WO2009023055A2 - Blockade of the inhibitory qa-1-cd94/nkg2a pathway for treatment of autoimmune disease - Google Patents
Blockade of the inhibitory qa-1-cd94/nkg2a pathway for treatment of autoimmune disease Download PDFInfo
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- WO2009023055A2 WO2009023055A2 PCT/US2008/006267 US2008006267W WO2009023055A2 WO 2009023055 A2 WO2009023055 A2 WO 2009023055A2 US 2008006267 W US2008006267 W US 2008006267W WO 2009023055 A2 WO2009023055 A2 WO 2009023055A2
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- UJKRUPHWCPAJIL-UHFFFAOYSA-N zorbamycin Natural products N=1C(C=2SC=C(N=2)C(=O)NCCC(N)=N)CSC=1CCNC(=O)C(C(C)(C)O)NC(=O)C(C)C(O)C(CCO)NC(=O)C(C(OC1C(C(O)C(O)C(C)O1)OC1C(C(OC(N)=O)C(O)C(CO)O1)O)C=1NC=NC=1)NC(=O)C1=NC(C(CC(N)=O)NCC(N)C(N)=O)=NC(N)=C1C UJKRUPHWCPAJIL-UHFFFAOYSA-N 0.000 description 1
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Definitions
- NK cells natural killer lymphocytes
- NK cells may also downregulate adaptive immune responses through elimination of antigen-presenting dendritic cells (DCs) or through production of inhibitory cytokines. Piccioli et al. (2002) J. Exp. Med. 195:335-41.
- NK cells are a subpopulation of lymphocytes involved in non-conventional immunity. These cells provide an efficient immunosurveillance mechanism by which undesired cells such as tumor cells or virally-infected cells can be eliminated. NK cell activity is regulated by a complex mechanism that involves both activating and inhibitory signals. See, e.g., Moretta et al. (2001) Annu. Rev. Immunol. 19:197-223; Moretta et al. (2004) EMBO J. 23(2):255-9; Ravetch et al. (2000) Science 290:84-89; Zambello et al. (2003) Blood 102:1797-805; and Moretta et al. (1997) Curr. Opin. Immunol. 9:694-701.
- NK cells are negatively regulated, i.e., inhibited from eliminating target cells, by certain major histocompatibility complex (MHC) class I-specific inhibitory receptors expressed on their cell surface.
- MHC major histocompatibility complex
- KIRs killer cell inhibitory receptors
- NKG2A NKG2A
- WO 2006/063844 discloses soluble HLA-E molecules and their use in diagnosing and treating cancers and inflammatory diseases. WO 2006/063844 further discloses the use of HLA-E ligands, including anti- HLA-E antibodies and paratope-containing fragments thereof, for the treatment of certain inflammatory diseases.
- the invention is based, at least in part, on the discovery by the inventors that the Qa-1-NKG2A interaction protects activated CD4 + T cells from lysis by a subset of
- NKG2A + NK cells and is essential for T cell expansion and development of immunologic memory.
- the invention is also based, at least in part, on the discovery by the inventors that blockade of this Qa-1-NKG2A interaction using antibodies specific for Qa-I results in potent NK-dependent elimination of activated autoreactive T cells and amelioration of experimental autoimmune encephalomyelitis.
- the invention is also based, at least in part, on the discovery by the inventors that engagement of the CD94/NKG2A receptor expressed on CD8 + cells by Qa-I expressed on autoreactive CD4 + T cells protects these pathogenic CD4 + T cells from suppression by CD8 + T regulatory (Treg) cells.
- the invention is further based, at least in part, on the discovery by the inventors that blockade of the Qa-1-NKG2A interaction can enhance the activity of CD8 + Treg cells, unleashing a robust CD8 suppressive activity that results in profound inhibition of autoreactive CD4 + T cells. Disruption of this interaction and the resulting inhibition are disclosed not only to abolish the development of experimental allergic encephalitis (EAE), which is a widely recognized model of multiple sclerosis, but also to induce complete remission of established EAE.
- EAE experimental allergic encephalitis
- the invention in an aspect is a method of treating a condition selected from autoimmune disease, graft rejection, graft-versus-host disease.
- the method according to this aspect of the invention includes the step of administering to a subject having the condition an effective amount of an agent that binds a Qa-I molecule, wherein binding of the Qa-I molecule by the agent permits natural killer (NK)-cell-mediated lysis of activated T cells, to treat the condition.
- NK natural killer
- the Qa-I molecule can be a polypeptide or a polynucleotide.
- the Qa-I molecule is a Qa-I polypeptide.
- the Qa-I polypeptide is HLA-E.
- the Qa-I molecule is a Qa-I polynucleotide, hi one embodiment the Qa-I polynucleotide is an ortholog of a murine Qa-I polynucleotide.
- the condition is an autoimmune disease
- the autoimmune disease is selected from acute disseminated encephalomyelitis, allergic angiitis and granulomatosis (Churg-Strauss disease), ankylosing spondylitis, autoimmune Addison's disease, autoimmune alopecia, autoimmune chronic active hepatitis, autoimmune encephalomyelitis, autoimmune hemolytic anemia, autoimmune neutropenia, autoimmune thrombocytopenic purpura, Behcet's syndrome, bullous pemphigoid, chronic bullous disease of childhood, chronic inflammatory demyelinating polyradiculoneuropathy, chronic neuropathy with monoclonal gammopathy, cicatricial pemphigoid, Crohn's disease, dermatitis herpetiformis, Eaton-Lambert myasthenic syndrome, epidermolysis bullosa acquisita, erythema nodosa
- condition is graft rejection.
- condition is graft-versus-host disease.
- agent is an antibody or fragment thereof that binds specifically to a Qa-I polypeptide.
- the agent, antibody, or fragment thereof that binds specifically to a Qa-I polypeptide interferes with interaction between Qa-I (or HLA-E) and CD94/NKG2A. In one embodiment according to this and other aspects of the invention the agent, antibody, or fragment thereof that binds specifically to a Qa-I polypeptide interferes with interaction between Qa-I (or HLA-E) and CD94/NKG2A, without interfering with interaction between Qa-I (or HLA-E) and CD8.
- the agent is a short interfering RNA (siRNA) that binds specifically to a Qa-I polynucleotide.
- siRNA short interfering RNA
- the invention in an aspect is a method of reducing activated T cells in a subject.
- the method according to this aspect of the invention includes the step of administering to the subject an effective amount of an agent that binds a Qa-I molecule, wherein binding of the Qa-I molecule by the agent permits natural killer (NK)-cell-mediated lysis of activated T cells, to reduce activated T cells in the subject.
- the Qa-I molecule can be a polypeptide or a polynucleotide, including in particular HLA-E, as disclosed herein.
- the subject has an inflammatory condition.
- the inflammatory condition specifically excludes vasculitides, such as anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitides.
- ANCA anti-neutrophil cytoplasmic antibody
- the invention in an aspect is an improvement in a method of treatment calling for adoptive transfer of T cells to a subject.
- the improvement according to this aspect of the invention includes the step of introducing into the T cells an effective amount of a vector that directs expression of a Qa-I polypeptide to increase Qa-I polypeptide expression on the surface of the T cells.
- the invention in an aspect is a method of promoting a T-cell-mediated immune response in a subject.
- the method according to this aspect of the invention includes the step of administering to the subject an effective amount of a vector that directs expression of a Qa-I polypeptide to increase Qa-I polypeptide expression on the surface of activated T cells in the subject.
- the invention in an aspect is a pharmaceutical composition that includes (a) an antigen or a polynucleotide encoding an antigen and (b) an effective amount of a vector that directs expression of a Qa-I polypeptide to increase Qa-I polypeptide expression on the surface of activated T cells.
- the antigen or polynucleotide encoding the antigen is a polynucleotide encoding an antigen.
- the invention in an aspect is a method of identifying an agent useful for reducing activated T cells.
- the method according to this aspect of the invention includes the steps of contacting under physiologic conditions cells that express a Qa-I molecule with a test agent that binds the Qa-I molecule, in presence of NK cells that express NKG2A; measuring a test amount of lysis of the cells that express the Qa-I molecule; and identifying the test agent as an agent useful for reducing activated T cells when the test amount of lysis exceeds a control amount of lysis obtained under similar conditions without the test agent.
- FIG. IA is a graph depicting development of experimental allergic encephalitis (EAE) in Rag2 ⁇ ' ⁇ (circles) or Rag2 ⁇ ' ⁇ Prfl ⁇ ' ⁇ (squares), Qa-I wild type (WT; filled symbols) or Qa-I -deficient mice (KO, open symbols).
- EAE experimental allergic encephalitis
- WT Qa-I wild type
- KO Qa-I -deficient mice
- FIG. 2 is a graph depicting T cell lysis by NK cells in a standard in vitro killing assay. Lysis of Qa-I WT (filled symbols) or Qa-I -deficient T cells (open symbols) by NKG2A + (circles) and NKG2A " (squares) NK cells was scored. Percentage of killing is shown at the indicated E:T (effector : target) ratios.
- FIG. 3 is a graph depicting T cell lysis by NK cells in a standard in vitro killing assay. Lysis of Qa-I-KO cells reconstituted with either Qdm- ⁇ 2 m-Qa-l fusion protein (QbQ, open squares) or a HSP60 peptide- ⁇ 2 m-Qa-l fusion protein (HbQ, open circles), or Qa-I WT (filled squares) and Qa-I -deficient OTII cells (filled circles) as controls, was measured as percentage of killing at the indicated E:T ratios.
- QbQ open squares
- HbQ HSP60 peptide- ⁇ 2 m-Qa-l fusion protein
- OTII cells filled circles
- FIG. 4 is a schematic drawing depicting the Qa-I genomic locus and R72A targeting strategy used to generate Qa-I R72A mutant knock-in mice. NEO r , neomycin- resistance gene. The R72A point mutation is shown in the third exon.
- FIG. 5 is a graph depicting the effect of treatment with anti-Qa-1 antibody on development of EAE. Disease development was monitored and scored as described in FIG. 1. Mice received no antibody (open circles) or anti-Qa-1 (filled circles), anti-NKl.l (open squares), or a combination of anti-Qa-1 and anti-NKl.l (filled squares).
- the invention provides methods and compositions relating to aspects of an inhibitory interaction between NK cells and activated T cells, whereby activated T cells can be either eliminated by blocking the inhibitory interaction or protected by augmenting the inhibitory interaction.
- the particular inhibitory interaction arises through the interaction between the class Ib MHC molecule Qa-l-Qdm on activated T cells and the CD94-NKG2A receptor on NK cells. It has been discovered according to the invention that this particular interaction (a) protects activated T cells from NK lysis and (b) is essential for clonal expansion and development of immunologic memory by self-reactive T cells.
- Qa-l-Qdm (hereinafter simply Qa-I unless otherwise specified) on activated T cells and CD94-NKG2A (hereinafter simply NKG2A unless otherwise specified) on NK cells protects activated T cells from NK lysis
- disruption of this interaction permits NK-cell-mediated lysis of activated T cells that express Qa-I on their cell surface.
- This disruption of the normal inhibitory interaction can thus be exploited in any setting where it is desirable to reduce T cell activation, for example in a variety of clinical conditions including autoimmune disease, graft rejection, graft- versus- host disease.
- the invention relates in part to methods for treating such conditions by disrupting the inhibitory interaction using an agent that binds to a Qa-I molecule, particularly a Qa-I polypeptide.
- the classical MHC class I (Ia) molecules (HLA-A, HLA-B and HLA-C) are highly polymorphic and are ubiquitously expressed on most somatic cells.
- non classical MHC class I (Ib) molecules (HLA-E, HLA-F and HLA-G) are broadly defined by a limited polymorphism and a restricted pattern of cellular expression.
- HLA-E is characterized by a low polymorphism and a broad mRNA expression on different cell types.
- This class I molecule is a heterodimer consisting of a heavy chain and a light chain ( ⁇ 2 -microglobulin, ⁇ 2 m).
- the heavy chain is approximately 45 kDa and its gene contains 8 exons.
- Exon 1 encodes the leader peptide
- exons 2 and 3 encode the Ct 1 and ⁇ 2 domains, which both bind peptide
- exon 4 encodes the ⁇ 3 domain
- exon 5 encodes a transmembrane region
- exons 6 and 7 encode a cytoplasmic tail.
- Cell surface expression of HLA-E requires the availability of / ⁇ -microglobulin (Ulbrecht et al. (1999) Eur J Immunol. 29:537-47) and of a set of highly conserved nonameric peptides derived from the leader sequence of various HLA class I molecules including HLA-A, -B, -C, and -G. Braud et al. (1997) Eur J Immunol.
- HLA-E also associates with peptides which derive either from viruses, including cytomegalovirus (CMV), Epstein-Barr virus (EBV), and influenza virus, or from stress proteins (e.g. HSP60). Ulbrecht et al. (1998) J Immunol.
- HLA-E Online Mendelian Inheritance in Man accession no. 143010, the entire disclosure of which is herein incorporated by reference
- HLA-E binds NK cells and some T cells, binding specifically to CD94/NKG2A, CD94/NKG2B, and CD94/NKG2C, and not to the inhibitory KIR receptors.
- HLA-E refers to wild type, full length HLA-E.
- HLA-E refers to wild type, full length HLA-E to which is bound a signal sequence of another MHC class I molecule.
- HLA-E refers to a polypeptide having an amino acid sequence as provided by GenBank accession no. BAB63328. The full length sequence provided by GenBank accession no.
- BAB63328 includes 358 amino acids, including its own 21-amino acid signal peptide. Reference herein to an HLA-E amino acid by number shall refer to numbering without the signal peptide. Nucleotide sequences encoding HLA-E are available as GenBank accession nos. BA000025 (genomic) and AB103600 (cDNA).
- Qa-I also known as Qal b and as Qa-l b , is a mouse cell surface antigen that is the physiological ligand for NKG2A. As used herein, "Qa-I" refers to wild type, full length Qa-I.
- Qa-I refers to a polypeptide having an amino acid sequence as provided by GenBank accession no. NP 034528.
- the full length sequence provided by GenBank accession no. NP_034528 includes 357 amino acids, including its own 20-amino acid signal peptide.
- Reference herein to a Qa-I amino acid by number shall refer to numbering without the signal peptide.
- a nucleotide sequence encoding Qa-I is available as GenBank accession no. NM_010398.
- Qa-I refers to a Qa-l-Qdm heterodimer.
- Qa-l-Qdm is a heterodimer composed of the MHC class Ib molecule Qa-I (H2-T23; the murine homologue of HLA-E), ⁇ 2 m, and peptides derived in TAP-dependent fashion from the MHC class I leader sequences (Qdm).
- Qa-l-Qdm The interaction between Qa-l-Qdm and CD94/NKG2A generally inhibits NK or CD8 + cytotoxic T lymphocyte (CTL) activity.
- CTL cytotoxic T lymphocyte
- Qa-I is expressed in many cell types at the RNA level (Trasny et al. (1987) J. Exp. Med. 166:341-61)
- expression of the Qa-l-Qdm surface protein is restricted to activated T and B lymphocytes and dendritic cells (Soloski et al. (1995) Immunol. Rev. 147:67-89; Sullivan et al. (2002) Immunity 17:95-105), allowing this ligand to selectively mark the central triad of immunological cells.
- NK cells refers to a sub-population of lymphocytes that is involved in non-conventional immunity.
- NK cells can be identified by virtue of certain characteristics and biological properties, such as the expression of specific surface antigens including CD 16, CD56, and/or CD57, the absence of the alpha/beta or gamma/delta T-cell receptor (TCR) complex on the cell surface, the ability to bind to and kill cells that fail to express "self MHC/HLA antigens by the activation of specific cytolytic enzymes, the ability to kill tumor cells or other diseased cells that express a ligand for NK-activating receptors, and the ability to release cytokines that stimulate or inhibit the immune response.
- TCR gamma/delta T-cell receptor
- NKG2A (OMIM 161555, the entire disclosure of which is herein incorporated by reference) is a member of the NKG2 group of transcripts. Houchins, et al. (1991) J. Exp.
- NKG2A is encoded by 7 exons spanning 25 kb, showing some differential splicing.
- NKG2A is an inhibitory receptor found on the surface of NK cells. Like inhibitory KIR receptors, it possesses an immunoreceptor tyrosine-based inhibition motif (ITIM) in its cytoplasmic domain.
- ITIM immunoreceptor tyrosine-based inhibition motif
- NKG2A refers to wild type, full length NKG2A.
- CD94 (OMIM 602894, the entire disclosure of which is herein incorporated by reference in its entirety) is an antigen preferentially expressed on NK cells. Chang et al. (1995) Eur. J. Immunol. 25:2433-2437. CD94 is expressed as three major transcripts of
- CD94 The amino acid sequence of CD94 is 27 to 32% identical to those of NKG2 family members NKG2A, NKG2C, NKG2D, and NKG2E. Due to the virtual absence of a cytoplasmic domain, CD94 requires association with other receptors forming disulfide- bonded heterodimers with NKG2A, NKG2C, and NKG2E. Lazetic et al. (1996) J.
- CD94 refers to wild type, full length CD94.
- the invention in an aspect provides a method of treating a condition selected from autoimmune disease, graft rejection, graft- versus-host disease.
- the method includes the step of administering to a subject having the condition an effective amount of an agent that binds a Qa-I molecule, wherein binding of the Qa-I molecule by the agent permits natural killer (NK)-cell-mediated lysis of activated T cells, to treat the condition.
- NK natural killer
- a Qa-I molecule is a Qa-I polynucleotide.
- a Qa-I polynucleotide As used herein a
- Qa-I polynucleotide refers to a polynucleotide encoding a murine Qa-I polypeptide or an ortholog thereof.
- a Qa-I polynucleotide is a gene encoding a murine Qa-I polypeptide
- a gene encoding HLA-E is an ortholog of the gene encoding the murine Qa-I polypeptide.
- a Qa-I molecule is a Qa-I polypeptide.
- a Qa-I polypeptide As used herein a "Qa-I-
- Qa-I refers to a polypeptide encoded by a polynucleotide encoding a murine Qa-I polypeptide or an ortholog thereof.
- a Qa-I polypeptide is encoded by a gene encoding a murine Qa-I polypeptide
- a polypeptide encoded by a gene encoding HLA-E is a polypeptide encoded by an ortholog of the gene encoding the murine Qa-I polypeptide.
- An agent that binds a Qa-I molecule in one embodiment is an agent that binds a Qa-I polypeptide. Binding of the agent to the Qa-I polypeptide interferes with interaction between Qa-I polypeptide expressed on the surface of a cell, e.g. a T cell, and NKG2A expressed on the surface of an NK cell.
- such an agent can be an antibody that binds specifically to a Qa-I polypeptide and inhibits NK-cell-mediated T- cell lysis.
- such an agent can be a fragment of an antibody that binds specifically to a Qa-I polypeptide and inhibits NK-cell-mediated T-cell lysis, provided the fragment binds specifically to a Qa-I polypeptide.
- binds specifically to means the agent or antibody can bind preferentially to a particular binding partner, under conditions that are relevant to the invention.
- Conditions under which specific binding is relevant to the invention include physiologic conditions (in vivo or in vitro) and assay conditions as described in the examples below.
- an agent or antibody is said to bind specifically to a Qa-I molecule in vitro when the antibody or agent, when added to a sample under physiologic conditions, wherein the sample contains both the Qa-I molecule and other molecules, binds to the Qa-I molecule but binds only a little or not at all to the other molecules in the sample.
- an antibody is said to bind specifically to a Qa-I polypeptide expressed on the surface of a cell in vivo when the antibody, when administered to a subject, binds to the Qa-I polypeptide expressed on the surface of a cell but binds only a little or not at all to other molecules expressed on the surface of a cell, hi one embodiment an antibody that binds only a little or not at all to other molecules expressed on the surface of a cell binds to such other molecules expressed on the surface of a cell only to an extent that is similar to that of isotype-matched antigen-nonspecific control antibodies.
- antibody refers to polyclonal, monoclonal, and engineered antibodies, including but not limited to chimeric and humanized antibodies.
- Antibodies are well known in the art and can be of any class selected from IgG, IgM, IgA, IgE, and IgD.
- Each antibody comprises one or more paired polypeptide heterodimers in which there is a heavy chain and a light chain, each with a variable domain and a constant domain. Together, the variable domains of each heavy and light chain heterodimer contribute to an antigen binding site (variable region).
- Each paired heterodimer further includes a class-specific Fc portion or fragment that includes paired portions of the heavy chain constant domains.
- the antibody is an IgG antibody.
- An IgG antibody can be selected or engineered either to include or to exclude sequences in the Fc portion that are involved in directing antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC). In this manner antibodies can include either depleting or non-depleting antibodies.
- ADCC antibody-dependent cellular cytotoxicity
- CDC complement-dependent cytotoxicity
- the antibody is a monoclonal antibody. Methods for generating and selecting monoclonal antibodies are well known in the art.
- the antibody is a chimeric antibody.
- a "chimeric antibody” is an engineered antibody molecule in which the constant region, or a portion thereof, is altered, replaced or exchanged so that the antigen binding site (variable region) is linked to a constant region of a different or altered class, effector function and/or species. Methods for making chimeric antibodies are well known in the art.
- the antibody is a humanized antibody.
- a "humanized” antibody refers to an engineered antibody in which the constant and variable framework region of one or more human immunoglobulins is fused with the binding region, e.g.
- humanized antibodies are designed to maintain the binding specificity of the non-human antibody from which the binding regions are derived, but to avoid an immune reaction against the non-human antibody when administered to a human. Methods for making humanized antibodies are well known in the art.
- the antibody is a human antibody.
- a human antibody includes an antibody obtained from transgenic mice or other animals that have been "engineered” to produce specific human antibodies in response to antigenic challenge. See, e.g., Green et al. (1994) Nature Genet. 7:13; Lonberg et al. (1994) Nature 368:856; Taylor et al. (1994) Int. Immunol. 6:579, the entire teachings of which are herein incorporated by reference.
- a fully human antibody also can be constructed by genetic or chromosomal transfection methods, as well as phage display technology, all of which are known in the art (see, e.g., McCafferty et al.
- Human antibodies may also be generated by in vitro activated B cells. See, e.g., U.S. Pat. Nos. 5,567,610 and 5,229,275, which are incorporated in their entirety by reference.
- a fragment of an antibody is a Fab fragment, a F(abO 2 fragment, or an Fd fragment, each of which includes at least one antigen binding site (variable region) derived from an antibody that binds specifically to a Qa-I polypeptide.
- the antibody fragment in one embodiment can be derived from any of the foregoing types of polyclonal, monoclonal, chimeric, humanized, or human antibodies.
- the antibody or fragment thereof can be isolated.
- isolated when used in reference to a material means the material is substantially or essentially free from components which normally accompany it as found in its native state.
- the antibody or fragment thereof that binds specifically to a Qa-I polypeptide binds to an epitope that includes to an amino acid residue selected from (or corresponding to) W65, D69, R72, R79, and Q155 of murine Qa-I (R65, D69, Q72, R79, and Hl 55, respectively, of HLA-E).
- the antibody or fragment thereof that binds specifically to a Qa-I polypeptide binds to an epitope that includes an amino acid residue selected from (or corresponding to) D69 or R72 of murine Qa-I. In one embodiment the antibody or fragment thereof that binds specifically to a Qa-I polypeptide binds to an epitope that includes R72 of murine Qa-I or Q72 in HLA-E.
- the antibody or fragment thereof that binds specifically to a Qa-I polypeptide interferes with the interaction between Qa-I and CD94/NKG2A. In one embodiment the antibody or fragment thereof that binds specifically to a Qa-I polypeptide interferes with the interaction between Qa-I and CD94/NKG2A without interfering with the interaction between Qa-I and CD8.
- An agent that binds a Qa-I molecule in one embodiment is an agent that binds a Qa-I polynucleotide.
- binding of the agent to the Qa-I polynucleotide reduces expression of Qa-I polypeptide, for example by RNA interference (RNAi) or antisense.
- RNAi RNA interference
- Such an agent can be a polynucleotide at least 16 nucleotides long having a sequence that is complementary to at least a portion of the Qa-I polynucleotide.
- the agent that binds a Qa-I polynucleotide is RNA and can be used in RNAi.
- the agent that binds a Qa-I polynucleotide is DNA and can be used in antisense.
- Methods of the invention also encompass use of isolated short RNA molecules that direct the sequence-specific degradation of Qa-I mRNA through a process known as RNA interference (RNAi).
- RNAi RNA interference
- Qa-I mRNA refers to an RNA transcript of a Qa-I polynucleotide encoding a Qa-I polypeptide.
- Qa-I mRNA is an RNA transcript for HLA-E.
- RNAi is now a well described mechanism for posttranscriptional gene silencing by double-stranded RNA (dsRNA) having complementary sequence to a target gene to be silenced.
- RNA segments 21-23 nucleotides (nt) in length are sequence-specific mediators of RNA degradation and are referred to herein as small interfering RNA (siRNA).
- siRNA small interfering RNA
- siRNAs small interfering RNAs
- nt dsRNAs 21- to 23 -nucleotide (nt) dsRNAs, in which one stand, the sense strand, is the complement of the target mRNA sequence.
- RISC RNA-induced silencing complex
- siRNA which can be chemically synthesized, various other systems in the form of potential effector molecules for posttranscriptional gene silencing are available, including short hairpin RNAs (shRNAs), long dsRNAs, short temporal RNAs, and micro RNAs (miRNAs).
- effector molecules either are processed into siRNA, such as in the case of shRNA, or directly aid gene silencing, as in the case of miRNA.
- the present invention thus encompasses the use of siRNA as well as any other suitable form of RNA to effect posttranscriptional gene silencing by RNAi.
- Use of shRNA has the advantage over use of chemically synthesized siRNA in that the suppression of the target gene is typically long- term and stable.
- Methods and materials for design of the RNAs that mediate RNAi and the methods for transfection of the RNAs into cells and animals are well known in the art and are readily commercially available. Verma NK et al. (2004) J Clin Pharm Ther 28:395-404; Mello CC et al.
- RNAs in one embodiment are chemically synthesized using appropriately protected ribonucleoside phosphoramidites and a conventional DNA/RNA synthesizer. Most conveniently, siRNAs are obtained from commercial RNA oligonucleotide synthesis suppliers listed herein.
- RNAs are not difficult to synthesize and are readily provided in a quality suitable for RNAi.
- a typical 0.2 micromole-scale RNA synthesis provides about 1 milligram of RNA, which is sufficient for 1000 transfection experiments using a 24-well tissue culture plate format.
- the Qa-I cDNA-specific siRNA can be designed by selecting a sequence that is not within 50-100 base pairs (bp) of the start codon and the termination codon, avoids intron regions, avoids stretches of 4 or more bases such as AAAA, CCCC, avoids regions with GC content ⁇ 30% or >60%, avoids repeats and low complexity sequence, and avoids single nucleotide polymorphism sites.
- the target sequence can have a GC content of around 50%.
- the siRNA may be designed by a search for a 23-nt sequence motif AA(Nl 9), wherein A is adenosine nucleotide and N is any nucleotide. If no suitable sequence is found, then a 23-nt sequence motif NA(N21) may be used with conversion of the 3' end of the sense siRNA to dTdT, wherein dT is deoxythymidine nucleotide.
- the siRNA can be designed by a search for NAR(N 17) YNN, wherein R is a purine base-containing nucleotide (purine nucleotide) and Y is a pyrimidine base- containing nucleotide (pyrimidine nucleotide) .
- the siRNA-targeted sequence can be further evaluated using a BLAST homology search to avoid off-target effects on other genes or sequences.
- Control RNA can have the same length and nucleotide composition as the siRNA but has at least 4 to 5 bases mismatched to the siRNA. For example, negative controls can be designed by scrambling targeted siRNA sequences.
- the RNA molecules of the present invention can comprise a 3' hydroxyl group.
- the RNA molecules can be single-stranded or double-stranded; such molecules can be blunt-ended or comprise overhanging ends (e.g., 5', 3') from about 1 to about 6 nucleotides in length (e.g., pyrimidine nucleotides, purine nucleotides), hi order to further enhance the stability of the RNA of the present invention, the 3' overhangs can be stabilized against degradation.
- the RNA can be stabilized by including purine nucleotides, such as adenosine or guanosine nucleotides.
- substitution of pyrimidine nucleotides by modified analogues e.g., substitution of uridine 2-nucleotide (UU) 3' overhangs by T- deoxythymidine (dTdT) is tolerated and does not affect the efficiency of RNAi.
- UU uridine 2-nucleotide
- dTdT T- deoxythymidine
- RNA molecules used in the methods of the present invention can be obtained using any of a number of techniques known to those of skill in the art.
- the RNA can be chemically synthesized or recombinantly produced using methods known in the art. Such methods are described in U.S. Published Patent Application Nos. US2002- 0086356A1 and US2003-0206884A1 that are herein incorporated by reference in their entirety.
- RNA molecules that are useful as sequence-specific mediators of Qa-I mRNA degradation and, thus, for inhibiting Qa-I expression.
- Expression of HLA-E can be inhibited in humans in order to prevent the protein from being translated and thus preventing interaction between HLA-E expressed on the surface of activated T cells with natural killer cells that express NKG2A.
- the selected sequence for a shRNA typically has a stem length from 25 to 29 nt and loop size between 4 and 23 nt.
- DNA insert sequences that encode for shRNA are typically around 70 bp.
- the insert includes 20 nt inverted repeats that code for a portion of the stem complementary to the target gene and 10 nt spacers that code for the hairpin structure.
- the portions of the stem structure that binds to the target mRNA are critical for silencing capability of the shRNA and are therefore designed to be completely complementary. Restriction site overhangs of the insert can be conveniently designed to be specific to the vector to be used.
- the first base of the shRNA corresponding to the target mRNA sequence starts with nucleotides that correspond to the transcription start site for the particular promoter.
- shRNAs can be generated in cell lines with the help of commercially available shRNA expression vectors such as pSilencerTM 2.0-U6 and 3.0-H1 vectors from Ambion (Austin, TX), the psiRNATM system including psiRNA-hH 1 , psiRNA-hH 1 neo, and psiRNAhHlzeo vectors from InvivoGen (San Diego, CA), the psi CHECKTM vectors which include silencing optimization capability, from Promega (Madison, WI), and siRNA expression cassettes (SECs) from Ambion's SilencerTM Express system.
- pSilencerTM 2.0-U6 and 3.0-H1 vectors from Ambion (Austin, TX)
- the psiRNATM system including psiRNA-hH 1 , psiRNA-hH 1 neo, and psiRNAhHlzeo vectors from InvivoGen (San
- the shRNA expression vectors are engineered plasmid vectors containing promoters of the type III class of Pol III promoters (Hl RNA, U 6 promoter), a cloning site for stem- looped RNA insert, and a 4 or 5-thymidine transcription termination signal.
- the polymerase III promoters have well-defined initiation and stop sites, and the transcripts lack a poly (A) tail. Five thymidines define the termination signal for these promoters, and transcript is cleaved after the second uridine, which generates the 3' UU overhang in expressed siRNA, similar to the 3' overhang of synthetic siRNA.
- RNA any suitable RNA can be used in the methods of the present invention, provided that it has sufficient homology to the Qa-I gene (or ortholog thereof) to mediate RNAi.
- the RNA for use in the present invention can correspond to the entire gene or a portion thereof. There is no upper limit on the length of the RNA that can be used.
- the RNA can range from about 21 base pairs (bp) of the gene to the full length of the gene or more.
- the RNA used in the methods of the present invention is about 1000 bp in length.
- the RNA is about 500 bp in length.
- the RNA is about 22 bp in length.
- the preferred length of the RNA of the invention is 21 to 23 nucleotides. Nucleotide sequences of murine Qa-I and human HLA-E are known. See, for example, GenBank Accession Nos. NM 010398 and BA000025, the entire contents of which are incorporated herein by reference.
- the invention also embraces antisense oligonucleotides that selectively bind to a nucleic acid molecule encoding Qa-I to decrease expression and activity of this protein.
- Antisense oligonucleotides can be designed to interfere with expression of Qa-I based on the known nucleotide sequence of the Qa-I polynucleotides.
- antisense oligonucleotide or “antisense” describes an oligonucleotide that is an oligoribonucleotide, oligodeoxyribonucleotide, modified oligoribonucleotide, or modified oligodeoxyribonucleotide which hybridizes under physiological conditions to DNA comprising a particular gene or to an mRNA transcript of that gene and, thereby, inhibits the transcription of that gene and/or the translation of that mRNA.
- the antisense oligonucleotide molecules are designed so as to interfere with transcription or translation of a target gene upon hybridization with the target gene or transcript.
- Antisense oligonucleotides that selectively bind to a nucleic acid molecule encoding Qa-I are particularly preferred. Those skilled in the art will recognize that the exact length of the antisense oligonucleotide and its degree of complementarity with its target will depend upon the specific target selected, including the sequence of the target and the particular bases which comprise that sequence. It is preferred that the antisense oligonucleotide be constructed and arranged so as to bind selectively with the target under physiological conditions, i.e., to hybridize substantially more to the target sequence than to any other sequence in the target cell under physiological conditions.
- antisense oligonucleotide molecules for use in accordance with the present invention.
- antisense oligonucleotides should comprise at least about 10 and, more preferably, at least about 15 consecutive bases which are complementary to the target, although in certain cases modified oligonucleotides as short as 7 bases in length have been used successfully as antisense oligonucleotides. See Wagner et al. (1995) Nat. Med. 1(11):1116-8.
- the antisense oligonucleotides comprise a complementary sequence of 20-30 bases.
- oligonucleotides may be chosen which are antisense to any region of the gene or mRNA transcripts, in preferred embodiments the antisense oligonucleotides correspond to N-terminal or 5 ' upstream sites such as translation initiation, transcription initiation or promoter sites, hi addition, 3 '-untranslated regions may be targeted by antisense oligonucleotides.
- the antisense is targeted, preferably, to sites in which mRNA secondary structure is not expected (see, e.g., Sainio et al. (1994) Cell MoI. Neurobiol. 14(5):439-57) and at which proteins are not expected to bind.
- the antisense oligonucleotides of the invention may be composed of "natural" deoxyribonucleotides, ribonucleotides, or any combination thereof.
- oligonucleotides may be prepared by art-recognized methods which may be carried out manually or by an automated synthesizer. They also may be produced recombinantly by vectors.
- the antisense oligonucleotides of the invention also may include "modified" oligonucleotides. That is, the oligonucleotides may be modified in a number of ways which do not prevent them from hybridizing to their target but which enhance their stability or targeting or which otherwise enhance their therapeutic effectiveness.
- modified oligonucleotide as used herein describes an oligonucleotide in which (1) at least two of its nucleotides are covalently linked via a synthetic internucleoside linkage (i.e., a linkage other than a phosphodiester linkage between the 5 ' end of one nucleotide and the 3' end of another nucleotide) and/or (2) a chemical group not normally associated with nucleic acid molecules has been covalently attached to the oligonucleotide.
- a synthetic internucleoside linkage i.e., a linkage other than a phosphodiester linkage between the 5 ' end of one nucleotide and the 3' end of another nucleotide
- Preferred synthetic internucleoside linkages are phosphorothioates, alkylphosphonates, phosphorodithioates, phosphate esters, alkylphosphonothioates, phosphoramidates, carbamates, carbonates, phosphate triesters, acetamidates, carboxymethyl esters and peptides.
- modified oligonucleotide also encompasses oligonucleotides with a covalently modified base and/or sugar.
- modified oligonucleotides include oligonucleotides having backbone sugars which are covalently attached to low molecular weight organic groups other than a hydroxyl group at the 3 ' position and other than a phosphate group at the 5 'position.
- modified oligonucleotides may include a 2 -O-alkylated ribose group.
- modified oligonucleotides may include sugars such as arabinose instead of ribose.
- Binding of the Qa-I molecule by the agent permits NK-cell-mediated lysis of activated T cells. Without meaning to be bound to any particular theory or mechanism, binding by the agent is believed to result in a reduced inhibition of NK-cell-mediated lysis of activated T cells. This is believed to reflect a reduced interaction between Qa-I expressed on the T cells and NKG2A expressed on the NK cells, either because there is reduced expression of Qa-I or because sites involved in the interaction between Qa-I and NKG2A are blocked or otherwise altered so to reduce their interaction.
- NK-cell-mediated lysis of target cells can be measured using any suitable technique.
- target cells are labeled with 51 Cr, e.g., by incubation in the presence of 50 ⁇ Ci OfNa 2 ( 51 Cr)O 4 for 1 hour at 37 0 C, washed to remove excess label, and then mixed with a source of NK cells. Typically a range of effector-to-target (E-T) ratios are studied in parallel.
- the mixed cells are then incubated under physiologic conditions for a period of time sufficient to permit lysis to occur in a positive control, and cell- free superaatants are then collected from the labeled, mixed, incubated cells. Radioactivity is then measured, in the cell-free supernatants and specific lysis calculated using a formula such as in Example 7 below.
- NK cells can be isolated using any suitable technique.
- NK cells are isolated from splenocytes or peripheral blood mononuclear cells by negative selection. Cells are incubated with anti-CD4, anti-CD8, and anti-B220 antibodies, then mixed with magnetic beads, and separated by magnetic cell sorting. Cells in the unbound fraction are collected as NK cells.
- a method of the invention can be used to treat a condition selected from autoimmune disease, graft rejection, and graft-versus-host disease.
- an autoimmune disease is a disease or disorder in which a host's immune system recognizes cells or tissue of host origin as foreign. An immune response directed against the host cells or tissue results in immune-mediated damage to the cells or tissue.
- Autoimmune diseases are well known in the art and include, without limitation, acute disseminated encephalomyelitis, allergic angiitis and granulomatosis (Churg- Strauss disease), ankylosing spondylitis, autoimmune Addison's disease, autoimmune alopecia, autoimmune chronic active hepatitis, autoimmune encephalomyelitis, autoimmune hemolytic anemia, autoimmune neutropenia, autoimmune thrombocytopenic purpura, Behcet's syndrome, bullous pemphigoid, chronic bullous disease of childhood, chronic inflammatory demyelinating polyradiculoneuropathy, chronic neuropathy with monoclonal gammopathy, cicatricial pemphigoid, Crohn's disease, dermatitis herpetiformis, Eaton-Lambert myasthenic syndrome, epidermolysis bullosa acquisita, erythema nodosa, glomerulonephritis, gluten-sensitive
- the autoimmune disease is multiple sclerosis.
- autoimmune diseases specifically exclude vasculitides, such as anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitides. These include such entities as Wegener's granulomatosis and microscopic polyangiitis.
- ANCA anti-neutrophil cytoplasmic antibody
- Graft rejection refers to acute and/or chronic immune-mediated damage to cells, tissues, or organs transplanted from one individual to another individual, i.e., from a donor to a recipient.
- the graft or transplant can be an allograft (donor and recipient of the same species) or a xenograft (donor and recipient of different species).
- Grafts include but are not limited to kidney, heart, liver, pancreas, lung, small intestine, bladder, bone, bone marrow, artery, vein, skin, muscle, and limb.
- an effective amount of the agent is administered to the subject to treat the condition.
- an "effective amount" refers to that amount that is sufficient to realize a desired biological effect.
- an effective amount is a therapeutically effective amount.
- Such an amount refers to that amount that is sufficient to realize a desired biological effect in a subject.
- an effective amount is an amount sufficient to treat an autoimmune disease.
- an effective amount is an amount sufficient to reduce activated T cells in a subject.
- an effective amount is an amount sufficient to increase expression of Qa-I polypeptide on the surface of activated T cells.
- the effective amount for any particular application can vary depending on such factors as the disease or condition being treated, the particular agent being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art can empirically determine the effective amount of a particular agent without necessitating undue experimentation.
- daily oral doses of active compounds will be from about 0.01 milligrams/kg per day to 1000 milligrams/kg per day. It is expected that oral doses in the range of 0.5 to 50 milligrams/kg, in one or several administrations per day, will yield the desired results. Dosage may be adjusted appropriately to achieve desired drug levels, local or systemic, depending upon the mode of administration. For example, it is expected that intravenous administration would be from an order to several orders of magnitude lower dose per day. In the event that the response in a subject is insufficient at such doses, even higher doses (or effective higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits. Multiple doses per day are contemplated to achieve appropriate systemic levels of compounds.
- the therapeutically effective amount can be initially determined from animal models.
- a therapeutically effective dose can also be determined from human data for active agents which have been tested in humans and for compounds which are known to exhibit similar pharmacological activities, such as other related active agents. Higher doses may be required for parenteral administration.
- the applied dose can be adjusted based on the relative bioavailability and potency of the administered compound. Adjusting the dose to achieve maximal efficacy based on the methods described above and other methods as are well-known in the art is well within the capabilities of the ordinarily skilled artisan.
- a subject refers to a mammal.
- a subject is a human.
- a subject is a non-human mammal, including but not limited to a mouse, rat, hamster, guinea pig, rabbit, cat, dog, sheep, goat, pig, cow, horse, and non- human primate.
- the term “treat” as used herein means to obtain a desired pharmacologic and/or physiologic effect.
- the effect may be prophylactic in terms of completely or partially preventing a particular condition or disease or sign or symptom thereof, and/or may be therapeutic in terms of a partial or complete cure for a condition or disease and/or adverse effect attributable to the condition or disease.
- “Treat” as used herein covers any treatment of (e.g.
- a condition or disease in a non-human such as a mammal, or more particularly a human, and includes: (a) preventing the condition disease from occurring in a subject that may be at risk of developing or predisposed to having a condition or disease but has not yet been diagnosed as having it; (b) inhibiting the condition or disease, i.e., arresting its development; or (c) relieving or ameliorating the condition or disease, i.e., cause regression of the condition or disease.
- the invention in an aspect provides a method of reducing activated T cells in a subject.
- the method includes the step of administering to the subject an effective amount of an agent that binds a Qa-I molecule, wherein binding of the Qa-I molecule by the agent permits natural killer (NK)-cell-mediated lysis of activated T cells, to reduce activated T cells in the subject.
- an agent that binds a Qa-I molecule wherein binding of the Qa-I molecule by the agent permits natural killer (NK)-cell-mediated lysis of activated T cells, to reduce activated T cells in the subject.
- an activated T cell is an activated CD4 + T cell.
- reduced activated T cells means to decrease the number of activated T cells compared to a control number of activated T cells, for example in paired representative blood samples obtained from a subject.
- activated T cells are said to be reduced if there are no more than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, or 5% of a control number of activated T cells.
- the number of activated T cells in a sample can be measured using any suitable technique, many of which are known in the art.
- the number of activated T cells is measured using fluorescence-activated cell sorting (FACS) analysis with antibodies specific for T cells and at least one T cell surface activation marker.
- the number of activated T cells is measured using an enzyme-linked immunosorbent assay (ELISA) specific for a secreted product of activated T cells.
- ELISA enzyme-linked immunosorbent assay
- secreted products can include, without limitation, various cytokines, including interleukins, interferons, tumor necrosis factor, and chemokines.
- the subject has an inflammatory condition.
- An inflammatory condition refers to a disorder characterized by an unwanted immune response.
- Inflammatory conditions include, but are not limited to, adrenalitis, alveolitis, angiocholecystitis, appendicitis, balanitis, blepharitis, bronchitis, bursitis, carditis, cellulitis, cervicitis, cholecystitis, chorditis, cochlitis, colitis, conjuctivitis, cystitis, dermatitis, diverticulitis, encephalitis, endocarditis, esophagitis, eustachitis, fibrositis, folliculitis, gastritis, gastroenteritis, gingivitis, glossitis, hepatosplenitis, keratitis, labyrinthitis, laryngitis, lymphangitis, mastitis, meningitis, metritis, mucitis, myocarditis, myositis, myringitis, nephritis, neuritis
- inflammatory conditions specifically exclude vasculitides, such as anti- neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitides.
- inflammatory conditions specifically exclude autoimmune disease, graft rejection, and graft- versus-host disease.
- the invention in an aspect provides an improvement of a method of treatment that calls for adoptive transfer of T cells to a subject.
- the improvement includes the step of introducing into the T cells an effective amount of a vector that directs expression of a Qa-I polypeptide to increase Qa-I polypeptide expression on the surface of the T cells.
- T cells particularly activated T cells
- the inhibitory interaction between T cells and NK cells will be promoted, thereby protecting the T cells from NK-cell-mediated lysis.
- Such protection of T cells against NK-cell-mediated lysis is advantageous whenever it is desirable to maintain or expand a population of T cells.
- a vector that directs expression of a Qa-I polypeptide.
- a "vector” may be any of a number of nucleic acid molecules into which a desired sequence may be inserted by restriction and ligation for transport between different genetic environments or for expression in a host cell.
- Vectors are typically composed of DNA although RNA vectors are also available.
- Vectors include, but are not limited to, plasmids, phagemids, and virus genomes.
- the vectors useful in the invention include, but are not limited to, plasmids, phagemids, viruses, other vehicles derived from viral or bacterial sources that have been manipulated by the insertion or incorporation of the nucleic acid sequences of the invention, and additional nucleic acid fragments (e.g., enhancers, promoters) which can be attached to the nucleic acid sequences of the invention.
- additional nucleic acid fragments e.g., enhancers, promoters
- Viral vectors are a preferred type of vector and include, but are not limited to, nucleic acid sequences from the following viruses: adenovirus; adeno-associated virus; retrovirus, such as Moloney murine leukemia virus; Harvey murine sarcoma virus; murine mammary tumor virus; rouse sarcoma virus; SV40-type viruses; polyoma viruses; Epstein-Barr viruses; papilloma viruses; herpes virus; vaccinia virus; polio virus; and RNA virus such as a retrovirus.
- viruses include, but are not limited to, nucleic acid sequences from the following viruses: adenovirus; adeno-associated virus; retrovirus, such as Moloney murine leukemia virus; Harvey murine sarcoma virus; murine mammary tumor virus; rouse sarcoma virus; SV40-type viruses; polyoma viruses; Epstein-Barr viruses; papilloma viruses; herpes virus
- a cloning vector is one which is able to replicate in a host cell, and which is further characterized by one or more endonuclease restriction sites at which the vector may be cut in a determinable fashion and into which a desired DNA sequence may be ligated such that the new recombinant vector retains its ability to replicate in the host cell.
- replication of the desired sequence may occur many times as the plasmid increases in copy number within the host bacterium or just a single time per host before the host reproduces by mitosis.
- replication may occur actively during a lytic phase or passively during a lysogenic phase.
- An expression vector is one into which a desired DNA sequence may be inserted by restriction and ligation such that it is operably joined to regulatory sequences and may be expressed as an RNA transcript.
- Vectors may further contain one or more marker sequences suitable for use in the identification of cells which have or have not been transformed or transfected with the vector. Markers include, for example, genes encoding proteins which increase or decrease either resistance or sensitivity to antibiotics or other compounds, genes which encode enzymes whose activities are detectable by standard assays known in the art, e.g., beta-galactosidase or alkaline phosphatase, and genes which visibly affect the phenotype of transformed or transfected cells, hosts, colonies or plaques, e.g., green fluorescent protein.
- Preferred vectors are those capable of autonomous replication and expression of the structural gene products present in the DNA segments to which they are operably joined.
- a coding sequence and regulatory sequences are said to be "operably joined” when they are covalently linked in such a way as to place the expression or transcription of the coding sequence under the influence or control of the regulatory sequences.
- "operably joined” and “operably linked” are used interchangeably and should be construed to have the same meaning.
- two DNA sequences are said to be operably j oined if induction of a promoter in the 5 ' regulatory sequences results in the transcription of the coding sequence and if the nature of the linkage between the two DNA sequences does not (1) result in the introduction of a frame-shift mutation, (2) interfere with the ability of the promoter region to direct the transcription of the coding sequences, or (3) interfere with the ability of the corresponding RNA transcript to be translated into a protein.
- a promoter region is operably joined to a coding sequence if the promoter region is capable of effecting transcription of that DNA sequence such that the resulting transcript can be translated into the desired protein or polypeptide.
- regulatory sequences needed for gene expression may vary between species or cell types, but shall in general include, as necessary, 5 ' non-transcribed and 5 ' non-translated sequences involved with the initiation of transcription and translation respectively, such as a TATA box, capping sequence, CAAT sequence, and the like. Often, such 5 ' non-transcribed regulatory sequences will include a promoter region which includes a promoter sequence for transcriptional control of the operably joined gene. Regulatory sequences may also include enhancer sequences or upstream activator sequences as desired.
- the vectors of the invention may optionally include 5' leader or signal sequences. The choice and design of an appropriate vector is within the ability and discretion of one of ordinary skill in the art.
- the invention embraces the use of the one or more cDNA or genomic sequences in expression vectors, to transfect host cells and cell lines, be these prokaryotic, e.g., E. coli, or eukaryotic, e.g., T cells, CHO cells, COS cells, yeast expression systems, and recombinant baculovirus expression in insect cells.
- prokaryotic e.g., E. coli
- eukaryotic e.g., T cells
- CHO cells CHO cells
- COS cells COS cells
- yeast expression systems recombinant baculovirus expression in insect cells.
- mammalian cells such as human, mouse, hamster, pig, goat, primate, etc. They may be of a wide variety of tissue types, including mast cells, fibroblasts, oocytes, and lymphocytes, and may be primary cells and cell lines. Specific examples include dendritic cells, peripheral blood leukocytes, bone marrow stem cells and embryonic stem
- the invention in one aspect, also permits the construction of "knock-outs” and “knock-ins” in cells and in animals of one or more of the Qa-I polynucleotides, providing materials for studying certain aspects of NK cell regulation of activated T cells.
- Expression vectors containing all the necessary elements for expression are commercially available and known to those skilled in the art.
- Cells are genetically engineered by the introduction into the cells of heterologous DNA or RNA encoding one or more Qa-I polynucleotides, fragments, or variants thereof.
- the heterologous DNA or RNA is placed under operable control of transcriptional elements to permit the expression of the heterologous DNA in the host cell.
- Preferred systems for mRNA expression in mammalian cells are those such as pcDNA/V5-GW/D-TOPO® and pcDNA3.1 (Invitrogen) that contain a selectable marker (which facilitates the selection of stably transfected cell lines) and contain the human cytomegalovirus (CMV) enhancer-promoter sequences.
- CMV cytomegalovirus
- suitable for expression in primate or canine cell lines is the pCEP4 vector (Invitrogen), which contains an Epstein Barr virus (EBV) origin of replication, facilitating the maintenance of plasmid as a multicopy extrachromosomal element.
- ESV Epstein Barr virus
- a particularly preferred virus for certain applications is the adeno-associated virus
- AAV a double-stranded DNA virus.
- the adeno-associated virus is capable of infecting a wide range of cell types and species and can be engineered to be replication-deficient. It further has advantages, such as heat and lipid solvent stability, high transduction frequencies in cells of diverse lineages, including hemopoietic cells, and lack of superinfection inhibition thus allowing multiple series of transductions. Reportedly, the adeno-associated virus can integrate into human cellular DNA in a site-specific manner, thereby minimizing the possibility of insertional mutagenesis and variability of inserted gene expression.
- adeno-associated virus infections have been followed in tissue culture for greater than 100 passages in the absence of selective pressure, implying that the adeno-associated virus genomic integration is a relatively stable event.
- the adeno-associated virus can also function in an extrachromosomal fashion.
- Adenovirus-based constructs can be constructed by subcloning the desired cDNA, e.g., a Qa-I polynucleotide, downstream from an appropriate expression cassette (for example, the CMV promoter/enhancer) into the EcoRV site of the pCOl vector containing the Ad5 adenoviral sequences required for homologous recombination.
- the resulting plasmid can then be linearized by restriction enzyme digestion and cotransfected in 293 cells with large CIaI fragment of the Ad5 dl324 viral DNA. Stratford-Perricaudet et al. (1993) J. Clin. Invest. 90:626-30.
- the resulting replication-defective recombinant adenoviral constructs are then purified from isolated plaques.
- the viral preparations are typically purified by two CsCl gradient centrifugations, dialyzed against buffer containing 10 mM Tris-Cl pH 7.5, 1 mM MgCl 2 and 135 mM NaCl and stored at -80°C in 10% glycerol.
- Viral titer is typically determined by plaque assay on 293 cells (Graham et al. (1973) Virology 52:456-463) and expressed as plaque forming units (pfu) per mL.
- Non-cytopathic viral vectors are based on non-cytopathic eukaryotic viruses in which non-essential genes have been replaced with the gene of interest.
- Non- cytopathic viruses include retroviruses, the life cycle of which involves reverse transcription of genomic viral RNA into DNA with subsequent proviral integration into host cellular DNA.
- retrovirus lenti virus
- Qa-I polynucleotide The preparation of a retrovirus (lenti virus) containing a Qa-I polynucleotide is described in the Examples.
- retroviruses and retroviruses have been approved for human gene therapy trials.
- the retroviruses are replication-deficient (i.e., capable of directing synthesis of the desired proteins, but incapable of manufacturing an infectious particle).
- retroviral expression vectors have general utility for the high-efficiency transduction of genes in vivo.
- Standard protocols for producing replication-deficient retroviruses including the steps of incorporation of exogenous genetic material into a plasmid, transfection of a packaging cell lined with plasmid, production of recombinant retroviruses by the packaging cell line, collection of viral particles from tissue culture media, and infection of the target cells with viral particles) are provided in Kriegler, M., "Gene Transfer and Expression, A Laboratory Manual," W.H. Freeman Co., New York (1990) and Murry, EJ. Ed. "Methods in Molecular Biology,” vol. 7, Humana Press, Inc., Cliffton, New Jersey (1991).
- Another preferred retroviral vector is the vector derived from the Moloney murine leukemia virus, as described in Nabel et al. (1990) Science 249:1285-8. These vectors reportedly were effective for the delivery of genes to all three layers of the arterial wall, including the media. Other preferred vectors are disclosed in Flugelman et al. (1992) Circulation 85:1110-7. Additional vectors that are useful for delivering nucleic acids are described in U.S. Patent No. 5,61 A, 122 by Mulligan, et. al.
- additional delivery methods may be used to deliver a Qa-I polynucleotide to a cell and facilitate uptake thereby.
- additional delivery methods include, but are not limited to, natural or synthetic molecules, other than those derived from bacteriological or viral sources, capable of delivering the isolated Qa-I polynucleotide to a cell.
- a preferred such delivery method of the invention is a colloidal dispersion system.
- Colloidal dispersion systems include lipid-based systems including oil-in-water emulsions, micelles, mixed micelles, and liposomes.
- a preferred colloidal system of the invention is a liposome.
- Liposomes are artificial membrane vessels which are useful as a delivery vector in vivo or in vitro. It has been shown that large unilamellar vesicles (LUV), which range in size from 0.2 - 4.0 ⁇ m can encapsulate large macromolecules. RNA, DNA, and intact virions can be encapsulated within the aqueous interior and be delivered to cells in a biologically active form. Fraley et al. (1981) Trends Biochem.
- a liposome In order for a liposome to be an efficient gene transfer vector, one or more of the following characteristics should be present: (1) encapsulation of the gene of interest at high efficiency with retention of biological activity; (2) preferential and substantial binding to a target cell in comparison to non-target cells; (3) delivery of the aqueous contents of the vesicle to the target cell cytoplasm at high efficiency; and (4) accurate and effective expression of genetic information.
- Liposomes may be targeted to a particular tissue, such as a T cell, by coupling the liposome to a specific ligand such as a monoclonal antibody, sugar, glycolipid, or protein. Additionally, the vector may be coupled to a nuclear targeting peptide, which will direct the Qa-I polynucleotide to the nucleus of the host cell.
- Liposomes are commercially available from Gibco BRL, for example, as LIPOFECTINTM and LIPOFECT ACETM, which are formed of cationic lipids such as N- [l-(2, 3 dioleyloxy)-propyl]-N, N, N-trimethylammonium chloride (DOTMA) and dimethyl dioctadecylammonium bromide (DDAB).
- LIPOFECTINTM LIPOFECTINTM and LIPOFECT ACETM
- DOTMA N-[l-(2, 3 dioleyloxy)-propyl]-N, N, N-trimethylammonium chloride
- DDAB dimethyl dioctadecylammonium bromide
- Methods for making liposomes are well known in the art and have been described in many publications. Liposomes also have been reviewed by Gregoriadis (1985) Trends in Biotechnology, 3:235-41. Novel liposomes for the intracellular delivery of macromolecules, including
- the vector can be introduced into the T cells using any suitable technique, hi one embodiment the vector is introduced into the T cells by electroporation. In one embodiment the vector is introduced into the T cells by contacting the cells with the vector in the presence of a suitable polycationic lipophilic agent such as Lipofectamine (Invitrogen). hi one embodiment the T cells are activated T cells at the time the vector is introduced into the cells, hi one embodiment the T cells are resting T cells at the time the vector is introduced into the cells.
- Methods of treatment calling for adoptive transfer of T cells to a subject are known in the art and include, without limitation, methods of treating cancer and infectious disease. The methods find use particularly in settings where a host's immune response to a particular antigen is inadequate or compromised. See, for example, U.S. Pat. No.
- Cancer refers to an uncontrolled growth of cells which interferes with the normal functioning of the bodily organs and systems. Cancers which migrate from their original location and seed vital organs can eventually lead to the death of the subject through the functional deterioration of the affected organs. Hemopoietic cancers, such as leukemia, are able to outcompete the normal hemopoietic compartments in a subject, thereby leading to hemopoietic failure (in the form of anemia, thrombocytopenia and neutropenia) ultimately causing death.
- a metastasis is a region of cancer cells, distinct from the primary tumor location resulting from the dissemination of cancer cells from the primary tumor to other parts of the body.
- Metastases are most often detected through the sole or combined use of magnetic resonance imaging (MRI) scans, computed tomography (CT) scans, blood and platelet counts, liver function studies, chest X-rays and bone scans in addition to the monitoring of specific symptoms.
- MRI magnetic resonance imaging
- CT computed tomography
- Cancers include, but are not limited to, basal cell carcinoma, biliary tract cancer; bladder cancer; bone cancer; brain and CNS cancer; breast cancer; cervical cancer; choriocarcinoma; colon and rectum cancer; connective tissue cancer; cancer of the digestive system; endometrial cancer; esophageal cancer; eye cancer; cancer of the head and neck; gastric (stomach) cancer; intra-epithelial neoplasm; kidney (renal) cancer; larynx cancer; leukemia; liver cancer; lung cancer (e.g.
- lymphoma including Hodgkin's and Non-Hodgkin's lymphoma; melanoma; myeloma; neuroblastoma; oral cavity cancer (e.g., lip, tongue, mouth, and pharynx); ovarian cancer; pancreatic cancer; prostate cancer; retinoblastoma; rhabdomyosarcoma; rectal cancer; cancer of the respiratory system; sarcoma; skin cancer; testicular cancer; thyroid cancer; uterine cancer; cancer of the urinary system, as well as other carcinomas and sarcomas.
- lymphoma including Hodgkin's and Non-Hodgkin's lymphoma
- melanoma myeloma
- neuroblastoma e.g., oral cavity cancer (e.g., lip, tongue, mouth, and pharynx)
- ovarian cancer pancreatic cancer
- prostate cancer retinoblastoma
- infectious disease refers to a disorder arising from the invasion of a host, superficially, locally, or systemically, by an infectious microorganism. Infectious microorganisms include bacteria, viruses, parasites and fungi.
- viruses that have been found in humans include but are not limited to:
- Retroviridae e.g. human immunodeficiency viruses, such as HIV-I (also referred to as HDTV-III, LAVE or HTLV-III/LAV, or HIV-III; and other isolates, such as HIV-LP; Picornaviridae (e.g. polio viruses, hepatitis A virus; enteroviruses, human Coxsackie viruses, rhinoviruses, echoviruses); Calciviridae (e.g. strains that cause gastroenteritis); Togaviridae (e.g. equine encephalitis viruses, rubella viruses); Flaviviridae (e.g. dengue viruses, encephalitis viruses, yellow fever viruses); Coronaviridae (e.g.
- coronaviruses coronaviruses
- Rhabdoviridae e.g. vesicular stomatitis viruses, rabies viruses
- Filoviridae e.g. ebola viruses
- Paramyxoviridae e.g. parainfluenza viruses, mumps virus, measles virus, respiratory syncytial virus
- Orthomyxoviridae e.g. influenza viruses
- Bunyaviridae e.g. Hantaan viruses, bunya viruses, phleboviruses and Nairo viruses
- Arenaviridae hemorrhagic fever viruses
- Reoviridae e.g.
- reoviruses reoviruses, orbiviurses and rotaviruses
- Birnaviridae Hepadnaviridae (Hepatitis B virus); Parvoviridae (parvoviruses); Papovaviridae (papilloma viruses, polyoma viruses); Adenoviridae (most adenoviruses); Herpesviridae (herpes simplex virus (HSV) 1 and 2, varicella zoster virus, cytomegalovirus (CMV), herpes virus; Poxviridae (variola viruses, vaccinia viruses, pox viruses); and Iridoviridae (e.g. African swine fever virus); and unclassified viruses (e.g.
- Both gram negative and gram positive bacteria serve as antigens in vertebrate animals.
- Such gram positive bacteria include, but are not limited to, Pasteurella species, Staphylococci species, and Streptococcus species.
- Gram negative bacteria include, but are not limited to, Escherichia coli, Pseudomonas species, and Salmonella species.
- infectious bacteria include but are not limited to, Helicobacter pyloris, Borrelia burgdorferi, Legionella pneumophilia, Mycobacteria sps (e.g. M. tuberculosis, M. avium, M. intracellular e, M. kansasii, M.
- Streptococcus pyogenes Group A Streptococcus
- Streptococcus agalactiae Group B Streptococcus
- Streptococcus viridans group
- Streptococcus faecalis Streptococcus bovis
- Streptococcus anaerobic sps.
- Streptococcus pneumoniae pathogenic Campylobacter sp., Enterococcus sp., Haemophilus influenzae, Bacillus anthracis, Corynebacterium diphtheriae,
- Corynebacterium sp. Erysipelothrix rhusiopathiae, Clostridium perfringens, Clostridium tetani, Enterobacter aerogenes, Klebsiella pneumoniae, Pasturella multocida, Bacteroides sp., Fusobacterium nucleatum, Streptobacillus moniliformis, Treponema pallidum, Treponema per pneumonia, Leptospira, Rickettsia, and Actinomyces israelii.
- fungi examples include Cryptococcus neoformans, Histoplasma capsulatum, Coccidioides immitis, Blastomyces dermatitidis, Chlamydia trachomatis, Candida albicans.
- Plasmodium spp. such as Plasmodium falciparum, Plasmodium malariae, Plasmodium ovale, and Plasmodium vivax and Toxoplasma gondii.
- Blood-borne and/or tissues parasites include Plasmodium spp., Babesia microti, Babesia divergens, Leishmania tropica, Leishmania spp., Leishmania braziliensis, Leishmania donovani, Trypanosoma gambiense and
- Trypanosoma rhodesiense Africann sleeping sickness
- Trypanosoma cruzi Choagas' disease
- Toxoplasma gondii Toxoplasma gondii.
- the vector directs expression of a Qa-I polypeptide and increases Qa-I polypeptide expression on the surface of the T cells.
- Expression of Qa-I polypeptide on the surface of a cell, including T cells, can be measured using any suitable technique. In one embodiment the expression is measured using FACS with a suitable antibody specific for the Qa-I polypeptide.
- increase Qa-I polypeptide expression means to increase the number of level of Qa-I polypeptide expression compared to a control level of Qa-I polypeptide expression, for example in paired samples.
- level of Qa-I polypeptide expression is said to be increased if there is an increase of at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% over a control level of Qa-I polypeptide expression.
- the invention in an aspect provides method of promoting a T-cell-mediated immune response in a subject.
- the method includes the step of administering to the subject an effective amount of a vector that directs expression of a Qa-I polypeptide to increase Qa-I polypeptide expression on the surface of activated T cells in the subject.
- the invention in an aspect provides a pharmaceutical composition that includes (a) an antigen or a polynucleotide encoding an antigen and (b) an effective amount of a vector that directs expression of a Qa-I polypeptide to increase Qa-I polypeptide expression on the surface of activated T cells.
- the pharmaceutical composition in one embodiment further includes a pharmaceutically acceptable carrier.
- the pharmaceutical composition further includes at least one additional therapeutic agent.
- An "antigen" refers to any molecule capable of provoking an immune response specific for that molecule.
- Antigens include but are not limited to cells, cell extracts, proteins, polypeptides, peptides, polysaccharides, polysaccharide conjugates, peptide and non-peptide mimics of polysaccharides and other molecules, small molecules, lipids, glycolipids, carbohydrates, viruses and viral extracts and multicellular organisms such as parasites and allergens.
- Antigens specifically include cancer antigens, microbial antigens, and allergens. Antigens also specifically include antigens per se as well as polynucleotides encoding a polypeptide antigen.
- a polynucleotide encoding a polypeptide antigen in one embodiment is an expression vector that includes a polynucleotide encoding the antigen, operably linked to an expression control sequence.
- An antigen can be an isolated antigen derived from a natural source. In one embodiment an antigen is an isolated antigen prepared by chemical synthesis.
- a cancer antigen as used herein is a compound, such as a peptide or protein, associated with a tumor or cancer cell surface and which is capable of provoking an immune response when expressed on the surface of an antigen presenting cell in the context of an MHC molecule.
- Some of these antigens are encoded, although not necessarily expressed, by normal cells. These antigens can be characterized as those which are normally silent (i.e., not expressed) in normal cells, those that are expressed only at certain stages of differentiation and those that are temporally expressed such as embryonic and fetal antigens.
- cancer antigens are encoded by mutant cellular genes, such as oncogenes (e.g., activated ras oncogene), suppressor genes (e.g., mutant p53), fusion proteins resulting from internal deletions or chromosomal translocations. Still other cancer antigens can be encoded by viral genes such as those carried on RNA and DNA tumor viruses. Cancer antigens can be prepared from cancer cells either by preparing crude extracts of cancer cells, for example, as described in Cohen, et al. (1994) Cancer Research, 54:1055, by partially purifying the antigens, by recombinant technology, or by de no vo synthesis of known antigens. Cancer antigens include but are not limited to antigens that are recombinantly expressed, an immunogenic portion of, or a whole tumor or cancer. Such antigens can be isolated or prepared recombinantly or by any other means known in the art.
- oncogenes e.g., activated ras oncogen
- a microbial antigen as used herein is an antigen of a microorganism and includes but is not limited to virus, bacteria, parasites, and fungi.
- antigens include the intact microorganism as well as natural isolates and fragments or derivatives thereof and also synthetic compounds which are identical to or similar to natural microorganism antigens and induce an immune response specific for that microorganism.
- a compound is similar to a natural microorganism antigen if it induces an immune response (humoral and/or cellular) to a natural microorganism antigen.
- Such antigens are used routinely in the art and are well known to those of ordinary skill in the art.
- An allergen refers to a substance (antigen) that can induce an allergic or asthmatic response in a susceptible subject.
- the list of allergens is enormous and can include pollens, insect venoms, animal dander dust, fungal spores and drugs (e.g. penicillin).
- Examples of natural, animal and plant allergens include but are not limited to proteins specific to the following genuses: Agropyron (e.g. Agropyron repens); Agrostis (e.g.
- Agrostis alba Alder; Alnus (Alnus gultinoasa); Alternaria (Alternaria alternata);
- Arrhenatherum e.g. Arrhenatherum elatius
- Artemisia Artemisia vulgaris
- Avena e.g. Avena sativa
- Betula Betula verrucosa
- Blattella e.g. Blattella germanica
- Bromus e.g. Bromus inermis
- Canine Canis familiaris
- Dactylis e.g.
- Dactylis glomerata Dermatophagoides (e.g. Dermatophagoides farinae); Felis (Felis domesticus); Festuca (e.g. Festuca elatior); Holcus (e.g. Holcus lanatus); Juniperus (e.g.
- Juniperus sabinoides Juniperus virginiana, Juniperus communis and Juniperus ashei);
- Lolium e.g. Lolium perenne or Lolium multiflorum
- Olea Olea europa
- Parietaria e.g.
- Paspalum e.g. Paspalum notatum
- Periplaneta e.g. Periplaneta americana
- Phalaris e.g. Phalaris arundinaced
- Phleum e.g. Phleum pratense
- Plantago e.g. Plantago lanceolata
- Poa e.g. Poa pratensis or
- Poa compressa Quercus (Quercus alba); Secale (e.g. Secale cereale); Sorghum (e.g.
- an antigen can be an autoantigen or self- antigen, i.e., an antigen derived from normal host tissue origin. Normal host tissue does not include cancer cells.
- an immune response mounted against a self-antigen in the context of an autoimmune disease, is an undesirable immune response and contributes to destruction and damage of normal tissue, whereas an immune response mounted against a cancer antigen is a desirable immune response and contributes to the destruction of the tumor or cancer.
- the invention in an aspect provides a pharmaceutical composition that includes a T cell containing a vector that directs expression of a Qa-I polypeptide.
- the pharmaceutical composition in one embodiment further includes a pharmaceutically acceptable carrier.
- the pharmaceutical composition further includes at least one additional therapeutic agent.
- the Qa-I polypeptide is HLA-E.
- the invention in an aspect provides a method of identifying an agent useful for reducing activated T cells.
- the method includes the steps of contacting under physiologic conditions cells that express a Qa-I molecule with a test agent that binds the Qa-I molecule, in presence of NK cells that express NKG2A; measuring a test amount of lysis of the cells that express the Qa-I molecule; and identifying the test agent as an agent useful for reducing activated T cells when the test amount of lysis exceeds a control amount of lysis obtained under similar conditions without the test agent.
- the method is an in vitro method.
- the physiologic conditions can include usual conditions of temperature, pH, salt, osmotic strength, and the like, well known in the art.
- the cells that express the Qa-I molecule are cells that naturally express the Qa-I molecule.
- the cells are T cells, hi one embodiment the cells are activated T cells, hi one embodiment the cells that express the Qa-I molecule are cells that do not naturally express the Qa-I molecule but contain a vector that directs expression of a Qa-I polypeptide.
- the test agent can be any agent selected from small molecules (i.e., molecules with molecular weight up to 1.5 kilodaltons), nucleic acid molecules, polysaccharides, polypeptides, antibodies, and fragments of antibodies, hi one embodiment the agent is a small molecule that is part of a library of small molecules.
- the method in one embodiment is adapted for high throughput screening. High throughput screening permits screening of multiple test agents in a short amount of time, e.g., tens, hundreds, thousands, or even more test agents in a day. Methods and devices useful for high throughput screening are well known in the art.
- the NK cells that express NKG2A are isolated NKG2A + NK cells. NKG2A + NK cells can be isolated as described in Example 1 below.
- Antibodies, antibody fragments, and siRNA can be combined with other therapeutic agents.
- the antibody, antibody fragment, or siRNA and other therapeutic agent may be administered simultaneously or sequentially.
- the other therapeutic agents When the other therapeutic agents are administered simultaneously they can be administered in the same or separate formulations, but are administered at the same time.
- the other therapeutic agents are administered sequentially with one another and with the antibody, antibody fragment, or siRNA, when the administration of the other therapeutic agents and the antibody, antibody fragment, or siRNA is temporally separated. The separation in time between the administration of these compounds may be a matter of minutes or it may be longer.
- Other therapeutic agents include but are not limited to anti-microbial agents, anti-cancer therapy, immunosuppressive agents, anti-inflammatory agents, etc.
- the antibody, antibody fragment, and siRNA of the invention may be administered to a subject with an anti-microbial agent.
- An anti-microbial agent refers to a naturally-occurring or synthetic compound which is capable of killing or inhibiting infectious microorganisms.
- the type of anti-microbial agent useful according to the invention will depend upon the type of microorganism with which the subject is infected or at risk of becoming infected.
- Anti-microbial agents include but are not limited to antibacterial agents, anti-viral agents, anti-fungal agents and anti-parasitic agents.
- anti-bacterial agents kill or inhibit bacteria, and include antibiotics as well as other synthetic or natural compounds having similar functions.
- Antibiotics are low molecular weight molecules which are produced as secondary metabolites by cells, such as microorganisms. In general, antibiotics interfere with one or more bacterial functions or structures which are specific for the microorganism and which are not present in host cells.
- Anti- viral agents can be isolated from natural sources or synthesized and are useful for killing or inhibiting viruses.
- Anti-fungal agents are used to treat superficial fungal infections as well as opportunistic and primary systemic fungal infections. Anti-parasite agents kill or inhibit parasites.
- anti-parasitic agents also referred to as parasiticides useful for human administration include but are not limited to albendazole, amphotericin B, benznidazole, bithionol, chloroquine HCl, chloroquine phosphate, clindamycin, dehydroemetine, diethylcarbamazine, diloxanide furoate, eflornithine, furazolidaone, glucocorticoids, halofantrine, iodoquinol, ivermectin, mebendazole, mefloquine, meglumine antimoniate, melarsoprol, metrifonate, metronidazole, niclosamide, nifurtimox, oxamniquine, paromomycin, pen
- Antibacterial agents kill or inhibit the growth or function of bacteria.
- a large class of antibacterial agents is antibiotics.
- Antibiotics which are effective for killing or inhibiting a wide range of bacteria, are referred to as broad spectrum antibiotics.
- Other types of antibiotics are predominantly effective against the bacteria of the class gram- positive or gram-negative. These types of antibiotics are referred to as narrow spectrum antibiotics.
- Other antibiotics which are effective against a single organism or disease and not against other types of bacteria are referred to as limited spectrum antibiotics.
- Antibacterial agents are sometimes classified based on their primary mode of action. In general, antibacterial agents are cell wall synthesis inhibitors, cell membrane inhibitors, protein synthesis inhibitors, nucleic acid synthesis or functional inhibitors, and competitive inhibitors.
- Anti-bacterial agents useful in the invention include but are not limited to natural penicillins, semi-synthetic penicillins, clavulanic acid, cephalosporins, bacitracin, ampicillin, carbenicillin, oxacillin, azlocillin, mezlocillin, piperacillin, methicillin, dicloxacillin, nafcillin, cephalothin, cephapirin, cephalexin, cefamandole, cefaclor, cefazolin, cefuroxine, cefoxitin, cefotaxime, cefsulodin, cefetamet, cefixime, ceftriaxone, cefoperazone, ceftazidine, moxalactam, carbapenems, imipenems, monobactems, euztreonam, vancomycin, polymyxin, amphotericin B, nystatin, imidazoles, clotrimazole, miconazole,
- Chloramphenicol Palmitate Chloramphenicol Pantothenate Complex ; Chloramphenicol Sodium Succinate; Chlorhexidine Phosphanilate; Chloroxylenol; Chlortetracycline Bisulfate ; Chlortetracycline Hydrochloride ; Cinoxacin; Ciprofloxacin; Ciprofloxacin
- Cyclacillin Cycloserine; Dalfopristin; Dapsone ; Daptomycin; Demeclocycline;
- Demeclocycline Hydrochloride Demecycline; Denofungin ; Diaveridine; Dicloxacillin;
- Dicloxacillin Sodium Dihydrostreptomycin Sulfate; Dipyrithione; Dirithromycin;
- Doxycycline Doxycycline
- Doxycycline Calcium Doxycycline Fosfatex
- Doxycycline Hyclate Droxacin Sodium; Enoxacin; Epicillin; Epitetracycline Hydrochloride; Erythromycin;
- Kanamycin Sulfate Kitasamycin; Levofuraltadone; Levopropylcillin Potassium;
- Lexithromycin Lincomycin; Lincomycin Hydrochloride; Lomefloxacin; Lomefloxacin Hydrochloride; Lomefloxacin Mesylate; Loracarbef; Mafenide; Meclocycline;
- Nifurpirinol Nifurquinazol; Nifurthiazole; Nitrocycline; Nitrofurantoin; Nitromide; Norfloxacin; Novobiocin Sodium; Ofloxacin; Ormetoprim; Oxacillin Sodium; Oximonam;
- Oxytetracycline Hydrochloride Paldimycin; Parachlorophenol; Paulomycin; Pefloxacin; Pefloxacin Mesylate; Penamecillin; Penicillin G Benzathine; Penicillin G Potassium;
- Aminosalicylate Piperacillin Sodium; Pirbenicillin Sodium; Piridicillin Sodium; Pirlimycin Hydrochloride; Pivampicillin Hydrochloride; Pivampicillin Pamoate;
- Pivampicillin Probenate Polymyxin B Sulfate; Porfiromycin ; Propikacin; Pyrazinamide;
- Rifampin Rifapentine; Rifaximin; Rolitetracycline; Rolitetracycline Nitrate; Rosaramicin; Rosaramicin Butyrate; Rosaramicin Propionate; Rosaramicin Sodium Phosphate;
- Rosaramicin Stearate Rosoxacin; Roxarsone; Roxithromycin; Sancycline; Sanfetrinem
- Sulfadoxine Sulfalene; Sulfamerazine; Sulfameter; Sulfamethazine; Sulfamethizole;
- Temocillin Tetracycline; Tetracycline Hydrochloride; Tetracycline Phosphate Complex;
- Tobramycin Tobramycin; Tobramycin Sulfate; Tosufloxacin; Trimethoprim; Trimethoprim Sulfate; Trisulfapyrimidines; Troleandomycin; Trospectomycin Sulfate; Tyrothricin; Vancomycin;
- Vancomycin Hydrochloride Virginiamycin
- Zorbamycin Vancomycin Hydrochloride
- Antiviral agents are compounds which prevent infection of cells by viruses or replication of the virus within the cell. There are many fewer antiviral drugs than antibacterial drugs because the process of viral replication is so closely related to DNA replication within the host cell, that non-specific antiviral agents would often be toxic to the host. There are several stages within the process of viral infection which can be blocked or inhibited by antiviral agents. These stages include, attachment of the virus to the host cell (immunoglobulin or binding peptides), uncoating of the virus (e.g. amantadine), synthesis or translation of viral mRNA (e.g. interferon), replication of viral RNA or DNA (e.g. nucleotide analogues), maturation of new virus proteins (e.g.
- Nucleotide analogues are synthetic compounds which are similar to nucleotides, but which have an incomplete or abnormal deoxyribose or ribose group. Once the nucleotide analogues are in the cell, they are phosphorylated, producing the triphosphate formed which competes with normal nucleotides for incorporation into the viral DNA or RNA. Once the triphosphate form of the nucleotide analogue is incorporated into the growing nucleic acid chain, it causes irreversible association with the viral polymerase and thus chain termination.
- Nucleotide analogues include, but are not limited to, acyclovir (used for the treatment of herpes simplex virus and varicella-zoster virus), gancyclovir (useful for the treatment of cytomegalovirus), idoxuridine, ribavirin (useful for the treatment of respiratory syncitial virus), dideoxyinosine, dideoxycytidine, zidovudine (azidothymidine), imiquimod, and resimiquimod.
- acyclovir used for the treatment of herpes simplex virus and varicella-zoster virus
- gancyclovir used for the treatment of cytomegalovirus
- idoxuridine used for the treatment of cytomegalovirus
- ribavirin used for the treatment of respiratory syncitial virus
- dideoxyinosine dideoxycytidine
- zidovudine zidovudine
- imiquimod imiquimod
- resimiquimod
- the interferons are cytokines which are secreted by virus-infected cells as well as immune cells.
- the interferons function by binding to specific receptors on cells adjacent to the infected cells, causing the change in the cell which protects it from infection by the virus, ⁇ and ⁇ -interferon also induce the expression of Class I and Class II MHC molecules on the surface of infected cells, resulting in increased antigen presentation for host immune cell recognition, ⁇ and ⁇ -interferons are available as recombinant forms and have been used for the treatment of chronic hepatitis B and C infection. At the dosages which are effective for anti-viral therapy, interferons have severe side effects such as fever, malaise and weight loss.
- Anti-viral agents useful in the invention include but are not limited to immunoglobulins, amantadine, interferons, nucleotide analogues, and protease inhibitors.
- Specific examples of anti-virals include but are not limited to Acemannan; Acyclovir; Acyclovir Sodium; Adefovir; Alovudine; Alvircept Sudotox; Amantadine Hydrochloride; Aranotin; Arildone; Atevirdine Mesylate; Avridine; Cidofovir; Cipamfylline; Cytarabine Hydrochloride; Delavirdine Mesylate; Desciclovir; Didanosine; Disoxaril; Edoxudine; Enviradene; Enviroxime; Famciclovir; Famotine Hydrochloride; Fiacitabine; Fialuridine; Fosarilate; Foscarnet Sodium; Fosfonet Sodium; Ganciclovir; Ganciclo
- Anti-fungal agents are useful for the treatment and prevention of infective fungi. Anti-fungal agents are sometimes classified by their mechanism of action. Some antifungal agents function as cell wall inhibitors by inhibiting glucose synthase. These include, but are not limited to, basiungin/ECB. Other anti-fungal agents function by destabilizing membrane integrity. These include, but are not limited to, immidazoles, such as clotrimazole, sertaconzole, fluconazole, itraconazole, ketoconazole, miconazole, and voriconacole, as well as FK 463, amphotericin B, BAY 38-9502, MK 991, pradimicin, UK 292, butenafine, and terbinafine. Other anti-fungal agents function by breaking down chitin (e.g. chitinase) or immunosuppression (501 cream).
- immidazoles such as clotrimazole, sertaconzole, fluconazole, it
- the antibody, antibody fragment, or siRNA may also be administered in conjunction with an anti-cancer therapy.
- Anti-cancer therapies include cancer medicaments, radiation and surgical procedures.
- a "cancer medicament” refers to an agent which is administered to a subject for the purpose of treating a cancer.
- treating cancer includes preventing the development of a cancer, reducing the symptoms of cancer, and/or inhibiting the growth of an established cancer.
- the cancer medicament is administered to a subject at risk of developing a cancer for the purpose of reducing the risk of developing the cancer.
- chemotherapeutic agents chemotherapeutic agents
- immunotherapeutic agents cancer vaccines
- hormone therapy and biological response modifiers.
- the chemotherapeutic agent may be selected from the group consisting of methotrexate, vincristine, adriamycin, cisplatin, non-sugar containing chloroethylnitrosoureas, 5-fluorouracil, mitomycin C, bleomycin, doxorubicin, dacarbazine, taxol, fragyline, Meglamine GLA, valrubicin, carmustaine and poliferposan, MMI270, BAY 12-9566, RAS famesyl transferase inhibitor, famesyl transferase inhibitor, MMP, MTA/LY231514, LY264618/Lometexol, Glamolec, CI-994, TNP-470, Hycamtin/Topotecan, PKC412, Valspodar/PSC833, Novantrone/Mitroxantrone, Metaret/Suramin, Batimastat, E7070, BCH-4556, CS-682,
- YM 116 Iodine seeds, CDK4 and CDK2 inhibitors, PARP inhibitors, D4809/Dexifosamide, Ifes/Mesnex/Ifosamide, Vumon/Teniposide, Paraplatin/Carboplatin, Plantinol/cisplatin, Vepeside/Etoposide, ZD 9331, Taxotere/Docetaxel, prodrug of guanine arabinoside, Taxane Analog, nitrosoureas, alkylating agents such as melphelan and cyclophosphamide, Aminoglutethimide, Asparaginase, Busulfan, Carboplatin, Chlorombucil, Cytarabine HCl, Dactinomycin, Daunorubicin HCl, Estramustine phosphate sodium, Etoposide (VP16-213), Floxuridine, Fluorouracil (5-FU), Flut
- the immunotherapeutic agent may be selected from the group consisting of Ributaxin, Herceptin, Quadramet, Panorex, IDEC- Y2B8, BEC2, C225, Oncolym, SMART M195, ATRAGEN, Ovarex, Bexxar, LDP-03, ior t6, MDX-210, MDX-11, MDX-22, OVl 03, 3622 W94, anti-VEGF, Zenapax, MDX-220, MDX-447, MELIMMUNE-2, MELIMMUNE-I, CEACIDE, Pretarget, NovoMAb-G2, TNT, Gliomab-H, GNI-250, EMD-72000, LymphoCide, CMA 676, Monopharm-C, 4B5, ior egf.r3, ior c5, BABS, anti-FLK-2, MDX-260, ANA Ab, SMART IDlO Ab, SMART ABL 364 Ab and ImmuRAIT-CEA, but it
- the cancer vaccine may be selected from the group consisting of EGF, Anti- idiotypic cancer vaccines, Gp75 antigen, GMK melanoma vaccine, MGV ganglioside conjugate vaccine, Her2/neu, Ovarex, M-Vax, O-Vax, L-Vax, STn-KHL theratope, BLP25 (MUC-I), liposomal idiotypic vaccine, Melacine, peptide antigen vaccines, toxin/antigen vaccines, MVA-based vaccine, PACIS, BCG vacine, TA-HPV, TA-CIN, DISC-virus and ImmuCyst/TheraCys, but it is not so limited.
- the antibody, antibody fragment, or siRNA of the invention may be administered to a subject with an immunosuppressive agent.
- an immunosuppressive agent refers to an agent which is administered to a subject for the purpose of down- regulating an immune response. These agents may be used in the treatment of graft rejection, graft- versus-host disease, and autoimmune disease.
- Immunosuppressive agents specifically include but are not limited to corticosteroids such as prednisone and methylprednisolone, azathioprine, cyclosporine A, tacrolimus, mycophenolate mofetil, rapamycin, polyclonal antibodies (e.g., antithymocyte globulin), and monoclonal antibodies (e.g. OKT3, basiliximab, and daclizumab).
- corticosteroids such as prednisone and methylprednisolone, azathioprine, cyclosporine A, tacrolimus, mycophenolate mofetil, rapamycin, polyclonal antibodies (e.g., antithymocyte globulin), and monoclonal antibodies (e.g. OKT3, basiliximab, and daclizumab).
- an anti-inflammatory agent refers to an agent which is administered to a subject for the purpose of down- regulating an inflammatory response.
- Anti-inflammatory agents are generally less potent than immunosuppressive agents, and they specifically include, without limitation, nonsteroidal anti-inflammatory agents, gold, methotrexate.
- the formulations of the invention are administered in pharmaceutically acceptable solutions, which may routinely contain pharmaceutically acceptable concentrations of salt, buffering agents, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients.
- an effective amount of the antibody, antibody fragment, or siRNA can be administered to a subject by any mode that delivers the antibody, antibody fragment, or siRNA to the desired surface.
- Administering the pharmaceutical composition of the present invention may be accomplished by any means known to the skilled artisan.
- Preferred routes of administration include but are not limited to oral, parenteral, intramuscular, intranasal, sublingual, intratracheal, inhalation, ocular, vaginal, and rectal.
- the compounds i.e., antibody, antibody fragment, or siRNA, and other therapeutic agents
- the compounds can be formulated readily by combining the active compound(s) with pharmaceutically acceptable carriers well known in the art.
- Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated.
- Pharmaceutical preparations for oral use can be obtained as solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
- Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
- disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
- the oral formulations may also be formulated in saline or buffers, i.e. EDTA for neutralizing internal acid conditions or may be administered without any carriers.
- oral dosage forms of the above component or components may be chemically modified so that oral delivery of the derivative is efficacious.
- the chemical modification contemplated is the attachment of at least one moiety to the component molecule itself, where said moiety permits (a) inhibition of proteolysis; and (b) uptake into the blood stream from the stomach or intestine.
- the increase in overall stability of the component or components and increase in circulation time in the body examples include: polyethylene glycol, copolymers of ethylene glycol and propylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone and polyproline.
- the location of release may be the stomach, the small intestine (the duodenum, the jejunum, or the ileum), or the large intestine.
- the stomach the small intestine (the duodenum, the jejunum, or the ileum), or the large intestine.
- One skilled in the art has available formulations which will not dissolve in the stomach, yet will release the material in the duodenum or elsewhere in the intestine.
- the release will avoid the deleterious effects of the stomach environment, either by protection of the antibody, antibody fragment, or siRNA (or derivative) or by release of the biologically active material beyond the stomach environment, such as in the intestine.
- a coating impermeable to at least pH 5.0 is essential.
- examples of the more common inert ingredients that are used as enteric coatings are cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose phthalate (HPMCP), HPMCP 50, HPMCP 55, polyvinyl acetate phthalate (PVAP), Eudragit L30D, Aquateric, cellulose acetate phthalate (CAP), Eudragit L, Eudragit S, and Shellac. These coatings may be used as mixed films.
- a coating or mixture of coatings can also be used on tablets, which are not intended for protection against the stomach. This can include sugar coatings, or coatings which make the tablet easier to swallow.
- Capsules may consist of a hard shell (such as gelatin) for delivery of dry therapeutic i.e. powder; for liquid forms, a soft gelatin shell may be used.
- the shell material of cachets could be thick starch or other edible paper.
- moist massing techniques can be used.
- the therapeutic can be included in the formulation as fine multi-particulates in the form of granules or pellets of particle size about 1 mm.
- the formulation of the material for capsule administration could also be as a powder, lightly compressed plugs or even as tablets. The therapeutic could be prepared by compression.
- Colorants and flavoring agents may all be included.
- the antibody, antibody fragment, or siRNA (or derivative) may be formulated (such as by liposome or microsphere encapsulation) and then further contained within an edible product, such as a refrigerated beverage containing colorants and flavoring agents.
- an edible product such as a refrigerated beverage containing colorants and flavoring agents.
- One may dilute or increase the volume of the therapeutic with an inert material.
- These diluents could include carbohydrates, especially mannitol, a-lactose, anhydrous lactose, cellulose, sucrose, modified dextrans and starch.
- Certain inorganic salts may be also be used as fillers including calcium triphosphate, magnesium carbonate and sodium chloride.
- Some commercially available diluents are Fast-Flo, Emdex, STA-Rx 1500, Emcompress and Avicell.
- Disintegrants maybe included in the formulation of the therapeutic into a solid dosage form.
- Materials used as disintegrates include but are not limited to starch, including the commercial disintegrant based on starch, Explotab.
- Sodium starch glycolate, Amberlite, sodium carboxymethylcellulose, ultramylopectin, sodium alginate, gelatin, orange peel, acid carboxymethyl cellulose, natural sponge and bentonite may all be used.
- Another form of the disintegrants are the insoluble cationic exchange resins.
- Powdered gums may be used as disintegrants and as binders and these can include powdered gums such as agar, Karaya or tragacanth. Alginic acid and its sodium salt are also useful as disintegrants.
- Binders may be used to hold the therapeutic agent together to form a hard tablet and include materials from natural products such as acacia, tragacanth, starch and gelatin. Others include methyl cellulose (MC), ethyl cellulose (EC) and carboxymethyl cellulose (CMC). Polyvinyl pyrrolidone (PVP) and hydroxypropylmethyl cellulose (HPMC) could both be used in alcoholic solutions to granulate the therapeutic.
- An anti-frictional agent may be included in the formulation of the therapeutic to prevent sticking during the formulation process.
- Lubricants may be used as a layer between the therapeutic and the die wall, and these can include but are not limited to; stearic acid including its magnesium and calcium salts, polytetrafluoroethylene (PTFE), liquid paraffin, vegetable oils and waxes. Soluble lubricants may also be used such as sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol of various molecular weights, Carbowax 4000 and 6000.
- stearic acid including its magnesium and calcium salts
- PTFE polytetrafluoroethylene
- Soluble lubricants may also be used such as sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol of various molecular weights, Carbowax 4000 and 6000.
- Glidants that might improve the flow properties of the drug during formulation and to aid rearrangement during compression might be added.
- the glidants may include starch, talc, pyrogenic silica and hydrated silicoaluminate.
- surfactant might be added as a wetting agent.
- Surfactants may include anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate and dioctyl sodium sulfonate.
- Cationic detergents might be used and could include benzalkonium chloride or benzethomium chloride.
- non-ionic detergents that could be included in the formulation as surfactants are lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50 and 60, glycerol monostearate, polysorbate 40, 60, 65 and 80, sucrose fatty acid ester, methyl cellulose and carboxymethyl cellulose.
- surfactants could be present in the formulation of the antibody, antibody fragment, or siRNA or derivative either alone or as a mixture in different ratios.
- compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
- the push- fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
- the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
- stabilizers may be added.
- Microspheres formulated for oral administration may also be used. Such microspheres have been well defined in the art. All formulations for oral administration should be in dosages suitable for such administration.
- the compositions may take the form of tablets or lozenges formulated in conventional manner.
- the compounds for use according to the present invention may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
- a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
- a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount.
- Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose
- the antibody, antibody fragment, or siRNA (or derivative) is delivered to the lungs of a mammal while inhaling and traverses across the lung epithelial lining to the blood stream.
- inhaled molecules include Adjei et al., 1990, Pharmaceutical Research, 7:565-569; Adjei et al. (1990) International Journal of Pharmaceutics, 63:135-144 (leuprolide acetate); Braquet et al. (1989) Journal of Cardiovascular Pharmacology, 13(suppl. 5):143-146 (endothelin-1); Hubbard et al.
- Contemplated for use in the practice of this invention are a wide range of mechanical devices designed for pulmonary delivery of therapeutic products, including but not limited to nebulizers, metered dose inhalers, and powder inhalers, all of which are familiar to those skilled in the art.
- Some specific examples of commercially available devices suitable for the practice of this invention are the Ultravent nebulizer, manufactured by Mallinckrodt, Inc., St. Louis, Missouri; the Acorn II nebulizer, manufactured by Marquest Medical Products, Englewood, Colorado; the Ventolin metered dose inhaler, manufactured by Glaxo Inc., Research Triangle Park, North Carolina; and the Spinhaler powder inhaler, manufactured by Fisons Corp., Bedford, Massachusetts.
- each formulation is specific to the type of device employed and may involve the use of an appropriate propellant material, in addition to the usual diluents, adjuvants and/or carriers useful in therapy. Also, the use of liposomes, microcapsules or microspheres, inclusion complexes, or other types of carriers is contemplated.
- Chemically modified antibody, antibody fragment, or siRNA may also be prepared in different formulations depending on the type of chemical modification or the type of device employed.
- Formulations suitable for use with a nebulizer will typically comprise antibody, antibody fragment, or siRNA (or derivative) dissolved in water at a concentration of about 0.1 to 25 mg of biologically active antibody, antibody fragment, or siRNA per mL of solution.
- the formulation may also include a buffer and a simple sugar (e.g., for antibody, antibody fragment, or siRNA stabilization and regulation of osmotic pressure).
- the nebulizer formulation may also contain a surfactant, to reduce or prevent surface induced aggregation of the antibody, antibody fragment, or siRNA caused by atomization of the solution in forming the aerosol.
- Formulations for use with a metered-dose inhaler device will generally comprise a finely divided powder containing the antibody, antibody fragment, or siRNA (or derivative) suspended in a propellant with the aid of a surfactant.
- the propellant may be any conventional material employed for this purpose, such as a chlorofluorocarbon, a hydrochlorofluorocarbon, a hydrofluorocarbon, or a hydrocarbon, including trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethanol, and
- Suitable surfactants include sorbitan trioleate and soya lecithin. Oleic acid may also be useful as a surfactant.
- Formulations for dispensing from a powder inhaler device will comprise a finely divided dry powder containing antibody, antibody fragment, or siRNA (or derivative) and may also include a bulking agent, such as lactose, sorbitol, sucrose, or mannitol in amounts which facilitate dispersal of the powder from the device, e.g., 50 to 90% by weight of the formulation.
- the antibody, antibody fragment, or siRNA (or derivative) should most advantageously be prepared in particulate form with an average particle size of less than 10 ⁇ m (micrometers), most preferably 0.5 to 5 ⁇ m, for most effective delivery to the distal lung. Nasal delivery of a pharmaceutical composition of the present invention is also contemplated.
- Nasal delivery allows the passage of a pharmaceutical composition of the present invention to the blood stream directly after administering the therapeutic product to the nose, without the necessity for deposition of the product in the lung.
- Formulations for nasal delivery include those with dextran or cyclodextran.
- a useful device is a small, hard bottle to which a metered dose sprayer is attached.
- the metered dose is delivered by drawing the pharmaceutical composition of the present invention solution into a chamber of defined volume, which chamber has an aperture dimensioned to aerosolize and aerosol formulation by forming a spray when a liquid in the chamber is compressed.
- the chamber is compressed to administer the pharmaceutical composition of the present invention.
- the chamber is a piston arrangement.
- Such devices are commercially available.
- a plastic squeeze bottle with an aperture or opening dimensioned to aerosolize an aerosol formulation by forming a spray when squeezed is used.
- the opening is usually found in the top of the bottle, and the top is generally tapered to partially fit in the nasal passages for efficient administration of the aerosol formulation.
- the nasal inhaler will provide a metered amount of the aerosol formulation, for administration of a measured dose of the drug.
- the compounds when it is desirable to deliver them systemically, may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
- Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
- the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
- compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
- the active compounds may be in powder form for constitution with a suitable vehicle, e.g., sterile pyro gen-free water, before use.
- a suitable vehicle e.g., sterile pyro gen-free water
- the compounds may also be formulated in rectal or vaginal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
- the compounds may also be formulated as a depot preparation.
- Such long acting formulations may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
- the pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
- Suitable liquid or solid pharmaceutical preparation forms are, for example, aqueous or saline solutions for inhalation, microencapsulated, encochleated, coated onto microscopic gold particles, contained in liposomes, nebulized, aerosols, pellets for implantation into the skin, or dried onto a sharp object to be scratched into the skin.
- the pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops or preparations with protracted release of active compounds, in whose preparation excipients and additives and/or auxiliaries such as disintegrants, binders, coating agents, swelling agents, lubricants, flavorings, sweeteners or solubilizers are customarily used as described above.
- the pharmaceutical compositions are suitable for use in a variety of drug delivery systems. For a brief review of methods for drug delivery, see Langer (1990) Science 249: 1527-1533, which is incorporated herein by reference.
- the antibody, antibody fragment, or siRNA and optionally other therapeutics may be administered per se (neat) or in the form of a pharmaceutically acceptable salt.
- the salts should be pharmaceutically acceptable, but non- pharmaceutically acceptable salts may conveniently be used to prepare pharmaceutically acceptable salts thereof.
- Such salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulphuric, nitric, phosphoric, maleic, acetic, salicylic, p-toluene sulphonic, tartaric, citric, methane sulphonic, formic, malonic, succinic, naphthalene-2-sulphonic, and benzene sulphonic.
- such salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts of the carboxylic acid group.
- Suitable buffering agents include: acetic acid and a salt (1-2% w/v); citric acid and a salt (1-3% w/v); boric acid and a salt (0.5-2.5% w/v); and phosphoric acid and a salt (0.8-2% w/v).
- Suitable preservatives include benzalkonium chloride (0.003-0.03% w/v); chlorobutanol (0.3-0.9% w/v); parabens (0.01-0.25% w/v) and thimerosal (0.004-0.02% w/v).
- the pharmaceutical compositions of the invention contain an effective amount of a antibody, antibody fragment, or siRNA and optionally therapeutic agents included in a pharmaceutically-acceptable carrier.
- pharmaceutically-acceptable carrier means one or more compatible solid or liquid filler, diluents or encapsulating substances which are suitable for administration to a human or other vertebrate animal.
- carrier denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application.
- the components of the pharmaceutical compositions also are capable of being commingled with the compounds of the present invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficiency.
- the therapeutic agent(s), including specifically but not limited to the antibody, antibody fragment, or siRNA, may be provided in particles.
- Particles as used herein means nano or microparticles (or in some instances larger) which can consist in whole or in part of the antibody, antibody fragment, or siRNA or the other therapeutic agent(s) as described herein.
- the particles may contain the therapeutic agent(s) in a core surrounded by a coating, including, but not limited to, an enteric coating.
- the therapeutic agent(s) also may be dispersed throughout the particles.
- the therapeutic agent(s) also may be adsorbed into the particles.
- the particles may be of any order release kinetics, including zero order release, first order release, second order release, delayed release, sustained release, immediate release, and any combination thereof, etc.
- the particle may include, in addition to the therapeutic agent(s), any of those materials routinely used in the art of pharmacy and medicine, including, but not limited to, erodible, nonerodible, biodegradable, or nonbiodegradable material or combinations thereof.
- the particles may be microcapsules which contain the antibody, antibody fragment, or siRNA in a solution or in a semi-solid state.
- the particles may be of virtually any shape.
- Both non-biodegradable and biodegradable polymeric materials can be used in the manufacture of particles for delivering the therapeutic agent(s).
- Such polymers may be natural or synthetic polymers.
- the polymer is selected based on the period of time over which release is desired.
- Bioadhesive polymers of particular interest include bioerodible hydrogels described by H.S. Sawhney, CP. Pathak and J.A. Hubell in Macromolecules, (1993) 26:581-587, the teachings of which are incorporated herein.
- the therapeutic agent(s) may be contained in controlled release systems.
- controlled release is intended to refer to any drug-containing formulation in which the manner and profile of drug release from the formulation are controlled. This refers to immediate as well as non-immediate release formulations, with non-immediate release formulations including but not limited to sustained release and delayed release formulations.
- sustained release also referred to as “extended release” is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that preferably, although not necessarily, results in substantially constant blood levels of a drug over an extended time period.
- delayed release is used in its conventional sense to refer to a drug formulation in which there is a time delay between administration of the formulation and the release of the drug there from. "Delayed release” may or may not involve gradual release of drug over an extended period of time, and thus may or may not be “sustained release.”
- Long-term sustained release implant may be particularly suitable for treatment of chronic conditions.
- Long-term release as used herein, means that the implant is constructed and arranged to deliver therapeutic levels of the active ingredient for at least 7 days, and preferably 30-60 days.
- Long-term sustained release implants are well-known to those of ordinary skill in the art and include some of the release systems described above.
- Example 1 Defective Expansion of Qa-I -Deficient CD4 + T Cells and NK Lysis
- CD4 + T cells isolated from either C57BL/6 (B6) Qa-I wild-type (WT) or B6 Qa-I -deficient (B ⁇ .Qa-l 7 ) mice were transferred into syngeneic Ragl' ⁇ or Rag2 ⁇ / ⁇ PrfV' ⁇ hosts.
- CD4 + T cells from spleens and lymph nodes were enumerated.
- mice C57BL/6, Rag2 ⁇ / ⁇ , Rag2 ⁇ / ⁇ Prf ⁇ ' , and Rag2 'A common gamma chain ( ⁇ :)-deficient mice were purchased from Taconic Laboratories. Qa-I -deficient mice that have been described previously (Hu et al. (2004) Nat Immunol 5:516-23) were backcrossed onto C57BL/6 for at least 11 generations. OTII TCR-transgenic mice provided by H. Ploegh (Harvard Medical School, Boston, MA) were crossed with B6.Qa-l " ⁇ mice. Mice were housed in a specific pathogen-free, viral antibody-free animal facility at the Dana-Farber Cancer Institute.
- CD4 and CD8 T cells were purified by negative selection after incubation for 30 min with rat anti-mouse CD8 (anti-CD8) or anti-CD4 antibody, in addition to anti-B220, anti-Mac-1, anti-Gr-1 and anti-NKl.l antibodies (BD Pharmingen). After washing, cells were incubated for 30 min with magnetic beads coated with sheep anti-rat antibody (Dynal) before isolation of CD4 and CD8 T cells by magnetic separation.
- NK cells (0.5 X 10 6 ) purified from splenocytes of Rag2 ⁇ ' ⁇ mice were co-transferred with Qa-I -deficient OTII cells into Rag2 ⁇ ' PrfV ' hosts.
- Splenocytes were incubated with CD4, CD 8 and B220 antibody, and mixed with magnetic beads and separated by magnetic cell sorting.
- the CD4 " , CD8 " and B220 " splenocytes were stained with biotinylated NKG2AB6 mAb (eBioscience), followed by incubation with magnetic microbeads coated with biotin antibody (Mytech) before magnetic cell sorting using MACS.
- DX5 mAb was then used to further purify the NKG2A " NK cell population in the flow through cells.
- Purified NK cells were cultured in RPMI- 1640 supplemented with 10% fetal calf serum (FCS) in the presence of 1000 U/ml human recombinant IL-2 (BD Pharmingen) for 5 days.
- FCS fetal calf serum
- mAbs against CD3 ⁇ 145-2C11
- CD8 53-6.7
- CD4 GKl.5
- B220 RA3-6B2
- MAC-I Ml/70
- GR-I RB6-8C5
- NKl.1 PK136
- Ly49I/C FITC-conjugated anti-NKG2A/C/E
- Purified and biotinylated-anti-NKG2AB6 were purchased from eBioscience.
- Anti-biotin and anti-DX5 beads were purchased from Miltenyi Biotec (Auburn, CA).
- Qa-I -deficient mice were determined. Total numbers of CD4 + and CD8 + T cells from pooled spleen and lymph node of 5- to 6-week-old Qa-I -deficient (KO) mice or Qa-I WT littermates (4-6 mice/group) were compared. CD4 and CD8 cells were isolated as described in Example 1. Adult Qa- 1 -deficient mice did not harbor reduced numbers of CD4 cells. Since continuous re-supply of T cells from the thymus might compensate for NK-dependent elimination of Qa-I -deficient T cells in peripheral tissues, this possibility was tested by removal of the thymus from adult Qa-I -deficient mice.
- Qa-I -deficient or WT mice were thymectomized or sham thymectomized at around 10 weeks age.
- the numbers of CD4 + and CD8 + cells in peripheral lymphoid tissues 6 weeks after either thymectomy or sham thymectomy of Qa-I WT or Qa-I -deficient mice at 10 wks of age (3 mice/group) were measured.
- CD4 and CD8 cells were isolated as described in Example 1.
- Qa-I -deficient mice displayed a substantial (>85%) reduction in CD4 + T cells compared with Qa-I WT mice.
- expression of Qa-I was essential to ensure an unimpaired lifespan of CD4 cells in peripheral tissues.
- mice that express the OTII TCR Qa-I WT or Qa-I -deficient mice bearing the OTII TCR transgene
- C57BL/6 2D2 TCR transgenic mice express a TCR recognizing the CNS autoantigen myelin oligodendrocyte glycoprotein (MOG) (Bettelli, E. et al. (2003) J. Exp. Med. 197:1073-1081) and were crossed with B6.Qa-l -deficient mice) were immunized with 25 ⁇ g OVA peptide emulsified in CFA (see Example 1).
- MOG myelin oligodendrocyte glycoprotein
- mice To deplete NK cells, one group of mice was injected i.v. with anti-NKl.l antibody (PKl 36, 100 ⁇ g/mouse, purchased from Pharmingen) at day -1 and day 6 after peptide immunization.
- PKl 36 100 ⁇ g/mouse, purchased from Pharmingen
- Control mice were injected with phosphate buffered saline (PBS) (3-4 mice/group).
- PBS phosphate buffered saline
- Virtually all peripheral T cells in OTII C57BL/6 (B6) mice are CD4 + T cells and these mice lack CD8 + T cells.
- OTII CD4 + T cells were purified from draining lymph node and were incubated with different concentrations of OVA peptide and irradiated splenocytes from B6 mice in RPMI 1640 medium supplemented with 10% FCS and 50 ⁇ M ⁇ -mercaptoethanol. Culture supernatants were collected after 48 hours of culture and cytokine concentrations in supernatants were determined by enzyme-linked immunosorbent assay (ELISA) kit (BD Pharmingen).
- ELISA enzyme-linked immunosorbent assay
- Qa-I -deficient CD4 + T cells displayed a >90% reduction in interferon gamma (IFN- ⁇ ) responses (measured in ng/ml). This reflected increased susceptibility of Qa-I -deficient CD4 + T cells to NK lysis, because antibody-dependent depletion of NK cells during in vivo priming (using anti-NKl.l antibody, see above) allowed Qa-I -deficient CD4 + T cells to develop unimpaired and restored peptide recall responses.
- IFN- ⁇ interferon gamma
- BM bone marrow
- mice Lethally-irradiated Rag2 ⁇ ' ⁇ or Rag2 ⁇ ' ⁇ Prfl '1' host mice were reconstituted with hematopoietic stem cell (HSC)-enriched bone marrow (10 6 /mouse) from Qa-I WT (Thyl.l) and Qa-I -deficient (KO; Thyl.2) mice and sacrificed and analyzed 4 or 12 weeks later.
- HSC hematopoietic stem cell
- the BM cells were harvested from femur and tibia under sterile conditions from Qa-I WT or Qa-I -deficient mice, and erythrocytes were lysed and enriched for hematopoietic stem cells by depletion of lineage-positive cells with anti-CD4, anti-CD8, anti-CD3, anti-Grl, anti-Macl, anti-CD19 and anti-DX antibodies, followed by sheep anti-rat IgG-conjugated immunomagnetic beads (Dynal, see Example 1). Cells (1 X 10 6 ) were then injected into irradiated (400 rads) Ragl 1' or Rag! 1' Prfl 'A mice. The total number of peripheral CD4 + and CD8 + T cells from spleen and LN were enumerated (see Example 1).
- BM chimeric hosts were immunized subcutaneously with PLP peptide (amino acids 172-183; PVYIYFNTWTTC; SEQ ID NO:2; New England Peptide (Gardner, MA)) 12 weeks after adoptive transfer of BM cells.
- PLP peptide amino acids 172-183; PVYIYFNTWTTC; SEQ ID NO:2; New England Peptide (Gardner, MA)
- MOG 35-55 MOG 35-55
- SEQ ID NO:3 New England Peptide (Gardner, MA)
- CFA supplied with 4 mg/ml of Mycobacterium tuberculosis
- FIG. IA shows that transfer of 2D2 CD4 + T cells (10 6 ) into Ragl' ⁇ hosts stimulated with 10 ⁇ g of MOG peptide and pertussis toxin resulted in fulminating EAE that was lethal within 3 weeks.
- Rag2 ⁇ ' mice reconstituted with Qa-I -deficient 2D2 CD4 + T cells developed little or no disease after challenge with MOG-CFA and pertussis toxin.
- FIG. IB shows that when 2D2 CD4 + T cells (1 x 10 6 ) from either Qa-I WT or Qa-I -deficient mice were transferred into C57BL/6 hosts (5 mice/group) and followed by immunization with 150 ⁇ g MOG 35-55 peptide with pertussis toxin on the same day to induce EAE and the development of EAE was measured, Qa-I -dependent protection of autoreactive T cells from NK lysis was not limited to lymphopenic Rag2 ⁇ ' hosts, because intravenous transfer of 2D2 Qa-I WT CD4 + T cells but not 2D2 Qa-I -deficient CD4 + T cells induced EAE in C57BL/6 recipients.
- OTII CD4 + T cells (1 X 10 6 ) were transferred into Rag2 ⁇ ' ⁇ or RagT 1' Prfl ' ' mice (4 mice/group) before immunization with OVA peptide (75 ⁇ g peptide— CFA) immediately after transfer. Mice were sacrificed 72 hours later and total OTII cells in the draining LN and spleen enumerated.
- OTII CD4 + T cells infected with lentivirus expressing either green fluorescent protein (GFP) control or Qdm- ⁇ 2 m-Qa-l fusion protein were also transferred into Rag2 ⁇ ' ⁇ or Rag2 ⁇ ' ⁇ Prf ⁇ ' ' hosts (4 mice/group) before immunization with OVA peptide (75 ⁇ g peptide-CFA). Seventy-two hours later, expansion of OTII cells was analyzed.
- GFP green fluorescent protein
- Full-length open reading frame (ORF) of Qa-I was amplified by reverse transcriptase- polymerase chain reaction (RT-PCR) from concanavalin A (ConA)-activated C57BL/6 spleen RNA, digested withif ⁇ r ⁇ HI-ATjoI, and cloned into pLenti6/V5 (Invitrogen) by using Barri ⁇ l and Xhol restriction sites. The construct was confirmed by sequencing. Enhanced GFP alone was cloned into pLenti6/V5 as a negative control. For mutation screening, a point mutation was introduced by site-directed mutagenesis according to manufacturer's instructions (Stratagene).
- Qdm- ⁇ 2 m-Qa-l and HSP60- ⁇ 2 m-Qa-l fusion proteins were made by overlapping PCR.
- Lentiviral stocks were generated by cotransfection of 293 T cells with the packaging plasmids pLPl, pLP2, and pLP/VSVG (Invitrogen) by using Lipofectamine 2000 (Invitrogen) according to the manufacturer's protocol. Viral supernatants were collected 72 h after transfection and the viral titer for all transfections was approximately 10 7 plaque-forming units/ml.
- Naive Qa-I -deficient CD4 T cells were infected with lentivirus at a MOI of 5-10 for 3-6h at 37°C with 5% CO 2 and either washed and used directly after a 3h infection or washed and rested for an additional 15h at 37°C with 5% CO 2 .
- NKG2A The expression status of NKG2A was established on NK cells in C57BL/6 mice.
- NK cells were enriched by negative selection before NKG2A + and NKG2A " NK cells were sequentially separated by positive selection, using NKG2AB6 and DX5 antibody, respectively, and purified cells were incubated with IL-2 for 5 days, about half of NK cells from C57BL/6 mice expressed NKG2A (NKG2A + NK cells) and half did not (NKG2A " NK cells).
- Both NKG2A phenotypes were stable after 1 week of in vitro culture with IL-2.
- Purified and biotinylated-anti-NKG2AB6 were purchased from eBioscience.
- Anti-biotin and anti-DX5 beads were purchased from Miltenyi Biotec (Auburn, CA).
- FIG. 2 shows that when NKG2A + and NKG2A " NK cells isolated from B6 mice and activated individually by IL-2 were used as effector killer cells to kill ConA-activated CD4 + T cells from Qa-I wild type and Qa-I -deficient mice in a standard killing assay, the NKG2A + but not NKG2A " NK cell subset lysed Qa-I -deficient cells. This finding indicated that lytic activity is invested in an NK subset that expresses NKG2A + and therefore can bind to Qa-l-Qdm. To validate the findings stated above, the following control experiments were conducted:
- H-2K b D b -deficient, H-2K b -deficient and H-2D b -deficient mice were purchased from Taconic Laboratories.
- H-2K b D b -deficient CD4 cells were activated by ConA for 48 hour and labeled with 51 Cr before use as targets of NKG2A + and NKG2A " NK cells, or H-2K b -deficient or H-2D b -deficient single knockout CD4 T cells were used as targets for NK cells, the NKG2A + subsets also lysed H-2D b -deficient cells due to the lack of Qdm peptide. Lysis was inhibited by addition of Qdm peptide (which reconstituted the Qa-l- Qdm complex on H2-D b -deficient cells). The addition of Qdm peptide also partially inhibited lysis of H-2K b D b double deficient cells by NKG2A + NK cells but not by NKG2A " NK cells.
- NKG2A + and NKG2A " NK cells against MHC-deficient target L cells were subject to in vitro killing by IL-2-activated NKG2A + or NKG2A " NK cells, with or without addition of Qdm peptide (30 ⁇ M), the lytic activity of NKG2A + and NKG2A " NK cells against MHC-deficient target L cells was similar to that exerted against H-2K b D b -deficient target cells: both NK subsets lysed L cells equally well and lysis by NKG2A + cells was partially inhibited by expression of Qa-l-Qdm.
- Qa-I -deficient OTII cells were infected with lentivirus expressing either a Qdm- ⁇ 2 m-Qa-l fusion protein (QbQ) or a HSP60 peptide- ⁇ 2 m-Qa-l fusion protein (HbQ) and used as target cell in the killing assay by NKG2A + NK cells.
- Qa-I WT and Qa-I -deficient OTII cells were used as control.
- FIG. 3 shows the protection of Qa-I -deficient CD4 cells from NK lysis by lentiviral-mediated surface expression of a covalent Qdm- ⁇ 2 m-Qa-l complex.
- Increased susceptibility of Qa-I -deficient CD4 + T cells to NK cell lysis reflected defective expression of surface Qa-l-Qdm (rather than altered development of CD4 + T cells in Qa-I -deficient mice), because lentiviral-dependent re-expression of Qa-I heavy chain covalently- attached to a Qdm peptide efficiently restored resistance of Qa-I -deficient cells to NK lysis.
- NKG2A + fraction of NK cells is selectively equipped to monitor cellular Qa-l-Qdm expression was supported by an examination of the regulatory activity of NK cell subsets.
- CD4 cells were purified from Qa-I WT and Qa-I -deficient OTII TCR transgenic mice, and splenic dendritic cells (DCs) were purified from Qa-I WT and Qa-I -deficient mice and activated by anti-CD40.
- NKG2A + and NKG2A " NK cells were purified from B6 mice and stimulated with 1000 U/ml IL-2 for 5 days.
- OTII CD4 + T cells (5 X 10 4 ) were stimulated with 1 ⁇ g/ml OVA peptide and 2.5 x 10 4 activated DC.
- IL-2-activated NK cells were added to cultures 48 hours before proliferation of CD4 + T cells was measured.
- NK cells into cultures containing Qa-I -deficient or Qa-I WT OTII CD4 cells revealed a dose-dependent inhibition of proliferation of the Qa-I -deficient OTII CD4 cells by NKG2A + but not NKG2A " NK cells.
- the surface phenotype and function of both NK subsets were stable after 5 days in culture in the presence of IL-2 in vitro.
- NKG2A + or NKG2 A NK cells were transferred into Rag2 ⁇ ' ⁇ common gamma chain ( ⁇ c)-deficient hosts to evaluate the stability of the NKG2A + subset in vivo.
- NK cells like other lymphocytes, undergo homeostatic expansion in lymphopenic hosts.
- two weeks after adoptive transfer of purified NKG2A + NKl.1 cells into Rag2 ' ' ' ⁇ c-deficient hosts these cells maintained expression of NKG2A on their surface, indicating that the NKG2A + phenotype marks a stable subset of NK cells in vivo.
- NK cells developing from fetal progenitors acquire expression of NKG2A and Ly49 in a random manner, differential expression of Ly49 gene products on NKG2A + and NKG2A " NK cells might account for their ability to lyse "activated self targets.
- NKG2 A + and NKG2 A ⁇ NK cells may also express different amounts of activating receptors such as NKG2D (Rabinovich, B.A. (2003) J. Immunol. 170:3572-3576).
- Ly49I/C FITC-conjugated anti-NKG2A/C/E was purchased from Pharmingen. Purified and biotinylated-anti-NKG2AB6 were purchased from eBioscience. Anti-biotin and anti-DX5 beads were purchased from Miltenyi Biotec (Auburn, CA).
- NKG2A-binding residues (D69, Q72, R75) are conserved between HLA-E and Qa-I.
- Five Qa-I mutations (D69A, R72A, R75A D162A and E 166A) were tested for their impact on the functional interaction of Qa-I with CD94-NKG2A.
- Qa-I R72A mutant knock-in mice were generated using the cre-loxP system.
- a BAC clone containing an 11 kilobase (kb) DNA fragment including the Qa-I gene (H2-T23) was identified and fully mapped.
- LoxP-flanked Neo r was introduced into the EcoRV site in intron 3 of the Qa-I gene without interrupting the splicing by avoiding the conserved splicing branch site.
- Neo r gene was deleted by crossing the germline transmitted litters to ⁇ II ⁇ -CR ⁇ mice, which were then crossed to C57BL/6 mice for 5 generations. Homozygous R72A mutant mice were obtained by intercrossing the heterozygous littermates.
- FIG. 4 shows the Qa-I genomic locus and R72A targeting strategy. Correct integration of the construct was confirmed by Southern blot analysis.
- anti-Qa-1 antibody was administered to mice during the period preceding clinical signs of disease and preceding the development of Qa-I -restricted CD8+ regulatory T cells (Jiang, H. (1992) Science 256:1213-1215; Hu, D. (2004) Nat Immunol 5:516-23).
- C57BL/6 mice were immunized s.c. with 150 ⁇ g MOG 35-55 emulsified in CFA (supplemented with 4 mg/ml of Mycobacterium tuberculosis) and injected i.p. on day 0 and day 2 with 200 ng pertussis toxin to induce EAE.
- anti-Qa-1 antibody Qa- l b , BD Pharmingen was administered three times at day 5, 9, and 12 after immunization (150 ⁇ g, i.v.).
- This monoclonal antibody was raised against a peptide corresponding to amino acids 161-179 of Qa-I and is a mouse IgGl, K isotype antibody.
- anti-NKl.l was administered (150 ⁇ g, i.v.) at day 3, 7 and 10 to deplete NK cells before administration of anti-Qa-1 antibody on days 5, 9, and 12 to determine whether altered disease development was NK cell dependent or not.
- a control group was given either PBS or mouse IgGl isotype control (5 mice per group).
- Clinical assessment of EAE was performed daily and scored as described in Example 5.
- FIG. 5 shows that this protocol markedly reduced the intensity of EAE.
- Example 11 Generation and Characterization of QaI-I D227 K Mutant Knock-in Mice
- a genomic 4 Kb Qa-I fragment containing a D- ⁇ K amino acid exchange mutation at pos 227 after site-directed mutagenesis was cloned into a replacement vector and transfected into the TCl ES cell line. Positive homologous recombinant clones identified by long-range PCR and southern blot were used for blastocysts injection to produce chimeras.
- Neo r gene was deleted after crossing to B6-EII ⁇ -CRE mice and back-crossed to C57BL/6 (B6) for 7 generations followed by inter-crossing to produce homozygous B6.Qa-l D227K mutant mice.
- Expression of cell surface Qa-I by activated (ConA-stimulated) CD4 cells from B6.Qa-l D227K knock-in mice was indistinguishable from Qa-I WT T cells.
- CTL Qa-I -restricted cytolytic T cells
- CD8 cells obtained from B6 mice immunized with irradiated activated OT-2 CD4 T cells two weeks earlier were transferred along with OT-2 CD4 + cells into Rag2 ⁇ ⁇ Prfl ⁇ ' hosts immunized with OT-2 peptide.
- Expansion of Qa-I WT and Qa-I R72A OT2 + CD4 + cells was substantially inhibited by CD8 + cells, while expansion of D227K OT-2 cells over the following two weeks was unimpaired.
- mice with MOG peptide before induction of EAE with MOG/CFA and pertussis toxin substantially inhibited development of EAE.
- pre-immunization of B6. Qa-I D227K mice with MOG peptide was followed by robust disease development.
- the Qa-I D227K mutation also prevented the development of CD8 Treg to a second self-antigen - PLP.
- B6.Qa-l R72A knock-in mice were completely protected from induction of EAE by pre- immunization as described above. This was accompanied by a markedly reduced anti- PLP EFN- ⁇ response upon restimulation of CD4 cells in vitro, suggesting the hypothesis that engagement of Qa-l/Qdm on CD4 cells by NKG2A on CD8 Treg impairs the suppressive activity of these cells.
- MOG-immune CD4 cells expressing the R72A mutation to Qa-I -restricted inhibition by CD8 + Treg in adoptive Rag2 ⁇ / ⁇ Prfr / ⁇ hosts was investigated. Since activated CD4 T cells that fail to engage inhibitory NKG2A receptors on NK cells are susceptible to NK cell lysis, potential source of NK cells in experiments was eliminated by using Qa-I R72A CD4 T cells.
- MOG-specif ⁇ c CD4 responses were measured in adoptive Rag2 'l' Prfl '/' hosts.
- CD8-dependent suppression of 2D2 + CD4 cells is normally attenuated by an interaction between Qa-l/Qdm expressed by CD4 target cells and NKG2A receptors expressed by CD8 Treg, genetic disruption of this interaction might suppress this virulent form of EAE, as was the case for disease induced by polyclonal MOG-reactive CD4 cells.
- Transfer of 10 6 2D2 + CD4 cells (5 x the lethal dose) into Ragl' ' P ⁇ ' ' ' hosts provoked lethal EAE by day 15 in the presence of CD8 + (or CD4 + ) Treg.
- transfer of 10 6 2D2 + CD4 cells expressing the Qa-I R72A mutation also induced lethal disease by day 15, co-transfer of CD8 + Treg completely abrogated any sign of disease.
- the MOG-specific response of 2D2 + CD4 T cells expressing the R72 A mutation was shown to be highly susceptible to dose-dependent suppression by CD8 Treg in vitro, as judged by diminished proliferation and IL-2 secretion, whereas CD4 cells bearing the Qa-I D227K mutation were fully resistant to CD8 Treg activity, as expected.
- the dependence of CD8 Treg activity on Qa-I recognition was confirmed by the finding that anti-Qa-1 antibody blocked CD8-dependent suppression of the CD4 cell IL-2 response.
- Example 16 Anti-NKG2A F(ab)2 Fragment Prevents Development and Induces Remission of EAE Blockade of Qa- 1 /Qdm-NKG2 A interaction by anti-NKG2 A F(ab % fragment (but not an isotype control IgG2a F(ab') 2 fragment) mimicked the effect of the R72A mutation: CD8 cells from MOG-immune donors (which mediate inefficient suppressive activity against CD4 cells expressing WT Qa-I) exerted substantial inhibitory activity when the host was also given anti-NKG2A F(ab') 2 fragment.
- mice were treated with two doses of 200 ⁇ g of anti-anti-NKG2 A F(abO 2 fragment one week apart. This group displayed complete and long term remission of disease, in contrast to the control group. This experiment indicates that antibody-dependent blockade of the Qal-NKG2A interaction is a potentially potent therapeutic approach for multiple sclerosis.
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Abstract
Methods and compositions useful for promoting and inhibiting natural killer (NK) cell-mediated lysis of activated T cells are provided. The methods and compositions relate more specifically to modulation of the interaction between major histocompatibility complex (MHC) class Ib molecule Qa-I or its human counterpart HLA-E, expressed on activated T cells, and the inhibitory receptor NKG2A, expressed on NK cells. Certain methods and compositions for promoting NK-cell-mediated lysis of activated T cells include the use of antibodies or fragments thereof that bind specifically to Qa-1 polypeptides. Methods for treating autoimmune disease, graft rejection, and graft- versus- host disease, as well as methods for reducing activated T cells are provided. Also provided are methods and compositions, based on increased expression of Qa-1 polypeptides, for inhibiting NK-cell-mediated lysis of activated T cells, thereby promoting a T-cell-mediated immune response. Methods for identifying additional agents useful for reducing activated T cells are also provided.
Description
BLOCKADE OF THE INHIBITORY QA-1— CD94/NKG2A PATHWAY FOR TREATMENT OF AUTOIMMUNE DISEASE
BACKGROUND OF THE INVENTION There is increasing evidence that maintenance of immunological self tolerance is an active process that requires the participation of cells belonging to both the adaptive and innate immune systems. Although considerable progress has been made in understanding the regulatory role of subsets of T lymphocytes in this process (Paust et al. (2005) Immunol. Rev. 204:195-207), the contribution of innate immune mechanisms to self tolerance is less well defined.
The ability of natural killer lymphocytes (NK cells) to recognize and efficiently lyse activated T cells in vitro may allow these cells to participate in this process, e.g. through inhibition of clonal expansion of T cells activated by foreign or self antigens in vivo. Rabinovich et al. (2003) J. Immunol. 170:3572-6; Xu et al. (2005) J. Neuroimmunol. 163:24-30. NK cells may also downregulate adaptive immune responses through elimination of antigen-presenting dendritic cells (DCs) or through production of inhibitory cytokines. Piccioli et al. (2002) J. Exp. Med. 195:335-41.
NK cells are a subpopulation of lymphocytes involved in non-conventional immunity. These cells provide an efficient immunosurveillance mechanism by which undesired cells such as tumor cells or virally-infected cells can be eliminated. NK cell activity is regulated by a complex mechanism that involves both activating and inhibitory signals. See, e.g., Moretta et al. (2001) Annu. Rev. Immunol. 19:197-223; Moretta et al. (2004) EMBO J. 23(2):255-9; Ravetch et al. (2000) Science 290:84-89; Zambello et al. (2003) Blood 102:1797-805; and Moretta et al. (1997) Curr. Opin. Immunol. 9:694-701. NK cells are negatively regulated, i.e., inhibited from eliminating target cells, by certain major histocompatibility complex (MHC) class I-specific inhibitory receptors expressed on their cell surface. Karre et al. (1986) Nature 319:675-8; Ohlen et al. (1989) Science 246:666-8. These inhibitory receptors, which include Ly-49 (in rodents), killer cell inhibitory receptors (KIRs) (in humans), and NKG2A (in both rodents and humans), bind to polymorphic determinants of certain MHC class I molecules or human leukocyte antigens (HLA) expressed on target cells and inhibit NK-cell-mediated lysis of target cells.
HLA-E and corresponding murine Qa-I are non-classical MHC class Ib molecules described to interact with the NK cell inhibitory receptor NKG2A. Braud et al. (1998) Nature 391:795-799.
International patent application publication WO 2006/070286 discloses monoclonal antibodies directed against NKG2A and their use in treating certain autoimmune and inflammatory disorders.
International patent application publication WO 2006/063844 discloses soluble HLA-E molecules and their use in diagnosing and treating cancers and inflammatory diseases. WO 2006/063844 further discloses the use of HLA-E ligands, including anti- HLA-E antibodies and paratope-containing fragments thereof, for the treatment of certain inflammatory diseases.
SUMMARY OF THE INVENTION
The invention is based, at least in part, on the discovery by the inventors that the Qa-1-NKG2A interaction protects activated CD4+ T cells from lysis by a subset of
NKG2A+ NK cells and is essential for T cell expansion and development of immunologic memory. As disclosed herein, the invention is also based, at least in part, on the discovery by the inventors that blockade of this Qa-1-NKG2A interaction using antibodies specific for Qa-I results in potent NK-dependent elimination of activated autoreactive T cells and amelioration of experimental autoimmune encephalomyelitis. These findings provide the basis for methods useful in the regulation of adaptive T-cell responses, including methods for elimination of antigen-activated T cells in the context of autoimmune disease, transplantation, graft-versus-host disease, and inflammatory disorders.
The invention is also based, at least in part, on the discovery by the inventors that engagement of the CD94/NKG2A receptor expressed on CD8+ cells by Qa-I expressed on autoreactive CD4+ T cells protects these pathogenic CD4+ T cells from suppression by CD8+ T regulatory (Treg) cells. In addition, the invention is further based, at least in part, on the discovery by the inventors that blockade of the Qa-1-NKG2A interaction can enhance the activity of CD8+ Treg cells, unleashing a robust CD8 suppressive activity that results in profound inhibition of autoreactive CD4+ T cells. Disruption of this interaction and the resulting inhibition are disclosed not only to abolish the development of
experimental allergic encephalitis (EAE), which is a widely recognized model of multiple sclerosis, but also to induce complete remission of established EAE.
The invention in an aspect is a method of treating a condition selected from autoimmune disease, graft rejection, graft-versus-host disease. The method according to this aspect of the invention includes the step of administering to a subject having the condition an effective amount of an agent that binds a Qa-I molecule, wherein binding of the Qa-I molecule by the agent permits natural killer (NK)-cell-mediated lysis of activated T cells, to treat the condition.
The Qa-I molecule according to this and other aspects of the invention can be a polypeptide or a polynucleotide. In one embodiment the Qa-I molecule is a Qa-I polypeptide. In one embodiment the Qa-I polypeptide is HLA-E. In one embodiment the Qa-I molecule is a Qa-I polynucleotide, hi one embodiment the Qa-I polynucleotide is an ortholog of a murine Qa-I polynucleotide. hi one embodiment according to this and other aspects of the invention, the condition is an autoimmune disease, hi one embodiment the autoimmune disease is selected from acute disseminated encephalomyelitis, allergic angiitis and granulomatosis (Churg-Strauss disease), ankylosing spondylitis, autoimmune Addison's disease, autoimmune alopecia, autoimmune chronic active hepatitis, autoimmune encephalomyelitis, autoimmune hemolytic anemia, autoimmune neutropenia, autoimmune thrombocytopenic purpura, Behcet's syndrome, bullous pemphigoid, chronic bullous disease of childhood, chronic inflammatory demyelinating polyradiculoneuropathy, chronic neuropathy with monoclonal gammopathy, cicatricial pemphigoid, Crohn's disease, dermatitis herpetiformis, Eaton-Lambert myasthenic syndrome, epidermolysis bullosa acquisita, erythema nodosa, glomerulonephritis, gluten-sensitive enteropathy, Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, hypersensitivity vasculitis, immune-mediated infertility, insulin resistance, insulin-dependent diabetes mellitus, Kawasaki's disease, linear IgA disease, mixed connective tissue disease, multifocal motor neuropathy with conduction block, multiple sclerosis, myasthenia gravis, paraneoplastic pemphigus, pemphigoid gestationis, pemphigus foliaceus, pemphigus vulgaris, pernicious anemia, polyangiitis overlap syndrome, polyarteritis nodosa, polymyositis/dermatomyositis, primary biliary sclerosis, psoriasis, rheumatoid arthritis, sarcoidosis, scleroderma, sclerosing cholangitis, Sjogren's
syndrome, stiff-man syndrome, systemic lupus erythematosus, Takayasu's arteritis, temporal arteritis, thromboangiitis obliterans, type I autoimmune polyglandular syndrome, type II autoimmune polyglandular syndrome, ulcerative colitis, and Wegener's granulomatosis. In one embodiment the autoimmune disease is multiple sclerosis.
In one embodiment according to this and other aspects of the invention the condition is graft rejection.
In one embodiment according to this and other aspects of the invention the condition is graft-versus-host disease. In one embodiment according to this and other aspects of the invention the agent is an antibody or fragment thereof that binds specifically to a Qa-I polypeptide.
In one embodiment according to this and other aspects of the invention the agent, antibody, or fragment thereof that binds specifically to a Qa-I polypeptide interferes with interaction between Qa-I (or HLA-E) and CD94/NKG2A. In one embodiment according to this and other aspects of the invention the agent, antibody, or fragment thereof that binds specifically to a Qa-I polypeptide interferes with interaction between Qa-I (or HLA-E) and CD94/NKG2A, without interfering with interaction between Qa-I (or HLA-E) and CD8.
In one embodiment according to this and other aspects of the invention the agent is a short interfering RNA (siRNA) that binds specifically to a Qa-I polynucleotide.
The invention in an aspect is a method of reducing activated T cells in a subject. The method according to this aspect of the invention includes the step of administering to the subject an effective amount of an agent that binds a Qa-I molecule, wherein binding of the Qa-I molecule by the agent permits natural killer (NK)-cell-mediated lysis of activated T cells, to reduce activated T cells in the subject. The Qa-I molecule according can be a polypeptide or a polynucleotide, including in particular HLA-E, as disclosed herein.
In one embodiment according to this aspect of the invention the subject has an inflammatory condition. In one embodiment according to this aspect of the invention the inflammatory condition specifically excludes vasculitides, such as anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitides.
The invention in an aspect is an improvement in a method of treatment calling for adoptive transfer of T cells to a subject. The improvement according to this aspect of the
invention includes the step of introducing into the T cells an effective amount of a vector that directs expression of a Qa-I polypeptide to increase Qa-I polypeptide expression on the surface of the T cells.
The invention in an aspect is a method of promoting a T-cell-mediated immune response in a subject. The method according to this aspect of the invention includes the step of administering to the subject an effective amount of a vector that directs expression of a Qa-I polypeptide to increase Qa-I polypeptide expression on the surface of activated T cells in the subject.
The invention in an aspect is a pharmaceutical composition that includes (a) an antigen or a polynucleotide encoding an antigen and (b) an effective amount of a vector that directs expression of a Qa-I polypeptide to increase Qa-I polypeptide expression on the surface of activated T cells. In one embodiment the antigen or polynucleotide encoding the antigen is a polynucleotide encoding an antigen.
The invention in an aspect is a method of identifying an agent useful for reducing activated T cells. The method according to this aspect of the invention includes the steps of contacting under physiologic conditions cells that express a Qa-I molecule with a test agent that binds the Qa-I molecule, in presence of NK cells that express NKG2A; measuring a test amount of lysis of the cells that express the Qa-I molecule; and identifying the test agent as an agent useful for reducing activated T cells when the test amount of lysis exceeds a control amount of lysis obtained under similar conditions without the test agent.
BRIEF DESCRIPTION OF THE DRAWINGS
The figures are illustrative only and are not required for enablement of the invention disclosed herein.
FIG. IA is a graph depicting development of experimental allergic encephalitis (EAE) in Rag2~'~ (circles) or Rag2~'~ Prfl~'~ (squares), Qa-I wild type (WT; filled symbols) or Qa-I -deficient mice (KO, open symbols). Disease development of EAE was monitored by daily clinical assessment. Clinical scoring was as follows: 0, no disease; 1, decreased tail tone; 2, hind limb weakness or partial paralysis; 3, complete hind limb paralysis; 4, front and hind limb paralysis; 5, moribund state.
FIG. IB is a graph depicting development of EAE in C57BL/6 hosts as a control for FIG. IA. WT, Qa-I wild type; KO, Qa-I -deficient. For EAE clinical scoring refer to Figure IA.
FIG. 2 is a graph depicting T cell lysis by NK cells in a standard in vitro killing assay. Lysis of Qa-I WT (filled symbols) or Qa-I -deficient T cells (open symbols) by NKG2A+ (circles) and NKG2A" (squares) NK cells was scored. Percentage of killing is shown at the indicated E:T (effector : target) ratios.
FIG. 3 is a graph depicting T cell lysis by NK cells in a standard in vitro killing assay. Lysis of Qa-I-KO cells reconstituted with either Qdm-β2m-Qa-l fusion protein (QbQ, open squares) or a HSP60 peptide-β2m-Qa-l fusion protein (HbQ, open circles), or Qa-I WT (filled squares) and Qa-I -deficient OTII cells (filled circles) as controls, was measured as percentage of killing at the indicated E:T ratios.
FIG. 4 is a schematic drawing depicting the Qa-I genomic locus and R72A targeting strategy used to generate Qa-I R72A mutant knock-in mice. NEOr, neomycin- resistance gene. The R72A point mutation is shown in the third exon.
FIG. 5 is a graph depicting the effect of treatment with anti-Qa-1 antibody on development of EAE. Disease development was monitored and scored as described in FIG. 1. Mice received no antibody (open circles) or anti-Qa-1 (filled circles), anti-NKl.l (open squares), or a combination of anti-Qa-1 and anti-NKl.l (filled squares).
DETAILED DESCRIPTION OF THE INVENTION
The invention provides methods and compositions relating to aspects of an inhibitory interaction between NK cells and activated T cells, whereby activated T cells can be either eliminated by blocking the inhibitory interaction or protected by augmenting the inhibitory interaction. The particular inhibitory interaction arises through the interaction between the class Ib MHC molecule Qa-l-Qdm on activated T cells and the CD94-NKG2A receptor on NK cells. It has been discovered according to the invention that this particular interaction (a) protects activated T cells from NK lysis and (b) is essential for clonal expansion and development of immunologic memory by self-reactive T cells.
Whereas interaction between Qa-l-Qdm (hereinafter simply Qa-I unless otherwise specified) on activated T cells and CD94-NKG2A (hereinafter simply NKG2A unless
otherwise specified) on NK cells protects activated T cells from NK lysis, disruption of this interaction permits NK-cell-mediated lysis of activated T cells that express Qa-I on their cell surface. This disruption of the normal inhibitory interaction can thus be exploited in any setting where it is desirable to reduce T cell activation, for example in a variety of clinical conditions including autoimmune disease, graft rejection, graft- versus- host disease. Indeed, the invention relates in part to methods for treating such conditions by disrupting the inhibitory interaction using an agent that binds to a Qa-I molecule, particularly a Qa-I polypeptide.
Conversely, whereas interaction between Qa-I on activated T cells and NKG2A on NK cells protects activated T cells from NK lysis, induction or augmentation of this interaction reduces NK-cell-mediated lysis of activated T cells that express Qa-I on their cell surface. This induction or enhancement of the normal inhibitory interaction can thus be exploited in any setting where it is desirable to maintain or increase T cell activation, for example in a variety of clinical conditions including cancer, infection, as well as in methods of treatment calling for adoptive transfer of T cells, e.g., treatment of cancer and infection.
As described in greater detail below, it has been discovered that Qa-I -deficient CD4+ T cells failed to undergo antigen-induced or homeostatic expansion secondary to increased susceptibility to lysis by a defined subset of NK cells that express NKG2A on their cell surface. Also as described in greater detail below, it has been further discovered that lenti viral-mediated expression of Qa-l-Qdm on autoreactive CD4+ T cells rescued expansion of self-reactive T cell clones, while antibody-dependent interruption of the Qa- 1-NKG2A interaction dampened development of experimental autoimmune encephalomyelitis (EAE), a widely used animal model of multiple sclerosis. The classical MHC class I (Ia) molecules (HLA-A, HLA-B and HLA-C) are highly polymorphic and are ubiquitously expressed on most somatic cells. In contrast, non classical MHC class I (Ib) molecules (HLA-E, HLA-F and HLA-G) are broadly defined by a limited polymorphism and a restricted pattern of cellular expression.
Among class Ib molecules, HLA-E is characterized by a low polymorphism and a broad mRNA expression on different cell types. Lee et al. (1988) J Immunol. 160:4951- 60. This class I molecule is a heterodimer consisting of a heavy chain and a light chain (β2-microglobulin, β2m). The heavy chain is approximately 45 kDa and its gene contains
8 exons. Exon 1 encodes the leader peptide, exons 2 and 3 encode the Ct1 and α2 domains, which both bind peptide, exon 4 encodes the α3 domain, exon 5 encodes a transmembrane region, and exons 6 and 7 encode a cytoplasmic tail. Cell surface expression of HLA-E requires the availability of /^-microglobulin (Ulbrecht et al. (1999) Eur J Immunol. 29:537-47) and of a set of highly conserved nonameric peptides derived from the leader sequence of various HLA class I molecules including HLA-A, -B, -C, and -G. Braud et al. (1997) Eur J Immunol. 27: 1164-9; Ulbrecht et al. (1998) J Immunol. 160:4375-85. Efficient loading of HLA-E with class Ia leader sequence peptide requires the transporter associated with antigen processing (TAP) protein which translocates short peptides from the cytoplasm to the endoplasmic reticulum. Braud et al. (1998) Curr. Biol. 8:1-10. HLA-E also associates with peptides which derive either from viruses, including cytomegalovirus (CMV), Epstein-Barr virus (EBV), and influenza virus, or from stress proteins (e.g. HSP60). Ulbrecht et al. (1998) J Immunol. 160:4375-85; Tomasec et al. (2000) Science 287:1031; Michaelsson et al. (2002) J Exp Med. 196:1403-14. HLA-E (Online Mendelian Inheritance in Man (OMIM) accession no. 143010, the entire disclosure of which is herein incorporated by reference) is a nonclassical MHC molecule that is expressed on the cell surface and regulated by the binding of peptides derived from the signal sequence of other MHC class I molecules. HLA-E binds NK cells and some T cells, binding specifically to CD94/NKG2A, CD94/NKG2B, and CD94/NKG2C, and not to the inhibitory KIR receptors. See, e.g., Braud et al. (1998) Nature 391 :795-799. Surface expression of HLA-E is sufficient to protect target cells from lysis by CD94/NKG2A+ NK cell clones. As used herein, "HLA-E" refers to wild type, full length HLA-E. hi one embodiment "HLA-E" as used herein refers to wild type, full length HLA-E to which is bound a signal sequence of another MHC class I molecule. hi one embodiment HLA-E refers to a polypeptide having an amino acid sequence as provided by GenBank accession no. BAB63328. The full length sequence provided by GenBank accession no. BAB63328 includes 358 amino acids, including its own 21-amino acid signal peptide. Reference herein to an HLA-E amino acid by number shall refer to numbering without the signal peptide. Nucleotide sequences encoding HLA-E are available as GenBank accession nos. BA000025 (genomic) and AB103600 (cDNA).
Qa-I, also known as Qalb and as Qa-lb, is a mouse cell surface antigen that is the physiological ligand for NKG2A. As used herein, "Qa-I" refers to wild type, full length Qa-I.
In one embodiment Qa-I refers to a polypeptide having an amino acid sequence as provided by GenBank accession no. NP 034528. The full length sequence provided by GenBank accession no. NP_034528 includes 357 amino acids, including its own 20-amino acid signal peptide. Reference herein to a Qa-I amino acid by number shall refer to numbering without the signal peptide. A nucleotide sequence encoding Qa-I is available as GenBank accession no. NM_010398. In one embodiment Qa-I refers to a Qa-l-Qdm heterodimer. Qa-l-Qdm is a heterodimer composed of the MHC class Ib molecule Qa-I (H2-T23; the murine homologue of HLA-E), β2m, and peptides derived in TAP-dependent fashion from the MHC class I leader sequences (Qdm). Aldrich et al. (1992) J. Immunol. 149:3773-7; Lo et al. (2000) Nat. Med. 6:215-8; Sullivan et al. (2002) Immunity 17:95-105. The interaction between Qa-l-Qdm and CD94/NKG2A generally inhibits NK or CD8+ cytotoxic T lymphocyte (CTL) activity. Moser et al. (2002) Nat. Immunol. 3:189-95.
Although Qa-I is expressed in many cell types at the RNA level (Trasny et al. (1987) J. Exp. Med. 166:341-61), expression of the Qa-l-Qdm surface protein is restricted to activated T and B lymphocytes and dendritic cells (Soloski et al. (1995) Immunol. Rev. 147:67-89; Sullivan et al. (2002) Immunity 17:95-105), allowing this ligand to selectively mark the central triad of immunological cells.
As used herein, "NK" cells refers to a sub-population of lymphocytes that is involved in non-conventional immunity. NK cells can be identified by virtue of certain characteristics and biological properties, such as the expression of specific surface antigens including CD 16, CD56, and/or CD57, the absence of the alpha/beta or gamma/delta T-cell receptor (TCR) complex on the cell surface, the ability to bind to and kill cells that fail to express "self MHC/HLA antigens by the activation of specific cytolytic enzymes, the ability to kill tumor cells or other diseased cells that express a ligand for NK-activating receptors, and the ability to release cytokines that stimulate or inhibit the immune response. Any of these characteristics and activities can be used to identify NK cells, using methods well known in the art.
NKG2A (OMIM 161555, the entire disclosure of which is herein incorporated by reference) is a member of the NKG2 group of transcripts. Houchins, et al. (1991) J. Exp.
Med. 173:1017-1020. NKG2A is encoded by 7 exons spanning 25 kb, showing some differential splicing. NKG2A is an inhibitory receptor found on the surface of NK cells. Like inhibitory KIR receptors, it possesses an immunoreceptor tyrosine-based inhibition motif (ITIM) in its cytoplasmic domain. As used herein "NKG2A" refers to wild type, full length NKG2A.
CD94 (OMIM 602894, the entire disclosure of which is herein incorporated by reference in its entirety) is an antigen preferentially expressed on NK cells. Chang et al. (1995) Eur. J. Immunol. 25:2433-2437. CD94 is expressed as three major transcripts of
0.8, 1.8, and 3.5 kb and a minor transcript of 5.5 kb in NK cell lines, and encodes a protein with a 147-amino acid extracellular domain and several motifs characteristic of C-type lectins. The amino acid sequence of CD94 is 27 to 32% identical to those of NKG2 family members NKG2A, NKG2C, NKG2D, and NKG2E. Due to the virtual absence of a cytoplasmic domain, CD94 requires association with other receptors forming disulfide- bonded heterodimers with NKG2A, NKG2C, and NKG2E. Lazetic et al. (1996) J.
Immunol. 157:4741-4745. As used herein, "CD94" refers to wild type, full length CD94. The invention in an aspect provides a method of treating a condition selected from autoimmune disease, graft rejection, graft- versus-host disease. The method includes the step of administering to a subject having the condition an effective amount of an agent that binds a Qa-I molecule, wherein binding of the Qa-I molecule by the agent permits natural killer (NK)-cell-mediated lysis of activated T cells, to treat the condition.
In one embodiment a Qa-I molecule is a Qa-I polynucleotide. As used herein a
"Qa-I polynucleotide" refers to a polynucleotide encoding a murine Qa-I polypeptide or an ortholog thereof. For example, in one embodiment a Qa-I polynucleotide is a gene encoding a murine Qa-I polypeptide, and a gene encoding HLA-E is an ortholog of the gene encoding the murine Qa-I polypeptide.
In one embodiment a Qa-I molecule is a Qa-I polypeptide. As used herein a "Qa-
1 polypeptide" and, equivalently, "Qa-I" by itself, refers to a polypeptide encoded by a polynucleotide encoding a murine Qa-I polypeptide or an ortholog thereof. For example, in one embodiment a Qa-I polypeptide is encoded by a gene encoding a murine Qa-I
polypeptide, and a polypeptide encoded by a gene encoding HLA-E is a polypeptide encoded by an ortholog of the gene encoding the murine Qa-I polypeptide.
An agent that binds a Qa-I molecule in one embodiment is an agent that binds a Qa-I polypeptide. Binding of the agent to the Qa-I polypeptide interferes with interaction between Qa-I polypeptide expressed on the surface of a cell, e.g. a T cell, and NKG2A expressed on the surface of an NK cell. In one embodiment such an agent can be an antibody that binds specifically to a Qa-I polypeptide and inhibits NK-cell-mediated T- cell lysis. In one embodiment such an agent can be a fragment of an antibody that binds specifically to a Qa-I polypeptide and inhibits NK-cell-mediated T-cell lysis, provided the fragment binds specifically to a Qa-I polypeptide.
As used herein, "binds specifically to" means the agent or antibody can bind preferentially to a particular binding partner, under conditions that are relevant to the invention. Conditions under which specific binding is relevant to the invention include physiologic conditions (in vivo or in vitro) and assay conditions as described in the examples below. For example, an agent or antibody is said to bind specifically to a Qa-I molecule in vitro when the antibody or agent, when added to a sample under physiologic conditions, wherein the sample contains both the Qa-I molecule and other molecules, binds to the Qa-I molecule but binds only a little or not at all to the other molecules in the sample. As a further example, an antibody is said to bind specifically to a Qa-I polypeptide expressed on the surface of a cell in vivo when the antibody, when administered to a subject, binds to the Qa-I polypeptide expressed on the surface of a cell but binds only a little or not at all to other molecules expressed on the surface of a cell, hi one embodiment an antibody that binds only a little or not at all to other molecules expressed on the surface of a cell binds to such other molecules expressed on the surface of a cell only to an extent that is similar to that of isotype-matched antigen-nonspecific control antibodies.
The term "antibody" as used herein refers to polyclonal, monoclonal, and engineered antibodies, including but not limited to chimeric and humanized antibodies. Antibodies are well known in the art and can be of any class selected from IgG, IgM, IgA, IgE, and IgD. Each antibody comprises one or more paired polypeptide heterodimers in which there is a heavy chain and a light chain, each with a variable domain and a constant domain. Together, the variable domains of each heavy and light chain heterodimer
contribute to an antigen binding site (variable region). Each paired heterodimer further includes a class-specific Fc portion or fragment that includes paired portions of the heavy chain constant domains. In one embodiment the antibody is an IgG antibody. An IgG antibody can be selected or engineered either to include or to exclude sequences in the Fc portion that are involved in directing antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC). In this manner antibodies can include either depleting or non-depleting antibodies.
In one embodiment the antibody is a monoclonal antibody. Methods for generating and selecting monoclonal antibodies are well known in the art. In one embodiment the antibody is a chimeric antibody. A "chimeric antibody" is an engineered antibody molecule in which the constant region, or a portion thereof, is altered, replaced or exchanged so that the antigen binding site (variable region) is linked to a constant region of a different or altered class, effector function and/or species. Methods for making chimeric antibodies are well known in the art. In one embodiment the antibody is a humanized antibody. A "humanized" antibody refers to an engineered antibody in which the constant and variable framework region of one or more human immunoglobulins is fused with the binding region, e.g. the complementarity determining region (CDR), of a non-human immunoglobulin, e.g., a mouse immunoglobulin. Such humanized antibodies are designed to maintain the binding specificity of the non-human antibody from which the binding regions are derived, but to avoid an immune reaction against the non-human antibody when administered to a human. Methods for making humanized antibodies are well known in the art.
In one embodiment the antibody is a human antibody. In addition to an antibody raised in a human, a human antibody includes an antibody obtained from transgenic mice or other animals that have been "engineered" to produce specific human antibodies in response to antigenic challenge. See, e.g., Green et al. (1994) Nature Genet. 7:13; Lonberg et al. (1994) Nature 368:856; Taylor et al. (1994) Int. Immunol. 6:579, the entire teachings of which are herein incorporated by reference. A fully human antibody also can be constructed by genetic or chromosomal transfection methods, as well as phage display technology, all of which are known in the art (see, e.g., McCafferty et al. (1990) Nature 348:552-553). Human antibodies may also be generated by in vitro activated B cells. See,
e.g., U.S. Pat. Nos. 5,567,610 and 5,229,275, which are incorporated in their entirety by reference.
In one embodiment a fragment of an antibody is a Fab fragment, a F(abO2 fragment, or an Fd fragment, each of which includes at least one antigen binding site (variable region) derived from an antibody that binds specifically to a Qa-I polypeptide. The antibody fragment in one embodiment can be derived from any of the foregoing types of polyclonal, monoclonal, chimeric, humanized, or human antibodies.
The antibody or fragment thereof can be isolated. The term "isolated" when used in reference to a material means the material is substantially or essentially free from components which normally accompany it as found in its native state. hi one embodiment the antibody or fragment thereof that binds specifically to a Qa-I polypeptide binds to an epitope that includes to an amino acid residue selected from (or corresponding to) W65, D69, R72, R79, and Q155 of murine Qa-I (R65, D69, Q72, R79, and Hl 55, respectively, of HLA-E). In one embodiment the antibody or fragment thereof that binds specifically to a Qa-I polypeptide binds to an epitope that includes an amino acid residue selected from (or corresponding to) D69 or R72 of murine Qa-I. In one embodiment the antibody or fragment thereof that binds specifically to a Qa-I polypeptide binds to an epitope that includes R72 of murine Qa-I or Q72 in HLA-E.
In one embodiment the antibody or fragment thereof that binds specifically to a Qa-I polypeptide interferes with the interaction between Qa-I and CD94/NKG2A. In one embodiment the antibody or fragment thereof that binds specifically to a Qa-I polypeptide interferes with the interaction between Qa-I and CD94/NKG2A without interfering with the interaction between Qa-I and CD8.
An agent that binds a Qa-I molecule in one embodiment is an agent that binds a Qa-I polynucleotide. Preferably binding of the agent to the Qa-I polynucleotide reduces expression of Qa-I polypeptide, for example by RNA interference (RNAi) or antisense. Such an agent can be a polynucleotide at least 16 nucleotides long having a sequence that is complementary to at least a portion of the Qa-I polynucleotide. In one embodiment the agent that binds a Qa-I polynucleotide is RNA and can be used in RNAi. In one embodiment the agent that binds a Qa-I polynucleotide is DNA and can be used in antisense.
Methods of the invention also encompass use of isolated short RNA molecules that direct the sequence-specific degradation of Qa-I mRNA through a process known as RNA interference (RNAi). As used herein, Qa-I mRNA refers to an RNA transcript of a Qa-I polynucleotide encoding a Qa-I polypeptide. In one embodiment Qa-I mRNA is an RNA transcript for HLA-E. RNAi is now a well described mechanism for posttranscriptional gene silencing by double-stranded RNA (dsRNA) having complementary sequence to a target gene to be silenced. The process is known to occur naturally in a wide variety of organisms, including embryos of mammals and other vertebrates. It has been demonstrated that dsRNA is processed to RNA segments 21-23 nucleotides (nt) in length, and furthermore, that they mediate RNA interference in the absence of longer dsRNA. Thus, these 21-23 nt fragments are sequence-specific mediators of RNA degradation and are referred to herein as small interfering RNA (siRNA). Methods of the invention encompass the use of these fragments (or recombinantly produced or chemically synthesized oligonucleotides of the same or similar nature) to enable the targeting of Qa-I mRNAs for degradation in mammalian cells useful in the therapeutic applications discussed herein.
Small interfering RNAs (siRNAs) are 21- to 23 -nucleotide (nt) dsRNAs, in which one stand, the sense strand, is the complement of the target mRNA sequence. These are the effector molecules for inducing RNAi, leading to posttranscriptional gene silencing with RNA-induced silencing complex (RISC). In addition to siRNA, which can be chemically synthesized, various other systems in the form of potential effector molecules for posttranscriptional gene silencing are available, including short hairpin RNAs (shRNAs), long dsRNAs, short temporal RNAs, and micro RNAs (miRNAs). These effector molecules either are processed into siRNA, such as in the case of shRNA, or directly aid gene silencing, as in the case of miRNA. The present invention thus encompasses the use of siRNA as well as any other suitable form of RNA to effect posttranscriptional gene silencing by RNAi. Use of shRNA has the advantage over use of chemically synthesized siRNA in that the suppression of the target gene is typically long- term and stable. Methods and materials for design of the RNAs that mediate RNAi and the methods for transfection of the RNAs into cells and animals are well known in the art and are readily commercially available. Verma NK et al. (2004) J Clin Pharm Ther 28:395-404;
Mello CC et al. (2004) Nature 431 :338-42; Dykxhoom DM et al. (2003) Nat Rev MoI Cell Biol 4:457-67; Proligo (Hamburg, Germany); Dharmacon Research (Lafayette, CO, USA); Pierce Chemical (part of Perbio Science, Rockford, EL, USA); Glen Research (Sterling, VA, USA); ChemGenes (Ashland, MA, USA); and Cruachem (Glasgow, UK). The RNAs in one embodiment are chemically synthesized using appropriately protected ribonucleoside phosphoramidites and a conventional DNA/RNA synthesizer. Most conveniently, siRNAs are obtained from commercial RNA oligonucleotide synthesis suppliers listed herein. In general, RNAs are not difficult to synthesize and are readily provided in a quality suitable for RNAi. A typical 0.2 micromole-scale RNA synthesis provides about 1 milligram of RNA, which is sufficient for 1000 transfection experiments using a 24-well tissue culture plate format.
The Qa-I cDNA-specific siRNA can be designed by selecting a sequence that is not within 50-100 base pairs (bp) of the start codon and the termination codon, avoids intron regions, avoids stretches of 4 or more bases such as AAAA, CCCC, avoids regions with GC content <30% or >60%, avoids repeats and low complexity sequence, and avoids single nucleotide polymorphism sites. The target sequence can have a GC content of around 50%. The siRNA may be designed by a search for a 23-nt sequence motif AA(Nl 9), wherein A is adenosine nucleotide and N is any nucleotide. If no suitable sequence is found, then a 23-nt sequence motif NA(N21) may be used with conversion of the 3' end of the sense siRNA to dTdT, wherein dT is deoxythymidine nucleotide.
Alternatively, the siRNA can be designed by a search for NAR(N 17) YNN, wherein R is a purine base-containing nucleotide (purine nucleotide) and Y is a pyrimidine base- containing nucleotide (pyrimidine nucleotide) . The siRNA-targeted sequence can be further evaluated using a BLAST homology search to avoid off-target effects on other genes or sequences. Control RNA can have the same length and nucleotide composition as the siRNA but has at least 4 to 5 bases mismatched to the siRNA. For example, negative controls can be designed by scrambling targeted siRNA sequences.
The RNA molecules of the present invention can comprise a 3' hydroxyl group. The RNA molecules can be single-stranded or double-stranded; such molecules can be blunt-ended or comprise overhanging ends (e.g., 5', 3') from about 1 to about 6 nucleotides in length (e.g., pyrimidine nucleotides, purine nucleotides), hi order to further enhance the stability of the RNA of the present invention, the 3' overhangs can be stabilized against
degradation. The RNA can be stabilized by including purine nucleotides, such as adenosine or guanosine nucleotides. Alternatively, substitution of pyrimidine nucleotides by modified analogues, e.g., substitution of uridine 2-nucleotide (UU) 3' overhangs by T- deoxythymidine (dTdT) is tolerated and does not affect the efficiency of RNAi. The absence of a 2' hydroxyl significantly enhances the nuclease resistance of the overhang in tissue culture medium.
The RNA molecules used in the methods of the present invention can be obtained using any of a number of techniques known to those of skill in the art. For example, the RNA can be chemically synthesized or recombinantly produced using methods known in the art. Such methods are described in U.S. Published Patent Application Nos. US2002- 0086356A1 and US2003-0206884A1 that are herein incorporated by reference in their entirety.
The methods described herein are used to identify or obtain RNA molecules that are useful as sequence-specific mediators of Qa-I mRNA degradation and, thus, for inhibiting Qa-I expression. Expression of HLA-E can be inhibited in humans in order to prevent the protein from being translated and thus preventing interaction between HLA-E expressed on the surface of activated T cells with natural killer cells that express NKG2A.
The selected sequence for a shRNA typically has a stem length from 25 to 29 nt and loop size between 4 and 23 nt. DNA insert sequences that encode for shRNA are typically around 70 bp. In one embodiment the insert includes 20 nt inverted repeats that code for a portion of the stem complementary to the target gene and 10 nt spacers that code for the hairpin structure. The portions of the stem structure that binds to the target mRNA are critical for silencing capability of the shRNA and are therefore designed to be completely complementary. Restriction site overhangs of the insert can be conveniently designed to be specific to the vector to be used. In one embodiment the first base of the shRNA corresponding to the target mRNA sequence starts with nucleotides that correspond to the transcription start site for the particular promoter. shRNAs can be generated in cell lines with the help of commercially available shRNA expression vectors such as pSilencer™ 2.0-U6 and 3.0-H1 vectors from Ambion (Austin, TX), the psiRNA™ system including psiRNA-hH 1 , psiRNA-hH 1 neo, and psiRNAhHlzeo vectors from InvivoGen (San Diego, CA), the psi CHECK™ vectors which include silencing optimization capability, from Promega (Madison, WI), and siRNA
expression cassettes (SECs) from Ambion's Silencer™ Express system. The shRNA expression vectors are engineered plasmid vectors containing promoters of the type III class of Pol III promoters (Hl RNA, U 6 promoter), a cloning site for stem- looped RNA insert, and a 4 or 5-thymidine transcription termination signal. The polymerase III promoters have well-defined initiation and stop sites, and the transcripts lack a poly (A) tail. Five thymidines define the termination signal for these promoters, and transcript is cleaved after the second uridine, which generates the 3' UU overhang in expressed siRNA, similar to the 3' overhang of synthetic siRNA.
Any suitable RNA can be used in the methods of the present invention, provided that it has sufficient homology to the Qa-I gene (or ortholog thereof) to mediate RNAi. The RNA for use in the present invention can correspond to the entire gene or a portion thereof. There is no upper limit on the length of the RNA that can be used. For example, the RNA can range from about 21 base pairs (bp) of the gene to the full length of the gene or more. In one embodiment, the RNA used in the methods of the present invention is about 1000 bp in length. In another embodiment, the RNA is about 500 bp in length. In yet another embodiment, the RNA is about 22 bp in length. In certain embodiments the preferred length of the RNA of the invention is 21 to 23 nucleotides. Nucleotide sequences of murine Qa-I and human HLA-E are known. See, for example, GenBank Accession Nos. NM 010398 and BA000025, the entire contents of which are incorporated herein by reference.
The invention also embraces antisense oligonucleotides that selectively bind to a nucleic acid molecule encoding Qa-I to decrease expression and activity of this protein. Antisense oligonucleotides can be designed to interfere with expression of Qa-I based on the known nucleotide sequence of the Qa-I polynucleotides. As used herein, the term "antisense oligonucleotide" or "antisense" describes an oligonucleotide that is an oligoribonucleotide, oligodeoxyribonucleotide, modified oligoribonucleotide, or modified oligodeoxyribonucleotide which hybridizes under physiological conditions to DNA comprising a particular gene or to an mRNA transcript of that gene and, thereby, inhibits the transcription of that gene and/or the translation of that mRNA. The antisense oligonucleotide molecules are designed so as to interfere with transcription or translation of a target gene upon hybridization with the target gene or transcript. Antisense oligonucleotides that selectively bind to a nucleic acid molecule
encoding Qa-I are particularly preferred. Those skilled in the art will recognize that the exact length of the antisense oligonucleotide and its degree of complementarity with its target will depend upon the specific target selected, including the sequence of the target and the particular bases which comprise that sequence. It is preferred that the antisense oligonucleotide be constructed and arranged so as to bind selectively with the target under physiological conditions, i.e., to hybridize substantially more to the target sequence than to any other sequence in the target cell under physiological conditions. Based upon the nucleotide sequences of nucleic acid molecules encoding Qa-I or upon allelic or homologous genomic and/or cDNA sequences, one of skill in the art can easily choose and synthesize any of a number of appropriate antisense oligonucleotide molecules for use in accordance with the present invention. In order to be sufficiently selective and potent for inhibition, such antisense oligonucleotides should comprise at least about 10 and, more preferably, at least about 15 consecutive bases which are complementary to the target, although in certain cases modified oligonucleotides as short as 7 bases in length have been used successfully as antisense oligonucleotides. See Wagner et al. (1995) Nat. Med. 1(11):1116-8. Most preferably, the antisense oligonucleotides comprise a complementary sequence of 20-30 bases. Although oligonucleotides may be chosen which are antisense to any region of the gene or mRNA transcripts, in preferred embodiments the antisense oligonucleotides correspond to N-terminal or 5 ' upstream sites such as translation initiation, transcription initiation or promoter sites, hi addition, 3 '-untranslated regions may be targeted by antisense oligonucleotides. Targeting to mRNA splice sites has also been used in the art but may be less preferred if alternative mRNA splicing occurs, hi addition, the antisense is targeted, preferably, to sites in which mRNA secondary structure is not expected (see, e.g., Sainio et al. (1994) Cell MoI. Neurobiol. 14(5):439-57) and at which proteins are not expected to bind. hi one set of embodiments, the antisense oligonucleotides of the invention may be composed of "natural" deoxyribonucleotides, ribonucleotides, or any combination thereof. That is, the 5' end of one native nucleotide and the 3' end of another native nucleotide may be covalently linked, as in natural systems, via a phosphodiester internucleoside linkage. These oligonucleotides may be prepared by art-recognized methods which may be carried
out manually or by an automated synthesizer. They also may be produced recombinantly by vectors.
In preferred embodiments, however, the antisense oligonucleotides of the invention also may include "modified" oligonucleotides. That is, the oligonucleotides may be modified in a number of ways which do not prevent them from hybridizing to their target but which enhance their stability or targeting or which otherwise enhance their therapeutic effectiveness.
The term "modified oligonucleotide" as used herein describes an oligonucleotide in which (1) at least two of its nucleotides are covalently linked via a synthetic internucleoside linkage (i.e., a linkage other than a phosphodiester linkage between the 5 ' end of one nucleotide and the 3' end of another nucleotide) and/or (2) a chemical group not normally associated with nucleic acid molecules has been covalently attached to the oligonucleotide. Preferred synthetic internucleoside linkages are phosphorothioates, alkylphosphonates, phosphorodithioates, phosphate esters, alkylphosphonothioates, phosphoramidates, carbamates, carbonates, phosphate triesters, acetamidates, carboxymethyl esters and peptides.
The term "modified oligonucleotide" also encompasses oligonucleotides with a covalently modified base and/or sugar. For example, modified oligonucleotides include oligonucleotides having backbone sugars which are covalently attached to low molecular weight organic groups other than a hydroxyl group at the 3 ' position and other than a phosphate group at the 5 'position. Thus modified oligonucleotides may include a 2 -O-alkylated ribose group. In addition, modified oligonucleotides may include sugars such as arabinose instead of ribose.
Binding of the Qa-I molecule by the agent permits NK-cell-mediated lysis of activated T cells. Without meaning to be bound to any particular theory or mechanism, binding by the agent is believed to result in a reduced inhibition of NK-cell-mediated lysis of activated T cells. This is believed to reflect a reduced interaction between Qa-I expressed on the T cells and NKG2A expressed on the NK cells, either because there is reduced expression of Qa-I or because sites involved in the interaction between Qa-I and NKG2A are blocked or otherwise altered so to reduce their interaction.
NK-cell-mediated lysis of target cells, including in particular CD4+ T cells, can be measured using any suitable technique. In one embodiment target cells are labeled with
51Cr, e.g., by incubation in the presence of 50 μCi OfNa2(51Cr)O4 for 1 hour at 370C, washed to remove excess label, and then mixed with a source of NK cells. Typically a range of effector-to-target (E-T) ratios are studied in parallel. The mixed cells are then incubated under physiologic conditions for a period of time sufficient to permit lysis to occur in a positive control, and cell- free superaatants are then collected from the labeled, mixed, incubated cells. Radioactivity is then measured, in the cell-free supernatants and specific lysis calculated using a formula such as in Example 7 below.
NK cells can be isolated using any suitable technique. In one embodiment NK cells are isolated from splenocytes or peripheral blood mononuclear cells by negative selection. Cells are incubated with anti-CD4, anti-CD8, and anti-B220 antibodies, then mixed with magnetic beads, and separated by magnetic cell sorting. Cells in the unbound fraction are collected as NK cells. hi one embodiment a method of the invention can be used to treat a condition selected from autoimmune disease, graft rejection, and graft-versus-host disease. As used herein an autoimmune disease is a disease or disorder in which a host's immune system recognizes cells or tissue of host origin as foreign. An immune response directed against the host cells or tissue results in immune-mediated damage to the cells or tissue. Autoimmune diseases are well known in the art and include, without limitation, acute disseminated encephalomyelitis, allergic angiitis and granulomatosis (Churg- Strauss disease), ankylosing spondylitis, autoimmune Addison's disease, autoimmune alopecia, autoimmune chronic active hepatitis, autoimmune encephalomyelitis, autoimmune hemolytic anemia, autoimmune neutropenia, autoimmune thrombocytopenic purpura, Behcet's syndrome, bullous pemphigoid, chronic bullous disease of childhood, chronic inflammatory demyelinating polyradiculoneuropathy, chronic neuropathy with monoclonal gammopathy, cicatricial pemphigoid, Crohn's disease, dermatitis herpetiformis, Eaton-Lambert myasthenic syndrome, epidermolysis bullosa acquisita, erythema nodosa, glomerulonephritis, gluten-sensitive enteropathy, Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, hypersensitivity vasculitis, immune-mediated infertility, insulin resistance, insulin- dependent diabetes mellitus, Kawasaki's disease, linear IgA disease, mixed connective tissue disease, multifocal motor neuropathy with conduction block, multiple sclerosis, myasthenia gravis, paraneoplastic pemphigus, pemphigoid gestationis, pemphigus
foliaceus, pemphigus vulgaris, pernicious anemia, polyangiitis overlap syndrome, polyarteritis nodosa, polymyositis/dermatomyositis, primary biliary sclerosis, psoriasis, rheumatoid arthritis, sarcoidosis, scleroderma, sclerosing cholangitis, Sjogren's syndrome, stiff-man syndrome, systemic lupus erythematosus, Takayasu's arteritis, temporal arteritis, thromboangiitis obliterans, type I autoimmune polyglandular syndrome, type II autoimmune polyglandular syndrome, ulcerative colitis, and Wegener's granulomatosis. In one embodiment the autoimmune disease is multiple sclerosis. For purposes of this invention, in one embodiment autoimmune diseases specifically exclude vasculitides, such as anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitides. These include such entities as Wegener's granulomatosis and microscopic polyangiitis.
Graft rejection refers to acute and/or chronic immune-mediated damage to cells, tissues, or organs transplanted from one individual to another individual, i.e., from a donor to a recipient. The graft or transplant can be an allograft (donor and recipient of the same species) or a xenograft (donor and recipient of different species). Grafts include but are not limited to kidney, heart, liver, pancreas, lung, small intestine, bladder, bone, bone marrow, artery, vein, skin, muscle, and limb.
An effective amount of the agent is administered to the subject to treat the condition. As used herein, an "effective amount" refers to that amount that is sufficient to realize a desired biological effect. In one embodiment an effective amount is a therapeutically effective amount. Such an amount refers to that amount that is sufficient to realize a desired biological effect in a subject. For example, in one embodiment an effective amount is an amount sufficient to treat an autoimmune disease. In one embodiment an effective amount is an amount sufficient to reduce activated T cells in a subject. In one embodiment an effective amount is an amount sufficient to increase expression of Qa-I polypeptide on the surface of activated T cells. The effective amount for any particular application can vary depending on such factors as the disease or condition being treated, the particular agent being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art can empirically determine the effective amount of a particular agent without necessitating undue experimentation.
Generally, daily oral doses of active compounds will be from about 0.01 milligrams/kg per day to 1000 milligrams/kg per day. It is expected that oral doses in the
range of 0.5 to 50 milligrams/kg, in one or several administrations per day, will yield the desired results. Dosage may be adjusted appropriately to achieve desired drug levels, local or systemic, depending upon the mode of administration. For example, it is expected that intravenous administration would be from an order to several orders of magnitude lower dose per day. In the event that the response in a subject is insufficient at such doses, even higher doses (or effective higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits. Multiple doses per day are contemplated to achieve appropriate systemic levels of compounds.
For any compound described herein the therapeutically effective amount can be initially determined from animal models. A therapeutically effective dose can also be determined from human data for active agents which have been tested in humans and for compounds which are known to exhibit similar pharmacological activities, such as other related active agents. Higher doses may be required for parenteral administration. The applied dose can be adjusted based on the relative bioavailability and potency of the administered compound. Adjusting the dose to achieve maximal efficacy based on the methods described above and other methods as are well-known in the art is well within the capabilities of the ordinarily skilled artisan.
As used herein a "subject" refers to a mammal. In one embodiment a subject is a human. In one embodiment a subject is a non-human mammal, including but not limited to a mouse, rat, hamster, guinea pig, rabbit, cat, dog, sheep, goat, pig, cow, horse, and non- human primate.
Generally, the term "treat" as used herein means to obtain a desired pharmacologic and/or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a particular condition or disease or sign or symptom thereof, and/or may be therapeutic in terms of a partial or complete cure for a condition or disease and/or adverse effect attributable to the condition or disease. "Treat" as used herein covers any treatment of (e.g. complete or partial), or prevention of, a condition or disease in a non- human, such as a mammal, or more particularly a human, and includes: (a) preventing the condition disease from occurring in a subject that may be at risk of developing or predisposed to having a condition or disease but has not yet been diagnosed as having it; (b) inhibiting the condition or disease, i.e., arresting its development; or (c) relieving or ameliorating the condition or disease, i.e., cause regression of the condition or disease.
The invention in an aspect provides a method of reducing activated T cells in a subject. The method includes the step of administering to the subject an effective amount of an agent that binds a Qa-I molecule, wherein binding of the Qa-I molecule by the agent permits natural killer (NK)-cell-mediated lysis of activated T cells, to reduce activated T cells in the subject.
In one embodiment an activated T cell is an activated CD4+ T cell. As used herein, "reduce activated T cells" means to decrease the number of activated T cells compared to a control number of activated T cells, for example in paired representative blood samples obtained from a subject. In various embodiments activated T cells are said to be reduced if there are no more than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, or 5% of a control number of activated T cells. The number of activated T cells in a sample can be measured using any suitable technique, many of which are known in the art. In one embodiment the number of activated T cells is measured using fluorescence-activated cell sorting (FACS) analysis with antibodies specific for T cells and at least one T cell surface activation marker. In one embodiment the number of activated T cells is measured using an enzyme-linked immunosorbent assay (ELISA) specific for a secreted product of activated T cells. Such secreted products can include, without limitation, various cytokines, including interleukins, interferons, tumor necrosis factor, and chemokines. In one embodiment the subject has an inflammatory condition. An inflammatory condition refers to a disorder characterized by an unwanted immune response. Inflammatory conditions include, but are not limited to, adrenalitis, alveolitis, angiocholecystitis, appendicitis, balanitis, blepharitis, bronchitis, bursitis, carditis, cellulitis, cervicitis, cholecystitis, chorditis, cochlitis, colitis, conjuctivitis, cystitis, dermatitis, diverticulitis, encephalitis, endocarditis, esophagitis, eustachitis, fibrositis, folliculitis, gastritis, gastroenteritis, gingivitis, glossitis, hepatosplenitis, keratitis, labyrinthitis, laryngitis, lymphangitis, mastitis, meningitis, metritis, mucitis, myocarditis, myositis, myringitis, nephritis, neuritis, orchitis, osteochondritis, otitis media, pericarditis, peritendonitis, peritonitis, pharyngitis, phlebitis, prostatitis, pulpritis, retinitis, rhinitis, salpingitis, scleritis, sclerochoroiditis, scrotitis, sinusitis, spondylitis, steatitis, stomatitis, synovitis, syringitis, tendonitis, tonsillitis, urethritis, and vaginitis. For purposes of this invention, inflammatory conditions specifically exclude vasculitides, such as anti-
neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitides. Also for purposes of this invention, in one embodiment inflammatory conditions specifically exclude autoimmune disease, graft rejection, and graft- versus-host disease.
The invention in an aspect provides an improvement of a method of treatment that calls for adoptive transfer of T cells to a subject. The improvement includes the step of introducing into the T cells an effective amount of a vector that directs expression of a Qa-I polypeptide to increase Qa-I polypeptide expression on the surface of the T cells.
Without meaning to be bound to any particular theory or mechanism, it is believed that by increasing expression of Qa-I polypeptide on the surface of T cells, particularly activated T cells, the inhibitory interaction between T cells and NK cells will be promoted, thereby protecting the T cells from NK-cell-mediated lysis. Such protection of T cells against NK-cell-mediated lysis is advantageous whenever it is desirable to maintain or expand a population of T cells.
The method involves use of a vector that directs expression of a Qa-I polypeptide. As used herein, a "vector" may be any of a number of nucleic acid molecules into which a desired sequence may be inserted by restriction and ligation for transport between different genetic environments or for expression in a host cell. Vectors are typically composed of DNA although RNA vectors are also available. Vectors include, but are not limited to, plasmids, phagemids, and virus genomes. In general, the vectors useful in the invention include, but are not limited to, plasmids, phagemids, viruses, other vehicles derived from viral or bacterial sources that have been manipulated by the insertion or incorporation of the nucleic acid sequences of the invention, and additional nucleic acid fragments (e.g., enhancers, promoters) which can be attached to the nucleic acid sequences of the invention. Viral vectors are a preferred type of vector and include, but are not limited to, nucleic acid sequences from the following viruses: adenovirus; adeno-associated virus; retrovirus, such as Moloney murine leukemia virus; Harvey murine sarcoma virus; murine mammary tumor virus; rouse sarcoma virus; SV40-type viruses; polyoma viruses; Epstein-Barr viruses; papilloma viruses; herpes virus; vaccinia virus; polio virus; and RNA virus such as a retrovirus. One can readily employ other vectors not named but known in the art.
A cloning vector is one which is able to replicate in a host cell, and which is further characterized by one or more endonuclease restriction sites at which the vector
may be cut in a determinable fashion and into which a desired DNA sequence may be ligated such that the new recombinant vector retains its ability to replicate in the host cell. In the case of plasmids, replication of the desired sequence may occur many times as the plasmid increases in copy number within the host bacterium or just a single time per host before the host reproduces by mitosis. In the case of phage, replication may occur actively during a lytic phase or passively during a lysogenic phase.
An expression vector is one into which a desired DNA sequence may be inserted by restriction and ligation such that it is operably joined to regulatory sequences and may be expressed as an RNA transcript. Vectors may further contain one or more marker sequences suitable for use in the identification of cells which have or have not been transformed or transfected with the vector. Markers include, for example, genes encoding proteins which increase or decrease either resistance or sensitivity to antibiotics or other compounds, genes which encode enzymes whose activities are detectable by standard assays known in the art, e.g., beta-galactosidase or alkaline phosphatase, and genes which visibly affect the phenotype of transformed or transfected cells, hosts, colonies or plaques, e.g., green fluorescent protein. Preferred vectors are those capable of autonomous replication and expression of the structural gene products present in the DNA segments to which they are operably joined.
As used herein, a coding sequence and regulatory sequences are said to be "operably joined" when they are covalently linked in such a way as to place the expression or transcription of the coding sequence under the influence or control of the regulatory sequences. As used herein, "operably joined" and "operably linked" are used interchangeably and should be construed to have the same meaning. If it is desired that the coding sequences be translated into a functional protein, two DNA sequences are said to be operably j oined if induction of a promoter in the 5 ' regulatory sequences results in the transcription of the coding sequence and if the nature of the linkage between the two DNA sequences does not (1) result in the introduction of a frame-shift mutation, (2) interfere with the ability of the promoter region to direct the transcription of the coding sequences, or (3) interfere with the ability of the corresponding RNA transcript to be translated into a protein. Thus, a promoter region is operably joined to a coding sequence if the promoter region is capable of effecting transcription of that DNA sequence such that the resulting transcript can be translated into the desired protein or polypeptide.
The precise nature of the regulatory sequences needed for gene expression may vary between species or cell types, but shall in general include, as necessary, 5 ' non- transcribed and 5 ' non-translated sequences involved with the initiation of transcription and translation respectively, such as a TATA box, capping sequence, CAAT sequence, and the like. Often, such 5 ' non-transcribed regulatory sequences will include a promoter region which includes a promoter sequence for transcriptional control of the operably joined gene. Regulatory sequences may also include enhancer sequences or upstream activator sequences as desired. The vectors of the invention may optionally include 5' leader or signal sequences. The choice and design of an appropriate vector is within the ability and discretion of one of ordinary skill in the art.
It will also be recognized that the invention embraces the use of the one or more cDNA or genomic sequences in expression vectors, to transfect host cells and cell lines, be these prokaryotic, e.g., E. coli, or eukaryotic, e.g., T cells, CHO cells, COS cells, yeast expression systems, and recombinant baculovirus expression in insect cells. Especially useful are mammalian cells such as human, mouse, hamster, pig, goat, primate, etc. They may be of a wide variety of tissue types, including mast cells, fibroblasts, oocytes, and lymphocytes, and may be primary cells and cell lines. Specific examples include dendritic cells, peripheral blood leukocytes, bone marrow stem cells and embryonic stem cells. The expression vectors require that the pertinent sequence, i.e., those nucleic acids described herein, be operably linked to a promoter.
The invention, in one aspect, also permits the construction of "knock-outs" and "knock-ins" in cells and in animals of one or more of the Qa-I polynucleotides, providing materials for studying certain aspects of NK cell regulation of activated T cells.
Expression vectors containing all the necessary elements for expression are commercially available and known to those skilled in the art. Cells are genetically engineered by the introduction into the cells of heterologous DNA or RNA encoding one or more Qa-I polynucleotides, fragments, or variants thereof. The heterologous DNA or RNA is placed under operable control of transcriptional elements to permit the expression of the heterologous DNA in the host cell. Preferred systems for mRNA expression in mammalian cells are those such as pcDNA/V5-GW/D-TOPO® and pcDNA3.1 (Invitrogen) that contain a selectable marker (which facilitates the selection of stably transfected cell lines) and contain the human
cytomegalovirus (CMV) enhancer-promoter sequences. Additionally, suitable for expression in primate or canine cell lines is the pCEP4 vector (Invitrogen), which contains an Epstein Barr virus (EBV) origin of replication, facilitating the maintenance of plasmid as a multicopy extrachromosomal element. A particularly preferred virus for certain applications is the adeno-associated virus
(AAV), a double-stranded DNA virus. The adeno-associated virus is capable of infecting a wide range of cell types and species and can be engineered to be replication-deficient. It further has advantages, such as heat and lipid solvent stability, high transduction frequencies in cells of diverse lineages, including hemopoietic cells, and lack of superinfection inhibition thus allowing multiple series of transductions. Reportedly, the adeno-associated virus can integrate into human cellular DNA in a site-specific manner, thereby minimizing the possibility of insertional mutagenesis and variability of inserted gene expression. In addition, wild-type adeno-associated virus infections have been followed in tissue culture for greater than 100 passages in the absence of selective pressure, implying that the adeno-associated virus genomic integration is a relatively stable event. The adeno-associated virus can also function in an extrachromosomal fashion.
Adenovirus-based constructs can be constructed by subcloning the desired cDNA, e.g., a Qa-I polynucleotide, downstream from an appropriate expression cassette (for example, the CMV promoter/enhancer) into the EcoRV site of the pCOl vector containing the Ad5 adenoviral sequences required for homologous recombination. The resulting plasmid can then be linearized by restriction enzyme digestion and cotransfected in 293 cells with large CIaI fragment of the Ad5 dl324 viral DNA. Stratford-Perricaudet et al. (1993) J. Clin. Invest. 90:626-30. The resulting replication-defective recombinant adenoviral constructs are then purified from isolated plaques. The viral preparations are typically purified by two CsCl gradient centrifugations, dialyzed against buffer containing 10 mM Tris-Cl pH 7.5, 1 mM MgCl2 and 135 mM NaCl and stored at -80°C in 10% glycerol. Viral titer is typically determined by plaque assay on 293 cells (Graham et al. (1973) Virology 52:456-463) and expressed as plaque forming units (pfu) per mL. In general, other preferred viral vectors are based on non-cytopathic eukaryotic viruses in which non-essential genes have been replaced with the gene of interest. Non- cytopathic viruses include retroviruses, the life cycle of which involves reverse
transcription of genomic viral RNA into DNA with subsequent proviral integration into host cellular DNA. The preparation of a retrovirus (lenti virus) containing a Qa-I polynucleotide is described in the Examples.
Adenoviruses and retroviruses have been approved for human gene therapy trials. In general, the retroviruses are replication-deficient (i.e., capable of directing synthesis of the desired proteins, but incapable of manufacturing an infectious particle). Such genetically altered retroviral expression vectors have general utility for the high-efficiency transduction of genes in vivo. Standard protocols for producing replication-deficient retroviruses (including the steps of incorporation of exogenous genetic material into a plasmid, transfection of a packaging cell lined with plasmid, production of recombinant retroviruses by the packaging cell line, collection of viral particles from tissue culture media, and infection of the target cells with viral particles) are provided in Kriegler, M., "Gene Transfer and Expression, A Laboratory Manual," W.H. Freeman Co., New York (1990) and Murry, EJ. Ed. "Methods in Molecular Biology," vol. 7, Humana Press, Inc., Cliffton, New Jersey (1991).
Another preferred retroviral vector is the vector derived from the Moloney murine leukemia virus, as described in Nabel et al. (1990) Science 249:1285-8. These vectors reportedly were effective for the delivery of genes to all three layers of the arterial wall, including the media. Other preferred vectors are disclosed in Flugelman et al. (1992) Circulation 85:1110-7. Additional vectors that are useful for delivering nucleic acids are described in U.S. Patent No. 5,61 A, 122 by Mulligan, et. al.
In addition to the foregoing vectors, other delivery methods may be used to deliver a Qa-I polynucleotide to a cell and facilitate uptake thereby. These additional delivery methods include, but are not limited to, natural or synthetic molecules, other than those derived from bacteriological or viral sources, capable of delivering the isolated Qa-I polynucleotide to a cell.
A preferred such delivery method of the invention is a colloidal dispersion system. Colloidal dispersion systems include lipid-based systems including oil-in-water emulsions, micelles, mixed micelles, and liposomes. A preferred colloidal system of the invention is a liposome. Liposomes are artificial membrane vessels which are useful as a delivery vector in vivo or in vitro. It has been shown that large unilamellar vesicles (LUV), which range in size from 0.2 - 4.0 μm can encapsulate large macromolecules. RNA, DNA, and
intact virions can be encapsulated within the aqueous interior and be delivered to cells in a biologically active form. Fraley et al. (1981) Trends Biochem. ScL 6:77. In order for a liposome to be an efficient gene transfer vector, one or more of the following characteristics should be present: (1) encapsulation of the gene of interest at high efficiency with retention of biological activity; (2) preferential and substantial binding to a target cell in comparison to non-target cells; (3) delivery of the aqueous contents of the vesicle to the target cell cytoplasm at high efficiency; and (4) accurate and effective expression of genetic information.
Liposomes may be targeted to a particular tissue, such as a T cell, by coupling the liposome to a specific ligand such as a monoclonal antibody, sugar, glycolipid, or protein. Additionally, the vector may be coupled to a nuclear targeting peptide, which will direct the Qa-I polynucleotide to the nucleus of the host cell.
Liposomes are commercially available from Gibco BRL, for example, as LIPOFECTIN™ and LIPOFECT ACE™, which are formed of cationic lipids such as N- [l-(2, 3 dioleyloxy)-propyl]-N, N, N-trimethylammonium chloride (DOTMA) and dimethyl dioctadecylammonium bromide (DDAB). Methods for making liposomes are well known in the art and have been described in many publications. Liposomes also have been reviewed by Gregoriadis (1985) Trends in Biotechnology, 3:235-41. Novel liposomes for the intracellular delivery of macromolecules, including nucleic acids, are also described in PCT International application no. PCT/US96/07572 (Publication No. WO 96/40060, entitled "Intracellular Delivery of Macromolecules").
The vector can be introduced into the T cells using any suitable technique, hi one embodiment the vector is introduced into the T cells by electroporation. In one embodiment the vector is introduced into the T cells by contacting the cells with the vector in the presence of a suitable polycationic lipophilic agent such as Lipofectamine (Invitrogen). hi one embodiment the T cells are activated T cells at the time the vector is introduced into the cells, hi one embodiment the T cells are resting T cells at the time the vector is introduced into the cells. Methods of treatment calling for adoptive transfer of T cells to a subject are known in the art and include, without limitation, methods of treating cancer and infectious disease. The methods find use particularly in settings where a host's immune response to
a particular antigen is inadequate or compromised. See, for example, U.S. Pat. No.
5,820,856 and U.S. Patent Application Publication No. 2002/0068053.
"Cancer" as used herein refers to an uncontrolled growth of cells which interferes with the normal functioning of the bodily organs and systems. Cancers which migrate from their original location and seed vital organs can eventually lead to the death of the subject through the functional deterioration of the affected organs. Hemopoietic cancers, such as leukemia, are able to outcompete the normal hemopoietic compartments in a subject, thereby leading to hemopoietic failure (in the form of anemia, thrombocytopenia and neutropenia) ultimately causing death. A metastasis is a region of cancer cells, distinct from the primary tumor location resulting from the dissemination of cancer cells from the primary tumor to other parts of the body. At the time of diagnosis of the primary tumor mass, the subject may be monitored for the presence of metastases. Metastases are most often detected through the sole or combined use of magnetic resonance imaging (MRI) scans, computed tomography (CT) scans, blood and platelet counts, liver function studies, chest X-rays and bone scans in addition to the monitoring of specific symptoms.
Cancers include, but are not limited to, basal cell carcinoma, biliary tract cancer; bladder cancer; bone cancer; brain and CNS cancer; breast cancer; cervical cancer; choriocarcinoma; colon and rectum cancer; connective tissue cancer; cancer of the digestive system; endometrial cancer; esophageal cancer; eye cancer; cancer of the head and neck; gastric (stomach) cancer; intra-epithelial neoplasm; kidney (renal) cancer; larynx cancer; leukemia; liver cancer; lung cancer (e.g. small cell and non-small cell); lymphoma including Hodgkin's and Non-Hodgkin's lymphoma; melanoma; myeloma; neuroblastoma; oral cavity cancer (e.g., lip, tongue, mouth, and pharynx); ovarian cancer; pancreatic cancer; prostate cancer; retinoblastoma; rhabdomyosarcoma; rectal cancer; cancer of the respiratory system; sarcoma; skin cancer; testicular cancer; thyroid cancer; uterine cancer; cancer of the urinary system, as well as other carcinomas and sarcomas. An "infectious disease" as used herein, refers to a disorder arising from the invasion of a host, superficially, locally, or systemically, by an infectious microorganism. Infectious microorganisms include bacteria, viruses, parasites and fungi.
Examples of viruses that have been found in humans include but are not limited to:
Retroviridae (e.g. human immunodeficiency viruses, such as HIV-I (also referred to as
HDTV-III, LAVE or HTLV-III/LAV, or HIV-III; and other isolates, such as HIV-LP; Picornaviridae (e.g. polio viruses, hepatitis A virus; enteroviruses, human Coxsackie viruses, rhinoviruses, echoviruses); Calciviridae (e.g. strains that cause gastroenteritis); Togaviridae (e.g. equine encephalitis viruses, rubella viruses); Flaviviridae (e.g. dengue viruses, encephalitis viruses, yellow fever viruses); Coronaviridae (e.g. coronaviruses); Rhabdoviridae (e.g. vesicular stomatitis viruses, rabies viruses); Filoviridae (e.g. ebola viruses); Paramyxoviridae (e.g. parainfluenza viruses, mumps virus, measles virus, respiratory syncytial virus); Orthomyxoviridae (e.g. influenza viruses); Bunyaviridae (e.g. Hantaan viruses, bunya viruses, phleboviruses and Nairo viruses); Arenaviridae (hemorrhagic fever viruses); Reoviridae (e.g. reoviruses, orbiviurses and rotaviruses); Birnaviridae; Hepadnaviridae (Hepatitis B virus); Parvoviridae (parvoviruses); Papovaviridae (papilloma viruses, polyoma viruses); Adenoviridae (most adenoviruses); Herpesviridae (herpes simplex virus (HSV) 1 and 2, varicella zoster virus, cytomegalovirus (CMV), herpes virus; Poxviridae (variola viruses, vaccinia viruses, pox viruses); and Iridoviridae (e.g. African swine fever virus); and unclassified viruses (e.g. the agent of delta hepatitis (thought to be a defective satellite of hepatitis B virus), the agents of non-A, non-B hepatitis (class 1 = internally transmitted; class 2 = parenterally transmitted (i.e. Hepatitis C); Norwalk and related viruses, and astroviruses).
Both gram negative and gram positive bacteria serve as antigens in vertebrate animals. Such gram positive bacteria include, but are not limited to, Pasteurella species, Staphylococci species, and Streptococcus species. Gram negative bacteria include, but are not limited to, Escherichia coli, Pseudomonas species, and Salmonella species. Specific examples of infectious bacteria include but are not limited to, Helicobacter pyloris, Borrelia burgdorferi, Legionella pneumophilia, Mycobacteria sps (e.g. M. tuberculosis, M. avium, M. intracellular e, M. kansasii, M. gordonae), Staphylococcus aureus, Neisseria gonorrhoeae, Neisseria meningitidis, Listeria monocytogenes, Streptococcus pyogenes (Group A Streptococcus), Streptococcus agalactiae (Group B Streptococcus), Streptococcus (viridans group), Streptococcus faecalis, Streptococcus bovis, Streptococcus (anaerobic sps.), Streptococcus pneumoniae, pathogenic Campylobacter sp., Enterococcus sp., Haemophilus influenzae, Bacillus anthracis, Corynebacterium diphtheriae,
Corynebacterium sp., Erysipelothrix rhusiopathiae, Clostridium perfringens, Clostridium tetani, Enterobacter aerogenes, Klebsiella pneumoniae, Pasturella multocida, Bacteroides
sp., Fusobacterium nucleatum, Streptobacillus moniliformis, Treponema pallidum, Treponema pertenue, Leptospira, Rickettsia, and Actinomyces israelii.
Examples of fungi include Cryptococcus neoformans, Histoplasma capsulatum, Coccidioides immitis, Blastomyces dermatitidis, Chlamydia trachomatis, Candida albicans.
Other infectious organisms (e.g., protists) include Plasmodium spp. such as Plasmodium falciparum, Plasmodium malariae, Plasmodium ovale, and Plasmodium vivax and Toxoplasma gondii. Blood-borne and/or tissues parasites include Plasmodium spp., Babesia microti, Babesia divergens, Leishmania tropica, Leishmania spp., Leishmania braziliensis, Leishmania donovani, Trypanosoma gambiense and
Trypanosoma rhodesiense (African sleeping sickness), Trypanosoma cruzi (Chagas' disease), and Toxoplasma gondii.
Other medically relevant microorganisms have been described extensively in the literature, e.g., see C.G.A Thomas, Medical Microbiology, Bailliere Tindall, Great Britain 1983, the entire contents of which is hereby incorporated by reference.
The vector directs expression of a Qa-I polypeptide and increases Qa-I polypeptide expression on the surface of the T cells. Expression of Qa-I polypeptide on the surface of a cell, including T cells, can be measured using any suitable technique. In one embodiment the expression is measured using FACS with a suitable antibody specific for the Qa-I polypeptide.
As used herein, "increase Qa-I polypeptide expression" means to increase the number of level of Qa-I polypeptide expression compared to a control level of Qa-I polypeptide expression, for example in paired samples. In various embodiments level of Qa-I polypeptide expression is said to be increased if there is an increase of at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% over a control level of Qa-I polypeptide expression.
The invention in an aspect provides method of promoting a T-cell-mediated immune response in a subject. The method includes the step of administering to the subject an effective amount of a vector that directs expression of a Qa-I polypeptide to increase Qa-I polypeptide expression on the surface of activated T cells in the subject.
The invention in an aspect provides a pharmaceutical composition that includes (a) an antigen or a polynucleotide encoding an antigen and (b) an effective amount of a vector
that directs expression of a Qa-I polypeptide to increase Qa-I polypeptide expression on the surface of activated T cells. The pharmaceutical composition in one embodiment further includes a pharmaceutically acceptable carrier. In one embodiment the pharmaceutical composition further includes at least one additional therapeutic agent. An "antigen" refers to any molecule capable of provoking an immune response specific for that molecule. Antigens include but are not limited to cells, cell extracts, proteins, polypeptides, peptides, polysaccharides, polysaccharide conjugates, peptide and non-peptide mimics of polysaccharides and other molecules, small molecules, lipids, glycolipids, carbohydrates, viruses and viral extracts and multicellular organisms such as parasites and allergens.
Antigens specifically include cancer antigens, microbial antigens, and allergens. Antigens also specifically include antigens per se as well as polynucleotides encoding a polypeptide antigen. A polynucleotide encoding a polypeptide antigen in one embodiment is an expression vector that includes a polynucleotide encoding the antigen, operably linked to an expression control sequence. An antigen can be an isolated antigen derived from a natural source. In one embodiment an antigen is an isolated antigen prepared by chemical synthesis.
A cancer antigen as used herein is a compound, such as a peptide or protein, associated with a tumor or cancer cell surface and which is capable of provoking an immune response when expressed on the surface of an antigen presenting cell in the context of an MHC molecule. Some of these antigens are encoded, although not necessarily expressed, by normal cells. These antigens can be characterized as those which are normally silent (i.e., not expressed) in normal cells, those that are expressed only at certain stages of differentiation and those that are temporally expressed such as embryonic and fetal antigens. Other cancer antigens are encoded by mutant cellular genes, such as oncogenes (e.g., activated ras oncogene), suppressor genes (e.g., mutant p53), fusion proteins resulting from internal deletions or chromosomal translocations. Still other cancer antigens can be encoded by viral genes such as those carried on RNA and DNA tumor viruses. Cancer antigens can be prepared from cancer cells either by preparing crude extracts of cancer cells, for example, as described in Cohen, et al. (1994) Cancer Research, 54:1055, by partially purifying the antigens, by recombinant technology, or by de no vo synthesis of known antigens. Cancer antigens include but are not limited to
antigens that are recombinantly expressed, an immunogenic portion of, or a whole tumor or cancer. Such antigens can be isolated or prepared recombinantly or by any other means known in the art.
A microbial antigen as used herein is an antigen of a microorganism and includes but is not limited to virus, bacteria, parasites, and fungi. Such antigens include the intact microorganism as well as natural isolates and fragments or derivatives thereof and also synthetic compounds which are identical to or similar to natural microorganism antigens and induce an immune response specific for that microorganism. A compound is similar to a natural microorganism antigen if it induces an immune response (humoral and/or cellular) to a natural microorganism antigen. Such antigens are used routinely in the art and are well known to those of ordinary skill in the art.
An allergen refers to a substance (antigen) that can induce an allergic or asthmatic response in a susceptible subject. The list of allergens is enormous and can include pollens, insect venoms, animal dander dust, fungal spores and drugs (e.g. penicillin). Examples of natural, animal and plant allergens include but are not limited to proteins specific to the following genuses: Agropyron (e.g. Agropyron repens); Agrostis (e.g.
Agrostis alba); Alder; Alnus (Alnus gultinoasa); Alternaria (Alternaria alternata);
Ambrosia {Ambrosia artemiisfolia; Anthoxanthum (e.g. Anthoxanthum odoratum); Apis
(e.g. Apis multiflorum); Arrhenatherum (e.g. Arrhenatherum elatius); Artemisia (Artemisia vulgaris); Avena (e.g. Avena sativa); Betula (Betula verrucosa); Blattella (e.g. Blattella germanica); Bromus (e.g. Bromus inermis); Canine (Canis familiaris); Chamaecyparis
(e.g. Chamaecyparis obtusa); Cryptomeria (Cryptomeria japonica); Cupressus (e.g.
Cupressus sempervirens, Cupressus arizonica and Cupressus macrocarpa); Dactylis (e.g.
Dactylis glomerata); Dermatophagoides (e.g. Dermatophagoides farinae); Felis (Felis domesticus); Festuca (e.g. Festuca elatior); Holcus (e.g. Holcus lanatus); Juniperus (e.g.
Juniperus sabinoides, Juniperus virginiana, Juniperus communis and Juniperus ashei);
Lolium (e.g. Lolium perenne or Lolium multiflorum); Olea (Olea europa); Parietaria (e.g.
Parietaria officinalis or Parietaria judaica); Paspalum (e.g. Paspalum notatum);
Periplaneta (e.g. Periplaneta americana); Phalaris (e.g. Phalaris arundinaced); Phleum (e.g. Phleum pratense); Plantago (e.g. Plantago lanceolata); Poa (e.g. Poa pratensis or
Poa compressa); Quercus (Quercus alba); Secale (e.g. Secale cereale); Sorghum (e.g.
Sorghum halepensis); Thuya (e.g. Thuya orientalis); and Triticum (e.g. Triticum aestivum).
In the context of autoimmune disease, an antigen can be an autoantigen or self- antigen, i.e., an antigen derived from normal host tissue origin. Normal host tissue does not include cancer cells. Thus an immune response mounted against a self-antigen, in the context of an autoimmune disease, is an undesirable immune response and contributes to destruction and damage of normal tissue, whereas an immune response mounted against a cancer antigen is a desirable immune response and contributes to the destruction of the tumor or cancer.
The invention in an aspect provides a pharmaceutical composition that includes a T cell containing a vector that directs expression of a Qa-I polypeptide. The pharmaceutical composition in one embodiment further includes a pharmaceutically acceptable carrier. In one embodiment the pharmaceutical composition further includes at least one additional therapeutic agent. In one embodiment the Qa-I polypeptide is HLA-E.
The invention in an aspect provides a method of identifying an agent useful for reducing activated T cells. The method includes the steps of contacting under physiologic conditions cells that express a Qa-I molecule with a test agent that binds the Qa-I molecule, in presence of NK cells that express NKG2A; measuring a test amount of lysis of the cells that express the Qa-I molecule; and identifying the test agent as an agent useful for reducing activated T cells when the test amount of lysis exceeds a control amount of lysis obtained under similar conditions without the test agent. In one embodiment the method is an in vitro method. In this embodiment the physiologic conditions can include usual conditions of temperature, pH, salt, osmotic strength, and the like, well known in the art. hi one embodiment the cells that express the Qa-I molecule are cells that naturally express the Qa-I molecule. In one embodiment the cells are T cells, hi one embodiment the cells are activated T cells, hi one embodiment the cells that express the Qa-I molecule are cells that do not naturally express the Qa-I molecule but contain a vector that directs expression of a Qa-I polypeptide.
The test agent can be any agent selected from small molecules (i.e., molecules with molecular weight up to 1.5 kilodaltons), nucleic acid molecules, polysaccharides, polypeptides, antibodies, and fragments of antibodies, hi one embodiment the agent is a small molecule that is part of a library of small molecules.
The method in one embodiment is adapted for high throughput screening. High throughput screening permits screening of multiple test agents in a short amount of time, e.g., tens, hundreds, thousands, or even more test agents in a day. Methods and devices useful for high throughput screening are well known in the art. In one embodiment the NK cells that express NKG2A are isolated NKG2A+ NK cells. NKG2A+ NK cells can be isolated as described in Example 1 below.
Antibodies, antibody fragments, and siRNA can be combined with other therapeutic agents. The antibody, antibody fragment, or siRNA and other therapeutic agent may be administered simultaneously or sequentially. When the other therapeutic agents are administered simultaneously they can be administered in the same or separate formulations, but are administered at the same time. The other therapeutic agents are administered sequentially with one another and with the antibody, antibody fragment, or siRNA, when the administration of the other therapeutic agents and the antibody, antibody fragment, or siRNA is temporally separated. The separation in time between the administration of these compounds may be a matter of minutes or it may be longer. Other therapeutic agents include but are not limited to anti-microbial agents, anti-cancer therapy, immunosuppressive agents, anti-inflammatory agents, etc.
The antibody, antibody fragment, and siRNA of the invention may be administered to a subject with an anti-microbial agent. An anti-microbial agent, as used herein, refers to a naturally-occurring or synthetic compound which is capable of killing or inhibiting infectious microorganisms. The type of anti-microbial agent useful according to the invention will depend upon the type of microorganism with which the subject is infected or at risk of becoming infected. Anti-microbial agents include but are not limited to antibacterial agents, anti-viral agents, anti-fungal agents and anti-parasitic agents. Phrases such as "anti-infective agent", "anti-bacterial agent", "anti-viral agent", "anti-fungal agent", "anti-parasitic agent" and "parasiticide" have well-established meanings to those of ordinary skill in the art and are defined in standard medical texts. Briefly, anti -bacterial agents kill or inhibit bacteria, and include antibiotics as well as other synthetic or natural compounds having similar functions. Antibiotics are low molecular weight molecules which are produced as secondary metabolites by cells, such as microorganisms. In general, antibiotics interfere with one or more bacterial functions or structures which are specific for the microorganism and which are not present in host cells. Anti- viral agents
can be isolated from natural sources or synthesized and are useful for killing or inhibiting viruses. Anti-fungal agents are used to treat superficial fungal infections as well as opportunistic and primary systemic fungal infections. Anti-parasite agents kill or inhibit parasites. Examples of anti-parasitic agents, also referred to as parasiticides useful for human administration include but are not limited to albendazole, amphotericin B, benznidazole, bithionol, chloroquine HCl, chloroquine phosphate, clindamycin, dehydroemetine, diethylcarbamazine, diloxanide furoate, eflornithine, furazolidaone, glucocorticoids, halofantrine, iodoquinol, ivermectin, mebendazole, mefloquine, meglumine antimoniate, melarsoprol, metrifonate, metronidazole, niclosamide, nifurtimox, oxamniquine, paromomycin, pentamidine isethionate, piperazine, praziquantel, primaquine phosphate, proguanil, pyrantel pamoate, pyrimethanmine-sulfonamides, pyrimethanmine-sulfadoxine, quinacrine HCl, quinine sulfate, quinidine gluconate, spiramycin, stibogluconate sodium (sodium antimony gluconate), suramin, tetracycline, doxycycline, thiabendazole, tinidazole, trimethroprim-sulfamethoxazole, and tryparsamide some of which are used alone or in combination with others.
Antibacterial agents kill or inhibit the growth or function of bacteria. A large class of antibacterial agents is antibiotics. Antibiotics, which are effective for killing or inhibiting a wide range of bacteria, are referred to as broad spectrum antibiotics. Other types of antibiotics are predominantly effective against the bacteria of the class gram- positive or gram-negative. These types of antibiotics are referred to as narrow spectrum antibiotics. Other antibiotics which are effective against a single organism or disease and not against other types of bacteria, are referred to as limited spectrum antibiotics. Antibacterial agents are sometimes classified based on their primary mode of action. In general, antibacterial agents are cell wall synthesis inhibitors, cell membrane inhibitors, protein synthesis inhibitors, nucleic acid synthesis or functional inhibitors, and competitive inhibitors.
Anti-bacterial agents useful in the invention include but are not limited to natural penicillins, semi-synthetic penicillins, clavulanic acid, cephalosporins, bacitracin, ampicillin, carbenicillin, oxacillin, azlocillin, mezlocillin, piperacillin, methicillin, dicloxacillin, nafcillin, cephalothin, cephapirin, cephalexin, cefamandole, cefaclor, cefazolin, cefuroxine, cefoxitin, cefotaxime, cefsulodin, cefetamet, cefixime, ceftriaxone,
cefoperazone, ceftazidine, moxalactam, carbapenems, imipenems, monobactems, euztreonam, vancomycin, polymyxin, amphotericin B, nystatin, imidazoles, clotrimazole, miconazole, ketoconazole, itraconazole, fluconazole, rifampins, ethambutol, tetracyclines, chloramphenicol, macrolides, aminoglycosides, streptomycin, kanamycin, tobramycin, amikacin, gentamicin, tetracycline, minocycline, doxycycline, chlortetracycline, erythromycin, roxithromycin, clarithromycin, oleandomycin, azithromycin, chloramphenicol, quinolones, co-trimoxazole, norfloxacin, ciprofloxacin, enoxacin, nalidixic acid, temafloxacin, sulfonamides, gantrisin, and trimethoprim; Acedapsone ; Acetosulfone Sodium; Alamecin; Alexidine; Amdinocillin; Amdinocillin Pivoxil; Amicycline; Amifloxacin; Amifloxacin Mesylate; Amikacin; Amikacin Sulfate;
Aminosalicylic acid; Aminosalicylate sodium; Amoxicillin; Amphomycin; Ampicillin; Ampicillin Sodium; Apalcillin Sodium; Apramycin; Aspartocin; Astromicin Sulfate; Avilamycin; Avoparcin; Azithromycin; Azlocillin; Azlocillin Sodium; Bacampicillin Hydrochloride; Bacitracin; Bacitracin Methylene Disalicylate; Bacitracin Zinc; Bambermycins; Benzoylpas Calcium; Berythromycin ; Betamicin Sulfate; Biapenem; Biniramycin; Biphenamine Hydrochloride ; Bispyrithione Magsulfex ; Butikacin; Butirosin Sulfate; Capreomycin Sulfate; Carbadox; Carbenicillin Disodium; Carbenicillin Indanyl Sodium; Carbenicillin Phenyl Sodium; Carbenicillin Potassium; Carumonam Sodium; Cefaclor; Cefadroxil; Cefamandole; Cefamandole Nafate; Cefamandole Sodium; Cefaparole; Cefatrizine; Cefazaflur Sodium; Cefazolin; Cefazolin Sodium;
Cefbuperazone; Cefdinir; Cefepime; Cefepime Hydrochloride; Cefetecol; Cefixime; Cefmenoxime Hydrochloride; Cefmetazole; Cefmetazole Sodium; Cefonicid Monosodium; Cefonicid Sodium; Cefoperazone Sodium; Ceforanide; Cefotaxime Sodium; Cefotetan; Cefotetan Disodium; Cefotiam Hydrochloride; Cefoxitin; Cefoxitin Sodium; Cefpimizole; Cefpimizole Sodium; Cefpiramide; Cefpiramide Sodium; Cefpirome Sulfate; Ceφodoxime Proxetil; Cefprozil; Cefroxadine; Cefsulodin Sodium; Ceftazidime; Ceftibuten; Ceftizoxime Sodium; Ceftriaxone Sodium; Cefuroxime; Cefuroxime Axetil; Cefuroxime Pivoxetil; Cefuroxime Sodium; Cephacetrile Sodium; Cephalexin; Cephalexin Hydrochloride; Cephaloglycin; Cephaloridine; Cephalothin Sodium; Cephapirin Sodium; Cephradine; Cetocycline Hydrochloride; Cetophenicol; Chloramphenicol ;
Chloramphenicol Palmitate ; Chloramphenicol Pantothenate Complex ; Chloramphenicol Sodium Succinate; Chlorhexidine Phosphanilate; Chloroxylenol; Chlortetracycline
Bisulfate ; Chlortetracycline Hydrochloride ; Cinoxacin; Ciprofloxacin; Ciprofloxacin
Hydrochloride; Cirolemycin ; Clarithromycin; Clinafloxacin Hydrochloride; Clindamycin;
Clindamycin Hydrochloride; Clindamycin Palmitate Hydrochloride; Clindamycin
Phosphate; Clofazimine ; Cloxacillin Benzathine; Cloxacillin Sodium; Cloxyquin; Colistimethate Sodium; Colistin Sulfate; Coumermycin; Coumermycin Sodium;
Cyclacillin; Cycloserine; Dalfopristin; Dapsone ; Daptomycin; Demeclocycline;
Demeclocycline Hydrochloride; Demecycline; Denofungin ; Diaveridine; Dicloxacillin;
Dicloxacillin Sodium; Dihydrostreptomycin Sulfate; Dipyrithione; Dirithromycin;
Doxycycline; Doxycycline Calcium ; Doxycycline Fosfatex; Doxycycline Hyclate; Droxacin Sodium; Enoxacin; Epicillin; Epitetracycline Hydrochloride; Erythromycin;
Erythromycin Acistrate; Erythromycin Estolate; Erythromycin Ethylsuccinate;
Erythromycin Gluceptate; Erythromycin Lactobionate; Erythromycin Propionate;
Erythromycin Stearate; Ethambutol Hydrochloride; Ethionamide; Fleroxacin; Floxacillin;
Fludalanine; Flumequine; Fosfomycin; Fosfomycin Tromethamine; Fumoxicillin; Furazolium Chloride; Furazolium Tartrate; Fusidate Sodium; Fusidic Acid; Gentamicin
Sulfate; Gloximonam; Gramicidin; Haloprogin; Hetacillin; Hetacillin Potassium;
Hexedine; Ibafloxacin; Imipenem; Isoconazole; Isepamicin; Isoniazid; Josamycin;
Kanamycin Sulfate; Kitasamycin; Levofuraltadone; Levopropylcillin Potassium;
Lexithromycin; Lincomycin; Lincomycin Hydrochloride; Lomefloxacin; Lomefloxacin Hydrochloride; Lomefloxacin Mesylate; Loracarbef; Mafenide; Meclocycline;
Meclocycline Subsalicylate; Megalomicin Potassium Phosphate; Mequidox;
Meropenem; Methacycline; Methacycline Hydrochloride; Methenamine; Methenamine
Hippurate; Methenamine Mandelate; Methicillin Sodium; Metioprim; Metronidazole
Hydrochloride; Metronidazole Phosphate; Mezlocillin; Mezlocillin Sodium; Minocycline; Minocycline Hydrochloride; Mirincamycin Hydrochloride ; Monensin ; Monensin Sodium
; Nafcillin Sodium; Nalidixate Sodium; Nalidixic Acid; Natamycin; Nebramycin;
Neomycin Palmitate; Neomycin Sulfate; Neomycin Undecylenate ; Netilmicin Sulfate;
Neutramycin; Nifuradene; Nifuraldezone; Nifuratel ; Nifuratrone; Nifurdazil; Nifurimide;
Nifurpirinol; Nifurquinazol; Nifurthiazole; Nitrocycline; Nitrofurantoin; Nitromide; Norfloxacin; Novobiocin Sodium; Ofloxacin; Ormetoprim; Oxacillin Sodium; Oximonam;
Oximonam Sodium; Oxolinic Acid; Oxytetracycline; Oxytetracycline Calcium;
Oxytetracycline Hydrochloride; Paldimycin; Parachlorophenol; Paulomycin; Pefloxacin;
Pefloxacin Mesylate; Penamecillin; Penicillin G Benzathine; Penicillin G Potassium;
Penicillin G Procaine; Penicillin G Sodium; Penicillin V; Penicillin V Benzathine;
Penicillin V Hydrabamine; Penicillin V Potassium; Pentizidone Sodium; Phenyl
Aminosalicylate; Piperacillin Sodium; Pirbenicillin Sodium; Piridicillin Sodium; Pirlimycin Hydrochloride; Pivampicillin Hydrochloride; Pivampicillin Pamoate;
Pivampicillin Probenate; Polymyxin B Sulfate; Porfiromycin ; Propikacin; Pyrazinamide;
Pyrithione Zinc; Quindecamine Acetate; Quinupristin; Racephenicol; Ramoplanin;
Ranimycin; Relomycin; Repromicin; Rifabutin; Rifametane; Rifamexil; Rifamide;
Rifampin; Rifapentine; Rifaximin; Rolitetracycline; Rolitetracycline Nitrate; Rosaramicin; Rosaramicin Butyrate; Rosaramicin Propionate; Rosaramicin Sodium Phosphate;
Rosaramicin Stearate; Rosoxacin; Roxarsone; Roxithromycin; Sancycline; Sanfetrinem
Sodium; Sarmoxicillin; Sarpicillin; Scopafungin ; Sisomicin; Sisomicin Sulfate;
Sparfloxacin; Spectinomycin Hydrochloride; Spiramycin; Stallimycin Hydrochloride;
Steffϊmycin; Streptomycin Sulfate; Streptonicozid; Sulfabenz ; Sulfabenzamide; Sulfacetamide; Sulfacetamide Sodium; Sulfacytine; Sulfadiazine; Sulfadiazine Sodium;
Sulfadoxine; Sulfalene; Sulfamerazine; Sulfameter; Sulfamethazine; Sulfamethizole;
Sulfamethoxazole; Sulfamonomethoxine; Sulfamoxole; Sulfanilate Zinc; Sulfanitran ;
Sulfasalazine; Sulfasomizole; Sulfathiazole; Sulfazamet; Sulfisoxazole; Sulfisoxazole
Acetyl; Sulfisoxazole Diolamine; Sulfomyxin; Sulopenem; Sultamicillin; Suncillin Sodium; Talampicillin Hydrochloride; Teicoplanin; Temafloxacin Hydrochloride;
Temocillin; Tetracycline; Tetracycline Hydrochloride; Tetracycline Phosphate Complex;
Tetroxoprim; Thiamphenicol; Thiphencillin Potassium; Ticarcillin Cresyl Sodium;
Ticarcillin Disodium; Ticarcillin Monosodium; Ticlatone; Tiodonium Chloride;
Tobramycin; Tobramycin Sulfate; Tosufloxacin; Trimethoprim; Trimethoprim Sulfate; Trisulfapyrimidines; Troleandomycin; Trospectomycin Sulfate; Tyrothricin; Vancomycin;
Vancomycin Hydrochloride; Virginiamycin; and Zorbamycin.
Antiviral agents are compounds which prevent infection of cells by viruses or replication of the virus within the cell. There are many fewer antiviral drugs than antibacterial drugs because the process of viral replication is so closely related to DNA replication within the host cell, that non-specific antiviral agents would often be toxic to the host. There are several stages within the process of viral infection which can be blocked or inhibited by antiviral agents. These stages include, attachment of the virus to
the host cell (immunoglobulin or binding peptides), uncoating of the virus (e.g. amantadine), synthesis or translation of viral mRNA (e.g. interferon), replication of viral RNA or DNA (e.g. nucleotide analogues), maturation of new virus proteins (e.g. protease inhibitors), and budding and release of the virus. Nucleotide analogues are synthetic compounds which are similar to nucleotides, but which have an incomplete or abnormal deoxyribose or ribose group. Once the nucleotide analogues are in the cell, they are phosphorylated, producing the triphosphate formed which competes with normal nucleotides for incorporation into the viral DNA or RNA. Once the triphosphate form of the nucleotide analogue is incorporated into the growing nucleic acid chain, it causes irreversible association with the viral polymerase and thus chain termination. Nucleotide analogues include, but are not limited to, acyclovir (used for the treatment of herpes simplex virus and varicella-zoster virus), gancyclovir (useful for the treatment of cytomegalovirus), idoxuridine, ribavirin (useful for the treatment of respiratory syncitial virus), dideoxyinosine, dideoxycytidine, zidovudine (azidothymidine), imiquimod, and resimiquimod.
The interferons are cytokines which are secreted by virus-infected cells as well as immune cells. The interferons function by binding to specific receptors on cells adjacent to the infected cells, causing the change in the cell which protects it from infection by the virus, α and β-interferon also induce the expression of Class I and Class II MHC molecules on the surface of infected cells, resulting in increased antigen presentation for host immune cell recognition, α and β-interferons are available as recombinant forms and have been used for the treatment of chronic hepatitis B and C infection. At the dosages which are effective for anti-viral therapy, interferons have severe side effects such as fever, malaise and weight loss. Anti-viral agents useful in the invention include but are not limited to immunoglobulins, amantadine, interferons, nucleotide analogues, and protease inhibitors. Specific examples of anti-virals include but are not limited to Acemannan; Acyclovir; Acyclovir Sodium; Adefovir; Alovudine; Alvircept Sudotox; Amantadine Hydrochloride; Aranotin; Arildone; Atevirdine Mesylate; Avridine; Cidofovir; Cipamfylline; Cytarabine Hydrochloride; Delavirdine Mesylate; Desciclovir; Didanosine; Disoxaril; Edoxudine; Enviradene; Enviroxime; Famciclovir; Famotine Hydrochloride; Fiacitabine; Fialuridine; Fosarilate; Foscarnet Sodium; Fosfonet Sodium; Ganciclovir; Ganciclovir Sodium;
Idoxuridine; Kethoxal; Lamivudine; Lobucavir; Memotine Hydrochloride; Methisazone; Nevirapine; Penciclovir; Pirodavir; Ribavirin; Rimantadine Hydrochloride; Saquinavir Mesylate; Somantadine Hydrochloride; Sorivudine; Statolon; Stavudine; Tilorone Hydrochloride; Trifluridine; Valacyclovir Hydrochloride; Vidarabine; Vidarabine Phosphate; Vidarabine Sodium Phosphate; Viroxime; Zalcitabine; Zidovudine; and Zinviroxime.
Anti-fungal agents are useful for the treatment and prevention of infective fungi. Anti-fungal agents are sometimes classified by their mechanism of action. Some antifungal agents function as cell wall inhibitors by inhibiting glucose synthase. These include, but are not limited to, basiungin/ECB. Other anti-fungal agents function by destabilizing membrane integrity. These include, but are not limited to, immidazoles, such as clotrimazole, sertaconzole, fluconazole, itraconazole, ketoconazole, miconazole, and voriconacole, as well as FK 463, amphotericin B, BAY 38-9502, MK 991, pradimicin, UK 292, butenafine, and terbinafine. Other anti-fungal agents function by breaking down chitin (e.g. chitinase) or immunosuppression (501 cream).
The antibody, antibody fragment, or siRNA may also be administered in conjunction with an anti-cancer therapy. Anti-cancer therapies include cancer medicaments, radiation and surgical procedures. As used herein, a "cancer medicament" refers to an agent which is administered to a subject for the purpose of treating a cancer. As used herein, "treating cancer" includes preventing the development of a cancer, reducing the symptoms of cancer, and/or inhibiting the growth of an established cancer. In other aspects, the cancer medicament is administered to a subject at risk of developing a cancer for the purpose of reducing the risk of developing the cancer. Various types of medicaments for the treatment of cancer are described herein. For the purpose of this specification, cancer medicaments are classified as chemotherapeutic agents, immunotherapeutic agents, cancer vaccines, hormone therapy, and biological response modifiers.
The chemotherapeutic agent may be selected from the group consisting of methotrexate, vincristine, adriamycin, cisplatin, non-sugar containing chloroethylnitrosoureas, 5-fluorouracil, mitomycin C, bleomycin, doxorubicin, dacarbazine, taxol, fragyline, Meglamine GLA, valrubicin, carmustaine and poliferposan, MMI270, BAY 12-9566, RAS famesyl transferase inhibitor, famesyl transferase inhibitor,
MMP, MTA/LY231514, LY264618/Lometexol, Glamolec, CI-994, TNP-470, Hycamtin/Topotecan, PKC412, Valspodar/PSC833, Novantrone/Mitroxantrone, Metaret/Suramin, Batimastat, E7070, BCH-4556, CS-682, 9-AC, AG3340, AG3433, Incel/VX-710, VX-853, ZDOlOl, ISI641, ODN 698, TA 2516/Marmistat, BB2516/Marmistat, CDP 845, D2163, PD183805, DX8951f, Lemonal DP 2202, FK 317, Picibanil/OK-432, AD 32/Valrubicin, Metastron/strontium derivative, Temodal/Temozolomide, Evacet/liposomal doxorubicin, Yewtaxan/Paclitaxel, Taxol/Paclitaxel, Xeload/Capecitabine, Furtulon/Doxifluridine, Cyclopax/oral paclitaxel, Oral Taxoid, SPU-077/Cisplatin, HMR 1275/Flavopiridol, CP-358 (774)/EGFR, CP-609 (754)/RAS oncogene inhibitor, BMS- 18275 I/oral platinum, UFT(TegafurAJracil), Ergamisol/Levamisole, Eniluracil/776C85/5FU enhancer, Campto/Levamisole, Camptosar/h-inotecan, Tumodex/Ralitrexed, Leustatin/Cladribine, Paxex/Paclitaxel, Doxil/liposomal doxorubicin, Caelyx/liposomal doxorubicin, Fludara/Fludarabine, Pharmarubicin/Epirubicin, DepoCyt, ZDl 839, LU 79553/Bis-Naphtalimide, LU 103793/Dolastain, Caetyx/liposomal doxorubicin, Gemzar/Gemcitabine, ZD
0473/Anormed, YM 116, Iodine seeds, CDK4 and CDK2 inhibitors, PARP inhibitors, D4809/Dexifosamide, Ifes/Mesnex/Ifosamide, Vumon/Teniposide, Paraplatin/Carboplatin, Plantinol/cisplatin, Vepeside/Etoposide, ZD 9331, Taxotere/Docetaxel, prodrug of guanine arabinoside, Taxane Analog, nitrosoureas, alkylating agents such as melphelan and cyclophosphamide, Aminoglutethimide, Asparaginase, Busulfan, Carboplatin, Chlorombucil, Cytarabine HCl, Dactinomycin, Daunorubicin HCl, Estramustine phosphate sodium, Etoposide (VP16-213), Floxuridine, Fluorouracil (5-FU), Flutamide, Hydroxyurea (hydroxycarbamide), Ifosfamide, hiterferon Alfa-2a, Alfa-2b, Leuprolide acetate (LHRH-releasing factor analogue), Lomustine (CCNU), Mechlorethamine HCl (nitrogen mustard), Mercaptopurine, Mesna, Mitotane (o.p'-DDD), Mitoxantrone HCl, Octreotide, Plicamycin, Procarbazine HCl, Streptozocin, Tamoxifen citrate, Thioguanine, Thiotepa, Vinblastine sulfate, Amsacrine (m- AMSA), Azacitidine, Erthropoietin, Hexamethylmelamine (HMM), Interleukin 2, Mitoguazone (methyl-GAG; methyl glyoxal bis-guanylhydrazone; MGBG), Pentostatin (2'deoxycoformycin), Semustine (methyl- CCNU), Teniposide (VM-26) and Vindesine sulfate, but it is not so limited.
The immunotherapeutic agent may be selected from the group consisting of Ributaxin, Herceptin, Quadramet, Panorex, IDEC- Y2B8, BEC2, C225, Oncolym,
SMART M195, ATRAGEN, Ovarex, Bexxar, LDP-03, ior t6, MDX-210, MDX-11, MDX-22, OVl 03, 3622 W94, anti-VEGF, Zenapax, MDX-220, MDX-447, MELIMMUNE-2, MELIMMUNE-I, CEACIDE, Pretarget, NovoMAb-G2, TNT, Gliomab-H, GNI-250, EMD-72000, LymphoCide, CMA 676, Monopharm-C, 4B5, ior egf.r3, ior c5, BABS, anti-FLK-2, MDX-260, ANA Ab, SMART IDlO Ab, SMART ABL 364 Ab and ImmuRAIT-CEA, but it is not so limited.
The cancer vaccine may be selected from the group consisting of EGF, Anti- idiotypic cancer vaccines, Gp75 antigen, GMK melanoma vaccine, MGV ganglioside conjugate vaccine, Her2/neu, Ovarex, M-Vax, O-Vax, L-Vax, STn-KHL theratope, BLP25 (MUC-I), liposomal idiotypic vaccine, Melacine, peptide antigen vaccines, toxin/antigen vaccines, MVA-based vaccine, PACIS, BCG vacine, TA-HPV, TA-CIN, DISC-virus and ImmuCyst/TheraCys, but it is not so limited.
The antibody, antibody fragment, or siRNA of the invention may be administered to a subject with an immunosuppressive agent. As used herein, an "immunosuppressive agent" refers to an agent which is administered to a subject for the purpose of down- regulating an immune response. These agents may be used in the treatment of graft rejection, graft- versus-host disease, and autoimmune disease. Immunosuppressive agents specifically include but are not limited to corticosteroids such as prednisone and methylprednisolone, azathioprine, cyclosporine A, tacrolimus, mycophenolate mofetil, rapamycin, polyclonal antibodies (e.g., antithymocyte globulin), and monoclonal antibodies (e.g. OKT3, basiliximab, and daclizumab).
The antibody, antibody fragment, or siRNA of the invention may be administered to a subject with an anti-inflammatory agent. As used herein, an "anti-inflammatory agent" refers to an agent which is administered to a subject for the purpose of down- regulating an inflammatory response. Anti-inflammatory agents are generally less potent than immunosuppressive agents, and they specifically include, without limitation, nonsteroidal anti-inflammatory agents, gold, methotrexate.
The formulations of the invention are administered in pharmaceutically acceptable solutions, which may routinely contain pharmaceutically acceptable concentrations of salt, buffering agents, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients.
For use in therapy, an effective amount of the antibody, antibody fragment, or siRNA can be administered to a subject by any mode that delivers the antibody, antibody fragment, or siRNA to the desired surface. Administering the pharmaceutical composition of the present invention may be accomplished by any means known to the skilled artisan. Preferred routes of administration include but are not limited to oral, parenteral, intramuscular, intranasal, sublingual, intratracheal, inhalation, ocular, vaginal, and rectal.
For oral administration, the compounds (i.e., antibody, antibody fragment, or siRNA, and other therapeutic agents) can be formulated readily by combining the active compound(s) with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated. Pharmaceutical preparations for oral use can be obtained as solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Optionally the oral formulations may also be formulated in saline or buffers, i.e. EDTA for neutralizing internal acid conditions or may be administered without any carriers.
Also specifically contemplated are oral dosage forms of the above component or components. The component or components may be chemically modified so that oral delivery of the derivative is efficacious. Generally, the chemical modification contemplated is the attachment of at least one moiety to the component molecule itself, where said moiety permits (a) inhibition of proteolysis; and (b) uptake into the blood stream from the stomach or intestine. Also desired is the increase in overall stability of the component or components and increase in circulation time in the body. Examples of such moieties include: polyethylene glycol, copolymers of ethylene glycol and propylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone and polyproline. Abuchowski
and Davis, 1981, "Soluble Polymer-Enzyme Adducts" In: Enzymes as Drugs, Hocenberg and Roberts, eds., Wiley-Interscience, New York, NY, pp. 367-383; Newmark, et al. (1982) J. Appl. Biochem. 4:185-189. Other polymers that could be used are poly-l,3-dioxolane and poly-l,3,6-tioxocane. Preferred for pharmaceutical usage, as indicated above, are polyethylene glycol moieties.
For the component (or derivative) the location of release may be the stomach, the small intestine (the duodenum, the jejunum, or the ileum), or the large intestine. One skilled in the art has available formulations which will not dissolve in the stomach, yet will release the material in the duodenum or elsewhere in the intestine. Preferably, the release will avoid the deleterious effects of the stomach environment, either by protection of the antibody, antibody fragment, or siRNA (or derivative) or by release of the biologically active material beyond the stomach environment, such as in the intestine.
To ensure full gastric resistance a coating impermeable to at least pH 5.0 is essential. Examples of the more common inert ingredients that are used as enteric coatings are cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose phthalate (HPMCP), HPMCP 50, HPMCP 55, polyvinyl acetate phthalate (PVAP), Eudragit L30D, Aquateric, cellulose acetate phthalate (CAP), Eudragit L, Eudragit S, and Shellac. These coatings may be used as mixed films.
A coating or mixture of coatings can also be used on tablets, which are not intended for protection against the stomach. This can include sugar coatings, or coatings which make the tablet easier to swallow. Capsules may consist of a hard shell (such as gelatin) for delivery of dry therapeutic i.e. powder; for liquid forms, a soft gelatin shell may be used. The shell material of cachets could be thick starch or other edible paper. For pills, lozenges, molded tablets or tablet triturates, moist massing techniques can be used. The therapeutic can be included in the formulation as fine multi-particulates in the form of granules or pellets of particle size about 1 mm. The formulation of the material for capsule administration could also be as a powder, lightly compressed plugs or even as tablets. The therapeutic could be prepared by compression.
Colorants and flavoring agents may all be included. For example, the antibody, antibody fragment, or siRNA (or derivative) may be formulated (such as by liposome or microsphere encapsulation) and then further contained within an edible product, such as a refrigerated beverage containing colorants and flavoring agents.
One may dilute or increase the volume of the therapeutic with an inert material. These diluents could include carbohydrates, especially mannitol, a-lactose, anhydrous lactose, cellulose, sucrose, modified dextrans and starch. Certain inorganic salts may be also be used as fillers including calcium triphosphate, magnesium carbonate and sodium chloride. Some commercially available diluents are Fast-Flo, Emdex, STA-Rx 1500, Emcompress and Avicell.
Disintegrants maybe included in the formulation of the therapeutic into a solid dosage form. Materials used as disintegrates include but are not limited to starch, including the commercial disintegrant based on starch, Explotab. Sodium starch glycolate, Amberlite, sodium carboxymethylcellulose, ultramylopectin, sodium alginate, gelatin, orange peel, acid carboxymethyl cellulose, natural sponge and bentonite may all be used. Another form of the disintegrants are the insoluble cationic exchange resins. Powdered gums may be used as disintegrants and as binders and these can include powdered gums such as agar, Karaya or tragacanth. Alginic acid and its sodium salt are also useful as disintegrants. Binders may be used to hold the therapeutic agent together to form a hard tablet and include materials from natural products such as acacia, tragacanth, starch and gelatin. Others include methyl cellulose (MC), ethyl cellulose (EC) and carboxymethyl cellulose (CMC). Polyvinyl pyrrolidone (PVP) and hydroxypropylmethyl cellulose (HPMC) could both be used in alcoholic solutions to granulate the therapeutic. An anti-frictional agent may be included in the formulation of the therapeutic to prevent sticking during the formulation process. Lubricants may be used as a layer between the therapeutic and the die wall, and these can include but are not limited to; stearic acid including its magnesium and calcium salts, polytetrafluoroethylene (PTFE), liquid paraffin, vegetable oils and waxes. Soluble lubricants may also be used such as sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol of various molecular weights, Carbowax 4000 and 6000.
Glidants that might improve the flow properties of the drug during formulation and to aid rearrangement during compression might be added. The glidants may include starch, talc, pyrogenic silica and hydrated silicoaluminate. To aid dissolution of the therapeutic into the aqueous environment a surfactant might be added as a wetting agent. Surfactants may include anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate and dioctyl sodium sulfonate. Cationic
detergents might be used and could include benzalkonium chloride or benzethomium chloride. The list of potential non-ionic detergents that could be included in the formulation as surfactants are lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50 and 60, glycerol monostearate, polysorbate 40, 60, 65 and 80, sucrose fatty acid ester, methyl cellulose and carboxymethyl cellulose. These surfactants could be present in the formulation of the antibody, antibody fragment, or siRNA or derivative either alone or as a mixture in different ratios.
Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push- fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. Microspheres formulated for oral administration may also be used. Such microspheres have been well defined in the art. All formulations for oral administration should be in dosages suitable for such administration.
For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner. For administration by inhalation, the compounds for use according to the present invention may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
Also contemplated herein is pulmonary delivery of the antibody, antibody fragment, or siRNA (or derivatives thereof). The antibody, antibody fragment, or siRNA (or derivative) is delivered to the lungs of a mammal while inhaling and traverses across the lung epithelial lining to the blood stream. Other reports of inhaled molecules include Adjei et al., 1990, Pharmaceutical Research, 7:565-569; Adjei et al. (1990) International Journal of
Pharmaceutics, 63:135-144 (leuprolide acetate); Braquet et al. (1989) Journal of Cardiovascular Pharmacology, 13(suppl. 5):143-146 (endothelin-1); Hubbard et al. (1989) Annals of Internal Medicine, Vol. HI, pp. 206-212 (αl- antitrypsin); Smith et al. (1989) J. Clin. Invest. 84:1145-1146 (a- 1 -proteinase); Oswein et al., 1990, "Aerosolization of Proteins", Proceedings of Symposium on Respiratory Drug Delivery II, Keystone, Colorado, March, (recombinant human growth hormone); Debs et al., 1988, J. Immunol. 140:3482-3488 (interferon-γ and tumor necrosis factor alpha) and Plate et al., U.S. Patent No. 5,284,656 (granulocyte colony stimulating factor). A method and composition for pulmonary delivery of drugs for systemic effect is described in U.S. Patent No. 5,451 ,569, issued September 19, 1995 to Wong et al.
Contemplated for use in the practice of this invention are a wide range of mechanical devices designed for pulmonary delivery of therapeutic products, including but not limited to nebulizers, metered dose inhalers, and powder inhalers, all of which are familiar to those skilled in the art. Some specific examples of commercially available devices suitable for the practice of this invention are the Ultravent nebulizer, manufactured by Mallinckrodt, Inc., St. Louis, Missouri; the Acorn II nebulizer, manufactured by Marquest Medical Products, Englewood, Colorado; the Ventolin metered dose inhaler, manufactured by Glaxo Inc., Research Triangle Park, North Carolina; and the Spinhaler powder inhaler, manufactured by Fisons Corp., Bedford, Massachusetts.
All such devices require the use of formulations suitable for the dispensing of antibody, antibody fragment, or siRNA (or derivative). Typically, each formulation is specific to the type of device employed and may involve the use of an appropriate propellant material, in addition to the usual diluents, adjuvants and/or carriers useful in therapy. Also, the use of liposomes, microcapsules or microspheres, inclusion complexes, or other types of carriers is contemplated. Chemically modified antibody, antibody fragment, or siRNA may also be prepared in different formulations depending on the type of chemical modification or the type of device employed.
Formulations suitable for use with a nebulizer, either jet or ultrasonic, will typically comprise antibody, antibody fragment, or siRNA (or derivative) dissolved in water at a concentration of about 0.1 to 25 mg of biologically active antibody, antibody fragment, or siRNA per mL of solution. The formulation may also include a buffer and a simple sugar
(e.g., for antibody, antibody fragment, or siRNA stabilization and regulation of osmotic pressure). The nebulizer formulation may also contain a surfactant, to reduce or prevent surface induced aggregation of the antibody, antibody fragment, or siRNA caused by atomization of the solution in forming the aerosol. Formulations for use with a metered-dose inhaler device will generally comprise a finely divided powder containing the antibody, antibody fragment, or siRNA (or derivative) suspended in a propellant with the aid of a surfactant. The propellant may be any conventional material employed for this purpose, such as a chlorofluorocarbon, a hydrochlorofluorocarbon, a hydrofluorocarbon, or a hydrocarbon, including trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethanol, and
1,1,1 ,2-tetrafluoroethane, or combinations thereof. Suitable surfactants include sorbitan trioleate and soya lecithin. Oleic acid may also be useful as a surfactant.
Formulations for dispensing from a powder inhaler device will comprise a finely divided dry powder containing antibody, antibody fragment, or siRNA (or derivative) and may also include a bulking agent, such as lactose, sorbitol, sucrose, or mannitol in amounts which facilitate dispersal of the powder from the device, e.g., 50 to 90% by weight of the formulation. The antibody, antibody fragment, or siRNA (or derivative) should most advantageously be prepared in particulate form with an average particle size of less than 10 μm (micrometers), most preferably 0.5 to 5 μm, for most effective delivery to the distal lung. Nasal delivery of a pharmaceutical composition of the present invention is also contemplated. Nasal delivery allows the passage of a pharmaceutical composition of the present invention to the blood stream directly after administering the therapeutic product to the nose, without the necessity for deposition of the product in the lung. Formulations for nasal delivery include those with dextran or cyclodextran. For nasal administration, a useful device is a small, hard bottle to which a metered dose sprayer is attached. In one embodiment, the metered dose is delivered by drawing the pharmaceutical composition of the present invention solution into a chamber of defined volume, which chamber has an aperture dimensioned to aerosolize and aerosol formulation by forming a spray when a liquid in the chamber is compressed. The chamber is compressed to administer the pharmaceutical composition of the present invention. In a specific embodiment, the chamber is a piston arrangement. Such devices are commercially available.
Alternatively, a plastic squeeze bottle with an aperture or opening dimensioned to aerosolize an aerosol formulation by forming a spray when squeezed is used. The opening is usually found in the top of the bottle, and the top is generally tapered to partially fit in the nasal passages for efficient administration of the aerosol formulation. Preferably, the nasal inhaler will provide a metered amount of the aerosol formulation, for administration of a measured dose of the drug.
The compounds, when it is desirable to deliver them systemically, may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
Alternatively, the active compounds may be in powder form for constitution with a suitable vehicle, e.g., sterile pyro gen-free water, before use.
The compounds may also be formulated in rectal or vaginal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long acting formulations may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
The pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols. Suitable liquid or solid pharmaceutical preparation forms are, for example, aqueous or saline solutions for inhalation, microencapsulated, encochleated, coated onto microscopic gold particles, contained in liposomes, nebulized, aerosols, pellets for implantation into the skin, or dried onto a sharp object to be scratched into the skin. The pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops or preparations with protracted release of active compounds, in whose preparation excipients and additives and/or auxiliaries such as disintegrants, binders, coating agents, swelling agents, lubricants, flavorings, sweeteners or solubilizers are customarily used as described above. The pharmaceutical compositions are suitable for use in a variety of drug delivery systems. For a brief review of methods for drug delivery, see Langer (1990) Science 249: 1527-1533, which is incorporated herein by reference.
The antibody, antibody fragment, or siRNA and optionally other therapeutics may be administered per se (neat) or in the form of a pharmaceutically acceptable salt. When used in medicine the salts should be pharmaceutically acceptable, but non- pharmaceutically acceptable salts may conveniently be used to prepare pharmaceutically acceptable salts thereof. Such salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulphuric, nitric, phosphoric, maleic, acetic, salicylic, p-toluene sulphonic, tartaric, citric, methane sulphonic, formic, malonic, succinic, naphthalene-2-sulphonic, and benzene sulphonic. Also, such salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts of the carboxylic acid group.
Suitable buffering agents include: acetic acid and a salt (1-2% w/v); citric acid and a salt (1-3% w/v); boric acid and a salt (0.5-2.5% w/v); and phosphoric acid and a salt (0.8-2% w/v). Suitable preservatives include benzalkonium chloride (0.003-0.03% w/v); chlorobutanol (0.3-0.9% w/v); parabens (0.01-0.25% w/v) and thimerosal (0.004-0.02% w/v).
The pharmaceutical compositions of the invention contain an effective amount of a antibody, antibody fragment, or siRNA and optionally therapeutic agents included in a pharmaceutically-acceptable carrier. The term pharmaceutically-acceptable carrier means one or more compatible solid or liquid filler, diluents or encapsulating substances which are suitable for administration to a human or other vertebrate animal. The term carrier denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application. The components of the pharmaceutical compositions also are capable of being commingled with the compounds of the present invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficiency.
The therapeutic agent(s), including specifically but not limited to the antibody, antibody fragment, or siRNA, may be provided in particles. Particles as used herein means nano or microparticles (or in some instances larger) which can consist in whole or in part of the antibody, antibody fragment, or siRNA or the other therapeutic agent(s) as described herein. The particles may contain the therapeutic agent(s) in a core surrounded by a coating, including, but not limited to, an enteric coating. The therapeutic agent(s) also may be dispersed throughout the particles. The therapeutic agent(s) also may be adsorbed into the particles. The particles may be of any order release kinetics, including zero order release, first order release, second order release, delayed release, sustained release, immediate release, and any combination thereof, etc. The particle may include, in addition to the therapeutic agent(s), any of those materials routinely used in the art of pharmacy and medicine, including, but not limited to, erodible, nonerodible, biodegradable, or nonbiodegradable material or combinations thereof. The particles may be microcapsules which contain the antibody, antibody fragment, or siRNA in a solution or in a semi-solid state. The particles may be of virtually any shape.
Both non-biodegradable and biodegradable polymeric materials can be used in the manufacture of particles for delivering the therapeutic agent(s). Such polymers may be natural or synthetic polymers. The polymer is selected based on the period of time over which release is desired. Bioadhesive polymers of particular interest include bioerodible hydrogels described by H.S. Sawhney, CP. Pathak and J.A. Hubell in Macromolecules, (1993) 26:581-587, the teachings of which are incorporated herein. These include polyhyaluronic acids, casein, gelatin, glutin, polyanhydrides, polyacrylic acid, alginate,
chitosan, poly(methyl methacrylates), poly(ethyl methacrylates), poly(butylmethacrylate), poly(isobutyl methacrylate), poly(hexylmethacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), and poly(octadecyl acrylate). The therapeutic agent(s) may be contained in controlled release systems. The term
"controlled release" is intended to refer to any drug-containing formulation in which the manner and profile of drug release from the formulation are controlled. This refers to immediate as well as non-immediate release formulations, with non-immediate release formulations including but not limited to sustained release and delayed release formulations. The term "sustained release" (also referred to as "extended release") is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that preferably, although not necessarily, results in substantially constant blood levels of a drug over an extended time period. The term "delayed release" is used in its conventional sense to refer to a drug formulation in which there is a time delay between administration of the formulation and the release of the drug there from. "Delayed release" may or may not involve gradual release of drug over an extended period of time, and thus may or may not be "sustained release."
Use of a long-term sustained release implant may be particularly suitable for treatment of chronic conditions. "Long-term" release, as used herein, means that the implant is constructed and arranged to deliver therapeutic levels of the active ingredient for at least 7 days, and preferably 30-60 days. Long-term sustained release implants are well-known to those of ordinary skill in the art and include some of the release systems described above.
The present invention is further illustrated by the following Examples, which in no way should be construed as further limiting. The entire contents of all of the references (including literature references, issued patents, published patent applications, and co-pending patent applications) cited throughout this application are hereby expressly incorporated by reference.
EXAMPLES
Example 1 Defective Expansion of Qa-I -Deficient CD4+ T Cells and NK Lysis
To define the contribution of Qa-I to protect expanding CD4+ T cells from NK lysis in Rag2-deficent hosts, CD4+ T cells isolated from either C57BL/6 (B6) Qa-I wild-type (WT) or B6 Qa-I -deficient (Bό.Qa-l7 ) mice were transferred into syngeneic Ragl'~ or Rag2~/~ PrfV'~ hosts. Fourteen days later, CD4+ T cells from spleens and lymph nodes were enumerated. C57BL/6, Rag2~/~, Rag2~/~ Prfϊ ', and Rag2'A common gamma chain (γ:)-deficient mice were purchased from Taconic Laboratories. Qa-I -deficient mice that have been described previously (Hu et al. (2004) Nat Immunol 5:516-23) were backcrossed onto C57BL/6 for at least 11 generations. OTII TCR-transgenic mice provided by H. Ploegh (Harvard Medical School, Boston, MA) were crossed with B6.Qa-l"Λ mice. Mice were housed in a specific pathogen-free, viral antibody-free animal facility at the Dana-Farber Cancer Institute. CD4 and CD8 T cells were purified by negative selection after incubation for 30 min with rat anti-mouse CD8 (anti-CD8) or anti-CD4 antibody, in addition to anti-B220, anti-Mac-1, anti-Gr-1 and anti-NKl.l antibodies (BD Pharmingen). After washing, cells were incubated for 30 min with magnetic beads coated with sheep anti-rat antibody (Dynal) before isolation of CD4 and CD8 T cells by magnetic separation.
Qa-I -deficient CD4+ T cells failed to undergo homeostatic expansion over a 2 week period in Rag2~'~ hosts, in contrast to vigorous expansion by Qa-I wild-type CD4 cells. Defective expansion of Qa-I -deficient CD4 cells in Rag!1' (NK cell sufficient) hosts was restored in Rag2~f~ Prfϊ'' (NK cell deficient) hosts. Expansion of Qa-I -deficient CD4+ T cells expressing the OTII T cell receptor (TCR), specific for chicken ovalbumin (OVA) peptide (amino acids 323-339; IS Q AVH AAH AEINE AGR; SEQ ID NO: 1; New England Peptide (Gardner, MA)) bound to MHC class IIb was also severely impaired in Rag2~'~ hosts and restored in Rag2~'~ Prfl~'~ hosts. This model measures antigen-dependent expansion of CD4 cells since significant numbers of OTII CD4+ T cells were not recovered at day 7 and 14 unless OVA peptide was provided at day 0.
To determine that perforin-dependent reduction of Qa-I -deficient CD4+ T cells in Rag!1' hosts depended on NK cells, purified Qa-I WT or Qa-I -deficient OTII CD4+ T cells were transferred (106/mouse) into Rag2~l~ or Rag2~/~ Prfl~'~ hosts along with immunization of 50 μg OVA peptide emulsified in complete Freund's adjuvant (CFA). Proliferation of OTII cells was monitored by enumeration of CD4+Vβ5+ cells in lymph
node (LN) and spleen 14 days later. NK cells (0.5 X 106) purified from splenocytes of Rag2~'~ mice were co-transferred with Qa-I -deficient OTII cells into Rag2~ ' PrfV ' hosts. Splenocytes were incubated with CD4, CD 8 and B220 antibody, and mixed with magnetic beads and separated by magnetic cell sorting. For purification of NKG2A+ NK cells, the CD4", CD8" and B220" splenocytes were stained with biotinylated NKG2AB6 mAb (eBioscience), followed by incubation with magnetic microbeads coated with biotin antibody (Mytech) before magnetic cell sorting using MACS. DX5 mAb was then used to further purify the NKG2A" NK cell population in the flow through cells. Purified NK cells were cultured in RPMI- 1640 supplemented with 10% fetal calf serum (FCS) in the presence of 1000 U/ml human recombinant IL-2 (BD Pharmingen) for 5 days. Purified mAbs against CD3ε (145-2C11), CD8 (53-6.7), CD4 (GKl.5), B220 (RA3-6B2), MAC-I (Ml/70), GR-I (RB6-8C5), NKl.1 (PK136), Ly49I/C, and FITC-conjugated anti-NKG2A/C/E were purchased from Pharmingen. Purified and biotinylated-anti-NKG2AB6 were purchased from eBioscience. Anti-biotin and anti-DX5 beads were purchased from Miltenyi Biotec (Auburn, CA).
Rag!1' Prfl~'~ hosts reconstituted with purified NK cells prevented antigen-induced expansion of Qa-I -deficient OTII+ CD4 cells. Thus, expression of Qa-I protected activated CD4 cells from NK lysis and was essential for both homeostatic and antigen-induced CD4 cell expansion.
Example 2 Decreased Lifespan of Qa-I -Deficient CD4+ T Cells
To test the hypothesis that Qa-I expression on CD4 cells protects them from NK-dependent destruction in vivo it was determined whether Qa-I -deficient mice harbor reduced numbers of CD4 cells. The peripheral T cell numbers in Qa-I WT and
Qa-I -deficient mice were determined. Total numbers of CD4+ and CD8+ T cells from pooled spleen and lymph node of 5- to 6-week-old Qa-I -deficient (KO) mice or Qa-I WT littermates (4-6 mice/group) were compared. CD4 and CD8 cells were isolated as described in Example 1. Adult Qa- 1 -deficient mice did not harbor reduced numbers of CD4 cells. Since continuous re-supply of T cells from the thymus might compensate for NK-dependent
elimination of Qa-I -deficient T cells in peripheral tissues, this possibility was tested by removal of the thymus from adult Qa-I -deficient mice.
To determine the rate of continuous re-supply of T cells from the thymus, Qa-I -deficient or WT mice were thymectomized or sham thymectomized at around 10 weeks age. The numbers of CD4+ and CD8+ cells in peripheral lymphoid tissues 6 weeks after either thymectomy or sham thymectomy of Qa-I WT or Qa-I -deficient mice at 10 wks of age (3 mice/group) were measured. CD4 and CD8 cells were isolated as described in Example 1. Within 6 weeks after thymic ablation, Qa-I -deficient mice displayed a substantial (>85%) reduction in CD4+ T cells compared with Qa-I WT mice. Thus, expression of Qa-I was essential to ensure an unimpaired lifespan of CD4 cells in peripheral tissues.
Example 3 Contribution of Qa-I Expression to Memory Development by CD4 Cells Impaired antigen-induced expansion of Qa-I -deficient OTII CD4+ T cells in
Rag!1' but not Rag2~'~ PrfV'' mice suggested that Qa-I expression protects activated CD4+ T cells from perforin-dependent killing (see Example 1).
To study memory development in mice that express the OTII TCR, Qa-I WT or Qa-I -deficient mice bearing the OTII TCR transgene (C57BL/6 2D2 TCR transgenic mice express a TCR recognizing the CNS autoantigen myelin oligodendrocyte glycoprotein (MOG) (Bettelli, E. et al. (2003) J. Exp. Med. 197:1073-1081) and were crossed with B6.Qa-l -deficient mice) were immunized with 25 μg OVA peptide emulsified in CFA (see Example 1).
To deplete NK cells, one group of mice was injected i.v. with anti-NKl.l antibody (PKl 36, 100 μg/mouse, purchased from Pharmingen) at day -1 and day 6 after peptide immunization. Control mice were injected with phosphate buffered saline (PBS) (3-4 mice/group). Virtually all peripheral T cells in OTII C57BL/6 (B6) mice are CD4+ T cells and these mice lack CD8+ T cells. Fourteen days after peptide immunization, OTII CD4+ T cells were purified from draining lymph node and were incubated with different concentrations of OVA peptide and irradiated splenocytes from B6 mice in RPMI 1640 medium supplemented with 10% FCS and 50 μM β-mercaptoethanol. Culture supernatants were collected after 48 hours of culture and cytokine concentrations in
supernatants were determined by enzyme-linked immunosorbent assay (ELISA) kit (BD Pharmingen).
After in vitro OVA peptide re-stimulation of purified CD4+ T cells from OVA-immune OTII donor mice, Qa-I -deficient CD4+ T cells displayed a >90% reduction in interferon gamma (IFN-γ) responses (measured in ng/ml). This reflected increased susceptibility of Qa-I -deficient CD4+ T cells to NK lysis, because antibody-dependent depletion of NK cells during in vivo priming (using anti-NKl.l antibody, see above) allowed Qa-I -deficient CD4+ T cells to develop unimpaired and restored peptide recall responses. Analysis of the cytokine response of Qa-I -deficient or Qa-I WT OTII CD4+ T cells 7-10 days after injection into Rag2~'~ Prfϊ'' hosts along with OTII peptide was carried out by transferring i.v. OTII CD4+ T cells (1 x 106) purified from both Qa-I WT and Qa-I -deficient mice into Rag2~ ' Prfl '' hosts, followed by immunization with 50 μg peptide emulsified in CFA. Spleen and draining LN were collected 14 days after transfer and I X lO5 pooled lymph node and spleen cells were restimulated with OVA peptide. EFN-γ secretion was measured 72 hours after stimulation.
The recall IFN-γ response of the two groups of CD4+ T cells was indistinguishable. Thus, Qa-I expression was essential for the development of CD4+ T cell memory responses following antigen stimulation in vivo.
Example 4
Defective Responses of Qa-I -Deficient CD4+ T Cells to Antigen in Bone Marrow
Chimeras
To address whether the loss of Qa-I expression by hematopoietic cells in Qa-I -deficient mice might enhance NK reactivity, as noted for MHC class Ia antigens, or otherwise alter NK cell development, mixed bone marrow (BM) chimeras containing both Qa-I+ and Qa-I" hematopoietic cells were analyzed. Lethally-irradiated Rag2~'~ or Rag2~'~ Prfl'1' host mice were reconstituted with hematopoietic stem cell (HSC)-enriched bone marrow (106/mouse) from Qa-I WT (Thyl.l) and Qa-I -deficient (KO; Thyl.2) mice and sacrificed and analyzed 4 or 12 weeks later. The BM cells were harvested from femur and tibia under sterile conditions from Qa-I WT or Qa-I -deficient mice, and erythrocytes were lysed and enriched for hematopoietic stem cells by depletion of lineage-positive cells with
anti-CD4, anti-CD8, anti-CD3, anti-Grl, anti-Macl, anti-CD19 and anti-DX antibodies, followed by sheep anti-rat IgG-conjugated immunomagnetic beads (Dynal, see Example 1). Cells (1 X 106) were then injected into irradiated (400 rads) Ragl1' or Rag!1' Prfl'A mice. The total number of peripheral CD4+ and CD8+ T cells from spleen and LN were enumerated (see Example 1).
The numbers of Qa-I -deficient CD4+ (and CD8+) lymphocytes were reduced at 4-6 weeks in Rag2~'~ but not Rag!1' Prfϊ'~ hosts, where KO and WT were very similar. However, by 12 wks of BM reconstitution, the numbers of Qa-I -deficient CD4+ T cells were similar to that of Qa-I WT CD4+ T cells (in both mice strains), similar to studies of intact Qa-I -deficient mice which indicated continuous T cell replenishment by the thymus (see Example 2).
To compare the impact of antigen stimulation on the Qa-I -deficient and Qa-I WT cohorts of CD4+ T cells in these BM chimeras, BM chimeric hosts were immunized subcutaneously with PLP peptide (amino acids 172-183; PVYIYFNTWTTC; SEQ ID NO:2; New England Peptide (Gardner, MA)) 12 weeks after adoptive transfer of BM cells. Fourteen days after immunization, total CD4+ and CD8+ T cell numbers in draining LN were enumerated (see Example 1). Both Qa-I WT and Qa-I -deficient CD4 cells were well represented in these chimeric mice.
When pooled (n=3) Qa-I WT (Thyl.l) and Qa-I -deficient (Thyl.2) CD4+ T cells were purified from draining LN and stimulated by immunization with PLP peptide together with irradiated splenocytes and IFN-γ secretion was measured after 48 hours, only Qa-IWT CD4+ T cells responded to peptide restimulation as judged by IFN-γ production.
When CD4+ T cells from the draining LN in these BM chimeras were analyzed for CD44 and CD5 expression by FACS, the Qa-I+ fraction of CD4+ T cells expressed substantially higher amounts of CD44 and CD5. Thus, expression of Qa-I was essential to allow antigen-stimulated CD4+ T cells to develop memory activity as judged by surface markers and cytokine recall responses.
Example 5
Defective EAE Induction by Qa-I -Deficient CD4+ T Cells Reflects Susceptibility to NK
Lysis
To investigate the potential impact of Qa-1-NKG2A interactions on expansion of autoreactive CD4+ T cells and consequent autoimmune disease, the response of CD4 T cells that express a transgenic TCR (2D2) specific for MOG autoantigen and induce EAE in adoptive hosts (Bettelli, E. et al. (2003) J. Exp. Med. 197:1073-1081) was analyzed. 2D2 CD4 T cells (1 x 106) purified from either Qa-I WT or Qa-I -deficient mice as described above were transferred i.v. into syngeneic Rag!'1' or Rag2~'' Prfl''' hosts (5 mice/group) that were immunized s.c. with 10 μg MOG 35-55 (MEVGWYRSPFSRVVHLYRNGK; SEQ ID NO:3; New England Peptide (Gardner, MA)) emulsified in CFA (supplemented with 4 mg/ml of Mycobacterium tuberculosis) and injected i.p. on days 0 and 2 with 200 ng pertussis toxin to induce EAE.
Clinical assessment of EAE was performed daily and scoring was as follows: 0, no disease; 1, decreased tail tone; 2, hind limb weakness or partial paralysis; 3, complete hind limb paralysis; 4, front and hind limb paralysis; 5, moribund state.
FIG. IA shows that transfer of 2D2 CD4+ T cells (106) into Ragl'~ hosts stimulated with 10 μg of MOG peptide and pertussis toxin resulted in fulminating EAE that was lethal within 3 weeks. In contrast, Rag2~ ' mice reconstituted with Qa-I -deficient 2D2 CD4+ T cells developed little or no disease after challenge with MOG-CFA and pertussis toxin. Defective responses of Qa-I -deficient autoreactive CD4 cells reflected increased susceptibility to perforin-dependent lysis, because Rag2~ ' Prfl'1' hosts reconstituted with 2D2+ Qa-I" or Qa-I+ CD4 cells developed robust EAE that led to death in approximately 3 weeks after disease induction.
FIG. IB shows that when 2D2 CD4+ T cells (1 x 106) from either Qa-I WT or Qa-I -deficient mice were transferred into C57BL/6 hosts (5 mice/group) and followed by immunization with 150 μg MOG 35-55 peptide with pertussis toxin on the same day to induce EAE and the development of EAE was measured, Qa-I -dependent protection of autoreactive T cells from NK lysis was not limited to lymphopenic Rag2~ ' hosts, because intravenous transfer of 2D2 Qa-I WT CD4+ T cells but not 2D2 Qa-I -deficient CD4+ T cells induced EAE in C57BL/6 recipients.
Thus, Qa-I expression by pathogenic autoreactive CD4+ T cells was essential for protection of these cells against perforin-dependent lysis and allowed them to induce EAE in both C57BL/6 WT and C57BL/6 Rag2~'~ hosts.
Example 6 Lentiviral-Mediated Expression of Qa-l-Qdm Confers Protection to CD4+ T Cells
The findings set forth in the previous examples that (a) responses of Qa-I -deficient CD4+ T cells to foreign and self antigens were defective in Rag2~'~ PrfV'' hosts and (b) depletion of NK cells restored peptide recall responses of Qa-I -deficient mice and enhanced the CD4 response in Qa-I WT OTII mice suggest that Qa-l-Qdm expression by CD4+ T cells may protect them from NK lysis.
To further evaluate this hypothesis, antigen-dependent responses of Qa-I WT OTII CD4+ T cells in Rag?1' or Rag?' Prfl^ hosts were analyzed. OTII CD4+ T cells (1 X 106) were transferred into Rag2~'~ or RagT1' Prfl '' mice (4 mice/group) before immunization with OVA peptide (75 μg peptide— CFA) immediately after transfer. Mice were sacrificed 72 hours later and total OTII cells in the draining LN and spleen enumerated.
The expansion of OTII cells in RagZ1' hosts was delayed compared to Rag!1' Prfl''' hosts, and the numbers of OTII cells in draining LN of Rag2~'~ mice were reduced by more than 50% on day 3 after stimulation compared with Rag2~'~ Prfl~'~ mice.
In addition, OTII CD4+ T cells infected with lentivirus expressing either green fluorescent protein (GFP) control or Qdm-β2m-Qa-l fusion protein were also transferred into Rag2~'~ or Rag2~'~ Prfϊ'' hosts (4 mice/group) before immunization with OVA peptide (75 μg peptide-CFA). Seventy-two hours later, expansion of OTII cells was analyzed. Full-length open reading frame (ORF) of Qa-I was amplified by reverse transcriptase- polymerase chain reaction (RT-PCR) from concanavalin A (ConA)-activated C57BL/6 spleen RNA, digested withiførøHI-ATjoI, and cloned into pLenti6/V5 (Invitrogen) by using BarriΑl and Xhol restriction sites. The construct was confirmed by sequencing. Enhanced GFP alone was cloned into pLenti6/V5 as a negative control. For mutation screening, a point mutation was introduced by site-directed mutagenesis according to manufacturer's instructions (Stratagene). For expression of peptide-sewed-in Qa-I molecules, Qdm-β2m-Qa-l and HSP60-β2m-Qa-l fusion proteins were made by overlapping PCR. Lentiviral stocks were generated by cotransfection of 293 T cells with the packaging plasmids pLPl, pLP2, and pLP/VSVG (Invitrogen) by using Lipofectamine 2000 (Invitrogen) according to the manufacturer's protocol. Viral supernatants were collected 72 h after transfection and the viral titer for all transfections was approximately 107 plaque-forming units/ml. Naive Qa-I -deficient CD4 T cells were infected with
lentivirus at a MOI of 5-10 for 3-6h at 37°C with 5% CO2 and either washed and used directly after a 3h infection or washed and rested for an additional 15h at 37°C with 5% CO2.
The expression of a Qdm-β2m-Qa-l fusion protein by OTII cells almost completely restored proliferation of OTII cells in Rag2~'~ hosts to amounts similar to that observed in Rag2~'~ Prfl~'~ hosts (the numbers of OTII cells in draining LN oϊRagl1' mice • of the previous experiment were reduced by more than 50% on day 3 after stimulation compared with Rag2~ ' Prfl '' hosts, see above).
This finding directly supports the hypothesis that antigen-induced proliferation of T cells requires Qa-1-Qdm-dependent protection from NK lysis.
Example 7 Qa-I -Deficient Activated CD4+ T Cells are Regulated by the NKG2A+ Subset of NK Cells
The expression status of NKG2A was established on NK cells in C57BL/6 mice. When NK cells were enriched by negative selection before NKG2A+ and NKG2A" NK cells were sequentially separated by positive selection, using NKG2AB6 and DX5 antibody, respectively, and purified cells were incubated with IL-2 for 5 days, about half of NK cells from C57BL/6 mice expressed NKG2A (NKG2A+ NK cells) and half did not (NKG2A" NK cells). Both NKG2A phenotypes were stable after 1 week of in vitro culture with IL-2. Purified and biotinylated-anti-NKG2AB6 were purchased from eBioscience. Anti-biotin and anti-DX5 beads were purchased from Miltenyi Biotec (Auburn, CA).
To establish which of the NK subgroups (NKG2A+ or NKG2A" NK cells) is responsible for killing of activated CD4+ T cells, an in vitro NK cytotoxic assay was employed. Target cells were labeled with 50 μCi OfNa2(51Cr)O4 for 1 hour at 37°C, washed 3 times with PBS, and then mixed (1 x 104/well) with effector cells in U-bottomed 96-well plates at different E-T (effector-target) ratios (10:1, 20:1, 40:1) in triplicate. After 4 hours of incubation, cell-free supernatants were collected and radioactivity measured by Micro-beta counter (Wallac). Percentage specific lysis was calculated by (sample release - spontaneous release) / (maximum release - spontaneous release).
FIG. 2 shows that when NKG2A+ and NKG2A" NK cells isolated from B6 mice and activated individually by IL-2 were used as effector killer cells to kill ConA-activated
CD4+ T cells from Qa-I wild type and Qa-I -deficient mice in a standard killing assay, the NKG2A+ but not NKG2A" NK cell subset lysed Qa-I -deficient cells. This finding indicated that lytic activity is invested in an NK subset that expresses NKG2A+ and therefore can bind to Qa-l-Qdm. To validate the findings stated above, the following control experiments were conducted:
Although NKG2A~ NK1.1+ cells did not lyse Qa-I -deficient CD4+ T cells, they efficiently lysed H-2Kb-deficient CD4+ T cells in a Qdm peptide-independent fashion. H-2KbDb-deficient, H-2Kb-deficient and H-2Db-deficient mice were purchased from Taconic Laboratories.
When H-2KbDb-deficient CD4 cells were activated by ConA for 48 hour and labeled with 51Cr before use as targets of NKG2A+ and NKG2A" NK cells, or H-2Kb-deficient or H-2Db-deficient single knockout CD4 T cells were used as targets for NK cells, the NKG2A+ subsets also lysed H-2Db-deficient cells due to the lack of Qdm peptide. Lysis was inhibited by addition of Qdm peptide (which reconstituted the Qa-l- Qdm complex on H2-Db-deficient cells). The addition of Qdm peptide also partially inhibited lysis of H-2KbDb double deficient cells by NKG2A+ NK cells but not by NKG2A" NK cells.
When L cells infected with lentivirus expressing either GFP (as a control) or Qa-I were subject to in vitro killing by IL-2-activated NKG2A+ or NKG2A" NK cells, with or without addition of Qdm peptide (30 μM), the lytic activity of NKG2A+ and NKG2A" NK cells against MHC-deficient target L cells was similar to that exerted against H-2KbDb-deficient target cells: both NK subsets lysed L cells equally well and lysis by NKG2A+ cells was partially inhibited by expression of Qa-l-Qdm. To test whether the protection of CD4+ T cells was mediated by the Qa- 1-Qdm ligand, Qa-I -deficient (Qa-I KO) OTII cells were infected with lentivirus expressing either a Qdm-β2m-Qa-l fusion protein (QbQ) or a HSP60 peptide-β2m-Qa-l fusion protein (HbQ) and used as target cell in the killing assay by NKG2A+ NK cells. Qa-I WT and Qa-I -deficient OTII cells were used as control. FIG. 3 shows the protection of Qa-I -deficient CD4 cells from NK lysis by lentiviral-mediated surface expression of a covalent Qdm-β2m-Qa-l complex. Increased susceptibility of Qa-I -deficient CD4+ T cells to NK cell lysis reflected defective
expression of surface Qa-l-Qdm (rather than altered development of CD4+ T cells in Qa-I -deficient mice), because lentiviral-dependent re-expression of Qa-I heavy chain covalently- attached to a Qdm peptide efficiently restored resistance of Qa-I -deficient cells to NK lysis. In contrast, lentiviral introduction of Qa-I heavy chain covalently linked to a different peptide (from HSP60) did not protect these cells. These findings indicated that protection of CD4+ T cells was mediated by the Qa-l-Qdm ligand rather than Qa-I complexed to other peptides.
The hypothesis that the NKG2A+ fraction of NK cells is selectively equipped to monitor cellular Qa-l-Qdm expression was supported by an examination of the regulatory activity of NK cell subsets. CD4 cells were purified from Qa-I WT and Qa-I -deficient OTII TCR transgenic mice, and splenic dendritic cells (DCs) were purified from Qa-I WT and Qa-I -deficient mice and activated by anti-CD40. NKG2A+ and NKG2A" NK cells were purified from B6 mice and stimulated with 1000 U/ml IL-2 for 5 days. OTII CD4+ T cells (5 X 104) were stimulated with 1 μg/ml OVA peptide and 2.5 x 104 activated DC. IL-2-activated NK cells were added to cultures 48 hours before proliferation of CD4+ T cells was measured.
Titration of NKG2A+ but not NKG2A" NK cells into cultures containing Qa-I -deficient or Qa-I WT OTII CD4 cells revealed a dose-dependent inhibition of proliferation of the Qa-I -deficient OTII CD4 cells by NKG2A+ but not NKG2A" NK cells. The surface phenotype and function of both NK subsets were stable after 5 days in culture in the presence of IL-2 in vitro.
To establish which NKG2A phenotype marks a stable subset of NK cells in vivo, NKG2A+ or NKG2 A" NK cells were transferred into Rag2~'~ common gamma chain (γc)-deficient hosts to evaluate the stability of the NKG2A+ subset in vivo. NK cells, like other lymphocytes, undergo homeostatic expansion in lymphopenic hosts. Two weeks after adoptive transfer of purified NKG2A+ NKl.1 cells into Rag2''' γc-deficient hosts, these cells maintained expression of NKG2A on their surface, indicating that the NKG2A+ phenotype marks a stable subset of NK cells in vivo.
Because NK cells developing from fetal progenitors acquire expression of NKG2A and Ly49 in a random manner, differential expression of Ly49 gene products on NKG2A+ and NKG2A" NK cells might account for their ability to lyse "activated self targets. NKG2 A+ and NKG2 A~ NK cells may also express different amounts of activating
receptors such as NKG2D (Rabinovich, B.A. (2003) J. Immunol. 170:3572-3576). Examination of Ly49C+I expression by NKG2A+ and NKG2A" NK cells indicated that roughly 2/3 of each NK subset is Ly49I+C. Ly49I/C, FITC-conjugated anti-NKG2A/C/E was purchased from Pharmingen. Purified and biotinylated-anti-NKG2AB6 were purchased from eBioscience. Anti-biotin and anti-DX5 beads were purchased from Miltenyi Biotec (Auburn, CA).
Example 8
Selective Disruption of the Interaction Between Qa-I and CD94-NKG2A by a Point Mutation (R72A) in Qa-I
As shown in the previous examples Qa-I -deficient CD4+ T cells were susceptible to lysis by NKG2A+ NK cells and failed to develop immunological memory in vivo. However, genetic deletion of Qa-I and insertion of a neomycin resistance (Neor) gene into the MHC class I locus might affect expression of linked MHC genes or alter surface protein display in a way that increases cellular susceptibility to lysis. A direct molecular approach to this question came from the definition of a Qa-I amino acid mutation that eliminated binding activity to the CD94— NKG2 A receptor but spared other Qa-I -dependent biological activities.
The solved structure of the human HLA-E molecule and mutagenic analysis of its interaction with CD94-NKG2 molecules (Wada, H. (2004) Eur. J. Immunol. 34:81-90) was utilized to identify potential residues that may be essential for the Qa-I interaction with CD94-NKG2A but do not interfere with its interaction with the T cell receptor. These residues (in HLA-E) included R65, D69, Q72, R75, R79, H155, D162 and E166, which are conserved in the mouse Qa-I molecule. The sequence alignment between HLA-E and Qa-I shows conservation around the alpha 1 region. The potential
NKG2A-binding residues (D69, Q72, R75) are conserved between HLA-E and Qa-I. Five Qa-I mutations (D69A, R72A, R75A D162A and E 166A) were tested for their impact on the functional interaction of Qa-I with CD94-NKG2A.
When L cells expressing different Qa-I mutants were used as stimulators to CD8 cells from B6.Tla mice immunized with Qa-I ConA blasts and expansion of CD8 cells after 3 days was measured, the R72 residue at the top of the alpha 1 domain of Qa-I was the most critical for functional interactions with the CD94-NKG2A receptor: Qa-I R72A
mutants failed to protect L cells from lysis by NKG2A+ NK cells but were fully able to target Qa-I -specific alloreactive CD8 T cell lysis.
When L cells were infected with lentivirus expressing either WT or Qa-I mutants and used as target cells of IL-2-activated NKG2A+ NK cells with or without addition of Qdm peptide (30 μM), mutations of Qa-I at R75, D162 and E166 did not impair Qa-I- NKG2A interactions and these Qa-I mutants fully protected L cells from NKG2A+ NK cell lysis (for lysis assay see Example 7). Although the D69A mutation impaired protection from NK lysis, this mutation also interfered with detection of the molecule by Qa-I antibody.
Example 9 Qa-I R72A Mutant Knock-in Mice Display the Qa-I -Deficient Phenotype
To assess the importance of the Qa-1-NKG2A interaction in vivo, Qa-I R72A mutant knock-in mice were generated using the cre-loxP system. To generate the Qa-I R72A mutant knock-in mice a BAC clone containing an 11 kilobase (kb) DNA fragment including the Qa-I gene (H2-T23) was identified and fully mapped. LoxP-flanked Neor was introduced into the EcoRV site in intron 3 of the Qa-I gene without interrupting the splicing by avoiding the conserved splicing branch site. After cloning the 3.5 kb Qa-I -containing fragment (from EcoRI to EcoRV) into a cloning vector, the R72A mutation was introduced by site-directed mutagenesis and confirmed by sequencing. This fragment was cloned into the Sail site of pLNTK (Gorman, J.R. (1996) Immunity 5:241-252) and the 2.7 kb fragment (EcoRV to Speϊ) was then cloned into the Xhol site to complete the replacement vector. After TCl embryonic stem cells were transfected with the targeting vector, positively-selected recombinants were identified by long-range PCR screening and Southern blot. The Neor gene was deleted by crossing the germline transmitted litters to ΕIIα-CRΕ mice, which were then crossed to C57BL/6 mice for 5 generations. Homozygous R72A mutant mice were obtained by intercrossing the heterozygous littermates.
FIG. 4 shows the Qa-I genomic locus and R72A targeting strategy. Correct integration of the construct was confirmed by Southern blot analysis.
When splenocytes from littermates (Qa-I -deficient [KO], Qa-I wild-type [WT], and Qa-I R72A knock-in [R72A]) were individually stimulated with ConA for 4Oh and
analyzed for surface Qa-I expression by FACS analysis using Qa-I antibody (BD Bioscience), the R72A mutant was expressed on activated T cells at amounts similar to the WT protein in WT mice. Of total cells gated, 92.7% of cells were Qa-I positive in the R72A mutant population and 96.4% of cells were Qa-I positive in the WT population. When CD4+ T cells from Qa- 1 WT, Qa- 1 -deficient, and Qa- 1 -R72 A mutant mice were activated by ConA for 48 hours, labeled with 51Cr, and used as targets for IL-2-activated NKG2A+ NK cells in a standard 4-hour killing assay (see Example 7), the Qa-I R72A mutant T cells were no longer protected from NK lysis and were as vulnerable as Qa-I -deficient T cells. When CD4+ T cells (1 x 106) were isolated from Qa-I WT, Qa-I -deficient, and
Qa-1-R72A mutant mice and i.v. transferred into Rag2~'~ and Rag2~1' Prfl'1' hosts (3 mice/group) and fourteen days later, host mice were killed and total CD4+ T cells were enumerated from spleen and LN, to examine homeostatic expansion, CD4+ T cells expressing the Qa-I R72A point mutation expressed the phenotype of Qa-I -deficient cells and failed to expand in Rag2~'~ hosts but expanded as well as Qa-I WT cells in Rag2~'~ Prfl '' hosts. These results reinforced findings with Qa-I -deficient mice that Qa-I -dependent protection of CD4+ T cell expansion and adaptive memory responses depends entirely on its interaction with CD94-NKG2A. The generation and validation of Qa-I R72A mutant mice also provided a unique mouse model to examine the functional outcome of defective Qa-1-NKG2A interactions on immune responses without affecting other antigen presenting properties of the Qa-I molecule.
Example 10
Antibody-Dependent Blockade ofQa-l-NKG2A Interaction with Anti-Qa-1 Antibody Inhibits Development of EAE
To determine whether blockade of the Qa-1-NKG2A interaction with Qa-I antibody inhibits the development of EAE, anti-Qa-1 antibody was administered to mice during the period preceding clinical signs of disease and preceding the development of Qa-I -restricted CD8+ regulatory T cells (Jiang, H. (1992) Science 256:1213-1215; Hu, D. (2004) Nat Immunol 5:516-23).
C57BL/6 mice were immunized s.c. with 150 μg MOG 35-55 emulsified in CFA (supplemented with 4 mg/ml of Mycobacterium tuberculosis) and injected i.p. on day 0
and day 2 with 200 ng pertussis toxin to induce EAE. To block the Qa-1-NKG2A interaction, anti-Qa-1 antibody (Qa- lb, BD Pharmingen) was administered three times at day 5, 9, and 12 after immunization (150 μg, i.v.). This monoclonal antibody was raised against a peptide corresponding to amino acids 161-179 of Qa-I and is a mouse IgGl, K isotype antibody. In a separate group, anti-NKl.l was administered (150 μg, i.v.) at day 3, 7 and 10 to deplete NK cells before administration of anti-Qa-1 antibody on days 5, 9, and 12 to determine whether altered disease development was NK cell dependent or not. A control group was given either PBS or mouse IgGl isotype control (5 mice per group). Clinical assessment of EAE was performed daily and scored as described in Example 5. FIG. 5 shows that this protocol markedly reduced the intensity of EAE. The therapeutic effects of anti-Qa-1 antibody injection in this experiment depended on the action of NK cells, because hosts depleted of NK cells with NKl.1 antibody did not display a therapeutic response to treatment with anti-Qa-1 antibody. These observations indicate that the autoimmune CD4+ T response responsible for EAE can be almost fully ameliorated by antibody-dependent blockade of the Qa-1-NKG2A interaction and associated NK-dependent elimination of pathogenic T cells.
Example 11 Generation and Characterization of QaI-I D227 K Mutant Knock-in Mice A genomic 4 Kb Qa-I fragment containing a D-^K amino acid exchange mutation at pos 227 after site-directed mutagenesis was cloned into a replacement vector and transfected into the TCl ES cell line. Positive homologous recombinant clones identified by long-range PCR and southern blot were used for blastocysts injection to produce chimeras. After confirmation of germline transmission, the Neor gene was deleted after crossing to B6-EIIα-CRE mice and back-crossed to C57BL/6 (B6) for 7 generations followed by inter-crossing to produce homozygous B6.Qa-l D227K mutant mice. Expression of cell surface Qa-I by activated (ConA-stimulated) CD4 cells from B6.Qa-l D227K knock-in mice was indistinguishable from Qa-I WT T cells. Expression of the Qa-I D227K mutation by L cells or activated CD4 cells failed to target these cells for lysis by Qa-I -restricted cytolytic T cells (CTL). In contrast, Qa-I -dependent resistance of activated B6.Qa-l D227K CD4 cells to lysis by NKG2A+ NK cells was unimpaired in vitro, and in vivo, as judged by homeostatic expansion in Rag-2''' and
hosts.
In contrast, cells from B6 Qa-I knock-in mice that express the Qa-I R72A mutation preventing binding between Qa-I and NKG2A revealed increased susceptibility of these cells to NK lysis and failure to expand in Rag-2'A hosts. Taken together, these observations indicate that the immunological impact of the interaction of Qa-I with the TCR/CD8 complex can be experimentally separated from the impact of the interaction of Qa-I with NKG2A using B6.Qa-l D227K and B6.Qa-l R72A knock-in mice.
Example 12
Qa-J -Restricted Suppressive Interaction Between CD8 and CD4 Cells Requires CD8 Co-Receptor Binding to the Qa-I Molecule on CD4 Cells
CD8 cells obtained from B6 mice immunized with irradiated activated OT-2 CD4 T cells two weeks earlier were transferred along with OT-2 CD4+ cells into Rag2~ ~Prfl~ ' hosts immunized with OT-2 peptide. Expansion of Qa-I WT and Qa-I R72A OT2+ CD4+ cells was substantially inhibited by CD8+ cells, while expansion of D227K OT-2 cells over the following two weeks was unimpaired. These findings indicate that (a) the Qa-I- restricted suppressive interaction between CD8 and CD4 cells requires CD8 co-receptor binding to the Qa-I molecule on CD4 cells and (b) the interaction between Qa-I and the TCR can be experimentally separated from the interaction of Qa-I (Qdm) with the NKG2A receptor, allowing dissection of their respective contributions to immunoregulation.
Example 13 Enhanced Susceptibility of Qa-I D227K Mutant Knock-In Mice to EAE
Pre-immunization of mice with MOG peptide before induction of EAE with MOG/CFA and pertussis toxin substantially inhibited development of EAE. In contrast, pre-immunization of B6. Qa-I D227K mice with MOG peptide was followed by robust disease development. Moreover, CD4 cells from B6.Qa-l D227K mice, but not B6 control littermates, displayed vigorous anti-MOG recall responses, as judged by production of the IFN-γ and IL- 17 pro-inflammatory cytokines. The Qa-I D227K mutation also prevented the development of CD8 Treg to a second self-antigen - PLP. Pre-immunization of C57BL/6 mice with PLP peptide without pertussis toxin induced PLP-specific CD8+ Treg that inhibited EAE upon subsequent
challenge with PLP/CFA and pertussis toxin. Immunization of B6.Qa-l D227K mice with PLP/CFA failed to protect these mice from the development of severe EAE upon challenge with PLP/CFA + pertussis toxin, in contrast to the disease protection displayed by Qa-I WT littermates. Loss of protection by Qa-I D227K knock-in mice was associated with substantially increased anti-PLP secondary IFN-γ responses by CD4 cells from these mice. Thus, expression of a Qa-I point mutation (D227K) that prevents interaction with the CD 8 co-receptor resulted in a markedly enhanced CD4 response to the PLP self- antigen and associated development of EAE.
Example 14
Suppression Is Attenuated by Engagement ofNKG2A on CD8+ Treg Cells
In contrast to C57BL/6 mice that express the Qa-I D227K mutation, B6.Qa-l R72A knock-in mice were completely protected from induction of EAE by pre- immunization as described above. This was accompanied by a markedly reduced anti- PLP EFN-γ response upon restimulation of CD4 cells in vitro, suggesting the hypothesis that engagement of Qa-l/Qdm on CD4 cells by NKG2A on CD8 Treg impairs the suppressive activity of these cells.
To directly test this hypothesis, the susceptibility of MOG-immune CD4 cells expressing the R72A mutation to Qa-I -restricted inhibition by CD8+ Treg in adoptive Rag2~/~Prfr/~ hosts was investigated. Since activated CD4 T cells that fail to engage inhibitory NKG2A receptors on NK cells are susceptible to NK cell lysis, potential source of NK cells in experiments was eliminated by using Qa-I R72A CD4 T cells. First, MOG-specifϊc CD4 responses were measured in adoptive Rag2'l'Prfl'/' hosts. Co-transfer of CD8 cells with MOG-immune Qa-I WT CD4 cells into Rag2~'~Prfϊ'~ hosts resulted in modest inhibition of EAE. In contrast, transfer of EAE by MOG-immune CD4 cells from R72 A donors was completely abolished by co-transfer of CD8 cells, despite the fact that isolated R72A CD4 cells induced levels of EAE that were at least as robust as CD4 cells from Qa-I WT littermate donors. Analysis of the in vitro recall response to MOG at 3 weeks revealed that co-transfer of CD8 cells with R72A CD4 cells virtually abolished the anti-MOG recall response, as judged by IFN-γ secretion.
A more stringent test of the impact of the Qa-I R72A mutation on the susceptibility of CD4 cells to CD8 Treg activity was based on analysis of the ability of
CD8 cells to inhibit CD4 cells that express the MOG-specific 2D2 TCR transgene. Transfer of 2D2+ CD4 cells into Rag2~/~Prfl'/' hosts initiated a progressive and lethal form of EAE that resulted in death from fulminant disease within 14-16 days after transfer. If CD8-dependent suppression of 2D2+ CD4 cells is normally attenuated by an interaction between Qa-l/Qdm expressed by CD4 target cells and NKG2A receptors expressed by CD8 Treg, genetic disruption of this interaction might suppress this virulent form of EAE, as was the case for disease induced by polyclonal MOG-reactive CD4 cells. Transfer of 106 2D2+ CD4 cells (5 x the lethal dose) into Ragl''Pφ''' hosts provoked lethal EAE by day 15 in the presence of CD8+ (or CD4+) Treg. While transfer of 106 2D2+ CD4 cells expressing the Qa-I R72A mutation also induced lethal disease by day 15, co-transfer of CD8+ Treg completely abrogated any sign of disease.
Abolition of EAE development by co-transfer of CD8 cells was associated with suppression of 2D2+ CD4 T cell expansion in Rag2'/'Prfl'/' hosts. Expansion of R72A 2D2 CD4 T cells was almost completely (>95%) suppressed by co-transfer of CD8 cells, while expansion of Qa-I WT 2D2 CD4 T cells was only slightly reduced by MOG- immune CD8 T cells. Since the residual Qa-I R72A 2D2+ CD4 cells displayed almost no response to MOG in vitro, failure of EAE development can be attributed to CD8- dependent suppression of the anti-MOG response of 2D2+ CD4 cells bearing the MOG- specific TCR. The MOG-specific response of 2D2+ CD4 T cells expressing the R72 A mutation was shown to be highly susceptible to dose-dependent suppression by CD8 Treg in vitro, as judged by diminished proliferation and IL-2 secretion, whereas CD4 cells bearing the Qa-I D227K mutation were fully resistant to CD8 Treg activity, as expected. The dependence of CD8 Treg activity on Qa-I recognition was confirmed by the finding that anti-Qa-1 antibody blocked CD8-dependent suppression of the CD4 cell IL-2 response.
Example 15
Disruption of the Qa-1—NKG2A Interaction Abrogates EAE in Non-Lymphopenic
B6.Qa-l R72A Mice Transfer of CD8 or CD4 Treg into non-lymphopenic hosts generally fails to induce remission after disease has begun. An experiment was performed to assess whether removal of the Qa-1/Qdm-NKG2A interaction might uncover CD8-dependent suppression
of EAE in non-lymphopenic B6.Qa-l R72A mice. Transfer of purified CD8 Treg into Qa-I R72A 2D2+ mice seven days after disease was initiated (by immunization with MOG/CFA + pertussis toxin) resulted in complete remission. Taken together, these observations indicate that genetic disruption of the Qa-l:Qdm-NKG2A interaction unleashes potent CD8-dependent suppressive activity that abrogates EAE not only in adoptive lymphopenic hosts but also in non-lymphopenic B6.Qa-l R72A mice.
Example 16 Anti-NKG2A F(ab)2 Fragment Prevents Development and Induces Remission of EAE Blockade of Qa- 1 /Qdm-NKG2 A interaction by anti-NKG2 A F(ab % fragment (but not an isotype control IgG2a F(ab')2 fragment) mimicked the effect of the R72A mutation: CD8 cells from MOG-immune donors (which mediate inefficient suppressive activity against CD4 cells expressing WT Qa-I) exerted substantial inhibitory activity when the host was also given anti-NKG2A F(ab')2 fragment. Thus, transfer of CD8 Treg along with injections of anti-NKG2A F(ab')2 fragment during a 9 day period after MOG immunization markedly attenuated subsequent development of EAE. Moreover, analysis of the CD4 recall response to MOG indicated a five- fold reduction in the IFN-γ recall response of CD4 cells from donors treated with CD8 Treg and anti-NKG2A F(ab')2 fragment. Taken together, these findings indicate that disruption of the NKG2A-dependent inhibitory signal from CD8 Treg unleashes potent suppression of pathogenic CD4 cells and abrogation of lethal EAE. A key question with respect to the clinical significance of this finding concerns its ability to reverse disease when given after animals had developed EAE. Approximately 19 days after immunization with MOG peptide plus pertussis toxin, when disease development had reached its peak, mice were treated with two doses of 200 μg of anti-anti-NKG2 A F(abO2 fragment one week apart. This group displayed complete and long term remission of disease, in contrast to the control group. This experiment indicates that antibody-dependent blockade of the Qal-NKG2A interaction is a potentially potent therapeutic approach for multiple sclerosis.
EQUIVALENTS
The foregoing written specification is considered to be sufficient to enable one skilled in the art to practice the invention. The present invention is not to be limited in scope by examples provided, since the examples are intended as a single illustration of one aspect of the invention and other functionally equivalent embodiments are within the scope of the invention. Various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and fall within the scope of the appended claims. The advantages and objects of the invention are not necessarily encompassed by each embodiment of the invention.
What is claimed is:
Claims
1. A method of treating a condition selected from autoimmune disease, graft rejection, graft- versus-host disease, comprising administering to a subject having the condition an effective amount of an agent that binds a Qa-I molecule, wherein binding of the Qa-I molecule by the agent permits natural killer (NK)-cell-mediated lysis of activated T cells, to treat the condition.
2. The method of claim 1, wherein the Qa-I molecule is a Qa-I polypeptide.
3. The method of claim 2, wherein the Qa-I polypeptide is HLA-E.
4. The method of claim 1, wherein the Qa-I molecule is a Qa-I polynucleotide.
5. The method of claim 4, wherein the Qa-I polynucleotide is an ortholog of a murine Qa-I polynucleotide.
6. The method of any one of claims 1-5, wherein the condition is an autoimmune disease.
7. The method of claim 6, wherein the autoimmune disease is selected from acute disseminated encephalomyelitis, allergic angiitis and granulomatosis (Churg-Strauss disease), ankylosing spondylitis, autoimmune Addison's disease, autoimmune alopecia, autoimmune chronic active hepatitis, autoimmune encephalomyelitis, autoimmune hemolytic anemia, autoimmune neutropenia, autoimmune thrombocytopenic purpura, Behcet's syndrome, bullous pemphigoid, chronic bullous disease of childhood, chronic inflammatory demyelinating polyradiculoneuropathy, chronic neuropathy with monoclonal gammopathy, cicatricial pemphigoid, Crohn's disease, dermatitis herpetiformis, Eaton-Lambert myasthenic syndrome, epidermolysis bullosa acquisita, erythema nodosa, glomerulonephritis, gluten-sensitive enteropathy, Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, hypersensitivity vasculitis, immune-mediated infertility, insulin resistance, insulin- dependent diabetes mellitus, Kawasaki's disease, linear IgA disease, mixed connective tissue disease, multifocal motor neuropathy with conduction block, multiple sclerosis, myasthenia gravis, paraneoplastic pemphigus, pemphigoid gestationis, pemphigus foliaceus, pemphigus vulgaris, pernicious anemia, polyangiitis overlap syndrome, polyarteritis nodosa, polymyositis/dermatomyositis, primary biliary sclerosis, psoriasis, rheumatoid arthritis, sarcoidosis, scleroderma, sclerosing cholangitis,. Sjogren's syndrome;- stiff-man syndrome, systemic lupus erythematosus, Takayasu's arteritis, temporal arteritis, thromboangiitis obliterans, type I autoimmune polyglandular syndrome, type II autoimmune polyglandular syndrome, ulcerative colitis, and Wegener's granulomatosis.
8. The method of claim 7, wherein the autoimmune disease is multiple sclerosis.
9. The method of any one of claims 1-5, wherein the condition is graft rejection.
10. The method of any one of claims 1 -5, wherein the condition is graft- versus-host disease.
11. The method of any one of claims 1 -3, wherein the agent is an antibody or fragment thereof that binds specifically to a Qa-I polypeptide.
12. The method of any one of claims 1, 4, and 5, wherein the agent is a short interfering RNA (siRNA) that binds specifically to a Qa-I polynucleotide.
13. A method of reducing activated T cells in a subject, comprising administering to the subject an effective amount of an agent that binds a Qa-I molecule, wherein binding of the Qa-I molecule by the agent permits natural killer (NK)- cell-mediated lysis of activated T cells, to reduce activated T cells in the subject.
14. The method of claim 13, wherein the Qa-I molecule is a Qa-I polypeptide.
15. The method of claim 14, wherein the Qa-I polypeptide is HLA-E.
16. The method of claim 13, wherein the Qa-I molecule is a Qa-I polynucleotide.
17. The method of claim 16, wherein the Qa-I polynucleotide is an ortholog of a murine Qa-I polynucleotide.
18. The method of any one of claims 13-15, wherein the agent is an antibody or fragment thereof that binds specifically to a Qa-I polypeptide.
19. The method of any one of claims 13, 16, and 17, wherein the agent is a short interfering RNA (siRNA) that binds specifically to a Qa-I polynucleotide.
20. The method of claim 13, wherein the subject has an inflammatory condition.
21. In a method of treatment calling for adoptive transfer of T cells to a subject, the improvement comprising introducing into the T cells an effective amount of a vector that directs expression of a Qa-I polypeptide to increase Qa-I polypeptide expression on the surface of the T cells.
22. The method of claim 21, wherein the Qa-I polypeptide is HLA-E.
23. A method of promoting a T-cell-mediated immune response in a subject, comprising administering to the subject an effective amount of a vector that directs expression of a Qa-I polypeptide to increase Qa-I polypeptide expression on the surface of activated T cells in the subject.
24. The method of claim 23, wherein the Qa-I polypeptide is HLA-E.
25. A pharmaceutical composition, comprising (a) an antigen or a polynucleotide encoding an antigen and (b) an effective amount of a vector that directs expression of a
Qa-I polypeptide to increase Qa-I polypeptide expression on the surface of activated T cells.
26. The pharmaceutical composition of claim 25, wherein the antigen or polynucleotide encoding the antigen is a polynucleotide encoding an antigen.
27. The pharmaceutical composition of claim 25, wherein the Qa-I polypeptide is HLA-E.
28. A pharmaceutical composition, comprising a T cell containing a vector that directs expression of a Qa-I polypeptide.
29. The pharmaceutical composition of claim 28, wherein the Qa-I polypeptide is HLA-E.
30. A method of identifying an agent useful for reducing activated T cells, comprising contacting under physiologic conditions cells that express a Qa-I molecule with a test agent that binds the Qa-I molecule, in presence of NK cells that express NKG2A; measuring a test amount of lysis of the cells that express the Qa-I molecule; and identifying the test agent as an agent useful for reducing activated T cells when the test amount of lysis exceeds a control amount of lysis obtained under similar conditions without the test agent.
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WO2012094252A1 (en) * | 2011-01-03 | 2012-07-12 | The Terasaki Family Foundation | Anti-hla-e antibodies, therapeutic immunomodulatory antibodies to human hla-e heavy chain, useful as ivig mimetics and methods of their use |
WO2013106586A3 (en) * | 2012-01-11 | 2013-09-19 | The Terasaki Family Foundation | Anti-hla class-ib antibodies mimic immunoreactivity and immunomodulatory functions of intravenous immunoglobulin (ivig) useful as therapeutic ivig mimetics and methods of their use |
WO2014008206A3 (en) * | 2012-07-05 | 2014-02-27 | The Terasaki Family Foundation | DIAGNOSTIC AND THERAPEUTIC POTENTIAL OF HLA-E MONOSPECIFIC MONOCLONAL IgG ANTIBODIES DIRECTED AGAINST TUMOR CELL SURFACE AND SOLUBLE HLA-E |
US10800847B2 (en) | 2012-01-11 | 2020-10-13 | Dr. Mepur Ravindranath | Anti-HLA class-IB antibodies mimic immunoreactivity and immunomodulatory functions of intravenous immunoglobulin (IVIG) useful as therapeutic IVIG mimetics and methods of their use |
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WO2012094252A1 (en) * | 2011-01-03 | 2012-07-12 | The Terasaki Family Foundation | Anti-hla-e antibodies, therapeutic immunomodulatory antibodies to human hla-e heavy chain, useful as ivig mimetics and methods of their use |
WO2013106586A3 (en) * | 2012-01-11 | 2013-09-19 | The Terasaki Family Foundation | Anti-hla class-ib antibodies mimic immunoreactivity and immunomodulatory functions of intravenous immunoglobulin (ivig) useful as therapeutic ivig mimetics and methods of their use |
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