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Antibodies directed against cd127

A CD127 and antibody technology, applied in the 27 field, can solve the problems of improving the antibody, increasing the maturation of dendritic cells, and not raising the maturation of dendritic cells

Active Publication Date: 2017-05-24
OSE IMMUNOTHERAPEUTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0028] Thus, although it is well recognized in the prior art that anti-CD127 antibodies are promising drug candidates for the treatment of immune-related diseases through the following mechanisms: IL-7-induced and / or IL-7-R-mediated mechanisms, and that the antibody can bind CD127 in the presence of TSLP receptors, and interfere with TSLP-induced and / or TSLP receptor-mediated mechanisms; however, their possible involvement in dendritic cell maturation, nor does it imply that the improvement consists in obtaining antibodies that do not show an effect of increasing the maturation of dendritic cells and / or also do not induce the internalization of CD127 and / or inhibit the internalization induced by IL-7

Method used

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  • Antibodies directed against cd127
  • Antibodies directed against cd127
  • Antibodies directed against cd127

Examples

Experimental program
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Effect test

Embodiment 1

[0281] Example 1. Preparation and selection of novel anti-human CD127 monoclonal antibodies (Mabs)

[0282] Rats were immunized with recombinant hCD127-Ig (hCD127 fused to a constant fragment of immunoglobulin (SinoBiologicals, Beijing, China; No. 10975-H03H)) and monoclonal antibodies were derived according to conventional techniques. The immunization protocol used was as follows: rats of LOU / CIgk1a strain were immunized with recombinant CD127Fc chimera (10975-H03H Sino Biological, Beijing, China). Fifty micrograms of protein were suspended in complete Freund's adjuvant and administered subcutaneously. After 20 days, a recall injection of the protein suspended in incomplete Freund's adjuvant was performed. Another similar recall injection was given on day 60, followed by a booster injection with 100 μg of protein on day 90 (4 days before splenocyte harvest).

[0283] Hybridomas were obtained by fusion of splenic mononuclear cells with the LOU rat immunocytoma IR983F (a non-...

Embodiment 2

[0287] Example 2. Evaluation of rCD127 recognition by anti-h-CD127 monoclonal antibodies by ELISA

[0288] Recombinant hCD127 (Sino Biologicals, Beijing, China; Cat. No. 10975-H08H) was immobilized on plastic, and increasing doses of monoclonal antibodies were added to measure binding. After incubation and washing, peroxidase-labeled mouse anti-rat kappa chain (AbdSerotec) was added and revealed by conventional methods. Binding of each antibody was confirmed.

Embodiment 3

[0289] Example 3. Inhibition of IL7 Signaling (pSTAT5)

[0290] Human peripheral blood mononuclear cells (PBMC) harvested from healthy volunteers by a ficoll gradient were incubated in serum-free medium containing various concentrations of the antibody of interest for 15 min at room temperature, and then incubated with 0.1 or 5 ng / ml recombinant human IL-7 (rhIL-7; AbD Serotec no. PHP046) was incubated at 37°C for 15 minutes. PBMCs not treated with rhIL-7 were analyzed as background signal, while cells treated with IL-7 without antibody were set as negative control. The PBMCs were then rapidly cooled and washed with FACS buffer to terminate the reaction. Cells were then incubated with cold Cytofix / Cytoperm solution (BD Bioscience, No. 554722) for 15 min, washed twice with Perm / Wash buffer (Bd Bioscience), and stained with anti-human CD3 FITC antibody (Bd Bioscience No. 557694) on ice for 30 min. minute. PBMCs were then washed twice with Perm / Wash buffer and permeabilized in...

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Abstract

The invention relates to antibodies directed against CD127, the alpha chain of the interleukin 7 (IL-7) receptor IL-7R), and which have antagonist properties for IL-7-IL-7R interaction, may present cytotoxic activity against CD127 positive cells but do not increase the maturation of dendritic cells (DCs) induced by TSLP, a cytokine also using CD127 as part of its receptor. Alternatively, or in addition, these antibodies do not induce the internalization of CD127 and / or inhibit the IL7-induced internalization of CD127. According to another aspect of the invention antibodies are provided which recognize a human CD127 epitope comprising sequences from the 2b site of CD127, in particular the epitope comprising comprises the human CD127 sequences of domain D1 and of the 2b site of CD127, in particular the epitope comprises at least one sequence from D1 comprising SEQ ID No: 115 (in particular comprising SEQ ID No: 10) and / or SEQ ID No: 111 and / or a sequence from the 2b site comprising the sequence of SEQ ID No: 116 and optionally also comprises SEQ ID No: 117 (in particular comprises SEQ ID No: 111).The antibodies of the invention are suitable for use inorder to remedy to a condition diagnosed in a human patient which results from pathogenesis related to lymphopoiesis, when IL-7 signalling pathways provide contribution to said pathogenesis, especially when an increase in the maturation, more precisely the upregulation of costimulatory molecules, of dendritic cells is undesirable.

Description

technical field [0001] Antibody against CD127 [0002] The present invention is concerned with the field of antibodies directed against the alpha subunit of the interleukin 7 (IL-7) receptor designated CD127 or p90 IL-7R or IL-7Rα, sometimes also called IL-7Ra, in particular The alpha chain of the receptor for human IL-7 expressed on human cells. These antibodies have antagonist properties against the IL-7-IL-7R interaction and may exhibit cytotoxic activity against CD127-positive cells but do not increase the maturation of dendritic cells (DCs) induced by TSLP using CD127 Cytokines as part of their receptors. Alternatively or additionally, these antibodies do not induce internalization of CD127 and / or inhibit IL7-induced internalization of CD127. According to another aspect of the present invention, an antibody recognizing the following epitope is provided: a human CD127 epitope comprising a sequence derived from the 2b site of CD127, particularly a human CD127 sequence co...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/28C07K14/705C12N15/13A61K39/395A61P37/02A61P37/08A61P35/02A61P35/00A61P31/12A61P29/00A61P11/00A61P3/10A61P1/00
CPCA61K2039/505C07K2317/24C07K2317/34C07K2317/76C07K2317/77C07K2317/92C07K2317/94G01N33/5041G01N2333/5418G01N2333/70546G01N2333/7155G01N2500/00C07K2317/732C07K16/2866A61P1/00A61P1/04A61P11/00A61P17/00A61P19/02A61P25/00A61P29/00A61P31/12A61P35/00A61P35/02A61P37/02A61P37/08A61P5/14A61P3/10A61K39/395A61P37/00C07K2317/565G01N33/6854
Inventor N·普瓦里耶C·马里B·瓦努夫
Owner OSE IMMUNOTHERAPEUTICS
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