Search

US-20260125491-A1 - COMPOSITIONS OF LANCL1 ANTIBODIES AND METHODS OF USE THEREOF FOR TREATING LIVER CANCER

US20260125491A1US 20260125491 A1US20260125491 A1US 20260125491A1US-20260125491-A1

Abstract

Compositions containing anti-LANCL1 antibodies, functional variants thereof, and methods of use thereof, are disclosed. An exemplary anti-LANCL1 antibody has a heavy chain variable region containing the CDRs, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:8, respectively, and a light chain variable region containing the CDRs, SEQ ID NO:21, SEQ ID NO:23, SEQ ID NO:24. Another exemplary anti-LANCL1 antibody has a heavy chain variable region containing the CDRs, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9 respectively, and a light chain variable region containing the CDRs, SEQ ID NO:22, SEQ ID NO:73, SEQ ID NO:25, respectively. The antibody can be a monoclonal antibody, a human antibody, a chimeric antibody, or a humanized antibody. The disclosed compositions can be used to treat a subject in need thereof, for example a subject diagnosed with liver cancer or a subject at risk of developing liver cancer e.g., HCC.

Inventors

  • Irene Oi Lin Lui Ng
  • Yu Man Tsui
  • Chui Yee Diana O

Assignees

  • THE UNIVERSITY OF HONG KONG

Dates

Publication Date
20260507
Application Date
20250919

Claims (20)

  1. 1 . An antibody or antigen-binding fragment thereof, comprising a heavy chain variable region comprising three complementarity determining regions (CDRs) and a light chain variable region comprising three CDRs, wherein: (i) the three heavy chain variable region CDRs comprise amino acid sequences selected from the group consisting of DYYMN (SEQ ID NO:5), DINPNNGGASYNQKFKG (SEQ ID NO:6), VINPYNGHTNYNQKFKG (SEQ ID NO:7), SGDGYYFAS (SEQ ID NO:8), FPYYGSSYRVDY (SEQ ID NO:9) respectively, or a functional variant thereof; (ii) the three light chain variable region CDRs comprise amino acids sequences selected from the group consisting of RASKSVSTSGYSYMH (SEQ ID NO:21), RASQSISNNLH (SEQ ID NO:22), LVSNLES (SEQ ID NO:23), QHIRELT (SEQ ID NO:24), QQINSWPLT (SEQ ID NO:25), YASQSIS (SEQ ID NO:73), respectively, or a functional variant thereof; and wherein the antibody or antigen binding fragment thereof binds to LanC Like Glutathione S-Transferase 1 (LANCL1) protein.
  2. 2 . The antibody or antigen-binding fragment thereof of claim 1 , wherein: (i) the three heavy chain variable region CDRs comprise the amino acid sequences: DYYMN (SEQ ID NO:5), DINPNNGGASYNQKFKG (SEQ ID NO:6), SGDGYYFAS (SEQ ID NO:8), respectively, or a functional variant thereof, and the three light chain variable region CDRs comprise the amino acid sequences: RASKSVSTSGYSYMH (SEQ ID NO:21), LVSNLES (SEQ ID NO:23), QHIRELT (SEQ ID NO:24) respectively, or a functional variant thereof; or (ii) the three heavy chain variable region CDRs comprise the amino acid sequences: DYYMN (SEQ ID NO:5), VINPYNGHTNYNQKFKG (SEQ ID NO:7), FPYYGSSYRVDY (SEQ ID NO:9) respectively, or a functional variant thereof, and the three light chain variable region CDRs comprise amino acid sequences: RASQSISNNLH (SEQ ID NO:22), YASQSIS (SEQ ID NO:73), QQINSWPLT (SEQ ID NO:25), respectively, or a functional variant thereof.
  3. 3 . The antibody or antigen-binding fragment of claim 1 , wherein: (a) the three heavy chain variable region CDRs comprise amino acids SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:8, respectively or a functional variant thereof, and the three light chain variable region CDRs comprise amino acids SEQ ID NO:21, SEQ ID NO:23, SEQ ID NO:24 respectively, or a functional variant thereof; (b) the three heavy chain variable region CDRs comprise amino acids SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9 respectively, or a functional variant thereof, and the three light chain variable region CDRs comprise amino acids SEQ ID NO:22, SEQ ID NO:73, SEQ ID NO:25, respectively, or a functional variant thereof; (c) the three heavy chain variable region CDRs comprise amino acids SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9 respectively, or a functional variant thereof, and the three light chain variable region CDRs comprise amino acids SEQ ID NO:21, SEQ ID NO:23, SEQ ID NO:24 respectively, or a functional variant thereof; or (d) the three heavy chain variable region CDRs comprise amino acids SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:8 respectively, or a functional variant thereof, and the three light chain variable region CDRs comprise amino acids SEQ ID NO:22, SEQ ID NO:73, SEQ ID NO:25, respectively, or a functional variant thereof.
  4. 4 . The antibody or antigen-binding fragment of claim 1 , wherein the functional variant has about 70%, about 75%, about 80%, about 85%, about 90%, about 95% or about 99% sequence identity to SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:21, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:22, SEQ ID NO:73 or SEQ ID NO:25.
  5. 5 . The antibody or antigen-binding fragment of claim 1 , comprising a light chain variable region comprising the amino acid sequence of SEQ ID NO:19 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:3.
  6. 6 . The antibody or antigen-binding fragment of claim 1 , comprising (a) a light chain variable region comprising the amino acid sequence of SEQ ID NO:20 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:4; b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:19 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:4 or (c) a light chain variable region comprising the amino acid sequence of SEQ ID NO:20 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:3.
  7. 7 . The antibody or antigen-binding fragment of claim 1 , comprising a humanized light chain variable region comprising the amino acid sequence of SEQ ID NO:76 or a functional variant thereof and a humanized heavy chain variable region comprising the amino acid sequence of SEQ ID NO:75 or a functional variant thereof.
  8. 8 . The antibody or antigen-binding fragment of claim 11 , wherein the chain variable region variant comprises: (a) the amino acid sequence of SEQ ID NO:80, 81 or 82 and/or (b) the heavy chain variable region variant comprises the amino acid sequence of SEQ ID NO:77, 78 or 79.
  9. 9 . The antibody or antigen binding fragment thereof of claim 1 , comprising one or more constant domains from an immunoglobulin constant region (Fc), wherein the constant domains are human constant domains selected from the group consisting of IgA, IgD, IgE, IgG, or IgM, optionally, wherein human IgG constant domain is selected from the group consisting of IgG1, IgG2, IgG3, or IgG4.
  10. 10 . The antibody or antigen-binding fragment of claim 1 , wherein the antibody is a monoclonal antibody, a human antibody, a chimeric antibody, or a humanized antibody.
  11. 11 . A humanized antibody comprising one or more human IgG constant domains, a heavy chain variable region comprising three complementarity determining regions (CDRs) and a light chain variable region comprising three CDRs, comprising (a) a humanized light chain variable region comprising the an amino acid sequence selected from the group consisting of SEQ ID NO:76, 80, 81 or 82 and a humanized heavy chain variable region comprising the amino acid sequence of SEQ ID NO:75, 77, 78 or 79, wherein: (i) each heavy chain variable region comprises the three heavy chain variable region CDRs comprising amino acid sequences selected from the group consisting of: DYYMN (SEQ ID NO:5), DINPNNGGASYNQKFKG (SEQ ID NO:6), VINPYNGHTNYNQKFKG (SEQ ID NO:7), SGDGYYFAS (SEQ ID NO:8), FPYYGSSYRVDY (SEQ ID NO:9) or a functional variant thereof; (ii) each light chain variable region comprises the three light chain variable region CDRs comprise amino acid sequences selected from the group consisting of: RASKSVSTSGYSYMH (SEQ ID NO:21), RASQSISNNLH (SEQ ID NO:22), LVSNLES (SEQ ID NO:23), QHIRELT (SEQ ID NO:24), YASQSIS (SEQ ID NO:73), QQINSWPLT (SEQ ID NO:25), or a functional variant thereof; and wherein the humanized antibody or antigen binding fragment thereof binds to human LanC Like Glutathione S-Transferase 1 (LANCL1) protein.
  12. 12 . The humanized antibody of claim 11 , wherein: (i) the three heavy chain variable region CDRs comprise amino acids DYYMN (SEQ ID NO:5), DINPNNGGASYNQKFKG (SEQ ID NO:6), SGDGYYFAS (SEQ ID NO:8), respectively, or DYYMN (SEQ ID NO:5), VINPYNGHTNYNQKFKG (SEQ ID NO:7), FPYYGSSYRVDY (SEQ ID NO:9) respectively, or a functional variant thereof; and (ii) the three light chain variable region CDRs comprise amino acid sequences: RASKSVSTSGYSYMH (SEQ ID NO:21), LVSNLES (SEQ ID NO:23), QHIRELT (SEQ ID NO:24) respectively, or RASQSISNNLH (SEQ ID NO:22), YASQSIS (SEQ ID NO:73), QQINSWPLT (SEQ ID NO:25), respectively, or a functional variant thereof.
  13. 13 . The humanized antibody of claim 12 , wherein: (i) the three heavy chain variable region CDRs comprise the amino acid sequences: DYYMN (SEQ ID NO:5), DINPNNGGASYNQKFKG (SEQ ID NO:6), SGDGYYFAS (SEQ ID NO:8), respectively, or a functional variant thereof, and the three light chain variable region CDRs comprise the amino acid sequences: RASKSVSTSGYSYMH (SEQ ID NO:21), LVSNLES (SEQ ID NO:23), QHIRELT (SEQ ID NO:24) respectively, or a functional variant thereof; or (ii) the three heavy chain variable region CDRs comprise the amino acid sequences: DYYMN (SEQ ID NO:5), VINPYNGHTNYNQKFKG (SEQ ID NO:7), FPYYGSSYRVDY (SEQ ID NO:9) respectively, or a functional variant thereof, and the three light chain variable region CDRs comprise amino acid sequences: RASQSISNNLH (SEQ ID NO:22), YASQSIS (SEQ ID NO:73), QQINSWPLT (SEQ ID NO:25), respectively, or a functional variant thereof.
  14. 14 . The humanized antibody of 13 , wherein: (a) the three heavy chain variable region CDRs comprise SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:8, respectively or a functional fragment thereof, and the three light chain variable region CDRs comprise SEQ ID NO:21, SEQ ID NO:23, SEQ ID NO:24 respectively, or a functional fragment thereof; (b) the three heavy chain variable region CDRs comprise SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9 respectively, or a functional fragment thereof, and the three light chain variable region CDRs comprise SEQ ID NO:22, SEQ ID NO:73, SEQ ID NO:25, respectively, or a functional fragment thereof; or (c) the three heavy chain variable region CDRs comprise SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:8 respectively, or a functional fragment thereof, and the three light chain variable region CDRs comprise SEQ ID NO:22, SEQ ID NO:73, SEQ ID NO:25, respectively, or a functional fragment thereof.
  15. 15 . A nucleic acid encoding the antibody or antigen-binding fragment of claim 14 .
  16. 16 . A pharmaceutical composition comprising the antibody or antigen-binding fragment of claim 1 , optionally wherein the antibody or fragment thereof is a humanized antibody, and one or more pharmaceutically acceptable carriers and/or excipients.
  17. 17 . A method of treating a subject in need thereof, comprising administering to the subject, an effective amount of the pharmaceutical composition of claim 25 , optionally, the subject has a disease or disorder caused by or characterized by increased presence of LanC Like Glutathione S-Transferase 1 (LANCL1) protein or a fragment thereof, wherein the pharmaceutical composition is effective to reduce the proliferation of tumor-initiating cells, sphere formation of hepatocellular carcinoma cells, and/or blocking or reducing the activity of LANCL1.
  18. 18 . The method of claim 16 , wherein the subject has liver cancer or is at risk of developing liver cancer.
  19. 19 . The method of claim 16 , wherein the liver cancer is hepatocellular carcinoma.
  20. 20 . The method of claim 16 , wherein the pharmaceutical composition is delivered via injection or infusion.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims benefit of U.S. Provisional Application No. 63/696,454, filed Sep. 19, 2024, is hereby incorporated herein by reference in its entirety. REFERENCE TO THE SEQUENCE LISTING The Sequence Listing submitted as an XML file named “UHK_01547_US_ST26”, created Dec. 8, 2025, and having a size of 81,030 bytes is hereby incorporated by reference pursuant to 37 C.F.R. § 1.834 (c)(1). FIELD OF THE INVENTION The disclosed invention is generally in the field of liver cancer and specifically in the area of therapeutic antibodies for treating liver cancer. BACKGROUND OF THE INVENTION Hepatocellular Carcinoma (HCC) is the third leading cause of cancer deaths globally, and more specifically, the second and third leading cause of cancer deaths in China and Hong Kong, respectively. Although surgical resection and liver transplantation are available, most HCCs are diagnosed at advanced stages and thus inoperable. The median survival rate of patients with inoperable HCC is in the order of weeks. Even if operated on, the tumor recurrence rate is high. The 5-year survival rate of HCC patients, even after surgical removal of the cancer, is only ˜20%. The high mortality rate of HCC is attributed, in part, to its aggressive behavior and lack of promising curative therapy. HCC is notoriously resistant to conventional chemotherapy, hence treatments for advanced HCCs are limited. Tumor initiation is crucial in both hepatocarcinogenesis, and tumor recurrence derived from residual tumor cell population after treatment. Targeting the cell surface proteins responsible for tumor initiation is one potential strategy for cancer treatment. Existing cell surface proteins that promote liver tumor initiation include CD13, CD24, CD47, CD90, CD133, and EpCAM. However, these proteins are limited for translational applications. For example, some of these proteins have low expression in terms of either a very low percentage of positive cells in a tumor or very few patients' samples showing detectable expression (such as CD90), implicating a lesser role of the protein in HCC initiation in a certain cohort of patients. Also, some surface proteins are detectable not only in HCC tumors but also at high levels in non-tumorous liver tissues. Targeting these proteins may cause a nonspecific cytotoxic effect on the surrounding non-tumorous liver tissues. Thus, there is an urgent need for more effective therapies for precise targeting of cell surface proteins for the treatment of HCC. It is an object of the present invention to provide monoclonal antibodies that specifically bind to LanC Like Glutathione S-Transferase 1 (LANCL1) protein or a portion of human LANCL1 protein. It is also an object of the present invention to provide compositions for treating HCC in a subject in need thereof. It is also an object of the present invention to provide methods for treating HCC in a subject. It is still an object of the present invention to provide methods for inhibiting HCC tumor growth in a subject in need thereof. Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present disclosure as it existed before the priority date of each claim of this application. Throughout this specification the word “comprise,” or variations such as “comprises” or “comprising,” will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps. SUMMARY OF THE INVENTION Liver tumor-initiating cells (LTICs) are self-renewing sub-populations of cells in Hepatocellular Carcinoma (HCC) which contribute to initiation of tumors and can be considered the culprit for resistance to HCC treatment (Yi, et al., Cancer Treat Rev., 39:290-296 (2013); Visvader and Lindeman, Nat Rev Cancer, 8:755-768 (2008); Tirino et al., FASEB J., 27:13-24 (2013)). LTICs are marked by unique cell-surface markers which are functional and can activate downstream cell signaling to exert their effects. The problem is that existing LTIC markers are limited in their capability for translational applications, thereby hindering the development of therapeutic applications against LTICs for cancer therapy. The disclosed compositions and methods solve this problem by providing human monoclonal antibodies which reduce the activity of LTIC surface markers and decrease the downstream signaling pathways triggered by these surface markers, thereby decreasing initiation of hepatocellular carcinoma. It was realized that development of human monoclonal antibodies which target and inhibit the activity of LanC Like Glutathione S-Transferase 1 (LANCL1), a LTIC marker common in hepatocellular ca