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BR-112020022482-B1 - COMPOSITION, ANTI-CD24 ANTIBODY, BIOSPECIFIC ANTIBODY AND CHIMERIC ANTIGEN RECEPTOR

BR112020022482B1BR 112020022482 B1BR112020022482 B1BR 112020022482B1BR-112020022482-B1

Abstract

The present invention relates to anti-CD24 antibodies that selectively bind to human CD24 expressed on cancer cells, but not to human CD24 expressed on non-cancerous cells, and the use of such antibodies in cancer therapy.

Inventors

  • Yang Liu
  • Pan Zheng
  • RHONDA FLORES
  • HUNG-YEN CHOU
  • ZHIHONG XUE
  • PEIYING YE
  • Martin DEVENPORT

Assignees

  • Children's Research Institute, Children's National Medical Center
  • OncoC4, Inc

Dates

Publication Date
20260310
Application Date
20190513
Priority Date
20180514

Claims (8)

  1. 1. Anti-CD24 antibody, characterized in that the antibody comprises (a) a variable heavy chain region comprising the sequence presented in SEQ ID NO: 31 or 30 and a variable light chain region comprising the sequence presented in SEQ ID NO: 35; or (b) a variable heavy chain region comprising the sequence presented in SEQ ID NO: 6 and a variable light chain region comprising the sequence presented in SEQ ID NO: 16.
  2. 2. Anti-CD24 antibody, according to claim 1, characterized in that it further comprises a constant (Fc) region of human immunoglobulin.
  3. 3. Anti-CD24 antibody, according to claim 1, characterized in that the variable region of the heavy chain comprises the sequence presented in SEQ ID NO: 6 and the variable region of the light chain comprises the sequence presented in SEQ ID NO: 16.
  4. 4. Anti-CD24 antibody, according to claim 1, characterized in that the variable region of the heavy chain comprising the sequence presented in SEQ ID NO: 30 and a variable region of the light chain comprising the sequence presented in SEQ ID NO: 35.
  5. 5. Anti-CD24 antibody, according to claim 1 or 2, characterized in that the variable region of the heavy chain comprising the sequence presented in SEQ ID NO: 31 and the variable region of the light chain comprising the sequence presented in SEQ ID NO: 35.
  6. 6. Bispecific antibody, characterized in that it comprises a first antibody domain comprising the anti-CD24 antibody, as defined in claim 1, and a second antibody domain comprising a second antibody or antigen-binding fragment thereof, wherein the biospecific antibody comprises the sequences presented in SEQ ID NOs: 17 and 18, or any of the sequences presented in SEQ ID NOs: 23-27 and 37-41.
  7. 7. Chimeric antigen receptor, characterized in that it comprises a single-chain antibody comprising anti-CD24 antibody, as defined in claim 1, wherein the chimeric antigen receptor comprises the sequence presented in SEQ ID NO: 28.
  8. 8. Composition, characterized in that it comprises the anti-CD24 antibody, as defined in claim 1.

Description

Field of Invention [001] The present invention relates to anti-CD24 antibodies that selectively bind to human CD24 expressed on cancer cells, but not to human CD24 expressed on non-cancerous cells. This invention also relates to the use of such antibodies in cancer therapy. Background of the Invention [002] CD24 is a mucin-like, highly glycosylated glycosylphosphatidylinositol (GPI)-linked cell surface protein. CD24 is expressed at higher levels in hematopoietic cells, including B cells, T cells, neutrophils, eosinophils, dendritic cells, and macrophages, as well as in non-hematopoietic cells, including neural cells, ganglion cells, epithelial cells, keratinocytes, muscle cells, pancreatic cells, and epithelial stem cells. In general, CD24 tends to be expressed at higher levels in progenitor cells and metabolically active cells, and to a lesser extent in terminally differentiated cells. The function of CD24 is not yet clear in most cell types, but diverse immunological functions of CD24 have been reported. [003] Although CD24 is found in many normal tissues and cell types, CD24 is overexpressed in nearly 70% of human cancers. High levels of CD24 expression detected by immunohistochemistry have been found in epithelial ovarian cancer (83%), breast cancer (85%), non-small cell lung cancer (45%), prostate cancer (48%), and pancreatic cancer (72%). CD24 is one of the most overexpressed proteins in cancer cells. CD24 expression is upregulated during tumorigenesis, suggesting its role in tumor progression and metastasis. CD24 overexpression in cancer has also been identified as an indicative marker of poor prognosis and a more aggressive disease course for cancer patients. In breast cancer, CD24 expression is significantly higher in invasive carcinoma than in benign or precancerous lesions. In non-small cell lung cancer, CD24 expression has been identified as an independent marker for overall patient survival. Furthermore, in esophageal squamous cell carcinoma, CD24 overexpression is suggestive of lymph node metastasis, low-grade tumor, and reduced survival time. Similar observations have been found in many other cancer types, including colon cancer, hepatocellular carcinoma, glioma, ovarian cancer, and prostate cancer. Although CD24 has been widely used as a prognostic marker, it has not yet been utilized as a neoantigen that could be a potential target for cancer therapy due to its expression in normal cancer types and potential toxicity. [004] Mature CD24 is a small, highly glycosylated 31-amino acid sialoglycoprotein with 16 potential O-glycosylation sites and 2 predicted N-glycosylation sites. Glycosylation is one of the most complex post-translational modifications of proteins. A deviation from the normal glycosylation pathway is known to occur in many cancer cells, leading to altered glycan expression and resulting in hyperglycosylation or hypoglycosylation of many cellular proteins. The altered glycosylation patterns found in cancer cells are the result of many contributing factors, including transcriptional dysregulation, dysregulation of chaperone-like proteins during glycosylation, and altered glycosidase and glycotransferase activities. Tumor-associated glycan alterations include longer or shorter branching of N-glycans, higher or lower density of O-glycans, production of truncated versions of normal counterparts (Tn, sTn, and T antigens), and production of rare forms of terminal structures with sialic acid and fucose (sLea and sLex epitopes). [005] Therefore, improved ways of identifying and treating cancer are needed in the literature, in particular methods and compositions capable of differentiating cancerous cells from non-cancerous cells. Summary of the Invention [006] The present invention relates to a monoclonal anti-CD24 antibody whose binding to CD24 is blocked by glycosylation present in normal cells, but not in cancer cells. The antibody therein can bind to a glycan-shielded epitope that is exposed in cancer cells, but not in non-cancerous cells. The antibody can bind to an epitope comprising the sequence shown in SEQ ID NO: 48. [007] In another aspect, the monoclonal antibody can bind to cancer cells with minimal or no reactivity to non-cancerous cells. [008] In another aspect, the monoclonal antibody can bind to tumor cells with minimal or no reactivity to non-tumor cells. [009] In another aspect, the monoclonal antibody can bind to circulating cancer cells with minimal or no reactivity to hematopoietic cells. [0010] In another aspect, the monoclonal antibody cannot bind to CD24 in cells without cancer-specific glycosylation patterns, but it can bind to CD24 in cells with cancer-specific glycosylation patterns. [0011] In another aspect, a composition, which may be a pharmaceutical composition, comprises the monoclonal antibody, or one or more antigen-binding fragments thereof. [0012] In another aspect, the composition is used to destroy cancer cells through antibody-mediated cellular cyto