Deoxygenated lipopolysaccharide (LPS), natural non-toxic LPS and their uses

Abstract

The present invention relates to enriched populations of modified lipopolysaccharide (LPS) molecular species in which the C1 position of the reducing end of the lipid A domain lacks a phosphate group and is substituted with a hydrophilic moiety at the C6' position of the non-reducing end of the lipid A domain, with the proviso that the hydrophilic moiety is not a hydroxyl group. The present invention also relates to compositions comprising the enriched populations of modified LPS, and to uses of the enriched populations of naturally occurring and / or modified LPS molecular species for treating and / or preventing cancer, inflammatory or infectious diseases, and for stimulating an immune response or vaccinating a subject.

Claims

1. A population of modified lipopolysaccharide (LPS) molecular species comprising at least 80% modified LPS molecular species, wherein the modified LPS molecular species are The lipid A domains lack a phosphate group at the C1 position of the reducing end, and The non-reducing C6' end of these lipid A domains is substituted with a hydrophilic moiety, however, the hydrophilic moiety is not a hydroxyl group. General formula B 【Chemistry 1】 It is, and in the formula, X and Y are independently -O- or -NH-, R1 is a hydroxyl group (-OH) and may be substituted, however, if substituted, the substitution shall not consist of a phosphate group (-OPO3H2), R2 is a phosphate group (-OPO3H2) or a hydroxyl group (-OH), and may be substituted. R3 is an oligosaccharide or polysaccharide moiety, and may be substituted. R4 and R6 are independent fatty acid residues and may be substituted. R5 and R7 are independently hydrogen or fatty acid residues, and may be substituted. A group of modified LPS molecular species.

2. The modified LPS molecular species is, General formula B 【Chemistry 2】 It is, and in the formula, X and Y are independently -O- or -NH-, R １ is a hydroxyl group (-OH), which may be substituted, however, if substituted, the substitution is a phosphate group (-OPO ３ H ２ ) is not the only one, R ２ is a phosphate group (-OPO ３ H ２ ) or a hydroxyl group (-OH), which may be substituted, R ３ This is an oligosaccharide or polysaccharide moiety containing a core oligosaccharide domain, which may be substituted. R ４ and R ６ are, independently of each other, fatty acid residues, which may be substituted, R ５ and R ７ These are, independently of each other, hydrogen atoms or fatty acid residues, and may be substituted. A group of modified LPS molecular species as described in claim 1.

3. The aforementioned group is given by the formula: 【Transformation 3】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 The group of modified LPS molecular species according to claim 1, comprising species selected from the group of and combinations thereof, wherein R at the C6' position is an oligosaccharide or polysaccharide moiety containing a core oligosaccharide domain, and X at the C1 position is an ethyl moiety.

4. The group of modified LPS molecular species according to any one of claims 1 to 3, wherein the modified LPS molecular species form particles having an average size of less than approximately 200 nm in diameter in an aqueous solution, so that they can be evaluated by dynamic light scattering (DLS) at 25°C.

5. A pharmaceutical composition comprising a group of modified LPS molecular species as described in any one of claims 1 to 4.

6. i. A group comprising a mixture of at least two modified LPS molecular species from formulas (I)(1)(a), (I)(1)(b), (I)(1)(c), (I)(1)(d), (I)(1)(e) and (I)(1)(f) as described in claim 3, or ii. A group comprising a mixture of at least two modified LPS molecular species from formulas (I)(2)(a), (I)(2)(b) and (I)(2)(c) as described in claim 3, or iii. A group comprising a mixture of at least two modified LPS molecular species from formulas (I)(3)(a), (I)(3)(b), and (I)(3)(c) as described in claim 3, or iv. A group comprising a mixture of at least two modified LPS molecular species from formulas (I)(5)(a) and (I)(5)(b) as described in claim 3, or v. A group comprising a mixture of at least two modified LPS molecular species from formulas (I)(6)(a) and (I)(6)(b) described in claim 3, or vi. A group comprising a mixture of at least two modified LPS molecular species from formulas (I)(7)(a), (I)(7)(b), (I)(7)(c) and (I)(7)(d) as described in claim 3, or vii. A group comprising a mixture of at least two modified LPS molecular species from formulas (I)(8)(a), (I)(8)(b), and (I)(8)(c) as described in claim 3, or viiii. A group comprising a mixture of at least two modified LPS molecular species from formulas (I)(9)(a), (I)(9)(b), (I)(9)(c), (I)(9)(d), (I)(9)(e) and (I)(9)(f) as described in claim 3, or ix. A group comprising a mixture of at least two modified LPS molecular species from formulas (II)(2)(a), (II)(2)(b), (II)(2)(c), and (II)(2)(d) as described in claim 3, or x. A group comprising a mixture of at least two modified LPS molecular species from formula (III)(1)(a), (III)(1)(b), (III)(1)(c), and (III)(1)(d) as described in claim 3, or xi. A group comprising a mixture of at least two modified LPS molecular species from formula (IV)(1)(a), (IV)(1)(b), and (IV)(1)(c) as described in claim 3, or xii. A group comprising a mixture of at least two modified LPS molecular species from formulas (V)(1)(a), (V)(1)(b), (V)(1)(c), (V)(1)(d), (V)(1)(e), (V)(1)(f), (V)(1)(g), (V)(1)(h), and (V)(1)(i) as described in claim 3, or xiiii. A group comprising a mixture of at least two modified LPS molecular species from formulas (VI)(1)(a), (VI)(1)(b), (VI)(1)(c), (VI)(1)(d), (VI)(1)(e), (VI)(1)(f), (VI)(1)(g), (VI)(1)(h), (VI)(1)(i), (VI)(1)(j) as described in claim 3, or xiv. A group comprising a mixture of at least two modified LPS molecular species from formula (VI)(2)(a), (VI)(2)(b), and (VI)(2)(c) as described in claim 3, or xv. A group comprising a mixture of at least two modified LPS molecular species from formula (VII)(1)(a), (VII)(1)(b), and (VII)(1)(c) as described in claim 3, or xvi. A group comprising a mixture of at least two modified LPS molecular species from formula (VIII)(1)(a), (VIII)(1)(b), (VIII)(1)(c), and (VIII)(1)(d) as described in claim 3, or xvii. A group comprising a mixture of at least two modified LPS molecular species from formulas (IX)(1)(a), (IX)(1)(b), (IX)(1)(c), and (IX)(1)(d) as described in claim 3, or xviiii. A group comprising a mixture of at least two modified LPS molecular species from formulas (X)(1)(a), (X)(1)(b), (X)(1)(c), and (X)(1)(d) as described in claim 3, or xix. A group comprising a mixture of at least two modified LPS molecular species from formulas (XI)(1)(a), (XI)(1)(b), (XI)(1)(c), and (XI)(1)(d) as described in claim 3, or xx. A group comprising a mixture of at least two modified LPS molecular species from formula (XIII)(2)(a) and (XIII)(2)(b) as described in claim 3, or xxi. A group comprising a mixture of at least two modified LPS molecular species from formula (XIII)(3)(a) and (XIII)(3)(b) as described in claim 3, or xxii. A group comprising a mixture of at least two modified LPS molecular species from formula (XIII)(4)(a) and (XIII)(4)(b) as described in claim 3, or xxiii. A group comprising a mixture of at least two modified LPS molecular species from formulas (XIII)(5)(a), (XIII)(5)(b), (XIII)(5)(c) and (XIII)(5)(d) as described in claim 3, or xxiv. A group comprising a mixture of at least two modified LPS molecular species from formulas (XIII)(6)(a), (XIII)(6)(b), (XIII)(6)(c), (XIII)(6)(d), (XIII)(6)(e) and (XIII)(6)(f) as described in claim 3, or xxv. A group comprising a mixture of at least two modified LPS molecular species from formulas (XIII)(7)(a), (XIII)(7)(b), (XIII)(7)(c), (XIII)(7)(d), (XIII)(7)(e) and (XIII)(7)(f) as described in claim 3, or xxvi. A group comprising a mixture of at least two modified LPS molecular species from formulas (XIII)(8)(a), (XIII)(8)(b), (XIII)(8)(c), (XIII)(8)(d), (XIII)(8)(e) and (XIII)(8)(f) as described in claim 3, or xxvii. A group comprising a mixture of at least two modified LPS molecular species from formula (XIII)(9)(a), (XIII)(9)(b), (XIII)(9)(c), (XIII)(9)(d), (XIII)(9)(e), (XIII)(9)(f), (XIII)(9)(g), (XIII)(9)(h), (XIII)(9)(i) and (XIII)(9)(j) as described in claim 3, The pharmaceutical composition according to claim 5, comprising:

7. A pharmaceutical composition or vaccine composition according to claim 5 or 6, further comprising at least one pharmaceutically acceptable excipient.

8. A pharmaceutical composition for use in treating and / or preventing cancer, inflammatory diseases, or infectious diseases in subjects requiring it, comprising an LPS molecular species, The aforementioned LPS molecular species A group of modified LPS molecular species according to any one of claims 1 to 4, or a pharmaceutical composition according to any one of claims 5 to 7; Selected from, Pharmaceutical composition.

9. A pharmaceutical composition for use in stimulating an immune response in a target that requires it, comprising an LPS molecular species, The aforementioned LPS molecular species A group of modified LPS molecular species according to any one of claims 1 to 4, or a pharmaceutical composition according to any one of claims 5 to 7; Selected from, Pharmaceutical composition.

10. A pharmaceutical composition for use in vaccinating subjects in need thereof, comprising an LPS molecular species, The aforementioned LPS molecular species A group of modified LPS molecular species according to any one of claims 1 to 4, or a pharmaceutical composition according to any one of claims 5 to 7; Selected from, Pharmaceutical composition.

11. The aforementioned LPS molecular species formula: 【Chemistry 4】 【change】 LPS molecular species selected from the LPS molecular species, A mixture of LPS molecular species of formulas (I)(0)(a) and (I)(0)(b), A mixture of at least two LPS molecular species of formula (II)(0), A mixture of at least two LPS molecular species of formula (II)(1)(a), (II)(1)(b), (II)(1)(c), and (II)(1)(d), A mixture of modified LPS molecular species of formula (I)(1)(a), (I)(1)(b), (I)(1)(c), (I)(1)(d), (I)(1)(e) and (I)(1)(f) as described in claim 3, A mixture of modified LPS molecular species of formula (I)(2)(a), (I)(2)(b) and (I)(2)(c) as described in claim 3, A mixture of modified LPS molecular species of formula (VI)(1)(a), (VI)(1)(b), (VI)(1)(c), (VI)(1)(d), (VI)(1)(e), (VI)(1)(f), (VI)(1)(g), (VI)(1)(h), (VI)(1)(i) and (VI)(1)(j) as described in claim 3, or A mixture of modified LPS molecular species of formula (I)(8)(a), (I)(8)(b) and (I)(8)(c) as described in claim 3, Selected from, In the formula, R at the C6' position is an oligosaccharide or polysaccharide moiety containing the core oligosaccharide domain, and X at the C1 position is an ethyl moiety. A pharmaceutical composition according to any one of claims 8 to 10.

12. The pharmaceutical composition according to claim 8 or 11, further comprising administering at least one additional therapeutic agent to the subject, in order to treat and / or prevent cancer, an inflammatory disease, or an infectious disease.

13. The pharmaceutical composition according to claim 12, wherein the at least one additional therapeutic agent is selected from the group consisting of chemotherapeutic agents, targeted therapy agents, cytotoxic agents, antibiotics, antiviral agents, cell cycle synchronizers, ligands for cell receptors, immunomodulators, apoptosis promoters, anti-angiogenic agents, cytokines, growth factors, antibodies or their antigen-binding fragments, cell therapies, and antigens.

14. The pharmaceutical composition according to claim 12, wherein the at least one additional therapeutic agent is a targeted therapy agent.

15. The pharmaceutical composition according to claim 14, wherein the targeted therapeutic agent is an anti-CD20 antibody or its antigen-binding fragment.

16. The pharmaceutical composition according to claim 12, wherein the at least one additional therapeutic agent is an immunostimulant.

17. The pharmaceutical composition according to claim 16, wherein the immunostimulant is an immune checkpoint inhibitor.

18. The pharmaceutical composition according to claim 17, wherein the immune checkpoint inhibitor is a PD-1 inhibitor.

19. A pharmaceutical composition according to any one of claims 9 to 11, further comprising administering at least one antigen to a subject requiring such vaccination or stimulating an immune response.

20. The subject requiring it is an animal other than a human, and the naturally occurring non-toxic LPS molecular species and / or modified LPS molecular species is formula (XII)(1): 【Transformation 5】 Selected from the LPS molecular species, in the formula, R at the C6' position is an oligosaccharide or polysaccharide moiety containing the core oligosaccharide domain. A pharmaceutical composition according to any one of claims 8 to 19.

21. It is a parts kit, A group of modified LPS molecular species according to any one of claims 1 to 4 or a pharmaceutical composition according to any one of claims 5 to 7, Additional medications, A parts kit that includes this.

Images