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1. WO2015189302 - ANTIBODIES DIRECTED AGAINST CD127

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Claims

1 . An antibody or an antigen-binding fragment of an antibody or antigen-binding antibody mimetic which binds specifically to CD127 and which recognizes an epitope comprising a sequence taken from the 2b site of CD127.

2. An antibody or an antigen-binding fragment of an antibody or antigen-binding antibody mimetic which binds specifically to CD127 and does not induce the internalization of CD127 and/or inhibits IL7-induced internalization of CD127.

3. An antibody or antigen-binding fragment thereof which binds specifically to CD127 and thereby disrupts the binding of CD127 to the yc common chain of cytokine receptors.

4. An antibody or an antigen-binding fragment of an antibody or antigen-binding antibody mimetic according to claim 1 which (i) does not induce the internalization of CD127 and/or inhibits IL7-induced internalization of CD127 and/or (ii) disrupts the binding of CD127 to the yc common chain of cytokine receptors when bound to CD127.

5. An antibody or an antigen-binding fragment of an antibody or antigen-binding antibody mimetic according to claim 2 which disrupts the binding of CD127 to the yc common chain of cytokine receptors when bound to CD127.

6. An antibody or antigen-binding fragment or mimetic thereof according to any of claims 1 to 5, which is an antagonist of IL-7R signaling induced by IL-7.

7. An antibody or antigen-binding fragment or mimetic thereof which specifically binds, in particular with a Kd lower than 5E-10 M, especially lower than 1 E-10 M, especially lower than 5E-1 1 M, and recognizes the epitope sequence of human CD127 comprising or consisting of the the sequence of SEQ ID No:1 16 (or SEQ ID No:86) and of sequence of SEQ ID No:1 10 (or SEQ ID No:1 15) and / or of SEQ ID No:1 1 1 (or SEQ ID No:1 17), in particular comprising or consisting of the sequences of SEQ ID No:1 10 and of SEQ ID No:1 1 1 ,

i. wherein the epitope sequence of human CD127 comprising SEQ ID No:1 10 does not extend to comprise the amino acids adjacent to said sequence in the sequence of human CD127 by more than 1 N-terminal amino acid or by more than 7 C- terminal amino acids; and/or

ii. wherein the epitope sequence of human CD127 comprising SEQ ID No:1 1 1 does not extend to comprise the amino acids adjacent to said sequence in the sequence of human CD127 by more than 30 N-terminal amino acid or by more than 30 C- terminal amino acids.

8. An antibody or antigen-binding fragment or mimetic thereof according to any of claims 1 to 6 which binds specifically to CD127 and does not increase the maturation of dendritic cells induced by TSLP.

9. An antibody or antigen-binding fragment or mimetic thereof according to any of claims 1 to 8 which binds specifically to CD127, comprising a VH chain comprising at least one of the following amino acid sequences:

• VHCDR1 SEQ ID No:10;

• VHCDR2 SEQ ID No:12;

• VHCDR3 SEQ ID No:14 or SEQ ID No:48; or

• VH SEQ ID No:22

and/or a VL chain comprising at least one of the following amino acid sequences:

• VLCDR1 SEQ ID No:16 or SEQ ID No:50;

• VLCDR2 SEQ ID No:18 or SEQ ID No:52;

• VLCDR3 SEQ ID No:20; or

• VL SEQ ID No:24;

in particular comprising at least two, three, four or five CDR sequences selected from the group consisting in VHCDR1 SEQ ID No:10, VHCDR2 SEQ ID No:12, VHCDR3 SEQ ID No:14 or SEQ ID No:48 , VLCDR1 SEQ ID No:16 or SEQ ID No:50, VLCDR2 SEQ ID No:18 or SEQ ID No:52 and VLCDR3 SEQ ID No:20.

10. An antibody according to claim 9 wherein

the VH chain consists in the VH chain with the sequence of SEQ ID No:2 or of SEQ ID No:6 or of SEQ ID No:54 or comprises the sequence of SEQ ID No:22 or of SEQ ID No:36 or of SEQ ID No:38 or of SEQ ID No:40; and

the VL chain consists in the VL chain with the sequence of SEQ ID No:4 or of SEQ ID No:56 or comprises the sequence of SEQ ID No:24 or of SEQ ID No:42 or of SEQ ID No:44 or of SEQ ID No:46.

1 1 . An antibody according to any of claims 1 to 10 which is a chimeric antibody or a humanized antibody or a deimmunized antibody, in particular a humanized and deimmunized antibody wherein the heavy chain has the sequence of SEQ ID No:52 and the light chain has the sequence of SEQ ID No:54.

12. A macromolecule which is a chimeric molecule comprising an antibody or an antigen- binding fragment or mimetic thereof according to any of claims 1 to 1 1 , wherein said antibody is associated with a functionally different molecule, said chimeric molecule being either a fusion chimeric protein or a conjugate resulting from covalent attachment of a chemical group or molecule, such as a PEG polymer or a labelled antibody.

13. A nucleic acid molecule encoding an antigen, antibody, antigen-binding fragment or mimetic thereof, or macromolecule according to any of claims 1 to 12, in particular an amino acid chosen from the group consisting of SEQ ID No:2; SEQ ID No:4; SEQ ID No:6; SEQ ID No:8; SEQ ID No:10;SEQ ID No:12;SEQ ID No:14;SEQ ID No:16;SEQ ID No:18;SEQ ID No:20; SEQ ID No:22; SEQ ID No:24; SEQ ID No:36; SEQ ID No:38; SEQ ID No:40; SEQ ID No:42; SEQ ID No:44; SEQ ID No:46; SEQ ID No:48; SEQ ID No:50; SEQ ID No:52; SEQ ID No:54 and SEQ ID No:56, in particular a nucleic acid molecule which is chosen from the group consisting of SEQ ID No:1 ; SEQ ID No:3; SEQ ID No:5; SEQ ID No:7; SEQ ID No:9;SEQ ID No:1 1 ;SEQ ID No:13;SEQ ID No:15; SEQ ID No:17; SEQ ID No:19; SEQ ID No:21 ; SEQ ID No:23; ; SEQ ID No:35; SEQ ID No:37; SEQ ID No:39; SEQ ID No:41 ; SEQ ID No:43; SEQ ID No:45; SEQ ID No:47; SEQ ID No:49; SEQ ID No:51 ; SEQ ID No:53 and SEQ ID No:55.

14. A pharmaceutical composition comprising a macromolecule, in particular an antibody or antigen-binding fragment or mimetic thereof, according to any of claims 1 to 12, or a nucleic acid according to claim 13 with a pharmaceutical vehicle, wherein said pharmaceutical composition optionally comprises a further, different, active ingredient, in particular an additional compound having a therapeutic immunomodulator effect in particular on cells involved in an autoimmune disease or an allergic disease, leukemia such as acute lymphoblastic leukemia, lymphoma, a cancer disease, a chronic viral infection, inflammatory diseases, transplantation, respiratory diseases or autoimmunity.

15. A macromolecule, in particular an antibody or antigen-binding fragment or mimetic thereof according to any of claims 1 to 12, or a nucleic acid according to claim 13 or a pharmaceutical composition of claim 14 for use as a therapeutically active ingredient in a combination or in an add-on therapeutic regimen in a patient in need thereof.

16. A macromolecule, in particular an antibody or antigen-binding fragment or mimetic thereof according to any of claims 1 to 12 or a nucleic acid of claim 13 or a pharmaceutical composition of claim 14 for use in the treatment of a patient, in particular a human patient, in need of transplantation and / or about to be transplanted and / or in a transplanted patient and/or a patient with or at risk of a disease, in particular an autoimmune disease such as rheumatoid arthritis, multiple sclerosis, type I diabetes, autoimmune thyroiditis or lupus, or an inflammatory disease such as inflammatory bowel disease (IBD) and encephalomyelitis, or an allergic disease, or a cancer disease, or a respiratory disease or a disease related to transplantation.

17. An antigen consisting of the epitope sequence(s) of human CD127 comprising or consisting of the sequence of SEQ ID No:1 16 (or SEQ ID No:86) and of SEQ ID No:1 10 (or SEQ ID No:1 15) and / or of SEQ ID No:1 1 1 (or SEQ ID No:1 17), in particular

comprising or consisting of the sequences of SEQ ID No:1 15 and of SEQ ID No:1 10 (or SEQ ID No:1 15) and of SEQ ID No:1 1 1 (or SEQ ID No:1 17),

(i) wherein the epitope sequence of human CD127 comprising SEQ ID No:1 10 does not extend to comprise the amino acids adjacent to said sequence in the sequence of human CD127 by more than 1 N-terminal amino acid or by more than 7 C-terminal amino acids; and/or

(ii) wherein the epitope sequence of human CD127 comprising SEQ ID No:1 1 1 does not extend to comprise the amino acids adjacent to said sequence in the sequence of human CD127 by more than 30 N-terminal amino acid or by more than 30 C-terminal amino acids.

18. A method of manufacturing an antibody comprising immunizing a non-human animal against an antigen as defined in claim 17.

19. A method of selecting an antibody, in particular an antibody obtained as in claim 18, an antigen-binding fragment or mimetic of such an antibody or another macromolecule, comprising or consisting of at least one of the following steps:

a. testing the binding capacity of the macromolecule to CD127, in particular to an antigen thereof as defined in claim 17;

b. testing the internalization of CD127 in CD127-expressing cells induced by the presence of the macromolecule;

c. testing the inhibition by the macromolecule of IL7-induced internalization of CD127 in CD127-expressing cells;

d. testing the increase of the maturation of DCs induced by TSLP in the presence of the macromolecule;

and optionally further comprising one or more of the following steps:

e. testing the inhibition by the macromolecule of IL-7 induced signalling, in particular STAT5 phosphorylation;

f. testing the inhibition by the macromolecule of TSLP-induced production of TARC; g. testing the inhibition by the macromolecule of the expression of α4, β7 and/or α4/β7 integrin expression, in particular cell surface expression on T-lymphocytes.