MXPA06015122A - COMPOSITIONS AND METHODS FOR TREATMENT OF NON-HODGKINâÇS LYMPHOMA - Google Patents

Abstract

The present invention is directed to compositions of matter useful for the treatment of non-hodgkinâÇs lymphoma in mammals and to methods of using those compositions for the same.

Description

COMPOSITIONS AND METHODS FOR THE TREATMENT OF NON-HODGKIN LYMPHOMA FIELD OF THE INVENTION The present invention is directed to compositions of matter useful for the treatment of hematopoietic tumor in mammals and to methods for using those compositions of matter therefor. BACKGROUND OF THE INVENTION Malignant tumors (cancer) are the second leading cause of death in the US, after heart disease (Boring et al., CA Cancel J. Clin. 43: 7 (1993)). Cancer is characterized by an increase in the number of abnormal cells, or neoplastic cells, derived from normal tissue, which proliferate to form a tumor mass, the invasion of tissues by these neoplastic tumor cells, and the generation of malignant cells. that eventually disperse through the blood or lymphatic system to regional lymph nodes and to distant sites through a process called metastasis. In a cancerous state, a cell proliferates under conditions in which normal cells do not grow. Cancer manifests itself in a wide variety of forms, characterized by different degrees of invasion and aggressiveness.

Cancers involving cells generated during hematopoiesis, a process by which cellular blood elements such as lymphocytes, leukocytes, platelets, erythrocytes, and natural killer cells are referred to as hematopoietic cancers. The lymphocytes that can be found in the blood and lymphatic tissue and are critical for immune response, are categorized into two main classes of lymphocytes: B lymphocytes (B cells) and T lymphocytes (T cells), which mediate cellular and humoral mediated immunity , respectively. The B cells mature within the bone marrow and leave the marrow expressing an antigen binding antibody on its cell surface. When a B cell without pretreatment first encounters the antigen for which the membrane-bound antibody is specific, the cell begins to divide rapidly and its progeny differentiate into memory B cells and effector cells termed "plasma cells". Memory B cells have a longer extension of life and continue to express membrane bound antibody with the same specificity as the original parent cell. Plasma cells do not produce antibody bound to membrane but on the contrary they produce the antibody in a form that can be secreted. Secreted antibodies are the molecule main effector of humoral immunity. Mature T cells within the thymus that provides an environment for the proliferation and differentiation of immature T cells. During T cell maturation, T cells undergo rearrangement of genes that produce the T cell receptor and positive and negative selection that helps determine the cell surface phenotype of the mature T cell. Cell surface markers characteristic of mature T cells are the T cell receptor complex: CD3 and one of the CD4 or CD8 co-receptors. In attempts to discover effective cellular targets for cancer therapy, the researchers have sought to identify transmembrane or other transmembrane-associated polypeptides that are specifically expressed on the surface of one or more particular types of cancer cells as compared to one or more. more normal non-cancerous cells. Often, these membrane associated polypeptides are more abundantly expressed on the surface of cancer cells compared to on the surface of cancer-free cells. The identification of these cell surface antigen polypeptides associated with tumor has resulted in the ability to target specifically to cancer cells for destruction by antibody-based therapies. In this regard, it is noted that antibody-based therapy has been shown to be very effective in the treatment of certain cancers. For example, HERCEPTIN® and RITUXAN® (both from Genentech Inc., South San Francisco, California) are antibodies that have been used successfully to treat breast cancer and non-Hodgkin's lymphoma, respectively. More specifically, HERCEPTIN® is a humanized monoclonal antibody derived from recombinant DNA that selectively binds to the extracellular domain of the proto-oncogene receptor for human epidermal growth factor 2 (HER2). Overexpression of HER2 protein is observed in 25 to 30% of primary breast cancers. RITUXAN® is a genetically engineered chimeric mouse / human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes. Both of these antibodies are produced recombinantly in CHO cells. In other attempts to discover effective cellular targets for cancer therapy, researchers have sought to identify (1) non-membrane associated polypeptides that are specifically produced by one or more particular types of cancer cells compared to one or more particular types of non-cancerous normal cells, (2) polypeptides that are produced by cancer cells at an expression level that is significantly higher than that of one or more normal non-cancerous cells or (3) polypeptides whose expression is specifically limited to only a single tissue type (or a very limited number of different types) in both the cancerous and non-cancerous state (e.g., normal prostate tissue and prostate tumor) ). These polypeptides can remain located intracellularly or can be secreted by the cancer cell. Still further, these polypeptides can be expressed not by the cancer cell itself but rather by cells being produced and / or secreting polypeptides having an enhancing or growth enhancing effect on cancer cells. These secreted polypeptides are often proteins that provide cancer cells with an advantage of growth and / or survival against normal cells and include such things as, for example, angiogenic factors, cell adhesion factors, growth factors, and the like. The identification of antagonists of these non-membrane associated polypeptides will be expected to serve as effective therapeutic agents for the treatment of these cancers. Furthermore, the identification of the expression pattern of these polypeptides would be useful for the diagnosis of particular cancers in mammals. Despite the previously identified advances in mammalian cancer therapy, there is a great need for additional therapeutic agents capable of detecting the presence of a tumor in a mammal and to effectively inhibit growth and / or survival of neoplastic cells, respectively. The present invention describes a polypeptide that is expressed at abnormally high levels in a wide variety of non-Hodgkin lymphomas, and provides methods and compositions for using this polypeptide as a diagnostic and / or therapeutic target in the diagnosis and treatment of non-Hodgkin lymphomas. . DESCRIPTION OF THE INVENTION The present invention relates to the identification of a cellular polypeptide (and its encoding nucleic acid, its variant or fragment) that is expressed differentially and / or highly by non-Hodgkin tumors in comparison with types of cells in normal counterpart. Interestingly and meaningfully, this cellular polypeptide is highly expressed across a broad spectrum of non-Hodgkin's lymphomas including B and T cell lymphoreses. The invention is also partly based on substantial penetration (as described herein) in the differential regulation of the polypeptide with respect to specific subsets of types of non-Hodgkin's lymphoma that provide significant advantages for tailoring therapeutic approaches if and when necessary, to selected subsets within a broad array of tumor types that collectively constitute the broad category of non-Hodgkin's lymphoma. This polypeptide is referred to herein as the UNQ733 Polypeptide and is expected to serve as an effective target for cancer therapy in mammals. Accordingly, in one aspect, the invention provides a method for inhibiting the growth of a non-Hodgkin lymphoma cell wherein the method comprises contacting the cell with an UNQ733 antagonist that causes inhibition of cell growth. In one embodiment, the UNQ733 antagonist binds to the UNQ733 Polypeptide. In one embodiment, the antagonist XUNQ733 binds to UNQ733 in a non-Hodgkin's lymphoma cell. In one embodiment, the UNQ733 antagonist causes death of a cell expressing and / or responds to UNQ733 In one embodiment, the UNQ733 antagonist is an antibody, an oligopeptide, small organic or inorganic molecule. In one embodiment, the binding of the oligopeptide antibody, small inorganic or organic molecule to the UNQ733 Polypeptide causes growth inhibition of a cell that expresses and / or responds to the polypeptide. In a modality, the cell is a cancer cell and the UNQ733 antagonist causes cell expression death and / or response to the UNQ733 Polypeptide. In one embodiment, the cell is a cancer cell and the binding of the antagonist to the UNQ733 Polypeptide causes death of the cell that expresses and / or responds to the polypeptide. In one embodiment, the antagonist UNQ733 is an oligopeptide antibody, small inorganic or organic molecule and binding of the oligopeptide antibody small inorganic or organic molecule to the UNQ733 polypeptide causes death of the cells expressing the polypeptide. In one embodiment, an UNQ733 antagonist inhibits the activation of UNQ733, for example by modulating enzymatic processing of the UNQ733 protein (for example by inhibiting a proprotein convertase that cleaves UNQ733). In one embodiment, an antibody is a monoclonal antibody, antibody fragment, chimeric antibody, humanized antibody, antibody human, multiple specific antibody or single chain antibody. Antibodies, UNQ733 binding oligopeptides and small inorganic or organic molecules that bind UNQ733 employed in the methods of the invention can optionally be conjugated to a growth inhibitory agent or cytotoxic agent such as a toxin, including for example a maytansinoid or calceamycin, an antibiotic, a radioactive isotope, a nucleolytic enzyme, or the like. In some embodiments of methods of the invention, a chemotherapeutic agent is also administered to the subject. Antibodies and binding oligopeptides UNQ733 used in the methods of the invention can be produced in any convenient host cell, including for example CHO cells and bacterial cells. In another aspect, the invention provides a method for therapeutically treating a mammal having non-Hodgkin lymphoma wherein the method comprises administering to the mammal a therapeutically effective amount of an antagonist to UNQ733, thereby resulting in effective therapeutic treatment of the lymphoma. . In one embodiment, the UNQ733 antagonist is an antibody, an oligopeptide, small organic or inorganic molecule. In one embodiment, the UNQ733 antagonist binds to the UNQ733 Polypeptide, resulting in the effective therapeutic treatment of the tumor. In one embodiment, an UNQ733 antagonist inhibits the activation of UNQ733, for example modulating the enzymatic processing of UNQ733 protein (for example by inhibiting a proprotein convertase that cleaves UNQ733). In one embodiment, an antibody is a monoclonal antibody, antibody fragment, chimeric antibody, humanized antibody, human antibody, multiple specific antibody or single chain antibody. Antibodies, UNQ733 binding oligopeptides and small inorganic or organic binding molecules UNQ733 used in the methods of the invention can optionally be conjugated to a growth inhibitory agent or cytotoxic agent such as a toxin, including for example a maytansinoid or calceamycin, an antibiotic, a radioactive isotope, a nucleolithic enzyme, or the like. In some embodiments of methods of the invention, a chemotherapeutic agent is also administered to the subject. Antibodies and binding oligopeptides UNQ733 used in the methods of the invention can be produced in any convenient host cell, including for example CHO cells and bacterial cells.

In one aspect, the invention provides a method for inhibiting the growth of a non-Hodgkin lymphoma comprising administering an UNQ733 antagonist to the lymphoma, whereby the growth of the lymphoma is inhibited. In one aspect, the invention provides a method for inhibiting the growth of a non-Hodgkin lymphoma comprising administering an UNQ733 antagonist to a cell that expresses and / or responds to UNQ733, whereby the growth of the lymphoma is inhibited. In one aspect, the invention provides a method for inhibiting growth of a non-Hodgkin's lymphoma comprising administering an UNQ733 antagonist to a cell present in / or adjacent to the lymphoma, whereby the growth of the lymphoma is inhibited. In one embodiment, the cell is not a non-Hodgkin's lymphoma cell (e.g., it is not a T or B cell); for example, the cell can be a stromal cell. In one embodiment, the UNQ733 antagonist binds the UNQ733 Polypeptide in a non-Hodgkin lymphoma cell. In one embodiment, the UNQ733 antagonist causes death of a non-Hodgkin lymphoma cell that expresses and / or responds to UNQ733. In one embodiment, the antagonist UNQ733 is an antibody, an oligopeptide, small inorganic or organic molecule. In one embodiment, the binding of the antibody, oligopeptide, small inorganic or organic molecule to the Polypeptide UNQ733 causes inhibition of the growth of the non-Hodgkin lymphoma cell that expresses and / or responds to the polypeptide. In one embodiment, the UNQ733 antagonist is an antibody, oligopeptide, small inorganic or organic molecule and linkage of oligopeptide antibody or small organic molecule to the UNQ733 Polypeptide causes death of the non-Hodgkin lymphoma cell that expresses and / or responds to the polypeptide. Optionally, the antibody is a monoclonal antibody, antibody fragment, chimeric antibody, humanized antibody, human antibody, multispecific antibody or single chain antibody. Antibodies, UNQ733 binding oligopeptides and small inorganic or organic binding molecules UNQ733 used in the methods of the invention can optionally be conjugated to a growth inhibitory agent or cytotoxic agent such as toxin, including, for example a maytansinoid or calceamycin, an antibiotic, a radioactive isotope, a nucleolithic enzyme, or the like. In one embodiment, an UNQ733 antagonist inhibits the activation of UNQ733, for example the modular enzymatic processing of UNQ733 protein (e.g., inhibiting a proprotein convertase that cleaves UNQ733). In some embodiments of the methods of the invention, an agent is also administered chemotherapeutic Antibodies and binding oligopeptides UNQ733 used in the methods of the invention can be produced in any convenient host cell, including for example CHO cells and bacterial cells. In another aspect, the invention provides a method for treating or preventing a cellular proliferative disorder associated with increased expression or activity of UNQ733, the method comprising administering to a subject in need of this treatment, an effective amount of an UNQ733 antagonist. In one embodiment, the cell proliferative disorder is cancer and the antagonist UNQ733 is an anti-UNQ733 antibody, an uncoagulated oligopeptide UNQ733, small organic or inorganic molecule of UNQ733 binding. In one embodiment, an UNQ733 antagonist inhibits the activation of UNQ733, for example by modulating enzymatic processing of the UNQ733 protein (for example by inhibiting a proproprotein convertase that cleaves UNQ733). Effective treatment or prevention of cellular proliferative disorder may be a result of direct killing or inhibition of cell growth that expresses and / or responds to the UNQ733 Polypeptide or by antagonizing the cell growth enhancing activity of the UNQ733 Polypeptide. In one modality, the Cell proliferative disorder is a non-Hodgkin's lymphoma. In one embodiment, the proliferative cell disorder in hyperplasia, which in one modality is diseased non-malignant amygdala tissue. In one aspect, the invention provides a method for diagnosing a non-Hodgkin lymphoma of interest comprising determining the level of UNQ733 in a tissue test sample comprising cells of origin for the lymphoma of interest and in a control sample of known cells. of the same tissue origin, where a higher level of UNQ733 in the test sample compared to the control sample is indicative of the presence of the lymphoma. In another aspect, the invention provides a method for determining whether an individual is at risk for non-Hodgkin's lymphoma comprising determining the level of UNQ733 in a test sample of tissue cells comprising cells of origin for the lymphoma of interest to the individual and in a control sample of known cells from the same tissue source, wherein a higher level of UNQ733 in the test sample, as compared to the control sample, is an indication that the individual is at risk for lymphoma. In one embodiment of the methods of the invention, the level of UNQ733 is determined based on the RNA level UNQ733 in the test sample. In one embodiment of methods of the invention, the level of UNQ733 is determined based on the level of the UNQ733 Polypeptide in the test sample. In one embodiment of methods of the invention, the level of UNQ733 is determined based on the level of protein activity UNQ733 in the sample. In some embodiments, the method comprises exposing the sample to an antibody, oligopeptide, small organic or inorganic molecule that binds to the UNQ733 Polypeptide and determines the binding of the antibody, oligopeptide, small organic or inorganic molecule to the UNQ733 Polypeptide in the sample. An antibody, UNQ733 binding oligopeptide or small organic or inorganic binding molecule UNQ733 used in the method can be labeled in optionally detectable form connected to a solid support or the like. In one aspect, the invention provides a method for monitoring biologically active agents for the treatment of non-Hodgkin lymphoma comprising combining a candidate agent with a transgenic mammal having a genome comprising an integrated transgene encoding UNQ733 operably linked to a promoter. , where the transgene results in the mammal that acquires the non-Hodgkin's lymphoma and determines the effect of the people in non-Hodgkin's lymphoma in the mammal. In still another aspect, the invention provides a method for monitoring biologically active agents for the treatment of non-Hodgkin's lymphoma comprising combining a candidate agent with a culture of transgenic mammalian cells., each cell of the culture comprises an integrated transgene encoding UNQ733 operatively linked to a promoter, wherein the transgene results in the mammal that acquires the non-Hodgkin's lymphoma, and determines the effect of the candidate agent on the culture of transgenic mammalian cells. In one embodiment of these methods, the candidate agent is an antibody or its fragment, an oligopeptide or a small organic or inorganic molecule. Yet another aspect of the present invention is directed to a method for binding an antibody, oligopeptide, small organic or inorganic molecule to a non-Hodgkin lymphoma cell that expresses and / or responds to UNQ733, wherein the method comprises contacting the cell with the antibody, oligopeptide, small organic or inorganic molecule under conditions that are suitable for antibody binding, oligopeptide, small organic or inorganic molecule to UNQ733 Polypeptide and allow linkage between them. In one modality, the link of the antibody, oligopeptide, small organic or inorganic molecule to UNQ733 in the cell inhibits a biological function UNQ733. In one embodiment, the antibody, oligopeptide, small organic or inorganic molecule does not compete with UNQ733 for binding to the cells. In one embodiment, the antibody, oligopeptide, small organic or inorganic molecule does not inhibit the binding of UNQ733 to the cells. In one embodiment, the antibody, oligopeptide, small organic or inorganic molecule binds to UNQ733 bound in the cell and inhibits binding of free UNQ733 (unbound) to the cells. In one embodiment, the binding molecule UNQ733 is an antibody. In one embodiment, the antibody is designated 3E7.9.20 (ATCC Deposit Number PTA-6026), 3F10.11.2 (ATCC Deposit Number PTA-6027), 3H1.4.8 (ATCC Deposit Number PTA-6028), 4A9.12.12 (ATCC Deposit Number PTA-6029), 5A8.11.6 (ATCC Deposit Number PTA-6030), 5F2.6.14 (ATCC Deposit Number PTA-6031), 9D6.11.15 (ATCC Deposit Number PTA-6032), 10G10 .15.16 (ATCC Deposit Number PTA-6033) or 12H4.11.3 (ATCC Deposit Number PTA-6034). In one embodiment, the antibody binds to the same epitope in UNQ733 as the antibody designated 3E7.9.20 (ATCC Deposit Number PTA-6026), 3F10.11.2 (ATCC Deposit Number PTA-6027), 3H1.4.8 (ATCC Deposit Number PTA-6028), 4A9.12.12 (ATCC Deposit Number PTA-6029), 5A8.11.6 (ATCC Deposit Number PTA-6030), 5F2.6.14 (ATCC Deposit Number PTA-6031), 9D6.11.15 (ATCC Deposit Number PTA-6032 ), 10G10.15.16 (ATCC Deposit Number PTA-6033) and / or 12H4.11.3 (ATCC Deposit Number PTA-6034). In one embodiment, the antibody competes with the antibody designated 3E7.9.20 (ATCC Deposit Number PTA-6026), 3F10.11.2 (ATCC Deposit Number PTA-6027), 3H1.4.8 (ATCC Deposit Number PTA-6028), 4A9.12.12 (ATCC Deposit Number PTA-6029), 5A8.11.6 (ATCC Deposit Number PTA-6030), 5F2.6.14 (ATCC Deposit Number PTA-6031), 9D6.11.15 (ATCC Deposit Number PTA-6032 ), 10G10.15.16 (ATCC Deposit Number PTA-6033) and / or 12H4.11.3 (ATCC Deposit Number PTA-6034) to bind to UNQ733 (for example, where UNQ733 is located in a cell-free environment is a protein secreted in vivo or in vitro, or linked to a cell (in vitro or in vivo)). In one aspect, the invention provides a method for targeting a therapeutic agent with a non-Hodgkin lymphoma in a host, the method comprising administering to the host the therapeutic agent in a form that binds to a molecule that binds UNQ733, wherein the agent targets the lymphoma in the host.

The molecule that binds UNQ733 can be any molecule capable of binding specifically to an UNQ733 protein in vivo, for example an antibody, an oligopeptide, a small organic or inorganic molecule. In one embodiment, the molecule that binds UNQ733 is a molecule capable of binding specifically to UNQ733 located in a cell (either in vitro or in vivo), for example where UNQ733 is bound to the surface of a non-Hodgkin lymphoma cell . In one embodiment, the molecule is an antibody. In one embodiment, the antibody is designated 3E7.9.20 (ATCC Deposit Number PTA-6026), 3F10.11.2 (ATCC Deposit Number PTA-6027), 3H1.4.8 (ATCC Deposit Number PTA-6028), 4A9.12.12 (ATCC Deposit Number PTA-6029), 5A8.11.6 (ATCC Deposit Number PTA-6030), 5F2.6.14 (ATCC Deposit Number PTA-6031), 9D6.11.15 (ATCC Deposit Number PTA-6032), 10G10 .15.16 (ATCC Deposit Number PTA-6033) or 12H4.11.3 (ATCC Deposit Number PTA-6034). In one embodiment, the antibody binds to the same epitope in UNQ733 as the antibody designated 3E7.9.20 (ATCC Deposit Number PTA-6026), 3F10.11.2 (ATCC Deposit Number PTA-6027), 3H1.4.8 (ATCC Deposit Number PTA-6028), 4A9.12.12 (ATCC Deposit Number PTA-6029), 5A8.11.6 (ATCC Deposit Number PTA-6030), 5F2.6.14 (ATCC Deposit Number PTA-6031), 9D6.11.15 (Number of Deposits).

ATCC deposit PTA-6032), 10G10.15.16 (ATCC Deposit Number PTA-6033) and / or 12H4.11.3 (ATCC Deposit Number PTA-6034). In a modality, the antibody competes with the antibody designated 3E7.9.20 (ATCC Deposit Number PTA-6026), 3F10.11.2 (ATCC Deposit Number PTA-6027), 3H1.4.8 (ATCC Deposit Number PTA-6028), 4A9.12.12 (ATCC Deposit Number PTA-6029), 5A8.11.6 (ATCC Deposit Number PTA-6030), 5F2.6.14 (ATCC Deposit Number PTA-6031), 9D6.11.15 (ATCC Deposit Number PTA-6032), 10G10 .15.16 (ATCC Deposit Number PTA-6033) and / or 12H4.11.3 (ATCC Deposit Number PTA-6034) to link to UNQ733 (for example, where UNQ733 is located in a cell-free environment is a protein secreted in live or in vitro, or it is linked to a cell (in vitro or in vivo)). In one embodiment, the therapeutic agent binds to the molecule that binds UNQ733 in the form of a multispecific (e.g., bi-specific) antibody. Other embodiments of the invention are directed to the use of (a) a UNQ733 Polypeptide (processed or unprocessed by a convertase protein, alone or in combination), (b) a nucleic acid encoding a processed or unprocessed UNQ733 Polypeptide or a vector or host cell comprising that nucleic acid, (c) an anti-UNQ733 polypeptide antibody, (d) a linker oligopeptide UNQ733, (e) a small organic or inorganic binding molecule UNQ733, or (f) an inhibitor of an enzyme in vivo (such as a proprotein convertase) that cleaves the UNQ733 protein, in the preparation of a medicament useful for the therapeutic treatment of a non-Hodgkin's lymphoma. In one aspect, the invention provides a binding molecule UNQ733 useful in a method of the invention described herein. For example, a binding molecule UNQ733 can be a molecule (such as an antibody) that binds to UNQ733 and inhibits the binding of UNQ733 or its receptor. In another example, an UNQ733 linker molecule can be a molecule (such as an antibody) that binds UNQ733 bound to a cell. In one embodiment, the binding molecule binds to UNQ733 which binds to a cell but does not inhibit UNQ733 which binds to a cell. In yet another example, a binding molecule UNQ733 is a molecule (such as an antibody) that binds UNQ733 only when the UNQ733 is bound to a cell. In one embodiment, the binding molecule ligates to a first UNQ733 Polypeptide only when the first polypeptide is bound to a cell but inhibits the binding of a second UNQ733 Polypeptide to a cell. In some embodiments, it is advantageous that a molecule in UNQ733 bond of the invention is conjugated to a therapeutic agent (e.g., a toxin, etc. as described in greater detail below). In one aspect, the invention provides a composition comprising an UNQ733 antagonist wherein the composition is suitable for administration to a subject having a non-Hodgkin's lymphoma. In one embodiment, the composition comprises a therapeutically effective amount of the UNQ733 antagonist. In one embodiment, the composition further comprises a carrier which in some embodiments is a pharmaceutically acceptable carrier. In one embodiment, the antagonist UNQ733 is an antibody. In one embodiment, the antibody is designated 3E7.9.20 (ATCC Deposit Number PTA-6026), 3F10.11.2 (ATCC Deposit Number PTA-6027), 3H1.4.8 (ATCC Deposit Number PTA-6028), 4A9.12.12 (ATCC Deposit Number PTA-6029), 5A8.11.6 (ATCC Deposit Number PTA-6030), 5F2.6.14 (ATCC Deposit Number PTA-6031), 9D6.11.15 (ATCC Deposit Number PTA-6032), 10G10 .15.16 (ATCC Deposit Number PTA-6033) or 12H4.11.3 (ATCC Deposit Number PTA-6034). In one embodiment, the antibody binds the same epitope in UNQ733 as the antibody designated 3E7.9.20 (ATCC Deposit Number PTA-6026), 3F10.11.2 (ATCC Deposit Number PTA-6027), 3H1.4.8 (ATCC Deposit Number PTA-6028), 4A9.12.12 (ATCC Deposit Number PTA-6029), 5A8.11.6 (ATCC Deposit Number PTA-6030), 5F2.6.14 (ATCC Deposit Number PTA-6031), 9D6.11.15 (ATCC Deposit Number PTA-6032 ), 10G10.15.16 (ATCC Deposit Number PTA-6033) and / or 12H4.11.3 (ATCC Deposit Number PTA-6034). In one embodiment, the antibody competes with the antibody designated 3E7.9.20 (ATCC Deposit Number PTA-6026), 3F10.11.2 (ATCC Deposit Number PTA-6027), 3H1.4.8 (ATCC Deposit Number PTA-6028), 4A9.12.12 (ATCC Deposit Number PTA-6029), 5A8.11.6 (ATCC Deposit Number PTA-6030), 5F2.6.14 (ATCC Deposit Number PTA-6031), 9D6.11.15 (ATCC Deposit Number PTA-6032 ), 10G10.15.16 (ATCC Deposit Number PTA-6033) and / or 12H4.11.3 (ATCC Deposit Number PTA-6034) to link to UNQ733 (for example, where UNQ733 is located in a cell-free environment, is a protein secreted in vivo or in vitro, or linked to a cell (in vitro or in vivo)). In still another aspect, the invention provides article of manufacture comprising a container and a composition contained in the container, wherein the composition comprises an UNQ733 antagonist as described herein. The article may also optionally comprise a fixed label to the container and / or a packaging insert included with the container, which relates to the use of the composition for therapeutic treatment of non-Hodgkin's lymphoma. In a modality, the invention provides a kit comprising a composition comprising an UNQ733 antagonist as described herein, optionally further comprising instructions for using the composition for treatment of non-Hodgkin's lymphoma. In one aspect, the invention provides composition comprising a UNQ733 Polypeptide linkage molecule, wherein the composition is suitable for detecting UNQ733 Polypeptide in a test sample from an individual suspected of having non-Hodgkin's lymphoma. In one embodiment, the linker molecule is an oligopeptide antibody, small organic or inorganic molecule. In one embodiment, the binding molecule is an antibody, wherein the antibody is capable of binding to UNQ733 in a detection assay such as western blotting, immunoprecipitation and / or immunostaining. In one embodiment, the molecule is an antibody. In one embodiment, the antibody is designated 3E7.9.20 (ATCC Deposit Number PTA-6026), 3F10.11.2 (ATCC Deposit Number PTA-6027), 3H1.4.8 (ATCC Deposit Number PTA-6028), 4A9. 12.12 (ATCC Deposit Number PTA-6029), 5A8.11.6 (Number of ATCC deposit PTA-6030), 5F2.6.14 (ATCC Deposit Number PTA-6031), 9D6.11.15 (ATCC Deposit Number PTA-6032), 10G10.15.16 (ATCC Deposit Number PTA-6033) or 12H4.11.3 ( ATCC deposit number PTA-6034). In one embodiment, the antibody binds to the same epitope in UNQ733 as the antibody designated 3E7.9.20 (ATCC Deposit Number PTA-6026), 3F10.11.2 (ATCC Deposit Number PTA-6027), 3H1.4.8 (ATCC Deposit Number PTA-6028), 4A9.12.12 (ATCC Deposit Number PTA-6029), 5A8.11.6 (ATCC Deposit Number PTA-6030), 5F2.6.14 (ATCC Deposit Number PTA-6031), 9D6.11.15 (Number of Deposits). ATCC deposit PTA-6032), 10G10.15.16 (ATCC Deposit Number PTA-6033) and / or 12H4.11.3 (ATCC Deposit Number PTA-6034). In one embodiment, the antibody competes with the antibody designated 3E7.9.20 (ATCC Deposit Number PTA-6026), 3F10.11.2 (ATCC Deposit Number PTA-6027), 3H1.4.8 (ATCC Deposit Number PTA-6028), 4A9.12.12 (ATCC Deposit Number PTA-6029), 5A8.11.6 (ATCC Deposit Number PTA-6030), 5F2.6.14 (ATCC Deposit Number PTA-6031), 9D6.11.15 (ATCC Deposit Number PTA-6032 ), 10G10.15.16 (ATCC Deposit Number PTA-6033) and / or 12H4.11.3 (ATCC Deposit Number PTA-6034) to bind to UNQ733 (for example, where UNQ733 is located in a cell-free environment, is a protein secreted in live or in vitro, or it is linked to a cell (in vitro or in vivo)). In one embodiment, the composition further comprises a carrier. In still another aspect, the invention provides a manufacturing article comprising a container of a composition contained in the container, wherein the composition comprises a UNQ733 Polypeptide binding molecule and is suitable for detecting UNQ733 Polypeptide in a test sample of a individual suspected of having non-Hodgkin's lymphoma. The article may further optionally comprise a label fixed to the container and / or a packaging insert included in the container, which relates to the use of the composition for non-Hodgkin's lymphoma detection. In one embodiment, the invention provides a kit comprising a composition comprising a UNQ733 Polypeptide linkage molecule, which optionally further comprises instructions for using the composition to detect non-Hodgkin's lymphoma. In one embodiment, the binding molecule is an antibody, wherein the antibody is capable of binding to UNQ733 in a detection assay such as western blotting, immunoprecipitation and / or immunostaining. In one embodiment, the molecule is an antibody. In one modality, the antibody is designated 3E7.9.20 (ATCC Deposit Number PTA-6026), 3F10.11.2 (ATCC Deposit Number PTA-6027), 3H1.4.8 (ATCC Deposit Number PTA-6028), 4A9.12.12 (Deposit Number ATCC PTA-6029), 5A8.11.6 (ATCC Deposit Number PTA-6030), 5F2.6.14 (ATCC Deposit Number PTA-6031), 9D6.11.15 (ATCC Deposit Number PTA-6032), 10G10.15.16 (Number of deposit ATCC PTA-6033) or 12H4.11.3 (Deposit number ATCC PTA-6034). In one embodiment, the antibody binds to the same epitope in UNQ733 as the antibody designated 3E7.9.20 (ATCC Deposit Number PTA-6026), 3F10.11.2 (ATCC Deposit Number PTA-6027), 3H1.4.8 (ATCC Deposit Number PTA-6028), 4A9.12.12 (ATCC Deposit Number PTA-6029), 5A8.11.6 (ATCC Deposit Number PTA-6030), 5F2.6.14 (ATCC Deposit Number PTA-6031), 9D6.11.15 (Number of Deposits). ATCC deposit PTA-6032), 10G10.15.16 (ATCC Deposit Number PTA-6033) and / or 12H4.11.3 (ATCC Deposit Number PTA-6034). In one embodiment, the antibody competes with the antibody designated 3E7.9.20 (ATCC Deposit Number PTA-6026), 3F10.11.2 (ATCC Deposit Number PTA-6027), 3H1.4.8 (ATCC Deposit Number PTA-6028), 4A9.12.12 (ATCC Deposit Number PTA-6029), 5A8.11.6 (ATCC Deposit Number PTA-6030), 5F2.6.14 (ATCC Deposit Number PTA-6031), 9D6.11.15 (ATCC Deposit Number PTA-6032 ), 10G10.15.16 (ATCC Deposit Number PTA-6033) and / or 12H4.11.3 (ATCC Deposit Number PTA-603) to link to UNQ733 (for example, where UNQ733 is located in a cell-free environment, is a protein secreted in vivo or in vitro, or is linked to a cell (in vitro or in vivo)). As described herein, an antibody of the invention may be in any convenient form for use in a method of the invention. For example, an antibody of the invention can be human, humanized, or chimeric. In one embodiment, an antibody of the invention is the humanized or chimeric form of the antibody designated 3E7.9.20 (ATCC Deposit Number PTA-6026), 3F10.11.2 (ATCC Deposit Number PTA-6027), 3H1.4.8 (Number of ATCC Deposit PTA-6028), 4A9.12.12 (ATCC Deposit Number PTA-6029), 5A8.11.6 (ATCC Deposit Number PTA-6030), 5F2.6.14 (ATCC Deposit Number PTA-6031), 9D6.11.15 ( ATCC Deposit Number PTA-6032), 10G10.15.16 (ATCC Deposit Number PTA-6033) or 12H4.11.3 (ATCC Deposit Number PTA-6034). In one embodiment, an antibody of the invention is a humanized chimeric or human antibody that binds the same epitope to UNQ733 as the antibody designated 3E7.9.20 (ATCC Deposit Number PTA-6026), 3F10.11.2 (Deposit number ATCC PTA-6027), 3H1.4.8 (ATCC Deposit Number PTA-6028), 4A9.12.12 (ATCC Deposit Number PTA-6029), 5A8.11.6 (ATCC Deposit Number PTA-6030), 5F2.6.14 (Number of deposit ATCC PTA-6031), 9D6.11.15 (ATCC Deposit Number PTA-6032), 10G10.15.16 (ATCC Deposit Number PTA-6033) and / or 12H4.11.3 (ATCC Deposit Number PTA-6034). In one embodiment, an antibody the invention is a humanized chimeric or human antibody that competes with the antibody designated 3E7.9.20 (ATCC Deposit Number PTA-6026), 3F10.11.2 (ATCC Deposit Number PTA-6027), 3H1. .8 (ATCC Deposit Number PTA-6028), 4A9.12.12 (ATCC Deposit Number PTA-6029), 5A8.11.6 (ATCC Deposit Number PTA-6030), 5F2.6.14 (ATCC Deposit Number PTA-6031) , 9D6.11.15 (ATCC Deposit Number PTA-6032), 10G10.15.16 (ATCC Deposit Number PTA-6033) and / or 12H4.11.3 (ATCC Deposit Number PTA-6034) to link to UNQ733 (for example, where UNQ733 is located in cell-free environment, is a protein secreted in vivo or in vitro, or is linked to a cell (in vitro or in vivo)). In one embodiment, an antibody of the invention comprises one, two, three, four, five, or all hypervariable regions, hypervariable loops and / or complementary determination region (CDR) sequences of the antibody designated 3E7.9.20 (ATCC Deposit Number PTA-6026), 3F10.11.2 (ATCC Deposit Number PTA-6027), 3H1.4.8 (ATCC Deposit Number PTA-6028), 4A9.12.12 (ATCC Deposit Number PTA-6029), 5A8 .11.6 (ATCC Deposit Number PTA-6030), 5F2.6.14 (ATCC Deposit Number PTA-6031), 9D6.11.15 (ATCC Deposit Number PTA-6032), 10G10.15.16 (ATCC Deposit Number PTA-6033) or 12H4.11.3 (ATCC Deposit Number PTA-6034). In one embodiment, an antibody of the invention comprises one or both of the variable domains or their portion of the antibody designated 3E7.9.20 (ATCC Deposit Number PTA-6026), 3F10.11.2 (ATCC Deposit Number PTA-6027), 3H1.4.8 (ATCC Deposit Number PTA-6028), 4A9.12.12 (ATCC Deposit Number PTA-6029), 5A8.11.6 (ATCC Deposit Number PTA-6030), 5F2.6.14 (ATCC Deposit Number PTA-6031), 9D6 .11.15 (ATCC Deposit Number PTA-6032), 10G10.15.16 (ATCC Deposit Number PTA-6033) or 12H4.11.3 (ATCC Deposit Number PTA-6034). In some embodiments, methods and compositions of the invention are directed to a non-Hodgkin's lymphoma which is a B-cell lymphoma (otherwise unspecified- "NOS" equal to not-otherwise-specified), diffuse large B-cell lymphoma. , follicular lymphoma, small lymphocytic lymphoma, malignant lymphoma (NOS), malignant T-cell lymphoma, anaplastic large cell lymphoma or lymphoma of lymphoid tissue associated with mucosa. Still further embodiments of the present invention will be apparent to the person skilled in reading a present specification. BRIEF DESCRIPTION OF THE DRAWINGS FIGURE 1 illustrates GeneLogic micro-row expression data of UNQ733 mRNA. FIGURE 2 illustrates profile of overexpression of UNQ733 mRNA in non-Hodgkin lymphomas estimated by in situ hybridization in tissue micro-row. FIGURE 3 illustrates expression profile of UNQ733 mRNA in normal human tissues as estimated by in situ hybridization. FIGURES 4A-D illustrate expression of UNQ733 mRNA in germinal centers and crypts. FIGURE 5 illustrates expression profile of UNQ733 mRNA in neoplastic tissues. FIGURES 6A-C illustrate cellular localization of UNQ733 mRNA in malignant non-Hodgkin lymphoma cells. FIGURE 7 illustrates Western blot analysis of UNQ733 protein. FIGURE 8 illustrates immunopresipitation data for UNQ733 protein. FIGURE 9 illustrates immunohistochemical data for UNQ733 protein. Expression is observed in a subset of cells in tonsil crypts (arrows) and in germinal centers (GC), which most consist of a follicular dendritic cell. FIGURE 10 illustrates flow cytometry data. FIGURE 11 illustrates the effect of a proprotein convertase in UNQ733. Tracks marked "v" refer to samples of vector reflection transducers. Tracks marked "733" refer to samples of UNQ733 transducers. FIGURE 12 illustrates proportions of various species of UNQ733 protein obtained when cells are contacted with or without furin inhibitor. FIGS. 13A-B illustrate flow cytometry data for UNQ733 protein that binds to lymphoid cells. FIGURE 14 illustrates flow cytometry data for detection of UNQ733 protein linked to non-Hodgkin lymphoid cells. FIGURES 15A-B illustrate binding of UNQ733 protein to lymphoblast C1R B cells in a dose-dependent manner (A) and competitive binding data indicating binding specificity of UNQ733 to these cells (B). FIGURE 16 illustrates UNQ733 binding in normal B cells that are unstimulated or stimulated with an agonistic antibody to CD40 and recombinant IL-4. FIGURE 17 shows a nucleotide sequence (SEQ ID N0: 1) of an UNQ733 cDNA. Underlined codons in bold are the predicted start and stop codons, respectively. FIGURE 18 shows the amino acid sequences (SEQ ID NOs: 2-4) of native and variant UNQ733 polypeptides. MODES FOR CARRYING OUT THE INVENTION I. Definitions The terms "polypeptide UNQ733" and "protein UNQ733" as used herein encompass native sequence polypeptides, polypeptide variants and fragments of a native sequence polypeptide and polypeptide variants (which are also defined herein). The UNQ733 polypeptide described herein can be one that is isolated from a variety of sources, such as human tissue type or from another source, or prepared by recombinant or synthetic methods. The terms "UNQ733 polypeptide" and "UNQ733 protein" also include variants of a UNQ733 polypeptide as described herein.

A "native sequence UNQ733 polypeptide" comprises a polypeptide having the same amino acid sequence as the corresponding UNQ733 polypeptide derived from nature. In one embodiment, a native sequence UNQ733 polypeptide comprises the amino acid sequence of SEQ ID NO: 2 (see Figure 18). In another embodiment, a native sequence UNQ733 polypeptide comprises an amino acid sequence that lacks the signal peptide. In one embodiment, a native sequence UNQ733 polypeptide comprises the amino acid sequence of SEQ ID N0: 3 (see Figure 18). In yet another embodiment, a native sequence UNQ733 polypeptide comprises an amino acid sequence that results from enzymatic cleavage of the sequence SEQ ID NO: 2 with a proprotein convertase. In one embodiment, a native sequence UNQ733 polypeptide comprises the amino acid sequence of SEQ ID N0: 4 (see Figure 18). This native sequence UNQ733 polypeptide can be isolated from nature or can be produced by recombinant or synthetic means. The term "native sequence UNQ733 polypeptide" specifically encompasses secreted or truncated forms of natural origin of the specific UNQ733 polypeptide (e.g., an extracellular domain sequence) variant forms of natural origin (eg, example combined forms in alternate form) and allelic variants of natural origin of the polypeptide. UNQ733 of native sequence is also reported in Marshall et al, J. Im unol. (2002), 169: 2381-2389; PCT publication number W09931117; and the PCT publication number 5WO02 / 08288. "UNQ733 polypeptide variant" means a UNQ733 polypeptide, preferably an active UNQ733 polypeptide, as defined herein having at least about 80% amino acid sequence identity with any of the native sequence UNQ733 polypeptide sequences, as described herein. These UNQ733 polypeptide variants include, for example, UNQ733 polypeptides wherein one or more amino acid residues are aggregated or deleted at the C or N terminus of a native amino acid sequence. In ordinary form, a variant of UNQ733 polypeptide will have at least about 80% amino acid sequence identity, in alternating form at least about 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88% 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity, to a UNQ733 polypeptide sequence of native sequence as describe here. Ordinarily, UNQ733 variant polypeptides are at least about 10 amino acids in length, in alternating form at least about 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600 amino acids in length or more. Optionally, variant 33 polypeptides, will have no more than one conservative amino acid substitution as compared to a native 33 polypeptide sequence, in alternating form no more than 2, 3, 4, 5, 6, 7, 8, 9, or 10 conservative amino acid substitutions compared to the native 33 polypeptide sequence. "Percent (%) amino acid sequence identity" with respect to the 33 polypeptide sequences identified herein, is defined as the percent amino acid residue in a candidate sequence that is identical to the amino acid residues in the 33 polypeptide sequence specifies, after aligning the sequences and entering spaces, if necessary to achieve the maximum percentage of sequence identity, and without considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining% amino acid sequence identity, can be achieved in various ways that are within the skill of the art, for example using publicly available computer software such as the BLAST, BLAST-2, ALIGN or Megalign programs (DNASTAR ). Those skilled in the art can determine appropriate parameters to measure alignment, including any algorithms required to achieve maximum alignment over the integral length of the sequences being compared. For the present purposes, however,% amino acid sequence identity values are generated using the computer program for comparison of ALIGN-2 sequences, wherein the complete source code for the ALIGN-2 program is provided in Table 1 to continuation. The computer program for sequence comparison ALIGN-2 has as author Genentech, Inc. and the source code shown in Table 1 below has been presented with the user documentation in the Copyright Office of the US. (U.S. Copyright Office) Washington D.C., 20559, where it was registered under the copyright registration of the US. number TXU510087. The ALIGN-2 program is publicly available through Genentech, Inc., South San Francisco, California or can be compiled from the source code provided in Table 1 below. The ALIGN-2 program must be compiled for use in a UNIX operating system, preferably digital UNIX V4.0D. All sequence comparison parameters are adjusted by the ALIGN-2 program and do not vary. In situations where ALIGN-2 is used for amino acid sequence comparison, the% amino acid sequence identity of a given amino acid sequence A, with or against a given amino acid sequence B (which can alternatively be described as a A sequence of amino acids A having or comprising a certain% sequence identity of amino acids a, with or against a given amino acid sequence B) is calculated as follows: 100 x fraction X / Y where X is the number of amino acid residues qualified as identical correspondences by the ALIGN-2 sequence alignment program in that program alignment of A and B, where Y is the total number of amino acid residues in B. It will be appreciated that when the amino acid sequence length A does not is equal to the amino acid sequence length of amino acids B, the% amino acid sequence identity from A to B will not equal to% amino acid sequence identity from B to A. As examples of% amino acid sequence identity calculations Using this method, Tables 2 and 3 demonstrate how to calculate the% amino acid sequence identity of the amino acid sequence designated "comparison protein" to the amino acid sequence designated "UNQ733", wherein "UNQ733" represents the sequence of amino acids of a hypothetical UNQ733 polypeptide of interest, "comparison protein" represents the amino acid sequence of a polypeptide against which the "UNQ733" polypeptide of interest is compared and "X," and "Y" and "Z" represent different amino acid residues hypotheticals Unless specifically stated otherwise, all values of% amino acid sequence identity used herein are obtained as described in FIG. The immediately preceding paragraph using the ALIGN-2 computer program. "Variant polynucleotide UNQ733" or "variant amino acid sequence UNQ733" means a nucleic acid molecule encoding a UNQ733 polypeptide, preferably an active UNQ733 polypeptide, as herein defines and has at least about 80% nucleic acid sequence identity with a nucleotide acid sequence encoding a native sequence UNQ733 polypeptide sequence as described herein. In ordinary form, a variant UNQ733 polypeptide will have at least about 80% sequence identity, in alternate form, at least approximately 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% nucleic acid sequence identity with a nucleic acid sequence encoding a native sequence UNQ733 polypeptide sequence as described herein. Variants do not cover the native nucleotide sequence. In ordinary form, variant polynucleotides UNQ733 are less than about 5 nucleotides in length, in alternating form at least about 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 , 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 , 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 210, 220, 230, 240, 250 , 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, or 1000 nucleotides in length, wherein in this context, the term "approximately" means the length of nucleotide sequence referred to plus or minus 10% of the referred length. "Percent (%) nucleic acid sequence identity" with respect to a UNQ733 nucleic acid sequence (encoding a native sequence UNQ733 polypeptide, eg, the nucleic acid sequence of SEQ ID NO: 1 in Figure 17 ) described herein, is defined as the percentage of nucleotides in a candidate sequence that are identical to the nucleotides in the UNQ733 nucleic acid sequence of interest, after aligning the sequences and inserting spaces, if necessary, to achieve the percent maximum sequence identity. Alignment for purposes of determining percent nucleic acid sequence identity can be achieved in various ways that are within the skill in the art, for example using computer software publicly available such as the software or BLAST, BLAST-2, ALIGN or Megalign program (DNASTAR). For the present purposes, however,% nucleic acid sequence identity values are generated using the computer program for comparison of ALIGN-2 sequences, wherein the complete source code for the ALIGN-2 program is provided in Table 1 following. The computer program for comparison of sequences ALIGN-2 has as author Genentech, Inc. and the source code shown in the following Table 1 has been presented with the user documentation in the Copyright Office of the U.S.A. (U.S. Copyright Office), Washington D.C., 20559, where it was registered under the copyright registration number of the US. number TXU510087. The ALIGN-2 program is publicly available through Genentech, Inc., South San Francisco, California or can be compiled from the source code provided in Table 1 below. The ALIGN-2 program must be compiled for use in a UNIX operating system, preferably digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary. In situations where ALIGN-2 is used to nucleic acid sequence comparisons,% nucleic acid sequence identity of a given nucleic acid sequence C a, with or against a given nucleic acid sequence D (which alternatively can be described as a given nucleic acid sequence C having or comprising a certain percent identity of nucleic acid sequence a, with or against a given nucleic acid sequence D) is calculated as follows: 100 x fraction W / Z where W is the number of nucleotides qualified as identical correspondences by the alignment sequence program ALIGN-2 the alignment of C and D, and where Z is the total number of nucleotides in D. It will be appreciated that when the length of the C nucleic acid sequence is not equal to the length of the nucleic acid sequence D, the% nucleic acid sequence identity of C to D will not match the% nucleic acid sequence identity of D to C. as examples of% nucleic acid sequence identity calculations, Tables 4 and 5, demonstrate how to calculate the% nucleic acid sequence identity of the designated nucleic acid sequence "DNA from comparison "as the nucleic acid sequence designated" DNA UNQ733", wherein" DNA UNQ733"represents a hypothetical UNQ733 nucleic acid sequence of interest," Comparison DNA "represents the nucleotide sequence of a nucleic acid molecule against which the nucleic acid molecule "DNA UNQ733" of interest is compared and "N", "L" and "V" each represent different hypothetical nucleotides. Unless specifically stated otherwise, all values of% nucleic acid sequence identity employed herein are obtained as described in the immediately preceding paragraph using the ALIGN-2 computer program. In other embodiments, variant UNQ733 polynucleotides or nucleic acid molecules that encode a UNQ733 polypeptide and that are capable of hybridizing preferably under conditions of severe hybridization and washing, to nucleotide sequences encoding a UNQ733 polypeptide as described herein. Variable polypeptides UNQ733 can be those encoded by a variant polynucleotide UNQ733. "Isolated" means a molecule / compound (such as a polypeptide) that has been identified and separated and / or recovered from a component, from its natural environment.

Pollutant components of its natural environment are materials that typically interfere with therapeutic uses for the molecule / compound (such as a polypeptide) and may include enzymes, hormones and other proteaseous or nonproteasese solutes. In some embodiments, a polypeptide or oligopeptide will be purified (1) to a degree sufficient to obtain at least 10 to 15 residues of internal or N-terminal amino acid sequences by the use of a spin-cup sequencer, or (2) a homogeneity by gel electrophoresis for example SDS-PAGE under non-reducing or reducing conditions using for example Coomassie blue or silver staining. Isolated polypeptide includes polypeptide in situ within recombinant cells, since at least one component of the natural environment of the UNQ733 polypeptide will not be present. In ordinary form, however, the isolated polypeptide will be prepared by at least one purification step. An "isolated" polynucleotide is a nucleic acid molecule encoding oligopeptide or polypeptide that is identified and separated from at least one contaminating nucleic acid molecule with which it is ordinarily associated in the natural source of the nucleic acid encoding polypeptide or oligopeptide. A molecule of The nucleic acid encoding the isolated polypeptide or oligopeptide is different from the form or environment in which it is found in nature. Nucleic acid molecules encoding oligopeptide or isolated polypeptide are therefore distinguished from the nucleic acid molecule encoding specific oligopeptide or polypeptide as it exists in natural cells. However, a nucleic acid molecule encoding an oligopeptide or isolated polypeptide includes an acid molecule. nucleic acid encoding oligopeptide or polypeptide contained in cells that ordinarily express the polypeptide or oligopeptide wherein for example the nucleic acid molecule is in a chromosomal or extrachromosomal location different from that of natural cells. The term "control sequences" refers to DNA sequences necessary for the expression of a coding sequence linked operatively in a particular host organism. The control sequences that are suitable for prokaryotes for example include a promoter, optionally an operator sequence, and a ribosome binding site. Eukaryotic cells are known to use promoters, polyadenylation signals and enhancers. Nucleic acid is "operably linked" when it is placed in a functional relationship with another nucleic acid sequence. For example, DNA for a secretory or pre-sequence leader is operably linked to DNA for a polypeptide if it is expressed as a preprotein that participates in the secretion of the polypeptide; an enhancer promoter is operably linked to a decoding sequence if it affects the transcription of the sequence; or a ribosome binding site is operably linked to a coding sequence if it is located to facilitate translation. In general, "operably linked" means that the linked DNA sequences are contiguous and in the case of a secretory leader, contiguous and in the readings phase. However, the ejoradotes do not have to be contiguous. The link is achieved by linking at convenient restriction sites. If these sites do not exist, the linkers or adapters of synthetic oligonucleotides are used according to conventional practice. "Severity" of the hybridization reactions is easily determined with a person with ordinary skill in the art and in general is an empirical calculation that depends on probe length, wash temperature and salt concentration. In general, longer probes require higher temperatures for adequate alignment while shorter probes require lower temperatures. Hybridization in general depends on the ability of denatured DNA to realign when complementary strands are present in an environment below its melting temperature. The greater the degree of desired homology between the probe and hybridizable sequence, the greater the relative temperature that can be used. As a result, it is concluded that higher relative temperatures will tend to make the reaction conditions more severe, while lower temperatures less, for additional details and explanation of the severity of hybridization reactions, see Ausubel et al., Current Protocols in Molecular Biology, Wiley Interscience Publishers, (1995). "Severe conditions" or "conditions of high severity", as defined herein, can be identified by those that: (1) use low ionic concentration and high temperature for washing, for example 0.015 M sodium chloride / 0.0015 M sodium citrate / sodium dodecyl sulfate 0.1% at 50 degrees C; (2) employing a denaturation agent during hybridization, such as formamide, for example 50% formamide (v / v) with 0.1% bovine serum albumin / Ficoll O.1% / 0.1% polvinylpyrrolidone / 50m sodium phosphate buffer at pH 6.5 with 750mM sodium chloride, 75mM sodium citrate 42 degrees C; or (3) hybridization overnight in a solution employing 50% formamide, 5 x SSC (0.75 M NaCl, 0.075 M sodium citrate), 50 mM sodium phosphate (pH 6.8), 0.1% sodium pyrophosphate, solution of Denhardt 5 x, sonicated salmon sperm DNA (50 pg / ml), SDS 0.1% and dextran sulfate 10% at 42 degrees C with a 10 minute wash at 42 degrees C in 0.2 x SSC (sodium chloride / sodium citrate) followed by a 10 minute high severity wash consisting of EDTA containing 0.1 x SSC at 55 degrees C. "Moderately severe conditions" can be identified as described by Sambrook et al., Molecular Cloning: A Laboratory Manual , New York: Cold Spring Harbor Press, 1989, which include the use of a washing solution and hybridization conditions (e.g., temperature, ionic strength and% SDS), less severe than those described above. An example of moderately severe conditions is incubation overnight at 37 degrees C in a solution comprising: 20% formamide, 5 x SSC (150 mM NaCl, 15 mM trisodium citrate), 50 mM sodium phosphate (pH 7.6), solutions of Denhardt 5 x, dextran sulfate %, and 20 mg / ml denatured sheared salmon sperm DNA, followed by washing the filters in 1 x SSC at approximately 37-50 degrees C. The person skilled in the art will recognize how to adjust the temperature, ion concentration , etc., as necessary to accommodate factors such as probe length and the like. The term "epitope tagging" when used herein, refers to a chimeric polypeptide comprising UNQ733 polypeptide or anti-UNQ733 antibody fused to a "polypeptide tag". The polypeptide tag has sufficient residues to provide an epitope against which an antibody can be produced, however short enough such that it does not interfere with activity to the polypeptide to which it is fused. The polypeptide tag of preference is also substantially unique such that the antibody does not substantially cross-react with other epitopes. Suitable polypeptide labels generally have at least six amino acid residues and usually between about 8 and 50 amino acid residues (preferably, between about 10 and 20 amino acid residues). Examples of polypeptide tags include detectable labels such as polyhistidine and alkaline phosphatase of human placenta. "Active" or "activity" for the present purposes refers to the form or forms of a UNQ733 Polypeptide that retain a biological and / or immunological activity of UNQ733 Polypeptide of natural origin, wherein "biological" activity refers to a biological function (either inhibitory or stimulant) caused by a UNQ733 polypeptide of natural or native origin different from the ability to induce the production of an antibody against an antigenic epitope that possesses a UNQ733 polypeptide of natural or native origin and an "immunological" activity. to the ability to induce the production of an antibody against an antigenic epitope possessing a UNQ733 Polypeptide of natural or native origin. The term "antagonist" is used in the broadest sense and includes any molecule that blocks, inhibits or neutralizes completely or in part a biological activity of a native UNQ733 polypeptide described herein. Suitable antagonist molecules specifically include antagonist antibodies or antibody fragments, fragments or amino acid sequence variants of native UNQ733 polypeptide, peptides, antisense oligonucleotides, small organic or inorganic molecules, etc. Methods for identifying antagonists of an UNQ733 polypeptide may comprise contacting a UNQ733 polypeptide with a candidate antagonist molecule and measuring a detectable change in one or more biological activities normally associated with the UNQ733 polypeptide. "Treat" or "treatment" or "aivio" refers to both therapeutic treatment and prophylactic or preventative measures, where the objective is to avoid or slow down (reduce) the white or objective pathological condition or disorder. Those that require treatment include those who already have the disorder as well as those tending to have the disorder or those to whom the disorder is avoided. A subject or mammal is "successfully" treated for a non-Hodgkin lymphoma if after receiving a therapeutic amount of a UNQ733 antagonist according to the methods of the invention, the patient shows observable and / or measurable reduction in or absence of one or more than the following: reduction in the number of cancer cells or absence of cancer cells; reduction in tumor size; inhibition (ie slow to some extent and preferably stop) infiltration of cancer cells into peripheral organs, including the spread of cancer in soft tissue and bones; inhibition (ie, braking to a certain extent and preferably stopping) tumor metastasis; inhibition to some extent of tumor growth; and / or relief to some extent, one or more of the symptoms associated with the specific cancer; reduce morbidity and mortality, and improve aspects of quality of life. To the extent that the UNQ733 antagonist can prevent growth and / or kill existing cancer cells, it can be cytostatic and / or cytotoxic. The reduction of these signs or symptoms can also be felt by the patient. The above parameters to estimate successful treatment and improvement in the disease are easily measurable by routine procedures familiar to a physician. For cancer therapy, efficacy can be measured, for example, by estimating the time to disease progression (TTP = time to disease progression) and / or determining the response rate (RR = response rate). Metastasis can be determined by organizing tests and by bone screening and testing for calcium and other enzymes to determine bone spread. CT scans or scans can also be performed to look for dissemination to the pelvis and lymph nodes in the area. X-rays of the chest and measurement of liver enzyme levels by known methods are used to look for metastases in the lungs and liver respectively. Other routine methods to monitor the disease include transrectal ultrasonography (TRUS = transrectal ultrasonography) and transrectal needle biopsy (TRNB = transrectal needle biopsy). "Chronic" administration refers to the administration of the agent or agents in a continuous mode in position to an acute mode, to maintain the initial therapeutic effect (activity) for a prolonged period of time. "Intermittent" administration is the treatment that is not performed consecutively without interruption, but rather is cyclic in nature. "Mammal" for treatment purposes to alleviate the symptoms of a cancer refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo animals, for sports or pets, such as dogs, cats, livestock, horses, sheep, pigs, goats, rabbits, etc. Preferably, the mammal is a human. Administration "in combination with" of one or more additional therapeutic agents, includes simultaneous (concurrent) and consecutive administration in any order "Carrier" as used herein includes pharmaceutically acceptable excipients or stabilizers that are not toxic to the cell or mammal exposed to them at the doses and concentrations employed. Often, the physiologically acceptable carrier is a buffered solution of aqueous pH. Examples of physiologically acceptable protiants include buffers such as phosphate, citrate and other organic acids; antioxidants including ascorbic acid; low molecular weight polypeptide (less than about 10 residues); proteins, such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates including glucose, mannose or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counter-ions such as sodium; and / or non-ionic surfactants such as TWEEN®, polyethylene glycol (PEG) and PLURONICS®. By "solid phase" or "solid support" is meant a non-aqueous matrix to which an antibody, oligopeptide-binding polypeptide UNQ733 or molecule small inorganic or organic binding UNQ733 polypeptide of the invention can adhere or connect. Examples of solid phases encompassed herein include those formed partially or wholly of glass (for example, controlled pore glass), polysaccharides (for example agarose), polyacrylamides, polystyrene, polyvinyl alcohol and silicones. In certain embodiments, depending on the context, the solid phase may comprise the well or cavity of a test plate; in others, it is a purification column (for example, an affinity chromatography column). This term also includes a discontinuous solid phase of discrete particles, such as those described in U.S. Pat. No. 4,275,149. A "liposome" is a small vesicle composed of various types of lipids, phospholipids and / or surfactant that is useful for delivering a drug (such as a UNQ733 polypeptide, an antibody thereof or an oligopeptide-binding UNQ733 polypeptide) to a mammal. The liposome components are disposed in common form in a bilayer formation, similar to the lipid arrangement of biological membranes. A "small" molecule or "small" organic small molecule is defined here as having a weight molecular weight less than 500 Daltons. An "effective amount" of an UNQ733 antagonist as described herein is a sufficient amount to carry out a specifically stated purpose. An "effective amount" can be determined empirically and routinely, in relation to the stated purpose. The term "therapeutically effective amount" refers to an amount of an UNQ733 antagonist effective to "treat" a disease or disorder in a subject or mammal. In the case of cancer, the therapeutically effective amount of the antagonist can reduce the number of cancer cells; reduce the size of tumor; inhibiting (i.e. halting to a certain extent and preferably stopping) infiltration of cancer cells into peripheral organs; inhibit (ie slow to a certain extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; and / or receiving to some extent one or more of the symptoms associated with cancer. See the definition here "try". In the proportion that the antagonist can prevent the growth and / or kill existing cancer cells, it can be cytostatic and / or cytotoxic. An "inhibitory amount of growth" of a Antagonist UNQ733 is an amount capable of inhibiting the growth of a cell, especially of a tumor, for example cancer cell, either in vitro or in vivo. An "inhibitory amount of growth" of an UNQ733 antagonist for purposes of inhibiting growth of neoplastic cells can be determined empirically and in a routine manner. A "cytotoxic amount" of an UNQ733 antagonist is an amount capable of causing the destruction of a cell, especially a tumor, for example cancer cells, either in vitro or in vivo. A "cytotoxic amount" of an UNQ733 antagonist for purposes of inhibiting growth of neoplastic cells can be determined empirically and in a routine manner. The term "antibody" is used in the broadest sense and specifically covers for example, anti-UNQ733 polypeptide monoclonal antibodies (including antagonist, binding and / or neutralizing antibodies), anti-UNQ733 polypeptide antibody compositions with polyepitopic specificity, polyclonal antibodies, anti-UNQ733 single chain polypeptide antibodies and anti-UNQ733 polypeptide antibody fragments (see below) as long as they exhibit biological activity or desired immunological. The term "immunoglobulin" (Ig) is used interchangeably with antibody herein. An antibody useful in methods of the invention is one that has been identified and separated and / or recovered from a component of its natural environment. Polluting components of its natural environment are materials that will interfere with therapeutic uses for the antibody, and may include enzymes, hormones and other proteinaceous or non-proteinaceous solutes. In preferred embodiments, the antibody will be purified (1) to greater than 95% by weight of antibody as determined by the Lowry method, and more preferably more than 99% by weight, (2) to a sufficient degree to obtain at least 15% by weight. internal or N-terminal amino acid sequence residues by the use of a centrifuge cup sequencer, or (3) to homogeneity by gel electrophoresis such as SDS-PAGE under reducing or non-reducing conditions using for example Coomassie blue or silver stain. The basic 4-chain antibody unit is a heterotetrameric glycoprotein composed of two light chains (L) and two heavy chains (H) (one IgM antibody consists of 5 of the basic heterotetramer units together with a polypeptide additionally called J chain, and therefore contains 10 antigen binding sites, whereas secreted IgA antibodies can polymerize to form polyvalent moieties comprising 2-5 of the 4 basic chain units together with the J chain). In the case of IgGs, the 4-chain unit in general is approximately 150, 000 daltons. Each L chain is linked to an H chain by a covalent disulfide bond, while the two H chains are linked together by one or more disulfide bonds depending on the H chain isotype. Each H and L chain also has intrachain chains regularly spaced . Each H chain has at the N end, a variable domain (VH) followed by three constant domains (CH) for each of the a and? and four CH domains for the isotypes ft and e. Each L chain has at the N end, a variable domain (VL) followed by a constant domain (CL) at its other end. The VL is aligned with the VH and CL is aligned with the first constant domain of the heavy chain (CH1). Particular amino acid residues are considered to form an inferium between the variable light and heavy chain domains. The pairing of a VH and VL together forms a single antigen binding site. For the structure and properties of different classes of antibodies, see, for example, Basic and Clinical Immunology, 8th edition, Daniel P. Stites, Abba I. Terr and Tristram G. Parslow (eds.), Appleton & Lange, Norwalk, CT, 1994, page 71 and Chapter 6. The L chain of any vertebrate species can be assigned to one of two clearly distinct types, called kappa and lambda, based on the amino acid sequences of their constant domains. Depending on the amino acid sequence of the constant domain of their heavy chains (CH), immunoglobulins can be assigned to different classes or isotypes. There are five classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, which have designated heavy chains, d, e,? , and μ, respectively. Classes a and a are further divided into sub-classes based on relatively minor differences in CH sequence and function, for example humans express the following subclasses: IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2. The term "variable" refers to the fact that certain segments of the variable domains differ widely in sequence among antibodies. The V domain mediates antigen binding and defines specificity of a particular antibody for its particular antigen. However, the variability is not evenly distributed to through the extension of 110-amino acids from the variable domains. In contrast, the V regions consist of relatively invariant stretches called reading frame regions (FRs) of 15-30 amino acids separated by shorter regions of extreme variability termed "hypervariable regions" which are each 9-12 amino acids of length. The variable domains of native heavy and light chains each comprise four FRs, which adopt substantially a β-sheet configuration, connected by three hypervariable regions that form loops that connect and in some cases are part of the β-sheet structure. The hypervariable regions in each channel are held together in immediate proximity by FRs and with the hypervariable regions of the other chain, they contribute to the formation of the antibody antigen binding site (see Kabat et al., Sequences of Proteins of Immunological Interest, 5th Edition, Public Health Service, National Institutes of Health, Bethesda, MD. (1991)). The constant domains do not directly involve linking an antibody with an antigen, but exhibit various effector functions, such as participation of the antibody in antibody-dependent cellular cytotoxicity (ADCC = antibody in antibody dependent cellular cytotoxicity). The term "hypervariable region" when used herein, refers to amino acid residues of an antibody that are responsible for antigen binding. The hypervariable region generally comprises amino acid residues from a "complementarity determining region" or "CDR" (for example about residues 24-34 (Ll), 50-56 (L2) and 89-97 (L3)). in VL, and around approximately 1-35 (Hl), 50-65 (H2) and 95-102 (H3) in VH; Kabat et al., Sequences of Proteins of Immunological Interest, 5th Edition, Public Health Service, National Institutes of Health, Bethesda, MD. (1991)) and / or those residues of a "hypervariable loop" (eg residues 26-32 (Ll), 50-52 (L2) and 91-96 (L3) in VL , and 26-32 (Hl), 53-55 (H2) and 96-101 (H3) in VH, Chothia and Lesk J. Mol. Biol. 196: 901-917 (1987)). The term "monoclonal antibody" as used herein, refers to an antibody that is obtained from a population of substantially homogeneous antibodies, ie the individual antibodies comprising the population are identical except for possible mutations of natural origin that may be present in smaller quantities. Monoclonal antibodies are highly specific, directed against a single antigenic site. In addition, in contrast to polyclonal antibody preparations that include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant in the antigen. In addition to their specificity, monoclonal antibodies are advantageous since they can be synthesized without being contaminated by other antibodies. The "monoclonal" modifier should not be considered to require production of the antibody by any particular method. For example, monoclonal antibodies useful in the present invention can be prepared by the hybridoma methodology first described by Kohler et al., Nature, 256: 495 (1975), or they can be made using recombinant DNA methods in eukaryotic bacterial cells of animals or plants (see for example U.S. Patent No. 4,816,567). "Monoclonal antibodies" can also be isolated from phage antibody library using the techniques described in Clackson et al., Nature, 352: 624-628 (1991) and Marks et al., J. Mol. Biol. , 222: 581-597 (1991), for example. The monoclonal antibodies present include "chimeric" antibodies wherein a portion of the Heavy and / or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular class or subclass of antibody, while the remainder of the chain side is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another class subclass of antibody, as well as fragments of these antibodies, provided that they exhibit the desired biological activity (see U.S. Patent Number 4,816,567; and Morrison et al., Proc. Nati. Acad. Sci. USA, 81: 6851-6855 (1984)). Chimeric antibodies of interest herein include "primatized" antibodies that comprise variable domain antigen-binding sequences derived from a non-human primate (eg, old world monkey, ape, etc.) and human constant region sequences. An "intact" antibody is one that comprises an antigen binding site as well as a CL and at least constant heavy chain domains, CH1, CH2 and CH3. The constant domains may be constant domains of native sequence (e.g. constant domains of human native sequence) or their amino acid sequence variant. Preferably, the antibody intact has one or more effector functions. "Antibody fragment" comprises a portion of the intact antibody, preferably the variable or antigen binding region of the intact antibody. Examples of antibody fragments include Fab, Fab ', F (ab') 2i and Fv fragments; diabodies; linear antibodies (see U.S. Patent No. 5,641,870, Example 2; Zapata et al., Protein Eng. 8 (10): 1057-1062 [1995]); single chain antibody molecules; and multispecific antibodies formed from antibody fragments. Papain digestion of antibodies produces two identical antigen binding fragments, called "Fab" fragments, and a residual "Fe" fragment, a designation that reflects the ability to easily crystallize. The Fab fragment consists of an entire L chain together with the variable region domain of the H chain (VH), and the first constant domain of a heavy chain (CHI). Each Fab fragment is monovalent with respect to the antigen binding, that is, it has a single antigen binding site. Pepsin treatment of an antibody produces a single large F (ab ') 2 fragment corresponding approximately to two disulfide linked Fab fragments having divalent antigen and is still able to bind antigens. Fab 'fragments differ from Fab fragments by having a few additional sites at the carboxy terminus of the CHI domain including one or more cysteines from the antibody hinge region. Fab'-SH is the designation here for Fab 'where the residues or cysteine residues of the constant domains contain a free thiol group. F (ab ') 2 antibody fragments were originally produced as pairs of Fab' fragments that have hinge cysteines between them. Other chemical coupling of antibody fragments are also known. The Fe fragment comprises the carboxy-terminal portions of both H chains held together by disulfide. The effector functions of antibodies are determined by sequences in the Fe region, this region is also the part recognized by Fe (Fcr) receptors that are found in certain cell types. "Fv" is the minimal antibody fragment that contains a complete antigen recognition and binding site. This fragment consists of a dimer of a light chain variable region domain and a closed or narrow noncovalent association heavy region. From the folding of these two domains emanate six loops hypervariables (3 loops each of region H and L) that contribute to amino acid residues for antigen binding and confer specificity of antigen binding to the antibody. However, even a single variable domain (or half of an Fv comprising only 3 CDRs specific for an antigen) has the ability to recognize and bind antigen, although at a lower affinity than the entire link site. "Single chain Fv" also abbreviated as "sFv" or "scFv" are antibody fragments comprising the VH and VL antibody domains connected in a single polypeptide chain. Preferably, the sFv polypeptide further comprises a polypeptide linker between the VH and VL domains that allow the sFv to form the desired structure for antigen binding. For a review of sFv, see Pluckthun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and oore eds. , Springer-Verlag, New York, pp. 269-315 (1994); Borrebaeck 1995, above. The term "diabodies" refers to small antibody fragments prepared by constructing sFv fragments (see preceding paragraph) with short linkers (approximately 5 to 10 residues) between the VH and VL domains in such a way that interpair chain but not intra chain of the V domain is achieved, resulting in a bivalent fragment, ie fragment having two antigen binding sites. Bispecific diabodies are heterodimers of two "crossover" scFv fragments wherein the VH and VL domains of the two antibodies are present in different polypeptide chains. Diabodies are described more fully for example in EP 404,097; WO 93/11161; and Hollinger et al., Proc. Nati Acad. Sci. USA, 90: 6444-6448 (1993). "Humanized" non-human antibody forms (e.g. rodents) are chimeric antibodies that contain minimal sequence derived from the non-human antibody. For the most part, humanized antibodies are human immunoglobulins (recipient antibody) wherein the residues of a hypervariable region of the container are replaced by residues from a hypervariable region of a non-human species (donor antibody) such as mouse, rat, rabbit or primate not human having the desired specificity, affinity and antibody capacity. In some cases, residues of the reading frame region (Fr) of the human immunoglobulin are replaced by corresponding non-human residues. In addition, humanized antibodies can comprise residues that are not found in the recipient antibody or in the donor antibody. These modifications are made to further refine the antibody performance. In general, the humanized antibody will substantially comprise all of at least one and typically two variable domains, wherein substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all substantially all of the FRs are those of a human immunoglobulin sequence. . The humanized antibody also comprises at least a portion of an immunoglobulin constant region (Fe), typically that of human immunoglobulin. For additional details see Jones et al., Nature 321: 522-525 (1986); Riechmann et al., Nature 332: 323-329 (1988); and Presta, Curr. Op. Struct. Biol. 2: 593-596 (1992). A "species-dependent antibody", for example an anti-human IgE antibody in a mammal, is an antibody that has a stronger binding affinity for an antigen of a first mammalian species that has a homologue of that antigen of a second mammalian species. . Typically, the species-dependent antibody "specifically binds" to a human antigen (i.e., a binding affinity value) (Kd) not greater than about 1 x 10"7 M, preferably not greater than about 1 x 10"8 and more preferably not greater than about 1 x 10 ~ 9 M) but has a binding affinity for an antigen homolog of a second non-human mammal species that is at least about 50 times, or at least about 500 times, or at least about 1000 times weaker than its binding affinity for the human antigen The species-dependent antibody can be of any of several types of antibodies as defined above, but preferably is a humanized or human antibody An "UNQ733 polypeptide binding oligopeptide" is an oligopeptide that binds, preferably specifically to an UNQ733 polypeptide as described herein, UNQ733 polypeptide binding oligopeptide can be synthesized clinically using known oligopeptide synthesis methodology or can be prepared and purified using recombinant technology.

Polypeptide binding oligonucleotides UNQ733 are usually at least about 5 amino acids in length, alternately, at least about 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 , 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43 , 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 amino acids of length or more, wherein these oligopeptides are capable of specifically binding to a UNQ733 polypeptide as described herein. Polypeptide binding oligonucleotides UNQ733 can be identified without undue experimentation using well known techniques. In this regard, it is noted that techniques for monitoring oligopeptide libraries by oligopeptides that are capable of specifically binding to a polypeptide target are well known in the art (see for example) U.S. Pat. numbers 5,556,762, 5,750,373, 4,708,871, 4,833,092, 5,223,409, 5,403,484, 5,571,689, 5,663,143; PCT publications numbers O 84/03506 and WO84 / 03564; Geysen et al., Proc. Nati Acad. Sci. U.S. A., 81: 3998-4002 (1984); Geysen et al., Proc. Nati Acad. Sci. U.S. ., 82: 178-182 (1985); Geysen et al., In Synthetic Peptides as Antigens, 130-149 (1986); Geysen et al., J. Immunol. Meth., 102: 259-274 (1987); Schoofs et al., J. Immunol., 140: 611-616 (1988), Cwirla, S. E. et al. (1990) Proc. Nati Acad. Sci. USA, 87: 6378; Lowman, H.B. et al. (1991) Biochemistry, : 10832; Clackson, T. et al. (1991) Nature, 352: 624; Marks, J. D. et al. (1991), J. Mol. Biol. , 222: 581; Kang, A.S. et al. (1991) Proc. Nati Acad. Sci. USA, 88: 8363, and Smith, G. P. (1991) Current Opin. Biotechnol., 2: 668). A "small organic or inorganic molecule of UNQ733 polypeptide binding" is a small organic or inorganic molecule other than an oligopeptide or antibody as defined herein that is ligated, preferably specifically to a UNQ733 polypeptide as described herein. An UNQ733 antagonist of molecule is preferably a small organic molecule. Organic link UNQ733 polypeptide can be identified and synthesized chemically using known methodology (see for example PCT publications numbers WO00 / 00823 and WO00 / 39585). Small organic polypeptide binding molecules UNQ733 are usually less than about 2000 daltons, in alternating form less than about 1500, 750, 500, 250 or 200 daltons in size, wherein these small organic molecules are capable of binding preferably specifically to an UNQ733 polypeptide, herein described as can be identified without undue experimentation using well-known techniques. In this aspect, it is noted that techniques for monitoring library with small organic molecule by molecules that are capable of binding to a polypeptide target are well known in the art (see for example PCT publications numbers WO00 / 00823 and WO00 / 39585). An antibody, oligopeptide or other small organic or inorganic molecule "that binds" to an antigen of interest, for example an UNQ733 polypeptide is one that binds the antigen with sufficient affinity such that the oligopeptide antibody or other small organic or inorganic molecule is useful as a therapeutic agent for targeting a cell or tissue that expresses the antigen and does not cross-react significantly other proteins. In these embodiments, the extent of binding of the oligopeptide antibody or other small organic or inorganic molecule to a "non-target" protein will be less than about 10 percent of the binding of the antibody, oligopeptide, or other small organic or inorganic molecule to its target protein. particular as determined by fluorescence activated cell sorting analysis (FACS = Fluorescence Activated Cell Sorting) or radioimmunoprecipitation (RIA radioimmunoprecipitation). Regarding the linkage an oligopeptide antibody or another small organic molecule or inorganic with a target molecule, the term "specific bound" or "specifically binds to" or is "specific for" a particular polypeptide or epitope on a particular polypeptide target means ligature that is measurably different from a non-specific interaction. The specific binding or specific binding can be measured for example by determining the binding of a molecule compared to binding of a control molecule which is generally a molecule of similar structure that has no binding activity. For example, specific binding can be determined by competition with a control molecule that is similar to the target, for example an excess of an unlabeled target. In this case, specific binding is indicated if the binding of the tagged target to a probe is competitively inhibited by a target without excessive labeling. The term "specific binding" or "specifically binds" or "is specific for" a particular polypeptide or epitope on a particular polypeptide target, as used herein, may be exhibited for example by a molecule having a Kd for the target of at least about 1CT4 M, alternating at least about 10"5 M, alternating at least about 1CT6 M, alternating at least about 1CT7 M, alternating at least about 10"s M, alternating at least about 1CT9 M, alternating at least about 10" 10 M, alternating at least about 10"11 M, alternating at least about 10 M, O greater. In one embodiment, the term "specific binding" refers to linking wherein a molecule binds or ligates with a particular polypeptide or epitope in a particular polypeptide without binding or substantially binding to any other polypeptide or polypeptide epitope. small organic or inorganic molecule, which "inhibits the growth of tumor cells expressing UNQ733 polypeptide" or a "growth inhibitory" antibody, oligopeptide or other small organic or inorganic molecule is one that results in an inhibition of measurable cell growth. Non-Hodgkin lymphoma expressing or over expressing the UNQ733 polypeptide The UNQ733 polypeptide can be ligated to the surface of a cell or it can be in an extracellular environment. Antibodies, oligopeptides or small organic or inorganic molecules of anti-UNQ733 polypeptide preferred growth inhibitors of tumor cells expressing UNQ733 polypeptide preferably with more than about 20%, preferably from about 20% to about 50%, preferably in more than about 50% (eg, from about 50% to about 100%) compared to the appropriate control, the control typically is tumor cells not treated with the antibody , oligopeptide or other small organic or inorganic molecule that is tested. In one embodiment, the inhibition of growth can be measured at an antibody concentration of about 0.1 to 30 μg / ml or about 0.5 nM to 200 nM in cell culture, where inhibition of growth is determined 1-10 days after exposure of the tumor cells to the antibody. The antibody is inhibitory to growth in vivo if administration of the anti-UNQ733 polypeptide antibody at about 1 g / kg to about 100 mg / kg body weight results in reduction in tumor size or tumor cell proliferation within about five days to three months after the first administration of the antibody or within approximately five to 30 days. An UNQ733 antagonist that "induces apoptosis" is one that induces programmed cell death as determined by binding or binding annexin V, DNA fragmentation, cell shrinkage, reticulum dilation endoplasmic, cell fragmentation and / or formation of membrane vesicles (called apoptotic bodies). The cell is usually the one that over expresses UNQ733 polypeptide. Preferably, the cell is a tumor cell of a non-Hodgkin's lymphoma. Various methods are available to evaluate cellular events associated with apoptosis. For example, it can be measured after phosphatidyl serine (PS) placement by annexin binding; DNA fragmentation can be assessed through regular pattern formation or DNA ladder type; and chromatin / nuclear condensation together with DNA fragmentation can be evaluated by an increase in hypodiploid cells. Preferably, the UNQ733 antagonist that induces apoptosis is that which results in approximately 2 to 50 times, preferably approximately 5 to 50 times, preferably approximately 10 to 50 times, induction of annexin binding to untreated cells in an assay of annexation link. "Effector functions" of antibodies refer to those biological activities that are attributed to the Fe region (a Fe region of native sequence or Fe region variant of amino acid sequence) of an antibody, and vary with the antibody isotype.

Examples of performed functions of antibody include: Clq bond and complementary pending cytotoxicity-Fe receptor binding; Antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; down-regulation of cell surface receptors (eg B-cell receptor); and activation of B cells. "Antibody-dependent cell-mediated cytotoxicity" or "ADCC" refers to a form of cytotoxicity wherein bound secreted Ig in Fe receptors (FcRs) present in certain cytotoxic cells (eg, natural killer cells (NK = Natural Killer), neutrophils and macrophages) allow these cytotoxic effector cells to bind specifically to a target cell containing antigen and subsequently to kill the target cell with cytotoxins. The antibodies "arm" the cytotoxic cells and are absolutely required for said extermination. The primary cells to mediate ADCC, NK cells, express only Fe / RUI, while monoliths express Fc RI, Fc / RII and Fc ^ RUI. FcR expression in hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol. 9: 457-92 (1991). To estimate the ADCC activity of a molecule of interest, an in vitro ADCC assay, such as that described in U.S. Pat. numbers 5,500,362 or 5,821,337 can be made. Useful effector cells for these assays include peripheral blood mononuclear cells (PBMC = "blood mononuclear cells") and natural killer (NK) cells. Alternatively, or additionally, the ADCC activity of the molecule of interest can be estimated in vivo, for example in an animal model, such as that described in Clynes et al. (USA) 95: 652-656 (1998). "Fe receptor" or "FcR" describes a receptor that binds to the Fe region of an antibody. The FcR is a human FcR of native sequence. Still further, a preferred FcR is one that binds an IgG antibody (a gamma receptor) and includes receptors of the subclasses Fc ^ RI, Fc RII and FcyRIII, including allelic variants and alternating combined forms of these receptors. Fc ^ RII receptors include Fc ^ RIIA (an "activation receptor") and Fc / RIIB (an "inhibition receptor"), which have similar amino acid sequences that differ primarily in their cytoplasmic domains. Fc ^ RIIA activation receptor contains an activation motif based on tyrosine immunoreceptor (ITAM = immunoreceptor tyrosine-based activation motif) in its domain cytoplasmic. Fc ^ RIIB inhibition receptor contains an immunoreceptor tyrosine-based inhibition motif (ITIM = immunoreceptor tyrosine-based inhibition motif) in its cytoplasmic domain. (See review M. in Daéron, Annu, Rev. Immunol., 15: 203-234 (1997)). FcRs are reviewed in Ravetch and Kinet, Annu. Rev. Immunol. 9: 457-492 (1991); Capel et al. , Immunomethods 4: 25-34 (1994); and de Haas et al., J. Lab. Clin. Med. 126: 330-41 (1995). Other FcRs, including those identified in the future, are covered by the term "FcR" here. The term also includes the neonatal receptor, FcRn, which is responsible for the transfer of maternal IgGs to the fetus (Guyer et al., J. Immunol. 117: 587 (1976) and Kim et al., J. Immunol., 24: 249 (1994)). "Human effector cells" are leukocytes that express one or more FcRs and perform effector functions. Preferably, the cell expresses at least Fc ^ RIII and performs ADCC effector function. Example of leukocytes that mediate ADCC include peripheral blood mononuclear cells (PBMC), natural killer cells (NK), monocytes, T cytotoxic cells and neutrophils; with PBMCs and preferred NK cells. Effector cells can be isolated from a native source, for example from blood. "Complement-dependent cytotoxicity" or "CDC" refers to the lysis of a target cell in the presence of complement. Activation of the classical complement pathway is initiated by the binding of the first component of the complement system (Clq) with antibodies (of the appropriate subclass) that are linked to its connate antigen. To estimate complement activation, a CDC assay, for example as described in Gazzano-Santoro et al., J. Immunol. Methods 202: 163 (1996), can be performed. The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by an unregulated increase in the number of cells (generally referred to herein as cell growth), which may be due to an abnormal increase in proliferation. cellular, abnormal decrease in cell death, or an imbalance of the amounts of cell proliferation and cell death. Examples of cancer include but are not limited to hematopoietic cancers or blood-related cancers, such as lymphoma, leukemia, myeloma or lymphoid malignancies, but also splenic cancers and cancers of the lymph nodes. The term "non-Hodgkin's lymphoma" or "NHL," as used herein, refers to cancer of the lymphatic system other than Hodgkin's lymphoma. Hodgkin lymphomas in General findings can be distinguished from non-Hodgkin lymphomas by the presence of Reed-Sternberg cells in Hodgkin's lymphomas and the absence of cells in non-Hodgkin's lymphomas. Examples of non-Hodgkin lymphomas encompassed by the term as used herein include any that is identified as such by a person skilled in the art (eg, an oncologist or pathologist) according to classification schemes known in the art such as Revised European-American lymphoma scheme (REAL = Revised European-American Lymphoma) as described in Color Atlas of Clinical Hematology, Third Edition; A. Víctor Hoffbrand and John E. Pettit (eds.) (Harcourt Publishers Limited 2000) (see in particular Fig. 11.57, 11.58 and / or 11.59). More specific examples include but are not limited to relapse or refractory NHL, low-grade frontal line NHL, stage III / IV NHL, chemotherapy-resistant NHL, leukemia and / or precursor B lymphoblastic lymphoma, small lymphocytic lymphoma, lymphatic leukemia Chronic B cell and / or prolymphocytic leukemia and / or small lymphocytic lymphoma, prolificcytic B-cell lymphoma, immunocytoma and / or lymphoplasmacytic lymphoma, marginal zone B-cell lymphoma, splenic marginal zone lymphoma, MALT-marginal zone lymphoma extranodal, lymphoma of nodal marginal zone, hair cell leukemia, plasma cell plasmacytoma and / or myomama, low grade / low grade follicular lymphoma, follicular NHL / intermediate grade, mantle cell lymphoma, central follicle lymphoma (follicular), NHL intermediate-grade diffuse, diffuse large B-cell lymphoma, aggressive NHL (including aggressive frontal line NHL and aggressive relapse NHL), relapse NHL after or refractory to anticancer stem cell transplantation, primary mediastinal large B-cell lymphoma, lymphoma primary effusion, high-grade immunoblastic NHL, high-grade lymphoblastic NHL, high-grade small unsplit NHL, bulky disease NHL, Burkitt's lymphoma, precursor (peripheral) T-cell lymphoblastic leukemia and / or lymphoma, lymphoma and / or adult T-cell leukemia, chronic T-cell lymphocytic leukemia and / or prolymphocytic leukemia, large granular lymphocytic leukemia, fungoides mycosis and / or sín Sezary's drome, extranodal natural T-cell / killer cell lymphoma (nasal type), enteropathy-type T-cell lymphoma, hepatosplenic T cell lymphoma, panniculitis-like T cell lymphoma, skin (cutaneous) lymphomas, large cell lymphoma anaplastic, angiocentric lymphoma, intestinal T cell lymphoma, peripheral T cell lymphoma (not otherwise specified) and anigioimmunoblastic T cell lymphoma.

The terms "cell proliferative disorder" and "proliferative disorder" refer to disorders that are associated with a certain degree of abnormal cell proliferation. In one embodiment, the cell proliferative disorder is cancer. "Tumor", as used herein, refers to all growth and proliferation of neoplastic cells, either malignant or benign, and all precancerous and cancerous cells and tissues. The terms "cancer", "cancerous", "cell proliferative disorder", "proliferative disorder" and "tumor" are not mutually exclusive as referred to herein. An antibody, oligopeptide or other small organic molecule that "induces cell death" is one that causes a viable cell to become non-viable. The cell is one that expresses an UNQ733 polypeptide and is of a cell type that expresses or specifically expresses an UNQ733 polypeptide. The cell may be cancerous or normal of the particular cell type. The UNQ733 polypeptide can be a transmembrane polypeptide that is expressed on the surface of a cancer cell or can be a polypeptide that is produced and secreted by a cancer cell. The cell can be a cancer cell, for example a B cell or T cell. In vitro cell death can be determined in the absence of complement and immune effector cells to distinguish cell death induced by antibody-dependent cell-mediated cytotoxicity (ADCC). or complement-dependent cytotoxicity (CDC). In this way, the assay for cell death can be performed using thermo-inactivated serum (ie, in the absence of complement) and in the absence of immune effector cells. To determine if the antibody, oligopeptide, or other small organic molecule is capable of inducing cell death, loss of membrane integrity as assessed by the absorption of propidium iodide (PI = propidium iodide), blue triptan (see Moore et al., Cytotechnology 17: 1-11 (1995)) or 7AAD can be estimated relative to untreated cells. Preferred cell death inducing antibodies, oligopeptides or other small organic molecules are those that induce PI absorption in the PI absorption assay in BT474 cells. A "cell expressing UNQ733 polypeptide" is a cell that expresses an endogenous or transected UNQ733 polypeptide, for example in a secreted form.

Expression of UNQ733 polypeptide can be determined in a detection or prognostic assay by evaluating levels of the UNQ733 protein present on and / or on the surface of a cell, and / or secreted by the cell (for example by an immunohistochemical assay using UNQ733 polypeptide prepared against an isolated UNQ733 polypeptide that can be prepared using recombinant DNA technology from a nucleic acid encoding the UNQ733 polypeptide; FACS analysis, etc.). Alternatively or additionally, levels of nucleic acid encoding UNQ733 polypeptide or mRNA in the cell can be measured, for example by fluorescent in situ hybridization using a nucleic acid-based probe corresponding to a nucleic acid encoding the UNQ733 polypeptide or its complement; (FISH; see W098 / 45479 published October, 1998), Southern technique, Northern technique or polymerase chain reaction (PCR) technique, such as quantitative real-time PCR (RT-PCR = real time quantitative PCR) ). One can also study expression of UNQ733 polypeptide by measuring release antigen in a biological fluid such as serum, for example using antibody-based assays (see also for example the patent of the E.U.A. No. 4,933,294 issued June 12, 1990; WO91 / 05264 published April 18, 1991; U.S. Patent No. 5,401,638 issued March 28, 1995; and Sias et al., J. Immunol. Methods 132: 73-80 (1990)). In addition to the above assays, various in vivo assays are available to the practitioner with skill. For example, cells within the patient's body can be exposed to an antibody that is optionally labeled with a detectable label, e.g., a radioactive isotope, and binding the antibody to cells in the patient can be evaluated, e.g., by external scavenging by radioactivity. or when analyzing a biopsy taken from a patient previously exposed to the antibody. As used herein, the term "immunoadhesin" designates antibody-like molecules that combine the binding specificity of a heterologous protein (an "adhesin") with the effector functions of constant immunoglobulin domains.

Structurally, the immunoadhesins comprise a fusion of an amino acid sequence with desired binding specificity that is different from the recognition of antigen and binding site of an antibody (ie, it is "heterologous"), and an immunoglobulin constant domain sequence. The adhesin part of a molecule of immunoadhesin is typically a contiguous amino acid sequence comprising at least the binding site of a receptor or a ligand. The immunoglobulin constant domain sequence in the immunoadhesin can be obtained from any immunoglobulin such as the subtypes IgG-1, IgG-2, IgG-3, or IgG-4, IgA (including IgA-1 and IgA-2), IgE, IgD or Ig. The word "tag" when used herein, refers to a detectable compound or composition that is conjugated directly or indirectly to the antibody, oligopeptide or other small organic or inorganic molecule, to generate an oligopeptide antibody or other small organic or inorganic molecule "labeled" " The label may be detectable by itself (eg, radioisotope labels or fluorescent labels) or in the case of an enzymatic label, may catalyze chemical alteration of a compound or substrate composition that is detected. The term "cytotoxic agent" as used herein, refers to a substance that inhibits or prevents the function of cells and / or causes destruction of cells. The term is intended to include radioactive isotopes (eg At211, I131, I125, Y90, Re186, Re188, Sm153, Bi212, P32 and radioactive isotopes of Lu), agents chemotherapeutics, for example methotrexate, adriamycin, vinca alkaloids (vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin or other intercalating agents, enzymes and their fragments such as nucleolytic enzymes, antibiotics and toxins such as toxins of small molecule, or enzymatically active toxins of bacterial, fangal, plant or animal origin, including fragments and / or their variants, and the various anti-tumor or anti-cancer agents described below. Other cytotoxic agents are described below. A tumoricidal agent causes destruction of tumor cells. A "chemotherapeutic agent" is a chemical compound useful in the treatment of cancer. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and CYTOXAN® cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa and uredopa; ethylene imines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylolmelamine; acetogenins (especially bulatacin and bulatacinone); delta-9-tetrahydrocannabinol (dronabinol, MARINOLO); beta-lapachona; lapachol; acidic colchicines betulinic; a camptothecin (including the synthetic analog topotecan (HYCAMTIN®), CPT-11 (irinotecan, CAMPTOSAR®), acetylcamptotecin, scopolectin, and 9-aminocamptothecin); Bryostatin; Callistatin; CC-1065 (including its synthetic analogs adozelesin, carzelesin and bizelesin); podophyllotoxin; podophyllinic acid; teniposide; cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues KW-2189 and CB1-TM1); eleutherobin; pancratistatin; a sarcodictiin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, colofosfamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine hydrochloride, melphalan, novembichin, phenesterin, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine and ranimnustine; antibiotics such as enediin antibiotics (eg calicheamicin, especially gammall calicheamicin and omegall calicheamicin (see, eg, Agnew, Chem Intl. Ed. Engl., 33: 183-186 (1994)), dinemicin, including dynemycin A; esperamycin, as well as neocarzinostatin chromophore and Chromophoric Chromoprotein Enediin Antibiotics), aclacinomisins, actinomycin, anthramycin, azacerin, bleomycins, catinomycins, carabicin, carminomycin, carcinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin ADRIAMYCIN® ( including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxidoxorubicin), epirubicin, esububicin, idarubicin, marcelomycin, mitomycin such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, chelamicin, rodorubicin, streptonigrin , streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, tiamiprin, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocythabin, floxuridine; androgens such as calusterone, dromostanolone propionate, epithiostanol, mepitiostane, testolactone; anti-adrenal such as aminoglutethimide, mitotane, trilostane; such folic acid replenisher as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamin; demecolcine; diaziquone; elfornitin; Accept yourself from eliptinio; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentine; londainin; maytansinoids such as maytansin and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2 ', 2"-trichlorotriethylamine, trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine), urethane, vindesine (ELDISINE®, FILDESIN®), dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman, gacitocin; arabinoside ("Ara-C"), thiotepa, taxoids, for example, TAXOL® placitaxel (Bristol-Myers Squibb Oncology, Princeton, NJ), placitaxel formulation in engineering nanoparticles-Cremofor ABRAXANE ™ free albumin (American Pharmaceutical Partners, Schaumberg, Illinois), and doxetaxel TAXOTERE® (Rhône-Poulenc Rorer, Antony, France); chloranbucil; gemcitabine (GEMZAR®); 6-thioguanine; mercaptopurine; methotrexate; analogous platinum such as cisplatin and carboplatin; vinblastine (VELBAN®); platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine (ONCOVIN®); Oxaliplatin; leucovovina; vinorelbine (NAVELBINE®); novantrone; edatrexate; Daunomycin; aminopterin; ibandronate; Topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine (XELODA®); pharmaceutically acceptable salts, acids or derivatives of any of the foregoing; as well as combinations of two or more of the above such as CHOP, an abbreviation for a combination therapy of cyclophosphamide, doxorubicin, vincristine and prednisolone, and FOLFOX, an abbreviation for the treatment regimen with oxaliplatin (ELOXATINMR) combined 5-FU and leucovovine . Also included in this definition are ante-hormonal agents that act to regulate, reduce, block or inhibit the effects of hormones that can promote the growth of cancer, and are often in the form of systematic or whole-body treatment. They can be the hormones themselves. Examples include anti-estrogens and selective estrogen receptor modulators (SERMs = selective estrogen receptor modulators), including for example tamoxifen (including tamoxifen NOLVADEX®), raloxifen EVISTA®, droloxifen, 4-hydroxy tamoxifen, trioxifen, cheoxifen, LY117018, onapristone, and toremifen FARESTON®; anti-progesterone; descending estrogen receptor regulators (ERDs = estrogen receptor down-regulators); agents that function to suppress or interrupt or inactivate the ovaries, for example hormone agonists for release of leutinizing hormone (LHRH = leutinizing hormone-releasing hormone) such as leuprodine acétate LUPRON® and ELIGARD®, goserelin acetate, buserelin acetate and tripterelin; other anti-androgens such as flutamide, nilutamide and bicalutamide; and aromatase inhibitors that inhibit the aromatase enzyme, which regulates estrogen production in the adrenal glands, such as for example 4 (5) -imidazoles, aminoglutethimide, megestrol MEGASE® acetate, AROMASIN® exemestane, formestani, fadrozole, vorozole RIVISOR®, FEMARA® letrozole, and ARIMIDEX® anastrozole. In addition, this definition of chemotherapeutic agents includes bisphosphonates such as clodronate (for example, BONEFOS® or OSTAC®), etidronate DIDROCAL®, NE-58095, zoledronic acid / zoledronate ZOMETA®, aronate FOSAMAX®, pamidronate AREDIA®, tiludronate SKELID®, or ACTONEL® risedronate; as well as troxacitabine (a 1,3-dioxolane nucleoside analog 9 cytokine) antisense oligonucleotides, particularly those that inhibit the expression of genes in signaling pathways involved in proliferation of aberrant cells, such as for example PKC-alpha, Raf, H-Ras, and epidermal growth factor receptor (EGF-R = epidermal growth factor receptor); vaccines such as THERATOPE® vaccine and gene therapy vaccines, for example ALLOVECTIN® vaccine, LEUVECTIN® vaccine, and VAXID® vaccine; Topoisomerase I inhibitor LURTOTECAN®; ABARELIX® rmRH; lapatinib ditosylate (a dual small molecule inhibitor of tyrosine kinase ErbB-2 and EGFR also known as GW572016); and the acid salts or pharmaceutically acceptable derivatives of any of the foregoing. A "growth inhibitory agent" when used herein, refers to a compound or composition that inhibits the growth of a non-Hodgkin lymphoma cell expressing UNQ733 polypeptide, either in vitro or in vivo. In this manner, the growth inhibitory agent can be that which significantly reduces the percent of cells expressing S-phase UNQ733 polypeptide. Examples of growth inhibitory agents include agents that block cell cycle progess (at a site other than the cell cycle). S phase), such as agents which induce the Gl brake and phase M brake. Classical M phase blockers include vincas (vincristine and vinblastine), taxanes and topoisomerase II inhibitors such as doxorubicin, epirubicin, daunorubicin, etoposide and bleomycin. Those that slow Gl are also spilled in the S phase brake, for example DNA alkylation agents such as tamoxifen, prednisone, dacarbazine, mechlorethamine, cisplatin, methotrexate, 5-fluorouracil and ara-C. More information can be found in The Molecular Basis of Cancer, Mendelsohn and Israel, eds. , Chapter 1, with the title "Cell cycle regulation, oncogenes, and antineoplastic drugs" by Murakami et al. (WB Saunders: Philadelphia, 1995), especially p. 13. The taxanes (paclitaxel and docetaxel) are anti-cancer drugs both derived from the yew tree. Docetaxel (TAXOTERE®, Rhone-Poulenc Rorer), derived from the European yew, is a semi-synthetic analog of paclitaxel (TAXOL®, Bristol-Myers Squibb). Paclitaxel and docetaxel promote the assembly of tubulin dimer microtubules and stabilize microtubules by avoiding depolymerization, which results in the inhibition of mitosis in cells. "Doxorubicin" is an anthracycline antibiotic. The complete chemical name of doxorubicin is (8S-cis) -10- [(3-amino-2,3,6-trideoxy-a-L-lixo- hexapyranosyl) oxy] -7,8,9, 10-tetrahydro-6,8,11-trihydroxy-8- (hydroxyacetyl) -l-methoxy-5,12-naphthacenylene. The term "cytokine" is a generic term for proteins released or released from a cell population that act in another cell as intercellular mediators. Examples of these cytokines are lymphokines, monokines and traditional polypeptide hormones. Among the cytokines include growth hormone such as human growth hormone, human growth hormone N-methionyl and bovine growth hormone; parathyroid hormone; thyroxine; insulin; proinsulin; relaxin; prorelaxin; glycoprotein hormones such as follicle stimulating hormone (FSH = follicle stimulating hormone), hormone to stimulate the thyroid (TSH = thyroid stimulating hormone) and luteinizing hormone (LH = luteinizing hormone); liver growth factor; fibroblast growth factor; prolactin; placental lactogen; tumor necrosis factor- a and - ß muleriana inhibitory substance; peptide associated with mouse gonadotropin; inhibin; activin; vascular endothelial growth factor (VEGF = vascular endothelial growth factor); integrin; thrombopoietin (TPO = thrombopoietin); growth factors of nerves such as NGF- / ?; platelet growth factor; transformation growth factors (TGFs = transforming growth factors) such as TGF- "and TGF- /?; insulin-like growth factor -I and -II; erythropoietin (EPO); osteoinductive factors; interferons such as interferon -c, -β and -?; colony stimulating factors (CSFs = colony stimulating factors) such as macrophage-CSF (M-CSF); granulocyte-macrophage-CSF (G -CSF); and granulocyte-CSF (G-CSF); interleukins (ILs) such as IL-1, IL-la, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-11, IL-12; a tumor necrosis factor such as TNF-α or TNF- / α; and other polypeptide factors including LIF and ligand equipment (KL). As used herein, the term "cytokine" includes proteins from natural sources or from recombinant cell culture and biologically active equivalents of the native sequence cytokines. The term "package insert" is used to refer to instructions usually included in commercial packages of therapeutic products, which contain information regarding the indications, use, dosage, administration, contraindications and / or warnings regarding the use of these therapeutic products.

Table 1 /* * * C-C increased from 12 to 15 * Z is average of EQ * B is average of ND * match with stop is _M; stop-stop = 0; J (joker) match = 0 * / #define _ -8 / * valué of a match with a stop * / int _day [26] [26] =. { / * A B C D E F G H I J K L M N O P Q R S T U V W X Y Z * / / * A * /. { 2, 0, -2, 0, 0, -4, 1, -1, -1, 0, -1, -2, -1, 0, _M, 1, 0, -2, 1, 1, 0, 0, -6, 0, -3, 0.}. , / * B * /. { 0, 3, -4, 3, 2, -5, 0, 1, -2, 0, 0, -3, -2, 2, _M, -1, 1, 0, 0, 0, 0, -2, -5, 0, -3, 1.}. , / * C * /. { -2, -4.15, -5, -5, -4, -3, -3, -2, 0, -5, -6, -5, -4, _M, -3, -5, -4 0, -2, 0, -2, -8, 0, 0, -5} , / * D * /. { 0, 3, -5, 4, 3, -6, 1, 1, -2, 0, 0, -4, -3, 2, _, -1, 2, -1, 0, 0, 0, -2, -7, 0, -4, 2.}. , / * E * /. { 0, 2, -5, 3, 4, -5, 0, 1, -2, 0, 0, -3, -2, 1, M, -l, 2, -1, 0, 0, 0, -2, -7, 0, -4, 3.}. , / * F V. { -4, - 5, -4, -6, -5, 9, -5, -2, 1, 0, -5, 2, or, - 4, _M, -5, -5, -4, -3 , - 3, 0, -1, 0, 0, 7, -5} , / * G * / Í 1, 0, -3, 1, 0, -5, 5, -2, -3, 0, -2, -4, -3, 0, _M, -1, -1, -3, 1, 0, 0, -1, -7, 0, -5, 0.}. , / * H * /. { -1, 1, -3, 1, 1, -2, -2, 6, -2, 0, 0, -2, -2, 2, _M, or, 3, 2, -i, -1, 0, -2, -3, 0, 0, 2.}. , / * I * / Í -1, -2, -2, -2, -2, 1, -3, -2, 5, 0, -2, 2, 2, - 2, _M, -2, - 2, -2, -1, 0, 0, 4, -5, 0, -1, -2} , / * J * /. { 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, or, _M, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0.}. , / * K V Í -1, 0, -5, 0, 0, -5, -2, 0, -2, 0, 5, -3, 0, 1, _M, -1, 1, 3, 0, 0, -2, -3, 0, -4, 0.}. , / * L * / Í -2, - 3, -6, -4, -3, 2, -4, -2, 2, 0, -3, 6, 4, - 3, _M, -3, - 2, -3, -3, -1, 0, 2, -2, 0, -1, -2} , / * M V. { -l, - 2, -5, -3, -2, 0, -3, -2, 2, 0, 0, 4, 6, - 2, _M, -2, -i, 0, -2, - 1, 0, 2, -4, 0, -2, -1} , / * N * /. { 0, 2, -4, 2, 1, -4, 0, 2, -2, 0, 1, -3, -2, 2, _M, -i, 1, o, 1, 0, 0, -2, -4, 0, -2, 1.}. , / * 0 * /. { M, M, M, M, M, M, M, M, M, M,, M, M, I or, M, M, M, M, M, M, M, M, M, M, M) , / * P * /. { 1, -1, -3, -1, -1, -5, -1, 0, -2, 0, -1, -3, -2, - 1, _M, 6, 0, 0, 1, 0 , 0, -1, -6, 0, -5, 0.}. , / * Q V. { o, 1, -5, 2, 2, -5, -1, 3, -2, 0, 1, -2, -1, 1, M, 0, 4, 1, -i, - 1, 0, -2, -5, 0, -4, 3.}. , / * R * /. { -2, 0, -4, -1, -1, -4, -3, 2, -2, 0, 3, -3, 0 0, _M, 0, 1, 6, 0, -1, 0, -2, 2, 0, -4, 0.}. , / * S * /. { 1, 0, 0, 0, 0, -3, 1, -1, -1, 0, 0, -3, -2 1, _M, 1, -1, 0, 2, 1, 0, -1, -2, 0, -3, 0.}. , / * T * /. { 1, 0, -2, 0, 0, -3, 0, -1, 0, 0, 0, -1, -1 0, _M, 0, -1, -1, 1, 3, 0, 0, -5, 0, -3, 0.}. , /* OR */ . { 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 0, _M, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0.}. , / * V * /. { 0, -2, -2, -2, -2, -1, -1, -2, 4, 0, -2, 2, 2, 2, _M, -1, -2, -2, -1, 0, 0, 4, -6, 0, -2, -2} , / * W * /. { -6, -5, -8, -7, -7, 0, -7, -3, -5, 0, -3, -2, -4, 4, _M, -6, -5, 2, -2, -5, 0, -6.17, 0, 0, -6} , / * X * /. { 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 0, _M, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0.}. , /* Y */ . { -3, -3, 0, -4, -4, 7, -5, 0, -1, 0, -4, -1, -2, 2, _M, -5, -4, -4, -3, -3, 0, -2, 0, 0.10, -4} , / * Z * /. { 0, 1, -5, 2, 3, -5, 0, 2, -2, 0, 0, -2, -1 1, _M, 0, 3, 0, 0, 0, 0, -2, -6, 0, -4, 4.}. }; / * * / #incl de < stdio.h > #include < ctype.h > #define MAXJMP 16 / * max jumps in to diag * / #define MAXGAP 24 / * do not continue to penalize gaps larger than this * / ttdefine JMPS 1024 / * max jmps in an path * / #define MX 4 / * save if there 's at least MX-1 bases since last jmp * / ttdefine DMAT 3 / * valué of matching bases * / ttdefine DMIS 0 / * penalty for mismatched bases * / ttdefine DINSO 8 / * penalty for a gap * / ttdefine DINS1 1 / * penalty for base * / ttdefine PINSO 8 / * penalty for a gap * / ttdefine PINS1 4 / * penalty for residue * / struct jmp. { short n [MAXJMP]; / * size of jmp (neg for dely) * / unsigned short x [MAXJMP]; / * base no. of jmp in seq x * /}; / * limits seq to 2? 16 -1 * / struct diag. { int score; / * score at last jmp * / long offset; / * offset of prev block * / short ijmp; / * current jmp index V struct jmp jp; / * list of jmps * /} struct path { int spc; / * number of leading spaces * / short n [JMPS]; / * size of jmp (gap) * / int x [JMPS]; / * loe of jmp (last elem before gap) V char * ofile; / * output file name * / char * namex [2]; / * seq names: getseqs () * / char * prog; / * prog name for err msgs * / char * seqx [2]; / * seqs: getseqsO * / int dmax; / * best diag: n () * / int dmaxO; / * final diag * / int dna; / * set if dna: main () * / int endgaps; / * set if criminalizing end gaps int gapx, gapy; / * total gaps in seqs * / int lenO, lenl; / * seq lens * / int ngapx, ngapy; / * total size of gaps * / int smax; / * max score: nw () * / int * xbm; / * bitmap for matching * / long offset; / * current offset in jrap file * / struct diag * dx; / * holds diagonals * / struct path pp [2]; / * holds path for seqs * / char * calloc (), * malloc (), * index (), * strcpy (); char * getseq (), * g_calloc (); Table 1 (conf) / * Needleman-Wunsch alignment program * * usage: progs filel file2 * where filel and file2 are two dna or two protein sequences. * The sequences can be in upper- or lower-case an may contain ambiguity * Any lines beginning with ';', '> 'or' < 'are ignored * Max file length is 65535 (limited by unsigned short x in the jmp struct) * A sequence with 1/3 or more of its elements ACGTU is assumed to be DNA * Output is in the file "align.out" * The program may create tmp file in / tmp to hold info approximately traceback. * Original version developed under BSD 4.3 on a vax 8650 * / #include "nw.h" #include "day.h" static _dbval [26] =. { 1,14,2,13,0,0,4,11,0,0,12,0,3,15,0,0,0,5,6,8,8,7,9,0 , io, o}; static _pbval [26] =. { 1, 2 | (1 «('D' - 'A')) I (1« ('?' -? ')), 4, 8, 16, 32, 64, 128, 256, OxFFFFFFF, 1 «10, 1 < < 11, 1 «12, 1« 13, 1 «14, 1« 15, 1 «16, 1« 17, 1 «18, 1« 19, 1 «20, 1« 21, 1 «22, 1« 23, 1 «24, 1« 25 | (1 «('?' - '?')) I (1« ('Q' - 'A')) }; main (ac, av) int aechar * av []; . { prog = av [0]; if (ac! = 3). { fprintf (stderr, "usage:% s filel file2 \ n", prog); fprintf (stderr, "where filel and file2 are two dna or two protein sequences. \ n"); fprintf (stderr, "The sequences can be in upper-or lower-case \ n"); fprintf (stderr, "Any lines beginning with ';' '< 'are ignored \ n "); fprintf (stderr," Output is in the file \ "align.out \" \ n "); exit (1);.}. namex [0] = av [1]; namex [ 1] = a [2]; seqx [0] = getseq (namex [0], & len0); seqxfl] = getseq (namex [1], & lenl); xbm = (dna)? _dbval: pbval; endgaps = 0; / * 1 to penalize endgaps * / ofile = "align. Out"; / * output file * / nw (); / * fill in the matrix, get the possible jmps * / readjmps (); / * get the current jmps * / print (); / * print stats, alignment * / cleanup (0); / * unlink any tmp files * /} / * do the alignment, return best score: main () * dna: valúes in Fitch and Smith, PNAS, 80, 1382-1386, 1983 * pro: PAM 250 valúes * When scores are equal, we prefer mismatches to any gap, prefer * to new gap to extending an ongoing gap, and prefer to gap in seqx * to a gap in seq y. * / nw (). { char * px, * py; / * seqs and ptrs * / int * ndely, * dely; / * keep track of dely * / int ndelx, delx; / * keep track of delx * / int * tmp; / * for swapping rowO, rowl / int mis; / * score for each type * / int insO, insl; / * insertion penalties * / register id; / * diagonal index * / register ij; / * jmp index * / register * col0, * coll; / * score for curr, last row * / register xx, yy; / * index into seqs * / dx = (struct diag *) g_calloc ("to get diags", lenO + lenl + 1, sizeof (struct diag)); ndely = (int *) g_calloc ("to get ndely", lenl + 1, sizeof (int)); dely = (int *) g_calloc ("to get dely", lenl + 1, sizeof (int)); colO = (int *) g_calloc ("to get colO", lenl + 1, sizeof (int)); coll = (int *) g_calloc ("to get coll", lenl + 1, sizeof (int)); insO = (dna)? DINSO: PINSO; insl = (dna)? DINS1: PINS1; smax = -10000; if (endgaps). { for (col0 [0] = dely [0] = -insO, yy = 1; yy < = lenl; yy ++). { col0 [yy] = dely [yy] = col0 [yy-l] - insl; ndely [yy] = yy; } colO [0] = 0; / * Waterman Bull Math Biol 84 * / } else for (yy = 1; yy < = lenl; yy ++) dely [yy] = -insO; / * fill in match matrix * / for (px = seqx [0], xx = 1; xx < = lenO; px ++, xx ++). { / * initialize first entry in col * / if (endgaps). { if (xx == 1) coll [0] = delx = - (insO + insl); else coll [0] = delx = col0 [0] - insl; ndelx = xx; } else { coll [0] = 0; delx = -insO; ndelx = 0; . nw (py = seqxfl], yy = 1; yy < = lenl; py ++ yy ++). { mis = colO [yy-1]; if (dna) mis + = (xbm [* px- 'A'] & xbm [* py- 1 A ']) DMAT: DMIS; else mis + = _day [* px- '?' ] [* py- 'A']; / * update penalty for the in x seq; * please new of the ongong of the ignore MAXGAP if weighting endgaps * / if (endgaps | | ndely [yy] <MAXGAP). { if (col0 [yy] - insO > = dely [yy]). { dely [yy] = col0 [yy] ; insO + insl); ndely [yy] = 1; } else { dely [yy] - = insl; ndely [yy] ++; } } else { if (col0 [yy] - (insO + insl) > = delytyy]). { dely [yy] colO [yy] (insO + insl); ndely [yy] = 1; } else ndely [yy] ++; / * update penalty for in and seq; * favor new overgong of the * / if (endgaps | | ndelx <MAXGAP). { if (coll [yy-l] - insO > = delx). { delx = coll [yy-l] - (insO + insl); ndelx = 1; } else { delx - = insl; ndelx ++; } } else { if (coll [yy-l] - (insO + insl) > = delx) delx = coll [yy-l] - (insO + insl); ndelx = 1; } else ndelx ++; / * pick the maximum score; we 're favoring * my over any of the and delx over dely * / ... nw id = xx - yy + lenl - 1; if (mis > = delx & mis > = delyfyy]) coll [yy] = mis; else if (delx > = delyfyy]). { coll [yy] = delx; ij = dx [id]. ijmp; if (dx [id]. jp.n [0] & (! dna | (ndelx > = MAXJMP &&xx> dxfid]. jp.x [ij] + MX) || my > dx [id]. score + DINSO)). { dx [id]. ijmp ++; if (++ ij> = MAXJMP). { write mps (id); ij = dx [id] .ijmp = 0; d [id]. offset = offset; offset + = sizeof (struct jmp) + sizeof (offset); } dx [id]. jp. n [ij] = ndelx; dx [id]. jp. x [i] = xx; dx [id] .score = delx; } else { coll [yy] = dely [yy]; ij = dx [id]. ijmp; if (dx [id]. jp.n [0] & (! dna | | (ndely [yy] > = MAXJMP & xx &dt; dx [id]. jp. x [ij] + MX) M mis > dx [id]. Score + DINSO)). { dx [id]. ijmp ++; if (++ ij> = MAXJMP). { writejmps (id); ij = dx [id] .ijmp = 0; dx [id]. offset = offset; offset + = sizeof (struct jmp) + sizeof (offset); dx [id]. jp. n [ij] = -ndely [yy]; dx [id]. jp. x [ij] = xx; dx [id] .score = dely [yy]; } if (xx == lenO & &y < lenl). { / * last col * / if (endgaps) coll [yy] - = insO + insl * (lenl-yy) if (colltyy] > smax). { smax = coll [yy]; dmax = id; } } } if (endgaps &&xx < lenO) coll [yy-l] - = insO + insl * (lenO-xx); if (coll [yy-l] > smax). { smax = coll [yy-l]; dmax = id; } tmp = colO; colO = coll; coll = tmp; } (void) free ((char *) ndely); (void) free ((char *) dely); (void) free ((char *) colO); (void) free ((char *) coll); } / * * * print () - only routine visible outside this module * * static: * getmat () - trace back best path, count matches: print () * pr_align () - print alignment of described in array p []: print () * dumpblock () - dump a block of lines with numbers, stars: pr_align () * nums () - put out a number line: dumpblock () * putlineO - put out a line (yam, [num], seq, [num]): dumpblock () * stars () - -put to line of stars: dumpblock () * stripname () - strip any path and prefix from a seqname * / #include "nw.h" #define SPC 3 #define P_LINE 256 / * maximum output line * / ftdefine P_SPC 3 / * space bet een ñame or num and seq * / extern _day [26] [26]; int olen; / * set output line length * / FILE * fx; / * output file * / print () print. { int lx, ly, firstgap, lastgap; / * overlap * / if ((fx = fopen (ofile, "w")) == 0). { fprintf (stderr, "% s: can not write% s \ n", prog, ofile); cleanup (1); } fprintf (fx, "< first sequence:% s (length =% d) \ n", namex [0], lenO); fprintf (fx, "< second sequence:% s (length =% d) \ n", namex [1], lenl); olen = 60; Ix = lenO; ly = lenl; firstgap = lastgap = 0; if (dmax < lenl - 1). { / * leading gap in x * / pp [0]. spc = firstgap = lenl - dmax - 1; ly - = ?? [0] spc; } else if (dmax > lenl - 1). { / * leading gap in and * / pp [l] .spc = firstgap = dmax - (lenl - 1); lx - = pp [l]. spc; } if (dmaxO < lenO - 1). { / * trailing gap in x * / lastgap = lenO - dmaxO -1; lx - = lastgap; } else if (dmaxO> lenO - 1). { / * trailing gap in and * / lastgap = dmaxO - (lenO - 1); ly - lastgap; } getmat (lx, ly, firstgap, lastgap); pr_align (); } / * * trace back the best path, count matches * / static getmat (lx, ly, firstgap, lastgap) getmat int lx, ly; / * "core" (minus endgaps) * / int firstgap, lastgap; / * leading trailing overlap * /? int nm, iO, il, sizO, sizl; char outx [32]; double pct; register nO, nl; register char * p0, * pl; / * get total matches, score * / iO = il = sizO = sizl = 0; pO = seqx [0] + pp [l] .spc; pl = seqx [l] + pp [0] .spc; nO = pp [l]. spc + 1; nl = pp [0]. spc + 1; nm = 0; while (* p0 & * pl). { if (sizO). { pl ++; nl ++; siz0--; } else if (sizl). { p0 ++; n0 ++; sizl--; } else { if (xbm [* p0- 'A'] & xbm [* pl- 'A']) nm ++; if (n0 ++ == pp [0] .x [iO]) sizO = pp [0] .n [iO ++]; if (nl ++ == pp [l] .x [il]) sizl = pp [1] .n [il ++]; pO ++; pl ++; } } / * pct homology: * if criminalizing endgaps, base is the shorter seq * else, knock off overhangs and take shorter core * / if (endgaps) lx = (lenO < lenl)? lenO: lenl; else lx = (lx < ly)? lx: ly; pct = 100. * (double) nm / (double) lx; fprintf (fx, "\ n"); fprintf (fx, "&d;% d match% s in an overlap of% d:% .2f percent similarity \ n", nm, (nm == 1)? "": "is", lx, pct); fprintf (fx, "<gaps in first sequence:% d", gapx); ... getmat if (gapx). { (void) sprintf (outx, "(% d% s% s)", ngapx, (dna)? "base": "residue", (ngapx == 1)? "": "s"); fprintf (fx, "% s", outx); fprintf (fx, ", gaps in second sequence:% d", gapy); if (gapy). { (void) sprintf (outx, "(% d% s% s)", ngapy, (dna)? "base": "residue", (ngapy == 1)? "": "s"); fprintf (fx, "% s", outx); } if (dna) fprintf (fx, "\ n < score:% d (match =% d, mismatch =% d, gap penalty =% d +% d per base) \ n", smax, DMAT, DMIS, DINSO , DINS1); else fprintf (f, "\ n < score:% d (Dayhoff ??? 250 matrix, gap penalty =% d +% d per residue) \ n", smax, PINSO, PINS1); if (endgaps) fprintf (fx, "<endgaps penalized.) left endgap:% d% s% s, right endgap:% d% s% s \ n", firstgap, (dna)? "base": "residue" , (firstgap == 1)? "": "s", lastgap, (dna)? "base": "residue", (lastgap == 1)? "": "s"); else fprintf (fx, "<endgaps not penalized \ n"); } static nm; / * matches in core - for checking * / static lmax; / * lengths of stripped file yams * / static ij [2]; / * jmp index for a path * / static nc [2]; / * number at start of current line * / static ni [2]; / * current elem number --for gapping * / sta ic siz [2]; static char * ps [2] / / * ptr to current element * / static char * po [2]; / * ptr to next output char slot * / static char out [2] [P_LINE]; / * output line * / static char star [P_LINE]; / * set by stars () * / / * * print alignment of described in struct path pp [] * / static pr_align () pr_align í int nn; / * char count * / int more; register i; for (i = 0, lmax = 0; i <2; i ++). { nn = stripname (namex [i]); if (nn> lmax) lmax = nn; nc [i] = 1; ni [i] = 1; if z [i] = ij [i] = 0; ps [i] = seqx [i]; po [i] = out [i]; } for (nn = nm = 0, more = 1; more;). { for (i = more = 0; i <2; i ++). { / * * do we have more of this sequence? * / if (! * ps [i]) continue; more ++; if (pp [i] .spc). { / * leading space * po [i] ++ = ''; pp [i]. spc-; } else if (siz [i]). { / * in a gap * / * po [i] ++ - siz [i] -; } else { / * we 're putting element * / * po [i] = * ps [i]; if (islower (* ps [i])) * ps [i] = toupper (* ps [i]); po [i] ++; ps [i] ++; / * * are we at next gap for this seq? * / if (ni [i] == pp [i] .x [ij [i]]). { / * * we need to merge all gaps * at this location * / siz [i] = pp [i]. n [ij [i] ++]; hile (ni [i] == pp [i]. x [ij [i]]) siz [i] + = pp [i] .n [ij [i] ++] } ni [i] ++; (++ nn == olen | |! more & & dumpblock (); for (i = 0; i < 2; i ++) po [i] = out [i]; nn = 0; } } } / * * dump to block of lines, including numbers, stars: pr_align () * / sta ic dumpblock () dumpblock. { register i; for (i = 0; i <2; i ++) * po [i] - = '\ 0'; ... dumpblock (void) putc ('\ n', fx); for (i = 0; i <2; i ++). { if (* out [i] & (* out [i]! = '* I I * (po [i])! =' ')). { if (i == 0) nums (i); if (i == 0 & & * out [1]) stars (); putline (i); if (i == 0 & & * out [1]) fprintf (fx, star); if (i == 1) nums (i); } } } / * * put out a number line: dumpblock () * / static nums (ix) nums int ix; / * index in out [] holding seq line * /. { char nline [P_LINE]; register i, j; register char * pn, * px * py; for (pn = nline, i = 0, i < lmax + P_SPC; i ++, pn ++) * pn = '1; for (i = nc [ix], py = out [ix]; * py; py ++, pn ++). { , if (* py == '' I I * py == '-') * pn = '|; else { if (i% 10 == 0 M (i == 1 & nc [ix]! = 1)) j = (i <0)? -i: i; for (px = pn;; j / = 10, px--) * px = j% 10 + '01; if (i <0) * px} else * pn = i ++; } } * pn = '\ 0'; nc [ix] = i; for (pn = nline; * pn; pn ++) (void) putc (* pn, fx); (void) putc ('\ n', fx); } / * * put out to line (yam, [num], seq, [num]): dumpblock () * / static putline (ix) putline int ix; . { .putline int i; register char * px; for (px = namex [ix], i = 0; * px & * px! = ':'; px ++, i ++) (void) putc (* px, fx); for (; i < lmax + P_SPC; i ++) (void) putcC ', fx); / * these count from 1: * ni [] is current element (from 1) * nc [] is number at start of current line * / for (px = out [ix]; * px; px ++) (void) putc ( * px &0x7F, fx); (void) putc ('\ n', fx); / * * put a line of stars (seqs always in out [0], out [l]) dumpblock () * / static stars () stars Í int i; register char * p0, * pl, cx, * px; if (! * out [0] I I (* out [0] == '' & * (by [0]) I I ! * out [l] II (* out [l] == '' & * (po [l]) == '')) return; px = star; for (i = lmax + P_SPC; i; i-) * px ++ = ''; for (pO = out [0], pl = out [l]; * p0 & * pl; p0 ++, pl ++). { if (isalpha (* p0) & isalpha (* pl)). { if (xbm [* pO-'A '] & xbm [* pl-'A']). { cx = '*'; nm ++; } else if (! dna & day [* pO-'A '] [* pl-'A'] > 0) else } else * px ++ } * px ++ = 1 \ n * px = '\ 0'; / * * strip path or prefix from pn, return len: pr_align () * / sta ic stripname (pn) stripname char * pn; / * file yña (may be path) * /. { register char * px, * py; py = 0; for (px = pn; * px; px ++) if (* px == '/') py = px + 1; if (py) (void) strcpy (pn, py); return (strlen (pn)); } / * * cleanupO - cleanup any tmp file * getseq () - read in seq, set dna, len, maxlen * g_calloc () - calloc () with error checkin * readjmps () - get the good jmps, from tmp file if necessary * writejmps () - write to filled array of jmps to a tmp file: nw () * / #include "nw.h" #include < sys / file.h > char * jname = "/ tmp / homgXXXXXX"; / * tmp file for jmps * / FILE * fj; int cleanup (); / * cleanup tmp file * / long lseek (); / * * remove any tmp file if we block * / cleanup (i) cleanup int i; í if (fj) (void) unlink (jname); exit (i); } / * * read, return ptr to seq, set dna, len, maxlen * skip lines starting with '< ', or' > '* seq in upper or lower case * / char * getseq (file, len) getseq char * file; / * file yam * / int * len / * seq len * /. { char line [1024], * pseq; register char * px, * py; int natgc, tlen; FILE * fp; if ((fp = fopen (file, "r")) == 0). { fprintf (stderr, "% s: can 't read% s \ n", prog, file); exit (1); } tlen = natgc = 0; while (fgetsdine, 1024, fp)). { if (* line == ';' | I * line == '< · | | * line == · >') continue; for (px = line; * px! = '\?'; px ++) if (isupper (* px) | | islower (* px)) tlen ++; } if ((pseq = malloc ((unsigned) (tlen + 6))) == 0). { fprintf (stderr, "% s: mallocO failed to get% d bytes for% s \ n", prog, tlen + 6, file); exit (1); } pseq [0] = pseqtl] = pseq [2] = pseq [3] = '\ 0'; ... getseq py = pseq + 4; * len = tlen; rewind (fp); while (fgets (line, 1024, fp)). { if (* line == ';' | | * line == '<' || * line == '>') continue; for (px = line; * px! = px ++). { if (isupper (* px)) * py ++ = * px; else if (islower (* px)) * py ++ = toupper (* px); if (index ("ATGCU", * (py-1))) natgc ++; } } * py ++ = '\ 01; * py = 1 \ 0 '; (void) fclose (fp); dna = natgc > (tlen / 3); return (pseq +); } char * g_calloc (msg, nx, sz) g_calloc char * msg; / * program, calling routine * / int nx, sz; / * number and size of elements * /. { char * px, * calloc (); if ((px = calloc ((unsigned) nx, (unsigned) sz)) == 0). { if (* msg) { fprintf (stderr, "% s: g_calloc () failed% s (n =% d, sz =% d) \ n", prog, msg, nx, sz); exit (1); } } return (px)} / * * get final jmps from dx [] or tmp file, set pp [], reset dmax: main () * / readjmps () readjmps. { int fd = -1; int siz, iO, il; register i, j, xx; if (fj) { (void) fclose (fj); if ((fd = open (jname, OR RDONLY, 0)) < 0). { fprintf (stderr, "% s: can not open ()% s \ n", prog, jname); cleanup (1); } } for (i = iO = il = 0, dmaxO = dmax, xx = lenO;; i ++) í while (1). { for (j = dx [dmax]. ijmp; j > = 0 & dx [dmax]. jp. x [j] > = xx; j--) ... readjmps if (j <0 & amp; dx [dmax]. offset && amp) fj). { (void) lseek (fd, dx [dmax]. offset, 0); (void) read (fd, (char *) & dx [dmax]. jp, sizeof (struct jmp)); (void) read (fd, (char *) & dx [dmax]. offset, sizeof (dx [dmax]. offset)); dx [dmax]. ijmp = MAXJMP- 1; } else break; } if (i> = JMPS) { fprintf (stderr, "% s: too many gaps in alignment \ n ", prog); cleanup (1);.}. if (j > = 0) { siz = dx [dmax]. p. n [j]; xx = dx [dmax]. jp. x [j]; dmax + = siz; if (siz < 0) { / gap in second seq * / pp [l] .n [il] = -siz; xx + = siz; / * id = xx - yy + lenl - 1 * / pp [l] .x [il] = xx - dmax + lenl - 1; gapy ++; ngapy - = siz; / * ignore MAXGAP when doing endgaps * / siz = (-siz <MAXGAP | | endgaps)? -siz: MAXGAP; il ++; } else if (siz > 0). { / * gap in first seq * / pp [0]. n [i0] = siz; pp [0]. x [iO] = xx; gapx ++; ngapx + = siz; / * ignore MAXGAP when doing endgaps * / siz = (siz <MAXGAP | | endgaps)? siz: MAXGAP; Í0 ++; } } else break; } / * reverse the order of jmps * / for (j = 0, i0 ~; j < iO; i0 ~). { i = pp [0] .n [j]; pp [0] .n [j] = pp [0]. n [iO]; pp [0] .n [i0] = i; i = pp [0] .x [j]; pp [0] .x [j] = pp [0] .x [i0]; pp [0] .x [i0] = i; } for (j = 0, il-; j < il; il-). { i = pp [l] .n [j]; pp [l] .n [j] = pp [1]. n [il]; pp [1]. n [i 1] = i; i = pp [l] .x [j]; pp [l] .x [j] = pp [l] .x [il]; pp [1]. x [i 1] = i; } (fd > = 0) (void) close (fd); (fj) { (void) unlink (jname) fj = 0; offset = 0; } / * * write a filled jmp struct offset of the prev one (if any): nw () * / ritejmps (ix) writejmps int ix; . { char * mktemp (); if (! fj) { if (mktemp (jname) < 0). { fprintf (stderr, "% s: can 't mktemp ()% s \ n", prog, jname); cleanup (1); } if ((fj = fopen (jname, "w")) == 0). { fprintf (stderr, "% s: can 't write% s \ n", prog, jname); exit (1); } (oid) fwrite ((char *) & dx [ix]. jp, sizeof (struct jmp), 1, fj (void) fwrite ((char *) & dx [ix] .offset, sizeof (dx [ix ] .offset), 1, fj.} Table 2 Polypeptide UNQ733 xxxxxxxxxxxxxxx (Length = 15 amino acids) Comparison protein XXXXXYYYYYYY (Length = 12 amino acids)% amino acid sequence identity = (the number of amino acid residues of identical correspondence between the two polypeptide sequences as determined by ALIGN-2) divided by (the total number of amino acid residues of the UNQ733 polypeptide) = 5 divided by 15 = 33.3% Table 3 UNQ733 polypeptide XXXXXXXXXX (Length = 10 amino acids) Comparison protein XXXXXYYYYYYZZYZ (Length = 15 amino acids)% amino acid sequence identity = (the number of amino acid residues of identical correspondence between the two polypeptide sequences as determined by ALIGN-2) divided by (the total number of amino acid residues of the UNQ733 polypeptide) = 5 divided by 10 = 50% Table 4 UNQ733 DNA (Length = 14 nucleotides) Comparison DNA (Length = 16 nucleotides)% amino acid sequence identity = (the number of amino acid residues of identical correspondence between the two polypeptide sequences as determined by ALIGN-2) divided by (the total number of amino acid residues of the UNQ733 polypeptide) = 6 divided by 14 = 42.9% Table 5 UNQ733 DNA (Length = 12 nucleotides) Comparison (Length = 9 nucleotides) % amino acid sequence identity = • (the number of amino acid residues of identical correspondence between the two polypeptide sequences as determined by ALIGN-2) divided by (the total number of amino acid residues of the UNQ733 polypeptide) = 4 divided by 12 = 33.3% II. Compositions and Methods of the Invention A. Anti-UNQ733 Antibodies In one embodiment, the present invention provides anti-UNQ733 polypeptide antibodies which may find use herein as therapeutic and / or diagnostic agents. Exemplary antibodies include polyclonal, monoclonal, humanized, bispecific and heteroconjugated antibodies. 1. Polyclonal Antibodies Polyclonal antibodies are preferably developed in animals by multiple subcutaneous (se) or intraperitoneal (ip) injections of the relevant antigen and an adjuvant. It may be useful to conjugate the relevant antigen (especially when using synthetic peptides) to a protein that is immunogenic in the species to be immunized. For example, the antigen can be conjugated in sea urchin hemocyanin (KLH = keyhole limpet hemocyanin), serum albumin, bovine thyroglobulin, or soybean trypsin inhibitor, using a bifunctional or derivatized agent, for example maleimidobenzoyl sulfosuccinamide ester (conjugated through cysteine residues), N-hydroxysuccinamide (via lysine residues), glutaraldehyde, succinic anhydride, S0C12, or R1N = C = NR, wherein R and R1 are different alkyl groups. Animals are immunized against the antigen, immunogenic conjugates, or derivatives to the combiner for example, 100 μ? g or 5 μg of the protein or conjugate (for rabbits or mice, respectively) with 3 volumes of Freund's complete adjuvant, and inject the solution intradermally at multiple sites. One month later, the animals are reinforced with 1/5 to 1/10 the original amount of peptide or conjugate in complete Freund's adjuvant, by subcutaneous injection in multiple sites. Seven to 14 days later, the animals are bled, and the serum is assayed for the antibody titer. The animals are reinforced until the title reaches a plateau. Conjugates can also be made in recombinant cell culture as protein fusions. Also, aggregation agents such as alum, are conveniently employed to ive the immune response. 2. Monoclonal antibodies Monoclonal antibodies can be made using the hybridoma method first described by Kohler et al., Nature, 256: 495 (1975), or they can be made by recombinant DNA methods (U.S. Patent No. 4,816,567). In the hybridoma method, a mouse or other appropriate host animal, such as a hamster, is immunized as described above to produce lymphocytes that produce or are capable of producing antibodies that will bind specifically to the protein used for immunization. Alternatively, lymphocytes can be immunized in vitro. After immunization, the lymphocytes are isolated and then fused with a myeloma cell line using a convenient fusion agent, such as polyethylene glycol, to form a hybridoma cell (Goding, Monoclonal Antibodies: Principles and Practice, pp.59-103 (Academic Press, 1986)). The hybridoma cells thus prepared are seeded and grown in a convenient culture medium, this medium preferably contains one or more substances that inhibit the growth or survival of parental myeloma cells without fusion (also referred to as fusion partners). For example, if Myeloma father cells lack hypoxanthine guanine phosphoribosyl transferase enzyme (HGPRT or HPRT), the selective culture medium for hybridomas will typically include hypoxanthine, aminopterin and thymidine (HAT medium), these substances prevent the growth of HGPRT deficient cells. Preferred fusion partner myeloma cells are those that are efficiently fused, support stable high-level production of antibody by select antibody-producing cells, and are sensitive to a selective medium that chooses it against unfused parent cells. Preferred myeloma cell lines are murine myeloma lines, such as those derived from MOPC-21 and MPC-11 mouse tumors available from the Salk Institute Cell Distribution Center, San Diego, California USA, and SP-2 and derivatives, eg cells X63-Ag8-653 available from American Type Culture Collection, Manassas, Virginia, USA. Mouse-human heteromyeloma cell lines and human myeloma have also been described for the production of human monoclonal antibodies (Kozbor, J. Immunol., 133: 3001 (1984); and Brodeur et al., Monoclonal Antibody Production Techniques and Applications, pp. 51-63 (Marcel Dekker, Inc., New York, 1987)).

The culture medium in which hybridoma cells are grown is tested for the production of monoclonal antibodies directed against the antigen. Preferably, the binding specificity of monoclonal antibodies produced by hybridoma cells is determined by hinmunoprecipitation or by an in vitro binding assay, such as radioimmunoassay (RIA) or enzyme-linked immunosorbent assay (ELISA). The binding affinity of the monoclonal antibody can for example be determined by Scatchard analysis described in Munson et al., Anal. Biochem., 107: 220 (1980). Once hybridoma cells producing antibodies of the desired affinity and / or activity specificity are identified, they can be subcloned by limiting dilution procedures and developed by standard methods (Goding, Monoclonal Antibodies: Principles and Practice, pp. 59- 103 (Academic Press, 1986)). Convenient culture medium for this purpose includes, for example, D-MEM medium or RPMI-1640. In addition, the hybridoma cells can be developed in vivo as ascites tumors in an animal, for example by i.p injection of the cells in mice. The monoclonal antibodies secreted by the suctions are conveniently separated from the culture medium, ascites fluid or serum by standard antibody purification procedures such as for example affinity chromatography (for example using Sepharose-G or protein A) or ion intercavity chromatography, hydroxylapatite chromatography, electrophoresis in gel, dialysis, etc. DNA encoding the monoclonal antibodies is easily isolated and sequenced using conventional procedures (for example by using oligonucleotide probes that are capable of specifically binding to genes encoding the heavy and light chains of murine antibodies). Hybridoma cells serve as a preferred source of this DNA. Once isolated, the DNA can be placed in expression vectors, which are transected in host cells such as E. coli cells, simian COS cells, Chinese hamster ovary cells (CHO = Chimney Hamster Ovary) or myeloma, which otherwise does not produce antibody protein, to obtain the synthesis of monoclonal antibodies in recombinant host cells. Review articles or recombinant expression in bacteria of DNA encoding the antibody include Skerra et al., Curr. Opinion in Immunol |, 5: 256-262 (1993) and Plückthun, Immunol. Revs. 130: 151-188 (1992). In a further embodiment, monoclonal antibodies or antibody fragments can be isolated from antibody phage libraries generated using the technique described in McCafferty et al., Nature, 348: 552-554 (1990). Clackson et al., Nature, 352: 624-628 (1991) and Marks et al., J. Mol. Biol. , 222: 581-597 (1991) describes the isolation of murine and human antibodies respectively using phage libraries.

Subsequent publications describe the production of high affinity human antibodies (nM range) by chain intermixing (Marks et al., Bio / Technology, 10: 779-783 (1992)), as well as combinatorial infection and in vivo recombination as a strategy to build very large phage libraries (Waterhouse et al., Nuc Acids, Res. 21: 2265-2266 (1993)). Thus, these techniques are viable alternatives to traditional monoclonal antibody hybridoma techniques for isolation of monoclonal antibodies. The DNA encoding the antibody can be modified to produce fusion or chimeric antibody polypeptides, for example it is to replace heavy chain and light chain constant domain sequences human (CH and CL) for homologous murine sequences (U.S. Patent Nos. 4,816,567; and Morrison, et al., Proc. Nati Acad. Sci. USA, 81: 6851 (1984)), or by fusion of the sequences of Immunoglobulin coding with little apart from the coding sequences for a polypeptide without immunoglobulin (heterologous polypeptide). Sequences of the polypeptides without immunoglobulin can substitute the constant domains of the antibody, or can be excluded by the variable domains of an antigen recombination site of an antibody to create a chimeric bivalent antibody comprising an antigen combining site having specificity for an antigen and another antigen combining site having specificity for an antigen. different antigen 3. Human and Humanized Antibodies The inventive UNQ733 antibodies in addition to offering humanized antibodies or human antibodies. Humanized forms of non-human antibodies (eg murine) are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab ', F (ab' >).; 2 or other antigen binding subsequences of antibodies), which contain minimal sequence derived from non-human immunoglobulin. Humanized antibodies include human immunoglobulins (recipient antibody) wherein residues of a region of complementary determination (CDR) of the container are replaced by residues of a CDR of a non-human species (donor antibody) such as mouse, rat or rabbit having the specificity, affinity and desired capacity. In some cases, Fv reading frame residues of the human immunoglobulin are replaced by corresponding non-human residues. Humanized antibodies may also comprise residues that are found in the recipient's antibody or in the CDR imported as a consequence of reading frame. In general, the humanized antibody comprises substantially all of at least one and typically two variable domains wherein all of substantially all of the CDR regions correspond to those which non-human immunoglobulin and all substantially all of the Fr regions are those of an immunoglobulin-granting sequence. human The antibody optimally humanized will also comprise at least a portion of an immunoglobulin constant region (Fe), typically that of a human immunoglobulin [Jones et al., Nature, 321: 522-525 (1986); Riechmann et al., Nature, 332: 323-329 (1988); and Presta, Curr. Op. Struct. Biol. , 2: 593-596 (1992)].

Methods for humanizing non-human antibodies are well known in the art. In general, a humanized antibody has one or more amino acid residues introduced into that of a non-human source. These non-human amino acid residues are often referred to as "import" residues that are typically taken from a "import" variable domain. Humanization can be performed essentially following the method of Winter et al. [Jones et al., Nature, 321: 522-525 (1986); Riechmann et al., Nature, 332: 323-327 (1988); Verhoeyen et al., Science, 239: 1534-1536 (1988)], by substituting rodent CDRs or CDR sequence for the corresponding sequences of a human antibody. Accordingly, these "humanized" antibodies are antibodies and chimeric (U.S. Patent No. 4,816,567), wherein substantially less than a variable domain of intact human has been replaced by the corresponding sequences of a non-human species. In practice, humanized antibodies are typically human antibodies wherein some CDR residues and possibly some FR residues are replaced by residues from analogous sites in rodent antibodies. The selection of two human variable domains both light and heavy to be used in producing humanized antibodies is very important to reduce antigenicity and response (HAMA) human anti-mouse antibody (HAMA) when the antibody is intended for human therapeutic use. According to the so-called "best fit", the variable domain sequences of a rodent antibody are monitored against the entire library known human variable domain sequences. The V domain sequence is closest to that of the rodent and the human reader framework region (FR) within it is accepted for the humanized antibody (Sims et al., J. Immunol., 151: 2296 (1993); Chothia et al., J. Mol. Biol., 196: 901 (1987)). Another method uses a particular reading frame region derived from the consensus sequence of all human antibodies of a particular subgroup of light or heavy chains. The same reading frame can be used for several different humanized antibodies (Cárter et al., Proc. Nati, Acad. Sci. USA, 89: 4285 (1992), Presta et al., J. Immunol. 151: 2623 (1993). ). In addition, it is important that antibodies are humanized with retention of high binding affinity for the antigen and other favorable biological properties. To achieve this goal, according to a method preferred, humanized antibodies are prepared by a process of analysis of the parent sequences and various conceptual humanized products using models three-dimensional sequences of the father and humanized sequences. Three-dimensional immunoglobulin models are commonly available and are familiar to those skilled in the art. Computer programs are available that illustrate and exhibit probable three-dimensional conformation structures of the selected candidate immunoglobulin sequences. Inspection of these exhibits allows analysis of the probable role of residues in the functioning of the candidate immunoglobulin sequences, that is, the analysis of residues that influences the ability of the candidate immunoglobulin to bind its antigen. In this manner, FR residues can be selected and combined from the import and recipient sequence, such that the desired antibody characteristic such as increased affinity for the target antigen (s) is achieved. The general, hypervariable region residues are directly and more substantially involved to influence antigen binding. Various forms of a humanized UNQ733 polypeptide antibody are contemplated. For example, him The humanized antibody can be an antibody fragment such as Fab, which optionally is conjugated with one or more cytotoxic agents in order to generate an immunoconjugate. Alternatively, the humanized antibody can be an intact antibody, such as an intact IgGl antibody. As an alternative to humanization, human antibodies can be generated. For example, it is now possible to produce transgenic animals (e.g., mice) that are capable, upon immunization, of producing a full repertoire of human antibodies in the absence of endogenous immunoglobulin production. For example, it has been described that homozygous removal of the heavy chain to antibody (JH) binding region gene in germline and chimeric mutant mice results in complete inhibition of endogenous antibody production. The transfer of the set of human germline immunoglobulin genes in this germline mutant ratio will result in the production of human antibodies against antigen test. See for example Jakobovits et al., Proc. Nati Acad. Sci. USA, 90: 2551 (1993); Jakobovits et al., Nature, 362: 255-258 (1993); Bruggemann et al., Year in Immuno. 7:33 (1993); U.S. Patent No. 5,545,806, 5,569,825, 5,591,669 (all of GenPharm); 5,545,807; and WO 97/17852. Alternatively, phage display technology (McCafferty et al., Nature 348: 552-553 [1990]) can be used to produce human antibodies and antibody fragments in vitro, from immunoglobulin variable domain gene repertoires (V) of non-immunized donors. In accordance with this technique, antibody V domain genes are cloned into either a major or minor coat protein gene of a filamentous bacteriophage, such as M13 or fd, and exhibit functional antibody fragments on the surface of the article phage Because the filamentous particle contains single-stranded DNA copies of the phage genome, selections based on the functional properties of the antibody also result in selection of the gene encoding the credit antibody for those properties. In this manner, the phage mimics some of the properties of the B cell. Phage display can be performed in a variety of formats, performed in eg, Johnson, Kevin S. and Chiswell, David J., Current Opinion in Structural Biology 3: 564 -571 (1993). Several sources of V gene segments can be used for phage display. Clackson et al., Nature, 352: 624-628 (1991), isolates a diverse set of anti-oxazolone antibodies from a small combinatorial library of V genes derived from the spleens of immunized mice. A repertoire of V genes from non-immunized human donors can be constructed and antibodies to a diverse set of antigen (including anti-antigens) can be analyzed essentially following the techniques described by Marks et al., J. Mol. Biol. 222: 581-597 (1991), or Griffith et al., EMBO J. 12: 725-734 (1993). See also U.S. Patent Nos. 5, 565, 332 and 5, 573, 905. As discussed above, human antibodies can also be generated by B cells activated in vitro (see U.S. Patent No. 5,567,610 and 5,229,275). 4. Antibody Fragments In certain circumstances, there are advantages to using antibody fragments, instead of whole antibodies. The smaller size of the fragments allows for rapid release and may lead to improved access to solid tumors. Various techniques have been developed by the production of antibody fragments. Traditionally, these fragments were derived by proteolytic digestion of intact antibodies (see for example Morimoto et al., Journal of Biochemical and Biophysical Methods 24: 107-117 (1992); and Brennan et al., Science, 229: 81 (1985)). However, these fragments can now be produced directly by recombinant host cells. Fab, Fv and ScFv antibody fragments can all be expressed in and secreted from E. coli, in this way allowing the easy production of large quantities of these fragments. Fragments of antibodies can be analyzed from the antibody phage libraries discussed above. Alternatively, Fab'-SH fragments can be directly recovered from E. coli and coupled guimically to form F (ab *) 2 fragments (Cárter et al., Bio / Technology 10: 163-167 (1992)). According to another discussion, F (ab ') 2 fragments can be analyzed directly from culture of recombinant host cells. Fragments of Fab and F (ab ') 2 with increased half-life in vivo comprise receptor receptor binding epitope residues are described in U.S. Patent No. 5,869,046. Other techniques for the production of antibody fragments will be apparent to the practitioner with skill in the art. In other embodiments, the selection antibody is a single chain Fv fragment (scFv). See WO 93/16185; U.S. Patent No. 5,571,894; and U.S. Patent No. 5,587, 458. Fv and sFv are the unique species with intact combination sites that are devoid of constant regions; in this way, they are suitable for reduced non-specific binding during put in vivo. SFv fusion proteins can be constructed to give fusion of an effector protein at either the amino or carboxy end of a sFv. See Antibody Engineering, ed. Borrebaeck, supra. The antibody fragment can also be a "linear antibody", for example, is described in U.S. Patent No. 5,641,870 for example. These linear antibody fragments may be monospecific or bispecific. 5. Bispecific Antibodies Bispecific antibodies are antibodies that have binding specificities for at least two epitopes. Exemplary bispecific antibodies may target two different epitopes of a UNQ733 polypeptide, as described herein. Other of these antibodies can combine a UNQ733 polypeptide binding site with a binding site for another polypeptide. Alternatively, an arm of the UNQ733 polypeptide antibody can be combined with an arm that binds to an activation molecule in a leukocyte such as a T cell receptor molecule (e.g. CD3), or Fe receptors for IgG (FcyR), such as Fc ^ Rl (CD64), Fc / RII (CD32), and Fc ^ RIII (CD16), to focus and localize cellular defense mechanisms to the cell ligand and / or express UNQ733 polypeptide . Bispecific antibodies may also be used to localize cytotoxic agents in cells expressing and / or binding UNQ733 polypeptide. These antibodies possess a polypeptide binding arm UNQ733 and an arm that binds the cytotoxic agent (eg, saporin, anti-interferon-a, vinca alkaloid, ricin A chain, methotrexate or radioactive isotope hapten). Bispecific antibodies can be repaired as full-length antibodies or antibody fragments (for example bispecific antibodies F (ab ') 2). No. 96/16673 describes a bispecific anti-ErbB2 / anti-Fcy antibody and US patent No. 5,837,234 describes a bispecific anti-ErbB2 / anti-Fc ^ RI antibody. An anti-ErbB2 / Fe bispecific antibody is shown in O98 / 02463. U.S. Patent No. 5,821,337 illustrates bispecific anti-ErbB2 / anti-CD3 antibody. Methods for producing bispecific antibodies are known in the art. Traditional production of bispecific antibodies of integral length is based on the co-expression of two light chain-immunoglobulin heavy chain pairs, wherein the two chains have different specificities (Millstein et al., Nature 305: 537-539 (1983)). Due to the random assortment of heavy and light chains of immunoglobulins, these hybridomas (quadromas) produce a potential mixture of 10 different antibody molecules from which only a correct first bispecific structure. Purifying a correct molecule, which is usually done by affinity chromatography steps, is rather problematic and product yields are low. Similar procedures are described in WO 93/08829, and in Traunecker et al., EMBO J. 10: 3655-3659 (1991). According to a different approach, variable domains of antibody with the desired binding specificities (antibody-antigen combining sites) are fused to immunoglobulin constant domain sequences. Preferably, the fusion is with a Ig heavy chain constant domain, comprising at least part of the hinge, CH2, and CH3 regions. It is preferred to have the first heavy chain-constant region (CH1) containing the necessary site for light chain binding, present in at least one of the mergers. DNAs encoding the immunoglobulin heavy chain fusions and, if desired, the immunoglobulin light chain, are inserted into separate expression reactors, and co-transfected into a convenient host cell. This provides greater flexibility for adjusting the mutual proportions of the three polypeptide fragments in modalities when different proportions of the three polypeptide chains employed in the construct provide the optimal yield of the desired bispecific antibody. Nevertheless, it is possible to insert the coding sequences for two or all three polypeptide chains into a single expression vector when the expression of at least two polypeptide chains in equal proportions results in high yields or when the proportions have no significant effect on the yield of the desired chain combination. In a preferred embodiment of this approach, bispecific antibodies are composed of a hybrid immunoglobulin heavy chain with a first binding specificity in one arm, and a light chain and a heavy immunoglobulin heavy chain pair (which provides a second binding specificity). ) in the other arm. It was found that this structure Asymmetric facilitates the separation of the desired bispecific compound from unwanted immunoglobulin chain combination, since the presence of an immunoglobulin light chain in only one half of the bispecific molecule allows for an easy separation form. This approach is described in WO 94/04690. For further details of generating bispecific antibodies see, for example, Suresh et al., Methods in Enzymology 121: 210 (1986). According to another approach described in U.S. Patent No. 5,731,168, the difference between a pair of antibody molecules can be engineered to maximize the percent of heterodimers that are recovered from the recombinant cell culture. The preferred derivative comprises at least a part of the CH3 domain. In this method, one or more small amino acid side chains from the inferium of the first antibody molecule are replaced with larger side chains (eg, thyroxine or tryptophan). "Compensatory cavities" of identical or similar size to the large side chains are created at the interface of the second antibody molecule by replacing large amino acid side chains with smaller (by example, alanine or threonine). This provides a mechanism for increasing the heterodimer yield over other unwanted end products such as homodimers. Bispecific antibodies include interlaced or "heteroconjugate" antibodies. For example, one of the antibodies in the heteroconjugate can be coupled with avidin, the other with biotin. These antibodies, for example, have been proposed to be targeted in cells of the immune system to unwanted cells (U.S. Patent No. 4,676,980), and by the treatment of HIV infection (WO 91/00360, O 92/200373, and EP 03089) . Heteroconjugate antibodies can be made using any convenient entanglement methods. Suitable interlacing agents are well known in the art, and are described in U.S. Patent No. 4,676,980, together with a number of interlacing techniques. Techniques for generating bispecific antibodies from antibody fragments have also been described in the literature. For example, bispecific antibodies can be prepared using the chemical bond. Brennan et al., Science 229: 81 (1985) describes a procedure wherein intact antibodies are proteolytically cleaved to generates fragments F (ab ') 2 - These fragments are reduced in the presence of the complexing agent dithiol, sodium arsenic, to stabilize neighborhood dithiols and avoid formation of intermolecular disulfide. The Fab 'fragments generated afterwards are converted into thionitrobenzoate derivatives (TNB). One of the Fab'-TNB derivatives is reconverted to the Fab'-thiol by reduction with mercaptoethylamine and mixed with an equimolar amount of the other Fab'-TNB derivative to form the bispecific antibody. The bispecific antibodies produced can be used as agents for the selective immobilization of enzymes. Recent progress has facilitated the direct recovery of Fab'-SH fragments from E. coli, which can be chemically coupled to form bispecific antibodies. Shalaby et al., J. Exp. Med. 175: 217-225 (1992) describes the production of an F (ab ') 2 molecule of fully humanised bispecific antibody. Each Fab 'fragment was secreted separately from E. coli and subjected to directed chemical coupling in vitro to form the bispecific antibody. The bispecific antibody thus formed was able to bind to cells that overexpress the ErbB2 receptor and normal human T cells, as well as trigger the lytic activity of human cytotoxic lymphocytes against human breast tumor targets. Various techniques for making and isolating bispecific antibody fragments directly from recombinant cell culture have also been described. For example, bispecific antibodies have been produced using leucine zippers. Kostelny et al., J. Immunol. 148 (5): 1547-1553 (1992). The leucine zipper peptides of the Fos and Jun proteins were linked in the Fab 'portions of two different antibodies by gene fusion. The antibody homodimers were reduced in the hinge region to form monomers and then re-oxidized to form the antibody heterodimers. This method can also be used for the production of antibody homodimers. The "body day" technology described by Hollinger et al., Proc. Nati Acad. Sci. USA 90: 6444-6448 (1993) has provided an alternative mechanism for producing bispecific antibody fragments. The fragments comprise a VH connected to a VL by a linker that is too short to allow pairing between two domains in the same chain. Accordingly, the VH and VL domains of one fragment are forced to pair with the complementary VL and VH domains of another fragment, thereby forming two sites of amphip link. Another strategy for producing the bispecific antibody fragment by the use of single chain Fv dimers (sFv) has also been reported. See Gruber et al., J. Immunol. , 152: 5368 (1994). Antibodies with more than two valencies are contemplated. For example, trispecific antibodies can be prepared. Tutt et al., J. Immunol. 147: 60 (1991). 6. Heteroconjugate Antibodies Heteroconjugate antibodies are also within the scope of the present invention. Heteroconjugate antibodies are composed of two antibodies covalently linked. These antibodies, for example, have been proposed to be targeted in cells of the immune system in unwanted cells [U.S. Patent No. 4,676,980], and for treatment of HIV infection [WO 91/00360; WO 92/200373; EP 03089]. It is contemplated that the antibodies can be prepared in vitro using known methods in synthetic protein chemistry, including those involving entanglement agents. For example, immunotoxins can be constructed using a disulfide exchange reaction or by forming a thioether bond. Examples of suitable reagents for this purpose include iminothiolate and methyl-4-mercaptobutyrimidate and those described for example, in U.S. Patent No. 4,676,980. 7. Multivalent Antibodies A multivalent antibody can be internalized (and / or catabolized) faster than a bivalent antibody by a cell that expresses an antibody to which antibodies bind. The antibodies of the present invention can be multivalent antibodies (which are different from the IgM class) with three or more amphiphilic binding sites (for example tetravalent antibodies), which can be easily produced by recombinant expression of nucleic acid encoding the polypeptide chains of the antibody. The multivalent antibody can comprise a dimerization domain and three or more ampigene binding sites. The preferred dimerization domain comprises (or consists of) an Fe region or a hinge region. In this scenario, the antibody will comprise an Fe region and three or more amino host amplicon sites terminal to the Fe region. The preferred multivalent antibody herein comprises (or consists of) three to about eight, but preferably four, ampigene binding sites. The multivalent antibody comprises at least one polypeptide chain (and preferably two polypeptide chains), wherein the polypeptide chain (s) comprises two or more domains. By example, the polypeptide chain (s) may comprise VD1- (XI) n-VD2- (X2) n-Fc, where VD1 is a first variable domain, VD2 is a second variable domain, Fe is a polypeptide chain of an Fe region , XI and X2 represent an amino acid or polypeptide, and n is 0 or 1. For example, the polypeptide chain (s) may comprise: VH-CH1-linker-flexible chain-VH-CH1-Fc region chain; or chain of region VH-CH1-VH-CH1-Fc. The multivalent antibody here preferably also comprises at least two (and preferably four) light chain variable domain polypeptides. The multivalent antibody here, for example, may comprise from about two to about eight light chain variable domain polypeptides. The light chain variable domain polypeptides contemplated herein comprise a light chain variable domain and optionally also comprise a CL domain. 8. Effector Function Engineering It may be desirable to modify the antibody of the invention with respect to effector function, for example, to improve cytotoxicity as measured by antigen-dependent cells (ADCC) and / or fully-dependent cytotoxicity (CDC) of the antibody . This can be achieved by entering one or more substitutions of amino acids in an Fe region of the antibody. Alternatively or additionally, one or more cysteine residues can be introduced into the Fe region, thereby allowing interchain chain disulfide formation in this region. The homodimeric antibody thus generated may have improved internalization capacity and / or increased mean cell killing by complement and antibody-dependent cellular cytotoxicity (ADCC). See Carón et al., Exp Med. 176: 1191-1195 (1992) and Shopes, B. J. Immunol. 148: 2918-2922 (1992). Homodimeric antibodies with enhanced anti-tumor activity can also be prepared using heterobifunctional crosslinkers as described in Wolff et al., Cancer Research 53: 2560-2565 (1993). Alternatively, an antibody can be engineered having dual Fe regions and thus can have enhanced complement lysis and ADCC capabilities. See Stevenson et al., Anti-Cancer Drug Design 3: 219-230 (1989). To increase the serum half-life of the antibody, a recovery receptor binding epitope can be incorporated into the antibody (especy an antibody fragment) as described in U.S. Patent No. 5,739,277, for example. As used here, the term "epitope of "recovery receptor link" refers to an epitope of the Fe region of an IgG molecule (eg, IgGi, IgG2, IgG3, or IgG4) that is responsible for increasing the serum half-life of the IgG molecule in vivo. Immunoconjugates The invention also relates to immunoconjugates, or antibody-drug conjugates (ADC), comprising an antibody conjugated to a cytotoxic agent such as a chemotherapeutic agent, a drug, a growth inhibitory agent, a toxin (e.g. enzymatically active toxin of bacterial, fungal, plant or animal origin, or its fragments), or a radioactive isotope (ie, a radioconjugate) .The use of antibody-drug conjugate for the in loco delivery of cytotoxic or cytostatic agents, ie drugs to kill or inhibit tumor cells in the treatment of cancer (Syrigos and Epenetos (1999) Anticancer Research 19: 605-614; Niculescu-Duvaz and Springer (1997) Adv. Drg Del. Rev. 26: 151-172; from US Pat. No. 4,975,278) theoretically allows targeted delivery of the drug portion to tumors, and their intracellular accumulation, wherein the systemic administration of these unconjugated drug agents can result in unacceptable levels of toxicity to normal cells as well as the tumor cells that are sought to be eliminated (Baldwin et al., (1986) Lancet pp. (Mar. 15, 1986): 603-05; Thorpe, (1985) "Antidody Carriers of Cytotoxic Agents In Cancer Therapy: A Review, "in Monoclonal Antibodies '84: Biological and Clinical Applications, A. Pinchera et al. (Eds.), Pp. 475-506). Maximum efficacy with minimal toxicity is sought in this way. Both polyclonal antibodies and monoclonal antibodies have been reported to be useful in these strategies (Rowly et al., (1986) Cancer Immunol., Immunotro., 21: 183-87). Drugs employed in these methods include daunomycin, doxorubicin, methotrexate vindesine (Rowly et al., (1986) supra). Toxins used in antibody-toxin conjugates include bacterial toxins such as diphtheria toxin, plant toxins such as ricin, small molecule toxins such as geldanamycin (Myler et al (2000) Jou. Of the Nat. Cancer Inst. 92 (19) : 1573-1581; Myler et al (2000) Bioorganic &Med Chem Letters 10: 1025-1028; Myler et al (2002) Bioconjugate Chem. 13: 786-791), maytansinoids (EP 1391213; Liu et al. , (1996) Proc. Nati, Acad. Sci. USA 93: 8618-8623), and calimeamycin (Lode et al (1998) Cancer Res. 58: 2928; Hinman et al. (1993) Cancer Res. 53: 3336- 3342). Toxins can perform their cytotoxic and cytostatic effects by mechanisms that include tubulin binding, DNA binding or topoisomerase inhibition. Some cytotoxic drugs tend to be inactive or less active when they are conjugated with large antibodies or protein receptor ligands. ZEVALIN® (ibritumomab tiuxetan, Biogen / Idec) is an antibody-radioisotope conjugate composed of a murine monoclonal IgGl kappa antibody directed on the contrary by the CD20 antigen found on the surface of normal and malignant B lymphocytes and X11ln or 90Y radioisotope bound by a thiourea linker-linker (Wiseman et al (2000) Eur. Jour Nucí Med. 27 (7): 766-77; Wiseman et al (2002) Blood 99 (12): 4336-42; Witzig et al (2002) J. Clin Oncol 20 (10): 2453-63; Witzig et al (2002) J. Clin Oncol 20 (15): 3262-69). Although ZEVALIN has activity against B-cell non-Hodgkin lymphoma (NHL), administration results in severe and prolonged cytopenias in most patients. MYLOTARG ™ (gemtuzumab ozogamicin, Wyeth Phbrazoaceuticals), an antibody drug conjugate composed of a hu CD33 antibody bound to calicheamicin, was approved in 2000 for treatment of acute myeloid leukemia by injection (Drugs of the Future (2000) 25 (7): 686; U.S. Patent Nos. 4970198; 5079233; 5585089; 5606040; 5693762; 5739116; 5767285; 5773001). Cantuzumab Mertansine (Immunogen, Inc.), an antibody drug conjugate composed of the huC242 antibody bound by an SPP disulfide linker with the maytansinoid drug moiety, DM1 advances to phase II trials for the treatment of cancers that express CanAg, such as colon, pancreatic, gastric cancer and others. MLN-2704 (Millennium Phbrazo., BZL Biologics, Immunogen Inc.), an antibody-drug conjugate composed of anti-prostate specific membrane antigen monoclonal antibody (PSMA prostes specific member antigen) bound to the maytansinoid drug moiety, DM1 is under development for the potential treatment of prostate tumors. The peptides auristatin, auristatin E (AE) and monomethylauristatin (MMAE), synthetic analogs of dolastatin, were conjugated with chimeric monoclonal antibodies cBR96 (specific to Lewis Y in carcinomas) and cAClO (specific to CD30 in hematological malignancies) (Doronina et al. 2003) Nature Biotechnology 21 (7): 778-784) and are under therapeutic development. Chemotherapeutic agents useful in the generation of these immunoconjugates have been described previously. Enzymatically active toxins and their fragments that can be used include diphtheria A chain, active fragments without diphtheria toxin binding, exotoxin A chain (from Pseudomonas aeruginosa), chain A resin, chain A open, chain modecin A, alpha-sarcin, Aleurites proteins fordii, diantine proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), inhibitor of momordica charantia, curcin, crotina, inhibitor of sapaonaria officinalis, gelonin, mitogeline, restrictocin, phenomycin, enomycin, and trichothenes. A variety of radionuclides are available for the production of radioconjugated antibodies. Examples include 212Bi, 131I, 131In, 90Y, and 186Re. Antibody conjugate and cytotoxic agent are made using a variety of bifunctional protein coupling agents such as N-sucinimidyl-3- (2-pyridyldithiol) propionate (SPDP), iminothiolane (IT), bifunctional imidoester derivatives (such as dimethyl adipimidate HC1), active esters (such as disucinimidyl suberate), aldehydes (such as glutaraldehyde), bis-azido compounds (such as bis (p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (such as bis- (p-diazoniumbenzoyl) - ethylenediamine), diisocyanates (such as toluene 2, 6-diisocyanate), and bis-active fluour compounds (such as 1,5-difluoro-2,4-dinitrobenzene). For example, a resin immunotoxin can be prepared as described in Vitetta et al., Science, 238: 1098 (1987). 1-isothiocyanatobenzyl-3-methyldiethylene triaminepentaacetic acid labeled with carbon-14-labeled (MX-DTPA) is an exemplary chelating agent for conjugating radionuclide to the antibody. See WO94 / 11026. Conjugates of an antibody and one or more small molecule toxins, such as calicheamicin, maytansinoids, a trichotene, and CC1065 and derivatives of these toxins having toxic activity, are also contemplated herein. aitansine and maytansinoids In one embodiment, an UNQ733 polypeptide antibody (iontegra length or fragments) of the invention is conjugated with one or more maytansinoid molecules. Maytansinoids are mitototic inhibitors that act by inhibiting tubulin polymerization. Maytansine was first isolated from the East African bush Maytenus serrata (U.S. Patent No. 3,896,111). Subsequently, it was discovered that certain microbes also produce maytansinoids, such as maytansinol and C-3 maitansinol esters (patent of the E.U.A number 4,151,042). Synthetic maitansinol and its derivatives and analogs are described, for example, in U.S. Patent Nos. 4,137,230; 4,248,870; 4,256,746; 4,260,608; 4,265,814; 4,294,757; 4,307,016; 4,308,268; 4,308,269; 4,309,428; 4,313,946; 4,315,929; 4,317,821; 4,322,348; 4,331,598; 4,361,650; 4,364,866; 4,424,219; 4,450,254; 4,362,663; and 4,371,533, the descriptions of which are hereby expressly incorporated by reference. Conjugates Maytansinoid-antibody In an attempt to improve its therapeutic index, maytansine and maytansinoid have been conjugated with antibodies that bind specifically to tumor cell antigens. Immunoconjugates containing maytansinoid and its therapeutic use are described, for example, in U.S. Patent Nos. 5,208,020, 5,416,064 and European Patent EP 0 425 235 Bl, the disclosure of which is hereby expressly incorporated by reference. Liu et al., Proc. Nati Acad. Sci. USA 93: 8618-8623 (1996) describes immunoconjugates comprising a maytansinoid designated DM1 linked to the monoclonal antibody C242 directed against human colorectal cancer. The conjugate was found to be highly cytotoxic towards cells of cultured colon cancer, and showed antitumor activity in a tumor growth assay in vivo. Chari et al., Cancer Research 52: 127-131 (1992) discloses immunoconjugates wherein a maytansinoid is conjugated via a disulfide linker to the murine A7 antibody that binds with an antigen or human colon cancer cell lines or another monoclonal antibody murine TA.l that binds to the HER-2 / neu oncogene. The cytotoxicity of TA .1-maitansonoid conjugate was tested in vitro in the human breast cancer cell line SK-BR-3, which expresses 3 x 105 HER-2 surface antigen per cell. The drug conjugate achieved a degree of cytotoxicity similar to the free maytansinoid drug, which can be increased by increasing the number of maytansinoid molecules per antibody molecule. The conjugate A7-maytansinoid showed low systemic cytotoxicity in mice. Conjugates maytansinoid-anti-UNQ733 Polypeptide antibody (immunoconjugates) Maytansinoid-anti-UNQ733 polypeptide antibody conjugates are prepared by chemical linking an anti-UNQ733 polypeptide antibody with a maytansinoid molecule without significantly decreasing the biological activity of either the antibody or the molecule maytansinoid. An average of 3 to 4 conjugated maytansinoid molecules per antibody molecule has shown efficacy in improving the cytotoxicity of target cells without adversely affecting the function or solubility of the antibody, although even a toxin / antibody molecule is expected to improve cytoxicity on the use of the naked antibody. Maytansinoids are well known in the art and can be synthesized by known techniques or isolated from natural sources. Suitable maytansinoids are described, for example, in U.S. Pat. No. 5,208,020 and in the other patents and publications that are not of patent referred previously. Preferred maytansinoids are maytansinol and maytansinol analogs modified in the aromatic ring and in other positions of the maytansinol molecule, such as various maytansol esters. There are many linking groups known in the art to produce antibody-maytansinoid conjugates, including for example those described in U.S. Pat. No. 5,208,020 or EP 0 425 235 Bl, and Chari et al., Cancer Research 52: 127-131 (1992). The linking groups include disulfide groups, thioether groups, labile acid groups, photolabile groups, labile peptidase groups, or esterase groups labile, as described in the patents identified above, disulfide and thioether groups are preferred. Antibody and maytansinoid conjugates can be made using a variety of bifunctional protein coupling agents such as N-succinimidyl-3- (2-pyridyldithio) propionate (SPDP), succinimidyl-4- (N-maleimidomethyl) cyclohexane-1-carboxylate, iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HC1), active esters (such as disuccinimidyl suberate), aldehydes (such as glutaraldehyde), bis-azido compounds (such as bis (p-azidobenzoyl) hexanediamine), derivatives bis-diazonium (such as bis- (p-diazonium benzoyl) -ethylenediamine), diisocyanates (such as toluene 2,6-diisocyanate), and bis-active fluorine compounds (such as 1,5-difluoro-2, -dinitrobenzene) . Particularly preferred coupling agents include N-succinimidyl-3- (2-pyridyldithio) propionate (SPDP) (Carlsson et al., Biochem. J. 173: 723-737 [1978]) and N-succinimidyl-4- (2-pyridylthio). pentanoate (SPP) to provide a disulfide bond. The linker can be connected to the maytansinoid molecule in various positions, depending on the type of linkage. For example, an ester link can formed by reaction with a hydroxyl group using conventional coupling techniques. The reaction can occur at the C-3 position having a hydroxyl group, the C-14 position modified with hydroxymethyl, the C-15 position modified with a hydroxyl group and the C-20 position having a hydroxyl group. In a preferred embodiment, the bond is formed at the C-3 position of maytansinol or an maytansinol analogue. Calicheamycin Another immunoconjugate of interest comprises an anti-UNQ733 polypeptide antibody conjugated to one or more caliciamycin molecules. The caliciamycin family of antibodies is capable of producing interruptions or breaks in double-stranded DNA at sub-picomolar concentrations. For the preparation of conjugates of the caliciamycin family, see the patents of the U.S.A. Nos. 5,712,374, 5,714,586, 5,739,116, 5,767,285, 5,770,701, 5,770,710, 5,773,001, 5,877,296 (all to American Cyanamid Company). Structural analogues of caliciamycin that may be used include but are not limited to and i1, to 21, to 21, N-acetyl- (Hinman et al., Cancer Research 53: 3336-3342 (1993), Lode et al., Cancer Research 58: 2925-2928 (1998) and US patents. previously mentioned granted to American Cyanamid). Another anti-tumor drug with which the antibody can be conjugated is QFA which is an antifolate. Both caliciamycin and QFA have intracellular sites of action and do not readily cross the plasma membrane. Thus, cellular absorption of these agents through antibody-mediated internalization greatly improves their cytotoxic effects. Other cytotoxic agents Other antitumor agents that can be conjugated to the anti-UNQ733 polypeptide antibodies of the invention include BCNU, streptozoicin, vincristine and 5-fluorouracil, the family of agents known collectively as LL-E33288 complex described in US Pat. Nos. 5,053,394, 5,770,710, as well as esperamicins (U.S. Patent No. 5,877,296). Enzymatically active toxins and their fragments that can be used include diphtheria A chain, non-binding active fragments of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin chain, Aleurites proteins fordii, proteins diantin, Phytolaca americana proteins (PAPI, ?????, and PAP-S), inhibitor of momordica charantia, curcin, crotina, inhibitor of sapaonaria officinalis, gelonin, mitogeline, restrictocin, phenomycin, enomycin and trichothecenes. See for example WO 93/21232 published October 28, 1993. The present invention further contemplates an immunoconjugate formed between an antibody and a compound with nucleolytic activity (eg, a ribonuclease or DNA endonuclease such as deoxyribonuclease, DNase). For selective destruction of the tumor, the antibody can comprise a highly radioactive atom. A variety of radioactive isotopes are available for the production of anti-UNQ733 antibodies. Examples include At211, I131, I125, Y90, Re186, Re188, Sm153, Bi212, P32, Pb212 and radioactive isotopes of Lu. When the conjugate is used for detection, it may comprise a radioactive atom for scintigraphic studies, for example tc99m or I123, or a spin tag for nuclear magnetic resonance imaging (NMR) (also known as magnetic resonance imaging, mri = magnetic resonant imaging), such as iodine-123 again, iodine-131, indium-111, fluorine-19, carbon-13, nitrogen-15, oxygen-17, gadolinium, manganese or iron. Radiolabels or others can be incorporated into the conjugate in known ways. For example, the peptide can be biosynthesized or can be synthesized by chemical amino acid synthesis using convenient amino acid precursors involving for example fluorine-19, instead of hydrogen. Labels such as tc99ra or I123, Re186, Re188 and In111 can be connected via a cysteine residue in the peptide. Itrium-90 can be connected by a lysine residue. The method IODOGEN (Fraker et al. (1978) Biochem. Biophys. Res. Commun. 80: 49-57 can be used to incorporate iodine-123. "Onoclonal Antibodies in Immunoscintigraphy" (Chatal, CRC Press 1989) describes other methods in detail. antibody and cytotoxic agent can be made using a variety of bifunctional protein coupling agents such as N-succinimidyl-3- (2-pyridyldithio) propionate (SPDP), succinimidyl-4- (N-maleimidomethyl) cyclohexane-1-carboxylate, iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HC1), active esters (such as disuccinimidyl suberate), aldehydes (such as glutaraldehyde), bis-azido compounds (such as bis (p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (such as bis- (p-diazoniumbenzoyl) -ethylenediamine), diisocyanates (such as toluene 2, 6- diisocyanate), and bis-active fluorine compounds (such as 1,5-difluoro-2,4-dinitrobenzene). For example, a ricin immunotoxin can be prepared as described in Vitetta et al., Science 238: 1098 (1987). L-isothiocyanatobenzyl-3-methyldiethylene triaminpentaacetic acid labeling with carbon-14 (MX-DTPA) is an exemplary chelating agent for conjugating radionucleotide with the antibody. See WO94 / 11026. The linker can be a "cleavable linker" that facilitates the release of the cytotoxic drug into the cells. For example, a labile acid linker, a peptidase-sensitive linker, photolabil linker, dimethyl linker or disulfide-containing linker (Chari et al., Cancer Research 52: 127-131 (1992), US Patent No. 5,208,020) may be employed. The compounds of the invention expressly contemplate, but are not limited to, ADC prepared with interlacing reagents: BMPS, EMCS, GMBS, HBVS, LC-SMCC, MBS, MPBH, SBAP, SIA, SIAB, SMCC, SMPB, SMPH, sulfo-EMCS, sulfo-GMBS, sulfO-KMUS, sulfo-MBS, sulfo-SIAB, sulfo-SMCC, and sulfo-SMPB, and SVSB (succinimidyl- (4-vinyl sulfone) benzoate) which are commercially available (for example, from Pierce Biotechnology, Inc., Rockford, IL., US A). See pages 467-498, 2003-2004 Applications Handbook and Catalog. PREPARATION OF ANTIBODY CONJUGATES - DRUG In the antibody-drug conjugates (ADC) of the invention, an antibody (Ab) is conjugated with one or more portions of drug (D), for example from about 1 to about 20 portions of drug per antibody, through a linker (L). The ADC of Formula I can be prepared by several routes, employing organic chemistry reactions, conditions and reagents known to those skilled in the art, including: (1) reaction of a nucleophilic group of an antibody with a bivalent linker reagent to form Ab-L, by a covalent bond, followed by reaction with a portion of drug D; and (2) reaction of a nucleophilic group of a drug moiety with a bivalent linker reagent to form D-L, by a covalent bond, followed by reaction with the nucleophilic moiety of the antibody. Ab- (L-D) p I Nucleophilic groups in antibodies include but are not limited to: (i) N-terminal amine groups, (ii) side chain amine groups for example lysine, (iii) side chain thiol groups, for example cysteine, and (iv) hydroxyl or amino sugar groups, wherein the antibody is glycosylated. Amine thiol and hydroxyl groups are nucleophilic and capable of reacting to form covalent bonds with nucleophilic groups in linker portions and linker reagents including: (i) active esters such as NHS, HOBt esters, haloformates, and acid halides; (ii) alkyl and benzyl halides such as haloacetamides; (iii) aldehydes, ketones, carboxyl groups, and maleimide. Certain antibodies have reducible interchain chains, ie cysteine bridges. Antibodies can be made reactive for conjugation with linker reagents by treatment with a reducing agent such as DTT (dithiothreitol). Each cysteine bridge in this way will theoretically form two reactive thiol nucleophiles. Additional nucleophilic groups can be introduced into antibodies through the reaction of lysines with 2-iminothiolane (Traut's reagent) resulting in conversion of an amine to a thiol.

Drug antibody conjugates of the invention can also be produced by modifying the antibody to introduce electrophilic portions, which can react with nucleophilic substituents in the linker reagent or drug. The sugars of glycosylated antibodies can be oxidized, for example with periodate oxidation reagents to form aldehyde or ketone groups which can react with the amine group of linker reagents or drug portions. The resulting Schiff imine base groups can form a stable bond or can be reduced, for example by boron hydride reagents to form stable amine bonds. In one embodiment, the reaction of the carbohydrate portion of a glycosylated antibody with either galactose oxidase or sodium meta-periodate can produce carbonyl groups (aldehyde and ketone) in the protein, which can react with appropriate groups on the drug (Hermanson , Bioconjugate Techniques). In another embodiment, proteins containing the N-terminal serine or threonine residues can react with sodium meta-periodate, resulting in production of an aldehyde in place of the first free amino acid (Geoghegan &Stroh, (1992) Bioconjugate Chem. : 138-146; US 5362852). This aldehyde can be reacted with a portion of the drug or nucleophile linker. Likewise, nucleophilic groups in a drug moiety include but are not limited to: amine, thiol, hydroxyl, hydrazide, oxime, hydrazine, thiosemicarbazone, hydrazine carboxylate, and aryl hydrazide groups capable of reacting to form covalent bonds with electrophilic groups in linker portions and linker reagents including: (i) active esters such as NHS, HOBt esters, haloformates, and acid halides; (ii) alkyl and benzyl halides such as haloacetamides; (iii) aldehydes,. ketones, carboxyl groups, and maleimide. Alternatively, a fusion protein comprising the anti-UNQ733 polypeptide antibody and cytotoxic agent, can be made, for example by recombinant techniques or peptide synthesis. The length of DNA may comprise respective regions that encode the two portions of the conjugate either adjacent to each other or separated by a region encoding a linker peptide that does not destroy the desired properties of the conjugate. In yet another embodiment, the antibody can be conjugated to a "receptor" (such as streptavidin) for use in the tumor pre-target, wherein the antibody-receptor conjugate is administered to the patient, followed by removal of unbound conjugate from the circulation using a release agent and then administration of a "ligand" (e.g., avidin) that is conjugated to a cytotoxic agent (e.g. radionucleotide). 10. Immunoliposomes The anti-UNQ733 polypeptide antibodies described herein can also be formulated as immunoliposomes. A "liposome" is a small vesicle composed of various types of lipids, phospholipids and / or surfactant or surfactant that are useful for the delivery of a drug to a mammal. The components of the liposome are commonly arranged in a bilayer formation, similar to the lipid arrangement of biological membranes. Liposomes containing the antibody, are prepared by methods known in the art, such as described in Epstein et al., Proc. Nati Acad. Sci. USA 82: 3688 (1985); Hwang et al., Proc. Nati Acad. Sci. USA 77: 4030 (1980); US Patents Nos. 4,485,045 and 4,544,545; and W097 / 38731 published October 23, 1997. Liposomes with improved circulation time are described in U.S. Pat. No. 5,013,556. Particularly useful liposomes can generated by the reverse phase evaporation method with a lipid composition comprising phosphatylcholine, cholesterol and phosphatidylethanolamine derivatized with PEG (PEG-PE). Liposomes are extruded through filters of defined pore size to result in liposomes with the desired diameter. Fab 'fragments of the antibody of the present invention can be conjugated to liposomes as described in Martin et al., J. Biol. Chem. 257: 286-288 (1982) by sulfide exchange reaction. A chemotherapeutic agent is optionally contained within the liposome. See Gabizon et al., J. National Cancer Inst. 81 (19): 1484 (1989). B. Linker Oligopeptides UNQ733 Polypeptide UNQ733 Polypeptide Linker Oligopeptides of the invention are oligopeptides that bind, preferably specifically to a UNQ733 polypeptide as described herein. Polypeptide binding oligonucleotides UNQ733 can be chemically synthesized using known oligopeptide synthesis methodology or can be prepared and purified using recombinant technology. Polypeptide binding oligonucleotides UNQ733 are usually at least about 5 amino acids in length, in alternating form at least about 6, 7, 8, 9, , 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 amino acids of length or more, wherein these oligopeptides are capable of binding, preferably specifically to a UNQ733 polypeptide as described herein. Polypeptide binding oligonucleotides UNQ733 can be identified without undue experimentation using well-known techniques. In this regard, it is noted that techniques for monitoring oligopeptide libraries by oligopeptides that are capable of specifically binding to a polypeptide target, are well known in the art (see for example U.S. Patent Nos. 5,556,762, 5,750,373, 4,708,871, 4,833,092, 5,223,409, 5,403,484, 5,571,689, 5,663,143, PCT Publication Nos. WO 84/03506 and WO84 / 03564, Geysen et al., Proc. Nati, Acad. Sci. USA, 81: 3998-4002 (1984), Geysen et al., Proc. Nati, Acad Sci USA, 82: 178-182 (1985), Geysen et al, in Synthetic Peptides as Antigens, 130-149 (1986), Geysen et al., J. Immunol. 102: 259-274 (1987); Schoofs et al., J. Immunol. , 140: 611-616 (1988), Cwirla, S. E. et al. (1990) Proc. Nati Acad. Sci. USA, 87: 6378; Lowman, H.B. et al. (1991) Biochemistry, 30: 10832; Clackson, T. et al. (1991) Nature, 352: 624; Marks, J. D. et al. (1991), J. Mol. Biol., 222: 581; Kang, A.S. and collaborators (1991) Proc. Nati Acad. Sci. USA, 88: 8363, and Smith, G. P. (1991) Current Opin. Biotechnol. , 2: 668). In this regard, the display of the bacteriophage (phage) is a well-known technique that allows to monitor large libraries of oligopeptide to identify member or members of those libraries that are capable of binding specifically to a polypeptide target. Phage display is a technique by which variant polypeptides are displayed as fusion proteins to the coat protein on the surface of the bacteriophage particles (Scott, J.K. and Smith, G.P. (1990) Science, 249: 386). The utility of the phage display lies in the fact that large libraries of selectively randomized protein variants (or randomly cloned cDNAs) can be quickly and efficiently sorted by those sequences that bind a target molecule with high affinity The display of peptide libraries (C irla, S. E. et al (1990) Proc. Nati, Acad. Sci. USA, 87: 6378) or protein (Lowman, H. B. et al. (1991) Biochemistry, 30: 10832; Clackson, T. et al. (1991) Nature, 352: 624; Marks, J. D. et al. (1991), J. Mol. Biol. , 222: 581; Kang, A.S. et al. (1991) Proc. Nati Acad. Sci. USA, 88: 8363) phage has been used to monitor millions of polypeptides or oligopeptides by those with specific binding proteins (Smith, G.P. (1991) Current Opin, Biotechnol., 2: 668). Classification of phage libraries of random mutants requires a strategy for constructing and propagating a large number of variants, a method for affinity purification using the target receptor and means for evaluating binding enrichment results. U.S. Patent Nos. 5,223,409, 5,403,484, 5,571,689, and 5,663,143. Although most phage display methods have used filamentous phage, lamboid phage display systems (WO 95/34683; US 5,627,024), T4 phage display systems (Ren et al., Gene, 215: 439 (1998); et al., Cancer Research, 58 (15): 3209-3214 (1998), Jiang et al., Infection &Immunity, 65 (11): 4770-4777 (1997), Ren et al., Gene, 195 ( 2): 303-311 (1997); Ren, Protein Sci., 5: 1833 (1996); Efimov et al., Virus Genes, 10: 173 (1995)) and T7 phage display systems (Smith and Scott, Methods in Enzymology, 217: 228-257 (1993); U.S. 5,766,905) are also known. Many other improvements and variations of the basic phage display concept have not been developed. These improvements reinforce the ability of display systems to monitor peptide libraries for binding to select target molecules and to display functional proteins with the potential to monitor these proteins for desired properties. Combinatorial reaction devices for phage display reactions have been developed (WO 98/14277) and phage display libraries have been used to analyze and control bimolecular interactions (WO 98/20169; WO 98/20159) and properties of restricted helical peptides ( WO 98/20036). WO 97/35196 describes a method for isolating an affinity ligand wherein a phage display library is contacted with a solution wherein the ligand will bind to a target molecule and a second solution wherein the affinity ligand will not bind to the target molecule. , to selectively isolate the binding ligand. WO 97/46251 describes a method for selecting a random phage display library with a affinity purified antibody and then isolate the binding phage, followed by a phage capture assay process using microplate wells to isolate the high affinity binding phage: The use of the protein A Staphlylococcus aureus as an affinity tag is also has reported (Li et al. (1998) Mol Biotech., 9: 187). WO 97/47314 describes the use of substrate subtraction libraries to distinguish enzyme specificities using a combinatorial library that can be a phage display library. A method for selecting enzymes suitable for using detergents using phage display is described in WO 97/09446. Additional methods for selecting specific binding proteins are described in U.S. Patent Nos. 5,498,538, 5,432,018, and WO 98/15833. Methods for generating peptide libraries and monitoring these libraries are also described in U.S. Patent Nos. 5,723,286, 5,432,018, 5,580,717, 5,427,908, 5,498,530, 5,770,434, 5,734,018, 5,698,426, 5,763,192, and 5,723,323. C. Small molecules of polypeptide binding UNQ733 Small molecules of polypeptide binding UNQ733 of preferences are organic molecules of different to oligopeptide or antibodies as defined herein that bind of preferences specifically to a UNQ733 polypeptide, as described herein. Small organic molecules of UNQ733 polypeptide binding can be identified and synthesized chemically using known methodology (see for example PCT publications numbers WOOO / 00823 and WOOO / 39585). Small organic molecules of UNQ733 polypeptide binding are usually less than about 200 daltons in size, alternately less than about 1500, 750, 500, 250 or 200 daltons in size, where these small organic molecules are capable of binding, preferably specifically to a UNQ733 polypeptide as described herein, can be identified without inhibiting experimentation using well-known techniques. In this regard, it is noted that techniques for monitoring organic small molecule libraries for molecules that are capable of binding to a polypeptide target are well known in the art (see for example PCT publications numbers WOOO / 00823 and WOOO / 39585). Small organic molecules polypeptide binding UNQ733 may for example be aldehydes, ketones, oximes, hydrazones, semicarbazones, carbazides, primary amines, secondary amines, tertiary amines, N-substituted hydrazines, hydrazides, alcohols, ethers, thiols, thioethers, disulfides, carboxylic acids, esters, amides, ureas, carbamates, carbonates, ketals, thioketals, acetals, thioacetals, aryl halides, aryl sulfonates, alkylaids, alkylsulfonates, aromatic compounds, heterocyclic compounds, anilines, alkenes, alkynes, diols, amino alcohols, oxazolidines, oxazolines, thiazolidines, thiazolines, enamines, sulfonamides, epoxides, aziridines, isocyanates, sulfonyl chloride, diazo compounds, acid chlorides, or the like. D. Supervision for anti-UNQ733 polypeptide antibodies, UNQ733 polypeptide binding oligopeptides and small molecules of UNQ733 polypeptide binding with the desired properties. Techniques for generating oligopeptide antibodies and small molecules that bind to UNQ733 polypeptides have been described above. In addition oligopeptide antibodies or other small molecules with certain biological characteristics may be selected as desired. The growth inhibitory effects of an oligopeptide anti-UNQ733 antibody or other small molecule of the invention can be estimated by methods known in the art, for example using cells expressing a UNQ733 Polypeptide either in endogenous form or following transection with the UNQ733 Polypeptide gene. For example, appropriate tumor cell lines and cells transected with UNQ733 polypeptide can be treated with an oligopeptide anti-UNQ733 polypeptide polyclonal antibody or other small molecule of the invention in various concentrations for a few days (eg 2-7 days) and dye with violet crystal or MTT or analyze by another colorimetric test. Another method for measuring proliferation would be to compare the uptake of 3H-thymidine by cells treated in the presence or absence of an anti-UNQ733 polypeptide antibody, peptide binding oligopeptide UNQ733 or small molecule of UNQ733 polypeptide linkage of the invention. After treatment, the cells are harvested and the amount of radioactivity incorporated in the DNA is quantified in a fade counter. Appropriate positive controls include treatment of a selected cell line with a known growth inhibitory antibody that inhibits the growth of that cell line. Inhibition of tumor cell growth in vivo can be determined in various ways known in the art. The tumor cell may be the one that overexpresses a UNQ733 polypeptide. The oligopeptide anti-UNQ733 polypeptide antibody linkage UNQ733 Polypeptide or small molecule organic binding polypeptide UNQ733 will inhibit the cell proliferation of a tumor cell expressing UNQ733 polypeptide in vitro or in vivo by about 25-100% compared to the untreated tumor cell, more preferably at about 30 -100%, and also preferably at about 50-100% or 70-100%, in one embodiment, at an antibody concentration of about 0.5 to 30 and g / ml. Growth inhibition can be measured at an antibody concentration of about 0.5 to 30 μg / ml as approximately 0.5 nM to 200 nM in cell culture, where inhibition of growth is determined 1-10 days after exposure of the tumor cells to the antibody. The antibody develops inhibitoryly in vivo if administration of the anti-UNQ733 polypeptide antibody at about 1 g / kg to about 100 mg / kg body weight results in reduction in tumor size or reduction of tumor cell proliferation within about 5 hours. days to 3 months after the first administration of the antibody, preferably between approximately 5 to 30 days. To select an anti-UNQ733 polypeptide antibody, UNQ733 Polypeptide linkage oligopeptide or small organic molecule binding polypeptide UNQ733 that induce cell death, loss of membrane integrity as indicated by absorption of propidium iodide (PI) blue triptan or 7AAD can be estimated relative to the control. An PI absorption assay can be performed in the absence of immune and complement effector cells. Tumor cells expressing UNQ733 polypeptide are incubated with either medium alone or medium containing the appropriate anti-UNQ733 polypeptide antibody (e.g. at approximately lC ^ g / ml), linking oligopeptide UNQ733 polypeptide or small organic linker molecule UNQ733 polypeptide. The cells are incubated for a period of 3 days. After each treatment, the cells are washed and taken eliquots in 12 x 75 tubes capped with a colander, 35 MI (lml per tube, 3 tubes per treatment group) to remove cell clumps. The tubes then receive PI (lC ^ g / ml). Samples can be analyzed using a FACSCAN® flow cytometer and FACSCONVERT® CellQuest software (Becton Dickinson). These anti-UNQ733 polypeptide antibodies, UNQ733 Polypeptide linkage oligopeptide, small organic linker molecules UNQ733 Polypeptide that induce statistically significant levels of cell death as determined by PI absorption, can selected as anti-ÜNQ733 polypeptide antibodies that induce cell death, UNQ733 polypeptide binding oligopeptides, or small organic molecules of UNQ733 polypeptide linkage. To monitor oligopeptide antibodies or other small organic molecules that bind to an epitope in a UNQ733 polypeptide linked by an antibody of interest, a rutionary cross-block assay as described in Antibodies, A Laboratory Manual, Cold Spring Harbor Laboratory, Ed Harlow and David Lane (1988), can be performed. This assay can be used to determine if an oligopeptide antibody or other small organic test molecule binds the same site or epitope as a known anti-UNQ733 polypeptide antibody. Alternatively or additionally, epitope mapping can be performed by methods known in the art. For example, the antibody sequence can be mutagenized such as by scanning the alanine, to identify contact residues. The mutant antibody is initially tested for binding with polyclonal antibody to ensure adequate folding. In a different method, peptides corresponding to different regions of a UNQ733 polypeptide can be used in competition assays with the test antibodies or with a test antibody and an antibody with a characterized or known epitope. E. Antibody-dependent Enzyme-Mediated Prodroga Therapy (ADEPT = Antibody Dependent Enzyme Mediated Prodrug Therapy) The antibodies of the present invention can also be employed in ADEPT by conjugating the antibody to a prodrug activation enzyme that converts a prodrug (eg, a chemotherapeutic agent). peptidyl, see O81 / 01145) to an active anti-cancer drug. See, for example, WO 88/07378 and U.S.A. Patent Number 4,975,278. The enzyme component of the immunoconjugate useful for ADEPT includes any enzyme capable of acting in a prodrug in such a way that it converts it into its more active cytotoxic form. Enzymes that are useful in the method of this invention include but are not limited to alkaline phosphatase useful for converting phosphate-containing prodrugs into free drugs; arylsulfatase useful for converting sulfate-containing prodrugs into free drugs; aminase cytokine useful for converting 5 non-toxic flourocytocin into the anti-cancer drug, 5 fluorouracil; proteases such as serratia protease, thermolysin subtilisin, carboxypeptidase and cathepsins (such as cathepsins B and L), which are useful for converting peptide containing prodrugs into free drugs; D-alanylcarboxypeptidases, useful for converting prodrugs containing D-amino acid substituents; enzymes that contain carbohydrates such as ß-galactosidase and neuraminidase useful for converting glycosylated prodrugs into free drugs; ? -lactamase useful for converting drugs derivatized with? -lactams into free drugs; and penicillin amidases such as penicillin V amidase or penicillin G amidase useful for converting derivatized drugs into their amine nitrogens with phenoxyacetyl or phenylacetyl groups, respectively in free drugs. Alternatively, antibodies with enzymatic activity, also known in the art as "aczymes", can be used to convert the prodrugs of the invention into free active drugs (see for example Massey, Nature 328: 457-458 (1987)). Antibody-aczyme conjugates can be prepared as described herein for delivery of the aczyme to a population of tumor cells. The enzymes of this invention can be covalently linked to anti-UNQ733 antibodies by techniques well known in the art such as the use of heterobifunctional interlacing reagents discussed above. Alternatively, fusion proteins and comprise at least the antigen binding region of an antibody of the invention linked to at least a functionally active portion of an enzyme of the invention, can be constructed using recombinant DNA techniques well known in the art ( See, for example, Neuberger et al., Nature 312: 604-608 (1984) F. Anti-UNQ733 Polypeptide Antibody Variants In addition to the anti-UNQ733 polypeptide antibodies described herein, it is contemplated that antibody variants of anti-UNQ733 polypeptide Anti-UNQ733 polypeptide antibody variants can be prepared by introducing appropriate nucleotide changes into the coding DNA and / or by synthesis of the desired antibody Those of skill in the art will appreciate that changes in amino acids can alter post-translational processes of the anti-UNQ733 polypeptide antibody, such as changing the number or position of gliol sites cosilation or alter the characteristics of membrane anchorage. Variations in anti-UNQ733 polypeptide antibodies described herein can be performed for example using any of the techniques and guides for conservative and non-conservative mutations established for example in U.S. Patent No. 5,364,934. Variations can be a substitution, deletion or insertion of one or more codons encoding the antibody that results in a change in the amino acid sequence as compared to the native sequence polypeptide or antibody. Optionally, the variation is by substitution of at least one amino acid with any other amino acid in one or more of the anti-UNQ733 polypeptide antibody domains. A guide to determine which amino acid residue can be inserted, replaced or eliminated without adversely affecting the desired activity can be found by comparing the sence of the anti-UNQ733 Polypeptide antibody with that of known homologous protein molecules and minimizing the number of amino acid sequence changes made in regions of high homology. Amino acid susbstitutions may be the result of replacing an amino acid with another amino acid having similar structural and / or chemical properties such as the replacement of a leucine with a serine, ie, conservative amino acid replacements. Insertions or deletions can optionally be in the range of approximately 1 to 5 amino acids. The allowed variation can be determined by systematically performing, inserting, deleting or substituting amino acids in the sequence and testing the resulting variations for activity exhibited by the parent sequence. Anti-UNQ733 polypeptide antibody and UNQ733 polypeptide fragment are provided herein. These fragments may be truncated at the N-terminus or C-terminus or may lack internal residues, for example when compared to a native antibody or integral length protein. Certain fragments lack amino acid residues that are not essential for a desired biological activity of the anti-UNQ733 antibody or UNQ733 polypeptide. Anti-UNQ733 antibody and UNQ733 polypeptide fragments can be prepared by any of a number of conventional techniques. Peptide fragments desired can be chemically synthesized. An alternative approach involves generating fragments of antibody or polypeptide by enzymatic digestion, for example by treating the protein with an enzyme known to cleave protein at sites defined by particular amino acid residues or by digesting the DNA with suitable restriction enzymes and isolating the fragment. wanted. Yet another convenient technique involves isolating and amplifying a DNA fragment encoding a desired polypeptide or antibody fragment by polymerase chain reaction (PCR). Oligonucleotides defining the desired ends of the DNA fragment are used in the 5 'and 3' primers and PCR. Preferably, fragments of polypeptide UNQ733 and antibody and anti-UNQ733 share at least one biological and / or immunological activity with the native anti-UNQ733 polypeptide antibody or the UNQ733 polypeptide described herein. In particular embodiments, conservative substitutions of interest are illustrated in Table 6 under the heading of preferred substitutions. If these substitutions result in a change in biological activity, then more substantial changes called exemplary substitutions in Table 6, or as described more below with reference to amino acid classes, are introduced and the products are monitored. Table 6 Substantial modifications based on immunological identity of the anti-UNQ733 antibody or UNQ733 polypeptide are achieved by selecting substitutions that differ significantly in their effect by maintaining (a) the major structure of the polypeptide in the area of substitution, for example as a helical or of daughter, (b) the load or hydrophobicity of the molecule at the target site or (c) the volume of the side chain. Amino acids are grouped according to similarities in the properties of their side chains (in AL Lehninger, in Biochemistry, second ed., Pp. 73-75, orth Publishers, New York (1975)): (1) non-polar: Ala ( A), Val (V), Leu (L), lie (I), Pro (P), Phe (F), Trp (W), Met (M) (2) polar without charge: Gly (G), Ser (S), Thr (T), Cis (C), Tyr (Y), Asn (N), Gln (Q) (3) Acidic: Asp (D), Glu (E) (4) Basic: Lys (K) ), Arg (R), His (H) Alternately, residues of natural origin can be divided into groups based on common side chain properties: (1) hydrophobic: Norleucine, Met, Ala, Val, Leu, lie; (2) neutral neurophilics: Cis, Ser, Thr, Asn, Gln; (3) Acidics: Asp, Glu; (4) basic: His, Lys, Arg; (5) residues that influence chain orientation: Gly, Pro; (6) aromatics: Trp, Tyr, Phe. Non-conservative substitutions involve exchanging a member of one of these classes for another class. These substituted residues can also be introduced at the conservative substitution sites or more preferably at the remaining (non-conserved) sites. Variations can be made using methods known in the art such as oligonucleotide-mediated mutagenesis (site-directed), alanine scanning and PCR mutagenesis. Site-directed mutagenesis [Cárter et al., Nucí. Acids Res., 1_3: 4331 (1986); Zoller et al., Nucí. Acids Res., 10: 6487 (1987)], cassette mutagenesis [Wells et al., Gene, 3_4: 315 (1985)], restriction reselection mutagenesis [Wells et al., Philos. Trans. R. Soc. London SerA, 317: 415 (1986)] or other known techniques, can be performed on the cloned DNA to produce the polypeptide antibody anti-UNQ733 variant polypeptide DNA UNQ733. Scanning amino acid analysis can also be used to identify one or more amino acids on a contiguous sequence. Among the preferred scanning amino acids are relatively small neutral amino acids. These amino acids include alanine, glycine, serine and cysteine. Alanine is typically a preferred scanning amino acid among this group, because it removes the side chain beyond the beta carbon and is less likely to alter the main chain conformation of the variant [Cunningham and Wells, Science, 244: 1081-1085 (1989)]. Alanine is also typically referred to because it is the most common amino acid. In addition, it is frequently found in both buried and exposed positions [Creighton, The Proteins, (W.H. Freeman &Co., N.Y.); Chothia, J. Mol. Biol. , 150: 1 (1976)]. If the alanine substitution does not produce adequate amounts of variant, an isothermal amino acid may be employed. Any cysteine residue not involved in maintaining the proper conformation of the anti-UNQ733 polypeptide antibody or UNQ733 polypeptide, can also be substituted, generally with serine to improve the oxidative stability of the molecule and avoid aberrant entanglement. In contrast, one or more cysteine bonds can be added to the anti-UNQ733 antibody or UNQ733 polypeptide to improve its stability (particularly when the antibody is an antibody fragment such as Fv fragment). A particularly preferred type of substitution variants involves replacing one or more hypervariable region residues of a parent antibody (eg, a human or humanized antibody). In general, the resulting variants or variants selected for further development will have improved biological properties with respect to the parent antibody from which they are generated. A convenient way to generate these substitution variants involves affinity maturation using phage display. Briefly, several hypervariable region sites (for example 6 to 7 sites) are mutated to generate all possible amino substitutions at each site. The antibody variants thus generated are displayed in a monovalent form of phagefilamentous particles as fusions to the gene III product of M13 packaged within each particle. The phage display variants are then monitored for their biological activity (e.g. binding affinity) as described herein. In order to identify candidate hypervariable region sites for modification, alanine scanning mutagenesis can be performed to identify hypervariable region residues that contribute significantly to antigen binding. Alternatively or additionally, it may be beneficial to analyze a crystal structure of the antigen complex of an antibody to identify contact points between the antibody and human UNQ733 polypeptide. These contact residues and neighboring residues are candidates for substitution according to the techniques elaborated here. Once these variants are generated, the panel of variants is subjected to supervision as described herein and antibodies with superior properties in one or more relevant assays can be selected for further development. Nucleic acid molecules encoding amino acid sequence variants of the anti-UNQ733 antibody are prepared by a variety of methods known in the art. These methods include but are not limited to, isolation of a natural source (in the case of naturally occurring amino acid sequence variants) or preparation by oligonucleotide-mediated (or site-directed) mutagenesis, PCR mutagenesis and cassette mutagenesis of a variant prepared previously or a non-variant version of the antibody anti-UNQ733. G. Modifications of anti-UNQ733 antibodies and UNQ733 polypeptides Covalent modifications of anti-UNQ733 polypeptide antibodies and UNQ733 polypeptides are included within the scope of this invention. One type of covalent modification includes reacting targeted or target amino acid residues of an anti-UNQ733 antibody or UNQ733 polypeptide with an organic derivatizing agent that is capable of reacting with selected side chains or the N or C terminal residues of the anti-UNQ733 polypeptide antibody or UNQ733 polypeptide. Derivatization with bifunctional agents is useful, for example to crosslink anti-UNQ733 antibody or UNQ733 polypeptide to a water-insoluble support matrix or surface for use in the method for purifying anti-UNQ733 antibodies and vice versa. Entanglement agents commonly employed include for example 1,1-bis (diazoacetyl) -2-phenylethane, glutaraldehyde, N-hydroxysuccinimide esters, for example, esters with 4-azidosalicylic acid, homobifunctional imidoesters, including disuccinimidyl esters such as 3,3 ' -dithiobis (succinimidylpropionate), bifunctional maleimides such as bis-N-maleimide-1,8-octane and agents such as methyl-3- [(p-azidophenyl) ditho] propioimidate. Other modifications include deamidation of glutaminyl and asparaginyl residues to the corresponding glutamyl and aspartyl residues, respectively, hydroxylation of proline and lysine, phosphorylation of hydroxyl groups of seryl or trionyl residues, methylation of the sineral chain a-amino groups lysine arginine and histidine [ TEA Creighton, Proteins: Structure and Molecular Properties, W.H. Freeman & Co., San Francisco, pp. 79-86 (1983)], acetylation of N-terminal amine and amidation of any C-terminal carboxyl group. Another type of covalent modification of the anti-UNQ733 antibody or UNQ733 polypeptide included within the scope of this invention comprises altering the native glycosylation pattern of the antibody or polypeptide. "Altering the native glycosylation pattern" herein is intended for purposes which means eliminating one or more carbohydrate moieties that are found in the anti-UNQ733 antibody or native sequence UNQ733 polypeptide (either by removing the underlying glycosylation site or by removing the glycosylation by chemical and / or enzymatic means), and / or add one or more sites of glycosylation that are not present in the anti-UNQ733 antibody or native sequence UNQ733 polypeptide. In addition, the phrase includes qualitative changes in the glycosylation of native proteins, involving a change in the nature and proportions of the various carbohydrate moieties present. The glycosylation of antibodies and other polypeptides is typically already N-linked or O-linked. N-linked refers to the connection of the carbohydrate moiety to the side chain of an asparagine residue. The tripeptide sequences asparagine-X-serine and asparagine-X-threonine, where X is any amino acid except proline, are the recognition sequences for enzymatic connection of the carbohydrate portion to the side chain asparagine. In this way, the presence of any of these tripeptide sequences in a polypeptide creates a potential glycosylation site. O-linked glycosylation refers to the connection of one of the sugars N-acetylgalactosamine, galactose or xylose to a hydroxyamino acid, most commonly serine or trionine, although 5-hydroxyproline or 5-hydroxylysine may also be employed. The addition of glycosylation sites to anti-UNQ733 antibody or UNQ733 polypeptide is conveniently achieved by altering the amino acid sequence such that it contains one or more of the above described tripeptide sequences (for N-linked glycosylation sites). The alteration may also be made by the addition of, or substitution by, one or more serine or trionine residues to the sequence of the original anti-UNQ733 antibody or original UNQ733 polypeptide (for O-linked glycosylation sites). The amino acid sequence of anti-UNQ733 antibody or UNQ733 polypeptide can be optionally altered through changes to the DNA, particularly by rasing the DNñ encoding the anti-UNQ733 antibody or UNQ733 polypeptide in preselected bases such that codons are generated which result in the desired amino acids. Another means of increasing the number of carbohydrate moieties in the anti-UNQ733 antibody or UNQ733 polypeptide is by chemical or enzymatic coupling of glycosides to the polypeptide. These methods are described in the art, for example in O 87/05330 published September 11, 1987, and in Aplin and Wriston, CRC Crit. Rev. Biochem. , pp. 259-306 (1981). The removal of carbohydrate moieties present in the anti-UNQ733 antibody or UNQ733 polypeptide can achieved in chemical or enzymatic form or by mutational substitution of codons that encode the amino acid residues that serve as targets for glycosylation. Chemical deglycosylation techniques are known in the art and are described, for example, by Hakimuddin, et al., Arch. Biochem. Biophis., 259: 52 (1987) and by Edge et al., Anal. Biochem., 118: 131 (1981). Enzymatic cleavage of carbohydrate moieties in polypeptides can be achieved by the use of a variety of endo- and exo-glycosidases as described by Thotakura et al., Eth. Enzymol., 138: 350 (1987). Another type of covalent modification of anti-UNQ733 antibody or UNQ733 polypeptide comprises linking the antibody or polypeptide to one of a variety of non-proteinaceous polymers, for example polyethylene glycol (PEG), polypropylene glycol or polyoxyalkylenes, in the manner set forth in the patents of the USA numbers 4,640,835; 4,496,689; 4,301,144; 4,670,417; 4,791,192 or 4,179,337. The antibody or polypeptide can also be entrapped in microcapsules prepared for example by coacervation or interfacial polymerization techniques (for example hydroxymethylcellulose or gelatin microcapsules and polymethylmethylmethacrylate microcapsules respectively), in systems of colloid drug supply (for example liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules), or in macroemulsions. These techniques are described in Remington's Pharmaceutical Sciences, 16th edition, Oslo, A., Ed., (1980). The anti-UNQ733 antibody or UNQ733 polypeptide of the present invention can also be modified in a form to produce chimeric molecules comprising anti-UNQ733 antibody or UNQ733 polypeptide fused together, heterologous polypeptide or amino acid sequence. In one embodiment, this chimeric molecule comprises a fusion of the anti-UNQ733 antibody or UNQ733 polypeptide with a tag polypeptide that provides an epitope to which an anti-tag antibody can selectively bind. The epitope tag is generally placed at the amino or carboxyl terminus of the anti-UNQ733 antibody or UNQ733 polypeptide. The presence of these epitope-tagged forms of the anti-UNQ733 antibody or UNQ733 polypeptide can be detected using an antibody against the tag polypeptide. Also providing the epitope tag allows the anti-UNQ733 antibody or UNQ733 polypeptide to be easily purified by purification of affinity using an anti-tag antibody or another type of affinity material that binds to the epitope tag. Various tag polypeptides and their respective antibodies are well known in the art. Examples include poly-histidine (poly-his) or poly-histidine-glycine (poly-his-gly) labels; the polypeptide flu HA tag and its antibody 12CA5 [Field et al., Mol. Cell. Biol. , 8 ^: 2159-2165 (1988)]; the c-myc tag and the 8F9, 3C7, 6E10, G4, B7 and 9E10 antibodies thereof [Evan et al., Molecular and Cellular Biology, 5: 3610-3616 (1985)]; and the Herpes Simplex virus glycoprotein D (gD) tag and its antibody [Paborsky et al., Protein Engineering, 3 (6): 547-553 (1990)]. Other tag polypeptides include the Flag peptide [Hopp et al., BioTechnology, 6: 1204-1210 (1988)]; The KT3 epitope peptide [Martin et al., Science, 255: 192-194 (1992)]; an epitope peptide from -tubulin [Skinner et al., J. Biol. Chem., 266: 15163-15166 (1991)]; and the T7 gene 10 peptide tag [Lutz-Freyermuth et al., Proc. Nati Acad. Sci. USA, 87: 6393-6397 (1990)]. In an alternate embodiment, the chimeric molecule may comprise a fusion of the anti-UNQ733 antibody or UNQ733 polypeptide with an immunoglobulin or a particular region of an immunoglobulin. For a way bivalent of the chimeric molecule (also referred to as an "immunoadhesin"), this fusion can be to the Fe region of an IgG molecule. Preferred IgG fusion include replacement of a soluble form (deleted or inactivated transmembrane domain) of an anti-UNQ733 antibody or UNQ733 polypeptide instead of at least one variable region within an Ig molecule. In a particularly preferred embodiment, the immunoglobulin fusion includes the hinge, CH2 and CH3 or the hinge CHi, CH2 and CH3 regions of an IgG1 molecule. For the production of immunoglobulin fusions see also the US patent. number 5,428,130 granted on June 27, 1995. H. Preparation of Anti-UNQ733 Antibodies and UNQ733 Polypeptide The following description relates primarily to production of anti-UNQ733 and UNQ733 polypeptide antibodies by culturing cells transformed or transfected with a vector containing nucleic acid encoding UNQ733 polypeptide and anti-UNQ733 antibody. Of course it is contemplated that alternating methods, which are well known in the art, may be employed to prepare anti-UNQ733 and UNQ733 polypeptide antibodies. For example, the amino acid sequence or its portions, can be produced by direct peptide synthesis using solid phase techniques [see, for example, Stewart et al., Solid-Phase Peptide Synthesis, .H. Freeman Co. , San Francisco, CA (1969); Merrifield, J. Am. Chem. Soc. , 85: 2149-2154 (1963)]. In vitro protein synthesis can be performed using manual or automated techniques. Automated synthesis can be logged, for example, using a Synthesizer from Applied Biosystems Peptide Synthesizer (Foster City, CA) using the manufacturer's instructions. Various portions of the anti-UNQ733 antibody or UNQ733 polypeptide can be chemically synthesized separately and combined using chemical or enzymatic methods to produce the desired anti-UNQ733 antibody or desired UNQ733 polypeptide. 1. Isolation of DNA Encoding Anti-UNQ733 Antibody or UNQ733 Polypeptide DNA encoding anti-UNQ733 antibody or UNQ733 polypeptide can be obtained from a cDNA library prepared from tissue that is considered to possess the anti-UNQ733 antibody or UNQ733 polypeptide mRNA and to express it at a detectable level. Accordingly, anti-UNQ733 antibody DNA or human UNQ733 polypeptide can be conveniently obtained from a library cDNA prepared from human tissue. The gene encoding anti-UNQ733 antibody or UNQ733 polypeptide can also be obtained from a genomic library. or by known synthetic methods (e.g., automated nucleic acid synthesis). Libraries can be monitored with probes (such as oligonucleotides of at least about 20-80 bases) designed to identify the gene of interest or the protein encoded by the. Supervision of the genomic library or cDNA with the selected probe can be performed using standard procedures such as described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989). An alternative means for isolating the gene encoding the anti-UNQ733 antibody or UNQ733 polypeptide is to use the PCR methodology [Sambrook et al., Supra; Dieffenbach et al., PCR Primer: A Laboratory Manual (Cold Spring Harbor Laboratory Press, 1995)]. Techniques for monitoring a cDNA library are well known in the art. The oligonucleotide sequences selected as probes should be of sufficient length and sufficiently unambiguous that false positives are reduced. The oligonucleotide is preferably labeled so that it can Detected before DNA hybridization in the library that is monitored. Labeling methods are well known in the art, and include the use of radiolabels such as ATP labeled 32P, biotinylation or enzyme labeling. Hybridization conditions, including moderate severity and high severity, are provided by Sambrook et al. , supra. Sequences identified in these library monitoring methods can be compared and aligned with other known sequences to be deposited and available in public databases such as GenBank or other private sequence databases. Sequence identity (already at the amino acid or nucleotide level) within defined regions of the molecule or through the integral length sequence, can be determined using methods known in the art and as described herein. Nucleic Acids having the protein coding sequence can be obtained by monitoring cDNA or selected genomic libraries using the deduced amino acid sequence described here for the first time, and if necessary using conventional primer extension methods as described in Sambrook et al. ., supra, to detect precursors and mRNA processing intermediates that may not have been reverse transcribed in cDNA. 2. Selection and Transformation of Host Cells Host cells are transfected or transformed with expression or cloning vectors described herein for production of anti-UNQ733 antibody or UNQ733 polypeptide and cultured in modified conventional nutrient medium as appropriate to induce promoters, select transformants, or amplify the genes that encode the desired sequences. The culture conditions, such as medium, temperature, pH and the like, can be selected by the person skillfully without due experimentation. In general, principles, protocols and practical techniques to maximize cell culture productivity can be found in Mammalian Cell Biotechnology: a Practical Approach, M. Butler, ed. (IRL Press, 1991) and Sambrook et al. , supra. Methods of transfection of eukaryotic cells and transformation of prokaryotic cells are known to the person with ordinary dexterity, for example, CaCl 2, CaPC > 4, measured by liposomes and electroporation. Depending on the host cell used, it is performed transformation using appropriate standard techniques for these cells. The calcium treatment employing calcium chloride, as described in Sambrook et al., Supra, or electroporation in general is employed for prokaryotes. Infection with Agrobacterium tumefaciens is used for the transformation of certain plant cells, as described by Shaw et al., Gene, 2J3: 315 (1983) and WO 89/05859 published June 29, 1989. For mammalian cells without these cell walls, the calcium phosphate precipitation method of Graham and van der Eb, Virology, 52: 456-457 (1978) can be used. General aspects of transitions of host system of mammalian cells have been described in U.S. Patent No. 4,399,216. Transformations in yeast are typically carried out according to the method of Van Solingen et al., J. Bact., 130: 946 (1977) and Hsiao et al., Proc. Nati Acad. Sci. (USA), 76: 3829 (1979). However, other methods for introducing DNA into cells, such as by nuclear microinjection, electroporation, fusion of bacterial protoplasts with intact cells, or polications, for example polybrene, polyornithine, may also be employed. For various techniques for transforming mammalian cells, see Keown et al., Method in Enzymology, 185: 527-537 (1990) and Mansour et al., Nature, 336: 348-352 (1988). Convenient host cells for cloning or expressing the DNA in the vectors present, include prokaryotic, yeast or higher eukaryotic cells. Suitable prokaryotes include but are not limited to eubacteria, such as Gram-negative or Gram-positive organisms, for example, Enterobacteriaceae such as E. coli. Various strains of E. coli are publicly available such as strain E. coli K12 MM294 (ATCC 31,446); E. coli X1776 (ATCC 31,537); the strain E. coli W3110 (ATCC 27,325) and K5 772 (ATCC 53, 635). Other suitable prokaryotic host cells include Enterobacteriaceae such as Escherichia, e.g., E. coli, Enterobacter, Erwinia, Klebsiella, Proteus, Salmonella, e.g., Salmonella typhimurium, Serratia, e.g., Serratia marcescans, and Shigella, as well as Bacilli such as B. subtilis and B. licheniformis (for example, B. licheniformis 41P described in DD 266,710 published April 12, 1989), Pseudomonas such as P. aeruginosa, and Streptomyces. These examples are illustrative rather than limiting. Strain 3110 is a particularly preferred parent or host host because it is a common host strain for fermentations of recombinant DNA product. From In preference, the host cell secretes minimal amounts of proteolytic enzymes. For example, strain W3110 can be modified to effect a genetic mutation in genes encoding proteins endogenous to the host, with examples of these hosts including strain 1A2 E. coli W3110, which has the complete tonA genotype; strain 9E4 E. coli 3110, which has the complete genotype tonA ptr3; strain 27C7 E. coli 3110 (ATCC 55,244), which has the complete genotype tonA ptr3 phoA E15 (argF-lac) 169 degP ompT kanr; strain 37D6 E. coli W3110, which has the complete genotype tonA ptr3 phoA E15 (argF-lac) 169 degP ompT rbsl ilvG kanr; strain 40B4 E. coli W3110, which is strain 37D6 with the deletion mutation degP not resistant to kanamycin; and an E. coli strain having mutant periplasmic protease described in U.S. Patent No. 4,946,783 issued Aug. 7, 1990. Alternately, in vitro cloning methods, e.g., PCR or other nucleic acid polymerase reactions, are convenient. . Whole-length antibody, antibody fragments, and antibody fusion proteins can be produced in bacteria, particularly when Fe effector function and glycosylation are not required, such as when the therapeutic antibody is conjugated to an agent cytotoxic (eg, a toxin) and the immunoconjugate itself shows effectiveness in killing tumor cells. Full-length antibodies have longer half-lives in circulation. Production in E. coli is faster and more efficient in cost. For expression of antibody fragments and polypeptides in bacteria, see, for example, U.S. 5,648,237 (Cárter et. Al.), U.S. 5,789,199 (Joly et al.), And U.S. 5,840,523 (Simmons et al.) Which describes the signal sequences and regio of initiation trainduction (TIR equal to translation initiation regio) to optimize expression and secretion, these patents are incorporated herein by reference. After expression, the antibody is isolated from the paste of E. coli cells in a soluble fraction and can be purified for example through a protein A or G column depending on the isotope. Final purification can be carried out similar to the process for purifying antibody expressed for example, in CHO cells. In addition to prokaryotes, eukaryotic microbes such as filamentous fungi or yeasts are suitable cloning or expression hosts for anti-UNQ733 antibody or UNQ733 polypeptide coding vectors. Saccharomyces cerevisiae is a commonly lower eukaryotic host microorganism employee. Others include .Schizosaccharomyces pombe (Beach and Nurse, Nature, 290: 140 [1981]; EP 139,383 published May 2, 1985); Kluyveromyces hosts (U.S. Patent No. 4,943,529; Fleer et al., Bio / Technology, 9: 968-975 (1991)) such as, for example, K. lactis (MW98-8C, CBS683, CBS4574, Louvencourt et al., J. Bacteriol., 15 (2) : 737-742 [1983]), K. fragilis (ATCC 12,424), K. bulgaricus (ATCC 16,045), K. wickeramii (ATCC 24,178), K. waltii (ATCC 56,500), K. drosophilarum (ATCC 36,906; Van den Berg et al., Bio / Technology, 8: 135 (1990)), K. thermotolerans, and K. marxianus; yarrowia (EP 402,226); Pichia pastoris (EP 183,070; Sreekrishna et al., J. Basic Microbiol., 28: 265-278 [1988]); Candida; Trichoderma reesia (EP 244,234); Neurospora crassa (Case et al., Proc. Nati, Acad. Sci. USA, 76: 5259-5263 [1979]); Schwanniomyces such as Schwanniomyces occidentalis (EP 394,538 published October 31, 1990); and filamentous fungi such as, for example, Neurospora, Penicillium, Tolypocladium (WO 91/00357 published January 10, 1991), and Aspergillus hosts such as A. nidulans (Ballance et al., Biochem. Biophys. Res. Commun., 112: 284-289 [1983], Tilburn et al., Gene, 26: 205-221 [1983], Yelton et al., Proc. Nati, Acad. Sci. USA, 81: 1470-1474 [1984]) and A. niger (Kelly and Hynes, EMBO J., 4: 475-479 [1985]). Methylotropic yeasts are convenient herein and include, but are not limited to, yeast capable of growing in methanol selected from the genera consisting of Hansenula, Candida, Kloeckera, Pichia, Saccharomyces, Torulopsis, and Rhodotorula. A list of specific species that are examples of this class of yeasts can be found in C. Anthony, The Biochemistry of Methylotrophs, 269 (1982). Convenient host cells for expression of anti-UNQ733 antibody or glycosylated UNQ733 polypeptide are derived from multicellular organisms. Examples of invertebrate cells include insect cells such as Drosophila of S2 and Espodoptera Sf9, as well as plant cells, such as cell cultures of cotton, corn, potato, soy, petunia, tomato, and tobacco. Numerous strains of baculoviruses and variants and corresponding hosts host permissive insects such as Spodoptera frugiperda (caterpillar), Aedes aegypti (mosquito), Aedes albopictus (mosquito), Drosophila melanogaster (fruit fly), and Bombyx morí have been identified . A variety of viral strains for transfection are publicly available, for example the L-1 variant of Autographa californica NPV and strain Bm-5 from Bombyx morí NPV, and these viruses can be used as the virus here according to the present invention, particularly for transfection of Spodoptera frugiperda cells. However, it has been the greatest interest in vertebrate cells, and the propagation of vertebrate cells in culture (tissue culture) has become a routine procedure. Examples of useful mammalian host cell lines are monkey kidney CVl line, transformed by SV40 (COS-7, ATCC CRL 1651); human embryonic kidney line (293 or 293 cells subcloned for growth in suspension culture, Graham et al., J. Gen Virol. 36:59 (1977)); babe hamster kidney cells (BHK, ATCC CCL 10); Chinese hamster ovary cells / -DHFR (CHO, Urlaub et al., Proc. Nati, Acad. Sci. USA 77: 4216 (1980)); mouse sertoli cells (TM4, Mather, Biol. Reprod. 23: 243-251 (1980)); monkey kidney cells (CVl ATCC CCL 70); African green monkey kidney cells (VERO-76, ATCC CRL-1587); human cervical carcinoma cells (HELA, ATCC CCL 2); canine kidney cells (MDCK, ATCC CCL 34); buffalo rat liver cells (BRL 3A, ATCC CRL 1442); human lung cells (138, ATCC CCL 75); human liver cells (Hep G2, HB 8065); mouse breast tumor (MMT 060562, ATCC CCL51); TRI cells (Mather et al., Annals N.Y. Acad. Sci. 383: 44-68 (1982)); MRC 5 cells; FS4 cells; and human hepatoma line (Hep G2). Host cells are transformed with the above-described cloning or expression vectors for production of anti-UNQ733 antibody or UNQ733 polypeptide and cultured in conventional nutrient medium modified as appropriate to induce promoters, select transformants or amplify the genes encoding the desired sequences. 3. Selection and Use of a Replicable Vector The nucleic acid (e.g., cDNA or genomic DNA) encoding anti-UNQ733 antibody or UNQ733 polypeptide can be inserted into a replicable vector for cloning (DNA amplification) or for expression. Various vectors are publicly available. The vector can, for example, be in the form of a plasmid, cosmid, viral particle, or phage. The appropriate nucleic acid sequence can be inserted into the vector by a variety of methods. In general, DNA is inserted into one or several appropriate restriction endonuclease sites using techniques known in the art. Vector components generally include, but are not limited to one or more of a signal sequence, an origin of replication, one or more marker genes, an improved element, a promoter, and a transcription termination sequence. Construction of convenient vectors containing one or more of these components employ standard ligation techniques that are known to the person with skill. The UNQ733 polypeptide can be reproduced recombinantly not only directly but also as a fusion polypeptide with a heterologous polypeptide, which may be a signal sequence or other polypeptide having a specific cleavage site at the N-terminus of the mature protein or polypeptide. In general, the signal sequence may be a component of the vector, or it may be a part of the DNA encoding UNQ733 polypeptide or anti-UNQ733 antibody that is inserted into the vector. The signal sequence may be a prokaryotic signal sequence selected for example from the group of alkaline phosphatase, penicillinase, LPP, or thermostable enterotoxin II leaders. For yeast secretion, the signal sequence may be for example the yeast invertase leader, leader factor (including factor leaders at Kluyveromyces, the latter being described in U.S. Patent No. 5,010,182), or acid phosphatase leader, the leader albicans glucoamylase (EP 362,179 published April 4, 1990), or the signal described in WO 90/13646 published November 15, 1990. In mammalian cell expression, mammalian signal sequences can be employed to direct the secretion of the protein, such as signal sequences of secreted polypeptides thereof or related species, as well as viral secretory leaders. Both expression and cloning vectors contain a nucleic acid sequence that allows the vector to replicate in one or more selected host cells. These sequences are well known for a variety of bacteria, yeasts and viruses. The origin of the application of plasmid pBR322 is suitable for most Gram-negative bacteria, the origin of plasmid 2μ is suitable for yeast, and various viral origins (SV40, polyoma, adenovirus, VSV or BPV) are useful for cloning vectors in mammalian cells. Expression and cloning vectors will typically contain a selection gene, also termed a selectable marker. Typical selection genes encode proteins' that (a) confer resistance to antibiotics or other toxins, for example ampicillin, neomycin, methotrexate, or tetracycline, (b) complement auxotropic deficiencies, or (c) provide critical nutrients not available from complex media,. for example the gene encoding D-alanine racemase for bacilli. An example of selection markers conentientes for mammalian cell are those that allow the identification of competent cells to absorb nucleic acid that encodes anti-UNQ733 antibody or UNQ733 polypeptide, such as DHFR or thymidine kinase. An appropriate host cell when wild-type DHFR is used in the CHO cell line deficient in DHFR activity, prepared and propagated as described by Urlaub et al., Proc. Nati Acad. Sci. USA, 77: 4216 (1980). A suitable selection gene for use in yeast is the trpl gene present in yeast plasmid YRp7 [Stinchcomb et al., Nature, 282: 39 (1979); Kingsman et al., Gene, 7: 141 (1979); Tschemper et al., Gene, 10: 157 (1980)]. The trpl gene provides a selection marker for a mutant strain of yeast lacking the ability to develop or grow in tryptophan, for example ATCC No. 44076 or PEP4-1 [Jones, Genetics, 85:12 (1977)]. Expression and cloning vectors usually contain a promoter operably linked to the nucleic acid sequence encoding anti- body antibody.

UNQ733 or UNQ733 polypeptide to direct mRNA synthesis. Promoters recognized by a variety of potential host cells are well known. Promoters suitable for use with prokaryotic hosts include the promoter /? -lactamase and lactose systems [Chang et al., Nature, 275: 615 (1978); Goeddel et al., Nature, 281: 544 (1979)], alkaline phosphatase, a tryptophan (trp) promoter system [Goeddel, Nucleic Acids Res., 8: 4057 (1980); EP 36,776], and hybrid promoters such as the tac promoter [de Boer et al., Proc. Nati Acad. Sci. USA, 80: 21-25 (1983)]. Promoters for use in bacterial systems also contain a Shine-Dalgarno (S.D.) sequence operably linked to DNA encoding anti-UNQ733 antibody or UNQ733 polypeptide. Examples of suitable promoter sequences for use with yeast hosts include promoters for 3-phosphoglycerate kinase [Hitzeman et al., J. Biol. Chem., 255: 2073 (1980)] or other glycolytic enzymes [Hess et al., J Adv. Enzyme Reg., 7: 149 (1968); Holland, Biochemistry, 17: 4900 (1978)], such as enolase, glyceraldehyde-3-phosphate dehydrogenase, hexokinase, pyruvate decarboxylase, phosphofructokinase, glucose-6-phosphate isomerase, 3-phosphoglycerate mutase, pyruvate kinase, triosephosphate isomerase, phosphoglucose isomerase, and glucokinase. Other yeast promoters that are inducible promoters have the additional advantage of controlled transcription by growth conditions, are the promoter regions for alcohol dehydrogenase 2, isocitochrome C, acid phosphatase, degradative enzymes associated with nitrogen metabolism, metallothionein, glyceraldehyde-3-phosphate dehydrogenase, and enzymes responsible for the use of maltose and galactose. Suitable vectors and promoters for use in yeast expression are further described in EP 73, 657. Transcription of anti-UNQ733 antibody or UNQ733 polypeptide of vectors in mammalian host cells is controlled for example by promoters obtained from virus genomes such as polyoma virus, avian pustulation virus (UK 2,211,504 published July 5, 1989), adenovirus (such as Adenovirus 2), bovine papilloma virus, avian sarcoma virus, cytomegalovirus, a retrovirus, hepatitis B virus and virus of Simium 40 (SV40), of heterologous mammalian promoters, for example the actin promoter or an immunoglobulin promoter, and of heat shock promoters, provided that these promoters are compatible with the host cell systems. Transcription of a DNA encoding the anti-UNQ733 antibody or UNQ733 polypeptide by higher eukaryotes can be increased by inserting an enhancer sequence into the vector. Mej orators are simple DNA action elements, usually from about 10 to 300 bp, which act on a promoter to increase their transcription. Many enhancer sequences are now known from mammalian genes (globin, elastase, albumin, α-fetoprotein and insulin). Typically, however, a virus enhancer of eukaryotic cells will be used. Examples include the SV40 enhancer on the late side of the replication origin (bp 100-270), the cytomegalovirus early enhancer or promoter, the polyoma enhancer on the late side of the replication origin, and adenovirus enhancers. The enhancer can be combined in the vector at a 5 'or 3' position to the anti-UNQ733 antibody coding sequence or UNQ733 polypeptide but is preferably located at a 5 'site of the promoter. Expression vectors employed in eukaryotic host cells (yeast, fungi, insects, plants, animals, humans or nucleated cells of other multicellular organisms) will also contain sequences necessary for the termination of transcription and to stabilize the mRNA. These sequences are commonly available from the regions without 5 ', occasionally 3' translation of DNAs or eukaryotic or viral or cDNAs. These regions contain nucleotide segments transcribed as polyadenylated fragments in the untranslated portion of the mRNA encoding anti-UNQ733 antibody or UNQ733 polypeptide. Still other vector methods, and suitable host cells for adaptation to the synthesis of anti-UNQ733 antibody or UNQ733 polypeptide in recombinant vertebrate cell culture are described in Gething et al., Nature, 293: 620-625 (1981); Mantei et al., Nature, 281: 40-46 (1979); EP 117,060; and EP 117, 058. 4. Culturing the Host Cells The host cells employed to produce the anti-UNQ733 antibody or UNQ733 polypeptide of this invention can be cultured in a variety of media. Commercially available media such as Ham's FIO (Sigma), Minimum Essential Medium ((MEM), (Sigma), RPMI-1640 (Sigma), and Dulbecco's modified Eagle Medium ((DMEM), Sigma) are suitable for culturing host cells In addition, any of the means described in Ham et al., Meth. Enz. 58:44 (1979), Barnes et al., Anal. Biochem.102: 255 (1980), Patents of the U.S.A. numbers 4,767,704; 4,657,866; 4,927,762; 4,560,655; or 5,122,469; O 90/03430; WO 87/00195; or the U.S. Patent. Re. 30,985, can be used as a culture medium for the host cells. Any of these media can be supplemented as necessary with hormones and / or other growth factors (such as insulin, transferin or epidermal growth factor), salts (such as sodium chloride, calcium, magnesium and phosphate), buffers (such as HEPES), nucleotides (such as adenosine and thymidine), antibiotics (such as the drug GENTAMYCINA®), trace elements (defined as inorganic compounds usually present in final concentrations in the micro-molar range) and glucose or an equivalent energy source. Any other necessary supplements may also be included at appropriate concentrations that will be known to those skilled in the art. The culture conditions such as temperature, pH and the like are those prevly employed with the host cell selected for expression and will be apparent to the person with ordinary skill in the art.

. Detection of Gene Amplification / Expression Gene amplification and / or expression can be measured in a sample directly, for example by conventional Southern techniques, Northern technique to quantitate mRNA transcription [Thomas, Proc. Nati Acad. Sci. USA, 77: 5201-5205 (1980)], dot transfer (DNA analysis) or in situ hybridization, using an appropriately labeled probe, based on the sequences provided herein. Alternatively, antibodies that can recognize specific duplexes, including DNA duplexes, RNA duplexes, and hybrid DNA-RNA duplexes or DNA-protein duplexes, can be used. The antibodies in turn can be labeled and the assay can be carried out when the duplex is bound to a surface, such that by forming the duplex on the surface, the presence of antibody bound to the duplex can be detected. Gene expression, in alternating form can be measured by immunological methods, such as immunohistochemical staining of cells or tissue sections and cell culture assay or body fluids, to directly quantify the expression of the gene product. Useful antibodies for immunohistochemical staining and / or assay of sample fluids can be monoclonal or polyclonal and can be prepared in any mammal. Conveniently, the antibodies can be prepared against a native sequence UNQ733 polypeptide or against a synthetic peptide based on the DNA sequence provided herein or against an exogenous sequence fused to the UNQ733 polypeptide DNA and encoding a specific antibody epitope. 6. Purification of Anti-UNQ733 Antibody and UNQ733 Polypeptide Forms of anti-UNQ733 antibody and UNQ733 polypeptide can be recovered from the culture medium or from host cell lysate. If it is membrane bound, it can be detached from the membrane using a convenient detergent solution (for example Triton-X 100) or by enzymatic cleavage. Cells employed in expression of anti-UNQ733 antibody and UNQ733 polypeptide can be disrupted by various physical or chemical means, such as freeze-thaw cycles, sonication, mechanical disruption or cell lysis agents. It may be convenient to purify anti-UNQ733 antibody and UNQ733 polypeptide from recombinant cell proteins or polypeptides. The following procedures are exemplary of procedures for convenient purification: by fractionation in an ion exchange column; ethanol precipitation, HPLC; chromatography on silica or on cation exchange resin such as DEAE; chromatofocusing; SDS-PAGE; precipitation of ammonium sulfate; gel filtration using for example Sephadex G-75; Protein A Sepharose columns to remove contaminants such as IgG; and metal chelation columns for ligating epitope-tagged forms of the anti-UNQ733 antibody and UNQ733 polypeptide. Various methods of protein purification can be employed and those methods are known in the art and described for example in Deutscher, Methods in Enzymology, 182 (1990); Scopes, Protein Purification: Principles and Practice, Springer-Verlag, New York (1982). The purification step (s) selected will depend, for example, on the nature of the production process employed and the anti-UNQ733 antibody and UNQ733 polypeptide produced. When combinatorial techniques are used, the antibody can be produced intracellularly, in the periplasmic space, or directly secreted into the medium. If the antibody is produced intracellularly, as a first step, the particulate debris, whether host cells or lysed fragments, is removed, for example. by centrifugation or ultra centrifugation. Cárter et al., Bio / Technology 10: 163-167 (1992) describes a method for isolating antibodies that are secreted in the periplasmic space of E. coli. Briefly, cell paste is thawed in the presence of sodium acetate (pH 3.5), EDTA, and phenylmethylsulfonyl fluoride (PMSF) in about 30 minutes. Cellular waste can be removed by centrifugation. When the antibody is secreted in the medium, on top of these expression systems in general, they are first concentrated using a commercially available protein concentration filter, for example an Amicon or Millipore Pellicon ultrafiltration unit. A protease inhibitor such as PMSF can be included in any of the above steps to inhibit proteolysis and antibiotics can be included to prevent the growth of adventitious contaminants. The antibody composition prepared from the cells can be purified using for example hydroxylapatite chromatography, gel electrophoresis, dialysis and affinity chromatography, with affinity chromatography which is the preferred purification technique. The suitability of protein A as an affinity ligand depends on the species and isotype of any immunoglobulin Fe domain that is present in the antibody. Protein A can be used to purify antibodies that are based on human heavy?,? 2 or? 4 chains (Lindmark et al., Immunol., Meth. 62: 1-13 (1983)). Protein G is recommended for all mouse isotypes and for? 3 (Guss et al., EMBO J. 5: 1567-1575 (1986)). The matrix to which the affinity ligand is connected is most often agarose, but other matrices are available. Mechanically stable matrices such as controlled pore glass or polystyrene vinyl benzene allow for faster flow rates and shorter processing times than can be achieved with agarose. When the antibody comprises a CH3 domain, the Bakerbond ABX ™ resin (J.T. Baker, Phillipsburg, NJ) is useful for purification. Other techniques for protein purification such as fractionation in an ion exchange column, ethanol precipitation, reverse phase HPLC, silica chromatography, neparin chromatography, perfarosa® chromatography in anion or cation exchange resin (such as acid column) polyaspartic) chromatofocusing, SDS-PAGE, and precipitation with ammonium sulfate, are also available depending on the antibody to be recovered.

Following any preliminary purification caps, the mixture comprising the antibody of interest and contaminants can be subjected to low pH hydrophobic interaction chromatography using buffer already at a pH between about 2.5-4.5, preferably at low salt concentrations ( for example about 0-0.25M salt). I. Pharmaceutical Formulations Therapeutic Formulations of Anti-UNQ733 Antibodies, Linker Oligopeptides, UNQ733 Polypeptide, Small Organic or Inorganic or Organic Binding Molecules, UNQ733 Polypeptide and / or UNQ733 Polypeptides Employed in Accordance with the Present Invention, Are Prepared for Storage When Mixing Polypeptide Antibody , oligopeptide or small organic / inorganic molecule having the desired degree of purity with optional pharmaceutically acceptable carriers, excipients or stabilizers (Remington 's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)), in the form of aqueous solutions or lyophilized formulations. Acceptable carriers, excipients or stabilizers are not toxic to containers at the doses and concentrations employed, and include buffers such as acetate, Tris, phosphate, citrate and other organic acids; antioxidants including ascorbic acid and methionine; conservatives (such as octadecyldimethylbenzyl ammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl or benzyl alcohol, alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol, and m-cresol. ); low molecular weight polypeptides (less than about 10 residues); proteins such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates including glucose, mannose or dextrins; chelating agents such as EDTA; toning agents such as trehalose and sodium chloride; sugars such as sucrose, mannitol, trehalose or sorbitol; surfactant such as polysorbate; salt forming counter ions such as sodium; metal complexes (eg, Zn-protein complexes); and / or non-ionic surfactants such as TWEEN®, PLURONICS® or polyethylene glycol (PEG). The antibody preferably comprises the antibody at a concentration of between 5-200 mg / ml, preferably between 10-100 mg / ml.

The present formulations may also contain more than one active compound as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other. For example, in addition to an anti-UNQ733 antibody, UNQ733 Polypeptide binding oligopeptide, or small organic or inorganic binding molecule to UNQ733 Polypeptide, it may be convenient to include in the formulation, an additional antibody, for example a second anti-UNQ733 antibody. which binds a different epitope on the UNQ733 polypeptide, or an antibody to some other target or target such as growth factor that affects the growth of the particular cancer. Alternatively, or additionally, the composition may further comprise a chemotherapeutic agent, cytotoxic agent, cytokine, growth inhibitory agent, anti-hormonal agent and / or cardioprotective agent. These molecules are conveniently present in combination in amounts that are effective for the intended purpose. The active ingredients can also be entrapped in microcapsules prepared, for example by coacervation techniques or by interfacial polymerization, for example hydroxymethylcellulose or gelatin microcapsules and poly- (methylmethacrylate) microcapsules, respectively in colloidal drug delivery systems (eg, liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or in macroemulsions. These techniques are described in Remington's Pharmaceutical Sciences, 16th edition, Osol, A. Ed. (1980). Sustained-release preparations can be made. Suitable examples of sustained-release preparations include semi-permeable matrices of solid hydrophobic polymers containing the antibody, these matrices being in the form of shaped articles, for example films or microcapsules. Examples of sustained release matrices include polyesters, hydrogels (e.g., poly (2-hydroxyethyl-methacrylate) or poly (inlylalcohol)), polylactides (U.S. Patent No. 3,773,919), copolymers of L-glutamic acid and? ethyl-L-glutamate, non-degradable ethylene vinyl acetate, lactic acid-degradable glycolic acid copolymers such as LUPRON DEPOT® (injectable microspheres composed of lactic acid-glycolic acid and leuprolide acetate copolymer), and poly-D-acid (-) -3-hydroxybutyric. The formulations to be used for In vivo administration must be sterile. This is easily achieved by filtration through sterile filtration membranes. J. Treatment with Anti-UNQ733 Antibodies, Linker Oligopeptides to UNQ733 Polypeptide and Small Inorganic / Organic Linkers to UNQ733 Polypeptide To determine the expression of UNQ733 Polypeptide in cancer, various detection assays are available. In one embodiment, overexpression of UNQ733 polypeptide can be analyzed by immunohistochemistry (IHC). Tissue sections embedded in paraffin from a tumor biopsy can be subjected to an IHC assay and given a staining intensity criterion of UNQ733 Polypeptide as follows: Grade 0 - no staining observed or membrane staining observed in less than 10% tumor cells. Rating 1+ - a weak / hardly perceptible membrane staining is detected in more than 10% of the tumor cells. The cells only stain part of their membrane. Qualification 2+ - a weak to moderate complete membrane staining is observed in more than 10% of the tumor cells. Qualification 3+ - moderate to strong complete membrane staining is observed in more than 10% of tumor cells. Those tumors with scores of 0 or 1+ for expression of UNQ733 polypeptide can be characterized as not over-expressing the UNQ733 polypeptide, while those with 2+ or 3+ scores can be characterized as overexpressing UNQ733 polypeptide. Alternatively, or additionally, FISH assays such as INFORM® (sold by Ventana, Arizona) or PATHVISION® (Vysis, Illinois) can be performed on formalin-fixed paraffin embedded tumor tissue to determine the extent of have) of over-expression of UNQ733 Polypeptide in the tumor. Amplification or overexpression of UNQ733 Polypeptide can be evaluated using an in vivo detection assay, for example by administration of a molecule (such as an antibody, oligopeptide or small organic molecule) that binds the molecule to be detected and is labeled with a detectable label (for example, a radioactive isotope or a fluorescent label) and external scanning of the patient for localization of the label.

As described above, the antibodies, oligopeptides and anti-UNQ733 organic small molecules of the invention have various non-therapeutic applications. The antibodies, oligopeptides and anti-UNQ733 organic / inorganic small molecules of the present invention may be useful to represent cancers expressing UNQ733 polypeptide (e.g. in radio-imaging). The antibodies, oligopeptides and organic small molecules are also useful for purification or immunoprecipitation of cell polypeptide UNQ733, for detection and quantification of UNQ733 polypeptide in vitro, for example in an ELISA or Western blot, to kill and eliminate cells expressing UNQ733 polypeptide from a population of mixed cells as a stage in the purification of other cells. Currently, depending on the stage of the cancer, cancer treatment involves one or a combination of the following therapies: surgery to remove cancerous tissue, radiation therapy and chemotherapy. Antibody therapy, oligopeptide or small organic molecule anti-UNQ733 may be especially convenient in older patients who do not tolerate well the toxicity and side effects of chemotherapy and metastatic disease where radiation therapy has limited utility. The antibodies, oligopeptides and small organic / inorganic anti-UNQ733 molecules that make Diana in tumor of the invention are useful for alleviating cancers expressing UNQ733 polypeptide upon initial diagnosis of the disease or during relapse. For therapeutic applications, the anti-UNQ733 antibody, oligopeptide or small organic / inorganic molecule can be used alone or combination therapy with, for example, hormones, antiangiotics or radiolabelling compounds, or with surgery, cryotherapy and / or radiotherapy. Treatment of antibody, oligopeptide or small organic / inorganic molecule anti-UNQ733 can be administered in conjunction with other forms of conventional therapy, either consecutively with pre- or postconventional therapy. Chemotherapeutic drugs such as TAXOTERE® (docetaxel), TAXOL® (palictaxel), estramustine and mitoxantrone are used to treat cancer, particularly in patients at good risk. In the present method of the invention, in order to treat or alleviate cancer, the cancer patient can be administered anti-UNQ733 antibody, oligopeptide or small organic / inorganic molecule in conjunction with treatment with one or more of the preceding chemotherapeutic agents. In particular, combination therapy with palictaxel and modified derivatives (see for example, EP0600517) is contemplated. The anti-UNQ733 antibody, oligopeptide or small organic / inorganic molecule will be administered with a therapeutically effective dose of the chemotherapeutic agent. In another embodiment, the anti-UNQ733 antibody, oligopeptide or small organic / inorganic molecule is administered in conjunction with chemotherapy to improve the activity and efficacy of the chemotherapeutic agent, for example paclitaxel. The Physicians' Desk Reference (PDR) describes doses of these agents that have been used in the treatment of various cancers. The dosage and dosage regimen of these aforementioned chemotherapeutic drugs that are therapeutically effective will depend on the particular cancer to be treated, the extent of the disease and other factors familiar to the physician with skill in the art and can be determined by the physician. In a particular embodiment, a conjugate comprising an anti-UNQ733 antibody, oligopeptide or small organic / inorganic molecule conjugated to a cytotoxic agent is administered to the patient. Preferably, the immunoconjugate bound to the UNQ733 protein is internalize by the cell, resulting in increased therapeutic efficacy of the immunoconjugate to kill the cancer cell to which it is linked. In a preferred embodiment, the cytotoxic agent targets or interferes with the nucleic acid in the cancer cell. Examples of these cytotoxic agents are described above and include maytansinoids, calicheamicins, ribonucleases and DNA endonucleases. Antibodies, oligopeptides, anti-UNQ733 organic / inorganic small molecules or toxin conjugates thereof are administered to a human patient, according to known methods such as intravenous administration, for example as a bolus or by continuous infusion over a period of time. time, by intramuscular, intraperitoneal, intracerobrospinal, subcutaneous, intra-articular, intrasynovial, intrathecal, oral, topical or inhalation routes. Intravenous or subcutaneous administration of the antibody, oligopeptide or small organic molecule is preferred. Other therapeutic regimens may be combined with administration of the anti-UNQ733 antibody, oligopeptide or small organic / inorganic molecule. The combined administration includes co-administration, using separate formulations or a single formulation pharmaceutical and consecutive administration in any order, where preferably there is a period of time while both (or all) active agents simultaneously exercise their biological activities. Preferably, this combined therapy results in a synergistic therapeutic effect. It may also be convenient to combine administration of the anti-UNQ733 antibody or antibodies, oligopeptides or small organic / inorganic molecules, with the administration of an antibody directed against another tumor antigen associated with the particular cancer. In another embodiment, the therapeutic treatment methods of the present invention involve the combined administration of an anti-UNQ733 antibody (or antibodies), oligopeptides or small organic / inorganic molecules and one or more chemotherapeutic agents or growth inhibitory agents, including administration of cocktails of different chemotherapeutic agents. Chemotherapeutic agents include estramustine phosphate, prednimustine, cisplatin, 5-fluorouracil, melphalan, cyclophosphamide, hydroxyurea and hydroxyureataxanes (such as paclitaxel and doxetaxel) and / or anthracycline anbitiotics. Programs of Preparation and dosage for these chemotherapeutic agents can be used according to the manufacturer's instructions or as empirically determined by the practitioner with skill. Preparation and dosage programs for this chemotherapy are also described in Chemotherapy Service Ed., M.C. Perry, Williams &; Wilkins, Baltimore, MD (1992). The antibody, oligopeptide or small organic / inorganic molecule can be combined with an anti-hormonal compound; for example an anti-estrogen compound such as tamoxifen; an anti-progesterone such as onapristone (see EP 616 812); or an anti-androgen such as flutamide, in doses that are known for these molecules. When the cancer to be treated is cancer independent of androgen, the patient has previously undergone anti-androgen therapy and after the cancer becomes independent of androgen, the oligopeptide antibody or small molecule organic / inorganic anti-UNQ733 (and optionally other agents as described herein) can be administered to the patient. At times, it may also be beneficial to co-administer a cardio-protective (to prevent or reduce myocardial dysfunction associated with the therapy) or a more cytokines, to the patient. In addition to the above therapeutic regimens, the patient may be subjected to surgical removal of cancer cells and / or radiation therapy, before, simultaneously with or subsequent to the antibody, oligopeptide or small organic / inorganic molecule therapy. Suitable doses for any of the above co-administered agents are those currently employed and can be reduced due to the combined action (synergy) of the agent and antibody, oligopeptide or small organic / inorganic molecule anti-UNQ733. For the prevention or treatment of disease, the dose and mode of administration will be chosen by the physician according to known criteria. The appropriate dose of antibody, oligopeptide or small organic / inorganic molecule will depend on the type of disease to be treated, as defined above, the severity and course of the disease, if the oligopeptide antibody or small organic / inorganic molecule is administered for preventive or preventive purposes. therapeutic, previous therapy, patient's clinical history and response to the oligopeptide antibody or small organic / inorganic molecule, and the discretion of the attending physician. The oligopeptide antibody or small organic / inorganic molecule is administered conveniently to the patient at a time or on a series of treatments. Preferably the oligopeptide antibody or small organic / inorganic molecule is administered by intravenous infusion or subcutaneous injections. Depending on the type and severity of the disease, about 1 μg / kg to about 50 mg / kg of body weight (for example about 0.l-15mg / kg / dose) of antibody may be an initial candidate dose for administration to a patient, if, for example, by one or more separate administrations, or by continuous infusion. A dosage regimen may comprise administering an initial loading dose of about 4 mg / kg, followed by a weekly maintenance dose of about 2 mg / kg of anti-UNQ733 antibody. However, other dose regimens may be useful. A typical daily dose may be in the range of about 1 ug / kg to 100 mg / kg or more, depending on the factors mentioned above. For repeated administration over several days or more, depending on the condition, the treatment is sustained until a desired suppression of disease symptoms occurs. The basis of this therapy can be easily monitored by conventional methods and trials and based on criteria known to the physician or another person with skill in the specialty. Apart from the administration of the antibody protein to the patient, the present application contemplates administering the antibody by gene therapy. This administration of nucleic acid encoding the antibody is encompassed by the term "administering a therapeutically effective amount of an antibody". See for example O96 / 07321 published March 14, 1996 concerning the use of gene therapy to generate intracellular antibodies. There are two main approaches for obtaining the nucleic acid (optionally contained in a vector) in the cells of the patient); in vivo and ex vivo. For in vivo delivery, the nucleic acid is injected directly from the patient, usually at the site where the antibody is required. For ex vivo treatment, the cells of the patient are removed, the nucleic acid is introduced into these isolated cells and the modified cells are administered to the patient either directly or for example encapsulated within porous membranes that are implanted in the patient (see for example U.S. Patent Nos. 4,892,538 and 5,283,187). There are a variety of techniques available to introduce nucleic acids into viable cells. The Techniques vary depending on whether the nucleic acid is transferred in cells grown in vitro or in vivo in the cells of the intended host. Suitable techniques for the transfer of nucleic acid in mammalian cells in vivo include the use of liposomes, electroporation, microinjection, cell fusion, DEAE-dextran, calcium phosphate precipitation method, etc. A vector commonly used for ex vivo delivery of the gene is a retroviral vector. Currently preferred in vivo nucleic acid transfer techniques include transaction with viral vectors (such as adenovirus, herpes simplex virus I or adeno-ciated virus) and lipid-based systems (lipids useful for lipid-mediated transfer of the gene are DOTMA, DOPE and DC-Chol for example). To review the gene therapy and gene tag protocols currently known see Anderson et al., Science 256: 808-813 (1992). See also WO 93/25673 and references cited therein. Anti-UNQ733 antibodies of the invention may be in different forms encompd by the definition of "antibody" herein. In this way, the antibodies include antibody of integral or intact length, fragments of antibody, antibody of native sequence or amino acid variants, immunoconjugates of chimeric or humanized fusion antibodies, and their functional fragments. In fusion antibodies, a sequence of antibodies is fused to a heterologous polypeptide sequence. The antibodies can be modified in the Fe region to provide desired effector functions. As discussed in more detail in the sections herein, with the appropriate Fe regions, the naked antibody bound to the cell surface can induce cytotoxicity, for example by antibody-dependent cellular cytotoxicity (ADCC) or by recruiting complement-dependent or complement-dependent cytotoxicity. some other mechanism. Alternatively, when it is convenient to eliminate or reduce effector function, to minimize side effects or therapeutic complications, certain other Fe regions may be employed. In one embodiment, the antibody competes to bind or bind substantially to, the same epitope as the antibodies of the invention. Antibodies having the biological characteristics of the present anti-UNQ733 antibodies of the invention are also contemplated, specifically including tumor targeting in vivo and any inhibition of proliferation cellular or cytotoxic characteristics. Methods for producing the above antibodies are described here in detail. The present anti-UNQ733 organic / inorganic oligopeptide and small molecule antibodies are useful for treating lymphoma expressing UNQ733 polypeptide, specifically non-Hodgkin's lymphoma or alleviating one or more symptoms of lymphoma in the mammal. Methods of the invention encompass the use of UNQ733 antagonists in the treatment and / or relief of symptoms of metastatic tumors associated with non-Hodgkin's lymphoma. The UNQ733 antagonist oligopeptide antibody or small organic / inorganic molecule is capable of binding at least a portion of the cancer cell that expresses an UNQ733 polypeptide in the mammal. In one embodiment, the oligopeptide antibody or small organic / inorganic molecule is effective to destroy or kill tumor cells that respond and / or express UNQ733 polypeptide or inhibit the growth of these tumor cells, in vitro or in vivo, by binding to the polypeptide UNQ733. This antibody includes a naked anti-UNQ733 antibody (unconjugated with no agent). Naked antibodies that have cell growth inhibition or cytotoxic properties may also be endowed with a cytotoxic agent to make them even more potent in tumor cell destruction. Cytotoxic properties can be conferred to an anti-UNQ733 antibody, for example by conjugate of the antibody with a cytotoxic agent, to form an immunoconjugate as described herein. In some embodiments, the cytotoxic agent or a growth inhibitory agent is a small molecule. In some embodiments, toxins such as calicheamicin or a maitancinoid and its analogs or derivatives are used. The invention provides a composition comprising an oligopeptide antibody or small organic / inorganic anti-UNQ733 molecule of the invention and a carrier. For the purposes of treating cancer, compositions may be administered to the patient in need of such treatment, wherein the composition may comprise one or more anti-UNQ733 antibodies present as an immunoconjugate or as the naked antibody. In a further embodiment, the compositions may comprise these oligopeptide antibodies or small organic / inorganic molecules in combination with other therapeutic agents such as cytotoxic agents or growth inhibitors including chemotherapeutic agents. The invention also provides formulations comprising an antibody, oligopeptide, small organic / inorganic molecule anti-UNQ733 of the invention and a carrier. In one embodiment, the formulation is a therapeutic formulation comprising a pharmaceutically acceptable carrier. Another aspect of the invention are isolated nucleic acids encoding antibodies-UNQ733. Nucleic acids that encode both the H and L chains and especially the hyper-variable region residues, chains encoding the antibody of native sequence as well as variants modifications and humanized versions of the antibody, are encompassed. The invention also provides methods useful for treating non-Hodgkin's lymphoma or alleviating one or more symptoms of lymphoma in a mammal, comprising administering a therapeutically effective amount of an oligopeptide antibody or small organic / inorganic anti-UNQ733 molecule to the mammal. The therapeutic compositions of oligopeptide antibody or small organic / inorganic molecule can be administered in the short term (acute) or chronic or intermittent as instructed by the physician. Methods are also provided for inhibiting the growth of, and killing a cell that responds and / or expresses UNQ733 polypeptide.

The invention also provides equipment and articles of manufacture comprising at least one oligopeptide antibody or small organic / inorganic molecule anti-UNQ733. Equipment containing oligopeptide antiserum or small organic / inorganic anti-UNQ733 molecules find utility for example for killing assays of UNQ733 polypeptide cells, for purification or immunoprecipitation of UNQ733 cell polypeptides. For example, for isolation purification of UNQ733 polypeptide, the kit may contain an antibody, oligopeptide or small organic / inorganic molecule anti-UNQ733 coupled to the beads (e.g. sepharose beads). Equipment containing oligopeptide antibodies or small organic / inorganic molecules can be provided for detection and quantification of UNQ733 polypeptide, in vitro, for example in an ELISA or Western blot. This oligopeptide antibody or small organic / inorganic molecule useful for detection can be provided with a label such as fluorescent or radiolabel. K. Articles of Manufacture and Equipment Another embodiment of the invention is an article of manufacture containing useful materials for the cancer treatment expressing UNQ733 polypeptide such as non-Hodgkin lympholas. The article of manufacture comprises a container and a packaging label or insert in or associated with the container. Convenient containers include, for example, bottles, ampoules, syringes, etc. The containers may be formed from a variety of materials such as glass or plastic. The container contains a composition that is effective for treating the cancer condition and can have a sterile access gate (for example, the container can be a vial or intravenous solution bag having a plug pierceable by a hypodermic injection needle). At least one active agent in the composition is an anti-UNQ733 antibody oligopeptide antibody or small organic / inorganic anti-UNQ733 molecule of the invention. The label or package insert indicates that the composition is used to treat cancer. The label or package insert will further comprise instructions for administering the oligopeptide antibody composition or small organic / inorganic molecule to the cancer patient. Additionally, the article of manufacture may further comprise a second container comprising a pharmaceutically acceptable buffer such as or static bacteria for injection (BWFI = bacteriostatic water for injection), saline buffered with phosphate, Ringer's solution and dextrose solution. It can also include other suitable materials from a commercial and user point of view, including other shock absorbers, diluents, needle filters and syringes. Equipment that is useful for various purposes is also provided, for example for cell killing assays or expression of UNQ733 polypeptide for purification or immunoprecipitation of cell polypeptide UNQ733. For isolation and purification of UNQ733 polypeptide, the kit may contain an oligopeptide antibody or small organic / inorganic anti-UNQ733 molecule coupled to the beads (eg, sepharose beads). Equipment containing oligopeptide antibodies or small organic / inorganic molecules can be provided for detection and quantification of UNQ733 polypeptide in vitro, for example in an ELISA or Western blot. As with the article of manufacture, the equipment comprises a container and a packaging label or insert in or associated with the container. The container contains a composition comprising at least one oligopeptide antibody or small organic / inorganic molecule of anti-UNQ733 polypeptide of the invention. Additional containers may be included which contain, for example, diluents and buffers, control antibodies. The label or packaging insert can provide a description of the composition as well as instructions for the intended use of detection or in vitro. L. UNQ733 polypeptides and nucleic acids encoding UNQ733 polypeptide - specific forms and applications. Nucleotide sequences (or their complement) that encode UNQ733 polypeptides have diverse applications in the molecular biology technique, including uses such as hybridization in chromosome cartography and in the generation of RNA and antisense DNA probes. Nucleic acid encoding UNQ733 polypeptide will also be useful for the preparation of UNQ733 polypeptides by the recombinant techniques described herein, wherein such UNQ733 polypeptides can find use, for example in the preparation of anti-UNQ733 antibodies as described herein. A UNQ733 polypeptide gene of native sequence and integral length or its portions, can be used as hybridization probes for a cDNA library to isolate other cDNAs (for example those encoding naturally occurring variants of the UNQ733 polypeptide or UNQ733 polypeptide of other species) having desired sequence identity to a native UNQ733 polypeptide sequence described herein. Optionally, the length of the waves will be from about 20 to about 50 bases. Hybridization probes can be derived from at least partially novel sub-regions of the integral length native nucleotide sequence, wherein those regions can be determined without undue experimentation or from genomic sequences including promoters, enhancer elements and sequence UNQ733 polypeptide introns. native By way of example, a monitoring method will comprise isolating the coding region of the UNQ733 polypeptide gene using the known DNA sequence to synthesize a select probe of about 40 bases. Hybridization probes can be labeled by a variety of labels including radionucleotides such as 32P or 35S or enzymatic labels such as alkaline phosphatase coupled to the probe by avidite / biotin coupling system. Labeled probes having a sequence complementary to that of the UNQ733 polypeptide gene of the present invention can be used to monitor libraries of human cDNA, genomic DNA or mRNA for determine which member of these libraries hybridize the probe. Hybridization techniques are described in greater detail in the following examples. Any EST sequences described in the present application can be similarly employed as probes using the methods described herein. Other fragments useful in the nucleic acids encoding the UNQ733 polypeptide include antisense or sense oligonucleotides comprising a single-stranded nucleic acid (either RNA or DNA) capable of binding to (sense) mRNA sequences UNQ733 polypeptide or DNA (antisense) of Polypeptide UNQ733. Antisense or sense oligonucleotides according to the present invention, comprise a fragment of the DNA coding region UNQ733. This fragment generally comprises at least about 14 nucleotides, preferably about 14 to 30 nucleotides. The ability to derive an antisense or sense oligonucleotide, based on a cDNA sequence encoding a given protein, is described for example in Stein and Cohen (Cancer Res. 48: 2659, 1988) and van der Krol et al. (BioTechniques 6: 958, 1988). Linking antisense or sense oligonucleotides to target nucleic acid sequences results in the duplex formation that blocks the transcription or translation of the target sequence by one of several means, including improved degradation of the duplexes, premature termination of transcription or translation or by other means. These methods are encompassed by the present invention. The antisense oligonucleotides in this manner can be used to block expression of a UNQ733 protein, wherein the UNQ733 protein may play a role in the induction of cancer in mammals. Oligonucleotides antisense or sense further comprise oligonucleotides having modified sugar-phosphodiester backbones (or other sugar bonds, such as those described in WO 91/06629) and wherein these sugar bonds are resistant to endogenous nucleases. Oligonucleotides with resistant sugar bonds are stable in vivo (ie, capable of resisting enzymatic degradation), but retain sequence specificity to be able to bind to target nucleotide sequences. Preferred intragenic sites for antisense binding include the region incorporating the translation start codon (5'-AUG / 5'-ATG) or the stop or stop codon (5'-UAA, 5'-UAG and 5-UGA / 5'-TAA, 5'-TAG and 5'-TGA) of the open reading mark (ORF) of the gen. These regions refer to a portion of the mRNA or gene spanning from about 25 to about 50 contiguous nucleotides in any direction (ie, 5 'or 3') from a start codon or translation stop. Other preferred regions for antisense binding include: introns; exons; intron-exon junctions; the open reading frame (ORF) or "coding region", which is the region between the translation start codon and the translation stop codon; the 5 'cap of an mRNA comprising a N7-methylated guanosine residue bound to the residue closest to 5' of the mRNA via a 5'-5 'triphosphate linkage and includes the 5' cap structure itself as well as the first 50 adjacent nucleotides to the top; the 5 'untranslated region (5'UTR), the portion of an mRNA in the 5' direction from the translation start codon, and thus including nucleotides between the 5 'cap site and the translation start codon of a corresponding mRNA or nucleotides in the gene; and the 3 'untranslated region (3'UTR), the portion of an mRNA in the 3' direction of the translation stop codon, and thus including nucleotides between the translation stop codon and the 3 'end of a mRNA or corresponding nucleotides in the gene.

Specific examples of preferred antisense compounds useful for inhibiting expression of UNQ733 Polypeptide include oligonucleotides containing modified major structures or non-natural internucleoside linkages. Oligonucleotides having modified major structures include those that retain a phosphorus atom in the main structure and those that do not have a phosphorus atom in the main structure. For the purposes of this specification, and as is sometimes referred to in the art, modified oligonucleotides that do not have a phosphorus atom in their main internucleoside structure can also be considered as oligonucleosides. Preferred modified oligonucleotide master structures include for example, phosphorothioates, chiral phosphorothioates, phosphorodithioates, phosphotriesters, aminoalkylphosphotriesters, methyl and other alkyl phosphonates including 3'-alkylene phosphonates, 5'-alkylene phosphonates and chiral phosphonates, phosphinates, phosphoroamidates including 31-amino phosphoroamidate and aminoalkylphosphoramidates, thionophosphoramidates, thionoalkyl phosphonates, thionoalkylphosphotriesters, selenophosphates and borane phosphates having normal 3'-5 'bonds, analogues 2'- 'linked to these, and those that have inverted polarity where one or more internucleotide links is a 3' to 3 ', 5' to 5 'or 2' to 2 'link. Preferred oligonucleotides having inverted polarity comprise a single 3 'to 3' link in the internucleotide link closest to 3 ', ie a single inverted nucleoside residue that can be abasic (the core is missing or has a hydroxyl group in place). Various salts, mixed salts and free acid forms are also included, U.S. Pat. Representatives illustrating the preparation of phosphorus-containing bonds include but are not limited to, U.S. Pat. Us.: 3, 687, 808; 4,469, 863; 4, 476, 301; 5, 023, 243; 5, 177.196; , 188, 897; 5, 264, 423; 5, 276, 019; 5, 278, 302; 5, 286, 717; , 321, 131; 5, 399, 676; 5, 405, 939; 5, 453, 496; 5, 55, 233; ,466, 677; 5, 476, 925; 5, 519, 126; 5, 536, 821; 5, 541, 306; , 550, 111; 5, 563, 253; 5, 571, 799; 5, 587, 361; 5, 194, 599; , 565, 555; 5, 527, 899; 5,721,218; 5,672,697 and 5, 625, 050, each of which is incorporated herein by reference. Preferred modified oligonucleotide master structures that do not include a phosphorus atom have major structures that are formed by short chain alkyl or cycloalkyl internucleoside linkages, internucleoside cycloalkyl or alkyl linkages and heteroatom in admixture, or one or more short chain heterocyclic or heteroaromatic internucleoside linkages. These include those that have morpholino bonds (formed in part of the sugar portion of a nucleoside); siloxane main structures; main structures sulfide, sulfoxide and sulfone; main structures formacetyl and thioformacetyl; main structures methylene formacetyl and thioformacetyl; riboacetyl main structures; main structures containing alkene; sulfamate main structures; main structures methyleneimino and methylenehydrazino; sulfonate and sulfonamide main structures; main structures amide; and others that have mixed N, O, S and CH2 component parts. US Patents Representative examples illustrating the preparation of these oligonucleosides include but are not limited to US Patents. Us : 5, 034, 506; 5, 166, 315; ,185,444; 5,214,134; 5,216, 141; 5, 235, 033; 5, 264, 562; ,264, 564; 5, 405, 938; 5, 434, 257; 5,466, 677; 5, 470, 967; ,489, 677; 5, 541, 307; 5, 561, 225; 5,596, 086; 5, 602, 240; , 610, 289; 5, 602, 240; 5, 608, 046; 5, 610, 289; 5, 618, 704; , 623, 070; 5, 663, 312; 5, 633, 360; 5, 677, 437; 5, 792, 608; , 646, 269 and 5,677,439, each of which here is Incorporates by reference. In other preferred antisense oligonucleotides, both the sugar and internucleoside link, that is to say the main structure, of the nucleotide units are replaced with nvoedose groups. The base units are maintained by hybridization with an appropriate target nucleic acid compound. A similar oligomeric compound, an oligonucleotide mimic that has been shown to have excellent hybridization properties, is referred to as a peptide nucleide acid (PNA = peptide nucleic acid). In PNA compounds, the sugar backbone of an oligonucleotide is replaced by an amide-containing backbone, in particular a backbone structure of aminoethylglycine. The nucleobases are retained and ligated directly or indirectly with nitrogen atoms from the amide portion of the main structure. Representative US patents illustrating the preparation of PNA compounds include, but are not limited to, U.S. Pat. Nos .: 5,539,082; 5,714,331; and 5,719,262, each of which is incorporated herein by reference. Additional illustration of PNA compounds can be found in Nielsen et al., Science, 1991, 254, 1497-1500.

Preferred antisense oligonucleotides incorporate phosphorothioate backbones and / or heteroatom backbones and in particular -CH 2 -NH-0-CH 2 -, -CH 2 -N (CH 3) -0-CH 2 - [known as methylene backbone (methylimino) or MI] , -CH2-0-N (CH3) -CH2-, -CH2-N (CH3) -N (CH3) -CH2- and -ON (CH3) -CH2-CH2- [wherein the native phosphodiester backbone is represented as -OPO-CH2-] described in the above reference of US patent No. 5,489,677, and the major amide structures of the US patent. No. 5,602,240 previously referred. Also preferred are antisense oligonucleotides having morpholino backbones from U.S. Pat. No. 5,034,506 referred to above. Modified oligonucleotides may also contain one or more portions of substituted sugar. Preferred oligonucleotides comprise one of the following at the 2 'position: OH; F; O-alkyl, S-alkyl, or N-alkyl; O-alkenyl, S-alkenyl, or N-alkenyl; O-alkynyl, S-alkynyl or N-alkynyl; or 0-alkyl-O-alkyl, wherein the alkyl, alkenyl and alkynyl can be Ci to Cio alkyl or C2 to C alkenyl and alkynyl substituted or unsubstituted. Particular preference is given to 0 [(CH2) nO] raCH3, 0 (CH2) n0CH3, 0 (CH2) nNH2, 0 (CH2) nCH3, 0 (CH2) nONH2, and O (CH2) n0N [(CH2) nCH3)] 2, where n and m are from 1 to about 10. Other preferred antisense oligonucleotides comprise one of the following at position 2 ': Ci a Cio lower alkyl, substituted lower alkyl, alkenyl, alkynyl, alkaryl, aralkyl, O-alkaryl or O-aralkyl, SH, SCH3, OCN, Cl, Br, CN, CF3, OCF3, SOCH3, S02 CH3, ON02 , N02, N3, NH2, heterocycloalkyl, heterocycloalkyl, aminoalkylamino, polyalkylamino, substituted silyl, an RNA cleavage group, a reporter group, an intercalator, a group to improve the pharmacokinetic properties of an oligonucleotide, or a group to improve the pharmacodynamic properties of an oligonucleotide, and other substituents that have similar properties. A preferred modification includes 2'-methoxyethoxy (2'-0-CH2CH2OCH3, also known as 21 -O- (2-methoxyethyl) or 2'-MOE) (Martin et al., Helv. Chim. Acta, 1995, 78, 486-504) that is, an alkoxyalkoxy group. A further preferred modification includes 2'-dimethylaminooxyethoxy, ie a group O (CH2) 2ON (CH3) 2, also known as 2'-DMAOE, as described in the following examples and 2'-dimethylaminoethoxyethoxy (also known in the art as 2 '-O-dimethylaminoethoxyethyl or 2' -DMAEOE), ie 2 '-0-CH2-0-CH2-N (CH2). A further preferred modification includes LNAs (Locked Nucleic Acids) wherein the 2'-hydroxyl group is bonded to the 3 'or 4' carbon atom of the sugar ring thereby forming a portion of bicyclic sugar. The preferred link is a methylene group (-CH2-) n bridging the 2'-oxygen acid and the 4'-carbon atom and wherein n is 1 or 2. LNAs and their preparation are described in O 98/39352 and WO 99/14226. Other preferred modifications include 2'-methoxy (2'-0-CH3), 2'-aminopropoxy (2'-OCH2CH2CH2 NH2), 2'-allyl (2'-CH2-CH = CH2), 2'-0-allyl (2 '-0-CH2-CH = CH2) and 2'-fluorine (2'-F). The modification 2 'can be in the arabino position (top) or the position or ribo (bottom). A 2'-preferred modification is 2'-F. Similar modifications can also be made at other positions in the oligonucleotide, particularly the 3 'position of the sugar in the 3' terminal nucleotide or in the linked 2'-5 'oligonucleotides and in the 5' position of the 5 'terminal oligonucleotide. Oligonucleotides can also have sugar mimetics such as cyclobutyl portions in place of pentofuranosyl sugar. US Patents, representative which illustrate the preparation of these modified sugar structures include but are not limited to US Patents. Nos .: 4,981,957; 5,118,800; 5,319,080; 5,359,044; 5,393,878; 5,446,137; 5, 466, 786; 5,514,785; 5,519,134; 5,567,811; 5,576,427; 5,591,722; 5,597,909; 5,610,300; 5,627,053; 5,639, 873; 5,646,265; 5,658,873; 5,670,633; 5,792,747; and 5,700,920, each of which is hereby incorporated by reference in its entirety. Oligonucleotides can also include modifications or substitutions of nucleobase (often referred to in the art simply as "base"). As used herein, "unmodified" or "natural" corebases include the bases purine adenine (A) and guanine (G), and the bases pyrimidine thymine (T), cytokine (C) and uracil (U). Modified nuclei, include other synthetic and natural bases such as 5-methylcytocin (5-me-C), 5-hydroxymethyl cytokine, xanthine, hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 2-thiouracil, 2-thiothimine and 2-thiocytocin, 5-halouracil and cytokine, 5-propynyl (-C = C-CH 3 or -CH 2 ~ C = CH) uracil and cytokine and others alkynyl derivatives of bases pyrimidine, 6-azo uracil, cytokine and thymine, 5-uracil (pseudoouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8- thioalkyl, 8-hydroxyl and other 8-substituted adenines and guanines, 5-halo, particularly 5-bromo, 5-trifluoromethyl and other uracils and 5-substituted cytokines, 7-methylguanine and 7-methyladenine, 2-F-adenine, 2- amino-adenine, 8-azaguanine and 8-azaadenine, 7-deazaguanine and 7-deazaadenine and 3-deazaguanine and 3-deazaadenine. Additional modified nucleobases include tricyclic pyrimidines such as phenoxazine cytidine (lH-pyrimido [5, 4-b] [1,4] benzoxazin-2 (3H) -one), phenothiazine cytidine clamps (lH-pyrimido [5, 4-b] [1,4] benzothiazin-2 (3H) -one), G-clamps (G-clamps) such as substituted phenoxazine cytidine (for example 9- (2-aminoethoxy) -H-pyrimido [5, 4-b] [1 , 4] benzoxazin-2 (3H) -one), carbazole cytidine (2H-pyrimido [4, 5-b] indol-2-one), pyridoindole cytidine (H-pyrido [3 ', 21:, 5] pyrrolo [ 2, 3-d] pyrimidin-2-one). Modified nucleobases may also include those in which the purine base or pyrimidine is replaced with other heterocycles, for example 7-deaza-adenine, 7-deazaguanosine, 2-aminopyridine and 2-pyridone. Additional core bases include those described in U.S. Pat. No. 3,687,808, those described in The Concise Encyclopedia of Polymer Science and Engineering, pages 858-859, Krosch itz, J. I., ed. John Wiley & Sons, 1990, and those described by Englisch et al., Angewandte Chemie, International Edition, 1991, 30, 613. Certain of these core bases are particularly useful for increasing the binding affinity of the oligomeric compound of the invention. These include substituted pyrimidines, 6-azapyrimidines and substituted N-2, N-6 and 0-6 purines, including 2-aminopropyladenine, 5-propynyluracil and 5-propynylcytokine. Substitutions 5-methylcytocin have been shown to increase duplex stability of nucleic acid by 0.6-1.2 degrees C (Sanghvi et al, Antisense Research and Applications, CRC Press, Boca Raton, 1993, pp. 276-278) and are preferred base substitutions. , even more particularly when combined with 2'-O-methoxyethyl sugar modifications. US Patents representatives illustrating the preparation of modified core bases include, but are not limited to: US Pat. No. 3,687,808, as well as US patents. Nos .: 4,845,205; 5,130,302; 5,134,066; 5,175,273; 5,367,066; 5,432,272; 5,457,187; 5,459,255; 5,484,908; 5,502,177; 5,525,711; 5,552,540; 5,587,469; 5,594,121, 5,596,091; 5,614,617; 5,645,985; 5,830,653; 5,763,588; 6,005,096; 5,681,941 and 5,750,692, each of which is incorporated herein by reference. Another modification of oligonucleotides antisense comprises chemical bonding with the oligonucleotide of one or more portions or conjugates that improve the activity, cellular distribution or cellular uptake of the oligonucleotide. The compounds of the invention may include conjugated groups covalently linked to functional groups such as primary or secondary hydroxyl groups. Conjugated groups of the invention include intercalators, reporter molecules, polyamines, polyamides, polyethylene glycols, polyethers, groups that improve the pharmacodynamic properties of oligomers and groups that improve the pharmacokinetic properties of oligomers. Typical conjugated groups include cholesterols, lipids, lipid cations, phospholipids, cationic phospholipids, biotin, phenazine, folate, phenanthridine, anthraquinone, acridine, fluoresceins, rhodamines, coumarins and dyes. Groups that improve pharmacodynamic properties, in the context of this invention include groups that improve oligomer uptake, improve oligomer resistance to degradation and / or reinforce specific sequence hybridization with RNA. Groups that improve the pharmacokinetic properties, in the context of this invention, include groups that improve the absorption of oligomers, distribution, metabolism or excretion. Conjugated portions include but are not limited to lipid portions such as a cholesterol moiety (Letsinger et al., Proc. Nati, Acad. Sci. USA, 1989, 86, 6553-6556), cholic acid (Manoharan et al., Bioorg. Med. Chem. Let., 1994, 4, 1053-1060), a thioether, for example hexyl-S-tritylthiol (Manoharan et al., Ann. NY Acad. Sci., 1992, 660, 306-309; Manoharan et al., Bioorg. Med. Chem. Let., 1993, 3, 2765-2770), to thiocholesterol (Oberhauser et al., Nucí Acids Res., 1992, 20, 533-538), an aliphatic chain, for example dodecanediol or undecyl residue ( Saison-Behmoaras et al., EMBO J., 1991, 10, 1111-1118; Kabanov et al., FEBS Lett., 1990, 259, 327-330; Svinarchuk et al., Biochimie, 1993, 75, 49-54. ), a phospholipid, for example di-hexadecyl-rac-glycerol or triethyl-ammonium 1,2-di-O-hexadecyl-rac-glycero-3-H-phosphonate (Manoharan et al., Tetrahedron Lett., 1995, 36 , 3651-3654; Shea et al., Nucí Acids Res., 1990, 18, 3777-3783), a polyamine or a polyethylene glycol chain (Manoharan et al., Nucleosides &Nucleotids, 1995, 14, 969-973 ), or adamantane acetic acid (Manoharan et al., Tetrahedron Lett., 1995, 36, 3651-3654), a palmitoyl moiety (Mishra et al., Biochim Biophys. Acta, 1995, 1264, 229-237), or an octadecylamine or hexylamino-carbonyl- oxycholesterol Oligonucleotides of the invention can also be conjugated to active drug substances, for example, aspirin, warfarin, phenylbutazone, ibuprofen, suprofen, fenbufen, ketoprofen, (S) - (+) - pranoprofen, carprofen, dansilsarcosine, acid 2, 3, 5 -triyodobenzoic acid, flufenamic acid, folinic acid, a benzothiadiazide, chlorothiazide, diazepine, indomethacin, a barbiturate, a cephalosporin, a sulfa drug, an antidiabetic, an antibacterial or an antibiotic. Drug oligonucleotide conjugates and their preparation are described in U.S. patent application. Serial number 09/334, 130 (filed June 15, 1999) and in the U.A. Nos.: 4, 828, 979; 4, 948, 882; 5, 218, 105; , 525, 465; 5,541, 313; 5, 545, 730; 5, 552, 538; 5, 578, 717, , 580, 731; 5, 580, 731; 5, 591, 584; 5,109, 124; 5, 118, 802; , 138.045; 5, 414, 077; 5,486, 603; 5, 512, 439; 5, 578, 718; , 608, 046; 4, 587, 044; 4, 605, 735; 4, 667, 025; 4, 762, 779; 4,789, 737; 4, 824, 941; 4, 835, 263; 4, 876, 335; 4, 904, 582; 4, 958, 013; 5, 082, 830; 5, 112, 963; 5, 214, 136; 5, 082, 830; ,112,963; 5,214,136; 5, 245, 022; 5, 254, 469, 5,258,506; , 262, 536; 5, 272, 250; 5, 292, 873; 5, 317, 098, 5, 371, 241, , 391, 723; 5, 416, 203, 5, 451, 463; 5.510, 475, 5, 512, 667; ,514,785; 5, 565, 552; 5, 567, 810; 5, 574, 142, 5, 585, 481; , 587, 371; 5, 595, 726; 5, 597, 696; 5, 599, 923; 5,599,928 and , 688, 941, each of which is incorporated herein by reference. It is not necessary that all the positions in a given compound be uniformly modified and in fact more than one of the aforementioned modifications can be incorporated in a single compound or even in a single nucleotide within an oligonucleotide. The present invention also includes antisense compounds that are chimeric compounds. "Chimeric" or "chimeric" antisense compounds, in the context of this invention,. they are antisense compounds, particularly oligonucleotides which contain two or more chemically distinct regions, each consisting of at least one monomer unit, ie a nucleotide in the case of an oligonucleotide compound. These oligonucleotides typically contain at least one region, wherein the oligonucleotide is modified to confer on the oligonucleotide increased resistance to nuclease degradation, increased cell uptake, and / or increased binding affinity for the target nucleic acid. A further region of the oligonucleotide can serve as a substrate for enzymes capable of cleaving RNA: DNA or RNA: RNA hybrids. As an example, RNAase H is a cellular endonuclease that cleaves the RNA strand of an RNA: DNA duplex. Activation of RNAase H, therefore results in cleavage of the target RNA, thereby greatly improving the inhibition efficiency of oligonucleotide gene expression. Consequently, comparable results can often be obtained with shorter oligonucleotides when chimeric oligonucleotides are employed, as compared to dioxoligonucleotide phosphorothioate which hybridize to the same target region. Chimeric antisense compounds of the invention can be formed as structures composed of two or more oligonucleotides, modified oligonucleotides, oligonucleotides and / or oligonucleotide mimetics as described above. Preferred chimeric antisense oligonucleotides incorporating at least one modified 2 'sugar (preferably 21 -O- (CH2) 2-O-CH3) at the 3' terminus to confer nuclease resistance and a region with at least 4 H-sugars contiguous to confer RNAase H activity. These compounds have also been referred to in the art as hybrids or limited internal sequences. Preferred limited internal sequences have a modified 2 'sugar region (preferably 21 -O- (CH2) 2-O-CH3) at 3' -terminal and the 5 'terminal separated by at least one region having at least 4 contiguous 2'H sugars and preferably incorporate phosphorothioate main structure bonds. US Patents representative illustrating the preparation of these hybrid structures include, but are not limited to, U.S. Pat. Numbers 5,013,830; 5,149,797; 5,220,007; 5,256,775; 5,366,878; 5,403,711; 5,491,133; 5,565,350; 5,623,065; 5,652,355; 5,652,356; and 5,700,922, each of which is incorporated herein by reference in its entirety. The antisense compounds used in accordance with this invention can be routinely processed through the well-known technique of solid phase synthesis. Equipment for this synthesis is distributed by several vendors including for example Applied Biosystems (Foster City, Calif.). Any other means for this synthesis known in the art can be used additionally or alternatively. It is well known to use similar techniques to prepare oligonucleotides such as phosphorothioates and alkylated derivatives. The compounds of the invention can also be mixed, encapsulated, conjugated or otherwise associated with other molecules, molecule structures or mixtures of compounds, such as for example liposomes, molecules directed to receptors, oral, rectal, topical or other formulations, to aid in absorption, dissolution and / or absorption. US Patents Representative examples illustrating the preparation of these assistance formulations for absorption, distribution and / or absorption include, but are not limited to, U.S. Pat. Nos. 5,108,921; 5,354,844; 5,416,016; 5,459,127; 5,521,291; 5,543,158; 5,547,932; 5,583,020; 5,591,721; 4,426,330; 4,534,899; 5,013,556; 5,108,921; 5,213,804; 5,227,170; 5,264,221; 5,356,633; 5,395,619; 5,416,016; 5,417,978; 5,462,854; 5,469,854; 5,512,295; 5,527,528; 5,534,259; 5,543,152; 5,556,948; 5,580,575; and 5,595,756, each of which is incorporated herein by reference. Other examples of sense or antisense oligonucleotides include those oligonucleotides that are covalently linked to organic portions, such as those described in WO 90/10048, and other portions that increase the affinity of the oligonucleotide for a target nucleic acid sequence, such as poly (). L-lysine). Still further, intercalating agents, such as ellipticine and alkylating agents or metal complexes can be connected to sense or antisense oligonucleotides to modify binding specificities of the antisense or sense oligonucleotide for the target nucleotide sequence. Sense or antisense oligonucleotides can be introduced into a cell containing the target nucleic acid sequence by any method of gene transfer, including for example CaP04-mediated DNA transection, electroporation or by using gene transfer vectors such as Epstein-Barr virus . In a preferred method, an antisense or sense oligonucleotide is inserted into a convenient retroviral vector. A cell containing the target nucleic acid sequence is contacted with the recombinant retroviral vector either in vivo or ex vivo. Suitable retroviral vectors include but are not limited to those derived from the murine retrovirus -MuLV, N2 (a retrovirus derived from M-MuLV), or the double copy vectors designated DCT5A, DCT5B and DCT5C (see WO 90/13641). Sense or antisense oligonucleotides can also be introduced into a cell containing the target nucleotide sequence by forming a conjugate with a ligand binding molecule, as described in WO 91/04753. Suitable ligand binding molecules include but are not limited to cell surface receptors, growth factors, other cytokines or other ligands that bind to cell surface receptors. Preferably, the conjugation of the ligand binding molecule does not substantially interfere with the ability of the ligand binding molecule to bind to its corresponding molecule or receptor or block entry of the sense or antisense oligonucleotide or its conjugated version in the cell. In alternate form, a sense or antisense oligonucleotide can be introduced into a cell containing the target nucleic acid sequence by formation of an oligonucleotide-lipid complex, as described in WO 90/10448. The sense or antisense oligonucleotide-lipid complex is preferably dissociated within the cell by an endogenous lipase. RNA molecules or antisense or sense DNA in general are at least about 5 nucleotides in length, in alternating form at least about 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 , 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 , 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 210, 220, 230, 240 , 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 6'30, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, or 1000 nucleotides in length, where in that context the term "approximately" means the reference nucleotide sequence length plus or minus 10 percent of that reference length. The probes can also be used in PCR techniques to generate a set of sequences for identification of closely related polypeptide UNQ733 coding sequences. Nucleotide sequences encoding an UNQ733 polypeptide can also be used to construct hybridization probes to map the gene encoding the UNQ733 polypeptide and for genetic analysis of individuals with genetic disorders. The nucleotide sequences provided herein can be mapped to a chromosome and specific regions of a chromosome using known techniques, such as in situ hybridization, binding analysis against known chromosomal markers and monitoring of hybridization with libraries. The UNQ733 polypeptide can be used in assays to identify other proteins or molecules involved in a binding interaction with the UNQ733 polypeptide. By these methods, inhibitors of ligand / receptor binding interaction can be identified. Proteins involved in these binding interactions can also be used to monitor peptide or small molecule inhibitors in the binding interaction. Supervisory assays can be designed to find major compounds that mimic the biological activity of a native UNQ733 polypeptide or a receptor for the UNQ733 polypeptide. These supervisory trials will exclude trials susceptible to high-performance monitoring due to chemical libraries, making them particularly convenient for identifying small molecule drug candidates. Small concentrated molecules include synthetic organic or inorganic compounds. The assays can be performed in a variety of formats, including protein-protein binding assays, biochemical monitoring assays, immunoassays and cell-based assays that are well characterized in the specialty . Nucleic acids encoding UNQ733 polypeptide or its modified forms can also be used to generate either transgenic animals or animals with "knock out" inoperable genes, which in turn are useful in the development and monitoring of therapeutically useful reagents. A transgenic animal (for example a mouse or rat) is an animal that has cells that contain a transgene, this transgene is introduced into the animal or an ancestor of the animal in a prenatal stage, for example embryonic. A transgene of a DNA that is integrated into the genome of a cell from which a transgenic animal develops. In one embodiment, cDNA encoding UNQ733 polypeptide can be used to clone genomic DNA encoding UNQ733 polypeptide according to established techniques and the genomic sequences employed to generate transgenic animals that contain cells expressing DNA encoding UNQ733 polypeptide. Methods for generating transgenic animals, particularly animals such as mice or rats, have become conventional in the art and are described, for example, in U.S. Pat. numbers 4,736,866 and 4,870,009. Typically, particular cells will be targeted for the incorporation of transpose UNQ733 polypeptide with tissue-specific enhancers. Transgenic animals that include a copy of a transgene encoding UNQ733 polypeptide introduced into the germ line of the animal and at an embryonic stage, can be used to examine the effect of increased expression of DNA encoding UNQ733 polypeptide. These animals can be used as animals and test for reagents that are considered to confer protection of, for example pathological conditions associated with its overexpression. According to this fasceta of the invention, an animal is treated with the reagent and a reduced incidence of the pathological condition, in comparison with untreated animals having the transgene, will indicate a potential therapeutic intervention for the pathological condition. Alternatively, non-human homologs of the UNQ733 polypeptide can be used to construct an animal with "knock out" genes UNQ733 gene having a defective or altered gene encoding the UNQ733 polypeptide as a result of homologous recombination between the endogenous gene encoding the polypeptide UNQ733 and an altered genomic DNA encoding the UNQ733 polypeptide introduced into an animal embryonic stem cell. For example, cDNA that encoding UNQ733 polypeptide can be used to clone genomic DNA encoding UNQ733 polypeptide according to established techniques. A portion of the genomic DNA encoding UNQ733 polypeptide can be deleted or replaced with another gene such as a gene encoding a selectable marker that can be used to monitor integration. Typically, several kilobases of unaltered flank DNA (both at the 5 'and 3' ends) are included in the vector [see for example Thomas and Capecchi, Cell, 51: 503 (1987) for a description of homologous recombination vectors] . The vector is introduced into a line of embryonic stem cells (for example by electroporation) and cells in which the introduced DNA has been recombined homologously with the endogenous DNA, are chosen [see for example Li et al., Cell, 69: 915 ( 1992)]. The selected cells are then injected into a blastocyst of an animal (eg, a mouse or rat) to form aggregation chimeras [see for example, Bradley, in Teratocarcinomas and Embryonic Stem Cells: A Practical Approach, E. J. Robertson, ed. (IRL, Oxford, 1987), pp. 113-152]. A chimeric embryo can then be implanted in a suitable pseudopregnant female adoptive animal and the embryo is brought to term to create an animal with "knock out" inoperative genes.

Progeny harboring homologously recombined DNA in their germ cells can be identified by standard techniques and used to develop animals in which all cells of the animal contain the homologously recombined DNA. Animals with inoperative "knock out" genes can be characterized, for example, by their ability to defend against certain pathological conditions and by their development of pathological conditions due to the absence of the UNQ733 polypeptide. Nucleic acid encoding the UNQ733 polypeptides can also be used in gene therapy. In gene therapy applications, genes are introduced into cells in order to achieve in vivo synthesis of a therapeutically effective gene product, for example for replacement of a defective gene. "Gene therapy" includes both conventional gene therapy, where a lasting effect is achieved by a single treatment and the administration of therapeutic gene agents, involving the one-time or repeated administration of a therapeutically effective DNA or mRNA. RNAs and antisense DNAs can be used as therapeutic agents to block the expression of certain genes in vivo. Whether it is shown that short antisense oligonucleotides they can be imported into cells where they act as inhibitors, despite their low intracellular concentrations caused by their absorption restricted by the cell membrane. (Zamecnik et al., Proc. Nati, Acad. Sci. USA 83: 4143-4146 [1986]). The oligonucleotides can be modified to improve their absorption, for example by replacing their negatively charged phosphodiester groups with uncharged groups. There are a variety of techniques available to introduce nucleic acids into viable cells. The techniques vary depending on whether the nucleic acid is transferred in cells grown in vitro or in vivo in the cells of the intended host. Suitable techniques for the transfer of nucleic acid in mammalian cells in vitro include the use of liposomes, electroporation, microinjection, cell fusion, DEAE-dextran, the method of calcium phosphate precipitation, and so on. Currently preferred in vivo gene transfer techniques include transection with viral vectors (typically retroviral) and protein-liposome-mediated transection with viral coating (Dzau et al., Trends in Biotechnology 11, 205-210 [1993]). In some situations, it is convenient to provide the source of nucleic acid with an agent which targets target cells such as an antibody specific for a cell surface membrane protein or the target cell, a ligand for a receptor in the target cell, etc. When liposomes are employed, proteins that bind to a cell surface membrane protein associated with endocytosis can be used to target and / or facilitate absorption, for example capsid proteins or their topical fragments for a particular cell type, antibodies to proteins that they undergo internalization in cyclic operation, proteins that target intracellular localization and improve intracellular half-life. The technique of receptor-mediated endocytosis is described, for example, by Wu et al., J. Biol. Chem. 262, 4429-4432 (1987); and Wagner et al., Proc. Acad. Sci. USA 87, 3410-3414 (1990). To review gene therapy and gene tagging protocols see Anderson et al., Science 256, 808-813 (1992). The nucleic acid molecules encoding the UNQ733 polypeptides or fragments thereof described herein are useful for identification of chromosomes. In this regard, there is a continuing need to identify new chromosome markers, since relatively few chromosome labeling reagents, based on Current sequence data are currently available. Each UNQ733 nucleic acid molecule of the present invention can be used as a chromosome marker. UNQ733 polypeptides and nucleic acid molecules of the invention can be used as a diagnostic for tissue typing, wherein UNQ733 polypeptides can be differentially expressed in one tissue compared to another, preferably in a diseased tissue as compared to a normal tissue thereof. tissue type, nucleic acid molecules UNQ733 will find use to generate probes for PCR, Northern analysis, Southern analysis and Western analysis. This invention encompasses methods for monitoring compounds to identify those that avoid the effect of the UNQ733 Polypeptide (antagonists). Supervisory assays for antagonist drug candidates are designed to identify compounds that bind or complex with the UNQ733 polypeptides encoded by the genes identified herein, or otherwise interfere with the interaction of the encoded polypeptides with other cellular proteins, including, for example, inhibit the expression of the cell UNQ733 polypeptide. These supervision trials will include trials susceptible to high-performance monitoring of chemical libraries, making them particularly suitable for identifying small molecule drug candidates. The assays can be performed in a variety of formats, including protein-protein binding assays, biochemical monitoring assays, immunoassays and cell-based assays, which are well characterized in the art. All assays for antagonists are common since they require contacting the drug candidate with the UNQ733 polypeptide encoded by a nucleic acid identified herein under conditions and for a sufficient time to allow these components to interact. In binding assays, the interaction is binding and the complex formed can be isolated or detected in the reaction mixture. In a particular embodiment, the UNQ733 polypeptide or the drug candidate is immobilized on a solid phase, for example in a microtiter plate, by covalent or non-covalent connections. Non-covalent connection is generally achieved by coating the solid surface with a solution of the UNQ733 polypeptide and drying. Alternatively, an immobilized antibody, for example a monoclonal antibody, specific for the UNQ733 polypeptide a immobilize can be used to anchor it to a solid surface. The assay is performed by adding the non-immobilized component, which may be labeled by a detectable label, to the immobilized component, for example the coated surface containing the anchored component. When the reaction is complete, the unreacted components are removed, for example by washing, and complexes anchored on the solid surface are detected. When the non-immobilized component originally carries a detectable label, the detection of the immobilized label on the surface indicates that the complexing occurred. When the non-immobilized component does not originally carry a label, the complexed can be detected, for example by using a labeled antibody that specifically binds the immobilized complex. If the candidate compound interacts with, but does not bind to, an UNQ733 polypeptide, its interaction with that polypeptide can be assayed by well known methods for detecting protein-protein interactions. These assays include traditional approaches such as, for example, entanglement, co-immunoprecipitation, and co-purification through gradients or chromatographic columns. In addition, protein-protein interactions they can be monitored by using a yeast-based genetic system described by Fields et al. (Fields and Song, Nature (London), 340: 245-246 (1989); Chien et al., Proc. Nati. Acad. Sci. USA, 88 : 9578-9582 (1991)) as described by Chevray and Nathans, Proc. Nati Acad. Sci. USA, 89: 5789-5793 (1991). Many transcription activators, such as GAL4 yeast, consisting of two physically discrete modular domains, one that acts as the DNA binding domain, as the other that functions as the activation-transcription domain. The yeast expression system described in the above publications (generally referred to as the "hybrid sos system") takes advantage of this property, and employs two hybrid proteins, one in which the target protein is fused to the DNA binding domain of GAL4 , and another in which the candidate activation proteins are fused to the activation domain. The expression of a GALl-lacZ reporter gene under the control of an activated GAL4 promoter depends on the reconstitution of GAL4 activity by protein-protein interaction. Colonies containing interaction polypeptides are detected with a chromogenic substrate for /? -galactosidase. A complete team (MATCHMAKER ™) to identify protein-protein interactions between Two specific proteins using the two-hybrid technique are commercially available from Clontech. This system can also be extended to map protein domains involved in specific protein interactions as well as to signal amino acid residues that are crucial for these interactions. Compounds that interfere with the interaction of a gene encoding a UNQ733 polypeptide identified herein and other intra- or extracellular components can be tested as follows: usually a reaction mixture is prepared containing the product of the gene and the intra- or extracellular component under conditions and for a time that allows interaction and linking of the two products. To test the ability of a candidate compound to inhibit binding, the reaction is carried out in the absence and in the presence of the test compound. In addition, a placebo can be added to a third reaction mixture, to serve as a positive control. The binding (complex formation) between the test compound and the intra- or extracellular component present in the mixture is monitored as previously described. The formation of a complex in the control reaction (s) but not in the reaction mixture containing the test compound indicates that the test compound interferes with the interaction of the test compound and its reaction partner. To assay antagonists, the UNQ733 polypeptide can be added to a cell together with the compound to be monitored for a particular activity and the ability of the compound to inhibit the activity of interest in the presence of the UNQ733 polypeptide indicates that the compound is an antagonist to the UNQ733 polypeptide. Alternatively, antagonists can be detected by combining the UNQ733 polypeptide and a potential antagonist with membrane bound UNQ733 polypeptide receptors or receptors encoded under conditions appropriate for a competitive inhibition assay. The UNQ733 polypeptide can be labeled, such as by radioactivity, such that the number of UNQ733 polypeptide molecules bound to the receptor can be used to determine the effectiveness of the potential antagonist. The gene encoding the receptor can be identified by numerous methods known to those skilled in the art, for example selection by adsorption-ligand desorption cycles and FACS classification. Coligan et al., Current Protocols in Immun., 1 (2): all points chapter 5 (1991). Preferably, expression cloning is employed where polyadenylate RNA is prepared from a cell responsive to the UNQ733 polypeptide and a cDNA library created from this RNA is jointly divided to be used to transfect COS cells or other cells that do not respond to the UNQ733 polypeptide. Transfected cells that develop in glass holders are exposed to the tagged UNQ733 polypeptide. The UNQ733 polypeptide can be labeled by a variety of means including iodination or inclusion of a recognition site for a site-specific protein kinase. Following fixation and incubation, the porta objects undergo autoradiographic analysis. Positive sets are identified and sub sets are prepared and re-transfected using an interactive process of sub-collection and re-monitoring, eventually resulting in a single clone encoding the putative receptor. As an alternating approach for receptor identification, tagged UNQ733 polypeptide can be bound by photo affinity with cell membrane or extract preparations expressing the receptor molecule. Interlaced material se. resolves by PAGE and exposes to X-ray film. The tagged complex containing receptor can be cleaved resolved into peptide fragments and subjected to micro-sequenced proteins.

The amino acid sequence obtained from micro-sequencing will be used to design a set of degenerate oligonucleotide probes to monitor a cDNA library to identify the gene encoding the putative receptor. In another trial for antagonists, mammalian cells or a membrane preparation expressing the receptor are incubated with labeled UNQ733 polypeptide in the presence of the candidate compound. The ability of the compound to improve or block this interaction can then be measured. More specific examples of potential antagonists include an oligonucleotide that binds to immunoglobulin fusions with UNQ733 polypeptide and in particular antibodies including, without limitation, poly- and monoclonal antibodies and antibody fragments, single chain antibodies, anti-idiotypic antibodies and versions chimeric or humanized of these antibodies or fragments, as well as human antibodies and antibody fragments. Alternatively, a potential antagonist can be a serologically related protein, for example a mutated form of the UNQ733 polypeptide that recognizes the receptor but does not impart effect, thereby inhibiting competitively the action of the UNQ733 polypeptide. Another potential UNQ733 antagonist is an antisense RNA or DNA construct prepared using antisense technology, wherein for example an RNA molecule or antisense DNA acts to directly block the translation of mRNA by hybridizing to target mRNA and preventing protein translation. Antisense technology can be used to control gene expression through triple helix formation or DNA or antisense RNA, both of these methods are based on linking a polynucleotide to DNA or RNA. For example, the 5 'coding portion of the polynucleotide sequence, which encodes the mature UNQ733 polypeptides herein, can be used to design an antisense RNA oligonucleotide from about 10 to 40 base pairs in length. A DNA oligonucleotide is designed to be complementary to a region of the gene involved in the transcription (triple helix - see Lee et al., Nucí Acid Res., 6: 3073 (1979); Cooney et al., Science, 241: 456 (1988), Dervan et al., Science, 251: 1360 (1991)), thus avoiding transcription and production of the UNQ733 polypeptide. The antisense RNA oligonucleotide hybridizes to the mRNA in vivo and blocks translation of the mRNA molecule in the UNQ733 polypeptide (antisense - Okano, Neurochem. , 56: 560 (1991); Oligodeoxynucleotides as Antisense Inhibitors of Gene Expression (CRC Press: Boca Raton, FL, 1988). Oligonucleotides described above can also be delivered to cells such that the RNA or antisense DNA can be expressed in vivo to inhibit the production of the UNQ733 polypeptide. When antisense DNA is employed, oligodeoxyribonucleotides derived from the translation-initiation site, for example between positions approximately -10 and +10 of the target gene nucleotide sequence, are preferred. Potential antagonists include small molecules that bind to the active site, the receptor binding site, or growth factor or other relevant binding site of the UNQ733 polypeptide, thereby blocking the normal biological activity of the UNQ733 polypeptide. Examples of small molecules include, but are not limited to, small peptides or peptide-like molecules, preferably soluble peptides and organic or synthetic non-peptidyl inorganic compounds. Ribozymes are enzymatic RNA molecules capable of catalyzing the specific cleavage of RNA. Ribozymes act by sequence-specific hybridization to the complementary target RNA, followed by endonucleolytic cleavage.

Specific ribizime cleavage sites within a potential RNA target can be identified by known techniques. For further details see, for example, Rossi, Current Biology, 4: 469-471 (1994), and PCT publication number WO 97/33551 (published September 18, 1997). Nucleic acid molecules in triple helix formation used to inhibit transcription should be single stranded and be composed of deoxynucleotides. The base composition of these oligonucleotides are designed in such a way as to promote triple helix formation by means of Hoogsteen base pairing rules, which require considerable amounts of purines or pyrimidines in an eva from a duplex. For further details see, for example in PCT publication number WO 97/33551, above. These small molecules may be denoted by any one or more of the supervisory assay discussed previously and / or any other monitoring techniques well known to those skilled in the art or the art. Nucleic acid encoding, isolated UNQ733 polypeptide can be used to recombinantly produce UNQ733 polypeptide using well techniques known in the specialty and as described here. In turn, the produced UNQ733 polypeptides can be used to generate anti-UNQ733 antibodies using techniques well known in the art and as described herein. Antibodies that specifically bind a UNQ733 polypeptide identified here, as well as other molecules identified for the monitoring assays described previously, can be administered for the treatment of various disorders, including cancer, in the form of pharmaceutical compositions. If the UNQ733 polypeptide is intracellular and whole antibodies are used as inhibitors, internalization antibodies are preferred. However, lipofections or liposomes may also be employed to deliver the antibody, or an antibody fragment, into cells. When antibody fragments are employed, the smallest inhibitory fragment that specifically binds to the binding domain of the target protein is preferred. For example, based on the variable region sequences of an antibody, peptide molecules can be designed that retain the ability to ligate the target protein sequence. These peptides can be chemically synthesized and / or produced by technology Recombinant DNA. See, for example, Marasco et al., Proc. Nati Acad. Sci. USA, 90: 7889-7893 (1993). The formulation herein may also contain more than one active compound as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other. Alternatively, or in addition, the composition may comprise an agent that improves its function, such as for example a cytotoxic agent, cytokine, chemotherapeutic agent or growth inhibitory agent. These molecules are conveniently present in combination in amounts that are effective for the intended purpose. The following examples are offered for illustrative purposes only and are not intended to limit the scope of the present invention in any way. All patents and literature references cited in the present specification are hereby incorporated by reference in their entirety. EXAMPLES MATERIALS AND METHODS Cell lines: Chinese hamster ovary, DP12 mutants (American Type Culture Collection (ATCC, Manassa, VA)) and PGSB (ATCC) were used for transient expression and production of recombinant proteins. T Jurkat lymphoma, Daudi B and BJAB cell lymphomas and Reh B cell leukemia were obtained from ATCC. RNA expression analysis: For the analysis of UNQ733 mRNA expression in multiple samples of human tumor and normal biopsy. Affymetrix data were obtained from Gene Logic, Inc. (Gaithersberg, MD). A total of 150 samples [6 normal samples; 62 cancer samples; and 82 samples without cancer disease] were analyzed. Gene Logic data were normalized using global scale adjustment with a target intensity of 100. The Affymetrix data for UNQ733 in Fig.l was generated from the probe equipment U133 ID 229152_at. For in situ hybridization, a 368-bp labeled 33P antisense riboprobe was generated from a unique UNQ733 PCR product using a primer with oligonucleotide sequence 5 '-CAG-GTG-ACC-AGG-TTT-ATC-GTG-3' ( SEQ ID NO: 5) and a sense control riboprobe with the 5'-AAT-ATT-CCA-GGG-CCA-GTC-ACT-3 '(SEQ ID NO: 6). Representative normal tissues and cancers include 3 lymphoma tissue microcysts (Cybrdi, Inc., Frederick, MD) were also monitored for in situ hybridization. Recombinant proteins: cDNA UNQ733 was generated by PCR amplification. from a multiple cDNA library human tissues The PCR product was cloned into pSVID, a vector based on pRK with a His8 tag. PGSB cells (ATCC) were transfected using Fugene 6 (Roche, Indianapolis, IN) and conditioned medium collected after 7 days. HisQ8 labeled polypeptide HisQ was purified by Ni chromatography followed by dialysis in a 10 mM citrate buffer, pH 3.0. An N-terminal UNQ733 human placental alkaline phosphatase fusion protein (UNQ733-AP) was generated by inserting the entire UNQ733 coding sequence into a pRK vector containing the AP gene. CHO cells were transfected using Fugene 6 (Roche) and supernatant was allowed to condition for 6 days. All experiments were used supernatant 733-AP and a control supernatant (Relt-AP) that was normalized for AP activity. Monoclonal anti-UNQ733 antibodies: BALB / c mice were immunized 15 times with 1.0 μg of UNQ733-His8 resuspended in adjuvant of monophosphoryl lipid A / trehalose dicornomycholate (Corixa, Hamilton, MT) in each plant of the hind paw at intervals of 3 to 4 days. Three days after the final reinforcement, popliteal lymph nodes were fused with myeloma cell line P3X63Ag8.653 (ATCC, Manassa, VA) using 50% polyethylene glycol and cultured in culture plates. 96-well tissue Culture supernatant were initially monitored for their ability to bind to UNQ733-His8. The selected hybridomas were then cloned by limiting dilution. Antibody clones were deposited with the ATCC under the Budapest Treaty. American Type Culture Collection (ATCC) is located at 10801 University Boulevard, Manassas, Virginia 20110-2209. Details of deposits are as follows: Deposit date ATCC number deposit 3E7.9.20 June 2, 2004 PTA- 6026 3F10.11.2 June 2, 2004 PTA- 6027 3H1.4.8 June 2, 2004 PTA- 6028 4A9.12.12 June 2, 2004 PTA- 6029 5A8.11.6 June 2, 2004 PTA- 6030 5F2.6.14 June 2, 2004 PTA- 6031 9D6.11.15 June 2, 2004 PTA- 6032 10G10.15.16 June 2, 2004 PTA- 6033 12H4.11.3 June 2, 2004 PTA- 6034 These deposits were made under the provisions of the Budapest Treaty in the international recognition of the deposit of microorganisms for the purpose of patent procedures and the underlying regulations (Budapest Treaty). This ensures the maintenance of a viable crop of the deposit for 30 years from the date of deposit. The deposits will be made available by ATCC under the terms of the Budapest Treaty, and an agreement between Genentech, Inc. and ATCC, which ensures permanent availability and without restriction of the progeny of the deposit culture to the public, before issuance of the patent of the USA pertinent or by leaving open to the public any patent applications of the US. or foreigners, whichever comes first, and ensure the progeny availability to whom is determined by the US Patent and Trademark Commissioner. who is entitled in accordance with 35 USC § 122 and the Commissioner's rules accordingly (including 37 CFR § 1.14 with particular reference to 886 OG 638). The assignee of the present application has agreed that if a crop of the materials on deposit died or was lost or destroyed when cultivated under In suitable conditions, the materials will be quickly replaced upon notification with another of them. The availability of the deposited material shall not be considered as a license to practice the invention in contravention of the rights granted under the authority of any government in accordance with its patent laws. Western blots and immunopresencipitation: Purified His8 tagged UNQ733 protein is subjected to 18% SDS-PAGE and immunoblot (Invitrogen, Carlsbad, CA). Transfers were incubated with 1 μg / ml of anti-UNQ733 Mab overnight at 4 ° C. Horseradish peroxidase Ig rabbit anti-mouse (Amersham; Piscataway, NJ) was used as a secondary antibody and the blots were revealed using the SuperSignal West Pico Luminol / Enhancer solution (Pierce; Rockford, IL). Immunoprecipitation was performed by adding 1 μg of purified Mab to 50 ng of purified His8 labeled UNQ733 in TBS [50 mM Tris, 150 mM NaCl], followed by protein A / G-agarose (Pierce), and incubated overnight at 4 ° C. ° C. The immunoprecipitates were recovered, washed with TBS and subjected to 18% SDS-PAGE. Transfers were incubated with India HisProbe (1: 5000; Pierce) to detect UNQ733 tagged with His8, washed in TBS + 0.05% Tween-20 and revealed as described above. Immunohistochemistry: Sections of frozen human tonsils (5 μ) were fixed in acetone at -20 ° C for 5 minutes, followed by OCT removal in TBST (Tris-buffered saline with Tween 20). Endogenous peroxidase, avidin and biotin were neutralized using the KPL blocking buffer (KPL, 37-00-84; Gaithersburg, D) and avidin Vector / biotin blocking kit (Vector, SP-2001; Burlingame, CA) respectively, followed by rinses with TBST. Slides were incubated for 30 minutes in 10% normal horse serum in 3% BSA / PBS for 30 minutes. Slides were then incubated in 10 μg / ml of anti-UNQ733 antibody (clone 3H1) for 30 minutes at room temperature. After washes in TBST, the slides were incubated with 2.5 g / ml biotinylated horse anti-mouse secondary antibody (Vector, BA-2001) for 30 minutes at room temperature. Following washing with TBST the slides were incubated with Vectastain ABC Elite reagents (Vector, PK-6100) for 30 minutes at room temperature, the slides were then rinsed with TBST, incubated with Pierce Metal Enhanced DAB (Pierce, 1856090) for four minutes, and rinsed in water. The slides are then they contrasted with Mayer's hematoxylin, dehydrated, mounted and covered for observation in bright field. Flow cytometry: For analysis of UNQ733 expression in tonsil cells, fresh human tonsil tissues are shredded and digested in 50 mg / ml of IV collagenase and 50 μg of DNase I (Sigma-Aldrich, St. Louis, MO, USA) ). The resulting cell suspension is subjected to negative selection of B cells with anti-CD19 microbeads in an autoMACS separator (Miltenyi Biotec, Auburn, CA). The CD19 fraction was blocked with Fe (Miltenyi Biotec) blocking reagent followed by anti-CD14-FITC staining (clone M5E2, BD Pharmingen, San Diego, CA) and anti-CD21-PE (clone B-ly4; BD Pharmingen ) in FACS wash [PBS + 0.5% bovine serum albumin] for 30 minutes at room temperature Cells were washed in FACS wash and fixed with FACSLyse solution (BD Pharmingen) for 20 minutes at room temperature. with FACS and treated with FACS Perm 2 solution (BD Pharmingen) The cells were washed in FACS and incubated with 10 μg / ml of Mab 12H4 specific to biotinylated UNQ733 for 30 minutes at room temperature after washing and incubated with SA-APC ( BD Pharmingen) The cells were analyzed on a BD flow cytometer FACSCaliber. FDC were passed as CD14 + CD21 + cells and monocytes passed as CD14 + CD21 ~ cells. For analysis of UNQ733 linkage labeled with Hisa to lymphoma cell lines, cells were incubated with. 50 // g / ml (4.5 μM) or 20 // g / ml (1.8 μM) of UNQ733 labeled Hise diluted in FACS at room temperature for 30 minutes. Washed cells and UNQ733 labeled His8 ligand was detected with 10 μg / ml anti-His6 (C-term) -FITC (Invitrogen). Alternately, UNQ733 labeled His8 ligated to cells was detected with 10 μg / ml of Mab 12H4 specific for biotinylated UNQ733 followed by SA-PE (BD Pharmingen). For analysis of UNQ733 linkage labeled His8 to B cells of human peripheral blood, peripheral blood was obtained from normal healthy human donors. Peripheral blood mononuclear cells were isolated using LSM lymphocyte separation medium (ICN, Costa Mesa, CA). B cells were purified using anti-CD19 microbeads and a MACS separator (Miltenyi Biotec). B cells were cultured in Dulbecco medium modified with Iscove + 10% fetal bovine serum in the presence or absence of 1 // g / ml of anti-CD40 (clone 5C3; BD Pharmingen) and 10 ng / ml of rIL-4 (Preprotech) for 48 hours before the flow cytometric analysis as described earlier. B cells were stained with anti-CD19-APC (clone HIB19; BD Pharmingen). Protein expression and sequencing: PGSB cells were transected transiently with UNQ733 labeled with Hiss using Fugene 6 (Roche). The cultures were incubated in the presence or absence of 10 μ? decanoyl-Arg-Val-Lys-Arg-chloromethyl ketone (Bachem, King of Prussia, PA), an inhibitor of proprotein convertase, adding to the cultures on day one. After 6 days in culture, supernatants were harvested, precipitated by affinity with Ni-NTA (Qiagen, Valencia, CA). The Ni-NTA ligated protein was subjected to 18% SDS-PAGE and transferred to PVDF for N-terminal sequencing by degradations in a Procise N-terminal sequencer (ABI, Foster City, CA). Protein binding assay: BJAB cells were incubated with serial dilutions of UNQ733-AP supernatant or a single concentration of Relt-AP control supernatant. After incubation for 1 hour at 4 ° C, cells were washed three times with PBS and transferred to a 96-well microplate. The cells were heated at 50 ° C for one hour to inactivate the activity of endogenous alkaline phosphatase. One-stage PNPP substrate buffer (Pierce) is added and the reaction was allowed to proceed for 30 minutes at room temperature in the darkness. Cells were centrifuged and an aliquot of substrate buffer was removed for absorbance analysis at 405 nm in a Spectra ax 250 microplate reader (Molecular Devices, Sunnyvale, CA). For competitive inhibition of UNQ733-AP binding, a fixed concentration (0.5X) of UNQ733-AP supernatant was used and incubated simultaneously by increasing concentrations of HQ-tagged UNQ733 or a control vehicle [10 mM citrate buffer, pH 3.0]. RESULTS UNQ733 is overexpressed in non-Hodgkin lymphoma and hyperplastic lymphoma. Oligonucleotide-based microarray expression data from more than 4800 human biopsy samples were analyzed for genes that showed high mRNA expression relative to normal tissue. Once this gene was designated UNQ733, it was found to be over-expressed in tumors of lymphoid origin (Fig. 1). Among the lymphoid tumors analyzed, it was found to be significantly over-expressed in 29 of 62 (46.8%) and non-Hodgkin's lymphomas. By this analysis over-expression of UNQ733 was also observed in 75 of 82 (91%) non-malignant amygdala tissue designated as hyperplastic by histopathology.

To further estimate the predominance of over-expression of UNQ733 in non-Hodgkin's lymphoma, we obtained three micro rows of lymphoma tissue (TMA) containing 173 nuclei of non-Hodgkin's lymphoma tissue. In situ hybridization was carried out in the TMAs using a specific probe of UNQ733. In 66 of 173 (38%) individual tumors, mRNA expression of UNQ733 was detected in malignant cells. On expression of UNQ733 is observed in B-cell lymphoma (NOS), diffuse large B-cell lymphoma, follicular lymphoma, small lymphocytic lymphoma, malignant lymphoma (NOS), malignant T-cell lymphoma, large-cell anaplastic lymphoma, and tissue lymphoma lymphoid associated mucosal. In situ hydridization was carried out in normal and neoplastic human tissue. Expression of mRNA UNQ733 is observed in the germinal centers of all normal lymphoid tissues including the spleen, lymph nodes, tonsils, and Peyer's patches (Figure 3). In tonsils, UNQ733 expression is detected in the germinal centers (Figure 4A, 4B) and crypts (Figures 4C, 4D). In addition, expression of UNQ733 was observed in serous salivary glands (not shown). In neoplastic tissue, expression was observed in the malignant cells of 38% (3/8) of non-Hodgkin lymphomas analyzed (Figures 5 and 6). Monoclonal antibodies against UNQ733 labeled recombinant HISa were generated and characterized. A panel of 9 Mabs with recombinant UNQ733 reactivity by ELISA was obtained and characterized in Western blot assays, immuno precipitation assays and immunohistochemical assays (IHC) to estimate binding to UNQ733 in cell-free and cell-associated environments. Two of the MAbs were found to detect recombinant UNQ733 in a Western blot assay, 10G10 and 12H4 (Fig. 7). These antibodies were able to detect UNQ733 labeled recombinant HIS8 in the Western blot. The majority of the monoclonal antibodies were able to immunoprecipitate UNQ733 (Figure 8). MAbs 3H1 were tested for their ability to bind UNQ733 in tonsil tissue frozen by IHC. The observed staining pattern was identical to the location of MRNA UNQ733 by in situ hybridization. Strong staining is observed in the crypts and weak staining in the germinal centers (Figure 9). The observed staining pattern was consistent with a follicular dendritic cell (FDC = Follicular dentridic cell).

To determine the identity of the type of cell that expresses in the tonsils, fresh tonsil tissue was obtained from surgical resections, and used in flow cytometry to delineate the FDCs and monocytes by expression of CD14 and CD21. Biotinylated 12-H4 MAb was used to detect intracellular UNQ733. Expression of protein UNQ733 is detected in the FDC population but not in monocytes (Figure 10), a finding consistent with immunohistochemical data. UNQ733 is processed by a proprotein convertase Proprotein convertases (PCs) are a family of proteolytic enzymes that cleave biologically inactive precursor proteins in their mature active forms. Members of this family of proteases recognize amino acid sequences with the motif (K / R) -X-X- (K / R) /. UNQ733 contains a putative PC cleavage site R-E-K-R / S30. Two protein species are typically observed when recombinant UNQ733-Hiss is analyzed by Western blotting (Figure 7). N-terminal sequencing of the proteins confirmed the presence of two species, the first one beginning with the 18FPVSQDQE sequence, which was consistent with the "full-length" protein predicted after excision of signal sequence. The second protein started with the SISDSDEL sequence that would be the predicted PC cleavage product of UNQ733. To confirm that the activity of one PC was responsible for the observed excision event, UNQ733-HISB was expressed in the presence and absence of a PC inhibitor, decanoyl-RVKR-chloromethyl ketone (Figure 11). Multiple species were still observed, but the proportion of "integral length" UNQ733 was substantially increased in supernatants treated with PC inhibitor (Figure 12). This indicates that UNQ733 is processed by a PC. UNQ733 binds to lymph cell lines and primary B cells. The binding of an UNQ733 to lymphoma cell lines was estimated by flow cytometry. The binding of UNQ733-His8 to both BJAB cells, a human B cell lymphoma (Figure 13A), and Jurkat cells, a human T cell lymphoma (Figure 13B) is detected using a FITC anti-His6 conjugated anti-detection antibody (Invitrogen ). Antibody binding is observed for both cell lines, with BJAB cells showing superior binding of UNQ733-His8 than Jurkat cells. These studies were extended to test the MAbs panel for the ability to detect UNQ733 binding in a subset of leukemia / lymphoma cell lines. human B cell. Several MAbs, including 10G10, were able to detect ligated UNQ733-His8 (not shown); 12H4 showed the best signal to interference ratio to detect UNQ733-His8 bound to BJAB. Reh and Daudi cells (Figure 14). To evaluate the specificity of the binding observed by the UNQ733-His8 molecule, a human placental alkaline phosphatase fusion protein-UNQ733 (UNQ733-AP), was used to detect bound UNQ733 and UNQ733-His8 was used to function as a competitor. The UNQ733-AP protein in tissue culture supernatants was found to bind to the lymphoblast cell line C1R B in a dose-dependent manner while a RELT-AP control AP fusion protein showed no linkage (Figure 15A). When tested in a competition assay, UNQ733-His8 was found to inhibit the binding of UNQ733-AP to C1R cells (Figure 15B). This indicated that the binding of UNQ733 to lymphoma B is specific. UNQ733 is expressed in follicular dendritic cells in the germinal centers of secondary lymphoid organs. Because the germinal centers are a site of selection of B cells, recombination of class switching, and somatic hypermutation, the role of UNQ733 in non-B cell biology neoplastic, is also evaluated. Peripheral blood mononuclear cells were obtained from normal healthy human donors and B cells were purified and analyzed for UNQ733 binding (Figure 16). It was observed that peripheral blood B cells in "resting" from multiple human donors bound UNQ733. When those PB B cells were first stimulated with an agonist-specific MAb to CD40 and recombinant IL-4, the binding of UNQ733 was found to increase two to five times depending on the donor (Figure 16). It appears that stimulation of B cells with anti-CD40 results in increased surface expression of the receptor for UNQ733.

Claims (38)

1. REVINDICATION 1. A method for inhibiting the growth of a non-Hodgkin lymphoma cell comprising contacting the cell with an UNQ733 antagonist that causes inhibition of cell growth.
2. 2. The method according to claim 1, characterized in that the cell is present in a non-Hodgkin's lymphoma.
3. 3. The method according to claim 1, characterized in that the antagonist UNQ733 binds to UNQ733 polypeptide.
4. 4. The method according to claim 3, characterized in that the antagonist UNQ733 is an antibody, an oligopeptide, a small inorganic or organic molecule.
5. 5. The method according to claim 4, characterized in that the antagonist UNQ733 is an antibody.
6. 6. The method according to claim 5, characterized in that the antibody is produced by a hybridoma having ATCC deposit number no. PTA-6026, PTA-6027, PTA-6028, PTA-6029, PTA-6030, PTA-6031, PTA-6032, PTA-6033 or PTA-6034, or their progeny.
7. 7. The method according to claim 5, characterized in that the antibody is a monoclonal antibody, antibody fragment, chimeric antibody, humanized antibody, human antibody, multi-specific antibody or single chain antibody.
8. 8. The method according to claim 5, characterized in that the antibody is conjugated to a growth inhibitory agent or cytotoxic agent.
9. 9. A method for inhibiting the growth of a non-Hodgkin's lymphoma, which comprises administering an UNQ733 antagonist to a mammal having non-Hodgkin's lymphoma.
10. The method according to claim 9, characterized in that the UNQ733 antagonist binds UNQ733 polypeptide in a cell that expresses and / or responds to UNQ733 polypeptide.
11. 11. The method according to claim 9, characterized in that the UNQ733 antagonist binds to a non-Hodgkin lymphoma cell.
12. The method according to claim 9, characterized in that the UNQ733 antagonist causes growth inhibition of a cell which expresses and / or responds to the UNQ733 polypeptide.
13. 13. The method according to claim 9, characterized in that the ÜNQ733 antagonist is an antibody, an oligopeptide, small organic or inorganic molecule that binds to UNQ733 polypeptide.
14. 14. The method according to claim 13, characterized in that the antagonist UNQ733 is an antibody.
15. 15. The method according to claim 14, characterized in that the antibody is produced by a hybridoma having ATCC deposit number no. PTA-6026, PTA-6027, PTA-6028, PTA-6029, PTA-6030, PTA-6031, PTA-6032, PTA-6033 or PTA-6034, or their progeny.
16. 16. The method according to claim 14, characterized in that the antibody is a monoclonal antibody, antibody fragment, chimeric antibody, humanized antibody, human antibody, multi-specific antibody or single chain antibody.
17. 17. The method according to claim 14, characterized in that the antibody is conjugated to a growth inhibitory agent or agent cytotoxic 18.
18. The method according to claim 9, characterized in that it further comprises administering a chemotherapeutic agent to a mammal.
19. The method according to claim 9, characterized in that the non-Hodgkin lymphoma is a B-cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, small lymphocytic lymphoma, malignant lymphoma, malignant T-cell lymphoma, lymphoma large anaplastic cells or lymphoma of associated mucosal lymphoid tissue.
20. 20. A method for treating or preventing a cellular proliferative disorder with increased expression or activity of UNQ733 polypeptide, the method comprising administering to a subject in need of this treatment an effective amount of an UNQ733 antagonist.
21. 21. The method according to claim 20, characterized in that the cell proliferative disorder is hyperplasia.
22. 22. The method according to claim 21, characterized in that the hyperplasia is diseased non-malignant tonsil tissue.
23. 23. The method according to claim 20, characterized in that the antagonist UNQ733 is an antibody, an oligopeptide, small organic or inorganic molecule that binds to UNQ733 polypeptide.
24. 24. The method according to claim 23, characterized in that the antagonist UNQ733 is an antibody.
25. 25. The method according to claim 24, characterized in that the antibody is produced by a hybridoma having ATCC deposit number no. PTA-6026, PTA-6027, PTA-6028, PTA-6029, PTA-6030, PTA-6031, PTA-6032, PTA-6033 or PTA-6034, or their progeny.
26. 26. The method according to claim 24, characterized in that the antibody is a monoclonal antibody, antibody fragment, chimeric antibody, humanized antibody, human antibody, multi-specific antibody or single chain antibody.
27. 27. The method according to claim 24, characterized in that the antibody is conjugated to a growth inhibitory agent or cytotoxic agent.
28. 28. A method to monitor biologically active agents for the treatment of lymphoma non-Hodgkin comprising administering a candidate agent to a transgenic mammal having a genome comprising an integrated transgene encoding the UNQ733 polypeptide operably linked as a promoter, wherein the transgene results in the mammal acquiring non-Hodgkin's lymphoma, and determine the effect of the agent on non-Hodgkin's lymphoma in the mammal.
29. 29. The method according to claim 28, characterized in that the candidate agent is an antibody, an oligopeptide, a small organic or inorganic molecule that binds to the UNQ733 polypeptide.
30. 30. Method for targeting a therapeutic agent with a non-Hodgkin lymphoma in a host, the method is characterized in that it comprises administering to the host the therapeutic agent in a form that binds to a molecule that binds the UNQ733 polypeptide, thereby the agent targets the lymphoma in the host.
31. 31. The method according to claim 30, characterized in that the molecule that binds the UNQ733 polypeptide is an antibody.
32. 32. The method according to claim 31, characterized in that the antibody is produced by a hybridoma that has ATCC deposit number no. PTA-6026, PTA-6027, PTA-6028, PTA-6029, PTA-6030, PTA-6031, PTA-6032, ??? - 6033 or PTA-6034, or their progeny.
33. 33. An antibody that binds to UNQ733 polypeptide, wherein the antibody is suitable for detecting the UNQ733 polypeptide in a detection assay.
34. 34. The composition of claim 33, characterized in that the detection assay is a Western blot, immunoprecipitation or immunostaining.
35. 35. An antibody that binds to UNQ733 polypeptide, wherein the antibody: (a) is produced by a hybridoma having deposit number ATCC PTA-6026, PTA-6027, PTA-6028, PTA-6029, PTA-6030, PTA -6031, PTA-6032, PTA-6033, PTA-6034, or its progeny; (b) ligates to the same epitope in Polypeptide UNQ733 as an antibody produced by a hybridoma having ATCC deposit number no. PTA-6026, PTA-6027, PTA-6028, PTA-6029, PTA-6030, PTA-6031, PTA-6032, PTA-6033 or PTA-6034; or (c) competes with an antibody produced by a hybridoma having deposit number ATCC PTA-6026, PTA-6027, PTA-6028, PTA-6029, PTA-6030, PTA-6031, PTA-6032, PTA-6033 or PTA-6034 to bind to the UNQ733 polypeptide.
36. 36. The antibody according to claim 35, characterized in that the antibody is conjugated to a growth inhibitory agent or cytotoxic agent.
37. 37. An antibody fragment of claim 35, characterized in that it comprises an antigen binding region.
38. 38. A humanized form of the antibody of claim 35.