# US 11,440,964 B2 · Method for treating a pathological condition involving the activation or proliferation of CD127 positive cells with an anti-CD127 antibody

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- Number: US 11,440,964 B2
- Document ID: US11440964B2
- Status: Granted
- Kind: B2
- Application number: 16/532,000
- Filed: 2019-08-05
- Published: 2019-12-19
- Granted: 2022-09-13
- Earliest claimed: 2014-06-10
- Assignees: Ose Immunotherapeutics
- Applicants: Ose Immunotherapeutics
- Inventors: Nicolas Poirier; Caroline Mary; Bernard Vanhove
- Web page: https://patentgrep.com/patent/US11440964B2

## CPC

- C07K 16/2866: {against receptors for cytokines, lymphokines, interferons}
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 5/14: of the thyroid hormones, e.g. T3, T4
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 17/00: Drugs for dermatological disorders
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/12: Antivirals
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/02: Immunomodulators
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- G01N 33/5041: {involving analysis of members of signalling pathways}
- G01N 33/6854: {Immunoglobulins}
- A61K 2039/505: {comprising antibodies}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/34: Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/732: Antibody-dependent cellular cytotoxicity [ADCC]
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C07K 2317/77: Internalization into the cell
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- C07K 2317/94: Stability, e.g. half-life, pH, temperature or enzyme-resistance
- G01N 2333/5418: IL-7
- G01N 2333/70546: Integrin superfamily, e.g. VLAs, leuCAM, GPIIb/GPIIIa, LPAM
- G01N 2333/7155: for interleukins [IL]
- G01N 2500/00: Screening for compounds of potential therapeutic value
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## 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: 110) 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 in order 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.

## Claims

### Claim 1

A method for treating a pathological condition, the method comprising:
administering an effective amount of a composition comprising an anti-human CD127 agent that antagonizes interleukin-7 receptor (IL-7R) signaling induced by interleukin-7 (IL7) to a patient with said pathological condition;
wherein the pathological condition is an autoimmune disease or an inflammatory disease involving the activation or proliferation of CD127 positive cells;
wherein said anti-human CD127 agent comprises an antibody or an antigen-binding fragment thereof which binds specifically to human CD127,
wherein said antibody or antigen-binding fragment thereof comprises a VH chain comprising the following amino acid sequences:
(a) VHCDR1 of SEQ ID No:10;
(b) VHCDR2 of SEQ ID No:12; and
(c) VHCDR3 of SEQ ID No:14 or of SEQ ID No:48;
and a VL chain comprising the following amino acid sequences:
(d) VLCDR1 of SEQ ID No:16 or of SEQ ID No:50;
(e) VLCDR2 of SEQ ID No:18 or of SEQ ID No:52; and
(f) VLCDR3 of SEQ ID No:20.

### Claim 2 (depends on 1)

The method according to claim 1, wherein activation or proliferation of CD127 positive cells is inhibited in the patient.

### Claim 3 (depends on 1)

The method according to claim 1, wherein the composition further comprises an additional active ingredient, wherein the additional active ingredient is an antibody targeting T-cells or a recombinant protein or antibody targeting accessory cells.

### Claim 4 (depends on 3)

The method according to claim 3, wherein the additional active ingredient has a therapeutic immunomodulatory effect on cells involved in an autoimmune disease, an allergic disease, leukemia, acute lymphoblastic leukemia, lymphoma, a chronic viral infection, an inflammatory disease, transplantation, or a respiratory disease.

### Claim 5 (depends on 3)

The method according to claim 3, wherein the antibody targeting T-cells is an anti-CD3, anti-ICOS, or anti-CD28 antibody, wherein the recombinant protein is CTLA4Ig, or wherein the antibody is an anti-CD40 antibody.

### Claim 6 (depends on 1)

The method according to claim 1, wherein the anti-human CD127 agent is administered in a combination or in an add-on therapeutic regimen in a patient in need thereof.

### Claim 7 (depends on 1)

The method according to claim 1, wherein the antibody or antigen-binding fragment thereof is covalently attached to a chemical group or a biological group.

### Claim 8 (depends on 1)

The method according to claim 1, wherein the patient is in need of transplantation or is about to have a transplant or has been given a transplant.

### Claim 9 (depends on 1)

The method according to claim 1, wherein the anti-human CD127 agent is a chimeric antibody or a humanized antibody or a deimmunized antibody.

### Claim 10 (depends on 1)

The method according to claim 1, wherein the composition is a pharmaceutical composition comprising the anti-human CD127 agent and a pharmaceutical vehicle.

### Claim 11 (depends on 1)

The method according to claim 1, wherein the antibody or antigen-binding fragment thereof comprises six CDR sequences consisting of VHCDR1 SEQ ID No:10, VHCDR2 SEQ ID No:12, VHCDR3 SEQ ID No:48, VLCDR1 SEQ ID No:50, VLCDR2 SEQ ID No:52, and VLCDR3 SEQ ID No:20.

### Claim 12 (depends on 1)

The method according to claim 1, wherein the antibody or antigen-binding fragment thereof disrupts the binding of CD127 to the γc common chain of cytokine receptors.

### Claim 13 (depends on 1)

The method according to claim 1, wherein the antibody or antigen-binding fragment thereof does not increase the maturation of dendritic cells induced by Thymic Stromal Lymphopoietin (TSLP).

### Claim 14 (depends on 1)

The method according to claim 1, wherein the antibody or antigen-binding fragment thereof does not induce internalization of CD127 in cells incubated with said antibody or antigen-binding fragment thereof as compared to cells incubated in the absence of said antibody or antigen-binding fragment thereof.

### Claim 15 (depends on 1)

The method according to claim 1, wherein the antibody or antigen-binding fragment thereof in presence of IL7 does not significantly decrease the cell surface expression of CD127, and/or inhibits the internalization of CD127, as compared to cells incubated with interleukin 7 (IL-7) and in the absence of said antibody or antigen-binding fragment thereof.

### Claim 16 (depends on 1)

The method according to claim 1, wherein the antibody or antigen-binding fragment thereof comprises
(i) a heavy chain comprising the sequence of SEQ ID NO:22, SEQ ID NO:36, SEQ ID NO:38, or SEQ ID NO:40; and
(ii) a light chain comprising the sequence of SEQ ID NO:24, SEQ ID NO:42, SEQ ID NO:44, or SEQ ID NO:46.

### Claim 17 (depends on 1)

The method according to claim 1, wherein the antibody or antigen-binding fragment thereof comprises:
(i) a heavy chain with the sequence of SEQ ID NO:2, SEQ ID NO:6, or SEQ ID NO:54; and
(ii) a light chain with the sequence of SEQ ID NO:4 or SEQ ID NO:56.