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EP-4737484-A1 - BISPECIFIC ANTIBODY TARGETING PD-L1 AND IL-1 AND USE THEREOF

EP4737484A1EP 4737484 A1EP4737484 A1EP 4737484A1EP-4737484-A1

Abstract

Provided is a bispecific antibody comprising a first moiety targeting PD-L1 and a second moiety targeting IL-1, wherein the first moiety comprises an anti-PD-L1 antibody or an antigen-binding fragment thereof, and the second moiety comprises an extracellular binding domain of an IL-1 receptor (IL-1R) or a variant thereof or an anti-IL-1β antibody or an antigen-binding fragment thereof. Further provided is the use of the bispecific antibody in the treatment of tumors.

Inventors

  • ZHANG, Tingyan
  • YANG, JIANFEI
  • NIU, GANG
  • ZHANG, CHUNLI
  • ZHANG, CHUNMING

Assignees

  • Phil Rivers Technology Co., Ltd

Dates

Publication Date
20260506
Application Date
20240628

Claims (20)

  1. A bispecific antibody comprising a first moiety targeting PD-L1 and a second moiety targeting IL-1, wherein the first moiety comprises an anti-PD-L1 antibody or an antigen-binding fragment thereof, and the anti-PD-L1 antibody comprises an HCDR1, an HCDR2, and an HCDR3 from a heavy chain variable region (VH) shown in SEQ ID NO: 17, and an LCDR1, an LCDR2, and an LCDR3 from a light chain variable region (VL) shown in SEQ ID NO: 18.
  2. The bispecific antibody of claim 1, wherein the anti-PD-L1 antibody comprises a sequence shown in SEQ ID NO: 17 or an amino acid sequence having at least 90% sequence identity therewith, and a sequence shown in SEQ ID NO: 18 or an amino acid sequence having at least 90% sequence identity therewith.
  3. The bispecific antibody of claim 1 or 2, wherein a heavy chain constant region of the anti-PD-L1 antibody is from an IgG1, and a light chain constant region of the anti-PD-L1 antibody is from a κ light chain.
  4. The bispecific antibody of any one of claims 1-3, wherein the second moiety comprises an extracellular binding domain of an IL-1 receptor (IL-1R) or a variant thereof.
  5. The bispecific antibody of any one of claims 1-4, wherein the second moiety comprises a sequence shown in SEQ ID NO: 14 or an amino acid sequence having at least 90% sequence identity therewith.
  6. The bispecific antibody of any one of claims 1-5, wherein the number of the second moiety is two, and the second moieties are respectively connected at an N-terminus of the VH of the anti-PD-L1 antibody, an N-terminus of the VL of the anti-PD-L1 antibody, a C-terminus of the heavy chain constant region of the anti-PD-L1 antibody, or a C-terminus of the light chain constant region of the anti-PD-L1 antibody via an identical or different linker sequence.
  7. The bispecific antibody of any one of claims 1-6, wherein the number of the second moiety is one, and the second moiety is connected at an N-terminus of the VH of the anti-PD-L1 antibody, an N-terminus of the VL of the anti-PD-L1 antibody, a C-terminus of the heavy chain constant region of the anti-PD-L1 antibody, or a C-terminus of the light chain constant region of the anti-PD-L1 antibody via a linker sequence.
  8. The bispecific antibody of any one of claims 1-7, wherein the first moiety further has an antigen-binding fragment of the anti-PD-L1 antibody in an Fab format connected via a linker sequence to a C-terminus of the heavy chain constant region of the anti-PD-L1 antibody.
  9. The bispecific antibody of any one of claims 1-8, wherein the second moiety is an anti-IL-1β antibody or an antigen-binding fragment thereof.
  10. The bispecific antibody of any one of claims 1-9, wherein the anti-IL-1β antibody comprises an HCDR1, an HCDR2, and an HCDR3 from a VH shown in SEQ ID NO: 15, and an LCDR1, an LCDR2, and an LCDR3 from a VL shown in SEQ ID NO: 16.
  11. The bispecific antibody of any one of claims 1-10, wherein the anti-IL-1β antibody comprises a sequence shown in SEQ ID NO: 15 or an amino acid sequence having at least 90% sequence identity therewith, and a sequence shown in SEQ ID NO: 16 or an amino acid sequence having at least 90% sequence identity therewith.
  12. The bispecific antibody of any one of claims 1-11, wherein a heavy chain constant region of the anti-IL-1β antibody is from an IgG1, and a light chain constant region of the anti-PD-L1 antibody is from a κ light chain.
  13. The bispecific antibody of any one of claims 1-12, wherein the antigen-binding fragment of the anti-IL-1β antibody is in an Fab or scFv format.
  14. The bispecific antibody of any one of claims 1-13, wherein a heavy chain constant region of the anti-PD-L1 antibody and/or a heavy chain constant region of the anti-IL-1β antibody are/is mutated so that a Knob-hole binding is capable of being formed between the heavy chain constant regions.
  15. The bispecific antibody of any one of claims 1-14, wherein the first moiety and the second moiety are connected via an identical or different linker sequence, and preferably, the linker sequence is selected from (G 4 S) 4 G, (G 4 S) 3 G, (G 4 S) 4 and (G 4 S) 3 .
  16. The bispecific antibody of any one of claims 1-15, wherein a heavy chain of the anti-PD-L1 antibody comprises a sequence shown in SEQ ID NO: 9 or an amino acid sequence having at least 90% sequence identity therewith, and a light chain of the anti-PD-L1 antibody comprises a sequence shown in SEQ ID NO: 8 or an amino acid sequence having at least 90% sequence identity therewith.
  17. The bispecific antibody of any one of claims 1-16, wherein a heavy chain of the anti-IL-1β antibody comprises a sequence shown in SEQ ID NO: 7 or an amino acid sequence having at least 90% sequence identity therewith, and a light chain of the anti-IL-1β antibody comprises a sequence shown in SEQ ID NO: 6 or an amino acid sequence having at least 90% sequence identity therewith.
  18. The bispecific antibody of any one of claims 1-17, wherein the antigen-binding fragment of the anti-PD-L1 antibody in an scFv format comprises a sequence shown in SEQ ID NO: 65 or an amino acid sequence having at least 90% sequence identity therewith.
  19. The bispecific antibody of any one of claims 1-18, wherein an antigen-binding fragment of the anti-IL-1β antibody in an scFv format comprises a sequence shown in SEQ ID NO: 64 or an amino acid sequence having at least 90% sequence identity therewith.
  20. The bispecific antibody of any one of claims 1-19, having any of the schematic antibody structures in Figures 1A-1I.

Description

Technical Field The present invention relates to a bispecific antibody, especially a bispecific antibody comprising a first moiety targeting PD-L1 and a second moiety targeting IL-1. The present disclosure also relates to use of the bispecific antibody in the treatment of a tumor. Background The mechanism of action is to target both PD-L1 on a surface of a tumor cell and IL-1R1 or IL-1β in a tumor microenvironment, so as to achieve a better therapeutic effect than a single drug or a combination of single drugs. Studies have shown that PD-L1 is highly expressed on surfaces of a variety of tumor cells. The PD-L1 on the surface of a tumor cell, after binding to PD-1 on the surface of a T cell, inhibits killing of the tumor cell by the T cell and reduces the proliferation of a CD8+ T cell while reducing the apoptosis of a Treg. An antibody targeting PD-L1 can inhibit the binding of PD-L1 to PD-1, thereby restoring the killing effect of the T cell on the tumor, which shows a significant therapeutic effect in treating patients with various types of tumors such as malignant melanoma, non-small cell lung cancer, renal cell carcinoma, bladder cancer, or gastric cancer. L-1β is a member of the IL-1 cytokine family. After binding to IL-1R1, IL-1α or IL-1β binds to an IL-1R accessory protein (IL-1RAcP) to form a complex. The complex can activate an IL-1R associated kinase (IRAK) and further, through NF-κB and other transcription factors, activates a nuclear gene finally. Studies have shown that IL-1β is upregulated in tumor microenvironments (TME) of a variety of cancers, including breast cancer, gastric cancer, pancreatic cancer, and lung cancer. It can change the components of the TME by recruiting an immunosuppressive cell such as an MDSC, a tumor-associated macrophage (TAM), a tumor-associated neutrophil (TAN), and Th17, which are themselves sources of IL-1β. In addition, recent studies have shown that a tumor itself is also a source of IL-1β, as it can establish a self-stimulating cycle to sustain the synthesis and release of IL-1β. It has also been demonstrated that a tumor-derived IL-1β can promote the expression of an angiogenic factor such as VEGF. In summary, a TME-derived IL-1β and a tumor-derived IL-1β can not only promote tumor growth and migration, but also participate in the development of tumor resistance to a drug by inducing anti-apoptotic signaling. It has been demonstrated that an antibody targeting IL-1β can inhibit the growth and migration of tumors, improve the infiltration of a CD8+ T cell into a tumor tissue, and reduce the immunosuppression. The latest preclinical and clinical data have shown that the combination of an immune checkpoint inhibitor with a drug which negatively regulates IL-1 signaling is a promising strategy for treating a solid tumor. And compared to a combination of single drugs, an antibody fusion protein or a bispecific antibody targeting both PD-L1 and IL-1R1 or both PD-L1 and IL-1β have the advantages of high specificity, strong targeting property, high safety level, convenient administration, and low development cost, and the like. Summary In an aspect, provided herein is a bispecific antibody comprising a first moiety targeting PD-L1 and a second moiety targeting IL-1, wherein the first moiety comprises an anti-PD-L1 antibody or an antigen-binding fragment thereof, and the anti-PD-L1 antibody comprises an HCDR1, an HCDR2, and an HCDR3 from a heavy chain variable region (VH) shown in SEQ ID NO: 17, and an LCDR1, an LCDR2, and an LCDR3 from a light chain variable region (VL) shown in SEQ ID NO: 18. In some embodiments, the anti-PD-L1 antibody comprises a sequence shown in SEQ ID NO: 17 or an amino acid sequence having at least 90% sequence identity therewith, and a sequence shown in SEQ ID NO: 18 or an amino acid sequence having at least 90% sequence identity therewith. In some embodiments, a heavy chain constant region of the anti-PD-L1 antibody is from an IgG1, and a light chain constant region of the anti-PD-L1 antibody is from a κ light chain. In some embodiments, the second moiety comprises an extracellular binding domain of an IL-1 receptor (IL-1R) or a variant thereof. In some embodiments, the second moiety comprises a sequence shown in SEQ ID NO: 14 or an amino acid sequence having at least 90% sequence identity therewith. In some embodiments, the number of the second moiety is two, and the second moieties are respectively connected at an N-terminus of the VH of the anti-PD-L1 antibody, an N-terminus of the VL of the anti-PD-L1 antibody, a C-terminus of the heavy chain constant region of the anti-PD-L1 antibody, or a C-terminus of the light chain constant region of the anti-PD-L1 antibody via an identical or different linker sequence. In some embodiments, the number of the second moiety is one, and the second moiety is connected at an N-terminus of the VH of the anti-PD-L1 antibody, an N-terminus of the VL of the anti-PD-L1 antibody, a C-terminus of the heavy chain