Therapeutic binding molecules

Patent metadata

Field	Value
Publication number	US-2022306754-A1
Application number	US-202217697041-A
Country	US
Kind code	A1
Filing date	Mar 17, 2022
Priority date	Mar 18, 2021
Publication date	Sep 29, 2022
Grant date	—

Abstract

The invention relates to binding molecules, such as antibodies, that bind to the chemokine receptor CCR9. More particularly, the invention relates to the treatment of CCR9-mediated diseases or conditions such as inflammatory bowel disease (IBD), and methods for the detection of CCR9, which make use of the binding molecules of the invention.

First claim

1 . A binding molecule that binds to CCR9 and comprises a heavy chain variable (VH) region having a set of CDRs HCDR1, HCDR2 and HCDR3 and a light chain variable (VL) region having a set of CDRs LCDR1, LCDR2 and LCDR3, wherein
(a) the VH region amino acid sequence comprises HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2 and HCDR3 of SEQ ID NO: 3, and wherein the VL region amino acid sequence comprises LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5 and LCDR3 of SEQ ID NO: 6; (b) the VH region amino acid sequence comprises HCDR1 of SEQ ID NO: 7, HCDR2 of SEQ ID NO: 8 and HCDR3 of SEQ ID NO: 9, and wherein the VL region amino acid sequence comprises LCDR1 of SEQ ID NO: 10, LCDR2 of SEQ ID NO: 11 and LCDR3 of SEQ ID NO: 12; or (c) the VH region amino acid sequence comprises HCDR1 of SEQ ID NO: 13, HCDR2 of SEQ ID NO: 14 and HCDR3 of SEQ ID NO: 15, and wherein the VL region amino acid sequence comprises LCDR1 of SEQ ID NO: 16, LCDR2 of SEQ ID NO: 17 and LCDR3 of SEQ ID NO: 18 or wherein any one or more of said HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 comprises 1, 2 or 3 amino acid substitutions compared to said sequences.

2 . The binding molecule of claim 1 , wherein the VH region amino acid sequence comprises HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2 and HCDR3 of SEQ ID NO: 3, and wherein the VL region amino acid sequence comprises LCDR2 of SEQ ID NO: 5 and LCDR3 of SEQ ID NO: 6 and LCDR1 having an amino acid sequence selected from:
(a) SEQ ID NO: 4; (b) SEQ ID NO: 19; (c) SEQ ID NO: 20; (d) SEQ ID NO: 21; and (e) SEQ ID NO: 22.

3 . The binding molecule of claim 1 , wherein:
(i) the VH region amino acid sequence comprises SEQ ID NO: 51, or a sequence having at least 80%, 85%, 90%, 95%, 98% or 99% sequence identity thereto and; the VL region amino acid sequence comprises SEQ ID NO: 52, or a sequence having at least 80%, 85%, 90%, 95%, 98% or 99% sequence identity thereto; (ii) the VH region amino acid sequence comprises SEQ ID NO: 51, or a sequence having at least 80%, 85%, 90%, 95%, 98% or 99% sequence identity thereto and; the VL region amino acid sequence comprises SEQ ID NO: 53, or a sequence having at least 80%, 85%, 90%, 95%, 98% or 99% sequence identity thereto; (iii) the VH region amino acid sequence comprises SEQ ID NO: 51, or a sequence having at least 80%, 85%, 90%, 95%, 98% or 99% sequence identity thereto and; the VL region amino acid sequence comprises SEQ ID NO: 54, or a sequence having at least 80%, 85%, 90%, 95%, 98% or 99% sequence identity thereto; (iv) the VH region amino acid sequence comprises SEQ ID NO: 51, or a sequence having at least 80%, 85%, 90%, 95%, 98% or 99% sequence identity thereto; and the VL region amino acid sequence comprises SEQ ID NO: 55; or a sequence having at least 80%, 85%, 90%, 95%, 98% or 99% sequence identity thereto; or (v) the VH region amino acid sequence comprises SEQ ID NO: 56, or a sequence having at least 80%, 85%, 90%, 95%, 98% or 99% sequence identity thereto and; the VL region amino acid sequence comprises SEQ ID NO: 57, or a sequence having at least 80%, 85%, 90%, 95%, 98% or 99% sequence identity thereto.

4 . The binding molecule of claim 1 , wherein:
(i) the VH region amino acid sequence comprises SEQ ID NO: 58, or a sequence having at least 80%, 85%, 90%, 95%, 98% or 99% sequence identity thereto; and wherein the VL region amino acid sequence comprises SEQ ID NO: 59, or a sequence having at least 80%, 85%, 90%, 95%, 98% or 99% sequence identity thereto; or (ii) the VH region amino acid sequence comprises SEQ ID NO: 60, or a sequence having at least 80%, 85%, 90%, 95%, 98% or 99% sequence identity thereto; and the VL region amino acid sequence comprises SEQ ID NO: 61, or a sequence having at least 80%, 85%, 90%, 95%, 98% or 99% sequence identity thereto.

5 . (canceled)

6 . (canceled)

7 . The binding molecule of claim 1 , wherein the binding molecule is an anti-CCR9 antibody, or an antigen-binding fragment thereof, optionally wherein the anti-CCR9 antibody, or antigen-binding fragment thereof is humanised, chimeric, or fully human.

8 . The binding molecule of claim 6 , which is:
(a) an IgG immunoglobulin or a fragment thereof, or (b) an IgG1 immunoglobulin or a fragment thereof.

9 . The binding molecule of claim 1 , wherein said binding molecule comprises an immunoglobulin Fc domain, or a fragment thereof that retains the ability to bind to one or more Fc receptors.

10 . The binding molecule of claim 9 , wherein the immunoglobulin Fc domain or fragment:
(a) is an IgG Fc domain or fragment thereof, (b) is a human IgG Fc domain or fragment thereof, (c) is a human IgG1 Fc domain or fragment thereof; (d) is modified compared to the corresponding wild-type Fc domain, wherein said modification leads to an increased affinity for one or more Fcγ receptors; (e) is modified compared to the corresponding wild-type Fc domain, wherein said modification leads to an enhanced antibody dependent cell-mediated cytotoxicity response; and/or (f) comprises an afucosylated N-linked glycan at amino acid position 297.

11 . The binding molecule of claim 1 , wherein the binding molecule is:
(a) afucosylated; (b) afucosylated at amino acid position 297; or (c) present in a composition comprising multiple copies of said binding molecule, wherein at least 50%, 75%, 80%, 90%, 95%, 98%, 99% or 100% of the copies of the binding molecule in the composition are afucosylated.

12 . The binding molecule of claim 1 , wherein the binding molecule:
(a) binds to human CCR9; (b) binds to human CCR9A and human CCR9B; (c) binds to cynomolgus CCR9; and/or (e) does not bind to CCR5, CCR8, CXCR1 or CXCR2.

13 . The binding molecule of claim 1 wherein the binding molecule:
(a) is capable of mediating antibody dependent cell-mediated cytotoxicity against a CCR9-expressing cell to which it binds;
(b) is capable of mediating antibody dependent cell-mediated cytotoxicity against a CCR9-expressing lymphocyte to which it binds;
(c) can be bound by an FcγR;
(d) can be bound by FcγRIIIa;
(e) is capable of cross-linking an immune effector cell to a CCR9-expressing cell;
(f) is capable of cross-linking an immune effector cell to a CCR9-expressing cell and activating antibody dependent cell-mediated cytotoxicity by the effector cell;
(g) is capable of inhibiting CCL25 induced CCR9 receptor internalisation;
(h) is capable of inhibiting CCL25 mediated migration of CCR9 expressing T cells to the gut,
(i) is capable of cross-linking an immune effector cell to a CCR9-expressing cell and activating antibody dependent cell-mediated cytotoxicity by the effector cell, thereby causing lysis of the CCR9-expressing cell; and/or
(j) is capable of depleting CCR9-expressing cells in a population of cells comprising CCR9-expressing cells and immune effector cells.

14 . The binding molecule of claim 1 , wherein the binding molecule is capable of binding to human CCR9 with an affinity (K D ) of about 0.1 nM, optionally 0.09 nM.

15 . A binding molecule that binds to CCR9, wherein the binding molecule competes for binding to CCR9 with the binding molecule of claim 1 .

16 . (canceled)

17 . The binding molecule of claim 15 , wherein said binding molecule comprises an immunoglobulin Fc domain, or a fragment thereof that retains the ability to bind to one or more Fc receptors and wherein the immunoglobulin Fc domain or fragment:
(a) is an IgG Fc domain or fragment thereof, (b) is a human IgG Fc domain or fragment thereof, (c) is a human IgG1 Fc domain or fragment thereof; (d) is modified compared to the corresponding wil

Assignees

• Medimmune Ltd

Inventors

• Nys Josquin
• Thom Albert
• Cariuk Peter
• Schofield Darren
• Riley Aidan
• Huntington Catherine
• Rees David
• Irving Lorraine
• Robinson Matthew

Classifications

• A61K39/00

  Medicinal preparations containing antigens or antibodies (materials for immunoassay G01N33/53) · CPC title

• C07K2317/77

  Internalization into the cell · CPC title

• C07K2317/92

  Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value · CPC title

• C07K2317/56

  variable (Fv) region, i.e. VH and/or VL · CPC title

• A61K2039/505

  comprising antibodies · CPC title