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WO-2026095745-A1 - NOVEL ANTIBODIES OR ANTIGEN-BINDING FRAGMENTS THEREOF DERIVED FROM PLASMA CELLS IN CANCER TISSUES, AND USES THEREOF

WO2026095745A1WO 2026095745 A1WO2026095745 A1WO 2026095745A1WO-2026095745-A1

Abstract

The present invention relates to novel antibodies or antigen-binding fragments thereof derived from plasma cells in cancer tissues of cancer patients, and uses thereof, and does not bind to normal cells and exhibits the activity of specifically binding to antigens of cancer cells. Therefore, the antibodies or antigen-binding fragments thereof can be effectively used in the diagnosis of cancer and, when bound to drugs such as an anticancer agent, the antibodies or antigen-binding fragments thereof can also be effectively used in the prevention or treatment of cancer and the like. In addition, the antibodies or antigen-binding fragments thereof are human antibodies or antigen-binding fragments thereof derived from plasma cells in the cancer tissues of cancer patients, and thus can be safely used in the diagnosis, prevention, or treatment of human breast cancer without having to undergo humanization in which specific amino acids of the variable region of the antibody are substituted in order to avoid or minimize an immune response in humans.

Inventors

  • SUNG, Chang Ohk
  • LEE, HEE JIN
  • KIM, WONKYUNG
  • OH, JI HYE
  • PARK, CHAEWON

Assignees

  • 재단법인 아산사회복지재단
  • 울산대학교 산학협력단

Dates

Publication Date
20260507
Application Date
20251104
Priority Date
20241104

Claims (16)

  1. A heavy chain variable region comprising CDR1-H having the amino acid sequence of SEQ ID NO. 1 or SEQ ID NO. 2, CDR2-H having the amino acid sequence of SEQ ID NO. 3 or SEQ ID NO. 4, and CDR3-H having the amino acid sequence of SEQ ID NO. 5 or SEQ ID NO. 6; and A light chain variable region comprising a CDR1-L having the amino acid sequence of SEQ ID NO. 7 or SEQ ID NO. 8, a CDR2-L having the amino acid sequence of SEQ ID NO. 9 or SEQ ID NO. 10, and a CDR3-L having the amino acid sequence of SEQ ID NO. 11 or SEQ ID NO. 12; comprising Antibody or its antigen-binding fragment.
  2. A heavy chain variable region comprising the amino acid sequence of SEQ ID NO. 13 or SEQ ID NO. 14; and A light chain variable region comprising the amino acid sequence of SEQ ID NO. 15 or SEQ ID NO. 16; comprising Antibody or its antigen-binding fragment.
  3. A heavy chain comprising the amino acid sequence of SEQ ID NO. 17 or SEQ ID NO. 18; and A light chain comprising the amino acid sequence of SEQ ID NO. 19 or SEQ ID NO. 20; comprising Antibody or its antigen-binding fragment.
  4. In any one of claims 1 to 3, An antibody or its antigen-binding fragment, wherein the antigen-binding fragment of the above antibody is a single-chain variable fragment (scFv).
  5. In any one of claims 1 to 3, The antibody or its antigen-binding fragment is an antibody or its antigen-binding fragment derived from cancer tissue.
  6. In any one of claims 1 to 3, The antibody or its antigen-binding fragment is an antibody or its antigen-binding fragment derived from plasma cells within cancer tissue.
  7. In any one of claims 1 to 3, The antibody or its antigen-binding fragment is an antibody or its antigen-binding fragment that specifically binds to cancer cell antigens.
  8. A gene encoding the antibody of any one of claims 1 to 3 or the antigen-binding fragment thereof.
  9. A recombinant expression vector comprising the gene of claim 8.
  10. A transformant in which the recombinant expression vector of claim 9 is introduced into a host cell.
  11. A method for producing an antibody that specifically binds to a cancer cell antigen or an antigen-binding fragment thereof, comprising the step of culturing the transformant of claim 9.
  12. A pharmaceutical composition for the prevention or treatment of cancer comprising, as an active ingredient, an antibody of any one of claims 1 to 3 or a binding fragment thereof.
  13. In claim 12, A pharmaceutical composition for the prevention or treatment of cancer, wherein the above cancer is breast cancer.
  14. a) a step of obtaining a tumor tissue sample and performing single-cell transcriptome sequencing; b) a step of identifying plasma cell clusters by analyzing the transcriptome sequencing data obtained in step a) above; and c) a step of selecting a clone having a full-length immunoglobulin sequence from the above plasma cell cluster; comprising, Method for screening plasma cell-derived antibodies within tumor tissue.
  15. In claim 14, In step b) above, the plasma cells are differentiated by stimulation of CD4 T cells and cancer cells.
  16. In claim 14, A method in which, in step b) above, the plasma cell is a clonally expanded plasma cell.

Description

Novel antibodies derived from plasma cells in cancer tissue or their antigen-binding fragments, and their uses Cross-citation with related applications This application claims the benefit of priority based on Korean Patent Application No. 10-2024-0154663 filed November 4, 2024, and all contents disclosed in the document of said Korean Patent Application are incorporated herein as part of this specification. Technology field The present invention relates to a novel antibody derived from plasma cells in cancer tissue or an antigen-binding fragment thereof, and the use thereof. Recently, as the effectiveness of immunotherapy for cancer patients has been verified, attempts to expand its application to anticancer treatment are continuing. However, one of the biggest challenges in anticancer immunotherapy is discovering targets or antibodies that are not expressed in normal cells but are specifically expressed only in cancer cells. This is because B cells recognize antigens through the B cell receptor (BCR), and since the diversity of the BCR can be set very high due to V(D)J recombination, somatic hypermutation, class switch recombination, etc., it is difficult to discover targets or antibodies that are expressed only in cancer cells. Plasma cells refer to B cells that have differentiated to produce large quantities of antibodies that match the structure of the B cell receptor (BCR) in response to stimulation by antigens and T cells. Theoretically, it is known that there are more than 10¹³ types of antibodies that can be produced in human plasma cells, due to the diversity of BCRs. Meanwhile, since the advancement of sequencing technology enabled single-cell RNA sequencing, it has been revealed that specific tumor-infiltrating T cells perform major functions in various cancers. However, regarding plasma cells that differentiate from B cells to produce antibodies, research on tumor-infiltrating plasma cells present within tumor microtissues is currently lacking. Plasma cell infiltration within tumor microtissues has been reported to be associated with favorable prognoses in various cancers, which may imply that plasma cells perform anti-tumor functions by producing specific antibodies. Against this technical background, the applicant performed single-cell sequencing on the cancer tissue of a cancer patient and performed transcriptome sequencing of plasma cells. Through this, antibodies secreted from plasma cells within the cancer tissue were derived, and it was confirmed that these antibodies bind specifically only to cancer tissue. Therefore, the novel antibody of the present invention is expected to be useful for the diagnosis, prevention, or treatment of cancer. Figure 1 shows a schematic diagram of B cells and T cells in tumor tissue and plasma cells that secrete antibodies. Figure 2 shows a schematic diagram of performing scRNA-GEX sequencing and scRNA-BCR sequencing from cancer tissues of three breast cancer patients. Figure 3 shows a plasma cell cluster identified through scRNA-GEX sequencing. Figure 4 shows immunoglobulin pairs in plasma cells and B cells. Figure 5 shows the immunoglobulin frequency and binding type in plasma cells and B cells. Figures 6a to 6c show a list of differentially expressed genes in IgG-positive plasma cells compared to IgM-positive plasma cells or Naive B cells. Figure 7 shows the strength of ligand-receptor interactions between B cells, CD4 T cells, and cancer cells. Figure 8 shows MHC-II pathway-related interactions between CD4 T cells and cancer cells, and between CD4 T cells and B cells. Figure 9 shows that the MHC-II pathway is activated by HLA-DRB1 and HLA-DRA, etc., within tumor tissue. Figure 10 shows the expression levels of CD40-CD40LG ligand and receptor genes in B cells and CD4 T cells. Figure 11 shows the results of cluster analysis for B cells. Figure 12 shows the results of a virtual time trajectory analysis for naive B cells. Figure 13 shows the IGHG1 expression and HLA-DRA expression levels in B cells and plasma cells. Figure 14 shows the results of the plasma cell clone analysis and six plasma cell clones for antibody production. Figure 15 shows the results of a virtual time trajectory analysis for the Ab#1 clone. Figure 16 shows the clonal frequency of B cells and plasma cells. Figure 17 shows six antibodies derived from a plasma cell clone. Figure 18 shows the results of immunostaining on immune and epithelial cells obtained from the patient's tonsil tissue. Figure 19a shows the results of immunostaining of the Ab#1 antibody in cancer tissue. Figure 19b shows the results of immunostaining of the Ab#1 antibody in normal cells surrounding the cancer tissue. Figure 20 shows the results of immunostaining of the Ab#2 antibody in cancer tissue. Figure 21 shows the results of immunostaining of antibodies Ab#3 to Ab#6 in cancer tissue. First, the terms used in the specification of the present invention will be explained. The term "antibody" as used in the present in