KR-102964997-B1 - Long-acting G-CSF to prevent neutropenia or reduce the duration of neutropenia

Abstract

The present invention relates to a method for preventing neutropenia in a patient or reducing the duration of neutropenia by administering a therapeutically effective amount of human hybrid (hy) Fc fusion granulocyte colony-stimulating factor (G-CSF) developed as a next-generation G-CSF (granulocyte colony-stimulating factor).

Inventors

• 엘탄-아흐메드, 세넴
• 사힌, 아뎀
• 온셀, 하티스
• 피날바슬리, 오누르
• 사라코글루, 나게한

Assignees

• 일코겐 일라익 사나이 비 티카렛 에이.에스.

Dates

Publication Date

20260513

Application Date

20200121

Priority Date

20190213

Claims (20)

1. A pharmaceutical composition for reducing the duration of neutropenia in a subject requiring this or for preventing neutropenia, The above subject is a subject who has received or is receiving anticancer chemotherapy, and The above pharmaceutical composition comprises a hybrid Fc fusion G-CSF (granulocyte colony-stimulating factor) of the following general formula (I), wherein The above hybrid Fc fusion G-CSF comprises the amino acid sequence of amino acid residues 31 to 449 of SEQ ID NO. 1, and The above pharmaceutical composition is administered to a subject in a dose range of 200 μg/kg to 400 μg/kg 24 hours after the above anticancer chemotherapy: [General Formula (I)] N'-GY-Z2-Z3-Z4-C' In the above formula, G is G-CSF and; N' is the N-terminus of the polypeptide and C' is the C-terminus of the polypeptide; Y is an amino acid sequence having 5 to 64 consecutive amino acid residues from the amino acid residue at position 162 toward the N-terminus among the amino acid residues at positions 99 to 162 of SEQ ID NO. 2; Z2 is an amino acid sequence having 4 to 37 consecutive amino acid residues from the amino acid residue at position 163 toward the C-terminus among the amino acid residues at positions 163 to 199 of SEQ ID NO. 2; Z3 is an amino acid sequence having 71 to 106 consecutive amino acid residues from the amino acid residue at position 220 toward the N-terminus among the amino acid residues at positions 115 to 220 of SEQ ID NO. 3; Z4 is an amino acid sequence having 80 to 107 consecutive amino acid residues from the amino acid residue at position 221 toward the C-terminus among the amino acid residues at positions 221 to 327 of SEQ ID NO. 3.
2. In Article 1, A pharmaceutical composition in which the above hybrid Fc fusion G-CSF is administered in a dose range of 250 μg/kg to 350 μg/kg.
3. delete
4. In Article 1, The above composition, comprising a hybrid Fc fusion G-CSF, is a pharmaceutical composition administered parenterally.
5. In Article 4, The above composition, comprising hybrid Fc fusion G-CSF, is a pharmaceutical composition administered subcutaneously.
6. In Article 1, The above-mentioned subject is a human undergoing anticancer therapy, and the pharmaceutical composition.
7. delete
8. delete
9. In Article 6, A pharmaceutical composition comprising a hybrid Fc fusion G-CSF, administered once to a human subject during a cycle of chemotherapy.
10. delete
11. In Article 9, A pharmaceutical composition comprising a hybrid Fc fusion G-CSF, administered once during every 2, 3, or 4 or more cycles of chemotherapy.
12. In Article 1, A pharmaceutical composition in which the above-mentioned neutropenia is moderate or severe.
13. In Article 1, A pharmaceutical composition comprising a hybrid Fc fusion G-CSF, wherein the composition is administered as a pharmaceutical composition comprising the hybrid Fc fusion G-CSF and a pharmaceutically acceptable carrier.
14. In Article 1, The above pharmaceutical composition is a pharmaceutical composition that exhibits non-linear pharmacokinetics with a supra-proportional increase in AUC with increasing dose.
15. A pharmaceutical composition for treating or preventing neutropenia by increasing neutrophil levels in a subject, The above pharmaceutical composition is administered to the subject requiring it 24 hours after anticancer chemotherapy, and The above subject is a subject who has received or is receiving anticancer chemotherapy, and The above pharmaceutical composition comprises a hybrid Fc fusion G-CSF of the following general formula (I) in a therapeutically effective dose range of 200 μg/kg to 400 μg/kg, and A pharmaceutical composition comprising the above hybrid Fc fusion G-CSF having an amino acid sequence of amino acid residues 31 to 449 of SEQ ID NO: 1: [General Formula (I)] N'-GY-Z2-Z3-Z4-C' In the above formula, G is G-CSF and; N' is the N-terminus of the polypeptide and C' is the C-terminus of the polypeptide; Y is an amino acid sequence having 5 to 64 consecutive amino acid residues from the amino acid residue at position 162 toward the N-terminus among the amino acid residues at positions 99 to 162 of SEQ ID NO. 2; Z2 is an amino acid sequence having 4 to 37 consecutive amino acid residues from the amino acid residue at position 163 toward the C-terminus among the amino acid residues at positions 163 to 199 of SEQ ID NO. 2; Z3 is an amino acid sequence having 71 to 106 consecutive amino acid residues from the amino acid residue at position 220 toward the N-terminus among the amino acid residues at positions 115 to 220 of SEQ ID NO. 3; Z4 is an amino acid sequence having 80 to 107 consecutive amino acid residues from the amino acid residue at position 221 toward the C-terminus among the amino acid residues at positions 221 to 327 of SEQ ID NO. 3.
16. In Article 15, A pharmaceutical composition in which the above hybrid Fc fusion G-CSF is administered in a dose range of 250 μg/kg to 350 μg/kg.
17. delete
18. In Article 15, The above composition, comprising a hybrid Fc fusion G-CSF, is a pharmaceutical composition administered parenterally.
19. In Article 15, The above composition, comprising hybrid Fc fusion G-CSF, is a pharmaceutical composition administered subcutaneously.
20. In Article 15, A pharmaceutical composition in which the subject is a human having less than 1.0 × 10⁹ /L of blood circulating neutrophils.

Description

Long-acting G-CSF to prevent neutropenia or reduce the duration of neutropenia Cross-reference of related applications The applicant claims the benefit of U.S. provisional application No. 62/804,988 filed on February 13, 2019. Field of invention The present disclosure relates to a method for preventing neutropenia in a patient or reducing the duration of neutropenia by administering a long-acting hybrid Fc fusion G-CSF. Leukopenia, characterized by reduced white blood cell (WBC) levels, and neutropenia, characterized by reduced neutrophil levels, are significant disorders that increase susceptibility to various types of infections. Neutropenia can be chronic, for example, in patients infected with HIV, or acute, for example, in cancer patients undergoing chemotherapy or radiation therapy. Various factors, such as anticancer chemotherapy drugs, anticancer radiation therapy, infectious diseases, congenital defects, or vitamin B12/B9 deficiencies, can cause neutropenia. A significant decrease in neutrophils, which makes patients more vulnerable to bacterial infections, is a common and serious complication in patients receiving anticancer therapy (chemotherapy and/or radiation therapy). Neutrophils are short-lived cells produced in the bone marrow that migrate extensively throughout the body; unlike other white blood cells, they can freely move into vein walls and body tissues to immediately attack any antigen. Neutropenia is classified according to the neutrophil count and the relative risk of infection. It is defined as an absolute neutrophil count (ANC) value of less than approximately 1.0 × 10⁹ /L. Based on the neutrophil count, it is classified as follows: moderate neutropenia (500–1000/μL) or severe neutropenia (< 500/μL). Febrile neutropenia (FN) refers to the occurrence of fever during the duration of significant neutropenia. Moderate and severe neutropenia or febrile neutropenia makes the course of treatment less effective by requiring a reduction in the dosage of drugs used in chemotherapy or delaying treatment. In patients with severe neutropenia or febrile neutropenia with an ANC value of less than 0.5 × 10⁹ /L, even a relatively mild infection can be severe and life-threatening. Recently, various forms of leukopenia and neutropenia are treated or controlled with granulocyte colony-stimulating factor (G-CSF) or polyethylene glycol (PEG) modified G-CSF derivatives. The prophylactic use of G-CSF is suggested in high-risk chemotherapy regimens with a greater than 20% risk of recessive neutropenia. In patients undergoing autologous peripheral blood stem cell transplantation, G-CSF is used to mobilize designated 34+ (CD34+) hematopoietic stem cell clusters into the peripheral blood after completion of cancer chemotherapy. G-CSF is also used for the mobilization of hematopoietic stem cells for allogeneic hematopoietic stem cell transplantation in patients who have undergone cross-blood stem cell transplantation. Furthermore, G-CSF preparations are used to treat neutropenia that increases neutrophil counts after hematopoietic stem cell transplantation, myelodysplastic syndrome, aplastic anemia, congenital and idiopathic neutropenia, and human immunodeficiency virus (HIV) infection. The main biological effect of G-CSF in vivo is to stimulate the growth and development of specific leukocytes known as granulocytes or neutrophils [see Welte et al., PNAS-USA 82:1526-1530, 1985, Souza et al, Science, 232:61-65, 1986 ]. Neutrophils produced in the bone marrow are regulated by G-CSF. Effects occur when G-CSF binds to granulocyte colony-stimulating receptors on the surface of cells in the bone marrow; these receptors are typically produced from progenitor cells of granulocytes and mature neutrophils, and their density is generated during the later stages of differentiation and maturation. Consequently, after binding to the receptor, G-CSF promotes the entry of progenitor cells, such as myeloblasts, promyelocytes, and myelocells, into the cell cycle in the bone marrow; this induces more frequent cell division, thereby promoting cell proliferation and extending the lifespan of granulocytes. Additionally, G-CSF contributes to increasing neutrophil counts by facilitating their rapid migration from the bone marrow into the bloodstream (4 to 24 hours). Furthermore, G-CSF contributes to the proliferation and differentiation of hematopoietic stem cells, such as CFU-G (colony-forming granulocytes). The amino acid sequence of human G-CSF (hG-CSF) was reported in the literature “Nagata et al. Nature 319:415-418, 1986.” hG-CSF is a monomeric protein that dimerizes G-CSF receptors by forming a 2:2 complex of two G-CSF molecules and two receptors [see “ Horan et al. (1996), Biochemistry 35(15): 4886-96 ”]. Recombinant, methionyl human G-CSF (r-metHuG-CSF), a 175-residue protein, was first produced in E. coli [see “ Hill et al. (1993), Proc. Natl. Acad. Sci. USA 90, 5167-5171 ”]. Filgrastim, the first of these G-CSF-containing dr