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US-12617861-B2 - Anti-OX40 antibody and method of treatment

US12617861B2US 12617861 B2US12617861 B2US 12617861B2US-12617861-B2

Abstract

Provided are an anti-OX40 antibody or antigen-binding fragment thereof, a preparation method thereof and the use for treating OX40-related diseases or conditions.

Inventors

  • Yizhen Yang
  • Yu Cai
  • XIONG LI
  • Lei Zhou
  • Weiguo Qing
  • Wei-guo Su

Assignees

  • HUTCHISON MEDIPHARMA LIMITED

Dates

Publication Date
20260505
Application Date
20210416
Priority Date
20200417

Claims (16)

  1. 1 . An isolated anti-OX40 antibody or antigen-binding fragment thereof, comprising a heavy variable region (VH) comprising the three heavy chain complementarity determining regions HCDR1, HCDR2 and HCDR3 of the heavy chain variable region (VH) of SEQ ID NO: 2 and a light variable region (VL) comprising the three light chain complementarity determining regions LCDR1, LCDR2 and LCDR3 of the variable chain light region (VL) of SEQ ID NO: 7, wherein, the antibody or antigen-binding fragment thereof does not comprise an Fc region variant which is human IgG1 N297A, and wherein the amino acid residues in the Fc region are numbered in accordance with the EU numbering system.
  2. 2 . The antibody or antigen-binding fragment thereof of claim 1 , comprising (1) heavy chain complementarity determining regions (HCDRs), HCDR1, HCDR2 and HCDR3, wherein the HCDR1 comprises the amino acid sequence as set forth in SEQ ID NO: 11, the HCDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 12, and the HCDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 13; and/or (2) light chain complementarity determining regions (LCDRs), LCDR1, LCDR2 and LCDR3, wherein the LCDR1 comprises the amino acid sequence as set forth in SEQ ID NO: 14, the LCDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 15, and the LCDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 16.
  3. 3 . The antibody or antigen-binding fragment thereof of claim 1 , comprising (1) a heavy chain variable region (VH) comprising an amino acid sequence identical to or having at least 90% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 2; and/or (2) a light chain variable region (VL) comprising an amino acid sequence identical to or having at least 90% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 7.
  4. 4 . The antibody or antigen-binding fragment thereof of claim 1 , comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH and VL are selected from (1) a VH comprising the amino acid sequence as set forth in SEQ ID NO: 1, and a VL comprising the amino acid sequence as set forth in SEQ ID NO: 6; (2) a VH comprising the amino acid sequence as set forth in SEQ ID NO: 2, and a VL comprising the amino acid sequence as set forth in SEQ ID NO: 7 or 9; (3) a VH comprising the amino acid sequence as set forth in SEQ ID NO: 3, and a VL comprising the amino acid sequence as set forth in SEQ ID NO: 9; or (4) a VH comprising the amino acid sequence as set forth in SEQ ID NO: 4 and a VL comprising the amino acid sequence as set forth in SEQ ID NO: 7 or 8.
  5. 5 . The antibody or antigen-binding fragment thereof of claim 4 , comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises the amino acid sequence as set forth in SEQ ID NO: 2, and wherein the VL comprises the amino acid sequence as set forth in SEQ ID NO: 7.
  6. 6 . The antibody or antigen-binding fragment thereof of claim 1 , (i) which is a murine antibody, a chimeric antibody, or a humanized antibody; (ii) which is a full-length antibody, a Fab, a Fab′ antibody, a Fab′-SH, a (Fab′) 2 antibody, a single-chain antibody, a scFv, a Fv, or a bispecific or multispecific antibody; and/or (iii) which comprises an Fc region, wherein the amino acid sequence of the Fc region is identical to the sequence of the Fc region of human IgG1, IgG2 or IgG4, or is a variant thereof.
  7. 7 . The antibody or antigen-binding fragment thereof of claim 1 , wherein said antibody comprises an Fc region that binds to FcγR, and is an OX40 antibody agonist and has an activity of activating OX40-mediated signal transduction.
  8. 8 . The antibody or antigen-binding fragment thereof of claim 7 , wherein said antibody comprises an Fc region, wherein the amino acid sequence of the Fc region is identical to the sequence of the Fc region of human IgG1, IgG2 or IgG4.
  9. 9 . The antibody or antigen-binding fragment thereof of claim 1 , wherein said antibody substantially does not bind to FcγR, and is an OX40 antibody antagonist and has an activity of blocking OX40-mediated signal transduction.
  10. 10 . The antibody or antigen-binding fragment thereof of claim 9 , comprising a variant of a native Fc region, wherein the binding of the Fc region variant to FcγR is reduced or eliminated compared to the native Fc region.
  11. 11 . An immunoconjugate or immune fusion, comprising the antibody or antigen-binding fragment thereof of claim 1 conjugated to a cytotoxic agent or label.
  12. 12 . A pharmaceutical composition, comprising the agonistic antibody of claim 7 and at least one pharmaceutically acceptable excipient.
  13. 13 . A pharmaceutical composition, comprising the antagonistic antibody of claim 9 and at least one pharmaceutically acceptable excipient.
  14. 14 . A method for ameliorating an OX40-related disease or condition in a subject in need thereof, comprising administering to the subject suffering from said disease or condition an effective amount of the antagonistic antibody of claim 9 , wherein the an OX40-related disease or condition is inflammation or autoimmune disease.
  15. 15 . A method for ameliorating an OX40-related disease or condition in a subject in need thereof, comprising administering to the subject suffering from said disease or condition an effective amount of the agonistic antibody of claim 7 , wherein the OX40-related disease or condition is a cancer.
  16. 16 . The method of claim 15 , wherein the OX40-related disease or condition is melanoma, optionally wherein the OX40-related disease or condition is metastatic melanoma.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application is a United States Application under 35 U.S.C. § 371 claiming priority to, and the benefit of, International Application No. PCT/CN2021/087617, filed on Apr. 16, 2021, which is based on and claims priority to Chinese patent application No. CN202010304381.8, which is filed on Apr. 17, 2020 and is entirely incorporated herein by reference for all purposes. TECHNICAL FIELD The present invention relates to an antibody, and in particular to an anti-OX40 antibody and antigen-binding fragment thereof, and method for preparing the antibody and use same for treating or preventing OX40-related diseases or conditions. BACKGROUND ART OX40 (also referred to as CD134, TNFRSF4 and ACT35) is a member of tumor-necrosis factor superfamily, which is mainly expressed on the surface of activated CD4″ T cells, CD8+T cells and regulatory T cells, and also on the surface of natural killer cells (NK cells). In activated T cells, the costimulatory signal mediated by OX40L-OX40 can stimulate helper T cells to produce and secrete cytokines, stimulate effector T cells to release granzyme and perforin, and cause effector T cells and memory T cells to proliferate. At the same time, the OX40L-OX40 signal can also inhibit the differentiation and activity of regulatory T cells and reduce the immunosuppressive function of regulatory T cells, thereby further enhancing immunoreactions. The important role of OX40 in a T-cell immune response makes OX40 agonists an important candidate for tumor immunotherapy, while OX40 inhibitors have potential application values in inflammation, allergic diseases and autoimmune diseases. In recent years, with a wide application of preparation techniques for monoclonal antibodies, monoclonal antibodies that specifically bind to OX40 have emerged, including two categories, i.e., OX40 agonists and OX40 inhibitors. Under physiological conditions, OX40 activates the corresponding signaling pathways in cells by binding to its ligand OX40L and trimerization. Therefore, OX40 agonist monoclonal antibodies always require cross-linking to function as an agonist antibody. Under in vitro and in vivo conditions, antibody cross-linking can be achieved by either coating on a solid surface or by Fc receptors, respectively. Fc receptors are a family of protein receptors that specifically bind to the Fc fragment of an antibody. In particular, Fcγ receptors can specifically bind to IgG and exert functions such as ADCC and ADCP. Fcγ receptors mainly include FcγRI, FcγRIIA, FcγRIIB, FcγRIIIA, FcγRIIIB, etc., which are expressed on the surface of a variety of blood cells, including B lymphocytes, dendritic cells, natural killer cells, macrophages, neutrophils, eosinophilic granulocytes, basophilic granulocytes, mast cells, platelets, etc. Under physiological conditions, Fcγ receptors can simultaneously bind to the Fc fragments of one or more IgG molecules, and achieve cross-linking of the IgG molecules while activating the receptor-mediated functions. OX40 agonist antibodies can activate OX40 molecules by binding to Fcγ receptors and cross-linking. OX40 antagonist antibodies can block the binding of OX40L to OX40, prevent the trimerization of OX40, thereby inhibiting OX40 activation-induced T cell activation and related inflammatory responses. Tumor cells can escape the recognition and attack of an immune system through multiple mechanisms to achieve immune escape, survive in the body and proliferate excessively. An important mechanism that mediates tumor immune escape is by costimulatory molecules named as immune checkpoints that are highly expressed in immune cells or tumor cells in tumor microenvironment. Immune checkpoints can be divided, based on their functions, into inhibitory immune checkpoints, represented by PD-1, PD-L1, CTLA-4, etc.; and activating immune checkpoints, represented by OX40 and 4-1BB. For inhibitory immune checkpoints, drugs such as antibodies can be used to block their inhibitory function, which is like releasing the brakes on immune cells, allowing immune cells to play their role in killing tumor cells. Tumor immunotherapy represented by PD-1, PD-L1 and CTLA-4 is becoming a very important treatment means and exhibits exciting results in clinical applications. The use of agonists to activate agonistic immune checkpoints, analogous to stepping on the gas pedal after releasing the brake, further increases the activities of immune cells, making the cells more effective in killing tumor cells, and ultimately achieving more effective therapeutical effects on a broader spectrum of tumors. It has been found in recent researches that various tumor-infiltrating T cells express OX40, and that OX40-positive tumor patients have a relatively longer survival time, suggesting OX40 plays a role in tumor immunity. In many preclinical animal models, the activation of OX40 led to stimulated T cells proliferation, enhanced effector T cells function, and inhibition of the