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CN-116948031-B - Anti-IL-23R antibodies and uses thereof

CN116948031BCN 116948031 BCN116948031 BCN 116948031BCN-116948031-B

Abstract

The invention relates to a novel antibody or an antibody fragment thereof of interleukin-23 receptor, which can effectively bind IL-23R, block the binding of IL-23R and human IL-23 alpha/IL-12 beta heterodimer ligand, and has good application prospect. The antibody or antigen binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a VH CDR1, a VH CDR2 and a VH CDR3, the light chain variable region comprises a VL CDR1, a VL CDR2 and a VL CDR3, wherein the VH CDR1 comprises the amino acid sequence shown as SEQ ID NO 3, 13 or 23, the VH CDR2 comprises the amino acid sequence shown as SEQ ID NO 4, 14 or 24, the VH CDR3 comprises the amino acid sequence shown as SEQ ID NO 5, 15 or 25, the VL CDR1 comprises the amino acid sequence shown as SEQ ID NO 8, 18 or 28, the VL CDR2 comprises the amino acid sequence shown as SEQ ID NO 9, 19 or 29, and the VL CDR3 comprises the amino acid sequence shown as SEQ ID NO 10, 20 or 30.

Inventors

  • WANG XIAOZE
  • WU ZHENHUA
  • XU TONG
  • NIE LEI
  • Mei Xiaofen
  • CHEN GANG
  • WANG HAIBIN
  • CHEN XUCHEN
  • PAN CHENXIAO

Assignees

  • 浙江博锐生物制药有限公司
  • 海正生物制药有限公司

Dates

Publication Date
20260508
Application Date
20211013

Claims (20)

  1. 1. An anti-IL-23R antibody or antigen-binding fragment thereof comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a VH CDR1, a VH CDR2 and a VH CDR3, the light chain variable region comprises a VL CDR1, a VL CDR2 and a VL CDR3, The amino acid sequences of the VH CDR1, the VH CDR2 and the VH CDR3 of the heavy chain variable region of the antibody or antigen binding fragment thereof are respectively shown in SEQ ID NO. 3, 4 and 5, and the amino acid sequences of the VL CDR1, the VL CDR2 and the VL CDR3 of the light chain variable region are respectively shown in SEQ ID NO. 8, 9 and 10.
  2. 2. The anti-IL-23R antibody or antigen-binding fragment thereof according to claim 1, wherein the amino acid sequence of the heavy chain variable region has at least 90% sequence identity to SEQ ID No. 1 and the amino acid sequence of the light chain variable region has at least 90% sequence identity to SEQ ID No. 6.
  3. 3. The anti-IL-23R antibody or antigen-binding fragment thereof according to claim 1, wherein the amino acid sequence of the heavy chain variable region has at least 95% sequence identity to SEQ ID No. 1 and the amino acid sequence of the light chain variable region has at least 95% sequence identity to SEQ ID No. 6.
  4. 4. The anti-IL-23R antibody or antigen-binding fragment thereof according to claim 1, wherein the amino acid sequence of the heavy chain variable region has at least 96% sequence identity to SEQ ID No. 1 and the amino acid sequence of the light chain variable region has at least 96% sequence identity to SEQ ID No. 6.
  5. 5. The anti-IL-23R antibody or antigen-binding fragment thereof of claim 1, wherein the amino acid sequence of the heavy chain variable region has at least 97% sequence identity to SEQ ID No. 1 and the amino acid sequence of the light chain variable region has at least 97% sequence identity to SEQ ID No. 6.
  6. 6. The anti-IL-23R antibody or antigen-binding fragment thereof according to claim 1, wherein the amino acid sequence of the heavy chain variable region has at least 98% sequence identity to SEQ ID No. 1 and the amino acid sequence of the light chain variable region has at least 98% sequence identity to SEQ ID No. 6.
  7. 7. The anti-IL-23R antibody or antigen-binding fragment thereof according to claim 1, wherein the amino acid sequence of the heavy chain variable region has at least 99% sequence identity to SEQ ID No. 1 and the amino acid sequence of the light chain variable region has at least 99% sequence identity to SEQ ID No. 6.
  8. 8. The anti-IL-23R antibody or antigen-binding fragment thereof according to claim 1, wherein the amino acid sequence of the heavy chain variable region is shown in SEQ ID No. 1 and the amino acid sequence of the light chain variable region is shown in SEQ ID No. 6.
  9. 9. The anti-IL-23R antibody or antigen-binding fragment thereof according to any one of claims 1-8, wherein the antibody or antigen-binding fragment thereof further comprises a heavy chain constant region and a light chain constant region.
  10. 10. The anti-IL-23R antibody or antigen-binding fragment thereof of claim 9, wherein the light chain constant region is a kappa chain constant region.
  11. 11. The anti-IL-23R antibody or antigen-binding fragment thereof of claim 10, wherein the heavy chain constant region is a heavy chain constant region of IgG 1.
  12. 12. The anti-IL-23R antibody or antigen-binding fragment thereof of claim 10, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain comprising or consisting of the amino acid sequence set forth in SEQ ID No. 34 and a light chain comprising or consisting of the amino acid sequence set forth in SEQ ID No. 31.
  13. 13. A nucleic acid molecule encoding the anti-IL-23R antibody or antigen-binding fragment thereof of any one of claims 1-12.
  14. 14. The nucleic acid molecule of claim 13, wherein the nucleic acid molecule encodes a heavy chain variable region and a light chain variable region of the antibody or antigen binding fragment thereof.
  15. 15. The nucleic acid molecule of claim 14, wherein the nucleic acid molecule encodes a heavy chain variable region having a nucleotide sequence that has at least 90% sequence identity to SEQ ID NO. 2, and wherein the nucleic acid molecule encodes a light chain variable region having a nucleotide sequence that has at least 90% sequence identity to SEQ ID NO. 7.
  16. 16. The nucleic acid molecule of claim 14, wherein the nucleic acid molecule encodes a heavy chain variable region having a nucleotide sequence that has at least 95% sequence identity to SEQ ID NO. 2, and wherein the nucleic acid molecule encodes a light chain variable region having a nucleotide sequence that has at least 95% sequence identity to SEQ ID NO. 7.
  17. 17. The nucleic acid molecule of claim 14, wherein the nucleic acid molecule encodes a heavy chain variable region having a nucleotide sequence with at least 96% sequence identity to SEQ ID NO. 2, and wherein the nucleic acid molecule encodes a light chain variable region having a nucleotide sequence with at least 96% sequence identity to SEQ ID NO. 7.
  18. 18. The nucleic acid molecule of claim 14, wherein the nucleic acid molecule encodes a heavy chain variable region having a nucleotide sequence with at least 97% sequence identity to SEQ ID NO. 2, and wherein the nucleic acid molecule encodes a light chain variable region having a nucleotide sequence with at least 97% sequence identity to SEQ ID NO. 7.
  19. 19. The nucleic acid molecule of claim 14, wherein the nucleic acid molecule encodes a heavy chain variable region having a nucleotide sequence with at least 98% sequence identity to SEQ ID NO. 2, and wherein the nucleic acid molecule encodes a light chain variable region having a nucleotide sequence with at least 98% sequence identity to SEQ ID NO. 7.
  20. 20. The nucleic acid molecule of claim 14, wherein the nucleic acid molecule encodes a heavy chain variable region having a nucleotide sequence with at least 99% sequence identity to SEQ ID NO. 2, and wherein the nucleic acid molecule encodes a light chain variable region having a nucleotide sequence with at least 99% sequence identity to SEQ ID NO. 7.

Description

Anti-IL-23R antibodies and uses thereof The application is a divisional application of Chinese application patent application with the application number 202111193581.1, the application date 2021, the 10 th and 13 th days and the application name of 'anti-IL-23R antibody' and application thereof. Technical Field The invention belongs to the field of biological medicine, and relates to an antibody and application thereof. Background Interleukin 23 (IL-23) is a heterodimeric cytokine composed of two protein subunits, the p19 subunit specific for IL-23 (IL-23. Alpha.) and the p40 subunit (IL-12. Beta., p40 subunit is used in conjunction with IL-12), which are typically produced by activated macrophages or dendritic cells and act on Th17 cells expressing the IL-23 receptor to promote their proliferation and stability. The process by which IL-23 induces IL-17 production by CD4+ T cells is mediated by activated Jak2, PI3K/Akt, STAT3 and NF-. Kappa.B. Other members of the Tyk2 and STAT families, such as STAT1, STAT4, STAT5, are also involved in this process. IL-23 receptors consist of the IL-12Rβ1 subunit and the IL-23R subunit, constituting heterodimers, in which IL-12Rβ1 binds to Tyk2 and IL-23R binds to Jak2.IL-23 binds to its receptor complex, which upon activation of Jak2 and Tyk2 downstream thereof, causes receptor complex phosphorylation and formation of STATs (1, 3,4, 5) docking sites. STATs then polymerize, phosphorylate, transfer into the nucleus and activate the corresponding genes. Only STAT4 is included in the IL-12-induced DNA-binding complex, whereas STAT3, STAT1, STAT4, and possibly STAT3/STAT4 dimer is included in the IL-23-induced DNA-binding complex. IL-23 has a strong phosphorylation of STAT3 in lymphocytes, and STAT4 has a relatively weak phosphorylation. After entering the nucleus, the phosphorylated STAT3 is combined with the promoter of the IL-17A, IL-17F gene to directly participate in the transcription and synthesis, and can also be combined with the specific transcription factor RORγt promoter of Th17 cells to up-regulate the expression of the gene, thereby indirectly promoting the synthesis of IL-17A, IL-17F. IL-23 is associated with the development of a variety of autoimmune diseases, such AS inflammatory enteritis including Crohn's Disease (CD), or Ulcerative Colitis (UC), psoriasis (PS), psoriatic Arthritis (PA), systemic Lupus Erythematosus (SLE), rheumatoid Arthritis (RA), ankylosing Spondylitis (AS). Inflammatory Bowel Disease (IBD) is a chronic recurrent disease represented by Crohn's Disease (CD) and Ulcerative Colitis (UC), and is a idiopathic intestinal inflammatory disease affecting the ileum, rectum and colon, and is manifested clinically by diarrhea, abdominal pain, and even hematochezia. In recent years, researchers verify that IL-23 is expressed at a high level in inflammatory mucous membrane of IBD patient through immunohistochemistry and real-time quantitative PCR technology, and the high expression can promote intestinal intraepithelial lymphocyte (IEL) and NK cell activation to generate cytotoxicity, and simultaneously stimulate partial subset of T cells in IBD focus to secrete high levels of inflammatory factors such as IFN-gamma, TNF, IL-2, IL-17A and the like, thereby promoting differentiation into Th17 cells and aggravating inflammatory response. The role of T cell abnormalities in the development and progression of psoriasis has been of increasing interest since the beginning of the 80 s of the last century. The IL-23/Th17 pathway has been more deeply known and understood in recent years. It is generally believed that dendritic cells and macrophages in the dermis of psoriatic patients produce IL-23, induce activation of Th17 cells and γδ T cells, and release inflammatory cytokines such as IL-17A, IL-17F, IL-22, IL-6, and tumor necrosis factor- α (TNF- α). IL-17A, IL-17F and IL-22 act on keratinocytes, resulting in typical pathological changes in psoriasis, such as epidermal hyperplasia, acanthosis and hyperkeratosis. Under the skin inflammation microenvironment, keratinocytes can produce more IL-23 and other inflammatory factors and chemotactic factors, so that the positive feedback circulation of IL-23/Th17 is formed, and the chronic inflammatory process of psoriasis is amplified and aggravated to chronic skin keratinization diseases. Symptoms were found to be positively correlated with the presence of IL23R positive T lymphocytes in SLE patients, and additionally IL-23 was abnormally elevated in the blood of SLE patients compared to normal. Rheumatoid arthritis is an autoimmune disease that is a major component of chronic inflammation of articular synovial cells. NK cells are important immune cells in the body, and can be involved in the occurrence of immune diseases and hypersensitivity reactions under specific conditions. IL-23 has close correlation with NK cell function, RA disease activity, bone destruction, etc. as an important pro-inflammatory factor. Ank