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EP-4741015-A2 - ANTIBODY POLYPEPTIDES AND USES THEREOF

EP4741015A2EP 4741015 A2EP4741015 A2EP 4741015A2EP-4741015-A2

Abstract

The present invention provides antibody polypeptides with binding specificity for human kallikrein-2 (hK2), wherein the antibody polypeptide comprises (a) a heavy chain variable region comprising the amino acid sequences of SEQ ID NO:1 and SEQ ID NO:2 and SEQ ID NO:3 and/or (b) a light chain variable region comprising the amino acid sequences of SEQ ID NO:4 and SEQ ID NO:5 and SEQ ID NO:6, and wherein the heavy chain variable region and light chain variable region comprise framework amino acid sequences from one or more human antibodies. The invention further provides use of said antibody polypeptides in the diagnosis and treatment of prostate cancer

Inventors

  • TIMMERMAND, Pär Oskar Vilhelmsson
  • TRAN, Amanda Thuy
  • STRAND, SVEN-ERIK
  • LAMMINMÄKI, Urpo Juhani
  • SJÖSTRÖM, Kjell

Assignees

  • Janssen Biotech, Inc

Dates

Publication Date
20260513
Application Date
20141119

Claims (20)

  1. An antibody polypeptide with binding specificity for human kallikrein-2 (hK2), wherein the antibody polypeptide comprises (a) a heavy chain variable region comprising the amino acid sequences of SEQ ID NO:1 and SEQ ID NO:2 and SEQ ID NO:3; and (b) a light chain variable region comprising the amino acid sequences of SEQ ID NO:4 and SEQ ID NO:5 and SEQ ID NO:6, wherein the heavy chain variable region and light chain variable region comprise framework amino acid sequences from one or more human antibodies, and the antibody polypeptide is linked, directly or indirectly, to a cytotoxic moiety.
  2. An antibody polypeptide according to Claim 1, wherein the antibody polypeptide exhibits an enhanced therapeutic ratio compared to an antibody comprising a heavy chain amino acid sequence of SEQ ID NO: 23 and a light chain amino acid sequence of SEQ ID NO: 24.
  3. An antibody polypeptide according to Claim 1 or 2 comprising or consisting of an intact antibody or an antigen-binding fragment selected from the group consisting of Fv fragments and Fab-like fragments.
  4. An antibody polypeptide according to any one of Claims 1-3 comprising a heavy chain variable region which comprises or consists of the amino acid sequence of SEQ ID NO: 8 and a light chain variable region which comprises or consists of the amino acid sequence of SEQ ID NO: 9.
  5. An antibody polypeptide according to any one of the preceding claims further comprising a heavy chain constant region, or part thereof, and/or a light chain constant region, or part thereof.
  6. An antibody polypeptide according to Claim 5, wherein the heavy chain constant region is of an immunoglobulin subtype selected from the group consisting of IgG1, IgG2, IgG3 and IgG4.
  7. An antibody polypeptide according to Claim 5 or 6 wherein the heavy chain constant region is of an immunoglobulin subtype IgG1.
  8. An antibody polypeptide according to any one of Claims 5 to 7 comprising a heavy chain constant region which comprises or consists of the amino acid sequence of SEQ ID NO: 10 and/or a light chain constant region which comprises or consists of the amino acid sequence of SEQ ID NO: 11.
  9. An antibody polypeptide according to any one of the preceding claims comprising a heavy chain which comprises or consists of the amino acid sequence of SEQ ID NO: 12 and/or a light chain which comprises or consists of the amino acid sequence of SEQ ID NO: 13.
  10. An antibody polypeptide according to any one of the preceding claims comprising a CH1, CH2 and/or CH3 region of an IgG heavy chain, preferably an IgG1, IgG2, IgG3 or IgG4 heavy chain.
  11. An antibody polypeptide according to any one of the preceding claims wherein the antibody polypeptide further comprises a detectable moiety.
  12. An antibody polypeptide according to any one of Claims 1-11 wherein the cytotoxic moiety and/or detectable moiety is joined to the antibody polypeptide indirectly, via a linking moiety.
  13. An antibody polypeptide according to Claim 12 wherein the linking moiety is a chelator selected from the group consisting of derivatives of 1,4,7,10-tetraazacyclododecane-1,4,7,10,tetraacetic acid (DOTA), deferoxamine (DFO), derivatives of diethylenetriaminepentaacetic avid (DTPA), derivatives of S-2-(4-Isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) and derivatives of 1,4,8,11-tetraazacyclodocedan-1,4,8,11-tetraacetic acid (TETA).
  14. An antibody polypeptide according to any one of the preceding claims wherein the cytotoxic moiety comprises or consists of one or more radioisotopes.
  15. An antibody polypeptide according to Claim 14 wherein the radioisotope is selected from the group consisting of beta-emitters, auger-emitters, conversion electronemitters, alpha-emitters, and low photon energy-emitters.
  16. An antibody polypeptide according to Claim 14 or 15 wherein the radioisotope is an alpha-emitter selected from 212 Bi, 213 Bi, 223 Ac, 225 Ac, 212 Pb, 255 Fm, 223 Ra, 149 Tb and 221 At.
  17. An antibody polypeptide according to any one of Claims 14 to 16 wherein the radioisotope is 225 Ac.
  18. An isolated nucleic acid molecule encoding an antibody polypeptide according to any one of the preceding claims or component polypeptide chain thereof.
  19. A nucleic acid molecule according to Claim 18 comprising the nucleotide sequence of SEQ ID NO: 14 and/or SEQ ID NO: 15.
  20. A pharmaceutical composition comprising an antibody polypeptide according to any one of the Claims 1 to 17 and a pharmaceutically acceptable excipient, diluent or carrier.

Description

Field of the Invention This invention pertains in general to the field of therapeutic and diagnostic agents and methods, particularly in field of prostate cancer. Background Prostate cancer is at the present time the most common form of cancer among men. The prostate is a walnut-sized gland in men that produces fluid that is a component in semen. The prostate has two or more lobes, or sections, enclosed by an outer layer of tissue. The prostate is located in front of the rectum and just below the urine bladder, and surrounds the urethra. The occurrence of prostate cancer is highest in the northwestern part of Europe and in the United States. The growth of the tumour is usually a process that takes place during a long period of time. Prostate cancer is normally a mild form of cancer. In fact, the majority of men diagnosed with prostate cancer survive and recover, with only a minority of the men encountering a more aggressive form of prostate cancer, which metastasizes in an early stage. This aggressive form of prostate cancer may only be curable if it is diagnosed at an early stage, before the cancer has spread to extracapsular tissue. Today, diagnosis and monitoring of prostate cancer is typically performed by measuring the concentration of a prostate specific antigen (PSA) in the blood of the patient. If the concentration of PSA is markedly high in several consecutive measurements, performed at different points of time, the assessment is that there is a probability of prostate cancer. At this point of time a biopsy may be performed to verify prostate cancer. PSA (also known as kallikrein III) is a protein, constituted of a single chain of 237 amino acids, which is produced in the secretory cells of the prostate. These secretory cells may be found in the whole prostate gland. PSA is well established and thoroughly researched marker in respect of prostate cancer. By comparison with healthy cells the production of PSA is lower in malignant cells and higher in hyperplastic cells. It is rather contradictory that in fact the concentration of PSA is higher in blood from men suffering from prostate cancer. However, one explanation may be that the malignant cells have a deteriorated cell structure, and are therefore more permeable to PSA. Another important serine protease suitable as a target for therapy of prostate cancer is human glandular kallikrein 2 (hK2). The gene coding hK2 is located on chromosome 19, together with the gene coding for PSA. hK2 is expressed mainly in the prostate tissue, just as PSA. In the prostate, PSA is present as an inactive pro-form and is activated through the peptidase action of hK2. Immunohistochemical research in respect of hK2 has shown that hK2 is expressed in relation to the level of differentiation. This means that hK2 is expressed in a higher yield in tissue of low differentiation, such as tissue subjected to prostate cancer, and in a lower yield in tissue of high differentiation, such as tissue subjected to benign prostatic hyperplasia (BPH) which is another common prostate problem. Today's therapies of prostate cancer are surgery (e.g., radical prostatectomy), radiation therapy (including, brachytherapy and external beam radiation therapy, high-intensity focused ultrasound (HIFU), chemotherapy, oral chemotherapeutic drugs, cryosurgery (freezing the tumor), hormonal therapy (such as antiandrogen therapy), castration or combinations of the foregoing. Most of these therapies (surgery and external radiation therapy) are, however, only (or primarily) useful for treatment of primary tumours and large metastases. Chemotherapy is used for disseminated of the cancer but for most of these patients, it is a palliative effect and/or prolonged survival. Other or complementary treatment modalities are therefore necessary to achieve considerable improvements of the disseminated malignant diseases, particular in cases of micrometastases. Therapy, such as immunotherapy or radioimmunotherapy, using targeting molecules such as antibodies and fragments could give the possibility of therapy of disseminated disease. Thus, there is a need for a new therapeutic agents and methods for treating and diagnosing prostate cancer. Summary of the Invention Accordingly, the present invention seeks to mitigate, alleviate or eliminate one or more of the above-identified deficiencies in the art and disadvantages singly or in any combination and solves at least the above mentioned problems by providing a therapeutic agents and methods according to the appended patent claims. A first aspect of the present invention provides an antibody polypeptide with binding specificity for human kallikrein-2 (hK2), wherein the antibody polypeptide comprises (a) a heavy chain variable region comprising the amino acid sequences of SEQ ID NO:1 and SEQ ID NO:2 and SEQ ID NO:3 CDRH1:SDYAWNSEQ ID NO: 1CDRH2:YISYSGSTTYNPSLKSSEQ ID NO: 2CDRH3:GYYYGSGFSEQ ID NO: 3 and/or (b) a light chain variable region comprising the amino acid sequ