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RU-2861649-C2 - METHOD FOR TREATING IgA NEPHROPATHY USING TACI-Fc FUSION PROTEIN

RU2861649C2RU 2861649 C2RU2861649 C2RU 2861649C2RU-2861649-C2

Abstract

FIELD: biotechnology. SUBSTANCE: methods for reducing the mean protein level in daily urine, reducing the albumin to creatinine ratio in urine, and reducing the level of IgA, IgG and IgM in a patient with primary IgA nephropathy are proposed. Methods comprise administering to a subject in need thereof a therapeutically effective amount of a TACI-Fc fusion protein or a pharmaceutical composition containing same. Furthermore, use of the TACI-Fc fusion protein in the manufacture of a medicament for reducing the mean protein level in daily urine, reducing the albumin to creatinine ratio in urine, and reducing the level of IgA, IgG and IgM in a patient with primary IgA nephropathy is proposed. EFFECT: therapy of IgA nephropathy. 8 cl, 7 dwg, 1 tbl, 1 ex

Inventors

  • FANG, JIANMIN
  • WANG, WENXIANG

Dates

Publication Date
20260506
Application Date
20220809
Priority Date
20210810

Claims (11)

  1. 1. A method for reducing the average daily urine protein level, reducing the urinary albumin to creatinine ratio (UACR), and reducing the level of immunoglobulins A (IgA), G (IgG), and M (IgM) in a patient with primary IgA nephropathy, comprising administering a therapeutically effective amount of a TACI-Fc fusion protein to a subject in need thereof, wherein the TACI-Fc fusion protein comprises:
  2. (i) the extracellular region of TACI or a fragment thereof that binds to Blys and/or APRIL; and
  3. (ii) the constant region of human immunoglobulin,
  4. wherein the TACI-Fc fusion protein comprises the amino acid sequence set forth in SEQ ID NO: 4.
  5. 2. The method of claim 1, wherein the TACI-Fc fusion protein is telitacicept.
  6. 3. The method according to claim 1 or 2, wherein the TACI-Fc fusion protein is administered at a dosage of 160 to 240 mg each time, more preferably 160 mg or 240 mg each time.
  7. 4. The method according to claim 1 or 2, wherein the TACI-Fc fusion protein is administered 2-4 times per month and/or administered continuously for about 2-50 weeks.
  8. 5. The method according to any one of claims 1, 2, wherein the TACI-Fc fusion protein is administered at a dosage of 160 mg or 240 mg once a week.
  9. 6. The method according to claim 1 or 2, wherein the TACI-Fc fusion protein is administered by subcutaneous injection, intramuscular injection, oral administration, or intravenous administration.
  10. 7. A method for reducing the average daily urine protein level, reducing the urinary albumin to creatinine ratio (UACR), and reducing the level of immunoglobulins A (IgA), G (IgG), and M (IgM) in a patient with primary IgA nephropathy, comprising administering a pharmaceutical composition comprising a TACI-Fc fusion protein to a subject in need thereof, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, wherein the TACI-Fc fusion protein comprises the amino acid sequence set forth in SEQ ID NO: 4.
  11. 8. Use of the TACI-Fc fusion protein in the manufacture of a medicament for reducing the average daily urine protein level, reducing the urine albumin to creatinine ratio (UACR), and reducing the level of immunoglobulins A (IgA), G (IgG), and M (IgM) in a patient with primary IgA nephropathy, wherein the TACI-Fc fusion protein comprises the amino acid sequence set forth in SEQ ID NO: 4.

Description

AREA OF TECHNOLOGY [0001] The present invention relates to a medicament for treating IgA nephropathy, an administration regimen, an administration interval and an administration method. LEVEL OF TECHNOLOGY [0002] IgA nephropathy (i.e., immunoglobulin A nephropathy, IgAN), similar to immune complex glomerulonephritis, presents with hematuria, proteinuria, and progressive renal failure of varying degrees. The pathogenesis of the disease is very complex. Genetic, environmental, and immune factors are believed to contribute to the development of IgA nephropathy. It is generally believed that a combination of factors leads to excessive production of abnormally glycosylated poly-IgA1 molecules, which are deposited in the thylakoid region of the kidneys, causing an inflammatory response and excessive complement activation in the thylakoid region, leading to the onset and progression of the disease. Patients eventually develop renal failure or end-stage renal disease, with up to 50% of patients requiring dialysis or kidney transplantation. According to Frost & Sullivan, the number of patients with IgA nephropathy worldwide increased from 8.8 million in 2015 to 9.3 million in 2020 (including 2.2 million in China). The total number of patients with IgA nephropathy worldwide is estimated to reach 9.7 million (including 2.3 million in China) in 2025 and 10.2 million (including 2.4 million in China) in 2030. Therefore, there is a huge need for clinical treatment of IgA nephropathy worldwide. [0003] However, there are currently no specific therapies or biologics approved for the treatment of IgA nephropathy worldwide. Currently, standard therapy is renal angiotensin-aldosterone system blockade and immunosuppression, including the use of corticosteroids, which typically have significant toxic side effects. As of July 20, 2021, only 11 new biologics for the treatment of IgA nephropathy are undergoing clinical trials worldwide (see Table 1). [0004] Therefore, there is a great clinical need for treatment of IgA nephropathy both in China and worldwide. SUMMARY OF THE INVENTION [0005] According to the deep analysis of clinical data, the TACI-Fc fusion protein of the present invention exhibits significant technical effects in the treatment of a patient with IgA nephropathy and cancer. [0006] In particular, the present invention provides a method of treating IgA nephropathy, comprising administering a therapeutically effective amount of a TACI-Fc fusion protein to a subject in need thereof, wherein the TACI-Fc fusion protein comprises: [0007] (i) the extracellular region of TACI or a fragment thereof that binds to Blys and/or APRIL; and [0008] (ii) a human immunoglobulin constant region. [0009] Furthermore, the extracellular region of TACI or a fragment thereof that binds to Blys and/or APRIL comprises the amino acid sequence presented in SEQ ID NO: 1. [0010] Furthermore, the human immunoglobulin constant region comprises an amino acid sequence as set forth in SEQ ID NO: 2, or an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity with SEQ ID NO: 2. [0011] Furthermore, the human immunoglobulin constant region comprises one or more amino acid modifications at positions 3, 8, 14, 15, 17, 110, 111 or 173 of SEQ ID NO: 2, wherein the modification is preferably a substitution, deletion or introduction of an amino acid. [0012] Furthermore, the replacement is selected from the group consisting of P3T, L8P, L14A, L15E, G17A, A110S, PUIS and A173T. [0013] Furthermore, the human immunoglobulin constant region comprises the amino acid sequence presented in SEQ ID NO: 3. [0014] In addition, human immunoglobulin is IgG1. [0015] In addition, the amino acid sequence of the TACI-Fc fusion protein is provided in SEQ ID NO: 4. SEQ ID NO: 4. [0016] In addition, the TACI-Fc fusion protein is telitacicept. [0017] Additionally, the TACI-Fc fusion protein is administered at a dose of 160 to 240 mg each time; in some specific embodiments, the TACI-Fc fusion protein is administered at a dose of 160 mg each time; in other specific embodiments, the TACI-Fc fusion protein is administered at a dose of 240 mg each time. [0018] In addition, the TACI-Fc fusion protein is administered 2-4 times per month. [0019] In addition, the TACI-Fc fusion protein is administered continuously for approximately 2-50 weeks. [0020] In addition, the TACI-Fc fusion protein is administered by subcutaneous injection, intramuscular injection, oral administration, or intravenous administration. [0021] In addition, IgA nephropathy is a primary IgA nephropathy. [0022] Furthermore, the subject in need of this is an adult or a child. [0023] The present invention further relates to a method of treating IgA nephropathy comprising administering a pharmaceutical composition comprising a TACI-Fc fusion protein to a subject in need thereof, wherein the pharmaceutical composition furt