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CN-122029431-A - STK 1-based therapeutic stratification

CN122029431ACN 122029431 ACN122029431 ACN 122029431ACN-122029431-A

Abstract

A method of therapeutic stratification comprising determining the level of a STK1 substance in a body fluid sample from a patient diagnosed with prostate cancer using an antibody or antigen binding fragment thereof that specifically binds to human TK1 in serum form. The method further comprises comparing the level of the STK1 material to a threshold level, selecting chemotherapy for the patient if the level of the STK1 material is at or above the threshold, and selecting Androgen Receptor Signaling Inhibitor (ARSI) therapy for the patient if the level of the STK1 material is below the threshold.

Inventors

  • K. Kumar Jagaramudi
  • G Wayne Kramer
  • S. LIND
  • T. Salvas

Assignees

  • 阿罗塞尔公司

Dates

Publication Date
20260512
Application Date
20241028
Priority Date
20231107

Claims (20)

  1. 1. A method of treating stratification, comprising: determining the level of serum thymidine kinase 1 (STK 1) material in a body fluid sample from a patient diagnosed with prostate cancer using an antibody or antigen-binding fragment thereof that specifically binds to human TK1 in serum form; comparing the STK1 material level with a threshold level, and Chemotherapy is selected for the patient if the level of the STK1 material is at or above a threshold, and Androgen Receptor Signaling Inhibitor (ARSI) therapy is selected for the patient if the level of the STK1 material is below the threshold.
  2. 2. A method according to claim 1, wherein determining the level of STK1 material comprises determining the level of STK1 material in a body fluid sample from a patient diagnosed with metastatic prostate cancer using an antibody or antigen binding fragment thereof that specifically binds to human TK1 in serum form.
  3. 3. A method according to claim 2, wherein determining the level of STK1 material comprises determining the level of STK1 material in a body fluid sample from a patient diagnosed with metastatic castration-resistant prostate cancer using an antibody or antigen binding fragment thereof that specifically binds to human TK1 in serum form.
  4. 4. The method according to any one of claims 1 to 3, wherein the chemotherapy is selected from the group consisting of docetaxel, cabazitaxel, mitoxantrone, estramustine, and any combination thereof, preferably docetaxel.
  5. 5. The method of any one of claims 1-4, wherein ARSI therapy comprises Androgen Synthesis Inhibitor (ASI) therapy, androgen Receptor Antagonist (ARA) therapy, and any combination thereof.
  6. 6. The method of claim 5, wherein the ASI is abiraterone.
  7. 7. The method of claim 5 or 6, wherein the ARA is selected from the group consisting of enzalutamide, apatamide, darostaamine, and any combination thereof.
  8. 8. The method according to any one of claims 1 to 7, wherein comparing the level of STK1 substance comprises comparing the level of STK1 with a threshold level selected from the interval of 0.5 to 0.7 μg/L, preferably from the interval of 0.55 to 0.65 μg/L, more preferably 0.61 μg/L.
  9. 9. A method according to any one of claims 1 to 8 wherein determining the level of STK1 material comprises determining the level of STK1 material in a serum sample or a plasma sample using an antibody or antigen binding fragment thereof that specifically binds to human TK1 in serum form.
  10. 10. The method of any one of claims 1 to 9, wherein determining the level of STK1 substance in the bodily fluid sample comprises: contacting the body fluid sample with an antibody or antigen binding fragment thereof that specifically binds to the serum form of human TK1, and The amount of antibody or antigen binding fragment thereof that binds to the STK1 material is measured.
  11. 11. The method of claim 10, further comprising correlating the measured amount of antibody or antigen binding fragment thereof that binds to the STK1 substance to the level of the STK1 substance.
  12. 12. A method according to claim 11, wherein correlating the measured amount of antibody or antigen binding fragment thereof comprises correlating the measured amount of antibody or antigen binding fragment thereof with the level of STK1 material using a predefined correlation between the measured amount of antibody or antigen binding fragment thereof that binds to recombinant human TK1 and the concentration of recombinant human TK 1.
  13. 13. A method according to any one of claims 1 to 12, wherein the antibody or antigen-binding fragment thereof is a monoclonal antibody or antigen-binding fragment thereof that specifically binds to human TK1 in serum form.
  14. 14. The method of claim 13, wherein the monoclonal antibody or antigen binding fragment thereof is selected from the group consisting of: A monoclonal antibody or antigen binding fragment thereof having specificity for GEAVAARKLF (SEQ ID NO: 1) of human TK 1; A monoclonal antibody or antigen-binding fragment thereof specific for at least one of NCPVPGKPGE (SEQ ID NO: 2), PVPGKPGEAV (SEQ ID NO: 3) and NCPVPGKPGEAV (SEQ ID NO: 4) of human TK1, and A monoclonal antibody or antigen binding fragment thereof specific for a conformation dependent epitope of human TK 1.
  15. 15. The method of claim 14, wherein the monoclonal antibody or antigen binding fragment thereof comprises: A Variable Heavy (VH) domain complementarity determining region 1 (CDR 1) having the amino acid sequence SEQ ID No. 5; a VH domain CDR2 having the amino acid sequence SEQ ID No. 6; a VH domain CDR3 having the amino acid sequence SEQ ID No. 7; A Variable Light (VL) domain CDR1 having the amino acid sequence SEQ ID NO. 8; VL domain CDR2 having the amino acid sequence SEQ ID NO 9, and VL domain CDR3 having the amino acid sequence SEQ ID NO 10.
  16. 16. The method of claim 14, wherein the monoclonal antibody or antigen binding fragment thereof comprises: A Variable Heavy (VH) domain complementarity determining region 1 (CDR 1) having the amino acid sequence SEQ ID No. 5; a VH domain CDR2 having the amino acid sequence SEQ ID No. 11; a VH domain CDR3 having the amino acid sequence SEQ ID No. 12; A Variable Light (VL) domain CDR1 having the amino acid sequence SEQ ID NO. 13; VL domain CDR2 having the amino acid sequence SEQ ID NO 9, and VL domain CDR3 having the amino acid sequence SEQ ID NO 10.
  17. 17. The method of claim 14, wherein the monoclonal antibody or antigen binding fragment thereof comprises: a Variable Heavy (VH) domain complementarity determining region 1 (CDR 1) having the amino acid sequence SEQ ID No. 14; A VH domain CDR2 having the amino acid sequence SEQ ID No. 15; a VH domain CDR3 having the amino acid sequence SEQ ID No. 16; A Variable Light (VL) domain CDR1 having the amino acid sequence SEQ ID NO. 17; VL domain CDR2 having the amino acid sequence SEQ ID NO. 18, and A VL domain CDR3 having the amino acid sequence SEQ ID NO. 19.
  18. 18. A method according to any one of claims 14 to 17, wherein determining the level of STK1 substance comprises determining the level of STK1 substance in the body fluid sample using a kit for determining the level of STK1 substance in the body fluid sample, the kit comprising: a first monoclonal antibody or a first antigen-binding fragment thereof, which has specificity for an epitope selected from the group consisting of: GEAVAARKLF (SEQ ID NO: 1) of human TK 1; At least one of NCPVPGKPGE (SEQ ID NO: 2), PVPGKPGEAV (SEQ ID NO: 3) and NCPVPGKPGEAV (SEQ ID NO: 4) of human TK1, and Conformation dependent epitope of human TK1, and A second monoclonal antibody or a second antigen-binding fragment thereof, which is specific for an epitope selected from the group consisting of: GEAVAARKLF (SEQ ID NO: 1) of human TK 1; At least one of NCPVPGKPGE (SEQ ID NO: 2), PVPGKPGEAV (SEQ ID NO: 3) and NCPVPGKPGEAV (SEQ ID NO: 4) of human TK1, and The conformation dependent epitope of human TK 1.
  19. 19. The method of claim 18, wherein one of the first monoclonal antibody or first antigen-binding fragment thereof and the second monoclonal antibody or second antigen-binding fragment thereof is immobilized or intended to be immobilized to a solid support.
  20. 20. The method of claim 18 or 19, wherein the kit is an enzyme-linked immunosorbent assay (ELISA) kit.

Description

STK 1-based therapeutic stratification Technical Field The present invention relates generally to the measurement of thymidine kinase 1 (TK 1), and more particularly to the stratification of treatment of prostate cancer patients based on measured serum TK1 (STK 1) levels. Background Thymidine kinase 1 (TK 1) (EC 2.7.1.21), also known as 2 '-deoxythymidine kinase or ATP-thymidine 5' -phosphotransferase, is an enzyme involved in the synthesis of deoxyribonucleic acid (DNA) precursors. TK1 phosphorylates thymidine to allow incorporation into DNA. Expression of TK1 is a marker of active cell proliferation, with low intracellular concentration in the G0/G1 phase and increased intracellular concentration in the S/G2 phase of the cell cycle. The form of TK1 is also present at high levels in serum and plasma of humans and animals suffering from malignant tumors. Thus, serum TK1 activity measurement has been used for monitoring and prognosis purposes for several different malignant diseases, but is mainly used for leukemias and lymphomas. Furthermore, TK1 is the only proliferation marker that can be measured in blood, which may provide great clinical benefit if tested as a routine laboratory test. Measurement of serum TK1 activity using radioactive substrate 125 I-dUrd (PROLIFIGEN. Delta. TK-REA, diaSorin Inc) has been done for decades, but this type of radiological enzyme assay has limited use and is preferred in the case of malignant blood tumors. In recent years, a non-radioactive TK1 activity assay (TK LIAISON. Delta. Analysis, diaSorin Inc.) has been available. The method is a sensitive and stable detection method, mainly provides information with clinical value in hematological malignancy, and is particularly suitable for monitoring treatment and predicting recurrence. Antibodies to human TK1 have been available for the last 15 years and are capable of determining TK1 protein levels opposite to TK1 activity in hematological as well as solid tumor diseases such as prostate cancer and several other forms of solid and hematological tumors. Jagarlamudi et al disclose differences in the specific activity and composition of active and inactive subunits of TK1 in serum of patients with hematological malignancies compared to patients with breast and prostate cancer. Serum thymidine kinase 1 is associated with Gleason score of patients with prostate carcinoma,Oncology Letters(2018), 16(5): 6171-6180 Published by Li et al discloses that serum TK1 concentration is a more reliable prognostic biomarker than total Prostate Specific Antigen (PSA) according to the Gleason score in the screening of Benign Prostatic Hyperplasia (BPH) or prostate malignancy. Jagarlamudi et al, AroCell TK 210 ELISA for determination of TK1 protein: age-related reference ranges and comparison with other TK1 assays,Biotechniques(2020) 68(6): 335-342, disclose that TK 210 ELISA analysis of serum from prostate and breast cancer patients has significantly higher TK1 protein levels than serum from healthy blood donors. Jagarlamudi et al Analytical and clinical characterization of an optimized dual monoclonal sandwich ELISA for the quantification of thymidine kinase 1 (TK1) protein in human blood samples,PLoS One(2022) 17(10): e027544 discloses that analysis of the subject operator profile (ROC) shows that measurement of STK1 protein levels has a higher sensitivity than enzyme activity measurements in prostate patients. Jagarlamudi et al, The combination of AroCell TK 210 ELISA with Prostate Health Index of prostate-specific antigen density can improve the ability to differentiate prostate cancer from noncancerous conditions,The Prostate(2019), 79(8): 856-863, disclose that serum TK1, measured by AroCell TK 210,210, 210 ELISA, is significantly higher in prostate cancer patients than in benign urinary system disease patients. Serum TK1 was related to prostate health index but not to Gleason score. Disclosure of Invention It is a general object of the present invention to achieve therapeutic stratification for patients diagnosed with prostate cancer. This and other objects are achieved by the embodiments disclosed herein. The invention is defined in the independent claims. Further embodiments of the invention are defined in the dependent claims. One aspect of the invention relates to a method of treating stratification. The method comprises determining the level of serum thymidine kinase 1 (STK 1) material in a body fluid sample from a patient diagnosed with prostate cancer using an antibody or antigen-binding fragment thereof that specifically binds to human TK1 in the serum form. The method further comprises comparing the level of the STK1 material to a threshold level, selecting chemotherapy for the patient if the level of the STK1 material is at or above the threshold, and selecting Androgen Receptor Signaling Inhibitor (ARSI) therapy for the patient if the level of the STK1 material is below the threshold. The invention enables treatment stratificati