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CN-121991239-A - Bispecific antibodies against TL1A and IL-23 and uses thereof

CN121991239ACN 121991239 ACN121991239 ACN 121991239ACN-121991239-A

Abstract

The present disclosure relates to a bispecific antibody comprising a first domain that specifically binds TNF-like ligand 1A (TL 1A), and a second domain that specifically binds interleukin-23 (IL-23). The disclosure also relates to methods of treating or preventing diseases associated with TL1A and/or IL-23 with the bispecific antibodies.

Inventors

  • LI DONGXIA
  • ZHOU JINGYUN
  • JIANG YANJING
  • LIU XUEWEI
  • ZHANG LILI
  • XIE XIAOJUAN
  • HUANG YUXIN
  • LI ZIQIANG

Assignees

  • 北京伟德杰生物科技有限公司

Dates

Publication Date
20260508
Application Date
20250523
Priority Date
20241106

Claims (20)

  1. 1. A bispecific antibody comprising a first domain that specifically binds TNF-like ligand 1A (TL 1A) and a second domain that specifically binds interleukin-23 (IL-23).
  2. 2. The bispecific antibody according to claim 1, characterized in that the first domain is an antibody or a functional fragment thereof which specifically binds TL1A, and/or The second domain is an antibody or functional fragment thereof that specifically binds IL-23.
  3. 3. The bispecific antibody according to claim 1 or 2, characterized in that the first domain comprises an antibody Fab fragment, fab 'fragment, F (ab') 2 fragment, fv fragment, scFv fragment, nanobody, heavy chain variable region (VH) fragment and/or light chain variable region (VL) fragment which specifically binds TL1A, and/or The second domain includes an antibody Fab fragment, fab 'fragment, F (ab') 2 fragment, fv fragment, scFv fragment, nanobody, heavy chain variable region (VH) fragment, and/or light chain variable region (VL) fragment that specifically binds IL-23.
  4. 4. The bispecific antibody according to any one of claims 1 to 3, characterized in that the first domain and the second domain are linked directly or via a linker, Preferably, the linker has an amino acid sequence as shown in the general formula (G n S) m , n and m are integers of 1 to 10 respectively, more preferably n is an integer of 1 to 4, and m is an integer of 1 to 3, or an amino acid sequence having 1, 2 or 3 amino acid insertions, substitutions or deletions compared to the amino acid sequence shown in the general formula (G n S) m ).
  5. 5. The bispecific antibody of any one of claims 1 to 4, wherein the first domain comprises (1) the following 3 heavy chain variable region complementarity determining regions (HCDR): HCDR1 having an amino acid sequence of HCDR1 contained in the heavy chain variable region as shown in SEQ ID No. 1 or 3, or an amino acid sequence having substitution, deletion or addition of one or more amino acids as compared with the amino acid sequence of HCDR1 contained in the heavy chain variable region; HCDR2 having an amino acid sequence of HCDR2 contained in the heavy chain variable region as set forth in any one of SEQ ID NOs 1 or 3, or an amino acid sequence having a substitution, deletion or addition of one or several amino acids compared to the amino acid sequence of HCDR2 contained in the heavy chain variable region; HCDR3 having an amino acid sequence of HCDR3 contained in the heavy chain variable region as set forth in any one of SEQ ID NOs 1 or 3, or an amino acid sequence having substitution, deletion or addition of one or several amino acids as compared with the amino acid sequence of HCDR3 contained in the heavy chain variable region, and/or (2) The following 3 light chain variable region complementarity determining regions (LCDR): LCDR1, which has the amino acid sequence of LCDR1 contained in the light chain variable region as shown in SEQ ID NO. 2 or 4, or has one or several amino acid substitutions, deletions or additions compared to the amino acid sequence of LCDR1 contained in the light chain variable region; LCDR2 having the amino acid sequence of LCDR2 contained in the light chain variable region as shown in SEQ ID No. 2 or 4 or having one or more amino acid substitutions, deletions or additions compared to the amino acid sequence of LCDR2 contained in said light chain variable region; LCDR3 having an amino acid sequence of LCDR3 contained in a light chain variable region as shown in SEQ ID No. 2 or 4 or having a substitution, deletion or addition of one or more amino acids compared to the amino acid sequence of LCDR3 contained in said light chain variable region; preferably, the first domain comprises: HCDR1, HCDR2 and HCDR3 contained in the heavy chain variable region as shown in SEQ ID No. 1, and LCDR1, LCDR2 and LCDR3 contained in the light chain variable region as shown in SEQ ID No. 2, or HCDR1, HCDR2 and HCDR3 contained in the heavy chain variable region as shown in SEQ ID No. 3, and LCDR1, LCDR2 and LCDR3 contained in the light chain variable region as shown in SEQ ID No. 4; Preferably, said HCDR1-3 and/or said LCDR1-3 are defined by an IMGT numbering system, a Kabat numbering system, a Chothia numbering system, a Contact numbering system or a combination thereof.
  6. 6. The bispecific antibody of any one of claims 1-5, wherein the first domain comprises: (1) Heavy chain variable regions and/or light chain variable regions wherein HCDR1-3 and/or LCDR1-3 are defined by the IMGT numbering system: (a) A heavy chain variable region comprising 3 HCDRs of HCDR1 of SEQ ID NO. 7, HCDR2 of SEQ ID NO. 8, HCDR3 of SEQ ID NO. 9, and/or a light chain variable region comprising 3 LCDRs of LCDR1 of SEQ ID NO. 10, LCDR2 of YAT, LCDR3 of SEQ ID NO. 11, or (B) A heavy chain variable region comprising 3 HCDRs, a HCDR1 of SEQ ID NO. 25, a HCDR2 of SEQ ID NO. 26, a HCDR3 of SEQ ID NO. 27, and/or a light chain variable region comprising 3 LCDRs, a LCDR1 of SEQ ID NO. 28, a LCDR2 of DAS, a LCDR3 of SEQ ID NO. 29; Or alternatively (2) Heavy chain variable regions and/or light chain variable regions wherein HCDR1-3 and/or LCDR1-3 are defined according to the Kabat numbering system: (a) A heavy chain variable region comprising 3 HCDRs of HCDR1 sequence SEQ ID NO. 12, HCDR2 sequence SEQ ID NO. 13, HCDR3 sequence SEQ ID NO. 14, and/or a light chain variable region comprising 3 LCDRs of LCDR1 sequence SEQ ID NO. 15, LCDR2 sequence SEQ ID NO. 16, LCDR3 sequence SEQ ID NO. 11, or (B) A heavy chain variable region comprising 3 HCDRs of HCDR1 sequence SEQ ID NO. 30, HCDR2 sequence SEQ ID NO. 31, HCDR3 sequence SEQ ID NO. 32, and/or a light chain variable region comprising 3 LCDRs of LCDR1 sequence SEQ ID NO. 33, LCDR2 sequence SEQ ID NO. 34, LCDR3 sequence SEQ ID NO. 29; Or alternatively (3) Heavy chain variable regions and/or light chain variable regions wherein HCDR1-3 and/or LCDR1-3 are defined by the Chothia numbering system: (a) Comprising 3 HCDR heavy chain variable regions of HCDR1 of SEQ ID NO. 17, HCDR2 of SEQ ID NO. 18, HCDR3 of SEQ ID NO. 14, and/or comprising 3 LCDR light chain variable regions of LCDR1 of SEQ ID NO. 15, LCDR2 of SEQ ID NO. 16, LCDR3 of SEQ ID NO. 11, or (B) A heavy chain variable region comprising 3 HCDRs of HCDR1 sequence SEQ ID NO. 35, HCDR2 sequence SEQ ID NO. 36, HCDR3 sequence SEQ ID NO. 32, and/or a light chain variable region comprising 3 LCDRs of LCDR1 sequence SEQ ID NO. 33, LCDR2 sequence SEQ ID NO. 34, LCDR3 sequence SEQ ID NO. 29; Or alternatively (4) Heavy chain variable regions and/or light chain variable regions, wherein HCDR1-3 and/or LCDR1-3 are defined by the Contact numbering system: (a) Comprising 3 HCDR heavy chain variable regions of HCDR1 of SEQ ID NO. 19, HCDR2 of SEQ ID NO. 20, HCDR3 of SEQ ID NO. 21, and/or comprising 3 LCDR light chain variable regions of LCDR1 of SEQ ID NO. 22, LCDR2 of SEQ ID NO. 23, LCDR3 of SEQ ID NO. 24, or (B) Comprising 3 heavy chain variable regions of HCDR1 of SEQ ID NO. 37, HCDR2 of SEQ ID NO. 38, HCDR3 of SEQ ID NO.39, and/or light chain variable regions of LCDR1 of SEQ ID NO. 40, LCDR2 of SEQ ID NO. 41, LCDR3 of SEQ ID NO. 42.
  7. 7. The bispecific antibody of any one of claims 1-6, wherein the first domain comprises: a heavy chain variable region having an amino acid sequence as shown in SEQ ID NO. 1 or 3, an amino acid sequence having one or more amino acid substitutions, deletions or additions as compared with it, or an amino acid sequence having at least 80% sequence identity thereto, and A light chain variable region having an amino acid sequence as shown in SEQ ID NO. 2 or 4, an amino acid sequence having one or more amino acid substitutions, deletions or additions as compared to it, or an amino acid sequence having at least 80% sequence identity thereto; preferably, the first domain comprises a heavy chain variable region having the amino acid sequence shown in SEQ ID NO. 1 and a light chain variable region having the amino acid sequence shown in SEQ ID NO. 2; preferably, the first domain comprises a heavy chain variable region having the amino acid sequence shown in SEQ ID NO. 3 and a light chain variable region having the amino acid sequence shown in SEQ ID NO. 4.
  8. 8. The bispecific antibody of any one of claims 1 to 7, wherein the second domain comprises the following 3 heavy chain variable region complementarity determining regions (HCDR): HCDR1 having an amino acid sequence of HCDR1 contained in the heavy chain variable region as shown in SEQ ID No. 5 or an amino acid sequence having one or more amino acid substitutions, deletions or additions compared to the amino acid sequence of HCDR1 contained in the heavy chain variable region; HCDR2 having the amino acid sequence of HCDR2 contained in the heavy chain variable region as shown in SEQ ID No. 5 or having one or more amino acid substitutions, deletions or additions compared to the amino acid sequence of HCDR2 contained in the heavy chain variable region; HCDR3 having an amino acid sequence of HCDR3 contained in the heavy chain variable region as shown in SEQ ID NO. 5 or an amino acid sequence having substitution, deletion or addition of one or several amino acids as compared with the amino acid sequence of HCDR3 contained in the heavy chain variable region, and/or The following 3 light chain variable region complementarity determining regions (LCDR): LCDR1, which has the amino acid sequence of LCDR1 contained in the light chain variable region as shown in SEQ ID NO. 6, or an amino acid sequence having substitution, deletion or addition of one or several amino acids as compared with the amino acid sequence of LCDR1 contained in the light chain variable region; LCDR2, which has the amino acid sequence of LCDR2 contained in the light chain variable region as shown in SEQ ID NO. 6, or an amino acid sequence having substitution, deletion or addition of one or several amino acids as compared with the amino acid sequence of LCDR2 contained in the light chain variable region; LCDR3, which has the amino acid sequence of LCDR3 contained in the light chain variable region as shown in SEQ ID NO. 6, or an amino acid sequence having substitution, deletion or addition of one or several amino acids as compared with the amino acid sequence of LCDR3 contained in the light chain variable region; Preferably, said HCDR1-3 and/or said LCDR1-3 are defined by an IMGT numbering system, a Kabat numbering system, a Chothia numbering system, a Contact numbering system or a combination thereof.
  9. 9. The bispecific antibody of any one of claims 1-8, wherein the second domain comprises: (1) Heavy chain variable regions and/or light chain variable regions wherein HCDR1-3 and/or LCDR1-3 are defined by the IMGT numbering system: A heavy chain variable region comprising 3 HCDRs of HCDR1 of SEQ ID NO. 43, HCDR2 of SEQ ID NO. 44, HCDR3 of SEQ ID NO. 45, and/or a light chain variable region comprising 3 LCDRs of LCDR1 of SEQ ID NO. 46, LCDR2 of GNS, LCDR3 of SEQ ID NO. 47; Or alternatively (2) Heavy chain variable regions and/or light chain variable regions wherein HCDR1-3 and/or LCDR1-3 are defined according to the Kabat numbering system: A heavy chain variable region comprising 3 HCDRs of HCDR1 sequence SEQ ID NO. 48, HCDR2 sequence SEQ ID NO. 49, HCDR3 sequence SEQ ID NO. 50, and/or a light chain variable region comprising 3 LCDRs of LCDR1 sequence SEQ ID NO. 51, LCDR2 sequence SEQ ID NO. 52, LCDR3 sequence SEQ ID NO. 47; Or alternatively (3) Heavy chain variable regions and/or light chain variable regions wherein HCDR1-3 and/or LCDR1-3 are defined by the Chothia numbering system: A heavy chain variable region comprising 3 HCDRs of HCDR1 sequence SEQ ID NO. 53, HCDR2 sequence SEQ ID NO. 54, HCDR3 sequence SEQ ID NO. 50, and/or a light chain variable region comprising 3 LCDRs of LCDR1 sequence SEQ ID NO. 51, LCDR2 sequence SEQ ID NO. 52, LCDR3 sequence SEQ ID NO. 47; Or alternatively (4) Heavy chain variable regions and/or light chain variable regions, wherein HCDR1-3 and/or LCDR1-3 are defined by the Contact numbering system: Comprising 3 heavy chain variable regions of HCDR1 of SEQ ID NO:55, HCDR2 of SEQ ID NO:56, HCDR3 of SEQ ID NO:57, and/or comprising 3 light chain variable regions of LCDR1 of SEQ ID NO:58, LCDR2 of SEQ ID NO:59, LCDR3 of SEQ ID NO: 60.
  10. 10. The bispecific antibody of any one of claims 1-9, wherein the second domain comprises: A heavy chain variable region having an amino acid sequence as shown in SEQ ID NO. 5, an amino acid sequence having one or more amino acid substitutions, deletions or additions thereto or an amino acid sequence having at least 80% sequence identity thereto, and A light chain variable region having an amino acid sequence as shown in SEQ ID NO. 6, an amino acid sequence having one or more amino acid substitutions, deletions or additions as compared to it, or an amino acid sequence having at least 80% sequence identity thereto.
  11. 11. An isolated nucleic acid molecule encoding the bispecific antibody of any one of claims 1 to 10.
  12. 12. An expression vector comprising the isolated nucleic acid of claim 10.
  13. 13. A host cell comprising the isolated nucleic acid molecule of claim 11 or the expression vector of claim 12.
  14. 14. A chimeric antigen receptor comprising an extracellular antigen-binding fragment, a transmembrane domain, and an intracellular signaling domain, wherein the extracellular antigen-binding fragment comprises the bispecific antibody of any one of claims 1-10.
  15. 15. A conjugate comprising the bispecific antibody of any one of claims 1 to 10, and a coupling moiety; Preferably, the coupling moiety is selected from the group consisting of detectable labels, radioisotopes, fluorescent substances, luminescent substances, colored substances, enzymes, polyethylene glycol (PEG), nuclides, nucleic acids, small molecule toxins, polypeptides having binding activity, proteins, receptors, ligands, and other active substances that inhibit tumor cell growth, promote tumor cell apoptosis or necrosis.
  16. 16. A pharmaceutical composition comprising the bispecific antibody of any one of claims 1 to 10, the isolated nucleic acid molecule of claim 11, or the expression vector of claim 12, and a pharmaceutically acceptable carrier; preferably, the pharmaceutical composition is selected from the form of a tablet, powder, granule, pill, injection, suspension, powder, emulsion, aerosol, gel, eye drop, sustained release agent or sustained release implant.
  17. 17. A kit comprising the pharmaceutical composition of claim 16, packaged in a container, Preferably, the container is selected from the group consisting of a glass ampoule, a glass bottle, a plastic ampoule, a plastic bottle, a plastic bag, and a prefilled syringe.
  18. 18. A kit comprising the bispecific antibody of any one of claims 1 to 10, and optionally, instructions for use.
  19. 19. Use of a bispecific antibody according to any one of claims 1 to 10, an isolated nucleic acid molecule according to claim 11, an expression vector according to claim 12, a chimeric antigen receptor according to claim 14, a conjugate according to claim 15 or a pharmaceutical composition according to claim 16 for the preparation of a medicament for the prevention and/or treatment of TL1A and/or IL-23 associated diseases.
  20. 20. A method of treating or preventing a disorder associated with TL1A and/or IL-23, comprising administering to a subject a therapeutically effective amount of the bispecific antibody of any one of claims 1 to 10, the isolated nucleic acid molecule of claim 11, the expression vector of claim 12, the chimeric antigen receptor of claim 14, the conjugate of claim 15, or the pharmaceutical composition of claim 16.

Description

Bispecific antibodies against TL1A and IL-23 and uses thereof Technical Field The present disclosure relates to bispecific antibodies directed against TL1A and IL-23 and uses thereof. Background TNF-like ligand 1A (TL 1A, also known as TNF superfamily member 15 (TNFSF 15)) is one of the tumor necrosis factor superfamily members, a type II membrane protein, which is expressed by antigen presenting cells (including dendritic cells, B cells and macrophages), cd4+ and cd8+ T cells and endothelial cells and can be expressed on the cell surface or secreted in the form of a soluble cytokine. TL1A is associated with the development and severity of Inflammatory Bowel Disease (IBD), the major types of IBD being Ulcerative Colitis (UC) and Crohn's Disease (CD). These diseases are very common and the number of available therapies is limited and some patients either do not respond to the initial treatment or over time the response disappears. Currently, the only therapy for patients who do not respond to first line therapy is surgery. Surgical treatment of IBD is invasive, and about one third of patients present a post-operative risk after receiving surgery. The pathogenesis of IBD is thought to involve an uncontrolled immune response, and heterogeneity of disease pathogenesis and clinical course suggests that targeted therapeutic approaches to treat these diseases are ideal therapeutic strategies. Thus, novel therapeutic approaches that specifically target the pathogenesis of IBD, drugs that inhibit TL1A activity are hot targets for developing therapies for IBD. IL-23 is a member of the IL12 cytokine family, a pro-inflammatory cytokine. There is evidence that IL-23 is a major contributor to intestinal inflammation compared to IL 12. First, in animal models of colitis, anti-IL-23-p 19 antibodies can induce remission in transgenic mice by down-regulating a variety of colitis cytokines and chemokines. Second, with respect to IL-23/IL12 antibodies, the recent literature suggests that blocking IL-23-p19 alone is better than blocking the p40 subunit, probably because IL12 is also associated with CD 40-mediated anti-inflammatory function. Finally, in whole genome association studies, the IL-23R gene has been associated with IBD. To date, the dynamic prospect of IL-23 pathway inhibition in the treatment of IBD is actively evolving. At present, no similar double-target medicine is approved to be marketed at home and abroad. Firstly, no monoclonal antibody medicine aiming at TL1A target is marketed at home and abroad, the fastest PRA023 of moesadong is developed, and the medicine enters into phase III clinic. Secondly, with regard to the reports of TL1A and IL-23 bispecific antibodies, the fastest currently advancing TL1A+IL12-p40 is entering phase I clinic, and no TL1A and IL-23-p19 bispecific antibodies are reported. Disclosure of Invention In order to solve one of the technical problems existing in the prior art, the disclosure provides a bispecific antibody which can better maintain the activity of each monoclonal antibody, can specifically bind to two targets of TNF-like ligand 1A (TL 1A) and interleukin-23 (IL-23) simultaneously, and has similar or even better biological activity as the monoclonal antibodies. One aspect of the present disclosure provides a bispecific antibody comprising a first domain that specifically binds TNF-like ligand 1A (TL 1A), and a second domain that specifically binds interleukin-23 (IL-23). In some embodiments, the first domain is an antibody or functional fragment thereof that specifically binds TL 1A. In some embodiments, the second domain is an antibody or functional fragment thereof that specifically binds IL-23. In some embodiments, the first domain comprises an antibody Fab fragment, fab 'fragment, F (ab') 2 fragment, fv fragment, scFv fragment, nanobody, heavy chain variable region (VH) fragment, and/or light chain variable region (VL) fragment that specifically binds to TL 1A. In some embodiments, the second domain comprises an antibody Fab fragment, fab 'fragment, F (ab') 2 fragment, fv fragment, scFv fragment, nanobody, heavy chain variable region (VH) fragment, and/or light chain variable region (VL) fragment that specifically binds to IL-23. In some embodiments, the first domain and the second domain are linked directly or through a linker. In some embodiments, the linker has an amino acid sequence as shown in formula (G nS)m, n, m are each integers from 1 to 10, more preferably n is an integer from 1 to 4, m is an integer from 1 to 3, or an amino acid sequence having 1, 2, or 3 amino acid insertions, substitutions, or deletions compared to the amino acid sequence shown in formula (G nS)m). In some embodiments, the bispecific antibody comprises a first domain and a second domain linked in any manner. In some embodiments, the bispecific antibody comprises a first domain-second domain from N-terminus to C-terminus. In some embodiments, the bispecific antibody comprises a second domain