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JP-2026514211-A - Nasal spray for preventing COVID-19 infection and its manufacture and use

JP2026514211AJP 2026514211 AJP2026514211 AJP 2026514211AJP-2026514211-A

Abstract

This disclosure relates to a fully human-derived ACE2-Fc fusion protein, pharmaceutical compositions, formulations, and kits containing the same (for example, a nasal spray containing the fusion protein). Furthermore, this disclosure relates to the application of the fusion protein in the widespread prevention of coronavirus infections, for example, SARS-CoV-2 coronavirus and its known and unknown variants (including, but not limited to, prototype Hu-1, alpha, beta, gamma, delta, mu, omicron, JN.1, and/or other potentially emerging variants). This disclosure also relates to a method for producing the fusion protein and a method for preventing and/or treating infection with SARS-CoV-2 coronavirus and its known and unknown variants using the fusion protein. Furthermore, this disclosure relates to the fusion protein and its pharmaceutical compositions and formulations for preventing the transmission of SARS-CoV-2 coronavirus and its known and unknown variants in previously infected subjects. [Selection Diagram] None

Inventors

  • 梁朋

Assignees

  • 四川三叶草生物制薬有限公司

Dates

Publication Date
20260507
Application Date
20240304
Priority Date
20230304

Claims (20)

  1. A fusion protein comprising multiple recombinant polypeptides, comprising human ACE2 protein or a fragment thereof, and human IgG Fc protein or a functional variant thereof.
  2. The fusion protein according to claim 1, wherein the human ACE2 protein or fragment thereof comprises the human ACE2 extracellular domain or fragment thereof.
  3. The fusion protein according to claim 1 or 2, wherein the human ACE2 protein or fragment comprises an amino acid sequence shown in any of SEQ ID NO: 5, 7, 11, 12, 13, or 14, or an amino acid sequence or fragment having at least 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.
  4. The fusion protein according to any one of claims 1 to 3, wherein the human ACE2 protein or fragment thereof comprises the amino acid sequence shown in SEQ ID NO: 5, or an amino acid sequence or fragment thereof having at least 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.
  5. The fusion protein according to any one of claims 1 to 4, wherein the human IgG Fc protein or its functional variant comprises one or more Fc region sequences or functional variants and fragments selected from human IgG1 Fc, IgG2 Fc, IgG3 Fc, and IgG4 Fc.
  6. The fusion protein according to any one of claims 1 to 5, wherein the human IgG Fc protein or its functional variant is selected from the human IgG1 Fc region sequence or its functional variants and fragments.
  7. The fusion protein according to any one of claims 1 to 6, wherein the human IgG Fc protein or its functional variant comprises the amino acid sequence shown in SEQ ID NO: 6 or 8, or a fragment thereof having at least 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.
  8. The fusion protein according to any one of claims 1 to 7, wherein the human IgG Fc protein or its functional variant comprises the amino acid sequence shown in SEQ ID NO: 6, or an amino acid sequence or fragment thereof having at least 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.
  9. A fusion protein according to any one of claims 1 to 8, which optionally includes a signal peptide.
  10. The fusion protein according to any one of claims 1 to 9, optionally comprising a peptide linker, wherein the human ACE2 protein or a fragment thereof and the human IgG Fc protein or a functional variant thereof are either directly bound or bound via the peptide linker.
  11. The fusion protein according to claim 10, wherein the peptide linker is selected from an arginine-serine peptide linker (-RS-), a valine-serine linker (-VS-), and a glycine-serine linker (-GS-).
  12. A fusion protein according to any one of claims 1 to 11, comprising a mutated sequence as an option.
  13. A fusion protein according to claim 1, comprising an amino acid sequence shown in any of SEQ ID NO: 1-18, or an amino acid sequence or fragment thereof having at least 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, or a combination thereof.
  14. A fusion protein according to claim 1, comprising an amino acid sequence shown in any of SEQ ID NO: 1-4 and 15-18, or an amino acid sequence or fragment having at least 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, for example, an amino acid sequence shown in any of SEQ ID NO: 1-4 or 15-18, or an amino acid sequence or fragment having at least 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.
  15. A fusion protein according to any one of claims 1 to 14, further comprising a detectable tag.
  16. A pharmaceutical composition comprising a fusion protein according to any one of claims 1 to 15 and any pharmaceutically acceptable carrier.
  17. The pharmaceutical composition according to claim 16, comprising the fusion protein described in any one of claims 1 to 15 in an amount of about 0.1 mg/ml to about 100 mg/ml, for example, about 0.50 mg/ml to about 20.00 mg/ml, about 1.25 mg/ml, about 2.50 mg/ml, or about 5.00 mg/ml.
  18. The pharmaceutical composition according to claim 16 or 17, wherein the pharmaceutically acceptable carrier comprises one or more combinations of buffering agents and osmotic pressure regulators.
  19. The pharmaceutical composition according to claim 18, wherein the buffering agent is selected from sodium dihydrogen phosphate monohydrate, disodium hydrogen phosphate dihydrate, or a combination thereof.
  20. The pharmaceutical composition according to claim 18 or 19, wherein the osmotic pressure adjusting agent comprises one or more combinations selected from the group consisting of sodium chloride, potassium chloride, glycerin, glucose, sorbitol, sucrose, xylitol, or mannitol.

Description

This disclosure relates to a fully human-derived ACE2-Fc fusion protein, pharmaceutical compositions, formulations, and kits (e.g., nasal sprays containing the fusion protein) for the prevention and treatment of coronavirus infection and for preventing the transmission of coronavirus. This disclosure further relates to a method for producing the fusion protein for preventing and/or treating infection with coronavirus SARS-CoV-2 and known and unknown variants thereof, and for preventing the transmission of coronavirus SARS-CoV-2 and known and unknown variants in previously infected subjects. Coronaviruses infect a variety of birds and mammals, including humans. Coronaviruses can cause annual outbreaks in human populations and usually cause mild respiratory illness, but tend to be more severe in infants, the elderly, and people with weakened immune systems. However, some coronaviruses, including Middle East Respiratory Syndrome Coronavirus (MERS-CoV), Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-1), and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), are highly pathogenic. Furthermore, the novel coronavirus mutates rapidly, and since the end of 2020, multiple variant SARS-CoV-2 strains (VOCs) with mutations that could lead to immunity evasion have begun to emerge. However, the long cycle from the research and development of a typical vaccine to its market launch makes it completely inadequate to address the threat that the novel coronavirus poses to work, health, and global pandemic control. Therefore, emergency response facilities with broad protective effects play a crucial role in reducing people's risk of infection, easing the pressure on infection prevention measures, and revitalizing social life. This disclosure provides methods, applications, and products (article of manufacture) that satisfy the above and other requirements. This application claims priority to Chinese Patent Application No. 202310217327.3, filed on March 4, 2023, the contents of which are incorporated herein by reference. This shows the mechanism by which the SARS-CoV-2 virus infects the host via the ACE2 receptor. Figures 2A to 2H show the affinity measurements of the ACE2-Fc fusion protein (SCB-719) with spike proteins from various different strains.The results of affinity measurements with the wild-type (Hu-1) spike protein are shown.The affinity measurement results for the Beta mutant spike protein are shown.The affinity measurement results for the Delta mutant spike protein are shown.The affinity measurement results for the Omicron mutant (BA.1) spike protein are shown.The results of affinity measurements with the Omicron mutant (BA 4/5) spike protein are shown.The results of affinity measurements with the Omicron mutant (XBB1.5) spike protein are shown.The results of affinity measurements with the Omicron mutant (EG5.1) spike protein are shown.The affinity measurement results for the JN. 1 mutant spike protein are shown. Figures 3A to 3D illustrate the principle of inhibiting SARS-CoV-2 virus infection with a nasal spray using the ACE2-Fc fusion protein.This shows how a nasal spray containing ACE2-Fc fusion protein is sprayed into the nasal cavity.This shows how viruses or virus-containing droplets transmitted through the air enter the nasal cavity.This demonstration shows how a soluble ACE2-Fc fusion protein nasal spray, developed using Fc fusion protein technology, covers the upper respiratory tract mucosa, primarily the nasal cavity, when sprayed into the nasal cavity, forming a first line of defense against viral invasion as an "invisible mask with biological function."This illustrates the process by which the SARS-CoV-2 virus enters a cell and the process by which the ACE2-Fc fusion protein prevents the virus from entering the cell. When transmissible viruses or virus-containing droplets are present in the air, the virus primarily infects upper respiratory tract cells. In this case, the ACE2-Fc fusion protein, distributed in the nasal cavity and upper respiratory tract, competitively binds to any mutant strain of the SARS-CoV-2 virus, blocking the site where the virus's spike protein binds to host cells, thereby preventing the virus from entering host cells via the spike protein and infecting the human body. Figures 4A to 4C show the purification and characterization of the ACE2-Fc fusion protein according to the embodiments of this disclosure.This figure shows the detection of ACE2-Fc fusion protein expression levels in CHO.This figure shows the affinity purification of ACE2-Fc fusion protein.This figure shows the purity detection of the ACE2-Fc fusion protein. Figures 5A to 5C exemplify the detection of the neutralizing activity of the ACE2-Fc fusion protein according to the embodiments of this disclosure against pseudoviruses of the novel coronavirus prototype and mutant strains.The mutant strains being detected include alpha, beta, gamma, delta, and omicron strains.The mutant strains detected in