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Cytotoxic anti-lag-3 monoclonal antibody and its use in the treatment or prevention of organ transplant rejection and autoimmune disease

A LAG-3, monoclonal antibody technology, applied in the direction of anti-receptor/cell surface antigen/cell surface determinant immunoglobulin, antibody medical components, cell culture active agents, etc., can solve problems affecting arterial thrombus stability and other issues

Active Publication Date: 2010-06-02
IMMUTEP +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, anti-CD40L antibodies also target activated platelets in humans and affect the stability of arterial thrombus (3)

Method used

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  • Cytotoxic anti-lag-3 monoclonal antibody and its use in the treatment or prevention of organ transplant rejection and autoimmune disease
  • Cytotoxic anti-lag-3 monoclonal antibody and its use in the treatment or prevention of organ transplant rejection and autoimmune disease
  • Cytotoxic anti-lag-3 monoclonal antibody and its use in the treatment or prevention of organ transplant rejection and autoimmune disease

Examples

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preparation example Construction

[0059] For the production of monoclonal antibodies, any technique that produces antibodies by culturing serial cell lines can be used. Examples include hybridoma technology (9), trioma technology, human B cell hybridoma technology (10).

[0060] The techniques described for the production of single chain antibodies (US Patent No. 4,946,778) can be readily used to produce single chain antibodies to the CD223 polypeptide. Additionally, transgenic mice can be used to express humanized antibodies to immunogenic CD223 polypeptides.

[0061] The first monoclonal antibody of the present invention (referred to as A9H12) is produced by a hybridoma deposited at CNCM on April 27, 2007, with accession number CNCM I-3755.

[0062] The second monoclonal antibody of the present invention (referred to as 31G11) is produced by a hybridoma deposited at CNCM on April 27, 2007 with accession number CNCM I-3756.

[0063] The present invention also relates to the use of the cytotoxic anti-LAG-3 m...

Embodiment 1

[0069] Example 1: Targeting LAG-3 positive cells with cytotoxic antibodies

[0070] Materials and methods

[0071] Animals and Transplantation

[0072] 8-12 weeks old male Lewis.1W (LEW.1W, haplotype RT1 u ) and Lewis.1A (LEW.1A, haplotype RT1 a ) congenic rats (Centre d'Elevage Janvier, Le Genest-Saint-Isle, France) differ across the entire MHC region. Heterotopic LEW.1W heart transplantation was performed as described above (11). Graft survival was assessed by palpable inspection of the abdominal wall.

[0073] anti-LAG-3 antibody

[0074] A synthetic peptide corresponding to the extra loop domain of the rat LAG-3 protein (NCBI accession number DQ438937; peptide DQPASIPALDLLQGMPSTRRHPPHR) linked to ovalbumin was used to immunize two rabbits. Preimmune and immune sera collected on day 63 (post-4 immunization) were assayed against immunogens and peptides by ELISA and against Con-A activated rat splenocytes by flow cytometry. Preimmune sera were negative in both assa...

Embodiment 2

[0101] Example 2: Generation of novel high affinity hLAG-3 mAbs

[0102] Materials and methods

[0103] CHO cells transfected with hLAG-3 (10 7 cells, intraperitoneal injection) to immunize mice three times, followed by intravenous injection of 10 μg IMP321 (clinical grade hLAG-3Ig recombinant protein) for boost. Three days after the boost, splenocytes were fused with the X63.AG8653 fusion partner to generate hybridoma cells. Hybridoma supernatants were screened for specific binding (FACS analysis) to hLAG-3 transfected CHO versus wild-type CHO cells.

[0104] A mouse IgG2a antibody (580.1E9H3A9H12, referred to as A9H12) was selected, subcloned to generate a stable cell line, and additionally cleared by CDC (complement-dependent cytotoxicity) and ADCC (antibody-dependent cellular cytotoxicity) LAG-3 + The cells were characterized for their potency, considering that the mouse IgG2a Fc region is known to be the most efficient Fc isotype in mice to deliver these activitie...

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Abstract

The present invention concerns a molecule binding to LAG-3 protein and causing depletion of LAG-3 + activated T cells particularly said molecule is a cytotoxic anti-LAG-3 monoclonal antibody or fragment thereof. It also concerns a method of treating or preventing organ transplant rejection or autoimmune diseases in a mammal comprising administering to said mammal a therapeutically effective amount of said antibody.

Description

technical field [0001] The invention belongs to the field of immunotherapy. More specifically, it relates to the treatment or prevention of organ transplant rejection or the treatment of autoimmune diseases. The present invention relates to binding to LAG-3 proteins and resulting in LAG-3 + Molecules that activate T cells are cleared. More specifically, it relates to cytotoxic LAG-3 specific monoclonal antibodies or fragments thereof. Background technique [0002] Lymphocyte activation gene-3 (lymphocyte activation gene-3, LAG-3, CD223) is up-regulated in the early stage of T cell activation. The present invention is based on the analysis of the effects of anti-LAG-3 cytotoxic antibodies in acute cardiac allograft rejection (in vivo animal studies) and in vitro experiments, wherein the selected LAG-3 monoclonal antibodies are administered at low doses (<0.1 μg / ml) effectively remove LAG-3 + Activated effector T cells. [0003] Selective depletion of activated T lym...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/00C07K16/28
CPCC07K16/2803C12N2501/998C12N5/0636C07K2317/92C07K2317/734C07K2317/732A61K2039/505A61P29/00A61P37/00A61P37/06
Inventor 弗雷德里克·特里贝尔伯纳德·万霍夫托马斯·奥德堡
Owner IMMUTEP
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