Antagonistic human light-specific human monoclonal antibodies

An antibody and species-specific technology, applied in the field of antagonistic antibodies to treat hLIGHT-mediated diseases

Active Publication Date: 2010-03-03
KYOWA HAKKO KIRIN CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Although the discussion shown above shows the role of LIGHT in inflammatory diseases (such as IBD or GVHD), so far no human anti-human LIGHT antibody has b

Method used

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  • Antagonistic human light-specific human monoclonal antibodies
  • Antagonistic human light-specific human monoclonal antibodies
  • Antagonistic human light-specific human monoclonal antibodies

Examples

Experimental program
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preparation example Construction

[0370] For long-term production of high-yield recombinant proteins, stable expression is preferred. For example, cell lines that stably express antibody molecules can be engineered. Host cells can be transformed with DNA controlled by appropriate expression control elements (e.g., promoters, enhancers, sequences, transcription terminators, polyadenylation sites, etc.) Vector transformation. After the introduction of exogenous DNA, engineered cells are cultured in enriched medium for 1-2 days, and then transferred to selective medium. A selectable marker in the recombinant plasmid makes it resistant to the selection factor and allows the cells to stably integrate the plasmid into their chromosomes and grow to produce foci that can be subsequently cloned and expanded into cell lines. This method can be used to engineer cell lines that express antibody molecules. Such engineered cell lines are particularly useful for screening and evaluating compositions that interact directly...

Embodiment 1

[0380] Example 1 Preparation of human anti-hLIGHT antibody

[0381] In this example, transchromosomal mice (KM mice) immunized with soluble recombinant hLIGHT are described. TM ) (WO 02 / 43478; WO 02 / 092812; Ishida and Lonberg, IBC's 11 th Antibody Engineering Meeting. Abstract (2000); and Kataoka, S. IBCs 13 th Antibody Engineering Meeting. Abstract (2002)) prepared human anti-hLIGHT monoclonal antibody. The antibodies of the present invention can specifically stain hLIGHT stably transfected cell lines (EL4-hLIGHT and HEK293-hLIGHT), but not their parental cell lines. Likewise, they can bind hLIGHT (Ware et al., 1986 Lymphokine Res 5313-24) endogenously expressed on the surface of human T cell hybridoma (II-23.D7) after activation. These data show that the antibody binds hLIGHT immunospecifically. The isolated antibodies recognized one or two epitopes on hLIGHT as determined by cross-blocking assays as described below. Furthermore, the antibodies were able to simultaneous...

Embodiment 2

[0657] Example 2 Identification of commercially available mouse anti-human monoclonal antibodies

[0658] Antibody cross-blocking. Cross-blocking assays were performed as described in Example 1 and using mouse anti-hLIGHT monoclonal antibodies from R&D Systems ("R&D mouse mAb") and Abnova ("Abnova mouse mAb") and the Human anti-hLIGHT monoclonal antibody to assess the hLIGHT epitope to which the antibody binds. The results are shown in Figure 11 .

[0659] The results showed that the R&D mouse mAb binds to the same epitope as human E1, E13, and E63 monoclonal antibodies ("human E antibodies"), and binds to the same epitope as human F19 and F23 monoclonal antibodies ("human F antibodies") bit. Thus, unlike the human anti-hLIGHT E&F monoclonal antibodies identified in Example 1 that immunospecifically bind only one of two different epitopes, this R&D mouse mAb binds both sets of hLIGHT epitopes simultaneously. That is, the human E antibody and the human F antibody identif...

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Abstract

Provided herein are antibodies, such as fully human antibodies, that immunospecifically bind to an hLIGHT polypeptide. Also provided are isolated nucleic acids encoding antibodies, such as fully humanantibodies, that immunospecifically bind to a hLIGHT polypeptide. Further provided are vectors and host cells comprising nucleic acids encoding antibodies, such as fully human antibodies, that immunospecifically bind to a hLIGHT polypeptide. Also provided are methods of making antibodies, such as fully human antibodies, that immunospecifically bind to a hLIGHT polypeptide. Also provided herein isa method of treating a hLIGHT- mediated disease in a subject comprising administering to the subject an antibody, such as a fully human antibody, that immunospecifically binds to a hLIGHT polypeptide. In preferred embodiments, that anti-hLIGHT antibodies provided herein will ameliorate, neutralize or otherwise inhibit hLIGHT biological activity in vivo (e.g., the hLIGHT- mediated production or secretion of CCL20, IL-8 or RANTES from a cell expressing a hLIGHT receptor). Also provided herein is a method for the detection of hLIGHT in a sample as well as a method for ameliorating, neutralizingor otherwise inhibiting hLIGHT activity, e.g., in a human subject suffering from a disorder in which hLIGHT activity is detrimental.

Description

[0001] introduction [0002] The present invention provides immunospecifically binding human LIGHT (hLIGHT) (lymphotoxin-like, exhibits inducible expression and competes with HSV glycoprotein D for HVEM, receptors expressed by T lymphocytes (lymphotoxin-like, exhibits inducible expression, competes with HSV glycoprotein D for HVEM, a receptor expressed by T lymphocytes)) polypeptides, hLIGHT polypeptide fragments or antibodies to other hLIGHT epitopes. In some embodiments, the antibody is a fully human antibody, preferably a fully human monoclonal antibody, which immunospecifically binds hLIGHT polypeptide, hLIGHT polypeptide fragment or hLIGHT epitope. The invention also provides isolated nucleic acids encoding antibodies that immunospecifically bind hLIGHT polypeptides, hLIGHT polypeptide fragments, or hLIGHT epitopes. The present invention further provides vectors or host cells comprising nucleic acids encoding nucleic acids that immunospecifically bind to hLIGHT polypeptide...

Claims

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Application Information

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IPC IPC(8): C07K16/28C12N15/13A61K39/395G01N33/53A61P37/06
Inventor 史蒂文·W·格兰杰加藤伸一郎卡尔·F·瓦莱
Owner KYOWA HAKKO KIRIN CO LTD
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