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Monoclonal antibodies against NKG2A

A monoclonal antibody, single-chain antibody technology, applied in the direction of antibodies, anti-animal/human immunoglobulin, anti-receptor/cell surface antigen/cell surface determinant immunoglobulin, etc. difficult to predict, etc.

Active Publication Date: 2012-10-31
INNATE PHARMA SA +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] Because antibodies bind to specific three-dimensional features of their targets, small changes in the amino acid sequence of the target protein can prevent it from binding together, making it difficult to predict whether a given antibody against a protein from one species will bind Homologous proteins sharing some but not all sequence identity

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  • Monoclonal antibodies against NKG2A
  • Monoclonal antibodies against NKG2A
  • Monoclonal antibodies against NKG2A

Examples

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preparation example Construction

[0122] The production of monoclonal or polyclonal antibodies is well known in the art, and any of a number of available techniques may be used (see, e.g., Kohler & Milstein, Nature 256:495-497 (1975); Kozbor et al., Immunology Today 4:72 (1983); Cole et al., pp. 77-96 in Monoclonal Antibodies and Cancer Therapy (1985)). Techniques for the production of single chain antibodies (US Patent No. 4,946,778) can be adapted to produce antibodies directed against a desired polypeptide (eg, NKG2A). Furthermore, transgenic mice or other organisms, such as other mammals, can be used to express humanized, chimeric or similarly modified antibodies. Alternatively, phage display technology can be used to identify antibodies and heterologous Fab fragments that specifically bind an antigen of choice (see, e.g., McCafferty et al., Nature 348:552-554 (1990); Marks et al., Biotechnology 10:779-783 (1992)). In a specific embodiment, the method comprises selecting from a library or repertoire a mo...

Embodiment 1

[0253] Example 1: Autologous mediated by a subset of CD94 / NKG2A+KIR-NK cells iDC kill

[0254] Polyclonal NK cells cultured in the presence of exogenous IL-2 initially exhibited strong lytic activity against iDCs. Thus, in this study, polyclonal NK cell populations isolated from AM, AC, and DB donors effectively killed autologous or allogeneic iDCs. However, in the presence of appropriate anti-HLA class I mAbs, the lytic activity against autologous iDC was enhanced.

[0255] These data may be the result of disrupted inhibitory interactions that occur between self class I HLA on DCs and inhibitory receptors on NK cells. On the basis of these results, we hypothesize that only a fraction of the entire NK cell pool exhibits spontaneous cytotoxicity against iDCs, and that due to potent inhibitory interactions between their receptors and HLA class I molecules, effect, other NK cells do not have this cytotoxicity. To analyze this possibility, NK cell clones isolated from donor...

Embodiment 2

[0263] Example 2 - Sensitivity of iDCs to NK-mediated cytotoxicity mirrors HLA-E class I molecular downregulation

[0264] Previous studies have demonstrated that iDCs and mDCs display significant differences in HLA class I surface expression. Thus, by using mAbs specific for monomorphic titan determinants of HLA-A, HLA-B, HLA-C, and HLA-E molecules, it has been demonstrated that maturing DCs greatly upregulate the expression of HLA class I at the cell surface. Express. Furthermore, upregulation of HLA class I represents a key mechanism by which mDCs become resistant to NK cell-mediated lysis.

[0265] To directly evaluate the expression of various HLA class I molecules on cells representing different DC maturation stages, we comparatively analyzed the expression of HLA-A, HLA-B, HLA-C, and HLA-E in monocytes (derived from the same individual expression on iDC and mDC). All HLA class I molecules were highly upregulated in mDCs compared to iDCs. Remarkably, they were si...

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Abstract

The present invention relates to methods of treating immune disorders, particularly autoimmune or inflammatory disorders, and methods of producing antibodies and other compounds for use in therapeutic strategies for treating such disorders. Generally, the present methods involve the use of antibodies or other compounds that prevent the stimulation of NKG2A receptors on NK cells, leading to the lysis of dendritic cells that contribute to the pathology of the disorders.

Description

technical field [0001] The present invention relates to monoclonal antibodies and fragments thereof directed against the NK cell surface receptor NKG2A, and methods of producing and evaluating such antibodies. Monoclonal antibodies and fragments thereof are useful in the treatment of immune diseases, especially autoimmune diseases and other diseases requiring regulation of NK cell function. In general, the methods of the present invention involve the use of antibodies and fragments thereof to prevent expression of HLA-E or Qa1 that contributes to the pathology of the disease being treated. b Stimulation of NKG2A receptors on lysed NK cells of cells such as dendritic cells or activated T cells. Background technique [0002] Maintaining effective immune surveillance without eliciting an autoimmune response requires accurate titration of effector T cell responses. Autoimmune diseases arise when the immune system mounts an immune response against self-antigens (see, eg, Ludewi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K16/28A61K39/395
Inventor 阿莱斯山德罗·莫雷塔埃马努埃拉·马尔切纳罗弗朗索瓦·罗马涅帕斯卡莱·安德烈
Owner INNATE PHARMA SA
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