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CN-122003441-A - Anti-PD-L1 and anti-4-1 BB bispecific antibodies for the treatment of tumors

CN122003441ACN 122003441 ACN122003441 ACN 122003441ACN-122003441-A

Abstract

The use of anti-4-1 BB and anti-PD-L1 bispecific antibodies in combination with chemotherapeutic agents in the manufacture of a medicament for the treatment of tumors is provided.

Inventors

  • CAI SHENGLI
  • KANG XIAOQIANG

Assignees

  • 南京维立志博生物科技股份有限公司

Dates

Publication Date
20260508
Application Date
20240926
Priority Date
20230927

Claims (20)

  1. Use of a bispecific antibody comprising a first antigen-binding region that specifically binds 4-1BB and a second antigen-binding region that specifically binds PD-L1 in the manufacture of a medicament for the treatment of a malignancy.
  2. The use of claim 1, wherein the first antigen binding region comprises a first heavy chain variable region and/or a first light chain variable region, wherein: the first heavy chain variable region: (i) HCDR1, HCDR2 and HCDR3 comprising a heavy chain variable region derived from a sequence comprising SEQ ID No. 7 or SEQ ID No. 9; (ii) Comprises or consists of the amino acid sequences of SEQ ID NO. 1, SEQ ID NO. 2 and SEQ ID NO. 3, or comprises or consists of an amino acid sequence having one, two or three modifications (preferably amino acid substitutions, preferably conservative substitutions) compared to the amino acid sequences of SEQ ID NO. 1, SEQ ID NO. 2 and SEQ ID NO. 3, respectively, or (Iii) Comprising or consisting of the amino acid sequence of SEQ ID NO. 7 or SEQ ID NO. 9, or comprising or consisting of an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO. 7 or SEQ ID NO. 9, or comprising or consisting of one or more (preferably NO more than 10, more preferably NO more than 5) amino acid modifications (preferably amino acid substitutions, more preferably conservative substitutions) compared to the amino acid sequence of SEQ ID NO. 7 or SEQ ID NO. 9, preferably, these amino acid modifications do not occur in the CDR regions, more preferably, these amino acid modifications occur in the FR regions, such as FR1, FR2, FR3 or FR4 regions; The first light chain variable region: (i) LCDR1, LCDR2 and LCDR3 comprising a light chain variable region derived from the sequence set forth in SEQ ID NO. 8 or SEQ ID NO. 10; (ii) Comprises LCDR1, LCDR2 and LCDR3, which comprises or consists of the sequences indicated in SEQ ID NO. 4, SEQ ID NO. 5 and SEQ ID NO. 6, respectively, or comprises or consists of an amino acid sequence having one, two or three modifications (preferably amino acid substitutions, preferably conservative substitutions) compared to the amino acid sequences of SEQ ID NO. 4, SEQ ID NO. 5 and SEQ ID NO. 6, respectively, or (Iii) Comprising or consisting of the amino acid sequence of SEQ ID NO. 8 or SEQ ID NO. 10, or comprising or consisting of an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO. 8 or SEQ ID NO. 10, or comprising or consisting of one or more (preferably NO more than 10, more preferably NO more than 5) amino acid modifications (preferably amino acid substitutions, more preferably conservative substitutions) compared to the amino acid sequence of SEQ ID NO. 8 or SEQ ID NO. 10, preferably such amino acid modifications do not occur in the CDR regions, more preferably such amino acid modifications occur in the FR regions, such as FR1, FR2, FR3 or FR4 regions; Wherein in SEQ ID NO. 8, X=S or G.
  3. The use of claim 1 or 2, wherein the first antigen binding region further comprises or consists of a first heavy chain constant region comprising or consisting of the amino acid sequence set forth in SEQ ID No. 19 or 20 and/or a first light chain constant region comprising or consisting of the amino acid sequence set forth in SEQ ID No. 21 or 22.
  4. The use of any one of claims 1-3, wherein the first antigen binding region activates 4-1BB signaling and is a monoclonal antibody.
  5. The use of any one of claims 1-4, wherein the second antigen-binding region that specifically binds PD-L1 comprises a second heavy chain variable region and a second light chain variable region, wherein the second heavy chain variable region comprises HCDR1, HCDR2, and HCDR3 consisting of the sequences of SEQ ID No. 11, SEQ ID No. 12, and SEQ ID No. 13, respectively, and the second light chain variable region comprises LCDR1, LCDR2, and LCDR3 consisting of the sequences of SEQ ID No. 14, SEQ ID No. 15, and SEQ ID No. 16, respectively.
  6. The use according to claim 5, wherein the second antigen binding region further comprises or consists of a second heavy chain constant region comprising or consisting of the amino acid sequence shown in SEQ ID NO. 19 or 20 and/or a second light chain constant region comprising or consisting of the amino acid sequence shown in SEQ ID NO. 21 or 22.
  7. The use as claimed in any one of claims 1-6, wherein the bispecific antibody comprises: (1) Chain 1-heavy chain of the second antigen binding region linked at the C-terminus with or without a linker to an antigen binding portion in the first antigen binding region, and (2) Chain 2 light chain of the second antigen binding region.
  8. The use as claimed in claim 7, wherein the linker comprises the amino acid sequence (Gly 4 Ser) n or (GlySer 4) n, where n is a positive integer from 1 to 7.
  9. The use as claimed in claim 7 or 8, wherein the bispecific antibody consists of two chains 1 and two chains 2.
  10. The use of any one of claims 7-9, wherein the antigen binding portion is selected from the group consisting of (i) a Fab fragment, (ii) a F (ab') 2 fragment, (iii) an Fd fragment, (iv) an Fv fragment, (v) a dAb fragment, (vi) a nanobody, and (vii) a single chain Fv (scFv) comprising the first heavy chain variable region and the first light chain variable region.
  11. The use of any one of claims 7-9, wherein the first antigen binding region and/or the second antigen binding region is a mouse antibody, a human antibody, a chimeric antibody, or a humanized antibody.
  12. The use of any one of claims 7-9, wherein the first antigen binding region and/or the second antigen binding region is an IgG1, igG2 or IgG4 isotype.
  13. The method of claim 7, wherein said chain 1 of said bispecific antibody comprises or consists of an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence set forth in SEQ ID NO. 25, and said chain 2 of said bispecific antibody comprises or consists of an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence set forth in SEQ ID NO. 26.
  14. The use of any one of claims 1-13, wherein the malignancy is bladder cancer, breast cancer, endometrial cancer, cervical cancer, advanced solid tumor, renal cell carcinoma, neuroendocrine tumor, gastric cancer, transitional cell carcinoma, urothelial cancer, hodgkin's lymphoma, non-hodgkin's lymphoma, colorectal cancer, non-small cell lung cancer, hepatocellular cancer, preferably the neuroendocrine tumor is a neuroendocrine cancer or neuroendocrine tumor, more preferably the neuroendocrine tumor is an extrapulmonary neuroendocrine tumor, more preferably the neuroendocrine tumor is an advanced neuroendocrine tumor.
  15. The use of claim 14, wherein the neuroendocrine cancer is advanced neuroendocrine cancer, preferably the neuroendocrine cancer is extrapulmonary neuroendocrine cancer or small cell lung cancer, more preferably the neuroendocrine cancer is unresectable locally advanced or metastatic neuroendocrine cancer.
  16. The method of claim 14 or 15, wherein the agent is administered to a subject with the malignancy who has not received systemic treatment or who has progressed on at least one line of chemotherapy, e.g., who has progressed on at least one line of platinum-containing chemotherapy, further wherein the subject comprises a subject who has progressed on two or more lines of chemotherapy.
  17. The use of any one of claims 1-16, comprising administering 0.2mg/kg to 200mg/kg of the bispecific antibody, preferably 0.8mg/kg to 25mg/kg of the bispecific antibody, more preferably 3.2mg/kg to 20mg/kg of the bispecific antibody, even more preferably 6mg/kg to 15mg/kg of the bispecific antibody, most preferably 10mg/kg to 15mg/kg of the bispecific antibody per dosing cycle or per administration to a subject.
  18. The use of any one of claims 1-16, comprising administering 50mg to 5000mg of the bispecific antibody, preferably 60mg to 4000mg of the bispecific antibody, more preferably 80mg to 3750mg of the bispecific antibody, most preferably 100mg to 350 mg of the bispecific antibody, e.g. 200mg、400mg、600mg、800mg、1000mg、1250mg、1500mg、1750mg、2000mg、2250mg、2500mg、2750mg、3000mg、3250mg、3500mg of the bispecific antibody, per dosing cycle or per administration to a subject.
  19. The use as claimed in claim 17 or 18, wherein the bispecific antibody is administered every 12 weeks, every 9 weeks, every 6 weeks, every 5 weeks, every 4 weeks, every 3 weeks, every 2 weeks, once a week or twice a week, three times a week.
  20. The use of any one of claims 1-19, wherein the bispecific antibody is formulated for intravenous infusion or subcutaneous injection.

Description

Anti-PD-L1 and anti-4-1 BB bispecific antibodies for the treatment of tumors Technical Field The present invention relates to the use of anti-4-1 BB and anti-PD-L1 bispecific antibodies in the treatment of tumors, in particular further to the use of anti-PD-L1 and anti-4-1 BB and their combination with chemotherapeutic agents in the preparation of a medicament for the treatment of tumors. Background Tumor immunotherapy has made significant progress in the last decade and has become an effective therapy for clinical use widely following surgery, radiotherapy, chemotherapy and targeted therapy. Tumor immunotherapy can trigger tumor immune response in a subject, activates the immune system of the subject to kill tumors by blocking an immune suppression pathway activated by cancer cells, and has the advantages of strong specificity, lasting effect, small side effect and the like. Programmed CELL DEATH protein 1, PD-1, is an immunosuppressive receptor expressed primarily on the surface of T cells, B cells, monocytes and natural killer cells, and its associated ligands are Programmed death ligand-1 (PD-L1) and Programmed death ligand-2 (PD-L2), respectively. Wherein, PD-L1 is widely expressed in various tumor cells and immune cells, and the expression level of the PD-L1 can be up-regulated by a plurality of cytokines such as Interferon (IFN) -gamma and the like in the tumor microenvironment. The PD-L1 on the surfaces of tumor cells and antigen presenting cells is combined with the PD-1 to continuously activate the PD-1/PD-L1 channel, so that the activation of tumor antigen specific T cells can be inhibited, and the anti-tumor activity of the T cells is weakened. The PD-1/PD-L1 antibody relieves the immunosuppression effect of the path by interfering the combination of PD-1 and PD-L1, and restores the anti-tumor immune response of the T cells. Immune checkpoint inhibitors are a research hotspot in the field of tumor immunotherapy at present, and a plurality of anti-PD- (L) 1 antibodies are marketed at home and abroad. Although the PD- (L) 1 inhibitor has a curative effect of 40-70% in melanoma, merkel cell carcinoma, hodgkin's lymphoma, microsatellite highly unstable tumor (MSI-H tumor) and other tumors, the effective rate of the PD- (L) 1 inhibitor is only 10-25% in tumors obtained by lots of immune checkpoint inhibitors, such as advanced small cell lung cancer, gastric cancer and the like (refer to the information of the specification of the market of each product). Furthermore, existing immune checkpoint inhibitors may suffer from primary and acquired drug resistance and the like or may cause immune related adverse events. Therefore, it is necessary to find other immune checkpoints in the tumor microenvironment, thereby reducing the generation of drug resistance and improving the anti-tumor curative effect. 4-1BB (CD 137) is one of the potential targets in tumor immunotherapy, and 4-1BB belongs to the Tumor Necrosis Factor (TNF) receptor family, and is mainly expressed in activated T cells, natural killer cells, regulatory T cells, dendritic cells, mast cells and other cells. Its ligand 4-1BBL is expressed predominantly in activated Antigen Presenting Cells (APCs), including dendritic cells, macrophages and B cells. 4-1BB is a T cell specific co-stimulatory molecule that plays a critical role in immunotherapy for the complete activation of T cells and other immune cells. The primary physiological functions of 4-1BB on T cells are the recruitment of TNF receptor-related factors 1 and 2 (TRAF 1 and TRAF 2) to form heterotrimers upon binding of 4-1BB and 4-1BBL, thereby activating the nuclear factor-activated B cell kappa light chain enhancer (NF-. Kappa.B), the amino terminal kinase (c-Jun-terminal, JNK), and the p38 mitogen-activated protein kinase (MAPK) dominant downstream signaling pathways that produce co-stimulatory signals, promote production and secretion of cytokines such as interleukins [ IL ] -2, IL-4, and IFN-. Gamma.) and promote activation of CD8+ and CD4+ T lymphocytes, wherein activation of NF-. Kappa.B enhances survival of CD8+ T lymphocytes by increasing expression of the anti-apoptotic genes bcl-XL and bfl-l. The 4-1BB not only activates the immune system through T cells, but also activates or regulates the immune system through natural killer cells, macrophages and B cells, thereby achieving the purpose of inhibiting tumor proliferation. In addition, combination therapies of anti-4-1 BB antibodies and other antibodies (such as anti-PD-1 antibodies) are also undergoing clinical trials. For example, there is a need for bispecific antibodies that can target both PD-L1 and 4-1BB to block the PD-1/PD-L1 pathway and provide a co-stimulatory signal via 4-1BB when PD-L1 cross-links are performed by PD-L1 expressing tumor cells. However, the bispecific antibody described in patent us_2017_0198050_a1 activates or induces 4-1BB signaling without cross-linking to target cells, raising concerns about the p