JP-2026076265-A - Compositions and vaccines for treating and/or preventing viral infections, including coronavirus infection, and methods for using the same.

Abstract

[Problem] To provide a novel composition and method for effectively stimulating antiviral immunity. [Solution] A composition comprising (a) a vector comprising a plasmid encoding at least one viral antigen; and (b) a vector comprising a CD1d recognition antigen; and (c) at least one pharmaceutically acceptable carrier, wherein at least one of vectors (a) and (b) is an intact, bacterial minicell or dead bacterial cell. [Selection Diagram] Figure 1

Inventors

• ブランバット、 ヒマンシュ
• マックディアミド、 ジェニファー

Assignees

• エンジーンアイシー モレキュラー デリバリー ピーティーワイ リミテッド

Dates

Publication Date

20260511

Application Date

20260123

Priority Date

20200324

Claims (20)

1. (a) A vector comprising a plasmid encoding at least one viral antigen; and (b) A vector containing the CD1d recognition antigen; and (c) at least one pharmaceutically acceptable carrier, A composition comprising, wherein at least one of vector (a) and vector (b) is an intact, bacterial-derived minicell or a dead bacterial cell.
2. The composition according to claim 1, wherein vector (a) is a first intact bacterial minicell or dead bacterial cell, and vector (b) is a second intact bacterial minicell or dead bacterial cell.
3. The composition according to claim 1, wherein vector (a) and vector (b) are identical, intact, bacterial-derived minicells or dead bacterial cells containing plasmids encoding a CD1d-recognizing antigen and at least one viral antigen.
4. The composition according to claim 1, wherein one of vectors (a) and (b) is not an intact, bacterial-derived minicell or dead bacterial cell, and the other of vectors (a) and (b) is an intact, bacterial-derived minicell or dead bacterial cell.
5. The viral antigens include: alpha coronavirus; bat coronavirus CDPHE15 and other coracocviruses; bat coronavirus HKU10 or rhinolophas fermecinum alpha coronavirus HuB-2013 and other decacoviruses; human coronavirus 229E and other dubinacoviruses; rat coronavirus Rn rat coronavirus and other lucacocviruses; ferret coronavirus or mincovirus 1 and other minakoviruses; miniopter bat coronavirus 1 or miniopter bat coronavirus HKU8 and other minunacoviruses; myotis rickettii alpha coronavirus Sax-2011 and other minakoviruses. Octacovirus; Nyctaras bertinus alpha coronavirus SC-2013 and other Nyctaras bertinus viruses; Pedacoviruses such as swine epidemic diarea virus or Scotophilus bat coronavirus 512; Rhinocerophas bat coronavirus HKU2 and other Rhinocerophas bat coronaviruses; Cetracoviruses such as human coronavirus NL63 or NL63-related bat coronavirus strain BtKYNL63-9b; Tegacoviruses such as alpha coronavirus 1; Beta coronavirus 1, human coronavirus OC43, China rat coronavirus HKU24, human coronavirus HKU1 or murine coronavirus and other E Nobecoviruses such as Hp-beta coronavirus Cho-chian 2013; Hedgehog coronavirus 1, Middle East Respiratory Syndrome-associated coronavirus (MERS-CoV), Pipistrelle bat coronavirus HKU5 or Tyronycteris bat coronavirus HKU4; Russet bat coronavirus GCCDC1, Russet bat coronavirus HKU9; Severe Acute Respiratory Syndrome-associated coronavirus, Severe Acute Respiratory Syndrome coronavirus (SARS-CoV), Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2, COVID-19); A composition according to any one of claims 1 to 4, comprising, or having characteristics thereof, a virus selected from the group consisting of -becovirus; delta coronavirus; undecocviruses such as phimosis coronavirus HKU20; buldecoviruses such as buldecovirus HKU11, swine coronavirus HKU15, munia coronavirus HKU13, or white-eye coronavirus HKU16; herdecoviruses such as night heron coronavirus HKU19; mudecoviruses such as van coronavirus HKU21; gamma coronavirus; segacoviruses such as beluga coronavirus SW1; and avian coronaviruses.
6. The composition according to any one of claims 1 to 5, wherein the viral antigen is encoded by a polynucleotide containing the sequence of SARS-CoV-2, or by a polynucleotide having at least 80% sequence identity with a polynucleotide containing the sequence of SARS-CoV-2.
7. A composition according to any one of claims 1 to 5, wherein the viral antigen comprises, or is characterized by, human coronavirus 229E, human coronavirus OC43, SARS-CoV, HCoV NL63, HKU1, MERS-CoV, or SARS-CoV-2.
8. The composition according to claim 7, wherein the viral antigen comprises or has the characteristics of SARS-CoV-2.
9. The composition according to claim 8, wherein the plasmid encodes at least one of the following: the spike (S) protein, the nucleocapsid (N) protein, the membrane (M) protein, and the envelope (E) protein of SARS-CoV-2.
10. The composition according to claim 9, wherein the plasmid encodes a spike (S) protein, a nucleocapsid (N) protein, a membrane (M) protein, and an envelope (E) protein.
11. The composition according to any one of claims 1 to 10, wherein the CD1d recognition antigen comprises a sphingoglycolipid.
12. CD1d-recognizing antigens include α-galactosylceramide (α-GalCer), C-glycoside of α-galactosylceramide (α-C-GalCer), 12-carbon acyl of galactosylceramide (β-GalCer), β-D-glucopyranosylceramide (β-GlcCer), l,2-diacyl-3-O-galactosyl-sn-glycerol (BbGL-II), diacylglycerol-containing glycolipid (Glc-DAG-s2), ganglioside (GD3), and gangly A composition according to any one of claims 1 to 11, selected from the group consisting of otriosylceramide (Gg3Cer), glycosylphosphatidylinositol (GPI), α-glucuronide ceramide (GSL-1 or GSL-4), isoglobotrihexosylceramide (iGb3), lipophosphoglycan (LPG), lysophosphatidylcholine (LPC), α-galactosylceramide analog (OCH), slate ceramide, and any derivative thereof.
13. A composition according to any one of claims 1 to 12, wherein the CD1d recognition antigen comprises α-GalCer.
14. A composition according to any one of claims 1 to 13, wherein the CD1d recognition antigen comprises a synthetic α-GalCer analog.
15. The CD1d recognition antigen includes synthetic α-GalCer analogs selected from 6′-deoxy-6′-acetamide α-GalCer (PBS57), naptylurea α-GalCer (NU-α-GC), NC-α-GalCer, 4ClPhC-α-GalCer, PyrC-α-GalCer, α-carba-GalCer, carba-α-D-galactose α-GalCer analog (RCAI-56), 1-deoxy-neo-inositol α-GalCer analog (RCAI-59), 1-O-methylated α-GalCer analog (RCAI-92), and HS44 aminocyclitol ceramide. The composition according to claim 14.
16. The composition according to any one of claims 1 to 15, wherein the CD1d recognition antigen is an IFNγ agonist.
17. The composition according to any one of claims 1 to 16, wherein the composition is formulated for oral administration, injection, intranasal administration, intrapulmonary administration, or topical administration.
18. A method for treating and/or vaccinating against a viral infection, comprising administering the composition described in any one of claims 1 to 16 to a subject in need of such a subject.
19. The target is, (a) If you have or are at risk of developing lymphopenia; and/or (b) When there is a risk of severe illness and/or serious complications due to viral infection; and/or (c) is approximately 50 years of age or older, approximately 55 years of age or older, approximately 60 years of age or older, or approximately 65 years of age or older; and/or (d) having one or more pre-existing conditions selected from the group consisting of diabetes, asthma, respiratory disease, hypertension, and heart disease; and/or (e) being immunodeficient; and/or (f) Immunity is weakened due to AIDS, cancer, cancer treatment, hepatitis, autoimmune disease, steroid administration, immunosenescence, or a combination thereof. The method according to claim 18.
20. The administration is (a) to increase the likelihood of survival after exposure to coronavirus; and/or, (b) Reduce the risk of coronavirus infection, The method according to any one of claims 18 to 19.

Description

Cross-reference to Related Applications This application claims the benefit of priority under 35 U.S.C § 119 to U.S. Provisional Application 62/994,057 filed on 24 March 2020, the entire contents of which are incorporated herein by reference. Severe acute respiratory syndrome (SARS, 2002-2004 [Ksiazek et al., 2003; Drosten et al., 2003]) and Middle East respiratory syndrome (MERS, 2012-present [Zaki et al., 2012]), which have occurred over the past 20 years, pose a significant threat to global public health. Respiratory syndromes caused by coronaviruses (CoVs) are known to be transmitted from person to person through close contact, leading to high morbidity and mortality rates among infected individuals. While SARS and MERS initially present with mild, flu-like symptoms such as fever, shortness of breath, and cough, severe cases are characterized by atypical interstitial pneumonia and diffuse alveolar damage. Both SARS-CoV and MERS-CoV can cause alveolar inflammation, pneumonia, and hypoxic lungs, leading to respiratory failure and multi-organ disease, and potentially causing acute respiratory distress syndrome (ARDS), the most severe form of acute lung injury, in which 50% of ARDS patients die [Lew et al., 2003]. For decades, antiviral drugs have been developed, but most are non-structural proteins involved in viral replication and assembly. Many of these proteins are highly conserved and have been shown to possess broad antiviral activity. Structural and accessory proteins are poorly conserved and have high mutation rates, allowing mutated viruses to evade the effects of antiviral drugs. Successful examples of antiviral drugs include the neuraminidase inhibitors oseltamivir (Tamiflu) and zanamivir (Relenza), used in the treatment and prevention of influenza A and B, respectively, and ribavirin, a guanosine analog that shows in vitro activity against numerous highly lethal emerging viruses. Monoclonal antibodies (mAbs) are thought to be useful in the prevention and treatment of highly pathogenic viral diseases by neutralizing viral structural proteins. Unfortunately, these mAbs need to target surface-exposed structural proteins, which tend to mutate frequently. Therefore, while mAbs effective against CoV infection in animal models target a wide variety of spike glycoproteins, these mAbs have been found to lack cross-protection against other related CoVs [Agnihothram et al, 2014]. Preclinical and clinical mAb formulations should ideally contain a cocktail of multiple mAbs targeting different epitopes to ensure the virus cannot escape neutralization. Vaccines have long been considered the gold standard for preventing and eradicating infectious diseases in human populations, and have also provided individuals with the benefit of long-term immune protection. Unfortunately, in human infections with highly pathogenic coronaviruses such as SARS-CoV and MERS-CoV, the most vulnerable populations are those over 65 years of age and those with comorbidities, and designing effective vaccines for these groups is considered difficult. Vaccines developed against SARS-CoV not only failed to protect animal models in the elderly population, but also resulted in immunopathological changes in younger populations, with enhanced SARS disease in vaccinated groups subsequently challenged with SARS-CoV [Bolles et al., 2011; Sheahan et al., 2011]. This is an illustration of the EnGeneIC Dream Vehicle (EDV ™ ), a composition comprising a combination of an intact bacterial minicell carrying α-galactosylceramide (α-GalCer), a CD1d-restricted iNKT cell antigen that stimulates IFNγ, and a bacterial minicell carrying a plasmid encoding a viral antigen.Figure 2D shows elevated CD8+ cytotoxic T cells (Figure 2A), NK cells (Figure 2B), NKT cells (Figure 2C), and iNKT cells (Figure 2D) from peripheral blood mononuclear cells (PBMCs) of patient 1-CB04-1 (72-year-old male) with advanced hepatocellular carcinoma, treated for 2 and 3 cycles with intact bacterial minicells containing EGFR-targeted, PNU-containing cells and intact bacterial minicells containing α-galactose-treated ceramide. It should be noted that this patient is elderly and severely immunocompromised. PNU is PNU-159682, a morpholinyl anthracycline derivative.This figure shows the activation of major immune cells in PBMCs of a 45-year-old woman with advanced colorectal cancer. The patient's CD8+ effector cytotoxic T cells (CD45RA+ CCR7-) significantly increased by the second and third cycles (Figure 3A). Similarly, an increase in NK cells was observed in the control PBMCs in the second and third cycles (Figure 3B). Interestingly, ELISA analysis of the patient's serum 3 hours after administration of each intact bacterial-derived minicell showed a spike in IFNγ, a phenomenon that occurs when α-galactosylceramide is effectively presented from antigen-presenting cells (APCs) to iNKT cells, triggering the release of IFNγ, a key mediator in fighting viral infection (Figure 3C).This figur