known as cholinergic differentiation factor) in CD4 T cells enhances (1) Tfh differentiation, (2) Germinal center B cell development, (3) and antibody responses.
- LIF Leukemia inhibitory factor
- the data demonstrate that LIF is a valuable cytokine target produced by CD4 T cells, and is useful to target for inhibiting or reducing immune responses, such as inflammatory and autoimmune responses, and inflammation (blocking LIF).
- the data also demonstrate that LIF can stimulate, induce, increase or enhance immune responses, such as by vaccines (enhancing LIF).
- the invention therefore provides methods for inhibiting, decreasing or reducing Tfh
- LIF Leukemia inhibitory factor, cholinergic differentiation factor
- a method includes administering an inhibitor of LIF (Leukemia inhibitory factor, cholinergic differentiation factor) to a subject in an amount effective to inhibit, decrease or reduce Tfh (follicular helper) cell differentiation, Germinal center B cell development or an antibody response in the subject; administering an inhibitor of LIF to a subject in an amount effective to inhibit or reduce development of memory T cells; administering an inhibitor of LIF (Leukemia inhibitory factor, cholinergic differentiation factor) to a subject in an amount effective to inhibit or reduce an undesirable or aberrant immune response in the subject; or administering to a subject an amount effective to inhibit or reduce an undesirable or aberrant inflammatory response or inflammation in the subject.
- LIF Leukemia inhibitory factor, cholinergic differentiation factor
- the invention also provides methods for stimulating, inducing or increasing an immune response; methods of stimulating, inducing or increasing development of memory T cells; methods of stimulating, inducing or increasing Tfh (follicular helper) cell differentiation, Germinal center B cell development or an antibody response; and methods for stimulating, inducing or increasing an immune response induced by a vaccine.
- a method includes administering a LIF polypeptide or subsequence thereof or an activator of LIF to a subject in an amount effective to stimulate, induce or increase an immune response in the subject; or administering LIF polypeptide or subsequence thereof or an activator of LIF to a subject in an amount effective to stimulate, induce or increase an immune response induced by the vaccine in the subject.
- LIF LIF polypeptides, subsequences thereof, nucleic acids encoding LIF, LIF inhibitory nucleic acids or antisense, etc.
- LIF activators and LIF inhibitors are provided.
- such methods include administering to a subject in need thereof an amount of a LIF polypeptide or subsequence thereof, or a LIF composition, to treat the subject.
- Non-limiting examples of such subjects in need of treatment include those having or at risk of acute or chronic undesirable or aberrant inflammatory response or inflammation, an autoimmune disease. Additional non-limiting examples of such subjects in need of treatment include those in need of a stimulated, induced or increased immune response, or an inhibited, decreased or reduced immune response. For example, an immune suppressed subject or a subject that is a candidate for a an immunization or a vaccine. Further non-limiting examples of such subjects in need of treatment include those in need of a stimulated, induced or increased memory T cell development, or an inhibited, decreased or reduced memory T cell development. Still further non-limiting examples of such subjects in need of treatment include those in need of a stimulated, induced or increased cell mediated or humoral immune response, or an inhibited, decreased or reduced cell mediated or humoral immune response.
- Methods of the invention include administering LIF (e.g., a LIF polypeptide, subsequence thereof, nucleic acids encoding LIF, LIF antisense, etc.), or a LIF activator or inhibitor, or a composition thereof, at various times, frequencies and in various quantities.
- LIF e.g., a LIF polypeptide, subsequence thereof, nucleic acids encoding LIF, LIF antisense, etc.
- a LIF activator or inhibitor e.g., a LIF activator or inhibitor, or a composition thereof, is administered prior to, substantially contemporaneously with or following development of a symptom in a subject who would benefit from treatment with LIF, or a LIF activator or inhibitor.
- Activators and inhibitors of LIF include molecules that bind to LIF (Leukemia inhibitory factor, cholinergic differentiation factor), or that act through an intermediary that in turn acts upon or binds to LIF.
- LIF Leukemia inhibitory factor, cholinergic differentiation factor
- such molecules include ligands, antibodies and
- LIF LIF subsequences thereof that bind to LIF
- such molecules include an inhibitory or antisense nucleic acid sequence of LIF (e.g., mammalian, such as human LIF).
- the invention further provides LIF polypeptides and subsequences of LIF, and LIF compositions (e.g., LIF pharmaceutical compositions and formulations, and adjuvant in combination with LIF) including LIF polypeptides and subsequences thereof, in which the peptide or subsequence thereof has one or more functions of LIF.
- LIF compositions e.g., LIF pharmaceutical compositions and formulations, and adjuvant in combination with LIF
- LIF polypeptides and subsequences thereof in which the peptide or subsequence thereof has one or more functions of LIF.
- a LIF polypeptide or subsequence thereof inhibits, decreases or reduces Tfh (follicular helper) cell differentiation, Germinal center B cell development or an antibody response, inhibits, decreases or reduces development of memory T cells, inhibits, decreases or reduces an undesirable or aberrant immune response; or inhibits, decreases or reduces an undesirable or aberrant inflammatory response or inflammation.
- a LIF polypeptide or subsequence stimulates, induces or increases an immune response, or stimulates, induces or increases an immune response induced by a vaccine (e.g., elicits, promotes or enhances an immune response against a vaccine antigen in vitro or in vivo).
- Figures 1A-1D show LIF expression and biological effects after infection or immunization.
- A) shows C57BL/6 mice infected with LCMV and microarray analysis performed post-infection on different CD4 populations.
- Leukemia inhibitory factor (LIF) is upregulated in follicular helper (Tfh) and germinal center Tfh (Tgc) over naive and non-Tfh populations.
- FIGS 2A-2F show LIF-/- and LIF+/- bone marrow (BM) chimera mice infected with 2xl0 5 pfu VACV. Splenocytes isolated at day 8 post-infection.
- LIF Leukemia inhibitory factor, cholinergic differentiation factor
- various immune responses e.g., stimulate, induce, increase or enhance, or inhibit, decrease or reduce an immune response.
- LIF can stimulate, induce, increase or enhance an immune response.
- LIF can also stimulate, induce, increase or enhance Tfh (follicular helper) cell differentiation, Germinal center B cell development or an antibody response.
- LIF can additionally stimulate, induce, increase or enhance development of memory T cells.
- LIF can furthermore stimulate, induce, increase or enhance an immune response, for example, a response induced by a vaccine.
- LIF and activators of LIF are useful for and the invention provides, among other things, methods for stimulating, inducing or increasing an immune response, development of memory T cells, and an immune response, such as an immune response induced by a vaccine.
- a method includes administering LIF or an activator of LIF to a subject in an amount effective to stimulate, induce, increase or enhance an immune response in the subject, administering LIF or an activator of LIF to a subject in an amount effective to stimulate, induce, increase or enhance Tfh (follicular helper) cell differentiation, Germinal center B cell development or an antibody response, administering LIF or an activator of LIF to a subject in an amount effective to stimulate, induce, increase or enhance development of memory T cells, and administering LIF or an activator of LIF to a subject in an amount effective to stimulate, induce, increase or enhance an immune response, such as a response induced by the vaccine in the subject.
- Tfh follicular helper
- Inhibitors of LIF can inhibit, decrease or reduce Tfh (follicular helper) cell differentiation, Germinal center B cell development or an antibody response. Inhibitors of LIF can also inhibit, decrease or reduce development of memory T cells. Inhibitors of LIF can furthermore inhibit, decrease or reduce an undesirable or aberrant immune response. LIF inhibitors can additionally inhibit, decrease or reduce an undesirable or aberrant inflammatory response or inflammation in the subject. Accordingly, LIF inhibitors are useful for and the invention provides, among other things, methods for inhibiting, decreasing or reducing such cell differentiation, Germinal center B cell development, antibody responses, undesirable and aberrant immune responses, and undesirable and aberrant inflammatory responses and inflammation.
- Tfh follicular helper
- a method includes administering an inhibitor of LIF to a subject in an amount effective to inhibit, decrease or reduce Tfh (follicular helper) cell differentiation, Germinal center B cell development or an antibody response in the subject, administering an inhibitor of LIF to a subject in an amount effective to inhibit, decrease or reduce development of memory T cells in the subject, administering an inhibitor of LIF to a subject in an amount effective to inhibit, decrease or reduce an undesirable or aberrant immune response in the subject, and administering an inhibitor of LIF to a subject in an amount effective to inhibit, decrease or reduce method for inhibiting or reducing an undesirable or aberrant inflammatory response or inflammation in the subject.
- Tfh follicular helper
- Inhibitors and activators of LIF "modulate" a LIF activity, function or expression.
- Modulate can mean any increase, stimulation, promotion, or enhancement, or decrease, reduction, inhibition, or prevention, in LIF activity, function or expression.
- modulating an immune response means that activity or function or an effect is that the immune response is detectably changed, e.g., an increase, stimulation, promotion, or enhancement, or decrease, reduction, inhibition, or prevention, of any immune function, such as inflammation, humoral or cell mediated immunity, activity, function or numbers of T and B cells, memory T cell development, function or activity, cytokine or chemokine production, antibody production, mitogen responsiveness, or symptoms thereof, which can be measured by a variety of methods disclosed herein or known to one of skill in the art.
- Exemplary activators of LIF detectably induce, increase, promote, stimulate or enhance an activity , function or expression of LIF.
- a LIF activator detectably induces, increases, promotes, stimulates or enhances one or more LIF activities or functions or LIF expression, which can include, for example, modulation of an immune response, as set forth herein or otherwise one that one of skill in the art would know.
- a LIF activator may act directly upon LIF. Such activators of LIF need not bind to LIF provided that they induce, increase, promote, stimulate or enhance one or more LIF activities or functions.
- a LIF activator may indirectly interact with LIF, for example, by acting through an intermediary, for example, the activator binds to or modulates a molecule that in turn binds to or modulates LIF.
- Exemplary inhibitors of LIF detectably reduce, decrease, inhibit, prevent or abrogate an activity or function of LIF.
- a LIF inhibitor detectably reduces, decreases, inhibits, presents or abrogates one or more LIF activities or functions.
- LIF activities and functions can include, for example, binding of LIF to a ligand, LIF mediated signaling or expression, or an immune response, as set forth herein or otherwise one that one of skill in the art would know.
- a LIF inhibitor may act directly upon LIF. Such inhibitors of LIF need not bind to LIF provided that they inhibit, reduce, suppress or in any way interfere with LIF function or activity.
- a LIF inhibitor may indirectly interact with LIF, for example, by acting through an intermediary, for example, the inhibitor binds to or modulates a molecule that in turn binds to or modulates LIF.
- LIF activators and inhibitors include ligands that bind to LIF or a subsequence thereof (e.g., SEQ ID NO: 1).
- ligands include polypeptides that bind to LIF, such as antibodies and LIF ligands.
- Additional exemplary LIF activators and inhibitors include antisense RNA and inhibitory nucleic acid against LIF.
- binding means a physical interaction at the molecular level (directly or indirectly). Typically, binding is that which is specific or selective for LIF, i.e., is statistically significantly higher than the background or control binding for the assay.
- specifically binds refers to the ability to preferentially or selectively bind to LIF. Specific and selective binding can be distinguished from non-specific binding using assays known in the art (e.g.,
- LIF antibody As used herein, the terms “LIF antibody,” “anti-LIF” and “anti-LIF antibody” refer to an antibody that specifically binds to LIF. Antibodies include monoclonal or polyclonal
- immunoglobulin molecules that belong to any class such as IgM, IgG, IgA, IgE, IgD, and any subclass thereof.
- IgG immunoglobulin molecules that belong to any class
- IgM immunoglobulin molecules that belong to any class
- IgG immunoglobulin molecules
- IgA immunoglobulin G
- IgE immunoglobulin molecule
- IgD immunoglobulin molecules that belong to any class thereof.
- subclasses for IgG are IgG], IgG 2 , IgGj and IgG .
- a “monoclonal” antibody refers to an antibody that is based upon, obtained from or derived from a single clone, including any eukaryotic, prokaryotic, or phage clone.
- a “monoclonal” antibody is therefore defined structurally, and not the method by which it is produced.
- Antibodies include full-length antibodies that include two heavy and two light chain sequences. Antibodies can have kappa or lambda light chain sequences, either full length as in naturally occurring antibodies, mixtures thereof (i.e., fusions of kappa and lambda chain sequences), and subsequences/fragments thereof. Naturally occurring antibody molecules contain two kappa or two lambda light chains.
- Antibodies include subsequences.
- Subsequences include all or a portion of a full- length antibody heavy or light chain, or a heavy or light chain variable region, which includes one or more CDRs of a heavy or light chain variable region sequence.
- a subsequence of a full length antibody heavy or light chain, or a heavy or light chain variable region has a length from about 20-30, 30-50, 50-100, 100-150, 150-200, 200-250, 250-300, 300-400, or 400-500, amino acid residues.
- Non-limiting representative antibody subsequences include but are not limited to Fab, Fab', F(ab') 2 , Fv, Fd, single-chain Fv (scFv), disulfide-linked Fvs (sdFv), V L , V H , Camel Ig, V-NAR, VHH, trispecific (Fab 3 ), bispecific (Fab 2 ), diabody ((V L -V H ) 2 or (V H -V L ) 2 ), triabody (trivalent), tetrabody (tetravalent), minibody ((scF v -C H 3) 2 ), bispecific single-chain Fv (Bis-scFv), IgGdeltaCH2, scFv-Fc, (scFv) 2 -Fc, affibody, aptamer, avimer or nanobody, or other antigen binding subsequences of an intact immunoglobulin.
- Antibodies include those that bind to
- Antibodies include antibodies and subsequences capable of binding to LIF in solution or in solid phase, present on one or more cells in vitro, in primary cell isolates, passaged cells, cultured cells and immortalized cells, or in vivo.
- Specific non-limiting cell types that can express LIF include Tfh and Tgc cells, as well as endothelial cells, epithelial cells from the uterus, intestine, lung and kidney, stromal cells and neuronal cells.
- Antibodies include mammalian, primatized, humanized, fully human antibodies and chimeras.
- a mammalian antibody is an antibody which is produced by a mammal, transgenic or non-transgenic, or a non-mammalian organism engineered to produce a mammalian antibody, such as a non-mammalian cell (bacteria, yeast, insect cell), animal or plant.
- a mammalian cell bacteria, yeast, insect cell
- the term "human” when used in reference to an antibody means that the amino acid sequence of the antibody is fully human, i.e., human heavy and human light chain variable and human constant regions. Thus, all of the amino acids are human or exist in a human antibody.
- An antibody that is non-human may be made fully human by substituting the non-human amino acid residues with amino acid residues that exist in a human antibody.
- Amino acid residues present in human antibodies, CDR region maps and human antibody consensus residues are known in the art (see, e.g., Kabat, Sequences of Proteins of Immunological Interest, 4 th Ed.US Department of Health and Human Services. Public Health Service ( 1 87); Chothia and Lesk (1987).
- a consensus sequence of human V H subgroup III based on a survey of 22 known human V H III sequences, and a consensus sequence of human V
- Human antibodies therefore include antibodies in which one or more amino acid residues have been substituted with one or more amino acids present in any other human antibody.
- humanized when used in reference to an antibody, means that the amino acid sequence of the antibody has non-human amino acid residues (e.g., mouse, rat, goat, rabbit, etc.) of one or more complementarity determining regions (CDRs) that specifically bind to the desired antigen in an acceptor human immunoglobulin molecule, and one or more human amino acid residues in the Fv framework region (FR), which are amino acid residues that flank the CDRs.
- CDRs complementarity determining regions
- FR Fv framework region
- Antibodies referred to as “primatized” are "humanized” except that the acceptor human immunoglobulin molecule and framework region amino acid residues may be any primate amino acid residue (e.g., ape, gibbon, gorilla, chimpanzees orangutan, macaque), in addition to any human residue.
- Human FR residues of the immunoglobulin can be replaced with corresponding non-human residues. Residues in the CDR or human framework regions can therefore be substituted with a corresponding residue from the non-human CDR or framework region donor antibody to alter, generally to improve, antigen affinity or specificity, for example.
- a humanized antibody may include residues, which are found neither in the human antibody nor in the donor CDR or framework sequences.
- FR substitution at a particular position that is not found in a human antibody or the donor non-human antibody may be predicted to improve binding affinity or specificity human antibody at that position.
- Antibody framework and CDR substitutions based upon molecular modeling are well known in the art, e.g., by modeling of the interactions of the CDR and framework residues to identify framework residues important for antigen binding and sequence comparison to identify unusual framework residues at particular positions (see, e.g., U.S. Patent No. 5,585,089; and Riechmann et al., Nature 332:323 (1988)).
- chimeric and grammatical variations thereof, when used in reference to an antibody, means that the amino acid sequence of the antibody contains one or more portions that are derived from, obtained or isolated from, or based upon two or more different species.
- a portion of the antibody may be human (e.g., a constant region) and another portion of the antibody may be non-human (e.g., a murine heavy or murine light chain variable region).
- an example of a chimeric antibody is an antibody in which different portions of the antibody are of different species origins. Unlike a humanized or primatized antibody, a chimeric antibody can have the different species sequences in any region of the antibody.
- LIF or an immunogenic fragment thereof optionally conjugated to a carrier such as keyhole limpet hemocyanin (KLH) or ovalbumin (e.g., BSA), or mixed with an adjuvant such as Freund's complete or incomplete adjuvant, and used to immunize an animal.
- KLH keyhole limpet hemocyanin
- BSA ovalbumin
- an adjuvant such as Freund's complete or incomplete adjuvant
- splenocytes from immunized animals that respond to LIF can be isolated and fused with myeloma cells.
- Monoclonal antibodies produced by hybridomas can be screened for reactivity with LIF, or an immunogenic fragment thereof.
- Hybridoma, recombinant, and phage display methods are known in the art (see, for example, U.S. Patent Nos. 4,902,614, 4,543,439, and 4,41 1,993; see, also Monoclonal Antibodies. Hybridomas: A New Dimension in Biological Analyses. Plenum Press, ennett, McKearn, and Bechtol (eds.), 1980, and Harlow et al., Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, 2nd ed. 1988).
- Animals that may be immunized include primates, mice, rats, rabbits, goats, sheep, cattle, or guinea pigs.
- Initial and any optional subsequent immunization may be through intravenous, intraperitoneal, intramuscular, or subcutaneous routes.
- antigen can be coupled to another protein such as ovalbumin or keyhole limpet hemocyanin (KLH), thyroglobulin and tetanus toxoid, or mixed with an adjuvant such as Freund's complete or incomplete adjuvant.
- KLH keyhole limpet hemocyanin
- thyroglobulin and tetanus toxoid or mixed with an adjuvant such as Freund's complete or incomplete adjuvant.
- Initial and any optional subsequent immunization may be through intraperitoneal, intramuscular, intraocular, or subcutaneous routes. Subsequent immunizations may be at the same or at different concentrations of antigen, and may be at regular or irregular intervals.
- Animals include those genetically modified to include human gene loci, which can be used to produce human antibodies.
- Transgenic animals such as human trans-chromosomic mice with one or more human immunoglobulin genes, are described, for example, in U.S. Patent No. 5,939,598, WO 02/43478, and WO 02/092812.
- animals are immunized LIF or cells that express LIF antigen.
- splenocytes from immunized mice that are high responders to the antigen can be isolated and fused with myeloma cells. Antibodies that bind to LIF can thereby be obtained.
- Humanized antibodies can be produced using techniques known in the art including, for example, CDR-grafting (EP 239,400; W091/09967; U.S. Patent Nos. 5,225,539; 5,530,101; and 5,585,089), veneering or resurfacing (EP 592, 106; EP 519,596; Padlan, Molecular Immunol. 28:489 (1991 ); Studnicka et al., Protein Engineering 7:805 (1994); Roguska. et al., Proc. Nat l Acad. Sci. USA 91 :969 (1994)), and chain shuffling (U.S. Patent No. 5,565,332). Human consensus sequences (Padlan, Mol. Immunol.
- Chimeric antibodies in which a variable domain from an antibody of one species is substituted for the variable domain of another species are described, for example, in Munro, Nature 312:597 (1984); Neuberger et al., Nature 312:604 (1984); Sharon et al., Nature 309:364 (1984); Morrison et al., Proc. Nat l Acad. Sci. USA 81 :6851 (1984); Boulianne et al., Nature 312:643 (1984); Capon et al., Nature 337:525 (1989); and Traunecker et al., Nature 339:68 (1989).
- LIF protein suitable for generating antibodies can be produced by any of a variety of standard protein purification or recombinant expression techniques.
- Forms of LIF suitable for generating an immune response include LIF subsequences, such as an immunogenic fragment.
- LIF expressing cells LIF containing preparations or extracts or fractions, partially purified LIF.
- a LIF sequence can be produced by standard peptide synthesis techniques, such as solid-phase synthesis.
- a portion of the protein may contain an amino acid sequence such as a T7 tag or polyhistidine sequence to facilitate purification of expressed or synthesized protein.
- the protein may be expressed in a cell and purified.
- the protein may be expressed as a part of a larger protein (e.g., a fusion or chimera) by recombinant methods.
- Suitable techniques that additionally may be employed in antibody methods include LIF based affinity purification, non-denaturing gel purification, HPLC or RP-HPLC, size exclusion, purification on protein A column, or any combination of these techniques.
- Antibody isotype can be determined using an ELISA assay, for example, a human Ig can be identified using mouse Ig- absorbed anti-human Ig.
- Non-limiting representative examples of antibodies that specifically bind to LIF include antibodies denoted as L9277, L9152, L0919, L0669 and LI 169 (Sigma-Aldrich) and anti-Human Leukemia Inhibitory Factor clone 4F7.2 antibody (MAB4306, Millipore), which binds to human LIF.
- antibodies include R&D Systems goat anti-mouse LIF (AB-449-NA) and rat anti-mouse LIF (clone 139124, MAB449), Millipore rat anti-mouse LIF (clone 2H2.2, MAB4307), mouse Anti-Human LIF Monoclonal Antibodies, Clones 9808 and 9824 (R&D Systems), and anti-LIF (J- 14F) (Santa Cruz Biotechnology, Inc. )
- LIF antibodies and functional (e.g., binding) subsequences can have substantially the same, greater or less relative activity for than a reference antibody.
- a LIF antibody can have substantially the same, greater or less relative binding affinity or avidity for LIF than a reference antibody.
- Such antibodies having measurable affinity for LIF compete for binding of the reference antibody to LIF.
- LIF antibodies and subsequences therefore include those that do not compete with a reference antibody for binding to LIF, and those that compete with a reference antibody for binding to LIF, and have substantially the same, greater or less relative binding affinity or avidity for binding to LIF as compared to a reference antibody.
- a LIF antibody competes for binding of antibody denoted as L9277, L9152, L0919, L0669 or LI 169 (Sigma- Aldrich), anti-Human Leukemia Inhibitory Factor clone 4F7.2 antibody (MAB4306, Millipore), anti- mouse LIF (AB-449-NA), rat anti-mouse LIF (clone 139124, MAB449), rat anti-mouse LIF (clone 2H2.2, MAB4307, Millipore), mouse Anti-Human LIF Monoclonal Antibodies, Clones 9808 or 9824, or anti-LIF (J-14F) to LIF.
- anti-Human Leukemia Inhibitory Factor clone 4F7.2 antibody MAB4306, Millipore
- anti- mouse LIF AB-449-NA
- rat anti-mouse LIF clone 139124, MAB449
- rat anti-mouse LIF clone 2H2.2,
- LIF antibodies and subsequences can have a binding affinity for binding to LIF within about K d 10 "2 M to about 3 ⁇ 4 10 " 15 M, or within about K d 10 ⁇ 6 M to about 3 ⁇ 4 10 " ' 2 M.
- binding affinity is less than 5xl0 "2 M, 10 "2 M, 5xl 0 "3 M, 10 "3 M 5xl0 M, 10 "4 M 5xl0 "5 M, 10 "5 M 5xl0 ⁇ 6 M, 10 '6 M 5xl0 "7 M, 10 "7 M 5xl0 “8 M, 10 "8 M 5xl0 “9 M, 10 "9 M 5xl0 “10 M, 10 "10 M 5x10 " “ M, 10 " “ M 5xl0 "12 M, 10 "12 M 5xl0 “13 M, 10 "13 M 5xl0 “14 M, 10 "14 M 5xl0 “15 M, and 10 " ' 5 M.
- LIF antibodies and subsequences can have a greater or less than 2-5, 5-10, 10-100, 100-1000 or 1000-10,000-fold binding affinity for binding to LIF, or any numerical value or range within or encompassing such values, than a reference antibody.
- an antibody or a functional subsequence thereof has a binding affinity within about 1-5000 fold (more or less than) of a reference antibody for binding to LIF.
- LIF antibodies and subsequences can have substantially the same binding affinity for LIF as a reference antibody.
- a LIF antibody has substantially the same binding affinity or avidity for LIF as antibody denoted as L9277, L9152, L0919, L0669 or LI 169 (Sigma- Aldrich), anti-Human Leukemia Inhibitory Factor clone 4F7.2 antibody (MAB4306, Millipore), anti- mouse LIF (AB-449-NA), rat anti-mouse LIF (clone 139124, MAB449), rat anti-mouse LIF (clone 2H2.2, MAB4307, Millipore), mouse Anti-Human LIF Monoclonal Antibodies, Clones 9808 or 9824, or anti-LIF (J- 14F).
- binding affinity can be determined by association (K a ) and dissociation (3 ⁇ 4) rate. Equilibrium affinity constant, , is the ratio of a / d . Association (K a ) and dissociation (Kj) rates can be measured using surface plasmon resonance (SPR) (Rich and Myszka, Ciirr. Opin. Biotechnol. 1 1 :54 (2000); Englebienne, Analyst. 123 : 1599 ( 1998)).
- SPR surface plasmon resonance
- LIF polypeptides and subsequences thereof, and amino acid substitutions thereof can be used to practice invention methods and uses. Such LIF polypeptides and subsequences thereof can exhibit sequence identity to a reference LIF polypeptide or subsequence thereof.
- An exemplary human LIF sequence is set forth as:
- a non-limiting exemplary LIF polypeptide or subsequence thereof includes or consists of a sequence at least 60% or more (e.g., 65%, 70%, 75%, 80%, 85%, 90%, 95%, etc.) identical to SEQ ID NO:l, wherein the LIF polypeptide or subsequence stimulates, induces, increases or enhances an immune response, Tfh (follicular helper) cell differentiation, Germinal center B cell development, an antibody response, development of memory T cells or an immune response, such as a response induced by a vaccine.
- Tfh follicular helper
- Additional LIF inhibitors include inhibitory and antisense nucleic acid sequences.
- Inhibitory, antisense and RNAi nucleic acids can modulate expression of LIF.
- Antisense includes single, double or triple stranded polynucleotides and peptide nucleic acids (PNAs) that bind RNA transcript or DNA (e.g., genomimc DNA).
- PNAs peptide nucleic acids
- a single stranded nucleic acid can target LIF transcript (e.g., niRNA).
- Oligonucleotides derived from the transcription initiation site of LIF gene, e.g., between positions -10 and +10 from the start site are another particular example.
- Triplex forming antisense can bind to double strand DNA thereby inhibiting transcription of the gene.
- RNAi is the use of double stranded RNA sequences for inhibiting gene expression (see, e.g., Kennerdell et al., Cell 95: 1017 (1998); and Fire et al., Nature. 391 : 806 (1998)). Double stranded RNA sequences from a LIF coding region may therefore be used to inhibit or prevent LIF expression in accordance with the methods and uses of the invention.
- Antisense and RNAi can be produced based upon nucleic acids encoding LIF sequences (e.g., SEQ ID NO: 1), such as nucleic acid encoding mammalian and human LIF (e.g., SEQ ID NO:2): (00491 ATGAAGGTCTTGGCGGCAGGAGTTGTGCCCCTGCTGTTGGTTCTGCACTGGAAA
- ATCGCCGTGTTGGCCCAGGCCTTCTAG SEQ ID NO:2.
- Methods are applicable to immune responses, cell mediated and/or antibody mediated (e.g., a humoral immune response). Methods are applicable to immune responses, including undesirable or aberrant immune responses, such as undesirable or aberrant inflammatory responses or inflammation. Methods are also applicable to acute or chronic immune responses, and acute or chronic undesirable or aberrant immune responses, such as acute or chronic undesirable or aberrant inflammatory responses or inflammation.
- an "undesirable immune response” or “aberrant immune response” refers to any immune response, activity or function that is greater or less than desired or physiologically normal.
- An undesirable immune response, function or activity can be a normal response, function or activity. Thus, normal immune responses so long as they are undesirable, even if not considered abnormal, are included within the meaning of these terms.
- An undesirable immune response, function or activity can also be an abnormal response, function or activity.
- An abnormal (aberrant) immune response, function or activity deviates from normal. Undesirable and aberrant immune responses can be humoral, cell-mediated or a combination thereof, either chronic or acute.
- an undesirable or aberrant immune response is where the immune response is hyper-responsive, such as in the case of an autoimmune disorder or disease.
- Another example of an undesirable or aberrant immune response is where an immune response leads to acute or chronic inflammatory response or inflammation in any tissue or organ, such as an allergy.
- Yet another example of an undesirable or aberrant immune response is where an immune response leads to destruction of cells, tissue or organ, such as a bone marrow transplant, as in graft vs. host disease (GVHD).
- GVHD graft vs. host disease
- Still another example of an undesirable or aberrant immune response is where the immune response is hypo-responsive, such as where response to an antigen is less than desired, e.g., tolerance has occurred.
- immune disorder and “immune disease” mean, an immune function or activity, that is greater than (e.g., autoimmunity) or less than (e.g., immunodeficiency) desired, and which is characterized by different physiological symptoms or abnormalities, depending upon the disorder or disease.
- immune disorders and diseases to which the invention applies include autoimmune disorders.
- Autoimmune disorders are generally characterized as an undesirable or aberrant increased or inappropriate response, activity or function of the immune system.
- Disorders and diseases that can be treated in accordance with the invention include, but are not limited to, disorders and disease that cause cell or tissue/organ damage in the subject.
- autoimmune disease encompasses a condition, disorder, dysfunction or disease that results when the immune system attacks the body's own cells, tissues or organs.
- autoimmune disease includes a disorder wherein the immune system of a mammal mounts a humoral or cellular immune response to the mammal's own cells, tissues or organs. It is understood that more than one type of cell, tissue or organ may be attacked in the course of autoimmune disease.
- automimmune diseases include rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, psoriatic arthritis, diabetes mellitus, multiple sclerosis, encephalomyelitis, myasthenia gravis, systemic lupus erythematosus (SLE), autoimmune thyroiditis, atopic dermatitis, eczematous dermatitis, psoriasis, Sjogren's Syndrome, Crohn's disease, aphthous ulcer, ulcerative colitis, asthma, allergic asthma, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, erythema nodosum leprosum, autoimmune uveitis, allergic encephalomyelitis, acute necrotizing hemorrhagic encephalopathy
- An undesirable or aberrant inflammatory response or inflammation may cause, directly or indirectly, cell, tissue or organ damage, either to multiple cells, tissues or organs, or specifically to a single cell type, tissue type or organ.
- Exemplary tissues and organs that can exhibit damage include epidermal or mucosal tissue, gut, bowel, pancreas, thymus, liver, kidney, spleen, skin, or a skeletal joint (e.g., knee, ankle, hip, shoulder, wrist, finger, toe, or elbow).
- Treatment in accordance with the invention can result in reducing, inhibiting or preventing progression or worsening of tissue damage.
- Such treatments can in turn lead to regeneration or restoration of a damaged organ or tissue, e.g., skin, mucosum, liver.
- Methods and uses of the invention include administering LIF polypeptide or subsequence thereof, or a LIF activator, in order to increase, stimulate enhance or promote an immune response in general. Such methods and uses can be used for treatment of chronic or acute immunosuppression or an immunocompromised subject, or an immunodeficiency.
- SCID severe combined immunodeficiency
- RAG 1/2 recombinase activating gene
- ADA adenosine deaminase
- y c interleukin receptor ⁇ chain
- JA 3 Janus-associated kinase 3
- primary T cell immunodeficiency such as DiGeorge syndrome, Nude syndrome,
- T cell receptor deficiency MHC class II deficiency
- TAP-2 deficiency MHC class I deficiency
- X-linked agammaglobulinemia (Bruton's tyrosine kinase deficiency); autosomal recessive agammaglobulinemia such as Mu heavy chain deficiency; surrogate light chain ( ⁇ 5/14.1) deficiency; Hyper-IgM syndrome either X-linked (CD40 ligand deficiency) and others; Ig heavy chain gene deletion; IgA deficiency; deficiency of IgG subclasses
- IgA deficiency with or without IgA deficiency); common variable immunodeficiency (CVID); antibody deficiency with normal immunoglobulins; transient hypogammaglobulinemia of infancy; interferon ⁇ receptor
- IFNGR1 interleukin 12 and interleukin 12 receptor deficiency
- immunodeficiencies also include disorders associated with or secondary to another disease (e.g., chromosomal instability or defective repair such as Bloom syndrome, Xeroderma pigmentosum, Fanconi anemia, ICF syndrome, Nijmegen breakage syndrome and Seckel syndrome; chromosomal defects such as Down syndrome (Trisomy
- abnormalities such as short-limbed skeletal dysplasia (short-limbed dwarfism) and cartilage-hair hypoplasia (metaphyseal chondroplasia); immunodeficiency associated with generalized growth retardation such as Schimke immuno-osseous dysplasia, Dubowitz syndrome, Kyphomelic dysplasia with SCID, Mulibrey's nannism, Growth retardation, facial anomalies and immunodeficiency and
- Progeria Hutchinson-Gilford syndrome
- immunodeficiency with dermatologic defects such as ectrodactyly-ectodermal dysplasia-clefting syndrome, immunodeficiency with absent thumbs, anosmia and ichthyosis, partial albinism, Dyskeratosis congenita, Netherton syndrome, Anhidrotic ectodermal dysplasia, Papillon-Lefevre syndrome and congenital ichthyosis
- hereditary metabolic defects such as acrodermatitis enteropathica, transcobalamin 2 deficiency, type 1 hereditary orotic aciduria, intractable diarrhea, abnormal facies, trichorrhexis and immunodeficiency, methylmalonic acidemia, biotin dependent carboxylase deficiency, mannosidosis, glycogen storage disease, type lb, Chediak-Higashi syndrome
- hypercatabolism of immunoglobulin such as familial hypercatabolism,
- Methods and uses of the invention include administering LIF polypeptide or subsequence thereof, or a LIF activator, in order to increase, stimulate enhance or promote a response elicited by vaccination or immunization.
- Such methods and uses can be used in particular with any pathogen infection to which a vaccination or immunization may be desired.
- Pathogens include, without limitation, bacteria, virus, fungi and parasites.
- Non-limiting examples of a bacterial pathogens include Bordetella, Borellia, Brucella,
- Mycobacterium Mycoplasma, Neisseria, Pseudomonas, Rickettsia, Staphlyococcus, Streptococcus,
- Salmonella, Shigella, Treponema, Vibrio, and Yersenia Salmonella, Shigella, Treponema, Vibrio, and Yersenia.
- Non-limiting examples of viral pathogens include a poxvirus, herpesvirus, hepatitis virus, immunodeficiency virus, flavivirus, papilloma virus (PV), polyoma virus, rhabdovirus, a myxovirus, an arenavirus, a coronavirus, adenovirus, reovirus, picornavirus, togavirus, bunyavirus, parvovirus and retrovirus.
- a poxvirus herpesvirus, hepatitis virus, immunodeficiency virus, flavivirus, papilloma virus (PV), polyoma virus, rhabdovirus, a myxovirus, an arenavirus, a coronavirus, adenovirus, reovirus, picornavirus, togavirus, bunyavirus, parvovirus and retrovirus.
- PV papilloma virus
- Non-limiting examples of poxvirus include vaccinia virus, Molluscum contagiosum, variola major or variola minor smallpox virus, cow pox, camel pox, sheep pox, and monkey pox.
- herpesvirus examples include alpha-herpesvirus, beta-herpesvirus, gamma- herpesvirus, Epstein Bar Virus (EBV), Cytomegalovirus (CMV), varicella zoster virus (VZV/HHV- 3), and human herpes virus 1, 2, 4, 5, 6, 7, and 8 (HHV-8, Kaposi's sarcoma-associated virus).
- EBV Epstein Bar Virus
- CMV Cytomegalovirus
- VZV/HHV- 3 varicella zoster virus
- HHV-8 Kaposi's sarcoma-associated virus
- Non-limiting examples of hepatitis virus include hepatitis A, B, C, D, E and G.
- HIV immunodeficiency virus
- human HIV such as HIV- l, HIV-2 and HIV-3.
- flavivirus examples include Yellow Fever virus, Dengue virus, Japanese Encephalitis and West Nile viruses.
- Non-limiting examples of papilloma virus include a human papilloma virus (HPV), such as HPV strain 1, 6, 11, 16, 18, 30, 31, 42, 43, 44, 45, 51, 52, and 54.
- HPV human papilloma virus
- Non-limiting examples of polyoma virus include BK virus (BKV) and JC virus (JCV).
- Non-limiting examples of rhabdovirus include rabies virus and vesiculovirus.
- Non-limiting examples of myxovirus include paramyxovirus and orthomyoxovirus.
- Non-limiting examples of paramyxovirus include measles, mumps, pneumovirus and respiratory syncytial virus (RSV).
- Non-limiting examples of orthomyoxo virus include influenza virus, such as influenza A, influenza B and influenza C.
- Non-limiting examples of arenavirus include lymphocytic choriomeningitis virus (LCMV), Junin virus, Lassa virus, Guanarito virus, Sabia virus and Machupo virus.
- LCMV lymphocytic choriomeningitis virus
- Junin virus Lassa virus
- Guanarito virus Lassa virus
- Sabia virus Machupo virus
- Non-limiting examples of coronavirus include a virus that causes a common cold, and severe acute respiratory syndrome (SARS).
- SARS severe acute respiratory syndrome
- Non-limiting examples of adenovirus include viral infections of bronchii, lung, stomach, intestine (gastroenteritis), eye (conjunctivitis), bladder (cystitis) and skin.
- Non-limiting examples of reovirus include a rotavirus, cypovirus and orbivirus.
- Non-limiting examples of picornavirus include a rhinovirus, apthovirus, hepatovirus, enterovirus and cardiovirus.
- Rhinovirus can cause the common cold.
- Non-limiting examples of togavirus include alphavirus, Sindbus virus, and rubellavirus.
- Non-limiting examples of bunya virus include hantavirus, phlebo virus and nairo virus.
- Non-limiting examples of retrovirus include an alpha, beta, delta, gamma, epsilon, lentivirus, spumavirus and human T-cell leukemia virus.
- Non-limiting examples of lentivirus include an immunodeficiency virus, such as
- immunodeficiency virus e.g., a bovine, porcine, equine, canine, feline or primate virus.
- Non-limiting examples of human T-cell leukemia viruses include human T-cell leukemia virus 1 and 2 (HTLV-1 and HTLV-2).
- Non-limiting examples of a fungal pathogen include yeasts and molds. More particular examples include Candida, Aspergillus, Cryptococcus, Histoplasma, Pneumocysti and Stachybotrys.
- Non-limiting examples of a parasite pathogen include protozoa. More particular examples include Plasmodium, which causes malaria, Leishmania, Toxoplasma and Trypanosoma.
- Pathogens and pathogen antigens useful in accordance with the invention methods include any pathogen or pathogen antigen, or live or attenuated or weakend pathogen, suitable as a vaccine or immunizing agent, which typically can or is likely to provide protection against the pathogen.
- pathogens and pathogen antigens include live pathogen, a pathogen antigen, pathogen extract, heat or ultraviolet light inactivated or attenuated or weakened pathogen.
- LIF polypeptides and subsequences thereof that exhibit sequence identity to a reference LIF polypeptide or subsequence thereof, and which have an ability to modulate an immune response, for example, stimulates, induces, increases or enhances an immune response, development of memory T cells, Tfh (follicular helper) cell differentiation, Germinal center B cell development, an antibody response, or an immune response, such as a response induced by a vaccine, in vitro or in vivo.
- a LIF polypeptide or subsequence thereof includes or consists of a sequence at least 60% or more (e.g., 65%, 70%, 75%, 80%, 85%, 90%, 95%, etc.) up to 100% identical to any LIF polypeptide or subsequence thereof (e.g., SEQ ID NO: l).
- a LIF polypeptide or subsequence thereof includes or consists of a LIF polypeptide or subsequence thereof set forth as SEQ ID NO: 1, wherein the LIF polypeptide or subsequence thereof has one or more amino acid additions, deletions or substitutions of SEQ ID NO: 1.
- a LIF polypeptide or subsequence is at least 80% or more, e.g., 80-85%, 85-90%, 90-95%, 95-100% identical to a LIF polypeptide or subsequence thereof set forth in SEQ ID NO: l .
- the invention provides isolated LIF polypeptides, including or consisting of a LIF
- subsequence which exhibits sequence identity to a reference LIF polypeptide or subsequence thereof (e.g., SEQ ID NO: 1), and which has one or more functions or activities of full length LIF.
- a reference LIF polypeptide or subsequence thereof e.g., SEQ ID NO: 1
- Such LIF subsequences can be from about 5 to 300 amino acids in length, for example, from 5 to 15, 20 to 25, 25, to 50, 50 to 100, 100 to 150, 150 to 200, or 200 to 300 amino acids in length, provided that said subsequence or portion is at least one amino acid less in length than a full-length LIF sequence (e.g., SEQ ID NO: l).
- a full-length LIF sequence e.g., SEQ ID NO: l
- a subsequence of a LIF polypeptide sequence or subsequence inhibits, decreases or reduces Tfh (follicular helper) cell differentiation, Germinal center B cell development or an antibody response, inhibits, decreases or reduces development of memory T cells, inhibits, decreases or reduces an undesirable or aberrant immune response, inhibits, decreases or reduces an undesirable or aberrant inflammatory response or inflammation.
- Tfh follicular helper
- a LIF subsequence stimulates, induces or increases an immune response, or stimulates, induces or increases Tfh (follicular helper) cell differentiation, Germinal center B cell development, an antibody response, or development of memory T cells, or stimulates, induces or increases an immune response, such as a response induced by a vaccine (e.g., elicits, promotes or enhances an immune response against a vaccine antigen in vitro or in vivo).
- a vaccine e.g., elicits, promotes or enhances an immune response against a vaccine antigen in vitro or in vivo.
- isolated when used as a modifier of a composition (e.g., LIF polypeptides and subsequences thereof, etc.), means that the compositions are made by the hand of man or are separated, completely or at least in part, from their naturally occurring in vivo environment.
- isolated compositions are substantially free of one or more materials with which they normally associate with in nature, for example, one or more protein, nucleic acid, lipid, carbohydrate, cell membrane.
- isolated does not exclude alternative physical forms of the composition, such as fusions/chimeras, multimers/oligomers, modifications (e.g., phosphorylation, glycosylation, lipidation) or derivatized forms, or forms expressed in host cells produced by the hand of man.
- an “isolated” composition e.g., LIF polypeptide or subsequence thereof
- LIF polypeptide or subsequence thereof can also be “substantially pure” or “purified” when free of most or all of the materials with which it typically associates with in nature.
- an isolated LIF polypeptide or subsequence thereof, that also is substantially pure or purified does not include polypeptides or polynucleotides present among millions of other sequences, such as peptides of an peptide library or nucleic acids in a genomic or cDNA library, for example.
- a “substantially pure” or “purified” composition can be combined with one or more other molecules. Thus, “substantially pure” or “purified” does not exclude
- compositions such as combinations of LIF polypeptide or subsequence thereof and adjuvants, vaccines (e.g., antigens), agents, drugs or therapies.
- adjuvants e.g., vaccines (e.g., antigens), agents, drugs or therapies.
- chimeric when used in reference to a sequence, means that the amino acid sequence contains one or more portions that are derived from, obtained or isolated from, or based upon two or more different proteins.
- a portion of the sequence may be a LIF polypeptide or subsequence thereof, and another portion of the sequence may be from a different peptide sequence, or a non-LIF polypeptide sequence.
- LIF polypeptides and subsequences thereof of the invention include those having at least partial sequence identity to one or more exemplary LIF polypeptide or a subsequence thereof (e.g., SEQ ID NO: 1).
- the percent identity of such sequences can be as little as 60%, or can be greater (e.g., 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, etc.).
- the percent identity can extend over the entire sequence length or a portion of the sequence.
- the length of the sequence sharing the percent identity is 2, 3, 4, 5 or more contiguous amino acids, e.g., 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, etc.
- the length of the sequence sharing the percent identity is 20 or more contiguous amino acids, e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, etc. contiguous amino acids. In further particular aspects, the length of the sequence sharing the percent identity is 35 or more contiguous amino acids, e.g., 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 45, 47, 48, 49, 50, etc., contiguous amino acids.
- the length of the sequence sharing the percent identity is 50 or more contiguous amino acids, e.g., 50-55, 55-60, 60-65, 65-70, 70-75, 75-80, 80-85, 85-90, 90-95, 95-100, 100-1 10, etc. contiguous amino acids.
- identity and grammatical variations thereof, mean that two or more referenced entities are the same. Thus, where two LIF polypeptides or subsequences thereof are identical, they have the same amino acid sequence. The identity can be over a defined area (region or domain) of the sequence. "Areas, regions or domains" of homology or identity mean that a portion of two or more referenced entities share homology or are the same. The extent of identity between two sequences can be ascertained using a computer program and mathematical algorithm known in the art. Such algorithms that calculate percent sequence identity (homology) generally account for sequence gaps and mismatches over the comparison region or area. For example, a BLAST (e.g.
- BLAST 2.0 search algorithm (see, e.g., Altschul et al., J. Mol. Biol. 215:403 (1990), publicly available through NCBI) has exemplary search parameters as follows: Mismatch -2; gap open 5; gap extension 2.
- a BLASTP algorithm is typically used in combination with a scoring matrix, such as PAM100, PAM 250, BLOSUM 62 or BLOSUM 50.
- FASTA e.g., FASTA2 and FASTA3
- SSEARCH sequence comparison programs are also used to quantitate the extent of identity (Pearson et al., Proc. Natl. Acad. Sci. USA 85:2444 (1988);
- LIF polypeptides and subsequences thereof that include modified and variant forms.
- the terms "modify” or “variant” and grammatical variations thereof mean that a LIF polypeptide or subsequence thereof deviates from a reference LIF sequence (e.g., SEQ ID NO: 1).
- Modified and variant LIF polypeptides and subsequences thereof may therefore have greater or less activity or function than a reference LIF polypeptide, or subsequence thereof, but at least retain partial activity or function of the reference sequence (e.g., SEQ ID NO: l).
- LIF polypeptides and subsequences thereof include sequences having substantially the same, greater or less relative activity or function as SEQ ED NO:l, for example, an ability to stimulate, induce or increase Tfh (follicular helper) cell differentiation, Germinal center B cell development or an antibody response in vitro or in vivo, an ability to stimulate, induce or increase development of memory T cells in vitro or in vivo, an ability to inhibit, decrease or reduce an undesirable or aberrant immune response in vitro or in vivo, an ability to inhibit, decrease or reduce an undesirable or aberrant inflammatory response or inflammation in vitro or in vivo, an ability to stimulate, induce or increase an immune response in vitro or in vivo, or an ability to stimulate, induce or increase an immune response induced by a vaccine in vitro or in vivo (e.g., elicit, promote or enhance an immune response against a vaccine antigen in vitro or in vivo).
- a vaccine in vitro or in vivo e.g., elicit
- Non-limiting examples of modifications include one or more amino acid substitutions (e.g., 1-3, 3-5, 5-10, 10-15, 15-20, 20-25, or more residues), additions (e.g., insertions or 1-3, 3-5, 5-10, 10-15, 15-20, 20-25, or more residues) and deletions (e.g., subsequences or fragments) of a reference LIF polypeptide or subsequence thereof.
- a modified or variant sequence retains at least part of a function or an activity of unmodified sequence.
- Such modified forms and variants can have less than, the same, or greater, but at least a part of, a function or activity of a reference sequence, for example, as described herein.
- substitutions include conservative and non-conservative amino acid substitutions.
- a "conservative substitution” is the replacement of one amino acid by a biologically, chemically or structurally similar residue.
- Biologically similar means that the substitution does not destroy a biological activity.
- Structurally similar means that the amino acids have side chains with similar length, such as alanine, glycine and serine, or a similar size.
- Chemical similarity means that the residues have the same charge or are both hydrophilic or hydrophobic.
- Particular examples include the substitution of one hydrophobic residue, such as isoleucine, valine, leucine or methionine for another, or the substitution of one polar residue for another, such as the substitution of arginine for lysine, glutamic for aspartic acids, or glutamine for asparagine, serine for threonine, and the like.
- a modification also includes one or more D-amino acids substituted for L-amino acids (and mixtures thereof), structural and functional analogues, for example, peptidomimetics having synthetic or non-natural amino acids or amino acid analogues and derivatized forms.
- structural and functional analogues for example, peptidomimetics having synthetic or non-natural amino acids or amino acid analogues and derivatized forms.
- polypeptides and peptides described herein further include compounds having amino acid structural and functional analogues, for example, peptidomimetics having synthetic or non-natural amino acids or amino acid analogues, so long as the mimetic has one or more functions or activities of a native polypeptide set forth herein.
- Non-natural and non-amide chemical bonds, and other coupling means can also be included, for example, glutaraldehyde, N-hydoxysuccinimide esters, bifunctional maleimides, or N, N'-dicyclohexylcarbodiimide (DCC).
- Non-amide bonds can include, for example, ketomethylene aminomethylene, olefin, ether, thioether and the like (see, e.g., Spatola (1983) in Chemistry and Biochemistry of Amino Acids. Peptides and Proteins, Vol. 7, pp 267-357, "Peptide and Backbone Modifications," Marcel Decker, NY).
- Modifications include cyclic structures such as an end-to-end amide bond between the amino and carboxy-terminus of the molecule or intra- or inter-molecular disulfide bond.
- Polypeptides, peptides and peptidomimetics can be produced and isolated using methods known in the art.
- Peptides can be synthesized, whole or in part, using chemical methods known in the art (see, e.g., Caruthers (1980). Nucleic Acids Res. Symp. Ser. 215; Horn (1980); and Banga,
- Enzymol. 289:3(1997)) and automated synthesis may be achieved, e.g., using the ABI 431A Peptide
- Synthesizer (Perkin Elmer) in accordance with the manufacturer's instructions. Peptides and peptide mimetics can also be synthesized using combinatorial methodologies. Synthetic residues and polypeptides incorporating mimetics can be synthesized using a variety of procedures and methodologies known in the art (see, e.g.. Organic Syntheses Collective Volumes, Gilman, et al. (Eds) John Wiley & Sons, Inc., NY). Modified peptides can be produced by chemical modification methods (see, for example, Belousov, Nucleic Acids Res. 25:3440 (1997); Frenkel, Free Radic. Biol. Med. 19:373 ( 1995); and Blommers, Biochemistry 33:7886 (1994).
- An addition can be the covalent or non-covalent attachment of any type of molecule to the sequence.
- Specific examples of additions include glycosylation, acetylation, phosphorylation, amidation, formylation, ubiquitination, and derivatization by protecting/blocking groups and any of numerous chemical modifications.
- Additional specific non-limiting examples of an addition include one or more additional amino acid residues.
- an addition is a fusion (chimeric) sequence, an amino acid sequence having one or more molecules not normally present in a reference native (wild type) sequence covalently attached to the sequence.
- a particular example is an amino acid sequence of another sequence to produce a chimera.
- a modified sequence having an amino acid addition is one in which a second heterologous sequence, i.e., heterologous functional domain is attached (covalent or non-covalent binding) that confers a distinct or complementary function.
- Heterologous functional domains are not restricted to amino acid residues.
- a heterologous functional domain can consist of any of a variety of different types of small or large functional moieties. Such moieties include nucleic acid, peptide,
- the invention provides LIF polypeptides and subsequences thereof and a heterologous domain, wherein the domain confers a distinct function, i.e. a heterologous functional domain.
- the invention provides LIF polypeptides and subsequences thereof that are detectably labeled.
- detectable labels include fluorophores, chromophores, radioactive isotopes (e.g., S35, P32, 1125), electron-dense reagents, enzymes, ligands and receptors.
- Enzymes are typically detected by their activity. For example, horseradish peroxidase is usually detected by its ability to convert a substrate such as 3,3-',5,5-'-tetramethylbenzidine (TMB) to a blue pigment, which can be quantified.
- TMB 3,3-',5,5-'-tetramethylbenzidine
- an addition is an insertion of an amino acid within any sequence of LIF polypeptides and subsequences thereof (e.g., SEQ ID NO: l ).
- an insertion is of one or more amino acid residues in a LIF polypeptide or subsequence thereof (e.g., SEQ ID NO: l).
- Modified LIF polypeptides and subsequences thereof also include one or more D-amino acids substituted for L-amino acids (and mixtures thereof), structural and functional analogues, for example, peptidomimetics having synthetic or non-natural amino acids or amino acid analogues and derivatized forms.
- LIF polypeptides and subsequences thereof including modified forms can be produced by any of a variety of standard protein purification or recombinant expression techniques.
- a LIF polypeptide or subsequence thereof can be produced by standard peptide synthesis techniques, such as solid-phase synthesis.
- a portion of the protein may contain an amino acid sequence such as a T7 tag or polyhistidine sequence to facilitate purification of expressed or synthesized protein.
- the protein may be expressed in a cell and purified.
- the protein may be expressed as a part of a larger protein (e.g., a fusion or chimera) by recombinant methods.
- LIF polypeptides and subsequences thereof including modified forms can be made using recombinant DNA technology via cell expression or in vitro translation.
- Polypeptide sequences including modified forms can also be produced by chemical synthesis using methods known in the art, for example, an automated peptide synthesis apparatus (see, e.g., Applied Biosystems, Foster City, CA).
- host cells that express LIF polypeptides and subsequences thereof.
- Host cells include but are not limited to prokaryotic and eukaryotic cells such as bacteria, fungi (yeast), plant, insect, and animal (e.g., mammalian, including primate and human, CHO cells and hybridomas) cells.
- prokaryotic and eukaryotic cells such as bacteria, fungi (yeast), plant, insect, and animal (e.g., mammalian, including primate and human, CHO cells and hybridomas) cells.
- bacteria transformed with recombinant bacteriophage nucleic acid, plasmid nucleic acid or cosmid nucleic acid expression vectors for example, bacteria transformed with recombinant bacteriophage nucleic acid, plasmid nucleic acid or cosmid nucleic acid expression vectors; yeast transformed with recombinant yeast expression vectors; plant cell systems infected with recombinant virus expression vectors (e.g., cauliflower mosaic virus, CaMV; tobacco mosaic virus, TMV) or transformed with recombinant plasmid expression vectors (e.g., Ti plasmid); insect cell systems infected with recombinant virus expression vectors (e.g., baculovirus); and animal cell systems infected with recombinant virus expression vectors (e.g., retroviruses, adenovirus, vaccinia virus), or transformed animal cell systems engineered for stable expression.
- the cells may be a primary cell isolate, cell culture (e.g., passage
- transfected when used in reference to a cell (e.g., a host cell) or organism, means a genetic change in a cell following incorporation of an exogenous molecule, for example, a protein or nucleic acid (e.g., a transgene) into the cell.
- a transfected or
- transformed cell is a cell into which, or a progeny thereof in which an exogenous molecule has been introduced by the hand of man, for example, by recombinant DNA techniques.
- a LIF nucleic acid or protein can be stably or transiently transfected or transformed
- the cell(s) can be propagated and the introduced protein expressed, or nucleic acid transcribed.
- a progeny of a transfected or transformed cell may not be identical to the parent cell, since there may be mutations that occur during replication.
- nucleic acid into target cells can be carried out by methods known in the art such as osmotic shock (e.g., calcium phosphate), electroporation, microinjection, cell fusion, etc.
- osmotic shock e.g., calcium phosphate
- electroporation e.g., electroporation
- microinjection e.g., cell fusion
- introduction of nucleic acid and polypeptide in vitro, ex vivo and in vivo can also be accomplished using other techniques.
- a polymeric substance such as polyesters, polyamine acids, hydrogel, polyvinyl pyrrolidone, ethylene-vinylacetate, methylcellulose, carboxymethylcellulose, protamine sulfate, or lactide/glycolide copolymers, polylactide/glycolide copolymers, or ethylenevinylacetate copolymers.
- a nucleic acid can be entrapped in microcapsules prepared by coacervation techniques or by interfacial polymerization, for example, by the use of hydroxymethylcellulose or gelatin-microcapsules, or poly (methylmethacrolate) microcapsules, respectively, or in a colloid system.
- Colloidal dispersion systems include macromolecule complexes, nano-capsules, microspheres, beads, and lipid-based systems, including oil-in-water emulsions, micelles, mixed micelles, and liposomes.
- Liposomes for introducing various compositions into cells are known in the art and include, for example, phosphatidylcholine, phosphatidylserine, lipofectin and DOTAP (e.g., U.S. Patent Nos. 4,844,904, 5,000,959, 4,863,740, and 4,975,282; and GIBCO-BRL, Gaithersburg, MD).
- Piperazine based amphilic cationic lipids useful for gene therapy also are known (see, e.g., U.S. Patent No. 5,861,397).
- Cationic lipid systems also are known (see, e.g., U.S. Patent No. 5,459,127).
- vesicles Polymeric substances, microcapsules and colloidal dispersion systems such as liposomes are collectively referred to herein as "vesicles.”
- treatment methods and uses are provided that include therapeutic and prophylactic methods and uses. Such methods and uses can, for example, stimulate, induce, increase, enhance, or inhibit, decrease or reduce, an immune response in a subject.
- a method includes administering to a subject in need of treatment an amount of a LIF polypeptide or subsequence thereof, or a LIF activator or inhibitor, to treat the subject.
- a method includes administering to a subject an amount of a LIF activator or inhibitor, or a LIF polypeptide or a subsequence thereof, sufficient to provide the subject with an immune response that is stimulated, induced, increased or enhanced, or inhibited, decreased or reduced.
- Therapeutic and prophylactic methods of treating a subject with a LIF activator or inhibitor, or a LIF polypeptide or a subsequence thereof include, for example, treatment of a subject having or at risk of having an immune disorder, such as an undesirable or aberrant immune response, inflammatory response, or inflammation. Such methods can treat the immune disorder, thereby providing the subject with a benefit.
- any LIF activator or inhibitor, or a LIF polypeptide or subsequence thereof can be administered or used.
- Non-limiting examples include a LIF antibody or subsequence thereof, or a LIF polypeptide or subsequence thereof (e.g., of SEQ ID NO:l), or an amino acid insertion, addition or substitution thereof.
- treatment methods will modulate an immune response.
- modulation can stimulate, induce, increase or enhance, or inhibit, decrease or reduce, as needed.
- proliferation, survival, differentiation, or activity of immune responses or cells e.g., T cells, B cells, macrophages, neutrophils, dendritic cells, etc.
- T cells e.g., T cells, B cells, macrophages, neutrophils, dendritic cells, etc.
- Methods of the invention include treatment methods, which result in any therapeutic or beneficial effect.
- an immune response is stimulated, induced, increased or enhanced, or inhibited, decreased or reduced.
- Methods of the invention further include inhibiting, decreasing or reducing one or more adverse (e.g., physical) symptoms, disorders, illnesses, diseases or complications caused by or associated with the immune response, such as (e.g., swelling, fever, rash, headache, infiltration of tissue or organs with immune cells, muscle or joint pain, nausea, vomiting, loss of appetite, etc.).
- adverse e.g., physical symptoms, disorders, illnesses, diseases or complications caused by or associated with the immune response, such as (e.g., swelling, fever, rash, headache, infiltration of tissue or organs with immune cells, muscle or joint pain, nausea, vomiting, loss of appetite, etc.).
- a therapeutic or beneficial effect of treatment is therefore any objective or subjective measurable or detectable improvement or benefit provided to a particular subject.
- a therapeutic or beneficial effect can but need not be complete ablation of all or any particular adverse symptom, disorder, illness, disease or complication caused by or associated with an immune response in a subject.
- a satisfactory clinical endpoint is achieved when there is an incremental improvement or a partial reduction in an adverse symptom, disorder, illness, disease or complication caused by or associated with an immune response, or an inhibition, decrease, reduction, suppression, prevention, limit or control of worsening or progression of one or more adverse symptoms, disorders, illnesses, diseases or complications caused by or associated with the immune response, over a short or long duration (hours, days, weeks, months, etc.).
- methods of the invention that include treatment of an inflammatory response or inflammation include reducing, inhibiting or preventing occurrence, progression, severity, frequency or duration of a symptom or characteristic of an inflammatory response or inflammation.
- an inflammatory response or inflammation is generally characterized by swelling, pain, headache, fever, nausea, skeletal joint stiffness or lack of mobility, rash, redness or other discoloration.
- an inflammatory response or inflammation is characterized by one or more of cell infiltration of the region, production of antibodies (e.g., autoantibodies), production of cytokines, lymphokines, chemokines, interferons and interleukins, cell growth and maturation factors (e.g., differentiation factors), cell proliferation, cell
- treatment will reduce, inhibit or prevent occurrence, progression, severity, frequency or duration of any one or more of such symptoms or characteristics of an inflammatory response or inflammation.
- a therapeutic or beneficial effect also includes reducing or eliminating the need, dosage frequency or amount of a second active such as another drug or other agent (e.g., small molecule, protein) used for treating a subject having or at risk of having an undesirable or aberrant immune response.
- a second active such as another drug or other agent (e.g., small molecule, protein) used for treating a subject having or at risk of having an undesirable or aberrant immune response.
- reducing an amount of an adjunct therapy for example, a reduction or decrease of a treatment for an undesirable or aberrant immune response, inflammatory response or inflammation is considered a beneficial effect.
- reducing or decreasing an amount of a pathogen (live or attenuated or weakened) or pathogen antigen used for vaccination or immunization of a subject to provide protection to the subject is considered a beneficial effect.
- Methods and compositions of the invention also include increasing, stimulating, promoting, enhancing, augmenting or inducing an immune response in a subject.
- a method includes administering to a subject an amount of a LIF activator, or a LIF polypeptide or subsequence thereof sufficient to increase, stimulate, promote, enhance, augment or induce an immune response in the subject.
- a method includes administering to a subject an amount of a LIF activator, or a LIF polypeptide or subsequence thereof, and administering pathogen (live or attenuated or weakened) or pathogen antigen sufficient to increase, stimulate, promote, enhance, augment or induce anti-pathogen immune response in the subject.
- Methods and compositions of the invention include administration of a LIF inhibitor (e.g., LIF antibody or inhibitory nucleic acid sequence, such as antisense RNA), or a LIF polypeptide or subsequence thereof, to a subject prior to an undesirable or aberrant immune response, inflammatory response or inflammation, administration prior to, substantially contemporaneously with or after a subject has been afflicted with an undesirable or aberrant immune response, inflammatory response or inflammation, and administration prior to, substantially contemporaneously with or after development of one or more adverse symptoms caused by or associated with an undesirable or aberrant immune response, inflammatory response or inflammation.
- a subject with an undesirable or aberrant immune response, inflammatory response or inflammation may have a chronic or acute undesirable or aberrant immune response, inflammatory response or inflammation, for example, a period of days, months, or years.
- Methods and compositions of the invention also include administration of a LIF activator or a LIF polypeptide or subsequence thereof to a subject prior to, substantially contemporaneously with or following a pathogen infection, or an adverse symptom, disorder, illness or disease caused by or associated with a pathogen infection or pathology.
- a subject infected with a pathogen may have a chronic or acute infection, for example, an infection for a period of days, months, or years.
- invention compositions e.g., LIF polypeptides or subsequences thereof
- methods can be combined with any compound, agent, drug, treatment or other therapeutic regimen or protocol having a desired therapeutic, beneficial, additive, synergistic or complementary activity or effect.
- exemplary combination compositions and treatments include second actives, such as anti-immune response, inflammatory response or inflammation compounds, agents and drugs, as well as agents that assist, promote, stimulate or enhance an immune response where desired.
- Such drugs, agents, treatments and therapies can be admimstered or performed prior to, substantially contemporaneously with or following any other method of the invention, for example, a therapeutic method of treating a subject for an undesirable or aberrant immune response, inflammatory response or inflammation, or a method of vaccination or immunization.
- a LIF activator or inhibitor, or a LIF polypeptide or subsequence thereof, can be any LIF activator or inhibitor, or a LIF polypeptide or subsequence thereof.
- the invention therefore provides combinations in which a method of the invention is used in a combination with any compound, agent, drug, therapeutic regimen, treatment protocol, process, remedy or composition, such as an anti-immune response, inflammatory response or inflammation, or an immune response stimulating, increasing, enhancing or augmenting protocol, such as pathogen vaccination or immunization set forth herein or known to one of skill in the art.
- the compound, agent, drug, therapeutic regimen, treatment protocol, process, remedy or composition can be administered or performed prior to, substantially contemporaneously with or following
- combination embodiments therefore include the foregoing or other compound, agent, drug, therapeutic regimen, treatment protocol, process, remedy or composition.
- Combination methods embodiments include, for example, second actives such as antiinflammatory or anti-inflammation agents and drugs and immune stimulating agents and drugs.
- Combination methods embodiments also include, for example, second actives such as anti-pathogen drugs (e.g., protease inhibitors, reverse transcriptase inhibitors, virus fusion inhibitors and virus entry inhibitors, antibodies to pathogen, live or attenuated or weakened pathogen, or a nucleic acid encoding all or a portion (e.g., an epitope) of any protein or proteinaceous pathogen antigen) immune stimulating agents and drugs, etc.
- anti-pathogen drugs e.g., protease inhibitors, reverse transcriptase inhibitors, virus fusion inhibitors and virus entry inhibitors, antibodies to pathogen, live or attenuated or weakened pathogen, or a nucleic acid encoding all or a portion (e.g., an epitope) of any protein or proteinaceous pathogen antigen) immune stimulating agents and drugs, etc.
- anti-inflammatory, anti-inflammation and anti-autoimmune disease agents include immunosuppressive agents such as corticosteroids (steroid receptor agonists) including budesonide, prednisone, flunisolide, flunisolide hydrofluoroalkane, estrogen, progesterone, dexamethasone and loteprednol; beta-agonists (e.g., short or long-acting) such as bambuterol, formoterol, salmeterol, albuterol; anticholinergics such as ipratropium bromide, oxitropium bromide, cromolyn and calcium-channel blocking agents; antihistamines such as terfenadine, astemizole, hydroxyzine, ⁇ ⁇ , tripelennamine, cetirizine, desloratadine, mizolastine, fexofenadine, olopatadine hydrochloride, norastemizo
- corticosteroids steroid
- anti-inflammatory and anti-inflammation agents include antibodies, receptors or receptor ligands, such as anti-IgE (e.g., rhuMAb-E25 omalizumab), -IgA and - IgG antibodies; antibodies and soluble receptors against cytokines such as IL-1 , IL-4, IL-5, EL-6, IL-9, IL-13, IL-16, and IL-21 or growth factors such as granulocyte/macrophage colony-stimulating factor; cytokines such as IL-10; mucolytics (depolymerize polymers of mucin or DNA/actin, or increase cough clearance) such as ambroxol and N-acetylcysteine; expectorants; and allergens (allergan), antigens, antigens, antigens, antigens, antigens, anti-IgE (e.g., rhuMAb-E25 omalizumab), -Ig
- Methods of the invention also include, among other things, methods that result in a reduced need or use of another compound, agent, drug, therapeutic regimen, treatment protocol, process, or remedy.
- a method of the invention has a therapeutic benefit if in a given subject a less frequent or reduced dose or elimination of another anti-inflammatory or anti-inflammation compound, agent, drug, therapeutic regimen, treatment protocol, process, or remedy.
- a method of the invention has a therapeutic benefit if in a given subject a less frequent or reduced dose or elimination of a vaccine.
- invention methods in which there is a desired outcome such as a therapeutic or prophylactic method that provides a benefit from treatment, vaccination or immunization with a LIF activator or inhibitor, or a LIF polypeptide or subsequence thereof can be administered in a sufficient or effective amount.
- a "sufficient amount” or “effective amount” or an “amount sufficient” or an “amount effective” refers to an amount that provides, in single or multiple doses, alone or in combination with one or more other compounds, treatments, therapeutic regimens or agents (e.g., a drug), a long term or a short term detectable or measurable improvement in a given subject or any objective or subjective benefit to a given subject of any degree or for any time period or duration (e.g., for minutes, hours, days, months, years, or cured).
- An amount sufficient or an amount effective can but need not be provided in a single administration and can but need not be achieved by a LIF activator or inhibitor, or a LIF polypeptide or subsequence thereof, alone, in a combination composition or method that includes a second active.
- an amount sufficient or an amount effective need not be sufficient or effective if given in single or multiple doses without a second or additional administration or dosage, since additional doses, amounts or duration above and beyond such doses, or additional antigens, compounds, drugs, agents, treatment or therapeutic regimens may be included in order to provide a given subject with a detectable or measurable improvement or benefit to the subject.
- An amount sufficient or an amount effective need not be therapeutically or prophylactically effective in each and every subject treated, nor a majority of subjects treated in a given group or population.
- An amount sufficient or an amount effective means sufficiency or effectiveness in a particular subject, not a group of subjects or the general population. As is typical for such methods, different subjects will exhibit varied responses to treatment.
- treatment methods include reducing or increasing numbers or an activity of immune cells (e.g., lymphocytes, T cells, antigen presenting cells, B cells, etc.) towards physiologically normal baseline levels.
- immune cells e.g., lymphocytes, T cells, antigen presenting cells, B cells, etc.
- circulating antibodies e.g., auto-antibodies
- Additional examples of a therapeutic benefit for an undesirable or aberrant immune response, immune disorder or immune disease is an improvement in a histopathological change caused by or associated with the immune response, disorder or disease. For example, preventing further or reducing skeletal joint infiltration or tissue destruction, or pancreas, thymus, kidney, liver, spleen, epidermal (skin) or mucosal tissue tissue, gut or bowel infiltration or tissue destruction.
- subject refers to an animal, typically a mammalian animal (mammal), such as humans, non-human primates (apes, gibbons, gorillas, chimpanzees, orangutans, macaques), a domestic animal (dogs and cats), a farm animal (poultry such as chickens and ducks, horses, cows, goats, sheep, pigs), and experimental animals (mouse, rat, rabbit, guinea pig).
- Subjects include animal disease models, for example, mouse and other animal models of inflammation, undesirable and aberrant immune responses, inflammatory and autoimmune diseases and others known to those of skill in the art (e.g., CIA, BXSB, EAE and SCDD murine models).
- Subjects appropriate for treatment include those having or at risk of having an undesirable or aberrant immune response, inflammatory response or inflammation, or vaccination or immunization, or a pathogen infection.
- Target subjects therefore include subjects that have an undesirable or aberrant immune response, inflammatory response or inflammation, or have been or are in need of vaccination or immunization, or have been exposed to or contacted with a pathogen, regardless of the type, timing or degree of onset, progression, severity, frequency, duration of the symptoms.
- the invention methods are therefore applicable to treating a subject who is at risk of undesirable or aberrant immune response, inflammatory response or inflammation, or vaccination or immunization, or a pathogen infection, but may not have a symptom of an undesirable or aberrant immune response, inflammatory response or inflammation, or a pathogen infection, or have been exposed to or contacted with the pathogen. Prophylactic methods are therefore included. Such subjects are considered in need of treatment due to being at risk.
- Target subjects need not be at increased risk but may be from the general population in which it is desired to inhibit, decrease or reduce an undesirable or aberrant immune response, inflammatory response or inflammation, or vaccination or immunization, or a pathogen infection.
- a child such as an infant or toddler in which it is desired to vaccinate or immunize against a pathogen can be administered a LIF activator or inhibitor, or a LIF polypeptide or subsequence thereof, alone or in combination with a pathogen antigen.
- a subject that is not specifically at risk of an undesirable or aberrant immune response, inflammatory response or inflammation, or vaccination or immunization, or pathogen infection, exposure to or contact, but nevertheless desires protection from an undesirable or aberrant immune response, inflammatory response or inflammation, or a pathogen infection or pathology, can be administered a LIF activator or inhibitor, or a LIF polypeptide or subsequence thereof.
- a LIF activator or inhibitor or a LIF polypeptide or subsequence thereof.
- Target subjects also include subjects having or at risk of having immunosuppression or are immunocompromised or have or are at risk of an immunodeficiency .
- Specific non-limiting examples of such subjects have or at risk of having an immunodeficiency, such as that caused by chemotherapy or radiotherapy (ionizing or chemical) or immune-suppressive therapy following a transplant (e.g., organ or tissue such as heart, liver, lung, bone marrow, etc.).
- a transplant e.g., organ or tissue such as heart, liver, lung, bone marrow, etc.
- Additional non- limiting examples include subjects having or at risk of having a graft vs. host disease, e.g., a subject that is a candidate for a transplant or a subject undergoing or having received a transplant.
- At risk subjects appropriate for treatment also include subjects exposed to environments in which subjects are at risk of a pathogen infection. Subjects appropriate for treatment therefore include human subjects exposed to pathogens.
- J "Prophylaxis" and grammatical variations thereof mean a method in which contact, administration or in vivo delivery to a subject is prior to an undesirable or aberrant immune response, inflammatory response or inflammation, or vaccination or immunization, or exposure to or contact with a pathogen.
- Administration or in vivo delivery to a subject can be performed prior to development of an adverse symptom, condition, complication, etc. caused by or associated with undesirable or aberrant immune response, inflammatory response or inflammation, or vaccination or immunization, or pathogen infection.
- a method can eliminate, prevent, inhibit, suppress, limit, decrease or reduce the probability of an undesirable or aberrant immune response, inflammatory response or inflammation, or a pathogen infection or susceptibility.
- a LIF activator or inhibitor, or a LIF polypeptide or subsequence may be administered systemically, regionally or locally, intravenously, orally (e.g., ingestion or inhalation), intramuscularly, intraperitoneally, intradermally, subcutaneously, intracavity, intracranially, transdermally (topical), parenterally, e.g. transmucosally or rectally.
- Exemplary administration and delivery routes include intravenous (i.v.), intraperitoneal (i.p.), intrartal, intramuscular, parenteral, subcutaneous, intra-pleural, topical, dermal, intradermal, transdermal, transmucosal, intra-cranial, intra-spinal, rectal, oral (alimentary), mucosal, inhalation, respiration, intranasal, intubation, intrapulmonary, intrapulmonary instillation, buccal, sublingual, intravascular, intrathecal, intracavity, iontophoretic, intraocular, ophthalmic, optical, intraglandular, intraorgan, intralymphatic.
- a LIF activator or inhibitor or a LIF polypeptide or subsequence thereof, can be
- a method can be practiced one or more times (e.g., 1-10, 1-5 or 1-3 times) an hour, day, week, month, or year.
- a non- limiting dosage schedule is 1-7 times per week, for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20 or more weeks, and any numerical value or range or value within such ranges.
- Doses can be based upon current existing protocols, empirically determined, using animal disease models or optionally in human clinical trials. Initial study doses can be based upon animal studies set forth herein, for a mouse, which weighs about 30 grams, and the amount of a LIF activator or inhibitor, or a LIF polypeptide or subsequence thereof administered that is determined to be effective. Exemplary non-limiting amounts (doses) are in a range of about 0.1 mg/kg to about 100 mg/kg, and any numerical value or range or value within such ranges. Greater or lesser amounts (doses) can be administered, for example, 0.01-500 mg/kg, and any numerical value or range or value within such ranges.
- the dose can be adjusted according to the mass of a subject, and will generally be in a range from about 1-10 ug/kg, 10-25 ug/kg, 25-50 ug/kg, 50-100 ug/kg, 100-500 ug/kg, 500-1,000 ug/kg, 1-5 mg/kg, 5-10 mg/kg, 10-20 mg/kg, 20-50 mg/kg, 50-100 mg/kg, 100-250 mg/kg, 250-500 mg/kg, or more, two, three, four, or more times per hour, day, week, month or annually.
- a typical range will be from about 0.3 mg/kg to about 50 mg/kg, 0-25 mg/kg, or 1.0-10 mg/kg, or any numerical value or range or value within such ranges.
- Doses can vary and depend upon whether the treatment is prophylactic or therapeutic, the type, onset, progression, severity, frequency, duration, or probability of the undesirable or aberrant immune response, inflammatory response or inflammation, vaccination or immunization, or pathogen infection to which treatment is directed, the clinical endpoint desired, previous or simultaneous treatments, the general health, age, gender, race or immunological competency of the subject and other factors that will be appreciated by the skilled artisan. The skilled artisan will appreciate the factors that may influence the dosage and timing required to provide an amount sufficient for providing a therapeutic or prophylactic benefit.
- a LIF activator or inhibitor, or a LIF polypeptide or subsequence thereof will be administered as soon as practical, typically within 1-2, 2-4, 4-12, 12-24 or 24-72 hours after a subject has a symptom or is exposed to or contacted with a pathogen, or within 1 -2, 2-4, 4-12, 12-24 or 24-48 hours after onset or development of one or more adverse symptoms, conditions, pathologies, complications, etc., associated with or caused by.
- a LIF activator or inhibitor, or a LIF polypeptide or subsequence thereof can be administered for a duration of 0-4 weeks, e.g., 2-3 weeks, prior to exposure to, contact or infection with pathogen, or at least within 1-2, 2-4, 4-12, 12-24, 24- 48 or 48-72 hours prior to exposure to, contact or infection with pathogen.
- a LIF activator or inhibitor, or a LIF polypeptide or subsequence thereof is administered at any appropriate time.
- the dose amount, number, frequency or duration may be proportionally increased or reduced, as indicated by the status of the subject.
- the dose amount, number, frequency or duration may also be proportionally increased or reduced, as indicated by any adverse side effects, complications or other risk factors of the treatment or therapy.
- LIF activators, inhibitors, and LIF polypeptides and subsequences thereof can be any amino acid
- compositions e.g., a pharmaceutically acceptable carrier or excipient.
- Such pharmaceutical compositions are useful for, among other things, administration to a subject in vivo or ex vivo.
- the term "pharmaceutically acceptable” and “physiologically acceptable” mean a biologically acceptable formulation, gaseous, liquid or solid, or mixture thereof, which is suitable for one or more routes of administration, in vivo delivery or contact.
- Such formulations include solvents (aqueous or non-aqueous), solutions (aqueous or non-aqueous), emulsions (e.g., oil- in-water or water-in-oil), suspensions, syrups, elixirs, dispersion and suspension media, coatings, isotonic and absorption promoting or delaying agents, compatible with pharmaceutical
- Aqueous and non-aqueous solvents, solutions and suspensions may include suspending agents and thickening agents.
- Such pharmaceutically acceptable carriers include tablets (coated or uncoated), capsules (hard or soft), microbeads, powder, granules and crystals.
- Supplementary active compounds e.g., preservatives, antibacterial, antiviral and antifungal agents
- compositions can be formulated to be compatible with a particular route of administration.
- pharmaceutical compositions include carriers, diluents, or excipients suitable for administration by various routes.
- routes of administration for contact or in vivo delivery which a composition can optionally be formulated include inhalation, respiration, intranasal, intubation, intrapulmonary instillation, oral, buccal, intrapulmonary, intradermal, topical, dermal, parenteral, sublingual, subcutaneous, intravascular, intrathecal, intraarticular, intracavity, transdermal, iontophoretic, intraocular, opthalmic, optical, intravenous (i.v.), intramuscular, intraglandular, intraorgan, intralymphatic.
- Formulations suitable for parenteral administration comprise aqueous and non-aqueous solutions, suspensions or emulsions of the active compound, which preparations are typically sterile and can be isotonic with the blood of the intended recipient.
- Non-limiting illustrative examples include water, saline, dextrose, fructose, ethanol, animal, vegetable or synthetic oils.
- penetrants can be included in the pharmaceutical composition.
- Penetrants are known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives.
- the active ingredient can be formulated into aerosols, sprays, ointments, salves, gels, or creams as generally known in the art.
- pharmaceutical compositions typically include ointments, creams, lotions, pastes, gels, sprays, aerosols, or oils.
- Carriers which may be used include Vaseline, lanolin, polyethylene glycols, alcohols, transdermal enhancers, and combinations thereof.
- Cosolvents and adjuvants may be added to the formulation.
- cosolvents contain hydroxyl groups or other polar groups, for example, alcohols, such as isopropyl alcohol; glycols, such as propylene glycol, polyethyleneglycol, polypropylene glycol, glycol ether; glycerol; polyoxyethylene alcohols and polyoxyethylene fatty acid esters.
- Adjuvants include, for example, surfactants such as, soya lecithin and oleic acid; sorbitan esters such as sorbitan trioleate; and polyvinylpyrrolidone.
- Supplementary compounds e.g., preservatives, antioxidants, antimicrobial agents including biocides and biostats such as antibacterial, antiviral and antifungal agents
- Pharmaceutical compositions may therefore include preservatives, antioxidants and antimicrobial agents.
- Preservatives can be used to inhibit microbial growth or increase stability of ingredients thereby prolonging the shelf life of the pharmaceutical formulation.
- Suitable preservatives include, for example, EDTA, EGTA, benzalkonium chloride or benzoic acid or benzoates, such as sodium benzoate.
- Antioxidants include, for example, ascorbic acid, vitamin A, vitamin E, tocopherols, and similar vitamins or provitamins.
- An antimicrobial agent or compound directly or indirectly inhibits, reduces, delays, halts, eliminates, arrests, suppresses or prevents contamination by or growth, infectivity, replication, proliferation, reproduction, of a pathogenic or non- pathogenic microbial organism.
- Classes of antimicrobials include, antibacterial, antiviral, antifungal and antiparasitics.
- Antimicrobials include agents and compounds that kill or destroy (-cidal) or inhibit (-static) contamination by or growth, infectivity, replication, proliferation, reproduction of the microbial organism.
- antibacterials include penicillins (e.g., penicillin G, ampicillin, methicillin, oxacillin, and amoxicillin), cephalosporins (e.g., cefadroxil, ceforanid, cefotaxime, and ceftriaxone), tetracyclines (e.g., doxycycline, chlortetracycline, minocycline, and tetracycline), aminoglycosides (e.g., amikacin, gentamycin, kanamycin, neomycin, streptomycin, netilmicin, paromomycin and tobramycin), macrolides (e.g., azithromycin, clarithromycin, and erythromycin), fluoroquinolones (e.g., ciprofloxacin, lomefloxacin, and norfloxacin), and other antibiotics including chloramphenicol, clindamycin,
- anti-virals include reverse transcriptase inhibitors; protease inhibitors; thymidine kinase inhibitors; sugar or glycoprotein synthesis inhibitors; structural protein synthesis inhibitors; nucleoside analogues; and viral maturation inhibitors.
- anti-virals include nevirapine, delavirdine, efavirenz, saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, zidovudine (AZT), stavudine (d4T), larnivudine (3TC), didanosine (DDI), zalcitabine (ddC), abacavir, acyclovir, penciclovir, ribavirin, valacyclovir, ganciclovir, 1,-D- ribofuranosyl-l ,2,4-triazole-3 carboxamide, 9->2-hydroxy-ethoxy methylguanine, adamantanamine, 5-iodo-2'-deoxyuridine, trifluorothymidine, interferon and adenine arabinoside.
- compositions and methods of the invention are known in the art (see, e.g., Remington: The Science and Practice of Pharmacy (2003) 20 th ed., Mack Publishing Co., Easton, PA; Remington's Pharmaceutical Sciences (1990) 18 th ed., Mack Publishing Co., Easton, PA; The Merck Index (1996) 12 th ed., Merck
- a LIF activator or inhibitor, or a LIF polypeptide or subsequence thereof, along with any adjunct agent, compound drug, composition, whether active or inactive, etc., can be packaged in unit dosage form (capsules, tablets, troches, cachets, lozenges) for ease of administration and uniformity of dosage.
- a "unit dosage form” as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active ingredient optionally in association with a pharmaceutical carrier (excipient, diluent, vehicle or filling agent) which, when administered in one or more doses, is calculated to produce a desired effect (e.g., prophylactic or therapeutic effect).
- Unit dosage forms also include, for example, ampules and vials, which may include a composition in a freeze-dried or lyophilized state; a sterile liquid carrier, for example, can be added prior to administration or delivery in vivo.
- Unit dosage forms additionally include, for example, ampules and vials with liquid compositions disposed therein. Individual unit dosage forms can be included in multi-dose kits or containers.
- compositions can be packaged in single or multiple unit dosage form for ease of administration and uniformity of dosage.
- kits that include LIF activators, inhibitors, LIF polypeptides and subsequences thereof, optionally with a second active, and pharmaceutical formulations thereof, packaged into suitable packaging material.
- a kit typically includes a label or packaging insert including a description of the components or instructions for use in vitro, in vivo, or ex vivo, of the components therein.
- a kit can contain a collection of such components, e.g., a LIF polypeptide or subsequence thereof and optionally a second active, such as another compound, agent, drug or composition.
- packaging material refers to a physical structure housing the components of the kit.
- the packaging material can maintain the components sterilely, and can be made of material commonly used for such purposes (e.g., paper, corrugated fiber, glass, plastic, foil, ampules, vials, tubes, etc.).
- Kits of the invention can include labels or inserts.
- Labels or inserts can include information identifying manufacturer, lot numbers, manufacturer location and date, expiration dates.
- Labels or inserts include "printed matter," e.g., paper or cardboard, or separate or affixed to a component, a kit or packing material (e.g., a box), or attached to an ampule, tube or vial containing a kit component.
- Labels or inserts can additionally include a computer readable medium, such as a bar-coded printed label, a disk, optical disk such as CD- or DVD-ROM/RAM, DVD, MP3, magnetic tape, or an electrical storage media such as RAM and ROM or hybrids of these such as magnetic/optical storage media, FLASH media or memory type cards.
- Labels or inserts can include identifying information of one or more components therein, dose amounts, clinical pharmacology of the active ingredient(s) including mechanism of action, pharmacokinetics and pharmacodynamics. Labels or inserts can include information identifying manufacturer information, lot numbers, manufacturer location and date.
- Labels or inserts can include information on a condition, disorder or disease (e.g., viral infection, vaccination or immunization) for which a kit component may be used.
- Labels or inserts can include instructions for the clinician or subject for using one or more of the kit components in a method, or treatment protocol or therapeutic regimen. Instructions can include dosage amounts, frequency or duration, and instructions for practicing any of the methods, treatment protocols or prophylactic or therapeutic regimes described herein.
- Exemplary instructions include, instructions for administering a LIF activator or inhibitor, or a LIF polypeptide or subsequence thereof.
- Labels or inserts can include information on any benefit that a component may provide, such as a prophylactic or therapeutic benefit. Labels or inserts can include information on potential adverse side effects, complications or reactions, such as warnings to the subject or clinician regarding situations where it would not be appropriate to use a particular composition. Adverse side effects or complications could also occur when the subject has, will be or is currently taking one or more other medications that may be incompatible with the composition, or the subject has, will be or is currently undergoing another treatment protocol or therapeutic regimen which would be incompatible with the composition and, therefore, instructions could include information regarding such incompatibilities.
- first, second, third, fourth, fifth, etc. predictor gene or a “positive or negative predictor gene” includes a plurality of such first, second, third, fourth, fifth, etc., genes, or a plurality of positive and/or negative predictor genes.
- Reference to a number with more (greater) or less than includes any number greater or less than the reference number, respectively.
- a reference to less than 30,000 includes 29,999, 29,998, 29,997, etc. all the way down to the number one (1); and less than 20,000, includes 19,999, 19,998, 19,997, etc. all the way down to the number one (1).
- Reference to a range of 1 - 5 fold therefore includes 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, fold, etc., as well as 1.1, 1.2, 1.3, 1.4, 1.5, fold, etc., 2.1, 2.2, 2.3, 2.4, 2.5, fold, etc., and so forth.
- Reference to a series of ranges includes ranges which combine the values of the boundaries of different ranges within the series. Thus, to illustrate reference to a series of ranges of 2-72 hours,
- 2- 48 hours, 4-24 hours, 4-18 hours and 6-12 hours includes ranges of 2-6 hours, 2, 12 hours, 2-18 hours, 2-24 hours, etc., and 4-27 hours, 4-48 hours, 4-6 hours, etc.
- the invention is generally disclosed herein using affirmative language to describe the numerous embodiments and aspects.
- the invention also specifically includes embodiments in which particular subject matter is excluded, in full or in part, such as substances or materials, method steps and conditions, protocols, or procedures.
- materials and/or method steps are excluded.
- the invention is generally not expressed herein in terms of what the invention does not include aspects that are not expressly excluded in the invention are nevertheless disclosed herein.
- This example includes a description of various materials and methods.
- mice C57BL/6J (WT) mice were purchased from Jackson Laboratory (Bar Harbor, ME). LIF ⁇ mice were generated as described (Escary et al., Nature 363:361 (1993)) and obtained from the Sendtner lab (Institut fur Klinische Neurobiologie). LIF " mice were backcrossed for greater than 10 generations on the B6 background. LIF " " and OTII TCR transgenic mice were bred and maintained under specific pathogen- free conditions. All animal studies were conducted on mice 6- 12 weeks of age in accordance with approved animal protocols.
- Naive OTII CD4 T cells were transduced with LIF-RV (LIF A, secreted form, or LIF B, intracellular form) or a GFP expressing control plasmid (pMIG), transferred into B6 mice, and subsequently immunized with 100 ⁇ g alum precipitated NP-Ova (Sigma; Biosearch Technologies) in PBS via intraperitoneal (i.p.) injection.
- LIF-RV LIF A, secreted form, or LIF B, intracellular form
- pMIG GFP expressing control plasmid
- bone marrow was isolated from wildtype or LIF A mice, and 3 million cells were transferred into lethally irradiated B6 recipients (total body irradiation, 2x 450R in a RS2000 X-ray irradiator, separated by 3 h). Mice were allowed to 'rest' for
- Flow cytometry Single cell suspensions of whole spleens were obtained by gentle mechanical disruption and ACK lysis (Gibco). Surface staining for flow cytometry used monoclonal antibodies to SLAM (CD150, Biolegend), CD4, CD8, CD44, CD62L, IgD, CD45.1 (eBiosciences), PD-1, FAS, B220, FITC-labeled GL7, biotinylated CD138 (BD Pharmingen), and FITC-labeled peanut agglutinin (PNA, Vector Laboratories).
- CXCR5 was detected using purified anti- CXCR5 (BD Pharmingen), followed by biotinylated anti-rat IgG (Jackson ImmunoResearch Laboratories), and PE- or APC-labeled streptavidin (eBioscience) in FACS buffer supplemented with 2% normal mouse serum as previously described (Johnston, et al., Science 325: 1006 (2009)). Samples were acquired on an LSRII containing DIVA software (BD Biosciences), and analyzed with Flow Jo software (Treestar, Inc).
- ELISA Antigen-specific IgG was quantified from mouse serum by ELISA 8 days following protein immunization or viral infection. 96-well Maxisorp microtiter plates (Nunc) were coated with NP-Ova or VACV cell lysate as the capture antigen. Following the primary incubation, samples were treated with biotinylated goat anti-mouse IgGy (Southern Biotech), subsequently incubated with HRP conjugated Avidin D (Vector Laboratories), and visualized using OPD (o- phenylenediamine dihydrochloride; Sigma) substrate.
- RNA and gene expression microarray analysis Splenocytes were isolated 8 days following an acute LCMV infection. CD4 T cells were purified by negative selection using magnetic beads (Miltenyi). Enriched cells were sorted as CD4 + CD44 l0 CD62L hi 7AAD " (naive) or
- This example includes a description of animal studies of LIF expression and biological effects after infection or immunization.
- C57BL/6 mice were infected with LCMV and microarray analysis performed 8 days postinfection on different CD4 populations: naive (CD4+CD441oCD62Lhi), non-Tfh
- FIG. 1 A shows that Leukemia inhibitory factor (LIF) is upregulated in follicular helper (Tfh) and germinal center Tfh (Tgc) over naive and non-Tfh populations.
- LIF Leukemia inhibitory factor
- This example includes a description of animal studies and data desmonstrating that LIF contributes to and/or enhances antibody responses, such as against Vaccinia virus.
- Bone marrow was transferred from LIF " " or LIF + " mice into irradiated wild-type B6 mice to generate bone marrow (BM) chimeric mice.
- LIF " " or LIF 4"7" BM chimera mice were infected with 2 l0 5 pfu VACV WR .
- Splenocytes were isolated at day 8 postinfection.
- Figure 2A The LIF- deficient BM chimeric mice also had decreased germinal center B cell (PNA + FAS + ) numbers compared to the control group, and some of these reductions were extreme ( Figures 2B and 2C).
- LIF-deflcient mice exhibited a significant reduction in both T FH (CXCR5 + , Figure 2D) and GC T FH (CXCR5 + PD-1 + , Figures 2E and 2F).
Abstract
[0188] The invention relates to LIF (Leukemia inhibitory factor, also known as cholinergic differentiation factor) and compositions thereof, and methods that employ LIF activators, LIF inhibitors and LIF sequences (polypeptides, subsequences thereof, nucleic acids encoding LIF, LIF antisense, etc.). Such methods include among other things, methods of inhibiting, decreasing or reducing Tfh (follicular helper) cell differentiation, Germinal center B cell development or an antibody response, methods for inhibiting or reducing an undesirable or aberrant immune response, and methods for inhibiting or reducing an undesirable or aberrant inflammatory response or inflammation. Such methods also include methods for stimulating, inducing or increasing an immune response, and methods for stimulating, inducing or increasing an immune response induced by a vaccine, as well as vaccination and immunization methods.
Description
Methods for Modulating LIF Activity, Treating Immune Disorders and Diseases, and
Stimulating Immune Responses
Related Applications
[0001] This application claims priority to application serial no. 61/259,003, filed November 6, 2009, which is expressly incorporated herein by reference in its entirety.
Government Sponsorship
[0002] This work was supported in part by Grants AI072543 and AI063107 from the National Institutes of Health. The government has certain rights in the invention.
Introduction
[0003] LIF (Leukemia inhibitory factor, also known as cholinergic differentiation factor) is a powerful cytokine known for it's crucial role in embryonic stem cells. LIF is highly expressed selectively by Tfh, which are the critical CD4 T cells for B cell help and antibody responses in vivo. LIF is further upregulated in germinal center Tfh (GC Tfh, or Tgc), which regulates the germinal center response.
Summary
[0004] The invention is based, at least in part, on data indicating that expression of LIF (Leukemia inhibitory factor, also known as cholinergic differentiation factor) in CD4 T cells enhances (1) Tfh differentiation, (2) Germinal center B cell development, (3) and antibody responses. The data demonstrate that LIF is a valuable cytokine target produced by CD4 T cells, and is useful to target for inhibiting or reducing immune responses, such as inflammatory and autoimmune responses, and inflammation (blocking LIF). The data also demonstrate that LIF can stimulate, induce, increase or enhance immune responses, such as by vaccines (enhancing LIF).
[0005] The invention therefore provides methods for inhibiting, decreasing or reducing Tfh
(follicular helper) cell differentiation, Germinal center B cell development or an antibody response; methods for inhibiting or reducing an undesirable or aberrant immune response; methods for inhibiting or reducing development of memory T cells; and methods for inhibiting or reducing an undesirable or aberrant inflammatory response or inflammation, comprising administering an inhibitor of LIF (Leukemia inhibitory factor, cholinergic differentiation factor). In various embodiments, a method includes administering an inhibitor of LIF (Leukemia inhibitory factor, cholinergic differentiation factor) to a subject in an amount effective to inhibit, decrease or reduce Tfh (follicular helper) cell differentiation, Germinal center B cell development or an antibody response in the subject; administering an inhibitor of LIF to a subject in an amount effective to inhibit or reduce development of memory T cells; administering an inhibitor of LIF (Leukemia inhibitory factor, cholinergic differentiation factor) to a subject in an amount effective to inhibit or
reduce an undesirable or aberrant immune response in the subject; or administering to a subject an amount effective to inhibit or reduce an undesirable or aberrant inflammatory response or inflammation in the subject.
[0006] The invention also provides methods for stimulating, inducing or increasing an immune response; methods of stimulating, inducing or increasing development of memory T cells; methods of stimulating, inducing or increasing Tfh (follicular helper) cell differentiation, Germinal center B cell development or an antibody response; and methods for stimulating, inducing or increasing an immune response induced by a vaccine. In various embodiments, a method includes administering a LIF polypeptide or subsequence thereof or an activator of LIF to a subject in an amount effective to stimulate, induce or increase an immune response in the subject; or administering LIF polypeptide or subsequence thereof or an activator of LIF to a subject in an amount effective to stimulate, induce or increase an immune response induced by the vaccine in the subject.
[0007] Accordingly, methods of treating a subject in need of treatment with LIF (LIF polypeptides, subsequences thereof, nucleic acids encoding LIF, LIF inhibitory nucleic acids or antisense, etc.), LIF activators and LIF inhibitors are provided. In various embodiments, such methods include administering to a subject in need thereof an amount of a LIF polypeptide or subsequence thereof, or a LIF composition, to treat the subject.
[0008] Non-limiting examples of such subjects in need of treatment include those having or at risk of acute or chronic undesirable or aberrant inflammatory response or inflammation, an autoimmune disease. Additional non-limiting examples of such subjects in need of treatment include those in need of a stimulated, induced or increased immune response, or an inhibited, decreased or reduced immune response. For example, an immune suppressed subject or a subject that is a candidate for a an immunization or a vaccine. Further non-limiting examples of such subjects in need of treatment include those in need of a stimulated, induced or increased memory T cell development, or an inhibited, decreased or reduced memory T cell development. Still further non-limiting examples of such subjects in need of treatment include those in need of a stimulated, induced or increased cell mediated or humoral immune response, or an inhibited, decreased or reduced cell mediated or humoral immune response.
[0009] Methods of the invention include administering LIF (e.g., a LIF polypeptide, subsequence thereof, nucleic acids encoding LIF, LIF antisense, etc.), or a LIF activator or inhibitor, or a composition thereof, at various times, frequencies and in various quantities. In particular embodiments, a LIF polypeptide or subsequence, a LIF activator or inhibitor, or a composition thereof, is administered prior to, substantially contemporaneously with or following development of a symptom in a subject who would benefit from treatment with LIF, or a LIF activator or inhibitor.
[0010] Activators and inhibitors of LIF include molecules that bind to LIF (Leukemia inhibitory factor, cholinergic differentiation factor), or that act through an intermediary that in turn acts upon or
binds to LIF. In particular embodiments, such molecules include ligands, antibodies and
subsequences thereof that bind to LIF (e.g., mammalian, such as human LIF). In additional particular embodiments, such molecules include an inhibitory or antisense nucleic acid sequence of LIF (e.g., mammalian, such as human LIF).
[0011] The invention further provides LIF polypeptides and subsequences of LIF, and LIF compositions (e.g., LIF pharmaceutical compositions and formulations, and adjuvant in combination with LIF) including LIF polypeptides and subsequences thereof, in which the peptide or subsequence thereof has one or more functions of LIF. In various embodiments, a LIF polypeptide or subsequence thereof inhibits, decreases or reduces Tfh (follicular helper) cell differentiation, Germinal center B cell development or an antibody response, inhibits, decreases or reduces development of memory T cells, inhibits, decreases or reduces an undesirable or aberrant immune response; or inhibits, decreases or reduces an undesirable or aberrant inflammatory response or inflammation. In additional embodiments, a LIF polypeptide or subsequence stimulates, induces or increases an immune response, or stimulates, induces or increases an immune response induced by a vaccine (e.g., elicits, promotes or enhances an immune response against a vaccine antigen in vitro or in vivo).
Description of Drawings
[0012] Figures 1A-1D show LIF expression and biological effects after infection or immunization. A) shows C57BL/6 mice infected with LCMV and microarray analysis performed post-infection on different CD4 populations. Leukemia inhibitory factor (LIF) is upregulated in follicular helper (Tfh) and germinal center Tfh (Tgc) over naive and non-Tfh populations. B-D) show NP-Ova protein immunized mice. The percentage of B) GC B cell and C) OT-II Tfh cell differentiation quantified by FACS. *, P < 0.05 unpaired t test, n = 6 mice/group. D) NP-Ova IgG ELISA at day 8.
[0013] Figures 2A-2F show LIF-/- and LIF+/- bone marrow (BM) chimera mice infected with 2xl05 pfu VACV. Splenocytes isolated at day 8 post-infection. A) aVACV serum IgG in LIF-/- vs LIF+/- BM chimeric mice, quantified by VACV ELISA. n > 7 mice per group; B) Representative FACS plots of germinal center B cells (PNA+FAS+) in LIF-/- vs LIF+/- mice; C) Germinal center B cell quantitation.; D) Tfh (CXCR5+) frequency. (P < 0.05); E) Representative FACS plots of GC Tfh (CXR5+PD1+); and F) GC Tfh quantitation. (P < 0.05). n > 4 mice per group. Data is from one study.
Detailed Description
[0014J The invention is based at least in part on LIF (Leukemia inhibitory factor, cholinergic differentiation factor), which is able to modulate various immune responses (e.g., stimulate, induce, increase or enhance, or inhibit, decrease or reduce an immune response). For example, LIF can stimulate, induce, increase or enhance an immune response. LIF can also stimulate, induce, increase
or enhance Tfh (follicular helper) cell differentiation, Germinal center B cell development or an antibody response. LIF can additionally stimulate, induce, increase or enhance development of memory T cells. LIF can furthermore stimulate, induce, increase or enhance an immune response, for example, a response induced by a vaccine. Accordingly, LIF and activators of LIF are useful for and the invention provides, among other things, methods for stimulating, inducing or increasing an immune response, development of memory T cells, and an immune response, such as an immune response induced by a vaccine. In respective embodiments, a method includes administering LIF or an activator of LIF to a subject in an amount effective to stimulate, induce, increase or enhance an immune response in the subject, administering LIF or an activator of LIF to a subject in an amount effective to stimulate, induce, increase or enhance Tfh (follicular helper) cell differentiation, Germinal center B cell development or an antibody response, administering LIF or an activator of LIF to a subject in an amount effective to stimulate, induce, increase or enhance development of memory T cells, and administering LIF or an activator of LIF to a subject in an amount effective to stimulate, induce, increase or enhance an immune response, such as a response induced by the vaccine in the subject.
[0015] Inhibitors of LIF can inhibit, decrease or reduce Tfh (follicular helper) cell differentiation, Germinal center B cell development or an antibody response. Inhibitors of LIF can also inhibit, decrease or reduce development of memory T cells. Inhibitors of LIF can furthermore inhibit, decrease or reduce an undesirable or aberrant immune response. LIF inhibitors can additionally inhibit, decrease or reduce an undesirable or aberrant inflammatory response or inflammation in the subject. Accordingly, LIF inhibitors are useful for and the invention provides, among other things, methods for inhibiting, decreasing or reducing such cell differentiation, Germinal center B cell development, antibody responses, undesirable and aberrant immune responses, and undesirable and aberrant inflammatory responses and inflammation. In respective embodiments, a method includes administering an inhibitor of LIF to a subject in an amount effective to inhibit, decrease or reduce Tfh (follicular helper) cell differentiation, Germinal center B cell development or an antibody response in the subject, administering an inhibitor of LIF to a subject in an amount effective to inhibit, decrease or reduce development of memory T cells in the subject, administering an inhibitor of LIF to a subject in an amount effective to inhibit, decrease or reduce an undesirable or aberrant immune response in the subject, and administering an inhibitor of LIF to a subject in an amount effective to inhibit, decrease or reduce method for inhibiting or reducing an undesirable or aberrant inflammatory response or inflammation in the subject.
[0016] Inhibitors and activators of LIF "modulate" a LIF activity, function or expression.
Modulate can mean any increase, stimulation, promotion, or enhancement, or decrease, reduction, inhibition, or prevention, in LIF activity, function or expression. For example, modulating an immune response means that activity or function or an effect is that the immune response is
detectably changed, e.g., an increase, stimulation, promotion, or enhancement, or decrease, reduction, inhibition, or prevention, of any immune function, such as inflammation, humoral or cell mediated immunity, activity, function or numbers of T and B cells, memory T cell development, function or activity, cytokine or chemokine production, antibody production, mitogen responsiveness, or symptoms thereof, which can be measured by a variety of methods disclosed herein or known to one of skill in the art.
[0017] Exemplary activators of LIF detectably induce, increase, promote, stimulate or enhance an activity , function or expression of LIF. Thus, a LIF activator detectably induces, increases, promotes, stimulates or enhances one or more LIF activities or functions or LIF expression, which can include, for example, modulation of an immune response, as set forth herein or otherwise one that one of skill in the art would know.
[0018| A LIF activator may act directly upon LIF. Such activators of LIF need not bind to LIF provided that they induce, increase, promote, stimulate or enhance one or more LIF activities or functions. For example, a LIF activator may indirectly interact with LIF, for example, by acting through an intermediary, for example, the activator binds to or modulates a molecule that in turn binds to or modulates LIF.
[0019] Exemplary inhibitors of LIF detectably reduce, decrease, inhibit, prevent or abrogate an activity or function of LIF. Thus, a LIF inhibitor detectably reduces, decreases, inhibits, presents or abrogates one or more LIF activities or functions. LIF activities and functions can include, for example, binding of LIF to a ligand, LIF mediated signaling or expression, or an immune response, as set forth herein or otherwise one that one of skill in the art would know.
[0020] A LIF inhibitor may act directly upon LIF. Such inhibitors of LIF need not bind to LIF provided that they inhibit, reduce, suppress or in any way interfere with LIF function or activity. For example, a LIF inhibitor may indirectly interact with LIF, for example, by acting through an intermediary, for example, the inhibitor binds to or modulates a molecule that in turn binds to or modulates LIF.
[0021] LIF activators and inhibitors include ligands that bind to LIF or a subsequence thereof (e.g., SEQ ID NO: 1). Non-limiting examples of ligands include polypeptides that bind to LIF, such as antibodies and LIF ligands. Additional exemplary LIF activators and inhibitors include antisense RNA and inhibitory nucleic acid against LIF.
[0022] The term "bind," or "binding," means a physical interaction at the molecular level (directly or indirectly). Typically, binding is that which is specific or selective for LIF, i.e., is statistically significantly higher than the background or control binding for the assay. The term "specifically binds" refers to the ability to preferentially or selectively bind to LIF. Specific and selective binding can be distinguished from non-specific binding using assays known in the art (e.g.,
immunoprecipitation, ELISA, flow cytometry, and Western blotting).
[0023] As used herein, the terms "LIF antibody," "anti-LIF" and "anti-LIF antibody" refer to an antibody that specifically binds to LIF. Antibodies include monoclonal or polyclonal
immunoglobulin molecules that belong to any class such as IgM, IgG, IgA, IgE, IgD, and any subclass thereof. Exemplary subclasses for IgG are IgG], IgG2, IgGj and IgG .
[0024) A "monoclonal" antibody refers to an antibody that is based upon, obtained from or derived from a single clone, including any eukaryotic, prokaryotic, or phage clone. A "monoclonal" antibody is therefore defined structurally, and not the method by which it is produced.
[0025] Antibodies include full-length antibodies that include two heavy and two light chain sequences. Antibodies can have kappa or lambda light chain sequences, either full length as in naturally occurring antibodies, mixtures thereof (i.e., fusions of kappa and lambda chain sequences), and subsequences/fragments thereof. Naturally occurring antibody molecules contain two kappa or two lambda light chains.
[0026J Antibodies include subsequences. Subsequences include all or a portion of a full- length antibody heavy or light chain, or a heavy or light chain variable region, which includes one or more CDRs of a heavy or light chain variable region sequence. In various aspects, a subsequence of a full length antibody heavy or light chain, or a heavy or light chain variable region, has a length from about 20-30, 30-50, 50-100, 100-150, 150-200, 200-250, 250-300, 300-400, or 400-500, amino acid residues.
[0027] Non-limiting representative antibody subsequences include but are not limited to Fab, Fab', F(ab')2, Fv, Fd, single-chain Fv (scFv), disulfide-linked Fvs (sdFv), VL, VH, Camel Ig, V-NAR, VHH, trispecific (Fab3), bispecific (Fab2), diabody ((VL-VH)2 or (VH-VL)2), triabody (trivalent), tetrabody (tetravalent), minibody ((scFv-CH3)2), bispecific single-chain Fv (Bis-scFv), IgGdeltaCH2, scFv-Fc, (scFv)2-Fc, affibody, aptamer, avimer or nanobody, or other antigen binding subsequences of an intact immunoglobulin. Antibodies include those that bind to more than one epitope (e.g., bispecific antibodies), or antibodies that can bind to one or more different antigens (e.g., bi- or multi- specific antibodies).
[0028] Antibodies include antibodies and subsequences capable of binding to LIF in solution or in solid phase, present on one or more cells in vitro, in primary cell isolates, passaged cells, cultured cells and immortalized cells, or in vivo. Specific non-limiting cell types that can express LIF include Tfh and Tgc cells, as well as endothelial cells, epithelial cells from the uterus, intestine, lung and kidney, stromal cells and neuronal cells.
[0029] Antibodies include mammalian, primatized, humanized, fully human antibodies and chimeras. A mammalian antibody is an antibody which is produced by a mammal, transgenic or non-transgenic, or a non-mammalian organism engineered to produce a mammalian antibody, such as a non-mammalian cell (bacteria, yeast, insect cell), animal or plant.
|0030] The term "human" when used in reference to an antibody, means that the amino acid sequence of the antibody is fully human, i.e., human heavy and human light chain variable and human constant regions. Thus, all of the amino acids are human or exist in a human antibody. An antibody that is non-human may be made fully human by substituting the non-human amino acid residues with amino acid residues that exist in a human antibody. Amino acid residues present in human antibodies, CDR region maps and human antibody consensus residues are known in the art (see, e.g., Kabat, Sequences of Proteins of Immunological Interest, 4th Ed.US Department of Health and Human Services. Public Health Service ( 1 87); Chothia and Lesk (1987). A consensus sequence of human VH subgroup III, based on a survey of 22 known human VH III sequences, and a consensus sequence of human V| kappa-chain subgroup I, based on a survey of 30 known human kappa I sequences is described in Padlan Mol. Immunol. 31 : 169 (1994); and Padlan Mol. Immunol. 28:489 (1991). Human antibodies therefore include antibodies in which one or more amino acid residues have been substituted with one or more amino acids present in any other human antibody.
[0031] The term "humanized" when used in reference to an antibody, means that the amino acid sequence of the antibody has non-human amino acid residues (e.g., mouse, rat, goat, rabbit, etc.) of one or more complementarity determining regions (CDRs) that specifically bind to the desired antigen in an acceptor human immunoglobulin molecule, and one or more human amino acid residues in the Fv framework region (FR), which are amino acid residues that flank the CDRs. Such antibodies typically have reduced immunogenicity and therefore a longer half-life in humans as compared to the non-human parent antibody from which one or more CDRs were obtained or are based upon.
[0032] Antibodies referred to as "primatized" are "humanized" except that the acceptor human immunoglobulin molecule and framework region amino acid residues may be any primate amino acid residue (e.g., ape, gibbon, gorilla, chimpanzees orangutan, macaque), in addition to any human residue. Human FR residues of the immunoglobulin can be replaced with corresponding non-human residues. Residues in the CDR or human framework regions can therefore be substituted with a corresponding residue from the non-human CDR or framework region donor antibody to alter, generally to improve, antigen affinity or specificity, for example. A humanized antibody may include residues, which are found neither in the human antibody nor in the donor CDR or framework sequences. For example, a FR substitution at a particular position that is not found in a human antibody or the donor non-human antibody may be predicted to improve binding affinity or specificity human antibody at that position. Antibody framework and CDR substitutions based upon molecular modeling are well known in the art, e.g., by modeling of the interactions of the CDR and framework residues to identify framework residues important for antigen binding and sequence comparison to identify unusual framework residues at particular positions (see, e.g., U.S. Patent No. 5,585,089; and Riechmann et al., Nature 332:323 (1988)).
[0033] The term "chimeric" and grammatical variations thereof, when used in reference to an antibody, means that the amino acid sequence of the antibody contains one or more portions that are derived from, obtained or isolated from, or based upon two or more different species. For example, a portion of the antibody may be human (e.g., a constant region) and another portion of the antibody may be non-human (e.g., a murine heavy or murine light chain variable region). Thus, an example of a chimeric antibody is an antibody in which different portions of the antibody are of different species origins. Unlike a humanized or primatized antibody, a chimeric antibody can have the different species sequences in any region of the antibody.
[0034j Methods of producing polyclonal and monoclonal antibodies are known in the art. For example, LIF or an immunogenic fragment thereof, optionally conjugated to a carrier such as keyhole limpet hemocyanin (KLH) or ovalbumin (e.g., BSA), or mixed with an adjuvant such as Freund's complete or incomplete adjuvant, and used to immunize an animal. Using hybridoma technology, splenocytes from immunized animals that respond to LIF can be isolated and fused with myeloma cells. Monoclonal antibodies produced by hybridomas can be screened for reactivity with LIF, or an immunogenic fragment thereof. Hybridoma, recombinant, and phage display methods are known in the art (see, for example, U.S. Patent Nos. 4,902,614, 4,543,439, and 4,41 1,993; see, also Monoclonal Antibodies. Hybridomas: A New Dimension in Biological Analyses. Plenum Press, ennett, McKearn, and Bechtol (eds.), 1980, and Harlow et al., Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, 2nd ed. 1988).
[0035] Animals that may be immunized include primates, mice, rats, rabbits, goats, sheep, cattle, or guinea pigs. Initial and any optional subsequent immunization may be through intravenous, intraperitoneal, intramuscular, or subcutaneous routes. Additionally, to increase the immune response, antigen can be coupled to another protein such as ovalbumin or keyhole limpet hemocyanin (KLH), thyroglobulin and tetanus toxoid, or mixed with an adjuvant such as Freund's complete or incomplete adjuvant. Initial and any optional subsequent immunization may be through intraperitoneal, intramuscular, intraocular, or subcutaneous routes. Subsequent immunizations may be at the same or at different concentrations of antigen, and may be at regular or irregular intervals.
[0036] Animals include those genetically modified to include human gene loci, which can be used to produce human antibodies. Transgenic animals, such as human trans-chromosomic mice with one or more human immunoglobulin genes, are described, for example, in U.S. Patent No. 5,939,598, WO 02/43478, and WO 02/092812. In brief, animals are immunized LIF or cells that express LIF antigen. Using conventional hybridoma technology, splenocytes from immunized mice that are high responders to the antigen can be isolated and fused with myeloma cells. Antibodies that bind to LIF can thereby be obtained.
[0037] Humanized antibodies can be produced using techniques known in the art including, for example, CDR-grafting (EP 239,400; W091/09967; U.S. Patent Nos. 5,225,539; 5,530,101; and
5,585,089), veneering or resurfacing (EP 592, 106; EP 519,596; Padlan, Molecular Immunol. 28:489 (1991 ); Studnicka et al., Protein Engineering 7:805 (1994); Roguska. et al., Proc. Nat l Acad. Sci. USA 91 :969 (1994)), and chain shuffling (U.S. Patent No. 5,565,332). Human consensus sequences (Padlan, Mol. Immunol. 31 : 169 (1994); and Padlan, Mol. Immunol. 28:489 (1991)) have previously used to produce humanized antibodies (Carter et al., Proc. Natl. Acad. Sci. USA 89:4285 (1992); and Presta et al., J. Immunol. 151 :2623 ( 1993)). Additional methods for producing human polyclonal antibodies and human monoclonal antibodies are described (see, e.g., Kuroiwa et al., Nat. Biotechnol. 20:889 (2002); WO 98/24893; WO 92/01047; WO 96/34096; WO 96/33735; U.S. Patent Nos.
5,413,923; 5,625,126; 5,633,425; 5,569,825; 5,661 ,016; 5,545,806; 5,814,318; 5,885,793; 5,916,771 ; and 5,939,598).
[0038] Methods for producing chimeric antibodies are known in the art (e.g., Morrison, Science 229: 1202 ( 1985); Oi et al., BioTechniques 4:214 ( 1986); Gillies et al., J. Immunol. Methods 125: 191 (1989); and U.S. Patent Nos. 5,807,715; 4,816,567; and 4,816,397). Chimeric antibodies in which a variable domain from an antibody of one species is substituted for the variable domain of another species are described, for example, in Munro, Nature 312:597 (1984); Neuberger et al., Nature 312:604 (1984); Sharon et al., Nature 309:364 (1984); Morrison et al., Proc. Nat l Acad. Sci. USA 81 :6851 (1984); Boulianne et al., Nature 312:643 (1984); Capon et al., Nature 337:525 (1989); and Traunecker et al., Nature 339:68 (1989).
[0039] LIF protein suitable for generating antibodies can be produced by any of a variety of standard protein purification or recombinant expression techniques. Forms of LIF suitable for generating an immune response include LIF subsequences, such as an immunogenic fragment.
Additional forms of LIF include LIF expressing cells, LIF containing preparations or extracts or fractions, partially purified LIF. For example, a LIF sequence can be produced by standard peptide synthesis techniques, such as solid-phase synthesis. A portion of the protein may contain an amino acid sequence such as a T7 tag or polyhistidine sequence to facilitate purification of expressed or synthesized protein. The protein may be expressed in a cell and purified. The protein may be expressed as a part of a larger protein (e.g., a fusion or chimera) by recombinant methods.
Suitable techniques that additionally may be employed in antibody methods include LIF based affinity purification, non-denaturing gel purification, HPLC or RP-HPLC, size exclusion, purification on protein A column, or any combination of these techniques. Antibody isotype can be determined using an ELISA assay, for example, a human Ig can be identified using mouse Ig- absorbed anti-human Ig.
[0040] Non-limiting representative examples of antibodies that specifically bind to LIF include antibodies denoted as L9277, L9152, L0919, L0669 and LI 169 (Sigma-Aldrich) and anti-Human Leukemia Inhibitory Factor clone 4F7.2 antibody (MAB4306, Millipore), which binds to human LIF. Further non-limiting representative examples of antibodies include R&D Systems goat anti-mouse
LIF (AB-449-NA) and rat anti-mouse LIF (clone 139124, MAB449), Millipore rat anti-mouse LIF (clone 2H2.2, MAB4307), mouse Anti-Human LIF Monoclonal Antibodies, Clones 9808 and 9824 (R&D Systems), and anti-LIF (J- 14F) (Santa Cruz Biotechnology, Inc. )
[0041] LIF antibodies and functional (e.g., binding) subsequences, can have substantially the same, greater or less relative activity for than a reference antibody. For example, a LIF antibody can have substantially the same, greater or less relative binding affinity or avidity for LIF than a reference antibody. Such antibodies having measurable affinity for LIF compete for binding of the reference antibody to LIF. LIF antibodies and subsequences therefore include those that do not compete with a reference antibody for binding to LIF, and those that compete with a reference antibody for binding to LIF, and have substantially the same, greater or less relative binding affinity or avidity for binding to LIF as compared to a reference antibody. In particular embodiments, a LIF antibody competes for binding of antibody denoted as L9277, L9152, L0919, L0669 or LI 169 (Sigma- Aldrich), anti-Human Leukemia Inhibitory Factor clone 4F7.2 antibody (MAB4306, Millipore), anti- mouse LIF (AB-449-NA), rat anti-mouse LIF (clone 139124, MAB449), rat anti-mouse LIF (clone 2H2.2, MAB4307, Millipore), mouse Anti-Human LIF Monoclonal Antibodies, Clones 9808 or 9824, or anti-LIF (J-14F) to LIF.
[0042] LIF antibodies and subsequences can have a binding affinity for binding to LIF within about Kd 10"2 M to about ¾ 10" 15 M, or within about Kd 10~6 M to about ¾ 10"'2 M. In particular embodiments, binding affinity is less than 5xl0"2 M, 10"2 M, 5xl 0"3 M, 10"3 M 5xl0 M, 10"4 M 5xl0"5 M, 10"5 M 5xl0~6 M, 10'6 M 5xl0"7 M, 10"7 M 5xl0"8 M, 10"8 M 5xl0"9 M, 10"9 M 5xl0"10 M, 10"10 M 5x10"" M, 10"" M 5xl0"12 M, 10"12 M 5xl0"13 M, 10"13 M 5xl0"14 M, 10"14 M 5xl0"15 M, and 10"' 5 M.
[0043] LIF antibodies and subsequences can have a greater or less than 2-5, 5-10, 10-100, 100-1000 or 1000-10,000-fold binding affinity for binding to LIF, or any numerical value or range within or encompassing such values, than a reference antibody. In one embodiment, an antibody or a functional subsequence thereof has a binding affinity within about 1-5000 fold (more or less than) of a reference antibody for binding to LIF.
[0044] LIF antibodies and subsequences can have substantially the same binding affinity for LIF as a reference antibody. In particular embodiments, a LIF antibody has substantially the same binding affinity or avidity for LIF as antibody denoted as L9277, L9152, L0919, L0669 or LI 169 (Sigma- Aldrich), anti-Human Leukemia Inhibitory Factor clone 4F7.2 antibody (MAB4306, Millipore), anti- mouse LIF (AB-449-NA), rat anti-mouse LIF (clone 139124, MAB449), rat anti-mouse LIF (clone 2H2.2, MAB4307, Millipore), mouse Anti-Human LIF Monoclonal Antibodies, Clones 9808 or 9824, or anti-LIF (J- 14F).
[0045] The term "substantially the same" when used in reference to antibody or functional subsequence binding affinity or avidity for antigen, means that the binding affinity is within 100 fold
of the binding affinity of a reference antibody for LIF or a subsequence thereof. Binding affinity can be determined by association (Ka) and dissociation (¾) rate. Equilibrium affinity constant, , is the ratio of a/ d. Association (Ka) and dissociation (Kj) rates can be measured using surface plasmon resonance (SPR) (Rich and Myszka, Ciirr. Opin. Biotechnol. 1 1 :54 (2000); Englebienne, Analyst. 123 : 1599 ( 1998)). Instrumentation and methods for real time detection and monitoring of binding rates are known and are commercially available (BiaCore 2000, Biacore AB, Upsala, Sweden; and Malmqvist, Biochem. Soc. Trans. 27:335 ( 1999)). Thus, for example, if binding of a reference antibody to LIF has a Kj 10"9 M, than an antibody which has substantially the same binding affinity as the reference LIF antibody will have a ¾ from 10"7 M to ¾ 10"" M for binding to LIF.
[0046] LIF polypeptides and subsequences thereof, and amino acid substitutions thereof, can be used to practice invention methods and uses. Such LIF polypeptides and subsequences thereof can exhibit sequence identity to a reference LIF polypeptide or subsequence thereof. An exemplary human LIF sequence is set forth as:
MKVLAAGVVPLLLVLHWKHGAGSPLPITPVNATCAIRHPCHNNLMNQIRSQLAQLNGSANALFILYY TAQGEPFPNNLDKLCGPNVTDFPPFHANGTEKAKLVELYRIVVYLGTSLGNITRDQKILNPSALSLH SKLNATADILRGLLSNVLCRLCSKYHVGHVDVTYGPDTSGKDVFQKKKLGCQLLGKYKQI IAVLAQA
F (SEQ ID NO: 1) .
[0047] A non-limiting exemplary LIF polypeptide or subsequence thereof includes or consists of a sequence at least 60% or more (e.g., 65%, 70%, 75%, 80%, 85%, 90%, 95%, etc.) identical to SEQ ID NO:l, wherein the LIF polypeptide or subsequence stimulates, induces, increases or enhances an immune response, Tfh (follicular helper) cell differentiation, Germinal center B cell development, an antibody response, development of memory T cells or an immune response, such as a response induced by a vaccine.
[0048] Additional LIF inhibitors include inhibitory and antisense nucleic acid sequences. Inhibitory, antisense and RNAi nucleic acids can modulate expression of LIF. Antisense includes single, double or triple stranded polynucleotides and peptide nucleic acids (PNAs) that bind RNA transcript or DNA (e.g., genomimc DNA). For example, a single stranded nucleic acid can target LIF transcript (e.g., niRNA). Oligonucleotides derived from the transcription initiation site of LIF gene, e.g., between positions -10 and +10 from the start site, are another particular example. Triplex forming antisense can bind to double strand DNA thereby inhibiting transcription of the gene.
"RNAi" is the use of double stranded RNA sequences for inhibiting gene expression (see, e.g., Kennerdell et al., Cell 95: 1017 (1998); and Fire et al., Nature. 391 : 806 (1998)). Double stranded RNA sequences from a LIF coding region may therefore be used to inhibit or prevent LIF expression in accordance with the methods and uses of the invention. Antisense and RNAi can be produced based upon nucleic acids encoding LIF sequences (e.g., SEQ ID NO: 1), such as nucleic acid encoding mammalian and human LIF (e.g., SEQ ID NO:2):
(00491 ATGAAGGTCTTGGCGGCAGGAGTTGTGCCCCTGCTGTTGGTTCTGCACTGGAAA
CATGGGGCGGGGAGCCCCCTCCCCATCACCCCTGTCAACGCCACCTGTGCCATACGCCA
CCCATGTCACAACAACCTCATGAACCAGATCAGGAGCCAACTGGCACAGCTCAATGGC
AGTGCCAATGCCCTCTTTATTCTCTATTACACAGCCCAGGGGGAGCCGTTCCCCAACAA
CCTGGACAAGCTATGTGGCCCCAACGTGACGGACTTCCCGCCCTTCCACGCCAACGGCA
CGGAGAAGGCCAAGCTGGTGGAGCTGTACCGCATAGTCGTGTACCTTGGCACCTCCCTG
GGCAACATCACCCGGGACCAGAAGATCCTCAACCCCAGTGCCCTCAGCCTCCACAGCA
AGCTCAACGCCACCGCCGACATCCTGCGAGGCCTCCTTAGCAACGTGCTGTGCCGCCTG
TGCAGCAAGTACCACGTGGGCCATGTGGACGTGACCTACGGCCCTGACACCTCGGGTAA
GGATGTCTTCCAGAAGAAGAAGCTGGGCTGTCAACTCCTGGGGAAGTATAAGCAGATC
ATCGCCGTGTTGGCCCAGGCCTTCTAG (SEQ ID NO:2).
[0050] Methods are applicable to immune responses, cell mediated and/or antibody mediated (e.g., a humoral immune response). Methods are applicable to immune responses, including undesirable or aberrant immune responses, such as undesirable or aberrant inflammatory responses or inflammation. Methods are also applicable to acute or chronic immune responses, and acute or chronic undesirable or aberrant immune responses, such as acute or chronic undesirable or aberrant inflammatory responses or inflammation.
[0051] As used herein, an "undesirable immune response" or "aberrant immune response" refers to any immune response, activity or function that is greater or less than desired or physiologically normal. An undesirable immune response, function or activity can be a normal response, function or activity. Thus, normal immune responses so long as they are undesirable, even if not considered abnormal, are included within the meaning of these terms. An undesirable immune response, function or activity can also be an abnormal response, function or activity. An abnormal (aberrant) immune response, function or activity deviates from normal. Undesirable and aberrant immune responses can be humoral, cell-mediated or a combination thereof, either chronic or acute.
[0052] One non-limiting example of an undesirable or aberrant immune response is where the immune response is hyper-responsive, such as in the case of an autoimmune disorder or disease. Another example of an undesirable or aberrant immune response is where an immune response leads to acute or chronic inflammatory response or inflammation in any tissue or organ, such as an allergy. Yet another example of an undesirable or aberrant immune response is where an immune response leads to destruction of cells, tissue or organ, such as a bone marrow transplant, as in graft vs. host disease (GVHD). Still another example of an undesirable or aberrant immune response is where the immune response is hypo-responsive, such as where response to an antigen is less than desired, e.g., tolerance has occurred.
[0053[ The terms "immune disorder" and "immune disease" mean, an immune function or activity, that is greater than (e.g., autoimmunity) or less than (e.g., immunodeficiency) desired, and which is
characterized by different physiological symptoms or abnormalities, depending upon the disorder or disease. Particular non-limiting examples of immune disorders and diseases to which the invention applies include autoimmune disorders. Autoimmune disorders are generally characterized as an undesirable or aberrant increased or inappropriate response, activity or function of the immune system. Disorders and diseases that can be treated in accordance with the invention include, but are not limited to, disorders and disease that cause cell or tissue/organ damage in the subject.
[0054] As used herein, the term "autoimmune disease" encompasses a condition, disorder, dysfunction or disease that results when the immune system attacks the body's own cells, tissues or organs. In particular, the term "autoimmune disease" includes a disorder wherein the immune system of a mammal mounts a humoral or cellular immune response to the mammal's own cells, tissues or organs. It is understood that more than one type of cell, tissue or organ may be attacked in the course of autoimmune disease.
[0055] Specific non-limiting examples of automimmune diseases include rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, psoriatic arthritis, diabetes mellitus, multiple sclerosis, encephalomyelitis, myasthenia gravis, systemic lupus erythematosus (SLE), autoimmune thyroiditis, atopic dermatitis, eczematous dermatitis, psoriasis, Sjogren's Syndrome, Crohn's disease, aphthous ulcer, iritis, conjunctivitis, keratoconjunctivitis, ulcerative colitis, asthma, allergic asthma, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, erythema nodosum leprosum, autoimmune uveitis, allergic encephalomyelitis, acute necrotizing hemorrhagic encephalopathy, idiopathic bilateral progressive sensorineural hearing loss, aplastic anemia, pure red cell anemia, idiopathic thrombocytopenia, polychondritis, Wegener's granulomatosis, chronic active hepatitis, Stevens- Johnson syndrome, idiopathic sprue, lichen planus, Graves' disease, sarcoidosis, primary biliary cirrhosis, uveitis posterior, interstitial lung fibrosis, Hashimoto's thyroiditis, autoimmune polyglandular syndrome, insulin-dependent diabetes mellitus, insulin-resistant diabetes mellitus, immune-mediated infertility, autoimmune Addison's disease, pemphigus vulgaris, pemphigus foliaceus, dermatitis herpetiformis, autoimmune alopecia, Vitiligo, autoimmune hemolytic anemia, autoimmune thrombocytopenic purpura, pernicious anemia, Guillain-Barre syndrome, acute rheumatic fever, sympathetic ophthalmia, Goodpasture's syndrome, systemic necrotizing vasculitis, antiphospholipid syndrome and allergies.
[00561 An undesirable or aberrant inflammatory response or inflammation may cause, directly or indirectly, cell, tissue or organ damage, either to multiple cells, tissues or organs, or specifically to a single cell type, tissue type or organ. Exemplary tissues and organs that can exhibit damage include epidermal or mucosal tissue, gut, bowel, pancreas, thymus, liver, kidney, spleen, skin, or a skeletal joint (e.g., knee, ankle, hip, shoulder, wrist, finger, toe, or elbow). Treatment in accordance with the invention can result in reducing, inhibiting or preventing progression or worsening of tissue damage.
Such treatments can in turn lead to regeneration or restoration of a damaged organ or tissue, e.g., skin, mucosum, liver.
[0057] Methods and uses of the invention include administering LIF polypeptide or subsequence thereof, or a LIF activator, in order to increase, stimulate enhance or promote an immune response in general. Such methods and uses can be used for treatment of chronic or acute immunosuppression or an immunocompromised subject, or an immunodeficiency.
[0058| Non-limiting examples of immunosuppression and immunodeficiency treatable in
accordance with the invention include severe combined immunodeficiency (SCID) such as recombinase activating gene (RAG 1/2) deficiency, adenosine deaminase (ADA) deficiency, interleukin receptor γ chain (yc) deficiency, Janus-associated kinase 3 (JA 3) deficiency and reticular dysgenesis; primary T cell immunodeficiency such as DiGeorge syndrome, Nude syndrome,
T cell receptor deficiency, MHC class II deficiency, TAP-2 deficiency (MHC class I deficiency),
ZAP70 tyrosine kinase deficiency and purine nucleotide phosphorylase (PNP) deficiency;
predominantly antibody deficiencies such as X-linked agammaglobulinemia (Bruton's tyrosine kinase deficiency); autosomal recessive agammaglobulinemia such as Mu heavy chain deficiency; surrogate light chain (γ5/14.1) deficiency; Hyper-IgM syndrome either X-linked (CD40 ligand deficiency) and others; Ig heavy chain gene deletion; IgA deficiency; deficiency of IgG subclasses
(with or without IgA deficiency); common variable immunodeficiency (CVID); antibody deficiency with normal immunoglobulins; transient hypogammaglobulinemia of infancy; interferon γ receptor
(IFNGR1 , IFNGR2) deficiency; interleukin 12 and interleukin 12 receptor deficiency;
immunodeficiency with thymoma; Wiskott-Aldrich syndrome (WAS protein deficiency); ataxia telangiectasia (ATM deficiency); X-linked lymphoproliferative syndrome (SH2D1 A/SAP
deficiency); and hyper IgE syndrome). Exemplary immunodeficiencies also include disorders associated with or secondary to another disease (e.g., chromosomal instability or defective repair such as Bloom syndrome, Xeroderma pigmentosum, Fanconi anemia, ICF syndrome, Nijmegen breakage syndrome and Seckel syndrome; chromosomal defects such as Down syndrome (Trisomy
21), Turner syndrome and Deletions or rings of chromosome 18 (18p- and 18q-); skeletal
abnormalities such as short-limbed skeletal dysplasia (short-limbed dwarfism) and cartilage-hair hypoplasia (metaphyseal chondroplasia); immunodeficiency associated with generalized growth retardation such as Schimke immuno-osseous dysplasia, Dubowitz syndrome, Kyphomelic dysplasia with SCID, Mulibrey's nannism, Growth retardation, facial anomalies and immunodeficiency and
Progeria (Hutchinson-Gilford syndrome); immunodeficiency with dermatologic defects such as ectrodactyly-ectodermal dysplasia-clefting syndrome, immunodeficiency with absent thumbs, anosmia and ichthyosis, partial albinism, Dyskeratosis congenita, Netherton syndrome, Anhidrotic ectodermal dysplasia, Papillon-Lefevre syndrome and congenital ichthyosis; hereditary metabolic defects such as acrodermatitis enteropathica, transcobalamin 2 deficiency, type 1 hereditary orotic
aciduria, intractable diarrhea, abnormal facies, trichorrhexis and immunodeficiency, methylmalonic acidemia, biotin dependent carboxylase deficiency, mannosidosis, glycogen storage disease, type lb, Chediak-Higashi syndrome; hypercatabolism of immunoglobulin such as familial hypercatabolism, intestinal lymphangiectasia; chronic muco-cutaneous candidiasis; hereditary or congenital hyposplenia or asplenia; and Ivermark syndrome.
[0059] Methods and uses of the invention include administering LIF polypeptide or subsequence thereof, or a LIF activator, in order to increase, stimulate enhance or promote a response elicited by vaccination or immunization. Such methods and uses can be used in particular with any pathogen infection to which a vaccination or immunization may be desired.
[0060] Pathogens include, without limitation, bacteria, virus, fungi and parasites.
[0061 J Non-limiting examples of a bacterial pathogens include Bordetella, Borellia, Brucella,
Burkholderia, Campylobacter, Chlamydia, Cosotridia, Heliobacter, Legionella, Listeria,
Mycobacterium, Mycoplasma, Neisseria, Pseudomonas, Rickettsia, Staphlyococcus, Streptococcus,
Salmonella, Shigella, Treponema, Vibrio, and Yersenia.
[0062] Non-limiting examples of viral pathogens include a poxvirus, herpesvirus, hepatitis virus, immunodeficiency virus, flavivirus, papilloma virus (PV), polyoma virus, rhabdovirus, a myxovirus, an arenavirus, a coronavirus, adenovirus, reovirus, picornavirus, togavirus, bunyavirus, parvovirus and retrovirus.
[0063] Non-limiting examples of poxvirus include vaccinia virus, Molluscum contagiosum, variola major or variola minor smallpox virus, cow pox, camel pox, sheep pox, and monkey pox.
[0064] Non-limiting examples of herpesvirus include alpha-herpesvirus, beta-herpesvirus, gamma- herpesvirus, Epstein Bar Virus (EBV), Cytomegalovirus (CMV), varicella zoster virus (VZV/HHV- 3), and human herpes virus 1, 2, 4, 5, 6, 7, and 8 (HHV-8, Kaposi's sarcoma-associated virus).
[0065] Non-limiting examples of hepatitis virus include hepatitis A, B, C, D, E and G.
[0066] Non-limiting examples of immunodeficiency virus (HIV) include human HIV, such as HIV- l, HIV-2 and HIV-3.
[0067] Non-limiting examples of flavivirus include Yellow Fever virus, Dengue virus, Japanese Encephalitis and West Nile viruses.
[0068] Non-limiting examples of papilloma virus include a human papilloma virus (HPV), such as HPV strain 1, 6, 11, 16, 18, 30, 31, 42, 43, 44, 45, 51, 52, and 54.
[0069] Non-limiting examples of polyoma virus include BK virus (BKV) and JC virus (JCV).
[0070] Non-limiting examples of rhabdovirus include rabies virus and vesiculovirus.
[0071] Non-limiting examples of myxovirus include paramyxovirus and orthomyoxovirus. Non- limiting examples of paramyxovirus include measles, mumps, pneumovirus and respiratory syncytial virus (RSV).
[0072] Non-limiting examples of orthomyoxo virus include influenza virus, such as influenza A, influenza B and influenza C.
[0073] Non-limiting examples of arenavirus include lymphocytic choriomeningitis virus (LCMV), Junin virus, Lassa virus, Guanarito virus, Sabia virus and Machupo virus.
[0074] Non-limiting examples of coronavirus include a virus that causes a common cold, and severe acute respiratory syndrome (SARS).
[0075] Non-limiting examples of adenovirus include viral infections of bronchii, lung, stomach, intestine (gastroenteritis), eye (conjunctivitis), bladder (cystitis) and skin.
[0076] Non-limiting examples of reovirus include a rotavirus, cypovirus and orbivirus.
[0077] Non-limiting examples of picornavirus include a rhinovirus, apthovirus, hepatovirus, enterovirus and cardiovirus. Rhinovirus can cause the common cold.
[0078] Non-limiting examples of togavirus include alphavirus, sindbus virus, and rubellavirus.
[0079] Non-limiting examples of bunya virus include hantavirus, phlebo virus and nairo virus.
[0080] Non-limiting examples of retrovirus include an alpha, beta, delta, gamma, epsilon, lentivirus, spumavirus and human T-cell leukemia virus.
[0081] Non-limiting examples of lentivirus include an immunodeficiency virus, such as
immunodeficiency virus (e.g., a bovine, porcine, equine, canine, feline or primate virus).
[0082] Non-limiting examples of human T-cell leukemia viruses include human T-cell leukemia virus 1 and 2 (HTLV-1 and HTLV-2).
[0083] Non-limiting examples of a fungal pathogen include yeasts and molds. More particular examples include Candida, Aspergillus, Cryptococcus, Histoplasma, Pneumocysti and Stachybotrys.
[0084] Non-limiting examples of a parasite pathogen include protozoa. More particular examples include Plasmodium, which causes malaria, Leishmania, Toxoplasma and Trypanosoma.
[0085] Pathogens and pathogen antigens, useful in accordance with the invention methods include any pathogen or pathogen antigen, or live or attenuated or weakend pathogen, suitable as a vaccine or immunizing agent, which typically can or is likely to provide protection against the pathogen. Non-limiting examples include live pathogen, a pathogen antigen, pathogen extract, heat or ultraviolet light inactivated or attenuated or weakened pathogen.
[0086] In accordance with the invention, there are also provided LIF polypeptides and subsequences thereof that exhibit sequence identity to a reference LIF polypeptide or subsequence thereof, and which have an ability to modulate an immune response, for example, stimulates, induces, increases or enhances an immune response, development of memory T cells, Tfh (follicular helper) cell differentiation, Germinal center B cell development, an antibody response, or an immune response, such as a response induced by a vaccine, in vitro or in vivo. In one embodiment, a LIF polypeptide or subsequence thereof includes or consists of a sequence at least 60% or more (e.g., 65%, 70%,
75%, 80%, 85%, 90%, 95%, etc.) up to 100% identical to any LIF polypeptide or subsequence thereof (e.g., SEQ ID NO: l).
[0087] In another embodiment, a LIF polypeptide or subsequence thereof includes or consists of a LIF polypeptide or subsequence thereof set forth as SEQ ID NO: 1, wherein the LIF polypeptide or subsequence thereof has one or more amino acid additions, deletions or substitutions of SEQ ID NO: 1. In particular aspects, a LIF polypeptide or subsequence is at least 80% or more, e.g., 80-85%, 85-90%, 90-95%, 95-100% identical to a LIF polypeptide or subsequence thereof set forth in SEQ ID NO: l .
[0088] A non-limiting LIF sequence from which a LIF polypeptide or subsequence thereof can be based upon or share sequence identity with a human LIF sequence set forth as:
MKVLAAGVVPLLLVLHWKHGAGSPLPITPVNATCAIRHPCHNNLMNQIRSQLAQLNGSANALFILYY TAQGEPFPNNLDKLCGPNVTDFPPFHANGTEKAKLVELYRIVVYLGTSLGNITRDQKILNPSALSLH SKLNATADILRGLLSNVLCRLCSKYHVGHVDVTYGPDTSGKDVFQKKKLGCQLLGKYKQI IAVLAQA
F (SEQ ID NO: 1) .
[0089] The invention provides isolated LIF polypeptides, including or consisting of a LIF
subsequence, which exhibits sequence identity to a reference LIF polypeptide or subsequence thereof (e.g., SEQ ID NO: 1), and which has one or more functions or activities of full length LIF.
[0090] Such LIF subsequences can be from about 5 to 300 amino acids in length, for example, from 5 to 15, 20 to 25, 25, to 50, 50 to 100, 100 to 150, 150 to 200, or 200 to 300 amino acids in length, provided that said subsequence or portion is at least one amino acid less in length than a full-length LIF sequence (e.g., SEQ ID NO: l).
[0091] In particular embodiments, a subsequence of a LIF polypeptide sequence or subsequence inhibits, decreases or reduces Tfh (follicular helper) cell differentiation, Germinal center B cell development or an antibody response, inhibits, decreases or reduces development of memory T cells, inhibits, decreases or reduces an undesirable or aberrant immune response, inhibits, decreases or reduces an undesirable or aberrant inflammatory response or inflammation. In additional
embodiments, a LIF subsequence stimulates, induces or increases an immune response, or stimulates, induces or increases Tfh (follicular helper) cell differentiation, Germinal center B cell development, an antibody response, or development of memory T cells, or stimulates, induces or increases an immune response, such as a response induced by a vaccine (e.g., elicits, promotes or enhances an immune response against a vaccine antigen in vitro or in vivo).
[0092] The term "isolated," when used as a modifier of a composition (e.g., LIF polypeptides and subsequences thereof, etc.), means that the compositions are made by the hand of man or are separated, completely or at least in part, from their naturally occurring in vivo environment.
Generally, isolated compositions are substantially free of one or more materials with which they normally associate with in nature, for example, one or more protein, nucleic acid, lipid, carbohydrate,
cell membrane. The term "isolated" does not exclude alternative physical forms of the composition, such as fusions/chimeras, multimers/oligomers, modifications (e.g., phosphorylation, glycosylation, lipidation) or derivatized forms, or forms expressed in host cells produced by the hand of man.
[0093] An "isolated" composition (e.g., LIF polypeptide or subsequence thereof) can also be "substantially pure" or "purified" when free of most or all of the materials with which it typically associates with in nature. Thus, an isolated LIF polypeptide or subsequence thereof, that also is substantially pure or purified does not include polypeptides or polynucleotides present among millions of other sequences, such as peptides of an peptide library or nucleic acids in a genomic or cDNA library, for example. A "substantially pure" or "purified" composition can be combined with one or more other molecules. Thus, "substantially pure" or "purified" does not exclude
combinations of compositions, such as combinations of LIF polypeptide or subsequence thereof and adjuvants, vaccines (e.g., antigens), agents, drugs or therapies.
[0094] The term "chimeric" and grammatical variations thereof, when used in reference to a sequence, means that the amino acid sequence contains one or more portions that are derived from, obtained or isolated from, or based upon two or more different proteins. For example, a portion of the sequence may be a LIF polypeptide or subsequence thereof, and another portion of the sequence may be from a different peptide sequence, or a non-LIF polypeptide sequence.
[0095] LIF polypeptides and subsequences thereof of the invention include those having at least partial sequence identity to one or more exemplary LIF polypeptide or a subsequence thereof (e.g., SEQ ID NO: 1). The percent identity of such sequences can be as little as 60%, or can be greater (e.g., 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, etc.). The percent identity can extend over the entire sequence length or a portion of the sequence. In particular aspects, the length of the sequence sharing the percent identity is 2, 3, 4, 5 or more contiguous amino acids, e.g., 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, etc. contiguous amino acids. In additional particular aspects, the length of the sequence sharing the percent identity is 20 or more contiguous amino acids, e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, etc. contiguous amino acids. In further particular aspects, the length of the sequence sharing the percent identity is 35 or more contiguous amino acids, e.g., 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 45, 47, 48, 49, 50, etc., contiguous amino acids. In yet further particular aspects, the length of the sequence sharing the percent identity is 50 or more contiguous amino acids, e.g., 50-55, 55-60, 60-65, 65-70, 70-75, 75-80, 80-85, 85-90, 90-95, 95-100, 100-1 10, etc. contiguous amino acids.
[0096] The term "identity" and grammatical variations thereof, mean that two or more referenced entities are the same. Thus, where two LIF polypeptides or subsequences thereof are identical, they have the same amino acid sequence. The identity can be over a defined area (region or domain) of the sequence. "Areas, regions or domains" of homology or identity mean that a portion of two or more referenced entities share homology or are the same. The extent of identity between two
sequences can be ascertained using a computer program and mathematical algorithm known in the art. Such algorithms that calculate percent sequence identity (homology) generally account for sequence gaps and mismatches over the comparison region or area. For example, a BLAST (e.g. , BLAST 2.0) search algorithm (see, e.g., Altschul et al., J. Mol. Biol. 215:403 (1990), publicly available through NCBI) has exemplary search parameters as follows: Mismatch -2; gap open 5; gap extension 2. For polypeptide sequence comparisons, a BLASTP algorithm is typically used in combination with a scoring matrix, such as PAM100, PAM 250, BLOSUM 62 or BLOSUM 50. FASTA (e.g., FASTA2 and FASTA3) and SSEARCH sequence comparison programs are also used to quantitate the extent of identity (Pearson et al., Proc. Natl. Acad. Sci. USA 85:2444 (1988);
Pearson, Methods Mol Biol. 132: 185 (2000); and Smith et al., J. Mol. Biol. 147: 195 ( 1981 )).
Programs for quantitating protein structural similarity using Delaunay-based topological mapping have also been developed (Bostick et al., Biochem Biophys Res Commun. 304:320 (2003)).
[0097] In accordance with the invention, there are provided LIF polypeptides and subsequences thereof that include modified and variant forms. As used herein, the terms "modify" or "variant" and grammatical variations thereof, mean that a LIF polypeptide or subsequence thereof deviates from a reference LIF sequence (e.g., SEQ ID NO: 1). Modified and variant LIF polypeptides and subsequences thereof may therefore have greater or less activity or function than a reference LIF polypeptide, or subsequence thereof, but at least retain partial activity or function of the reference sequence (e.g., SEQ ID NO: l). Thus, LIF polypeptides and subsequences thereof include sequences having substantially the same, greater or less relative activity or function as SEQ ED NO:l, for example, an ability to stimulate, induce or increase Tfh (follicular helper) cell differentiation, Germinal center B cell development or an antibody response in vitro or in vivo, an ability to stimulate, induce or increase development of memory T cells in vitro or in vivo, an ability to inhibit, decrease or reduce an undesirable or aberrant immune response in vitro or in vivo, an ability to inhibit, decrease or reduce an undesirable or aberrant inflammatory response or inflammation in vitro or in vivo, an ability to stimulate, induce or increase an immune response in vitro or in vivo, or an ability to stimulate, induce or increase an immune response induced by a vaccine in vitro or in vivo (e.g., elicit, promote or enhance an immune response against a vaccine antigen in vitro or in vivo).
[0098] Non-limiting examples of modifications include one or more amino acid substitutions (e.g., 1-3, 3-5, 5-10, 10-15, 15-20, 20-25, or more residues), additions (e.g., insertions or 1-3, 3-5, 5-10, 10-15, 15-20, 20-25, or more residues) and deletions (e.g., subsequences or fragments) of a reference LIF polypeptide or subsequence thereof. In particular embodiments, a modified or variant sequence retains at least part of a function or an activity of unmodified sequence. Such modified forms and variants can have less than, the same, or greater, but at least a part of, a function or activity of a reference sequence, for example, as described herein.
[0099] Specific non-limiting examples of substitutions include conservative and non-conservative amino acid substitutions. A "conservative substitution" is the replacement of one amino acid by a biologically, chemically or structurally similar residue. Biologically similar means that the substitution does not destroy a biological activity. Structurally similar means that the amino acids have side chains with similar length, such as alanine, glycine and serine, or a similar size. Chemical similarity means that the residues have the same charge or are both hydrophilic or hydrophobic. Particular examples include the substitution of one hydrophobic residue, such as isoleucine, valine, leucine or methionine for another, or the substitution of one polar residue for another, such as the substitution of arginine for lysine, glutamic for aspartic acids, or glutamine for asparagine, serine for threonine, and the like.
[0100] A modification also includes one or more D-amino acids substituted for L-amino acids (and mixtures thereof), structural and functional analogues, for example, peptidomimetics having synthetic or non-natural amino acids or amino acid analogues and derivatized forms. Accordingly, polypeptides and peptides described herein further include compounds having amino acid structural and functional analogues, for example, peptidomimetics having synthetic or non-natural amino acids or amino acid analogues, so long as the mimetic has one or more functions or activities of a native polypeptide set forth herein. Non-natural and non-amide chemical bonds, and other coupling means can also be included, for example, glutaraldehyde, N-hydoxysuccinimide esters, bifunctional maleimides, or N, N'-dicyclohexylcarbodiimide (DCC). Non-amide bonds can include, for example, ketomethylene aminomethylene, olefin, ether, thioether and the like (see, e.g., Spatola (1983) in Chemistry and Biochemistry of Amino Acids. Peptides and Proteins, Vol. 7, pp 267-357, "Peptide and Backbone Modifications," Marcel Decker, NY).
[0101] Modifications include cyclic structures such as an end-to-end amide bond between the amino and carboxy-terminus of the molecule or intra- or inter-molecular disulfide bond.
[0102] Polypeptides, peptides and peptidomimetics can be produced and isolated using methods known in the art. Peptides can be synthesized, whole or in part, using chemical methods known in the art (see, e.g., Caruthers (1980). Nucleic Acids Res. Symp. Ser. 215; Horn (1980); and Banga,
A.K., Therapeutic Peptides and Proteins, Formulation, Processing and Delivery Systems (1995)
Technomic Publishing Co., Lancaster, PA). Peptide synthesis can be performed using various solid phase techniques (see, e.g., Roberge Science 269:202 (1995); Merrifield, Methods
Enzymol. 289:3(1997)) and automated synthesis may be achieved, e.g., using the ABI 431A Peptide
Synthesizer (Perkin Elmer) in accordance with the manufacturer's instructions. Peptides and peptide mimetics can also be synthesized using combinatorial methodologies. Synthetic residues and polypeptides incorporating mimetics can be synthesized using a variety of procedures and methodologies known in the art (see, e.g.. Organic Syntheses Collective Volumes, Gilman, et al. (Eds) John Wiley & Sons, Inc., NY). Modified peptides can be produced by chemical
modification methods (see, for example, Belousov, Nucleic Acids Res. 25:3440 (1997); Frenkel, Free Radic. Biol. Med. 19:373 ( 1995); and Blommers, Biochemistry 33:7886 (1994).
[0103] An addition can be the covalent or non-covalent attachment of any type of molecule to the sequence. Specific examples of additions include glycosylation, acetylation, phosphorylation, amidation, formylation, ubiquitination, and derivatization by protecting/blocking groups and any of numerous chemical modifications. Additional specific non-limiting examples of an addition include one or more additional amino acid residues. In particular embodiments, an addition is a fusion (chimeric) sequence, an amino acid sequence having one or more molecules not normally present in a reference native (wild type) sequence covalently attached to the sequence. A particular example is an amino acid sequence of another sequence to produce a chimera.Another particular example of a modified sequence having an amino acid addition is one in which a second heterologous sequence, i.e., heterologous functional domain is attached (covalent or non-covalent binding) that confers a distinct or complementary function. Heterologous functional domains are not restricted to amino acid residues. Thus, a heterologous functional domain can consist of any of a variety of different types of small or large functional moieties. Such moieties include nucleic acid, peptide,
carbohydrate, lipid or small organic compounds, such as a drug (e.g., an antiviral), a metal (gold, silver), radioisotope. Thus, in other embodiments the invention provides LIF polypeptides and subsequences thereof and a heterologous domain, wherein the domain confers a distinct function, i.e. a heterologous functional domain.
[0104] Further non-limiting examples of additions are detectable labels. Thus, in another embodiment, the invention provides LIF polypeptides and subsequences thereof that are detectably labeled. Specific examples of detectable labels include fluorophores, chromophores, radioactive isotopes (e.g., S35, P32, 1125), electron-dense reagents, enzymes, ligands and receptors. Enzymes are typically detected by their activity. For example, horseradish peroxidase is usually detected by its ability to convert a substrate such as 3,3-',5,5-'-tetramethylbenzidine (TMB) to a blue pigment, which can be quantified.
[0105] Another non-limiting example of an addition is an insertion of an amino acid within any sequence of LIF polypeptides and subsequences thereof (e.g., SEQ ID NO: l ). In a particular embodiment, an insertion is of one or more amino acid residues in a LIF polypeptide or subsequence thereof (e.g., SEQ ID NO: l).
[0106] Modified LIF polypeptides and subsequences thereof also include one or more D-amino acids substituted for L-amino acids (and mixtures thereof), structural and functional analogues, for example, peptidomimetics having synthetic or non-natural amino acids or amino acid analogues and derivatized forms.
[0107] LIF polypeptides and subsequences thereof including modified forms can be produced by any of a variety of standard protein purification or recombinant expression techniques. For example,
a LIF polypeptide or subsequence thereof can be produced by standard peptide synthesis techniques, such as solid-phase synthesis. A portion of the protein may contain an amino acid sequence such as a T7 tag or polyhistidine sequence to facilitate purification of expressed or synthesized protein. The protein may be expressed in a cell and purified. The protein may be expressed as a part of a larger protein (e.g., a fusion or chimera) by recombinant methods.
[0108] LIF polypeptides and subsequences thereof including modified forms can be made using recombinant DNA technology via cell expression or in vitro translation. Polypeptide sequences including modified forms can also be produced by chemical synthesis using methods known in the art, for example, an automated peptide synthesis apparatus (see, e.g., Applied Biosystems, Foster City, CA).
|0109] In accordance with the invention, there are provided host cells that express LIF polypeptides and subsequences thereof. Host cells include but are not limited to prokaryotic and eukaryotic cells such as bacteria, fungi (yeast), plant, insect, and animal (e.g., mammalian, including primate and human, CHO cells and hybridomas) cells. For example, bacteria transformed with recombinant bacteriophage nucleic acid, plasmid nucleic acid or cosmid nucleic acid expression vectors; yeast transformed with recombinant yeast expression vectors; plant cell systems infected with recombinant virus expression vectors (e.g., cauliflower mosaic virus, CaMV; tobacco mosaic virus, TMV) or transformed with recombinant plasmid expression vectors (e.g., Ti plasmid); insect cell systems infected with recombinant virus expression vectors (e.g., baculovirus); and animal cell systems infected with recombinant virus expression vectors (e.g., retroviruses, adenovirus, vaccinia virus), or transformed animal cell systems engineered for stable expression. The cells may be a primary cell isolate, cell culture (e.g., passaged, established or immortalized cell line), or part of a plurality of cells, or a tissue or organ ex vivo or in a subject (in vivo).
[0110] The term "transformed" or "transfected" when used in reference to a cell (e.g., a host cell) or organism, means a genetic change in a cell following incorporation of an exogenous molecule, for example, a protein or nucleic acid (e.g., a transgene) into the cell. Thus, a "transfected" or
"transformed" cell is a cell into which, or a progeny thereof in which an exogenous molecule has been introduced by the hand of man, for example, by recombinant DNA techniques.
[0111] A LIF nucleic acid or protein can be stably or transiently transfected or transformed
(expressed) into the host cell and progeny thereof. The cell(s) can be propagated and the introduced protein expressed, or nucleic acid transcribed. A progeny of a transfected or transformed cell may not be identical to the parent cell, since there may be mutations that occur during replication.
[0112] Introduction of nucleic acid into target cells (e.g., host cells) can be carried out by methods known in the art such as osmotic shock (e.g., calcium phosphate), electroporation, microinjection, cell fusion, etc. Introduction of nucleic acid and polypeptide in vitro, ex vivo and in vivo can also be accomplished using other techniques. For example, a polymeric substance, such as polyesters,
polyamine acids, hydrogel, polyvinyl pyrrolidone, ethylene-vinylacetate, methylcellulose, carboxymethylcellulose, protamine sulfate, or lactide/glycolide copolymers, polylactide/glycolide copolymers, or ethylenevinylacetate copolymers. A nucleic acid can be entrapped in microcapsules prepared by coacervation techniques or by interfacial polymerization, for example, by the use of hydroxymethylcellulose or gelatin-microcapsules, or poly (methylmethacrolate) microcapsules, respectively, or in a colloid system. Colloidal dispersion systems include macromolecule complexes, nano-capsules, microspheres, beads, and lipid-based systems, including oil-in-water emulsions, micelles, mixed micelles, and liposomes.
[0113] Liposomes for introducing various compositions into cells are known in the art and include, for example, phosphatidylcholine, phosphatidylserine, lipofectin and DOTAP (e.g., U.S. Patent Nos. 4,844,904, 5,000,959, 4,863,740, and 4,975,282; and GIBCO-BRL, Gaithersburg, MD). Piperazine based amphilic cationic lipids useful for gene therapy also are known (see, e.g., U.S. Patent No. 5,861,397). Cationic lipid systems also are known (see, e.g., U.S. Patent No. 5,459,127).
Polymeric substances, microcapsules and colloidal dispersion systems such as liposomes are collectively referred to herein as "vesicles."
[0114] In accordance with the invention, treatment methods and uses are provided that include therapeutic and prophylactic methods and uses. Such methods and uses can, for example, stimulate, induce, increase, enhance, or inhibit, decrease or reduce, an immune response in a subject. In one embodiment, a method includes administering to a subject in need of treatment an amount of a LIF polypeptide or subsequence thereof, or a LIF activator or inhibitor, to treat the subject. In another embodiment, a method includes administering to a subject an amount of a LIF activator or inhibitor, or a LIF polypeptide or a subsequence thereof, sufficient to provide the subject with an immune response that is stimulated, induced, increased or enhanced, or inhibited, decreased or reduced.
[0115] Therapeutic and prophylactic methods of treating a subject with a LIF activator or inhibitor, or a LIF polypeptide or a subsequence thereof, include, for example, treatment of a subject having or at risk of having an immune disorder, such as an undesirable or aberrant immune response, inflammatory response, or inflammation. Such methods can treat the immune disorder, thereby providing the subject with a benefit.
[0116] In methods and uses of the invention, any LIF activator or inhibitor, or a LIF polypeptide or subsequence thereof, can be administered or used. Non-limiting examples include a LIF antibody or subsequence thereof, or a LIF polypeptide or subsequence thereof (e.g., of SEQ ID NO:l), or an amino acid insertion, addition or substitution thereof.
[0117] In particular methods and embodiments, treatment methods will modulate an immune response. Such modulation can stimulate, induce, increase or enhance, or inhibit, decrease or reduce, as needed. For example, proliferation, survival, differentiation, or activity of immune
responses or cells (e.g., T cells, B cells, macrophages, neutrophils, dendritic cells, etc.), can be modulated.
[0118] Methods of the invention include treatment methods, which result in any therapeutic or beneficial effect. In various methods embodiments, an immune response is stimulated, induced, increased or enhanced, or inhibited, decreased or reduced. Methods of the invention further include inhibiting, decreasing or reducing one or more adverse (e.g., physical) symptoms, disorders, illnesses, diseases or complications caused by or associated with the immune response, such as (e.g., swelling, fever, rash, headache, infiltration of tissue or organs with immune cells, muscle or joint pain, nausea, vomiting, loss of appetite, etc.).
[0119] A therapeutic or beneficial effect of treatment is therefore any objective or subjective measurable or detectable improvement or benefit provided to a particular subject. A therapeutic or beneficial effect can but need not be complete ablation of all or any particular adverse symptom, disorder, illness, disease or complication caused by or associated with an immune response in a subject. Thus, a satisfactory clinical endpoint is achieved when there is an incremental improvement or a partial reduction in an adverse symptom, disorder, illness, disease or complication caused by or associated with an immune response, or an inhibition, decrease, reduction, suppression, prevention, limit or control of worsening or progression of one or more adverse symptoms, disorders, illnesses, diseases or complications caused by or associated with the immune response, over a short or long duration (hours, days, weeks, months, etc.).
[0120] Accordingly, methods of the invention that include treatment of an inflammatory response or inflammation include reducing, inhibiting or preventing occurrence, progression, severity, frequency or duration of a symptom or characteristic of an inflammatory response or inflammation. At the whole body, regional or local level, an inflammatory response or inflammation is generally characterized by swelling, pain, headache, fever, nausea, skeletal joint stiffness or lack of mobility, rash, redness or other discoloration. At the cellular level, an inflammatory response or inflammation is characterized by one or more of cell infiltration of the region, production of antibodies (e.g., autoantibodies), production of cytokines, lymphokines, chemokines, interferons and interleukins, cell growth and maturation factors (e.g., differentiation factors), cell proliferation, cell
differentiation, cell accumulation or migration and cell, tissue or organ damage. Thus, treatment will reduce, inhibit or prevent occurrence, progression, severity, frequency or duration of any one or more of such symptoms or characteristics of an inflammatory response or inflammation.
[0121] A therapeutic or beneficial effect also includes reducing or eliminating the need, dosage frequency or amount of a second active such as another drug or other agent (e.g., small molecule, protein) used for treating a subject having or at risk of having an undesirable or aberrant immune response. For example, reducing an amount of an adjunct therapy, for example, a reduction or decrease of a treatment for an undesirable or aberrant immune response, inflammatory response or
inflammation is considered a beneficial effect. In addition, reducing or decreasing an amount of a pathogen (live or attenuated or weakened) or pathogen antigen used for vaccination or immunization of a subject to provide protection to the subject is considered a beneficial effect.
[0122] Methods and compositions of the invention also include increasing, stimulating, promoting, enhancing, augmenting or inducing an immune response in a subject. In one embodiment, a method includes administering to a subject an amount of a LIF activator, or a LIF polypeptide or subsequence thereof sufficient to increase, stimulate, promote, enhance, augment or induce an immune response in the subject. In another embodiment, a method includes administering to a subject an amount of a LIF activator, or a LIF polypeptide or subsequence thereof, and administering pathogen (live or attenuated or weakened) or pathogen antigen sufficient to increase, stimulate, promote, enhance, augment or induce anti-pathogen immune response in the subject.
[0123] Methods and compositions of the invention include administration of a LIF inhibitor (e.g., LIF antibody or inhibitory nucleic acid sequence, such as antisense RNA), or a LIF polypeptide or subsequence thereof, to a subject prior to an undesirable or aberrant immune response, inflammatory response or inflammation, administration prior to, substantially contemporaneously with or after a subject has been afflicted with an undesirable or aberrant immune response, inflammatory response or inflammation, and administration prior to, substantially contemporaneously with or after development of one or more adverse symptoms caused by or associated with an undesirable or aberrant immune response, inflammatory response or inflammation. A subject with an undesirable or aberrant immune response, inflammatory response or inflammation, may have a chronic or acute undesirable or aberrant immune response, inflammatory response or inflammation, for example, a period of days, months, or years.
[0124] Methods and compositions of the invention also include administration of a LIF activator or a LIF polypeptide or subsequence thereof to a subject prior to, substantially contemporaneously with or following a pathogen infection, or an adverse symptom, disorder, illness or disease caused by or associated with a pathogen infection or pathology. A subject infected with a pathogen may have a chronic or acute infection, for example, an infection for a period of days, months, or years.
[0125] Invention compositions (e.g., LIF polypeptides or subsequences thereof) and methods can be combined with any compound, agent, drug, treatment or other therapeutic regimen or protocol having a desired therapeutic, beneficial, additive, synergistic or complementary activity or effect. Exemplary combination compositions and treatments include second actives, such as anti-immune response, inflammatory response or inflammation compounds, agents and drugs, as well as agents that assist, promote, stimulate or enhance an immune response where desired. Such drugs, agents, treatments and therapies can be admimstered or performed prior to, substantially contemporaneously with or following any other method of the invention, for example, a therapeutic method of treating a
subject for an undesirable or aberrant immune response, inflammatory response or inflammation, or a method of vaccination or immunization.
[0126] A LIF activator or inhibitor, or a LIF polypeptide or subsequence thereof, can be
administered as a combination composition, or administered separately, such as concurrently or in series or sequentially (prior to or following) administering a second active, to a subject. The invention therefore provides combinations in which a method of the invention is used in a combination with any compound, agent, drug, therapeutic regimen, treatment protocol, process, remedy or composition, such as an anti-immune response, inflammatory response or inflammation, or an immune response stimulating, increasing, enhancing or augmenting protocol, such as pathogen vaccination or immunization set forth herein or known to one of skill in the art. The compound, agent, drug, therapeutic regimen, treatment protocol, process, remedy or composition can be administered or performed prior to, substantially contemporaneously with or following
administration of a LIF activator or inhibitor, or a LIF polypeptide or subsequence or thereof, to a subject. Specific non-limiting examples of combination embodiments therefore include the foregoing or other compound, agent, drug, therapeutic regimen, treatment protocol, process, remedy or composition.
[0127] Combination methods embodiments include, for example, second actives such as antiinflammatory or anti-inflammation agents and drugs and immune stimulating agents and drugs. Combination methods embodiments also include, for example, second actives such as anti-pathogen drugs (e.g., protease inhibitors, reverse transcriptase inhibitors, virus fusion inhibitors and virus entry inhibitors, antibodies to pathogen, live or attenuated or weakened pathogen, or a nucleic acid encoding all or a portion (e.g., an epitope) of any protein or proteinaceous pathogen antigen) immune stimulating agents and drugs, etc.
[0128] Particular non-limiting examples of anti-inflammatory, anti-inflammation and anti- autoimmune disease agents include immunosuppressive agents such as corticosteroids (steroid receptor agonists) including budesonide, prednisone, flunisolide, flunisolide hydrofluoroalkane, estrogen, progesterone, dexamethasone and loteprednol; beta-agonists (e.g., short or long-acting) such as bambuterol, formoterol, salmeterol, albuterol; anticholinergics such as ipratropium bromide, oxitropium bromide, cromolyn and calcium-channel blocking agents; antihistamines such as terfenadine, astemizole, hydroxyzine, ΰΜο ηεηήβητίηβ, tripelennamine, cetirizine, desloratadine, mizolastine, fexofenadine, olopatadine hydrochloride, norastemizole, levocetirizine, levocabastine, azelastine, ebastine and loratadine; antileukotnenes (e.g., anti-cysteinyl leukotrienes (CysLTs)) such as oxatomide, montelukast, zafirlukast and zileuton; phosphodiesterase inhibitors (e.g., PDE4 subtype) such as ibudilast, cilomilast, BAY 19-8004, theophylline (e.g., sustained-release) and other xanthine derivatives (e.g., doxofylline); thromboxane antagonists such as seratrodast, ozagrel hydrochloride and ramatroban; prostaglandin antagonists such as COX-1 and COX-2 inhibitors (e.g.,
celecoxib and rofecoxib), aspirin; potassium channel openers; and methotrexate (anti-metabolite), mycophenolate mofetil (purine biosynthesis inhibitor), and hydroxychloroquine (anti-malarial).
[0129] Additional specific examples of anti-inflammatory and anti-inflammation agents include antibodies, receptors or receptor ligands, such as anti-IgE (e.g., rhuMAb-E25 omalizumab), -IgA and - IgG antibodies; antibodies and soluble receptors against cytokines such as IL-1 , IL-4, IL-5, EL-6, IL-9, IL-13, IL-16, and IL-21 or growth factors such as granulocyte/macrophage colony-stimulating factor; cytokines such as IL-10; mucolytics (depolymerize polymers of mucin or DNA/actin, or increase cough clearance) such as ambroxol and N-acetylcysteine; expectorants; and allergens (allergan
immunotherapy) .
[0130] Methods of the invention also include, among other things, methods that result in a reduced need or use of another compound, agent, drug, therapeutic regimen, treatment protocol, process, or remedy. For example, for an undesirable or aberrant immune response, inflammatory response or inflammation, a method of the invention has a therapeutic benefit if in a given subject a less frequent or reduced dose or elimination of another anti-inflammatory or anti-inflammation compound, agent, drug, therapeutic regimen, treatment protocol, process, or remedy. For example, for vaccination or immunization, a method of the invention has a therapeutic benefit if in a given subject a less frequent or reduced dose or elimination of a vaccine. Thus, in accordance with the invention, methods of reducing need or use of another treatment or therapy are provided.
[0131] In invention methods in which there is a desired outcome, such as a therapeutic or prophylactic method that provides a benefit from treatment, vaccination or immunization with a LIF activator or inhibitor, or a LIF polypeptide or subsequence thereof can be administered in a sufficient or effective amount. As used herein, a "sufficient amount" or "effective amount" or an "amount sufficient" or an "amount effective" refers to an amount that provides, in single or multiple doses, alone or in combination with one or more other compounds, treatments, therapeutic regimens or agents (e.g., a drug), a long term or a short term detectable or measurable improvement in a given subject or any objective or subjective benefit to a given subject of any degree or for any time period or duration (e.g., for minutes, hours, days, months, years, or cured).
[0132] An amount sufficient or an amount effective can but need not be provided in a single administration and can but need not be achieved by a LIF activator or inhibitor, or a LIF polypeptide or subsequence thereof, alone, in a combination composition or method that includes a second active. In addition, an amount sufficient or an amount effective need not be sufficient or effective if given in single or multiple doses without a second or additional administration or dosage, since additional doses, amounts or duration above and beyond such doses, or additional antigens, compounds, drugs, agents, treatment or therapeutic regimens may be included in order to provide a given subject with a detectable or measurable improvement or benefit to the subject.
|0133] An amount sufficient or an amount effective need not be therapeutically or prophylactically effective in each and every subject treated, nor a majority of subjects treated in a given group or population. An amount sufficient or an amount effective means sufficiency or effectiveness in a particular subject, not a group of subjects or the general population. As is typical for such methods, different subjects will exhibit varied responses to treatment.
[0134| In the case of an undesirable or aberrant immune response, treatment methods include reducing or increasing numbers or an activity of immune cells (e.g., lymphocytes, T cells, antigen presenting cells, B cells, etc.) towards physiologically normal baseline levels. Similarly, a reduction or decrease of circulating antibodies (e.g., auto-antibodies) towards normal is considered a successful treatment outcome.
[0135] Additional examples of a therapeutic benefit for an undesirable or aberrant immune response, immune disorder or immune disease is an improvement in a histopathological change caused by or associated with the immune response, disorder or disease. For example, preventing further or reducing skeletal joint infiltration or tissue destruction, or pancreas, thymus, kidney, liver, spleen, epidermal (skin) or mucosal tissue tissue, gut or bowel infiltration or tissue destruction.
[0136] The term "subject" refers to an animal, typically a mammalian animal (mammal), such as humans, non-human primates (apes, gibbons, gorillas, chimpanzees, orangutans, macaques), a domestic animal (dogs and cats), a farm animal (poultry such as chickens and ducks, horses, cows, goats, sheep, pigs), and experimental animals (mouse, rat, rabbit, guinea pig). Subjects include animal disease models, for example, mouse and other animal models of inflammation, undesirable and aberrant immune responses, inflammatory and autoimmune diseases and others known to those of skill in the art (e.g., CIA, BXSB, EAE and SCDD murine models).
[0137] Subjects appropriate for treatment include those having or at risk of having an undesirable or aberrant immune response, inflammatory response or inflammation, or vaccination or immunization, or a pathogen infection. Target subjects therefore include subjects that have an undesirable or aberrant immune response, inflammatory response or inflammation, or have been or are in need of vaccination or immunization, or have been exposed to or contacted with a pathogen, regardless of the type, timing or degree of onset, progression, severity, frequency, duration of the symptoms.
[0138] The invention methods are therefore applicable to treating a subject who is at risk of undesirable or aberrant immune response, inflammatory response or inflammation, or vaccination or immunization, or a pathogen infection, but may not have a symptom of an undesirable or aberrant immune response, inflammatory response or inflammation, or a pathogen infection, or have been exposed to or contacted with the pathogen. Prophylactic methods are therefore included. Such subjects are considered in need of treatment due to being at risk.
[0139] Target subjects need not be at increased risk but may be from the general population in which it is desired to inhibit, decrease or reduce an undesirable or aberrant immune response,
inflammatory response or inflammation, or vaccination or immunization, or a pathogen infection. For example, a child such as an infant or toddler in which it is desired to vaccinate or immunize against a pathogen can be administered a LIF activator or inhibitor, or a LIF polypeptide or subsequence thereof, alone or in combination with a pathogen antigen. In another non-limiting example, a subject that is not specifically at risk of an undesirable or aberrant immune response, inflammatory response or inflammation, or vaccination or immunization, or pathogen infection, exposure to or contact, but nevertheless desires protection from an undesirable or aberrant immune response, inflammatory response or inflammation, or a pathogen infection or pathology, can be administered a LIF activator or inhibitor, or a LIF polypeptide or subsequence thereof. Such subjects are also considered in need of treatment.
[0140] Target subjects also include subjects having or at risk of having immunosuppression or are immunocompromised or have or are at risk of an immunodeficiency . Specific non-limiting examples of such subjects have or at risk of having an immunodeficiency, such as that caused by chemotherapy or radiotherapy (ionizing or chemical) or immune-suppressive therapy following a transplant (e.g., organ or tissue such as heart, liver, lung, bone marrow, etc.). Additional non- limiting examples include subjects having or at risk of having a graft vs. host disease, e.g., a subject that is a candidate for a transplant or a subject undergoing or having received a transplant.
[0141] At risk subjects appropriate for treatment also include subjects exposed to environments in which subjects are at risk of a pathogen infection. Subjects appropriate for treatment therefore include human subjects exposed to pathogens.
[0142 J "Prophylaxis" and grammatical variations thereof mean a method in which contact, administration or in vivo delivery to a subject is prior to an undesirable or aberrant immune response, inflammatory response or inflammation, or vaccination or immunization, or exposure to or contact with a pathogen. Administration or in vivo delivery to a subject can be performed prior to development of an adverse symptom, condition, complication, etc. caused by or associated with undesirable or aberrant immune response, inflammatory response or inflammation, or vaccination or immunization, or pathogen infection. In such case, a method can eliminate, prevent, inhibit, suppress, limit, decrease or reduce the probability of an undesirable or aberrant immune response, inflammatory response or inflammation, or a pathogen infection or susceptibility.
[0143] Administration of a LIF activator or inhibitor, or a LIF polypeptide or subsequence thereof, for treatment of an undesirable or aberrant immune response, inflammatory response or
inflammation, vaccination or immunization, or a pathogen infection can be at any time. Methods of the invention may be practiced by any mode of administration or delivery, or by any route, via systemic, regional and local administration or delivery. For example, a LIF activator or inhibitor, or a LIF polypeptide or subsequence, may be administered systemically, regionally or locally, intravenously, orally (e.g., ingestion or inhalation), intramuscularly, intraperitoneally, intradermally,
subcutaneously, intracavity, intracranially, transdermally (topical), parenterally, e.g. transmucosally or rectally. Exemplary administration and delivery routes include intravenous (i.v.), intraperitoneal (i.p.), intrartenal, intramuscular, parenteral, subcutaneous, intra-pleural, topical, dermal, intradermal, transdermal, transmucosal, intra-cranial, intra-spinal, rectal, oral (alimentary), mucosal, inhalation, respiration, intranasal, intubation, intrapulmonary, intrapulmonary instillation, buccal, sublingual, intravascular, intrathecal, intracavity, iontophoretic, intraocular, ophthalmic, optical, intraglandular, intraorgan, intralymphatic.
[01441 A LIF activator or inhibitor, or a LIF polypeptide or subsequence thereof, can be
administered as a combination (e.g., with a second active), or separately concurrently or in sequence (sequentially or serially) in accordance with the methods as a single or multiple dose e.g., one or more times hourly, daily, weekly, monthly or annually or between about 1 to 10 weeks, or for as long as appropriate, for example, to achieve a desired effect or activity. Thus, a method can be practiced one or more times (e.g., 1-10, 1-5 or 1-3 times) an hour, day, week, month, or year. The skilled artisan will know when it is appropriate to delay or discontinue administration. A non- limiting dosage schedule is 1-7 times per week, for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20 or more weeks, and any numerical value or range or value within such ranges.
[0145] Doses can be based upon current existing protocols, empirically determined, using animal disease models or optionally in human clinical trials. Initial study doses can be based upon animal studies set forth herein, for a mouse, which weighs about 30 grams, and the amount of a LIF activator or inhibitor, or a LIF polypeptide or subsequence thereof administered that is determined to be effective. Exemplary non-limiting amounts (doses) are in a range of about 0.1 mg/kg to about 100 mg/kg, and any numerical value or range or value within such ranges. Greater or lesser amounts (doses) can be administered, for example, 0.01-500 mg/kg, and any numerical value or range or value within such ranges. The dose can be adjusted according to the mass of a subject, and will generally be in a range from about 1-10 ug/kg, 10-25 ug/kg, 25-50 ug/kg, 50-100 ug/kg, 100-500 ug/kg, 500-1,000 ug/kg, 1-5 mg/kg, 5-10 mg/kg, 10-20 mg/kg, 20-50 mg/kg, 50-100 mg/kg, 100-250 mg/kg, 250-500 mg/kg, or more, two, three, four, or more times per hour, day, week, month or annually. A typical range will be from about 0.3 mg/kg to about 50 mg/kg, 0-25 mg/kg, or 1.0-10 mg/kg, or any numerical value or range or value within such ranges.
[0146] Doses can vary and depend upon whether the treatment is prophylactic or therapeutic, the type, onset, progression, severity, frequency, duration, or probability of the undesirable or aberrant immune response, inflammatory response or inflammation, vaccination or immunization, or pathogen infection to which treatment is directed, the clinical endpoint desired, previous or simultaneous treatments, the general health, age, gender, race or immunological competency of the subject and other factors that will be appreciated by the skilled artisan. The skilled artisan will
appreciate the factors that may influence the dosage and timing required to provide an amount sufficient for providing a therapeutic or prophylactic benefit.
[0147] Typically, for therapeutic treatment, a LIF activator or inhibitor, or a LIF polypeptide or subsequence thereof will be administered as soon as practical, typically within 1-2, 2-4, 4-12, 12-24 or 24-72 hours after a subject has a symptom or is exposed to or contacted with a pathogen, or within 1 -2, 2-4, 4-12, 12-24 or 24-48 hours after onset or development of one or more adverse symptoms, conditions, pathologies, complications, etc., associated with or caused by. For prophylactic treatment in connection with vaccination or immunization, a LIF activator or inhibitor, or a LIF polypeptide or subsequence thereof can be administered for a duration of 0-4 weeks, e.g., 2-3 weeks, prior to exposure to, contact or infection with pathogen, or at least within 1-2, 2-4, 4-12, 12-24, 24- 48 or 48-72 hours prior to exposure to, contact or infection with pathogen. For an acute or chronic undesirable or aberrant immune response, inflammatory response or inflammation, or vaccination or immunization, or a pathogen infection, a LIF activator or inhibitor, or a LIF polypeptide or subsequence thereof, is administered at any appropriate time.
[0148] The dose amount, number, frequency or duration may be proportionally increased or reduced, as indicated by the status of the subject. The dose amount, number, frequency or duration may also be proportionally increased or reduced, as indicated by any adverse side effects, complications or other risk factors of the treatment or therapy.
[0149] LIF activators, inhibitors, and LIF polypeptides and subsequences thereof can be
incorporated into pharmaceutical compositions, e.g., a pharmaceutically acceptable carrier or excipient. Such pharmaceutical compositions are useful for, among other things, administration to a subject in vivo or ex vivo.
[0150] As used herein the term "pharmaceutically acceptable" and "physiologically acceptable" mean a biologically acceptable formulation, gaseous, liquid or solid, or mixture thereof, which is suitable for one or more routes of administration, in vivo delivery or contact. Such formulations include solvents (aqueous or non-aqueous), solutions (aqueous or non-aqueous), emulsions (e.g., oil- in-water or water-in-oil), suspensions, syrups, elixirs, dispersion and suspension media, coatings, isotonic and absorption promoting or delaying agents, compatible with pharmaceutical
administration or in vivo contact or delivery. Aqueous and non-aqueous solvents, solutions and suspensions may include suspending agents and thickening agents. Such pharmaceutically acceptable carriers include tablets (coated or uncoated), capsules (hard or soft), microbeads, powder, granules and crystals. Supplementary active compounds (e.g., preservatives, antibacterial, antiviral and antifungal agents) can also be incorporated into the compositions.
[0151] Pharmaceutical compositions can be formulated to be compatible with a particular route of administration. Thus, pharmaceutical compositions include carriers, diluents, or excipients suitable for administration by various routes. Exemplary routes of administration for contact or in vivo
delivery which a composition can optionally be formulated include inhalation, respiration, intranasal, intubation, intrapulmonary instillation, oral, buccal, intrapulmonary, intradermal, topical, dermal, parenteral, sublingual, subcutaneous, intravascular, intrathecal, intraarticular, intracavity, transdermal, iontophoretic, intraocular, opthalmic, optical, intravenous (i.v.), intramuscular, intraglandular, intraorgan, intralymphatic.
[0152] Formulations suitable for parenteral administration comprise aqueous and non-aqueous solutions, suspensions or emulsions of the active compound, which preparations are typically sterile and can be isotonic with the blood of the intended recipient. Non-limiting illustrative examples include water, saline, dextrose, fructose, ethanol, animal, vegetable or synthetic oils.
[0153] For transmucosal or transdermal administration (e.g., topical contact), penetrants can be included in the pharmaceutical composition. Penetrants are known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. For transdermal administration, the active ingredient can be formulated into aerosols, sprays, ointments, salves, gels, or creams as generally known in the art. For contact with skin, pharmaceutical compositions typically include ointments, creams, lotions, pastes, gels, sprays, aerosols, or oils. Carriers which may be used include Vaseline, lanolin, polyethylene glycols, alcohols, transdermal enhancers, and combinations thereof.
[0154] Cosolvents and adjuvants may be added to the formulation. Non-limiting examples of cosolvents contain hydroxyl groups or other polar groups, for example, alcohols, such as isopropyl alcohol; glycols, such as propylene glycol, polyethyleneglycol, polypropylene glycol, glycol ether; glycerol; polyoxyethylene alcohols and polyoxyethylene fatty acid esters. Adjuvants include, for example, surfactants such as, soya lecithin and oleic acid; sorbitan esters such as sorbitan trioleate; and polyvinylpyrrolidone.
[0155] Supplementary compounds (e.g., preservatives, antioxidants, antimicrobial agents including biocides and biostats such as antibacterial, antiviral and antifungal agents) can also be incorporated into the compositions. Pharmaceutical compositions may therefore include preservatives, antioxidants and antimicrobial agents.
[0156] Preservatives can be used to inhibit microbial growth or increase stability of ingredients thereby prolonging the shelf life of the pharmaceutical formulation. Suitable preservatives are known in the art and include, for example, EDTA, EGTA, benzalkonium chloride or benzoic acid or benzoates, such as sodium benzoate. Antioxidants include, for example, ascorbic acid, vitamin A, vitamin E, tocopherols, and similar vitamins or provitamins.
[0157] An antimicrobial agent or compound directly or indirectly inhibits, reduces, delays, halts, eliminates, arrests, suppresses or prevents contamination by or growth, infectivity, replication, proliferation, reproduction, of a pathogenic or non- pathogenic microbial organism. Classes of antimicrobials include, antibacterial, antiviral, antifungal and antiparasitics. Antimicrobials include
agents and compounds that kill or destroy (-cidal) or inhibit (-static) contamination by or growth, infectivity, replication, proliferation, reproduction of the microbial organism.
[0158j Exemplary antibacterials (antibiotics) include penicillins (e.g., penicillin G, ampicillin, methicillin, oxacillin, and amoxicillin), cephalosporins (e.g., cefadroxil, ceforanid, cefotaxime, and ceftriaxone), tetracyclines (e.g., doxycycline, chlortetracycline, minocycline, and tetracycline), aminoglycosides (e.g., amikacin, gentamycin, kanamycin, neomycin, streptomycin, netilmicin, paromomycin and tobramycin), macrolides (e.g., azithromycin, clarithromycin, and erythromycin), fluoroquinolones (e.g., ciprofloxacin, lomefloxacin, and norfloxacin), and other antibiotics including chloramphenicol, clindamycin, cycloserine, isoniazid, rifampin, vancomycin, aztreonam, clavulanic acid, imipenem, polymyxin, bacitracin, amphotericin and nystatin.
[0159] Particular non-limiting classes of anti-virals include reverse transcriptase inhibitors; protease inhibitors; thymidine kinase inhibitors; sugar or glycoprotein synthesis inhibitors; structural protein synthesis inhibitors; nucleoside analogues; and viral maturation inhibitors. Specific non-limiting examples of anti-virals include nevirapine, delavirdine, efavirenz, saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, zidovudine (AZT), stavudine (d4T), larnivudine (3TC), didanosine (DDI), zalcitabine (ddC), abacavir, acyclovir, penciclovir, ribavirin, valacyclovir, ganciclovir, 1,-D- ribofuranosyl-l ,2,4-triazole-3 carboxamide, 9->2-hydroxy-ethoxy methylguanine, adamantanamine, 5-iodo-2'-deoxyuridine, trifluorothymidine, interferon and adenine arabinoside.
[0160] Pharmaceutical formulations and delivery systems appropriate for the compositions and methods of the invention are known in the art (see, e.g., Remington: The Science and Practice of Pharmacy (2003) 20th ed., Mack Publishing Co., Easton, PA; Remington's Pharmaceutical Sciences (1990) 18th ed., Mack Publishing Co., Easton, PA; The Merck Index (1996) 12th ed., Merck
Publishing Group, Whitehouse, NJ; Pharmaceutical Principles of Solid Dosage Forms (1993), Technonic Publishing Co., Inc., Lancaster, Pa.; Ansel and Stoklosa, Pharmaceutical Calculations (2001) 1 1th ed., Lippincott Williams & Wilkins, Baltimore, MD; and Poznansky et al, Drug Delivery Systems (1980), R. L. Juliano, ed., Oxford, N.Y., pp. 253-315).
[0161] A LIF activator or inhibitor, or a LIF polypeptide or subsequence thereof, along with any adjunct agent, compound drug, composition, whether active or inactive, etc., can be packaged in unit dosage form (capsules, tablets, troches, cachets, lozenges) for ease of administration and uniformity of dosage. A "unit dosage form" as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active ingredient optionally in association with a pharmaceutical carrier (excipient, diluent, vehicle or filling agent) which, when administered in one or more doses, is calculated to produce a desired effect (e.g., prophylactic or therapeutic effect). Unit dosage forms also include, for example, ampules and vials, which may include a composition in a freeze-dried or lyophilized state; a sterile liquid carrier, for example, can be added prior to administration or delivery in vivo. Unit dosage
forms additionally include, for example, ampules and vials with liquid compositions disposed therein. Individual unit dosage forms can be included in multi-dose kits or containers.
Pharmaceutical formulations can be packaged in single or multiple unit dosage form for ease of administration and uniformity of dosage.
[0162] The invention provides kits that include LIF activators, inhibitors, LIF polypeptides and subsequences thereof, optionally with a second active, and pharmaceutical formulations thereof, packaged into suitable packaging material. A kit typically includes a label or packaging insert including a description of the components or instructions for use in vitro, in vivo, or ex vivo, of the components therein. A kit can contain a collection of such components, e.g., a LIF polypeptide or subsequence thereof and optionally a second active, such as another compound, agent, drug or composition.
[0163] The term "packaging material" refers to a physical structure housing the components of the kit. The packaging material can maintain the components sterilely, and can be made of material commonly used for such purposes (e.g., paper, corrugated fiber, glass, plastic, foil, ampules, vials, tubes, etc.).
[0164] Kits of the invention can include labels or inserts. Labels or inserts can include information identifying manufacturer, lot numbers, manufacturer location and date, expiration dates. Labels or inserts include "printed matter," e.g., paper or cardboard, or separate or affixed to a component, a kit or packing material (e.g., a box), or attached to an ampule, tube or vial containing a kit component. Labels or inserts can additionally include a computer readable medium, such as a bar-coded printed label, a disk, optical disk such as CD- or DVD-ROM/RAM, DVD, MP3, magnetic tape, or an electrical storage media such as RAM and ROM or hybrids of these such as magnetic/optical storage media, FLASH media or memory type cards.
[0165] Labels or inserts can include identifying information of one or more components therein, dose amounts, clinical pharmacology of the active ingredient(s) including mechanism of action, pharmacokinetics and pharmacodynamics. Labels or inserts can include information identifying manufacturer information, lot numbers, manufacturer location and date.
[0166] Labels or inserts can include information on a condition, disorder or disease (e.g., viral infection, vaccination or immunization) for which a kit component may be used. Labels or inserts can include instructions for the clinician or subject for using one or more of the kit components in a method, or treatment protocol or therapeutic regimen. Instructions can include dosage amounts, frequency or duration, and instructions for practicing any of the methods, treatment protocols or prophylactic or therapeutic regimes described herein. Exemplary instructions include, instructions for administering a LIF activator or inhibitor, or a LIF polypeptide or subsequence thereof.
[0167] Labels or inserts can include information on any benefit that a component may provide, such as a prophylactic or therapeutic benefit. Labels or inserts can include information on potential
adverse side effects, complications or reactions, such as warnings to the subject or clinician regarding situations where it would not be appropriate to use a particular composition. Adverse side effects or complications could also occur when the subject has, will be or is currently taking one or more other medications that may be incompatible with the composition, or the subject has, will be or is currently undergoing another treatment protocol or therapeutic regimen which would be incompatible with the composition and, therefore, instructions could include information regarding such incompatibilities.
[0168] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described herein.
[0169] All applications, publications, patents and other references, GenBank citations and ATCC citations cited herein are incorporated by reference in their entirety. In case of conflict, the specification, including definitions, will control.
[0170] All of the features disclosed herein may be combined in any combination. Each feature disclosed in the specification may be replaced by an alternative feature serving a same, equivalent, or similar purpose. Thus, unless expressly stated otherwise, disclosed features (e.g., compound structures) are an example of a genus of equivalent or similar features.
[0171] As used herein, the singular forms "a", "and," and "the" include plural referents unless the context clearly indicates otherwise. Thus, for example, reference to "a first, second, third, fourth, fifth, etc. predictor gene" or a "positive or negative predictor gene" includes a plurality of such first, second, third, fourth, fifth, etc., genes, or a plurality of positive and/or negative predictor genes.
[0172] As used herein, all numerical values or numerical ranges include integers within such ranges and fractions of the values or the integers within ranges unless the context clearly indicates otherwise. Thus, to illustrate, reference to a range of 90-100%, includes 91%, 92%, 93%, 94%, 95%, 95%, 97%, etc., as well as 91.1%, 91.2%, 91.3%, 91.4%, 91.5%, etc., 92.1%, 92.2%, 92.3%, 92.4%, 92.5%, etc., and so forth.
[0173] Reference to a number with more (greater) or less than includes any number greater or less than the reference number, respectively. Thus, for example, a reference to less than 30,000, includes 29,999, 29,998, 29,997, etc. all the way down to the number one (1); and less than 20,000, includes 19,999, 19,998, 19,997, etc. all the way down to the number one (1).
[0174] As used herein, all numerical values or ranges include fractions of the values and integers within such ranges and fractions of the integers within such ranges unless the context clearly indicates otherwise. Thus, to illustrate, reference to a numerical range, such as a percentage range, 90-100%, includes 91%, 92%, 93%, 94%, 95%, 95%, 97%, etc., as well as 91.1%, 91.2%, 91.3%, 91.4%, 91.5%, etc., 92.1%, 92.2%, 92.3%, 92.4%, 92.5%, etc., and so forth. Reference to a range of
1 - 5 fold therefore includes 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, fold, etc., as well as 1.1, 1.2, 1.3, 1.4, 1.5, fold, etc., 2.1, 2.2, 2.3, 2.4, 2.5, fold, etc., and so forth.
[0175] Reference to a series of ranges includes ranges which combine the values of the boundaries of different ranges within the series. Thus, to illustrate reference to a series of ranges of 2-72 hours,
2- 48 hours, 4-24 hours, 4-18 hours and 6-12 hours, includes ranges of 2-6 hours, 2, 12 hours, 2-18 hours, 2-24 hours, etc., and 4-27 hours, 4-48 hours, 4-6 hours, etc.
[0176] The invention is generally disclosed herein using affirmative language to describe the numerous embodiments and aspects. The invention also specifically includes embodiments in which particular subject matter is excluded, in full or in part, such as substances or materials, method steps and conditions, protocols, or procedures. For example, in certain embodiments or aspects of the invention, materials and/or method steps are excluded. Thus, even though the invention is generally not expressed herein in terms of what the invention does not include aspects that are not expressly excluded in the invention are nevertheless disclosed herein.
|0177] A number of embodiments of the invention have been described. Nevertheless, one skilled in the art, without departing from the spirit and scope of the invention, can make various changes and modifications of the invention to adapt it to various usages and conditions. Accordingly, the following examples are intended to illustrate but not limit the scope of the invention claimed.
Examples
Example 1
This example includes a description of various materials and methods.
[0178] Mice: C57BL/6J (WT) mice were purchased from Jackson Laboratory (Bar Harbor, ME). LIF ~ mice were generated as described (Escary et al., Nature 363:361 (1993)) and obtained from the Sendtner lab (Institut fur Klinische Neurobiologie). LIF " mice were backcrossed for greater than 10 generations on the B6 background. LIF" " and OTII TCR transgenic mice were bred and maintained under specific pathogen- free conditions. All animal studies were conducted on mice 6- 12 weeks of age in accordance with approved animal protocols.
[0179] Adoptive transfers, bone marrow chimeras, immunizations & infections: Naive OTII CD4 T cells were transduced with LIF-RV (LIF A, secreted form, or LIF B, intracellular form) or a GFP expressing control plasmid (pMIG), transferred into B6 mice, and subsequently immunized with 100 μg alum precipitated NP-Ova (Sigma; Biosearch Technologies) in PBS via intraperitoneal (i.p.) injection. To create LIF bone marrow chimera mice, bone marrow was isolated from wildtype or LIFA mice, and 3 million cells were transferred into lethally irradiated B6 recipients (total body irradiation, 2x 450R in a RS2000 X-ray irradiator, separated by 3 h). Mice were allowed to 'rest' for
8 weeks prior to infection with 2x10^ plaque forming units of VACVWR by i.p. injection.
[0180] Flow cytometry: Single cell suspensions of whole spleens were obtained by gentle mechanical disruption and ACK lysis (Gibco). Surface staining for flow cytometry used monoclonal antibodies to SLAM (CD150, Biolegend), CD4, CD8, CD44, CD62L, IgD, CD45.1 (eBiosciences), PD-1, FAS, B220, FITC-labeled GL7, biotinylated CD138 (BD Pharmingen), and FITC-labeled peanut agglutinin (PNA, Vector Laboratories). The majority of surface stains were done for 30 min at 4°C in FACS buffer (PBS + 0.5% BSA + 0.1% NaN3). CXCR5 was detected using purified anti- CXCR5 (BD Pharmingen), followed by biotinylated anti-rat IgG (Jackson ImmunoResearch Laboratories), and PE- or APC-labeled streptavidin (eBioscience) in FACS buffer supplemented with 2% normal mouse serum as previously described (Johnston, et al., Science 325: 1006 (2009)). Samples were acquired on an LSRII containing DIVA software (BD Biosciences), and analyzed with Flow Jo software (Treestar, Inc).
[0181] ELISA: Antigen-specific IgG was quantified from mouse serum by ELISA 8 days following protein immunization or viral infection. 96-well Maxisorp microtiter plates (Nunc) were coated with NP-Ova or VACV cell lysate as the capture antigen. Following the primary incubation, samples were treated with biotinylated goat anti-mouse IgGy (Southern Biotech), subsequently incubated with HRP conjugated Avidin D (Vector Laboratories), and visualized using OPD (o- phenylenediamine dihydrochloride; Sigma) substrate.
[0182] Statistical analysis: All statistical tests were performed using Prism 5, and p values were calculated using two-tailed, unpaired Student t tests, with a 95% confidence interval. Error bars represent the SEM. P < 0.05 = *, P < 0.005 = **. P < 0.0005 = ***.
[0183] RNA and gene expression microarray analysis: Splenocytes were isolated 8 days following an acute LCMV infection. CD4 T cells were purified by negative selection using magnetic beads (Miltenyi). Enriched cells were sorted as CD4+CD44l0CD62Lhi7AAD" (naive) or
CD4+CD44hiCD62Llo7AAD~ and on the basis of CXCR5 and GL7 expression: non-Tfh
(CXCR5l0GL7), Tfh (CXCR5+GL7 ), and GC Tfh (CXCR5+GL7+) using a FACSAria (BD
Biosciences). Approximately 1 x 106 cells from each condition (in duplicate) were sorted directly into RNALater (Ambion). RNA was isolated using Qiagen RNAeasy Mini spin columns (Qiagen), including QiaShredder and on-column digestion of genomic DNA. RNA quality of all samples was confirmed by BioA alyzer Nano gel (Agilent), then probes were generated by single round linear amplification using the Ovation Pico system (Nugen) and used on Affymetrix 430 2.0 chips. Data were analyzed using Genespring (Agilent), Microsoft Excel, and Prism (5.0).
Example 2
This example includes a description of animal studies of LIF expression and biological effects after infection or immunization.
[0184] C57BL/6 mice were infected with LCMV and microarray analysis performed 8 days postinfection on different CD4 populations: naive (CD4+CD441oCD62Lhi), non-Tfh
(CD4+CD44hiCD62LloCXCR51o), Tfh (CD4+CD44hiCD62LloCXCR5hiGL71o), and Tgc (CD4+CD44hiCD62LloCXCR5hiGL7hi). Figure 1 A shows that Leukemia inhibitory factor (LIF) is upregulated in follicular helper (Tfh) and germinal center Tfh (Tgc) over naive and non-Tfh populations.
[0185] In order to determine the effect of LIF on Tfh development and function, naive OT-II T cells transduced with control plasmid expressing GFP (pMIG), the secreted form of LIF (LIF A), or the intracellular form of LIF (LIF B) were transfered into C57BL/6 mice prior to immunization with NP-Ova/alum. Eight days post-immunization, the percentage of GC B cell (Figure IB) and OT-II Tfh cell (Figure 1C) differentiation was quantified by FACS. *, P < 0.05 unpaired t test. Data is representative of 2 studies, n = 6 mice/group. Figure ID shows NP-Ova IgG ELISA at day 8. The data show that secreted LIF expression drove increased germinal centers, increased Tfh numbers and increased antibody responses. Therefore, LIF controls Tfh cells and germinal centers.
Example 3
This example includes a description of animal studies and data desmonstrating that LIF contributes to and/or enhances antibody responses, such as against Vaccinia virus.
[0186] Bone marrow was transferred from LIF" " or LIF+ " mice into irradiated wild-type B6 mice to generate bone marrow (BM) chimeric mice. Eight weeks following reconstitution, LIF" " or LIF4"7" BM chimera mice were infected with 2 l05 pfu VACVWR. Splenocytes were isolated at day 8 postinfection. In the absence of LIF, a 50% loss of anti-VACV IgG was observed (Figure 2A). The LIF- deficient BM chimeric mice also had decreased germinal center B cell (PNA+FAS+) numbers compared to the control group, and some of these reductions were extreme (Figures 2B and 2C). LIF-deflcient mice exhibited a significant reduction in both TFH (CXCR5+, Figure 2D) and GC TFH (CXCR5+PD-1+, Figures 2E and 2F).
[0187] The defects in B cell responses to vaccinia virus appear due to lack of LIF production by CD4 T cells and development of Tfh. These data indicate a major role for LIF in the early CD4 T cell dependent antibody response and germinal centers induced by the smallpox vaccine. This is also consistent with the 2x increase in antibody responses observed when mice were immunized with protein in the presence of elevated LIF expression in CD4 T cells (Figure ID).
Claims
1. A method for inhibiting, decreasing or reducing Tfh (follicular helper) cell differentiation,
Germinal center B cell development or an antibody response, comprising administering an inhibitor of LIF (Leukemia inhibitory factor, cholinergic differentiation factor) to a subject in an amount effective to inhibit, decrease or reduce Tfh (follicular helper) cell differentiation, Germinal center B cell development or an antibody response in the subject.
2. A method for inhibiting or reducing an undesirable or aberrant immune response, comprising administering an inhibitor of LIF (Leukemia inhibitory factor, cholinergic differentiation factor) to a subject in an amount effective to inhibit or reduce an undesirable or aberrant immune response in the subject.
3. A method for inhibiting or reducing an undesirable or aberrant inflammatory response or
inflammation, comprising administering an inhibitor of LIF (Leukemia inhibitory factor, cholinergic differentiation factor) to a subject in an amount effective to inhibit or reduce an undesirable or aberrant inflammatory response or inflammation in the subject.
4. A method for inhibiting, decreasing or reducing memory T cell development, comprising
administering an inhibitor of LIF (Leukemia inhibitory factor, cholinergic differentiation factor) to a subject in an amount effective to inhibit, decrease or reduce memory T cell development in the subject.
5. The method of any of claims 1 to 4, wherein the inhibitor binds to LIF (Leukemia inhibitory factor, cholinergic differentiation factor).
6. The method of any of claims 1 to 4, wherein the inhibitor comprises an antibody or a fragment thereof that binds to LIF, or an antisense nucleic acid sequence of LIF.
7. The method of claim 6, wherein the antibody or fragment thereof comprises an Fab, Fab', F(ab')2, Fv, Fd, single-chain Fv (scFv), disulfide-linked Fvs (sdFv), VL, VH, trispecific (Fab3), bispecific (Fab2), diabody ((VL-VH)2 or (VH-VL)2), triabody (trivalent), tetrabody (tetravalent), minibody ((scFv-CH3)2), bispecific single-chain Fv (Bis-scFv), IgGdeltaCH2, scFv-Fc or (scFv)2-Fc fragment.
8. The method of claim 6, wherein the antibody is human or humanized.
9. The method of claim 6, wherein the antibody competes with an antibody denoted as L9277,
L9152, L0919, L0669 or LI 169 (Sigma- Aldrich), anti-Human Leukemia Inhibitory Factor clone
4F7.2 antibody (MAB4306, Millipore), AB-449-NA (R&D Systems goat anti-mouse LIF)), clone 139124, MAB449 (rat anti-mouse LIF), clone 2H2.2, MAB4307 (Millipore rat anti-mouse LIF), clone 4F7.2 antibody (MAB4306, Millipore), anti-mouse LIF (AB-449-NA), rat anti-mouse LIF (clone 139124, MAB449), rat anti-mouse LIF (clone 2H2.2, MAB4307, Millipore), mouse Anti- Human LIF Monoclonal Antibodies, Clones 9808 or 9824, or anti-LIF (J-14F) to LIF for binding to human LIF.
10. The method of claim 6, wherein the antibody does not compete with an antibody denoted as L9277, L9152, L0919, L0669 or LI 169 (Sigma- Aldrich), anti-Human Leukemia Inhibitory Factor clone 4F7.2 antibody (MAB4306, Millipore), AB-449-NA (R&D Systems goat anti-mouse LIF)), clone 139124, MAB449 (rat anti-mouse LIF), or clone 2H2.2, MAB4307 (Millipore rat anti-mouse LIF), mouse Anti-Human LIF Monoclonal Antibodies, Clones 9808 or 9824, or anti-LIF (J-14F) for binding to human LIF.
11. The method of claim 6, wherein the antisense binds to a nucleic acid encoding a mammalian LIF.
12. The method of claim 6, wherein the antisense binds to a nucleic acid encoding a human LIF.
13. The method of claim 6, wherein the antisense binds to a nucleic acid encoding all or a portion of a human LIF (Leukemia inhibitory factor, cholinergic differentiation factor) sequence set forth as:
MKVLAAGVVPLLLVLHWKHGAGSPLPITPVNATCAIRHPCHNNLMNQIRSQLAQLNGSANALFILY YTAQGEPFPNNLDKLCGPNVTDFPPFHANGTEKAKLVELYRIVVYLGTSLGNITRDQKILNPSALS LHSKLNATADILRGLLSNVLCRLCSKYHVGHVDVTYGPDTSGKDVFQKKKLGCQLLGKYKQIIAVL AQAF (SEQ ID NO : 1 ) .
14. The method of claim 3, wherein the undesirable or aberrant inflammatory response or
inflammation is acute or chronic.
15. The method of claim 2, wherein the undesirable or aberrant immune response comprises an autoimmune disease.
16. The method of claim 15, wherein the autoimmune disease comprises: rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, psoriatic arthritis, diabetes mellitus, multiple sclerosis, encephalomyelitis, myasthenia gravis, systemic lupus erythematosus (SLE), autoimmune thyroiditis, atopic dermatitis, eczematous dermatitis, psoriasis, Sjogren's Syndrome, Crohn's disease, aphthous ulcer, iritis, conjunctivitis, keratoconjunctivitis, ulcerative colitis, asthma, allergic asthma, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, erythema nodosum leprosum, autoimmune uveitis, allergic encephalomyelitis, acute necrotizing
hemorrhagic encephalopathy, idiopathic bilateral progressive sensorineural hearing loss, aplastic anemia, pure red cell anemia, idiopathic thrombocytopenia, polychondritis, Wegener's granulomatosis, chronic active hepatitis, Stevens- Johnson syndrome, idiopathic sprue, lichen planus, Graves' disease, sarcoidosis, primary biliary cirrhosis, uveitis posterior, interstitial lung fibrosis, Hashimoto's thyroiditis, autoimmune polyglandular syndrome, insulin-dependent diabetes mellitus, insulin-resistant diabetes mellitus, immune-mediated infertility, autoimmune Addison's disease, pemphigus vulgaris, pemphigus foliaceus, dermatitis herpetiformis, autoimmune alopecia, Vitiligo, autoimmune hemolytic anemia, autoimmune thrombocytopenic purpura, pernicious anemia, Guillain-Barre syndrome, acute rheumatic fever, sympathetic ophthalmia, Goodpasture's syndrome, systemic necrotizing vasculitis, antiphospholipid syndrome or an allergy.
17. The method of claim 2, wherein the undesirable or aberrant immune response comprises a cell- mediated or humoral immune response.
18. The method of any of claims 1 to 4, wherein production or suppression of one or more antibodies is reduced, decreased, inhibited, or suppressed.
19. A method for stimulating, inducing, increasing or enhancing Tfh (follicular helper) cell
differentiation, Germinal center B cell development or an antibody response, comprising administering an activator of LIF, or a L1F polypeptide or subsequence thereof to a subject in an amount effective to stimulate, induce, increase or enhance Tfh (follicular helper) cell
differentiation, Germinal center B cell development or an antibody response in the subject.
20. A method for stimulating, inducing, increasing or enhancing an immune response, comprising administering an activator of LIF, or a LIF polypeptide or subsequence thereof to a subject in an amount effective to stimulate, induce, increase or enhance an immune response in the subject.
21. A method for stimulating, inducing or increasing an immune response induced by a vaccine, comprising administering LIF (Leukemia inhibitory factor, cholinergic differentiation factor), an activator of LIF (Leukemia inhibitory factor, cholinergic differentiation factor), or a LIF polypeptide or subsequence thereof to a subject in an amount effective to stimulate, induce or increase an immune response induced by the vaccine in the subject.
22. A method for stimulating, inducing or increasing memory T cell development in the subject, comprising administering an activator of LIF (Leukemia inhibitory factor, cholinergic
differentiation factor), or a LIF polypeptide or subsequence thereof to a subject in an amount effective to stimulate, induce or increase memory T cell development in the subject.
23. The method of claim 22, wherein the memory T cells respond to a pathogen or pathogen antigen.
24. The method of claim 23, wherein the pathogen antigen comprises a bacterial, viral, fugal or parasite antigen.
25. The method of claims 20 or 21, wherein the immune response comprises a cell-mediated or humoral immune response.
26. The method of claim 21 , wherein the vaccine comprises a bacterial, viral, fugal or parasite antigen.
27. The method of claims 20 or 21, wherein the immune response stimulated, induced or increased is against a bacterial, viral, fungal, or parasite pathogen.
28. The method of claim 21, wherein the vaccine is administered prior to, during or following administration of an activator of LIF or a LIF polypeptide or subsequence thereof.
29. The method of claims 19, 20, 21 or 22, wherein the subject is immunosuppressed or
immunocompromised or has an immunodeficiency syndrome.
30. The method of any of claims 1 to 4, 19, 20, 21 or 22, wherein the subject is a mammal.
31. The method of any of claims 1 to 4, 19, 20, 21 or 22, wherein the subject is a human.
32. The method of any of claims 1 to 4, 19, 20, 21 or 22, wherein the LIF (Leukemia inhibitory factor, cholinergic differentiation factor) is mammalian.
33. The method of any of claims 1 to 4, 19, 20, 21 or 22, wherein the LIF (Leukemia inhibitory factor, cholinergic differentiation factor) is human.
34. The method of any of claims 1 to 4, 19, 20, 21 or 22, wherein the LIF (Leukemia inhibitory factor, cholinergic differentiation factor) comprises all or a portion of a human LIF (Leukemia inhibitory factor, cholinergic differentiation factor) sequence set forth as:
MKVLAAGVVPLLLVLHWKHGAGSPLPITPVNATCAIRHPCHNNLMNQIRSQLAQLNGSANALFILY YTAQGEPFPNNLDKLCGPNVTDFPPFHANGTEKAKLVELYRIVVYLGTSLGNITRDQKILNPSALS LHSKLNATADILRGLLSNVLCRLCSKYHVGHVDVTYGPDTSGKDVFQKKKLGCQLLGKYKQIIAVL AQAF (SEQ ID NO: 1) .
35. The method of any of claims 1 to 4, 19, 20, 21 or 22, wherein the LIF inhibitor or activator binds to a mammalian LIF (Leukemia inhibitory factor, cholinergic differentiation factor).
36. The method of any of claims 1 to 4, 19, 20, 21 or 22, wherein the LIF inhibitor or activator binds to a human LIF (Leukemia inhibitory factor, cholinergic differentiation factor) sequence set forth as:
MKVLAAGVVPLLLVLHWKHGAGSPLPITPVNATCAIRHPCHNNLMNQIRSQLAQLNGSANALFILY YTAQGEPFPNNLDKLCGPNVTDFPPFHANGTEKAKLVELYRIVVYLGTSLG ITRDQKILNPSALS LHSKLNAT DILRGLLSNVLCRLCSKYHVGHVDVTYGPDTSGKDVFQKKKLGCQLLGKYKQI IAVL AQAF (SEQ ID NO : 1 ) .
37. A method for vaccinating a subject against a pathogen, comprising administering an activator of LIF (Leukemia inhibitory factor, cholinergic differentiation factor) or a LIF polypeptide or subsequence thereof and a pathogen, pathogen antigen to a subject in an amount effective to vaccinate the subject against the pathogen.
38. The method of claim 37, wherein the pathogen comprises a bacterial, viral, fugal or parasite pathogen.
39. The method of claim 37, wherein the method provides the subject with protection against one or more physiological conditions, disorders, illness, diseases or symptoms caused by or associated with pathogen infection or pathology.
40. The method of claim 37, wherein the LIF activator, LIF polypeptide or subsequence thereof is administered prior to, substantially contemporaneously with or following administration of the subject with the pathogen or pathogen antigen.
41. The method of claim 37, wherein the LIF activator, LIF polypeptide or subsequence thereof is administered within 2-72 hours, 2-48 hours, 4-24 hours, 4-18 hours, or 6-12 hours of
administration of the subject with the pathogen or pathogen antigen.
42. A peptide comprising or consisting subsequence of human LIF (Leukemia inhibitory factor, cholinergic differentiation factor) sequence set forth as:
MKVLAAGVVPLLLVLHWKHGAGSPLPITPVNATCAIRHPCHNNLMNQIRSQLAQLNGSANALFILY YTAQGEPFPNNLDKLCGPNVTDFPPFHANGTEKAKLVELYRI VYLGTSLGNITRDQKILNPSALS LHSKLNATADILRGLLSNVLCRLCSKYHVGHVDVTYGPDTSGKDVFQKKKLGCQLLGKYKQIIAVL AQAF (SEQ ID NO: 1) , wherein the subsequence stimulates, induces, increases or enhances development of memory T cells, Tfh (follicular helper) cell differentiation, Germinal center B cell development, an antibody response, an immune response, or an immune response induced by a vaccine.
43. The peptide of claim 42, wherein the amino acid substitution is 1-2, 2-3, 3-4 or 5-6 a
conservative, non-conservative, or conservative and non-conservative amino acid substitutions.
44. The peptide of claim 42, wherein the polypeptide is isolated or purified.
45. The peptide of claim 42, wherein the subsequence is from about 5 to 300 amino acids in length provided that said subsequence is at least one amino acid less in length than the full-length LIF sequence.
46. The peptide of claim 45, wherein the subsequence is from about 5 to 15, 20 to 25, 25, to 50, 50 to 100, 100 to 150, 150 to 200, or 200 to 300 amino acids in length, provided that said subsequence or portion is at least one amino acid less in length than a full-length LIF sequence.
47. A pharmaceutical composition comprising the peptide of any of claims 40 to 45.
48. The pharmaceutical composition of claim 47, further comprising an adjuvant.
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