MX2008004319A - Immunomodulatory compositions and uses therefor - Google Patents

Abstract

The poxvirus proteins designated A41L and 130L bind to three receptor-like protein tyrosine phosphatases (RPTP), leukocyte common antigen related protein (LAR), RPTPδ, and RPTP-Ïâ, that are present on the cell surface of immune cells. When a host is infected with the poxvirus, binding of A41L to cell surface proteins on the host cells results in suppression of the immune response. The present invention provides agents such as antibodies, and antigen-binding fragments thereof, small molecules, aptamers, small interfering RNAs, and peptide-IgFc fusion polypeptides that interact with one or more of LAR, RPTP-δ, and RPTP-Ïâexpressed by immune cells or interact with a polynucleotide encoding the RPTP. Also provided are RPTP Ig domain oligomers and Fc fusion polypeptides. Such agents are useful for treating an immunological disorder in a subject according to the methods described herein.

Description

IMMUNOMODULATOR COMPOSITIONS AND USES FOR THE SAME DECLARATION CONCERNING LIST OF SEQUENCES PROVIDED ON CD-ROM The sequence listing associated with this application is provided on CD-ROM instead of hard copy, and is thus incorporated by reference into this specification. Three CD-ROMs are provided, which contain identical copies of the sequence listing: CD-ROM No. 1 is marked as COPY 1, contains the file seq_930118_401.app.txt which is 0.76 MB and created on September 29, 2006; CD-ROM No. 2 is marked as COPY 2, it contains the file seq_930118_401.app.txt which is 0.76 MB and created on September 29, 2006; CD-ROM No. 3 is marked as CRF (computer readable form), it contains the file seq_930118 401. app.txt which is 0.76 MB and created on September 29, 2006.

CROSS REFERENCE TO RELATED REQUESTS This application claims the benefit of the provisional application for E.U.A. No. 60/721, 876 filed on September 29, 2005; provisional application of E.U.A. No. 60 / 784,710 filed on March 22, 2006; and provisional application of E.U.A. No. 60/801, 992 filed May 19, 2006, which are hereby incorporated by reference in their entirety.

FIELD OF THE INVENTION The present invention provides agents that affect the function of one or more of three receptor-like protein tyrosine phosphatases (PTWRs), leukocyte-common antigen-related protein (LAR), PDTP-d, and RPTP-s, present on the cell surface of immune cells, in the same manner or similar as poxvirus proteins, such as A41 L and 130L. Said agents are useful for altering the immune response of an immune cell and for treating immune disorders in a subject.

DESCRIPTION OF THE RELATED TECHNIQUE The poxviruses form a group of double-stranded DNA viruses that replicate in the cytoplasm of a cell and have adapted to replicate in numerous different hosts. An adaptive mechanism of many poxviruses involves the acquisition of host genes that allow viruses to evade the host's immune system and / or facilitate viral replication (Bugert and Darai, Virus Genes 21: 111 (2000); Alcami et al, Semin. Virol., 8: 419 (1998), McFadden and Barry, Semin. Virol. 8: 429 (1998)). This process is facilitated by the relatively large size and complexity of the poxvirus genome. Vaccinia virus, a prototype poxvirus widely used as a smallpox vaccine, has a genome of approximately 190 kilobases, which could potentially code for more than 200 proteins (Goebel et al., Virology 179: 247 (1990)). Even though the entire vaccinia virus genome has been sequenced, the function of many of the potential open reading frames (ORFs), and the existence of polypeptides encoded by them, remain unknown. Certain poxvirus polypeptides contribute to the virulence of the virus. An ORF designated A41 L is present in several different poxviruses, including Cowpox virus (CPV), vaccinia virus (Copenhagen, Ankara, Tian Tan and WR strains) and variola virus (including the Harvey, India-1967 and Garcia strains). -1966). The A41 L gene encodes a glycoprotein (here called A41 L polypeptide) which is a viral virulence factor, which is secreted by cells infected by a poxvirus (see, e.g., U.S. Patent No. 6,852,486; International Patent WO 98/37217; Ng et al., J. Gen. Virol. 82: 2095-105 (2001)). A41 L acts, at least in part, on a host infected with a poxvirus to suppress a specific immune response to the virus. The identification of additional viral virulence factors and the identification of cellular polypeptides that are expressed by immune cells and that interact with A41L would be useful and beneficial in treating immune disorders, such as, for example, inflammatory diseases and autoimmune diseases, including multiple sclerosis. , rheumatoid arthritis, and systemic lupus erythematosus (SLE). There is a need to identify and develop compositions that can be used for the treatment and prophylaxis of said immunological diseases and disorders.

BRIEF DESCRIPTION OF THE INVENTION The various embodiments described herein relate to compositions and methods for preventing and treating immunological diseases and disorders. In one embodiment, an isolated antibody, or antigen-binding fragment thereof, is provided, (a) that specifically binds to at least two receptor-like protein tyrosine phosphatase (PTNP) polypeptides selected from (i) a protein related to leukocyte common antigen (LAR); (ii) RPTP-s; and (iii) RPTP-d; and (b) that competitively inhibits the binding of a poxvirus polypeptide to at least two RPTP polypeptides. In another embodiment, an isolated antibody, or antigen-binding fragment thereof, specifically binds to at least one receptor-like protein tyrosine phosphatase (PTTR) present on the cell surface of an immune cell, wherein at least one RPTP is RPTP-s or RPTP-d, and wherein the binding of the antibody, or antigen-binding fragment thereof, to the PTTP that is present on the cell surface of the immune cell suppresses the immune response of the immune cell. In a specific embodiment, the antibody is a polyclonal antibody or a monoclonal antibody. In certain other specific embodiments, the antigen binding fragment is selected from F (ab ') 2, Fab', Fab, Fd, Fv, and single chain Fv (scFv). In another embodiment, the poxvirus polypeptide is either A41 L or Yaba 130L-like disease virus. In addition, a composition comprising any of the antibodies, or antigen-binding fragments thereof, and a pharmaceutically suitable excipient is provided herein. In another embodiment, a method for suppressing an immune response in a subject comprising administering the composition to the subject is also provided. In yet another embodiment, it is a method of treating an immunological disease or disorder in a subject comprising administering the composition to the subject. In another embodiment, a manufacturing method is provided to produce the composition. Also provided here is a bispecific antibody comprising (a) a first antigen-binding portion that is capable of specifically binding to a receptor-like protein tyrosine phosphatase (PRTP), wherein the PTTP is selected from (i) protein related to leukocyte common antigen (LAR); (ii) RPTP-s; and (iii) RPTP-d; and (b) a second antigen-binding portion that is capable of specifically binding to an RPTP, wherein the PTTP is selected from (i) leukocyte-common antigen-related protein (LAR); (ii) RPTP-s; and (iii) RPTP-d, wherein the first antigen-binding portion and the second antigen-binding portion are different, and wherein the bispecific antibody suppresses the immune response of an immune cell. A composition comprising the bispecific antibody and a pharmaceutically suitable excipient is also provided. In another embodiment, a method for suppressing an immune response in a subject comprising administering the composition to the subject is also provided. In yet another embodiment, it is a method of treating an immunological disease or disorder in a subject comprising administering the composition to the subject. In another embodiment, a manufacturing method for producing the bispecific antibody is also provided. In another embodiment, a fusion polypeptide comprising (a) a polypeptide of immunoglobulin-like domain 2 of a first receptor-like protein tyrosine phosphatase (PTTP); (b) a polypeptide of immunoglobulin-like domain 3 of a second PTPM; and (c) an immunoglobulin or mutein Fe polypeptide thereof, wherein each of the first PTPN and the second PTPR is selected from (i) leukocyte-common antigen-related protein (LAR); (ii) RPTP-s; and (iii) RPTP-d, and wherein the first and second PSTNs are the same or different. In a particular embodiment, the first PSTN and the second PSTN are the same. In another specific modality, the first RPTP is RPTP-s and the second RPTP is RPTP-d, and wherein the fusion polypeptide further comprises a polypeptide domain-like immunoglobulin 1 of RPTP-s. In still another embodiment, the first PTPM is PTPM-d and the second PTPM is PTPM-d, wherein the fusion polypeptide further comprises a polypeptide of immunoglobulin 1-like domain of PTPM-d. A composition comprising the fusion polypeptide and a pharmaceutically suitable excipient is also provided. In another embodiment, a method for suppressing an immune response in a subject comprising administering the composition to the subject is also provided. In yet another embodiment, it is a method of treating an immunological disease or disorder in a subject comprising administering the composition to the subject. In another embodiment, a manufacturing method is provided to produce the fusion polypeptide. Also provided herein is a composition comprising (a) at least one immunoglobulin-like domain-like polypeptide of a first receptor-like tyrosine phosphatase protein (PTWR) and (b) at least one immunoglobulin-like domain-like polypeptide. a second PSTN, wherein the first and second PSTNs are the same or different and are selected from (i) protein related to leukocyte common antigen (LAR); (ii) RPTP-s; and (iii) RPTP-d. In a specific embodiment, the first PSTN and the second PSTN are the same, and in another specific mode, the first PSTN and the second PSTN are different. In a specific embodiment, the first PTPM is PTPP-s and the second PTPM is PTPP-s, and the composition further comprises a polypeptide of immunoglobulin 1-like domain of PTPP-s. In another specific modality, the first RPTP is RPTP-d and the second RPTP is RPTP-d, and the composition further comprises a polypeptide domain-like immunoglobulin 1 of RPTP-d. Also provided is a composition comprising a polypeptide dimer wherein the dimer comprises (a) a first monomer comprising a polypeptide of immunoglobulin-like domain 2 and an immunoglobulin-like domain 3 polypeptide of a first receptor-like protein tyrosine phosphatase (RPTP); and (b) a second monomer comprising a polypeptide of immunoglobulin-like domain 2 and an immunoglobulin-like domain polypeptide 3 of a second PTPM, wherein the first and second PTPM are the same or different and are selected from (i) protein related to leukocyte common antigen (LAR); (ii) RPTP-s; and (iii) RPTP-d. In a particular embodiment, the first PWTP and the second PWTP are different. In another particular embodiment, the first PWTP and the second PWTP are the same. In a specific embodiment, the first monomer further comprises a domain similar to immunoglobulin 1 of the first PTPM, and the second monomer further comprises a domain similar to immunoglobulin 1 of the second PTPM. In another specific embodiment, the first monomer is fused to an immunoglobulin Fe polypeptide, and the second monomer is fused to an immunoglobulin Fe polypeptide. In other specific embodiments, each of the compositions described herein further comprises a pharmaceutically suitable excipient. In another embodiment, a method for suppressing an immune response in a subject comprising administering the composition to the subject is also provided. In yet another embodiment, it is a method of treating an immunological disease or disorder in a subject comprising administering the composition to the subject. In another embodiment, a manufacturing method for producing the composition is provided. In another embodiment, a fusion polypeptide comprising a poxvirus polypeptide fused to a mutein Fe polypeptide is provided, wherein the mutein Fe polypeptide comprises the amino acid sequence of the Fe portion of a human IgG1 immunoglobulin comprising at least a mutation, wherein at least one mutation is a substitution or deletion of a cysteine residue in the hinge region, wherein the substituted or deleted cysteine residue is the cysteine residue most proximal to the amino terminus of the region of hinge of a Fe portion of wild-type human IgG1 immunoglobulin, and wherein the poxvirus polypeptide is capable of binding to a receptor-like protein tyrosine phosphatase (PTWP) selected from (i) leukocyte-common antigen-related protein (LAR); (ii) RPTP-s; and (iii) RPTP-d. In a particular embodiment, the mutein Fe polypeptide comprises at least one second mutation, wherein at least one second mutation is a substitution of at least one amino acid in the CH2 domain such that the capacity of the fusion polypeptide for binding to an IgG Fe receptor is reduced. Also provided herein is a composition comprising any of the fusion polypeptides and further comprising a pharmaceutically suitable excipient. Also provided are compositions comprising (a) the antibody or antigen-binding fragment thereof, described above, and (b) a pharmaceutically suitable excipient. In another embodiment, a method for suppressing an immune response in a subject comprising administering the composition to the subject is also provided. In yet another embodiment, it is a method of treating an immunological disease or disorder in a subject comprising administering the composition to the subject. In another embodiment, a manufacturing method for producing the fusion polypeptide is provided. In one embodiment, an isolated antibody, or antigen-binding fragment thereof, is provided that specifically binds to at least two receptor-like tyrosine phosphatase protein (TTPP) polypeptides selected from protein related to leukocyte-common antigen (LAR ); (ii) RPTP-s; and (iii) RPTP-d; and (b) competitively inhibits the binding of A41 L to at least two RPTP polypeptides. In particular embodiments, the antibody specifically binds to LAR and RPTP-s; the antibody binds specifically to LAR and RPTP-d; or the antibody binds specifically to RPTP-s and RPTP-d. In another particular embodiment, the antibody specifically binds to LAR, RPTP-s, and RPTP-d. In another embodiment, an isolated antibody, or antigen-binding fragment thereof, is provided that specifically binds either to a sigma receptor-like protein tyrosine phosphatase (RPTP-s) or receptor-delta-like protein tyrosine phosphatase ( RPTP-d) or both, wherein the binding of the antibody, or antigen-binding fragment thereof, inhibits the binding of A41L to RPTP-s, PTTP-d, or both. In yet another embodiment, an isolated antibody, or antigen-binding fragment thereof, is provided, which (a) specifically binds to at least two receptor-like protein tyrosine phosphatase (PTNP) polypeptides selected from common antigen-related protein. to leukocytes (LAR), (n) RPTP-s, and (m) RPTP-d, and (b) suppresses the immune response of an immune cell that expresses at least one of the RPTP polypeptides. In particular embodiments, the antibody specifically binds to LAR and RPTP-s, the antibody specifically binds to LAR and RPTP-d, or the antibody binds specifically to RPTP-s and RPTP-d. In another particular embodiment, the antibody specifically binds to LAR, RPTP -s, and RPTP-d In yet another embodiment, an isolated antibody, or antigen-binding fragment thereof, (a) specifically binds to at least two receptor-like protein tyrosine phosphatases (PTNP) polypeptides selected from ( i) protein related to antigen common to leukocytes (LAR), (n) RPTP-s, and (ni) RPTP-d, and (b) inhibits the binding of A41 L to an immune cell that expresses at least one of LAR, (II) PTPN -s, and (ni) RPTP-d In particular embodiments, the antibody specifically binds to LAR and RPTP-s, the antibody specifically binds to LAR and RPTP-d, or the antibody binds specifically to RPTP-s and PTPN -d In another particular embodiment, the antibody specifically binds to LAR, RPTP-s, and RPTP-d. In one embodiment, an isolated antibody, or antigen-binding fragment thereof, that specifically binds a protein tyrosine phosphatase is provided. similar to receptor-sigma (RPTP-s), wherein the binding of the antibody, or antigen-binding fragment thereof, to RPTP-s that is present on the cell surface of an immune cell suppresses the immune response of the immune cell In another embodiment, an isolated antibody, or antigen-binding fragment thereof, is provided which specifically binds a pro receptor-delta-like tyrosine phosphatase (RPTP-d) thein, wherein the binding of the antibody, or antigen-binding fragment thereof, to RPTP-d that is present on the cell surface of an immune cell suppresses the immune response of the immune cell that expresses RPTP-d. In yet another embodiment, an isolated antibody, or antigen-binding fragment thereof, that specifically binds either to a sigma-receptor-like protein tyrosine phosphatase (RPTP-s) or receptor-delta-like protein tyrosine phosphatase is provided. (RPTP-d) or both RPTP-s and an RPTP-d, where the antibody binding, or antigen-binding fragment thereof, either with RPTP-s or RPTP-d or both an RPTP-s or an RPTP-d that are present on the cell surface of an immune cell suppresses the immune response of the immune cell. In certain embodiments, with respect to any of the antibodies described above, the antibody is a polyclonal antibody. In other embodiments, the antibody is a monoclonal antibody. In another specific embodiment, the monoclonal antibody is selected from a mouse monoclonal antibody, a human monoclonal antibody, a rat monoclonal antibody, and a hamster monoclonal antibody. A host cell expressing the monoclonal antibody is also provided herein; and in certain specific embodiments, the host cell is a hybridoma cell. In another particular embodiment, the antibody is a humanized antibody or a chimeric antibody. In another embodiment, a host cell expressing the humanized antibody or a chimeric antibody is provided. In another particular embodiment, a composition is provided comprising any of the antibodies described above (or antigen-binding fragment thereof) and a pharmaceutically suitable carrier. In another embodiment, a manufacturing method is also provided for producing any of the aforementioned antibodies, or antigen-binding fragments thereof. In other specific embodiments, with respect to any of the antigen-binding fragments of any of the antibodies described above, the antigen-binding fragment is selected from F (ab ') 2, Fab', Fab, Fd, and Fv. In another specific embodiment, the antigen-binding fragment is of human, mouse, chicken or rabbit origin. In another additional specific embodiment, the antigen binding fragment is a single chain Fv (scFv). In another particular embodiment, a composition is provided comprising any of the antigen binding fragments of any of the antibodies described above and a pharmaceutically suitable carrier. In another embodiment, there is also provided an isolated antibody comprising an anti-idiotype antibody, or antigen-binding fragment thereof, that specifically binds to any of the aforementioned antibodies, or an antigen-binding fragment thereof. In certain embodiments, the anti-idiotype antibody is a polyclonal antibody. In other certain embodiments, the anti-idiotype antibody is a monoclonal antibody. A host cell expressing the anti-idiotype antibody is also provided herein. In certain specific embodiments, the host cell is a hybridoma cell. In another particular embodiment, a composition comprising the anti-idiotype antibody, or antigen-binding fragment thereof, and a pharmaceutically suitable carrier is provided. In one embodiment, a bispecific antibody is also provided comprising (a) a first antigen-binding portion that is capable of specifically binding to an RPTP, wherein the PTPR is selected from (i) leukocyte-related antigen-related protein ( LAR); (ii) RPTP-s; and (iii) RPTP-d; and (b) a second antigen-binding portion that is capable of specifically binding to an RPTP, wherein the PTTP is selected from (i) leukocyte-common antigen-related protein (LAR); (ii) RPTP-s; and (iii) RPTP-d, wherein the bispecific antibody suppresses the immune response of an immune cell. In a specific embodiment, the first antigen-binding portion is capable of specifically binding to LAR and the second antigen-binding portion is capable of specifically binding to RPTP-s. In another specific embodiment, the first antigen binding portion is capable of specifically binding to LAR and the second antigen binding portion is capable of specifically binding to RPTP-d. In yet another specific embodiment, the first antigen-binding portion is capable of specifically binding to RPTP-s and the second antigen-binding portion is capable of specifically binding to RPTP-d. In another particular embodiment, a composition comprising the bispecific antibody and a pharmaceutically suitable carrier is provided. In another embodiment, a fusion polypeptide comprising at least one immunoglobulin-like domain of a PTNP selected from (i) leukocyte-common antigen-related protein (LAR) is provided; (ii) RPTP-s; and (iii) RPTP-d, fused to at least one immunoglobulin constant region domain. In a specific embodiment, at least one immunoglobulin-like domain of the PTPN is fused to an immunoglobulin Fe polypeptide. In a particular embodiment, the Fe polypeptide is derived from a human IgG1 immunoglobulin. In another specific modality, the RPTP is LAR and the fusion polypeptide suppresses the immune response of an immune cell. In a specific embodiment, the Fe polypeptide is a mutein Fe polypeptide comprising a substitution or deletion of a cysteine residue in the hinge region, and wherein the substituted or deleted cysteine residue is the cysteine residue most proximal to the amino terminal of the hinge region of the Fe portion of a wild-type IgG1 immunoglobulin. In yet another specific embodiment, the Fe polypeptide is a mutein Fe polypeptide comprising at least one substitution of an amino acid residue in the CH2 domain of the mutein Fe polypeptide, such that the ability of the fusion polypeptide to bind to an Fe IgG receptor is reduced. In another additional specific embodiment, the mutein Fe polypeptide further comprises a substitution or deletion of a cysteine residue in the hinge region, wherein the substituted or deleted cysteine residue is the cysteine residue most proximal to the amino terminus of the cysteine. hinge region of the Fe portion of a wild-type IgG1 immunoglobulin. In yet another specific modality, the PTTP is RPTP-s, and the fusion polypeptide suppresses the immune response of an immune cell. In another specific embodiment, the RPTP is RPTP-d, and wherein the fusion polypeptide suppresses the immune response of an immune cell. In another particular embodiment, a composition comprising the fusion polypeptide and a pharmaceutically suitable carrier is provided. In one embodiment, an agent that specifically binds to at least two receptor-like tyrosine phosphatase protein (TTPP) polypeptides selected from protein related to leukocyte common antigen (LAR) is provided.; (ii) RPTP-s; and (ii) RPTP-d; and (b) alters the binding of A41 L to either LAR, RPTP-s, and RPTP-d. In a certain embodiment, the agent alters the binding of A41 L to any of LAR, RPTP-s, and RPTP-d present on the cell surface of an immune cell. In other specific embodiments, the agent is selected from an antibody or antigen-binding fragment thereof; a small molecule; an aptamer; and a peptide-lgFc fusion polypeptide. In another particular embodiment, a composition comprising the agent and a pharmaceutically suitable carrier is provided. In one embodiment, there is also provided an agent that specifically alters the expression of at least two receptor-like tyrosine phosphatase protein (TTPP) polypeptides selected from leukocyte-common antigen-related protein (LAR), (n) RPTP-s, and (ni) RPTP-d In a particular embodiment, the agent comprises an antisense polynucleotide, and in another particular embodiment, the agent comprises a short interfering RNA (siRNA). In another particular embodiment, a composition comprising the agent and a pharmaceutically suitable carrier In another embodiment, a method is provided for identifying an agent that suppresses the immune response of an immune cell comprising (a) contacting (1) a candidate agent, (2) an immune cell that expresses at minus one protein tyrosine phosphatase in the form of receptor peptide (PTWP) selected from (i) protein related to antigen common to leukocytes (LAR), (n) RPTP-s, and (ni) RPTP-d, and (3) A41 L, under conditions and for a time sufficient to allow the interaction between at least one PO-PTP peptide and A41 L, and (b) determine a binding level of A41 L to the immune cell in the presence of the agent candidate and compare a binding level of A41L to the immune cell in the absence of the candidate agent, wherein a decrease in the level of A41L to the immune cell in the presence of the candidate agent indicates that the candidate agent suppresses the immune response of the immune cell. In a specific embodiment, the immune cell expresses at least two RPTP polypeptides selected from (i) LAR, (n) RPTP-s, and (ni) RPTP-d A method is also provided here to identify an agent that inhibits binding of A41 L to at least two receptor-like protein tyrosine phosphatase (PRTP) polypeptides comprising: (a) contacting (1) a candidate agent; (2) a biological sample comprising at least two RPTP polypeptides selected from (i) protein related to leukocyte common antigen (LAR); (ii) RPTP-s; and (iii) RPTP-d; and (3) A41 L, under conditions and for a time sufficient to allow interaction between at least two polypeptides of RPTP and A41 L; and (b) determining a binding level of A41 L to at least two RPTP polypeptides in the presence of the candidate agent and comparing a binding level of A41 L to at least two RPTP polypeptides in the absence of the candidate agent, wherein a decrease in the level of A41L to at least two RPTP polypeptides in the presence of the candidate agent indicates that the candidate agent inhibits the binding of A41L to at least two RPTP polypeptides. In another embodiment, a method is provided for suppressing an immune response in a subject comprising administering to a composition comprising a pharmaceutically suitable carrier and an antibody, or antigen-binding fragment thereof, that specifically binds to a similar protein tyrosine phosphatase. to receiver (RPTP) -s. In one embodiment, a method is provided for suppressing an immune response in a subject comprising administering a composition comprising a pharmaceutically suitable carrier and an antibody, or antigen-binding fragment thereof, that specifically binds a protein tyrosine phosphatase similar to receiver (RPTP) -d. In another embodiment, a method is provided for suppressing an immune response in a subject comprising administering a composition comprising a pharmaceutically suitable carrier and an antibody, or antigen-binding fragment thereof, which (a) binds specifically to minus two receptor-like protein tyrosine phosphatase (PTNP) polypeptides selected from (i) leukocyte-common antigen-related protein (LAR); (ii) RPTP-s; and (iii) RPTP-d. In one embodiment, a method is provided for treating an immune disease or disorder in a subject comprising administering to the subject a pharmaceutically suitable carrier and an agent that either (a) alters a biological activity of at least one protein tyrosine phosphatase in the form of receptor polypeptide (RPTP), wherein the RPTP is either RPTP-s or RPTP-d; or (b) alters a biological activity of at least two RPTP polypeptides selected from protein related to leukocyte common antigen (LAR); (ii) RPTP-s; and (iii) RPTP-d. In a specific embodiment, the immunological disease or disorder is an autoimmune disease or an inflammatory disease. In a certain modality, the autoimmune or inflammatory disease is multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, graft versus host disease, sepsis, diabetes, psoriasis, atherosclerosis, Sjogren's syndrome, progressive systemic sclerosis, scleroderma, acute coronary syndrome, reperfusion ischemic, Crohn's disease, endometriosis, glomerulonephritis, myasthenia gravis, idiopathic pulmonary fibrosis, asthma, acute respiratory distress syndrome (ARDS), vasculitis, or inflammatory autoimmune myositis. In another particular embodiment, the agent is selected from an antibody, or antigen-binding fragment thereof; a small molecule; an aptamer; an antisense polynucleotide; a small interfering RNA (siRNA); and a peptide-lgFc fusion polypeptide. In one embodiment, a method is provided for treating a disease or disorder associated with alteration of at least one of cell migration, cell proliferation, and cell differentiation in a subject comprising administering to the subject a pharmaceutically suitable carrier and an agent that is either (a) alters a biological activity of at least one receptor-like protein tyrosine phosphatase (PTWP) -or RPTP-d; or (b) alters a biological activity of at least two RPTP polypeptides selected from (i) leukocyte-common antigen related protein (LAR); (I) RPTP-s; and (iii) RPTP-d. In certain embodiments, the disease or disorder is an immunological disease or disorder, a cardiovascular disease or disorder, a metabolic disease or disorder, or a proliferative disease or disorder. In a particular embodiment, the immunological disease or disorder is an autoimmune disease or an inflammatory disease. In another modality, the immunological disease or disorder is multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, graft versus host disease, sepsis, diabetes, psoriasis, atherosclerosis, Sjogren's syndrome, progressive systemic sclerosis, scleroderma, acute coronary syndrome, reperfusion. ischemic, Crohn's disease, endometriosis, glomerulonephritis, myasthenia gravis, idiopathic pulmonary fibrosis, asthma, acute respiratory distress syndrome (ARDS), vasculitis, or inflammatory autoimmune myositis. In another particular embodiment, the cardiovascular disease or disorder is atherosclerosis, endocarditis, hypertension, or peripheral ischemic disease. In another particular embodiment, the agent is selected from an antibody, or antigen-binding fragment thereof; a small molecule; an aptamer; an antisense polynucleotide; a small interfering RNA (siRNA); and a peptide-lgFc fusion polypeptide. In another embodiment, a method of manufacturing is provided for producing an agent that suppresses the immune response of an immune cell, comprising (a) identifying an agent that suppresses the immune response of an immune cell, wherein the step of identifying comprises ( 1) contacting (i) a candidate agent; (ii) an immune cell that expresses at least one tyrosine phosphatase protein in the form of a receptor polypeptide (PTNP) selected from a protein related to leukocyte common antigen (LAR); RPTP-s; and RPTP-d; and (iii) A41 L, under conditions and for a sufficient time to allow interaction between at least one RPTP polypeptide and A41 L; and (2) determining a level of binding of A41L to the immune cell in the presence of the candidate agent and comparing a binding level of A41L to the immune cell in the absence of the candidate agent, wherein a decrease in the binding level of A41. The immune cell in the presence of the candidate agent indicates that the candidate agent suppresses the immune response of the immune cell; and (b) producing the agent identified in step (a). In certain embodiments, the agent is selected from an antibody, or antigen-binding fragment thereof; a small molecule; an aptamer; an antisense polynucleotide; a small interfering RNA (siRNA); and a peptide-lgFc fusion polypeptide. In another certain embodiment, the agent is an antibody, or antigen-binding fragment thereof. In one embodiment, a fusion polypeptide comprises an A41 L polypeptide fused in frame with a mutein Fe polypeptide, wherein the mutein Fe polypeptide comprises the amino acid sequence of the Fe portion of a human IgG1 immunoglobulin, wherein the polypeptide Mutein Fe differs from the Fe portion of a wild-type human IgG1 immunoglobulin because it comprises at least two mutations, wherein a first mutation in the mutein Fe polypeptide comprises substitution of at least one amino acid in the CH2 domain in such a way that the ability of the fusion polypeptide to bind to an IgG Fe receptor is reduced, and wherein a second mutation in the mutein Fe polypeptide is a substitution or deletion of a cysteine residue in the hinge region, wherein the cysteine residue is the cysteine residue most proximal to the amino terminus of the hinge region of a wild type human IgG1 immunoglobulin. In a specific embodiment, the mutein Fe polypeptide comprises substitution of at least two amino acids in the CH2 domain. In another specific embodiment, the mutein Fe polypeptide comprises substitution of at least three amino acids in the CH2 domain. In yet another specific embodiment, the amino acid that is substituted in the CH2 domain is located in a position corresponding to the EU 235 position number in the CH2 domain of a human IgG immunoglobulin. In another additional specific embodiment, a first amino acid that is substituted is located at a position corresponding to EU 234 position number in the CH2 domain of a human IgG immunoglobulin and a second amino acid that is substituted is located at a position corresponding to number of position EU 235 in the CH2 domain of a human IgG immunoglobulin. In yet another specific embodiment, a first amino acid that is substituted is located in a position corresponding to EU 234 position number in the CH2 domain of a human IgG immunoglobulin, a second amino acid that is substituted is located in a position corresponding to number of EU position 235 in the CH2 domain of a human IgG immunoglobulin, and a third amino acid which is substituted is located at a position corresponding to EU 237 position number in the CH2 domain of a human IgG immunoglobulin. In a certain specific embodiment, the leucine residue located in a position corresponding to EU 235 position number in the CH2 domain of a human IgG immunoglobulin is substituted with a glutamic acid residue or an alanine residue. In another particular embodiment, the leucine residue located in a position corresponding to EU 234 position number in the CH2 domain of a human IgG immunoglobulin is substituted with an alanine residue. In another additional specific embodiment, the glycine residue located in a position corresponding to EU 237 position number in the CH2 domain of a human IgG immunoglobulin is substituted with an alanine residue. In another particular embodiment, the mutein Fe polypeptide further comprises substitution or deletion of at least one non-cysteine residue in the hinge region. In another particular modality, the mutein Fe polypeptide comprises a deletion of at least two amino acid residues in the hinge region, wherein at least two amino acid residues include a cysteine residue and the adjacent C-terminal residue, wherein the residue of cysteine is the cysteine residue most proximal to the amino terminus of the hinge region of a wild-type human IgG1 immunoglobulin. In a specific embodiment, the fusion polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 73. Also provided herein is a method for suppressing an immune response in a subject comprising administering a composition comprising a pharmaceutically suitable carrier and the fusion polypeptide comprising an A41 L polypeptide fused in frame with a mutein Fe polypeptide described above. In a particular embodiment, the fusion polypeptide either (a) alters a biological activity of at least one of receptor-like protein tyrosine phosphatase (RPTP) -s and RPTP-d; or (b) alters a biological activity of at least two RPTP polypeptides selected from (i) leukocyte-common antigen related protein (LAR); (ii) RPTP-s; and (iii) RPTP-d. In another embodiment, a method is provided for treating an immunological disease or disorder in a subject comprising administering to the subject a pharmaceutically suitable carrier and the fusion polypeptide comprising an A41 L polypeptide fused in frame with a previously described mutein Fe polypeptide. . In a specific embodiment, the fusion polypeptide either (a) alters a biological activity of at least one of receptor-like protein tyrosine phosphatase (RPTP) -s and RPTP-d; or (b) alters a biological activity of at least two RPTP polypeptides selected from (i) leukocyte-common antigen related protein (LAR); (ii) RPTP-s; and (iii) RPTP-d. In another particular embodiment, the immunological disease or disorder is an autoimmune disease or an inflammatory disease, wherein in certain embodiments, the autoimmune or inflammatory disease is multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, graft versus host disease, sepsis, diabetes , psoriasis, atherosclerosis, Sjogren's syndrome, progressive systemic sclerosis, scleroderma, acute coronary syndrome, ischemic reperfusion, Crohn's disease, endometriosis, glomerulonephritis, myasthenia gravis, idiopathic pulmonary fibrosis, asthma, acute respiratory distress syndrome (ARDS), vasculitis, or inflammatory autoimmune myositis. In one embodiment, a method is provided for treating a disease or disorder associated with alteration of at least one of cell migration, cell proliferation, and cell differentiation in a subject comprising administering to the subject a pharmaceutically suitable carrier and the fusion polypeptide that comprises an A41L polypeptide fused in frame with a mutein Fe polypeptide described above. In a particular embodiment, the fusion polypeptide either (a) alters a biological activity of at least one of receptor-like tyrosine phosphatase protein (PTPN) -s or PTPR-d; or (b) alters a biological activity of at least two RPTP polypeptides selected from (i) leukocyte-common antigen related protein (LAR); (ii) RPTP-s; and (iii) RPTP-d. In another embodiment, the disease or disorder is an immunological disease or disorder, a cardiovascular disease or disorder, a metabolic disease or disorder, or a proliferative disease or disorder. In a specific embodiment, the immunological disease or disorder is an autoimmune disease or an inflammatory disease. In another specific modality, the immunological disease or disorder is multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, graft versus host disease, sepsis, diabetes, psoriasis, atherosclerosis, Sjogren's syndrome, progressive systemic sclerosis, scleroderma, acute coronary syndrome, reperfusion ischemic, Crohn's disease, endometriosis, glomerulonephritis, myasthenia gravis, idiopathic pulmonary fibrosis, asthma, acute respiratory distress syndrome (ARDS), vasculitis, or inflammatory autoimmune myositis. In yet another specific embodiment, the cardiovascular disease or disorder is atherosclerosis, endocarditis, hypertension, or peripheral ischemic disease. In another embodiment, a manufacturing method is provided for producing the fusion polypeptide comprising an A41 L polypeptide fused in frame with a previously described mutein Fe polypeptide. In another embodiment, an isolated antibody, or antigen-binding fragment thereof, is provided which (a) specifically binds to at least one protein tyrosine phosphatase in the form of receptor polypeptide (PTWP) selected from (i) protein related to leukocyte common antigen (LAR); (ii) RPTP-s; and (iii) RPTP-d; and (b) competitively inhibits the binding of a 130L polypeptide to at least one RPTP polypeptide, wherein the amino acid sequence of the 130L polypeptide is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 85 or SEQ. ID NO: 150. In a particular embodiment, the 130L polypeptide specifically binds to at least two RPTP polypeptides selected from (i) LAR; (ii) RPTP-s; and (iii) RPTP-d, and in another particular embodiment, the 130L polypeptide specifically binds to (i) LAR; (ii) RPTP-s; and (iii) RPTP-d. In certain specific embodiments, the antibody, or antigen-binding fragment thereof, specifically binds to LAR and RPTP-s. In another specific embodiment, the antibody, or antigen-binding fragment thereof, specifically binds to LAR and RPTP-d. In yet another specific embodiment, the antibody, or antigen-binding fragment thereof, specifically binds to RPTP-s and RPTP-d. In another embodiment, the antibody or antigen-binding fragment alters the immune response of an immune cell that expresses at least one of the RPTP polypeptide. In a specific modality, the alteration of the immune response of the immune cell is to suppress the immune response of the immune cell.

In another embodiment, an isolated antibody, or antigen-binding fragment thereof, is provided, which (a) specifically binds to at least one tyrosine phosphatase protein in the form of a receptor polypeptide (RPTP) selected from (i) related protein. with leukocyte common antigen (LAR); (ii) RPTP-s; and (iii) RPTP-d; and (b) inhibits the binding of a 130L polypeptide to an immune cell that expresses at least one of (i) LAR; (ii) RPTP-s; and (iii) RPTP-d, wherein the amino acid sequence of the 130L polypeptide is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 85 or SEQ ID NO: 150. In a specific embodiment, the sequence of amino acids of polypeptide 130L (a) comprises the amino acid sequence set forth in SEQ ID NO: 85 or SEQ ID NO: 150; (b) is at least 95% identical to SEQ ID NO: 85 or SEQ ID NO: 150; (c) is at least 90% identical to SEQ ID NO: 85 or SEQ ID NO: 150; or (d) is at least 85% identical to SEQ ID NO: 85 or SEQ ID NO: 150. In certain specific embodiments, the antibody, or antigen-binding fragment thereof, specifically binds to LAR and RPTP-s . In another specific embodiment, the antibody, or antigen-binding fragment thereof, specifically binds to LAR and RPTP-d. In yet another specific embodiment, the antibody, or antigen-binding fragment thereof, specifically binds to RPTP-s and RPTP-d. In another specific embodiment, the antibody, or antigen-binding fragment thereof, specifically binds to LAR, RPTP-s, and RPTP-d. Here too an isolated antibody, or antigen-binding fragment thereof, is provided which binds specifically to either sigma-receptor-like protein tyrosine phosphatase (RPTP-s) or receptor-delta-like protein tyrosine phosphatase (RPTP-d). ) or both, wherein the antibody binding, or antigen-binding fragment thereof, alters the immune response of an immune cell that expresses to PTRA selected from (i) protein related to leukocyte-common antigen (LAR); (ii) RPTP-s; and (iii) RPTP-d. In certain modalities, the alteration of the immune response of the immune cell is to suppress the immune response of the immune cell. In certain particular embodiments, any of the antibodies described above and herein is a polyclonal antibody. In another particular embodiment, the antibody is a monoclonal antibody. In a certain embodiment, the monoclonal antibody is selected from a mouse monoclonal antibody, a human monoclonal antibody, a rat monoclonal antibody, and a hamster monoclonal antibody. Also provided herein is a host cell expressing the antibody, and in particular embodiments, the host cell is a hybridoma cell. In other embodiments, any of the antibodies described above and herein is a humanized antibody or a chimeric antibody. Also provided herein is a host cell that expresses the humanized antibody or chimeric antibody. In other particular embodiments, the antigen-binding fragment is selected from F (ab ') 2, Fab', Fab, Fd, and Fv. In a particular embodiment, the antigen-binding fragment is of human, mouse, chicken or rabbit origin. In another particular embodiment, the antigen binding fragment is a single chain Fv (scFv). An isolated antibody comprising an anti-idiotype antibody, or antigen-binding fragment thereof, that binds specifically to any of the antibodies described above and herein. In a particular embodiment, the anti-idiotype antibody is a polyclonal antibody. In another particular embodiment, the anti-idiotype antibody is a monoclonal antibody. In another embodiment, it is a composition comprising an anti-idiotype antibody, or antigen-binding fragment thereof, and a pharmaceutically suitable carrier. Also provided herein, in another embodiment, is a composition comprising any of the antibodies, or antigen-binding fragment thereof, and a pharmaceutically suitable carrier. Also provided herein is a manufacturing method for producing any of the antibodies, or antigen-binding fragment thereof, described above and herein. Also provided herein is an agent that (a) specifically binds to at least one protein tyrosine phosphatase in the form of receptor polypeptide (PTNP) selected from (i) protein related to leukocyte common antigen (LAR); (ii) RPTP-s; and (iii) RPTP-d; and (b) alters the binding of a 130L polypeptide to any of LAR, RPTP-s, and RPTP-d, wherein the amino acid sequence of the 130L polypeptide is at least 80% identical to the amino acid sequence set forth in either SEQ ID NO: 85 or SEQ ID NO: 150. In certain embodiments, the amino acid sequence of polypeptide 130L (a) comprises the amino acid sequence set forth in SEQ ID NO: 85 or SEQ ID NO: 150; (b) is at least 95% identical to SEQ ID NO: 85 or SEQ ID NO: 150; (c) is at least 90% identical to SEQ ID NO: 85 or SEQ ID NO: 150; or (d) is at least 85% identical to SEQ ID NO: 85 or SEQ ID NO: 150. In a specific embodiment, the agent specifically binds to at least two RPTP polypeptides selected from (i) LAR; (I) RPTP-s; and (iii) RPTP-d. In another specific embodiment, the agent alters the binding of the 130L polypeptide to an immune cell that expresses either LAR, RPTP-s, and RPTP-d. In a particular embodiment, the agent is selected from an antibody or antigen-binding fragment thereof; a small molecule; an aptamer; and a peptide-lgFc fusion polypeptide. Also provided herein is a composition comprising any of the agents described above and herein and a pharmaceutically suitable carrier. In another embodiment, a method is provided for identifying an agent that suppresses the immune response of an immune cell comprising: (a) contacting (1) a candidate agent; (2) an immune cell that expresses at least one receptor-like protein tyrosine phosphatase (PRTP) polypeptide selected from (i) leukocyte-common antigen-related protein (LAR); (ii) RPTP-s; and (iii) RPTP-d; and (3) a 130L polypeptide, wherein the amino acid sequence of the 130L polypeptide is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 85 or SEQ ID NO: 150, under conditions and for a sufficient time to allow interaction between at least one RPTP polypeptide and 130L polypeptide; and (b) determining a level of binding of the 130L polypeptide to the immune cell in the presence of the candidate agent and comparing a level of binding of the 130L polypeptide to the immune cell in the absence of the candidate agent, wherein a decrease in the level of the 130L polypeptide the immune cell in the presence of the candidate agent indicates that the candidate agent suppresses the immune response of the immune cell. In certain embodiments, the amino acid sequence of polypeptide 130L (a) comprises the amino acid sequence set forth in SEQ ID NO: 85 or SEQ ID NO: 150; (b) is at least 95% identical to SEQ ID NO: 85 or SEQ ID NO: 150; (c) is at least 90% identical to SEQ ID NO: 85 or SEQ ID NO: 150; or (d) is at least 85% identical to SEQ ID NO: 85 or SEQ ID NO: 150. In a particular embodiment, the immune cell expresses at least two RPTP polypeptides selected from (i) LAR; (ii) RPTP-s; and (iii) RPTP-d. Also provided herein, in another embodiment, is a method for identifying an agent that inhibits the binding of a 130L polypeptide to at least one receptor-like protein tyrosine phosphatase (PRTP) polypeptide comprising: (a) contacting (1) ) a candidate agent; (2) a biological sample comprising an RPTP polypeptide selected from (i) protein related to leukocyte common antigen (LAR); (ii) RPTP-s; and (iii) RPTP-d; and (3) the 130L polypeptide, wherein the amino acid sequence of the 130L polypeptide is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 85 or SEQ ID NO: 150, under conditions and for a sufficient time to allow interaction between the RPTP polypeptide and the 130L polypeptide; and (b) determining a level of binding of the 130L polypeptide to the RPTP polypeptide in the presence of the candidate agent and comparing a level of binding of the 130L polypeptide to the RPTP polypeptide in the absence of the candidate agent, wherein a decrease in the level of the 130L polypeptide to the polypeptide RPTP in the presence of the candidate agent indicates that the candidate agent inhibits binding of the 130L polypeptide to the RPTP polypeptide. In certain embodiments, the amino acid sequence of polypeptide 130L (a) comprises the amino acid sequence set forth in SEQ ID NO: 85 or SEQ ID NO: 150; (b) is at least 95% identical to SEQ ID NO.85 or SEQ ID NO: 150; (c) is at least 90% identical to SEQ ID NO: 85 or SEQ ID NO: 150; or (d) is at least 85% identical to SEQ ID NO: 85 or SEQ ID NO: 150. A manufacturing method for producing an agent that suppresses the immune response of an immune cell, which comprises: a) identifying an agent that suppresses the immune response of an immune cell, wherein the step of identifying comprises: (1) contacting (i) a candidate agent; (ii) an immune cell that expresses at least one protein tyrosine phosphatase in the form of receptor polypeptide (PTWP) selected from protein related to leukocyte-common antigen (LAR); RPTP-s; and RPTP-d; and (iii) a 130L polypeptide, wherein the amino acid sequence of the 130L polypeptide is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 85 or SEQ ID NO: 150, under conditions and for a sufficient time to allow interaction between at least one RPTP polypeptide and 130L polypeptide; and (2) determining a level of binding of the 130L polypeptide to the immune cell in the presence of the candidate agent and comparing a level of binding of the 130L polypeptide to the immune cell in the absence of the candidate agent, wherein a decrease in the level of binding of the 130L polypeptide to the immune cell in the presence of the candidate agent indicates that the candidate agent suppresses the immune response of the immune cell; and (b) producing the agent identified in step (a). In certain embodiments, the amino acid sequence of polypeptide 130L (a) comprises the amino acid sequence set forth in SEQ ID NO: 85 or SEQ ID NO: 150; (b) is at least 95% identical to SEQ ID NO: 85 or SEQ ID NO: 150; (c) is at least 90% identical to SEQ ID NO: 85 or SEQ ID NO: 150; or (d) is at least 85% identical to SEQ ID NO: 85 or SEQ ID NO: 150. In a specific embodiment, the agent is selected from an antibody, or antigen-binding fragment thereof; a small molecule; an aptamer; an antisense polynucleotide; a small interfering RNA (siRNA); and a peptide-lgFc fusion polypeptide. In yet another specific embodiment, the agent is an antibody, or antigen-binding fragment thereof. In another embodiment, a fusion polypeptide comprising a 130L polypeptide fused to a Fe polypeptide is provided. In a particular embodiment, the Fe polypeptide is a Fe polypeptide of human IgG. In a specific embodiment, the human IgG Fe polypeptide is a Mutein Fe polypeptide, wherein the mutein Fe polypeptide comprises the amino acid sequence of the Fe portion of a human IgG1 immunoglobulin, wherein the mutein Fe polypeptide differs from the Fe portion of a wild type human IgG1 immunoglobulin because it comprises at least two mutations, wherein a first mutation in the mutein Fe polypeptide comprises substitution of at least one amino acid in the CH2 domain such that the capacity of the polypeptide of fusion to bind to an IgG Fe receptor is reduced, and wherein a second mutation in the mutein Fe polypeptide is a substitution or deletion of a cysteine residue in the hinge region, where the cysteine residue is the residue of cysteine more proximal to the amino terminus of the hinge region of a wild type human IgGl immunoglobulin. In another specific embodiment, the mutein Fe polypeptide comprises substitution of at least two amino acids in the CH2 domain. In yet another specific embodiment, the mutein Fe polypeptide comprises substitution of at least three amino acids in the CH2 domain. In certain embodiments, the amino acid that is substituted is located at a position corresponding to EU 235 position number in the CH2 domain of a human IgG immunoglobulin. In other certain embodiments, a first amino acid that is substituted is located in a position corresponding to EU 234 position number in the CH2 domain of a human IgG immunoglobulin and a second amino acid that is substituted is located in a position corresponding to number of EU 235 position in the CH2 domain of a human IgG immunoglobulin. In another certain modality, a first amino acid that is substituted is located in a position corresponding to EU 234 position number in the CH2 domain of a human IgG immunoglobulin, a second amino acid which is substituted is located in a position corresponding to EU 235 position number in the CH2 domain of a human IgG immunoglobulin, and a third amino acid which is substituted is located at a position corresponding to EU 237 position number in the CH2 domain of a human IgG immunoglobulin. In a particular embodiment, the leucine residue located in a position corresponding to EU 235 position number in the CH2 domain of a human IgG immunoglobulin is substituted with a glutamic acid residue or an alanine residue. In another particular embodiment, the leucine residue located in a position corresponding to EU 234 position number in the CH2 domain of a human IgG immunoglobulin is substituted with an alanine residue. In another additional particular embodiment, the glycine residue located in a position corresponding to EU 237 position number in the CH2 domain of a human IgG immunoglobulin is substituted with an alanine residue. In yet another specific embodiment, the mutein Fe polypeptide further comprises substitution or deletion of at least one non-cysteine residue in the hinge region. In a particular embodiment, the mutein Fe polypeptide comprises a deletion of at least two amino acid residues in the hinge region, wherein at least two amino acid residues include a cysteine residue and the adjacent C-terminal residue, in wherein the cysteine residue is the cysteine residue most proximal to the amino terminus of the hinge region of a wild type human IgG1 immunoglobulin. In a specific embodiment, the fusion polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 149. In another embodiment, a method for suppressing an immune response in a subject is provided wherein the method comprises administering a composition comprising a carrier. pharmaceutically suitable and the fusion polypeptide comprising a 130L polypeptide fused to a Fe polypeptide as described above and herein. In a particular embodiment, the fusion polypeptide either (a) alters a biological activity of at least one of a receptor-like protein tyrosine phosphatase (PTNR) selected from (i) leukocyte-common antigen-related protein (LAR); (ii) RPTP-s; and (iii) RPTP-d; or (b) alters a biological activity of at least two RPTP polypeptides selected from (i) LAR; (ii) RPTP-s; and (iii) RPTP-d. In another embodiment, a method is provided for treating an immunological disease or disorder in a subject comprising administering to the subject a pharmaceutically suitable carrier and a fusion polypeptide comprising a 130L polypeptide fused to a Fe polypeptide as described above and herein. In a specific embodiment, the fusion polypeptide either (a) alters a biological activity of at least one of receptor-like protein tyrosine phosphatase (RPTP) -s and RPTP-d; or (b) alters a biological activity of at least two RPTP polypeptides selected from (i) leukocyte-common antigen related protein (LAR); (ii) RPTP-s; and (iii) RPTP-d. In certain embodiments, the immunological disease or disorder is an autoimmune disease or an inflammatory disease. In particular modalities, the autoimmune or inflammatory disease is multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, graft versus host disease, sepsis, diabetes, psoriasis, atherosclerosis, Sjogren's syndrome, progressive systemic sclerosis, scleroderma, acute coronary syndrome, ischemic reperfusion , Crohn's disease, endometriosis, glomerulonephritis, myasthenia gravis, idiopathic pulmonary fibrosis, asthma, acute respiratory distress syndrome (ARDS), vasculitis, or inflammatory autoimmune myositis. In another embodiment, a method is provided for treating a disease or disorder associated with alteration of at least one of cell migration, cell proliferation, and cell differentiation in a subject comprising administering to the subject a pharmaceutically suitable carrier and a fusion polypeptide that comprises a 130L polypeptide fused to a Fe polypeptide as described above and herein. In a specific embodiment, the fusion polypeptide either (a) alters a biological activity of at least one of receptor-like protein tyrosine phosphatase (RPTP) -s or RPTP-d; or (b) alters a biological activity of at least two RPTP polypeptides selected from (i) leukocyte-common antigen related protein (LAR); (ii) RPTP-s; and (iii) RPTP-d. In another specific embodiment, the disease or disorder is an immunological disease or disorder, a cardiovascular disease or disorder, a metabolic disease or disorder, or a proliferative disease or disorder. In yet another specific embodiment, the immunological disease or disorder is an autoimmune disease or an inflammatory disease. In certain modalities, the immunological disease or disorder is multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, graft versus host disease, sepsis, diabetes, psoriasis, atherosclerosis, Sjogren's syndrome, progressive systemic sclerosis, scleroderma, acute coronary syndrome, ischemic reperfusion. , Crohn's disease, endometriosis, glomerulonephritis, myasthenia gravis, idiopathic pulmonary fibrosis, asthma, acute respiratory distress syndrome (ARDS), vasculitis, or inflammatory autoimmune myositis. In other certain modalities, the cardiovascular disease or disorder is atherosclerosis, endocarditis, hypertension or peripheral ischemic disease. Also provided herein is a manufacturing method for producing the fusion polypeptide comprising a 130L polypeptide fused to a Fe polypeptide as described above and herein. All US patents, US patent application publications, US patent applications, patent applications, foreign patents, foreign patent applications, and publications that are not patents referred to in this specification and / or listed on the worksheet data of the application, are hereby incorporated by reference, in their entirety.

BRIEF DESCRIPTION OF THE DRAWINGS Figures 1A to 1 F provide an alignment of the amino acid sequence of RPTP-s (SEQ ID NO: 29), RPTP-d (SEQ ID NO: 37), and LAR (SEQ ID NO: 25). The leader peptide sequence, the immunoglobulin-like domains (1st Ig domain, 2nd Ig domain, 3rd Ig domain); fibronectin III repeat region (FNIII); Transmembrane region (TM region); and phosphatase domains (D1 and D2) of each PTWP are marked in the alignment. The first amino acid of each region is shown in bold. A protease digestion site in each phosphatase is denoted underlined. The amino acids in identity regions are denoted by "*" and amino acids in regions of similarity are indicated by points. The alignment was generated using the CLUSTALW program (Thompson et al., Nucleic Acids Res. 22: 4673-80 (1991)) and "GeneDoc" (Nicholas et al., E ß? / EL V? / Ews 4:14). 1991)). Figure 2 presents a scheme of a fusion polypeptide A41 L encoded by a recombinant expression construct (A4 ILCRFC) for expression of the fusion polypeptide used for tandem affinity purification (TAP). The encoded fusion polypeptide includes mature A41 L of Cowpox virus that was fused at its amino terminus to the carboxy terminus of the human growth hormone ladder peptide (GH leader). The tandem affinity tag (CRFC) was fused to the carboxy terminus of A41 L and included an epitope hemagglutinin of (YPYDVDYA, SEQ ID NO: 67) of human influenza virus (HA) in frame with a C-TAG protein (EDQVDPRLIDGK (SEQ ID NO: 68), derived from the heavy chain of human protein C); HRV3C protease site of human rhinovirus (HRV3C digestion site) (LEVLFQGP (SEQ ID NO: 69), and a mutein derivative of the Fe portion of a human IgG immunoglobulin (Mutein FC). scheme of the TAP procedure to identify cellular polypeptides that bind to A41 L. Figures 4A to 4C illustrate peptides of LAR, RPTP-d, and RPTP-s identified by tandem affinity purification (TAP) with A41 L. The figure 4A illustrates the peptide sequences (bold) within LAR (SEQ ID NO: 70) that was identified by LC / MS / MS after TAP Figure 4B illustrates the peptide sequences (bold) within RPTP-s (SEQ. ID NO: 71) that was identified by LC / MS / MS after TAP Figure 4C illustrates the peptide sequences (bold) within RPTP-d (SEQ ID N0.72) that was identified by LC / MS / MS after TAP Figure 5 shows an amino acid sequence alignment between (i) an A41 L / Fc fusion polypeptide comprises a signal peptide sequence A41 L, a polypeptide A41 L, and a polypeptide Fe of human IgGI (A41 L / Fc) (SEQ ID NO: 74) and (ii) a fusion polypeptide of A41 L / mutein Fe it comprises a human growth hormone signal peptide sequence, a variant of A41L polypeptide, and a mutein Fe polypeptide (A41 L / Mutein Fe) (SEQ ID NO: 73). The consensus sequence (SEQ ID NO: 75) is also shown. The vertical dotted lines indicate the amino terminal and carboxy terminal ends of the A41 L polypeptide. Figure 6 provides an alignment of the amino acid sequence of a 130L polypeptide (Access to GenBank No. CAC21368.1) (SEQ ID NO: 85) of Yaba disease virus (YLDV) and A4 L (SEQ ID NO: 87) (Access to GenBank No. AAMI 3618) of Cowpox virus. Figures 7A to 7C illustrate peptides of LAR, RPTP-d, and RPTP-s identified by tandem affinity purification (TAP) with Yaba 130L-like disease virus. Figure 7A illustrates the peptide sequences (bold and underlined) within LAR (SEQ ID NO: 155) that were identified by LC / MS / MS after TAP. Figure 7B illustrates the peptide sequences (bold and underlined) within RPTP-s (SEQ ID NO: 156) that were identified by LC / MS / MS after TAP. Figure 7C illustrates the peptide sequences (bold and underlined) within RPTP-d (SEQ ID NO: 157) that were identified by CL / MS / MS after TAP. Figure 8A illustrates interferon-gamma (IFN-γ) production in peripheral non-adherent blood mononuclear cells (PBMCs) in the presence of protein conjugate related to human leukocyte-Fe common antigen (Lar-hFc). Figures 8B and 8C present the production level of IFN-? in a mixed lymphocyte reaction (MLR) in the presence of Lar-hFc. Dendritic cells derived from monocytes (104) from the donor Do476 (Figure 8B) and from a second donor Do495 (Figure 8C) were combined with non-adherent PBMCs to which Lar-hFc in various concentrations were added. The production of IFN-? was determined by ELISA. Human IgG was added at the concentrations shown as a control. Figure 9 presents the elution profile of a Fe lg-1-lg-2-lg-3-Fc fusion polypeptide of LAR that was ied to a CLAR column with gel filtration. Figures 10A and 10B present an immunoblot of LAR-lg domain constructs fused to human IgG Fe, which were combined with A41 IL. The complexes were isolated by immunoprecipitation with protein A. The Fe portion of the LAR-Ig-Fc constructs was detected using an anti-Fc antibody (Figure 10A), and the presence of A41 L was determined by immunoblotting with an anti-A41 antibody. L (figure 10B).DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the discovery that three receptor-like protein tyrosine phosphatases (RPTPs), leukocyte antigen-related protein (LAR), receptor tyrosine phosphatase-delta protein (RPTP-d), and protein tyrosine phosphatase-sigma of receptor (RPTP-s), present an immunoregulatory function. The expression of LAR, RPTP-d, and RPTP-s by immune cells was described by identifying polypeptides expressed by immune cells that interacted with the polypeptides of poxvirus, A41 L and 130L of Yaba-like disease virus (YLDV).

The presence of LAR on the cell surface of immune cells (e.g., a macrophage, cell line of THP-1) was shown to identify cells expressing polypeptides, which interacted with poxvirus polypeptide A41 L (see, e.g. , U.S. Patent No. 6,852,486). Unexpectedly, as described herein, RPTP-d and RPTP-s are also expressed by immune cells and bind to A41 L as well as another poxvirus 130L polypeptide. Previous studies indicated that RPTP-d and RPTP-s are predominantly expressed in brain and nervous system tissue (see, e.g., Pulido et al., Proc. Nati, Acad. Sci USA 92: 11686-90 (1995 )). More recent studies suggest that LAR, RPTP-d and RPTP-s play a role in axon guidance regulation in Drosophila (see, e.g., Johnson et al., Physiol., Rev. 83: 1-21 (2003)). ) and in the development and maintenance of excitatory synapses (see, e.g., Dunah et al., Nat. Neurosci., 8: 458-67 (2005)). The 130L viral polypeptide that specifically binds to and / or interacts with LAR, PTTP-d and PTTP-s is not homologous to A41 L (see FIG. 6). Yaba-like disease virus (YLDV) belongs to the genus Yatapoxvirus of Chrodopoxvirinae. The genus has three members: tanapox virus, monkey yaba tumor virus, and YLDV. In primates, YLDV causes an acute febrile illness that is characteristically accompanied by localized disease lesions (see, e.g., Knight et al., Virology 172: 116-24 (1989)). The YLDV gene called 130L encodes a secreted protein having an estimated molecular weight of approximately 21 Kd (see, e.g., Lee et al., Virology 281: 170-92 (2001)).

Poxvirus polypeptides, such as A41 L and 130L, act at least in part in a host infected with a poxvirus to suppress a specific immune response to the virus. Suppression of an immune response in the virally infected host produces an environment in the host. which virus can continue rephcation and infection As described herein, the identification of host cells and components of host cells, including pohpeptides, that interact with poxvirus polypeptides such as A41 L and 130L can lead to the development of therapeutic molecules that alter an immune response Poxvirus polypeptides can act by inhibiting or blocking the function of host factors such as interferons, complement, atocins, and / or chemokines, or by inhibiting, blocking, or altering the effect of inflammation and fever (see also, v. g, U.S. Patent No. 6,852,486) For example, in the presence of a polypeptide derived from LAR (i.e. domains similar to immunoglobulin 1, 2, and 3 of LAR fused to a Fe polypeptide of human IgG), peripheral blood monocytes are stimulated to produce interferon-gamma (IFN-γ) Without wishing to be limited by theory, because IFN-? is involved in the elimination of pathogens by stimulating and inducing vain aspects of the immune response, A41 L can inhibit the ability of LAR to contribute to the manifestation of an immune response to the invading poxvirus by inhibiting the ability of LAR to stimulate IFN production -? The increased production of IFN-? it is also associated with immunological diseases and autoimmune diseases, such as systemic lupus erythematosus (SLE). Therefore, A41 L, 130L, or an agent, macromolecule or compound that simulates the interaction between A41L or 130L and LAR, for example, can be effective immunosuppressive agents. The poxvirus polypeptides, such as A41L and 130L, or other agents, polypeptides, molecules or compounds that act as the poxvirus polypeptide to suppress the immune response of an immune cell can be used to treat or prevent an immunological disease or disorder. Here compositions and methods for treating diseases and disorders, including inflammatory diseases and autoimmune diseases, are provided by contacting an immune cell with a molecule, compound or composition that interacts with one or more of LAR, RPTP-d, and RPTP-s to inhibit (reduce, abolish, suppress, prevent) the immune response of the immune cell. Said compounds or compositions may also be useful for treating a cardiovascular disease or a metabolic disease as described herein. Alternatively, a molecule, compound or composition that interacts with one or more of LAR, RPTP-d, and RPTP-s and that is useful for the treatment of an inflammatory or autoimmune disease, a cardiovascular disease, or a metabolic disease may increase the immune response of the immune system. The compositions and methods are provided herein for treating or preventing, inhibiting, slowing the progression of, or reducing the symptoms associated with, an immunological disease or disorder, a cardiovascular disease or disorder, a metabolic disorder or disorder, or a disease or disorder. proliferative An immunological disorder includes an inflammatory disease or disorder and an autoimmune disease or disorder. Although inflammation or an inflammatory response is a normal and protective response of the host to an injury, inflammation can cause harm desired. For example, atherosclerosis is, at least in part, a pathological response to arterial injury and the consequent cascade of inflammation. Examples of immunological disorders that can be treated with an antibody or antigen-binding fragment thereof (or other agent) that binds to or interacts with one or more of LAR, RPTP-d, and RPTP-s described JO here include but are not limited to multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus (SLE), graft versus host disease (GVHD), sepsis, diabetes, psoriasis, atherosclerosis, Sjogren's syndrome, progressive systemic sclerosis, scleroderma, coronary syndrome acute, ischemic reperfusion, Crohn's disease, endometriosis, glomerulonephritis, myasthenia gravis, idiopathic pulmonary fibrosis, asthma, acute respiratory distress syndrome (ARDS), vasculitis, or inflammatory autoimmune myositis and other inflammatory and degenerative muscle diseases (e.g., dermatomyositis, polymyositis, juvenile dermatomyositis, myositis de inclusion bodies). A disease or cardiovascular disorder that can be treated, which may include a disease and disorder that can also be considered an immunological disease / disorder, includes, for example, atherosclerosis, endocarditis, hypertension or peripheral ischemic disease. A metabolic disease or disorder that can be treated, which may also include a disease and disorder that can also be considered an immunological disease / disorder, includes for example, diabetes, obesity, and diseases associated with abnormal or altered mitochondrial function. As used herein, the term "isolated" means that a material is removed from its original environment (e.g., the natural environment if it is occurring naturally). For example, a naturally occurring nucleic acid or polypeptide present in a living animal is not isolated, but the same nucleic acid or polypeptide, separated from some or all of the co-existing materials in the natural system, is isolated. Said nucleic acid could be part of a vector and / or said nucleic acid or polypeptide could be part of a composition, and yet be isolated because the vector or composition is not part of the natural environment for the nucleic acid or polypeptide. The term "gene" means the segment of DNA involved in the production of a polypeptide chain; it includes preceding regions and that follow the coding region "front and back" as well as intervention sequences (introns) between individual coding segments (exons). As used herein and in the appended claims, the singular forms "a," "an," "the" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, the reference to "an agent" includes a plurality of said agents, and the reference to "the cell" includes reference to one or more cells and equivalents thereof known to those skilled in the art, and so on The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that of other certain modalities, for example, a modality of any composition of matter, composition, method or procedure, or the like, described herein may "consist of" or "consist essentially of" the described features.

A4 L A41 Polypeptides refers to a genetic locus in viruses that are members of the poxvirus family, including for example, variola, myxoma, Shope's fibroma virus, camelpox, monkeypox, ecromelia, cowpox, and vaccinia virus. The A41 L gene encodes a glycoprotein (here called A41 L polypeptide) which is a viral virulence factor, which is secreted by cells infected with a poxvirus (see, e.g., International patent application publication WO 98/37217; Ng et al., J. Gen. Virol. 82: 2095-105 (2001)). Poxviruses, whose genomes are double-stranded DNA, have been adapted to replicate in several host species by acquiring host genes that allow viruses to evade the host's immune system and / or facilitate viral replication (see, eg. , Bugert et al. Virus Genes 21: 1 1 1-33 (2000); Alcami et al., Immunol. Today 21: 447-55 (2000); McFadden et al., J. Leukoc. Biol. 57: 731-38 (1995)). Polypeptides encoded by the genomes of various poxviruses can affect an immune response by inhibiting or blocking the function of host factors such as interferons, complement, cytokines, and / or chemokines, or by inhibiting, blocking or altering, the effect of inflammation and fever. For example, a recombinantly expressed A41 L polypeptide binds to chemokines induced by IFN-α, such as Mig and IP-10 (see, e.g., International patent application publication WO 98/37217), and A41 L is unites LAR (see, e.g., US Patent No. 6,852,486). An A41 L polypeptide as used herein refers to any of a number of A41 L polypeptides (which may be referred to in the art by nomenclature other than A41 L) encoded by the genome of any of a number of poxviruses, including but not limited to variola, myxoma, Shope fibroma virus (rabbit fibroid virus), camel pox, monkeypox, ecromelia, cowpox, and vaccinia virus (see examples of genome sequences (including nucleotide sequences encoding A41 polypeptides L) in access to GenBank Nos. NC_001559; NC_00161; Y16780; X69198; NC_003310; NC_005337; AY603355; NC_03391; AF438165; U94848; AY243312; AF380138; L22579; M35027; NC_003663; X94355; AF482758; NC_001 132; AF170726; NC_001266; AF170722; F36852 (polypeptide only) An A41 L polypeptide can comprise any of the amino acid sequence described herein or known in the art, or a variant of said amino acid sequence (including logos) Exemplary amino acid sequences of polypeptides are shown in A41 L SEQ ID NOs: 1-8 and GenBank accession NP_063835 We (SEQ ID NO:.. 10); NP_042191 (SEQ ID NO: 1 1); CAA49088 (SEQ ID NO: 12); NP_536578 (SEQ ID NO: 13); P33854 (SEQ ID NO: 14); P24766 (SEQ ID NO: 15); P21064 (SEQ ID NO: 16); AA50551 (SEQ ID NO: 17); NP_570550 (SEQ ID NO: 18); NP-570548 (SEQ ID NO: 19); AAL73867 (SEQ ID NO: 20); AAL73865 (SEQ ID NO: 21). An A41 L polypeptide may also include a variant A41 L polypeptide comprising an amino acid sequence that differs by at least one amino acid from an A41 L polypeptide sequence described herein or known in the art. The A41 L polypeptide variant may differ from a wild type amino acid sequence due to the insertion, deletion, addition, and / or substitution of at least one amino acid and may differ due to insertion, deletion, addition, and / or substitution of at least two, three, four, five, six, seven, eight, nine or ten amino acids or can differ by any number of amino acids between 10 and 45 amino acids. Variants of A41 L polypeptides include, for example, naturally occurring polymorphisms (ie, A41 L orthologous polypeptides encoded by the genomes of different poxvirus strains) or recombinantly engineered A41 L polypeptide variants or by genetic engineering. In certain embodiments, a variant of an A41 L polypeptide retains at least one functional or biological activity of the wild type A41 L polypeptide and in other certain embodiments, a variant of A41 L polypeptide retains at least one, and in certain embodiments, all functions or biological activities of the wild type A41 L polypeptide. A functional or biological activity of an A41 L polypeptide or a variant thereof can be determined in accordance with the methods described herein and known in the art, said function or activity includes the ability (1) to bind to or interact with at least one of, or at least two of, or all three of PTPs, LAR, RPTP-d, and RPTP-s receivers; (2) to bind to an antibody that specifically binds to a wild type A41 L polypeptide; and (3) to suppress an immune response from a cell that expresses at least one of LAR, RPTP-d, and RPTP-s. A variant A41 L polypeptide that retains a functional or biological activity of a wild type A41 L polypeptide exhibits a comparable level of function or activity (i.e., does not differ in a statistically significant way) at the level of functional or biological activity shown by wild-type A41 L polypeptide. Variants of A41 L polypeptide and polynucleotides encoding these variants can be identified by sequence comparison. As used herein, two amino acid sequences have 100% amino acid sequence identity if the amino acid residues of the two amino acid sequences are the same when aligned for maximum correspondence. Similarly, two polynucleotides have 100% nucleotide sequence identity if the nucleotide residues of the two sequences are the same when aligned for maximum correspondence. Sequence comparisons can be made using any method including using computer algorithms well known to those skilled in the art. Such algorithms include Align or the BLAST algorithm (see, eg, Altschul, J. Mol. Biol. 219: 555-565, 1991; Henikoff and Henikoff, Proc. Nati. Acad. Sci. USA 52: 10915-10919 , 1992), which are available on the NCBI website (see [online] InternetxURL: http: // www / ncbi.nlm.nih.gov/cgi- bin / BLAST). The default parameters can be used. In addition, standard software programs are available, such as those included in LASERGENE bioinformatics computing suite (DNASTAR, Inc., Madison, Wl); CLUSTALW program (Thompson et al., Nucleic Acids Res. 22: 4673-80 (1991)); and "GeneDoc" (Nicholas et al., EMBNEW News 4:14 (1991)). Other methods for comparing two nucleotides or amino acid sequences to determine optimal alignment are practiced by those skilled in the art (see, for example, Peruski and Peruski, The Internet and the New Biology: Tools for Genomic and Molecular Research (ASM Press , Inc. 1997), Wu et al. (Eds.), "Information Superhighway and Computer Databases of Nucleic Acids and Proteins," in Methods in Gene Biotechnology, pages 123-151 (CRC Press, Inc. 1997); and Bishop (ed.), Guide to Human Genome Computing, 2a. Ed. (Academic Press, Inc. 1998)). In certain embodiments, the amino acid sequence of a variant of A41 L polypeptide is at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 98% identical to Polypeptide A41 Corresponding wild-type L or to an A41 L polypeptide described herein and / or known in the art (see, e.g., SEQ ID NOs: 1-21). Alternatively, a variant A41 L polypeptide can be identified by comparing the nucleotide sequence of a polynucleotide encoding the variant with a polynucleotide encoding an A41 L polypeptide. In particular embodiments, the nucleotide sequence of a polynucleotide encoding the variant of A41 L polypeptide is at least 70%, 75%, 80%, 85%, 90%, or 95% identical to one or more of the polynucleotide sequences encoding A41 L polypeptides, which are described herein. Polynucleotide variants also include polynucleotides that differ in nucleotide sequence identity due to the degeneracy of the genetic code but encode an A41 L polypeptide having an amino acid sequence described herein or known in the art. As described herein, an A41 L polypeptide, including variants and fragments of A41 L polypeptide and fusion polypeptides as described herein (which interact with or bind to at least one, two, or three of LAR, RPTP-d , and RPTP-s, or that interacts with or binds to at least one, two, or three of LAR5 RPTP-d, and RPTP-s), present on the surface of a cell, can be used to alter (v .gr., suppress or increase) the immune response of an immune cell. In one embodiment, A41 L or a variant thereof or an A41 L fusion polypeptide, as described herein, can be used to treat a patient who presents an acute response. For example, an A41 L polypeptide, variant or fragment thereof can suppress an immune response associated with a disease or condition such as acute respiratory distress syndrome (ARDS). ARDS, which can develop in adults and children, often follows a direct pulmonary or systemic attack (eg, sepsis, pneumonia, aspiration) that injures the alveolar-capillary unit. Several cytokines are associated with the development of the syndrome, including, for example, tumor necrosis factor-alpha (TNF-a), interieucin-beta (IL-β), IL-10, and soluble intercellular adhesion molecule 1 (if CAM -1 ). The increased or decreased level of these factors and cytokines in a biological sample can be easily determined by methods and tests described herein and routinely practiced in the art for monitoring the acute state and for monitoring the effect of the treatment. To reduce or minimize the possibility or degree of an immune response that is specific for A41 L, the A41 L, variant of A41 L derivative or fragment thereof, may be administered in a limited number of doses, may be produced or derive in a manner that alters the glycosylation of A41 L, can be administered under conditions that reduce or minimize the antigenicity of A41 L. For example, A41 L can be administered before, concurrent with, or subsequent to administration in the host of a second composition that suppresses an immune response, particularly a response that is specific for A41 L. In addition, those skilled in the art are familiar with methods for increasing the half-life and / or improving the pharmacokinetic properties of a polypeptide, such as by pegylation of the polypeptide. In certain other embodiments, a fragment of A41 L polypeptide can alter the immune response of an immune cell. Said fragment of A41 L interacts with or binds to at least one of, at least two of, or all three of the PTPs receptor, LAR, RPTP-d, and RPTP-s. The fragment may comprise at least 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive amino acids. In certain modalities, the A41 L fragment comprises at least any number of amino acids between 20 and 50 consecutive amino acids of an A41 L polypeptide, and in other embodiments, the A41 L fragment comprises at least any number of amino acids between 50 and 100 consecutive amino acids of an A41L polypeptide. Fragments of A41 L also include truncations of an A41 L polypeptide. A truncated A41 L polypeptide may lack at least 1, 2-10, 11-20, 21-30, 31 -40, or 50 amino acids either end terminal amino or the terminal carboxy terminus or both the terminal amino terminus and the carboxy terminus of a full length A41 L polypeptide. In certain embodiments, the A41 L fragment lacks the entire amino terminal half or carboxy terminal moiety of the full length A41 L polypeptide. In other embodiments, the A41L polypeptide fragment (including a truncated fragment) can be conjugated, fused to, or otherwise linked to a portion that is not an A41 L polypeptide or fragment. For example, the A41 L polypeptide fragment can be linked to another molecule capable of altering the immune response of an immune cell (e.g., suppressing the immune cell immune response), said immune cell can be the same cell, the same type of cell, or a cell different from the cell affected by the A41 L polypeptide or fragment. An example of an A41 L fusion polypeptide includes an A41 L polypeptide, variant, or fragment thereof as described herein fused in frame with an immunoglobulin Fe (Ig) polypeptide. A Fe polypeptide of an immunoglobulin comprises the heavy chain CH2 and CH3 domain and a portion of or all of the hinge region that is located between CH1 and CH2. Historically, a Fe fragment was derived by digestion with papain from an immunoglobulin and included the hinge region of the immunoglobulin. The Fe regions are monomeric polypeptides that can be linked to dimeric or multimeric forms by covalent (e.g., particularly disulfide bonds) and non-covalent association. The number of intermolecular disulfide bonds between monomeric subunits of Fe polypeptides varies depending on the class of immunoglobulin (e.g., IgG, IgA, IgE) or subclass (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, human Ig2). Fragments of a Fe polypeptide, such as a Fe polypeptide that is truncated at the C-terminus (that at least 1, 2, 3, 4, 5, 10, 15, 20, or more amino acids have been removed or deleted) , they can also be used. In certain embodiments, the Fes polypeptide described herein contains multiple cysteine residues, such as at least some or the cysteine residues in the hinge region, to allow interchain chain disulfide bonds to form between the Fe polypeptide portions of two proteins. A41 L / Fc fusion separated, thereby forming fusion polypeptide dimers A41 L / Fc. In other embodiments, if retention of antibody-dependent cell-mediated cytotoxicity (ADCC) and complement fixation (and complement-associated cytotoxicity (CDC)) is desired, the Fe polypeptide comprises substitutions or deletions of cysteine residues in the hinge region. such that a Fe polypeptide fusion protein is monomeric and does not form a dimer (see, e.g., U.S. Patent Application Publication No. 2005/0175614). The Fe portion of the immunoglobulin mediates certain effector functions of an immunoglobulin. Three general categories of effector functions associated with the Fe region include (1) activation of the classical complement cascade, (2) effector cell interaction, and (3) immunoglobulin compartmentalization. Currently, a Fe polypeptide, and any of one or more constant region domains, and fusion proteins comprising at least one immunoglobulin constant region domain can be easily prepared in accordance with recombinant molecular biology techniques with which he is familiar one skilled in the art. A polypeptide A41 L or variant, or fragment thereof, can be fused in frame with an immunoglobulin Fe polypeptide (A41 L-Fc fusion polypeptide) that is prepared using the nucleotide and encoded amino acid sequences derived from the animal species for which the polypeptide is intended of fusion A4 IL-lgFc. One skilled in the art of molecular biology can easily prepare such fusion polypeptides in accordance with methods described herein and routinely practiced in the art. In one embodiment, the Fe polypeptide is of human origin and can be of any of the immunoglobulin classes, such as IgG1, IgG2, IgG3, IgG4 or human IgA. In a certain embodiment, the Fe polypeptide is derived from a human IgG1 immunoglobulin (see Kabat et al., Supra). In another embodiment, the A41 L-Fc fusion polypeptide comprises a Fe polypeptide of a non-human animal, for example, but not limited to, a mouse, rat, rabbit or hamster. The amino acid sequence of a Fe polypeptide derived from an immunoglobulin of a host species to which an A41 L-Fc fusion polypeptide can be administered is likely to be less immunogenic or non-immunogenic than a Fe polypeptide from a non-syngeneic host. As described herein, immunoglobulin sequences from a variety of species are available in the art, for example, in Kabat et al. in Sequences of Proteins of Immunological Interest, 4a. ed., (U.S. Dept. of Health and Human Services, U.S. Government Printing Office, 1991)). As described herein, an A41 L polypeptide (or variant or fragment thereof) that is fused in frame to a Fe polypeptide can comprise any of the A41 L polypeptides described herein or known in the art. For example, an A41 L polypeptide having the amino acid sequence of the A41 L polypeptide encoded by the genome of the Brighton Red strain of cowpox can be fused in frame to an immunoglobulin Fe region. Also as described herein, the Fe moiety of the fusion polypeptide can be derived from a human or non-human immunoglobulin. By way of example, the Fe portion of an A4 IL-Fc fusion polypeptide can comprise the amino acid sequence of all or a portion of the hinge region, CH2 domain, and CH3 domain of a human immunoglobulin, for example, a lgG1. Said illustrative fusion polypeptide is illustrated in Figure 5. An A4 IL-Fc A4 fusion polypeptide may further comprise a signal peptide sequence that facilitates post-translational transport of the polypeptide into the host cell in which the fusion polypeptide is voiced. The signal peptide sequence can be derived from an A41 L signal peptide sequence encoded by the poxvirus genome from which the A41 L sequence was obtained. Alternatively, the signal peptide sequence can comprise an amino acid sequence that is derived from an unrelated polypeptide, such as human growth hormone. A Fe polypeptide as described herein also includes Fe polypeptide variants. One such Fe polypeptide variant has one or more cysteine residues (such as one or more cysteine residues in the hinge region) that forms a disulfide bond of interchain substituted with another amino acid, such as serine, to reduce the number of interchain disulfide bonds that can be formed between the two heavy chain constant region polypeptides that form a Fe polypeptide. In addition, or alternatively, the cysteine residue plus A terminal amino of the hinge region forming a disulfide bond with a light chain constant region in a complete immunoglobulin molecule can be substituted, for example, with a serine residue. Alternatively, one or more cysteine residues may be deleted from the wild-type hinge of the Fe polypeptide. Another example of a Fe polypeptide variant is a variant having one or more amino acids involved in an effector function substituted or deleted in such a way that the Fe polypeptide has a reduced level of an effector function. For example, amino acids in the Fe region can be substituted to reduce or abolish the binding of a component of the complement cascade (see, e.g., Duncan et al., Nature 332: 563-64 (1988)).; Morgan et al., Immunology 86: 319-24 (1995)) or to reduce or abolish the ability of the Fe polypeptide to bind to an IgG Fe receptor expressed by an immune cell (Wines et al., J Immunol. 164: 5313 -18 (2000), Chappel et al., Proc. Nati, Acad. Sci USA 88: 9036 (1991), Canfield et al., J. Exp. Med. 173: 1483 (1991); Duncan et al., Supra. ); or to alter antibody-dependent cellular cytotoxicity. Said variant Fe polypeptide that differs from the wild-type Fe polypeptide is also referred to herein as a mutein Fe polypeptide. In one embodiment, an A41 L polypeptide (or fragment or variant thereof) is fused in frame with an Fe polypeptide comprising at least one substitution of a residue that in the wild type Fe region polypeptide contributes to the binding of a Fe polypeptide or immunoglobulin to one or more Fe IgG receptors expressed in certain immune cells. Said mutein Fe polypeptide comprises at least one substitution of an amino acid residue in the CH2 domain of the mutein Fe polypeptide, such that the ability of the fusion polypeptide to bind to an IgG Fe receptor, such as a Fe receptor. of IgG present on the surface of an immune cell, is reduced. By way of background, three different types of IgG Fe receptors are expressed on human leukocytes, which are distinguishable by structural and functional properties, as well as by antigenic structures, whose differences are detected by CD-specific monoclonal antibodies. The Fe receptor of IgGs are designated Fc? RI (CD64), Fc? RII (CD32), and Fc? RIII (CD 16) and are differentially expressed on overlapping sets of leukocytes. Fc? RI (CD64), a high affinity receptor expressed on monocytes, macrophages, neutrophils, myeloid precursors, and dendritic cells, comprise isoforms la and Ib. Fc? RII (CD32), composed of Ha5 isoforms Ubi, Ilb2, Ilb3, and He, is a low affinity receptor that is the most widely distributed type of human Fc? R; it is expressed in most types of blood leukocytes, as well as in Langerhans cells, dendritic cells, and platelets. Fc? RIII (CD 16) has two isoforms, both of which are capable of binding IgGI and human IgG3. The Fey Rllla isoform has an intermediate affinity for IgG and is expressed on macrophages, monocytes, natural killer (NK) cells, and subsets of T cells. Fc? Rlllb is a low affinity receptor for IgG and is selectively expressed on neutrophils. The residues in the amino terminal portion of the CH2 domain that contributes to IgG receptor binding include residues at positions Leu234-Ser239 (Leu-Leu-Gly-Gly-Pro-Ser (SEQ ID NO: 80) (numbering system of EU, Kabat et al., Supra) (see, e.g., Morgan et al., Immunology 86: 319-24 (1995), and references cited therein.) These positions correspond to positions 15-20 of the amino acid sequence of a human lgG1 Fe polypeptide (SEQ ID NO: 79) The substitution of the amino acid in one or more of these six positions (ie, one, two, three, four, five or all six) in the domain CH2 results in a reduction in the ability of the Fe polypeptide to bind to one or more of the Fe receptor of IgGs (or isoforms thereof) (see, e.g., Burton et al., Adv. Immunol., 51: 1 ( 1992), Hulett et al., Adv. Immunol., 57: 1 (1994), Jefferis et al., Immunol Rev. 163: 59 (1998), Lund et al., J Immunol., 147: 2657 (1991); Sarmay et al., Mol. Immunol., 29: 633 (1992); Lund et al. l., Mol. Immunol. 29:53 (1992); Morgan et al., Supra). In addition to the substitution of one or more amino acids at positions EU 234-239, one, two, or three or more amino acids adjacent to this region (either to the carboxy terminal side of position 239 or to the amino terminal side of position 234) ) can also be replaced. By way of example, the substitution of the leucine residue at position 235 (corresponding to position 16 of SEQ ID NO: 79) with a glutamic acid residue or an alanine residue cancels or reduces, respectively, the affinity of a Immunoglobulin (such as human IgG3) for Fc? RI (Lund et al., 1991, supra); Canfield et al., Supra; Morgan et al., Supra). As another example, the replacement of the leucine residues at positions 234 and 235 (corresponding to positions 15 and 16 of SEQ ID NO: 79), for example, with alanine residues, cancels the binding of an immunoglobulin to FcyRIla (see, e.g., Wines et al., supra). Alternatively, leucine at position 234 (corresponding to position 15 of SEQ ID NO: 79), leucine at position 235 (corresponding to position 16 of SEQ ID NO: 79), and glycine at position 237 (which corresponds to position 18 of SEQ ID NO: 79), each can be substituted with a different amino acid, such as leucine at position 234 can be substituted with a residue of alanine (L234A), leucine in 235 can be substituted with a alanine residue (L235A) or with a glutamic acid residue (L235E), and the glycine residue at position 237 can be substituted with another amino acid, for example an alanine residue (G237A). In one embodiment, a mutein Fe polypeptide that is fused in frame to a viral polypeptide (or variant or fragment thereof) comprises one, two, three, four, five, or six mutations at positions 15-20 of SEQ ID NO: 79 corresponding to positions 234-239 of a CH2 domain of human IgGI (EU numbering system) as described herein. An illustrative Lutein Fe polypeptide has the amino acid sequence set forth in SEQ ID NO: 77 in which substitutions corresponding to (L234A), (L235E), and (G237A) can be found in positions 13, 14, and 16 of SEQ ID NO: 77 In another embodiment, a Mutein Fe polypeptide comprises a mutation of a cysteine residue in the hinge region of a Fe polypeptide. In one embodiment, the cysteine residue most proximal to the amino terminus of the hinge region of a Fe ( e.g., the cysteine residue most proximal to the amino terminus of the hinge region of the Fe portion of a wild-type IgG1 immunoglobulin) is deleted or substituted with another amino acid. That is, by way of illustration, the cysteine residue in position 1 of SEQ ID NO: 79 is deleted, or the cysteine residue in position 1 is substituted with another amino acid which is incapable of forming a disulfide bond, by example, with a serine residue. In another embodiment, a Mutein Fe polypeptide comprises a deletion or substitution of the cysteine residue most proximal to the amino terminus of the hinge region of a Fe polypeptide further comprising deletion or substitution of the adjacent C-terminal amino acid. In a certain embodiment, this cysteine residue and the adjacent C-terminal residue are both deleted from the hinge region of a mutein Fe polypeptide. In a specific embodiment, the cysteine residue at position 1 of SEQ ID NO: 79 and the aspartic acid at position 2 of SEQ ID NO: 79 are deleted. Fe polypeptides comprising deletion of these cysteine and aspartic acid residues in the hinge region can be expressed efficiently in a host cell, and in certain cases, can be expressed more efficiently in a cell than a Fe polypeptide that retains cysteine residues and wild type aspartate. In a specific embodiment, a mutein Fe polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 77, which differs from the wild-type Fe polypeptide (SEQ ID NO: 79) wherein the cysteine residue at position 1 of SEQ. ID NO: 79 is deleted and the aspartic acid in position 2 of SEQ ID NO: 79 is deleted and the leucine residue in position 15 of SEQ ID NO: 79 is replaced with a residue of alanine, the leucine residue in position 16 is substituted with a glutamic acid residue, and glycine at position 18 is substituted with an alanine residue (see also figure 5). Thus, an illustrative Lutein Fe polypeptide comprises an amino acid sequence in its portion of KTHTCPPCPAPEAEGAPS (SEQ ID NO 81) (see SEQ ID NO: 77, an illustrative mutein Fe sequence) Other Fe vanants encompass similar amino acid sequences of known Fe-peptide sequences that have only minor changes, for example by way of illustration and not limitation, covalent chemical modifications, insertions, deletions and / or substitutions, which may also include conservative substitutions. The amino acid sequences that are similar to one another may share substantial regions of sequence homology. similarly, the nucleotide sequences encoding the vanants of Fe may encompass substantially similar nucleotide sequences and have only minor changes, for example, by way of illustration and not limitation, covalent chemical modifications, insertions, deletions, and / or substitutions, which may also include silent mutations due to the degeneracy of the genetic code. Nucleotide sequences that are similar to one another may share regions of substantial sequence homology. An Fe polypeptide or at least one immunoglobulin constant region, or portion thereof, when it is merged to a peptide or popeptide of interest acts, at least in part, as a carrier or carrier portion that prevents degradation and / or increases half-life, reduces toxicity, reduces immunogenicity, and / or increases the biological activity of the peptide such as by forming dimers or other multimers (see, e.g., US patents) Nos. 6,018,026; 6,291, 646; 6,323,323; 6,300,099; 5,843,725). (See also, e.g., U.S. Patent No. 5,428,130, U.S. Patent No. 6,660,843, U.S. Patent Application Publication Nos. 2003/064480, 2001/053539, 2004/087778, 2004/077022; 2004 / 071712; 2004/057953/2004/053845 / 2004/044188; 2004/001853; 2004/082039). An A41 L polypeptide (or variant or fragment thereof) fused in frame with a Fe polypeptide or Fe polypeptide variant (e.g., a mutein Fe polypeptide) can comprise a peptide linker between the A41 L polypeptide and polypeptide Fe. The linker can be a single amino acid (such as for example a glycine residue) or it can be two, three, four, five, six, seven, eight, nine or ten amino acids, or it can be any number of amino acids between and 20 amino acids. By way of illustration but not limitation, a linker may comprise at least two amino acids that are encoded by a nucleotide sequence that is a restriction enzyme recognition site. Examples of such restriction enzyme recognition sites include, for example, ßamHI, C / al, EcoRI, HincftW, Kpn \,? / Col, Nhe \, Pml \, Psft, Sa / I, and? Ol. An A41 L polypeptide, fragment thereof, or variant thereof, fused in frame with a mutein Fe polypeptide can be used to suppress an immune response in a subject when administered with a pharmaceutically or physiologically suitable carrier or excipient in accordance with the methods described herein and known to those skilled in the art. Such fusion polypeptides can alter a biological activity of at least one of the RPTP polypeptides described herein (ie, LAR, RPTP-s, RPTP-d), at least two of the RPTP polypeptides or the three RPTP polypeptides. In certain embodiments, an A41 L polypeptide, fragment thereof, or variant thereof, fused in frame with a mutein Fe polypeptide is used to treat an immunological disease or disorder (including an autoimmune disease or an inflammatory disease), which is describe in detail here. As described herein, mutein A41 1 / Fc polypeptides can also be used to treat a disease or disorder associated with disruption of cell migration, cell proliferation or cell differentiation, including but not limited to an immunological disease or disorder, a disease or cardiovascular disorder, a metabolic disease or disorder, or a proliferative disease or disorder. The A41 L polypeptide fragments include fragments of A41 L polypeptide variant. The A41 L polypeptide fragments also include A41 L fragments that have an amino acid sequence that differs from full length A41 L from which the fragments are derived, which is the A41 L polypeptide fragment variant has at least 99%, 98%, 97%, 95%, 90%, 87%, 85% or 80% amino acid sequence identity with a portion of the A41 L polypeptide. full length Variants of A41 L polypeptide fragments that have the ability to alter (suppress or increase) the immune response of an immune cell retain the comparable ability to alter the immune response of an immune cell. Variants of A41 L polypeptide and A41 L polypeptide fragment variants that retain the ability to alter the immune response of an immune cell include variants that contain conservative amino acid substitutions. A variety of criteria known to those skilled in the art indicate whether the amino acids at a particular position in a peptide or polypeptide are conservative (or similar). For example, a similar amino acid or a conservative amino acid substitution is one in which an amino acid residue is replaced by an amino acid residue having a similar side chain, such as amino acids with basic side chains (e.g., lysine, arginine, histidine); Acid side chains (eg, aspartic acid, glutamic acid); uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, histidine); non-polar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan); beta-branched side chains (e.g., threonine, valine, isoleucine), and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan). Proline, which is considered more difficult to classify, shares properties with amino acids that have aliphatic side chains (e.g., leucine, valine, isoleucine, and alanine). Under certain circumstances, the replacement of glutamic acid by glutamine or aspartic acid with asparagine can be considered a similar substitution since glutamine and asparagine are glutamic acid amide derivatives and aspartic acid, respectively. As understood in the art "similarity" between two polypeptides is determined by comparing the sequence of amino acids and amino acid substitutes conserved thereon of the polypeptide with the sequence of a second polypeptide (e.g., using GENEWORKS, Align, or the algorithm). BLAST, as described here). By way of example, a variant of A41 L described herein has a conservative substitution of an arginine residue with a lysine residue at position 50 of SEQ ID NO: 82 (GenBank Ace No. AAM13618, May 20, 2003) to provide SEQ ID NO: 83 (see also, e.g., Hu et al., Virology 181: 716-20 (1991); Hu et al., Virology 204: 343-56 (1994)). This variant of A41 L retains the functions and properties of the wild-type A4 IL polypeptide. A variant A41 L polypeptide also includes a variant that interacts with or binds to only one or two (ie, LAR and RPTP-d, LAR and RPTP-s, or RPTP-d and RPTP-s) but not all three of LAR, RPTP-d, and RPTP-s. Said variant comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1-1 5, 16-25, 26-35, or 36-45 substitutions, deletions or insertions of amino acids compared to the wild-type A41 L polypeptide. The binding of A41 L to each of the RPTPs can be determined in accordance with methods described herein and practiced in the art. The source of the polypeptides for binding studies include, for example, A41 L and isolated RPTPs, or fragments thereof, or single cell lines capable of recombinant expression of one of A41 L, LAR, RPTP-d, and RPTP- s. Variants of full-length A41 L polypeptides or A41 L fragments can be easily prepared by methods and techniques of genetic engineering and recombinant molecular biology. The analysis of the amino acid sequence of a primary and secondary A41 L polypeptide and computer modeling to analyze the tertiary structure of the polypeptide can help to identify specific amino acid residues that can be substituted without altering the structure and as a consequence, potentially the function , of the A41 L polypeptide. Modifying DNA encoding an A41 L polypeptide or fragment can be performed by a variety of methods, including site-specific mutagenesis or targeted DNA site, such methods include DNA amplification using primers to introduce and amplify alterations in the DNA template, such as splicing by PCR overlap extension (SOE). Mutations can be introduced at a particular site by synthesizing oligonucleotides containing a mutant sequence, flanked by restriction sites that allow ligation to fragments of the native sequence. After ligation, the resulting reconstructed sequence encodes a variant (or derivative) having the desired amino acid insertion, substitution or deletion. Site-directed mutagenesis is typically performed using a phage vector that has single-stranded or double-stranded forms, such as an M13 phage vector, which is well known and commercially available. Other suitable vectors containing a phage origin of a single replication chain can be used (see, e.g., Veira et al., Meth.

Enzymol. 15: 3 (1987)). In general, site-directed mutagenesis is carried out by preparing a single-chain vector encoding the protein of interest. An oligonucleotide primer containing the desired mutation within a region of DNA homology in the single-stranded vector is annealed to the vector followed by addition of a DNA polymerase, such as E. coli DNA polymerase I (Klenow fragment) , which uses the double-stranded region as an initiator to produce a heteroduplex in which one strand encodes the altered sequence and the other original sequence. Additional description regarding site-directed mutagenesis can be found, for example, in Kunkel et al. (Meth. Enzymol. 154: 367 (1987)) and in the patents of E.U.A. Nos. 4,518,584 and 4,737,462. The heteroduplex is introduced into appropriate bacterial cells, and clones that include the desired mutation are selected. The resulting altered DNA molecules can be expressed recombinantly in appropriate host cells to produce the variant, modified protein. Oligonucleotide-directed (or segment-specific) site-specific mutagenesis procedures can be used to provide an altered polynucleotide having particular codons altered in accordance with the desired substitution, deletion or insertion. Protein deletion or truncation derivatives can also be constructed using convenient restriction endonuclease sites adjacent to the desired deletion. After the restriction, the pendants can be filled and the DNA can be religated. Illustrative methods for making the alterations discussed above are described in Sambrook et al. (Molecular Cloning: A Laboratory Manual, 3rd ed., Cold Spring Harbor Laboratory Press, NY 2001). Alternatively, random mutagenesis techniques, such as alanine screen mutagenesis, subjectively mutated polymerase chain mutagenesis, and oligonucleotide directed mutagenesis can be used to prepare variants of A41 L polypeptide and fragment variants (see, e.g. , Sambrook et al., Supra). Tests to assess whether the variant is doubled in a conformation comparable with the non-variant polypeptide or fragment include, for example, the ability of the protein to react with mono- or polyclonal antibodies that are specific for native or split epitopes, retention of functions of ligand binding, and the sensitivity or resistance of the mutant protein to digestion with proteases (see Sambrook et al., supra). Variants of A41 L as described herein can be identified, characterized, and / or made in accordance with these methods described herein or other methods known in the art, which are routinely practiced by those skilled in the art. Mutations that are made or identified in the nucleic acid molecules encoding an A41 L polypeptide preferably retain the reading frame of the coding sequences. In addition, the mutations will preferably not create regions of complementarity that when transcribed could hybridize to produce secondary mRNA structures, such as loops or pins, that would adversely affect translation of the mRNA. Although a mutation site can be predetermined, the nature of the mutation per se need not be predetermined. For example, to select optimal characteristics of a mutation at a given site, random mutagenesis can be constructed at the target codon and expressed mutants selected gain or loss or retention of biological activity. An A41 L polynucleotide is any polynucleotide that encodes an A41L polypeptide or at least a portion (or fragment) of an A41 L polypeptide or a variant thereof, or that is complementary to said polynucleotide. The nucleotide sequences of polynucleotides encoding A41 L, or their orthologs, can be found, for example, in the genomic sequences of poxviruses provided in GenBank entries for which access numbers are provided herein, in access to GenBank Nos. NC_001559; NC_001611; Y16780; X69198; NC_003310; NC_005337; AY603355; NC_003391; AF438165; U94848; AY243312; AF380138; L22579; M35027; NC_003663; X94355; AF482758; NC_001132; AF170726; NC_001266; AF170722 and which can be deduced from the amino acid sequences described herein (e.g., SEQ ID NOs: 1- 21). The polynucleotides comprise at least 15 consecutive nucleotides or at least 30, 35, 40, 50, 55 or 60 consecutive nucleotides, in certain embodiments at least 70, 75, 80, 90, 100, 110, 120, 125 or 130 consecutive nucleotides, and in other modalities at least 135, 140, 145, 150, 155, 160 or 170 consecutive nucleotides, and in other modalities at least 180, 190, 200, 225, 250, 275, 300, 325, 350 , 375, 400, 405, 410, 420, 425, 445, 450, 475, 500, 525, 530, 545, 550, 575, 600, 625, 650 or 660 consecutive nucleotides including sequences encoding a A41 L polypeptide, or nucleotide sequences that are complementary to said sequence. Certain polynucleotides that encode an A41 L polypeptide, variant or fragment thereof can also be used as probes, primers, short interfering RNAs (siRNAs), or antisense oligonucleotides, as described herein. The polynucleotides may be single-stranded DNA or RNA (encoders or antisense) or double-stranded (eg, genomic or synthetic) or DNA (eg, cDNA or synthetic) RNA. Polynucleotide variants can also be identified by hybridization methods. Suitable moderately astringent conditions include, for example, pre-washing in a solution of 5X SSC, 0.5% SDS, 1.0 mM EDTA (pH 8.0); hybridization at 50 ° C-70 ° C, 5X SSC for 1-16 hours; followed by washing once or twice at 22-65 ° C for 20-40 minutes with one or more of each of 2X, 0.5X, and 0.2X SSC containing 0.05-0.1% SDS. For additional astringency, conditions may include a wash in 0.1 X SSC and 0.1% SDS at 50-60 ° C for 15 minutes. As understood by those skilled in the art, variations in astringency of hybridization conditions can be achieved by altering the time, temperature, and / or concentration of the solutions used for the steps of pre-hybridization, hybridization, and washing. Suitable conditions may also depend in part on the particular nucleotide sequences of the probe used (ie, for example, the content of guanine plus cytosine (G / C) versus adenine plus thymidine (A / T)). Accordingly, one skilled in the art will appreciate that suitably astringent conditions can be easily selected without extraordinary experimentation when a desired selectivity of the probe is identified. 130L Polypeptides As described herein, the 130L gene encodes a glycoprotein (here referred to as 130L polypeptide) which is likely a viral virulence factor and which is secreted by cells infected with YLDV. Similar to other poxviruses, the YLDV genome is double-stranded DNA, and the virus has adapted to replicate in some other host species by acquiring host genes that allow the virus to evade the host's immune system and / or facilitate viral replication (see, e.g., Najarro et al., J Gen. Virol. 84: 3325-36 (2003)). Polypeptides encoded by the genomes of several poxviruses can affect an immune response by inhibiting or blocking the function of host factors such as interferons, complement, cytokines, and / or chemokines, or by inhibiting, blocking or altering the effect of inflammation and fever. A 130L polypeptide, as used herein, refers to any of a number of 130L polypeptides encoded by the yatapox virus genome of Yaba disease virus (see examples of genome sequences (including nucleotide sequences encoding 130L polypeptides) for viruses of disease similar to Yaba in access to GenBank Nos. AJ293568.1 and NCJD02642.1). A 130L polypeptide can comprise any of the amino acid sequence described herein or known in the art, or a variant of said amino acid sequence (including orthologs). Exemplary amino acid sequences of 130L polypeptides are set forth in SEQ ID NO: 85 (see Access to GenBank No. CAC21368.1) and Access to GenBank No. NP_073515.1 (SEQ ID NO: 144). A 130L polypeptide may also include a 130L polypeptide variant comprising an amino acid sequence that differs by at least one amino acid from a 130L polypeptide sequence described herein or known in the art. The 130L polypeptide variant may differ from a wild-type amino acid sequence due to the insertion, deletion, addition and / or substitution of at least one amino acid and may differ due to the insertion, deletion, addition and / or substitution of at least two, three, four, five, six, seven, eight, nine or ten amino acids or can differ by any number of amino acids between 10 and 45 amino acids. Variants of 130L polypeptides include, for example, a naturally occurring polymorphism (ie, 130L polypeptide orthologs encoded by genomes of different strains of yatapoxvirus) or recombinantly engineered 130L polypeptide variants or by genetic engineering. In certain embodiments, a variant of a 130L polypeptide retains at least one functional or biological activity of the wild-type 130L polypeptides and in other certain embodiments, a 130L polypeptide variant retains at least one, and in certain embodiments, all of the functions or biological activities of the wild-type 130L polypeptides. A functional or biological activity of 130L polypeptides or a variant thereof can be determined in accordance with methods described herein and known in the art, whose function or activity includes the ability (1) to bind to or interact with at least one of, or at least two of, or all three of the PTPs, LAR, RPTP-d, and RPTP-s receivers; (2) to bind to an antibody that specifically binds a wild-type 130L polypeptide; and (3) to suppress an immune response from a cell that expresses at least one of LAR, RPTP-d, and RPTP-s. A 130L polypeptide variant that retains a functional or biological activity of a wild-type 130L polypeptide shows a comparable level of function or activity (i.e., does not differ in a statistically significant or biologically meaningful way) at the level of functional or biological activity presented by the wild-type 130L polypeptides. Variants of 130L polypeptides and polynucleotides encoding these variants can be identified by sequence comparison. As you use here, two amino acid sequences have 100% amino acid sequence identity if the amino acid residues of the two amino acid sequences are the same when aligned for maximum correspondence. Similarly, two polynucleotides have 100% nucleotide sequence identity if the nucleotide residues of the two sequences are the same when aligned for maximum correspondence. Sequence comparisons can be made using any method including the use of computer algorithms well known to those skilled in the art. Such algorithms include A gn or the BLAST algorithm (see, v gr, Altschul, J Mol Biol 2 J 9 555-565 , 1991, Henikoff and Henikoff, Proc Nati Acad ScL USA 89 10915-10919, 1992), which are available on the NCBI website (see [online] Internet <URL http // www / ncbi nlm nih gov / cgi-bin / BLAST) Default parameters can be used In addition, standard software programs are available, such as those included in LASERGENE bioinformatics computing suite (DNASTAR, Inc, Madison, Wl ), CLUSTALW program (Thompson et al, Nucleic Acids Res 22 4673-80 (1991)), and "GeneDoc" (Nicholas et al, EMBNEW News 4 14 (1991)) Other methods for comparing two nucleotide or amino acid sequences when determining optimal alignment are put into practice by those skilled in the art (see, for example, Peruski and Peruski, The Internet and the New Biology Tools for Genomic and Molecular Research (ASM Press, Inc. 1997), Wu et al (eds), " Information Superhighway and Computer Databases of Nucleic Acids and Proteins, "in Methods m Gene Biotechnology, pages 123-151 (CRC Press, Inc 1997), and Bishop (ed), Guide to Human Genome Computing, 2nd Ed (Academic Press, Inc 1998 )) In certain modalities, the amino acid sequence of a variety The peptide 130L is at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 98% identical to the corresponding wild type 130L peptide or a 130L peptide described herein and / or known in the art (see, vgr, SEQ ID NO 85 (having the signal peptide sequence (SEQ ID NO: 151)) or SEQ ID NO: 150 (mature 130L polypeptides)). Alternatively, a 130L polypeptide variant can be identified by comparing the nucleotide sequence of a polynucleotide encoding the variant with a polynucleotide encoding a 130L polypeptide. In particular embodiments, the nucleotide sequence of a polynucleotide encoding a 130L polypeptide variant is at least 70%, 75%, 80%, 85%, 90% or 95% identical to one or more of the polynucleotide sequences that encode 130L polypeptides, which are described herein. Polynucleotide variants also include polynucleotides that differ in nucleotide sequence identity due to the degeneracy of the genetic code but encode a 130L polypeptide having an amino acid sequence described herein or known in the art. As described herein, a 130L polypeptide, which includes variants and fragments of 130L polypeptides and fusion polypeptides as described herein (which interact with or bind to at least one, two, or three of LAR, RPTP-d, and RPTP-s), present on the surface of a cell, can be used to alter (e.g., suppress or increase) the immune response of an immune cell. In one embodiment, a 130L polypeptide or a variant thereof or a 130L fusion polypeptide as described herein can be used to treat a patient that presents an acute response. For example, a 130L polypeptide, variant or fragment thereof can suppress an immune response associated with a disease or condition such as acute respiratory distress syndrome (ARDS). ARDS, which can develop in adults and children, often follows a direct pulmonary or systemic attack (eg, sepsis, pneumonia, aspiration) that injures the alveolar-capillary unit. Several cytokines are associated with the development of the syndrome, including, for example, tumor necrosis factor-alpha (FNT-a), interleukin-beta (IL-β), IL-10, and soluble intercellular adhesion molecule 1 (if CAM -1 ). The increased or decreased level of these factors and cytokines in a biological sample can be easily determined by methods and tests described herein and routinely practiced in the art for monitoring the acute state and for monitoring the effect of the treatment. To reduce or minimize the possibility or degree of an immune response that is specific for 130L, the 130L polypeptide, 130L variant, derivative or fragment thereof, or fusion protein comprising the same can be administered in a limited number of dose, can be produced or derived in a manner that alters the glycosylation of 130L, and / or can be administered under manure conditions that reduce or minimize the antigenicity of 130L. For example130L can be administered before, concurrent with, or subsequent to the administration in the host of a second composition that suppresses an immune response, particularly a response that is specific for 130L. In certain other embodiments, a 130L polypeptide fragment may alter the immune response of an immune cell. Said 130L fragment interacts with or binds to at least one of, at least two of, or all three of the PTPs receptor, LAR, RPTP-d, and RPTP-s. The fragment may comprise at least 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive amino acids. In certain embodiments, the 130L fragment comprises at least any number of amino acids between 20 and 50 consecutive amino acids of a 130L polypeptide, and in other embodiments, the 130L fragment comprises at least any number of amino acids between 50 and 100 consecutive amino acids of a 130L polypeptide. The 130L fragments also include truncations of a 130L polypeptide. A truncated 130L polypeptide may lack at least 1, 2-10, 11-20, 21-30, 31-40, or 50 amino acids either from the amino terminus or the carboxy terminal end or both the amino terminal end as the carboxy terminal of a full-length 130L polypeptide. In certain embodiments, the 130L fragment lacks the entire amino terminal half or carboxy terminal half of the 130L polypeptide. In other embodiments, the 130L polypeptide fragment (including a truncated fragment) can be conjugated, fused to, or otherwise linked to a portion that is not a 130L polypeptide or fragment. For example, the 130L polypeptide fragment can be linked to another molecule capable of altering the immune response of an immune cell (e.g., suppressing the immune response of the immune cell), said immune cell can be the same cell , the same type of cell, or a cell different from the cell affected by the 130L polypeptide or fragment. In addition, those skilled in the art are familiar with methods for increasing the half-life and / or improving the pharmacokinetic properties of a polypeptide, such as by pegylation of the polypeptide.

An example of a 130L fusion polypeptide includes a variant 130L polypeptide, or fragment thereof as described herein fused in frame with an immunoglobulin Fe (Ig) polypeptide. A Fe polypeptide of an immunoglobulin comprises the heavy chain CH2 and CH3 domain and a portion of or all of the hinge region that is located between CH1 and CH2. Historically, a Fe fragment was derived by digestion with papain from an immunoglobulin and included the hinge region of the immunoglobulin. The Fe regions are monomeric polypeptides that can be linked to dimeric or multimeric forms by covalent (e.g., particularly disulfide bonds) and non-covalent association. The number of intermolecular disulfide bonds between monomeric subunits of Fe polypeptides varies depending on the class of immunoglobulin (e.g., IgG, IgA, IgE) or subclass (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, human Ig2). Fragments of a Fe polypeptide, such as a Fe polypeptide that is truncated at the C-terminus (that at least 1, 2, 3, 4, 5, 10, 15, 20, or more amino acids have been removed or deleted) , they can also be used. In certain embodiments, the Fes polypeptide described herein contains multiple cysteine residues, such as at least some or the cysteine residues in the hinge region, to allow interchain chain disulfide bonds to form between the Fe polypeptide portions of two proteins. separate 130L / Fc fusion, thereby forming 130L / Fc fusion polypeptide dimers. In other embodiments, if retention of antibody-dependent cell-mediated cytotoxicity (ADCC) and complement fixation (and complement-associated cytotoxicity (CDC)) is desired, the Fe polypeptide comprises substitutions or deletions of cysteine residues in the region of hinge in such a way that a Fe polypeptide fusion protein is monomeric and does not form a dimer (see, e.g., U.S. Patent Application Publication No. 2005/0175614). The Fe portion of the immunoglobulin mediates certain effector functions of an immunoglobulin. Three general categories of effector functions associated with the Fe region include (1) activation of the classical complement cascade, (2) effector cell interaction, and (3) immunoglobulin compartmentalization. Currently, a Fe polypeptide, and any of one or more constant region domains, and fusion proteins comprising at least one immunoglobulin constant region domain can be easily prepared in accordance with recombinant molecular biology techniques with which he is familiar one skilled in the art. A 130L polypeptide or variant, or fragment thereof, can be fused in frame with an immunoglobulin Fe polypeptide (130L-Fc fusion polypeptide) which is prepared using the nucleotide and the encoded amino acid sequences derived from the animal species for which Use is intended for the 130L-lgFc fusion polypeptide. One skilled in the art of molecular biology can easily prepare said fusion polypeptides in accordance with methods described herein and routinely practiced in the art. In one embodiment, the Fe polypeptide is of human origin and can be of any of the immunoglobulin classes, such as IgG1, IgG2, IgG3, IgG4 or human IgA. In a certain embodiment, the Fe polypeptide is derived from a human IgG1 immunoglobulin (see Kabat et al., Supra). In another embodiment, the 130L-Fc fusion polypeptide comprises a Fe polypeptide of a non-human animal, for example, but not limited to, a mouse, rat, rabbit or hamster. The amino acid sequence of a Fe polypeptide derived from an immunoglobulin of a host species to which a 130L-Fc fusion polypeptide can be administered is likely to be less immunogenic or non-immunogenic than a Fe polypeptide from a non-syngeneic host. As described herein, immunoglobulin sequences from a variety of species are available in the art, for example, in Kabat et al. (in Sequences of Proteins of Immunological Interest, 4th ed., (U.S. Dept. of Health and Human Services, U.S. Government Printing Office, 1991)). As described herein, a 130L polypeptide (or variant or fragment thereof) that is fused to a Fe polypeptide can comprise any of the 130Ls polypeptides described herein or known in the art. For example, a 130L polypeptide having the amino acid sequence of the 130L polypeptide encoded by the genome of a Yaba-like disease virus (see, e.g., access to GenBank Nos. AJ293568.1 and NC 002642) can be fused to an immunoglobulin Fe region (see, e.g., SEQ ID NO: 154). Also as described herein, the Fe moiety of the fusion polypeptide can be derived from a human or non-human immunoglobulin. By way of example, the Fe portion of a 130L-Fc fusion polypeptide can comprise the amino acid sequence of all or a portion of the hinge region, CH2 domain, and CH3 domain of a human immunoglobulin, e.g. lgG1 A 130L-Fc fusion polypeptide may further comprise a signal peptide sequence that facilitates post-translational transport of the polypeptide into the host cell in which the fusion polypeptide is expressed. The signal peptide sequence can be derived from a 130L signal peptide sequence encoded by the poxvirus genome from which the 130L sequence was obtained. Alternatively, the signal peptide sequence may comprise an amino acid sequence that is derived from an unrelated polypeptide, such as human growth hormone. A Fe polypeptide as described herein also includes Fe polypeptide variants. One such Fe polypeptide variant has one or more cysteine residues (such as one or more cysteine residues in the hinge region) that forms a disulfide bond of interchain substituted with another amino acid, such as serine, to reduce the number of interchain disulfide bonds that can be formed between the two heavy chain constant region polypeptides that form a Fe polypeptide. In addition, or alternatively, the cysteine residue plus A terminal amino of the hinge region forming a disulfide bond with a light chain constant region in a complete immunoglobulin molecule can be substituted, for example, with a serine residue. Alternatively, one or more cysteine residues may be deleted from the wild-type hinge of the Fe polypeptide. Another example of a Fe polypeptide variant is a variant having one or more amino acids involved in an effector function substituted or deleted in such a way that the Fe polypeptide has a reduced level of an effector function. For example, amino acids in the Fe region can be substituted to reduce or abolish the binding of a component of the complement cascade (see, e.g., Duncan et al., Nature 332: 563-64 (1988)).; Morgan et al., Immunology 86: 319-24 (1995)) or to reduce or abolish the ability of the Fe polypeptide to bind to an IgG Fe receptor expressed by an immune cell (Wines et al., J Immunol. 164: 5313 -18 (2000); Chappel et al., Proc. Nati. Acad. Sel USA 88: 9036 (1991); Canfield et al., J. Exp. Med. 173: 1483 (1991); Duncan et al., Supra. ); or to alter antibody-dependent cellular cytotoxicity. Said variant Fe polypeptide that differs from the wild-type Fe polypeptide is also referred to herein as a mutein Fe polypeptide. In one embodiment, an A41 L polypeptide (or fragment or variant thereof) is fused in frame with an Fe polypeptide comprising at least one substitution of a residue that in the wild type Fe region polypeptide contributes to the binding of a Fe polypeptide or immunoglobulin to one or more Fe IgG receptors expressed in certain immune cells. Said mutein Fe polypeptide comprises at least one substitution of an amino acid residue in the CH2 domain of the mutein Fe polypeptide, such that the ability of the fusion polypeptide to bind to an IgG Fe receptor, such as a Fe receptor. of IgG present on the surface of an immune cell, is reduced. As described herein, residues in the amino terminal portion of the CH2 domain that contributes to IgG receptor binding include residues at positions Leu234-Ser239 (Leu-Leu-Gly-Gly-Pro-Ser (SEQ ID NO: 152) (EU numbering system, Kabat et al., supra) (see, e.g., Morgan et al., Immunology 86: 319-24 (1995), and references cited therein.) Substitution of the amino acid in a or more of these six positions (ie, one, two, three, four, five or all six) in the CH2 domain results in a reduction in the ability of the Fe polypeptide to bind to one or more of the Fe receptor of IgGs ( or isoforms thereof) (see, e.g., Burton et al., Adv. Immunol., 51: 1 (1992), Hulett et al., Adv. Immunol., 57: 1 (1994); Jefferis et al., Immunol Rev. 163: 59 (1998), Lund et al., J Immunol., 147: 2657 (1991), Sarmay et al., Mol Immunol 29: 633 (1992), Lund et al., Mol. Immunol. : 53 (1992), Morgan et al., Supra.) In addition to the substitution of one or more amino acids in the US positions 234-239, one, two, or three or more amino acids adjacent to this region (either to the carboxy terminal side of position 239 or to the amino terminal side of position 234) can also be substituted. By way of example, substitution of the leucine residue at position 235 with a glutamic acid residue or an alanine residue cancels or reduces, respectively, the affinity of an immunoglobulin (such as human IgG3) for Fc? RI (Lund et al. al., 1991, supra; Canfield et al., supra; Morgan et al., supra). As another example, the replacement of the leucine residues at positions 234 and 235 (corresponding to positions 234 and 235, for example, with alanine residues, abolishes the binding of an immunoglobulin to Fc? Rlla (see, v. Gr., Wines et al., supra.) Alternatively, leucine at position 234, leucine at position 235, and glycine at position 237, each can be substituted with a different amino acid, such as leucine at position 234 can be substituted with an alanine residue (L234A), leucine at 235 can be substituted with an alanine residue (L235A) or with a glutamic acid residue (L235E), and the glycine residue at position 237 can be substituted with another amino acid, for example an alanine residue (G237A) In one embodiment, a mutein Fe polypeptide that is fused in frame to a 130L polypeptide (or variant or fragment thereof) comprises one, two, three, four, five, or six mutations located between positions 15-20 of SEQ ID NO: 145 or between positions 13-18 of SEQ ID NO: 146 (substitutions at the positions corresponding to EU 234, 235, and 237) corresponding to positions 234-239 of a CH2 domain of IgGI (EU numbering system) as described here. In another modality, a mutein Fe polypeptide comprises a mutation of a cysteine residue in the hinge region of a Fe polypeptide. In one embodiment, the cysteine residue most proximal to the amino terminus of the hinge region of a Fe polypeptide (v. ., for example, the cysteine residue most proximal to the amino terminus of the hinge region of the Fe portion of a wild-type IgG1 immunoglobulin) is deleted or substituted with another amino acid. That is, by way of illustration, the cysteine residue in position 1 of SEQ ID NO: 145 is deleted, or the cysteine residue in position 1 is substituted with another amino acid that is incapable of forming a disulfide bond, by example, with a serine residue. In another embodiment, a mutein Fe polypeptide comprises a deletion or substitution of the cysteine residue most proximal to the amino terminus of the hinge region of a Fe polypeptide further comprising deletion or substitution of the adjacent C-terminal amino acid. In a certain embodiment, this cysteine residue and the adjacent C-terminal residue are both deleted from the hinge region of a mutein Fe polypeptide. In a specific embodiment, the cysteine residue in position 1 of SEQ ID NO: 145 and the aspartic acid in position 2 of SEQ ID NO: 145 are deleted. Fe polypeptides comprising deletion of these cysteine and aspartic acid residues in the hinge region are expressed more efficiently in a cell comprising a recombinant expression construct encoding said Fe polypeptide. In a specific embodiment, a mutein Fe polypeptide comprises the sequence of amino acids set forth in SEQ ID NO: 146, which differs from the wild type Fe polypeptide (SEQ ID NO: 145) wherein the cysteine residue more proximal to the amino terminus of the hinge region of a Fe polypeptide is deleted and the adjacent C-terminal aspartic acid is deleted and the leucine residue corresponding to EU234 is substituted with an alanine residue, the leucine residue corresponding to EU235 is substituted with a glutamic acid residue, and the glycine corresponding to EU237 is substituted with an alanine residue (see SEQ ID NO: 146). Therefore, an illustrative Lutein Fe polypeptide has an amino acid sequence at its amino terminus of KTHTCPPCPAPEAEGAPS (SEQ ID NO: 148) (positions 1-18 of SEQ ID NO: 146). Other Fe variants encompass similar amino acid sequences of known Fe polypeptide sequences having only minor changes, for example by way of illustration and not limitation, covalent chemical modifications, insertions, deletions and / or substitutions, which may also include conservative substitutions. . The amino acid sequences that are similar to one another may share substantial regions of sequence homology. Similarly, the nucleotide sequences encoding the Fe variants may encompass substantially similar nucleotide sequences and have only minor changes, for example, by way of illustration and not limitation, covalent chemical modifications, insertions, deletions, and / or substitutions, which can also include silent mutations due to the degeneracy of the genetic code. Nucleotide sequences that are similar to one another may share regions of substantial sequence homology. An Fe polypeptide or at least one immunoglobulin constant region, or portion thereof, when fused to a peptide or polypeptide of interest acts, at least in part, as a portion of vehicle or carrier that prevents degradation and / or increases half-life, reduces toxicity, reduces immunogenicity, and / or increases the biological activity of the peptide such as by forming dimers or other multimers (see, e.g., US Patent Nos. 6,018,026; 6,291, 646; 6,323,323; 6,300,099; 5,843,725). (See also, e.g., U.S. Patent No. 5,428,130, U.S. Patent No. 6,660,843, U.S. Patent Application Publication Nos. 2003/064480, 2001/053539, 2004/087778, 2004/077022, 2004/071712; 2004/057953/2004/053845 / 2004/044188; 2004/001853; 2004/082039). A 130L polypeptide (or variant or fragment thereof) fused in frame with a Fe polypeptide or Fe polypeptide variant (e.g., a mutein Fe polypeptide) can comprise a peptide linker between the mutein Fe polypeptide) can comprising a peptide linker between 130L polypeptide and Fe polypeptide. The linker can be a single amino acid (such as a glycine residue) or can be two, three, four, five, six, seven, eight, nine or ten amino acids, or it can be any number of amino acids between 10 and 20 amino acids. By way of illustration but not limitation, a linker may comprise at least two amino acids that are encoded by a nucleotide sequence that is a restriction enzyme recognition site. Examples of such restriction enzyme recognition sites include, for example, ßamHI, C / al, EcoRI, Hind \\\, Kpn \,? / Col, Nhe \, Pml \, Pst \, Sa / I, and X 70l. A 130L polypeptide, fragment thereof, or variant thereof, fused in frame with a mutein Fe polypeptide can be used to suppress an immune response in a subject when administered with a pharmaceutically or physiologically suitable carrier or excipient in accordance with methods described herein and known to those skilled in the art. Such fusion polypeptides can alter a biological activity of at least one of the RPTP polypeptides described herein (ie, LAR, RPTP-s, RPTP-d), at least two of the RPTP polypeptides or the three RPTP polypeptides. In certain embodiments, a 130L polypeptide, fragment thereof, or variant thereof, fused in frame with a mutein Fe polypeptide is used to treat an immunological disease or disorder (including an autoimmune disease or an inflammatory disease), which are described with detail here. As described herein, the 130L polypeptides / mutein Fe polypeptide can be used to treat a disease or disorder associated with disruption of cell migration, cell proliferation or cell differentiation, including but not limited to an immunological disease or disorder, a disease or cardiovascular disorder, a metabolic disease or disorder, or a proliferative disease or disorder. The 130L polypeptide fragments include fragments of 130L polypeptide variant. The 130L polypeptide fragments also include 130L fragments having an amino acid sequence that differs from full-length 130L from which the fragments are derived, which is the 130L polypeptide fragment variant has at least 99%, 98%, 97%, 95%, 90%, 87%, 85% or 80% amino acid sequence identity with a portion of the full-length 130L polypeptide. Variants of 130L polypeptide fragments that have the ability to alter (suppress or increase) the immune response of an immune cell retain the comparable ability to alter the immune response of an immune cell. 130L polypeptide variants and 130L polypeptide fragment variants that retain the ability to alter the immune response of an immune cell include variants that contain conservative amino acid substitutions. A variety of criteria known to those skilled in the art indicate whether the amino acids at a particular position in a peptide or polypeptide are conservative (or similar). For example, a similar amino acid or a conservative amino acid substitution is one in which an amino acid residue is replaced by an amino acid residue having a similar side chain, such as amino acids with basic side chains (e.g., lysine, arginine, histidine); acidic side chains (e.g., aspartic acid, glutamic acid); uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, histidine); non-polar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan); beta-branched side chains (e.g., threonine, valine, isoleucine), and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan). Proline, which is considered more difficult to classify, shares properties with amino acids that have aliphatic side chains (e.g., leucine, valine, isoleucine, and alanine). Under certain circumstances, the replacement of glutamic acid by glutamine or aspartic acid with asparagine can be considered a similar substitution since glutamine and asparagine are glutamic acid amide and aspartic acid derivatives, respectively. As understood in the art "similarity" between two polypeptides is determined by comparing the sequence of amino acids and amino acid substitutes conserved thereon of the polypeptide with the sequence of a second polypeptide (e.g., using GENEWORKS, Align, or the algorithm). BLAST, as described here). A 130L polypeptide variant also includes a variant that interacts with or binds to only one or two (ie, LAR and RPTP-d, LAR and RPTP-s, or RPTP-d and RPTP-s) but not all three of LAR, RPTP-d, and RPTP-s. Said variant comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11-15, 16-25, 26-35, or 36-45 amino acid substitutions, deletions or insertions compared with the wild-type 130L polypeptide. The binding of 130L to each of the RPTPs can be determined in accordance with methods described herein and practiced in the art. The source of the polypeptides for binding studies include, for example, 130L and isolated RPTPs, or fragments thereof, or single cell lines capable of recombinant expression of one of 130L, LAR, RPTP-d, and RPTP-s . Variants of full length 130L polypeptides or 130L fragments can be easily prepared by genetic engineering and recombinant molecular biology methods and techniques. The analysis of the amino acid sequence of a 130L polypeptide and computer modeled to analyze the tertiary structure of the polypeptide can help to identify specific amino acid residues that can be substituted without altering the structure and as a consequence, potentially the function, of the 130L polypeptide . The modification of DNA encoding a 130L polypeptide or fragment can be performed by a variety of methods, including site-specific mutagenesis or targeted DNA site, such methods include DNA amplification using primers to introduce and amplify alterations in the DNA template, such as splicing by PCR overlap extension (SOE). Mutations can be introduced at a particular site by synthesizing oligonucleotides containing a mutant sequence, flanked by restriction sites that allow ligation to fragments of the native sequence. After ligation, the resulting reconstructed sequence encodes a variant (or derivative) having the desired amino acid insertion, substitution or deletion. Site-directed mutagenesis is typically performed using a phage vector that has single-stranded or double-stranded forms, such as an M13 phage vector, which is well known and commercially available. Other suitable vectors containing a phage origin of a single replication chain can be used (see, e.g., Veira et al., Meth. Enzymol 15: 3 (1987)). In general, site-directed mutagenesis is carried out by preparing a single-chain vector encoding the protein of interest. An oligonucleotide primer containing the desired mutation within a region of DNA homology in the single-stranded vector is annealed to the vector followed by the addition of a DNA polymerase, such as E. coli DNA polymerase I (Klenow fragment), which uses the double-stranded region as an initiator to produce a heteroduplex in which one strand encodes the altered sequence and the other original sequence. Additional description regarding site-directed mutagenesis can be found, for example, in Kunkel et al. (Meth. Enzymol. 154: 367 (1987)) and in the patents of E.U.A. Nos. 4,518,584 and 4,737,462. The heteroduplex is introduced into appropriate bacterial cells, and clones that include the desired mutation are selected. The resulting altered DNA molecules can be expressed recombinantly in appropriate host cells to produce the variant, modified protein. Oligonucleotide-directed (or segment-specific) site-specific mutagenesis procedures can be used to provide an altered polynucleotide having particular codons altered in accordance with the delease substitution, deletion or insertion. Protein deletion or truncation derivatives can also be constructed using convenient restriction endonuclease sites adjacent to the desired deletion. After the restriction, the pendants are filled and the DNA is religated. Illustrative methods for making the alterations discussed above are described in Sambrook et al. (Molecular Cloning: A Laboratory Manual, 3d ed., Cold Spring Harbor Laboratory Press, NY 2001). Alternatively, random mutagenesis techniques, such as alanine scanning mutagenesis, subjectively mislabeled polymerase chain mutagenesis, and oligonucleotide directed mutagenesis can be used to prepare 130L polypeptide variants and fragment variants (see, e.g., Sambrook et al., Supra). Tests to assess whether the variant is doubled in a conformation comparable with the non-variant polypeptide or fragment include, for example, the ability of the protein to react with mono- or polyclonal antibodies that are specific for native or split epitopes, retention of functions of ligand binding, and the sensitivity or resistance of the mutant protein to digestion with proteases (see Sambrook et al., supra). Variants of 130L as described herein can be identified, characterized, and / or made in accordance with these methods described herein or other methods known in the art, which are routinely practiced by those skilled in the art. Mutations that are made or identified by the nucleic acid molecules encoding a 130L polypeptide preferably retain the reading frame of the coding sequences. In addition, the mutations will preferably not create regions of complementarity that when transcribed could hybridize to produce secondary mRNA structures, such as loops or pins, that would adversely affect translation of the mRNA. Although a mutation site can be predetermined, the nature of the mutation per se need not be predetermined. For example, to select optimal characteristics of a mutation at a given site, random mutagenesis can be constructed at the target codon and expressed mutants selected gain or loss or retention of biological activity. A 130L polynucleotide is any polynucleotide that encodes a 130L polypeptide or at least a portion (or fragment) of a 130L polypeptide or a variant thereof, or that is complementary to said polynucleotide. The nucleotide sequences of 130L-encoding polynucleotides, or their orthologs, can be found, for example, in the genomic sequences of poxviruses provided in GenBank entries for which access numbers are provided herein, in access to GenBank Nos. AJ293568 and NC_002642 and which can be deduced from the amino acid sequences described herein (e.g., SEQ ID NO: 85 and SEQ ID NO: 150). The polynucleotides comprise at least 15 consecutive nucleotides or at least 30, 35, 40, 50, 55 or 60 consecutive nucleotides, in certain embodiments at least 70, 75, 80, 90, 100, 110, 120, 125 or 130 consecutive nucleotides, and in other embodiments at least 135, 140, 145, 150, 155, 160 or 170 consecutive nucleotides, and in other embodiments at least 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 405, 410, 420, 425, 445, 450, 475, 500, 525, 530, 545 , 550, 575, 600, 625, 650, or 660 consecutive nucleotides that include sequences encoding a 130L polypeptide, or nucleotide sequences that are complementary to said sequence. Certain polynucleotides that encode a 130L polypeptide, variant or fragment thereof can also be used as probes, primers, short interfering RNA (siRNA), or antisense oligonucleotides, as described herein. The polynucleotides may be single-stranded DNA or RNA (encoders or antisense) or double-stranded (eg, genomic or synthetic) or DNA (eg, cDNA or synthetic) RNA. Polynucleotide variants can also be identified by hybridization methods. Suitable moderately astringent conditions include, for example, pre-washing in a solution of 5X SSC, 0.5% SDS, 1.0 mM EDTA (pH 8.0); Hybridization at 50 ° C-70 ° C, 5X SSC for 1-16 hours; followed by washing once or twice at 22-65 ° C for 20-40 minutes with one or more of each of 2X, 0.5X, and 0.2X SSC containing 0.05-0.1% SDS. For additional astringency, conditions may include a wash in 0.1 X SSC and 0.1% SDS at 50-60 ° C for 15 minutes. As understood by those skilled in the art, variations in astringency of hybridization conditions can be achieved by altering the time, temperature, and / or concentration of the solutions used for the steps of pre-hybridization, hybridization, and washing. Suitable conditions may also depend in part on the particular nucleotide sequences of the probe used (ie, for example, the content of guanine plus cytosine (G / C) versus adenine plus thymidine (A / T)). Accordingly, one skilled in the art will appreciate that suitably astringent conditions can be easily selected without extraordinary experimentation when a desired selectivity of the probe is identified.

Protein tyrosine receptor phosphatases (PTWR): LAR, PTTP-d, and RPTP-s The protein related to common leukocyte antigen (LAR), protein tyrosine phosphatase similar to receptor-d (RPTP-d), and RPTP-s are members of protein tyrosine phosphatases similar to type II receptor (PTPs). These RPTPs (also referred to herein as protein tyrosine phosphatases (PTP) or protein tyrosine receptor phosphatases) have three immunoglobulin-like domains (similar to Ig), a series of motifs similar to type III fibronectin in the extracellular domain, a site of potential proteolytic processing, a transmembrane element, and two phosphatase domains cytoplasmic domains D1 and D2 (see, e.g., Alonso et al., Cell 117: 699-711 (2004), see figure 2 therein; Streuli et al., J Exp. Med. 168: 1523 (1988); Charbonneau et al., Annu., Rev. Cell Biol. 8: 463-93 (1992); Pan et al., J. Biol. Chem. 268 : 19284-91 (1993), Walton et al., Neuron 11: 387-400 (1993), Yan et al., J Biol. Chem. 268: 24880-86 (1993), Zhang et al., Biochem. 302: 39-47 (1994); Pulido et al., J. Biol. Chem. 270: 6722-28 (1995)). Several alternatively spliced variants of LAR have been identified, and are believed to be regulated by development (O'Grady et al., J. Biol. Chem. 269: 25193 (1994); Zhang and Longo, J Cell. Biol. : 415 (1995); Honkaniemi et al., Mol. Brain, Res. 61: 1 (1998)). Multiple isoforms of RPTP-d, and RPTP-s as well as LAR appear to be generated by tissue-specific alternative splicing (see, e.g., Pulido et al., Proc. Nati. Acad. Sci USA 92 11686-90 (1995 )) In humans, LAR gene maps for chromosome Ip32, a region that is frequently deleted in tumors of neuroectodermal origin (Jipk et al, Cytogenet Cell Genet 61 266 (1992)) Protein tyrosine phosphatases such as LAR, RPTP -d, and RPTP-s Desfosfoplan Tyrosyl Phosphoproteins That Are Components of Cell Transduction Signal Pathways The regulated phosphorylation and dephosphopylation of tyrosine residues from substrates is an important control mechanism for cellular procedures such as cell growth, cell proliferation, metabolism, differentiation and locomotion Therefore, the activities of protein tyrosine phosphatases and protein tyrosine kinases that regulate reversible tyrosine phosphorylation must be integrated and regulated in a cell. Abnormal regulation results in the manifestation of several diseases and disorders (See, v. G, Tonks and Neel, Curr Opin Cell Biol 13 182-95 (2001)) Without wishing to be limited by theory, the biological specificity of the receptor PTPs (RPTPs) can be derived from their cognate ligands. Certain biological functions of LAR, PTWP-d, and RPTP-s have been suggested by the results of animal studies with private gene expression Altering the expression of the LAR gene results in the development of defective mammary gland due to altered terminal differentiation of the alveoli during pregnancy (Schaapveid et al, Dev Biol 188 134-46 (1996)), some defects in The size of! anterior brain and hippocampal organization (Yeo et al, J Neurosa Res 47 348-60 (1997)), and possibly, defects in glucose metabolism (Ren et al., Diabetes 47: 493-97 (1998)) . In contrast, the deletion of RPTP-d affects the long-term potentiation of the hippocampus and learning (Ren et al., EMBO J. 19: 2775-85 (2000)), and mice deficient in RPTP-s have defects in brain development, including reduction in the size of the hypothalamus, olfactory bulb and pituitary gland (Elchebly et al., Nat. Genet 21: 330-33 (1999); Wallace et al., Nat. Genet. 21: 334- 38 (1999)). The results of several studies have suggested a number of biological patents for LAR: altering the ability of the cells to proliferate (see, e.g., Yang et al., Carcinogenesis 21: 125; Tisi et al., J Neurobiol. : 477 (2000)); suppress the growth of tumor cells (Zhai et al., Mol.Carcinogen.14: 103 (1995)); dephosphorylating the insulin receptor and affecting glucose homeostasis (Ahmad and Goldstein, J Biol. Chem. 272: 448 (1997); Ren et al., Diabetes 47: 493 (1998)); regulate cell matrix interactions (Pulido et al., supra); regulate morphogenesis and function of the synapse (see, e.g., Dunah et al., Nat. Neurosci., 8: 458-67 (2005); and affect the function of immune cells (U.S. Patent No. 6,852,486). Although studies have indicated that RPTP-d and RPTP-s can also affect cell adhesion (Pulido et al., Supra) and morphogenesis and function of the synapse (see, e.g., Dunah et al., Supra), none have suggested that these two phosphatases can also affect the function of immune cells, therefore, the modalities described here refer to the unexpected discovery that the three phosphatases, LAR, RPTP-d and RPTP-s are expressed by immune cells.

LAR, RPTP-d and RPTP-s are cellular targets of the viral proteins A41 L and 130L. The binding of these viral proteins to any of these phosphatases can affect the function of immune cells. In particular, A4 IL or 130L can suppress an immune response and act as a suppressor of the host's immune system. Illustrative isoforms of LAR to which A41 L and 130L can bind and alter function include LAR comprising a sequence of amino acids exposed at access to GenBank Nos. NP_002832 (SEQ ID NO: 22) (encoded by a polynucleotide having the sequence of nucleotides exposed in NM_002840 (SEQ ID NO: 23)); SEQ ID NO: 24 (AAH48768) (encoded by a polynucleotide having the nucleotide sequence set forth in BCO48768 (SEQ ID NO: 65)); CAI14894 (SEQ ID NO: 25); GenBank NP_569707 (SEQ ID NO: 26) (encoded by a polynucleotide having the nucleotide sequence set forth in NM_130440 (SEQ ID NO: 27)); and CAI14895 (SEQ ID NO: 28). Illustrative isoforms of RPTP-s to which A4 IL or 130L can bind and alter function include RPTP-s comprising a sequence of amino acids set forth in GenBank NP 002841 (SEQ ID NO: 29) (encoded by a polynucleotide having the nucleotide sequence set forth in NM_002850 (SEQ ID NO: 30)); NP_570924 (SEQ ID NO: 31) (encoded by a polynucleotide having the nucleotide sequence set forth in NM_130854 (SEQ ID NO: 32)); GenBank NP_570923 (SEQ ID NO: 33) (encoded by a polynucleotide having the nucleotide sequence set out in NM_130853 (SEQ ID NO: 34)); and NP_570925 (SEQ ID NO: 35) (encoded by a polynucleotide having the nucleotide sequence set forth in NM_130855 (SEQ ID NO: 36)); and Q13332 (SEQ ID NO: 64)). Illustrative isoforms of RPTP-d to which a viral protein can bind and alter function include RPTP-d comprising a sequence of amino acids set forth in GenBank NP_002830 (SEQ ID NO: 37) (encoded by a polynucleotide having the sequence of nucleotides set forth in NM_002839 (SEQ ID NO: 38)); NP_569075 (SEQ ID NO: 39) (encoded by a polynucleotide having the nucleotide sequence set forth in NM_120391 (SEQ ID NO: 40)); NP_569076 (SEQ ID NO: 41) (encoded by a polynucleotide having the nucleotide sequence set forth in NM_130392 (SEQ ID NO: 42)); and NP_569077 (SEQ ID NO: 43) (encoded by a polynucleotide having the nucleotide sequence set forth in NM_130393 (SEQ ID NO: 44)). The LAR, RPTP-d, and RPTP-s polypeptides described herein also include variants or each respective RPTP, and which have an amino acid sequence similar to the amino acid sequences described herein. Variants include, for example, polymorphisms that occur naturally. { e.g., such as allelic variants) or recombinantly engineered RTPT polypeptide variants or by genetic engineering. A variant of RPTP has at least 70%, 75%, 80%, 85%, 90%, 95% or 98% identity or similarity to the wild-type PTPN. A variety of criteria known to those skilled in the art indicate whether the amino acids at a particular position in a peptide or polypeptide are conservative or the like.

For example, a similar amino acid or a conservative amino acid substitution is one in which an amino acid residue is replaced by an amino acid residue having a similar side chain, such as amino acids with basic side chains (eg, lysine, arginine, histidine); acidic side chains (e.g., aspartic acid, glutamic acid); uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, histidine); non-polar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan); beta-branched side chains (e.g., threonine, valine, Isoleucine), and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan). Proline, which is considered more difficult to classify, shares properties with amino acids having aliphatic side chains (e.g., leucine, valine, isoleucine, and alanine). Under certain circumstances, the replacement of glutamic acid by glutamine or aspartic acid with asparagine can be considered a similar substitution since glutamine and asparagine are glutamic acid amide derivatives and aspartic acid, respectively. The percent identity or similarity between two RPTPs that have an amino acid sequence can be easily determined by alignment methods (eg, using GENEWORKS, Align or the BLAST algorithm), which are also described here and are familiar to a skilled in the art. A variant of RPTP can also be easily prepared by methods and techniques of genetic engineering and recombinant molecular biology as described herein with respect to variants of A41 L polypeptide. In brief, the analysis of the primary and secondary amino acid sequence of an RPTP and Computer modeling to analyze the tertiary structure of the polypeptide can help identify specific amino acid residues that can be substituted. The modification of DNA encoding an RPTP polypeptide or fragment can be performed by a variety of methods, including site-specific mutagenesis or targeted DNA site, said methods include DNA amplification using primers to introduce and amplify alterations in the DNA template, such as splicing by PCR overlap extension (SOE). Mutations can be introduced at a particular site by synthesizing oligonucleotides containing a mutant sequence, flanked by restriction sites that allow ligation to fragments of the native sequence. After ligation, the resulting reconstructed sequence encodes a variant (or derivative) having the desired amino acid insertion, substitution or deletion. As described herein, site-directed mutagenesis is typically performed using a phage vector that has single-stranded or double-stranded forms, such as an M13 phage vector, which is well known and commercially available, (see, e.g., Veira et al., Meth. Enzymol. 15: 3 (1987); Kunkel et al., Meth Enzymol. 154: 367 (1987)) and in the patent of E.U.A. Nos. 4,518,584 and 4,737,462). Oligonucleotide-directed (or segment-specific) site-specific mutagenesis procedures can be used to provide an altered polynucleotide having particular codons altered in accordance with the desired substitution, deletion or insertion. Protein deletion or truncation derivatives can also be constructed using convenient restriction endonuclease sites adjacent to the desired deletion. Illustrative methods for making the alterations discussed above are described in Sambrook et al. (Molecular Cloning: A Laboratory Manual, 3rd ed., Cold Spring Harbor Laboratory Press, NY 2001). Alternatively, random mutagenesis techniques, such as alanine screening mutagenesis, subject-to-error polymerase chain mutagenesis, and oligonucleotide-directed mutagenesis can be used to prepare RPTP polypeptide variants and fragment variants (see, e.g., Sambrook et al., supra). Tests to assess whether the variant is doubled in a conformation comparable with the non-variant polypeptide or fragment include, for example, the ability of the protein to react with mono- or polyclonal antibodies that are specific for native or split epitopes, retention of functions of ligand binding, and the sensitivity or resistance of the mutant protein to digestion with proteases (see Sambrook et al., supra). Variants of RPTP as described herein can be identified, characterized, and / or made in accordance with these methods described herein or other methods known in the art, which are routinely practiced by those skilled in the art. Mutations that are made or identified in the nucleic acid molecules encoding an RPTP polypeptide preferably retain the reading frame of the coding sequences. In addition, the mutations will preferably not create regions of complementarity that when transcribed could hybridize to produce secondary mRNA structures, such as loops or pins, that would adversely affect translation of the mRNA. Although a mutation site can be predetermined, the nature of the mutation per se need not be predetermined. For example, to select optimal characteristics of a mutation at a given site, random mutagenesis can be constructed at the target codon and expressed mutants selected gain or loss or retention of biological activity. A variant of PTPM retains at least one biological activity or function (eg, phosphatase activity, mediates or initiates a signal transduction event associated with wild-type PTPN, binds to at least one cognate ligand, and as is further described in detail here) of the wild type RPTP. Preferably, the PTPM retains the ability to interact with its cognate ligand (s) and to dephosphorylate a phosphorylated substrate by tyrosine. Polynucleotide variants can also be identified by hybridization methods. Suitable moderately astringent conditions include, for example, pre-washing in a solution of 5X SSC, 0.5% SDS, 1.0 mM EDTA (pH 8.0); Hybridization at 50 ° C-70 ° C, 5X SSC for 1-16 hours; followed by washing once or twice at 22-65 ° C for 20-40 minutes with one or more each of 2X, 0.5X, and 0.2X SSC containing 0.05-0.1% SDS. For additional astringency, conditions may include a wash in 0.1 X SSC and 0.1% SDS at 50-60 ° C for 15 minutes. As understood by those skilled in the art, variations in astringency of hybridization conditions can be achieved by altering the time, temperature, and / or concentration of the solutions used for the steps of pre-hybridization, hybridization, and washing. Suitable conditions may also depend in part on the particular nucleotide sequences of the probe used (ie, for example, the content of guanine plus cytosine (G / C) versus adenine plus thymidine (A / T)). Accordingly, one of ordinary skill in the art will appreciate that the conditions suitably J Or astringents can be easily selected without extraordinary experimentation when a desired selectivity of the probe is identified. Each of the RPTPs has a signal peptide sequence of about 20-30 amino acids at the amino terminus (see, e.g., Pulido et al., Supra) (see also, e.g., reports of the base of GenBank data). The signal peptides are not exposed on the cell surface of a secreted or transmembrane protein because either the signal peptide is digested during the translocation of the protein or the signal peptide remains anchored in the outer cell membrane (said peptide also it is called a signal anchor) (see, eg, Nielsen et al., Protein Engineering 10: 1-6 (1997); Nielsen et al., In J. Glasgow et al., Eds., Proc. Sixth Int. Conf. On Intelligent Systems for Molecular Biology, 122-30 (AAAI Press 1998)). Accordingly, the signal peptide sequence of an RPTP would probably not be part of a binding site on the extracellular portion of the PTTP to which a ligand would bind, such as A41 L or an antibody or antigen binding fragment of the same that binds specifically to the extracellular portion of the PTWP. As described herein, the extracellular portion of the PTWT that is exposed on the outer surface of a cell (such as an immune cell), which does not include the signal peptide (also referred to herein as the mature PTNP), comprises three domains similar to immunoglobulin. The immunoglobulin domains (or immunoglobulin-like domains) are referred to herein as the first, second and third immunoglobulin domains JO (alternatively, referred to as lg-1, lg-2, lg-3 or as a domain similar to immunoglobulin 1, domain similar to immunoglobulin 2 and domain similar to immunoglobulin 3), wherein the first immunoglobulin domain is the domain that is closer to the NTP of the PTWN (see figures 1A-1F). The first immunoglobulin domain is immediately adjacent to the The carboxy terminus of the signal peptide (see FIGS. 1A-1 F). Therefore, as used herein, the first immunoglobulin-like domain of an RPTP is the immunoglobulin-like domain that is closest to the amino terminus of the PTWR; the second immunoglobulin-like domain of an RPTP is the immunoglobulin-like domain that is between the first and third domains similar to immunoglobulin of an RPTP; and the third immunoglobulin-like domain of an RPTP is the immunoglobulin-like domain that is closest to the carboxy terminus of the PTWP. One skilled in the art of protein will understand that the terms or boundaries of the domains do not necessarily correspond to exact amino acid positions in the primary sequence as shown, for example, in Figures 1A-1F. Therefore, for example, the immunoglobulin domains, fibronectin III repeats, and the catalytic domains can include one, two, three, four, five, six, seven, eight or more amino acids at positions adjacent to the amino terminal and / or the carboxy terminal end of each domain. One skilled in the art can easily determine when the positions in a PTPN correspond to each of the PTP Ig-like domains using the sequences and figures provided herein and the sequences known in the art (both the amino acid and the coding nucleotides). For example, but not limited to, the lg-1 domain of LAR corresponds to amino acid positions 31-125 of SEQ ID NO: 25; the lg-2 domain of LAR corresponds to amino acid positions 1 1 1-227; and the lg-3 domain of LAR corresponds to amino acid positions 228-316. For RPTP-s, the lg-1 domain corresponds to amino acid positions 31-125; the lg-2 domain corresponds to amino acid positions 127-240; and the Ig-3 domain corresponds to amino acid positions 241 -329. For RPTP-d, the lg-1 domain corresponds to amino acid positions 22-1 16; the lg-2 domain corresponds to amino acid positions 1 18-231; and the Ig-3 domain corresponds to amino acid positions 232-320. As described herein, the amino acids at each terminal end of the domains may vary depending on the particular PTPR or variant thereof (such as an allelic variant, a cell type variant, or the like), an Ig domain variant includes an Ig domain of LAR, RPTP-d, or RPTP-s that is 99%, 98%, 97%, 96%, 95%, or 90%, 85%, or 80% identical to the sequences for each immunoglobulin-like domain of each RPTP described here. 5 In one embodiment, the extracellular portion of LAR, RPTP-d, or RPTP-s can be used to alter (increase or suppress in a statistically or biologically significant way) the immune response of an immune cell. In another embodiment, an extracellular portion of a PTWR (also referred to herein as LAR, RPTP-d, or RPTP-s) which comprises at least JO minus one, two or all three of the immunoglobulin-like domains of LAR, pTTP-d, or pTTP-s and does not include one or more of the fibronectin domains of the pTTP can be used to alter the immune response of a cell immune. For ease of reference, the last polypeptides (ie, an RPTP (LAR, RPTP-d, or RPTP-s) comprising at least one, two or all three of the immunoglobulin-like domains, such as a monomer or oligomers as described herein) are removed here as RPTP-like domain polypeptides. In certain modalities, the immune response of an immune cell increases. The extracellular portion or fragment of the PTNP, such as at least one, two or all three of the immunoglobulin-like domains can be ad- ministered to a host or subject such that at least one ligand that binds to the PTTP expressed on an immune cell binds to the fragment of exogenously added RPTP. The ligand can be soluble or the ligand can be expressed on the cell surface of the same cell as the immune cell that expresses the PTTP, or the ligand can be a cell surface protein that is expressed by another cell. Therefore, a LAR, RPTP-d, or soluble RPTP-s can interact with the ligand and reduces the amount of ligand available to bind to the PTTP expressed on an immune cell, ie, the ligand is blocked from binding to the PTTP expressed on the cell, in turn inhibiting, preventing, decreasing, reducing or canceling, the function, activity (eg, phosphatase activity), or signaling event associated with the binding of J O linking to the PTWP. In another embodiment, an extracellular portion (e.g., at least one, two or all three of the immunoglobulin-like domains) of either LAR, PTTP-d, or PTWR-s can suppress an immune response. A ligand, which can be either a soluble ligand or a ligand that is a cell surface protein, can interact with an RPTP on the cell surface of an immune cell, and this interaction can induce an inflammatory response or can induce the expression or production of a cytokine (e.g., but not limited to, cytokines described herein including IFN-?) that induces or exacerbates an inflammatory or autoimmune response. The The interaction of one or more of the LARs, T-PTP, or PTPRs expressed on an immune cell with said ligand (soluble or a cell surface protein) can be inhibited, prevented or blocked by soluble PSTN that first interacts with or it binds to the ligand.

In a certain embodiment, at least one, or at least two or all three of the immunoglobulin-like domains are linked (i.e., bound or fused) to a non-RPTP portion. The portion can be ligated to the RPTP fragment by covalent or non-covalent attachment of the portion to the fragment, for example, using conjugation methods, which vary depending on the nature of the portion (such as if the portion is a carbohydrate or a polypeptide or small molecule), and with which those skilled in the particular art are familiar. Alternatively, when the non-RPTP portion is a peptide or polypeptide, the portion can be recombinantly linked to form a fusion RPTP fragment polypeptide. For example, recombinant expression of constructs comprising a polynucleotide encoding a fusion polypeptide comprising at least one, at least two, or the three immunoglobulin-like domains (or a portion thereof) of the PTNP can be prepared. fused to, for example, at least one immunoglobulin constant region domain (Ig) or at least two Ig constant region domains of an immunoglobulin Fe polypeptide. In one embodiment, the second and third immunoglobulin-like domains of LAR, RPTP-d, or RPTP-s are fused to an immunoglobulin Fe polypeptide.; and in another embodiment, the first, second and third immunoglobulin-like domains of LAR, or of RPTP-d, or of RPTP-s are fused to an immunoglobulin Fe polypeptide. In certain embodiments, the first immunoglobulin-like domain of LAR, RPTP-d, or RPTP-s is fused to an immunoglobulin Fe polypeptide. In another embodiment, the second immunoglobulin-like domain of LAR, RPTP-d, or RPTP-s is fused to an immunoglobulin Fe polypeptide; In yet another embodiment, the third immunoglobulin-like domain of LAR, RPTP-d, or RPTP-s is fused to an immunoglobulin Fe polypeptide. In other embodiments, the first and second immunoglobulin-like domains of LAR, RPTP-d, or RPTP-s are fused to an immunoglobulin Fe polypeptide; in other embodiments, the first and third immunoglobulin-like domains of LAR, RPTP-d, or RPTP-s are fused to an immunoglobulin Fe polypeptide. In certain cases, the use of the immunoglobulin-like first domain alone (i.e., in the absence of the second and / or third immunoglobulin-like domains) or a polypeptide having the immunoglobulin-like first domain and the second immunoglobulin-like domain (e. say, in the absence of the third Ig-like domain) fused to a Fe polypeptide may be less effective in suppressing an immune response in an immune cell or in a host in a manner similar to A41 L. Without wishing to be limited by any particular theory , and as described herein, because A41 L does not bind to the first immunoglobulin-like domain alone in the absence of the second and third Ig-like domains, an RPTP Ig-like domain that incorporates only the first domain may be less effective to interact with a ligand or cell surface polypeptide to effect suppression of an immune response in the same manner as A41 L. In other embodiments, a soluble TPRP (ie, an Ig-like domain of the RPTP polypeptide) can comprise one, two or three immunoglobulin-like domains in the various combinations described above which are not bound or fused to a non-RPTP portion. For example, an IgP-like domain of the RPTP polypeptide may comprise the first, second and third Ig-like domains of an RPTP (LAR, RPTP-d, or RPTP-s); the second and third domains similar to lg of an RPTP. In certain alternative embodiments, an IgT-like domain polypeptide of RPTP may comprise the first and second or first and third Ig-like domains of an RPTP; or each domain similar to Ig alone. Soluble RPTP-like Ig-like domain polypeptides can also exist as multimers, such as dimers and trimers. The multimers may be formed by non-covalent interactions under conditions that favor such interactions (which include physiological conditions) or may be formed by a combination of covalent and non-covalent interactions. Alternatively, the multimers can be formed by chemically or recombinantly linking at least two monomeric RPTP Ig-like domain polypeptides. The multimers may comprise, for example, homodimers or heterodimers. For example, a homodimer may comprise (1) a first monomer of at least one, two or three immunoglobulin-like domains of an RPTP and (2) a second monomer thereof at least one, two or three domains similar to immunoglobulin from the same RPTP. In certain specific embodiments, for example, a homodimer may comprise a first and second monomer such that each comprises the second and third (or, alternatively, the first, second, and third) immunoglobulin-like domains of LAR. In another embodiment, each monomer (e.g., the second and third immunoglobulin-like domains or the first, second, and third immunoglobulin-like domains) of a homodimer is derived from RPTP-d, and in another embodiment, each monomer it is derived from RPTP-s. Alternatively, the oligomers, such as dimers, can be heterodimers, and each monomer is derived from a different PTPR (i.e., LAR, PTP-d or PTPP-s). In a certain embodiment, a heterodimer may comprise a first monomer, which includes the second and third (or, alternatively, the first, second and third) immunoglobulin-like domains of LAR and a second monomer, which includes the second and third (or , alternatively, the first, second, and third) immunoglobulin-like domains, of either RPTP-d or RPTP-s. In another embodiment, a first monomer of a heterodimer comprises the second and third (or, alternatively, the first, second, and third) domains similar to immunoglobulin of RPTP-d, and the second monomer of the heterodimer includes the corresponding immunoglobulin-like domains of RPTP-s. In certain other embodiments, homodimers or heterodimers comprise a first and a second monomer, and each monomer comprises only an immunoglobulin-like domain of an RPTP. In other embodiments, each monomer of a homodimer or a heterodimer comprises the first and third immunoglobulin-like domains of a PTPN; and in certain other embodiments, each monomer comprises the first and second immunoglobulin-like domains of an RPTP. Thus a homodimer may comprise two monomers, each composed of the first and second immunoglobulin-like domains of LAR, or each monomer may be composed of the first and third immunoglobulin-like domains of LAR. The homodimers can be similarly constructed for each of RPTP-d and RPTP-s. The heterodimers can be prepared from a first and second monomer, which are different, for example, a first monomer can comprise the first and second immunoglobulin-like domains or first and third immunoglobulin-like domains of LAR and the second monomer can comprise the first and second immunoglobulin-like domains or first and third immunoglobulin-like domains, respectively of either RPTP-d or RPTP-s. In other embodiments, the heterodimers may comprise a first monomer comprising the first and second immunoglobulin-like domains, or first and third immunoglobulin-like domains, of pTTP-d and the second monomer may comprise the first and second immunoglobulin-like domains, or first and third immunoglobulin-like domains, respectively, of RPTP-s. In other embodiments, an immunoglobulin-like domain of an RPTP can be fused to an immunoglobulin domain of a different PTTP. For example, the first immunoglobulin-like domain of RPTP-d or RPTP-s can be fused to the second and third immunoglobulin-like domains of LAR. A number of combinations of immunoglobulin-like domains of each of the three RPTPs described herein can be contemplated to provide a soluble TPRTP molecule that comprises altogether two or three immunoglobulin-like domains. As described above, the RPTP Ig domain polypeptides can be prepared recombinantly using molecular biology techniques or can be combined non-covalently or covalently fused with or without one or more linker amino acids or spacers. JO A Fe polypeptide of an immunoglobulin that can be fused to an RPTP Ig-like domain polypeptide, as described in detail above, comprises the heavy chain CH2 and CH3 domain and a portion of or all of the hinge region that is located between CH1 and CH2. Historically, the Fe fragment was derived by digestion with papain from an immunoglobulin and included the hinge region of the immunoglobulin. The Fe regions are monomeric polypeptides that can be linked in the dimeric or multimeric forms by covalent (e.g., particularly disulfide bonds) and non-covalent association. The number of intermolecular disulfide bonds between monomeric subunits of Fe polypeptides vary depending on the class of immunoglobulin (e.g., IgG, IgA, IgE) or subclass of immunoglobulin (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, IgA2 human). Fragments of a Fe polypeptide, such as a Fe polypeptide that is truncated at the C-terminus (which is at least 1, 2, 3, 4, 5, 10, 15, 20, or more amino acids has been removed or deleted ), can also be used. In certain embodiments, the Fe polypeptides described herein contain multiple cysteine residues, such as at least some or all of the cysteine residues in the hinge region, to allow interchain disulfide bonds to form between the Fe-1 polypeptide portions. two fusion proteins of separate RPTPs / Fc domains, thus forming melting dimers of domains of RPTP (s) / Fe polypeptide. In other embodiments, if retention of antibody-dependent cell-mediated cytotoxicity (ADCC) is desired and complement fixation (and complement-associated cytotoxicity (CDC)), the Fe polypeptide comprises substitutions or deletions of cysteine residues in the hinge region such that a Fe polypeptide fusion protein is monomeric and does not form a dimer ( see, e.g., U.S. Patent Application Publication No. 2005/0175614). The Fe portion of the immunoglobulin mediates certain effector functions of an immunoglobulin. Three general categories of effector functions associated with the Fe region include (1) activation of the classical complement cascade, (2) effector cell interaction, and (3) immunoglobulin compartmentalization. Currently, a Fe polypeptide, and any of one or more constant region domains, and fusion proteins comprising at least one immunoglobulin constant region domain can be easily prepared in accordance with recombinant molecular biology techniques with which he is familiar one skilled in the art. A Fe polypeptide is preferably prepared using the nucleotide sequence and the encoded amino acid sequence derived from the animal species for which the fusion polypeptide is intended.

IgFc. In one embodiment, the Fe polypeptide is of human origin and can be of any of the immunoglobulin classes, such as IgG1 and IgG2. An Fe polypeptide, as described herein, also includes Fe polypeptide variants. One such polypeptide variant Fe has one or more cysteine residues (such as one or more cysteine residues in the hinge region) that forms a bond of disulfide with another Fe polypeptide substituted with another amino acid, such as serine, to reduce the number of disulfide bonds formed between two Fe polypeptides. Alternatively, one or more cysteine residues may be deleted from the wild-type hinge of the Fe polypeptide. Another example of a variant Fe polypeptide is a variant having one or more amino acids involved in an effector function substituted or deleted such that the Fe polypeptide has a reduced level of an effector function. For example, amino acids in the Fe region can be substituted to reduce or abolish the binding of a component of the complement cascade (see, e.g., Duncan et al., Nature 332: 563-64 (1988); Morgan et al. al., Immunology 86: 319-24 (1995)) or to reduce or abolish the ability of the Fe polypeptide to bind to an IgG Fe receptor expressed by an immune cell (Wines et al., J. Immunol. 164: 5313- 18 (2000), Chappel et al., Proc. Nati, Acad. Sci USA 88: 9036 (1991), Canfield et al., J Exp. Med. 173: 1483 (1991), Duncan et al., Supra); or to alter antibody-dependent cellular cytotoxicity. Said variant Fe polypeptide which differs from the wild-type Fe polypeptide is also referred to herein as a mutein-Fe polypeptide. In a modality, at least one immunoglobulin like domain of an RPTP (LAR, RPTP-d, RPTP-s, or variant thereof) is fused in frame with a Fe polypeptide comprising at least one substitution of a residue that in the Wild type Fe region polypeptide contributes to the binding of a Fe or immunoglobulin polypeptide to one or more IgG Fe receptors expressed on certain immune cells. Said mutein Fe polypeptide comprises at least one substitution of an amino acid residue in the CH2 domain of the mutein Fe polypeptide, such that the ability of the fusion polypeptide to bind to an IgG Fe receptor, such as a Fe receptor. of IgG present on the surface of an immune cell, is reduced. The types of Fe IgG receptors expressed on human leukocytes were described in detail above. As described in detail herein, the residues of the amino terminal portion of the CH2 domain that contributes to IgG Fe receptor binding include residues at positions Leu234-Ser239 (Leu-Leu-Gly-Gly-Pro-Ser (SEQ ID NO : 80) (EU numbering system, Kabat et al., Supra) (see, e.g., Morgan et al., Immunology 86: 319-24 (1995), and references cited therein.) These positions correspond to positions 15-20 of the amino acid sequence of a human IgG1 Fe polypeptide (SEQ ID NO: 79) The substitution of the amino acid in one or more of these six positions (i.e., one, two, three, four, five) or all six) in the CH2 domain results in a reduction in the ability of the Fe polypeptide to bind to one or more of the IgG Fe receptors (or isoforms thereof) (see, e.g., Burton et al. , Adv. Immunol., 51: 1 (1992); Hulett et al., Adv. Immunol. 57: 1 (1994); Jefferis et al., Immunol. Rev. 163: 59 (1998); Lund et al., J Immunol. 147: 2657 (1991); Sarmay et al., Mol. Immunol. 29: 633 (1992); Lund et al., Mol. Imm? Nol. 29:53 (1992); Morgan et al., Supra). In addition to the substitution of one or more amino acids at positions 234-239 of the EU, one, two, or three or more amino acids adjacent to this region (either to the carboxy terminal side of position 239 or to the amino terminal side of the position 234) can also be substituted. By way of example, the substitution of the leucine residue at position 235 (corresponding to position 16 of SEQ ID NO: 79) with a glutamic acid residue or an alanine residue nullifies or reduces, respectively, the affinity of a immunoglobulin (such as human IgG3) for FcyRI (Lund et al., 1991, supra; Canfield et al., supra; Morgan et al., supra). As another example, the replacement of the leucine residues at positions 234 and 235 (corresponding to positions 15 and 16 of SEQ ID NO.79), for example, with alanine residues, cancels the binding of an immunoglobulin to FcyRIla (see , v gr, Wines et al, supra) Alternatively, leucine at position 234 (corresponding to position 15 of SEQ ID NO 79), leucine at position 235 (corresponding to position 16 of SEQ ID NO 79), and glycine at position 237 (corresponding to position 18 of SEQ ID NO 79), each can be substituted with a different amino acid, such as leucine at position 234 can be substituted with a residue of alanine (L234A), leucine at 235 can be substituted with an alanine residue (L235A) or with a glutamic acid residue (L235E), and the glycine residue at position 237 can be substituted with another amino acid, for example an alanine residue (G237A) a modality, a po peptide of mutein that is fused in the frame to a viral pohpeptide (or variant or fragment thereof) comprises one, two, three, four, five or six mutations at positions 15-20 of SEQ ID NO 79 corresponding to positions 234-239 of a CH2 domain of IgG1 human (EU numbering system) as described herein An Illustrative lutein Fe pope peptide has the amino acid sequence set forth in SEQ ID NO 77 in which the substitutions corresponding to (L234A), (L235E), and (G237A) can be found in positions 13, 14, and 16 of SEQ ID NO 77 In another embodiment, a mutein-F polypeptide comprises a mutation of a cysteine residue in the hinge region of a Fe peptide. In one embodiment, the cysteine residue more proximal to the amino terminus of the hinge region of a Fe polypeptide (vgr, eg, the cysteine residue more proximal to the amino terminus of the hinge region of the Fe portion of a wild-type IgG1 immunoglobulin) is deleted or replaced with another amino acid. That is, by way of illustration, the cysteine residue in position 1 of SEQ ID NO: 79 is deleted, or the cysteine residue in position 1 is substituted with another amino acid which is incapable of forming a disulfide bond, by example, with a serine residue. In another embodiment, a mutein Fe polypeptide comprises a deletion or substitution of the cysteine residue most proximal to the amino terminus of the hinge region of a Fe polypeptide further comprising deletion or substitution of the adjacent C-terminal amino acid. In a certain embodiment, this cysteine residue and the adjacent C-terminal residue are both deleted from the hinge region of a mutein Fe polypeptide. In a specific embodiment, the cysteine residue at position 1 of SEQ ID NO: 79 and the aspartic acid at position 2 of SEQ ID NO: 79 are deleted. Fe polypeptides comprising deletion of these cysteine and aspartic acid residues in the hinge region can be efficiently expressed in a host cell, and in certain cases, can be expressed more efficiently in a cell than a Fe polypeptide that retains the cysteine residues and wild type aspartate. In a specific mode, a mutein Fe polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 77, which differs from the wild-type Fe polypeptide (SEQ ID NO: 79) wherein the cysteine residue at position 1 of SEQ ID NO: 79 is deleted and the aspartic acid at position 2 of SEQ ID NO.79 is deleted and the leucine residue at position 15, corresponding to position EU234, of SEQ ID NO: 79 is replaced with an alanine residue, the residue of leucine in position 16 (corresponding to EU235) is substituted with a glutamic acid residue, and glycine in position 18, corresponding to EU237, is substituted with an alanine residue (see also figure 5). Thus, an illustrative Lutein Fe polypeptide comprises an amino acid sequence in its amino terminal portion of KTHTCPPCPAPEAEGAPS (SEQ ID NO: 81) (see SEQ ID NO: 77, an illustrative Fe lutein sequence). Other Fe variants encompass similar amino acid sequences of known Fe polypeptide sequences having only minor changes, for example by way of illustration and not limitation, covalent chemical modifications, insertions, deletions and / or substitutions, which may also include conservative substitutions. . The amino acid sequences that are similar to one another may share substantial regions of sequence homology. Similarly, the nucleotide sequences encoding the Fe variants may encompass substantially similar nucleotide sequences and have only minor changes, for example, by way of illustration and not limitation, covalent chemical modifications, insertions, deletions, and / or substitutions, which can also include silent mutations due to the degeneracy of the genetic code. Nucleotide sequences that are similar to one another may share regions of substantial sequence homology.

An Fe polypeptide or at least one immunoglobulin constant region, or portion thereof, when fused to a peptide or polypeptide of interest acts, at least in part, as a carrier or carrier portion that prevents degradation and / or increases half-life, reduces toxicity, reduces immunogenicity, and / or increases the biological activity of the peptide such as by forming dimers or other multimers (see, e.g., US Patent Nos. 6,018,026; 6,291,646; 6,323,323; 6,300,099; 5,843,725). (See also, e.g., U.S. Patent No. 5,428,130, U.S. Patent No. 6,660,843, U.S. Patent Application Publication Nos. 2003/064480, 2001/053539, 2004/087778, 2004/077022; 2004 / 071712; 2004/057953/2004/053845 / 2004/044188; 2004/001853; 2004/082039). Alternative portions to a constant region of immunoglobulin such as a Fe polypeptide that can be linked or fused to a peptide that alters the immune response of an immune cell include, for example, a linear polymer (e.g., polyethylene glycol, polylysine, dextran). , etc., see, for example, U.S. Patent No. 4,289,872, International Patent Application Publication No. WO 93/21259); a lipid; a cholesterol group (such as a steroid); a carbohydrate or oligosaccharide. Nucleotide sequences encoding Fe polypeptides of various classes and immunoglobulin isotypes of various species are known and are available in GenBank and Kabat databases (Kabat et al., In Sequences of Proteins of Immunological Interest, 4th ed. , (US Dept. of Health and Human Services, US Government Printing Office, 1991), see also updates of the online Kabat database), any sequence of which can be used to prepare a recombinant construct in accordance with of molecular biology routinely put into practice by those skilled in the art. To minimize the immunogenicity of the Fe polypeptide in the host or subject to which an RPTP fragment fusion polypeptide can be administered, the Fe polypeptide sequence is typically chosen from immunoglobulins of the same species, i.e., for example, a Human Fe polypeptide sequence is fused to an RPTP fragment that will be administered to a human subject or host. The methods described herein for identifying cell surface molecules such as RPTPS that interact with and / or bind to poxvirus polypeptides such as A41 L or 130L, can also be used to identify intracellular molecules that interact with, are ligands for , form a complex with, or otherwise be associated with, the RPTPs described herein (ie, LAR, RPTP-d, and / or RPTP-s). Without wishing to be bound by theory, the identification of intracellular molecules that interact with one or more of LAR, PTPN-d, and PTPN-s by virtue of the interaction between a poxvirus polypeptide and PTPN can identify particular pathways (and components). of them) involved in, or that when disturbed or activated, result in the manifestation of a disease or disorder. Such intracellular molecules (eg, placoglobulin and liprin-1-β that interact with at least LAR identified by TAP-TAG procedures using A41 L) that are associated with one or more of the PTPNs and that are involved with one or more Signal transduction pathways may be targeted for agents and compositions that are useful for treating an immune disease or disorder, cardiovascular disease or disorder, or metabolic disease or disorder, as described herein. Alternatively, the agents described herein that interact with one or more of LAR, RPTP-d, and RPTP-s and that are useful for treating a disease or disorder and / or altering the immune response of an immune cell can affect the interaction between the RPTP and the intracellular molecule, and therefore can alter one or more biological activities of the cell.

Agents The binding of a poxvirus polypeptide, such as A41L or 130L, to LAR, RPTP-d, and RPTP-s alters at least one biological function of these phosphatases, and as described herein the interaction between A41L or 130L with LAR, RPTP-d, and RPTP-s expressed on the cell surface of an immune cell can alter (e.g., suppresses or increases) the immune response of the cell. The alteration of the immune response of an immune cell can also be effected by a bioactive agent (compound or molecule) in a manner similar to a poxvirus polypeptide. Bioactive agents include, for example, small molecules, nucleic acids (such as aptamers, siRNAs, antisense nucleic acids), antibodies and fragments thereof, and fusion proteins (such as peptide-Fc fusion proteins and fusion proteins). of Ig region of RPTP-Fc). An agent can interact with and join at least one of LAR, RPTP-d, and RPTP-s at a location on the PTNW that is the same or proximal to the same location as where A41 L or 130L joins. Alternatively, alteration of the immune response by an agent in a manner similar to the effect of A41 L (or 130L) may result from the binding or interaction of the agent with the PTWP at a site distal to that in which the polypeptide of the agent binds. poxvirus. Binding studies, including competitive binding tests, and functional tests, which indicate the level of immune response of a cell, can be performed in accordance with methods described herein and practiced in the art to determine and compare the ability and level with which an agent binds to and affects the immune response of an immune cell. Here methods are provided to identify an agent that alters (e.g., suppresses or increases in a statistically or biologically significant way) immune response of an immune cell and to characterize and determine the level of suppression or increase of said agent once identified. . Said methods, which are described in greater detail herein and are familiar to those skilled in the art, including but not limited to, binding tests, such as immunoassays (e.g., ELISA, radioimmunoassay, immunoblotting, etc.), competitive binding tests, and surface plasmon resonance. These methods comprise contacting (mixing, combining with, or in some way allowing interaction) between one (1) candidate agent; (2) an immune cell that expresses at least one of LAR, RPTP-s, and RPTP-d; and (3) a poxvirus polypeptide, such as A41 L or 130L, under conditions and for a time sufficient to allow interaction between at least one RPTP polypeptide and the poxvirus polypeptide. Conditions for a particular test include temperature, pH regulators (including salts, cations, media), and other components that maintain the integrity of the cell, agent, and poxvirus polypeptide with which one skilled in the art will be familiar. and / or that can be easily determined. The interaction or level of binding of A41 L (or 130L) to the immune cell in the presence of the candidate agent can be easily determined and compared to the level of binding of A41 L (or 130L) to the cell in the absence of the agent. A decrease in the binding level of A41 L (or 130L) to the immune cell in the presence of the candidate agent indicates that the candidate agent suppresses the immune response of the immune cell. In another embodiment, a method for identifying an agent that alters (suppresses or increases) the immune response of an immune cell comprises determining the level of immune response of an immune cell that expresses at least one of LAR, RPTP-s, and PTPN -d in the presence of the agent. In certain specific embodiments, an agent that suppresses the immune response of an immune cell is identified. Immune responses can be determined in accordance with methods practiced in the art such as cytokine measurement levels, proliferation and stimulation. Immune responses of an immune cell can also be determined by evaluating changes in cell adhesion and cell migration and by examining the tyrosine cell typing pattern of cellular proteins, including but not limited to cytoskeletal proteins and other proteins that affect cell adhesion and migration. Numerous tests and techniques are practiced by those skilled in the art to determine the interaction between or binding between a biological molecule and a cognate ligand. Accordingly, the interaction between a poxvirus polypeptide such as A4 IL or 130L and any or more of LAR, RPTP-s, and RPTP-d, including the effect of a bioactive agent on this interaction and / or binding in the presence of the agent , can be easily determined by said tests and techniques as described in detail here.

Small Molecules Bioactive agents can also include natural and synthetic molecules, for example, small molecules that bind to form a poxvirus polypeptide (e.g., A41 L or 130L), or one or more of LAR, RPTP-s, and RPTP-d, and / or to a complex between the poxvirus polypeptide (e.g., A41 L or 130L) and any of LAR, RPTP-s, and RPTP-d. Candidate agents for use in a screening method for an agent that alters (suppresses or increases) the immune response of an immune cell and / or that inhibits binding of the poxvirus polypeptide (e.g., A41 L or 130L) to at least one, at least two, or all three of LAR, RPTP-s, and RPTP-d, may be provided as "libraries" or collections of compounds, compositions or molecules.

Such molecules typically include compounds known in the art as "small molecules" and have molecular weights less than 105 daltons, less than 104 daltons, or less than 103 daltons. For example, members of a library of test compounds can be administered to a plurality of samples, each containing at least one tyrosine phosphatase polypeptide as provided herein, and then the samples are tested for their ability to increase or inhibit LAR-mediated dephosphorylation, RPTP-s, and RPTP-d of, or binding to, a substrate, the ability to inhibit or increase the binding of the phosphatase to the poxvirus polypeptide (e.g., A41 L or 130L); and / or the ability of the test compounds to modulate the immune response of immune cells. The compounds thus identified as being capable of affecting at least one function of the polypeptide of poxvirus LAR, RPTP-s, and RPTP-d are of value for therapeutic and / or diagnostic purposes, since they allow the treatment and / or detection of diseases associated with activity of LAR, RPTP-s and / or RPTP-d. Said compounds are also of value in research directed at molecular signaling mechanisms involving any or more of LAR, RPTP-s, and RPTP-d. Candidate agents can also be provided as members of a combination library, which preferably includes synthetic agents prepared in accordance with a plurality of predetermined chemical reactions performed in a plurality of reaction vessels. For example, several starting compounds can be prepared in accordance with one or more of solid phase synthesis, registered random mixing methodologies, and registered reaction splitting techniques that allow a given constituent to pass in tracked form by a plurality of permutations. and / or combinations of reaction conditions. The resulting products comprise a selectable library followed by iterative synthesis and selection procedures, such as a synthetic combinatorial library of peptides (see e.g., International patent applications Nos. PCT / US91 / 08694 and PCT / US91 / 04666) or other compositions that may include small molecules as provided herein (see, e.g., International Patent Application No. PCT / US94 / 08542, EP Patent No. 0774464, US Patent No. 5,798,035, U.S. Patent No. 5,789,172, U.S. Patent No. 5,751, 629, which are hereby incorporated by reference in their entirety). Those skilled in the art will appreciate that a diverse classification of such libraries can be prepared in accordance with established and tested procedures in accordance with the present disclosure. Examples of methods for the synthesis of molecular libraries can be found in the art, for example in De Witt et al., Proc. Nati Acad. Sci. U.S.A. 90: 6909 (1993); Erb et al., Proc. Nati Acad. Sci. USA 91: 1 1422 (1994); Zuckermann et al., J Med. Chem. 37: 2678 (1994); Cho et al., Science 261: 1303 (1993); Carrell et al., Angew. Chem. Int. Ed. Engl. 33: 2059 (1994); Carell et al., Angew. Chem. Int. Ed. Engl. 33: 2061 (1994); and in Gallop et al., J Med. Chem. 37: 1233 (1994). Compound libraries can be presented in solution (e.g., Houghten, Biotechniques 13: 412-21 (1992)); or in spheres (Lam, Nature 354: 82-84 (1991)); chips (Fodor, Nature 364: 555-56 (1993)); bacteria (Ladner, U.S. Patent No. 5,223,409); spores (Ladner, supra); plasmids (Culi et al., Proc. Nati, Acad. Sci. USA 89: 1865-69 (1992)); or in phages (Scott and Smith, Science 249: 386-390 (1990); Devlin, Science 249: 404-406 (1990); CwMa et al., Proc. Nati. Acad. Sci. USA 87: 6378-82 ( 1990), Felici, J. Mol. Biol. 222: 301-10 (1991), Ladner, supra).

Immunoglobulin constant peptide-constant fusion polypeptides In one embodiment, a bioactive agent that is used for altering the immune response of an immune cell and that can be used to treat an immunological disease or disorder is a region fusion fusion polypeptide. peptide-immunoglobulin (Ig) constant, which includes a peptide-lgFc fusion polypeptide. The peptide can be any molecule that ocher naturally or recombinantly prepared. A peptide-lg constant region fusion polypeptide, such as a peptide-lgFc fusion polypeptide (also referred to in the art as a peptibody (see, e.g., U.S. Patent No. 6,660,843)), comprises a biologically active peptide or polypeptide capable of altering the activity of a protein of interest, such as an RPTP ((LAR, RPTP-s, and / or RPTP-d) expressed by an immune cell, which is fused with a portion, so minus a constant region domain (e.g., CH1, CH2, CH3, and / or CH4), or the Fe (CH2-CH3) polypeptide of an immunoglobulin.The Fe polypeptide is also referred to herein as the Fe or Fe region. In one embodiment, the peptide portion of the fusion polypeptide is capable of interacting with or binding to at least one of, at least two of, or all three of LAR, RPTP-s, and RPTP-d, and perform the same biological activity as a poxvirus polypeptide (e.g., A41 L or 130L) when it binds to at least one of the RPTPs , thus suppressing (inhibiting, preventing, decreasing or canceling) the immune response of the immune cell expressing the PTWR. Here methods are provided to identify a peptide that is capable of altering (e.g., suppressing) the immune response of an immune cell (i.e., a peptide that acts as a simulator of A41 L or 130L). For example, said peptide can be identified by determining its ability to inhibit or block the binding of A41 L (or 130L) to a cell that expresses at least one of the RPTPs. Alternatively, a candidate peptide can be allowed to make contact or interact with an immune cell that expresses at least one of the RPTPs, and the ability of the candidate peptide to suppress or increase the immune response of the immune cell can be measured from according to methods described herein and practiced in the art. Candidate peptides may be provided as members of a combinatorial library, which includes synthetic peptides prepared in accordance with a plurality of predetermined chemical reactions performed in a plurality of reaction vessels. For example, various starting peptides can be prepared according to standard peptide synthesis techniques with which one skilled in the art will be familiar. Peptides that alter the immune response of an immune cell can be identified and isolated from combinatorial libraries (see, e.g., international patent applications Nos. PCT / US91 / 08694 and PCT / US91 / 04666) and peptide libraries from phage display (see, e.g., Scott et al., Science 249: 386 (1990); Devlin et al., Science 249: 404 (1990); Cwirla et al., Science 276: 1696-99 (1997 U.S. Patent No. 5,223,409; U.S. Patent No. 5,733,731; U.S. Patent No. 5,498,530; U.S. Patent No. 5,432,018; U.S. Patent No. 5,338,665;; U.S. Patent No. 5,922,545; "International Application Publications"; Nos. WO 96/40987 and WO 98/15833). In phage display peptide libraries, the random peptide sequences are fused to a phage coat protein such that the peptides are displayed on the outer surface of a filamentous particle. Typically, the displayed peptides make contact with a ligand or binding molecule of interest to allow interaction between the peptide and the ligand or binding molecule, unbound phages are removed, and the bound phages are eluted and subsequently enriched by successive rounds of affinity purification and repropagation. Peptides with the highest affinity for the ligand or binding molecule or target molecule of interest (e.g., the RPTPs described herein) can be sequenced to identify key residues, which can identify peptides within one or more families of structurally related peptides. The comparison of peptide sequences can also indicate which residues in said peptides can be safely substituted or deleted by mutagenesis. These peptides can then be incorporated into libraries of additional peptides that can be selected and peptides with optimized affinity can be identified. Additional methods for identifying peptides that can alter the immune response of an immune cell and therefore be useful for treating and / or preventing an immune disease or disorder include, but are not limited to, (1) structural analysis of protein-protein interaction such as by analyzing the crystal structure of the RPTP target (see, eg, Jia, Biochem Cell Biol 75: 17-26 (1997)) to identify and determine the orientation of critical residues of the PTWP, which will be useful to designate a peptide (see, e.g., Takasaki et al., Nature Biotech 15: 1266-70 (1997)); (2) a peptide library comprising peptides fused to a peptidoglycan-associated lipoprotein and displayed on the outer surface of bacteria such as E. coli; (3) generating a peptide library by altering the translation of polypeptides to generate peptides associated with RNA; and (4) generating peptides by digestion of polypeptides with one or more proteases. (See also, e.g., U.S. Patent Nos. 6,660,843, 5,773,569, 5,869,451, 5,932,946, 5,608,035, 5,786,331, 5,880,096). A peptide can comprise any number of amino acids between 3 and 75 amino acids, 3 and 60 amino acids, 3 and 50 amino acids, 3 and 40 amino acids, 3 and 30 amino acids, 3 and 20 amino acids, or 3 and 10 amino acids. A peptide that has the ability to alter the immune response of an immune cell (e.g., in certain embodiments, to suppress the immune response of the immune cell and in certain other modalities, to increase the immune response of the immune cell) as well they can be derived to add or insert amino acids that are useful for constructing a peptide-Ig constant region protein (such as amino acids that are linker sequences or that are spacer sequences). A peptide that can be used to construct a peptide-Ig constant region fusion polypeptide (including a peptide-lgFc fusion polypeptide) can be derived from a poxvirus polypeptide, such as an A41 L polypeptide or 130L polypeptides. A41 L or 130L polypeptides can be randomly generated by proteolytic digestion using any one or more of several proteases, isolated, and then analyzed for their ability to alter the immune response of an immune cell. Such peptides can also be generated using recombinant methods described herein and practiced in the art. Randomly generated peptides can also be used to prepare peptide combinatorial libraries or phage libraries as described herein and in the art. Alternatively, the amino acid sequences of portions of A41L or 130L that interact with LAR, RPTP-s, and / or RPTP-d can be determined by computer modeling the phosphatase, or a portion of the phosphatase, for example, the extracellular portion or the Ig domain, and / or x-ray crystallography (which may include preparation and analysis of phosphatase crystals alone or of the viral phosphatase-polypeptide complex). As described in detail above, a Fe polypeptide of an immunoglobulin comprises the heavy chain CH2 and CH3 domain and a portion of or the entire hinge region that is located between CH1 and CH2. The Fe regions are monomeric polypeptides that can be linked to dimeric or multimeric forms by covalent (e.g., particularly disulfide bonds) and non-covalent association. The number of intermolecular disulfide bonds between monomer subunits of Fe polypeptides varies depending on the class of immunoglobulin (e.g., IgG, IgA, IgE) or subclass (e.g., human IgG1, IgG2, IgG3, IgG4, IgA1). , lgA2). Currently, a Fe polypeptide, and any one or more constant region domains, and fusion proteins comprising at least one immunoglobulin constant region domain (Ig) can be easily prepared in accordance with recombinant molecular biology techniques with which a The person skilled in the art is very familiar. The Fe polypeptide is preferably prepared using the nucleotide and the encoded amino acid sequences derived from the animal species for which use the peptide-lgFc fusion polypeptide is designed. In one embodiment, the Fe polypeptide is of human origin and can be of any of the immunoglobulin classes, such as human IgG1 and IgG2. A Fe polypeptide, as described herein, also includes Fe polypeptide variants. One of those Fe polypeptide variants has one or more cysteine residues (such as one or more cysteine residues in the hinge region) that form a linker. disulfide with another Fe polypeptide substituted with another amino acid, such as serine, to reduce the number of disulfide bonds formed between two Fe polypeptides. Alternatively, one or more cysteine residues may be deleted from the wild-type hinge of the Fe polypeptide. Another example of a Fe polypeptide variant is a variant having one or more amino acids involved in an effector function substituted or deleted in such a way that the Fe polypeptide has a reduced level of an effector function. For example, amino acids in the Fe region can be substituted to reduce or abolish the binding of a component of the complement cascade (see, e.g., Duncan et al., Nature 332: 563-64 (1988)).; Morgan et al., Immunology 86: 319-24 (1995)) or to reduce or abolish the ability of the Fe polypeptide to bind to an IgG Fe receptor expressed by an immune cell (Wines et al., J. Immunol. 5313-18 (2000); Chappel et al., Proc. Nati, Acad. Sci. USA 88: 9036 (1991), Canfield et al., J. Exp. Med. 173: 1483 (1991); Duncan et al. , supra); or to alter the antibody-dependent cellular cytotoxicity. Said variant Fe polypeptide that differs from the wild-type Fe polypeptide is also referred to herein as a mutein Fe polypeptide. In one embodiment, a peptide as described herein is fused in frame with a Fe polypeptide comprising at least one substitution of a residue that in the wild-type Fe region polypeptide contributes to the binding of a Fe or immunoglobulin polypeptide to one or more IgG Fe receptors expressed on certain immune cells. Said mutein Fe polypeptide comprises at least one substitution of an amino acid residue in the CH2 domain of the mutein Fe polypeptide, such that the ability of the fusion polypeptide to bind to an IgG Fe receptor, such as a Fe receptor. of IgG present on the surface of an immune cell, is reduced. The types of Fe IgG receptors expressed on human leukocytes were described in detail above. The residues in the amino terminal portion of the CH2 domain that contributes to the binding of the IgG Fe receptor include residues at positions Leu234-Ser239 (Leu-Leu-Gly-Gly-Pro-Ser (SEQ ID NO: 80) (numbering system EU, Kabat et al., Supra) (see, e.g., Morgan et al., Immunology 86: 319-24 (1995), and references cited therein.) These positions correspond to positions 15-20 of the amino acid sequence of a human lgG1 Fe polypeptide (SEQ ID NO: 79) The substitution of the amino acid in one or more of these six positions (ie, one, two, three, four, five or all six) in the CH2 domain results in a reduction in the ability of the Fe polypeptide to bind to one or more of the Fe receptor of IgGs (or isoforms thereof) (see, e.g., Burton et al., Adv. Immunol., 51: 1). (1992), Hulett et al., Adv. Immunol., 57: 1 (1994), Jefferis et al., Immunol., Rev. 163: 59 (1998), Lund et al., J. Immunol., 147: 2657 (1991). ); Sarmay et al., Mol. Immunol., 29: 633 (1992); et al., Mol. Immunol. 29:53 (1992); Morgan et al., Supra). In addition to the substitution of one or more amino acids at the positions of EU 234-239, one, two or three or more amino acids adjacent to this region (either to the carboxy terminal side of position 239 or to the amino terminal side of position 234). ) can also be replaced. By way of example, the substitution of the leucine residue at position 235 (corresponding to position 16 of SEQ ID NO: 79) with a glutamic acid residue or an alanine residue cancels or reduces, respectively, the affinity of a immunoglobulin (such as human IgG3) for Fc? RI (Lund et al., 1991, supra; Canfield et al., supra; Morgan et al., supra). As another example, the replacement of the leucine residue at positions 234 and 235 (corresponding to positions 15 and 16 of SEQ ID NO.79), for example, with alanine residues, cancels the binding of an immunoglobulin to FcyRIla ( see, e.g., Wines et al., supra). Alternatively, leucine at position 234 (corresponding to position 15 of SEQ ID NO: 79), leucine at position 235 (corresponding to position 16 of SEQ ID NO: 79), and glycine at position 237 (which corresponds to position 18 of SEQ ID NO: 79), each can be substituted with a different amino acid, such as leucine at position 234 can be substituted with a residue of alanine (L234A), leucine at 235 can be substituted with a alanine residue (L235A) or with a glutamic acid residue (L235E), and the glycine residue at position 237 can be substituted with another amino acid, for example an alanine residue (G237A). In one embodiment, a mutein Fe polypeptide that is fused in frame to a viral polypeptide (or variant or fragment thereof) comprises one, two, three, four, five, or six mutations at positions 15-20 of SEQ ID NO: 79 corresponding to positions 234-239 of a CH2 domain of human IgGI (EU numbering system) as described herein. An illustrative lutein Fe polypeptide has the amino acid sequence set forth in SEQ ID NO: 77 in which the substitutions corresponding to (L234A), (L235E), and (G237A) can be found in positions 13, 14, and 16 of SEQ ID NO: 77 In another embodiment, a mutein Fe polypeptide comprises a mutation of a cysteine residue in the hinge region of a Fe polypeptide. In one embodiment, the cysteine residue more proximal to the amino terminus of the hinge region of a Fe ( e.g., the cysteine residue most proximal to the amino terminal of the hinge region of the Fe portion of a wild-type IgG1 immunoglobulin) is deleted or substituted with another amino acid. That is, by way of illustration, the cysteine residue in position 1 of SEQ ID NO: 79 is deleted, or the cysteine residue in position 1 is substituted with another amino acid which is incapable of forming a disulfide bond, by example, with a serine residue. In another embodiment, a Mutein Fe polypeptide comprises a deletion or substitution of the cysteine residue closest to the amino terminus of the hinge region of a Fe polypeptide further comprising deletion or substitution of the adjacent C-terminal amino acid. In a certain embodiment, this cysteine residue and the adjacent C-terminal residue are both deleted from the hinge region of a mutein Fe polypeptide. In a specific embodiment, the cysteine residue in position 1 of SEQ ID NO: 79 and the aspartic acid in position 2 of SEQ ID NO: 79 are deleted. Fe polypeptides comprising the deletion of these cysteine and aspartic acid residues in the hinge region can be efficiently expressed in a host cell, and in certain cases, can be expressed more efficiently in a cell than a Fe polypeptide that retains the residues of wild-type cysteine and aspartate. In a specific embodiment, a mutein Fe polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 77, which differ from the wild-type Fe polypeptide (SEQ ID NO: 79) wherein the cysteine residue at position 1 of SEQ. ID NO: 79 is deleted and the aspartic acid in position 2 of SEQ ID NO: 79 is deleted and the leucine residue in position 15 of SEQ ID NO: 79 is replaced with a residue of alanine, the leucine residue in position 16 is substituted with a glutamic acid residue, and glycine at position 18 is substituted with an alanine residue (see also figure 5). Therefore, an illustrative Lutein Fe polypeptide comprises an amino acid sequence in its amino terminal portion of KTHTCPPCPAPEAEGAPS (SEQ ID NO: 81) (see SEQ ID NO: 77, an illustrative Fe mutein sequence). Other variants of Fe encompass similar amino acid sequences of known Fe polypeptide sequences having only minor changes, for example a manner of illustration and not limitation, covalent chemical modifications, insertions, deletions and / or substitutions, which may also include conservative substitutions. . Amino acid sequences that are similar to one another may share regions of substantial sequence homology. Similarly, nucleotide sequences encoding the Fe variants can encompass substantially similar nucleotide sequences and have only minor changes, for example, by way of illustration and not limitation, covalent chemical modifications, insertions, deletions and / or substitutions, They can also include silent mutations due to degeneration of the genetic code. Nucleotide sequences that are similar to one another may share regions of substantial sequence homology. A Fe polypeptide or at least one immunoglobulin constant region, or portion thereof, when fused to a peptide or polypeptide of interest acts, at least in part, as a portion of vehicle or carrier that prevents degradation and / or increases half-life, reduces toxicity, reduces immunogenicity, and / or increases the biological activity of the peptide such as by forming dimers or other multimers (see, e.g., US Pat. Nos. 6,018,026; 6,291, 646; 6,323,323; 6,300,099; 5,843,725). (See also, e.g., U.S. Patent No. 5,428, 130; U.S. Patent No. 6,660,843; U.S. Patent Application Publication Nos. 2003/064480; 2001/053539; 2004/087778; 2004/077022; 2004; / 071712; 2004/057953/2004/053845 / 2004/044188; 2004/001853; 2004/082039). Alternative portions to a constant region of immunoglobulin such as a Fe polypeptide that can be linked or fused to a peptide that alters the immune response of an immune cell include, for example, a linear polymer (e.g., polyethylene glycol, polylysine, dextran , etc., see, for example, U.S. Patent No. 4,289,872, International Patent Application Publication No. WO 93/21259); a lipid; a cholesterol group (such as a spheroid); a carbohydrate or oligosaccharide.

Nucleic Acid Molecules In certain embodiments, polynucleotides and oligonucleotides are provided that are complementary to at least a portion of a sequence encoding an RPTP (LAR, RPTP-s, or RPTP-d) (e.g., a nucleic acid of short interference, an antisense polynucleotide, a ribozyme, or a peptide nucleic acid) and which can be used to alter the expression of genes and / or protein. As described herein, these polynucleotides that specifically bind to, or hybridize to, nucleic acid molecules that encode an RPTP (LAR, RPTP-s, or RPTP-d) can be prepared using the nucleotide sequences provided herein and available in the art (e.g., SEQ ID NOS: 23 and 27 encoding LAR; SEQ ID NOS: 30, 32, 34, 36 encoding RPTP-s; and SEQ ID NOS: 38, 40, 42, 44 that encode RPTP-d). In another embodiment, nucleic acid molecules such as aptamers that are not sequence specific can also be used to alter the expression of genes and / or protein.

RNA interference (RNA) By way of background, RNA interference refers to the silencing procedure of post-transcriptional genes specific for sequence in animals mediated by short interfering RNAs (siRNAs) (Zamore et al., Cell, 101 : 25-33 (2000), Fire et al., Nature 391: 806 (1998), Hamilton et al., Science 286: 950-51 (1999), Lin et al., Nature 402: 128-29 (1999). ), Sharp, Genes &Dev. 13: 139-41 (1999), and Strauss, Science 286: 886 (1999), Sandy et al., Biotechniques 39: 215-24 (2005)); patent of E.U.A. Nos. 6,506,559; 6,573,099; International patent application publication No. WO 01/75164). Inhibition is sequence specific because a nucleotide sequence of a portion of the target gene (eg, a gene that expresses an RPTP described herein) is chosen to produce inhibitory RNA. The post-transcriptional gene silencing procedure is thought to be a cell defense mechanism used to prevent the expression of foreign genes (Fire et al., Trends Genet 15: 358 (1999)). The method comprises introducing into the cell a nucleic acid molecule, generally RNA, with partial or complete double-stranded character. The presence of dsRNA in cells triggers the RNA response through a mechanism that has yet to be characterized. This mechanism appears to be different from other mechanisms involving specific ribonucleases of double-stranded RNA, such as the interferon response resulting from the activation of cinase protein PKR mediated by dsRNA and 2 ', 5'-oligoadenylate synthetase resulting in non-specific digestion of mRNA by ribonuclease L (see, e.g., U.S. Patent Nos. 6,107,094; 5,898,031; Clemens et al., J Interferon Cytokine Res. 17: 503-24 (1997); Adah et al., Curr Med. Chem. 8: 1 189 (2001)). The presence of long dsRNA in the cells stimulates the activity of a ribonuclease III enzyme referred to as a cutter (Bass, Cell 101: 235 (2000); Zamore et al., Cell, 101: 25-33 (2000); Hammond et al. , Nature 404: 293 (2000)). The cutter is involved in the dsRNA procedure in the short pieces of dsRNA known as siRNA (Zamore et al., Cell 101: 25-33 (2000); Bass, Cell 101: 235 (2000); Berstein et al., Nature 409: 363 (2001)). Short interfering RNAs derived from the activity cutter are typically from about 21 to about 23 nucleotides in length and comprise approximately 19 base pair duplexes (e.g., a dsRNA molecule 21-22 nucleotides long containing a duplex nucleus) of 19 base pairs and two unpaired nucleotides at each 3 'end) (Zamore et al., 2000, supra, Elbashir et al., 2001, supra, Dykxhoorn et al., Nat. Rev. Mol. Cell Biol. : 457-67 (2003)). The cutter has also been implicated in the excision of small temporal RNAs of 21 and 22 nucleotides (RNAst) of precursor RNA from the structure discussed that are involved in translation control (Hutvagner et al., Science 293: 834 (2001)). The RNA response also has an endonuclease complex, commonly referred to as an RNA-induced silencing complex (RISC), that mediates the digestion of single-stranded RNA that has sequence complementarity to the antisense strand of the siRNA duplex.

Digestion of the target RNA occurs in the middle of the region complementary to the antisense chain of the siRNA duplex (Elbashir et al., 2001, supra). Short interfering RNAs can be used to modulate (decrease or inhibit) the expression of LAR, RPTP-s, and / or RPTP-d genes. The description herein refers to compounds, compositions, and methods useful for modulating the expression and activity of genes encoding the RPTPs, LAR, RPTP-s, and RPTP-d, by RNA interference using small nucleic acid molecules. In particular, nucleic acid molecules, such as short-interfering RNA (siRNA), micro-RNA (miRNA), and short-pin RNA (shRNA) molecules can be used in accordance with the methods described herein to modulate expression of LAR, RPTP-s, and / or RPTP-d, or variants thereof. A siRNA polynucleotide preferably comprises a double-stranded RNA (dsRNA) but can comprise a single-stranded RNA (see, e.g., Martinez et al., Cell 110: 563-74 (2002)). A cRNA polynucleotide may comprise other naturally occurring, recombinant or synthetic single-stranded or double-stranded nucleotide polymers (ribonucleotides or deoxyribonucleotides or a combination of both) and / or nucleotide analogs as provided and known and used by the experts in the art. At least one strand of a double stranded siRNA polynucleotide has at least one, and preferably two nucleotides that "hang" (ie, do not form base pairs with a complementary base in the opposite strand) at the 3 end. 'either of a chain, or preferably both chains, of the siRNA polynucleotide. Typically, each strand of the siRNA polynucleotide duplex has a pendant of two nucleotides at the 3 'end. The pendants of two nucleotides can be a thymidine dinucleotide (TT) or can comprise other bases, for example, a CT dinucleotide or a TG dinucleotide, or any other dinucleotide (see, e.g., patent application publication). International No. WO 01/75164). Alternatively, the siRNA polynucleotide may have shaved ends, ie, cad nucleotide in a duplex chain is perfectly complementary (eg, by Watson-Crick base pairing) with a nucleotide of the opposite strand. A siRNA can be transcribed using as a template a DNA (genomic, cDNA, or synthetic) containing an RNA polymerase promoter, for example, a U6 promoter or the Hl RNA polymerase III promoter, or the siRNA can be a molecule of synthetically derived RNA. The double-stranded structure of a siRNA can be formed by an individual self-complementary RNA strand or two complementary RNAs. The RNA duplex formation can be initiated either inside or outside the cell. The RNA may be introduced in an amount to supply at least one copy per cell or at least 5, 10, 50, 100, 250, 500 or 1000 copies per cell. Polynucleotides that are siRNA polynucleotides can be derived from a single-stranded polynucleotide comprising a single-stranded oligonucleotide fragment (e.g., from about 15-30 nucleotides, from about 19-25 nucleotides, or from about 19-22 nucleotides, which should be understood to include any nucleotide integer including and between 15 and 30) and its reverse complement, typically separated by a spacer sequence. According to certain embodiments, digestion of the separator provides the single-stranded oligonucleotide fragment and its reverse complement, such that they can be quenched to form the double-stranded siRNA polynucleotide. Optionally, additional process steps may result in the addition or removal of one, two, three or more nucleotides of the 3 'end and / or the 5' end of either or both chains. In certain embodiments, the separator is of a length that allows the fragment and its reverse complement to be tempered and form a double-stranded structure (e.g., such as a pin polynucleotide) prior to digesting the separator (and, optionally, subsequent process steps that may result in the addition or removal of one, two, three, four or more nucleotides of the 3 'end and / or the end 5 'either from one or both chains). A spacer sequence can therefore be any polynucleotide sequence that is located between two regions of complementary polynucleotide sequences which, when tuned to a double-stranded nucleic acid, comprises a siRNA polynucleotide. A sequence of separator may comprise at least 4 nucleotides, although in certain embodiments the separator may comprise 5, 6, 1, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 , 20, 21 -25, 26-30, 31 -40, 41-50, 51 -70, 71-90, 91 -1 10, 11 1-150, 151-200 or more nucleotides. Examples of siRNA polynucleotides derived from a single nucleotide chain comprising two complementary nucleotide sequences separated by a separator have been described (e.g., Brummelkamp et al., 2002 Science 296: 550; Paddison et al., 2002 Genes Develop. 16: 948; Paul et al. Nat. Biotechnol. 20: 505-508 (2002); Grabarek et al., Biotechniques 34: 734-44 (2003)). A suitable vector for expression of a siRNA polynucleotide can comprise a recombinant nucleic acid construct that contains one or more promoters for transcription of an RNA molecule, for example, the U6 snRNA promoter (see, e.g., Miyagishi et al. al, Nat. Biotechnol., 20: 497-500 (2002), Lee et al., Nat. Biotechnol., 20: 500-505 (2002), Paul et al., Nat. Biotechnol., 20: 505-508 (2002). Grabarek et al., BioTechniques 34: 73544 (2003), see also Sui et al., Proc. Nati, Acad. Sci USA 99: 5515-20 (2002)). Each strand of a siRNA polynucleotide can be transcribed separately, each under the direction of a separate promoter, and then hybridized within the cell to form the siRNA polynucleotide diplex. Each strand can also be transcribed from separate vectors (see Lee et al., Supra). Alternatively, sense and antisense sequences specific for a sequence of RPTP (LAR, RPTP-s, and / or RPTP-d) can be transcribed under the control of a single promoter such that the siRNA polynucleotide forms a pin molecule (Paul et al., Supra). In this case, the complementary chain of the specific siRNA sequences are separated by a separator comprising at least four nucleotides, but can comprise at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 nucleotides or more nucleotides as described herein. In addition, siRNA transcribed under the control of a U6 promoter that forms a pin can have an extension of approximately four uridine at the 3 'end and which acts as the transcription termination signal (Miyagishi et al., Supra; Paul et al. ., supra). By way of illustration, if the target sequence is 19 nucleotides, the siRNA polynucleotide (which starts at the 5 'end) has a sense sequence of 19 nucleotides followed by a separator (having two uridine nucleotides adjacent to the terminus). 3 'of the sense sequence of 19 nucleotides), and the separator is linked to an antisense sequence of 19 nucleotides followed by a terminator sequence of 4 uridines, which results in a pendant. Short interfering RNA polynucleotides with such pendants effectively interfere with the expression of the target polypeptide (see Miyagishi et al., Supra; Paul et al., Supra). A recombinant construct can also be prepared using another RNA polymerase III promoter, the Hl RNA promoter, which can be operably linked to specific RNAi polynucleotide sequences, which can be used for the transcription of pin structures comprising the specific sequences of siRNA or transcript separated from each strand of a siRNA duplex polynucleotide (see, e.g., Brummelkamp et al., Science 296: 550-53 (2002); Paddison et al., supra). Useful DNA vectors for the insertion of sequences for transcription of a siRNA polynucleotide include pSUPER vector (see, e.g., Brummelkamp et al, supra), pAV vectors derived from pCWRSVN (see, v gr, Paul et al, supra). ), and pIND (see, v. g, Lee et al, supra), or the like. RPTP polypeptides can be expressed in mammalian cells, yeast, bacteria, or other cells under the control of appropriate promoters, therefore the systems are provided and are available to identify and characterize siRNA polynucleotides that are capable of interfering with polypeptide expression as provided herein. Cloning and expression vectors suitable for use with procapotic and eucapotic hosts are described, for example, in Sambrook, et al. al, Molecular Cloning A Laboratory Manual, third edition, Cold Spring Harbor, New York, (2001) These siRNAs can be used to inhibit, diminish or cancel the expression of one or more of LAR, RPTP-s, and RPTP-d, or variants thereof, thereby altering the immune response of an immune cell, and can be used to treat a subject or host who has an inflammatory or autoimmune disease, or a cardiovascular or metabolic disease related to the expression or overexpression of one or more of the RPTPs. Interference from the expression of LAR, RPTP-s, and rat RPTP-d in hippocampal neurons have been effective using siRNA molecules (Dunah et al, Nat Neurosa 8 458-67 (2005)) In one embodiment, a molecule of ARNic has IARN activity that affects the expression of LAR RNA, wherein the siRNA molecule comprises a sequence complementary to an RNA molecule encoding a LAR polypeptide or variant thereof, including, but not limited to, those sequences described herein In another embodiment, a siRNA molecule has IARN activity that affects the expression of RNA of RPTP-s or RPTP-d, wherein the siRNA molecule comprises a sequence complementary to an RNA coding it encodes an RPTP-s, respectively, or vanant polypeptide thereof, including, but not limited to, those sequences described herein. In certain other embodiments, a siRNA molecule has an IARN activity that affects the expression of at least two of LAR RNA, RTPP-s RNA, and RPTP-d RNA Such siRNAs that inhibit, effect a decrease or cancel the expression of at least two encoded RPTP (s) recognize, bind to, or hybridize to portions of the coding sequence that are common and identical to at least two nucleotide sequences of RPTP In another embodiment, a siRNA can inhibit, effect a decrease or cancel the expression of LAR RNA, RPTP-s RNA and RPTP RNA -d and recognize, bind to, or hybridize to portions of the coding sequence that are common and identical to the three nucleotide sequences of RPTP As described herein, nucleotide sequences that encode each of LAR, RPTP-s, and RPTP-d shares sequence identity at particular locations in the polynucleotides Such homologous or identical sequences can be identified according to methods known in the art and described herein, for example using sequence alignments. RNAi molecules can be designed to direct said homologous sequences, for example using perfectly complementary sequences or incorporating non-canonical base pairs, for example uncoupling and / or unstable base pairs, which can provide additional target sequences (see, e.g., US patent application) No. 2005/0137155). A siRNA molecule comprises an antisense strand having a nucleotide sequence that is complementary to a nucleotide sequence or a portion thereof encoding a LAR polypeptide, RPTP-s, and / or RPTP-d and may further comprise a sense chain, wherein the sense chain comprises a nucleotide sequence of a LAR gene or mRNA, RPTP-s, and / or RPTP-d, or a portion thereof. In one embodiment a siRNA molecule comprises an antisense strand having about 15, 16, 17, 18, 19, 20 or 21 nucleotides and in another mode about 19 to about 30 (e.g., about 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29 or 30) nucleotides, wherein the antisense strand is complementary to an RNA sequence encoding one or more of LARs, RPTP-s, and RPTP-d . In certain other embodiments, the siRNA further comprises a sense strand having about 16, 17, 18, 19, 20 or 21 nucleotides and in another mode about 19 to about 30 (e.g., about 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30) nucleotides. The sense chain and the antisense chain are distinct nucleotide sequences with at least about 19 complementary nucleotides. The nucleotide sequence of the siRNA polynucleotide can be identical to a portion of a polynucleotide sequence encoding an SPTP as described herein or the nucleotide sequence can differ by one, two, three or four nucleotides. Single-point mutations in relation to the target sequence have been found to be effective for inhibition. A variety of algorithms are available to determine the sequence of siRNA molecules. In general, regions of a target polynucleotide sequence that are to be avoided when designing a siRNA include (1) regions within 50-100 base pairs of the start codon or stop codon; (2) intron regions; (3) extensions of 4 or more identical bases; (4) regions with GC content less than 30% or greater than 60%; and (5) repeats and low complex sequence. An algorithm that can be used to design a siRNA that inhibits the expression of a LAR gene, RPTP-s, and RPTP-d and / or mRNA is referred to as the Tuschl rules (Elbashir et al., Nature 41 1: 494 -98 (2001); Elbashir et al., EMBO J. 20: 6877-88 (2001); Elbashir et al., Methods 26: 199-213 (2002)). A target region is selected which is 50-100 nucleotides towards the 3 'end of a start codon, whose sequence comprises in order of preference (1) sequence motif of 23 nucleotides AA (N g); (2) 23 nucleotide sequence motif (NA (N21); convert the 3 'end of the sense siRNA to TT; (3) NAR (Ni7) YNN, where R = A or G (purine); Y - T or C (pyrimidine), and N = any nucleotide The target sequence must have a GC content of about 50% Another method referred to as rational siRNA design (Dharmacon, Inc.) assigns point values to particular sequence characteristics (see , eg, Reynolds et al., Nat. Biotechnol., 22: 326-30 (2004).) In addition, several suppliers design and manufacture RNAi molecules based on the target sequence using proprietary algorithms (see, v.gr. ., Ambion, Inc., Austin, TX, algorithm developed by Cenix Bioscience; Qiagen, 5 Inc., Valencia, CA) A siRNA can be unmodified or chemically modified and can be chemically synthesized, expressed from a vector, or enzymatically Synthesized The use of chemically modified siRNA improves several properties of native siRNA molecules, p For example, J O increase resistance to degradation by nuclease in vivo and / or through enhanced cellular uptake (see, e.g., U.S. Patent Application No. 2005/0137155). Inhibition of gene expression refers to the absence (or observable decrease) in the level of protein product and / or mRNA of a target gene encoding LAR, RPTP-s, or RPTP-d. Specifically, it refers to the ability to inhibit the target gene without manifesting effects on other genes in the cell. The consequences of inhibition can be confirmed by examining the properties of the cell or organism or by biochemical techniques such as hybridization of RNA solution, nuclease protection, Northern hybridization, reverse transcription, monitoring of gene expression with a microarray antibody binding, enzyme-linked immunosorbent assay (ELISA), Western blotting, radioimmunoassay (RIA), other immunoassays, and fluorescence activated cell analysis (FACS).

For RNA-mediated inhibition in a whole cell line or organism, gene expression is conveniently tested using a reporter or drug resistance gene whose protein product is easily tested. Examples of reporter genes include acetohydroxy acid synthase (AHAS), alkaline phosphatase (AP), beta galactosidase (LacZ), beta glucuronidase (GUS) 3 chloramphenicol acetyltransferase (CAT), green fluorescent protein (GFP), horseradish peroxidase (HRP), luciferase (Luc), nopaline synthase (NOS), octopine synthase (OCS), and derivatives thereof. Multiple selectable markers are available that confer resistance to ampicillin, bleomycin, chloramphenicol, gentamicin, hygromycin, kanamycin, lincomycin, methotrexate, phosphinothricin, puromycin, and tetracycline.

Antisense polynucleotides and ribozymes Antisense polynucleotides are linked in a sequence-specific manner to nucleic acids such as mRNA or DNA. The identification of oligonucleotides and ribozymes to be used as antisense agents and the identification of DNA encoding genes for directed delivery involves methods well known in the art. For example, the desirable properties, lengths and other characteristics of said oligonucleotides are well known. Antisense technology can be used to control gene expression through interference with the binding of polymerases, transcription factors, or other regulatory molecules (see Gee et al., In Huber and Carr, Molecular and Immunologic Approaches, Futura Publishing Co. (Mt. Kisco, NY, 1994)). An antisense polynucleotide can also alter gene expression of either LAR, RPTP-s, and / or RPTP-d by specifically hybridizing to a portion of the encoding gene or mRNA that is not translated and can be a sequence that is a regulatory sequence . Said antisense molecule can be designated to hybridize with a control region of an RPTP gene (e.g., promoter, enhancer or transcription initiation site) and en bloc transcription of the gene or translation en bloc by inhibiting the binding of a transcription to ribosomes. When bound to mRNA having complementary sequences, the antisense prevents mRNA translation (see, e.g., U.S. Patent No. 5, 168,053, U.S. Patent No. 5,190,931, U.S. Patent No. 5,135,917; US No. 5,087,617; Clusel et al., Nucleic Acids Res. 21: 3405-341 1 (1993), which describes bar-like antisense oligonucleotides with weights). Triplex molecules refer to individual strands of DNA that bind to duplex DNA to form a collinear triple molecule, thus preventing transcription (see, e.g., U.S. Patent No. 5,176,996, which describes methods for making synthetic oligonucleotides that are link to target sites in duplex DNA, see also, e.g., Helene, Anticancer Drug Des 6: 569-84 (1991), Helene et al., Ann. N Y. Acad. Sc / 660: 27-36 (1992); Maher, Bioassays 14: 807-15 (1992)). An antisense polynucleotide comprises a nucleotide sequence that is complementary to a sense polynucleotide that encodes protein, for example, complementary to the coding strand of a double-stranded cDNA molecule or complementary to a mRNA sequence. Accordingly, an antisense polynucleotide can be linked by hydrogen to a sense polynucleotide. The antisense polynucleotide can be complementary to an entire PTPN coding strand, or only to a portion thereof. In one embodiment, an antisense polynucleotide molecule is antisense to a coding region of a polynucleotide encoding LAR, RPTP-s, or RPTP-d. The antisense polynucleotide may comprise a sequence that is antisense to a portion of the nucleotide sequence that is unique to LAR, RPTP-s, or RPTP-d or may comprise a sequence that is antisense to a portion of the coding sequence that is similar or identical in each of the polynucleotides encoding LAR, RPTP-s, or RPTP-d. The term "coding region" refers to the region of the nucleotide sequence that comprises codons that are translated into amino acid residues. In another embodiment, the antisense nucleic acid molecule is antisense to a "non-coding region" of the coding strand of a nucleotide sequence encoding either LAR, RPTP-s, or pTTP-d. The term "non-coding region" refers to 5 'and 3' sequences that flank the coding region that bo are translated into amino acids (ie, also referred to as 5 'and 3' untranslated regions). Given the coding strand sequences encoding the RPTPs described herein and available in the art, the antisense polynucleotide can be designated in accordance with the Watson and Crick base pairing rules. The antisense polynucleotide can be complementary to the entire coding region of an RPTP mRNA, for example, or it can be an oligonucleotide that is antisense to only a portion of the coding or non-coding region of the RPTP mRNA. For example, the antisense oligonucleotide may be complementary to the region surrounding the translation initiation site of RPTP mRNA. An antisense oligonucleotide can be, for example, about 5, 10, 15, 20, 25, 30, 35, 40, 45 or 50 nucleotides or more in length. An antisense nucleic acid can be constructed using chemical and enzymatic synthesis reactions using methods known in the art. For example, an antisense nucleic acid (e.g., an antisense oligonucleotide) that is chemically synthesized using naturally occurring nucleotides or variably modified nucleotides designed to increase the biological stability of the molecules or to increase the physical stability of the duplex formed between the sense and antisense nucleic acids, e.g., phosphorothioate derivatives and nucleotides substituted with acridine can be used. Antisense oligonucleotides are typically designed to resist degradation by endogenous nucleolytic enzymes using linkages such as phosphorothioate, methylphosphonate, sulfone, sulfate, cetyl, phosphorodithioate, phosphoramidate, phosphate esters, and other such linkages (see, e.g., Agrwal et al, Tetrahedron Lett.28: 3539-42 (1987); Miller et al., J.

Am. Chem. Soc. 93: 6657-65 (1971); Stec et al., Tetrahedron Lett. 26: 2191-2194 (1985); Moody et al., Nucleic Acids Res. 12: 4769-82 (1989); Uznanski et al., Nucleic Acids Res. 17: 4863-71 (1989); Letsinger et al., Tetrahedron 40: 137-43 (1984); Eckstein, Annu. Rev. Biochem. 54: 367-402 (1985); Eckstein, Trends Biol. Sci 14: 97-100 (1989); Stein, in: Oligodeoxynucleotides. Antisense Inhibitors of Gene Expression, Cohen, ed., Macmillan Press, London, pp. 97-117 (1989); Jager et al., Biochemistry 27: 7237-46 (1988)). Examples of modified nucleotides that can be used to generate the antisense nucleic acid include 5-fluorourazole, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5- (carboxyhydroxymethyl) uracil, 5-carboxymethylaminomethyl -2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methaladenine, 2-methylguanine, 3-methylcytosine, -methycytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine, 5'-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N6-isopentenyladenine, uracil-5 acid -oxyacetic (v), wibutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methyl ester, uracil-5 acid -oxyacetic (v), 5-methyl-2-thiouracil, 3- (3-amino-3-N-2-carboxypropyl) uraci lo, (acp3) w, and 2,6-diaminopurine. Alternatively, the antisense polynucleotide (or oligonucleotide) can be produced biologically using an expression vector in which a nucleic acid has been subcloned in an antisense orientation (ie, RNA transcribed from the inserted nucleic acid will be of an antisense orientation to a target nucleotide of interest An antisense polynucleotide that is specific for one or more polynucleotides encoding LAR, RPTP-s, or RPTP-d is typically administered to a subject or generated in situ such that the hybrid antisense polynucleotide with or binds an mRNA and / or cellular genomic DNA encoding the PTWR to thereby inhibit the expression of the protein, by inhibiting transcription and / or translation. Hybridization can be by conventional nucleotide complementarity resulting in the formation of a stable duplex or, for example, when an antisense polynucleotide binds to DNA duplex, the polynucleotide antisense bound binds through specific interactions in the larger groove of the double helix An antisense polynucleotide can be administered to a host or subject by direct injection into a tissue site Alternatively, antisense polynucleotides can be modified or manipulated by genetic engineering to target selected cells and then administered systemically For example, for systemic administration, the antisense molecules can be modified in such a way that they bind specifically to receptors or antigens expressed on a selected cell surface, v. g, linking the acid molecules antisense nucleic acid to peptides or antibodies that bind to cell surface antigens or receptors An antisense polynucleotide can also be delivered to the cells using the vectors described herein and used in the art. To achieve sufficient intracellular concentrations of the antisense molecules, a vector can be constructed so that the antisense polynucleotide is placed under the control of a strong pol II or pol III promoter. In yet another embodiment, the antisense polynucleotide is an a-anomeric nucleic acid molecule. An a-anomeric nucleic acid molecule forms specific double-stranded hybrids with complementary RNA in which, contrary to the usual β units, the strands run parallel to one another (Gaultier et al (1987) Nucleic Acids. Res. 15: 6625-6641). The antisense nucleic acid molecule can also comprise a 2'-o-methylribonucleotide (Inoue et al., Nucleic Acids Res. 15: 6131-6148 (1987)) or a chimeric RNA-DNA analogue (Inoue et al., FEBS Lett 215: 327-330 (1987)). In another modality, the immune response of an immune cell can be altered by contacting a cell expressing one or more of LAR, RPTP-s, or RPTP-d with a ribozyme. A ribozyme is a catalytic RNA molecule with ribonuclease activity that is capable of specifically digesting a single-stranded nucleic acid, such as an mRNA, for which the ribozyme has a complementary region, resulting in specific inhibition or interference with the ribozyme. cellular gene expression. At least five known classes of ribozymes are involved in the digestion and / or ligation of RNA strands (e.g., hammerhead ribozymes, described in Haselhoff and Gerlach (Nature 334: 585-591 (1988)). The ribozymes can be directed to any RNA transcript and can catalytically digest said transcripts (see, e.g., US Patent No. 5,272,262).; patent of E.U.A. No. 5,144,019; and patent of E.U.A. Nos. 5, 168,053, 5, 180,818, 5.1 16.742 and 5.093.246). Therefore, a ribozyme that is specific for a nucleic acid encoding PTPR can be designed based on the nucleotide sequence of a PTPN, as described herein and is available in the art. For example, a derivative of a Tetrahymena L-19 IVS RNA can be constructed in which the nucleotide sequence of the active site is complementary to the nucleotide sequence to be digested in an mRNA encoding PTPR. (See, e.g., Cech et al, U.S. Patent No. 4,987,071, and Cech et al, U.S. Patent No. 5,116,742.) Alternatively, an mRNA molecule encoding an RPTP can be used to select a catalytic RNA having a specific ribonuclease activity from a stock of RNA molecules (see, e.g., Bartel et al., Science 261: 141 1-18 (1993)).

Peptide Nucleic Acids In another embodiment, peptide nucleic acids (PNAs) can be prepared by modifying the deoxyribose-phosphate base structure of a polynucleotide (or a portion thereof) that encodes any of the RPTPs described herein (see, e.g., Hyrup B. et al., Bioorganic &Medicinal Chemistry 4: 5-23) (1996)). The terms "peptide nucleic acid" or "PNA" refers to a simulation of nucleic acid, for example, a DNA simulation, in which the deoxyribose phosphate base structure is replaced by a pseudopeptide base structure wherein only the four natural nucleobases are retained. The neutral bas structure of a PNA has been shown to allow specific hybridization to DNA and RNA under conditions of low ionic strength. Synthesis of PNA oligomers can be performed using standard solid-phase peptide synthesis protocols (see, e.g., Hyrup B., supra, Perry-O'Keefe et al., Proc. Nati. Acad. Sci USA 93: 14670-75 (1996)). A PNA molecule that is specific for one or more of LAR, RPTP-s, and RPTP-d can be used as an antisense or anti-gene agent for modulation of sequence-specific gene expression, for example, by inducing disruption of transcription or translation or inhibiting replication.

Aptamers Aptamers are DNA or RNA molecules, generally single-stranded, that have been selected from random collections based on their ability to bind to other molecules, including nucleic acids, proteins, lipids, etc. Unlike antisense polynucleotides, short interfering RNA (siRNA), or ribozymes that bind to a polynucleotide that comprises a sequence encoding a polypeptide of interest and that alter transcription or translation, aptamers can be targeted and bound to polypeptides. Aptamers can be selected from random or unmodified oligonucleotide libraries for their ability to bind to specific targets, in this case, LAR, RPTP-d, and / or RPTP-s (see, e.g., US patent No 6,867,289; U.S. Patent No. 5,567,588). Aptamers have the ability to form a variety of bi-and three-dimensional structures and have sufficient chemical versatility disposable within their monomers to act as ligands (i.e., to form specific binding pairs) with virtually any chemical compound, since be monomeric or polymeric. Molecules of any size or composition can serve as targets. An iterative in vitro selection procedure can be used to enrich the library for species with high affinity to the target. This procedure involves repetitive cycles of incubation of the library with a desired objective, separation of free oligonucleotides from those attached to the target, and amplification of their set of bound oligonucleotides, such as using the polymerase chain reaction (PCR). From the selected sub-population of sequences having high affinity for the target, a sub-population can be subcloned and the particular aptamers examined in further detail to identify aptamers that alter a biological function of the target (see, e.g. , U.S. Patent No. 6,699,843). The aptamers can comprise any deoxyribonucleotide or ribonucleotide or modifications of these bases, such as deoxythiophosphate (or phosphorothioate), which has sulfur in place of oxygen as one of the non-bridge-forming ligands attached to phosphorus.

The monothiophosphates sS have a sulfur atom and therefore are chiral around the center of the phosphorus. The dithiophosphates are substituted in both oxygens and therefore are achiral. Phosphorothioate nucleotides are commercially available or can be synthesized by several different methods known in the art.

Antibodies and antigen binding fragments Antibodies that bind specifically to LAR, RPTP-d, or to RPTP-s are provided here; antibodies that bind specifically to LAR and RPTP-d; antibodies that specifically bind to LAR and RPTP-s; antibodies that specifically bind to RPTP-d and RPTP-s; and antibodies that specifically bind to LAR, RPTP-d and RPTP-s, and methods to make and use these antibodies. These specific antibodies can be polyclonal or monoclonal, prepared by immunization of animals and subsequent isolation of the antibody, or the antibodies can be recombinant antibodies. The antibodies described herein are useful for affecting the immune response of an immune cell that expresses at least one of LAR, RPTP-d and RPTP-s. In certain embodiments, the antibodies suppress the immune response of an immune cell that expresses at least one of LAR, RPTP-d and RPTP-s. Such antibodies include those that exhibit a similar effect on the immune cell as the poxvirus protein A41 L or 130L. These antibodies are capable of competitively inbreeding the binding and / or alteration (ie, preventing, blocking, decreasing) of the binding of A41 L (or alternatively, 130L) to an immune cell. In one embodiment, an antibody or antigen-binding fragment thereof specifically binds to at least two RPTPs, which can be any two of LAR, RPTP-d and RPTP-s, and competitively inhibits the binding of A41 L (or 130L) to at least two RPTP polypeptides. In another embodiment, said antibody inhibits the binding of A41 L (or 130L) to an immune cell that expresses either LAR, RPTP-d and RPTP-s. Therefore, the antibody or antigen-binding fragment thereof suppresses the immune response of the immune cell, which expresses either LAR, RPTP-d and RPTP-s. In a particular embodiment, an antibody, or antigen-binding fragment thereof, specifically binds both RPTP-d and RPTP-s and inhibits binding of A41L or 130L to RPTP-d or to RPTP-s or both to RPTP -d as RPTP-s. In another embodiment, an antibody or antigen-binding fragment thereof specifically binds to all three of LAR, RPTP-d and RPTP-s. The antibodies described herein may be useful for treating or preventing, inhibiting, slowing the progression of, or reducing the symptoms associated with, an immune disease or disorder, a cardiovascular disease or disorder, a metabolic disorder or disorder, or a disease or disorder proliferative An immunological disorder includes an inflammatory disease or disorder and an autoimmune disease or disorder. Although inflammation or an inflammatory response is a normal and protective response of the host to an injury, the inflammation can cause unwanted damage. For example, atherosclerosis is, at least in part, a pathological response to arterial injury and the consequent cascade of inflammation. Examples of immune disorders that can be treated with an antibody or antigen-binding fragment thereof described herein include but are not limited to multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus (SLE), graft versus host disease (GVHD), sepsis. , diabetes, psoriasis, atherosclerosis, Sjogren's syndrome, progressive systemic sclerosis, scleroderma, acute coronary syndrome, ischemic reperfusion, Crohn's disease, endometriosis, glomerulonephritis, myasthenia gravis, idiopathic pulmonary fibrosis, asthma, acute respiratory distress syndrome (ARDS), vasculitis, or inflammatory autoimmune myositis and other inflammatory and degenerative muscle diseases (e.g., dermatomyositis, polymyositis, juvenile dermatomyositis, myositis of inclusion bodies). A disease or cardiovascular disorder that can be treated, which may include a disease and disorder that is also considered an immunological disease / disorder, includes for example, atherosclerosis, endocarditis, hypertension, or peripheral ischemic disease. A metabolic disease or disorder includes diabetes, obesity, and diseases and disorders associated with abnormal or altered mitochondrial function. Any one or more of the RPTPs described herein can also be used in methods for selecting samples that contain antibodies, for example, samples of purified antibodies, antisera, or cell culture supernatants, or any other biological sample that may contain one or more antibodies specific for one or more of the RPTPs One or more of the RPTPs may also be used in methods to identify and select from a biological sample one or more B cells that are producing an antibody that specifically binds to one or more of the RPTPs (v gr, plaque forming tests and the like) B cells can then be used as a source of specific antibody encoder that can be cloned and / or modified by recombinant molecular biology techniques known in the art and described herein As used herein, an antibody is said to be "specific", "specific to" or "specifically bind to" "one or more of LAR, RPTP-d and RPTP-s if it reacts at a detectable level with one or more RPTPs, preferably with an affinity constant, Ka, greater than or equal to about 104 M "1, or greater than or equal to about 105 M'1, greater than or equal to about 106 M" 1, greater than or equal to about 107 M "1, or greater than or equal to 108 M "1 The affinity of an antibody for its cognate antigen is also commonly expressed as a KD dissociation constant, and an anti-RPTP antibody binds specifically to one or more RPTPs if it binds with a Kp less than or equal to 10 ~ 4 M, less than or equal to about 10"5 M, less than or equal to about 10 ~ 6 M, less than or equal to 10 ~ 7 M, or less than or equal to 10'8 M The binding affinities of Patterns or antibodies can be easily determined using conventional techniques, for example, those described by Scatchard et al (Ann NY Acad Sa USA 51 660 (1949)) and by surface plasmon resonance (SPR, BIAcore ™, Biosensor, Piscataway, NJ ) For surface plasmon resonance, the target molecules are immobilized on a solid phase and exposed to ligands in a mobile phase that runs along a cell in flux If ligand binding to the immobilized target occurs, the local refractive index changes, which lead to a change in the SPR angle, which can be monitor in real time when detecting changes in the intensity of reflected light The rates of change of the surface plasmon resonance signal can be analyzed to give apparent rate constants for the association and dissociation phases of the binding reaction. of these values gives the apparent equilibrium constant (affinity) (see, v gr, Wolff et al, Cancer Res 53 2560-2565 (1993)) The binding properties of an antibody to a PTWP described here generally can be determined and evaluated using immunodetection methods including, for example, an enzyme-linked immunosorbent assay (ELISA), immunoprecipitation, immunoblotting, countercurrent immunoelectrophoresis, radioimmunoassays, point transfer tests, inhibition or competition tests, and the like, which can be readily carried out by those skilled in the art (see, v. g., US Pat. Nos. 4,376.1 10 and 4,486,530, Harlow et al, Antibodies A Laboratory Manual, Cold Spring Harbor Laboratory (1988)) Immunoassay methods may include controls and procedures to determine whether the antibodies specifically bind to LAR, PTTP-d, and / or RPTP-s and do not recognize or react in a crossed with other protein tyrosine phosphatases, particularly other receptor-like protein tyrosine phosphatases. In addition, an immunoassay performed for detection of anti-RPTP (ie, anti-LAR, anti-RPTP-d, and / or anti-RPTP-s) antibodies that are produced in response to immunization of a host with an RPTP conjugated to A particular vehicle polypeptide can incorporate the use of PTTP that is conjugated to a different vehicle polypeptide than that used for immunization to reduce or eliminate detection of antibodies that specifically bind to the immunizing carrier polypeptide. Alternatively, an RPTP described herein that is not conjugated to a carrier molecule can be used in an immunoassay to detect immunospecific antibodies. In certain embodiments, an antibody as described herein is specific only for one of LAR, RPTP-d, and RPTP-s. That is, for example, an antibody that specifically binds to LAR does not bind specifically to either RPTP-d or RPTP-s; an antibody that binds specifically to RPTP-d does not bind specifically to LAR or to RPTP-s; and an antibody that binds specifically to RPTP-s does not bind specifically to LAR or to RPTP-d. Said antibodies that specifically bind only to an RPTP described herein bind to an epitope (antigenic determinant) comprising an amino acid sequence of the PTPN that is not identical or similar to an amino acid sequence present in another PTPN, or said antibodies are specifically bind to a conformational epitope that is present only in the PTWP to which the antibody binds specifically. The specificity of an antibody for a particular PTTP can be easily determined using any of the various immunoassays available in the art and described herein. In other embodiments, an antibody or antigen-binding fragment thereof specifically binds to at least two of LAR, RPTP-d, and RPTP-s (ie, LAR and RPTP-d; LAR and RPTP-s, or RPTP-d and RPTP-s), and in other embodiments, an antibody or antigen-binding fragment thereof specifically binds to the three RPTPs described herein. An antibody that specifically binds to LAR, RPTP-d, and RPTP-s recognizes an epitope (antigenic determinant) that is commonly present in each of the RPTPs. An antigenic determinant or epitope that is common to at least two of LAR, PTPN-d, and PTPN-s may comprise an amino acid sequence that is identical or similar in each of at least two RPTPs, or may comprise an epitope conformational common to at least two of the RPTPs, or may comprise a similar chemical structure, eg, a chemical structure resulting from the distribution of surface charge (s) of the amino acids that are included in the epitope. By way of example, the amino acid sequence set forth in SEQ ID NO: 54 (YSAPANLYV) is common to each of LAR, RPTP-d, and RPTP-s. An antibody that binds to an epitope comprising this amino acid sequence located in the second immunoglobulin-like domain of each PWTP would therefore bind specifically to each of LAR, PTPN-d, and PTPR-s. Antibodies can generally be prepared by any of a variety of techniques known to those skilled in the art. See, e.g., Harlow et al., Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory (1988); Peterson, ILAR J. 46: 314-19 (2005)). Any of the RPTPs described herein, or peptides or fragments thereof, or a cell expressing one or more of the RPTPs can be used as an immunogen to immunize an animal for production of either polyclonal antibodies or monoclonal antibodies. Fragments of each PTWT that can be used as an immunogen can include larger fragments, such as the extracellular region (which includes the three immunoglobulin (Ig) domains and the fibronectin domains) and the intracellular region (which includes the two catalytic domains of phosphatase D1 and D2), or smaller fragments thereof. An immunogen may comprise a portion of the extracellular region, such as at least one of the Ig domains or a portion thereof or at least one of the fibronectin domains or a portion thereof. RPTP peptide and polypeptide immunogens can be used to generate and / or identify antibodies or antigen-binding fragments thereof that are capable of altering (increasing or decreasing in a statistically significant or biologically significant manner, preferably decreasing) the immune response of an immune cell.

Exemplary peptide immunogens may comprise 6, 7, 8, 9, 10, 11, 12, 20-25, 21 -50, 26-30, 31 -40, 41 -50, 51 -60, 61 -70 or 71 -75 consecutive amino acids of LAR, RPTP-d, or RPTP-s as provided here (or a variant thereof). For example, peptides derived from the Ig domains, such as SEQ ID NO: 53 (SGALQIEQSEESDQGK); SEQ ID NO: 54 (YSAPANLYV); SEQ ID NO: 55 (WMLGAEDLTPEDDMPIGR); and SEQ ID NO: 56 (NVLELNDVR) of RPTP-d can be used as immunogens. Examples of peptides derived from the repeats of fibronectin III RPTP-d include SEQ ID NO: 57 (GPPSEPVLTQTSEQAPSSAPR); SEQ ID NO: 58 (SPQGLGASTAEISAR); SEQ ID NO: 59 (YTAVDGEDDKPHEILGIPSDTTK); SEQ ID NO: 60 (VGFGEEMVK); and SEQ ID NO: 61 (GPGPYSPSVQFR). Examples of peptides derived from the repeats of fibronectin RPTP-s include SEQ ID NO: 45 (SIGQGPPSES WTR); SEQ ID NO: 46 (HNVDDSLLTTVGSLLEDETYVR); SEQ ID NO: 47 (VLAFTSVGDGPLSDPIQVK); SEQ ID NO: 48 (TEVGPGPESSPVWR); SEQ ID NO: 49 (WEPPAGTAEDQVLGYR); and SEQ ID NO: 50 (TSVLLSWEFPDNYNSPTPYK). An antibody that specifically binds to an antigenic determinant (epitope) present in the intracellular portion of a PTWP would not be expected to competitively inhibit binding (or altering the binding) of a poxvirus polypeptide such as A4 IL or 130L to the PTWP due to that the viral polypeptide likely alters an immune cell immune response by binding to the extracellular portion of a cell surface antigen such as LAR, RPTP-d, and / or RPTP-s. An antibody that binds specifically to the intracellular portion of an RPTP can be used in combination with an antibody (or other agent) that alters the immune response of an immune cell and that competitively inhibits the binding of A41 L or 130L to at least an RPTP. Accordingly, peptides and fragments comprising amino acid sequences of the intracellular domain, particularly the catalytic domains, either D1 or D2, can also be used as immunogens (eg, SEQ ID NO: 51 (TEVGPGPESSPVWR) of RPTP-s) . Peptides and fragments of RPTP that are useful as immunogens include portions of an RPTP to which A41 L or 130L binds. The RPTP domain that interacts with A41 L or 130L can be identified by constructing extracellular domain RPTP polypeptides whereby one or more of the extracellular domains is deleted. By way of example, a fusion polypeptide, for example, can exclude fibronectin domains from an SPTP, and therefore comprises only one, two or three Ig-like SPTP domains. Said RPTP Ig polypeptide-like domain can be fused to an immunoglobulin Fe polypeptide, or mutein thereof, and comprises the first immunoglobulin-like domain of an RPTP, the first and second immunoglobulin-like domains, the first and third domains similar to immunoglobulin, the second or third immunoglobulin-like domains, or the three immunoglobulin-like domains fused to a Fe polypeptide. Such a domain similar to RPTP Ig polypeptides may also be useful for identifying and determining the extent to which a polypeptide of poxvirus binds or a cell ligand binds to an RPTP domain similar to immunoglobulin (s). A method for determining the amino acid sequence of a poxvirus polypeptide binding site, or a portion of the binding site, of any of LAR, RPTP-d, and RPTP-s, includes peptide mapping techniques. For example, LAR, RPTP-d, or RPTP-s peptides can be randomly generated by proteolytic digestion using any one or more of several proteases, the separated and / or isolated peptides (e.g., by gel electrophoresis, column chromatography ), followed by determination of which peptide (s) a poxvirus polypeptide, such as A41 L or 130L, binds, and then sequence analysis of the peptides. The RPTP peptides can also be generated using recombinant methods described herein and practiced in the art. Peptides randomly generated by recombinant methods can also be used to prepare combinatorial libraries of phage peptides or libraries as described herein and in the art. Alternatively, the amino acid sequences of portions of LAR, RPTP-s, and / or RPTP-d that interact with a poxvirus polypeptide can be determined by computer modeling the phosphatase, or a portion of the phosphatase, eg, the extracellular portion or the Ig domain, and / or x-ray crystallography (which may include preparation and analysis of phosphatase crystals alone or of the viral phosphatase-polypeptide complex). Immunogenic peptides of LAR, RPTP-d, or RPTP-s can also be determined by computer analysis of the amino acid sequence of the PTWP to determine a graph of hydrophilic character. Portions of the PTWT that are accessible to an antibody are most likely portions of the protein that are in contact with the aqueous environment and are hydrophilic. The hydrophilic character regions can be determined using computer programs available to those skilled in the art and assigning a "hydrophilic index" to each amino acid in a protein and then plotting a profile. The preparation of an immunogen, particularly polypeptide fragments or peptides, for injection into animals may include covalent coupling of the RPTP or peptide fragment (or variant thereof), to another immunogenic protein, eg, a carrier protein such as hemocyanin of lapa (KLH) or bovine serum albumin (BSA) or similar. A polypeptide or peptide immunogen can include one or more additional amino acids either at the N-terminus or C-terminus that facilitates the conjugation process (e.g., the addition of a cysteine to facilitate the conjugation of a peptide to KLH). Other amino acid residues within a polypeptide or peptide can be substituted to avoid conjugation at the position of the particular amino acid to a carrier polypeptide (e.g., substituting a cysteine residue for serine at internal positions of a polypeptide / peptide) or can be substituted to facilitate solubility or to increase immunogenicity. An antibody as contemplated and described herein may belong to any class of immunoglobulin, for example IgG, IgE, IgM, IgD or IgA. It can be obtained or derived from an animal, for example, poultry (e.g., chickens) and mammals, which include but are not limited to mouse, rat, hamster, rabbit or other rodent, cow, horse, sheep, goat, camel, human or other primate. The antibody can be an internalizing antibody. In one such technique, an animal is immunized with an RPTP or fragment thereof as described herein as an antigen to generate polyclonal antisera. Suitable animals include, for example, rabbits, sheep, goats, pigs, cattle, and may also include smaller mammalian species, such as mice, rats and hamsters, or other species. Polyclonal antibodies that specifically bind to LAR, RPTP-d, and / or RPTP-s can be prepared using methods described herein and practiced by those skilled in the art (see, for example, Green et al., "Production of Polyclonal Antisera, "in Immunochemical Protocols (Manson, ed.), Pages 1-5 (Humana Press 1992); Harlow et al., Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory (1988); Williams et al., "Expression of foreign proteins in E.coli using plasmid vectors and purification of specific polyclonal antibodies," in DNA Cloning 2: Expression Systems, 2a. edition, Glover et al. (eds.), page 15 (Oxford University Press 1995)). Although polyclonal antibodies are typically produced in animals such as rats, mice, rabbits, goats, cattle or sheep, an anti-RPTP antibody can also be obtained from a subhuman primate.

General techniques for producing antibodies useful for diagnosis and therapy in baboons can be found, for example, in International Patent Application Publication No. WO 91/11465 (1991) and Losman et al., Int. J. Cancer 46: 310, 1990. In addition, the LAR, RPTP-d, and / or RPTP-s polypeptide, fragment or peptide thereof, or a cell expressing one or more of these RPTPs used as an immunogen can be emulsified in an adjuvant. See, e.g., Harlow et al., Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory (1988). Adjuvants typically used for immunization of non-human animals include but are not limited to Freund's complete adjuvant, incomplete Freund's adjuvant, montanide ISA, Ribi adjuvant system (RAS) (Corixa Corporation, Seattle, WA), and antigen adsorbed on nitrocellulose . The immunogen can be injected into the animal by any number of different routes, including intraperitoneally, intravenously, intramuscularly, intradermally, intraocularly or subcutaneously. In general, after the first injection, the animals receive one or more booster immunizations according to a preferred program which may vary in accordance with, inter alia, the antigen, the adjuvant (if any) and / or the species of a particular animal. The immune response can be monitored by periodically collecting blood from the animal, separating the sera from the collected blood, and analyzing the sera in an immunoassay, such as an ELISA test or Ouchterlony diffusion test, or the like, to determine the antibody titer. specific. Once an adequate antibody titer is established, blood can be obtained from the animals periodically to accumulate the polyclonal antisera. Polyclonal antibodies that specifically bind to LAR, RPTP-d, and / or RPTP-s can then be purified from said antisera, for example, by affinity chromatography using protein A or protein G immobilized on a suitable solid support (see, v., Coligan, supra, p 2.7.1-2.7.12; 2.9.1-2.9.3; Baines et al., Purification of Immunoglobulin G (IgG), in Methods in Molecular Biology, 10: 9- 104 (The Humana Press, Inc. (1992).) Alternatively, affinity chromatography can be performed where an RPTP or an antibody specific for an Ig constant region of the particular immunized animal species is immobilized on a suitable solid support Monoclonal antibodies that specifically bind to LAR, RPTP-d, and / or RPTP-s and hybridomas, which are examples of immortal eukaryotic cell lines, that produce monoclonal antibodies having the desired binding specificity, can also be prepared , for example, using tea technique of Kohler and Milstein (Nature, 256: 495-97 (1976), Eur. J. Immunol. (5: 511-19 (1975)) and improvements thereto (see, e.g., Coligan et al. (Eds.), Current Protocols in Immunology, 1: 2.5.1-2.6.7 (John Wiley & amp; Sons 1991), U.S. Patent Nos. 4,902,614, 4,543,439, and 4,41 1, 993, Monoclonal Antibodies, Hybridomas: A New Dimension in Biological Analyzes, Plenu Press, Kennett et al. (Eds.) (1980); Antibodies: A Laboratory Manual, Harlow and Lane (eds.), Cold Spring Harbor Laboratory Press (1988), see also, eg, Brand et al., Planta Med. 70: 986-92 (2004); Pasqualini et al. al., Proc. Nati, Acad. Sci. USA 101: 257-59 (2004)). An animal, for example, a rat, hamster, or more commonly, a mouse, is immunized with an RPTP immunogen prepared as described above. The presence of specific antibody production can be monitored after the initial injection (the injections can be administered by any of several routes, as described herein for the generation of polyclonal antibodies) and / or after a booster injection upon obtaining a serum sample and detect the presence of an antibody that binds to LAR, RPTP-d, and / or RPTP-s using any of several immunodetection methods known in the art and described herein. From animals that produce antibodies that bind to LAR, RPTP-d, and / or RPTP-s, lymphoid cells, most commonly spleen cells or lymph nodes, are removed to obtain B lymphocytes, which are lymphoid cells that are antibody-forming cells. Lymphoid cells, typically spleen cells, can be immortalized by fusion with a drug-sensitized myeloma cell fusion pattern (e.g., plasmacytoma), preferably one that is syngeneic with the immunized animal and optionally has other desirable properties (e.g., inability to express endogenous Ig gene products, e.g., P3X63 -Ag 8.653 (ATCC No. CRL 1580); NSO, SP20)). Lymphoid cells and myeloma cells can be combined for a few minutes with a membrane fusion promoting agent, such as polyethylene glycol or a non-ionic detergent, and then plated at a density in a selective medium that supports cell growth. of hybridoma, but not unfused myeloma cells. A preferred screening medium is HAT (hypoxanthine, aminopterin, thymidine). After a sufficient time, usually about one to two weeks, cell colonies are observed. The antibodies produced by the cells can be tested for LAR binding activity, RPTP-d, and / or RPTP-s. Hybridomas are cloned (e.g., by cloning by limited dilution or by soft agar plate isolation) and positive clones that produce an antibody specific for the antigen are selected and cultured. Hybridomas that produce monoclonal antibodies with high affinity and specificity for LAR, RPTP-d, and / or RPTP-s are preferred. Monoclonal antibodies can be isolated from the supernatants of hybridoma cultures. An alternative method for the production of a murine monoclonal antibody is to inject the hybridoma cells into the peritoneal cavity of a syngeneic mouse, for example, a mouse that has been treated (e.g., pristano-initiated) to promote formation. of ascites fluid containing the monoclonal antibody. Contaminants can be removed from the fluid from subsequently harvested roosts (usually within 1-3 weeks) by conventional techniques, such as chromatography (eg, size exclusion, ion exchange), gel filtration, precipitation, extraction, or similar (see, eg, Coligan, supra, p.2.7.1-2.7.12; 2.9.1-2.9.3; Baines et al, Purification of Immunoglobulin G (IgG), in Methods in Molecular Biology, 10: 9-104 (The Human Press, Inc. (1992).) For example, antibodies can be purified by affinity chromatography using an appropriate ligand selected based on particular properties of the monoclonal antibody (e.g. heavy or light chain, binding specificity, etc.) Examples of a suitable ligand, immobilized on a solid support, include Protein A, Protein G, an anti-constant region antibody (light chain or heavy chain), an anti-antibody -idiotype, a LAR, RPTP-d, and / or RPTP-s or fragment of the same or an antibody that specifically binds to LAR, RPTP-d, and / or RPTP-s can be a human monoclonal antibody. Human monoclonal antibodies can be generated by any number of techniques with which those skilled in the art will be familiar. Such methods include, but are not limited to, Epstein Barr virus (EBV) transformation of human peripheral blood cells (e.g., containing B lymphocytes), in vitro immunization of human B cells, fusion of spleen cells from immunized transgenic mice carrying inserted human immunoglobulin genes, isolation of V region phage library from human immunoglobulin, or other methods as is known in the art and based on the description herein. For example, human monoclonal antibodies can be obtained from transgenic mice that have been engineered to produce specific human antibodies in response to antigenic challenge. Methods for obtaining human antibodies from transgenic mice are described, for example, in Green et al, Nature Genet. 7:13 (1994); Lonberg et al., Nature 368: 856 (1994); Tailor et al., Int. Immun. 6: 579 (1994); patent of E.U.A. No. 5,877,397; Bruggemann et al., Curr. Opin. Biotechnol. 8: 455-58 (1997); Jakobovits et al., Ann. N Y. Acad. Set. 764: 525-35 (1995). In this technique, elements of the human heavy and light chain locus are artificially engineered into strains of mice derived from embryonic stem cell lines containing target alterations of the endogenous murine heavy and light chain loci. (See also Bruggemann et al., Curr Opin, Biotechnol 8: 455-58 (1997)). For example, human immunoglobulin transgenes can be mini-gene constructs, or transloci in yeast artificial chromosomes, which undergo rearrangement of B cell-specific DNA and hypermutation in mouse lymphoid tissue. Human monoclonal antibodies can be obtained by immunizing transgenic mice, which can then produce human antibodies specific for the antigen. Lymphoid cells of the immunized transgenic mice can be used to produce human antibody secreting hybridomas according to the methods described herein. Polyclonal sera containing human antibodies can also be obtained from the blood of immunized animals. Another method for generating monoclonal antibodies specific for human antigens includes immortalizing human peripheral blood cells by transforming EBV See, v. G, U.S. Patent No. 4,464,456 Said immortalized B cell line (or nfoblastoid cell lines) that produce a monoclonal antibody that specifically binds to LAR, RPTP-d, and / or RPTP-s can be identified by immunodetection methods as provided herein, eg, an ELISA, and then isolated by standard cloning techniques Stability of the lymphoblastoid cell line that produce an anti-LAR antibody, RPTP-d, and / or RPTP-s can be enhanced by fusing the transformed cell line with a mupno myeloma to produce a mouse-human hybrid cell line in accordance with methods known in the art. technique (see, v. g, Glasky et al, Hyhndoma 8 377-89 (1989)) Another method for generating human monoclonal antibodies is immuno in vitro, which includes initiating human spleen B cells with antigen, followed by fusion of B cells initiated with a heterohy- drhous fusion pattern. See, v. g, Boerner et al, J Immunol 147 86-95 (1991) In certain embodiments, a B cell that is producing an anti-RPTP antibody is selected, and the light chain and heavy chain variable regions are cloned from the B cell in accordance with molecular biology techniques known in the art (WO 92/02551, US Patent No. 5,627,052, Babcook et al, Proc Nati Acad Sa USA 93 7843-48 (1996)) and described herein B cells from an immunized animal are isolated from the spleen, lymph nodes, or peripheral blood sample by selecting a cell that is producing a antibody that binds specifically to LAR, RPTP-d, and / or RPTP-s. B cells can also be isolated from humans, for example, from a peripheral blood sample. Methods for detecting individual B cells that are producing an antibody with the desired specificity are well known in the art, for example, by plaque formation, fluorescence-activated cell distribution, in vitro stimulation followed by detection of specific antibody, and the like . Methods for selection of B-cells producing specific antibodies include, for example, preparing a suspension of individual B-cell cells in mild gills containing LAR, RPTP-d, and / or RPTP-s or fragment thereof. Binding of the specific antibody produced by the B cell to the antigen results in the formation of a complex, which may be visible as an immunoprecipitate. After the B cells that produce the specific antibody are selected, the genes of the specific antibody can be cloned by isolating and amplifying DNA or mRNA in accordance with methods known in the art and described herein. Chimeric antibodies, specific for LAR, RPTP-d, and / or RPTP-s, including humanized antibodies, can also be generated. A chimeric antibody has at least one constant region domain derived from a first mammalian species and at least one variable region domain derived from a second distinct mammalian species. See, e.g., Morrison et al., Proc. Nati Acad. Sci. USA, 81: 6851-55 (1984). In one embodiment, a chimeric antibody can be constructed by cloning the polynucleotide sequence encoding at least one variable region domain derived from a non-human monoclonal antibody, such as the variable region derived from a murine, rat or hamster monoclonal antibody, in a vector containing a nucleic acid sequence encoding at least one human constant region (see, e.g., Shin et al., Methods Enzymol., 178: 459-76 (1989)); Walls et al., Nucleic Acids Res. 21: 2921-29 (1993)). By way of example, the polynucleotide sequence encoding the light chain variable region of a murine monoclonal antibody can be inserted into a vector containing a nucleic acid sequence encoding the human kappa light chain constant region sequence. In a separate vector, the polynucleotide sequence encoding the heavy chain variable region of the monoclonal antibody can be cloned in frame with sequences encoding the constant region of human IgGI. The particular human constant region selected may depend on the effector functions desired for the particular antibody (e.g., complement fixation, binding to a particular Fe receptor, etc.). Another method known in the art for generating chimeric antibodies is homologous recombination (e.g., U.S. Patent No. 5,482,856). Preferably, the vectors will be transfected into eukaryotic cells for stable expression of the chimeric antibody. A non-human / human chimeric antibody can also be engineered to create a "humanized" antibody. Said humanized antibody may comprise a plurality of CDRs derived from an immunoglobulin of a non-human mammalian species, at least one variable human framework region, and at least one constant region of human immunoglobulin. Humanization in certain embodiments may provide an antibody that has decreased binding affinity for LAR, RPTP-d, and / or RPTP-s when compared, for example, with either a non-human monoclonal antibody from which a variable region of LAR binding is obtained, d, and / or RPTP-s, or a chimeric antibody having said V region and at least one human C region, as described above. Useful strategies for designing humanized antibodies can therefore include, for example by way of illustration and not limitation, the identification of framework regions of human variable that are more homologous to regions of the non-human framework of the chimeric antibody. To be limited by theory, such a strategy may increase the likelihood that the humanized antibody will retain the specific binding affinity for LAR, RPTP-d, and / or RPTP-s, which in some preferred embodiments may be substantially the same affinity for LAR, RPTP-d, and / or RPTP-s, and in certain other modalities may be a higher affinity for LAR, RPTP-d, and / or RPTP-s (see, v gr, Jones et al, Nature 321 522- 25 (1986), Riechmann et al, Nature 332 323-27 (1988)) The design of a humanized antibody can therefore include determining CDR loop conformations and structural determinants of non-human variable regions, for example, by computer modeling, and then by comparing CDR loops and determinants to known human CDR loop structures and determinants (see, v, Padlan et al, FASEB 9 133-39 (1995), Chothia et al, Nature, 342 377-83 (1989)) Computer modeling can also be used to compare pl human structural antilles selected by sequence homology with non-human variable regions (see, v. g, Bajorath et al, Ther Immunol 2 95-103 (1995), EP-0578515-A3) If the humanization of non-human CDRs gives As a result of a decrease in binding affinity, computer modeling can help identify specific amino acid residues that could be changed by site-directed mutagenesis techniques and other mutagenesis to partially, completely, or supra-optimally restore (ie, increase to a level greater than that of the non-humanized antibody) affinity Those skilled in the art are familiar with these techniques and will readily appreciate numerous variations and modifications to such design strategies. One method of this type for preparing a humanized antibody is called repair. Framework (FR) refers to the selective replacement of FR waste from, v gr, a heavy or light rodent casdena region V, by human FR residues to provide a xenogeneic molecule comprising an antigen-binding site that retains substantially all of the native FR polypeptide fold structure. are based on the understanding that the ligand-binding features of an antigen-binding site are determined primarily by the structure and relative arrangement of heavy and light chain CDR assemblies within the antigen-binding surface (cf. .gr., Davies et al., Ann. Rev. Biochem. 59: 439-73, (1990)). Therefore, the antigen binding specificity can be conserved in a humanized antibody when the CDR structures, their interaction with one another, and their interaction with the rest of the V region domains are carefully maintained. By using repair techniques, the outer RF residues (eg, solvent accessible) that are easily found by the immune system are selectively replaced by human waste to provide a hybrid molecule that comprises either a weakly immunogenic repair surface , or substantially non-immunogenic. The repair procedure makes use of the sequence data available for human antibody variable domains compiled by Kabat et al., In Sequences of Proteins of Immunological Interest, 4a. ed., (U.S. Dept. of Health and Human Services, U.S. Government Printing Office, 1991), updates the Kabat database, and other data sets of E.U.A. and foreign (both nucleic acid and protein). The solvent accessibilities of region V amino acids can be deduced from the known three-dimensional structure for human and murine antibody fragments. Initially, the FR amino acid sequence of the variable domains of an antibody molecule of interest is compared to corresponding FR sequences of human variable domains obtained from the databases and publications identified above. The most homologous human V regions are then compared residue by residue to corresponding mupno amino acids Residues in the human FR that differ from the human counterpart are replaced by the residues present in the human portion using recombinant techniques well known in the art. waste is only carried out with portions that are at least partially exposed (solvent accessible), and care is taken in the replacement of amino acid residues that can have a significant effect on the tertiary structure of the V region domains, such such as proline, glycine and charged amino acids In this way, the "repaired" antigen-binding site is designed to retain the rodent CDR residues, the residues substantially adjacent to the CDRs, the residues identified as buried or mostly buried ( inaccessible to solvent), it is believed that waste participates in non-covalent contacts (v gr, e lethostatic and hydrophobic) between heavy and light chain domains, and the residues of conserved structural regions of the FRs that are thought to influence the "canonical" tertiary structures of the CDR loops (see, v gr, Chothia et al, Nature , 342 377-383 (1989)) These design criteria are then used to prepare recombinant nucleotide sequences which are combined with the heavy chain and light chain CDRs of an antigen-binding site in human-occurring FRs that it can be used to transfect mammalian cells for the expression of recombinant human antibodies that exhibit the antigen specificity of the rodent molecule molecule. For particular uses, antigen-binding fragments of antibodies may be desired. The antibody fragments, F (ab ') 2, Fab, Fab', Fv, and Fd, can be obtained, for example, by proteolytic hydrolysis of the antibody, for example, digestion with pepsin or papain of whole antibodies in accordance with conventional methods. As an illustration, the antibody fragments can be produced by enzymatic digestion of antibodies with pepsin to provide a fragment denoted F (ab ') 2. This fragment can be further digested using a thiol reducing agent to produce a monovalent fragment of Fab '. Optionally, the A digestion reaction can be performed using a blocking group for the sulfhydryl groups resulting from the digestion of disulfide bonds. As an alternative, an enzymatic digestion of an antibody using papain produces two monovalent Fab fragments and one Fe fragment (see, e.g., U.S. Patent No. 4,331, 647; Nisonoff et al., Arch. Biochem.

Biophys. 89: 230 (1960); Porter, Biochem. J. 73: 1 19 (1959); Edelman et al., In Methods in Enzymology 1: 422 (Academic Press 1967); Weir, Handbook of Experimental Immunology, Blackwell Scientific, Boston (1986)). Antibody binding fragments can be removed from the Fe fragments by affinity chromatography, for example, using immobilized protein A, protein G, a specific antibody of Fe, or immobilized RPTP polypeptide or a fragment thereof. Other methods for digesting antibodies, such as heavy chain separation to form monovalent light-heavy chain (Fd) fragments, subsequent fragment digestion, or other enzymatic, chemical or genetic techniques can also be used, provided the fragments are bound to the PTTP that is recognized by the intact antibody. An antibody fragment can also be any synthetic or genetically engineered protein that acts as an antibody in that it binds to a specific antigen to form a complex. For example, antibody fragments include isolated fragments consisting of the light chain variable region, Fv fragments consisting of the variable regions of the heavy and light chains, recombinant single chain polypeptide molecules in which the variable chain regions light and heavy are connected by a peptide linker (scFv proteins), and minimal recognition units consisting of amino acid residues that simulate the hypervariable region. The antibody comprises at least one variable region domain. The variable region domain can be of any size or composition of amino acids and will generally comprise at least one hypervariable sequence of amino acids responsible for antigen binding and which is adjacent to or in frame with one or more framework sequences. In general terms, the variable region domain (V) can be any arrangement of heavy chain (VH) and / or light (VL) variable domains of immunoglobulin. Thus, for example, the V region domain can be monomeric and be a VH or VL domain, which is capable of independently binding antigen with acceptable affinity. Alternatively, the V region domain can be dimeric and contains VH-VH, VH-VL, or VL-VL dimers. Preferably, the V region dimer comprises at least one V H chain and at least one V L chain that are non-covalently associated (hereinafter referred to as F v). If desired, the chains can be covalently coupled either directly, for example by a disulfide bond between the two variable domains, or through a linker, e.g., a peptide linker, to form a single chain Fv ( scFv). A minimum recognition unit is an antibody fragment comprising a single complementarity determining region (CDR). Said CDR peptides can be obtained by constructing polynucleotides encoding the CDR of an antibody of interest. Polynucleotides are prepared, for example, using the polymerase chain reaction to synthesize the variable region using mRNA isolated from or contained within antibody producing cells with a template in accordance with methods practiced by those skilled in the art (see , for example, Larrick et al., Methods: A Companion to Methods in Enzymology 2: 106, (1991), Courtenay-Luck, "Genetic Manipulation of Monoclonal Antibodies," in Monoclonal Antibodies: Production, Engineering and Clinical Application, Ritter et al. al. (eds.), page 166 (Cambridge University Press 1995); and Ward et al., "Genetic Manipulation and Expression of Antibodies," in Monoclonal Antibodies: Principies and Applications, Birch et al., (eds.), page 137 (Wiley-Liss, Inc. 1995)). Alternatively, said CDR peptides and another antibody fragment can be synthesized using an automated peptide synthesizer. In accordance with certain embodiments, the non-human, human or humanized heavy and light chain variable regions of any of the Ig molecules described herein can be constructed as scFv polypeptide fragments (single chain antibodies). See, e.g., Bird et al., Science 242: 423-426 (1988); Huston et al., Proc. Nati Acad. Sci. USA 85: 5879-83 (1988)). Multifunctional scFv fusion proteins can be generated by linking a sequence of polynucleotides encoding a scFv polypeptide in frame with at least one polynucleotide sequence encoding any of a variety of known effector proteins. These methods are known in the art, and are described, for example, in EP-B 1 0318554, U.S. Pat. No. 5,132,405, patent of E.U.A. No. 5,091, 513, and US patent. No. 5,476,786. By way of example, the effector proteins may include immunoglobulin constant region sequences. See, e.g., Hollenbaugh et al., J. Immunol Methods 1 88: 1-7 (1995). Other examples of effector proteins are enzymes. As a non-limiting example, said enzyme may provide a biological activity for therapeutic purposes (see, e.g., Siemers et al., Bioconjug, Chem. 8: 510-19 (1997)), or they may provide detectable activity, such as horseradish peroxidase catalyzed conversion of any of a number of well-known substrates into a detectable product, for diagnostic uses. The scFv, in certain embodiments, can be fused to peptide or polypeptide domains that allow the detection of specific binding between the fusion protein and antigen (e.g., one or more of the RPTPs described herein). For example, the fusion polypeptide domain can be an affinity tag polypeptide. The binding of the scFv fusion protein to a binding partner (e.g., one or more of the RPTPs or fragment thereof described herein) can therefore be detected using a polypeptide or affinity peptide tag, such as an avidin, streptavidin or a His tag (e.g., polyhistidine), by any of a variety of techniques with which those skilled in the art will be familiar. Detection techniques can also include, for example, binding of an avidin or streptavidin fusion protein to biotin or a biotin mimetic sequence (see, e.g., Luo et al., J. Biotechnol. 65: 225 ( 1998) and references cited therein), direct covalent modification of a fusion protein with a detectable portion (e.g., a market portion), non-covalent attachment of the fusion protein to a specific labeled reporter molecule, enzymatic modification of a substrate detectable by a fusion protein that includes a portion having enzymatic activity, or immobilization (covalent or non-covalent) of the fusion protein on a solid phase support. A scFv fusion protein comprising an RPTP-specific immunoglobulin-derived polypeptide can be fused to another polypeptide such as an effector peptide having desirable affinity properties (see, e.g., U.S. Patent No. 5,100,788; WO 89 / 03422; U.S. Patent No. 5,489,528; U.S. Patent No. 5,672,691; WO 93/24631; U.S. Patent No. 5,168,049; U.S. Patent No. 5,272,254; EP 511,747); As provided herein, the scFv polypeptide sequences can be fused to fusion polypeptide sequences, including effector protein sequences, which can include full length fusion polypeptides and which may alternatively contain variants or fragments thereof. Antibodies can also be identified and isolated from human immunoglobulin phage libraries, from rabbit immunoglobulin phage libraries, from mouse immunoglobulin phage libraries, and / or chicken immunoglobulin phage libraries (see, v. ., Winter et al., Annu. Rev. / m / nunol., 12: 433-55 (1994); Burton et al., Adv. Immunol. 57: 191-280 (1994); patent of E.U.A. No. 5,223,409; Huse et al., Science 246: 1275-81 (1989); Schlebusch et al., Hybridoma 16: 47-52 (1997) and references cited therein; Rader et al., J Biol. Chem. 275: 13668-76 (2000); Popkov et al., J Mol. Biol. 325: 325-35 (2003); Andris-Widhopf et al., J. Immunol. Methods 242: 159-31 (2000)). Antibodies isolated from immunoglobulin libraries of human or non-human species can be genetically engineered according to methods described herein and known in the art to "humanize" the antibody or fragment thereof. Combinatorial libraries of immunoglobulin variable region genes can be created in phage vectors that can be selectively determined to select fragments of Ig (Fab, Fv, scFv, or multimers thereof) that specifically bind to a PTWP described herein ( see, e.g., U.S. Patent No. 5,223,409, Huse et al., Science 246: 1275-81 (1989), Sastry et al., Proc. Nati, Acad. Sci. USA 86: 5728-32 (1989). ), Alting-Mees et al., Strategies in Molecular Biology 3: 1-9 (1990), Kang et al., Proc. Nati, Acad. Sci. USA 88: 4363-66 (1 991); Hoogenboom et al. , J Molec, Biol. 227: 381-388 (1992), Schlebusch et al., Hyb. Doma 16: 47-52 (1997) and references cited therein, US Patent No. 6,703,015). For example, a library containing a plurality of polynucleotide sequences encoding Ig variable region fragments can be inserted into the genome of a filamentous bacteriophage, such as M 13 or a variant thereof, in the frame with the coding sequence. a phage coating protein such as gene III or gene VIII. A fusion protein can be a fusion of the coating protein with the light chain variable region domain and / or the heavy chain variable region domain. In accordance with certain embodiments, the Fab fragments of immunoglobulin can also be displayed in a phage particle (see, e.g., U.S. Patent No. 5,698,426). The heavy and light chain immunoglobulin cDNA expression libraries can also be prepared in phage lambda, for example, using vectors lmmunoZap ™ (H) and? LmmunoZap ™ (L) (Stratagene, La Jolla, California). Briefly, the mRNA is isolated from a population of B cellsa and used to create heavy and light chain immunoglobulin cDNA expression libraries in the vectors lmmunoZap (H) and? LmmunoZap (L). These vectors can be selectively determined individually or co-expressed to form Fab fragments or antibodies (see Huse et al., Supra, see also Sastry et al., Supra). Positive plates can be subsequently converted to a non-lytic plasmid which allows the high level expression of E. coli monoclonal antibody fragments. The phage displaying an Ig fragment (e.g., a V region or Ig Fab) that binds to LAR, RPTP-d, and / or RPTP-s can be selected by mixing the phage library with LAR, RPTP- d, and / or RPTP-s or a fragment thereof, or by contacting the phage library with said immobilized polypeptide or peptide molecules in a solid matrix under conditions and for a sufficient time to allow binding. Unbound phages are removed by washing, and the specifically bound phages (ie, phage containing an RPTP specific Ig fragment) are then eluted (see, e.g., Messmer et al., Biotechniques 30: 798 -802 (2001)). The eluted phage can be propagated in an appropriate host bacterium, and generally, successive rounds of PTTP binding and elution can be repeated to increase the yield of the phages expressing the specific RPTP immunoglobulin. Phage display techniques can also be used to select fragments of Ig or single chain antibodies that bind to LAR, RPTP-d, and / or RPTP-s. For examples of suitable vectors having multicloning sites in which the candidate nucleic acid molecules (e.g., DNA) encoding said antibody fragments or related peptides can be inserted, see, e.g., McLafferty et al. ., Gene 128: 29-36 (1993); Scott et al., Science 249: 386-90 (1990); Smith et al., Meth. Enzymol. 277: 228-57 (1993); Fisch et al., Proc. Nati Acad. Sci USA 93: 7761-66 (1996)). The inserted DNA molecules may comprise randomly generated sequences, or may encode variants of a known peptide or polypeptide domain (such as A41 L) that specifically binds to LAR, RPTP-d, and / or RPTP-s. Generally, the nucleic acid insert encodes a peptide of up to 60 amino acids, or it can encode a peptide of 3 to 35 amino acids, or it can encode a peptide of 6 to 20 amino acids. The peptide encoded by the inserted sequence is displayed on the surface of the bacteriophage. The phage expressing a binding domain for the PTPN can be selected on the basis of specific binding to an immobilized PTPR or a fragment thereof. Well known recombinant genetic techniques can be used to construct fusion proteins containing the fragment. For example, a polypeptide comprising a tandem array of two or more selected PTTP-binding peptide domains of similar or different fineness can be generated to maximize the binding affinity for LAR, RPTP-d, and / or RPTP. -s of the resulting product. Combinatorial mutagenesis strategies using phage libraries can also be used to humanize non-human variable regions (see, e.g., Rosok et al., J Biol. Chem. 271 .22611-18 (1996); Rader et al. , Proc. Nati, Acad. Sci. USA 95: 8910-15 (1998)). Humanized variable regions that have binding affinity that is minimally reduced or that is comparable to the non-human variable region can be selected, and the nucleotide sequences encoding the humanized variable regions can be determined by standard techniques (see, Sambrook et al. , Molecular Cloning A Laboratory Manual, Cold Spring Harbor Press (2001)) The affinity-selected Ig coding sequence can then be cloned into another suitable vector for expression of the Ig fragment or, optionally, cloned into a vector containing regions. Ig constants, for expression of whole immunoglobulin chains Similarly, portions or fragments, such as Fab and Fv fragments, of RPTP specific antibodies can be constructed using conventional recombinant DNA or enzymatic digestion techniques to incorporate the variable regions of a gene encoding an antibody specific for LAR, RPTP-d, and / or RPTP-s Within a modality, in a hibpdoma the variable regions of a gene expressing a monoclonal antibody of interest are amplified using nucleotide primers. These primers can be synthesized by a person skilled in the art, or can be purchased from sources commercially available (see, v. g, Stratagene (La Jolla, California), which sells primers to amplify mouse and human variable regions. The primers can be used to amplify heavy and light chain variable regions, which can then be inserted into such vectors. such as ImmunoZAP ™ H or ImmunoZAP ™ L (Stratagene), respectively. These vectors can then be introduced into systems based on E. coli, yeast or mammals for expression. Large amounts of a single chain protein containing a fusion of the VH and V domains can be produced using these methods (see Bird et al., Science 242: 423-426 (1988)). In addition, such techniques can be used to humanize a non-human V antibody region without altering the binding specificity of the antibody. In certain other embodiments, the specific RPTP antibodies are multimeric antibody fragments. Useful methodologies are generally described, for example, in Hayden et al., Curr Opin. Immunol. 9: 201-12 (1997) and Coloma et al., Nat. Biotechnol. 15: 159-63 (1997). For example, multimeric antibody fragments can be created by phage techniques to form miniantibodies (U.S. Patent No. 5,910,573) or diabodies (Holliger et al., Cancer Immunol. Immunother 45: 128-30 (1997)). Multimeric fragments which are multimers of a specific RPV Fv can be generated. Multimeric antibodies include bispecific and bifunctional antibodies comprising a primer-specific Fv for an antigen associated with a second Fv having a different antigen specificity (see, e.g., Drakeman et al., Expert Opin. 6: 1 169-78 (1997); Koelemij et al., J. Immunother. 22: 514-24 (1999); Marvin et al., Acta Pharmacol. Without. 26: 649-58 (2005); Das et al., Methods Mol. Med. 109: 329 '-46 (2005)). For example, in one embodiment, a bispecific antibody comprises an Fv, or other antigen-binding fragment described herein, that specifically binds to LAR and comprises an Fv, or other antigen-binding fragment, that specifically binds to RPTP- s. Similarly, in another embodiment, a bispecific antibody comprises an Fv, or other antigen-binding fragment described herein, that specifically binds to LAR and comprises an Fv, or other antigen-binding fragment, that specifically binds to RPTP -d. In yet another embodiment, a bispecific antibody comprises an Fv, or other antigen binding fragment described herein, that specifically binds to RPTP-s and comprises an Fv, or other antigen-binding fragment, that specifically binds to RPTP- d. In certain other embodiments, a multivalent antibody or bispecific antibody comprises an Fv, or other antigen binding fragment, which specifically binds to at least one of LAR, RPTP-d, and RPTP-s, and further comprises an Fv, or another antigen binding fragment, which is specific for a non-PTO polypeptide, such as, for example, a cell surface antigen that when bound by a specific antibody contributes to, facilitates, or is capable of altering (suppressing or increasing) the immune response of an immune cell. The introduction of amino acid mutations in RPTP-binding immunoglobulin molecules may be useful to increase the specificity or affinity for PTWT, or to alter an effector function. Immunoglobulins with higher affinity for LAR, RPTP-d, and / or RPTP-s can be generated by site-directed mutagenesis of particular residues. Computer-aided three-dimensional molecular modeling can be used to identify the amino acid residues to be changed in order to improve the affinity for PTWT (see, e.g., Mountain et al., Biotechnol. Genet. Eng. 10: 1-142 (1992)). Alternatively, combinatorial libraries for CDRs can be generated in M13 phage and selectively determined for immunoglobulin fragments with improved affinity (see, e.g., Glaser et al., J Immunol., 149: 3903-13 (1992); Barbas et al. ., Proc. Nati, Acad. Sci. USA 91: 3809-13 (1994), U.S. Patent No. 5,792, 456). In certain embodiments, the antibody can be genetically engineered to have an altered effector function. For example, the antibody may have an altered capacity (increased or decreased in a biologically or statistically significant manner) to mediate complement-dependent cytotoxicity (CDC) or antibody-dependent cellular cytotoxicity (ADCC) or an altered ability to bind to effector cells by Fe receptors present in the effector cells. effector functions can be altered by site-directed mutagenesis (see, e.g., Duncan et al., Nature 332: 563-64 (1988); Morgan et al., Immunology 86: 319-24 (1995); Eghtedarzedeh; -Kondri et al., Biotechniques 25: 830-34 (1997)). For example, mutation of the glycosylation site on the Fe portion of the immunoglobulin may alter the ability of the immunoglobulin to fix complement (see, e.g., Wright et al., Trends Biotechnol., 15: 26-32 (1997)). ). Other mutations in the constant region domains may alter the ability of the immunoglobulin for fixation or complement to effect ADCC (see, e.g., Duncan et al., Nature 332: 563-64 (1988); Morgan et al., Immunology 86: 319-24 (1995); Sensel et al., Mol. Immunol 34: 1019-29 (1997)). (See also, e.g., U.S. Patent Publications Nos. 2003/01 18592; 2003/0133939). The nucleic acid molecules encoding an antibody or fragment thereof that specifically binds to an RPTP, as described herein, can be propagated and expressed in accordance with any of a variety of well-known methods for excision., ligation, transformation and transfection of nucleic acid. Therefore, in certain embodiments, expression of an antibody fragment may be preferred in a prokaryotic host cell, such as Escherichia coli (see, e.g., Pluckthun et al., Methods Enzymol., 178: 497-515 (1989 )). In certain other embodiments, expression of the antibody or an antigen-binding fragment thereof may be preferred in a eukaryotic host cell, including yeast (e.g., Saccharomyces cerevisiae, Schizosaccharomyces pombe, and Pichia pastoris); animal ululas (including mammalian cells); or plant cells. Examples of suitable animal cells include, but are not limited to, myeloma, COS, CHO or hybridoma cells. Examples of plant cells include tobacco, corn, soy and rice cells. By methods known to those skilled in the art and based on the present disclosure, a nucleic acid vector can be designated to express foreign sequences in a particular host system, and then polynucleotide sequences that encode the PTTP binding antibody (or fragment of it) can be inserted. The regulatory elements will vary according to the particular host. One or more replicable expression vectors containing a polynucleotide encoding a variable and / or constant region can be prepared and used to transform an appropriate cell line, for example, a non-producing myeloma cell line, such as an NSO line of mouse or a bacterium, such as E. coli, in which the production of the antibody will occur, in order to obtain efficient transcription and translation, the polynucleotide sequence in each vector must include appropriate regulatory sequences, particularly a promoter sequence and leader operatively linked to the variable domain sequence. Particular methods for producing antibodies in this manner are generally well known and routinely used. For example, molecular biology procedures are described in Sambrook et al. (Molecular Cloning, A Laboratory Manual, 2nd ed., Cold Spring Harbor Laboratory, New York, 1989; see also Sambrook et al., 3rd ed., Cold Spring Harbor Laboratory, New York, (2001)). DNA sequencing can be performed as described in Sanger et al. (Proc. Nati. Acad. Sci. USA 74: 5463 (1977)) and the manual of sequencing of Amersham International foot and including improvements thereto. Site-directed mutagenesis of a variable region (V region) of immunoglobulin, framework region, and / or constant region can be performed in accordance with any of the numerous methods described herein and practiced in the art (Kramer et al. ., Nucleic Acids Res. 12: 9441 (1984); Kunkel Proc. Nati. Acad. Sci. USA 82: 488-92 (1985); Kunkel et al, Methods Enzymol 154 367-82 (1987)) Methods of random mutagenesis to identify residues that are either important for binding to an RPTP (LAR, RPTP-d, and RPTP-s,) or that do not alter the binding of the antigen to the antibody when altered can also be performed in accordance with procedures that are routinely practiced by one skilled in the art (v. g., alanine screening mutagenesis, mutagenesis by polymerase chain reaction subject to error, and mutagenesis). directed or gonucleotides (see, v. g, Sambrook et al Molecular Cloning A Laboratory Manual, 3rd ed., Cold Spring Harbor Laboratory Press, NY (2001))) In addition, numerous publications describe suitable techniques for the preparation of antibodies by DNA manipulation, creation of expression vectors, and transformation of appropriate cells (Mountain et al, in Biotechnology and Genetic Engineepng Reviews (ed Tombs, MP, 10, Chapter 1, Intercept, And over, UK (1992)), International Patent Publication No. WO 91/09967) Antibodies and antigen-binding fragments thereof which specifically bind to LAR, RPTP-d, and RPTP-s, may also be useful as reagents for immunochemical analysis to detect the presence of one or more of the RPTPs in a biological sample. In certain embodiments, an antibody that specifically binds to at least one of LAR, RPTP-d, and RPTP-s, can be used to detecting the expression of at least one PTPN In certain particular embodiments, an antibody or a panel of antibodies can be exposed to cells expressing PTPR, and the expression of PTPR can be determined by detection using another PTPR-specific antibody that is binds to a different epitope to the antibody or antibodies initially allowed to interact with the cells. For such purpose, an RPTP binding immunoglobulin (or fragment thereof) as described herein may contain a detectable portion or tag such as an enzyme, cytotoxic agent, or other reporter molecule, including a dye, radionuclide, luminescent group, fluorescent group, or biotin, or similar. The specific RPTP immunoglobulin or fragment thereof can be radiolabeled for diagnostic or therapeutic applications. Techniques for radiolabeled antibodies are known in the art (see, e.g., Adams, In Vivo 12: 1-21 (1998), Hiltunen, Acta Oncol. 32: 831-9 (1993)). Effector or reporter molecules can be linked to the antibody through any available amino acid side chain, terminal amino acid or unbound carbohydrate functional group on the antibody, provided that the binding or binding procedure does not adversely affect binding properties in such a way that the utility of the molecule is canceled. Particular functional groups include, for example, any amino, imino, thiol, hydroxyl, carboxyl or free aldehyde group. The binding of the antibody or antigen-binding fragment thereof and the effector and / or reporter molecule (s) can be achieved by said groups and an appropriate functional group on the effector or reporter molecule. The link can be direct or indirect through separation or bridging groups (see, e.g., International patent application publication Nos. WO 93/06231, WO 92/22583, WO 90/091195, and WO 89 / 01476; see also, e.g., commercial suppliers such as Pierce Biotechnology, Rockford, IL). As provided herein and in accordance with methodologies well known in the art, polyclonal and monoclonal antibodies can be used for the affinity isolation of LAR, RPTP-d, and RPTP-s and / or fragments thereof (see, v.gr ., Hermanson et al., Immobilized Affinity League Techniques, Academic Press, Inc. New York, (1992)). In short, an antibody (or antigen-binding fragment thereof) can be immobilized on a solid support material, which is then contacted with a sample containing an RPTP. The sample interacts with the immobilized antibody under conditions and for a time that is sufficient to allow binding of the PTTP to the immobilized antibody; binding components (ie, those components not related to the PTWR) of the sample are removed; and then the PTTP is released from the immobilized antibody using an appropriate elution solution. In certain embodiments, anti-idiotype antibodies that specifically recognize and bind to an antibody (or antigen-binding fragment thereof) that specifically binds to LAR, RPTP-d, and / or RPTP-s are provided, and methods to use these anti-idiotype antibodies are also provided. Anti-idiotype antibodies can be generated as polyclonal antibodies or as monoclonal antibodies by the methods described herein, using an anti-LAR antibody, anti-RPTP-d, or anti-RPTP-s (or antigen-binding fragment thereof) as an immunogen. The anti-idiotype antibodies or fragments thereof can also be generated by any of the recombinant genetic engineering methods described above or by selection of phage display. The anti-idiotype antibodies can then be engineered to provide a chimeric or humanized anti-idiotype antibody, in accordance with the description provided in detail herein. An anti-idiotype antibody can bind specifically to the antigen-binding site of the anti-RPTP antibody such that binding of the antibody to the PTWR is competitively inhibited. Alternatively, an anti-idiotype antibody as provided herein may not competitively inhibit the binding of an anti-RPTP antibody to the PTTP. In one embodiment, an anti-idiotype antibody can be used to alter the immune response of an immune cell. In certain embodiments, an anti-idiotype antibody can be used to suppress the immune response of an immune cell and to treat an immune disease or disorder. An anti-idiotype antibody binds specifically to an antibody that specifically binds to LAR, RPTP-d, and / or RPTP-s, and the antigen-binding site of the anti-idiotype antibody simulates the epitope of the PTWT, i.e. , the anti-idiotype antibody will bind to cognate ligands as well as antibodies that specifically bind to the PTWP. Therefore, an anti-idiotype antibody can be useful to prevent, block or reduce the binding of a cognate ligand that when said ligand binds to an RPTP, stimulates, induces or increases the immune response of an immune cell. The anti-idiotype antibodies are also useful for immunoassays to determine the presence of anti-RPTP antibodies in a biological sample. For example, immunoassays, such as an ELISA and other assays described herein that are practiced with those skilled in the art, can be used to determine the presence of an induced immune response by administering (i.e., immunizing) a host with a RPTP polypeptide or fragment thereof as described herein. In certain embodiments, an antibody specific for LAR, RPTP-d, and / or RPTP-s may be an antibody or antigen-binding fragment thereof that is expressed as an intracellular protein. Such intracellular antibodies are also referred to as intrabodies and may comprise a Fab fragment, an Fv fragment, a scFv molecule, a scFv-Fc function antibody, or a bispecific antibody, all of which may be made as described herein and in accordance with methods practiced in the art (see, e.g., Lobato et al., Curr. Mol. Med. 4: 519-28 (2004); Strube et al., Methods 34: 179-83 ( 2004), Lecerf et al., Proc. Nati, Acad. Sci. USA 98: 4764-49 (2001); (Weisbart et al., Int. J. Oncol 25: 1 113-18 (2004)). which would be useful in the form of an intrabody includes an antibody that specifically binds to the intracellular portion of an RPTP, eg, an antibody that binds to an epitope within a region of the intracellular portion of LAR, RPTP-d, and / or RPTP-s, for example, which includes the catalytic domains D1 and D2 and a region comprising a peptide having the sequence set forth in SEQ ID NO: 51. Working frame ions flanking the CDR regions can be modified to improve the levels of expression, stability, and / or solubility of an intrabody in an intracellular reducing environment (see, e.g., Auf der Maur et al., Methods 34: 215-24 (2004); Strube et al., Supra; Worn et al., J Biol. Chem. 275: 2795-803 (2000)). An intrabody can be targeted to a particular cellular site or organelle, for example by constructing a vector comprising a polynucleotide sequence that encodes the variable regions of an intrabody that can be operatively fused to a polynucleotide sequence encoding a particular target antigen within of the cell (see, eg, Graus-Porta et al., Mol Cell Biol. 15: 1 182-91 (1995); Lener et al., Eur. J. Biochem. 267: 1196-205 ( 2000), Popkov et al., Cancer Res. 65: 972-81 (2005)). Various types of intrabodies have been investigated as therapeutic agents to treat cancer (see, eg, Weisbart et al, supra, Popkov et al, supra, Krauss et al., Breast Dis. 1 1: 1 13-24 (1999). )) and to treat neurodegenerative diseases such as Parkinson's disease (Zhou et al., Mol.Ther.10: 1023-31 (2004)) and Huntington's disease (Murphy et al., Brain Res. Mol. Brain Res. : 141 -45 (2004), Colby et al., J Mol. Biol. 342: 901-12 (2004); Colby et al., Proc. Nati. Acad. Sci. USA 101: 17616-21 (2004), Erratum in Proc. Nati. Acad. Sci. USA 102: 955 (2005)). An intrabody can be introduced into a cell by a variety of techniques available to one skilled in the art including by means of a gene therapy vector, a mixture of lipids (e.g., Provectin ™ manufactured by Imgenex Corporation, San Diego, CA), photochemical internalization methods, or other methods known in the art.

Expression of A41 L, 130L, RPTPs, and Polypeptide Agents The polypeptides described herein including A41 L, 130L, RPTPs (LAR, RPTP-d, and RPTP-s) and fusion polypeptides (e.g. peptide-lgFcs, RPTP Ig -Fe domain fusion polypeptides can be expressed using vectors and constructs, particularly the recombinant expression of constructs, which includes any polynucleotide encoding said polypeptides. The host cells are genetically engineered with vectors and / or constructs to produce these polypeptides and fusion proteins, or fragments or variants thereof, by recombinant techniques. Each of the fusion polypeptides and polypeptides described herein can be expressed in mammalian cells, yeast, bacteria or other cells under the control of appropriate promoters. Cell-free translation systems can also be used to produce said proteins using RNAs derived from DNA constructs. Suitable cloning and expression vectors for use with prokaryotic and eukaryotic hosts are described, for example, in Sambrook, et al., Molecular Cloning: A Laboratory Manual, third edition, Cold Spring Harbor, New York, (2001). Generally, recombinant expression vectors include origins of replication, selectable markers that allow transformation of the host cell, for example, the E. coli ampicillin resistance gene and TRP1 gene of S. cerevisiae, and a promoter derived from a gene highly expressed to direct the transcription of a structural sequence towards the 3 'end. Promoters can be derived from operons that encode glycolytic enzymes such as 3-phosphoglycerate kinase (PGK), factor a, acid phosphatase, or term shock proteins, among others. The heterologous structural sequence is assembled in appropriate phase with translation initiation and termination sequences. Optionally, a heterolologous sequence can encode a fusion protein that includes an amino terminal or carboxy terminal peptide or polypeptide identification that imparts desired characteristics, e.g., that stabilizes the produced polypeptide or that simplifies the purification of the expressed recombinant product. Such identification peptides include a polyhistidine tag (his tag) or FLAG® epitope tag (DYKDDDDK, SEQ ID NO: 62), beta-galatosidase, alkaline phosphatase, GST, or the XPRESS ™ epitope tag (DLYDDDDK, SEQ ID NO: 63; Invitrogen Life Technologies, Carlsbad, CA) and the like (see, e.g., U.S. Patent No. 5,011,912; Hopp et al., (Bio / Technology 6: 1204 (1988)). The affinity sequence can be supplied by a vector, such as, for example, a hexa-histidine tag that is provided in pBAD / His (Invitrogen) Alternatively, the affinity sequence can be added either synthetically or engineered in the primers used to recombinantly generate the coding nucleic acid sequence (e.g., using the polymerase chain reaction) Host cells containing recombinant expression constructs described can be genetically engineered (transduced, transformed or transfected) with the vectors and / or expression constructs (eg, a cloning vector, a shuttle vector, or an expression construct). The vector or construct can be in the form of a plasmid, a viral particle, a phage, etc. Genetically engineered host cells can be cultured in modified conventional nutrient media as appropriate to activate promoters, select transformants or amplify particular genes or coding nucleotide sequences. The selection and maintenance of culture conditions for particular host cells, such as temperature, pH and the like, will be readily apparent to one skilled in the art. Preferably, the host cell can be adapted to sustained propagation in culture to give a cell line in accordance with established methodologies in the technology. In certain embodiments, the cell line is an immortal cell line, which refers to a cell line that can be repeatedly passed (at least ten times while it remains viable) in the culture following the growth of the log phase. In other embodiments, the host cell used to generate a cell line is a cell that is capable of unregulated growth, such as a cancer cell, or a transformed cell, or a malignant cell.

Useful bacterial expression constructs are constructed by inserting into an expression vector a structural DNA sequence encoding a desired protein together with suitable translation initiation and termination signals in operable reading phase with a functional promoter. The construct may comprise one or more selectable phenotypic markers and an origin of replication to ensure maintenance of the construction of the vector and, if desirable, to provide amplification within the host. Prokaryotic hosts suitable for transformation include E. coli, Bacillus subtilis, Salmonella typhimuñum and several species within the genera Pseudomonas, Streptomyces and Staphylococcus, although others may also be used as the material of choice. Any other plasmid or vector can be used provided they are replicable and viable in the host. Thus, for example, the nucleic acids as provided herein can be included in any of a variety of expression vector constructs as a recombinant expression construct for expressing a polypeptide. Such vectors and constructs include chromosomal, non-chromosomal and synthetic DNA sequences, eg, bacterial plasmids; Phage DNA; baculovirus; yeast plasmids; vectors derived from plasmid and phage DNA combinations; Viral DNA, such as vaccinia, adenovirus, avian poxvirus, and pseudorabies. However, any other vector can be used to prepare a recombinant expression construct as long as it is replicable and viable in the host.

The appropriate DNA sequence (s) can be inserted into the vector by a variety of procedures. In general, the DNA sequence is inserted into a suitable restriction endonuclease s (s) by procedures known in the art Standard techniques for cloning, DNA isolation, amplification and purification, for enzymatic reactions involving gauze DNA, DNA polymerase, restriction endonucleases and the like, and vain separation techniques are those known and commonly used by those skilled in the art. the technique Numerous standard techniques are described, for example, in Ausubel et al. (Current Protocols in Molecular Biology (Greene Publ Assoc Inc &John Wiley &Sons, Inc., 1993)), Sambrook et al (Molecular Cloning A Laboratory Manual, 3rd Ed., (Cold Spring Harbor Laboratory 2001)), Maniatis et al. (Molecular Cloning, (Cold Spring Harbor Laboratory 1982)), and elsewhere The DNA sequence encoding a polypeptide in the expression vector is operably linked to at least one appropriate expression control sequence (v. Gr, a promoter). or a regulated promoter) to direct mRNA synthesis Representative examples of said expression control sequences include LTR or SV40 promoter, the lac or trp of E coli, the PL phage lambda promoter, and other known promoters to control the expression of genes in procapotic or eukaryotic cells or their virus Promoting regions can be selected from any desired gene using CAT (chloramphenicol transferase) vectors or other vectors with selectable markers The promoter is of particular bacteria include lad, lacZ, T3, T5, T7, gpt, lambda PR, PL, and trp. Eukaryotic promoters include CMV immediately early, HSV thymidine kinase, SV40, early and late LTRs of retroviruses, and mouse metallothionein-l. The selection of the appropriate vector and promoter and the preparation of certain recombinant expression constructs comprising at least one regulated promoter or promoter operatively linked to a nucleic acid described herein is well within the level of the art. The design and selection of regulated, inducible promoters and / or tightly regulated promoters are known in the art and will depend on the particular host cell and expression system. The pBAD expression system (Invitrogen Life Technologies, Carlsbad, CA) is an example of a tightly regulated expression system using the E. coli arabinose operon (PBAD or PARA) (see Guzman et al., J. Bacteriology 177 : 4121-30 (1995); Smith et al., J. Biol. Chem. 253: 6931-33 (1978); Hirsh et al., Cell 1 1: 545-50 (1977)), which controls the metabolic pathway of arabinose. A variety of vectors using this system are commercially available. Other examples of tightly regulated promoter-drive expression systems include PET expression systems (see US Patent No. 4,952,496) available from Stratagene (La Jolla, CA) or tet-regulated expression systems (Gossen et al., Proc. Nati, Acad. Sci. USA 89: 5547-51 (1992), Gossen et al., Science 268: 1766-69 (1995)). The acceptor vector of pLP-TRE2 (BD Biosciences Clontech, Palo Alto, CA) is designed to be used with CLONTECH 's Creator ™ cloning equipment to rapidly generate a tetracycline - regulated expression construct for tightly controlled, inducible expression of a gene of interest using the site-specific Cre-lox recombination system (see, e.g., Sauer, Methods 14: 381-92 (1998); Furth, J. Mamm. Gland Biol. Neoplas., 2: 373 (1997) ), which has also been used for immortalization of host cells (see, e.g., Cascio, Artif. Organs 25: 529 (2001)). The vector can be a viral vector such as a retroviral vector. For example, retroviruses from which retroviral plasmid vectors can be derived include, but are not limited to, Moloney murine leukemia virus, splenic necrosis virus, Rous sarcoma virus, Harvey sarcoma virus, avian leukosis, gibbon leukemia virus, human immunodeficiency virus, adenovirus, myeloproliferative sarcoma virus, and breast tumor virus. A viral vector also includes one or more promoters. Suitable promoters that can be used include, but are not limited to, retroviral LTR; the SV40 promoter; and the human cytomegalovirus (CMV) promoter described in Miller et al., Biotechniques 7: 980-990 (1989), or any other promoter (e.g., eukaryotic cell promoters including, for example, histone, polypeptide promoters). III, and β-actin). Other viral promoters that can be used include, but are not limited to, adenovirus promoters, thymidine kinase (TK) promoters, and parvovirus B19 promoters. The retroviral plasmid vector is used to transduce packaging cell lines (e.g., PE501, PA317,? -2,? -AM, PA12, T19-14X, VT-19-17-H2,? CRE,? CRIP , GP + E-86, GP + envAml2, DAN; see also, e.g., Miller, Human Gene Therapy, 1: 5-14 (1990)) to form producer cell lines. The vector can transduce the packaging cells through any means known in the art, such as, for example, electroporation, the use of liposomes, and calcium phosphate precipitation. The producer cell line generates infectious retroviral vector particles that include the nucleic acid sequence (s) encoding the polypeptides or fusion protein as described herein. Said retroviral vector particles can then be used, to transduce eukaryotic cells, either in vitro or in vivo. Eukaryotic cells that can be transduced include, for example, embryonic stem cells, embryonic carcinoma cells, hematopoietic stem cells, hepatocytes, fibroblasts, myoblasts, keratinocytes, endothelial cells, bronchial epithelial cells, and other cell lines adapted to the culture. As another example, host cells transduced by a recombinant viral construct that directs the expression of polypeptides or fusion proteins can produce viral particles that contain expressed polypeptides or fusion proteins that are derived from portions of a host cell membrane incorporated by the particles. viral during viral budding. Nucleic acid sequences encoding polypeptides can be cloned into a baculovirus shuttle vector, which is then recombined with a baculovirus to generate a recombinant baculovirus expression construct that is used to infect, for example, Sf9 host cells (see, v gr, Baculovirus Expression Protocols, Methods m Molecular Biology Vol 39, Richardson, Ed (Human Press 1995), Piwnica-Worms, "Expression of Proteins in Insect Cells Using Baculoviral Vectors," Section II, Chapter 16 in Short Protocols m Molecular Biology , 2nd Ed, Ausubel et al, eds, (John Wiley & amp; amp;; Sons 1992), pages 16-32 to 16-48)Methods for identifying and characterizing agents that alter the immune response of an immune cell Here methods are provided to identify and select an agent that alters (suppresses or increases in a statistically significant or biologically meaningful manner, preferably suppresses) the immune response of an immune cell or to determine the ability of an agent described herein to alter the immune response of an immune cell. In one embodiment, a method is provided for identifying an agent that suppresses the immune response of an immune cell comprising contacting (mixing, combining or in some way allow the interaction of (1) a candidate agent, (2) an immune cell that expresses at least one of RPTPs, LAR, RPTP-d, and RPTP-s, and (3) a poxvirus polypeptide such as A41 L or 130L, under conditions and for a sufficient time to allow interaction between at least one PTPN and the poxvirus popeptide, and then erase the binding level of the poxvirus peptide (i.e., A41L or 130L) to the immune cell in the presence and absence of the candidate agent A decrease in binding of the poxvirus polypeptide to the immune cell in the presence of the candidate agent indicates that the candidate agent suppresses the immune response of the immune cell. In certain embodiments, an immune cell expresses at least two of LAR, RPTP-d, and RPTP-s (such as LAR and RPTP-d, LAR and RPTP-s, and RPTP-d and RPTP-s) and in others particular modalities, an immune cell expresses all three RPTPs. The immune cell may be present in or isolated from a biological sample as described herein. For example, the immune cell can be obtained from a primary or long-term cell culture or it can be present in or isolated from a biological sample obtained from a subject (human or non-human animal). In another embodiment, a method is provided for identifying an agent that inhibits the binding of a poxvirus polypeptide, such as A41 L or 130L, to at least two RPTPs (which is, at least two of LAR, RPTP-d, and RPTP-s). The method comprises contacting (mixing, combining or in some way allowing the interaction between (1) a candidate agent, (2) a biological sample comprising at least two RPTP polypeptides selected from (i) LAR, (ii) PTPN -s; and (iii) RPTP-d, and (3) the poxvirus polypeptide under conditions and for a time sufficient to allow interaction between at least two RPTP polypeptides and the poxvirus polypeptide. poxviruses to at least two RPTP polypeptides are then administered in the presence of the candidate agent and compared to the level of binding of the poxvirus peptide to each of at least two RPTP polypeptides in the absence of the candidate agent. Poxvirus polypeptide binding of at least two RPTP polypeptides in the presence of the candidate agent indicates that the candidate agent inhibits the binding of the poxvirus polypeptide of at least two RPTP polypeptides. In the embodiment, the candidate agent is contacted with a biological sample comprising LAR, RPTP-s, and RPTP-d and the level of binding in the presence and absence of the agent to which each of the phosphatases is determined. Appropriate conditions for allowing the interaction of the reaction components according to this method and other methods described herein include, for example, appropriate concentrations of reagents and components (including the poxvirus polypeptide and the candidate agent and the RPTP (s), temperature and pH regulators with which a person skilled in the art will be familiar.Concentrations of reaction components, pH regulators, temperature and sufficient period to allow interaction of the reaction components can be determined and / or adjusted in accordance with the methods described herein and with which those skilled in the art will be familiar, to implement the methods described herein, one skilled in the art will also readily appreciate and understand what controls are appropriately included when these methods are put into practice. Numerous tests and techniques are practiced by those skilled in the art to determine the interaction between or binding between a biological molecule and a cognate ligand. Accordingly, the interaction between a polypeptide of poxvirus, A41 L and / or 130L, and any or more of LAR, RPTP-s, and RPTP-d including the effect of a bioactive agent on this interaction and / or binding in the presence of the The agent can be easily determined by such tests and techniques, which may include a competitive test format. Illustrative methods include but are not limited to fluorescence resonance energy transfer, fluorescence polarization, time-resolved fluorescence resonance energy transfer. , proximity tests by scmilation, tests by reporter genes, fluorescence-extinguished enzyme substrate, chromogenic enzyme substrate and electroluminescence, immunoassays (such as enzyme-linked immunosorbent assays (ELISA), radoimmunoassay, immunoblotting, immunohistochemistry and the like), resonance of surface plasmon, cell-based tests such as those that use reporter genes and functional tests (v gr, tests that measure dephosphonlation of a phospho-substrate by tyrosine by one or more of LAR, RPTP-s, and RPTP-d and tests that measure immune function and immune response) Many of the methods described herein and known to those skilled in the art will be adapted to selection of altormy diseases to analyze large numbers of bioactive agents such as from libraries of compounds to determine the effect of an agent on the binding, interaction or biological function of the poxvirus polypeptide and / or LAR, RPTP-s, and RPTP-d and the effect of an agent on the immune response of an immune cell (see, v., High Throughput Screening The Discovery of Bioactive Substances, Devlin, ed, (Marcel Dekker New York, 1997)) The techniques and test formats may also include secondary reagents, such as specific antibodies, which are useful for detecting and / or amplifying a signal indicating the formation of a complex, such as between a poxvirus polypeptide (e.g., A41 L or 130L) and an RPTP. One or more of the test components or secondary reagents can be attached to a detectable portion (or marker or reporter molecule) such as an enzyme, cytotoxicity agent or other reporter molecule, including a dye, radionuclide, luminescent group, fluorescent group, a biotin or similar. Techniques for radiolabeling antibodies and other polypeptides are known in the art (see, e.g., Adams, In Vivo 12: 1-21 (1998)).; Hiltunen, Acta Oncol. 32: 831-9 (1993)). The detectable portion can be attached to a polypeptide (e.g., an antibody) such as through any available amino acid side chain, terminal amino acid or carbohydrate functional group located on the polypeptide, provided that the binding or linking process does not adversely affect the binding properties in such a way that the usefulness of the molecule is nullified. Particular functional groups include, for example, any free amino group, imino, thiol, hydr, carb or aldehyde. The binding of the detectable polypeptide and portion can be achieved by said groups and an appropriate functional group in the detectable portion. The link can be direct or indirect through separation or bridging groups (see, e.g., international patent application publications Nos. WO 93/06231, WO 92/22583, WO 90/091 195, and WO 89 / 01476, see also, e.g., commercial suppliers such as Pierce Biotechnology, Rockford, IL) A "biological sample" as used herein refers in certain embodiments to a sample containing at least one of LAR, PTPN- s, and RPTP-d or a poxvirus polypeptide or variant thereof A biological sample can be a blood sample (from which the serum or plasma can be prepared) biopsy specimen, body fluids (v gr, lung wash, ascites, mucosal washes, synovial fluid), bone marrow, lymph nodes, tissue explant, organ culture, or any other tissue or cell preparation of a subject or biological source A sample may also be referred to a tissue preparation or cells in which the morphological integrity or physical state has been altered, for example, by dissection, dissociation, solubilization, fractionation, homogenization, biochemical or chemical extraction, spraying, hofilization, sonication or any other methods for processing a sample derived from a subject or biological source. biological source can be a human or a non-human animal, a culture of primary cells (v. gr, immune cells, virus-infected cells), or cell line adapted to culture, including but not limited to genetically engineered cell lines that can contain sequences of chromosomally integrated or episomal recombinant nucleic acids, immortalized or immortalizable cell lines, hybrid cell lines of somatic cells, differentiated or differentiable cell lines, transformed cell lines and the like Candidate agents include but are not limited to an antibody, or antibody from same, as described herein, and which may also include a biospecific or biofunctional antibody, chimeric antibody, human or humanized antibody, scFv, or diantibody and the like. Additional agents described herein that are useful for altering the immune response of an immune cell (in certain embodiments, by suppressing the immune response of an immune cell) and for treating an immunological disease or disorder include but are not limited to small molecules, fusion polypeptides peptide-immunoglobulin constant region such as peptide-lgFc fusion polypeptide, aptamers, siRNA polynucleotides, antisense nucleic acids, ribozymes and peptide nucleic acids.

Immune cells and immune responses An immune cell is any cell of the immune system, including a lymphocyte or a non-lymphoid cell such as an accessory cell. Lymphocytes are cells that recognize and respond specifically to foreign antigens, and accessory cells are those that are not specific for certain antigens but are involved in the cognitive and activation phases of immune responses. For example, mononuclear phagocytes (macrophages), and other leukocytes (e.g., granulocytes, including neutrophils, eosinophils, basophils) and dendritic cells function as accessory cells in the induction of an immune response. The activation of lymphocytes by a foreign antigen leads to the induction or provocation of numerous effector mechanisms that function to eliminate the antigen. Accessory cells such as mononuclear phagocytes that have an effect or are involved with the effector mechanisms are also called effector c. The main classes of lymphocytes include B lymphocytes (cells B), T lymphocytes (T cells), and natural killer cells (NK), which are large granulated lymphocytes. B cells are capable of producing antibodies. T lymphocytes are further subdivided into helper T cells (CD4 +) and cytolytic or cytotoxic T cells (CD8 +). Auxiliary cells secrete cytokines that promote the proliferation and differentiation of T cells and other cells including B cells and macrophages, and recruit and activate inflammatory leukocytes. Another subgroup of T cells, called regulatory T cells or suppressor T cells actively suppress the activation of the immune system and prevent pathological autoreactivity, ie, autoimmune disease. Immunosuppressive cytokines, TGF-beta and interleukin-10 (IL-10), have also been implicated in regulatory T cell function. In general, an immune response may include a humoral response, in which antibodies specific for antigens are produced by differentiated B lymphocytes known as plasma cells. An immune response may also include in addition to or instead of a humoral response, a cell-mediated response in which several types of T lymphocytes act to eliminate antigens by a number of mechanisms.

For example, helper T cells that are capable of recognizing specific antigens may respond by releasing soluble mediators such as cytokines to recruit additional cells of the immune system to participate in an immune response. Also, cytotoxic T cells that are capable of specific antigen recognition may respond by binding to and destroying or damaging a cell or particle that has antigen. An immune response in a host or subject can be determined by any number of well-known immunological methods described herein and with which those skilled in the art will be familiar. Such tests include, but are not necessarily limited to, in vivo or in vitro determination of soluble antibodies, soluble mediators such as cytokines (e.g., IFN- ?, IL-2, IL-4, IL-10, IL-12). , and TGF-β), lymphokines, chemokines, hormones, growth factors and the like, as well as other mediators of small peptides, carbohydrates, nucleotides and / or soluble lipids; the state of cellular activation changes as determined by altered functional or structural properties of cells of the immune system, for example cell proliferation, altered motility, induction of specialized activities such as expression of specific genes or cytolytic behavior; cell differentiation by cells of the immune system, including altered surface antigen expression profiles or the onset of apoptosis (programmed cell death). The procedures for performing these and similar tests can be found, for example, in Lefkovits (Immunology Methods Handbook: The Comprehensive Sourcebook of Techniques, 1998). See also Current Protocols in Immunology; Weir, Handbook of Experimental Immunology, Blackwell Scientific, Boston, MA (1986); Mishell and Shigii (eds.) Selected Methods in Cellular Immunology, Freeman Publishing, San Francisco, CA (1979); Green and Reed, Science 281: 1309 (1998) and references cited therein). The ability of a poxvirus polypeptide such as A41L or 130L, or a fragment or variant thereof, and of an agent (e.g., an antibody or antigen-binding fragment thereof that specifically binds to LAR, PTPN- s, and / or RPTP-d; nucleic acid molecule (such as a siRNA aptamer, antisense polynucleotide); IgGc fusion polypeptide) described herein to suppress the immune response of an immune cell and therefore be useful for the treatment of an immunological disease or disorder, such as an autoimmune disease or inflammatory disease or disorder, cardiovascular disease or disorder, a metabolic disease or disorder, or a proliferative disease or disorder, can be determined and evaluated in any of a number of animal models described herein and used by those skilled in the art (see, e.g., reviews of Taneja et al., Nat. Immunol., 2: 781-84 (2001); Lam-Tse et al., Springer Semin. Immunopathol. 24: 297-321 (2002)). For example, mice having three Tyro3, Mer, and AxI genes encoding receptor tyrosine kinases, voided exhibit several symptoms of autoimmune diseases, including rheumatoid arthritis and SLE (Lu et al., Science 293: 228-29 (2001)) . A murine model of spontaneous lupus-like disease has been described using hybrid NZB / WF1 mice (see, e.g., Drake et al., Immunol Rev. 144: 51-74 (1995)). An animal model for type I diabetes can allow testing of agents and molecules that affect the initiation, modulation and / or protection of the animal against diseases using transgenic (Tg) MHC mice. Mice expressing the HLA-DQ8 translagen (HLA-DQ8 is the predominant predisposition gene in human type I diabetes) and the HLA-DQ6 transgene (which is protective of diabetes) were crossed with RIP mice (rat insulin promoter) ). B7-1-Tg to provide transgenic HLA-DQ8 RIP.B7-1 mice that develop spontaneous diabetes (see Wakeland et al., Curr Opin. Immunol., 11: 701-707 (1999); Wen et al., J Exp. Med. 191: 97-104 (2000)). (See also Brondum et al., Horm Metab. Res. 37 Suppl 1: 56-60 (2005)). Animal models that can be used to characterize agents that are useful for the treatment of rheumatoid arthritis include a model of collagen-induced arthritis (see, e.g., Kakimoto, Chin. Med. Sci. J. 6: 78-83 (1991 ); Myers et al., Life Sci. 61: 1861-78 (1997)) and an arthritis model induced by anti-collagen antibody (see, e.g., Kakimoto, supra). Other applicable animal models for immunological diseases include an experimental autoimmune encaphilomyelitis model (also called experimental allergic encephalomyelitis model), an animal model of multiple sclerosis; a model of psoriasis using AGRI 29 mice that are deficient in type I and type II interferon receptors and deficient for the recombination 2 activation gene (Zenz et al., Nature 437: 369-75 (2005); Boyman et al. al., J Exp. Med. 199: 731-36 (2004), published online on February 23, 2004); and a mouse model TNBS (2,4,6-trinitrobenzenesulfonic acid) for inflammatory bowel disease. Numerous animal models for cardiovascular diseases are available and include models described in van Vlijmen et al., J Clin. Invest. 93: 1403-10 (1994); Kiriazis et al., Annu. Rev. Physiol. 62: 321-51 (2000); Babu et al., Methods Mol. Med. 1 12: 365-77 (2005).

Treatment of Immunological Disorders and Diseases In another embodiment, methods are provided to treat and / or prevent immunological diseases and disorders, particularly an inflammatory disease or disorder, an autoimmune disease or disorder, a cardiovascular disease or disorder, a disease or metabolic disorder or disease or proliferative disorder as described here. A subject in need of such treatment may be a human or may be a primate or human or other animal (i.e., veterinary use) that has developed symptoms of an immunological disease or is at risk of developing an immunological disease. Examples of non-human primates and other animals include but are not limited to farm animals, pets and zoo animals (eg, horses, cows, buffaloes, llamas, goats, rabbits, cats, dogs, chimpanzees, orangutans, gorillas , monkeys, elephants, bears, big cats, etc.). In certain embodiments, compositions are provided comprising an antibody, or an antigen fragment thereof, bispecific antibody, fusion polypeptide, RPTP Ig domain polypeptide (monomer or multimer), macromolecule, nucleic acid or other agent, as described here more a pharmaceutically acceptable excipient. As described herein, a method is provided for altering (e.g., suppressing or increasing) an immune response in a subject (host or patient) having or at risk of developing an immunological disease or disorder by administering a composition comprising a pharmaceutically acceptable carrier and an antibody, or antigen-binding fragment thereof, that specifically binds to at least one of LAR, RPTP-s, and RPTP-d. In particular embodiments, the antibody or antigen-binding fragment thereof is capable of inhibiting, preventing or competing with the binding of A41L or 130L to RPTP. In certain embodiments, the composition comprises an antibody, or antigen-binding fragment thereof, that specifically binds to RPTP-s, and in another certain embodiment, the composition comprises an antibody or antigen-binding fragment thereof, which is binds specifically to RPTP-d. A method is also provided for altering (e.g., suppressing or increasing) an immune response in a subject (host or patient) having or at risk of developing an immunological disease or disorder by administering a composition comprising a vehicle pharmaceutically acceptable and an antibody (ie, at least) or antigen-binding fragment thereof, which specifically binds to at least two of LAR, RPTP-s, and RPTP-d (e.g., LAR and RPTP-s; LAR and RPTP-d; RPTP-s and RPTP-d). In a particular embodiment, said method suppresses an immune response in a subject. Alternatively, the composition comprises an antibody, or antigen-binding fragment thereof, that specifically binds to the three RPTPs. In certain embodiments, the composition comprises a pharmaceutically acceptable carrier and at least one antibody that binds to all three of LAR, RPTP-s, and RPTP-d. In other embodiments, the composition comprises any two or more of the antibodies, or antigen-binding fragments thereof, described herein. Accordingly, a composition for altering (suppressing or increasing) an immune response comprises at least one antibody and binds to LAR, at least one antibody that binds to RPTP-s, and at least one antibody that binds to RPTP-d. In another embodiment, the composition comprises at least one antibody that binds to LAR, and at least one antibody that binds both RPTP-s and RPTP-d. Here also is contemplated and described a composition comprising at least a first antibody that binds to any two of LAR, RPTP-s, and RPTP-d and at least one second antibody that binds to RPTP that is not specifically recognized by at least one first antibody. In another embodiment, a method is provided for treating an immunological disease or disorder wherein the method comprises administering to a subject in need thereof a pharmaceutically acceptable carrier and an agent that alters the biological activity of at least one of LAR, PTPN- s, or RPTP-d, or that alters a biological activity of at least two of the three LARs, RPTP-s, and RPTP-d. An agent as described herein (including an antibody, antigen-binding fragment thereof); a small molecule; an aptamer; an antisense polynucleotide; a small interfering RNA (siRNA); a peptide-lgFc fusion polypeptide or peptide Ig constant region domain fusion polypeptide; an RPTP Ig-like domain polypeptide (monomer or multimer), and a domain-lg constant region domain fusion polypeptide similar to RPTP Ig, all of which are described here in detail), which is useful for treating a disease or immunological disorder is capable of altering (increasing or decreasing in a statistically significant or biologically meaningful way) at least one biological activity (function) of at least one PTPN. In other modalities, the agent alters at least one biological function of one, two or three of the LARs, PTNTs, and PTTP-d. As described herein, these tyrosine phosphatases dephosphorylate the tyrosyl phosphoproteins, and together with the protein tyrosine kinases regulate the reversible tyrosine phosphorylation in a dynamic relationship that is integrated into a cell. Regulated phosphorylation and deforphorylation of tyrosine residues from substrates in the signal transduction pathway is a major control mechanism for cellular procedures such as cell growth, cell proliferation, metabolism, differentiation and locomotion. An agent used to treat an immunological disease or disorder can therefore affect or alter any or more of the biological activities or functions of at least one, two or three of LAR, PTNTs, and PTLDs including (1) the ability to dephosphorylate a tyrosyl phosphorylated substrate (i.e., it affects the catalytic activity); (2) the ability to affect cell proliferation; (3) the ability to affect cellular metabolism; (4) the ability to affect cell differentiation; and (5) the ability to affect cellular locomotion; (6) the ability to affect the function of another component in the same signal transduction pathway. The agents, compositions, antibodies or fragments thereof, fusion polypeptides, RPTP Ig domain polypeptides, molecule and methods described herein can be used to treat (ie, cure, prevent, alleviate the symptoms of, or slow down, inhibit or stop the progression of) an immunological disease or disorder. A particular disease or disorder can be treated by administering an effective amount of a particular agent, which can be readily determined by experts in the medical art. Such diseases and disorders which are autoimmune or inflammatory disorders include but are not limited to multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, (SLE), graft versus host disease (GVHD), sepsis, diabetes, psoriasis, atherosclerosis, Sjogren's syndrome. , progressive systemic sclerosis, scleroderma, acute coronary syndrome, ischemic reperfusion, Crohn's disease, endometriosis, glomerulonephritis, myasthenia gravis, ideopathic pulmonary fibrosis, asthma, acute respiratory distress syndrome (ARDS), vasculitis, or inflammatory autoimmune myositis. An immune disorder or disease also includes a cardiovascular disease or disorder, metabolic disease or disorder, or a proliferative disease or disorder. A cardiovascular disease or disorder that can be treated in accordance with the methods and agents described herein, includes, for example, atherosclerosis, endocarditis, hypertension, or peripheral ischemic disease. Metabolic diseases that are also immune disorders or diseases include diabetes, Crohn's disease and inflammatory bowel disease. An illustrative proliferative disease is cancer. As used herein, a patient (or subject) can be any mammal, including a human, who may have or suffer from an immunological disease or disorder, or who may be free of detectable disease. Accordingly, the treatment can be administered to a subject who has an existing disease, or the treatment can be prophylactic, administered to a subject who is at risk of developing the disease or condition. A pharmaceutical composition may be a sterile aqueous or nonaqueous solution, suspension or emulsion, which further comprises a pharmaceutically acceptable excipient (pharmaceutically acceptable or suitable excipient or carrier) (i.e., a non-toxic material that does not interfere with the activity of the active ingredient). ). Said compositions may be in the form of a solid, liquid or gas (aerosol). Alternatively, the compositions described herein can be formulated as a lyophilizate, or compounds can be encapsulated within liposomes using technology known in the art. The pharmaceutical compositions may also contain other components, which may be biologically active or inactive. Such components include, but are not limited to, pH regulators (eg, saline regulated at its neutral pH or saline regulated at its pH with phosphate), carbohydrates (e.g., glucose, mannose, sucrose, or dextrans). ), mannitol, proteins, polypeptides or amino acids such as glycine, antioxidants, chelating agents such as EDTA or glutathione, stabilizers, colorants, flavoring agents and suspending and / or preservatives. Any suitable excipient or vehicle known to those skilled in the art for use in pharmaceutical compositions can be used in the compositions described herein. The excipients for therapeutic use are well known, and are described, for example, in Remingtons Pharmaceutical Sciences, Mack Publishing Co. (A.R. Gennaro, ed., 1985). In general, the type of excipient is selected based on the administration model. The pharmaceutical compositions can be formulated for any suitable manner of administration, including for example topical, oral, nasal, intrathecal, rectal, vaginal, intraocular, subconjunctival, sublingual or parenteral administration, including subcutaneous, intravenous, intramuscular, intramuscular, intracavernosal injection or infusion. , intrameatal or intraurethral. For parenteral administration, the carrier preferably comprises water, saline, alcohol, a fat, a wax or a pH regulator. For oral administration, any of the above excipients or a solid carrier or excipient, such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, kaolin, glycerin, starch dextrins, sodium alginate, carboxymethylcellulose, ethylcellulose, glucose, sucrose and / or magnesium carbonate may be used A pharmaceutical composition (v. gr, for oral administration or injection delivery) may be in the form of a liquid A liquid pharmaceutical composition may include, for example, one or more of the following a sterile diluent such as water for injection, saline solution, preferably physiological saline solution, Ringer's solution, isotonic sodium chloride, fixed oils which can serve as the solvent or suspension medium, polyethylene glycols, ghuprene, propylene glycol or other solvents, antibacterial agents, antioxidants, chelating agents, pH regulators and agents for adjustment of tonicity such as sodium chloride or dextrose A parenteral preparation can be enclosed in ampoules, disposable syringes or multi-dose vials of glass or plastic The use of physiological saline is preferred, an injectable pharmaceutical composition is preferably sterile The agents described herein, including antibodies and antigen-binding fragment thereof, and biospecific antibody that specifically bind to at least one of LAR, PTP-s, and RPTP-d, small molecules, nucleic acid molecules, polypeptides of domain similar to RPTP Ig, and peptide and pohpeptide fusion proteins, can be formulated for sustained or slow release. Such compositions can generally be prepared using well-known technology and administered, for example, orally, rectally or subcutaneously, or by implantation the desired target site. Sustained-release formulations may contain a dispersed agent in a vehicle matrix and / or contained within a reservoir surrounded by a membrane control membrane. speed The excipients for use within said formulations are biocompatible and can also be biodegradable, preferably, the formulation provides a relatively constant level of active component release. The amount of active compound within a sustained release formulation depends on the site of implantation, the expected rate and duration of release and the nature of the condition to be treated or prevented The dosage of the composition for treatment of an immunological disease or disorder can be determined in accordance with parameters understood by a person skilled in the medical art. Accordingly , the appropriate dose can dep ender of the conditions of the patient (v gr, human) that is, stage of the disease, general health status, as well as age, gender and weight and other factors familiar to a medical technician. The pharmaceutical compositions can be administered from a appropriate manner to the disease to be treated (or prevented) as determined by those skilled in the medical art. An appropriate dose and appropriate duration and frequency of administration will be determined by factors such as the condition of the patient, the type and severity of the Patient's disease, the particular form of the active ingredient and method of administration In general, an appropriate dose and treatment provides the composition (s) in an amount sufficient to provide therapeutic and / or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or overall and / or disease-free longer survival, or a reduction in sev symptoms). For prophylactic use, a dose should be sufficient to prevent, treat the onset of, or decrease the severity of, a disease associated with an immunological disease or disorder. Optimal doses can generally be determined using experimental models and / or clinical trials. The optimal dose may depend on the patient's body mass, weight or blood volume. In general, the amount of polypeptide such as an antibody or antigen-binding fragment thereof, or a fusion polypeptide, or RPTP Ig-domain polypeptide as described herein, present in a dose, or produced in situ by DNA present in one dose, it varies from about 0.01 μg to about 1000 μg per kg of host. The use of the minimum dose that is sufficient to provide effective therapy is usually preferred. Patients can usually be monitored for therapeutic or prophylactic effectiveness using tests appropriate to the condition being treated or prevented, such tests will be familiar to those skilled in the art. Suitable dose sizes will vary with patient size, but will typically range from about 1 ml to about 500 ml for a 10-60 kg subject. For pharmaceutical compositions comprising an agent that is a nucleic acid molecule including an aptamer, siRNA, antisense or ribozyme, or peptides-nucleic acid, the nucleic acid molecule may be present within a variety of delivery systems known to the skilled artisan. in the art, including nucleic acid, and bacterial, viral and mammalian expression systems such as, for example, recombinant expression constructs as provided herein. Techniques for incorporating DNA into said expression systems are well known to the experts. The DNA can also be "naked", as described herein, for example, in Ulmer et al., Science 259: 1745-49, 1993 and reviewed by Cohen, Science 259: 1691-1692, 1993. Naked DNA intake can be increased by coating the DNA on biodegradable spheres, which are efficiently transported in the cells. Nucleic acid molecules can be delivered to a cell according to any of several methods described in the art (see, e.g., Akhtar et al., Trends Cell Bio 2: 139 (1992)).; Delivery Strategies for Antisense Oligonucleotide Therapeutics, ed. Akhtar, 1995, Maurer et al., Mol. Membr. Biol. 16: 129-40 (1999); Hofland and Huang, Handb. Exp. Pharmacol. 137: 165-92 (1999); Lee et al., ACS Symp. Ser. 752: 1 84-92 (2000); patent of E.U.A. No. 6,395,713; International Patent Application Publication No. WO 94/02595); Seibo et al., Int. J. Cancer 87: 853-59 (2000); Seibo et al., Tumor Biol. 23: 103-12 (2002); patent application publications of E.U.A. Nos. 2001/0007666, and 2003/077829). Such delivery methods known to those skilled in the art include but are not restricted to encapsulation in liposomes, by iontophoresis or by incorporation in other vehicles, such as biodegradable polymers; hydrogels, cyclodextrins (see, eg, Gonzalez et al., Bioconjug, Chem. 10: 1068-74 (1999), Wang et al., international application publications Nos. WO 03/47518 and WO 03/46185); poly (lactic-co-glycolic acid) (PLGA) and PLCA microspheres (also useful for the delivery of peptides and polypeptides and other substances) (see, e.g., US Patent No. 6,447,796; of US No. 2002/130430); biodegradable nanocapsules; and bioadhesive microspheres, or by proteinaceous vectors (International Application Publication No. WO 00/53722). In another embodiment, nucleic acid molecules for use in altering (suppressing or increasing) an immune response in an immune cell and for treating an immunological disease or disorder can also be formulated and complexed with polyethylene imine and derivatives thereof, such as polyethylene imine-polyethylene glycol-N-acetyl] galactosamine derivatives (PEI-PEG-GAL) or polyethylene imine-polyethylene glycol-tri-N-acetylgalactosamine (PEI-PEG-triGAL) (see also, e.g., patent application publication) of US No. 2003/0077829). Manufacturing methods are also provided herein to produce an agent that alters (suppresses or increases) the immune response of an immune cell and that is useful for treating a subject that has or is at risk of developing an immune disease or disorder. In one embodiment, said manufacturing method comprises (a) identifying an agent that suppresses the immune response of an immune cell in accordance with methods described herein and practiced in the art. For example, the identification of an agent comprises contacting (i) a candidate agent; (ii) an immune cell that expresses at least one receptor-like protein tyrosine phosphatase (PRTP) polypeptide selected from protein related to leukocyte common antigen (LAR); RPTP-s; and RPTP-d; and (iii) A41 L, under conditions and for a time sufficient to allow interaction between at least one RPTP polypeptide and a poxvirus polypeptide, such as A41 L and 130L. Then, the binding of the poxvirus polypeptide to the immune cell in the presence of the candidate agent is determined and compared to the binding of the poxvirus polypeptide to the immune cell in the absence of the candidate agent, wherein a decrease in binding of the poxvirus polypeptide to the immune cell in the presence of the candidate agent indicates that the candidate agent suppresses the immune response of the immune cell. The agent is then produced in accordance with methods known in the art to produce the agent. The agent can be any agent described herein, such as, for example, an antibody, an antigen-binding fragment thereof, bispecific antibody, a small molecule; an aptamer; an antisense polynucleotide; Small interfering RNA (siRNA); polypeptide domain similar to RPTP Ig (monomer or multimer) and fusion polypeptide to IgFc. In a particular embodiment, the agent is an antibody, or antigen-binding fragment thereof, which can be produced in accordance with the methods described herein and which are adapted for large-scale manufacture. For example, production methods include cell culture in batches, which is monitored and controlled to maintain appropriate growing conditions. The purification of the antibody, or antigen-binding fragment thereof, can be carried out in accordance with methods described herein and known in the art and which comport with the guidelines of domestic and external regulatory agencies. The following examples are offered for the purpose of illustration of the present invention and should not be considered as limiting the scope of this invention.

EXAMPLES EXAMPLE 1 Identification of RPTPs expressed on immune cells that bind to A41L This example describes a method for identifying cell surface polypeptides that bind to A41 L. A recombinant expression vector comprising a polynucleotide encoding a Cowpox A41L fusion polypeptide was constructed for a tandem affinity purification procedure (TAP). ) (also called TAP tag procedure) (see also, eg, Rigaut et al. Nat. Biotech. 17: 1030-32 (1999); Puig et al., Methods 24: 218-29 (2001); Knuesel et al. Mol. Cell. Proteomics 2: 1225-33 (2003)). The construct called A41 LCRFC was prepared and the fusion polypeptide was expressed and isolated according to standard molecular biology and affinity purification methods and techniques. A construction scheme is provided in Figure 2. Construction A41 LCRFC included a nucleotide sequence encoding a mature A41 L coding sequence of Cowpox virus fused to the C-terminus of the human growth hormone leader peptide. The tandem affinity tag of CRFC was fused to the C-terminus of A41 L. The CRFC tag included a human influenza virus hemagglutinin peptide, the HA epitope, the amino acids YPYDVDYA (SEQ ID NO: 67), for the which antibodies are available, allowing the detection of the expression of the fusion polypeptide by immunochemistry methods, such as distribution of fluorescence activated cells (FACS) or immunoblotting. Fused to the carboxyl terminal end of the HA epitope was a C-protein tag, amino acids EDQ VDPRLIDGK (SEQ ID NO: 68), which are derived from the human protein C heavy chain. The carboxyl terminus of the C protein tag was fused to the human rhinovirus HRV3C protease site, amino acids LEVLFQGP (SEQ ID NO: 69); and the carboxyl terminus of the HRV3C protease site was fused to a mutein derivative of the Fe portion of a human IgG. A scheme illustrating the TAP labeling procedure is presented in Figure 3. Ten μg of the A4ILCRFC fusion polypeptide that bound protein A was incubated with cell lysates prepared from 5 x 06 monocytes A variety of normal cells and tumor cells they can be used to identify cellular peptides that bind to or interact with A41L, including B cells and T cells (activated or non-activated), macrophages, epithelial cells, fibroblasts, and cell lines such as Ravi (B-cell lymphoma), THP-1 (acute monocytic leukemia) and Jurkat (T-cell leukemia) The complexes of A41 LCRFC / cell lysate were washed and then digested by protease HRV3C, which released A41 L and associated proteins Chloride was added of calcium (1 M) to the complexes of A41 L / l of cell liberated, which were then applied to an affinity resin of anti-protein C tag Calcium chloride was required for the interaction of the anti-C tag and the C-tag epitope The complexes bound to the anti-protein C tag affinity were washed in a pH buffer containing calcium chloride and then eluted by calcium chelation using EGTA The subsequent eluent was digested with trypsin and the A41 I complexes were subjected to direct tandem mass spectrometry to identify A41 L and its associated proteins. The sequences of the peptides generated by trypsin were identified by mass spectrometry. The peptides were identified as portions of the protein. tyrosine phosphatases similar to receptor, LAR, RPTP-s, and RPTP-delta as shown in Figures 4A, 4B, and 4C, respectively EXAMPLE 2 Preparation of A4IL-Fc fusion polypeptides This example describes the preparation of recombinant expression vectors for the expression of a fusion polypeptide of A41 L-Fc and a fusion polypeptide of A41 L-mutein. The recombinant expression vectors were prepared according to methods routinely practiced by experts in the molecular biology art. A polynucleotide encoding A4IL-Fc and a polynucleotide encoding A41 L-mutein Fe were cloned into the multiple cloning site of the vector, pDC409 (see, e.g., U.S. Patent No. 6,512,095 and U.S. Patent No. 6,680,840, and references cited therein). The amino acid sequence of the A41 L-Fc polypeptide is set forth in SEQ ID NO: 74, and the amino acid sequence of the A41 L-mutein Fe polypeptide is set forth in SEQ ID NO: 73 (see Figure 5). The nucleotide sequence encoding the mutein polypeptide Fe (human IgG1) (SEQ ID NO: 77) is set forth in SEQ ID NO: 78. Ten to twenty micrograms of each expression plasmid were transfected into HEK293T cells or COS-7 cells (American Type Deposit of Tissues (ATCC), Manassas, VA) which were grown in standard tissue culture plates of 10 cm in diameter at approximately 80% confluence. The transfection was performed using Lipofectamine ™ Plus ™ (Invitrogen Corp., Carlsbad, CA). The transfected cells were cultured for 48 hours and then the supernatant of the cell cultures was harvested. The A41 L fusion proteins were purified by affinity chromatography of protein A sepharose in accordance with standard procedures.

EXAMPLE 3 Identification of RPTPS expressed in immune cells that bind to disease viruses similar to Yaba 130L This example describes a method for identifying cell surface polypeptides that bind to 130L. A recombinant expression vector comprising a polynucleotide encoding a 130L fusion polypeptide was constructed for a tandem affinity purification (TAP) process (also called TAP labeling procedure) as described in example 1. The construct is prepared and the fusion polypeptide expressed and isolated in accordance with standard molecular biology techniques and methods and affinity purification. The 130L tandem affinity tag construct included a nucleotide sequence encoding a mature 130L amino acid sequence of YLDV, which was fused to a nucleotide sequence encoding the C-terminus of the signal peptide amino acid sequence of Human growth hormone (MATGSRTSLLLAFGLLCLPWLQEGSA (SEQ ID NO: 153) (ie, the 5 'end of the nucleotide sequence encoding 130L is fused to the 3' end of the nucleotide sequence encoding the signal peptide). of affinity in tandem was fused to the C-terminus of 130 L. The label included a human influenza virus hemagglutinin peptide, the HA epitope, amino acids YPYDVDYA (SEQ ID NO: 141), for which the antibodies are commercially available, allowing the detection of expression of the fusion polypeptide by immunochemical methods, such as fluorescence-activated cell distribution (FACS) or immunotransfusion erence: Fused to the carboxyl terminal end of the HA epitope was the C-protein tag, amino acids EDQVDPRLIDGK (SEQ ID NO: 142), which is derived from the heavy chain of human protein C. A human rhinovirus HRV3C protease site, amino acids LEVLFQGP (SEQ ID NO: 143), was fused to the carboxyl end of the C protein tag; and to the carboxyl terminus of the HRV3C protease site is fused a mutein derivative of the Fe portion of a human IgG (e.g., SEQ ID NO: 146). Ten μg of the recombinantly expressed 130L fusion polypeptides were allowed to bind to a protein A affinity matrix. The 130L fusion polypeptide that bound protein A was incubated with used cells prepared from 5 x 10 6 monocytes. A variety of types of normal cells and tumor cells can be used to identify cellular polypeptides that bind to or interact with 130L, including B cells and T cells (activated or unactivated), macrophages, epithelial cells, fibroblasts, and cell lines such as Raji (B cell lymphoma), THP-I (acute monolithic leukemia), and Jurkat (T cell leukemia). The complexes of 130L fusion polypeptides / cell lysate were washed and then subjected to digestion by the HRV3C protease, which releases 130L proteins and associated proteins. Calcium chloride (1M) was added to the 130L complexes released / cell lysate, which were then applied to an O protein anti-tag affinity resin. Calcium chloride was required for the interaction of anti-C tag and label epitope C. Complexes that bind to anti-protein C protein affinity resin were washed in a pH buffer containing calcium chloride and then flowed by calcium chelation using EGTA. The subsequent eluent was digested with trypsin and the digested 130L complexes were subjected to direct tandem mass spectrometry to identify 130L and its associated proteins. The sequences of the peptides generated by trypsin were identified by mass spectrometry. Peptides were identified as portions of receptor-like tyrosine phosphatase proteins, LAR, RPTP-s, and RPTP-d as shown in Figures 7A, 7B, and 7C, respectively.

EXAMPLE 4 Induction of IFN-GAMMA in non-adherent PBMCS by a fusion protein of LAR (lg domains) -FC This example describes the production of IFN-? in peripheral blood mononuclear cells (PBMCs) in the presence and absence of heterologous donor cells. A recombinant expression vector for the expression of the LAR-Fc fusion protein was prepared according to methods routinely practiced by those skilled in the art of molecular biology. A nucleotide sequence encoding the first immunoglobulin-like domain (lg-1), the second immunoglobulin-like domain (lg-2), and the third immunoglobulin-like domain (lg-3) of LAR were fused in frame a sequence of nucleotides encoding a mutein Fe polypeptide. The mutein Fe polypeptide was derived from a human IgG1 immunoglobulin. The expression construct was transfected into cells and the expressed fusion polypeptide was isolated from the cell supernatants by protein A affinity chromatography. The human PBMCs were isolated from freshly extracted whole blood according to standard methods in the art. The PBMCs were enriched for nonadherent PBMC by placing the PBMCs in a tissue culture flask in RPMI containing 2% human serum for 2 hours and then gently stirring the supernatant from the cell culture containing the non-adherent cells. Non-adherent cells (2x105) were then cultured alone or in a mixed lymphocyte reaction with 104 dendritic cells derived from monocytes from each of the two heterologous donors (Do476 and Do495) at 0.8, 4, 20, and 100 μg / ml LAR-Fc or human IgG. After 18 hours, the production of IFN-? by non-adherent PBMCs was determined by measurement. The concentration of IFN-? in the cell supernatants was determined by ELISA (DuoSet human IFN-γ ELISA, Cat. No. D6285, R &D Systems, Minneapolis, MN). As shown in Figures 8A-8C, the LAR-Fc fusion protein increased the secretion of IFN-α. by non-adherent PBMC in the reaction of mixed lymphocytes (Figures 8B and 8C). In addition, non-adherent PBMC treated with LAR-Fe produced IFN-? in the absence of an antigenic stimulus (Figure 8A).

EXAMPLE 5 Filtration chromatography in the LAR (lg domain fusion protein) -FC This example describes size exclusion chromatography of the LAR Ig1-Ig2-Ig3-Fc fusion polypeptide (LAR-Fc). The LAR-Fc fusion polypeptide was prepared as described in Example 4. The fusion polypeptide was then analyzed by HPLC using a gel filtration column to obtain an estimated molecular weight of the fusion polypeptide. The elution profile is presented in Figure 9. The apparent molecular weight of the polypeptide was determined by comparing the elution time (minutes) with elution times of standardized molecular weight marker polypeptides. The molecular weight estimated in accordance with the gel filtration method was approximately 260,000 Daltons. The LAR-Fc fusion peptide is expected to form a dimer by virtue of the interaction between two Fe polypeptides, and the calculated molecular weight is 140,000 Daltons. These data suggest that the Stake radius of the fusion polypeptide is higher than predicted if the fusion polypeptide dimer had a globular structure. Without wishing to be bound by theory, the Ig domains of each of the two LAR Fe fusion polypeptides can interact with each other to form a dimeric structure, independent and different from the interaction between the Fe portions of two polypeptides of fusion.

EXAMPLE 6 Interaction between Ig domains of A41 L and LAR This example describes the interaction between A41 L and the immunoglobulin-like domains of LAR. Recombinant expression vectors for the expression of LAR-Fc fusion polypeptides were prepared using standard molecular biology techniques and as described in example 2. Fusion polypeptides included TAP-Fc fusion polypeptides: a fusion polypeptide with the first, second and third immunoglobulin-like domains with TAP sequences, which included a human IgG Fe polypeptide sequence (LAR lg1-2-3-tapFC); a fusion polypeptide of the first immunoglobulin-like domain of LAR fused to TAP-Fc (LAR lg1-tapFC); and a fusion polypeptide of the first and second immunoglobulin-like domains fused to TAP-Fc (LAR lgl-lg2-tapFC). The TAP constructs were expressed in 293-T17 cells. Cells that were transfected with this expression vector encoding LAR lgl-lg2-tapFC did not express the fusion polypeptide. Also included was a purified LAR Igl-Ig2-Ig3-Fc fusion polypeptide and a P35-FC polypeptide (non-RPTP control, not A41 L polypeptide). The immunoprecipitation reactions were performed. Cells were transfected with recombinant expression constructs encoding each of the previously described TAP-Fc fusion polypeptides, cultured, and supernatants of harvested cells. The supernatants were combined with purified A41 L polypeptide (monomer) to which conjugated spheres of protein A were added. The fusion polypeptides of P35-FC and LAR Ig1-Ig2-Ig3-Fc, included as controls, were purified polypeptides and incubated with A41 L purified. The fusion polypeptides were then isolated from the immunoprecipitates and subjected to SDS-PAGE. The presence of A41 L bound to the LAR fusion polypeptides was analyzed by immunoblotting. The results are presented in Figures 10A-10B. A41 L bound to the LAR fusion polypeptides that included the three immunoglobulin-like domains but did not bind to the LAR Igl-tapFC fusion polypeptide. From the foregoing, it will be appreciated that, while specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without departing from the spirit and scope of the invention. Those skilled in the art will recognize, or may confirm, using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. It is intended that said equivalents be encompassed by the following claims.

Claims (1)

NOVELTY OF THE INVENTION CLAIMS

1 - . 1 - An isolated antibody, or antigen-binding fragment thereof, (a) that specifically binds to at least two receptor-like protein tyrosine phosphatase (PTNP) polypeptides selected from (i) protein related to leukocyte-common antigen (LAR); (ii) RPTP-s; and (iii) RPTP-d; and (b) that competitively inhibits the binding of a poxvirus polypeptide to at least two RPTP polypeptides. 2. An isolated antibody, or antigen-binding fragment thereof, that specifically binds to at least one receptor-like protein tyrosine phosphatase (PTTR) present on the cell surface of an immune cell, wherein at least one RPTP is RPTP-s or RPTP-d, and wherein the binding of the antibody, or antigen-binding fragment thereof, to the PTTP that is present on the cell surface of the immune cell suppresses the immune response of the immune cell. 3. The antibody according to any of claim 1 or 2, further characterized in that the antibody is a polyclonal antibody or a monoclonal antibody. 4. The antigen-binding fragment according to any of claim 1 or 2, further characterized in that the antigen-binding fragment is selected from F (ab ') 2, Fab', Fab, Fd, Fv, and Fv of a single chain (scFv). 5. The antibody according to any of claim 1 or claim 2, further characterized in that the poxvirus polypeptide is either A41 L or Yaba 130L-like disease virus. 6. A bispecific antibody comprising (a) a first antigen-binding portion that is capable of specifically binding to a receptor-like protein tyrosine phosphatase (PTTP), wherein the PTTP is selected from (i) antigen-related protein. common to leukocytes (LAR); (ii) RPTP-s; and (iii) RPTP-d; and (b) a second antigen-binding portion that is capable of specifically binding to an RPTP, wherein the PTTP is selected from (i) protein related to leukocyte-common antigen (LAR); (ii) RPTP-s; and (iii) RPTP-d, wherein the first antigen-binding portion and the second antigen-binding portion are different, and wherein the bispecific antibody suppresses the immune response of an immune cell. 7. A fusion polypeptide comprising (a) an immunoglobulin-like domain-like polypeptide of a first receptor-like tyrosine phosphatase protein (PTPN); (b) a polypeptide of immunoglobulin-like domain 3 of a second PTPM; and (c) an immunoglobulin or mutein Fe polypeptide thereof, wherein each of the first PTPN and the second PTPR is selected from (i) leukocyte-common antigen-related protein (LAR); (ii) RPTP-s; and (iii) RPTP-d, and wherein the first and second PSTNs are the same or different. 8. - The fusion polypeptide according to claim 7, further characterized in that the first PWTP and the second PWTP are the same. 9. The fusion polypeptide according to claim 7, further characterized in that the first PTPM is PTPM-s and the second PTPM is PTPM-s, and wherein the fusion polypeptide further comprises a polypeptide of domain similar to immunoglobulin 1 of RPTP-s; or wherein the first RPTP is RPTP-d and the second RPTP is RPTP-d, and wherein the fusion polypeptide further comprises a polypeptide domain-like immunoglobulin 1 of RPTP-d. 10. A composition comprising (a) at least one immunoglobulin-like domain-like polypeptide of a first receptor-like tyrosine phosphatase protein (PTWP) and (b) at least one immunoglobulin-like domain-like polypeptide 3 second PSTN, wherein the first and second PSTN are the same or different and selected from (i) protein related to leukocyte common antigen (LAR); (ii) RPTP-s; and (iii) RPTP-d. 11. The composition according to claim 10, further characterized in that the first PWTP and the second PWTP are the same. 12. The composition according to claim 10, further characterized in that the first PTPR is PTPR-s and the second PTPR is PTPR-s, and wherein a composition further comprises a polypeptide domain-like immunoglobulin 1 of PTPR-s; or wherein the first RPTP is RPTP-d and the second RPTP is RPTP-d, and wherein a composition further comprises a polypeptide domain similar to immunoglobulin 1 of RPTP-d. 13. A composition comprising a polypeptide dimer wherein the dimer comprises (a) a first monomer comprising a polypeptide of immunoglobulin-like domain 2 and a polypeptide of immunoglobulin-like domain 3 of a first receptor-like protein tyrosine phosphatase (RPTP); and (b) a second monomer comprising a polypeptide of immunoglobulin-like domain 2 and an immunoglobulin-like domain polypeptide 3 of a second PTPM, wherein the first and second PTPR are the same or different and selected from (i) protein related to leukocyte common antigen (LAR); (ii) RPTP-s; and (iii) RPTP-d. 14 - The composition according to claim 13, further characterized in that the first PWTP and the second PWTP are different. 15. The composition according to claim 13, further characterized in that the first PWTP and the second PWTP are the same. 16. The composition according to claim 13, further characterized in that the first monomer comprises a domain similar to immunoglobulin 1 of the first PTPM, and wherein the second monomer further comprises a domain similar to immunoglobulin 1 of the second PTPM 17- The composition according to claim 13, further characterized in that the first monomer is fused to an immunoglobulin Fe polypeptide, and wherein the second monomer is fused to an immunoglobuhne Fe polypeptide. 18 - The composition according to any of the claim 10 or claim 13, further characterized by additionally comprising a pharmaceutically suitable excipient 19 - A pope fusion peptide comprising a poxvirus polypeptide fused to a mutein Fe polypeptide, wherein the polypeptide Mutein Fe comprises the amino acid sequence of the Fe moiety of a human IgG immunoglobu comprising at least one mutation, wherein at least one mutation is a substitution or deletion of a cysteine residue in the hinge region, wherein the substituted or deleted cysteine residue is the cysteine residue most proximal to the amino terminus of the hinge region of a Fe portion of wild type human IgG immunoglobulin, and wherein the poxvirus polypeptide is capable of binding to a protein receptor-like tyrosine phosphatase (RPTP) selected from (i) protein related to leukocyte-common antigen (LAR), (n) RPTP-s, and (n) RPTP-d 20 - The fusion polypeptide according to claim 19 , further characterized in that the mutein Fe polypeptide comprises at least one second mutation, wherein at least one second mutation is a substitution of at least one amino acid in the CH2 d domain. e such that the ability of the fusion polypeptide to bind to an IgG Fe receptor is reduced. 21. A composition comprising the fusion polypeptide of claim 7 or claim 19 and a pharmaceutically suitable excipient. 22. A composition comprising (a) the antibody or antigen-binding fragment thereof, of any of claim 1 or 2, and (b) a pharmaceutically suitable excipient. 23. A composition comprising the bispecific antibody of claim 6 and a pharmaceutically suitable excipient. 24. The use of a composition of claim 18, in the manufacture of a medicament useful for suppressing an immune response in a subject. 25. The use of a composition of claim 21, in the manufacture of a medicament useful for suppressing an immune response in a subject. 26. The use of a composition of claim 22, in the manufacture of a medicament useful for suppressing an immune response in a subject. 27. The use of a composition of claim 23, in the manufacture of a medicament useful for suppressing an immune response in a subject. 28. - The use of a composition of claim 18, in the manufacture of a medicament useful for treating an immunological disease or disorder in a subject. 29. The use of a composition of claim 21, in the manufacture of a medicament useful for treating an immunological disease or disorder in a subject. 30. The use of a composition of claim 22, in the manufacture of a medicament useful for treating an immunological disease or disorder in a subject. 31. The use of a composition of claim 23, in the manufacture of a medicament useful for treating an immunological disease or disorder in a subject. 32. A manufacturing method for producing the antibody of any of claim 1 or 2. 33.- A manufacturing method for producing the bispecific antibody of claim 6. 34.- A manufacturing method for producing the fusion polypeptide of any of claim 7 or 19. 35. A manufacturing method for producing the composition of any of claim 10 or claim 13.