Patent Publication Number: US-2018044669-A1

Title: Compositions for inhibiting checkpoint gene expression and uses thereof

Description:
RELATED APPLICATIONS 
     This application claims the benefit of U.S. provisional patent application Ser. No. 62/126,368, filed on Feb. 27, 2015, the contents of which are incorporated herein by reference in its entirety. 
    
    
     BACKGROUND OF THE INVENTION 
     Field of the Invention 
     The present invention relates to compounds, compositions, and methods of use for the inhibition of checkpoint gene expression or for diagnosing, treating and/or preventing diseases and/or conditions that respond to the inhibition of checkpoint gene expression. 
     Summary of the Related Art 
     The immune system is a hosts defense against foreign antigens; however, in order to function properly a variety of checks and balances are required to protect against self-antigens (i.e., autoimmunity) and, at the same time, provide an appropriate response against foreign. Immune-activating and immune-suppressive receptors and ligands provide these regulatory checks and balances (see Pardoll et al., The blockade of immune checkpoints in cancer immunotherapy, Nat. Rev. Canc. 12, 252 (2012)). 
     Immune checkpoints refer to a group of endogenous immune-suppressive ligands and receptors that are crucial for the maintenance of self-tolerance and the protection of tissues from damage when the immune system is responding to an infection. (see Y. L. Wu, et al., Immunotherapies: The Blockade of Inhibitory Signals, Int. J. Biol. Sci. 8, 1420 (2012)) In response to the induction of an immune response expression of checkpoints increases. These checkpoints act as regulatory feedback to maintain immune homeostasis. 
     In patients with cancer, tumor mutations give rise to tumor-specific antigens that can be recognized by the immune system, particularly T-cells, leading to elimination of cancer cells. However, to defend themselves, tumor cells can co-opt immune checkpoint pathways to suppress the immune response in the tumor microenvironment and evade the host immune system by inhibiting T cells that might otherwise attack the tumor cells. (see J. F. Grosso &amp; M. N. Jure-Kunkel; CTLA-4 blockade in tumor models: an overview of preclinical and translational research, Cancer Immun. 13, 5 (2013); M. E. Turnis, et al.; Combinatorial immunotherapy: PD-1 may not be LAG-ing behind any more, OncoImmunology 1, 1172 (2012)). 
     Many previous cancer immunotherapies have likely been limited by these suppressive mechanisms. Thus there is a need to over these immunosuppressive mechanisms in order to enhance antitumor immunotherapy applications. 
     BRIEF SUMMARY OF THE INVENTION 
     The present invention is directed to compounds, compositions, and methods useful for modulating PD1, PDL1, IDO1, LAG3, TIM3, CTLA4, IDO2, CEACAM1, OX40, and/or OX40L mRNA or protein expression using gene silencing compounds comprising two or more single stranded antisense oligonucleotides that are linked through their 5′-ends to allow the presence of two or more accessible 3′-ends. The gene silencing compounds according to the invention effectively inhibit or decrease PD1, PDL1, IDO1, LAG3, TIM3, CTLA4, IDO2, CEACAM1, OX40, and/or OX40L mRNA or protein expression. 
     Provided herein are methods, compounds, and compositions for modulating expression of PD1, PDL1, IDO1, LAG3, TIM3, CTLA4, IDO2, CEACAM1, OX40, and/or OX40L mRNA and protein. In certain embodiments, compounds useful for modulating expression of PD1, PDL1, IDO1, LAG3, TIM3, CTLA4, IDO2, CEACAM1, OX40, and/or OX40L mRNA and protein are gene silencing compounds. 
     In certain embodiments, modulation can occur in a cell or tissue. In certain embodiments the cell is a tumor cell. In certain embodiments, the tissue is a tumor. In certain embodiments, the cell or tissue is in an animal. In certain embodiments, the animal is a human. In certain embodiments, PD1, PDL1, IDO1, LAG3, TIM3, CTLA4, IDO2, CEACAM1, OX40, and/or OX40L mRNA levels are reduced. In certain embodiments, PD1, PDL1, IDO1, LAG3, TIM3, CTLA4, IDO2, CEACAM1, OX40, and/or OX40L protein levels are reduced. Such reduction can occur in a time-dependent manner or in a dose-dependent manner. 
     Also provided are methods, compounds, and compositions useful for preventing, treating, and ameliorating diseases, disorders, and conditions. In certain embodiments, such diseases, disorders, and conditions are hyperproliferative diseases, disorders, and conditions. In certain embodiments such hyperproliferative diseases, disorders, and conditions include cancer as well as associated malignancies and metastases. 
     In certain embodiments, methods of treatment include administering a PD1, PDL1, IDO1, LAG3, TIM3, CTLA4, IDO2, CEACAM1, OX40, and/or OX40L gene silencing compound or composition to an individual in need thereof. In certain embodiments, the gene silencing compound or composition is administered intratumorally. 
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     The invention relates to the therapeutic and prophylactic use of gene silencing compounds, also referred to as 3 rd  generation antisense (3GA) compounds, to down-regulate checkpoint mRNA or protein expression. Such molecules are useful, for example, in providing compositions for modulation of checkpoint gene expression or for treating and/or preventing diseases and/or conditions that are capable of responding to modulation of checkpoint gene expression in patients, subjects, animals or organisms. 
     The objects of the present invention, the various features thereof, as well as the invention itself may be more fully understood from the following description, when read together with the accompanying drawings in which the following terms have the ascribed meaning. Unless specific definitions are provided, the nomenclature utilized in connection with, and the procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well-known and commonly used in the art. Standard techniques may be used for chemical synthesis, and chemical analysis. Where permitted, all patents, applications, published applications and other publications, GENBANK Accession Numbers and associated sequence information obtainable through databases such as National Center for Biotechnology Information (NCBI) and other data referred to throughout in the disclosure herein are incorporated by reference for the portions of the document discussed herein, as well as in their entirety. 
     The term “2′-O-substituted” means substitution of the 2′ position of the pentose moiety with an -O-lower alkyl group containing 1-6 saturated or unsaturated carbon atoms (for example, but not limited to, 2′-O-methyl), or with an -O-aryl or allyl group having 2-6 carbon atoms, wherein such alkyl, aryl or allyl group may be unsubstituted or may be substituted, (for example, with 2′-O-methoxyethyl, ethoxy, methoxy, halo, hydroxyl, trifluoromethyl, cyano, nitro, acyl, acyloxy, alkoxy, carboxyl, carbalkoxyl, or amino groups); or with a hydroxyl, an amino or a halo group, but not with a 2′-H group. In some embodiments the oligonucleotides of the invention include four or five 2′-O-alky nucleotides at their 5′ terminus, and/or four or five 2′-O-alky nucleotides at their 3′ terminus. 
     The term “3”, when used directionally, generally refers to a region or position in a polynucleotide or oligonucleotide 3′ (toward the 3′end of the nucleotide) from another region or position in the same polynucleotide or oligonucleotide. 
     The term “3′ end” generally refers to the 3′ terminal nucleotide of the component oligonucleotides. “Two or more oligonucleotides linked at their 3′ ends” generally refers to a linkage between the 3′ terminal nucleotides of the oligonucleotides which may be directly via 5′, 3′ or 2′ hydroxyl groups, or indirectly, via a non-nucleotide linker. Such linkages may also be via a nucleoside, utilizing both 2′ and 3′ hydroxyl positions of the nucleoside. Such linkages may also utilize a functionalized sugar or nucleobase of a 3′terminal nucleotide. 
     The term “5′”, when used directionally, generally refers to a region or position in a polynucleotide or oligonucleotide 5′ (toward the 5′end of the nucleotide) from another region or position in the same polynucleotide or oligonucleotide. 
     The term “5′ end” generally refers to the 5′ terminal nucleotide of the component oligonucleotides. “Two or more single-stranded antisense oligonucleotides linked at their 5′ ends” generally refers to a linkage between the 5′ terminal nucleotides of the oligonucleotides which may be directly via 5′, 3′ or 2′ hydroxyl groups, or indirectly, via a non-nucleotide linker. Such linkages may also be via a nucleoside, utilizing both 2′ and 3′ hydroxyl positions of the nucleoside. Such linkages may also utilize a functionalized sugar or nucleobase of a 5′terminal nucleotide. 
     The term “about” generally means that the exact number is not critical. Thus, oligonucleotides having one or two fewer nucleoside residues, or from one to several additional nucleoside residues are contemplated as equivalents of each of the embodiments described above. 
     The term “accessible” generally means when related to a compound according to the invention, that the relevant portion of the molecule is able to be recognized by the cellular components necessary to elicit an intended response to the compound. 
     The term “agonist” generally refers to a substance that binds to a receptor of a cell and induces a response. An agonist can be a naturally occurring substance such as bacterial DNA or a synthetic composition. A synthetic agonist often mimics the action of a naturally occurring substance such as a ligand. 
     The term “antigen” generally refers to a substance that is recognized and selectively bound by an antibody or by a T cell antigen receptor. Antigens may include but are not limited to peptides, proteins, lipids, carbohydrates, nucleosides, nucleotides, nucleic acids, and combinations thereof. Antigens may be natural or synthetic and generally induce an immune response that is specific for that antigen. 
     “Antisense activity” means any detectable or measurable activity attributable to the hybridization of a gene silencing compound to its target nucleic acid. In certain embodiments, antisense activity is a decrease in the amount or expression of a target nucleic acid or protein encoded by such target nucleic acid. 
     As used herein, “Gene silencing oligonucleotide (GSO)”, “Gene silencing compound”, or “3 rd  generation antisense (3GA)” compound are used interchangeably to refer to an oligomeric compound comprising two or more single stranded antisense oligonucleotides that are linked through their 5′-ends to allow the presence of two or more accessible 3′-ends. Gene silencing compounds are capable of undergoing hybridization to a target nucleic acid through hydrogen bonding. 
     “Antisense inhibition” means reduction of target nucleic acid levels or target protein levels in the presence of a gene silencing compound complementary to a target nucleic acid as compared to target nucleic acid levels or target protein levels in the absence of the gene silencing compound. 
     “Antisense oligonucleotide” means a single-stranded oligonucleotide having a nucleobase sequence that permits hybridization to a corresponding region or segment of a target nucleic acid. 
     The term “biologic instability” generally refers to a molecule&#39;s ability to be degraded and subsequently inactivated in vivo. For oligonucleotides, such degradation results from exonuclease activity and/or endonuclease activity, wherein exonuclease activity refers to cleaving nucleotides from the 3′ or 5′ end of an oligonucleotide, and endonuclease activity refers to cleaving phosphodiester bonds at positions other than at the ends of the oligonucleotide. 
     The term “cancer” generally refers to, without limitation, any malignant growth or tumor caused by abnormal or uncontrolled cell proliferation and/or division. Cancers may occur in humans and/or mammals and may arise in any and all tissues. Treating a patient having cancer may include administration of a compound, pharmaceutical formulation or vaccine according to the invention such that the abnormal or uncontrolled cell proliferation and/or division, or metastasis is affected. 
     The term “carrier” generally encompasses any excipient, diluent, filler, salt, buffer, stabilizer, solubilizer, oil, lipid, lipid containing vesicle, microspheres, liposomal encapsulation, or other material for use in pharmaceutical formulations. It will be understood that the characteristics of the carrier, excipient or diluent will depend on the route of administration for a particular application. The preparation of pharmaceutically acceptable formulations containing these materials is described in, for example,  Remington&#39;s Pharmaceutical Sciences,  18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990. 
     The term “co-administration” or “co-administered” generally refers to the administration of at least two different substances. Co-administration refers to simultaneous administration, as well as temporally spaced order of up to several days apart, of at least two different substances in any order, either in a single dose or separate doses. 
     The term “in combination with” generally means administering two or more agents (e.g., a gene silencing compound according to the invention and another agent) such that there is an overlap of an effect of each agent on the patient. Such administration may be done in any order, including simultaneous administration, as well as temporally spaced order from a few seconds up to several days apart. In some embodiments, the administration of the agents are spaced sufficiently close together such that a combinatorial effect is achieved. Such combination treatment may also include more than a single administration of the compound according to the invention and/or independently the other agent. The administration of the compound according to the invention and the other agent may be by the same or different routes. In some embodiments, administration of at least one agent is made while the other agent is still present at a therapeutic level in the subject. 
     The term “complementary” is intended to mean the capacity for pairing between nucleobases of a first nucleic acid and a second nucleic acid. 
     “Contiguous nucleobases” means nucleobases immediately adjacent to each other. 
     The term “individual” or “subject” or “patient” generally refers to a mammal, such as a human. 
     “CEACAM1 nucleic acid” means any nucleic acid encoding CEACAM1. For example, in certain embodiments, a CEACAM1 nucleic acid includes a DNA sequence encoding CEACAM1, an RNA sequence transcribed from DNA encoding CEACAM1 (including genomic DNA comprising introns and exons), and an mRNA sequence encoding CEACAM1. “CEACAM1 mRNA” means an mRNA encoding a CEACAM1 protein. 
     “CTLA4 nucleic acid” means any nucleic acid encoding CTLA4. For example, in certain embodiments, a CTLA4 nucleic acid includes a DNA sequence encoding CTLA4, an RNA sequence transcribed from DNA encoding CTLA4 (including genomic DNA comprising introns and exons), and an mRNA sequence encoding CTLA4. “CTLA4 mRNA” means an mRNA encoding a CTLA4 protein. 
     “Fully complementary” or “100% complementary” means each nucleobase of a first nucleic acid has a complementary nucleobase in a second nucleic acid. In certain embodiments, a first nucleic acid is an antisense compound and a target nucleic acid is a second nucleic acid. 
     “Hybridization” means the annealing of complementary nucleic acid molecules. In certain embodiments, complementary nucleic acid molecules include an antisense compound and a target nucleic acid. 
     “IDO1 nucleic acid” means any nucleic acid encoding IDO1. For example, in certain embodiments, a IDO1 nucleic acid includes a DNA sequence encoding IDO1, an RNA sequence transcribed from DNA encoding IDO1 (including genomic DNA comprising introns and exons), and an mRNA sequence encoding IDO1. “IDO1 mRNA” means an mRNA encoding an IDO1 protein. 
     “IDO2 nucleic acid” means any nucleic acid encoding IDO2. For example, in certain embodiments, a IDO2 nucleic acid includes a DNA sequence encoding IDO2, an RNA sequence transcribed from DNA encoding IDO2 (including genomic DNA comprising introns and exons), and an mRNA sequence encoding IDO2. “IDO2 mRNA” means an mRNA encoding an IDO2 protein. 
     “Inhibiting PD1, PDL1, IDO1, LAG3, TIM3, CTLA4, IDO2, CEACAM1, OX40, and/or OX40L mRNA or protein expression” means reducing expression of PD1, PDL1, IDO1, LAG3, TIM3, CTLA4, IDO2, CEACAM1, OX40, and/or OX40L mRNA and/or protein levels in the presence of a gene silencing compound according to the invention as compared to expression of PD1, PDL1, IDO1, LAG3, TIM3, CTLA4, IDO2, CEACAM1, OX40, and/or OX40L mRNA and/or protein levels in the absence of a gene silencing compound according to the invention. 
     The term “kinase inhibitor” generally refers to molecules that antagonize or inhibit phosphorylation-dependent cell signaling and/or growth pathways in a cell. Kinase inhibitors may be naturally occurring or synthetic and include small molecules that have the potential to be administered as oral therapeutics. Kinase inhibitors have the ability to rapidly and specifically inhibit the activation of the target kinase molecules. Protein kinases are attractive drug targets, in part because they regulate a wide variety of signaling and growth pathways and include many different proteins. As such, they have great potential in the treatment of diseases involving kinase signaling, including cancer, cardiovascular disease, inflammatory disorders, diabetes, macular degeneration and neurological disorders. A non-limiting example of a kinase inhibitor is sorafenib. 
     “LAG3 nucleic acid” means any nucleic acid encoding LAG3. For example, in certain embodiments, a LAG3 nucleic acid includes a DNA sequence encoding LAG3, an RNA sequence transcribed from DNA encoding LAG3 (including genomic DNA comprising introns and exons), and an mRNA sequence encoding LAG3. “LAG3 mRNA” means an mRNA encoding a LAG3 protein. 
     The term “linear synthesis” generally refers to a synthesis that starts at one end of an oligonucleotide and progresses linearly to the other end. Linear synthesis permits incorporation of either identical or non-identical (in terms of length, base composition and/or chemical modifications incorporated) monomeric units into an oligonucleotide. 
     The term “mammal” is expressly intended to include warm blooded, vertebrate animals, including, without limitation, humans, non-human primates, rats, mice, cats, dogs, horses, cattle, cows, pigs, sheep and rabbits. 
     The term “nucleoside” generally refers to compounds consisting of a sugar, usually ribose, deoxyribose, pentose, arabinose or hexose, and a purine or pyrimidine base. 
     The term “nucleotide” generally refers to a nucleoside comprising a phosphorous-containing group attached to the sugar. 
     The term “modified nucleoside” or “nucleotide derivative” generally is a nucleoside that includes a modified heterocyclic base, a modified sugar moiety, or any combination thereof. In some embodiments, the modified nucleoside or nucleotide derivative is a non-natural pyrimidine or purine nucleoside, as herein described. For purposes of the invention, a modified nucleoside or nucleotide derivative, a pyrimidine or purine analog or non-naturally occurring pyrimidine or purine can be used interchangeably and refers to a nucleoside that includes a non-naturally occurring base and/or non-naturally occurring sugar moiety. For purposes of the invention, a base is considered to be non-natural if it is not guanine, cytosine, adenine, thymine or uracil and a sugar is considered to be non-natural if it is not β-ribo-furanoside or 2′-deoxyribo-furanoside. 
     The term “modified oligonucleotide” as used herein describes an oligonucleotide in which at least two of its nucleotides are covalently linked via a synthetic linkage, i.e., a linkage other than a phosphodiester linkage between the 5′ end of one nucleotide and the 3′ end of another nucleotide in which the 5′ nucleotide phosphate has been replaced with any number of chemical groups. The term “modified oligonucleotide” also encompasses 2′-O,4′-C-methylene-b-D-ribofuranosyl nucleic acids, arabinose nucleic acids, substituted arabinose nucleic acids, hexose nucleic acids, peptide nucleic acids, morpholino, and oligonucleotides having at least one nucleotide with a modified base and/or sugar, such as a 2′-O-substituted, a 5-methylcytosine and/or a 3′-O-substituted ribonucleotide. 
     The term “nucleic acid” encompasses a genomic region or an RNA molecule transcribed therefrom. In some embodiments, the nucleic acid is mRNA. 
     The term “linker” generally refers to any moiety that can be attached to an oligonucleotide by way of covalent or non-covalent bonding through a sugar, a base, or the backbone. The non-covalent linkage may be, without limitation, electrostatic interactions, hydrophobic interactions, π-stacking interactions, hydrogen bonding and combinations thereof. Non-limiting examples of such non-covalent linkage includes Watson-Crick base pairing, 
     Hoogsteen base pairing, and base stacking. The linker can be used to attach two or more nucleosides or can be attached to the 5′ and/or 3′ terminal nucleotide in the oligonucleotide. Such linker can be either a non-nucleotide linker or a nucleoside linker. 
     The term “non-nucleotide linker” generally refers to a chemical moiety, other than a linkage directly between two nucleotides that can be attached to an oligonucleotide by way of covalent or non-covalent bonding. Preferably such non-nucleotide linker is from about 2 angstroms to about 200 angstroms in length, and may be either in a cis or trans orientation. 
     The term “internucleotide linkage” generally refer to a chemical linkage to join two nucleosides through their sugars (e.g. 3′-3′, 2′-3′, 2′-5′, 3′-5′, 5′-5′) consisting of a phosphorous atom and a charged, or neutral group (e.g., phosphodiester, phosphorothioate, phosphorodithioate or methylphosphonate) between adjacent nucleosides. 
     The term “oligonucleotide” refers to a polynucleoside formed from a plurality of linked nucleoside units, which may include, for example, deoxyribonucleotides or ribonucleotides, synthetic or natural nucleotides, phosphodiester or modified linkages, natural bases or modified bases natural sugars or modified sugars, or combinations of these components. The nucleoside units may be part of viruses, bacteria, cell debris or oligonucleotide-based compositions (for example, siRNA and microRNA). Such oligonucleotides can also be obtained from existing nucleic acid sources, including genomic or cDNA, but are preferably produced by synthetic methods. In certain embodiments each nucleoside unit includes a heterocyclic base and a pentofuranosyl, trehalose, arabinose, 2′-deoxy-2′-substituted nucleoside, 2′-deoxy-2′-substituted arabinose, 2′-O-substituted arabinose or hexose sugar group. The nucleoside residues can be coupled to each other by any of the numerous known internucleoside linkages. Such internucleoside linkages include, without limitation, phosphodiester, phosphorothioate, phosphorodithioate, methylphosphonate, alkylphosphonate, alkylphosphonothioate, phosphotriester, phosphoramidate, siloxane, carbonate, carboalkoxy, acetamidate, carbamate, morpholino, borano, thioether, bridged phosphoramidate, bridged methylene phosphonate, bridged phosphorothioate, and sulfone internucleoside linkages. The term “oligonucleotide” also encompasses polynucleosides having one or more stereospecific internucleoside linkage (e.g., (R P )- or (S P )-phosphorothioate, alkylphosphonate, or phosphotriester linkages). As used herein, the terms “oligonucleotide” and “dinucleotide” are expressly intended to include polynucleosides and dinucleosides having any such internucleoside linkage, whether or not the linkage comprises a phosphate group. In certain exemplary embodiments, these internucleoside linkages may be phosphodiester, phosphorothioate or phosphorodithioate linkages, or combinations thereof. In exemplary embodiments, the nucleotides of the synthetic oligonucleotides are linked by at least one phosphorothioate internucleotide linkage. The phosphorothioate linkages may be mixed Rp and Sp enantiomers, or they may be stereoregular or substantially stereoregular in either Rp or Sp form (see Iyer et al. (1995) Tetrahedron Asymmetry 6:1051-1054). In certain embodiments, one or more of the oligonucleotides within the antisense compositions of the invention contain one or more 2′-O,4′-C-methylene-b-D-ribofuranosyl nucleic acids, wherein the ribose is modified with a bond between the 2′ and 4′ carbons, which fixes the ribose in the 3′-endo structural conformation. 
     “OX40 nucleic acid” means any nucleic acid encoding OX40. For example, in certain embodiments, a OX40 nucleic acid includes a DNA sequence encoding OX40, an RNA sequence transcribed from DNA encoding OX40 (including genomic DNA comprising introns and exons), and an mRNA sequence encoding OX40. “OX40 mRNA” means an mRNA encoding an OX40 protein. 
     “OX40L nucleic acid” means any nucleic acid encoding OX40L. For example, in certain embodiments, a OX40L nucleic acid includes a DNA sequence encoding OX40L, an RNA sequence transcribed from DNA encoding OX40L (including genomic DNA comprising introns and exons), and an mRNA sequence encoding OX40L. “OX40L mRNA” means an mRNA encoding an OX40L protein. 
     “PD1 nucleic acid” means any nucleic acid encoding PD1. For example, in certain embodiments, a PD1 nucleic acid includes a DNA sequence encoding PD1, an RNA sequence transcribed from DNA encoding PD1 (including genomic DNA comprising introns and exons), and an mRNA sequence encoding PD1. “PD1 mRNA” means an mRNA encoding a PD1 protein. 
     “PDL1 nucleic acid” means any nucleic acid encoding PDL1. For example, in certain embodiments, a PDL1 nucleic acid includes a DNA sequence encoding PDL1, an RNA sequence transcribed from DNA encoding PDL1 (including genomic DNA comprising introns and exons), and an mRNA sequence encoding PDL1. “PDL1 mRNA” means an mRNA encoding a PDL1 protein. 
     The term “peptide” generally refers to oligomers or polymers of amino acids that are of sufficient length and composition to affect a biological response, for example, antibody production or cytokine activity whether or not the peptide is a hapten. The term “peptide” may include modified amino acids (whether or not naturally or non-naturally occurring), where such modifications include, but are not limited to, phosphorylation, glycosylation, pegylation, lipidization, and methylation. 
     The term “pharmaceutically acceptable” means a non-toxic material that does not interfere with the effectiveness of a compound according to the invention or the biological activity of a compound according to the invention. 
     The term “physiologically acceptable” refers to a non-toxic material that is compatible with a biological system such as a cell, cell culture, tissue, or organism. Preferably, the biological system is a living organism, such as a mammal, particularly a human. 
     The term “prophylactically effective amount” generally refers to an amount sufficient to prevent or reduce the development of an undesired biological effect. 
     “Portion” means a defined number of contiguous (i.e., linked) nucleobases of a nucleic acid. In certain embodiments, a portion is a defined number of contiguous nucleobases of a target nucleic acid. In certain embodiments, a portion is a defined number of contiguous nucleobases of an antisense compound. 
     “Single-stranded oligonucleotide” means an oligonucleotide which is not hybridized to a complementary strand. 
     “Specifically hybridizable” refers to a gene silencing compound having a sufficient degree of complementarity between an antisense oligonucleotide and a target nucleic acid to induce a desired effect, while exhibiting minimal or no effects on non-target nucleic acids under conditions in which specific binding is desired, i.e., under physiological conditions in the case of in vivo assays and therapeutic treatments. 
     “Targeting” or “targeted” means the process of design and selection of a gene silencing compound that will specifically hybridize to a target nucleic acid and induce a desired effect. 
     “Target nucleic acid,” “target RNA,” “target mRNA,” and “target RNA transcript” all refer to a nucleic acid capable of being targeted by gene silencing compounds. 
     “Target segment” means the sequence of nucleotides of a target nucleic acid to which a gene silencing compound is targeted. “5′ target site” refers to the 5′-most nucleotide of a target segment. “3′ target site” refers to the 3′-most nucleotide of a target segment. 
     The term “therapeutically effective amount” or “pharmaceutically effective amount” generally refers to an amount sufficient to affect a desired biological effect, such as a beneficial result, including, without limitation, prevention, diminution, amelioration or elimination of signs or symptoms of a disease or disorder. Thus, the total amount of each active component of the pharmaceutical composition or method is sufficient to show a meaningful patient benefit, for example, but not limited to, healing of chronic conditions characterized by immune stimulation. Thus, a “pharmaceutically effective amount” will depend upon the context in which it is being administered. A pharmaceutically effective amount may be administered in one or more prophylactic or therapeutic administrations. When applied to an individual active ingredient, administered alone, the term refers to that ingredient alone. When applied to a combination, the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially or simultaneously. 
     “TIM3 nucleic acid” means any nucleic acid encoding TIM3. For example, in certain embodiments, a TIM3 nucleic acid includes a DNA sequence encoding TIM3, an RNA sequence transcribed from DNA encoding TIM3 (including genomic DNA comprising introns and exons), and an mRNA sequence encoding TIM3. “TIM3 mRNA” means an mRNA encoding a TIM3 protein. 
     The term “treatment” generally refers to an approach intended to obtain a beneficial or desired result, which may include alleviation of symptoms, or delaying or ameliorating a disease progression. 
     The term “gene expression” generally refers to process by which information from a gene is used in the synthesis of a functional gene product, which may be a protein. The process may involve transcription, RNA splicing, translation, and post-translational modification of a protein, and may include mRNA, preRNA, ribosomal RNA, and other templates for protein synthesis. 
     In certain embodiments provided are methods, compounds, and compositions for inhibiting PD1, PDL1, IDO1, LAG3, TIM3, CTLA4, IDO2, CEACAM1, OX40, or OX40L mRNA or protein expression. In certain embodiments the compounds are antisense oligonucleotides, double stranded or single-stranded siRNA compounds, or gene silencing compounds. 
     As used herein, gene silencing compounds according to the invention comprise two or more single-stranded antisense oligonucleotides linked at their 5′ ends, wherein the compounds have two or more accessible 3′ ends. The general structure of the oligonucleotide-based compounds of the invention may be described by the following formula I: 
       3′-Nn . . . N1N2N3N4-5′-L-5′-N8N7N6N5 . . . Nm-3′  (Formula I),
 
     wherein L is a nucleotide linker or non-nucleotide linker; N1-N8, at each occurrence, is independently a nucleotide or nucleotide derivative; Nm and Nn, at each occurrence, are independently a nucleotide or nucleotide derivative; and wherein m and n are independently numbers from 0 to about 40. 
     The linkage at the 5′ ends of the component oligonucleotides is independent of the other oligonucleotide linkages and may be directly via 5′, 3′ or 2′ hydroxyl groups, or indirectly, via a non-nucleotide linker or a nucleoside, utilizing either the 2′ or 3′ hydroxyl positions of the nucleoside. Linkages may also utilize a functionalized sugar or nucleobase of a 5′ terminal nucleotide. 
     In certain embodiments provided are gene silencing compounds targeted to a mouse or human PD1 nucleic acid. In certain embodiments, the mouse PD1 nucleic acid is the sequence set forth in GENBANK Accession No. NM_008798 (incorporated herein as SEQ ID NO: 387) or the human PD1 nucleic acid is the sequence set forth in GENBANK Accession No. NM_005018 (incorporated herein as SEQ ID NO: 388). 
     In certain embodiments provided are gene silencing compounds targeted to a mouse or human PDL1 nucleic acid. In certain embodiments, the mouse PDL1 nucleic acid is the sequence set forth in GENBANK Accession No. NM_021893 (incorporated herein as SEQ ID NO: 389) or the human PDL1 nucleic acid is the sequence set forth in GENBANK Accession No. NM_014143 (incorporated herein as SEQ ID NO: 390). 
     In certain embodiments provided are gene silencing compounds targeted to a mouse or human IDO1 nucleic acid. In certain embodiments, the mouse IDO1 nucleic acid is the sequence set forth in GENBANK Accession No. NM_008324 (incorporated herein as SEQ ID NO: 391) or the human IDO1 nucleic acid is the sequence set forth in GENBANK Accession No. NM_002164 (incorporated herein as SEQ ID NO: 392). 
     In certain embodiments provided are gene silencing compounds targeted to a mouse or human LAG3 nucleic acid. In certain embodiments, the mouse LAG3 nucleic acid is the sequence set forth in GENBANK Accession No. NM_008479 (incorporated herein as SEQ ID NO: 393) or the human LAG3 nucleic acid is the sequence set forth in GENBANK Accession No. NM_002286 (incorporated herein as SEQ ID NO: 394). 
     In certain embodiments provided are gene silencing compounds targeted to a mouse or human TIM3 nucleic acid. In certain embodiments, the mouse TIM3 nucleic acid is the sequence set forth in GENBANK Accession No. NM_134250 (incorporated herein as SEQ ID NO: 395) or the human TIM3 nucleic acid is the sequence set forth in GENBANK Accession No. NM_032782 (incorporated herein as SEQ ID NO: 396). 
     In certain embodiments provided are gene silencing compounds targeted to a mouse or human CTLA4 nucleic acid. In certain embodiments, the mouse CTLA4 nucleic acid is the sequence set forth in GENBANK Accession No. NM_009843 (incorporated herein as SEQ ID NO: 397) or the human CTLA4 nucleic acid is the sequence set forth in GENBANK Accession No. NM_005214 (incorporated herein as SEQ ID NO: 398). 
     In certain embodiments provided are gene silencing compounds targeted to a mouse or human IDO2 nucleic acid. In certain embodiments, the mouse IDO2 nucleic acid is the sequence set forth in GENBANK Accession No. NM_145949 (incorporated herein as SEQ ID NO: 399) or the human IDO2 nucleic acid is the sequence set forth in GENBANK Accession No. NM_194294 (incorporated herein as SEQ ID NO: 400). 
     In certain embodiments provided are gene silencing compounds targeted to a mouse or human CEACAM1 nucleic acid. In certain embodiments, the mouse CEACAM1 nucleic acid is the sequence set forth in GENBANK Accession No. NM_001039187 (incorporated herein as SEQ ID NO: 401) or the human CEACAM1 nucleic acid is the sequence set forth in GENBANK Accession No. NM_001205344 (incorporated herein as SEQ ID NO: 402). 
     In certain embodiments provided are gene silencing compounds targeted to a mouse or human OX40 nucleic acid. In certain embodiments, the mouse OX40 nucleic acid is the sequence set forth in GENBANK Accession No. NM_011659 (incorporated herein as SEQ ID NO: 403) or the human OX40 nucleic acid is the sequence set forth in GENBANK Accession No. NM_003327 (incorporated herein as SEQ ID NO: 404). 
     In certain embodiments provided are gene silencing compounds targeted to a mouse or human OX40L nucleic acid. In certain embodiments, the mouse OX40L nucleic acid is the sequence set forth in GENBANK Accession No. NM_009452 (incorporated herein as SEQ ID NO: 405) or the human OX40L nucleic acid is the sequence set forth in GENBANK Accession No. NM_003326 (incorporated herein as SEQ ID NO: 406). 
     Certain embodiments provide gene silencing compounds comprising two oligonucleotides each, independently, consisting of 12 to 30 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 387, SEQ ID NO: 388, SEQ ID NO: 389, SEQ ID NO: 390, SEQ ID NO: 391, SEQ ID NO: 392, SEQ ID NO: 393, SEQ ID NO: 394, SEQ ID NO: 395, SEQ ID NO: 396, SEQ ID NO: 397, SEQ ID NO: 398, SEQ ID NO: 399, SEQ ID NO: 400, SEQ ID NO: 401, SEQ ID NO: 402, SEQ ID NO: 403, SEQ ID NO: 404, SEQ ID NO: 405, or SEQ ID NO: 406. Certain embodiments provide compounds comprising two oligonucleotides each, independently, consisting of 15 to 25 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 387, SEQ ID NO: 388, SEQ ID NO: 389, SEQ ID NO: 390, SEQ ID NO: 391, SEQ ID NO: 392, SEQ ID NO: 393, SEQ ID NO: 394, SEQ ID NO: 395, SEQ ID NO: 396, SEQ ID NO: 397, SEQ ID NO: 398, SEQ ID NO: 399, SEQ ID NO: 400, SEQ ID NO: 401, SEQ ID NO: 402, SEQ ID NO: 403, SEQ ID NO: 404, SEQ ID NO: 405, or SEQ ID NO: 406. Certain embodiments provide compounds comprising a modified oligonucleotide consisting of 18 to 21 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 387, SEQ ID NO: 388, SEQ ID NO: 389, SEQ ID NO: 390, SEQ ID NO: 391, SEQ ID NO: 392, SEQ ID NO: 393, SEQ ID NO: 394, SEQ ID NO: 395, SEQ ID NO: 396, SEQ ID NO: 397, SEQ ID NO: 398, SEQ ID NO: 399, SEQ ID NO: 400, SEQ ID NO: 401, SEQ ID NO: 402, SEQ ID NO: 403, SEQ ID NO: 404, SEQ ID NO: 405, or SEQ ID NO: 406. In certain embodiments, the two oligonucleotide of the gene silencing compound each, independently, comprise at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or at least 21 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 387, SEQ ID NO: 388, SEQ ID NO: 389, SEQ ID NO: 390, SEQ ID NO: 391, SEQ ID NO: 392, SEQ ID NO: 393, SEQ ID NO: 394, SEQ ID NO: 395, SEQ ID NO: 396, SEQ ID NO: 397, SEQ ID NO: 398, SEQ ID NO: 399, SEQ ID NO: 400, SEQ ID NO: 401, SEQ ID NO: 402, SEQ ID NO: 403, SEQ ID NO: 404, SEQ ID NO: 405, or SEQ ID NO: 406. 
     Certain embodiments provide gene silencing compounds comprising two oligonucleotides each, independently, consisting of 12 to 30 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 387, SEQ ID NO: 389, SEQ ID NO: 391, SEQ ID NO: 393, SEQ ID NO: 395, SEQ ID NO: 397, SEQ ID NO: 399, SEQ ID NO: 401, SEQ ID NO: 403, or SEQ ID NO: 405. Certain embodiments provide compounds comprising two oligonucleotides each, independently, consisting of 15 to 25 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 387, SEQ ID NO: 389, SEQ ID NO: 391, SEQ ID NO: 393, SEQ ID NO: 395, SEQ ID NO: 397, SEQ ID NO: 399, SEQ ID NO: 401, SEQ ID NO: 403, or SEQ ID NO: 405. Certain embodiments provide compounds comprising a modified oligonucleotide consisting of 18 to 21 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 387, SEQ ID NO: 389, SEQ ID NO: 391, SEQ ID NO: 393, SEQ ID NO: 395, SEQ ID NO: 397, SEQ ID NO: 399, SEQ ID NO: 401, SEQ ID NO: 403, or SEQ ID NO: 405. In certain embodiments, the two oligonucleotide of the gene silencing compound each, independently, comprise at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or at least 21 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 387, SEQ ID NO: 389, SEQ ID NO: 391, SEQ ID NO: 393, SEQ ID NO: 395, SEQ ID NO: 397, SEQ ID NO: 399, SEQ ID NO: 401, SEQ ID NO: 403, or SEQ ID NO: 405. 
     Certain embodiments provide gene silencing compounds comprising two oligonucleotides each, independently, consisting of 12 to 30 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 388, SEQ ID NO: 390, SEQ ID NO: 392, SEQ ID NO: 394, SEQ ID NO: 396, SEQ ID NO: 398, SEQ ID NO: 400, SEQ ID NO: 402, SEQ ID NO: 404, or SEQ ID NO: 406. Certain embodiments provide compounds comprising two oligonucleotides each, independently, consisting of 15 to 25 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 388, SEQ ID NO: 390, SEQ ID NO: 392, SEQ ID NO: 394, SEQ ID NO: 396, SEQ ID NO: 398, SEQ ID NO: 400, SEQ ID NO: 402, SEQ ID NO: 404, or SEQ ID NO: 406. Certain embodiments provide compounds comprising a modified oligonucleotide consisting of 18 to 21 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 388, SEQ ID NO: 390, SEQ ID NO: 392, SEQ ID NO: 394, SEQ ID NO: 396, SEQ ID NO: 398, SEQ ID NO: 400, SEQ ID NO: 402, SEQ ID NO: 404, or SEQ ID NO: 406. In certain embodiments, the two oligonucleotide of the gene silencing compound each, independently, comprise at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or at least 21 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 388, SEQ ID NO: 390, SEQ ID NO: 392, SEQ ID NO: 394, SEQ ID NO: 396, SEQ ID NO: 398, SEQ ID NO: 400, SEQ ID NO: 402, SEQ ID NO: 404, or SEQ ID NO: 406. 
     Certain embodiments provide gene silencing compounds comprising two oligonucleotides each, independently, consisting of 12 to 30 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 387. Certain embodiments provide compounds comprising two oligonucleotides each, independently, consisting of 15 to 25 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 387. Certain embodiments provide compounds comprising a modified oligonucleotide consisting of 18 to 21 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 387. In certain embodiments, the two oligonucleotide of the gene silencing compound each, independently, comprise at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or at least 21 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 387. 
     Certain embodiments provide gene silencing compounds comprising two oligonucleotides each, independently, consisting of 12 to 30 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 388. Certain embodiments provide compounds comprising two oligonucleotides each, independently, consisting of 15 to 25 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 388. Certain embodiments provide compounds comprising a modified oligonucleotide consisting of 18 to 21 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 388. In certain embodiments, the two oligonucleotide of the gene silencing compound each, independently, comprise at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or at least 21 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 388. 
     Certain embodiments provide gene silencing compounds comprising two oligonucleotides each, independently, consisting of 12 to 30 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 389. Certain embodiments provide compounds comprising two oligonucleotides each, independently, consisting of 15 to 25 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 389. Certain embodiments provide compounds comprising a modified oligonucleotide consisting of 18 to 21 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 389. In certain embodiments, the two oligonucleotide of the gene silencing compound each, independently, comprise at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or at least 21 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 389. 
     Certain embodiments provide gene silencing compounds comprising two oligonucleotides each, independently, consisting of 12 to 30 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 390. Certain embodiments provide compounds comprising two oligonucleotides each, independently, consisting of 15 to 25 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 390. Certain embodiments provide compounds comprising a modified oligonucleotide consisting of 18 to 21 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 390. In certain embodiments, the two oligonucleotide of the gene silencing compound each, independently, comprise at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or at least 21 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 390. 
     Certain embodiments provide gene silencing compounds comprising two oligonucleotides each, independently, consisting of 12 to 30 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 391. Certain embodiments provide compounds comprising two oligonucleotides each, independently, consisting of 15 to 25 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 391. Certain embodiments provide compounds comprising a modified oligonucleotide consisting of 18 to 21 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 391. In certain embodiments, the two oligonucleotide of the gene silencing compound each, independently, comprise at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or at least 21 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 391. 
     Certain embodiments provide gene silencing compounds comprising two oligonucleotides each, independently, consisting of 12 to 30 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 392. Certain embodiments provide compounds comprising two oligonucleotides each, independently, consisting of 15 to 25 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 392. Certain embodiments provide compounds comprising a modified oligonucleotide consisting of 18 to 21 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 392. In certain embodiments, the two oligonucleotide of the gene silencing compound each, independently, comprise at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or at least 21 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 392. 
     Certain embodiments provide gene silencing compounds comprising two oligonucleotides each, independently, consisting of 12 to 30 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 393. Certain embodiments provide compounds comprising two oligonucleotides each, independently, consisting of 15 to 25 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 393. Certain embodiments provide compounds comprising a modified oligonucleotide consisting of 18 to 21 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 393. In certain embodiments, the two oligonucleotide of the gene silencing compound each, independently, comprise at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or at least 21 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 393. 
     Certain embodiments provide gene silencing compounds comprising two oligonucleotides each, independently, consisting of 12 to 30 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 394. Certain embodiments provide compounds comprising two oligonucleotides each, independently, consisting of 15 to 25 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 394. Certain embodiments provide compounds comprising a modified oligonucleotide consisting of 18 to 21 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 394. In certain embodiments, the two oligonucleotide of the gene silencing compound each, independently, comprise at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or at least 21 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 394. 
     Certain embodiments provide gene silencing compounds comprising two oligonucleotides each, independently, consisting of 12 to 30 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 395. Certain embodiments provide compounds comprising two oligonucleotides each, independently, consisting of 15 to 25 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 395. Certain embodiments provide compounds comprising a modified oligonucleotide consisting of 18 to 21 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 395. In certain embodiments, the two oligonucleotide of the gene silencing compound each, independently, comprise at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or at least 21 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 395. 
     Certain embodiments provide gene silencing compounds comprising two oligonucleotides each, independently, consisting of 12 to 30 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 396. Certain embodiments provide compounds comprising two oligonucleotides each, independently, consisting of 15 to 25 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 396. Certain embodiments provide compounds comprising a modified oligonucleotide consisting of 18 to 21 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 396. In certain embodiments, the two oligonucleotide of the gene silencing compound each, independently, comprise at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or at least 21 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 396. 
     Certain embodiments provide gene silencing compounds comprising two oligonucleotides each, independently, consisting of 12 to 30 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 397. Certain embodiments provide compounds comprising two oligonucleotides each, independently, consisting of 15 to 25 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 397. Certain embodiments provide compounds comprising a modified oligonucleotide consisting of 18 to 21 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 397. In certain embodiments, the two oligonucleotide of the gene silencing compound each, independently, comprise at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or at least 21 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 397. 
     Certain embodiments provide gene silencing compounds comprising two oligonucleotides each, independently, consisting of 12 to 30 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 398. Certain embodiments provide compounds comprising two oligonucleotides each, independently, consisting of 15 to 25 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 398. Certain embodiments provide compounds comprising a modified oligonucleotide consisting of 18 to 21 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 398. In certain embodiments, the two oligonucleotide of the gene silencing compound each, independently, comprise at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or at least 21 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 398. 
     Certain embodiments provide gene silencing compounds comprising two oligonucleotides each, independently, consisting of 12 to 30 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 399. Certain embodiments provide compounds comprising two oligonucleotides each, independently, consisting of 15 to 25 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 399. Certain embodiments provide compounds comprising a modified oligonucleotide consisting of 18 to 21 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 399. In certain embodiments, the two oligonucleotide of the gene silencing compound each, independently, comprise at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or at least 21 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 399. 
     Certain embodiments provide gene silencing compounds comprising two oligonucleotides each, independently, consisting of 12 to 30 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 400. Certain embodiments provide compounds comprising two oligonucleotides each, independently, consisting of 15 to 25 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 400. Certain embodiments provide compounds comprising a modified oligonucleotide consisting of 18 to 21 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 400. In certain embodiments, the two oligonucleotide of the gene silencing compound each, independently, comprise at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or at least 21 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 400. 
     Certain embodiments provide gene silencing compounds comprising two oligonucleotides each, independently, consisting of 12 to 30 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 401. Certain embodiments provide compounds comprising two oligonucleotides each, independently, consisting of 15 to 25 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 401. Certain embodiments provide compounds comprising a modified oligonucleotide consisting of 18 to 21 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 401. In certain embodiments, the two oligonucleotide of the gene silencing compound each, independently, comprise at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or at least 21 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 401. 
     Certain embodiments provide gene silencing compounds comprising two oligonucleotides each, independently, consisting of 12 to 30 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 402. Certain embodiments provide compounds comprising two oligonucleotides each, independently, consisting of 15 to 25 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 402. Certain embodiments provide compounds comprising a modified oligonucleotide consisting of 18 to 21 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 402. In certain embodiments, the two oligonucleotide of the gene silencing compound each, independently, comprise at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or at least 21 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 402. 
     Certain embodiments provide gene silencing compounds comprising two oligonucleotides each, independently, consisting of 12 to 30 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 403. Certain embodiments provide compounds comprising two oligonucleotides each, independently, consisting of 15 to 25 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 403. Certain embodiments provide compounds comprising a modified oligonucleotide consisting of 18 to 21 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 403. In certain embodiments, the two oligonucleotide of the gene silencing compound each, independently, comprise at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or at least 21 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 403. 
     Certain embodiments provide gene silencing compounds comprising two oligonucleotides each, independently, consisting of 12 to 30 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 404. Certain embodiments provide compounds comprising two oligonucleotides each, independently, consisting of 15 to 25 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 404. Certain embodiments provide compounds comprising a modified oligonucleotide consisting of 18 to 21 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 404. In certain embodiments, the two oligonucleotide of the gene silencing compound each, independently, comprise at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or at least 21 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 404. 
     Certain embodiments provide gene silencing compounds comprising two oligonucleotides each, independently, consisting of 12 to 30 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 405. Certain embodiments provide compounds comprising two oligonucleotides each, independently, consisting of 15 to 25 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 405. Certain embodiments provide compounds comprising a modified oligonucleotide consisting of 18 to 21 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 405. In certain embodiments, the two oligonucleotide of the gene silencing compound each, independently, comprise at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or at least 21 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 405. 
     Certain embodiments provide gene silencing compounds comprising two oligonucleotides each, independently, consisting of 12 to 30 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 406. Certain embodiments provide compounds comprising two oligonucleotides each, independently, consisting of 15 to 25 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 406. Certain embodiments provide compounds comprising a modified oligonucleotide consisting of 18 to 21 nucleotides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 406. In certain embodiments, the two oligonucleotide of the gene silencing compound each, independently, comprise at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or at least 21 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 406. 
     In certain embodiments, the nucleobase sequence of the oligonucleotides of the gene silencing compound are, independently, at least 90% complementary over its entire length to a nucleobase sequence of SEQ ID NO: 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, or 406. In certain embodiments, the nucleobase sequence of the oligonucleotides of the gene silencing compound are, independently, at least 95% complementary over its entire length to a nucleobase sequence of SEQ ID NO: 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, or 406. In certain embodiments, the oligonucleotides of the gene silencing compound are at least 99% complementary over its entire length to SEQ ID NO: 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, or 406. In certain embodiments, the nucleobase sequence of the oligonucleotides of the gene silencing compound are 100% complementary over its entire length to a nucleobase sequence of SEQ ID NO: 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, or 406. 
     In certain embodiments, the oligonucleotides of the gene silencing compound are, independently, 12 to 30 nucleotides in length. In other words, the oligonucleotides are from 12 to 30 linked nucleobases. In other embodiments, the oligonucleotides, independently, consist of 15 to 28, 18 to 24, 19 to 22, or 20 linked nucleobases. In certain such embodiments, the oligonucleotides, independently, consist of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 linked nucleobases in length, or a range defined by any two of the above values. 
     In certain embodiments, a target region is a structurally defined region of the target nucleic acid. For example, a target region may encompass a 3′ UTR, a 5′ UTR, an exon, an intron, an exon/intron junction, a coding region, a translation initiation region, translation termination region, or other defined nucleic acid region. The structurally defined regions for PD1, PDL1, IDO1, LAG3, TIM3, CTLA4, IDO2, CEACAM1, OX40, or OX40L can be obtained by accession number from sequence databases such as NCB&#39; and such information is incorporated herein by reference. In certain embodiments, a target region may encompass the sequence from a 5′ target site of one target segment within the target region to a 3′ target site of another target segment within the same target region. 
     Certain embodiments provide a composition comprising a 3GA compound as described herein, or a salt thereof, and a pharmaceutically acceptable carrier or diluent. Certain embodiments provide a composition comprising two or more 3GA compounds as described herein, or a salt thereof, and a pharmaceutically acceptable carrier or diluent. The two or more 3GA compounds can inhibit the mRNA or protein expression of the same target or can inhibit the mRNA or protein expression of different targets. 
     In certain embodiments, the 3GA compounds according to the invention comprise two identical or different sequences linked at their 5′-5′ ends via a phosphodiester, phosphorothioate or non-nucleoside linker. 3GA compounds according to the invention that comprise identical sequences are able to bind to a specific mRNA via Watson-Crick hydrogen bonding interactions and inhibit mRNA and protein expression. Gene silencing compounds according to the invention that comprise different sequences are able to bind to two or more different regions of one or more mRNA target and inhibit mRNA and protein expression. Such compounds are comprised of heteronucleotide sequences complementary to target mRNA and form stable duplex structures through Watson-Crick hydrogen bonding. 
     In certain embodiments, gene silencing compounds according to the invention are useful in treating and/or preventing diseases wherein inhibiting PD1, PDL1, IDO1, LAG3, TIM3, CTLA4, IDO2, CEACAM1, OX40, or OX40L expression would be beneficial. Gene silencing compounds according to the invention include, but are not limited to, antisense oligonucleotides comprising naturally occurring nucleotides, modified nucleotides, modified oligonucleotides and/or backbone modified oligonucleotides. 
     The oligonucleotides of the 3GA compounds are linked through their 5′-ends to allow the presence of two or more accessible 3′-ends. In certain embodiments, the oligonucleotides are linked through one or more of the non-nucleotide linkers listed in Table 1. In certain embodiments, a single linker listed in Table 1 is used to link the oligonucleotides of the gene silencing compounds. In certain embodiments, the linker is small molecule linker such as glycerol or a glycerol homolog of the formula HO—(CH 2 ) o —CH(OH)—(CH 2 ) p —OH, wherein o and p independently are integers from 1 to about 6, from 1 to about 4 or from 1 to about 3. In some other embodiments, the small molecule linker is a derivative of 1,3-diamino-2-hydroxypropane. Some such derivatives have the formula HO—(CH 2 ) m —C(O)NH—CH 2 —CH(OH)—CH 2 —NHC(O)—(CH 2 ) m —OH, wherein m is an integer from 0 to about 10, from 0 to about 6, from 2 to about 6 or from 2 to about 4. Representative non-nucleotide linkers are set forth in Table 1. 
     
       
         
           
               
             
               
                 TABLE 1 
               
               
                   
               
               
                 Representative Non-Nucleotide Linkers 
               
               
                   
               
             
            
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Glycerol (1,2,3-Propanetriol) 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 1,2,4-Butanetriol 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 2-(hydroxymethyl)-1,3-propanediol 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 2-(hydroxymethyl)1,4-butanediol 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 1,3,5-Pentanetriol 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 1,1,1-Tris(hydroxymethyl)ethane 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 1,1,1-Tris(hydroxymethyl)nitromethane 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 1,1,1-Tris(hydroxymethyl)propane 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 1,2,6-Hexanetriol 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 3-Methyl-1,3,5-pentanetriol 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 1,2,3-Heptanetriol 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 2-Amino-2-(hydroxymethyl)-1,3-propanediol 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 N-[Tris(hydroxymethyl)methyl]acrylamide 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 cis-1,3,5-Cyclohexanetriol 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 cis-1,3,5-Tri(hydroxymethyl)cyclohexane 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 1,3,5-Trihydroxyl-benzene 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 3,5,-Di(hydroxymethyl)phenol 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 1,3,5,-Tri(hydroxymethyl)benzene 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 1,3-Di(hydroxyethoxy)-2-hydroxyl-propane 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 1,3-Di(hydroxypropoxy)-2-hydroxyl-propane 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 2-Deoxy-D-ribose 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 1,2,4,-Trihydroxyl-benzene 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 D-Galactoal 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 1,6-anhydro-β-D-Glucose 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 1,3,5-Tris(2-hydroxyethyl)-Cyanuric acid 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Gallic acid 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 3,5,7-Trihydroxyflavone 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 4,6-Nitropyrogallol 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Ethylene glycol 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 1,3-Propanediol 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 1,2-Propanediol 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 1,4-Butanediol 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 1,3-Butanediol 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 2,3-Butanediol 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 1,4-Butanediol 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 1,5-Pentanediol 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 2,4-Pentanediol 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 1,6-Hexanediol 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 1,2-Hexanediol 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 1,5-Hexanediol 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 2,5-Hexanediol 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 1,7-Heptanediol 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 1,8-Octanediol 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 1,2-Octanediol 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 1,9-Nonanediol 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 1,12-Dodecanediol 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Triethylene glycol 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Tetraethylene glycol 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Hexaethylene glycol 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 2-(1-Aminopropyl)-1,3-propanediol 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 1,2-Dideoxyribose 
               
               
                   
               
            
           
         
       
     
     In some embodiments, the small molecule linker is glycerol or a glycerol homolog of the formula HO—(CH 2 ) o —CH(OH)—(CH 2 ) p —OH, wherein o and p independently are integers from 1 to about 6, from 1 to about 4 or from 1 to about 3. In some other embodiments, the small molecule linker is a derivative of 1,3-diamino-2-hydroxypropane. Some such derivatives have the formula HO—(CH 2 ) m —C(O)NH—CH 2 —CH(OH)—CH 2 —NHC(O)—(CH 2 ) m —OH, wherein m is an integer from 0 to about 10, from 0 to about 6, from 2 to about 6 or from 2 to about 4. 
     In certain embodiments, the two or more oligonucleotides of the gene silencing compounds of the invention can be linked as shown in Table 2. 
     
       
         
           
               
             
               
                 TABLE 2 
               
               
                   
               
               
                 Oligoribonucleotide Formulas II-V 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 Formula II 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 Formula III 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 Formula IV 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 Formula V 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
            
           
         
       
     
     In certain embodiments of Formulas II and/or V, L is a linker or a nucleotide linkage and Domain A and/or Domain B are antisense oligonucleotides that are designed to selectively hybridize to the same target RNA sequence or different target RNA sequences. 
     In certain embodiments of Formulas II, III, IV or V, L is a linker and Domain A and/or Domain B and/or Domain C and/or Domain D are antisense oligonucleotides that are designed to selectively hybridize to the same target RNA sequence or different target RNA sequences. For example, in one embodiment, Domain A and/or Domain B and/or Domain C of Formulas II and/or III are antisense oligonucleotides that are designed to selectively hybridize to the same target RNA sequence. In this embodiment, Domain A and/or Domain B and/or Domain C can be designed to hybridize to the same region on the target RNA sequence or to different regions of the same target RNA sequence. 
     In a further embodiment of this aspect of the invention, Domain A, Domain B, Domain C, and Domain D are independently RNA or DNA-based oligonucleotides. In certain aspects of this embodiment, the oligonucleotides comprise mixed backbone oligonucleotides. 
     In another embodiment, one or more of Domain A and/or Domain B and/or Domain C and/or Domain D is an antisense oligonucleotide that is designed to selectively hybridize to one target RNA sequence and one or more of the remaining Domain A and/or Domain B and/or Domain C and/or Domain D is an antisense oligonucleotide that is designed to selectively hybridized to a different target RNA sequence. 
     In another embodiment, one or more of Domain A and/or Domain B and/or Domain C and/or Domain D is an RNA-based oligonucleotide hybridized to a complimentary RNA-based oligonucleotide such that the domain comprises an siRNA molecule. 
     These gene silencing compounds of the invention can be prepared by the art recognized methods such as phosphoramidate or H-phosphonate chemistry which can be carried out manually or by an automated synthesizer. The synthetic antisense oligonucleotides of the invention may also be modified in a number of ways without compromising their ability to hybridize to mRNA. Such modifications may include at least one internucleotide linkage of the oligonucleotide being an alkylphosphonate, phosphorothioate, phosphorodithioate, methylphosphonate, phosphate ester, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate hydroxyl, acetamidate or carboxymethyl ester or a combination of these and other internucleotide linkages between the 5′ end of one nucleotide and the 3′ end of another nucleotide in which the 5′ nucleotide phosphodiester linkage has been replaced with any number of chemical groups. 
     The synthetic antisense oligonucleotides of the invention may comprise combinations of internucleotide linkages. For example, U.S. Pat. No. 5,149,797 describes traditional chimeric oligonucleotides having a phosphorothioate core region interposed between methylphosphonate or phosphoramidate flanking regions. Additionally, U.S. Pat. No. 5,652,356 discloses “inverted” chimeric oligonucleotides comprising one or more nonionic oligonucleotide region (e.g. alkylphosphonate and/or phosphoramidate and/or phosphotriester internucleoside linkage) flanked by one or more region of oligonucleotide phosphorothioate. Various synthetic antisense oligonucleotides with modified internucleotide linkages can be prepared according to standard methods. In certain embodiments, the phosphorothioate linkages may be mixed Rp and Sp enantiomers, or they may be made stereoregular or substantially stereoregular in either Rp or Sp form. 
     Other modifications of gene silencing compounds of the invention include those that are internal or at the end(s) of the oligonucleotide molecule and include additions to the molecule of the internucleoside phosphate linkages, such as cholesterol, cholesteryl, or diamine compounds with varying numbers of carbon residues between the amino groups and terminal ribose, deoxyribose and phosphate modifications which cleave, or crosslink to the opposite chains or to associated enzymes or other proteins which bind to the genome. Examples of such modified oligonucleotides include oligonucleotides with a modified base and/or sugar such as 2′-O,4′-C-methylene-b-D-ribofuranosyl, or arabinose instead of ribose, or a 3′, 5′-substituted oligonucleotide having a sugar which, at both its 3′ and 5′ positions, is attached to a chemical group other than a hydroxyl group (at its 3′ position) and other than a phosphate group (at its 5′ position). 
     Other examples of modifications to sugars of the oligonucleotide-based compounds of the invention include modifications to the 2′ position of the ribose moiety which include but are not limited to 2′-O-substituted with an -O-alkyl group containing 1-6 saturated or unsaturated carbon atoms, or with an -O-aryl, or -O-allyl group having 2-6 carbon atoms wherein such -O-alkyl, -0-aryl or -O-allyl group may be unsubstituted or may be substituted, for example with halo, hydroxyl, trifluoromethyl, cyano, nitro, acyl, acyloxy, alkoxy, carboxy, carbalkoxyl or amino groups. None of these substitutions are intended to exclude the presence of other residues having native 2′-hydroxyl group in the case of ribose or 2′ H- in the case of deoxyribose. 
     The gene silencing compounds according to the invention can comprise one or more ribonucleotides. For example, U.S. Pat No. 5,652,355 discloses traditional hybrid oligonucleotides having regions of 2′-O-substituted ribonucleotides flanking a DNA core region. U.S. Pat. No. 5,652,356 discloses an “inverted” hybrid oligonucleotide that includes an oligonucleotide comprising a 2′-O-substituted (or 2′ OH, unsubstituted) RNA region which is in between two oligodeoxyribonucleotide regions, a structure that “inverted relative to the “traditional” hybrid oligonucleotides. Non-limiting examples of particularly useful oligonucleotides of the invention have 2′-O-alkylated ribonucleotides at their 3′, 5′, or 3′ and 5′ termini, with at least four, and in some exemplary embodiments five, contiguous nucleotides being so modified. Non-limiting examples of 2′-O-alkylated groups include 2′-O-methyl, 2′-O-ethyl, 2′-O-propyl, 2′-O-butyls and 2′-O-methoxy-ethyl. 
     The oligonucleotide-based compounds of the invention may conveniently be synthesized using an automated synthesizer and phosphoramidite approach further described in Example 1. In some embodiments, the oligonucleotide-based compounds of the invention are synthesized by a linear synthesis approach. 
     An alternative mode of synthesis is “parallel synthesis”, in which synthesis proceeds outward from a central linker moiety. A solid support attached linker can be used for parallel synthesis, as is described in U.S. Pat. No. 5,912,332. Alternatively, a universal solid support (such as phosphate attached controlled pore glass) support can be used. 
     Parallel synthesis of the oligonucleotide-based compounds of the invention has several advantages over linear synthesis: (1) parallel synthesis permits the incorporation of identical monomeric units; (2) unlike in linear synthesis, both (or all) the monomeric units are synthesized at the same time, thereby the number of synthetic steps and the time required for the synthesis is the same as that of a monomeric unit; and (3) the reduction in synthetic steps improves purity and yield of the final immune modulatory oligoribonucleotide product. 
     At the end of the synthesis by either linear synthesis or parallel synthesis protocols, the oligonucleotide-based compounds of the invention may conveniently be deprotected with concentrated ammonia solution or as recommended by the phosphoramidite supplier, if a modified nucleoside is incorporated. The product oligonucleotide-based compounds is preferably purified by reversed phase HPLC, detritylated, desalted and dialyzed. 
     In certain embodiments, the oligonucleotides of the gene silencing compound according to the invention are selected from the non-limiting list of the oligonucleotides shown in Table 3 below. The oligonucleotides shown in Table 3 have phosphorothioate (PS) linkages, but may also include phosphodiester linkages. Those skilled in the art will recognize, however, that other linkages, based on phosphodiester or non-phosphodiester moieties may be included. 
     
       
         
           
               
               
               
               
               
             
               
                 TABLE 3 
               
               
                   
               
               
                 Oligo #/ 
                   
                   
                   
                   
               
               
                 SEQ ID 
                   
                   
                 Target 
                   
               
               
                 NO: 
                 Target 
                 Species 
                 Site 
                 Sequence 5′ → 3′ 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 1 
                 PD1 
                 Mouse 
                 58 
                 GCCGGACCCACATGCCCAG 
               
               
                   
               
               
                 2 
                 PD1 
                 Mouse 
                 65 
                 GGTACCTGCCGGACCCACA 
               
               
                   
               
               
                 3 
                 PD1 
                 Mouse 
                 115 
                 GCCACCCTGATTGCCAGCT 
               
               
                   
               
               
                 4 
                 PD1 
                 Mouse 
                 198 
                 GGTGGCATTTGCTCCCTCT 
               
               
                   
               
               
                 5 
                 PD1 
                 Mouse 
                 755 
                 GGTGTCTTCTCTCGTCCCT 
               
               
                   
               
               
                 6 
                 PD1 
                 Mouse 
                 848 
                 GCTGAGCCCCTACGTCCCA 
               
               
                   
               
               
                 7 
                 PD1 
                 Mouse 
                 1161 
                 CCCCAGCTCTGCACCTTGT 
               
               
                   
               
               
                 8 
                 PD1 
                 Mouse 
                 1589 
                 CTAGCTCTGCTGGTTCCCT 
               
               
                   
               
               
                 9 
                 PD1 
                 Human 
                 69 
                 GCGCCTGTGGGATCTGCAT 
               
               
                   
               
               
                 10 
                 PD1 
                 Human 
                 108 
                 GCCAGCCCAGTTGTAGCAC 
               
               
                   
               
               
                 11 
                 PD1 
                 Human 
                 285 
                 GCTTGTCCGTCTGGTTGCT 
               
               
                   
               
               
                 12 
                 PD1 
                 Human 
                 495 
                 CCCTTCTCTCTGTCACCCT 
               
               
                   
               
               
                 13 
                 PD1 
                 Human 
                 496 
                 GCCCTTCTCTCTGTCACCC 
               
               
                   
               
               
                 14 
                 PD1 
                 Human 
                 497 
                 TGCCCTTCTCTCTGTCACC 
               
               
                   
               
               
                 15 
                 PD1 
                 Human 
                 616 
                 GCCAGGACCCAGACTAGCA 
               
               
                   
               
               
                 16 
                 PD1 
                 Human 
                 620 
                 GACGGCCAGGACCCAGACT 
               
               
                   
               
               
                 17 
                 PD1 
                 Human 
                 895 
                 CCATCCTCAGGCCTCAGTG 
               
               
                   
               
               
                 18 
                 PD1 
                 Human 
                 897 
                 GTCCATCCTCAGGCCTCAG 
               
               
                   
               
               
                 19 
                 PD1 
                 Human 
                 899 
                 GTGTCCATCCTCAGGCCTC 
               
               
                   
               
               
                 20 
                 PD1 
                 Human 
                 901 
                 CAGTGTCCATCCTCAGGCC 
               
               
                   
               
               
                 21 
                 PD1 
                 Human 
                 1003 
                 GCACCCTGCCTGCTTCTCC 
               
               
                   
               
               
                 22 
                 PD1 
                 Human 
                 1005 
                 CTGCACCCTGCCTGCTTCT 
               
               
                   
               
               
                 23 
                 PD1 
                 Human 
                 1137 
                 GTGACACCTGCTGCCTGGG 
               
               
                   
               
               
                 24 
                 PD1 
                 Human 
                 1161 
                 ATCTGGCCCTCCCTGTAGG 
               
               
                   
               
               
                 25 
                 PD1 
                 Human 
                 1163 
                 GCATCTGGCCCTCCCTGTA 
               
               
                   
               
               
                 26 
                 PD1 
                 Human 
                 1165 
                 CTGCATCTGGCCCTCCCTG 
               
               
                   
               
               
                 27 
                 PD1 
                 Human 
                 1167 
                 GACTGCATCTGGCCCTCCC 
               
               
                   
               
               
                 28 
                 PD1 
                 Human 
                 1169 
                 GTGACTGCATCTGGCCCTC 
               
               
                   
               
               
                 29 
                 PD1 
                 Human 
                 1412 
                 CTCCTGTGCCCAGTCTTGG 
               
               
                   
               
               
                 30 
                 PD1 
                 Human 
                 1512 
                 CCCACCACAGCCAGGAGCT 
               
               
                   
               
               
                 31 
                 PD1 
                 Human 
                 1513 
                 GCCCACCACAGCCAGGAGC 
               
               
                   
               
               
                 32 
                 PD1 
                 Human 
                 1563 
                 GCCTGAGGTGCTGCCTGGG 
               
               
                   
               
               
                 33 
                 PD1 
                 Human 
                 1591 
                 CTGCCTCAGCTTCCCTGCC 
               
               
                   
               
               
                 34 
                 PD1 
                 Human 
                 1592 
                 ACTGCCTCAGCTTCCCTGC 
               
               
                   
               
               
                 35 
                 PD1 
                 Human 
                 1615 
                 CCTCCAGCTCTGCCTGCCC 
               
               
                   
               
               
                 36 
                 PD1 
                 Human 
                 1616 
                 GCCTCCAGCTCTGCCTGCC 
               
               
                   
               
               
                 37 
                 PD1 
                 Human 
                 1720 
                 GCCCTCCTGACCTTGGGAC 
               
               
                   
               
               
                 38 
                 PD1 
                 Human 
                 1722 
                 CTGCCCTCCTGACCTTGGG 
               
               
                   
               
               
                 39 
                 PD1 
                 Human 
                 1724 
                 CCCTGCCCTCCTGACCTTG 
               
               
                   
               
               
                 40 
                 PD1 
                 Human 
                 1894 
                 CCTTCCCACCCAGGCCCTG 
               
               
                   
               
               
                 41 
                 PD1 
                 Human 
                 1896 
                 TACCTTCCCACCCAGGCCC 
               
               
                   
               
               
                 42 
                 PD1 
                 Human 
                 1898 
                 TGTACCTTCCCACCCAGGC 
               
               
                   
               
               
                 43 
                 PD1 
                 Human 
                 1900 
                 CCTGTACCTTCCCACCCAG 
               
               
                   
               
               
                 44 
                 PD1 
                 Human 
                 1996 
                 CTGGATGCTGGTGGCCCTG 
               
               
                   
               
               
                 45 
                 PD1 
                 Human 
                 1997 
                 CCTGGATGCTGGTGGCCCT 
               
               
                   
               
               
                 46 
                 PD1 
                 Human 
                 2024 
                 CCCAGCCACTCAGGTGCCT 
               
               
                   
               
               
                 47 
                 PD1 
                 Human 
                 2032 
                 TCCCTTGTCCCAGCCACTC 
               
               
                   
               
               
                 48 
                 PD1 
                 Human 
                 2034 
                 GATCCCTTGTCCCAGCCAC 
               
               
                   
               
               
                 49 
                 PDL1 
                 Mouse 
                 219 
                 CAAGCAGGTCCAGCTCCCG 
               
               
                   
               
               
                 50 
                 PDL1 
                 Mouse 
                 316 
                 CTCCCCCTGAAGTTGCTGT 
               
               
                   
               
               
                 51 
                 PDL1 
                 Mouse 
                 436 
                 TTGTAGTCCGCACCACCGT 
               
               
                   
               
               
                 52 
                 PDL1 
                 Mouse 
                 1399 
                 GGTGACCTCTGTGTTCCCT 
               
               
                   
               
               
                 53 
                 PDL1 
                 Mouse 
                 2152 
                 GCCTGCCTCTGCCTCCCTA 
               
               
                   
               
               
                 54 
                 PDL1 
                 Mouse 
                 3311 
                 GCCCAGCCTGTTCCTTCAG 
               
               
                   
               
               
                 55 
                 PDL1 
                 Human 
                 571 
                 GGTAGCCCTCAGCCTGACA 
               
               
                   
               
               
                 56 
                 PDL1 
                 Human 
                 892 
                 CCATCATTCTCCCTTTTCT 
               
               
                   
               
               
                 57 
                 PDL1 
                 Human 
                 1075 
                 ATTGCCTGCATCCCACGGG 
               
               
                   
               
               
                 58 
                 PDL1 
                 Human 
                 1080 
                 CCCACATTGCCTGCATCCC 
               
               
                   
               
               
                 59 
                 PDL1 
                 Human 
                 1103 
                 TTCAGTGCTTGGGCCTTTT 
               
               
                   
               
               
                 60 
                 PDL1 
                 Human 
                 1163 
                 GGCTCCCTGTTTGACTCCA 
               
               
                   
               
               
                 61 
                 PDL1 
                 Human 
                 1182 
                 GTATCAAGGTCTCCCTCCA 
               
               
                   
               
               
                 62 
                 PDL1 
                 Human 
                 1230 
                 TCCTTTCTCCCTGTCACAG 
               
               
                   
               
               
                 63 
                 PDL1 
                 Human 
                 1296 
                 ATTCTCAACCCGTCTTCCT 
               
               
                   
               
               
                 64 
                 PDL1 
                 Human 
                 1855 
                 TCTGTTTGCTTCCTCAGCT 
               
               
                   
               
               
                 65 
                 PDL1 
                 Human 
                 1904 
                 GGGTGGCAGTCTGAGGTCT 
               
               
                   
               
               
                 66 
                 PDL1 
                 Human 
                 1911 
                 GGACAGTGGGTGGCAGTCT 
               
               
                   
               
               
                 67 
                 PDL1 
                 Human 
                 2142 
                 TTCCCCTCGCATCATCCTT 
               
               
                   
               
               
                 68 
                 PDL1 
                 Human 
                 2192 
                 TCCCAGACCACATTGGCCT 
               
               
                   
               
               
                 69 
                 PDL1 
                 Human 
                 2901 
                 TGCACCCTGGAGAGCCCAT 
               
               
                   
               
               
                 70 
                 PDL1 
                 Human 
                 3128 
                 GCTGGTGGCATTCAAGGGT 
               
               
                   
               
               
                 71 
                 PDL1 
                 Human 
                 3173 
                 CGAAACCTCCAGGAAGCCT 
               
               
                   
               
               
                 72 
                 PDL1 
                 Human 
                 3196 
                 GATCTCCCAGGGCATCTGA 
               
               
                   
               
               
                 73 
                 PDL1 
                 Human 
                 3397 
                 GCCTTGCTCAGCCACAATT 
               
               
                   
               
               
                 74 
                 PDL1 
                 Human 
                 3402 
                 TATGTGCCTTGCTCAGCCA 
               
               
                   
               
               
                 75 
                 IDO1 
                 Mouse 
                 138 
                 CTAGCCACAAGGACCCAGG 
               
               
                   
               
               
                 76 
                 IDO1 
                 Mouse 
                 264 
                 ATGTACCCCAGGGCCAGGT 
               
               
                   
               
               
                 77 
                 IDO1 
                 Mouse 
                 295 
                 ATCCCCTCGGTTCCACACA 
               
               
                   
               
               
                 78 
                 IDO1 
                 Mouse 
                 492 
                 CCCTTGTCGCAGTCCCCAC 
               
               
                   
               
               
                 79 
                 IDO1 
                 Mouse 
                 817 
                 GAAGATGCTGCTCTGGCCT 
               
               
                   
               
               
                 80 
                 IDO1 
                 Mouse 
                 1145 
                 CAGTCCCTCTGCTTTCCAC 
               
               
                   
               
               
                 81 
                 IDO1 
                 Human 
                 172 
                 GCAGAGCAAAGCCCACTTC 
               
               
                   
               
               
                 82 
                 IDO1 
                 Human 
                 184 
                 CCTGTGGATTTGGCAGAGC 
               
               
                   
               
               
                 83 
                 IDO1 
                 Human 
                 388 
                 CTCCATGACCTTTGCCCCA 
               
               
                   
               
               
                 84 
                 IDO1 
                 Human 
                 507 
                 CTTTTTCTTCCAGTTTGCC 
               
               
                   
               
               
                 85 
                 IDO1 
                 Human 
                 619 
                 CAGCTGCTATTTCCACCAA 
               
               
                   
               
               
                 86 
                 IDO1 
                 Human 
                 816 
                 GTTGCCTTTCCAGCCAGAC 
               
               
                   
               
               
                 87 
                 IDO1 
                 Human 
                 823 
                 GCTGGGGGTTGCCTTTCCA 
               
               
                   
               
               
                 88 
                 IDO1 
                 Human 
                 849 
                 CCCTTCATACACCAGACCG 
               
               
                   
               
               
                 89 
                 IDO1 
                 Human 
                 956 
                 TGTCCTCCACCAGCAGTCT 
               
               
                   
               
               
                 90 
                 IDO1 
                 Human 
                 1138 
                 GCAGATGGTAGCTCCTCAG 
               
               
                   
               
               
                 91 
                 IDO1 
                 Human 
                 1187 
                 TCCTTTGGCTGCTGGCTTG 
               
               
                   
               
               
                 92 
                 IDO1 
                 Human 
                 1239 
                 GCCTCCAGTTCCTTTGGCT 
               
               
                   
               
               
                 93 
                 IDO1 
                 Human 
                 1246 
                 AATCAGTGCCTCCAGTTCC 
               
               
                   
               
               
                 94 
                 IDO1 
                 Human 
                 1327 
                 GTGCTCTTGTTGGGTTACA 
               
               
                   
               
               
                 95 
                 IDO1 
                 Human 
                 1627 
                 GCCTCGGCCTCCCAAAGTG 
               
               
                   
               
               
                 96 
                 IDO1 
                 Human 
                 1745 
                 TAGCTGGGACTACAGGTGC 
               
               
                   
               
               
                 97 
                 IDO1 
                 Human 
                 1767 
                 TCTCCTGCCTCAGCCTCCC 
               
               
                   
               
               
                 98 
                 IDO1 
                 Human 
                 1774 
                 ACGCCATTCTCCTGCCTCA 
               
               
                   
               
               
                 99 
                 IDO1 
                 Human 
                 1792 
                 GCTCCGCCTCCCAGGTTCA 
               
               
                   
               
               
                 100 
                 IDO1 
                 Human 
                 1815 
                 GGCACAATCTTGGCTCACT 
               
               
                   
               
               
                 101 
                 LAG3 
                 Mouse 
                 25 
                 GCTCCTCCAGACCCAGTCC 
               
               
                   
               
               
                 102 
                 LAG3 
                 Mouse 
                 321 
                 GGCCTCCCCAGCCCTCCAA 
               
               
                   
               
               
                 103 
                 LAG3 
                 Mouse 
                 355 
                 GGAGCAGGTCCTCCCTCAT 
               
               
                   
               
               
                 104 
                 LAG3 
                 Mouse 
                 422 
                 AGCTCTTTCCCAGGCCCTG 
               
               
                   
               
               
                 105 
                 LAG3 
                 Mouse 
                 585 
                 CCCCTGGTGAAGGTCAAGG 
               
               
                   
               
               
                 106 
                 LAG3 
                 Mouse 
                 590 
                 GGCATCCCCTGGTGAAGGT 
               
               
                   
               
               
                 107 
                 LAG3 
                 Mouse 
                 601 
                 GTCTAGGCGAGGGCATCCC 
               
               
                   
               
               
                 108 
                 LAG3 
                 Mouse 
                 953 
                 GGCACTCGGTTCTGGCCCT 
               
               
                   
               
               
                 109 
                 LAG3 
                 Mouse 
                 1044 
                 GACACAGCCCCAGGTCCCA 
               
               
                   
               
               
                 110 
                 LAG3 
                 Mouse 
                 1108 
                 GCTCCAGACCCAGAACCTT 
               
               
                   
               
               
                 111 
                 LAG3 
                 Mouse 
                 1161 
                 GGGCAGCTCCACCCTAGAA 
               
               
                   
               
               
                 112 
                 LAG3 
                 Mouse 
                 1260 
                 GCCACTCTTTCCAGCCACG 
               
               
                   
               
               
                 113 
                 LAG3 
                 Mouse 
                 1295 
                 GCCAGACCCACAGCCTCAA 
               
               
                   
               
               
                 114 
                 LAG3 
                 Mouse 
                 1316 
                 CAGGTGTAGGTCCCAGCCT 
               
               
                   
               
               
                 115 
                 LAG3 
                 Mouse 
                 1349 
                 GCATTGAGCTGCTGTCCCT 
               
               
                   
               
               
                 116 
                 LAG3 
                 Mouse 
                 1524 
                 GGCCTCCTGAATCTCCAGC 
               
               
                   
               
               
                 117 
                 LAG3 
                 Mouse 
                 1573 
                 GCCTCTGGCCCTCGTACAG 
               
               
                   
               
               
                 118 
                 LAG3 
                 Mouse 
                 1819 
                 CCAGCTCCTCTATCTTCCT 
               
               
                   
               
               
                 119 
                 LAG3 
                 Mouse 
                 1918 
                 CTGCCTCGGCTCCAGGTCA 
               
               
                   
               
               
                 120 
                 LAG3 
                 Mouse 
                 1936 
                 GCTGCTGAGACCTGCTGGC 
               
               
                   
               
               
                 121 
                 LAG3 
                 Mouse/ 
                 1315 
                 AGGTGTAGGTCCCAGCCTG 
               
               
                   
                   
                 Human 
                   
                   
               
               
                   
               
               
                 122 
                 LAG3 
                 Mouse/ 
                 1822 
                 GCTCCAGCTCCTCTATCTT 
               
               
                   
                   
                 Human 
                   
                   
               
               
                   
               
               
                 123 
                 LAG3 
                 Mouse/ 
                 1062 
                 GCCATCTCTGTAGGTGAGG 
               
               
                   
                   
                 Human 
                   
                   
               
               
                   
               
               
                 124 
                 LAG3 
                 Mouse/ 
                 1356 
                 GACAGTGGCATTGAGCTGC 
               
               
                   
                   
                 Human 
                   
                   
               
               
                   
               
               
                 125 
                 LAG3 
                 Human 
                 3 
                 TCTCTGGGCCTTCACCCCT 
               
               
                   
               
               
                 126 
                 LAG3 
                 Human 
                 123 
                 CTGGGCAGATCAGGCAGCC 
               
               
                   
               
               
                 127 
                 LAG3 
                 Human 
                 167 
                 GGGAGGGATGACCAGAGGC 
               
               
                   
               
               
                 128 
                 LAG3 
                 Human 
                 229 
                 GGGAGGTGGAGGAAGGGGT 
               
               
                   
               
               
                 129 
                 LAG3 
                 Human 
                 346 
                 CTGAGCCTCCCACATCTCT 
               
               
                   
               
               
                 130 
                 LAG3 
                 Human 
                 395 
                 GCTTCACTGGAGCCACCCA 
               
               
                   
               
               
                 131 
                 LAG3 
                 Human 
                 494 
                 GGCTGAGATCCTGGAGGGG 
               
               
                   
               
               
                 132 
                 LAG3 
                 Human 
                 524 
                 GCTGCCAAGTGACCCCTGC 
               
               
                   
               
               
                 133 
                 LAG3 
                 Human 
                 648 
                 GGACCCACGCTCAGCACCG 
               
               
                   
               
               
                 134 
                 LAG3 
                 Human 
                 736 
                 CCATAGCGAGAAGTCCCCG 
               
               
                   
               
               
                 135 
                 LAG3 
                 Human 
                 834 
                 TGGCCCAGGCGCAGACGGA 
               
               
                   
               
               
                 136 
                 LAG3 
                 Human 
                 1034 
                 CCATGGGGCTGACTTGGGG 
               
               
                   
               
               
                 137 
                 LAG3 
                 Human 
                 1359 
                 TTGAGCTGCTGTTCCTGCA 
               
               
                   
               
               
                 138 
                 LAG3 
                 Human 
                 1433 
                 GCAGCTTCCCCAGGGATCC 
               
               
                   
               
               
                 139 
                 LAG3 
                 Human 
                 1499 
                 GGGATGGGGTGTCCAGAGA 
               
               
                   
               
               
                 140 
                 LAG3 
                 Human 
                 1554 
                 TGGGAAAGGAGCTGGGCCT 
               
               
                   
               
               
                 141 
                 LAG3 
                 Human 
                 1593 
                 AGAAGCCTCTCCCCCTGGT 
               
               
                   
               
               
                 142 
                 LAG3 
                 Human 
                 1636 
                 GGCACCTGGGCTAGACAGC 
               
               
                   
               
               
                 143 
                 LAG3 
                 Human 
                 1848 
                 GGTTCTTGCTCCAGCTCCT 
               
               
                   
               
               
                 144 
                 LAG3 
                 Human 
                 1940 
                 GCTGAGATCTGCTGGCTGC 
               
               
                   
               
               
                 145 
                 LAG3 
                 Human/ 
                 1972 
                 GCTGCTGACAGGGAGTTTA 
               
               
                   
                   
                 Mouse 
                   
                   
               
               
                   
               
               
                 146 
                 LAG3 
                 Human/ 
                 642 
                 ACGCTCAGCACCGTGTAGC 
               
               
                   
                   
                 Mouse 
                   
                   
               
               
                   
               
               
                 147 
                 LAG3 
                 Human/ 
                 1234 
                 AGGAGGAGTCCACTTGGCA 
               
               
                   
                   
                 Mouse 
                   
                   
               
               
                   
               
               
                 148 
                 LAG3 
                 Human/ 
                 1366 
                 AGTGGCATTGAGCTGCTGT 
               
               
                   
                   
                 Mouse 
                   
                   
               
               
                   
               
               
                 149 
                 TIM3 
                 Mouse 
                 222 
                 AATCCCTTGCCCCAGCACA 
               
               
                   
               
               
                 150 
                 TIM3 
                 Mouse 
                 319 
                 GAGATCGCCCTTTAGCTGG 
               
               
                   
               
               
                 151 
                 TIM3 
                 Mouse 
                 386 
                 TGCAGCAGTAGGTCCCATG 
               
               
                   
               
               
                 152 
                 TIM3 
                 Mouse 
                 462 
                 GGAGTGACCTTGGCTGCTT 
               
               
                   
               
               
                 153 
                 TIM3 
                 Mouse 
                 661 
                 CCCAGCAGAGACTCCCACT 
               
               
                   
               
               
                 154 
                 TIM3 
                 Mouse 
                 782 
                 CATTTGCCAACCCTCCTGG 
               
               
                   
               
               
                 155 
                 TIM3 
                 Mouse 
                 887 
                 GCTGGCTGTTGACGTAGCA 
               
               
                   
               
               
                 156 
                 TIM3 
                 Mouse 
                 1273 
                 TTAGCCCTTTATTCCCCCT 
               
               
                   
               
               
                 157 
                 TIM3 
                 Mouse 
                 1416 
                 CCTCCTGCCTAAGGTTCCC 
               
               
                   
               
               
                 158 
                 TIM3 
                 Mouse 
                 1425 
                 ACTTATCACCCTCCTGCCT 
               
               
                   
               
               
                 159 
                 TIM3 
                 Mouse 
                 1517 
                 GAGCCTCATCTCCAGCCTC 
               
               
                   
               
               
                 160 
                 TIM3 
                 Mouse 
                 1526 
                 TCACTGTCCGAGCCTCATC 
               
               
                   
               
               
                 161 
                 TIM3 
                 Mouse 
                 1668 
                 CTGACTGCACGCAAGCCCC 
               
               
                   
               
               
                 162 
                 TIM3 
                 Mouse 
                 1767 
                 GAGCAGAGGACAACCCCCA 
               
               
                   
               
               
                 163 
                 TIM3 
                 Mouse 
                 1953 
                 CTGCTCTGCCATGCTCCCA 
               
               
                   
               
               
                 164 
                 TIM3 
                 Mouse 
                 2138 
                 GTCAGTTCCCCTTGAGCAC 
               
               
                   
               
               
                 165 
                 TIM3 
                 Mouse 
                 2220 
                 CTGCCTTCGTATGTCCCAG 
               
               
                   
               
               
                 166 
                 TIM3 
                 Mouse 
                 2461 
                 CACAGTTGCTCCCCAATGC 
               
               
                   
               
               
                 167 
                 TIM3 
                 Mouse 
                 2570 
                 AGCCAGGACCTCCACAGCT 
               
               
                   
               
               
                 168 
                 TIM3 
                 Mouse 
                 2596 
                 GTCTCCCTTCCATACCCAC 
               
               
                   
               
               
                 169 
                 TIM3 
                 Human 
                 59 
                 CTGCCAGGTCTACAGTCAC 
               
               
                   
               
               
                 170 
                 TIM3 
                 Human 
                 281 
                 CAGCAGCAGCAGCAGGACA 
               
               
                   
               
               
                 171 
                 TIM3 
                 Human 
                 338 
                 GGCATTCTGACCGACCTCC 
               
               
                   
               
               
                 172 
                 TIM3 
                 Human 
                 457 
                 TCCCTTTCATCAGTCCTGA 
               
               
                   
               
               
                 173 
                 TIM3 
                 Human 
                 740 
                 GAGGCTCCCCAGTGTCTGT 
               
               
                   
               
               
                 174 
                 TIM3 
                 Human 
                 803 
                 GGCCAATCTAGAGTCCCGT 
               
               
                   
               
               
                 175 
                 TIM3 
                 Human 
                 1110 
                 GTGAGGGTTGCTGCCTGCT 
               
               
                   
               
               
                 176 
                 TIM3 
                 Human 
                 1235 
                 GCAGTGGACAGAACCTCCA 
               
               
                   
               
               
                 177 
                 TIM3 
                 Human 
                 1304 
                 CAGTGCAGGTCCCAGTTCA 
               
               
                   
               
               
                 178 
                 TIM3 
                 Human 
                 1442 
                 GAGCTCCAGAGACCCCACG 
               
               
                   
               
               
                 179 
                 TIM3 
                 Human 
                 1456 
                 GCCCGAATTTCCTGGAGCT 
               
               
                   
               
               
                 180 
                 TIM3 
                 Human 
                 1506 
                 CAGCACCCAGTTTTCCCTA 
               
               
                   
               
               
                 181 
                 TIM3 
                 Human 
                 1549 
                 GCCCCTTTAGACTTTCTGT 
               
               
                   
               
               
                 182 
                 TIM3 
                 Human 
                 1640 
                 TGCCATTGCACTCCAGCCT 
               
               
                   
               
               
                 183 
                 TIM3 
                 Human 
                 1716 
                 ATCCCAGCCACTCAGGAGG 
               
               
                   
               
               
                 184 
                 TIM3 
                 Human 
                 1725 
                 ATGCCTGTAATCCCAGCCA 
               
               
                   
               
               
                 185 
                 TIM3 
                 Human 
                 1863 
                 GCTCACGCCTGTAATCCCA 
               
               
                   
               
               
                 186 
                 TIM3 
                 Human 
                 1877 
                 GGCTGGATGTGGTGGCTCA 
               
               
                   
               
               
                 187 
                 TIM3 
                 Human 
                 2053 
                 GCCACATCTCAGCCCTGCA 
               
               
                   
               
               
                 188 
                 TIM3 
                 Human 
                 2246 
                 GCCTTTGCCTTCTTTCCAC 
               
               
                   
               
               
                 189 
                 CTLA4 
                 Mouse 
                 106 
                 GGTCCTCAGGGAGCAGAGT 
               
               
                   
               
               
                 190 
                 CTLA4 
                 Mouse 
                 191 
                 AGGCCAAGTCCTAGAAGGC 
               
               
                   
               
               
                 191 
                 CTLA4 
                 Mouse 
                 253 
                 TGGGTCACCTGTATGGCTT 
               
               
                   
               
               
                 192 
                 CTLA4 
                 Mouse 
                 344 
                 AGTCACCCGGACCTCATCA 
               
               
                   
               
               
                 193 
                 CTLA4 
                 Mouse 
                 416 
                 GCCCACTGTATTCTTCTCT 
               
               
                   
               
               
                 194 
                 CTLA4 
                 Mouse 
                 497 
                 GTCAACAGCTCTCAGTCCT 
               
               
                   
               
               
                 195 
                 CTLA4 
                 Mouse 
                 563 
                 GTTGCCCATGCCCACAAAG 
               
               
                   
               
               
                 196 
                 CTLA4 
                 Mouse 
                 567 
                 TCCCGTTGCCCATGCCCAC 
               
               
                   
               
               
                 197 
                 CTLA4 
                 Mouse 
                 647 
                 CCCCAAGCTAACTGCGACA 
               
               
                   
               
               
                 198 
                 CTLA4 
                 Mouse 
                 735 
                 TCACATAGACCCCTGTTGT 
               
               
                   
               
               
                 199 
                 CTLA4 
                 Mouse 
                 760 
                 CATTCTGGCTCTGTTGGGG 
               
               
                   
               
               
                 200 
                 CTLA4 
                 Mouse 
                 1084 
                 CCTTGACCCCACACCATAA 
               
               
                   
               
               
                 201 
                 CTLA4 
                 Mouse 
                 1135 
                 CTCTTCCTTCACCCCCTTC 
               
               
                   
               
               
                 202 
                 CTLA4 
                 Mouse 
                 1434 
                 CTCCCCAGCCAAACCTCCC 
               
               
                   
               
               
                 203 
                 CTLA4 
                 Mouse 
                 1436 
                 AGCTCCCCAGCCAAACCTC 
               
               
                   
               
               
                 204 
                 CTLA4 
                 Mouse 
                 1470 
                 GACCTCGAGTCCAACCTGA 
               
               
                   
               
               
                 205 
                 CTLA4 
                 Mouse 
                 1484 
                 GCCAGTTGGTGCAGGACCT 
               
               
                   
               
               
                 206 
                 CTLA4 
                 Mouse 
                 1542 
                 ACTCCATCACCATCGGTTT 
               
               
                   
               
               
                 207 
                 CTLA4 
                 Mouse 
                 1552 
                 CCCAGTTTACACTCCATCA 
               
               
                   
               
               
                 208 
                 CTLA4 
                 Mouse 
                 1794 
                 TCCCATCCTACCATCTGCT 
               
               
                   
               
               
                 209 
                 CTLA4 
                 Human 
                 129 
                 GGGAGCGGTGTTCAGGTCT 
               
               
                   
               
               
                 210 
                 CTLA4 
                 Human 
                 211 
                 AGGAGAGTGCAGGGCCAGG 
               
               
                   
               
               
                 211 
                 CTLA4 
                 Human 
                 346 
                 CGGACCTCAGTGGCTTTGC 
               
               
                   
               
               
                 212 
                 CTLA4 
                 Human 
                 504 
                 CCATGGCCCTCAGTCCTTG 
               
               
                   
               
               
                 213 
                 CTLA4 
                 Human 
                 574 
                 CCGTTGCCTATGCCCAGGT 
               
               
                   
               
               
                 214 
                 CTLA4 
                 Human 
                 953 
                 GGGTTCCGCATCCAACTTT 
               
               
                   
               
               
                 215 
                 CTLA4 
                 Human 
                 1007 
                 CATCCCAGCTCTGTCTTTC 
               
               
                   
               
               
                 216 
                 CTLA4 
                 Human 
                 1067 
                 GCATCCCCATATTAATCCC 
               
               
                   
               
               
                 217 
                 CTLA4 
                 Human 
                 1136 
                 CTCCCTGCCTTTTCCTTCT 
               
               
                   
               
               
                 218 
                 CTLA4 
                 Human 
                 1308 
                 ACCTTTAGCATCACTGGCT 
               
               
                   
               
               
                 219 
                 CTLA4 
                 Human 
                 1514 
                 AGTGTCCTGAGCTCCTCCA 
               
               
                   
               
               
                 220 
                 CTLA4 
                 Human 
                 1537 
                 CCTTGTGTTCTACCTGGTG 
               
               
                   
               
               
                 221 
                 CTLA4 
                 Human 
                 1570 
                 CCTCATCCAGTTTCCAAGC 
               
               
                   
               
               
                 222 
                 CTLA4 
                 Human 
                 1606 
                 CTCAGCACAATTCCACGCA 
               
               
                   
               
               
                 223 
                 CTLA4 
                 Human 
                 1632 
                 AGCCCCAAAGCACATGTCA 
               
               
                   
               
               
                 224 
                 CTLA4 
                 Human 
                 1747 
                 ATACCTGTGGGTCTCCTGG 
               
               
                   
               
               
                 225 
                 CTLA4 
                 Human 
                 1822 
                 GCCTTCTTCTGTCCATGGC 
               
               
                   
               
               
                 226 
                 CTLA4 
                 Human 
                 1844 
                 GCACCCCATTCTGCCACCT 
               
               
                   
               
               
                 227 
                 CTLA4 
                 Human/ 
                 744 
                 TCACATAGACCCCTGTTGT 
               
               
                   
                   
                 Mouse 
                   
                   
               
               
                   
               
               
                 228 
                 CTLA4 
                 Human/ 
                 1117 
                 TTGGGCTGTGCCATTCCCT 
               
               
                   
                   
                 Mouse 
                   
                   
               
               
                   
               
               
                 229 
                 IDO2 
                 Mouse 
                 49 
                 TGCCCCAGAGGAATGCCCA 
               
               
                   
               
               
                 230 
                 IDO2 
                 Mouse 
                 127 
                 GTGGTATCTCCCCAAGGAC 
               
               
                   
               
               
                 231 
                 IDO2 
                 Mouse 
                 279 
                 CAGTCCAGGAGAGGCATCC 
               
               
                   
               
               
                 232 
                 IDO2 
                 Mouse 
                 440 
                 GGAGTCCCAAGTTCCTGGA 
               
               
                   
               
               
                 233 
                 IDO2 
                 Mouse 
                 510 
                 TCCAACGGTCCTTCTGGGT 
               
               
                   
               
               
                 234 
                 IDO2 
                 Mouse 
                 639 
                 GCCTCCATTCCCTGAACCA 
               
               
                   
               
               
                 235 
                 IDO2 
                 Mouse 
                 801 
                 GGATTGTCCTTCCACCCAG 
               
               
                   
               
               
                 236 
                 IDO2 
                 Mouse 
                 873 
                 GCTGCACTTCCTCCAGAGT 
               
               
                   
               
               
                 237 
                 IDO2 
                 Mouse 
                 971 
                 GCGGCATGTAGTCCCTCAT 
               
               
                   
               
               
                 238 
                 IDO2 
                 Mouse 
                 1047 
                 CCAGGACCAGAGGCCAGTA 
               
               
                   
               
               
                 239 
                 IDO2 
                 Mouse 
                 1215 
                 GTACCCCCAGTGCCCCTGT 
               
               
                   
               
               
                 240 
                 IDO2 
                 Mouse 
                 1280 
                 CACCAGGACACAGGAGGGC 
               
               
                   
               
               
                 241 
                 IDO2 
                 Mouse 
                 1617 
                 GCTCCCACGGGACCTGACT 
               
               
                   
               
               
                 242 
                 IDO2 
                 Mouse 
                 1782 
                 TGAGGAGGTCATGGCTGCA 
               
               
                   
               
               
                 243 
                 IDO2 
                 Mouse 
                 1911 
                 GGGACGAGGGAGGTAGGGA 
               
               
                   
               
               
                 244 
                 IDO2 
                 Mouse 
                 2058 
                 GTTTGAGGCCCATCAGACC 
               
               
                   
               
               
                 245 
                 IDO2 
                 Mouse 
                 2345 
                 GCTCAGTGGCTCATCCCTG 
               
               
                   
               
               
                 246 
                 IDO2 
                 Mouse 
                 2638 
                 GGCTGTCCCAGGTCACAGA 
               
               
                   
               
               
                 247 
                 IDO2 
                 Mouse 
                 2748 
                 GGTGACTTCCAGGTCTGCA 
               
               
                   
               
               
                 248 
                 IDO2 
                 Mouse 
                 2756 
                 CCCGTGCTGGTGACTTCCA 
               
               
                   
               
               
                 249 
                 IDO2 
                 Human 
                 156 
                 GGTGTCCATTGCCTTCTGT 
               
               
                   
               
               
                 250 
                 IDO2 
                 Human 
                 214 
                 GCCTGGTGGGTGAAGTGTC 
               
               
                   
               
               
                 251 
                 IDO2 
                 Human 
                 222 
                 TTGTGGTGGCCTGGTGGGT 
               
               
                   
               
               
                 252 
                 IDO2 
                 Human 
                 284 
                 ATTCGGTCTGTGGGGCTCC 
               
               
                   
               
               
                 253 
                 IDO2 
                 Human 
                 561 
                 CTCCTTCCTGCCAGACATA 
               
               
                   
               
               
                 254 
                 IDO2 
                 Human 
                 633 
                 GCCCCAAGTTCCTGGAGAC 
               
               
                   
               
               
                 255 
                 IDO2 
                 Human 
                 713 
                 CCCAATTTCCAGGAATCCG 
               
               
                   
               
               
                 256 
                 IDO2 
                 Human 
                 722 
                 CTCCAGGTTCCCAATTTCC 
               
               
                   
               
               
                 257 
                 IDO2 
                 Human 
                 757 
                 TGCAGGCTCTCTCCCCCAG 
               
               
                   
               
               
                 258 
                 IDO2 
                 Human 
                 802 
                 GGCACTGCTTCTTTCTCTA 
               
               
                   
               
               
                 259 
                 IDO2 
                 Human 
                 1137 
                 AGTCACCACTTTCCTTGCT 
               
               
                   
               
               
                 260 
                 IDO2 
                 Human 
                 1207 
                 GGTGCTGAGTGGATGTCTT 
               
               
                   
               
               
                 261 
                 IDO2 
                 Human 
                 1253 
                 CAGCAAGTGGTCCTGTCCA 
               
               
                   
               
               
                 262 
                 IDO2 
                 Human 
                 1363 
                 GGCTTCCCATGCTTTGCCT 
               
               
                   
               
               
                 263 
                 IDO2 
                 Human 
                 1415 
                 TCCACCTGTGCCCCTGTCT 
               
               
                   
               
               
                 264 
                 IDO2 
                 Human 
                 1464 
                 ACTCCAAGGTCTTATCCCT 
               
               
                   
               
               
                 265 
                 IDO2 
                 Human 
                 1573 
                 TGATCCCAGGCAGAACCCT 
               
               
                   
               
               
                 266 
                 IDO2 
                 Human 
                 1593 
                 GGGCTGAGATCCTTCCTGG 
               
               
                   
               
               
                 267 
                 IDO2 
                 Human 
                 1745 
                 TGGGGGTTCTGCATGAGGA 
               
               
                   
               
               
                 268 
                 IDO2 
                 Human 
                 1752 
                 ACTCCTCTGGGGGTTCTGC 
               
               
                   
               
               
                 269 
                 IDO2 
                 Human 
                 1837 
                 AGTAATGTATCCCCAGGCA 
               
               
                   
               
               
                 270 
                 IDO2 
                 Human 
                 1945 
                 AAGAGGGCTGGTCTGGGAC 
               
               
                   
               
               
                 271 
                 CEACAM1 
                 Mouse 
                 291 
                 GTAGTGTTTCCCTTGTACC 
               
               
                   
               
               
                 272 
                 CEACAM1 
                 Mouse 
                 294 
                 GCCGTAGTGTTTCCCTTGT 
               
               
                   
               
               
                 273 
                 CEACAM1 
                 Mouse 
                 299 
                 CTATAGCCGTAGTGTTTCC 
               
               
                   
               
               
                 274 
                 CEACAM1 
                 Mouse 
                 1110 
                 GTGAGGAACAGAATCCGGG 
               
               
                   
               
               
                 275 
                 CEACAM1 
                 Mouse 
                 1526 
                 TTCCTGCTTCTGGTTTGTT 
               
               
                   
               
               
                 276 
                 CEACAM1 
                 Mouse 
                 1530 
                 CCATTTCCTGCTTCTGGTT 
               
               
                   
               
               
                 277 
                 CEACAM1 
                 Mouse 
                 1531 
                 GCCATTTCCTGCTTCTGGT 
               
               
                   
               
               
                 278 
                 CEACAM1 
                 Mouse 
                 2474 
                 CCATGCTGGAACTCTGTCT 
               
               
                   
               
               
                 279 
                 CEACAM1 
                 Mouse 
                 2485 
                 CTGCACAGGCTCCATGCTG 
               
               
                   
               
               
                 280 
                 CEACAM1 
                 Mouse 
                 2486 
                 CCTGCACAGGCTCCATGCT 
               
               
                   
               
               
                 281 
                 CEACAM1 
                 Mouse 
                 2500 
                 CTGTGGGATTGAAACCTGC 
               
               
                   
               
               
                 282 
                 CEACAM1 
                 Mouse 
                 2507 
                 GGTGTTACTGTGGGATTGA 
               
               
                   
               
               
                 283 
                 CEACAM1 
                 Mouse 
                 2513 
                 GCAGAAGGTGTTACTGTGG 
               
               
                   
               
               
                 284 
                 CEACAM1 
                 Mouse 
                 2533 
                 GTCTGAGCAGGTGGGGTGC 
               
               
                   
               
               
                 285 
                 CEACAM1 
                 Mouse 
                 2536 
                 GCAGTCTGAGCAGGTGGGG 
               
               
                   
               
               
                 286 
                 CEACAM1 
                 Mouse 
                 2568 
                 TGTCCAGGTAGCCAGGCCT 
               
               
                   
               
               
                 287 
                 CEACAM1 
                 Mouse 
                 2570 
                 AATGTCCAGGTAGCCAGGC 
               
               
                   
               
               
                 288 
                 CEACAM1 
                 Human 
                 103 
                 GCCCTGTCTTCACCTGTGG 
               
               
                   
               
               
                 289 
                 CEACAM1 
                 Human 
                 111 
                 TCCTGCTGGCCCTGTCTTC 
               
               
                   
               
               
                 290 
                 CEACAM1 
                 Human 
                 126 
                 GTGCCCCATGGTGTCTCCT 
               
               
                   
               
               
                 291 
                 CEACAM1 
                 Human 
                 1021 
                 TGGCGTGGCAGGTATAGGA 
               
               
                   
               
               
                 292 
                 CEACAM1 
                 Human 
                 1403 
                 GCCCCAGGTGAGAGGCCAT 
               
               
                   
               
               
                 293 
                 CEACAM1 
                 Human 
                 1440 
                 AACCAGGGCCACTACTCCA 
               
               
                   
               
               
                 294 
                 CEACAM1 
                 Human 
                 1463 
                 GCCAGGGCTACTGCTATCA 
               
               
                   
               
               
                 295 
                 CEACAM1 
                 Human 
                 1851 
                 GGTTTCCTACAGACTCCCA 
               
               
                   
               
               
                 296 
                 CEACAM1 
                 Human 
                 1908 
                 GTTCTGGTCCCTCTTTCCC 
               
               
                   
               
               
                 297 
                 CEACAM1 
                 Human 
                 2230 
                 GGTGCTTAGACCCTGATCC 
               
               
                   
               
               
                 298 
                 CEACAM1 
                 Human 
                 2396 
                 CTGCCTTGAACAGAGCCCA 
               
               
                   
               
               
                 299 
                 CEACAM1 
                 Human 
                 2414 
                 AACCCCTCCCTCTCAGCAC 
               
               
                   
               
               
                 300 
                 CEACAM1 
                 Human 
                 2436 
                 GCTGGTTCCCTCCTGAAGC 
               
               
                   
               
               
                 301 
                 CEACAM1 
                 Human 
                 2473 
                 CCTTTCCCAAGTTCCTAGC 
               
               
                   
               
               
                 302 
                 CEACAM1 
                 Human 
                 2489 
                 GGGCAGCTCTCTGATTCCT 
               
               
                   
               
               
                 303 
                 CEACAM1 
                 Human 
                 2700 
                 GCTCCTGACCAAGGGACCT 
               
               
                   
               
               
                 304 
                 CEACAM1 
                 Human 
                 2894 
                 AGCAGAGGCCAAGGTTTCC 
               
               
                   
               
               
                 305 
                 CEACAM1 
                 Human 
                 2924 
                 CTCCCACTTCTCAAGGACC 
               
               
                   
               
               
                 306 
                 CEACAM1 
                 Human 
                 3019 
                 TCACAGCCCCATTTCCCCA 
               
               
                   
               
               
                 307 
                 CEACAM1 
                 Human 
                 3323 
                 GCACAGTCCGTGTCAGGGT 
               
               
                   
               
               
                 308 
                 OX40 
                 Mouse 
                 20 
                 GTATGCAGAGTCCCATGAT 
               
               
                   
               
               
                 309 
                 OX40 
                 Mouse 
                 121 
                 CCTTGCAGGGTGTGGCTAT 
               
               
                   
               
               
                 310 
                 OX40 
                 Mouse 
                 161 
                 CCTTGTCTGCTTTCTGCCT 
               
               
                   
               
               
                 311 
                 OX40 
                 Mouse 
                 270 
                 TGTGACCACTGGGGTAGGT 
               
               
                   
               
               
                 312 
                 OX40 
                 Mouse 
                 495 
                 GAGGTTGGGTGCCTGGTCT 
               
               
                   
               
               
                 313 
                 OX40 
                 Mouse 
                 509 
                 GCCGCTGTCCTGCCGAGGT 
               
               
                   
               
               
                 314 
                 OX40 
                 Mouse 
                 544 
                 GGAGGGCAGGGAACACAGT 
               
               
                   
               
               
                 315 
                 OX40 
                 Mouse 
                 572 
                 CTGGTTGTTGCCTGGAGAA 
               
               
                   
               
               
                 316 
                 OX40 
                 Mouse 
                 593 
                 ATTGGTCCAGGGCTTGCAG 
               
               
                   
               
               
                 317 
                 OX40 
                 Mouse 
                 642 
                 CCAAGCTGTCACTGGCTGG 
               
               
                   
               
               
                 318 
                 OX40 
                 Mouse 
                 693 
                 GGGTCTCCCAGAGCAGTGT 
               
               
                   
               
               
                 319 
                 OX40 
                 Mouse 
                 845 
                 AGTCAAGGGAGCCAGCAGG 
               
               
                   
               
               
                 320 
                 OX40 
                 Mouse 
                 904 
                 GGTTTGGGAGTGTTAGGCA 
               
               
                   
               
               
                 321 
                 OX40 
                 Mouse 
                 941 
                 CTCCTGGATCGGGGTCCTG 
               
               
                   
               
               
                 322 
                 OX40 
                 Mouse 
                 1010 
                 GCCCCATAAAATCCACTCC 
               
               
                   
               
               
                 323 
                 OX40 
                 Mouse 
                 1021 
                 GGGTTGTCCGTGCCCCATA 
               
               
                   
               
               
                 324 
                 OX40 
                 Mouse 
                 1038 
                 GGCAGGCATCAGGATATGG 
               
               
                   
               
               
                 325 
                 OX40 
                 Mouse 
                 1069 
                 GCCCAGCACCTAGAACGGT 
               
               
                   
               
               
                 326 
                 OX40 
                 Mouse 
                 1080 
                 GCCCAGAGCCAGCCCAGCA 
               
               
                   
               
               
                 327 
                 OX40 
                 Mouse 
                 1126 
                 TTAGGAGCACCACCAGGCA 
               
               
                   
               
               
                 328 
                 OX40 
                 Human 
                 82 
                 CCCAGGAGGAGCAGAGCCG 
               
               
                   
               
               
                 329 
                 OX40 
                 Human 
                 192 
                 TGCAGCGGCTCACCATCCC 
               
               
                   
               
               
                 330 
                 OX40 
                 Human 
                 273 
                 AGGGCTTGCACGGCTTGGA 
               
               
                   
               
               
                 331 
                 OX40 
                 Human 
                 300 
                 TCCCACTTCTGAGGTTACA 
               
               
                   
               
               
                 332 
                 OX40 
                 Human 
                 312 
                 GCTTCCGCTCACTCCCACT 
               
               
                   
               
               
                 333 
                 OX40 
                 Human 
                 342 
                 AGACTGTGTCCTGTGTGGC 
               
               
                   
               
               
                 334 
                 OX40 
                 Human 
                 347 
                 GCGGCAGACTGTGTCCTGT 
               
               
                   
               
               
                 335 
                 OX40 
                 Human 
                 401 
                 GGCACAGTCAACTCCAGGC 
               
               
                   
               
               
                 336 
                 OX40 
                 Human 
                 462 
                 AGTTGGTCCAGGGCTTGCA 
               
               
                   
               
               
                 337 
                 OX40 
                 Human 
                 485 
                 GGTGTGCTTCCCAGCCAAG 
               
               
                   
               
               
                 338 
                 OX40 
                 Human 
                 746 
                 CCGGAGCAGGTACAGGGCC 
               
               
                   
               
               
                 339 
                 OX40 
                 Human 
                 762 
                 GCAGCCTCTGGTCCCTCCG 
               
               
                   
               
               
                 340 
                 OX40 
                 Human 
                 763 
                 GGCAGCCTCTGGTCCCTCC 
               
               
                   
               
               
                 341 
                 OX40 
                 Human 
                 823 
                 TGCTCCTCTTGGATGGGGG 
               
               
                   
               
               
                 342 
                 OX40 
                 Human 
                 865 
                 GGCCCAGGTCAGATCTTGG 
               
               
                   
               
               
                 343 
                 OX40 
                 Human 
                 967 
                 GTTGGCCCAGGAGCGTGGC 
               
               
                   
               
               
                 344 
                 OX40 
                 Human 
                 1036 
                 GCAGGAGGTATGCATGGCA 
               
               
                   
               
               
                 345 
                 OX40 
                 Human 
                 1058 
                 GTTTTTATTGTGGTCCCGC 
               
               
                   
               
               
                 346 
                 OX40 
                 Human 
                 1075 
                 GACTCCCGTCTGCCAAGGT 
               
               
                   
               
               
                 347 
                 OX40L 
                 Mouse 
                 141 
                 CCCTTCCCCTTCCATCTCT 
               
               
                   
               
               
                 348 
                 OX40L 
                 Mouse 
                 167 
                 TCCAGATTCTCATCCAGGG 
               
               
                   
               
               
                 349 
                 OX40L 
                 Mouse 
                 182 
                 GGCCTTGATCCGTTTTCCA 
               
               
                   
               
               
                 350 
                 OX40L 
                 Mouse 
                 218 
                 ACCACCAGCCTTAGCGTCT 
               
               
                   
               
               
                 351 
                 OX40L 
                 Mouse 
                 226 
                 TCCCAGAGACCACCAGCCT 
               
               
                   
               
               
                 352 
                 OX40L 
                 Mouse 
                 240 
                 CCCTGCTCCCTTGATCCCA 
               
               
                   
               
               
                 353 
                 OX40L 
                 Mouse 
                 303 
                 TGGAGGGTCCTTTGCCGGA 
               
               
                   
               
               
                 354 
                 OX40L 
                 Mouse 
                 399 
                 GTTCTGCACCTCCATAGTT 
               
               
                   
               
               
                 355 
                 OX40L 
                 Mouse 
                 454 
                 AGGAGCCCTTCAGGTAGAT 
               
               
                   
               
               
                 356 
                 OX40L 
                 Mouse 
                 565 
                 CCAAAGAGGCCACCACAGT 
               
               
                   
               
               
                 357 
                 OX40L 
                 Mouse 
                 650 
                 ACAATCAGCTCCCCATCAT 
               
               
                   
               
               
                 358 
                 OX40L 
                 Mouse 
                 753 
                 CCTGTGTCCCGTCCACCCT 
               
               
                   
               
               
                 359 
                 OX40L 
                 Mouse 
                 817 
                 AGGGTAGGCTCTGCATTCA 
               
               
                   
               
               
                 360 
                 OX40L 
                 Mouse 
                 895 
                 GCAGGCTCAAGGCAATCCT 
               
               
                   
               
               
                 361 
                 OX40L 
                 Mouse 
                 1069 
                 TGGACACCACCCTTTCCAT 
               
               
                   
               
               
                 362 
                 OX40L 
                 Mouse 
                 1157 
                 CCCCCATGAGATGAGAGAC 
               
               
                   
               
               
                 363 
                 OX40L 
                 Mouse 
                 1173 
                 AATCTTCTTTCCAAGCCCC 
               
               
                   
               
               
                 364 
                 OX40L 
                 Mouse 
                 1193 
                 AGTCCTGCTTTCCACGGGG 
               
               
                   
               
               
                 365 
                 OX40L 
                 Mouse 
                 1298 
                 GGTGGGTATCATAGTCCCT 
               
               
                   
               
               
                 366 
                 OX40L 
                 Mouse 
                 1439 
                 CCTTCTTGGCCTTTATCCT 
               
               
                   
               
               
                 367 
                 OX40L 
                 Human 
                 494 
                 GGGCTCCTCATCCTTCTGG 
               
               
                   
               
               
                 368 
                 OX40L 
                 Human 
                 712 
                 GTTCATGCTGGTGCCTGGT 
               
               
                   
               
               
                 369 
                 OX40L 
                 Human 
                 814 
                 GGGAGGGCCAGGATCTGCT 
               
               
                   
               
               
                 370 
                 OX40L 
                 Human 
                 1104 
                 CCTTCACTCCTTGCTCCTC 
               
               
                   
               
               
                 371 
                 OX40L 
                 Human 
                 1120 
                 GATTCATAACCCCACTCCT 
               
               
                   
               
               
                 372 
                 OX40L 
                 Human 
                 1139 
                 GTTCATACCACCTTTGGCA 
               
               
                   
               
               
                 373 
                 OX40L 
                 Human 
                 1276 
                 GGCTCTCTTCAAGTCCTGA 
               
               
                   
               
               
                 374 
                 OX40L 
                 Human 
                 1378 
                 CACATCCCCAGACAGTTCT 
               
               
                   
               
               
                 375 
                 OX40L 
                 Human 
                 1383 
                 AGCATCACATCCCCAGACA 
               
               
                   
               
               
                 376 
                 OX40L 
                 Human 
                 1492 
                 GTCCAGTTCCCTGCTATCC 
               
               
                   
               
               
                 377 
                 OX40L 
                 Human 
                 1569 
                 TGCTTTGCCTGTCTGTGGC 
               
               
                   
               
               
                 378 
                 OX40L 
                 Human 
                 1577 
                 GCATGTGTTGCTTTGCCTG 
               
               
                   
               
               
                 379 
                 OX40L 
                 Human 
                 1828 
                 ATTCCATTGAAGCCCTGGC 
               
               
                   
               
               
                 380 
                 OX40L 
                 Human 
                 2127 
                 CAGCCCTCCACCTTTCTGG 
               
               
                   
               
               
                 381 
                 OX40L 
                 Human 
                 2367 
                 GTCCACAGTAGGCCCTCCA 
               
               
                   
               
               
                 382 
                 OX40L 
                 Human 
                 2376 
                 CAGTGCCTGGTCCACAGTA 
               
               
                   
               
               
                 383 
                 OX40L 
                 Human 
                 2387 
                 AGTATTTAGCCCAGTGCCT 
               
               
                   
               
               
                 384 
                 OX40L 
                 Human 
                 2729 
                 CCCAAAGCGAGTGAGCACC 
               
               
                   
               
               
                 385 
                 OX40L 
                 Human 
                 2754 
                 ACATGGGAAGAGCAGGCCA 
               
               
                   
               
               
                 386 
                 OX40L 
                 Human 
                 2808 
                 GGTGGAGTGAGGCTGGTGC 
               
               
                   
               
            
           
         
       
     
     Compound names for the 3 rd  generation antisense (3GA) compounds according to the invention are based on the target and oligonucleotide target site(s) as depicted Table 3. For example, “3GA 384” comprises two copies of Oligo # 384 linked at their 5′ ends (e.g., 3′-CCACGAGTGAGCGAAACCC-5′-X-5′-CCCAAAGCGAGTGAGCACC-3′, wherein X represents a non-nucleotidic linker). Alternatively, a 3GA compound comprising two different oligonucleotides such as Oligo # 385 and Oligo # 386 (e.g., 3′-ACCGGACGAGAAGGGTACA-5′-X-5′-GGTGGAGTGAGGCTGGTGC-3′, wherein X represents a non-nucleotidic linker) will be referred to herein, for example, as “3GA 385/386”. 
     Certain embodiments provide gene silencing compounds comprising two oligonucleotides independently selected from the oligonucleotides listed in Table 3. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, or 386, or combinations thereof. In certain embodiments, the oligonucleotides of the gene silencing compound are the same. In certain embodiments, the oligonucleotides of the gene silencing compounds are different. 
     In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, or 386, and is at least 80% complimentary to its target site with SEQ ID NO: 387, SEQ ID NO: 388, 
     SEQ ID NO: 389, SEQ ID NO: 390, SEQ ID NO: 391, SEQ ID NO: 392, SEQ ID NO: 393, SEQ ID NO: 394, SEQ ID NO: 395, SEQ ID NO: 396, SEQ ID NO: 397, SEQ ID NO: 398, SEQ ID NO: 399, SEQ ID NO: 400, SEQ ID NO: 401, SEQ ID NO: 402, SEQ ID NO: 403, SEQ ID NO: 404, SEQ ID NO: 405, or SEQ ID NO: 406. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, or 386, and is at least 85% complimentary to its target site with SEQ ID NO: 387, SEQ ID NO: 388, SEQ ID NO: 389, SEQ ID NO: 390, SEQ ID NO: 391, SEQ ID NO: 392, SEQ ID NO: 393, SEQ ID NO: 394, SEQ ID NO: 395, SEQ ID NO: 396, SEQ ID NO: 397, SEQ ID NO: 398, SEQ ID NO: 399, SEQ ID NO: 400, SEQ ID NO: 401, SEQ ID NO: 402, SEQ ID NO: 403, SEQ ID NO: 404, SEQ ID NO: 405, or SEQ ID NO: 406. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, or 386, and is at least 90% complimentary to its target site with SEQ ID NO: 387, SEQ ID NO: 388, SEQ ID NO: 389, SEQ ID NO: 390, SEQ ID NO: 391, SEQ ID NO: 392, SEQ ID NO: 393, SEQ ID NO: 394, SEQ ID NO: 395, SEQ ID NO: 396, SEQ ID NO: 397, SEQ ID NO: 398, SEQ ID NO: 399, SEQ ID NO: 400, SEQ ID NO: 401, SEQ ID NO: 402, SEQ ID NO: 403, SEQ ID NO: 404, SEQ ID NO: 405, or SEQ ID NO: 406. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, or 386, and is at least 95% complimentary to its target site with SEQ ID NO: 387, SEQ ID NO: 388, SEQ ID NO: 389, SEQ ID NO: 390, SEQ ID NO: 391, SEQ ID NO: 392, SEQ ID NO: 393, SEQ ID NO: 394, SEQ ID NO: 395, SEQ ID NO: 396, SEQ ID NO: 397, SEQ ID NO: 398, SEQ ID NO: 399, SEQ ID NO: 400, SEQ ID NO: 401, SEQ ID NO: 402, SEQ ID NO: 403, SEQ ID NO: 404, SEQ ID NO: 405, or SEQ ID NO: 406. 
     In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 49, 50, 51, 52, 53, 54, 75, 76, 77, 78, 79, 80, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, or 365, and is at least 80% complimentary to its target site with SEQ ID NO: 387, SEQ ID NO: 389, SEQ ID NO: 391, SEQ ID NO: 393, SEQ ID NO: 395, SEQ ID NO: 397, SEQ ID NO: 399, SEQ ID NO: 401, SEQ ID NO: 403, or SEQ ID NO: 405. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 49, 50, 51, 52, 53, 54, 75, 76, 77, 78, 79, 80,101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, or 365, and is at least 85% complimentary to its target site with SEQ ID NO: 387, SEQ ID NO: 389, SEQ ID NO: 391, SEQ ID NO: 393, SEQ ID NO: 395, SEQ ID NO: 397, SEQ ID NO: 399, SEQ ID NO: 401, SEQ ID NO: 403, or SEQ ID NO: 405. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 49, 50, 51, 52, 53, 54, 75, 76, 77, 78, 79, 80,101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, or 365, and is at least 90% complimentary to its target site with SEQ ID NO: 387, SEQ ID NO: 389, SEQ ID NO: 391, SEQ ID NO: 393, SEQ ID NO: 395, SEQ ID NO: 397, SEQ ID NO: 399, SEQ ID NO: 401, SEQ ID NO: 403, or SEQ ID NO: 405. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 49, 50, 51, 52, 53, 54, 75, 76, 77, 78, 79, 80,101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, or 365, and is at least 95% complimentary to its target site with SEQ ID NO: 387, SEQ ID NO: 389, SEQ ID NO: 391, SEQ ID NO: 393, SEQ ID NO: 395, SEQ ID NO: 397, SEQ ID NO: 399, SEQ ID NO: 401, SEQ ID NO: 403, or SEQ ID NO: 405. 
     In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, or 386, and is at least 80% complimentary to its target site within SEQ ID NO: 388, SEQ ID NO: 390, SEQ ID NO: 392, SEQ ID NO: 394, SEQ ID NO: 396, SEQ ID NO: 398, SEQ ID NO: 400, SEQ ID NO: 402, SEQ ID NO: 404, or SEQ ID NO: 406. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, or 386, and is at least 85% complimentary to its target site within SEQ ID NO: 388, SEQ ID NO: 390, SEQ ID NO: 392, SEQ ID NO: 394, SEQ ID NO: 396, SEQ ID NO: 398, SEQ ID NO: 400, SEQ ID NO: 402, SEQ ID NO: 404, or SEQ ID NO: 406. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, or 386, and is at least 90% complimentary to its target site within SEQ ID NO: 388, SEQ ID NO: 390, SEQ ID NO: 392, SEQ ID NO: 394, SEQ ID NO: 396, SEQ ID NO: 398, SEQ ID NO: 400, SEQ ID NO: 402, SEQ ID NO: 404, or SEQ ID NO: 406. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, or 386, and is at least 95% complimentary to its target site within SEQ ID NO: 388, SEQ ID NO: 390, SEQ ID NO: 392, SEQ ID NO: 394, SEQ ID NO: 396, SEQ ID NO: 398, SEQ ID NO: 400, SEQ ID NO: 402, SEQ ID NO: 404, or SEQ ID NO: 406. 
     In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, or 8, and is at least 80% complimentary to SEQ ID NO: 387. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, or 8, and is at least 85% complimentary to SEQ ID NO: 387. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, or 8, and is at least 90% complimentary to SEQ ID NO: 387. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, or 8, and is at least 95% complimentary to SEQ ID NO: 387. 
     In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, and is at least 80% complimentary to SEQ ID NO: 388. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, and is at least 85% complimentary to SEQ ID NO: 388. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, and is at least 90% complimentary to SEQ ID NO: 388. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, and is at least 95% complimentary to SEQ ID NO: 388. 
     In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 49, 50, 51, 52, 53, 54, and is at least 80% complimentary to SEQ ID NO: 389. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 49, 50, 51, 52, 53, 54, and is at least 85% complimentary to SEQ ID NO: 389. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 49, 50, 51, 52, 53, 54, and is at least 90% complimentary to SEQ ID NO: 389. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 49, 50, 51, 52, 53, 54, and is at least 95% complimentary to SEQ ID NO: 389. 
     In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, and is at least 80% complimentary to SEQ ID NO: 390. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, and is at least 85% complimentary to SEQ ID NO: 390. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, and is at least 90% complimentary to SEQ ID NO: 390. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, and is at least 95% complimentary to SEQ ID NO: 390. 
     In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 75, 76, 77, 78, 79, 80, and is at least 80% complimentary to SEQ ID NO: 391. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 75, 76, 77, 78, 79, 80, and is at least 85% complimentary to SEQ ID NO: 391. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 75, 76, 77, 78, 79, 80, and is at least 90% complimentary to SEQ ID NO: 391. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 75, 76, 77, 78, 79, 80, and is at least 95% complimentary to SEQ ID NO: 391. 
     In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, and is at least 80% complimentary to SEQ ID NO: 392. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, and is at least 85% complimentary to SEQ ID NO: 392. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, and is at least 90% complimentary to SEQ ID NO: 392. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, and is at least 95% complimentary to SEQ ID NO: 392. 
     In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, and is at least 80% complimentary to SEQ ID NO: 393. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, and is at least 85% complimentary to SEQ ID NO: 393. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, and is at least 90% complimentary to SEQ ID NO: 393. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, and is at least 95% complimentary to SEQ ID NO: 393. 
     In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, and is at least 80% complimentary to SEQ ID NO: 394. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, and is at least 85% complimentary to SEQ ID NO: 394. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, and is at least 90% complimentary to SEQ ID NO: 394. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, and is at least 95% complimentary to SEQ ID NO: 394. 
     In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, and is at least 80% complimentary to SEQ ID NO: 395. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, and is at least 85% complimentary to SEQ ID NO: 395. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, and is at least 90% complimentary to SEQ ID NO: 395. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, and is at least 95% complimentary to SEQ ID NO: 395. 
     In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, and is at least 80% complimentary to SEQ ID NO: 396. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, and is at least 85% complimentary to SEQ ID NO: 396. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, and is at least 90% complimentary to SEQ ID NO: 396. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, and is at least 95% complimentary to SEQ ID NO: 396. 
     In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, and is at least 80% complimentary to SEQ ID NO: 397. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, and is at least 85% complimentary to SEQ ID NO: 397. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, and is at least 90% complimentary to SEQ ID NO: 397. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, and is at least 95% complimentary to SEQ ID NO: 397. 
     In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, and is at least 80% complimentary to SEQ ID NO: 398. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, and is at least 85% complimentary to SEQ ID NO: 398. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, and is at least 90% complimentary to SEQ ID NO: 398. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, and is at least 95% complimentary to SEQ ID NO: 398. 
     In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, and is at least 80% complimentary to SEQ ID NO: 399. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, and is at least 85% complimentary to SEQ ID NO: 399. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, and is at least 90% complimentary to SEQ ID NO: 399. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, and is at least 95% complimentary to SEQ ID NO: 399. 
     In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, and is at least 80% complimentary to SEQ ID NO: 400. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, and is at least 85% complimentary to SEQ ID NO: 400. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, and is at least 90% complimentary to SEQ ID NO: 400. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, and is at least 95% complimentary to SEQ ID NO: 400. 
     In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, and is at least 80% complimentary to SEQ ID NO: 401. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, and is at least 85% complimentary to SEQ ID NO: 401. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, and is at least 90% complimentary to SEQ ID NO: 401. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, and is at least 95% complimentary to SEQ ID NO: 401. 
     In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, and is at least 80% complimentary to SEQ ID NO: 402. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, and is at least 85% complimentary to SEQ ID NO: 402. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, and is at least 90% complimentary to SEQ ID NO: 402. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, and is at least 95% complimentary to SEQ ID NO: 402. 
     In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, and is at least 80% complimentary to SEQ ID NO: 403. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, and is at least 85% complimentary to SEQ ID NO: 403. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, and is at least 90% complimentary to SEQ ID NO: 403. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, and is at least 95% complimentary to SEQ ID NO: 403. 
     In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, and is at least 80% complimentary to SEQ ID NO: 404. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, and is at least 85% complimentary to SEQ ID NO: 404. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, and is at least 90% complimentary to SEQ ID NO: 404. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, and is at least 95% complimentary to SEQ ID NO: 404. 
     In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, and is at least 80% complimentary to SEQ ID NO: 405. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, and is at least 85% complimentary to SEQ ID NO: 405. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, and is at least 90% complimentary to SEQ ID NO: 405. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, and is at least 95% complimentary to SEQ ID NO: 405. 
     In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, or 386, and is at least 80% complimentary to SEQ ID NO: 406. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, or 386, and is at least 85% complimentary to SEQ ID NO: 406. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, or 386, and is at least 90% complimentary to SEQ ID NO: 406. In certain embodiments, the gene silencing compounds comprise two oligonucleotides each, independently, comprising a portion of at least 12 contiguous nucleobases of SEQ ID NOs: 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, or 386, and is at least 95% complimentary to SEQ ID NO: 406. 
     In certain embodiments, the invention provides a composition comprising a 3GA compound according to the invention and one or more vaccines, antigens, antibodies, cytotoxic agents, chemotherapeutic agents (both traditional chemotherapy and modern targeted therapies), kinase inhibitors, allergens, antibiotics, agonist, antagonist, antisense oligonucleotides, ribozymes, RNAi molecules, siRNA molecules, miRNA molecules, aptamers, proteins, gene therapy vectors, DNA vaccines, adjuvants, co-stimulatory molecules or combinations thereof. 
     In certain embodiments, the invention provides a method for inhibiting PD1, PDL1, IDO1, LAG3, TIM3, CTLA4, IDO2, CEACAM1, OX40, and/or OX40L mRNA or protein expression, the method comprising contacting a cell with a gene silencing compound according to the invention. In certain embodiments, the cell can be contacted with two or more gene silencing compounds targeting different regions of the same checkpoint. In certain embodiments, the cell can be contacted with two or more gene silencing compounds targeting different checkpoints. 
     Certain embodiments further provide a method to reduce PD1, PDL1, IDO1, LAG3, TIM3, CTLA4, IDO2, CEACAM1, OX40, and/or or OX40L mRNA or protein expression in an animal comprising administering to the animal a gene silencing compound or composition as described herein to reduce PD1, PDL1, IDO1, LAG3, TIM3, CTLA4, IDO2, CEACAM1, OX40, or OX40L mRNA or protein expression in the animal. In certain embodiments, the animal is a human. In certain embodiments, reducing PD1, PDL1, IDO1, LAG3, TIM3, CTLA4, IDO2, CEACAM1, OX40, or OX40L mRNA or protein expression prevents, treats, ameliorates, or slows progression of disease. In certain embodiments reducing PD1, PDL1, IDO1, LAG3, TIM3, CTLA4, IDO2, CEACAM1, OX40, or OX40L mRNA or protein expression inhibits immune system tolerance. In certain embodiments two or more gene silencing compounds targeting different regions of the same checkpoint can be administered. In certain embodiments two or more gene silencing compounds targeting different checkpoints can be administered. 
     In certain embodiments provided are methods for inhibiting immune system tolerance to tumors comprising administering to the animal a gene silencing compound or composition as described herein to reduce PD1, PDL1, IDO1, LAG3, TIM3, CTLA4, IDO2, CEACAM1, OX40, and/or OX40L mRNA or protein expression in the animal. In certain embodiments, the animal is a human. In certain embodiments, the gene silencing compound or composition as described herein is administered intratumorally. Thus, the inhibition of PD1, PDL1, IDO1, LAG3, TIM3, CTLA4, IDO2, CEACAM1, OX40, or OX40L mRNA or protein expression may provide a potentially useful immunotherapy strategy for patients with cancer. In certain embodiments two or more gene silencing compounds targeting different regions of the same checkpoint can be administered. In certain embodiments two or more gene silencing compounds targeting different checkpoints can be administered. 
     In certain embodiments provided are methods for preventing tumor growth and tumor volume. In certain embodiments provided are methods for reducing tumor growth and tumor volume. 
     In certain embodiments provided are methods, compounds, and compositions for the treatment, prevention, or amelioration of diseases, disorders, and conditions associated with PD1, PDL1, IDO1, LAG3, TIM3, CTLA4, IDO2, CEACAM1, OX40, or OX40L in an individual in need thereof Also contemplated are methods and compounds for the preparation of a medicament for the treatment, prevention, or amelioration of a disease, disorder, or condition associated with PD1, PDL1, IDO1, LAG3, TIM3, CTLA4, IDO2, CEACAM1, OX40, or OX40L. In certain embodiments two or more gene silencing compounds targeting different regions of the same checkpoint can be administered. In certain embodiments two or more gene silencing compounds targeting different checkpoints can be administered. 
     PD1, PDL1, IDO1, LAG3, TIM3, CTLA4, IDO2, CEACAM1, OX40, or OX40L associated diseases, disorders, and conditions include hyperproliferative diseases, e.g., cancer, carcinomas, sarcomas, lymphomas, and leukemias as well as associated malignancies and metastases. PD1, PDL1, IDO1, LAG3, TIM3, CTLA4, IDO2, CEACAM1, OX40, or OX40L associated diseases, disorders, and conditions can also include autoimmune diseases and disorders. 
     In certain embodiments provided are PD1, PDL1, IDO1, LAG3, TIM3, CTLA4, IDO2, CEACAM1, OX40, or OX40L gene silencing compounds for use in treating, preventing, or ameliorating a PD1, PDL1, IDO1, LAG3, TIM3, CTLA4, IDO2, CEACAM1, OX40, or OX40L associated disease. In certain embodiments, PD1, PDL1, IDO1, LAG3, TIM3, CTLA4, IDO2, CEACAM1, OX40, or OX40L gene silencing compounds are capable of inhibiting the expression of PD1, PDL1, IDO1, LAG3, TIM3, CTLA4, IDO2, CEACAM1, OX40, or OX40L mRNA and/or PD1, PDL1, IDO1, LAG3, TIM3, CTLA4, IDO2, CEACAM1, OX40, or OX40L protein in a cell, tissue, or animal. 
     Certain embodiments provide methods comprising administering to an animal a gene silencing compounds as described herein. In certain embodiments two or more gene silencing compounds targeting different regions of the same checkpoint can be administered. In certain embodiments two or more gene silencing compounds targeting different checkpoints can be administered. 
     Also provided are methods and gene silencing compounds for the preparation of a medicament for the treatment, prevention, or amelioration of disease. 
     Certain embodiments provide the use of gene silencing compounds as described herein in the manufacture of a medicament for treating, ameliorating, or preventing disease. 
     Certain embodiments provide gene silencing compounds as described herein for use in treating, preventing, or ameliorating disease as described herein by combination therapy with an additional agent or therapy as described herein. Agents or therapies can be co-administered or administered concomitantly. 
     Certain embodiments provide the use of a gene silencing compound as described herein in the manufacture of a medicament for treating, preventing, or ameliorating disease as described herein by combination therapy with an additional agent or therapy as described herein. Agents or therapies can be co-administered or administered concomitantly. 
     Certain embodiments provide the use of a gene silencing compound as described herein in the manufacture of a medicament for treating, preventing, or ameliorating disease as described herein in a patient who is subsequently administered an additional agent or therapy as described herein. 
     In any of the methods according to the invention, the gene silencing compound according to the invention can variously act by producing direct gene expression modulation effects alone and/or in combination with any other agent useful for treating or preventing the disease or condition that does not diminish the gene expression modulation effect of the gene silencing compound according to the invention. In any of the methods according to the invention, the agent(s) useful for treating or preventing the disease or condition includes, but is not limited to, vaccines, antigens, antibodies, preferably monoclonal antibodies, cytotoxic agents, kinase inhibitors, allergens, antibiotics, siRNA molecules, antisense oligonucleotides, TLR antagonist (e.g. antagonists of TLR3 and/or TLR7 and/or antagonists of TLR8 and/or antagonists of TLR9), chemotherapeutic agents (both traditional chemotherapy and modern targeted therapies), targeted therapeutic agents, activated cells, peptides, proteins, gene therapy vectors, peptide vaccines, protein vaccines, DNA vaccines, adjuvants, and co-stimulatory molecules (e.g. cytokines, chemokines, protein ligands, trans-activating factors, peptides or peptides comprising modified amino acids), or combinations thereof. For example, in the treatment of cancer, it is contemplated that the oligonucleotide-based compound according to the invention may be administered in combination with one or more chemotherapeutic compound, targeted therapeutic agent and/or monoclonal antibody. Alternatively, the agent can include DNA vectors encoding for antigen or allergen. Alternatively, the gene silencing compound according to the invention can be administered in combination with other compounds (for example lipids or liposomes) to enhance the specificity or magnitude of the gene expression modulation of the oligonucleotide-based compound according to the invention. 
     In any of the methods according to the invention, administration of gene silencing compounds according to the invention, alone or in combination with any other agent, can be by any suitable route, including, without limitation, parenteral, mucosal, oral, sublingual, intratumoral, transdermal, topical, inhalation, intrathecal, intranasal, aerosol, intraocular, intratracheal, intrarectal, vaginal, by gene gun, dermal patch or in eye drop or mouthwash form. In any of the methods according to the invention, administration of gene silencing compounds according to the invention, alone or in combination with any other agent, can be directly to a tissue or organ such as, but not limited to, the bladder, liver, lung, kidney or lung. In certain embodiments, administration of gene silencing compounds according to the invention, alone or in combination with any other agent, is by intratumoral administration. In certain embodiments, administration of gene silencing compounds according to the invention, alone or in combination with any other agent, is by mucosal administration. In certain embodiments, administration of gene silencing compounds according to the invention, alone or in combination with any other agent, is by oral administration. In certain embodiments, administration of gene silencing compounds according to the invention, alone or in combination with any other agent, is by intrarectal administration. In certain embodiments, administration of gene silencing compounds according to the invention, alone or in combination with any other agent, is by intrathecal administration. In certain embodiments, administration of gene silencing compounds according to the invention, alone or in combination with any other agent, is directly to the bladder. In certain embodiments, administration of gene silencing compounds according to the invention, alone or in combination with any other agent, is directly to the lung. 
     Administration of the therapeutic compositions of gene silencing compounds according to the invention can be carried out using known procedures using an effective amount and for periods of time effective to reduce symptoms or surrogate markers of the disease. For example, an effective amount of a gene silencing compound according to the invention for treating a disease and/or disorder could be that amount necessary to alleviate or reduce the symptoms, or delay or ameliorate the disease and/or disorder. In the context of administering a composition that modulates gene expression, an effective amount of a gene silencing compound according to the invention is an amount sufficient to achieve the desired modulation as compared to the gene expression in the absence of the gene silencing compound according to the invention. The effective amount for any particular application can vary depending on such factors as the disease or condition being treated, the particular compound 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 compound without necessitating undue experimentation. 
     When administered systemically, the therapeutic composition is preferably administered at a sufficient dosage to attain a blood level of gene silencing compound according to the invention from about 0.0001 micromolar to about 10 micromolar. For localized administration, much lower concentrations than this may be effective, and much higher concentrations may be tolerated. Preferably, a total dosage of gene silencing compound according to the invention ranges from about 0.001 mg per patient per day to about 200 mg per kg body weight per day. In certain embodiments, the total dosage may be 0.08, 0.16, 0.32, 0.48, 0.32, 0.64, 1, 10 or 30 mg/kg body weight administered daily, twice weekly or weekly. It may be desirable to administer simultaneously, or sequentially a therapeutically effective amount of one or more of the therapeutic compositions of the invention to an individual as a single treatment episode. 
     The methods according to this aspect of the invention are useful for model studies of gene expression. The methods are also useful for the prophylactic or therapeutic treatment of human or animal disease. For example, the methods are useful for pediatric and veterinary inhibition of gene expression applications. 
     The examples below are intended to further illustrate certain preferred embodiments of the invention, and are not intended to limit the scope of the invention. 
     Example 1 
     Preparation of Oligonucleotide-Based Compounds 
     The oligonucleotide-based compounds of the invention were chemically synthesized using phosphoramidite chemistry on automated DNA/RNA synthesizer. TAC protected (Except U) 2′-O-TBDMS RNA monomers, A, G, C and U, were purchased from Sigma-Aldrich. 7-deaza-G, inosine and loxoribine monomers were purchased from ChemGenes Corporation. 0.25M 5-ethylthio-1H-tetrazole, PAC-anhydride Cap A and Cap B were purchased from Glen Research. 3% trichloroacetic acid (TCA) in dichloromethane (DCM) and 5% 3H-1,2-Benzodithiole-3-one-1,1-dioxide (Beaucage reagent) were made in house. 
     Oligonucleotide-based compounds of the invention were synthesized at 1-2 μM scale using a standard RNA synthesis protocol. 
     Cleavage and Base Deprotection 
     Oligonucleotide-based compounds of the invention were cleaved from solid support and the solution was further heated at 65° C. to removing protecting groups of exo cyclic-amines. The resulting solution was dried completely in a SpeedVac. 
     IE HPLC Purification 
     Oligonucleotide-based compounds of the invention were purified by ion exchange HPLC. 
     Column: Dionex DNAPac 100 column (22×250) 
     Column Heater: ChromTech TL-105 HPLC column heater, temperature is set to 80° C. 
     Buffer A: 20 mM Tris-HCl, pH 7.0, 20% acetinitrile 
     Buffer B: 3.0 M NaCl, 20 mM Tris-HCl, pH 7.0, 20% acetonitrile 
     Flow rate: 10 ml/min 
     Gradient:
         0-2 min: 0% B   2-11 min: 0% B to 35% B   11-41 min: 35% B to 90% B   41-45 min: 100% B       

     Crude solution of oligonucleotide-based compounds of the invention was injected into HPLC. Above gradient is performed and the fractions were collected. All fractions containing more than 90% desired product were mixed, and then the solution was concentrated to almost dry by RotoVap. RNAse-free water was added to make final volume of 10 ml. 
     C-18 Reversed Phase Desalting 
     CC-18 Sep-Pak cartridge purchased from Waters was first conditioned with 10 ml of acetonitrile followed by 10 ml of 0.5 M sodium acetate. 10 ml of the solution of oligonucleotide-based compounds of the invention was loaded. 15 ml of water was then used to wash out the salt. The oligonucleotide-based compounds of the invention was eluted out by 1 ml of 50% acetonitrile in water. 
     The solution is placed in SpeedVac for 30 minutes. The remaining solution was filter through a 0.2 micro filter and then was lyophilized to dryness. The solid was then re-dissolved in water to make the desired concentration. 
     The final solution was stored below 0° C. 
     Capillary Electrophoresis 
     Oligonucleotide-based compounds of the invention were analyzed by capillary electrophoresis according to the following conditions. 
     Instrument: Beckman 5010 
     Capillary: 62 cm ssDNA capillary 
     Sample preparation: 0.2 OD of oligonucleotide-based composition according to the invention was dissolved in 200ul of RNAse-free water. 
     Injection: electro-kinetic injection at 5KV for 5 seconds. 
     Running condition: 14KV for 50 minutes at 30° C. 
     Ion Exchange HPLC Analysis 
     Oligonucleotide-based compounds of the invention were analyzed by ion exchange HPLC according to the following conditions: 
     Column: Dionex DNAPac guard column (22×250) 
     Column Heater: ChromTech TL-105 HPLC column heater, temperature is set to 80° C. 
     Buffer A: 100 mM Tris-HCl, pH 8.0, 20% acetinitrile 
     Buffer B: 2.0 M LiCl, 100 mM Tris-HCl, pH 8.0, 20% acetonitrile 
     Flow rate: 2 ml/min 
     Gradient:
         0-2 min: 0% B   2-10 min: 0% B to 100% B   10-15 min: 100% B       

     PAGE Analysis 
     0.3 OD of oligonucleotide-based compounds of the invention was loaded on 20% polyacrylamide gel and was running at constant power of 4 watts for approximately 5 hours. The gel was viewed under short wavelength UV light. 
     Dual Luciferase Reporter System Assay 
     Hepa 1-6 cells are co-transfected with GSO and target plasmid simultaneously using LIPOFECTAMINE® 2000 on day one (20,000 c/well). RLuc siRNA was used as the positive control and GSO mu/hu universal control was used as the negative control. On day two (24 hours post-transfection), luminescence measurements for both reporter genes are taken separately: Firefly luciferase: expression serves as the normalizer for the assay; Renilla luciferase: substrate includes a “stop” reagent to quench luminescence from firefly. Separate luminescence measurements are taken to correspond to renilla-target transcript expression. Substrate includes DTT to lyse cells. Results are shown in Table 4A and Table 4B. 
     
       
         
           
               
               
               
             
               
                 TABLE 4A 
               
               
                   
               
               
                   
                   
                 % KD 
               
               
                   
                   
                 Luciferase 
               
               
                 3GA 
                   
                 Screen 
               
               
                 # 
                 GSO sequence 
                 (25 nM) 
               
               
                   
               
             
            
               
                  1 
                 3′-GACCGTACACCCAGGCCG-5′-X- 
                 72.80 
               
               
                   
                 5′-GCCGGACCCACATGCCCAG-3′ 
                   
               
               
                   
               
               
                  2 
                 3′-ACACCCAGGCCGTCCATGG-5′-X- 
                 74.00 
               
               
                   
                 5′-GGTACCTGCCGGACCCACA-3′ 
                   
               
               
                   
               
               
                  3 
                 3′-TCGACCGTTAGTCCCACCG-5′-X- 
                 73.10 
               
               
                   
                 5′-GCCACCCTGATTGCCAGCT-3′ 
                   
               
               
                   
               
               
                  4 
                 3′-TCTCCCTCGTTTACGGTGG-5′-X- 
                 62.60 
               
               
                   
                 5′-GGTGGCATTTGCTCCCTCT-3′ 
                   
               
               
                   
               
               
                  5 
                 3′-TCCCTGCTCTCTTCTGTGG-5′-X- 
                 20.80 
               
               
                   
                 5′-GGTGTCTTCTCTCGTCCCT-3′ 
                   
               
               
                   
               
               
                  6 
                 3′-ACCCTGCATCCCCGAGTCG-5′-X- 
                 52.80 
               
               
                   
                 5′-GCTGAGCCCCTACGTCCCA-3′ 
                   
               
               
                   
               
               
                  7 
                 3′-TGTTCCACGTCTCGACCCC-5′-X- 
                 76.50 
               
               
                   
                 5′-CCCCAGCTCTGCACCTTGT-3′ 
                   
               
               
                   
               
               
                  8 
                 3′-TCCCTTGGTCGTCTCGATC-5′-X- 
                 71.50 
               
               
                   
                 5′-CTAGCTCTGCTGGTTCCCT-3′ 
                   
               
               
                   
               
               
                  9 
                 3′-TACGTCTAGGGTGTCCGCG-5′-X- 
                 76.32 
               
               
                   
                 5′-GCGCCTGTGGGATCTGCAT-3′ 
                   
               
               
                   
               
               
                 10 
                 3′-CACGATGTTGACCCGACCG-5′-X- 
                 80.51 
               
               
                   
                 5′-GCCAGCCCAGTTGTAGCAC-3′ 
                   
               
               
                   
               
               
                 11 
                 3′-TCGTTGGTCTGCCTGTTCG-5′-X- 
                 64.70 
               
               
                   
                 5′-GCTTGTCCGTCTGGTTGCT-3′ 
                   
               
               
                   
               
               
                 12 
                 3′-TCCCACTGTCTCTCTTCCC-5′-X- 
                 63.00 
               
               
                   
                 5′-CCCTTCTCTCTGTCACCCT-3′ 
                   
               
               
                   
               
               
                 13 
                 3′-CCCACTGTCTCTCTTCCCG-5′-X- 
                 71.30 
               
               
                   
                 5′-GCCCTTCTCTCTGTCACCC-3′ 
                   
               
               
                   
               
               
                 14 
                 3′-CCACTGTCTCTCTTCCCGT-5′-X- 
                 61.91 
               
               
                   
                 5′-TGCCCTTCTCTCTGTCACC-3′ 
                   
               
               
                   
               
               
                 15 
                 3′-ACGATCAGACCCAGGACCG-5′-X- 
                 53.22 
               
               
                   
                 5′-GCCAGGACCCAGACTAGCA-3′ 
                   
               
               
                   
               
               
                 16 
                 3′-TCAGACCCAGGACCGGCAG-5′-X- 
                 73.38 
               
               
                   
                 5′-GACGGCCAGGACCCAGACT-3′ 
                   
               
               
                   
               
               
                 17 
                 3′-GTGACTCCGGACTCCTACC-5′-X- 
                 53.02 
               
               
                   
                 5′-CCATCCTCAGGCCTCAGTG-3′ 
                   
               
               
                   
               
               
                 18 
                 3′-GACTCCGGACTCCTACCTG-5′-X- 
                 51.62 
               
               
                   
                 5′-GTCCATCCTCAGGCCTCAG-3′ 
                   
               
               
                   
               
               
                 19 
                 3′-CTCCGGACTCCTACCTGTG-5′-X- 
                 56.13 
               
               
                   
                 5′-GTGTCCATCCTCAGGCCTC-3′ 
                   
               
               
                   
               
               
                 20 
                 3′CCGGACTCCTACCTGTGAC-5′-X- 
                 46.22 
               
               
                   
                 5′-CAGTGTCCATCCTCAGGCC-3′ 
                   
               
               
                   
               
               
                 21 
                 3′-CCTCTTCGTCCGTCCCACG-5′-X- 
                 68.62 
               
               
                   
                 5′-GCACCCTGCCTGCTTCTCC-3′ 
                   
               
               
                   
               
               
                 22 
                 3′-TCTTCGTCCGTCCCACGTC-5′-X- 
                 73.88 
               
               
                   
                 5′-CTGCACCCTGCCTGCTTCT-3′ 
                   
               
               
                   
               
               
                 23 
                 3′-GGGTCCGTCGTCCACAGTG-5′-X- 
                 61.92 
               
               
                   
                 5′-GTGACACCTGCTGCCTGGG-3′ 
                   
               
               
                   
               
               
                 24 
                 3′-GGATGTCCCTCCCGGTCTA-5′-X- 
                 40.93 
               
               
                   
                 5′-ATCTGGCCCTCCCTGTAGG-3′ 
                   
               
               
                   
               
               
                 25 
                 3′-ATGTCCCTCCCGGTCTACG-5′-X- 
                 41.82 
               
               
                   
                 5′-GCATCTGGCCCTCCCTGTA-3′ 
                   
               
               
                   
               
               
                 26 
                 3′-GTCCCTCCCGGTCTACGTC-5′-X- 
                 57.94 
               
               
                   
                 5′-CTGCATCTGGCCCTCCCTG-3′ 
                   
               
               
                   
               
               
                 27 
                 3′-CCCTCCCGGTCTACGTCAG-5′-X- 
                 58.14 
               
               
                   
                 5′-GACTGCATCTGGCCCTCCC-3′ 
                   
               
               
                   
               
               
                 28 
                 3′-CTCCCGGTCTACGTCAGTG-5′-X- 
                 63.13 
               
               
                   
                 5′-GTGACTGCATCTGGCCCTC-3′ 
                   
               
               
                   
               
               
                 29 
                 3′-GGTTCTGACCCGTGTCCTC-5′-X- 
                 59.63 
               
               
                   
                 5′-CTCCTGTGCCCAGTCTTGG-3′ 
                   
               
               
                   
               
               
                 30 
                 3′-TCGAGGACCGACACCACCC-5′-X- 
                 77.64 
               
               
                   
                 5′-CCCACCACAGCCAGGAGCT-3′ 
                   
               
               
                   
               
               
                 31 
                 3′-CGAGGACCGACACCACCCG-5′-X- 
                 80.53 
               
               
                   
                 5′-GCCCACCACAGCCAGGAGC-3′ 
                   
               
               
                   
               
               
                 32 
                 3′-GGGTCCGTCGTGGAGTCCG-5′-X- 
                 62.62 
               
               
                   
                 5′-GCCTGAGGTGCTGCCTGGG-3′ 
                   
               
               
                   
               
               
                 33 
                 3′-CCGTCCCTTCGACTCCGTC-5′-X- 
                 73.27 
               
               
                   
                 5′-CTGCCTCAGCTTCCCTGCC-3′ 
                   
               
               
                   
               
               
                 34 
                 3′-CGTCCCTTCGACTCCGTCA-5′-X- 
                 78.22 
               
               
                   
                 5′-ACTGCCTCAGCTTCCCTGC-3′ 
                   
               
               
                   
               
               
                 35 
                 3′-CCCGTCCGTCTCGACCTCC-5′-X- 
                 60.58 
               
               
                   
                 5′-CCTCCAGCTCTGCCTGCCC-3′ 
                   
               
               
                   
               
               
                 36 
                 3′-CCGTCCGTCTCGACCTCCG-5′-X- 
                 54.52 
               
               
                   
                 5′-GCCTCCAGCTCTGCCTGCC-3′ 
                   
               
               
                   
               
               
                 37 
                 3′-CAGGGTTCCAGTCCTCCCG-5′-X- 
                 71.63 
               
               
                   
                 5′-GCCCTCCTGACCTTGGGAC-3′ 
                   
               
               
                   
               
               
                 38 
                 3′-GGGTTCCAGTCCTCCCGTC-5′-X- 
                 69.94 
               
               
                   
                 5′-CTGCCCTCCTGACCTTGGG-3′ 
                   
               
               
                   
               
               
                 39 
                 3′-GTTCCAGTCCTCCCGTCCC-5′-X- 
                 71.58 
               
               
                   
                 5′-CCCTGCCCTCCTGACCTTG-3′ 
                   
               
               
                   
               
               
                 40 
                 3′-GTCCCGGACCCACCCTTCC-5′-X- 
                 57.15 
               
               
                   
                 5′-CCTTCCCACCCAGGCCCTG-3′ 
                   
               
               
                   
               
               
                 41 
                 3′-CCCGGACCCACCCTTCCAT-5′-X- 
                 51.93 
               
               
                   
                 5′-TACCTTCCCACCCAGGCCC-3′ 
                   
               
               
                   
               
               
                 42 
                 3′-CGGACCCACCCTTCCATGT-5′-X- 
                 31.04 
               
               
                   
                 5′-TGTACCTTCCCACCCAGGC-3′ 
                   
               
               
                   
               
               
                 43 
                 3′GACCCACCCTTCCATGTCC-5′-X- 
                 44.89 
               
               
                   
                 5′-CCTGTACCTTCCCACCCAG-3′ 
                   
               
               
                   
               
               
                 44 
                 3′-GTCCCGGTGGTCGTAGGTC-5′-X- 
                 61.72 
               
               
                   
                 5′-CTGGATGCTGGTGGCCCTG-3′ 
                   
               
               
                   
               
               
                 45 
                 3′-TCCCGGTGGTCGTAGGTCC-5′-X- 
                 52.12 
               
               
                   
                 5′-CCTGGATGCTGGTGGCCCT-3′ 
                   
               
               
                   
               
               
                 46 
                 3′TCCGTGGACTCACCGACCC-5′-X- 
                 76.87 
               
               
                   
                 5′-CCCAGCCACTCAGGTGCCT-3′ 
                   
               
               
                   
               
               
                 47 
                 3′-CTCACCGACCCTGTTCCCT-5′-X- 
                 68.50 
               
               
                   
                 5′-TCCCTTGTCCCAGCCACTC-3′ 
                   
               
               
                   
               
               
                 48 
                 3′-CACCGACCCTGTTCCCTAG-5′-X- 
                 74.30 
               
               
                   
                 5′-GATCCCTTGTCCCAGCCAC-3′ 
                   
               
               
                   
               
               
                 49 
                 3′-GCCCTCGACCTGGACGAAC-5′-X- 
                 67.80 
               
               
                   
                 5′-CAAGCAGGTCCAGCTCCCG-3′ 
                   
               
               
                   
               
               
                 50 
                 3′-TGTCGTTGAAGTCCCCCTC-5′-X- 
                 76.40 
               
               
                   
                 5′-CTCCCCCTGAAGTTGCTGT-3′ 
                   
               
               
                   
               
               
                 51 
                 3′-TGCCACCACGCCTGATGTT-5′-X- 
                 84.40 
               
               
                   
                 5′-TTGTAGTCCGCACCACCGT-3′ 
                   
               
               
                   
               
               
                 52 
                 3′-TCCCTTGTGTCTCCAGTGG-5′-X- 
                 58.30 
               
               
                   
                 5′-GGTGACCTCTGTGTTCCCT-3′ 
                   
               
               
                   
               
               
                 53 
                 3′-ATCCCTCCGTCTCCGTCCG-5′-X- 
                 76.10 
               
               
                   
                 5′-GCCTGCCTCTGCCTCCCTA-3′ 
                   
               
               
                   
               
               
                 54 
                 3′-GACTTCCTTGTCCGACCCG-5′-X- 
                 70.30 
               
               
                   
                 5′-GCCCAGCCTGTTCCTTCAG-3′ 
               
               
                   
               
               
                 Where X is glycerol 
               
            
           
         
       
     
                                 TABLE 4B                           % KD               Luciferase               Screen           3GA #   (25 nM)                                                    55   72.55           56   16.18           57   68.59           58   82.08           59   64.04           60   61.19           61   55.65           62   29.88           63   44.00           64   73.27           65   69.04           66   76.39           67   67.30           68   84.30           69   61.65           70   59.28           71   60.44           72   49.61           73   65.21           74   52.34           75   82.43           76   68.25           77   83.97           78   82.25           79   67.84           80   41.54           81   80.09           82   53.95           83   74.05           84   2.78           85   53.89           86   53.70           87   34.15           88   77.07           89   23.27           90   41.99           91   41.36           92   60.45           93   58.99           94   74.51           95   10.33           96   9.46           97   42.36           98   27.05           99   24.30           100   10.54           101   85.55           102   60.69           103   63.04           104   59.83           105   57.80           106   71.35           107   74.39           108   74.04           109   80.27           110   89.98           111   86.33           112   88.35           113   84.67           114   57.13           115   56.03           116   77.36           117   72.63           118   74.24           119   79.93           120   86.42           121   57.13           122   49.63           123   65.62           124   72.63           125   96.00           126   71.45           127   −0.08           128   4.49           129   60.37           130   67.01           131   10.42           132   72.11           133   66.46           134   58.22           135   40.56           136   75.82           137   69.22           138   69.06           139   79.03           140   10.17           141   25.50           142   84.19           143   81.61           144   70.57           145   78.67           146   66.46           147   58.98           148   69.06           149   97.18           150   81.25           151   30.14           152   73.42           153   79.87           154   63.67           155   71.18           156   64.26           157   84.39           158   91.96           159   87.62           160   85.37           161   90.51           162   90.48           163   88.20           164   82.16           165   79.86           166   88.55           167   91.35           168   81.98           169   94.67           170   84.41           171   82.59           172   31.12           173   67.25           174   36.58           175   55.38           176   73.10           177   77.05           178   91.25           179   83.86           180   85.21           181   72.85           182   61.27           183   81.35           184   68.97           185   67.13           186   57.30           187   79.41           188   41.38           189   50.80           190   52.18           191   63.14           192   82.52           193   41.99           194   73.39           195   76.17           196   85.66           197   98.60           198   47.11           199   42.47           200   87.17           201   74.36           202   58.24           203   59.21           204   42.36           205   74.17           206   76.54           207   30.41           208   68.55           209   69.73           210   59.73           211   54.92           212   56.90           213   69.09           214   77.40           215   39.73           216   39.23           217   41.13           218   23.48           219   79.92           220   29.57           221   64.50           222   73.89           223   81.38           224   70.29           225   69.92           226   81.70           227   59.46           228   81.39           229   88.01           230   75.84           231   58.18           232   29.33           233   61.77           234   72.38           235   45.83           236   39.94           237   66.24           238   49.78           239   23.03           240   59.57           241   41.65           242   44.50           243   18.23           244   37.51           245   58.43           246   70.66           247   74.80           248   70.32           249   90.70           250   73.19           251   81.50           252   87.92           253   76.82           254   55.60           255   42.30           256   44.52           257   81.17           258   64.45           259   79.46           260   41.81           261   46.85           262   83.04           263   78.00           264   69.88           265   59.09           266   39.05           267   34.97           268   83.20           269   86.16           270   49.03           271   70.17           272   86.40           273   67.96           274   44.65           275   65.68           276   66.68           277   76.67           278   39.46           279   69.63           280   68.44           281   57.77           282   67.85           283   61.74           284   69.87           285   58.11           286   41.07           287   42.40           288   42.09*           289   61.77*           290   33.46*           291   49.08*           292   43.43*           293   40.08*           294   57.06*           295   87.34*           296   76.54*           297   36.96*           298   96.71*           299   70.53*           300   88.21*           301   76.86*           302   85.21*           303   74.25*           304   70.61*           305   83.52*           306   65.18*           307   84.36*           308   91.72           309   93.78           310   86.49           311   79.67           312   78.18           313   68.73           314   49.06           315   51.92           316   64.80           317   49.86           318   60.88           319   54.14           320   54.27           321   64.20           322   57.54           323   64.73           324   24.73           325   −3.86           326   58.29           327   85.58           328   38.27           329   54.35           330   37.69           331   42.71           332   77.86           333   34.95           334   29.20           335   41.76           336   55.25           337   56.23           338   44.34           339   42.26           340   33.54           341   32.88           342   46.91           343   25.39           344   53.54           345   68.08           346   65.26           347   70.49           348   33.62           349   78.29           350   87.30           351   92.56           352   82.30           353   62.64           354   84.10           355   72.48           356   87.25           357   68.93           358   77.23           359   74.70           360   43.71           361   86.31           362   52.57           363   38.62           364   64.49           365   66.70           366   77.24           367   89.81           368   77.82           369   62.31           370   80.21           371   58.76           372   71.34           373   65.23           374   65.58           375   78.67           376   67.01           377   32.15           378   49.07           379   53.07           380   58.24           381   72.09           382   63.90           383   68.54           384   15.69           385   25.43           386   40.49                        
For 3GA compounds numbers 55 through 386 listed in Table 4B, glycerol is the non-nucleotidic linker.
 
     Flow Cytometric Analysis 
     Whole blood samples with anticoagulant EDTA from mice in study were stained for 30 minutes in the dark at room temperature with the following labeled antibodies from BD Biosciences in the presence of mouse Fc blocker (Affymetrix eBioscience, 14-0161): rat anti-mouse CD3-Alexa Fluor 647 (557869), rat anti-mouse CD4-Alexa Fluor 647 (557681), rat anti-mouse CD8-Alexa Fluor 488 (557668) or the corresponding isotype controls. Red blood cells were lysed with freshly prepared 1×RBC lysis buffer (eBioscience, 00-4300) and washed with flow cytometry staining buffer (BD Biosciences, 554657). Resuspended cell suspensions in the flow cytometry staining buffer were run on BD Accuri C6 to acquire data and analyzed by FLOWJO (TreeStar). 
     IC50 Analysis 
     Hepa 1-6 cells are co-transfected with 3GA and target plasmid simultaneously using LIPOFECTAMINE® 2000 on day one (20,000 c/well). Concentration of 3GAs were ranging from 0.019 to 41.7 nM with a 3-fold increment. RLuc siRNA was used as the positive control and 3GA mu/hu universal control was used as the negative control. On day two (24 hours post-transfection), luminescence measurements for both reporter genes are taken separately: Firefly luciferase: expression serves as the normalizer for the assay; Renilla luciferase: substrate includes a “stop” reagent to quench luminescence from firefly. Separate luminescence measurements are taken to correspond to renilla-target transcript expression. Substrate includes DTT to lyse cells. IC50 of 3GAs was calculated using GraphPad Prism 6. Results are shown in Table 5. 
     
       
         
           
               
               
               
               
               
             
               
                 TABLE 5 
               
               
                   
               
               
                 3GA 
                   
                 Target 
                 GSO Sequence 
                 IC 50   
               
               
                 # 
                 target 
                 Site 
                 5′ to 3′ 
                 (nM) 
               
               
                   
               
             
            
               
                  75 
                 mIDO1 
                  138  
                 CTAGCCACAAGGACCCAGG 
                 33.1   
               
               
                   
               
               
                  81 
                 hIDO1 
                  172  
                 GCAGAGCAAAGCCCACTTC 
                  3.49  
               
               
                   
               
               
                  92 
                   
                 1239  
                 GCCTCCAGTTCCTTTGGCT 
                  1.53  
               
               
                   
               
               
                   3 
                 mPD1 
                  115  
                 GCCACCCTGATTGCCAGCT 
                 59.0   
               
               
                   
               
               
                  10 
                 hPD1 
                  108  
                 GCCAGCCCAGTTGTAGCAC 
                  3.87  
               
               
                   
               
               
                  33 
                   
                 1591  
                 CTGCCTCAGCTTCCCTGCC 
                  1.57  
               
               
                   
               
               
                  46 
                   
                 2024  
                 CCCAGCCACTCAGGTGCCT 
                  3.16  
               
               
                   
               
               
                  54 
                 mPD-L1 
                 3311  
                 GCCCAGCCTGTTCCTTCAG 
                 14.4   
               
               
                   
               
               
                  55 
                 hPD-L1 
                  571  
                 GGTAGCCCTCAGCCTGACA 
                  5.00  
               
               
                   
               
               
                  58 
                   
                 1080  
                 CCCACATTGCCTGCATCCC 
                  2.42  
               
               
                   
               
               
                  64 
                   
                 1855  
                 TCTGTTTGCTTCCTCAGCT 
                  2.51  
               
               
                   
               
               
                 158 
                 mTIM3 
                 1425  
                 ACTTATCACCCTCCTGCCT 
                  5.55  
               
               
                   
               
               
                 169 
                 hTIM3 
                   59  
                 CTGCCAGGTCTACAGTCAC 
                 13.8   
               
               
                   
               
               
                 180 
                   
                 1506  
                 CAGCACCCAGTTTTCCCTA 
                  6.10  
               
               
                   
               
               
                 183 
                   
                 1716  
                 ATCCCAGCCACTCAGGAGG 
                 32.7   
               
               
                   
               
               
                 110 
                 mLAG3 
                 1108  
                 GCTCCAGACCCAGAACCTT 
                  6.49  
               
               
                   
               
               
                 124 
                 hLAG3 
                 1356/ 
                 GACAGTGGCATTGAGCTGC 
                 11.9   
               
               
                   
                   
                 1369  
                   
                   
               
               
                   
               
               
                 122 
                   
                 1822/ 
                 GCTCCAGCTCCTCTATCTT 
                  9.10  
               
               
                   
                   
                 1841  
                   
                   
               
               
                   
               
               
                 143 
                   
                 1848  
                 GGTTCTTGCTCCAGCTCCT 
                  5.03  
               
               
                   
               
               
                 195 
                 mCTLA4 
                  563  
                 GTTGCCCATGCCCACAAAG 
                 19.6   
               
               
                   
               
               
                 225 
                 hCTLA4 
                 1822  
                 GCCTTCTTCTGTCCATGGC 
                  1.71  
               
               
                   
               
               
                 247 
                 mIDO2 
                 2748  
                 GGTGACTTCCAGGTCTGCA 
                  0.247 
               
               
                   
               
               
                 249 
                 hID02 
                  156  
                 GGTGTCCATTGCCTTCTGT 
                  2.73  
               
               
                   
               
               
                 259 
                   
                 1137  
                 AGTCACCACTTTCCTTGCT 
                  3.36  
               
               
                   
               
               
                 262 
                   
                 1363  
                 GGCTTCCCATGCTTTGCCT 
                  1.28  
               
               
                   
               
               
                 361 
                 mOX40L 
                 1069  
                 TGGACACCACCCTTTCCAT 
                  0.673 
               
               
                   
               
               
                 368 
                 hOX40L 
                  712  
                 TGGTCCGTGGTCGTACTTG 
                  0.553 
               
               
                   
               
               
                 370 
                   
                 1104  
                 CTCCTCGTTCCTCACTTCC 
                  5.01  
               
               
                   
               
            
           
         
       
     
     In Vivo Mouse Tumor Model 
     Colon tumor can be implanted in BALB/c mice by subcutaneous injection of 10 6  CT26.WT cells at right flank (Tumor 1) and 10 6  CT26.CL25 cells at left flank (Tumor 2) on day 0. Treatment can be initiated on day 6 or when tumor size reached to 70 to 80 mm 3  by intra-tumor injection of gene silencing compound according to the invention at various dosages (e.g., 2 mg/kg, 5 mg/kg, 12.5 mg/kg, or 25 mg/kg) on day 6, 10, 13, 16, 20, and 22. 
     Tumor growth can be monitored twice per week throughout the study period. The study can be terminated with blood, spleen and tumor tissues collected for further evaluation. T lymphocyte population in blood and spleen samples were detected and analyzed by flow cytometry. Spleen IFN-γ-producing cells were detected with ELISPOT assay after culture of spleen cells for 24 hours with tumor antigen beta-gal or AH1 peptide. Tumor tissues were analyzed for gene expression by RT-PCR. 
     EQUIVALENTS 
     Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific substances and procedures described herein. For example, antisense oligonucleotides that overlap with the oligonucleotides may be used. Such equivalents are considered to be within the scope of this invention, and are covered by the following claims.