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EP-4735020-A1 - G-CSF DIMER FOR USE IN THE TREATMENT OR PREVENTION OF CHEMOTHERAPY OR RADIOTHERAPY INDUCED NEUTROPENIA

EP4735020A1EP 4735020 A1EP4735020 A1EP 4735020A1EP-4735020-A1

Abstract

The present application provides methods for treating or preventing a condition characterized by compromised white blood cell production (e.g., chemotherapy-induced neutropenia, radiotherapy-induced neutropenia, or infection) in an individual (e.g., human individual, such as an individual having cancer) by administering a granulocyte colony-stimulating factor (G-CSF) dimer simultaneously with or after administration of a chemotherapeutic agent or a radiotherapy.

Inventors

  • HUANG, ZHIHUA
  • WANG, SHUFANG
  • LI, Simon Xi-Ming
  • SHI, Shaoze

Assignees

  • Evive Biotechnology (Shanghai) Ltd

Dates

Publication Date
20260506
Application Date
20240628

Claims (20)

  1. A method for treating or preventing a condition characterized by compromised white blood cell production in a human individual in need thereof, the method comprising administering to the human individual an effective amount of a granulocyte colony-stimulating factor (G-CSF) dimer within less than 24 hours after administration of a chemotherapeutic agent or a radiotherapy to the human individual.
  2. The method of claim 1, wherein the condition characterized by compromised white blood cell production comprises one or more of chemotherapy-induced neutropenia, radiotherapy-induced neutropenia, reduced hematopoietic function, reduced immune function, reduced neutrophil count, reduced neutrophil mobilization, mobilization of peripheral blood progenitor cells, sepsis, infectious diseases, leucopenia, low engraftment of bone marrow during transplantation, low bone marrow recovery in treatment of radiation, chemical or chemotherapeutic induced bone marrow aplasia or myelosuppression, radiotherapy-induced bone marrow aplasia or myelosuppression, and acquired immune deficiency syndrome.
  3. The method of claim 1 or 2, wherein the condition characterized by compromised white blood cell production is chemotherapy-induced neutropenia or radiotherapy-induced neutropenia.
  4. The method of any one of claims 1-3, wherein the G-CSF dimer is administered within about 6 hours after administration of the chemotherapeutic agent or the radiotherapy.
  5. The method of any one of claims 1-4, wherein the G-CSF dimer is administered within about 3 hours after administration of the chemotherapeutic agent or the radiotherapy.
  6. The method of any one of claims 1-5, wherein the G-CSF dimer is administered within about 2 hours after administration of the chemotherapeutic agent or the radiotherapy.
  7. The method of any one of claims 1-6, wherein the G-CSF dimer is administered within about 0.5 hour after administration of the chemotherapeutic agent or the radiotherapy.
  8. The method of any one of claims 1-7, wherein the G-CSF dimer is administered simultaneously with the administration of the chemotherapeutic agent or the radiotherapy.
  9. The method of any one of claims 1-8, wherein the chemotherapeutic agent is a myelosuppressive chemotherapeutic agent.
  10. The method of claim 9, wherein the myelosuppressive chemotherapeutic agent is selected from the group consisting of epirubicin, docetaxel, cyclophosphamide, doxorubicin, etoposide, cisplatin, paclitaxel, topotecan, vincristine, methylprednisolone, cytarabine, and a combination thereof.
  11. The method of any one of claims 1-10, wherein the human individual is administered two or more chemotherapeutic agents comprising: i) epirubicin and cyclophosphamide; ii) docetaxel and cyclophosphamide; iii) doxorubicin and cyclophosphamide; iv) docetaxel and doxorubicin; v) docetaxel, doxorubicin, and cyclophosphamide; or vi) cyclophosphamide, doxorubicin, and vincristine.
  12. The method of any one of claims 1-11, wherein the human individual is administered the chemotherapeutic agent or the radiotherapy to treat cancer.
  13. The method of claim 12, wherein the cancer is selected from the group consisting of breast cancer, non-small cell lung cancer, small cell lung cancer, esophageal cancer, nasopharyngeal cancer, head and neck squamous cell carcinoma, cervical cancer, uterine corpus cancer, ovarian cancer, sarcoma, urothelial cancer, germ cell tumor, prostate cancer, colorectal cancer, pancreatic cancer, multiple myeloma, diffuse large B-cell lymphoma, and non-Hodgkin’s lymphoma.
  14. The method of any one of claims 1-13, wherein the human individual is administered at least 4 cycles of the chemotherapeutic agent or the radiotherapy, wherein the G-CSF dimer is administered within less than 24 hours after administration of the chemotherapeutic agent or the radiotherapy in Cycle 1.
  15. The method of claim 14, wherein the method further comprises administering an effective amount of the G-CSF dimer after about 24 hours of administration of the chemotherapeutic agent or the radiotherapy in each cycle of at least Cycles 2-4.
  16. The method of any one of claims 1-14, wherein the human individual is administered at least 4 cycles of the chemotherapeutic agent or the radiotherapy, and wherein the G-CSF dimer is administered within less than 24 hours after administration of the chemotherapeutic agent or the radiotherapy in each cycle of the at least 4 cycles.
  17. The method of any one of claims 14-16, wherein each cycle is about 21 days.
  18. The method of any one of claims 1-17, wherein the G-CSF dimer comprises two monomeric subunits, and wherein each monomeric subunit comprises a G-CSF monomer and a dimerization domain.
  19. The method of claim 18, wherein the G-CSF monomer comprises the amino acid sequence of SEQ ID NO: 1.
  20. The method of claim 18 or 19, wherein within each monomeric subunit, the G-CSF monomer is connected to the dimerization domain via an optional linker.

Description

G-CSF DIMER FOR USE IN THE TREATMENT OR PREVENTION OF CHEMOTHERAPY OR RADIOTHERAPY INDUCED NEUTROPENIA CROSS REFERENCE TO RELATED APPLICATIONS This patent application claims priority benefit of PCT/CN2023/105090 filed on June 30, 2023, the content of which is incorporated herein by reference in its entirety. REFERENCE TO AN ELECTRONIC SEQUENCE LISTING The contents of the electronic sequence listing (720622002041SEQLIST. xml; Size: 34,709 bytes; and Date of Creation: June 20, 2024) is herein incorporated by reference in its entirety. FIELD OF THE INVENTION The present invention relates to methods for treating or preventing a condition characterized by compromised white blood cell production (e.g., chemotherapy-induced neutropenia, radiotherapy-induced neutropenia, or infection) in an individual (e.g., human individual, such as an individual having cancer) by administering a granulocyte colony-stimulating factor (G-CSF) dimer simultaneously with or after administration of a chemotherapeutic agent or a radiotherapy. BACKGROUND OF THE INVENTION Cytotoxic chemotherapy is still one of the major treatments of cancer. The biggest disadvantage of chemotherapy treatment is that this treatment would indiscriminately kill healthy cells with rapid proliferation and differentiation together with tumor cells. The toxicity caused by chemotherapy is mainly reflected in the hematopoietic system, which is clinically known as chemotherapy-induced neutropenia. Neutropenia is characterized by a neutrophil count in the peripheral blood of lower than 1.8×109/L for an adult and 1.5×109/L for a child. Neutropenia is often a precursor of infection -the lower the neutrophil count is, the higher the risk of infection is. Neutropenia may also delay the next treatment cycle, which directly impacts on the therapeutic effects of chemotherapy. Recombinant human granulocyte colony-stimulating factor (rhG-CSF) has been widely used in chemotherapy-induced and/or radiotherapy-induced neutropenia as a standard supportive therapy for chemotherapy-treated cancer patients. G-CSF is a hematopoietic glycoprotein produced by stromal cells, macrophages, endothelial cells, fibroblasts, and monocytes. G-CSF binds to G-CSF receptor (G-CSFR) expressed on precursor cells in the bone marrow to promote the growth and differentiation of various types of blood cells, e.g., neutrophils, which play critical roles in the body’s defense against bacterial infections. G-CSF can also activate mature neutrophils to participate in immune response, or synergize with other hematopoietic growth factors such as stem cell factor, Flt-3 ligand, and GM-CSF to perform hematopoietic functions. G-CSF-based drugs, such as filgrastimand its biosimilars Filgrastim-aafi Filgrastim-sndzFilgrastim-ayoware used to manage neutropenia for patients receiving chemotherapy medications. However, these filgrastim or similar drugs requires daily administration because of their short 3.5 hours half-life. Other G-CSF drugs, such as pegfilgrastim (e.g., ) and eflapegrastim (e.g., ROLVEDONTM) , can be administered once per chemotherapy cycle because of the extended half-life of 30-50 hours through pegylated technology or fusion protein strategy. At present, the recommended dosing regimen for both eflapegrastim (HM10460A) and pegfilgrastim is next-day administration following cytotoxic chemotherapy, which requires patients typically in a weakened and uncomfortable state after undergoing chemotherapy, to travel to the hospital again. Burris et al. (J Oncol Pract. 2010; 6 (3) : 133-40) conducted randomized clinical trials to compare data on severe (grade 4) neutropenia duration and febrile neutropenia incidence in patients receiving chemotherapy with pegfilgrastim administered the same day or 24 hours after chemotherapy, and the results showed that the mean cycle-1 severe neutropenia duration was 1.2 and 0.9 days longer in the same-day group compared with the next-day group in the breast cancer and the lymphoma study, respectively. Further, in the breast and lymphoma studies, the absolute neutrophil count profile for same-day patients was earlier, deeper, and longer compared with that for next-day patients. The conclusion for this study confirmed that for patients receiving pegfilgrastim with chemotherapy, pegfilgrastim administered 24 hours after chemotherapy completion is recommended. A more flexible dosing regimen and/or a better G-CSF-based drug that eases patient burden while providing comparable or superior efficacy in the treatment of neutropenia is desired. The contents of each of the publications, patents, patent applications, and published patent applications referred to herein are incorporated herein by reference in their entirety. BRIEF SUMMARY OF THE INVENTION One aspect of the present application provides a method for treating or preventing a condition characterized by compromised white blood cell production (e.g., chemotherapy-induced neutropenia, radiotherapy-induced neutropenia, or in