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US-20260125477-A1 - ANTIBODIES BINDING B7-H3 AND USES THEREOF

US20260125477A1US 20260125477 A1US20260125477 A1US 20260125477A1US-20260125477-A1

Abstract

The application provides an isolated monoclonal antibody or an antigen binding portion thereof, that specifically binds to B7-H3. Also provided is a nucleic acid molecule that encodes the antibody or antigen binding portion thereof, and an expression vector, a host cell and a method for expressing the antibody or antigen binding portion thereof. The application further provides an immunoconjugate, a bispecific molecule, a chimeric antigen receptor, an oncolytic virus, and a pharmaceutical composition that comprise the antibody or antigen binding portion thereof, and a treatment method using the antibody or antigen binding portion thereof of the disclosure.

Inventors

  • Jiangmei Li
  • Yunyun CHEN
  • Ting Mao
  • Yanan GUO
  • Wenqi Hu
  • Feng Li

Assignees

  • Beijing Mabworks Biotech Co., Ltd.

Dates

Publication Date
20260507
Application Date
20220318

Claims (19)

  1. 1 . An isolated monoclonal antibody or an antigen binding portion thereof, capable of binding to B7-H3, comprising i) a heavy chain variable region, wherein the heavy chain variable region comprises a VH CDR1 region, a VH CDR2 region and a VH CDR3 region, and ii) a light chain variable region, wherein the light chain variable region comprises a VL CDR1 region, a VL CDR2 region and a VL CDR3 region, wherein the VH CDR1 region, the VH CDR2 region, the VH CDR3 region, the VL CDR1 region, the VL CDR2 region, and the VL CDR3 region comprise the amino acid sequences of (1) SEQ ID NOs: 1, 2, 3, 4, 5 and 6, respectively; or (2) SEQ ID NOs: 18, 19, 20, 9, 21 and 22, respectively.
  2. 2 . The isolated monoclonal antibody or the antigen binding portion thereof of claim 1 , wherein the heavy chain variable region comprises an amino acid sequence having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NOs: 29 or 35.
  3. 3 . The isolated monoclonal antibody or the antigen binding portion thereof of claim 1 , wherein the light chain variable region comprises an amino acid sequence having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NOs: 30 or 36.
  4. 4 . The isolated monoclonal antibody or the antigen binding portion thereof of claim 2 , wherein the heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to (1) SEQ ID NOs: 29 and 30, respectively; or (2) SEQ ID NOs: 35 and 36, respectively.
  5. 5 . An isolated monoclonal antibody or an antigen binding portion thereof, capable of binding to B7-H3, comprising i) a heavy chain variable region, wherein the heavy chain variable region comprises a VH CDR1 region, a VH CDR2 region and a VH CDR3 region, wherein the VH CDR1 region, the VH CDR2 region and the VH CDR3 region have identity to a VH CDR1 region, a VH CDR2 region and a VH CDR3 region of a specified VH sequence, respectively; and/or ii) a light chain variable region, wherein the light chain variable region comprises a VL CDR1 region, a VL CDR2 region and a VL CDR3 region, wherein the VL CDR1 region, the VL CDR2 region, and the VL CDR3 region have identity to a VL CDR1 region, a VL CDR2 region and a VL CDR3 region of a specified VL sequence, respectively, wherein the specified VH sequence and the specified VL sequence are selected from the group consisting of (1) the specified VH sequence and the specified VL sequence set forth in SEQ ID NOs: 29 and 30, respectively; (2) the specified VH sequence and the specified VL sequence set forth in SEQ ID NOs: 35 and 36, respectively.
  6. 6 . The isolated monoclonal antibody or the antigen binding portion thereof of claim 1 , comprising a heavy chain constant region and a light chain constant region, wherein the heavy chain constant region is a human IgG1 constant region, and the light chain constant region is a human κ constant region.
  7. 7 . The isolated monoclonal antibody or the antigen binding portion thereof of claim 6 , wherein the heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 44, and the light chain constant region comprises the amino acid sequence of SEQ ID NO: 45.
  8. 8 . The isolated monoclonal antibody or the antigen binding portion thereof of claim 1 , which is an afucosylated monoclonal antibody or an antigen binding portion thereof.
  9. 9 . The isolated monoclonal antibody or the antigen binding portion thereof of claim 1 , which is able to (a) bind to human B7-H3, (b) bind to monkey B7-H3, (c) bind to mouse B7-H3, (d) bind to B7-H3 + cells, (e) activate immune cells, (f) induce antibody dependent cell mediated cytotoxicity against B7-H3 + cells, and/or (g) provide in vivo anti-tumor effect.
  10. 10 . (canceled)
  11. 11 . A nucleic acid molecule encoding the isolated monoclonal antibody or the antigen binding portion thereof of claim 1 .
  12. 12 . A pharmaceutical composition, comprising the isolated monoclonal antibody or the antigen binding portion thereof of claim 1 , and a pharmaceutically acceptable carrier.
  13. 13 . A method for treating a B7-H3 associated disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 12 .
  14. 14 . The method of claim 13 , wherein the B7-H3 associated disease is a B7-H3 + tumor.
  15. 15 . The method of claim 14 , wherein the tumor is selected from the group consisting of breast cancer, melanoma, prostate cancer, head and neck squamous cell carcinoma, lung cancer, non-small cell lung cancer, central nervous system neuroblastoma, glioblastoma, desmoplastic small round cell tumor, diffuse pontine glioma, medulloblastoma, pancreatic cancer, liver cancer, colorectal cancer, non-Hodgkin lymphoma, esophageal cancer, ovarian cancer, bladder cancer, small cell carcinoma, endometrial cancer, kidney cancer, gastric cancer, acute myeloid leukemia, hepatocellular carcinoma, hypopharyngeal squamous cell carcinoma, and urothelial cell carcinoma.
  16. 16 . A method for enhancing an immune response in a subject in need thereof, comprising administering to the subject an effective amount of the isolated monoclonal antibody or the antigen binding portion thereof of claim 1 .
  17. 17 . The method of claim 16 , wherein the enhancement of an immune response includes activation of immune cells.
  18. 18 . An expression vector, comprising the nucleic acid molecule of claim 11 .
  19. 19 . A host cell, comprising the expression vector of claim 17 .

Description

FIELD OF THE INVENTION The present application relates to an antibody specifically binding human B7-H3, and its preparation and uses, especially its use in treating B7-H3 associated diseases such as cancers. BACKGROUND OF THE INVENTION T cell proliferation and activation rely on dual signals. The interaction between the T cell receptor with the peptide presented by the MHC on an antigen-presenting cell or a tumor cell provides the first signal which is essential for T cell activation but does not induce cell proliferation or cytokine release. The second signal, i.e., the co-stimulatory signal, determines T cells undergo activation/proliferation, unresponsiveness, or apoptosis. The B7-CD28 co-stimulatory signaling pathway plays an important role in regulation of T cell activation and suppression, wherein the CD28 molecules are expressed on T cells while the B7 molecules are generally present on activated antigen-presenting cells. Till now more than 10 B7 proteins have been discovered and are divided into 3 groups according to the signals and functions they transduce during T cell activation, i.e., i) co-stimulatory, ii) co-inhibitory, and iii) co-stimulatory/inhibitory. B7-H3, also known as CD276, is a co-stimulatory/inhibitory molecule of the B7 family. When initially discovered, it was deemed as a co-stimulatory molecule that promotes T cell activation and IFN-γ production. However, studies in recent years suggest that the B7-H3 plays an inhibitory role in adaptive immunity, e.g., to suppress T cell activation/proliferation or release of effector cytokines (mainly IFN-γ and IL-2), to inhibit NK cell activity, and etc. (Prasad DVR. et al., (2004) J Immunol 173(4):2500-2506; Castriconi R. et al., (2004) Proc Natl Acad Sci USA 101(34):12640-12645). B7-H3's seemingly contradictory regulatory activity may be mediated by different receptors, but only a few researches have been done for B7-H3 receptors. B7-H3 is a type I transmembrane protein, sharing 20%-27% similarity to the other B7 family members. It is encoded by the gene located on chromosome 15q24, and contains an extracellular domain, a transmembrane domain, and a short intracellular domain. The intracellular domain is quite short and is not known to have any signaling motif. In addition, the human B7-H3 protein may contain one or two pairs of extracellular domains due to exon duplication, resulting in two subtypes, i.e., 2IgB7-H3 and 4IgB7-H3. The previous one subtype contains one pair of immunoglobulin variable region (IgV)-like and immunoglobulin constant region (IgC)-like extracellular domains, while the latter one contains two pairs of identical IgV-like and IgC-like extracellular domains, and is the main subtype found in human cells. The B7-H3 mRNAs are ubiquitously expressed in normal tissues, while the B7-H3 protein molecules are lowly expressed in only a few tissues (Flem-Karlsen K. et al., (2018) Trends Cancer 4(6):401-404). For example, weak staining was found in the cytoplasm of salivary gland acinar cells, gastric epithelial cells, and adrenal gland cells, and also weak staining was found in the basement membrane of stomach, gallbladder, prostate, cervix and endometrium. The B7-H3 proteins are highly expressed by several malignant tumors. Various studies have shown that the B7-H3 molecules are expressed in 33.0% of the renal cell carcinoma patients and 91.8% of hepatocellular carcinoma patients. It should be noted that the percent of patients with B7-H3 expression is quite low in renal cell carcinoma and systemic hematologic cancers (33.0% and 36.7% respectively, p<0.001) while at least 52.3% of patients of other solid cancers have B7-H3 expression. Among the gastrointestinal cancers, the percent of patients with B7-H3 expression is the highest in hepatocellular carcinoma (91.8%), and the lowest in gastric cancer (58.0%). Among the malignant urogenital cancers, the percent of patients with B7-H3 expression is the lowest in renal cell carcinoma and the highest in ovarian cancer (88.3%). Among all the cancers, 59.5% of the patients (15877/26703) are B7-H3 positive. On one hand, it was found that the pancreatic cancer patients with high B7-H3 expression have better prognosis after surgeries than those with low B7-H3 expression (Loos M. et al., (2009) BMC Cancer 9: 463). On the other hand, it is believed B7-H3 contributes to immunosuppressive tumor microenvironment, promoting cancer stem cells in e.g., squamous cell carcinoma evade from immune surveillance (Wang C. et al., (2021) Cell Stem Cell 28(9): 1597-1613; Jin M Z, Jin W L., (2020) Signal Transduct Target Ther 5(1): 166). B7-H3 also promotes cancer occurrence and development by several non-immune pathways. For example, it induces VEGFA expression in colorectal cancer cells, promotes epithelial-to-mesenchymal transition in colorectal cancer, and fuels the tumors by triggering aerobic glycolysis (Wang R Q et al., (2020) Cell Death Dis (2020) 11(1):55; Jiang B. et al., (2016) Oncotarget 7(22):