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EP-4087879-B1 - ANTI-MUCI-SEA ANTIBODIES

EP4087879B1EP 4087879 B1EP4087879 B1EP 4087879B1EP-4087879-B1

Inventors

  • RUBINSTEIN, DANIEL
  • WRESCHNER, DANIEL

Dates

Publication Date
20260506
Application Date
20210311

Claims (18)

  1. An isolated monoclonal antibody or antigen-binding fragment thereof which binds to the MUC1 SEA domain, wherein said antibody comprises: a heavy chain complementarity determining region (CDRH) 1 denoted by SEQ ID NO. 25, CDRH2 denoted by SEQ ID NO. 26, CDRH3 denoted by SEQ ID NO. 27, and a light chain complementarity determining region (CDRL) 1 denoted by SEQ ID NO. 28, a CDRL2 denoted by SEQ ID NO. 29, and a CDRL3 denoted by SEQ ID NO. 30.
  2. The isolated monoclonal antibody or antigen-binding fragment thereof according to claim 1, wherein said antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein: said heavy chain variable region is encoded by a nucleic acid sequence which is at least 70% identical to the nucleic acid sequence denoted by SEQ ID NO. 1 and wherein said light chain variable region is encoded by a nucleic acid sequence which is at least 70% identical to SEQ ID NO. 2.
  3. The isolated monoclonal antibody or antigen binding fragment according to claim 2 wherein said heavy chain variable region is encoded by a nucleic acid sequence which is at least 80% identical to the nucleic acid sequence denoted by SEQ ID NO. 1 and wherein said light chain variable region is encoded by a nucleic acid sequence which is at least 80% identical to SEQ ID NO. 2.
  4. The isolated monoclonal antibody or antigen binding fragment according to claim 2 wherein said heavy chain variable region is encoded by a nucleic acid sequence which is at least 90% identical to the nucleic acid sequence denoted by SEQ ID NO. 1 and wherein said light chain variable region is encoded by a nucleic acid sequence which is at least 90% identical to SEQ ID NO. 2
  5. The isolated monoclonal antibody according to any one of claims 1 to 4, wherein said antibody comprises: a heavy chain variable region comprising the amino acid sequence denoted by SEQ ID NO. 13 or a variant thereof and a light chain variable region comprising the amino acid sequence denoted by SEQ ID NO. 14, or a variant thereof.
  6. The isolated monoclonal antibody or antigen-binding fragment thereof according to any one of claims 1 to 4, wherein said antibody is a mouse antibody, a chimeric antibody, a humanized antibody, or wherein said antigen-binding fragment thereof is Fv, single chain Fv (scFv), single chain Fv-Fc (scFv-Fc), Fab', Fab, F(ab') 2 or F(ab) 2 .
  7. An isolated nucleic acid molecule or expression vector comprising a nucleotide sequence encoding an antibody or any antigen-binding fragment thereof according to any one of claims 1-6.
  8. An isolated host cell transfected with the expression vector according to claim 7.
  9. An immunoconjugate comprising the antibody or antigen-binding fragment thereof according to any one of claims 1-6 and an additional cytotoxic or therapeutic agent.
  10. The immunoconjugate according to claim 9 wherein said cytotoxic agent is selected from a group consisting of alkylating drugs, anthracyclines, pyrimidine derivatives, vinca alkaloids, photodynamic drugs, platinum-containing compounds, taxanes, topoisomerase inhibitors, ribosome inactivating agents, agents that induce DNA damage, tubulin inhibitors, anti-mitotic agents, radioisotopes, cytotoxic antibodies and bacterial toxins and pseudomonas exotoxin.
  11. A bispecific antibody comprising the antibody or antigen-binding fragment thereof according to any one of claims 1-6 and a second antibody binding a different antigen target.
  12. A pharmaceutical composition comprising as an active ingredient the isolated monoclonal antibody or antigen-binding fragment thereof according to any one of claims 1-6, or immunoconjugate according to any one of claims 9 or 10, the bispecific antibody of claim 11 and a pharmaceutically acceptable carrier, excipient, or diluent, optionally comprising an additional therapeutic agent.
  13. A therapeutically effective amount of at least one isolated monoclonal antibody or antigen-binding fragment thereof according to any one of claims 1-6, or the immunoconjugate according to any one of claims 9 or 10, the bispecific antibody of claim 11, or the pharmaceutical composition according to claim 12 for use in the treatment or amelioration of a disease or disorder.
  14. The therapeutically effective amount for use according to claim 13, wherein said disease or disorder is a MUC1 expressing cancer.
  15. The therapeutically effective amount for use according to claim 14, wherein said cancer is selected from the group consisting of, lung carcinoma, prostate carcinoma, breast carcinoma, ovarian carcinoma, colon carcinoma, pancreatic carcinoma, multiple myeloma, and acute myelogenous leukemia.
  16. A method of diagnosing a disease or disorder in a subject, wherein said disease or disorder is associated with MUC-1 expression, said method comprising: a. contacting a biopsy obtained from said patient with at least one isolated monoclonal antibody or antigen-binding fragment thereof according to any one of claims 1-6; and b. detecting said isolated monoclonal antibody or any antigen-binding fragment thereof; wherein detection of cells over-expressing MUC1 SEA in the biopsy indicates that the subject is diagnosed with said disease or disorder.
  17. An isolated anti-MUC1 SEA monoclonal antibody or antigen-binding fragment thereof according to any one of claims 1-6 for use as an imaging agent to image a disease or disorder associated with MUC1 expression in a subject in need thereof, wherein said antibody or antigen-binding fragment thereof are detectably labelled with a radioisotope or a visualizable agent in order to be visualized, and wherein the detection of cells and/or tissues labelled with said isotope or visualizable agent indicates the presence, the location and/or extent of metastases of said disease or disorder in said subject.
  18. The isolated anti-MUC1 SEA monoclonal antibody or antigen-binding fragment thereof for use according to claim 17 wherein said disease or disorder is a MUC1 expressing cancer.

Description

TECHNOLOGICAL FIELD The present invention relates to antibodies specifically directed against the junction of the alpha and beta chains (which comprises the SEA domain) of MUC1, a glycoprotein present on the cell surface of human cells and to methods and uses thereof in the detection and treatment of cancer, as well as in the detection and treatment of a variety of non-malignant diseases and disorders. BACKGROUND ART References considered to be relevant as background to the presently disclosed subject matter are listed below: [1] G. Rivalland, B. Loveland, P. Mitchell, Update on Mucin-1 immunotherapy in cancer: a clinical perspective, Expert Opin Biol Ther, 15 (2015) 1773-1787.[2] J. Taylor-Papadimitriou, J.M. Burchell, R. Graham, R. Beatson, Latest developments in MUC1 immunotherapy, Biochem Soc Trans, 46 (2018) 659-668.[3] J.M. Burchell, A. Mungul, J. Taylor-Papadimitriou, O-linked glycosylation in the mammary gland: changes that occur during malignancy, J Mammary Gland Biol Neoplasia, 6 (2001) 355-364.[4] W. Fiedler, S. DeDosso, S. Cresta, J. Weidmann, A. Tessari, M. Salzberg, B. Dietrich, H. Baumeister, S. Goletz, L. Gianni, C. Sessa, A phase I study of PankoMab-GEX, a humanised glyco-optimised monoclonal antibody to a novel tumour-specific MUC1 glycopeptide epitope in patients with advanced carcinomas, Eur J Cancer, 63 (2016) 55-63.[5] K. Ryuko, D.J. Schol, F.G. Snijdewint, S. von Mensdorff-Pouilly, R.J. Poort-Keesom, Y.A. Karuntu-Wanamarta, R.A. Verstraeten, K. Miyazaki, P. Kenemans, J. Hilgers, Characterization of a new MUC1 monoclonal antibody (VU-2-G7) directed to the glycosylated PDTR sequence of MUC1, Tumour Biol, 21 (2000) 197-210.[6] M.A. Tarp, A.L. Sorensen, U. Mandel, H. Paulsen, J. Burchell, J. Taylor-Papadimitriou, H. Clausen, Identification of a novel cancer-specific immunodominant glycopeptide epitope in the MUC1 tandem repeat, Glycobiology, 17 (2007) 197-209.[7] D. Zhou, L. Xu, W. Huang, T. Tonn, Epitopes of MUC1 Tandem Repeats in Cancer as Revealed by Antibody Crystallography: Toward Glycopeptide Signature-Guided Therapy, Molecules, 23 (6) (2018) 1326.[8] T. Kimura, O.J. Finn, MUC1 immunotherapy is here to stay, Expert Opin Biol Ther, 13 (2013) 35-49.[9] N.K. Ibrahim, K.O. Yariz, I. Bondarenko, A. Manikhas, V. Semiglazov, A. Alyasova, V. Komisarenko, Y. Shparyk, J.L. Murray, D. Jones, S. Senderovich, A. Chau, F. Erlandsson, G. Acton, M. Pegram, Randomized phase II trial of letrozole plus anti-MUC1 antibody AS1402 in hormone receptor-positive locally advanced or metastatic breast cancer, Clin Cancer Res, 17 (2011) 6822-6830.[10] D.B. Rubinstein, M. Karmely, R. Ziv, I. Benhar, O. Leitner, S. Baron, B.Z. Katz, D.H. Wreschner, MUC1/X protein immunization enhances cDNA immunization in generating anti-MUC1 alpha/beta junction antibodies that target malignant cells, Cancer Res, 66 (2006) 11247-11253.[11] E. Pichinuk, I. Benhar, O. Jacobi, M. Chalik, L. Weiss, R. Ziv, C. Sympson, A. Karwa, N.I. Smorodinsky, D.B. Rubinstein, D.H. Wreschner, Antibody targeting of cell-bound MUC1 SEA domain kills tumor cells, Cancer Res, 72 (2012) 3324-3336.[12] D.B. Rubinstein, M. Karmely, E. Pichinuk, R. Ziv, I. Benhar, N. Feng, N.I. Smorodinsky, D.H. Wreschner, The MUC1 oncoprotein as a functional target: immunotoxin binding to alpha/beta junction mediates cell killing, Int J Cancer, 124 (2009) 46-54.[13] D.V. Gold, Z. Karanjawala, D.E. Modrak, D.M. Goldenberg, R.H. Hruban, PAM4-reactive MUC1 is a biomarker for early pancreatic adenocarcinoma, Clin Cancer Res, 13 (2007) 7380-7387. Acknowledgement of the above references herein is not to be inferred as meaning that these are in any way relevant to the patentability of the presently disclosed subject matter. BACKGROUND The MUC1 glycoprotein is over-expressed by a variety of high-incidence, high-mortality human epithelial malignancies, including breast, prostate, pancreas, ovarian, lung, and colon carcinomas, as well as by the malignant plasma cells of multiple myeloma, and by the myelogenous cells of acute myelogenous leukemia. Because of its preferentially high expression by malignant cells, and because it is expressed on the cell surface and therefore is an exposed molecule, MUC1 has been studied as both a target for directed cancer therapy and as a marker of disease progression [1, 2]. Structurally, the MUC1 molecule is a transmembrane glycoprotein (termed MUC-TM). MUC-TM is a heterodimer consisting of an extracellular domain containing between 20 to 125 repeats of a 20 amino acid-long sequence (termed the variable number tandem repeat, VNTR), a transmembrane domain, and a short cytoplasmic tail mediating intracellular signaling (see Figure 1A). The MUC1 molecule is auto-proteolytically cleaved within the SEA module, a highly-conserved domain of 120 amino acids. This results in a large extracellular α subunit containing the tandem repeat array bound in a strong non-covalent interaction to a transmembrane β subunit containing the transmembrane and cytoplasmic d