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

Abstract

To provide novel, low-toxicity LPS molecules or groups thereof, derived from naturally occurring LPS, that retain a core oligosaccharide domain. [Solution] A concentrated population of modified lipopolysaccharide (LPS) molecular species, wherein the lipid A domain lacks a phosphate group at the C1 position of the reducing end, and the non-reducing end of the lipid A domain is substituted with a hydrophilic moiety at the C6' position, provided that the hydrophilic moiety is not a hydroxyl group. The present invention also relates to compositions comprising a concentrated population of modified LPS, and to the use of naturally occurring LPS molecular species and / or concentrated populations of modified LPS molecular species for treating and / or preventing cancer, inflammatory diseases or infections, for stimulating immune responses, or for vaccinating targets.

Description

[Technical Field]

[0001] The present invention - The lipid A domain lacks a phosphate group at the C1 position of the reducing end, and -The lipid A domain is substituted at the C6' position of the non-reducing end with a hydrophilic moiety, however, the hydrophilic moiety is not a hydroxyl group, and this relates to a concentrated population of modified lipopolysaccharide (LPS) molecular species.

[0002] The present invention also relates to compositions comprising concentrated populations of modified LPS, and to the use of concentrated populations of naturally occurring LPS molecular species and / or modified LPS molecular species for treating and / or preventing cancer, inflammatory diseases or infections, and for stimulating immune responses or for vaccinating targets. [Background technology]

[0003] Antigens in vaccine compositions often have low immunogenicity and require additional components to help stimulate protective immunity based on antibody and effector T cell function. These additional components, called adjuvants, provide the necessary support to enhance the immunogenicity of the vaccine antigen.

[0004] For decades, adjuvants used in vaccines and immunotherapies have been developed empirically without understanding their mechanisms of action. These include widely used Freund's adjuvants (a mixture of paraffin oil and surfactants with an emulsified aqueous antigen solution of heat-sterilized Mycobacterium tuberculosis or Mycobacterium butyricum), alum adjuvants (typically precipitates of aluminum phosphate and aluminum hydroxide to which the antigen is adsorbed), oil-in-water emulsions (such as MF59 from Novartis or AS03 from GlaxoSmithKline, both squalene-based with an emulsified aqueous antigen solution), or saponin-based adjuvants (so-called "immunostimulatory complexes" or ISCOMs, which are cage-like nanoparticles of cholesterol, phospholipids, and formulated saponins with the antigen). However, these empirically designed adjuvants fall far short of providing an optimal response. Furthermore, substantial populations still exist that fail to achieve adequate serum conversion rates or protective antibody titers, not to mention the decline in vaccine responsiveness in healthy adults or diseased patients after 40-50 years of age.

[0005] More recently, studies have suggested that most adjuvants enhance T and B cell responses not by directly affecting lymphocytes, but by involving components of the innate immune system. The focus has been on developing native or synthetic agonists, obtained either by chemosynthesis or targeted molecular biology, for pattern recognition receptors (PRRs), which are clearly defined as adjuvants. Almost all members of the PRR family have been studied intensively and are potential adjuvant targets, including Toll-like receptors (TLRs), which are of particular interest in this invention.

[0006] A specific TLR is Toll-like receptor 4 (TLR4, also known as CD284), which is a transmembrane protein that forms a complex with the MD-2 and CD14 coreceptors to constitute the mammalian receptor for bacterial lipopolysaccharide (LPS).

[0007] LPS is a phosphoglycolipid found in the outer membranes of Gram-negative bacteria, spirochetes (e.g., Leptospira), cyanobacteria, and some Gram-positive bacteria (e.g., Negativictes). LPS consists of two distinct regions: an internal phospholipid called "lipid A," which contains numerous disaccharides, typically 2-9 long-chain fatty acids, and is responsible for most of the biological properties of LPS; and a polysaccharide moiety containing a central "core oligosaccharide" domain (branched oligosaccharides such as 9-saccharides and 10-saccharides) and an outer "O antigen" domain (made from linear or branched repeating carbohydrate polymers, with a highly variable number, properties, and spatial arrangement of sugar residues). However, LPS from some bacteria lacks the O antigen domain, and their "polysaccharide" moiety is limited to "oligosaccharides," containing only the core oligosaccharide domain (although in some cases, it may be capped with a capping antigen having a distal trisaccharide biosynthetically and genetically distinct from the O antigen, as in Bordetella pertussis, for example). Therefore, these LPS are sometimes called LOS for lipooligosaccharides.

[0008] The lipid A domain contains a disaccharide (most often a β-1,6-glucosamine [GlcN] disaccharide, a β-1,6-diaminoglucose [DAG] disaccharide, or a β-1,6-disaccharide containing one GlcN residue and one DAG residue), with numerous long-chain fatty acids acting as hydrophobic anchors for LPS to the outer membrane. Typically, the lipid A disaccharide is substituted with phosphate groups at the C1 and C4' positions, most often with branched or linear fatty acid chains of 10–18 carbons, some hydroxylated at the C3 position, with so-called β-hydroxy fatty acids attached at the C2, C3, C2', and C3' positions. This 3-OH group can be further esterified with other fatty acids (e.g., non-hydroxylated fatty acids, 2-hydroxylated fatty acids, possibly 3-hydroxylated fatty acids, or even lipid moieties) if present. These secondary fatty acids are also known as acyloxyacyl fatty acids. Therefore, the total number of fatty acids per lipid A molecule can be 2 to 9. The lipid A domain is further substituted at the C6' position by a polysaccharide moiety (including a complete or cleaved core oligosaccharide domain and optionally an O antigen domain and / or any other capping antigen) via a glycoside conjugated to a 3-deoxy-d-mann-octa-2-urosonic acid (Kdo) molecule, in the most common case.

[0009] When activated, TLR4 induces the expression of intracellular signaling pathways NF-κB and TRIF, pro-inflammatory cytokine secretion (such as IL-1, TNFα, IFNγ, and IL-12), and costimulatory molecules. This response is activated by small amounts of LPS, ultimately activating innate immunity and then priming the adaptive immune system, for example, by maturing antigen-presenting cells (such as dendritic cells, macrophages, and B cells) or by amplifying the function of T cells and B cells. For these reasons, LPS has long been recognized as a potent adjuvant.

[0010] However, LPS is not without its drawbacks when used as an adjuvant: (1) LPS is mostly naturally toxic and pyrogenic, as it can trigger a strong immune response in the host, causing fever, uncontrolled production of pro-inflammatory cytokines, and often leading to septic shock. This toxicity has been shown to arise from the lipid A domain, particularly from the phosphates at the C1 and C4' positions. As a result, the EMA, FDA, and other regulatory agencies have stringent requirements to eliminate the toxicity of LPS in pharmaceuticals. (2) While the lipid A domain has long been known to be responsible for TLR4 activation, evidence suggests that the core oligosaccharide domain, and the O antigen domain, if present, are also involved in TLR4 activation. Their presence (1) improves LPS solubility and therefore its bioavailability compared to isolated lipid A, and (2) maintains the native three-dimensional lipid A conformation. Furthermore, the core oligosaccharide domain, and the O antigen domain, if present, define the antigenicity of the molecule. They can also bind to sugar-dependent receptors such as C-type lectin receptors (CLRs). However, these domains are often removed consciously or unconsciously when preparing LPS-based adjuvants.

[0011] Various LPS-based molecules have been developed that exhibit less toxicity than "wild-type" LPS. Among these, monophosphoryl lipid A (MPL) is the most well-known LPS-based adjuvant. MPL, produced by GlaxoSmithKline, is obtained by controlled hydrolysis of Salmonella enterica serotype Minnesota R595 LPS by removing (1) the core oligosaccharide domain at the C6' position of the lipid A domain, (2) the phosphate at the C1 position of the lipid A domain, and (3) the acyl chain at the C3 position of the lipid A domain. MPL is currently used as a so-called "adjuvant" in many vaccines (Garcon & Di Pasquale, 2017. Hum Vaccin Immunother. 13(1):19-33): -AS01: Liposome-based combination of MPL and saponin QS-21 in the Mosquirix® vaccine against malaria caused by the parasitic Plasmodium falciparum. -AS02: Oil-in-water emulsion of MPL and saponin QS-21, -AS04: Adsorption of MPL to alum in Fendrix® and Cervarix® vaccines against hepatitis B virus (HBV) and human papillomavirus (HPV), respectively. -AS15: A liposome-based combination of MPL, saponin QS-21, and CpG7909.

[0012] Other LPS-based immunoadjuvants include synthetic lipid A analogs. Some of these molecules exhibit reduced toxicity with respect to "wild-type" lipid A and promote a protective immune response after vaccination. Furthermore, their synthesis results in higher molecular homogeneity and batch reproducibility compared to chemically obtained MPLs. Examples of such synthetic lipid A analogs include RC-529, E6020, glucopyranosyl lipid A (GLA), ONO-4007, E5564, and CRX-526.

[0013] However, these molecules, while having low toxicity, (1) lack their core oligosaccharide domain and, where applicable, their O antigen domain; (2) do not react well with human TLR4 diversity, which takes advantage of the natural heterogeneity and diversity of lipid A in the bacterial kingdom; and (3) have limited solubility in common organic solvents, low solubility in aqueous media, and very low concentrations (10 -8 Even at levels less than M, there is a tendency for aggregation, which complicates formulation and therefore makes them still not optimal.

[0014] Therefore, there is still a need for low-toxicity LPS molecules derived from naturally occurring LPS (due to the natural heterogeneity and diversity of lipid A structures) that retain their core oligosaccharide domain and, where applicable, the O antigen domain (for improved biological activity).

[0015] Here, the present inventors provide modified LPS molecular species that lack a phosphate group at the C1 position of the lipid A domain but retain its polysaccharide portion (core oligosaccharide domain and, if applicable, the O antigen domain). These modified LPS molecular species may also exhibit fatty acid release at secondary positions such as acyl-oxy-acyl at C2 and C2', if present, but may also exhibit fatty acid release at C3 and C3'.

[0016] The combination of these characteristics significantly reduces the toxicity of the different LPS and LOS tested. In some cases, detoxification can be further amplified by the additional release of primary ester-bonded fatty acids.

[0017] Therefore, these modified, low-toxicity LPS and LOS molecules are the closest to naturally occurring LPS molecular species in terms of composition and three-dimensional structure. This not only improves their binding to the TLR4 receptor in terms of biological activity or solubility, but also improves their properties compared to MPL and its synthetic analogues. [Overview of the project]

[0018] The present invention relates to an enriched population of modified lipopolysaccharide (LPS) molecular species comprising at least 80% of the modified LPS molecular species as defined in the claims.

[0019] The present invention further relates to a composition comprising an enriched population of modified LPS molecular species as defined in the claims.

[0020] The present invention further relates to concentrated populations of naturally occurring, non-toxic LPS molecular species and / or modified LPS molecular species, or compositions thereof, for use in subjects requiring treatment and / or prevention of cancer, inflammatory or infectious diseases, or for use in subjects requiring stimulation of an immune response, or for use in subjects requiring vaccination, as defined in the claims.

[0021] The present invention further relates to a parts kit as defined in the claims. [Modes for carrying out the invention]

[0022] definition In this invention, the following terms have the following meanings:

[0023] As used herein, the terms “lipopolysaccharide” or “LPS” refer to phosphoglycolipids present in the outer membranes of Gram-negative bacteria, spirochetes (e.g., Leptospira), cyanobacteria, and some Gram-positive bacteria (e.g., Negativictes). LPS typically consists of two distinct regions: an internal phospholipid containing numerous disaccharides, typically 2 to 9 long-chain fatty acids, called “lipid A,” which is responsible for most of the biological properties of LPS; and a polysaccharide moiety containing a central “core oligosaccharide” domain (branched oligosaccharides such as 9-saccharides and 10-saccharides) and an outer antigen domain, such as an “O antigen” domain (made from linear or branched repeating carbohydrate polymers, where the number, properties, and spatial arrangement of sugar residues are highly variable), and / or a “capping antigen” domain. LPS from some bacteria lack an O antigen domain, and their “polysaccharide” moiety is limited to “oligosaccharides” containing only the core oligosaccharide domain; therefore, these LPS are sometimes referred to as LOS for lipooligosaccharides. However, while the LPS of some bacteria does not possess an O antigen domain, in the case of Bordetella pertussis, for example, it is capped with a capping antigen that has a distal trisaccharide biosynthetically and genetically distinct from the O antigen.

[0024] As used herein, the term “Lipid A” refers to the hydrophobic portion of a lipopolysaccharide (LPS) molecule. It is typically a β-1,6-glucosamine (GlcN) disaccharide, a β-1,6-diaminoglucose (DAG) disaccharide, or a mixed β-1,6-glucosamine-diaminoglucose disaccharide, and is typically phosphorylated at the C1 and C4' positions and acylated with 4 to 7 fatty acids at the C2, C3, C2' and / or C3' positions. The carbon numbering of the disaccharides forming Lipid A is well known in the art and has been conventionally used by those skilled in the art. Simply put, carbon numbering without an apostrophe (') refers to the carbons of the sugar that form the reducing side of the disaccharide in the Lipid A domain. Carbon numbering with an apostrophe (') refers to the carbons of the sugar that form the non-reducing side of the disaccharide in the Lipid A domain. As used herein, the term “Lipid A” also encompasses precursors and altered structures of the classical disaccharide lipid A that forms the hydrophobic portion of the LPS molecule. Such precursors and altered structures may be found naturally in the LPS molecule of several bacterial species or obtained during modification, and may include, for example, lipid X and other lipid A skeletons containing monosaccharide skeletons that hold the sugars forming the reducing side of the lipid A domain, as well as optionally, a portion of the sugars that form the non-reducing side of the lipid A domain.

[0025] As used herein, the terms “fatty acid” or “fatty acid residue” refer to aliphatic monocarboxylic acids, which often, though not always, have an even number of carbon atoms. A fatty acid molecule has two distinct regions: a long hydrocarbon chain (hydrophobic and not very chemically reactive) and a carboxylic acid group (highly hydrophilic and readily forms ester and amide bonds). In relation to LPS, a fatty acid may be a “primary fatty acid” esterified or amidated at the C2, C3, C2', and C3' positions of the lipid A domain. Fatty acids may also be “secondary fatty acids” (also called “estrido-bonded fatty acids” or “acyloxyacyl fatty acids”), i.e., fatty acids esterified at the 3-OH group of other fatty acids, such as primary fatty acids. Fatty acids can be classified into short-chain, medium-chain, long-chain, and very long-chain fatty acids according to the length of their aliphatic chains. As used herein, the terms “short-chain fatty acid” or “SCFA” refer to a fatty acid having an aliphatic tail of five or fewer carbon atoms, e.g., 1, 2, 3, 4, or 5 carbon atoms. As used herein, the term “medium-chain fatty acid” or “MCFA” refers to a fatty acid having an aliphatic tail of 6 to 12 carbon atoms, e.g., 6, 7, 8, 9, 10, 11, or 12 carbon atoms. As used herein, the term “long-chain fatty acid” or “LCFA” refers to a fatty acid having an aliphatic tail of 13 to 21 carbon atoms, e.g., 13, 14, 15, 16, 17, 18, 19, 20, or 21 carbon atoms. As used herein, the term “very long-chain fatty acid” or “VLCFA” refers to a fatty acid having an aliphatic tail of 22 or more carbon atoms, e.g., 22, 23, 24, 25, 26, 27, 28, 29, or 30 or more carbon atoms. Fatty acids can be additionally or alternatively classified as saturated or unsaturated fatty acids according to their degree of saturation. As used herein, the term “saturated fatty acid” refers to a fatty acid whose aliphatic chain does not contain any double-C=C- bonds. As used herein, the term “unsaturated fatty acid” refers to a fatty acid that contains at least one or more double-C=C- bonds in its aliphatic chain. In such cases, the double-C=C- bonds may be either cis or trans.

[0026] As used herein, the terms “core oligosaccharide” or “core-OS” refer to the chain of sugar residues found in Gram-negative lipopolysaccharides (LPS). The composition of the core-OS domain is highly variable among bacterial species and strains. Core-OS is typically divided into two regions, referred to as the “inner core” and the “outer core,” with the inner core directly binding to the C6’ position (corresponding to R3 in formula I) of the lipid A domain via an (α2→6) ketoside bond.

[0027] As used herein, the term “inner core” refers to the first 3 to 6 sugar residues, which may be linear or branched. Typically, the inner core includes, but is not limited to, 3-deoxy-d-mann-octa-2-urosonic acid (Kdo), d-glycero-d-talo-octa-2-urosonic acid (Ko), or 4-amino-4-deoxy-l-arabinose (Ara4N) residues, or combinations thereof, extending from the C6' position (corresponding to R3 in Formula I) of the lipid A domain from proximal to distal, a first 3-deoxy-d-mann-octa-2-urosonic acid (Kdo) residue, or d-glycero-d-talo-octa-2-urosonic acid (Ko) residue, or typically d-glycero-d-talo-octa-2-urosonic acid (Ko) linearly or branchedly substituted by one or two further sugar residues. The most distal of these residues, or a single Kdo molecule, may be modified with a phosphate group or an ethanolamine group. These residues are distal to 2-3 heptose residues, but may also contain further hexose residues, and may be optionally phosphorylated. LPS species containing only the lipid A domain and inner core region have traditionally been called "deeprough LPS".

[0028] As used herein, the term "3-deoxy-d-manno-octa-2-urosonic acid" or "Kdo" refers to the urosonic acid of 2-ketooctose having the following formula (and carbon numbers shown in italics): [ka]

[0029] As used herein, the term “outer core” refers to a linear or branched hexose chain attached to the most distal sugar residue, typically a heptose residue, of the inner core. This hexose chain typically contains 1 to 6 or more hexose residues, including but not limited to glucose, mannose, galactose, and combinations thereof.

[0030] LPS molecular species containing a lipid A domain and a complete core-OS domain (i.e., having an inner core and an outer core region) have traditionally been called "rough-type LPS."

[0031] As used herein, the term “O antigen” typically refers to a polysaccharide contained within an LPS molecular species and bound to the core-OS domain. The composition of the O antigen domain is highly diverse among bacterial species and strains. LPS molecular species containing a lipid A domain, a complete core-OS domain (i.e., having inner and outer core regions), and an O antigen domain have traditionally been called “smooth LPS.”

[0032] As used herein, the terms “capping antigen” or “capping sugar” typically refer to a sugar moiety contained within an LPS molecular species and bound to the core-OS domain in place of or in addition to the O antigen domain. Such capping antigens are biosynthetically and genetically distinct from the classical O antigen domain. The composition of capping antigens is highly diverse among bacterial species and strains.

[0033] As used herein, the terms “toxicity” or “pyrogenicity” when referring to LPS molecular species mean the ability of the LPS molecular species to induce an acute or chronic inflammatory response when administered to a subject. Acute or chronic inflammatory responses may be characterized by the production of inflammatory mediators, including but not limited to IL-6, IL-1β, and TNF-α. Depending on the amount and structural characteristics of the administered LPS molecular species, these acute or chronic inflammatory responses may range from fever and chills to irreversible and fatal septic shock. Means and methods for evaluating the toxicity and / or pyrogenicity of LPS molecular species are well known in the art. Examples of such means and methods include, but are not limited to, the rabbit pyrotherapeutic test (RPT) and C2 in chicken embryos. 50 Lethal dose, C in GalN-sensitized mice 50 This includes, but is not limited to, in vivo studies such as lethal dose and acute toxicity studies in normal mice, as well as in vitro studies such as monocyte activation studies (MAT).

[0034] The rabbit pyrogen test (RPT) is performed in accordance with the European Pharmacopoeia (Ph.Eur. 5.1.10, this section incorporated herein by reference) and involves measuring the rise in body temperature of three rabbits after intravenous injection of the test solution (such as the composition containing LPS to be tested). The temperature is first measured before injection of the test solution, then the test solution is injected, and the body temperature of each rabbit is measured for 3 hours. If the sum of the temperatures of the three rabbits rises by less than 1.15°C, the test solution is considered non-pyrogenic; if the sum of the temperatures of the three rabbits rises by more than 2.65°C, the test solution is considered pyrogenic; and if the sum of the temperatures of the three rabbits rises between 1.15°C and 2.65°C, the test should be repeated to confirm the result.

[0035] The monocyte activation assay (MAT) is listed in the European Pharmacopoeia as an official method for detecting pyrogens (January 2010 - Ph.Eur.9.8, Section 2.6.30, this section is incorporated herein by reference). The MAT is based on the activation of monocytes by pyrogens, resulting in the production of cytokines detectable by immunological assays (e.g., ELISA). Different variants of the MAT exist depending on (1) the source of monocytes, including whole blood, isolated primary monocytes (e.g., PBMCs), or monocyte cell lines, and (2) the ELISA readouts, including IL-6, IL-1β, and TNF-α. All of them mimic the human pyrogen response in vitro.

[0036] For further details regarding means and methods for evaluating the toxicity and / or pyrogenity of LPS molecular species, please refer to Chapters 5.1.10 and 2.6.30 of the European Pharmacopoeia, which are incorporated herein by reference.

[0037] Detailed explanation This invention relates to modified LPS molecular species and enriched populations containing them.

[0038] In one embodiment, the enriched population of modified LPS molecular species contains at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, and at least 99% of the total amount of LPS molecular species in the population that are the modified LPS molecular species according to the present invention.

[0039] According to the present invention, the modified LPS molecular species lacks a phosphate group at the C1 position of the reducing end of its lipid A domain, and is substituted at the C6' position of the non-reducing end of its lipid A domain with a monosaccharide, oligosaccharide, or polysaccharide moiety.

[0040] According to the present invention, the modified LPS molecular species may, alternatively, not have a phosphate group at the C4' position of the non-reducing end of its lipid A domain, and may be substituted with a monosaccharide, oligosaccharide, or polysaccharide moiety at the C6' position of the non-reducing end of its lipid A domain.

[0041] According to the present invention, the modified LPS molecular species may, alternatively, not have phosphate groups at the C1 position of the reducing end and the C4' position of the non-reducing end of its lipid A domain, and the C6' position of the non-reducing end of its lipid A domain may be substituted with a monosaccharide, oligosaccharide, or polysaccharide moiety.

[0042] In one embodiment, the modified LPS molecular species further contains fewer or more fatty acid chains compared to the classic (i.e., unmodified) E. coli or Salmonella enterica LPS molecule.

[0043] In one embodiment, the modified LPS molecular species further comprises shorter and / or longer fatty acid chains compared to the classic (i.e., unmodified) Escherichia coli or Salmonella enterica LPS molecules.

[0044] In one embodiment, the modified LPS molecular species is defined by general formula A: [ka] And in the formula, Y is -O- or -NH-, R2 is either a phosphate group (-OPO3H2) or a hydroxyl group (-OH), and may be substituted. R3 is a monosaccharide, oligosaccharide, or polysaccharide, and may be substituted, preferably R3 is a core oligosaccharide (i.e., inner core, or inner core and outer core) which may be substituted with an O antigen domain. R6 is a fatty acid residue and may be substituted. R7 is a hydrogen atom or a fatty acid residue, and may be substituted. Z is a hydroxyl group (-OH) and may be substituted, however, if substituted, the substitution must not consist of a phosphate group (-OPO3H2), or Z is [ka] And here, X is -O- or -NH-, R1 is a hydroxyl group (-OH), and may be substituted, however, if substituted, the substitution must not be a phosphate group (-OPO3H2). R4 is a fatty acid residue and may be substituted. R5 is a hydrogen atom or a fatty acid residue, and may be substituted.

[0045] In one embodiment, the modified LPS molecular species is defined by general formula A: [ka] And in the formula, Y is -O- or -NH-, R2 is a hydroxyl group (-OH) and may be substituted, however, if substituted, the substitution must not be a phosphate group (-OPO3H2). R3 is a monosaccharide, oligosaccharide, or polysaccharide, and may be substituted, preferably R3 is a core oligosaccharide (i.e., inner core, or inner core and outer core) which may be substituted with an O antigen domain. R6 is a fatty acid residue and may be substituted. R7 is a hydrogen atom or a fatty acid residue, and may be substituted. Z is a hydroxyl group (-OH) and may be substituted, however, if substituted, the substitution must not consist of a phosphate group (-OPO3H2), or Z is [ka] And here, X is -O- or -NH-, R1 is a hydroxyl group (-OH), and may be substituted, however, if substituted, the substitution must not be a phosphate group (-OPO3H2). R4 is a fatty acid residue and may be substituted. R5 is a hydrogen atom or a fatty acid residue, and may be substituted.

[0046] In one embodiment, the modified LPS molecular species is general formula B: [ka] 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 must not be a phosphate group (-OPO3H2). R2 is either a phosphate group (-OPO3H2) or a hydroxyl group (-OH), and may be substituted. R3 is a monosaccharide, oligosaccharide, or polysaccharide, and may be substituted, preferably R3 is a core oligosaccharide (i.e., inner core, or inner core and outer core) which may be substituted with an O antigen domain. R4 and R6 are independent fatty acid residues and may be substituted. R5 and R7 are, independently of each other, hydrogen or fatty acid residues, and may be substituted.

[0047] In one embodiment, the modified LPS molecular species is general formula B: [ka] And in the formula, X and Y are independently -O- or -NH-, R1 is either a phosphate group (-OPO3H2) or a hydroxyl group (-OH), and may be substituted. R2 is a hydroxyl group (-OH) and may be substituted, however, if substituted, the substitution must not be a phosphate group (-OPO3H2). R3 is a monosaccharide, oligosaccharide, or polysaccharide, and may be substituted, preferably R3 is a core oligosaccharide (i.e., inner core, or inner core and outer core) which may be substituted with an O antigen domain. R4 and R6 are independent fatty acid residues and may be substituted. R5 and R7 are, independently of each other, hydrogen or fatty acid residues, and may be substituted.

[0048] In one embodiment, the modified LPS molecular species is general formula B: [ka] And in the formula, X and Y are independently -O- or -NH-, R1 and R2 are hydroxyl groups (-OH) and may be substituted, however, if substituted, the substitution must not consist of a phosphate group (-OPO3H2). R3 is a monosaccharide, oligosaccharide, or polysaccharide, and may be substituted, preferably R3 is a core oligosaccharide (i.e., inner core, or inner core and outer core) which may be substituted with an O antigen domain. R4 and R6 are independent fatty acid residues and may be substituted. R5 and R7 are, independently of each other, hydrogen or fatty acid residues, and may be substituted.

[0049] In one embodiment, the modified LPS molecular species is defined by general formula A: [ka] And in the formula, Y is -O- or -NH-, R2 is either a phosphate group (-OPO3H2) or a hydroxyl group (-OH), and may be substituted. R3 is a monosaccharide, oligosaccharide, or polysaccharide, and may be substituted, preferably R3 is a core oligosaccharide (i.e., inner core, or inner core and outer core) which may be substituted with an O antigen domain. R6 is a fatty acid residue and may be substituted. R7 is a hydrogen atom or a fatty acid residue, and may be substituted. Z is a hydroxyl group (-OH).

[0050] In one embodiment, X is -O- and Y is -O-. Therefore, in this embodiment, the disaccharide of the lipid A domain is the β-1,6-glucosamine [GlcN] disaccharide.

[0051] In one embodiment, X is -NH- and Y is -NH-. Therefore, in this embodiment, the disaccharide of the lipid A domain is β-1,6-diaminoglucose [DAG] disaccharide.

[0052] In one embodiment, X is -O- and Y is -NH-. In another embodiment, X is -NH- and Y is -O-. Thus, in these embodiments, the disaccharide of the lipid A domain is a β-1,6-disaccharide containing one GlcN residue and one DAG residue.

[0053] In one embodiment, Z is a hydroxyl group (-OH).

[0054] In one embodiment, R2 is a hydroxyl group (-OH). In one embodiment, Z and R2 are hydroxyl groups (-OH).

[0055] In one embodiment, Z is an optional hydroxyl group (-OH), however, if substituted, the substitution is not from a phosphate group (-OPO3H2). In one embodiment, R2 is a hydroxyl group (-OH) and may be substituted. In one embodiment, Z and R2 are optional hydroxyl groups (-OH), however, if substituted, the substitution of Z is not from a phosphate group (-OPO3H2).

[0056] In one embodiment, Z is a phosphate group (-OPO3H2), but R2 is not a phosphate group.

[0057] In one embodiment, Z is [ka] X is as defined above, and R1, R4, and R5 are as defined below.

[0058] In one embodiment, R1 is a hydroxyl group (-OH). In one embodiment, R2 is a hydroxyl group (-OH). In one embodiment, R1 and R2 are hydroxyl groups (-OH).

[0059] In one embodiment, R1 is a hydroxyl group (-OH) and may be substituted, however, if substituted, the substitution is not from a phosphate group (-OPO3H2). In one embodiment, R2 is a hydroxyl group (-OH) and may be substituted. In one embodiment, R1 and R2 are hydroxyl groups (-OH) and may be substituted, however, if substituted, the substitution of R1 is not from a phosphate group (-OPO3H2).

[0060] In one embodiment, R1 is a phosphate group (-OPO3H2), but R2 is not a phosphate group. In one embodiment, R2 is a phosphate group (-OPO3H2), but R1 is not a phosphate group.

[0061] In one embodiment, Z is a hydroxyl group (-OH) substituted with a further substituent, however the substitution is not from a phosphate group (-OPO3H2). In one embodiment, R1 is a hydroxyl group (-OH) substituted with a further substituent, however the substitution is not from a phosphate group (-OPO3H2). In one embodiment, R2 is a hydroxyl group (-OH) substituted with a further substituent.

[0062] In one embodiment, Z is a phosphate group (-OPO3H2) substituted with a further substituent. In one embodiment, R1 is a phosphate group (-OPO3H2) substituted with a further substituent. In one embodiment, R2 is a phosphate group (-OPO3H2) substituted with a further substituent.

[0063] Such further substituents include, but are not limited to, the ethanolamine group "EA" (-CH2-CH2-NH2), the phosphorylethanolamine group "PEA" (-OPO3H-CH2-CH2-NH2), the diphosphorylethanolamine group "PPEA" (-OPO3H2-PO3H-CH2-CH2-NH2), 4-amino-4-deoxy-l-arabinose (lArap4N) residues, glucosamine residues, galactosamine residues, and the like. Additionally, such further substituents include, but are not limited to, alkyl groups, aminoalkyl groups, aryl groups, carboxyalkyl groups, cycloalkyl groups, ether or polyether groups, haloalkyl groups, heteroaryl groups, nitrooxyalkyl groups, and the like.

[0064] As used herein, the term "alkyl" refers to the compound of the formula C n H 2n+1This refers to a hydrocarbyl radical, where n is a number of 1 or more. In one embodiment, the alkyl group contains 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms, and more preferably 1 to 3 carbon atoms. The alkyl group may be linear or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl.

[0065] As used herein, either by itself or as part of another substituent, the term "aminoalkyl" refers to a group -alkyl-NH2, where alkyl is as defined herein.

[0066] As used herein, either by itself or as part of another substituent, the term “aryl” refers to a polyunsaturated aromatic hydrocarbyl group having a monocycle (i.e., phenyl) or multiple aromatic rings fused together (e.g., naphthyl), and typically containing 5 to 12 atoms, preferably 6 to 10 atoms. Non-limiting examples of aryls include phenyl, naphthalenyl, and the like.

[0067] As used herein, either by itself or as part of another substituent, the term "carboxyalkyl" refers to a group-alkyl-COOH, where alkyl is as defined herein.

[0068] As used herein, the term "cycloalkyl," either by itself or as part of another substituent, refers to the formula C n H 2n-1 This refers to a saturated cyclic hydrocarbyl radical (wherein n is a number of 1 or more), or a plurality of saturated cyclic hydrocarbyl rings condensed together. In one embodiment, the cycloalkyl group contains 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, and more preferably 1 to 5 carbon atoms.

[0069] As used herein, either by itself or as part of another substituent, the term "ether" refers to a hydrocarbyl radical having an oxygen atom bonded to two carbon atoms. The ether may be straight-chain or branched. Examples of ethers include, but are not limited to, dimethyl ether, diethyl ether, dipropyl ether, dibutyl ether, dipentyl ether, dihexyl ether, diheptyl ether, dioctyl ether, etc. When an ether group is repeated in a polymeric fashion, it refers to a "polyether". Examples of polyethers include polyethylene glycol ((-CH2CH2O-) n ), polypropylene glycol ((-CH2CH(CH3)O-) n ), polytetramethylene glycol ((-CH2CH2CH2CH2O-) n ), paraformaldehyde ((-CH2O-) n ), etc., but are not limited to these.

[0070] The term "haloalkyl" refers to an alkyl radical as defined herein, where one or more hydrogens are replaced by a halogen as defined herein, either by itself or as part of another substituent. The term "halogen" means fluoro, chloro, bromo, or iodo. Non-limiting examples of haloalkyls include fluoromethyl, difluoromethyl, trifluoromethyl, etc.

[0071] As used herein, either by itself or as part of another substituent, the term "heteroaryl" refers to an aryl group as defined herein, where at least one carbon atom is replaced by a heteroatom. In other words, it refers to a monocyclic aromatic ring system containing 5 to 12 carbon atoms or a ring system containing two rings fused together, typically a ring system containing 5 to 6 atoms, where one or more carbon atoms are replaced by oxygen, nitrogen, and / or sulfur atoms, and the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatoms may optionally be quaternized. Non-limiting examples of such heteroaryls include oxazolyl, thiazolyl, imidazolyl, furanyl, and pyrrolyl.

[0072] As used herein, either by itself or as part of another substituent, the term "nitrooxyalkyl" refers to the group-alkyl-ONO2, where alkyl is as defined herein.

[0073] In one embodiment, Z is a hydroxyl group (-OH) substituted with the therapeutic agent. In one embodiment, R1 is a hydroxyl group (-OH) substituted with the therapeutic agent. In one embodiment, R2 is a hydroxyl group (-OH) substituted with the therapeutic agent. In this embodiment, any suitable therapeutic agent can be conjugated to the LPS molecular species either directly or through a suitable linker.

[0074] Means and methods for conjugating therapeutic agents with LPS molecular species are well known in the art. Examples of therapeutic agents suitable for conjugation with LPS molecular species include, but are not limited to, peptides, polypeptides, proteins, polymers, nucleic acid molecules, small molecules, mimetic drugs, synthetic drugs, inorganic molecules, organic molecules, radioisotopes, nanoparticles, and vectors.

[0075] Examples of suitable therapeutic agents for conjugate with LPS molecular species, either alternatively or additionally, include, but are not limited to, chemotherapeutic agents, targeted therapies, cytotoxic agents, antibiotics, antivirals, cell cycle synchronizers, ligands for cell receptors, immunomodulators, apoptosis promoters, anti-angiogenic agents, cytokines, growth factors, antibodies or their antigen-binding fragments, and antigens.

[0076] It should be clear that several therapeutic agents can be classified into multiple categories.

[0077] In one embodiment, the therapeutic agent is a chemotherapeutic agent.

[0078] As used herein, the term “chemotherapeutic agent” refers to any molecule that is effective in inhibiting tumor growth.

[0079] Suitable examples of chemotherapeutic agents include those listed in subgroup L01 of the Anatomical Therapeutic Chemistry Classification System.

[0080] Suitable examples of chemotherapeutic agents include: i. Alkylating agents, for example. • Nitrogen mustard containing chlormethine, cyclophosphamide, ifosfamide, trophosfamide, chlorambucil, melphalan, prednimustine, bendamustine, uramustine, chlornafadin, chlorophosphamide, estralnustine, mechloretamine, mechloretamine oxide hydrochloride, nobenbitin, phenesterine, uracil mustard, etc. Nitrosourea containing carmustine, lomustine, semustine, fotemustine, nimustine, ranimustine, streptozocin, chlorozotocin, etc. Alkyl sulfonates including busulfan, mannosulfan, and threosulfan, Aziridines containing carbocone, thiotepa, triadicone, triethylenemelamine, benzodopa, metredopa, uredopa, etc.; hydrazines containing procarbazine, etc. Triazenes containing dacarbazine, temozolomide, etc.; ethyleneimines and methylamelamines containing altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphaarnide, trimethylomelamamine, etc. • In addition, mitobronitol, pipobromane, actinomycin, bleomycin, mitomycin (including mitomycin C, etc.), plicamycin, and others, ii. Acetogenins, for example, bratacin, bratacinone, etc. iii. Benzodiazepines, e.g., 2-oxoquazepam, 3-hydroxyphenazepam, bromazepam, camazepam, carburazepam, chlordiazepoxide, sinazepam, cinorazepam, clonazepam, cloniprazepam, chlorazepate, siprazepam, delarazepam, demoxepam, desmethylflunitrazepam, debazepide, diazepam, diclarazepam, difludiazepam, doxefazepam, elzepam, ethylcarburazepate, ethyldi Razepate, ethyl loflazepate, flubromazepam, flutazepam, fludiazepam, flunitrazepam, flurazepam, flutemazepam, flutoprazepam, fosazepam, gidazepam, harazepam, ikurazepam, irazepine, kenazepine, ketazolam, lorazepam, lormetazepam, rufladom, meclonazepam, medazepam, mennitrazepam, metaclazepam, motrazepam, N-desalkylflurazepam, nihoxibam, nimetazepam, nitema Zepam, nitrazepam, nitrazepate, nordazepam, nortetrazepam, oxazepam, phenazepam, pinazepam, pivoxazepam, prazepam, proflazepam, cuzepam, QH-II-66, lectrazepam, RO4491533, Ro5-4864, SH-I-048A, surazepam, temazepam, tetrazepam, tifluadom, tolfazepam, triflunordazepam, tucrazepam, urdazepam, alphendazam, clobazam, CP-14 14S, Lofendazam, Triflubazam, Glyisopam, GYKI-52466, GYKI-52895, Nerisopam, Tarampanel, Tofisopam, Azinazolam, Alprazolam, Bromazolam, Clonazolam, Estazolam, Flualprazolam, Flubromazolam, Flunitrazolam, Nitrazolam, Pyrazolam, Triazolam, Bretazenil, Climazolam, EVT-201, FG-8205, Flumazenil, GL-II-73, Imidazennil, 123I-Iomazenil, L-655,708, Loprazolam, Midazolam, PWZ-029, Imazolam, Ro15-4513, Ro48-6791, Ro48-8684, Ro4938581, Salmazenil, SH-053-R-CH3-2'F, Cloxazolam, Flutazolam, Haloxazolam, Mexazolam, Oxazolam, Bentazepam, Cloth Azepam, brotizolam, cyclotizolam, dechloroethizolam, etizolam, fluclotizolam, islapafant, JQ1, metizolam, olanzapine, terenzepine, lopirazepam, zapizolam, razobazam, lipazepam, zolazepam, zomebazam, zometapine, premazepam, clazolam, anthramycin, avizafone, rilmazafone, etc. iv. Antimetabolites, for example, Folic acid antagonists including aminopterin, methotrexate, pemetrexed, pralatrexate, pteropterin, larcitrexed, denopterin, trimethrexate, pemetrexed, etc. • Purine analogs including pentostatin, cladribine, clofarabine, fludarabine, nerarabine, thioguanine, and mercaptopurine. Pyrimidine analogs including fluorouracil, capecitabine, doxifluridine, tegafur, tegafur / gimeracil / oteracil, carmofur, floxuridine, cytarabine, gemcitabine, azacitidine, decitabine, and others, • Hydroxycarbamide, etc. v. Androgens, for example, carsterone, dromostanolone propionate, epithiostanol, mepitiostane, testolactone, etc. vi. Anti-adrenaline, for example, aminoglutethimide, mitotane, trilostane, etc. vii. Folic acid supplements, for example, fluorophosphate, viii. Maytansinoids, for example, maytansine, anthamitosine, etc. ix. Platinum analogs, for example, platinum, carboplatin, cisplatin, dicycloplatin, nedaplatin, oxaliplatin, satraplatin, etc. x. Anti-hormone drugs, for example. • Anti-estrogen drugs including tamoxifen, raloxifen, aromatase inhibitor 4(5)-imidazole, 4-hydroxytamoxifen, trioxyfen, keoxyfen, LY117018, onapristone, toremifene, etc. • Antiandrogens including flutamide, nilutamide, bicalutamide, leuprolide, goserelin, etc. xi. Trichothecenes, for example, T-2 toxin, beracrine A, lolidinin A, angidin, etc. xii. Toxoids, for example, cabazitaxel, docetaxel, larotaxel, ortataxel, paclitaxel, tesetaxel, etc. xiii. Others, for example, camptothecin (including its synthetic analog topotecan), bryostatin, callistatin, CC-1065 (including its synthetic analogs adzeresin, karzeresin, and bizeresin), cryptophycin (including cryptophycin 1 and cryptophycin 8), dorastatin, duocalmycin (including its synthetic analogs KW-2189 and CBI-TMI), eleuterobin, pancratistatin, sarcodicin, spor Dzhistatin, acrasinomycin, ausramycin, azaserin, bleomycin, kactinomycin, carabicin, canninomycin, cardinophilin, chromomycin, dactinomycin, daunorubicin, detobicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolidine-doxorubicin, deoxydoxorubicin, etc.), epil Bicin, esorubicin, idanrubicin, marcelomycin, mycophenolic acid, nogalarnycin, peplomycin, podphylromycin, puromycin, keramycin, rhodorubicin, streptoglin, streptozocin, tubercidine, ubenimex, dinostatin, zolubicin, acegraton, aldofsphamide glycoside, aminolevulinic acid, amsacrin, bestlovesil, bisantren, e Datraxate, Defofamine, Demecolsin, Diadicone, Elhornitine, Elliptinium acetate, Epotilon, Etoglucid, Gallium nitrate, Hydroxyurea, Lentinan, Ronidamin, Mitoguazone, Mitoxantrone, Mopidamol, Nitracrine, Fenamet, Pirarubicin, Podophyllic acid, 2-Ethylhydrazide, PSK (registered trademark), Lazoxane, Rhizoxin, Schizophyllan, Spirogennanium, Tenuazonic acid, 2,2',This includes, but is not limited to, 2''-trichlorotriethylalunine, urethane, vindesine, dacarbazine, manomustine, mitobromitol, mitractol, pipobromane, gasitosine, arabinoside, 6-thioguanine, vinblastine, etoposide, vincristine, vinorelbine, navelbine, novantrone, teniposide, daunomycin, xeloda, ibandronate, CPT-11, topoisomerase inhibitor RFS2000, topoisomerase I inhibitor SN38, difluoromethylornithine, retinoic acid, etc.

[0081] In one embodiment, the therapeutic agent is a targeted therapy agent.

[0082] As used herein, the term “targeted therapy agent” refers to any molecule that targets one or more specific target molecules (e.g., proteins) involved in tumor development, tumor progression, tumor metastasis, tumor cell proliferation, cell repair, etc.

[0083] Suitable examples of targeted therapies include, but are not limited to, tyrosine kinase inhibitors, serine / threonine kinase inhibitors, and monoclonal antibodies.

[0084] Suitable examples of targeted therapies include HER1 / EGFR inhibitors (e.g., brigatinib, erlotinib, gefitinib, olmutinib, osimertinib, rosiletinib, vandetanib, etc.), HER2 / neu inhibitors (e.g., afatinib, lapatinib, neratinib, etc.), C-kit and PDGFR inhibitors (e.g., axitinib, masitinib, pazopanib, sunitinib, sorafenib, toceranib, etc.), and FLT3 inhibitors. (e.g., restaurtinib), VEGFR inhibitors (e.g., axitinib, cedilanib, lenvatinib, nintedanib, pazopanib, regorafenib, semaxanib, sorafenib, sunitinib, tivozanib, toceranib, vandetanib, etc.), RET inhibitors (e.g., vandetanib, entrectinib, etc.), c-MET inhibitors (e.g., cabozantinib, etc.), bcr-abl inhibitors (e.g., imatinib, dasati) (e.g., nilotinib, ponatinib, radotinib), Src inhibitors (e.g., bosutinib, dasatinib), Janus kinase inhibitors (e.g., restaurtinib, momerotinib, ruxolitinib, pacritinib), MAP2K inhibitors (e.g., cobimetinib, selumetinib, trametinib, binimetinib), EML4-ALK inhibitors (e.g., alectinib, brigatinib, ceritinib, crizotinib), bru Ton inhibitors (e.g., ibrutinib), mTOR inhibitors (e.g., everolimus, temsirolimus), Hedgehog inhibitors (e.g., sonidecib, bismodegib), CDK inhibitors (e.g., palbociclib, ribociclib), anti-HER1 / EGFR monoclonal antibodies (e.g., cetuximab, nesitumumab, panitumumab), anti-HER2 / neu monoclonal antibodies (e.g., ado-trastuzumab)This includes, but is not limited to, emtansine, pertuzumab, trastuzumab, trastuzumab-dkst, etc., anti-EpCAM monoclonal antibodies (e.g., catumakisomab, edrecolomab, etc.), anti-VEGF monoclonal antibodies (e.g., bevacizumab, bevacizumab-awwb, etc.), anti-CD20 monoclonal antibodies (e.g., ibritumomab, obinutuzumab, ocrelizumab, ofatumumab, rituximab, tositumomab, etc.), anti-CD30 monoclonal antibodies (e.g., brentuximab, etc.), anti-CD33 monoclonal antibodies (e.g., gemtuzumab, etc.), anti-CD52 monoclonal antibodies (e.g., alemtuzumab, etc.), and their antigen-binding fragments.

[0085] In one embodiment, the therapeutic agent is a cytotoxic agent.

[0086] As used herein, the term “cytotoxic agent” refers to any molecule that causes cell death by any mechanism.

[0087] Suitable examples of cytotoxic agents include, but are not limited to, taxanes, anthracyclines, alkylating agents, vinca alkaloids, antimetabolites, platinum compounds, steroids, and chemotherapeutic agents.

[0088] Preferred taxanes include, but are not limited to, cabazitaxel, docetaxel, lalotaxel, ortataxel, paclitaxel, and tesetaxel.

[0089] Preferred examples of anthracyclines include, but are not limited to, acralubicin, amrubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, pirarubicin, barurubicin, and doxorubicin.

[0090] Suitable examples of alkylating agents include nitrogen mustards (e.g., chlormethine, cyclophosphamide, ifosfamide, trophosphamide, chlorambucil, melphalan, prednimustine, bendamustine, uramustine, etc.), nitrosoureas (e.g., carmustine, lomustine, semustine, fotemustine, nimustine, ranimustine, streptozocin, etc.), and alkyl sulfonates (e.g., busulfan, mannosulfonate). This includes, but is not limited to, phans, treosulfan, etc., aziridines (e.g., carbocone, thiotepa, triadicone, triethylenemelamine, benzodopa, metredopa, uredopa, etc.), hydrazines (e.g., procarbazine, etc.), triazenes (e.g., dacarbazine, temozolomide, etc.), altretamine, mitobronitol, pipobromane, actinomycin, bleomycin, mitomycin, and plicamycin.

[0091] Suitable examples of vinca alkaloids include, but are not limited to, vinblastine, vincristine, vinflunin, vindesine, and vinorelbine.

[0092] Suitable examples of antimetabolites include, but are not limited to, folate antimetabolites (e.g., aminopterin, methotrexate, pemetrexed, pralatrexate, larcitrexed, pemetrexed, etc.), purine analogs (e.g., pentostatin, cladribine, clofarabine, fludarabine, nerarabine, thioguanine, mercaptopurine, etc.), pyrimidine analogs (e.g., fluorouracil, capecitabine, doxifluridine, tegafur, tegafur / gimeracil / oteracil, carmofur, floxuridine, cytarabine, gemcitabine, azacitidine, decitabine, etc.), and hydroxycarbamides.

[0093] Suitable examples of platinum-based agents include, but are not limited to, carboplatin, cisplatin, dicycloplatin, nedaplatin, oxaliplatin, and satraplatin.

[0094] Suitable examples of steroids include, but are not limited to, estrogen receptor modulators, androgen receptor modulators, and progesterone receptor modulators.

[0095] Preferred examples of chemotherapeutic agents are described herein.

[0096] In one embodiment, the therapeutic agent is an antibiotic.

[0097] Suitable examples of antibiotics include those listed in subgroup J01 of the Anatomical Therapeutic Chemistry Classification System.

[0098] Suitable examples of antibiotics include: i. Aminoglycosides, for example, amikacin, gentamicin, kanamycin, neomycin, netylmycin, streptomycin, tobramycin, paramycin, etc. ii. Ansamycin, for example, geldanamycin, herbimycin, etc. iii. Carbasephalosins, for example, loracalbef, iv. Carbapenems, for example, ertapenam, doripenem, imipenem, cilastatin, meropenem, etc. v. First-generation cephalosporins, such as cefadroxil, cefazolin, cephalothin, cephalexin, etc. vi. Second-generation cephalosporins, such as cefracrol, cephamandol, cefoxitine, cefprodil, cefuroxime, etc. vii. Third-generation cephalosporins, such as cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, etc. viii. Fourth-generation cephalosporins, such as cefepime, ix. Fifth-generation cephalosporins, such as ceftobiprole, x. Glycopeptides, for example, teicoplanin, vancomycin, etc. xi. Macrolides, for example, axithromycin, clarithromycin, dylithromycin, erythromycin, roxithromycin, troleandmycin, telithromycin, spectinomycin, etc. xii. Monobactams, for example, axtreme leonam, xiii. Penicillins, for example, amoxicillin, ampicillin, axlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin, naphcillin, oxacillin, penicillin, peperacillin, ticalcillin, etc. xiv. Antibiotic polypeptides, e.g., bacitracin, colistin, polymyxin B, etc. xv. Quinolones, for example, ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, remefloxacin, moxifloxacin, norfloxacin, orfloxacin, trovafloxacin, etc. xvi. Sulfonamides, for example, mafenide, prontosil, sulfacetamide, sulfamethizol, sulfanilamide, sulfasalazine, sulfisoxazole, trimethoprim, trimethoprim-sulfamethoxazole, etc. xvii. Tetracyclines, for example, demeclocycline, doxycycline, minocycline, oxytetracycline, tetracycline, and xviii. Others include, but are not limited to, arspenamine, chloramphenicol, clindamycin, lincomycin, ethambutol, fosfomycin, fusidic acid, furazolidone, isoniazid, linezolid, metronidazole, mupirocin, nitrofurantoin, platensimycin, pyrazinamide, quinupristin / dalfopristin, rifampicin / rifampicin, tinidazole, etc.

[0099] In one embodiment, the therapeutic agent is an antiviral drug.

[0100] Suitable examples of antiviral drugs include those listed in subgroup J05 of the Anatomical Therapeutic Chemistry Classification System.

[0101] Suitable examples of antiviral drugs include acemannan, acyclovir, acyclovir sodium, adamanthanamine, adefovir, adenine arabinoside, alovudine, albilceptosudotoxin, amantadine hydrochloride, aranothine, allyldone, atevirdin mesylate, avidin, cidofovir, sipamphylline, cytarabine hydrochloride, BMS806, C31G, carrageenan, zinc salts, cellulose sulfate, cyclodextrin, dapivine, and dapivine mesylate. Ravirdin, decyclovir, dextrin 2-sulfate, didanosine, disoxalil, dolutegravir, edoxudine, enviradine, envirodyne, etravirine, famciclovir, famotin hydrochloride, phiacitabine, fialuridine, fosalilate, foscarnet sodium, phosphonet sodium, FTC, ganciclovir, ganciclovir sodium, GSK1265744, 9-2-hydroxyethoxymethylgua Nin, ibalizumab, idoxuridine, interferon, 5-iodine-2'-deoxyuridine, IQP-0528, ketoxal, lamivudine, lobucavir, maraviloc, memotin pirodavir, penciclovir, raltegravir, ribavirin, rimantadine hydrochloride, rilpivirine (TMC-278), saquinavir mesylate, SCH-C, SCH-D, somantadine hydrochloride, sorivudine, statron, stabudine, T20, tyrolone hydrochloride This includes, but is not limited to, TMC120, TMC125, trifluridine, trifluorothymidine, tenofovir, tenofovir alefenamide, tenofovir disoproxil fumarate, tenofovir prodrugs, UC-781, UK-427, UK-857, valacyclovir, valacyclovir hydrochloride, vidarabine, vidarabine phosphate, vidarabine sodium phosphate, viroxime, zalcitabine, zidovudine, and dinviroxime.

[0102] In one embodiment, the therapeutic agent is a cell cycle synchronizer.

[0103] As used herein, the term “cell cycle synchronizer” refers to any molecule that, upon administration, can unify the cell cycle of a population of cells into the same phase.

[0104] Suitable examples of cell cycle synchronizers include, but are not limited to, affidicorin, butyrolactone I, colchicine, cycloheximide, demecolsin, dimethyl sulfoxide, 5-fluorodeoxyuridine, Hoechst33342, mimosine, nocodazole, roscovitine, and thymidine.

[0105] In one embodiment, the therapeutic agent is a ligand for a cell receptor.

[0106] As used herein, the term “ligand to a cell receptor” refers to any molecule that binds to a cell receptor (e.g., cell surface receptors, intracellular receptors, or co-receptors, including transcription factors), including agonists and antagonists, as well as partial agonists, inverse agonists, and allosteric modulators.

[0107] Suitable examples of ligands for cell receptors include AATYK receptor, acetylcholine receptor, ADGRG receptor, adiponectin receptor, adrenergic α1 receptor, adrenergic α2 receptor, adrenergic β1 receptor, adrenergic β2 receptor, adrenergic β3 receptor, adrenomedullin receptor, AMPA receptor, anaphylatoxin receptor, angiopoietin receptor, angiotensin receptor, anti-Müllerian hormone receptor, apelin receptor, asialoglycoprotein receptor, AXL receptor, and benzodiazepine receptor. Body, bile acid receptor, bombesin receptor, bone morphogenetic protein receptor, bradykinin receptor, brain-specific angiogenesis inhibitor, cadherin receptor, calcitonin receptor, calcitonin receptor-like receptor, calcium-sensing receptor, cannabinoid receptor, CD97 receptor, chemokine receptor, cholecystokinin receptor, complement receptor, corticotropin-releasing hormone receptor, CysLT receptor, cytokine receptor, DDR receptor, dopamine receptor, EBI2 receptor, ectodiprasrin A receptor, EGF module-containing mucin-like hormone receptor, EGF receptor, E Ndothelin receptor, EPH receptor, estrogen receptor, FGF receptor, free fatty acid receptor, frizzled receptor, FSH receptor, GABAB receptor, galanin receptor, GHB receptor, ghrelin receptor, glucagon receptor, glucagon-like peptide receptor, glutamate receptor, glycine receptor, gonadotropin receptor, gonadotropin-releasing hormone receptor, GPRC6A receptor, growth factor receptor, growth hormone receptor, growth hormone-releasing hormone receptor, guanylate cyclase-binding receptor, HGF receptor, histamine receptor, hydroxycarboxylic acid receptor Immunoglobulin receptor, insulin receptor, kainate receptor, KiSS1-derived peptide receptor, latrophyllin receptor, leptin receptor, leukotriene B4 receptor, lipoprotein receptor-associated protein receptor, LTK receptor, luteinizing hormone / chorionic gonadotropin receptor, lysophosphatidic acid receptor, lysophospholipid receptor, mannose receptor, MAS receptor, melanin-concentrating hormone receptor, melanocortin receptor, melatonin receptor, methosthera-like protein receptor, motilin receptor, MuSK receptor, N-acetylglucosamine receptor,Neuromedin receptor, neuropeptide B / W receptor, neuropeptide FF receptor, neuropeptide S receptor, neuropeptide Y receptor, neuropilin receptor, neurotensin receptor, N-formyl peptide receptor, nicotinic acetylcholine receptor, NMDA receptor, nuclear receptor, olfactory receptor, opioid receptor, opsin receptor, orexin receptor, oxoeicosanoid receptor, oxoglutarate receptor, oxytocin receptor, parathyroid hormone receptor, PDGF receptor, pituitary cyclase-activated polypeptide type I receptor, platelet-activating factor receptor, progestin and adipo-Q receptor, prokinetisin receptor, prolactin receptor, prolactin-releasing peptide receptor, prostacyclin receptor, prostaglandin receptor, protease-activated receptor, PTK7 receptor, purinergic adenosine receptor, purinergic P2X receptor, purinergic P2Y receptor, relaxin receptor, RE This list includes, but is not limited to, ligands that bind to T receptors, retinoic acid-inducible orphan G protein-coupled receptors, ROR receptors, ROS receptors, RYK receptors, scavenger receptors, secretin receptors, serine / threonine-specific protein kinase receptors, serotonin receptors, blunting receptors, somatostatin receptors, sphingosine-1-phosphate receptors, SREB receptors, interferon-stimulating gene-stimulating factor (STING) receptors, succinate receptors, tachykinin receptors, thromboxane receptors, tyrotropin receptors, thyroid-stimulating hormone-releasing hormone receptors, Toll-like receptors, trace amine-related receptors, transferrin receptors, Trk receptors, tumor necrosis factor receptors, tyrosine phosphatase receptors, urotensin-II receptors, vasoactive intestinal peptide receptors, vasopressin receptors, VEGF receptors, vomeronasal receptors, and zinc-activated ion channel receptors.

[0108] In one embodiment, the therapeutic agent is an immunomodulator.

[0109] Suitable examples of immunomodulators include, but are not limited to, immunostimulants and immunosuppressants.

[0110] Suitable examples of immunostimulants include those listed in subgroup L03 of the Anatomical Therapeutic Chemistry Classification System.

[0111] Suitable examples of immunostimulants include cytokines (e.g., filgrastim, pegfilgrastim, lenograstim, morglamostim, salglamostim, ancestim, albuinterferon, interferon alpha-2a, peginterferon alpha-2a, interferon alpha-2b, peginterferon alpha-2b, interferon alpha-n1, interferon alpha-con-1, interferon alpha-n3, interferon beta-1a, interferon beta-1b, interferon gamma, aldesleukin, oprelbequin, etc.); and immune checkpoint inhibitors (e.g., CTLA4, PD-1, PD-L1, LAG-3, B7-H3). Inhibitors of B7-H4, TIM3, A2AR, GITR, CD47, TNFR2, CD19 and / or IDO, e.g., nivolumab, pembrolizumab, semiprimab, spartalizumab, canrelizumab, cintilimab, tislerizumab, tripalimab, AMP-224, AMP-514, pizilizumab, MPDL3280A, MDX-1105, MEDI-4736, Allerumab, ipilimumab, tremelimumab, pizilizumab, IMP321, MGA271, BMS-986016, lirirumab, urerumab, PF-05082566, IPH2101, MEDI-6469, CP-870, 893, mogamulizumab, valirumab, avelumab, galiximab, AUNP12, indoximod, NLG-919, INCB024360, etc.Toll-like receptor agonists (e.g., buprenorphine, carbamazepine, ethanol, fentanyl, GS-9620, imiquimod, lephytrimod, levorphanol, methadone, morphine, (+)-morphine, morphine-3-glucuronide, oxcarbazepine, oxycodone, pethidine, reximod, SD-101, tapentadol, chilsotrimod, VTX-2337, glucuronoxylomannan from Cryptococcus) MALP-2 from Mycoplasma, MALP-404 from Mycoplasma, OspA from Borrelia, porin from Neisseria or Haemophilus, hsp60, hemagglutinin, LcrV from Yersinia, bacterial flagellin, lipopolysaccharide, lipoteichoic acid, lipomannan from Mycobacterium, glycosylphosphatidylinositol, lysophosphatidylserine, lipophosphoglycan from Leishmania, Saccharomyces Zymosan, Pam2CGDPKHPKSF, Pam3CSK4, CpG oligodeoxynucleotide, poly(I:C) nucleic acid sequences, poly(A:U) nucleic acid sequences, double-stranded viral RNA, etc.); STING receptor agonists (e.g., those described in International Publication No. 2017100305, vadimezan, CL656, ADU-S100, 3'3'-cGAMP, 2'3'-cGAMP, MLRR-S2CDG, MLRR- This includes, but is not limited to, S2cGAMP, cyclic di-GMP, DMXAA, DiABZI, CD1 ligand, growth hormone, immunocyanin, pegademase, prolactin, tasonelmin, female steroids, histamine dihydrochloride, polyICLC, vitamin D, lentinan, prelixafor, lokinimex, mifamultide, glatiramer acetate, thymopentin, thymosin α1, thymrin, polyinosinic acid: polycytidylic acid, pyrotimod, Bacillus Calmette-Guerin, melanoma vaccine, and siplucel-T.

[0112] Suitable examples of immunosuppressants include those listed in subgroup L04 of the Anatomical Therapeutic Chemistry Classification System.

[0113] Suitable examples of immunosuppressants include: i. Antimetabolites, for example Folic acid antagonists including aminopterin, methotrexate, pemetrexed, pralatrexate, pteropterin, larcitrexed, denopterin, trimethrexate, pemetrexed, etc. • Purine analogs including pentostatin, cladribine, clofarabine, fludarabine, nerarabine, thioguanine, and mercaptopurine. Pyrimidine analogs including fluorouracil, capecitabine, doxifluridine, tegafur, tegafur / gimeracil / oteracil, carmofur, floxuridine, cytarabine, gemcitabine, azacitidine, decitabine, and others, (e.g., hydroxycarbamide), ii. Macrolides, for example, tacrolimus, cyclosporine, pimecrolimus, abethymus, gusperimus, etc. iii. Immunomodulatory imitation drugs, such as lenalidomide, pomalidomide, thalidomide, apremilast, etc. iv. IL-1 receptor antagonists (e.g., Anakinra), v. mTOR inhibitors (e.g., sirolimus, everolimus, ridafololimus, temsirolimus, umilolimus, zotarolimus, etc.), vi. Serum-targeted antibodies, such as eculizumab, adalimumab, aferimomab, certolizumab pegol, golimumab, infliximab, nererimomab, mepolizumab, omalizumab, falalimomab, elcilimomab, lebrikizumab, ustekinumab, secukinumab, etc. vii. Cell-targeting antibodies, e.g., muromonab-CD3, otelixizumab, teprizumab, bicilizumab, crenoliximab, keriximab, zanolimmab, efalizumab, erulizumab, obinutuzumab, rituximab, ocrelizumab, pascolizumab, gomiliximab, lumiliximab, teneliximab, tralizumab, aselizumab, galiximab, gabirimomab, luprizumab, belimumab, bricibimod, ipilimumab tremelimumab, vertilimumab, redelimumab, meterimumab, natalizumab, tocilizumab, odolimumab, basiliximab, daclizumab, inorimomab, zolimomab aritox, atrolimumab, sedelizumab, fontrizumab, masurimomab, morolimumab, pexerizumab, reslizumab, loberizumab, cyprizumab, talizumab, terimomab aritox, bapariximab, bepalimomab zolimab aritumab, etc. viii. Fusion antibodies, such as abatacept, belatacept, etanercept, pegsnercept, aflibercept, alefacept, lilonacept, etc., are included but not limited to these.

[0114] In one embodiment, the therapeutic agent is an apoptosis promoter.

[0115] As used herein, the term “apoptosis promoter” refers to any molecule that, when administered, can induce apoptosis or programmed cell death in cells.

[0116] Suitable examples of apoptosis-promoting agents include, but are not limited to, histone deacetylase inhibitors (e.g., sodium butyrate, depsipeptide, etc.), bortezomib, deguerin, favopyridol, fenretinide, fludarabine, kaempferol, miltefosine, narcyclacin, ovatocrax, oblimersen, and oncrasin.

[0117] In one embodiment, the therapeutic agent is an anti-angiogenic agent.

[0118] As used herein, the term “anti-angiogenic agent” refers to a molecule that reduces or prevents angiogenesis, the process by which blood vessels grow and develop. Suitable examples of anti-angiogenic agents include, but are not limited to, inhibitors of any of the vascular endothelial growth factors VEGF-A, VEGF-B, VEGF-C, or VEGF-D, which are major inducers of angiogenesis in normal and pathological conditions and are essential for embryonic angiogenesis.

[0119] Additionally or alternatively, anti-angiogenic agents may also inhibit other angiogenic factors, such as, but are not limited to, members of the fibroblast growth factor (FGF) family including FGF-1 (acidic), FGF-2 (basic), FGF-4, or FGF-5, or angiopoietin-1, a factor that signals through endothelial cell-specific Tie2 receptor tyrosine kinase, or the receptor for any of these angiogenic factors.

[0120] In one embodiment, the therapeutic agent is a cytokine.

[0121] Preferred examples of cytokines include, but are not limited to, chemokines, tumor necrosis factor, interleukins, and colony-stimulating factors.

[0122] Suitable examples of chemokines include chemokine CC motif ligands (CCL) 1, CCL 2, CCL 3, CCL 4, CCL 5, CCL 6, CCL 7, CCL 8, CCL 9, CCL 11, CCL 12, CCL 13, CCL 14, CCL 15, CCL 16, CCL 17, CCL 18, CCL 19, CCL 20, CCL 21, CCL 22, CCL 23, CCL 24, CCL 25, CCL 26, CCL 27, and CCL 28. This includes, but is not limited to, chemokine CXC motif ligands (CXCL) 1, CXCL2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8, CXCL9, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL15, CXCL16, CXCL17, fractalkines, and chemokine C motif ligands (XCL) 1 and XCL2.

[0123] Suitable examples of tumor necrosis factors include, but are not limited to, tumor necrosis factor (TNF)α, lymphotoxin, OX40L, CD40LG, Fas ligand, CD70, CD153, 4-1BB ligand, TNF-related apoptosis-inducing ligand (TRAIL), receptor activator of nuclear factor κ-β ligand (RANKL), proliferation-inducing ligand (APRIL), B cell activator (BAFF), and ectodiprasrin A (EDA).

[0124] Suitable examples of interleukins include interleukin-(IL-)1α, IL-1β, IL-1Ra, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20, IL-21, IL-22, IL-2 3, IL-24, IL-25, IL-26, IL-27, IL-28, IL-29, IL-30, IL-31, IL-32, IL-33, IL-34, IL-35, IL-36α, I Includes, but is not limited to, L-36β, IL-36γ, IL-36Ra, IL-37, IL-38, interferon (IFN)α, IFNβ, IFNκ and IFNω.

[0125] Preferred examples of colony-stimulating factors include, but are not limited to, granulocyte-macrophage colony-stimulating factor (GM-CSF) (including granulocyte-colony-stimulating factor (G-CSF) and macrophage colony-stimulating factor (M-CSF)), hematopoietin, and thrombopoietin.

[0126] In one embodiment, the therapeutic agent is a growth factor.

[0127] Suitable examples of growth factors include fibroblast growth factor (FGF) 1, FGF2, FGF3, FGF4, FGF5, FGF6, FGF7, FGF8, FGF9, FGF10, FGF11, FGF12, FGF13, FGF14, FGF16, FGF17, FGF18, FGF19, FGF20, FGF21, FGF23, transforming growth factor (TGF) α, epidermal growth factor (EGF), heparin-bound EGF-like growth factor (HB-EGF), and transforming growth factor This includes, but is not limited to, (TGF)β, insulin-like growth factor (IGF) 1, IGF 2, platelet-derived growth factor (PDGF) subunit A (PDGFA), PDGF subunit B (PDGFB), PDGF subunit C (PDGFC), PDGF subunit D (PDGFD), vascular endothelial growth factor (VEGF)-A, VEGF-B, VEGF-C, VEGF-D, placental growth factor (PGF), nerve growth factor (NGF), and hepatocyte growth factor (HGF).

[0128] In one embodiment, the therapeutic agent is an antibody or its antigen-binding fragment.

[0129] Preferred examples of antibodies or their antigen-binding fragments include, but are not limited to, monoclonal antibodies, polyclonal antibodies, bispecific antibodies, multispecific antibodies, antibody fragments and antibody mimics, such as scFv, di-scFv, tri-scFv, single-domain antibodies, nanobodies, bispecific T-cell engagers (BiTEs), Fab, F(ab')2, Fab', chemically linked Fab, X-Link Fab, tandem-scFv / BiTE, diabodies, tandem diabodies, diabodies-Fc fusions, tandem diabodies-Fc fusions, tandem diabodies-CH3 fusions, tetra-scFv-Fc fusions, bivariable-domain immunoglobulins, knobholes, chain exchange operation domains, cross-Mab, quadruple-chain-derived bispecific antibodies, single-domain-based antibodies, affibodies, affin, affimers, afitins, alphabodies, antikalin, avimers, DARPins, Kunitz-domain peptides, monobodies and nanoCLAMPs.

[0130] In one embodiment, the therapeutic agent is an antigen.

[0131] As used herein, the term “antigen” refers to any substance that, after any incubation period (typically several days to several weeks in humans), induces a state of susceptibility and / or immune response and reacts in a demonstrable manner with antibodies and / or immune cells of a sensitized subject in vivo or in vitro.

[0132] Preferred examples of antigens include, but are not limited to, pathogen-associated antigens (e.g., antigens of viruses, fungi, or bacteria, or immunogenic molecules derived therefrom), autoantigens (e.g., cellular antigens including cells containing normal transplant antigens and / or tumor-associated antigens, RR-Rh antigens, and antigens characteristic of or specific to certain cells, tissues, or bodily fluids), allergen-associated antigens (e.g., those related to environmental allergens including plants, pollen, mold, dust, insects, dandruff, and venom; occupational allergens including latex, dandruff, urethane, epoxy resins, etc.; foods including shellfish, peanuts, eggs, dairy products, etc.; and drugs including antibiotics and anesthetics), neoantigens, and vaccines.

[0133] Examples of antigens include 17-IA, 4-1BB, 4Dc, 6-keto-PGF1a, 8-iso-PGF2a, 8-oxo-dG, A1 adenosine receptor, A33, ACE, ACE-2, activin, activin A, activin AB, activin B, activin C, activin RIA, activin RIA ALK-2, and activin RIB. ALK-4, Activin RIIA, Activin RIIB, ADAM, ADAM10, ADAM12, ADAM15, ADAM17 / TACE, ADAM8, ADAM9, ADAMTS, ADAMTS4, ADAMTS5, Adresin, aFGF, ALCAM, ALK, ALK-1, ALK-7, Alpha-1-Antitrypsin, Alpha-V / Beta-1 Antagonist, ANG, Ang, APAF-1, APE, APJ, APP, APRIL, AR, ARC, ART, Artemin, Anti-Id, ASPAR TIC, atrial natriuretic peptide, av / b3 integrin, Axl, b2M, B7-1, B7-2, B7-H, B lymphocyte-stimulating factor (BlyS), BACE, BACE-1, Bad, BAFF, BAFF-R, Bag-1, BAK, Bax, BCA-1, BCAM, Bcl, BCMA, BDNF, b-ECGF, bFGF, BID, Bik, BIM, BLC, BL-CAM, BLK, BMP, BMP-2, BMP-2a, BMP-3 osteogenin, BMP-4, BMP-2b, BMP-5, BMP-6Vgr-1, BMP-7 (OP-1), BMP-8 (BMP-8a, OP-2), BMPR, BMPR-IA (ALK-3), BMPR-IB (ALK-6), BRK-2, RPK-1, BMPR-II (BRK-3), BMP, β-NGF, BOK, Bombecin, Bone-derived neurotrophic factor, BPDE, BPDE-DNA, BTC, Complement factor 3 (C3), C3a, C4, C5, C5a, C10, CA125, CAD-8, Calcitonin, cAMP, Carcinoembryonic antigen (CEA), Cancer-associated antigen, Cathepsin A, Cathepsin B, Ca Cathepsin C / DPPI, Cathepsin D, Cathepsin E, Cathepsin H, Cathepsin L, Cathepsin O, Cathepsin S, Cathepsin V, Cathepsin X / Z / P, CBL, CCI, CCK2, CCL, CCL1, CCL11, CCL12, CCL13, CCL14, CCL15, CCL16, CCL17, CCL18, CCL19, CCL2, CCL20, CCL21, CCL22, CCL23, CCL24, CCL25, CCL26, CCL27, CCL28, CCL3, CCL4, CCL5, CCL6, CCL7, C CL8, CCL9 / 10, CCR, CCR1, CCR10, CCR10, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CD1, CD2, CD3, CD3E, CD4, CD5, CD6, CD7, CD8, CD10, C D11a, CD11b, CD11c, CD13, CD14, CD15, CD16, CD18, CD19, CD20, CD21, CD22, CD23, CD25, CD27L, CD28, CD29, CD30, CD30L, CD32, CD33 (p67 protein CD34, CD38, CD40, CD40L, CD44, CD45, CD46, CD49a, CD52, CD54, CD55, CD56, CD61, CD64, CD66e, CD74, CD80(B7-1), CD89, CD95, CD123, CD137, CD138, CD140a, CD146, CD147, CD148, CD152, CD164, CEACAM5, CFTR, cGMP, CINC, botulinum toxin, Clostridium perfringens toxin, CKb8-1, CLC, CMV, CMVUL, CNTF, CNTN-1, COX, C-Ret, CRG-2, CT-1, CTACK, CTGF, CTLA-4, CX3CL1, CX3CR1, CXCL, CXCL1, CXCL2 , CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8, CXCL9, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL15 CXCL16, CXCR, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, Cyber-related antigen, DAN, DCC, DcR3, DC-SIGN, complement regulatory factor (disintegration-promoting factor), des(1-3)-IGF-I (brain IGF-1), Dhh, Jigokisin, DNAM-1, Dnase, Dpp, DPPIV / CD26, Dtk, ECAD EDA, EDA-A1, EDA-A2, EDAR, EGF, EGFR (ErbB-1), EMA, EMMPRIN, ENA, EDA, EDA, EGF, eNOS, Eot , エオタキシン1, EpCAM, エフリンB2 / EphB4, EPO, ERCC, E-セレクチン, ET-1, factor IIa, factor VII, factor VIIIc, factor IX, line-dimensional bud cell activity FAP, Fas, FcR1, FEN-1, FEN-1, FGF, FGF-19, FGF-2, FGF3, FGF-8, FGFR, FGFR-3, FEN-1, FL, F LIP, Flt-3, Flt-4, egg cell stimulation ホルモン, フラクタルカイン, FZD1, FZD2, FZD3, FZD4, FZD5, FZD6, FZD7, FZD8, FZD9, FZD10, G250, Gas6, GCP-2, GCSF, GD2, GD3, GDF, GDF-1, GDF-3 (Vgr-2), GDF-5 (BMP-14, CDMP-1), GDF-6 (BMP-13, CDMP-2), GDF-7 (BMP-12, CDMP-3), GDF-8 (Myostatin), GDF-9, GDF-15 (MIC-1), GDNF, GDNF, GFAP, GFRa-1, GFR-Alpha-1, GFR-Alpha-2, GFR-Alpha-3, GITR, Glucagon, Glut4, Glycoprotein IIb / IIIa (GPIIb / IIIa), GM-CSF, gp130, gp72, GRO, Growth Hormone Releasing Hormone, Hapten (NP Cap or NIP Cap), HB-EGF, HCC, HCMV gB Envelope Glycoprotein, HCMV gH envelope, HCMV UL, hematopoietic growth factor (HGF), Hep B gp120, heparanase, Her2, Her2 / neu (ErbB-2), Her3 (ErbB-3), Her4 (ErbB-4), herpes simplex virus (HSV) gB glycoprotein, HSV gD glycoprotein, HGFA, high molecular weight melanoma-associated antigen (HMW-MAA), HIV gp120, HIV IIIB gp 120V3 loop, HLA, HLA-DR, HM1.24, HMFGPEM, HRG, Hrk, human cardiac myosin, human cytomegalovirus (HCMV), human growth hormone (HGH), HVEM, 1-309, IAP, ICAM, ICAM-1, ICAM-3, ICE, ICOS, IFNg, Ig, IgA receptor, IgE, IGF, IGF-binding protein, IGF-1R, IGFBP, IGF-I, IGF- II, IL, IL-1, IL-1R, IL-2, IL-2R, IL-4, IL-4R, IL-5, IL-5R, IL-6, IL-6R, IL-8, IL-9, IL-10, IL-12, IL-13, IL-15, IL-18, IL-18R, IL-23, Interferon (INF)-alpha, INF-beta, INF-gamma, Inhibin, iNOS, Insulin A chain, Insulin B chain, Insulin-like Growth Factor 1, Integrin Alpha 2, Integrin Alpha 3, Integrin Alpha 4, Integrin Alpha 4 / Beta 1, Integrin Alpha 4 / Beta 7, Integrin Alpha 5 (Alpha V), Integrin Alpha 5 / Beta 1, Integrin Alpha 5 / Beta 3, Integrin Alpha 6, Integrin Beta 1, Integrin Beta 2, Integrin Beta 2, Interferon Gamma, IP-10, I-TAC, JE, Kallikrein 2, Kallikrein 5, Kallikrein 6, Kallikrein 11, Kallikrein 12, Kallikrein 14, Kallikrein 15, Kallikrein L1, Kallikrein L2, Kallikrein L3, Kallikrein L4, KC, KDR, Keratinocyte Growth Factor (KGF), Laminin 5, LAMP, LAP, LAP (TGF-1), Latent TGF-1, Latent TGF-1bp1, LBP, LDGF, LECT2, Lefty, Lewis Y antigen, Lewis Y-related antigen, LFA-1, LFA-3, Lfo, LIF, LIGHT, lipoprotein, LIX, LKN, Lptn, L-selectin, LT-a, LT-b, LTB4, LTBP-1, lung surface, luteinizing hormone, lymphotoxin beta receptor, Mac-1, MAdCAM, MAG, MAP2, MARC, MCAM, MCAM, MCK-2, MCP, M-CSF, MDC, Mer, METALLOPROTEASES, MGDF receptor, MGMT, MHC (HLA-DR), MIF, MIG, MIP, MIP-1-alpha, MK, MMA C1, MMP, MMP-1, MMP-10, MMP-11, MMP-12, MMP-13, MMP-14, MMP-15, MMP-2, MMP-24, MMP-3, MMP-7, MMP-8, MMP-9, MPIF, Mpo, MSK, MSP, Mucin (Muc1), MUC18, Mullerian inhibitor, Mug, MuSK, NAIP, NAP, NCAD, NC adherin, NCA90, NCAM, NCAM, Neprilysin, Neurotrophin-3, -4 or -6, Neuroturin, Nerve growth factor (NGF), NGFR, NGF-beta, nNOS, NO, NOS, Npn, NRG-3, NT, NTN, OB, OGG1, OPG, OPN, OSM, OX40L, OX40R, p150, p95, PADPr, parathyroid hormone, PARC, PARP, PBR, PBSF, PCAD, P-cadherin, PCNA, PDGF, PDGF, PDK-1, PECAM, PEM, PF4, PGE, PGF, PGI2, PGJ2, PIN, PLA2, placental alkaline phosphatase (PLAP), PlGF, PLP, PP14, proinsulin, prorelaxin, protein C, PS, PSA, PSCA, prostate-specific membrane antigen (PSMA), PTEN, PTHrp, Ptk, PTN, R51, RANK, RANKL, RANTES, relaxin A chain, relaxin B chain, renin, relaxin, respiratory syncytial virus (RSV) F, RSV Fgp, Ret, Rheumatoid Factor, RLIP76, RPA2, RSK, S100, SCF / KL, SDF-1, SERINE, Serum Albumin, sFRP-3, Shh, SIGIRR, SK-1, SLAM, SLPI, SMAC, SMDF, SMOH, SOD, SPARC, Stat, STEAP, STEAP-II, TACE, TACI, TAG-72 (Tumor-Associated Glycoprotein-72), TARC, TCA-3, T Cell Receptor (e.g., T Cell Receptor Alpha / Beta), TdT, TECK, TEM1, TEM5, TEM7, TEM8, TERT, Testicular PLAP-like Alkaline Phosphatase TfR, TGF, TGF-alpha, TGF-beta, TGF-beta Pan-specific TGF-beta RI (ALK-5), TGF-beta RII, TGF-beta RIIb, TGF-beta RIII, TGF-beta 1, TGF-beta 2, TGF-beta 3, TGF-beta 4, TGF-beta 5, thrombin, thymus Ck-1, thyroid-stimulating hormone, Tie, TIMP, TIQ, tissue factor, TMEFF2, Tmpo, TMPRSS2, TNF, TNF-alpha, TNF-alpha-beta, TNF-beta 2, TNFc, TNF-RI, TNF-RII, TNFRSF10A (TRAIL R1 Apo-2, DR4), TNFRSF10B (TRAIL R2 DR5, Killer, TRICK-2A, TRICK-B), TNFRSF10C (TRAIL R3 DcR1, LIT, TRID), TNFRSF10D (TRAIL R4 DcR2, TRUNDD), TNFRSF11A (Rank ODFR、TRANCE R)、TNFRSF11B(OPG OCIF、TR1)、TNFRSF12(TWEAK R FN14)、TNFRSF13B(TACI)、TNFRSF13C(BAFF R)、TNFRSF14(HVEM). ATAR、HveA、LIGHTR、TR2)、TNFRSF16(NGFR p75NTR)、TNFRSF17(BCMA)、TNFRSF18(GITR AITR)、TNFRSF19(TROY TAJ、TRADE)、TNFRSF19L(RELT) TNFRSF1A(TNF RI). CD120a, p55–60, TNFRSF1B(TNF RII CD120b, p75–80), TNFRSF26(TNFRH3), TNFRSF3(LTbR TNF RIII, TNFC R), TNFRSF4(OX40). ACT35, TXGP1R, TNFRSF5(CD40 p50), TNFRSF6(Fas Apo-1, APT1, CD95), TNFRSF6B(DcR3 M68, TR6), TNFRSF7(CD27), TNFRSF8(CD30), TNFRSF9(4-1BB). CD137, ILA, TNFRSF21 (DR6), TNFRSF22 (DcTRAIL R2 TNFRH2), TNFRST23 (DcTRAIL R1 TNFRH1), TNFRSF25 (DR3 Apo-3, LARD, TR-3, TRAMP, WSL-1), TNFSF10 (TRAIL). Apo-2 polymer TL2) TNFSF11(TRANCE / RANK dimer ODF) TNFSF12(TWEAK). Apo-3リンド, DR3リンド, TNFSF13(APRIL TALL2), TNFSF13B(BAFF LIGHT, TALL1, THANK, TNFSF20), TNFSF14(LIGHT WHY LTg, TNFSF15(TL1A / VEGI), TNFSF18 (GITR, AITR, TL6), TNFSF1A, TNF-a Connectin, DIF, TNFSF2, TNFSF1B (TNF-bLTa, TNFSF1), TNFSF3 (LTb).TNFC, p33), TNFSF4 (OX40 ligand gp34, TXGP1), TNFSF5 (CD40 ligand CD154, gp39, HIGM1, IMD3, TRAP), TNFSF6 (Fas ligand Apo-1 ligand, APT1 ligand), TNFSF7 (CD27 ligand CD70), TNFSF8 (CD30 ligand CD153), TNFSF9 (4-1BB ligand CD137 ligand), TP-1, t-PA, Tpo, TRAIL, TRAIL R, TRAIL-R1, TRAIL-R2, TRANCE, transferrin receptor, TRF, Trk, TROP-2, TSG, TSLP, tumor-associated antigen CA125, tumor-associated antigen expression Lewis Y-associated carbohydrate, TWEAK, TXB2, TXB2, Ung, uPAR, uPAR-1, urokinase, VCAM, VCAM-1, VECAD, VE-Cadherin, VE-cadherin-2, VEFGR-1(flt-1), VEGF, VEGFR, VEGFR-3(flt-4), VEGI, VIM, viral antigen, VLA, VLA-1, VLA-4, VNR integrin, von Willebrand factor, WIF-1, WNT1, WNT2, WNT2B / 13, WNT3, WNT3A, WNT4, WNT5A, WNT5B, WNT6, WNT7A, WNT7B, WNT8A, WNT8B, WNT 9A, WNT9A, WNT9B, WNT10A, WNT10B, WNT11, WNT16, XCL1, XCL2, XCR1, XCR1, XEDAR, XIAP, XPD, HMGB1, IgA, Aβ, CD81, CD97, CD98, DDR1, DKK1, EREG, Hsp90, IL-17 / IL-17R, IL-20 / IL-20R, Oxidized LDL, PCSK9, Prekallikrein, RON, TMEM16F, SOD1, Chromogranin A, Chromogranin B, Tau, VAP1, High Molecular Weight Kininogen, IL-31, IL-31R, Nav1.1, Nav 1.2, Nav1.3, Nav1.4, Nav1.5, Nav1.6, Nav1.7, Nav1.8, Nav1.9, EPCR, C1, C1q, C1r, C1s, C2, C2a, C2b, C3, C3a, C3b, C4, C4a, C4b, C5, C5a, C5b, C6, C7, C 8, C9, factor B, factor D, factor H, properdin, sclerostin, fibrinogen, fibrin, prothrombin, thrombin, tissue factor, factor V, factor Va, factor VII, factor VIIa, factor VIII, factor VIIIa, factor IX, factor IXa, factor X, factor Xa, XI Factors, Factor XIa, Factor XII, Factor XIIa, Factor XIII, Factor XIIIa, TFPI, Antithrombin III, EPCR, Thrombomodulin, TAPI, tPA, Plasminogen, Plasmin, PAI-1, PAI-2, GPC3, Syndecan-1, Syndecan-2, Syndecan-3, Syndecan-4, LPA, SIP, Acetylcholine receptor, AdipoR1, AdipoR2, ADP-ribosylcyclase-1, Alpha-4 / Beta-7 integrin, Alpha-5 / Beta-1 integrin, Alpha-v / Beta-6 integrin,Alpha-v-beta 1 integrin, angiopoietin ligand-2, Angptl2, Anthrax, Cadherin, carbonic anhydrase-IX, CD105, CD155, CD158a, CD37, CD49b, CD51, CD70, CD72, claudin-18, Clostridium difficile toxin, CS1, Delta-like protein ligand 4, DHICA oxidase, Dickkopf-1 ligand, dipeptidyl peptidase IV, EPOR, RSV F protein, factor Ia, FasL, folate receptor alpha, glucan Gon receptor, glucagon-like peptide 1 receptor, glutamate carboxypeptidase II, GMCSFR, hepatitis C virus E2 glycoprotein, hepcidin, IL-17 receptor, IL-22 receptor, IL-23 receptor, IL-3 receptor, Kit tyrosine kinase, leucine-rich alpha-2-glycoprotein 1 (LRG1), lysosphingolipid receptor, membrane glycoprotein OX2, mesothelin, MET, MICA, MUC-16, myelin-related glycoprotein, neuropilin-1, neuropilin-2, Nogo receptor, PLXNA1, PLXNA2, PLX NA3, PLXNA4A, PLXNA4B, PLXNB1, PLXNB2, PLXNB3, PLXNC1, PLXND1, programmed cell death ligand 1, proprotein convertase PC9, P-selectin glycoprotein ligand-1, RAGE, reticulon 4, RF, RON-8, SEMA3A, SEMA3B, SEMA3C, SEMA3D, SEMA3E, SEMA3F, SEMA3G, SEMA4A, SEMA4B, SEMA4C, SEMA4D, SEMA4F, SEMA4G, SEMA5A, SEMA5B, SEMA6A, SEMA6B, SEM This includes, but is not limited to, A6C, SEMA6D, SEMA7A, Shiga-like toxin II, sphingosine-1-phosphate receptor-1, ST2, Staphylococcus lipoteichoic acid, tenascin, TG2, thymic interstitial lymphoprotein receptor, TNF superfamily receptor 12A, transmembrane glycoprotein NMB, TREM-1, TREM-2, trophoblast glycoprotein, TSH receptor, TTR, tubulin and ULBP2, as well as growth factor and hormone receptors, molecules present in their soluble forms and not fixed to cells in the body fluids of organisms.

[0134] Suitable examples of pathogen-associated antigens include vaccinia, aviipoxvirus, turkey influenza virus, bovine leukemia virus, feline leukemia virus, avian influenza, avian pneumonia virus, canine parvovirus, equine influenza, FHV, Newcastle disease virus (NDV), avian / Pennsylvania / 1 / 83 influenza virus, infectious bronchitis virus, dengue virus, measles virus, rubella virus, pseudorabies, Epstein-Barr virus, HIV, SIV, EHV, BHV, HCMV, Hantaan, C. tetani, mumps, morbillivirus, herpesvirus type 1, and herpes simplex virus. Antigens derived from, but not limited to, pesvirus type 2, human cytomegalovirus, hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis E virus, respiratory syncytial virus, human papillomavirus, influenza virus, Bordetella, Vitreostilla, Salmonella, Neisseria, Borrelia, Chlamydia, malaria parasite, Toxoplasma, Cryptococcus, Streptococcus, Staphylococcus, Haemophilus, Dipteria, Tetanus, Escherichia coli, Candida, Aspergillus, Actinomycetes, Burkholderia, Moraxella, Pseudomonas, Vibrio, Enteramoeba, Giardia, and Trypanasoma.

[0135] Suitable examples of autoantigens include lupus autoantigen, Smith, Ro, La, U1-RNP, fibrillin, nuclear antigen, histone, glycoprotein gp70, ribosomal protein, pyruvate dehydrogenase, dehydrolipoamide acetyltransferase (PCD-E2), hair follicle antigen, human tropomyosin isoform 5 (hTM5), proinsulin, insulin, IA2, GAD65, type II collagen, human cartilage gp39 (HCgp39), gp130-RAPS, dnaJp1, citrullinated proteins and peptides (citrullinated type II). This includes, but is not limited to, collagen (including citrullinated vimentin and citrullinated fibrinogen), myelin basic proteins, proteolipidoproteins (PLPs), myelin oligodendrocyte glycoproteins (MOGs), thyroid-stimulating factor receptors (TSH-Rs), acetylcholine receptors (AchRs), gliadins, PLPs, glucose-6-phosphate isomerase, thyroglobulins, thyroid globulins, various tRNA synthetases, proteinase-3s, and myeloperoxidases (including their fragments).

[0136] Suitable examples of tumor-associated antigens include MART-1 / Melan-A, gplOO, dipeptidyl peptidase IV (DPPIV), adenosine deaminase-binding protein (ADAbp), cyclophyllin b, colorectal-associated antigen (CRC)-C017-1A / GA733, carcinoembryonic antigen (CEA) and its immunogenic epitopes CAP-1 and CAP-2, etv6, amll, prostate-specific antigen (PSA) and its immunogenic epitopes PSA-1, PSA-2, and PSA-3, prostate-specific membrane antigen (PSMA), T cell receptor / CD3-zeta chain, and the MAGE family of tumor antigens (e.g., MAGE-A1, MAGE-A2, MAGE-A3, MAGE-A4, MAGE-A5, MAGE-A6, MAGE-A7, MAGE-A8, MAGE-A9, MAGE-A10, MAGE-A1 1. MAGE-A12, MAGE-Xp2 (MAGE-B2), MAGE-Xp3 (MAGE-B3), MAGE-Xp4 (MAGE-B4), MAGE-C1, MAGE-C2, MAGE-C3, MAGE-C4, MAGE-C5), GAGE ​​family of tumor antigens (e.g., GAGE-1, GAGE-2, GAGE-3, GAGE-4, GAGE-5, GAGE-6, GAGE-7, GAGE -8, GAGE-9), BAGE, RAGE, LAGE-1, NAG, GnT-V, MUM-1, CDK4, tyrosinase, p53, MUC family (e.g., MUC1, MUC16, etc.), HER2 / neu, p21ras, RCAS1, alpha-fetoprotein, E-cadherin, alpha-catenin, beta-catenin and gamma-catenin, pl20ctn, gpl00.sup.This includes, but is not limited to, Pmelll7, PRAME, NY-ESO-1, cdc27, adenomatous adenomatous polyposis protein (APC), fodrin, connexin 37, Ig-idiotype, pl5, gp75, GM2 and GD2 gangliosides, cancer antigens such as Smad family brain glycogen phosphorylases, SSX-1, SSX-2 (HOM-MEL-40), SSX-1, SSX-4, SSX-5, SCP-1 and CT-7, c-erbB-2, and viral antigens such as HPV-16 and HPV-18 E6 and E7 antigens, as well as nuclear antigen (EBNA)-1 encoded by EBV (including their fragments). Further examples of tumor-associated antigens are described, for example, in Li et al., 2004. Cancer Immunol Immunother. 53(3):139-43; and Novellino et al., 2005. Cancer Immunol Immunother. 54(3):187-20, which are incorporated herein by reference in their entirety.

[0137] In one embodiment, R3 is a hydrophilic portion, but the hydrophilic portion is not a hydroxyl group.

[0138] Examples of hydrophilic moieties include, but are not limited to, methoxy, phenol, carboxylic acids and their salts, methyl and ethyl esters of carboxylic acids, amides, amino, cyano, ammonium salts, sulfonium salts, phosphonium salts, epoxy groups, acrylates, sulfonamides, nitro, guanidinium, amines, acrylamides, and pyridinium groups.

[0139] Further examples of hydrophilic portions include, but are not limited to, hydrophilic polymers. In one embodiment, R3 is a hydrophilic polymer. Examples of hydrophilic polymers include, but are not limited to, polystyrene sulfonic acid, poly-N-alkylvinylpyridinium halogen, poly(meth)acrylic acid, poly-N-vinylpyrrolidone, polyhydroxyethyl methacrylate, polyvinyl ether, polyethylene glycol, polyethyleneimine, polypropylene oxide, and (poly)peptides.

[0140] Further examples of hydrophilic parts include, but are not limited to, monosaccharides, disaccharides, oligosaccharides, and polysaccharides.

[0141] In one embodiment, R3 is a sugar selected from the group comprising agarose, dextran, starch, cellulose, amylose, and amylopectin.

[0142] In one embodiment, R3 is a monosaccharide.

[0143] In one embodiment, R3 is a 3-deoxy-d-manno-octa-2-urosonic acid (Kdo) residue or d-glycero-d-talo-octa-2-urosonic acid (Ko).

[0144] In one embodiment, R3 is a Kdo or Ko residue substituted with a further substituent.

[0145] Such further substituents may be linear or branched and may include, but are not limited to, monosaccharides, oligosaccharides, or polysaccharides containing 1 to 200 sugar residues.

[0146] Additional or alternative substituents may include, but are not limited to, phosphate groups, diphosphate groups, phosphorylethanolamine groups "PEA" (-OPO3H-CH2-CH2-NH2), diphosphorylethanolamine groups "PPEA" (-OPO3H2-PO3H-CH2-CH2-NH2), Kdo residues, Kdo2 residues, Ko residues, aminoarabinose (AraN) residues, galactosamine (GalN) residues, glucosamine (GlcN) residues, and others.

[0147] In one embodiment, R3 is a core oligosaccharide domain (i.e., an inner core, or an inner core and an outer core). In one embodiment, the core oligosaccharide domain typically contains 1 to 12 sugar residues. In one embodiment, the core oligosaccharide domain contains more than 2 sugar residues, such as 3, 4, 5 or more to 12.

[0148] In one embodiment, the core oligosaccharide domain may contain one or more non-carbohydrate structural elements in its main chain.

[0149] In one embodiment, R3 is a core oligosaccharide domain, and one or more sugar residues and / or one or more non-carbohydrate structural elements are substituted with further substituents, where applicable.

[0150] Such further substituents include, but are not limited to, phosphate groups, phosphorylethanolamine groups "PEA" (-OPO3H-CH2-CH2-NH2), diphosphorylethanolamine groups "PPEA" (-OPO3H2-PO3H-CH2-CH2-NH2), acetate groups, methyl groups, formyl groups, choline, phosphocholine, and amino acids.

[0151] In one embodiment, R3 is a core oligosaccharide domain, and one or more sugar residues and / or one or more non-carbohydrate structural elements are substituted with a therapeutic agent, where applicable. Preferred examples of such therapeutic agents are described herein as agents suitable for conjugation at positions Z, R1 and / or R2 of formulas A and B.

[0152] Additional or alternative substituents may include, but are not limited to, linear or branched monosaccharides, oligosaccharides, and polysaccharides.

[0153] In one embodiment, R3 is a core oligosaccharide domain that is further substituted with an antigen, such as an O antigen domain and / or a capping antigen, either directly or through a linker domain, but not limited to these. In one embodiment, the core oligosaccharide domain and / or antigen domain contain 1 to 200 sugar residues, either independently of each other or together. In one embodiment, the core oligosaccharide domain and / or antigen domain may contain one or more non-carbohydrate structural elements in their back chains.

[0154] In one embodiment, R3 is a core oligosaccharide domain further substituted with an antigen domain such as an O antigen domain and / or a capping antigen, where one or more sugar residues are substituted with further substituents.

[0155] Such further substituents include, but are not limited to, phosphate groups, phosphorylethanolamine groups "PEA" (-OPO3H-CH2-CH2-NH2), diphosphorylethanolamine groups "PPEA" (-OPO3H2-PO3H-CH2-CH2-NH2), acetate groups, methyl groups, formyl groups, choline or phosphocholine, and amino acids.

[0156] In one embodiment, R3 is a core oligosaccharide domain further substituted with an antigen domain such as an O antigen domain and / or a capping antigen, where one or more sugar residues are substituted with a therapeutic agent. Preferred examples of such therapeutic agents are described herein as agents suitable for conjugation at positions Z, R1 and / or R2 of formulas A and B.

[0157] In one embodiment, R5 is hydrogen. Therefore, in this embodiment, X-R5 may be a hydroxyl group (-OH) or an amine group (-NH2).

[0158] In one embodiment, R7 is hydrogen. Therefore, in this embodiment, Y-R7 may be a hydroxyl group (-OH) or an amine group (-NH2).

[0159] In one embodiment, X-R5 is a hydroxyl group (-OH) or amine group (-NH2) substituted with a further substituent. Thus, in one embodiment, Y-R7 may be a hydroxyl group (-OH) or amine group (-NH2) substituted with a further substituent.

[0160] In one embodiment, R4 is a primary fatty acid residue. In one embodiment, R5 is a primary fatty acid residue. In one embodiment, R6 is a primary fatty acid residue. In one embodiment, R7 is a primary fatty acid residue.

[0161] In one embodiment, the primary fatty acid is independently selected from short-chain fatty acids (SCFAs), medium-chain fatty acids (MCFAs), long-chain fatty acids (LCFAs), and very long-chain fatty acids (VLCFAs).

[0162] In one embodiment, the primary fatty acid residues may be independently saturated or unsaturated.

[0163] In one embodiment, the primary fatty acid residues may be linear or branched independently.

[0164] In one embodiment, the primary fatty acid residue may independently contain a hydroxyl group (-OH) at the C2 position of the fatty acid chain; that is, the primary fatty acid residue may independently be a 2-hydroxy fatty acid residue.

[0165] In one embodiment, the primary fatty acid residue may independently contain a hydroxyl group (-OH) at the C3 position of the fatty acid chain; that is, the primary fatty acid residue may independently be a 3-hydroxy fatty acid residue.

[0166] In one embodiment, the primary fatty acid residue contains a hydroxyl group (-OH) at the C3 position of the fatty acid chain, and the primary fatty acid residue can be esterified at the C3 position with a secondary fatty acid residue (i.e., an estrid bond fatty acid residue, also called an acyloxyacyl fatty acid).

[0167] In one embodiment, the secondary fatty acid is independently selected from short-chain fatty acids (SCFAs), medium-chain fatty acids (MCFAs), long-chain fatty acids (LCFAs), and very long-chain fatty acids (VLCFAs).

[0168] In one embodiment, the secondary fatty acid residues may be independently saturated or unsaturated.

[0169] In one embodiment, the secondary fatty acid residues may be independently linear or branched.

[0170] In one embodiment, the secondary fatty acid residue may independently contain a hydroxyl group (-OH) at the C2 position of the fatty acid chain; that is, the secondary fatty acid residue may independently be a 2-hydroxy fatty acid residue.

[0171] In one embodiment, the secondary fatty acid residue may independently contain a hydroxyl group (-OH) at the C3 position of the fatty acid chain; that is, the secondary fatty acid residue may independently be a 3-hydroxy fatty acid residue.

[0172] In one embodiment, where the secondary fatty acid residue contains a hydroxyl group (-OH) at the C3 position of the fatty acid chain, the secondary fatty acid residue may be substituted at this position.

[0173] In one embodiment, the modified LPS molecular species is i. Fewer or more fatty acid chains compared to the classic E. coli or Salmonella enterica LPS molecule, and / or ii. May contain shorter and / or longer fatty acid chains compared to the classic E. coli or Salmonella enterica LPS molecule. The classic E. coli or Salmonella enterica LPS molecule contains six fatty acid chains, of which four are primary fatty acid chains. 14 Therefore, one secondary fatty acid chain is C 14 Therefore, one secondary fatty acid chain is C 12 That is the case.

[0174] In one embodiment, the modified LPS molecule contains four primary fatty acid residues, of which four primary fatty acid residues are esterified with a secondary fatty acid residue at the C3 position. In one embodiment, the modified LPS molecule contains four primary fatty acid residues, of which at least three primary fatty acid residues are esterified with a secondary fatty acid residue at the C3 position. In one embodiment, the modified LPS molecule contains four primary fatty acid residues, of which at least two primary fatty acid residues are esterified with a secondary fatty acid residue at the C3 position. In one embodiment, the modified LPS molecule contains up to four primary fatty acid residues, of which up to one primary fatty acid residue is esterified with a secondary fatty acid residue at the C3 position. In one embodiment, the modified LPS molecule contains up to three primary fatty acid residues, of which up to two primary fatty acid residues are esterified with a secondary fatty acid residue at the C3 position. In one embodiment, the modified LPS molecule contains up to three primary fatty acid residues, of which up to one primary fatty acid residue is esterified with a secondary fatty acid residue at the C3 position. In one embodiment, the modified LPS molecular species contains up to two primary fatty acid residues, of which up to two primary fatty acid residues are esterified with a secondary fatty acid residue at the C3 position. In another embodiment, the modified LPS molecular species contains up to two fatty acid residues, of which up to one fatty acid is esterified with a secondary fatty acid residue at the C3 position.

[0175] In one embodiment, the modified LPS molecular species contains primary fatty acid residues with up to 18 carbon atoms, 17 carbon atoms, 16 carbon atoms, 15 carbon atoms, 14 carbon atoms, 13 carbon atoms, 12 carbon atoms, 11 carbon atoms, 10 carbon atoms, 9 carbon atoms, 8 carbon atoms, 7 carbon atoms, 6 carbon atoms, 5 carbon atoms, 4 or fewer carbon atoms, preferably up to 14 carbon atoms.

[0176] In addition or alternatively, in one embodiment in which the modified LPS molecular species comprises four primary fatty acid residues, at least one of the four primary fatty acid residues, e.g., 1, 2, 3, or 4, does not contain 14 carbon atoms. In one embodiment in which the modified LPS molecular species comprises four primary fatty acid residues, at least one of the four primary fatty acid residues, e.g., 1, 2, 3, or 4, contains 18 carbon atoms, 17 carbon atoms, 16 carbon atoms, 15 carbon atoms, 13 carbon atoms, 12 carbon atoms, 11 carbon atoms, 10 carbon atoms, 9 carbon atoms, 8 carbon atoms, 7 carbon atoms, 6 carbon atoms, 5 carbon atoms, and 4 or fewer carbon atoms.

[0177] In one embodiment, the modified LPS molecular species contains secondary fatty acid residues containing up to 32 carbon atoms, 31 carbon atoms, 30 carbon atoms, 29 carbon atoms, 28 carbon atoms, 27 carbon atoms, 26 carbon atoms, 25 carbon atoms, 24 carbon atoms, 23 carbon atoms, 22 carbon atoms, 21 carbon atoms, 20 carbon atoms, 19 carbon atoms, 18 carbon atoms, 17 carbon atoms, 16 carbon atoms, 15 carbon atoms, 14 carbon atoms, 13 carbon atoms, 12 carbon atoms, 11 carbon atoms, 10 carbon atoms, 9 carbon atoms, 8 carbon atoms, 7 carbon atoms, 6 carbon atoms, 5 carbon atoms, 4 or fewer carbon atoms, preferably up to 14 carbon atoms.

[0178] In addition or alternatively, in one embodiment, the modified LPS molecular species comprises two secondary fatty acid residues, at least one of the two secondary fatty acid residues, for example, one or two, does not contain 12 carbon atoms. In one embodiment, the modified LPS molecular species comprises secondary fatty acid residues, and at least one of the two secondary fatty acid residues, for example, one or two, contains 18 carbon atoms, 17 carbon atoms, 16 carbon atoms, 15 carbon atoms, 14 carbon atoms, 13 carbon atoms, 11 carbon atoms, 10 carbon atoms, 9 carbon atoms, 8 carbon atoms, 7 carbon atoms, 6 carbon atoms, 5 carbon atoms, 4 carbon atoms or less.

[0179] In addition or alternatively, in one embodiment, the modified LPS molecular species comprises two secondary fatty acid residues, at least one of the two secondary fatty acid residues, for example, one or two, does not contain 14 carbon atoms. In one embodiment, the modified LPS molecular species comprises secondary fatty acid residues, and at least one of the two secondary fatty acid residues, for example, one or two, contains 18 carbon atoms, 17 carbon atoms, 16 carbon atoms, 15 carbon atoms, 13 carbon atoms, 12 carbon atoms, 11 carbon atoms, 10 carbon atoms, 9 carbon atoms, 8 carbon atoms, 7 carbon atoms, 6 carbon atoms, 5 carbon atoms, 4 carbon atoms or less.

[0180] In one embodiment, the modified LPS molecular species may originate from any Gram-negative bacteria and / or any Gram-positive bacteria that contain LPS in their membranes. Examples of Gram-negative bacteria include, but are not limited to, bacteria of the genera Acidobacterium, Acfific, Armatimonas, Bacteroides, Cardycerica, Chlamydia, Chlorobacterium, Chloroflex, Chrysiogenes, Cyanobacteria, Deferibacteria, Deinococcus thermomus, Dictyoglomus, Elsimicrobia, Fibrobacteria, Fusobacterium, Gematimonadetes, Lentisphaera, Nitrospira, Planctomyces, Proteobacteria, Spirochete, Synadistetes, Tenericutes, Thermodesulfobacteria, Thermomicrobia, Thermotoge, and Vercomicrobium (including any of their subtaxons).

[0181] In one embodiment, the modified LPS molecular species may be derived from Gram-negative bacteria of the Proteobacteria phylum, including but not limited to bacteria of the Alphaproteobacteria, Betaproteobacteria, Gammaproteobacteria, Deltaproteobacteria, Epsilonproteobacteria, Zetaproteobacteria, Asidithiobasilia, Hydrogenophilia, and Oligoflexia classes.

[0182] Examples of Gram-positive bacteria containing LPS in their membranes include, but are not limited to, Listeria monocytogenes (from the phylum Firmicutes). In one embodiment, the modified LPS molecular species are derived from the genus Bordetella (Proteobacteria phylum), including but not limited to Bordetella ansorpii, Bordetella avium, Bordetella bronchialis, Bordetella bronchipetica, Bordetella flavilis, Bordetella hingii, Bordetella hormesii, Bordetella muralis, Bordetella parapeltaxis, Bordetella pertussis, Bordetella petryi, Bordetella pseudohinzii, Bordetella sputigena, Bordetella trematum, Bordetella tumbae, and Bordetella tumulicola. In one embodiment, the modified LPS molecular species are derived from Bordetella pertussis, Bordetella hingii, or Bordetella trematum.

[0183] In one embodiment, the modified LPS molecular species is derived from the genus Vitreostilla (Proteobacteria phylum), including but not limited to Vitreostilla bezziatoides, Vitreostilla filiformis, and Vitreostilla stercoralia. In one embodiment, the modified LPS molecular species is derived from the bacterial species Vitreostilla filiformis.

[0184] In one embodiment, the modified LPS molecular species is derived from the genus Salmonella (from the phylum Proteobacteria), including but not limited to Salmonella bongoli and Salmonella enterica (further including, but not limited to, Salmonella enterica subspecies enterica, Salmonella enterica salamae, Salmonella enterica arrowrie, Salmonella enterica diarizonae, Salmonella enterica houtenae, and Salmonella enterica indica). In one embodiment, the modified LPS molecular species is derived from the bacterial species Salmonella enterica, preferably the bacterial subspecies Salmonella enterica, more preferably the bacterial serotype Salmonella enterica serotype Minnesota or Salmonella enterica serotype Typhimurium.

[0185] In one embodiment, the modified LPS molecular species is derived from the genus Escherichia (derived from the phylum Proteobacteria), including but not limited to Escherichia albertii, Escherichia coli, Escherichia fergusoni, Escherichia hermannii, Escherichia marmotae, and Escherichia vanith. In one embodiment, the modified LPS molecular species is derived from the bacterial species Escherichia coli, preferably the bacterial strain Escherichia coli K12 or Escherichia coli J5.

[0186] In one embodiment, the modified LPS molecular species are Actinobacillus actinomycetemucomitans, Actinobacillus alstolicis, Actinobacillus capsulatus, Actinobacillus delphinicola, Actinobacillus ecri, Actinobacillus hominis, Actinobacillus indrycus, Actinobacillus lignieresii, Actinobacillus minou, Actinobacillus muris, and The Actinobacillus genus (derived from the Proteobacteria phylum) includes, but is not limited to, Actinobacillus prunomonie, Actinobacillus porcinus, Actinobacillus rosii, Actinobacillus scotiae, Actinobacillus seminis, Actinobacillus succinogenes, Actinobacillus suissii, and Actinobacillus ureae. In one embodiment, the modified LPS molecular species is derived from the bacterial species Actinobacillus prunomonie.

[0187] In one embodiment, the modified LPS molecular species are Burkholderia alpine, Burkholderia ambifaria, Burkholderia ansina, Burkholderia arboris, Burkholderia cenocephalus, Burkholderia cepacian, Burkholderia contaminance, Burkholderia diffuser, Burkholderia dorosa, Burkholderia gladioli, Burkholderia grumae, Burkholderia humptiduensis, Burkholderia lata, Burkholderia lathe, Burkholderia marei, Burkholderia metallica, Burkholderia multiborans, and Burkholderia It is derived from the genus Burkholderia (from the phylum Proteobacteria), including but not limited to A. oklahomensis, Burkholderia pyrantali, Burkholderia pseudomalai, Burkholderia pseudomultivolans, Burkholderia praque, Burkholderia pyrosinia, Burkholderia seminaris, Burkholderia singapolensis, Burkholderia singularis, Burkholderia stabilis, Burkholderia stagnus, Burkholderia territory, Burkholderia tyrandensis, Burkholderia yuvonensis, and Burkholderia betnamiensis. In one embodiment, the modified LPS molecular species is derived from the bacterial species Burkholderia pseudomalai.

[0188] In one embodiment, the modified LPS molecular species is derived from the genus Moraxella (from the phylum Proteobacteria), including but not limited to Moraxella atlante, Moraxella boebri, Moraxella bobis, Moraxella bobokli, Moraxella canis, Moraxella caprae, Moraxella catarrhalis, Moraxella cavier, Moraxella cuniculi, Moraxella equii, Moraxella lachnata, Moraxella chira rinkornii, Moraxella nonalycufasierra, Moraxella oblonga, Moraxella osloensis, Moraxella pullanimarium, Moraxella porsi, and Moraxella saccharotica. In one embodiment, the modified LPS molecular species is derived from the bacterial species Moraxella catarrhalis.

[0189] In one embodiment, modified LPS molecular species are derived from the genus Neisseria (derived from the phylum Proteobacteria), including but not limited to Neisseria animalis, Neisseria animalolis, Neisseria basiliformis, Neisseria canis, Neisseria cinerea, Neisseria densiae, Neisseria elongata, Neisseria flava, Neisseria flavecens, Neisseria gonolloe, Neisseria iguanae, Neisseria lactamica, Neisseria macacae, Neisseria meninchidis, Neisseria mucosa, Neisseria oralis, Neisseria perflava, Neisseria faringis, Neisseria polysaccharea, Neisseria scheiganii, Neisseria sicca, Neisseria subflava, Neisseria wazwashii, Neisseria webelii, and Neisseria zuodegmatis. In one embodiment, the modified LPS molecular species is derived from the bacterial species Neisseria sicca.

[0190] In one embodiment, the modified LPS molecular species include Pseudomonas aeruginosa, Pseudomonas alcaligenes, Pseudomonas amygdali, Pseudomonas angyriseptica, Pseudomonas antarctica, Pseudomonas argentinensis, Pseudomonas asplenii, Pseudomonas aurantiaca, Pseudomonas aureofasciens, Pseudomonas aberlanae, Pseudomonas azotoformans, Pseudomonas barealica, Pseudomonas brachifodae, Pseudomonas borboli, and Pseudomonas brassica. Pseudomonas alum, Pseudomonas brenneli, Pseudomonas caricapapaye, Pseudomonas sedrina, Pseudomonas chlororaffis, Pseudomonas sikhorii, Pseudomonas citronellolis, Pseudomonas coronafaciens, Pseudomonas colgata, Pseudomonas colgata, Pseudomonas cremocolorata, Pseudomonas dennitrificans, Pseudomonas entomophylla, Pseudomonas fixeta, Pseudomonas flavesens, Pseudomonas fluorescens, Pseudomonas fragile Pseudomonas fluva, Pseudomonas gessardii, Pseudomonas helianti, Pseudomonas ribanensis, Pseudomonas lundensis, Pseudomonas luteola, Pseudomonas mandelii, Pseudomonas marginalis, Pseudomonas mediterranea, Pseudomonas meliae, Pseudomonas mendocina, Pseudomonas meridiana, Pseudomonas migrae, Pseudomonas montellii, Pseudomonas mossellii, Pseudomonas mucidolens, Pseudomonas nitroredusens, Pseudomonas oleoballis, Pseudomonas orientalis, Pseudomonas origihabitans, Pseudomonas panasis, Pseudomonas parafluva, Pseudomonas pertusinogena, Pseudomonas plecoglossida, Pseudomonas protegens, Pseudomonas proteoritica, Pseudoalligenes, Pseudomonas putida, Pseudomonas resinovolans, Pseudomonas rhodesiae, Pseudomonas sabastanoi, Pseudomonas straminea, Pseudomonas stazzeri,The species derived from the genus Pseudomonas (from the phylum Proteobacteria) includes, but is not limited to, Pseudomonas cynxantha, Pseudomonas syringae, Pseudomonas taetrolens, Pseudomonas tibervalensis, Pseudomonas torasii, Pseudomonas tomato, Pseudomonas veronii, and Pseudomonas viridiflava. In one embodiment, the modified LPS molecular species is derived from the bacterial species Pseudomonas aeruginosa or Pseudomonas fluorescein.

[0191] In one embodiment, the modified LPS molecular species are Vibrio adaptus, Vibrio erogenes, Vibrio estivus, Vibrio aestuarianus, Vibrio agariborans, Vibrio arvensis, Vibrio alphaxensis, Vibrio arginoticus, Vibrio anguilarum, Vibrio areninigrae, Vibrio altablorum, Vibrio atlanticus, Vibrio attypicus, Vibrio azureus, Vibrio brasiliensis, Vibrio bubulus, Vibrio carbiensis, Vibrio... Campberry, Vibrio casei, Vibrio chagasi, Vibrio cholerae, Vibrio cincinnatiensis, Vibrio coraliiriticus, Vibrio crasostreae, Vibrio cyclotrophicus, Vibrio diabolicus, Vibrio diazotrophicus, Vibrio ezrae, Vibrio fluvialis, Vibrio fortis, Vibrio fanisii, Vibrio gallicus, Vibrio gazogenes, Vibrio giganteus, Vibrio harioticoly, Vibrio harvey, Vibrio hepatarius, Bi Vibrio hypocampi, Vibrio hispanicus, Vibrio ichthyoenteri, Vibrio indicus, Vibrio canaloae, Vibrio lentus, Vibrio litralis, Vibrio rogei, Vibrio mediteranei, Vibrio mechnicoffii, Vibrio mimicus, Vibrio maitili, Vibrio natriegens, Vibrio navarensis, Vibrio neonatus, Vibrio neptunius, Vibrio nereis, Vibrio nigripalcritudo, Vibrio audalii, Vibrio orientalis, Vibrio pa This includes Vibrio cinii, Vibrio parahemorticus, Vibrio pectenishida, Vibrio penaeishida, Vibrio pomeroi, Vibrio ponticus, Vibrio proteoritis, Vibrio rotiferianus, Vibrio ruba, Vibrio rumoiensis, Vibrio salmonicida, Vibrio scophthalmi, Vibrio splendida, Vibrio superstes, Vibrio tapetis, Vibrio tasmaniensis, Vibrio tsbiasi, Vibrio vulnificus, Vibrio wodanis, and Vibrio cuii,These are derived from the genus Vibrio (derived from the phylum Proteobacteria), but are not limited to these. In one embodiment, the modified LPS molecular species is derived from the bacterial species Vibrio fischeri.

[0192] In one embodiment, the modified LPS molecular species is represented by general formula A, where, Y is -O-, Z is a hydroxyl group (-OH), R2 is a phosphate group (-OPO3H2), R3 is a monosaccharide, oligosaccharide, or polysaccharide, and may be substituted, preferably R3 is a core oligosaccharide (i.e., inner core, or inner core and outer core) which may be substituted with an antigen domain such as an O antigen domain and / or a capping antigen, but is not limited to this. R6 is a fatty acid residue and may be substituted. R7 is a hydrogen atom or a fatty acid residue, and may be substituted.

[0193] In one embodiment, the modified LPS molecular species is represented by general formula A, where, Y is -O-, Z is a phosphate group (-OPO3H2), R2 is a hydroxyl group (-OH), R3 is a monosaccharide, oligosaccharide, or polysaccharide, and may be substituted, preferably R3 is a core oligosaccharide (i.e., inner core, or inner core and outer core) which may be substituted with an antigen domain such as an O antigen domain and / or a capping antigen, but is not limited to this. R6 is a fatty acid residue and may be substituted. R7 is a hydrogen atom or a fatty acid residue, and may be substituted.

[0194] In one embodiment, the modified LPS molecular species is represented by general formula A, where, Y is -O-, Z is a hydroxyl group (-OH), R2 is a hydroxyl group (-OH), R3 is a monosaccharide, oligosaccharide, or polysaccharide, and may be substituted, preferably R3 is a core oligosaccharide (i.e., inner core, or inner core and outer core) which may be substituted with an antigen domain such as an O antigen domain and / or a capping antigen, but is not limited to this. R6 is a fatty acid residue and may be substituted. R7 is a hydrogen atom or a fatty acid residue, and may be substituted.

[0195] In one embodiment, the modified LPS molecular species is represented by general formula B, where, X and Y are -O-, R1 is a hydroxyl group (-OH), R2 is a phosphate group (-OPO3H2), R3 is a monosaccharide, oligosaccharide, or polysaccharide, and may be substituted, preferably R3 is a core oligosaccharide (i.e., inner core, or inner core and outer core) which may be substituted with an antigen domain such as an O antigen domain and / or a capping antigen, but is not limited to this. R4 and R6 are independent fatty acid residues and may be substituted. R5 and R7 are, independently of each other, hydrogen or fatty acid residues, and may be substituted.

[0196] In one embodiment, the modified LPS molecular species is represented by general formula B, where, X and Y are -O-, R1 is a phosphate group (-OPO3H2), R2 is a hydroxyl group (-OH), R3 is a monosaccharide, oligosaccharide, or polysaccharide, and may be substituted, preferably R3 is a core oligosaccharide (i.e., inner core, or inner core and outer core) which may be substituted with an antigen domain such as an O antigen domain and / or a capping antigen, but is not limited to this. R4 and R6 are independent fatty acid residues and may be substituted. R5 and R7 are, independently of each other, hydrogen or a fatty acid residue, and may be substituted.

[0197] In one embodiment, the modified LPS molecular species has the general formula B, wherein X and Y are -O-, R1 is a hydroxyl group (-OH), R2 is a hydroxyl group (-OH), R3 is a monosaccharide, oligosaccharide or polysaccharide, which may be substituted, and preferably, R3 is a core oligosaccharide (i.e., inner core, or inner core and outer core) which may be substituted with an antigen domain such as, but not limited to, an O antigen domain and / or a capping antigen. R4 and R6 are, independently of each other, fatty acid residues, and may be substituted. R5 and R7 are, independently of each other, hydrogen or a fatty acid residue, and may be substituted.

[0198] In one embodiment, the modified LPS molecular species, as seen in FIGS. 2 to 4, FIGS. 6 to 17, FIG. 27, FIGS. 29 to 33, and FIGS. 36 to 43, are of formula (I)(1)(a), (I)(1)(b), (I)(1)(c), (I)(1)(d), (I)(1)(e), (I)(1)(f), (I)(2)(a), (I)(2)(b), (I)(2)(c), (I)(3)(a), (I)(3)(b), (I)(3)(c), (I)(5)(a), (I)(5)(b), (I)(6)(a), (I)(6)(b), (I)(7)(a), (I)(7)(b), (I)(7)(c), (I)(7)(d), (I)(8)(a), (I)(8)(b), (I)(8)(c), (I)(9)(a), (I)(9)(b), (I)(9)(c), (I)(9)(d), (I)(9)(e), (I)(9)(f), (II)(1)(a), (II)(1)(b), (II)(1)(c), (II)(1)(d), (II)(2)(a), (II)(2)(b), (II)(2)(c), (II)(2)(d), (III)(1)(a), (III)(1)(b), (III)(1)(c), (III)(1)(d), (IV)(1)(a), (IV)(1)(b), (IV)(1)(c), (V)(1)(a), (V)(1)(b), (V)(1)(c), (V)(1)(d), (V)(1)(e), (V)(1)(f), (V)(1)(g), (V)(1)(h), (V)(1)(i), (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), (VI)(2)(a), (VI)(2)(b), (VI)(2)(c), (VII)(1)(a), (VII)(1)(b), (VII)(1)(c), (VIII)(1)(a), (VIII)(1)(b), (VIII)(1)(c), (VIII)(1)(d), (IX)(1)(a), (IX)(1)(b), (IX)(1)(c), (IX)(1)(d), (X)(1)(a), (X)(1)(b), (X)(1)(c), (X)(1)(d), (XI)(1)(a), (XI)(1)(b), (XI)(1)(c), (XI)(1)(d), (XII)(1), (XIII)(2)(a),(XIII)(2)(b), (XIII)(3)(a), (XIII)(3)(b), (XIII)(4)(a), (XIII)(4)(b), (XIII)(5) (a), (XIII)(5)(b), (XIII)(5)(c), (XIII)(5)(d), (XIII)(6)(a), (XIII)(6)(b), (XIII) (6)(c), (XIII)(6)(d), (XIII)(6)(e), (XIII)(6)(f), (XIII)(7)(a), (XIII)(7)(b), (XI II)(7)(c), (XIII)(7)(d), (XIII)(7)(e), (XIII)(7)(f), (XIII)(8)(a), (XIII)(8)(b), The compounds are selected from those of (XIII)(8)(c), (XIII)(8)(d), (XIII)(8)(e), (XIII)(8)(f), (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) and their combinations, wherein the R at the C6' position is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and optionally an antigen domain such as an O antigen domain and / or a capping antigen, and the X at the C1 position is an ethyl moiety.

[0199] The same LPS members are in 2~24 and 7~17. (I)( 1)(a)、(I)(1)(b)、(I)(1)(c)、(I)(1)(d)、(I)(1)(e)、(I)(1)(f)、(I)(2)( (a)、(I)(2)(b)、(I)(2)(c)、(I)(3)(a)、(I)(3)(b)、(I)(3)(c)、(I)(5)(a) 、(I)(5)(b)、(I)(6)(a)、(I)(6)(b)、(I)(7)(a)、(I)(7)(b)、(I)(7)(c)、(I )(7)(d)、(I)(8)(a)、(I)(8)(b)、(I)(8)(c)、(I)(9)(a)、(I)(9)(b)、(I)( (9)(c)、(I)(9)(d)、(I)(9)(e)、(I)(9)(f)、(II)(2)(a)、(II)(2)(b)、(II)( (2)(c)、(II)(2)(d)、(III)(1)(a)、(III)(1)(b)、(III)(1)(c)、(III)(1)( (d)、(IV)(1)(a)、(IV)(1)(b)、(IV)(1)(c)、(V)(1)(a)、(V)(1)(b)、(V)(1)( (c)、(V)(1)(d)、(V)(1)(e)、(V)(1)(f)、(V)(1)(g)、(V)(1)(h)、(V)(1)(i) 、(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)、(VI)(2)(a)、(VI )(2)(b)、(VI)(2)(c)、(VII)(1)(a)、(VII)(1)(b)、(VII)(1)(c)、(VIII)(1 )(a)、(VIII)(1)(b)、(VIII)(1)(c)、(VIII)(1)(d)、(IX)(1)(a)、(IX)(1) (b)(IX)(1)(c)、(IX)(1)(d)、(X)(1)(a)、(X)(1)(b)、(X)(1)(c)、(X)(1)( (d)、(XI)(1)(a)、(XI)(1)(b)、(XI)(1)(c)、(XI)(1)(d)、(XIII)(2)(a)、(X III)(2)(b)、(XIII)(3)(a)、(XIII)(3)(b)、(XIII)(4)(a)、(XIII)(4)(b)、(XIII)(5)(a), (XIII)(5)(b), (XIII)(5)(c), (XIII)(5)(d), (XIII)(6)(a), (XIII)(6)(b), (XIII)(6)(c), (XIII)(6)(d), (XIII)(6)(e), (XIII)(6)(f), (XI II)(7)(a), (XIII)(7)(b), (XIII)(7)(c), (XIII)(7)(d), (XIII)(7)(e), (XIII)(7)(f), (XIII)(8)(a), (XIII)(8)(b), (XIII)(8)(c), (XIII)(8)(d), (XIII)( A compound is selected from those compounds and combinations thereof of 8)(e), (XIII)(8)(f), (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), wherein the R at the C6' position is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and optionally an antigen domain such as an O antigen domain and / or a capping antigen, and the X at the C1 position is an ethyl moiety.

[0200] In one embodiment, the modified LPS molecular species are as shown in Figures 2-4, 6-17 and 27, and are of formula (I)(1)(a), (I)(1)(b), (I)(1)(c), (I)(1)(d), (I)(1)(e), (I)(1)(f), (I)(2)(a), (I)(2)(b), (I)(2)(c), (I)(3)(a), (I)(3)(b), (I)(3)(c), (II)(1)(a), (II)(1)(b), (II)(1)(c), (II)(1)(d), (II)(2)(a), (I I)(2)(b), (II)(2)(c), (II)(2)(d), (III)(1)(a), (III)(1)(b), (III)(1)(c), (III)(1)(d), (IV)(1)(a), (IV)(1)(b), (IV)(1)(c), (V)(1)(a), (V)(1)(b), (V)(1)(c), (V)(1)(d), (V)(1)(e), (V)(1)(f), (V)(1)(g), (V)(1)(h), (V)(1)(i), (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), (VI)(2)(a), (VI)(2)(b), (V I)(2)(c), (VII)(1)(a), (VII)(1)(b), (VII)(1)(c), (VIII)(1)(a), (VIII)(1)(b), (VIII)(1)(c), (VIII)(1)(d), (IX)(1)(a), (IX) The compounds are selected from those of (1)(b), (IX)(1)(c), (IX)(1)(d), (X)(1)(a), (X)(1)(b), (X)(1)(c), (X)(1)(d), (XI)(1)(a), (XI)(1)(b), (XI)(1)(c), (XI)(1)(d), and (XII)(1), and combinations thereof, wherein the R at the C6' position is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and, optionally, an antigen domain such as an O antigen domain and / or a capping antigen.

[0201] In one embodiment, the modified LPS molecular species are as shown in Figures 2-4 and 7-17, with formulas (I)(1)(a), (I)(1)(b), (I)(1)(c), (I)(1)(d), (I)(1)(e), (I)(1)(f), (I)(2)(a), (I)(2)(b), (I)(2)(c), (I)(3)(a), (I)(3)(b), (I)(3)(c), (II)(2)(a), (II)(2)(b), (II)(2)(c), (II)(2)(d), (II I)(1)(a), (III)(1)(b), (III)(1)(c), (III)(1)(d), (IV)(1)(a), (IV)(1)(b), (IV)(1)(c), (V)(1)(a), (V)(1)(b), (V)(1)( c), (V)(1)(d), (V)(1)(e), (V)(1)(f), (V)(1)(g), (V)(1)(h), (V)(1)(i), (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), (VI)(2)(a), (VI)(2)(b), (VI)(2)(c), (VI I)(1)(a), (VII)(1)(b), (VII)(1)(c), (VIII)(1)(a), (VIII)(1)(b), (VIII)(1)(c), (VIII)(1)(d), (IX)(1)(a), (IX)(1)(b The compounds are selected from (IX)(1)(c), (IX)(1)(d), (X)(1)(a), (X)(1)(b), (X)(1)(c), (X)(1)(d), (XI)(1)(a), (XI)(1)(b), (XI)(1)(c), and (XI)(1)(d) and their combinations, wherein the R at the C6' position is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and optionally an antigen domain such as an O antigen domain and / or a capping antigen.

[0202] In one embodiment, the modified LPS molecular species are as shown in Figures 2-4 and 29-33, and are of formula (I)(1)(a), (I)(1)(b), (I)(1)(c), (I)(1)(d), (I)(1)(e), (I)(1)(f), (I)(2)(a), (I)(2)(b), (I)(2)(c), (I)(3)(a), (I)(3)(b), (I)(3)(c), (I)(5)(a), (I)(5)(b), (I)(6)(a), (I)(6)(b), (I)(7)(a), (I)(7)(b), ( The compounds are selected from those of I)(7)(c), (I)(7)(d), (I)(8)(a), (I)(8)(b), (I)(8)(c), (I)(9)(a), (I)(9)(b), (I)(9)(c), (I)(9)(d), (I)(9)(e), and (I)(9)(f) and their combinations, wherein the R at the C6' position is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and optionally an antigen domain such as an O antigen domain and / or cap antigen, and the X at the C1 position is an ethyl moiety.

[0203] In one embodiment, the modified LPS molecular species is selected from the compounds of formula (I)(1)(a), (I)(1)(b), (I)(1)(c), (I)(1)(d), (I)(1)(e), (I)(1)(f), (I)(2)(a), (I)(2)(b), (I)(2)(c), (I)(3)(a), (I)(3)(b), (I)(3)(c) and combinations thereof, as shown in Figures 2-4, where the R at the C6' position is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and optionally an antigen domain such as an O antigen domain and / or a capping antigen.

[0204] In one embodiment, the modified LPS molecular species is selected from compounds of formula (I)(1)(a), (I)(1)(b), (I)(1)(c), (I)(1)(d), (I)(1)(e), (I)(1)(f) and combinations thereof, as shown in Figure 2, where the R at the C6' position is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and optionally an antigen domain such as an O antigen domain and / or a capping antigen.

[0205] In one embodiment, the modified LPS molecular species is selected from compounds of formula (I)(2)(a), (I)(2)(b), (I)(2)(c) and combinations thereof, as shown in Figure 3, where R at the C6' position is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and optionally an antigen domain such as an O antigen domain and / or a capping antigen.

[0206] In one embodiment, the modified LPS molecular species is selected from compounds of formula (I)(3)(a), (I)(3)(b), (I)(3)(c) and combinations thereof, as shown in Figure 4, where R at the C6' position is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and optionally an antigen domain such as an O antigen domain and / or a capping antigen.

[0207] In one embodiment, the modified LPS molecular species is selected from the compounds of formula (I)(5)(a), (I)(5)(b) and combinations thereof, as shown in Figure 29, where R at the C6' position is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and optionally an antigen domain such as an O antigen domain and / or a capping antigen.

[0208] In one embodiment, the modified LPS molecular species is selected from the compounds of formula (I)(6)(a), (I)(6)(b) and combinations thereof, as shown in Figure 30, where R at the C6' position is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and optionally an antigen domain such as an O antigen domain and / or a capping antigen, and X at the C1 position is an ethyl moiety.

[0209] In one embodiment, the modified LPS molecular species is selected from the compounds of formula (I)(7)(a), (I)(7)(b), (I)(7)(c), (I)(7)(d) and combinations thereof, as shown in Figure 31, where R at the C6' position is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and optionally an antigen domain such as an O antigen domain and / or a capping antigen.

[0210] In one embodiment, the modified LPS molecular species is selected from the compounds of formula (I)(8)(a), (I)(8)(b), (I)(8)(c) and combinations thereof, as shown in Figure 32, where R at the C6' position is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and optionally an antigen domain such as an O antigen domain and / or a capping antigen, and X at the C1 position is an ethyl moiety.

[0211] In one embodiment, the modified LPS molecular species is selected from the compounds of formula (I)(9)(a), (I)(9)(b), (I)(9)(c), (I)(9)(d), (I)(9)(e), (I)(9)(f) and combinations thereof, as shown in Figure 33, where the R at the C6' position is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain, and optionally an antigen domain such as an O antigen domain and / or a capping antigen.

[0212] In one embodiment, the modified LPS molecular species is selected from the compounds of formula (II)(1)(a), (II)(1)(b), (II)(1)(c), (II)(1)(d), (II)(2)(a), (II)(2)(b), (II)(2)(c), and (II)(2)(d) and combinations thereof, as shown in Figures 6-7, where the R at the C6' position is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and optionally an antigen domain such as an O antigen domain and / or a capping antigen.

[0213] In one embodiment, the modified LPS molecular species is selected from the compounds of formula (II)(1)(a), (II)(1)(b), (II)(1)(c), (II)(1)(d) and combinations thereof, as shown in Figure 6, where R at the C6' position is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and optionally an antigen domain such as an O antigen domain and / or a capping antigen.

[0214] In one embodiment, the modified LPS molecular species is selected from the compounds of formula (II)(2)(a), (II)(2)(b), (II)(2)(c), (II)(2)(d) and combinations thereof, as shown in Figure 7, where R at the C6' position is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and optionally an antigen domain such as an O antigen domain and / or a capping antigen.

[0215] In one embodiment, the modified LPS molecular species is selected from the compounds of formula (III)(1)(a), (III)(1)(b), (III)(1)(c), (III)(1)(d) and combinations thereof, as shown in Figure 8, where R at the C6' position is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and optionally an antigen domain such as an O antigen domain and / or a capping antigen.

[0216] In one embodiment, the modified LPS molecular species is selected from the compounds of formula (XII)(1) and combinations thereof, as shown in Figure 27, where R at the C6' position is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and optionally an antigen domain such as an O antigen domain and / or a capping antigen.

[0217] In one embodiment, the modified LPS molecular species is selected from the compounds of formula (IV)(1)(a), (IV)(1)(b), (IV)(1)(c) and combinations thereof, as shown in Figure 9, where R at the C6' position is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and optionally an antigen domain such as an O antigen domain and / or a capping antigen.

[0218] In one embodiment, the modified LPS molecular species is selected from the compounds of formula (V)(1)(a), (V)(1)(b), (V)(1)(c), (V)(1)(d), (V)(1)(e), (V)(1)(f), (V)(1)(g), (V)(1)(h), (V)(1)(i) as shown in FIG. 10 and combinations thereof, and R at the C6’ position is a monosaccharide, oligosaccharide or polysaccharide moiety containing the core oligosaccharide domain and optionally an antigen domain such as an O antigen domain and / or a capping antigen.

[0219] In one embodiment, the modified LPS molecular species is selected from the compounds 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), (VI)(1)(j), (VI)(2)(a), (VI)(2)(b), (VI)(2)(c) as seen in FIGS. 11 - 12 and combinations thereof, and R at the C6’ position is a monosaccharide, oligosaccharide or polysaccharide moiety containing the core oligosaccharide domain and optionally an antigen domain such as an O antigen domain and / or a capping antigen.

[0220] In one embodiment, the modified LPS molecular species is selected from the compounds 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), (VI)(1)(j) as seen in FIG. 11 and combinations thereof, and R at the C6’ position is a monosaccharide, oligosaccharide or polysaccharide moiety containing the core oligosaccharide domain and optionally an antigen domain such as an O antigen domain and / or a capping antigen.

[0221] In one embodiment, the modified LPS molecular species is selected from the compounds of formula (VI)(2)(a), (VI)(2)(b), (VI)(2)(c) and combinations thereof, as shown in Figure 12, where R at the C6' position is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and optionally an antigen domain such as an O antigen domain and / or a capping antigen.

[0222] In one embodiment, the modified LPS molecular species is selected from the compounds of formula (VII)(1)(a), (VII)(1)(b), (VII)(1)(c) and combinations thereof, as shown in Figure 13, where R at the C6' position is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and optionally an antigen domain such as an O antigen domain and / or a capping antigen.

[0223] In one embodiment, the modified LPS molecular species is selected from the compounds of formula (VIII)(1)(a), (VIII)(1)(b), (VIII)(1)(c), (VIII)(1)(d) and combinations thereof, as shown in Figure 14, where R at the C6' position is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and optionally an antigen domain such as an O antigen domain and / or a capping antigen.

[0224] In one embodiment, the modified LPS molecular species is selected from the compounds of formula (IX)(1)(a), (IX)(1)(b), (IX)(1)(c), (IX)(1)(d) and combinations thereof, as shown in Figure 15, where R at the C6' position is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and optionally an antigen domain such as an O antigen domain and / or a capping antigen.

[0225] In one embodiment, the modified LPS molecular species is selected from the compounds of formula (X)(1)(a), (X)(1)(b), (X)(1)(c), (X)(1)(d) and combinations thereof, as shown in Figure 16, where R at the C6' position is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and optionally an antigen domain such as an O antigen domain and / or a capping antigen.

[0226] In one embodiment, the modified LPS molecular species is selected from the compounds of formula (XI)(1)(a), (XI)(1)(b), (XI)(1)(c), (XI)(1)(d) and combinations thereof, as shown in Figure 17, where R at the C6' position is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and optionally an antigen domain such as an O antigen domain and / or a capping antigen.

[0227] In one embodiment, the modified LPS molecular species are represented by formulas (XIII)(2)(a), (XIII)(2)(b), (XIII)(3)(a), (XIII)(3)(b), (XIII)(4)(a), (XIII)(4)(b), (XIII)(5)(a), (XIII)(5)(b), (XIII)(5)(c), and (XIII)(5) as shown in Figures 36 to 43. (d), (XIII)(6)(a), (XIII)(6)(b), (XIII)(6)(c), (XIII)(6)(d), (XIII)(6)(e), (XIII)(6)(f) , (XIII)(7)(a), (XIII)(7)(b), (XIII)(7)(c), (XIII)(7)(d), (XIII)(7)(e), (XIII)(7)(f), (X A selection is made from the compounds and combinations thereof of III)(8)(a), (XIII)(8)(b), (XIII)(8)(c), (XIII)(8)(d), (XIII)(8)(e), (XIII)(8)(f), (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), (XIII)(9)(j), where R at the C6' position is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and optionally an antigen domain such as an O antigen domain and / or a capping antigen, and X at the C1 position is an ethyl moiety.

[0228] In one embodiment, the modified LPS molecular species is selected from the compounds of formula (XIII)(2)(a), (XIII)(2)(b) and combinations thereof, as shown in Figure 36, where R at the C6' position is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and optionally an antigen domain such as an O antigen domain and / or a capping antigen.

[0229] In one embodiment, the modified LPS molecular species is selected from the compounds of formula (XIII)(3)(a), (XIII)(3)(b) and combinations thereof, as shown in Figure 37, where R at the C6' position is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and optionally an antigen domain such as an O antigen domain and / or a capping antigen.

[0230] In one embodiment, the modified LPS molecular species is selected from the compounds of formula (XIII)(4)(a), (XIII)(4)(b) and combinations thereof, as shown in Figure 38, where R at the C6' position is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and optionally an antigen domain such as an O antigen domain and / or a capping antigen, and X at the C1 position is an ethyl moiety.

[0231] In one embodiment, the modified LPS molecular species is selected from compounds of formula (XIII)(5)(a), (XIII)(5)(b), (XIII)(5)(c), (XIII)(5)(d) and combinations thereof, as shown in Figure 39, where the R at the C6' position is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and optionally an antigen domain such as an O antigen domain and / or a capping antigen.

[0232] In one embodiment, the modified LPS molecular species is selected from the compounds of formula (XIII)(6)(a), (XIII)(6)(b), (XIII)(6)(c), (XIII)(6)(d), (XIII)(6)(e), (XIII)(6)(f) and combinations thereof, as shown in Figure 40, where the R at the C6' position is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and optionally an antigen domain such as an O antigen domain and / or a capping antigen.

[0233] In one embodiment, the modified LPS molecular species is selected from the compounds of formula (XIII)(7)(a), (XIII)(7)(b), (XIII)(7)(c), (XIII)(7)(d), (XIII)(7)(e), (XIII)(7)(f) and combinations thereof, as shown in Figure 41, where the R at the C6' position is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and optionally an antigen domain such as an O antigen domain and / or a capping antigen.

[0234] In one embodiment, the modified LPS molecular species is selected from the compounds of formula (XIII)(8)(a), (XIII)(8)(b), (XIII)(8)(c), (XIII)(8)(d), (XIII)(8)(e), (XIII)(8)(f) and combinations thereof, as shown in Figure 42, where R at the C6' position is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and optionally an antigen domain such as an O antigen domain and / or a capping antigen, and X at the C1 position is an ethyl moiety.

[0235] In one embodiment, the modified LPS molecular species is selected from the compounds of 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), (XIII)(9)(j) and combinations thereof, as shown in Figure 43, wherein the R at the C6' position is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and optionally an antigen domain such as an O antigen domain and / or a capping antigen.

[0236] In one embodiment, the modified LPS molecular species is soluble in aqueous solution. In one embodiment, the modified LPS molecular species does not precipitate in aqueous solution. The term "aqueous solution" includes, but is not limited to, any aqueous solution such as water, saline solution, or buffer solution.

[0237] In one embodiment, the modified LPS molecular species is soluble in water and / or phosphate-buffered saline (PBS). In one embodiment, the modified LPS molecular species does not precipitate in water and / or PBS.

[0238] The solubility and / or precipitation of LPS molecular species can be readily evaluated using techniques well known to those skilled in the art. Such techniques include, but are not limited to, dynamic light scattering (DLS), scanning electron microscopy (SEM), and Fourier transform infrared spectroscopy (FT-IR).

[0239] In one embodiment, the modified LPS molecular species form particles, preferably supramolecular particles, in an aqueous solution.

[0240] In one embodiment, the particles of the modified LPS molecular species according to the present invention are in an aqueous solution, preferably in water and / or PBS, with a diameter of less than about 500 nm, preferably about 490 nm, about 480 nm, about 470 nm, about 460 nm, about 450 nm, about 440 nm, about 430 nm, about 420 nm, about 410 nm, about 400 nm, about 390 nm, about 380 nm, about 370 nm, about 360 nm, about 350 nm, about 340 nm, about 330 nm, about 320 nm, about 310 nm, about 300 nm, about 290 nm, about 280 nm, about 270 nm, about 260 nm, about The average sizes are approximately 250nm, 240nm, 230nm, 220nm, 210nm, 200nm, 190nm, 180nm, 170nm, 160nm, 150nm, 140nm, 130nm, 120nm, 110nm, 100nm, 90nm, 80nm, 70nm, 60nm, 50nm, 40nm, 30nm, and 20nm, and preferably a DLS with a scattering angle Θ=90°, incident laser wavelength λ=633nm, and temperature of 25℃, so that it can be evaluated by DLS, for example. In one embodiment, the particles of the modified LPS molecular species according to the present invention have an average size of less than about 30 nm in diameter in an aqueous solution, preferably in water and / or PBS, and can be evaluated by DLS, preferably with a scattering angle Θ=90°, incident laser wavelength λ=633 nm and temperature of 25°C.

[0241] In one embodiment, the particles of the modified LPS aqua species according to the present invention are in aqueous solution, preferably in water and / or PBS, with diameters of approximately 6 nm to 500 nm, approximately 6 nm to 450 nm, approximately 6 nm to 400 nm, approximately 6 nm to 350 nm, approximately 6 nm to 300 nm, approximately 6 nm to 250 nm, approximately 6 nm to 200 nm, approximately 6 nm to 150 nm, approximately 6 nm to 100 nm, approximately 6 nm to 75 nm, approximately 6 nm to 60 nm, approximately 6 nm to 50 nm, approximately 6 nm to 40 nm, approximately 6 nm to 35 nm, approximately 6 nm to 34 nm, approximately 6 nm to 33 nm, approximately 6 nm to 32 nm, approximately 6 nm to 31 nm, approximately 6 nm to 30 nm, approximately 6 nm to 29 nm, and approximately 6 The average size is in the range of nm to approximately 28 nm, approximately 6 nm to approximately 27 nm, approximately 6 nm to approximately 26 nm, approximately 6 nm to approximately 25 nm, approximately 6 nm to approximately 24 nm, approximately 6 nm to approximately 23 nm, approximately 6 nm to approximately 22 nm, approximately 6 nm to approximately 21 nm, approximately 6 nm to approximately 20 nm, approximately 6 nm to approximately 19 nm, approximately 6 nm to approximately 18 nm, approximately 6 nm to approximately 17 nm, approximately 6 nm to approximately 16 nm, approximately 6 nm to approximately 15 nm, approximately 6 nm to approximately 14 nm, approximately 6 nm to approximately 13 nm, approximately 6 nm to approximately 12 nm, approximately 6 nm to approximately 11 nm, and approximately 6 nm to approximately 10 nm, and preferably a DLS with a scattering angle Θ = 90°, incident laser wavelength λ = 633 nm, and temperature of 25°C, so that it can be evaluated by DLS, for example.

[0242] In one embodiment, the particles of the modified LPS molecular species according to the present invention are in aqueous solution, preferably in water and / or PBS, with diameters of approximately 9 nm to 500 nm, approximately 9 nm to 450 nm, approximately 9 nm to 400 nm, approximately 9 nm to 350 nm, approximately 9 nm to 300 nm, approximately 9 nm to 250 nm, approximately 9 nm to 200 nm, approximately 9 nm to 150 nm, approximately 9 nm to 100 nm, approximately 9 nm to 90 nm, approximately 8 nm to 80 nm, approximately 9 nm to 75 nm, approximately 9 nm to 50 nm, approximately 9 nm to 40 nm, approximately 9 nm to 35 nm, approximately 9 nm to 34 nm, approximately 9 nm to 33 nm, approximately 9 nm to 32 nm, approximately 9 nm to 31 nm, approximately 9 nm to 30 nm, and approximately 9 nm to 29 The average size is in the range of nm, approximately 9nm to approximately 28nm, approximately 9nm to approximately 27nm, approximately 9nm to approximately 26nm, approximately 9nm to approximately 25nm, approximately 9nm to approximately 24nm, approximately 9nm to approximately 23nm, approximately 9nm to approximately 22nm, approximately 9nm to approximately 21nm, approximately 9nm to approximately 20nm, approximately 9nm to approximately 19nm, approximately 9nm to approximately 18nm, approximately 9nm to approximately 17nm, approximately 9nm to approximately 16nm, approximately 9nm to approximately 15nm, approximately 9nm to approximately 14nm, approximately 9nm to approximately 13nm, approximately 9nm to approximately 12nm, approximately 9nm to approximately 11nm, and approximately 9nm to approximately 10nm, and preferably a DLS with a scattering angle Θ=90°, incident laser wavelength λ=633nm and a temperature of 25°C, so that it can be evaluated by DLS, for example.

[0243] In one embodiment, the particles of the modified LPS molecular species according to the present invention are in an aqueous solution, preferably in water and / or PBS, with diameters of approximately 10 nm to 500 nm, approximately 10 nm to 450 nm, approximately 10 nm to 400 nm, approximately 10 nm to 350 nm, approximately 10 nm to 300 nm, approximately 10 nm to 250 nm, approximately 10 nm to 200 nm, approximately 10 nm to 150 nm, approximately 10 nm to 100 nm, approximately 10 nm to 75 nm, approximately 10 nm to 50 nm, approximately 10 nm to 40 nm, approximately 10 nm to 35 nm, approximately 10 nm to 34 nm, approximately 10 nm to 33 nm, approximately 10 nm to 32 nm, approximately 10 nm to 31 nm, approximately 10 nm to 30 nm, approximately 10 nm to 29 nm, and approximately 1 The average size is in the range of 0nm to approximately 28nm, approximately 10nm to approximately 27nm, approximately 10nm to approximately 26nm, approximately 10nm to approximately 25nm, approximately 10nm to approximately 24nm, approximately 10nm to approximately 23nm, approximately 10nm to approximately 22nm, approximately 10nm to approximately 21nm, approximately 10nm to approximately 20nm, approximately 10nm to approximately 19nm, approximately 10nm to approximately 18nm, approximately 10nm to approximately 17nm, approximately 10nm to approximately 16nm, approximately 10nm to approximately 15nm, approximately 10nm to approximately 14nm, approximately 10nm to approximately 13nm, approximately 10nm to approximately 12nm, and approximately 10nm to approximately 11nm, and preferably a DLS with a scattering angle Θ=90°, incident laser wavelength λ=633nm and temperature of 25℃, so that it can be evaluated by DLS, for example.

[0244] In one embodiment, the particles of the modified LPS molecular species according to the present invention are in an aqueous solution, preferably in water and / or PBS, with diameters of approximately 14 nm to 500 nm, approximately 14 nm to 450 nm, approximately 14 nm to 400 nm, approximately 14 nm to 350 nm, approximately 14 nm to 300 nm, approximately 14 nm to 250 nm, approximately 14 nm to 200 nm, approximately 14 nm to 150 nm, approximately 14 nm to 100 nm, approximately 14 nm to 75 nm, approximately 14 nm to 50 nm, approximately 14 nm to 40 nm, approximately 14 nm to 35 nm, approximately 14 nm to 34 nm, approximately 14 nm to 33 nm, approximately 14 nm to 32 nm, approximately 14 nm to 31 nm, and approximately 1 The average size is in the range of 4nm to approximately 30nm, approximately 14nm to approximately 29nm, approximately 14nm to approximately 28nm, approximately 14nm to approximately 27nm, approximately 14nm to approximately 26nm, approximately 14nm to approximately 25nm, approximately 14nm to approximately 24nm, approximately 14nm to approximately 23nm, approximately 14nm to approximately 22nm, approximately 14nm to approximately 21nm, approximately 14nm to approximately 20nm, approximately 14nm to approximately 19nm, approximately 14nm to approximately 18nm, approximately 14nm to approximately 17nm, approximately 14nm to approximately 16nm, and approximately 14nm to approximately 15nm, and preferably a DLS with a scattering angle Θ=90°, incident laser wavelength λ=633nm and temperature of 25℃, so that it can be evaluated by DLS, for example.

[0245] In one embodiment, the modified LPS molecular species is less toxic and / or pyrogenic than the classic E. coli or Salmonella enterica LPS molecule.

[0246] Means and methods for evaluating the toxicity and / or pyrogenicity of LPS molecular species are well known in the art.

[0247] Examples of such means and methods include, but are not limited to, the rabbit pyrotherapeutic test (RPT) and C in chicken embryos. 50 Lethal dose, C in GalN-sensitized mice 50 This includes, but is not limited to, in vivo studies such as lethal dose and acute toxicity studies in normal mice, as well as in vitro studies such as monocyte activation studies (MAT).

[0248] The Rabbit Pyrmogenicity Test (RPT) involves measuring the rise in body temperature of three rabbits after intravenous injection of a test solution (such as a composition containing LPS to be tested). The temperature is first measured before injection of the test solution, then the test solution is injected, and the body temperature of each rabbit is measured for 3 hours. If the combined temperature rise of the three rabbits is less than 1.15°C, the test solution is considered non-pyrogenic. If the combined temperature rise of the three rabbits exceeds 2.65°C, the test solution is considered pyrogenic. If the combined temperature rise of the three rabbits is between 1.15°C and 2.65°C, the test should be repeated to confirm the result.

[0249] The monocyte activation assay (MAT) is based on the activation of monocytes by pyrogens, resulting in the production of cytokines detectable by immunological assays (e.g., ELISA). Different variants of the MAT exist depending on (1) the source of monocytes, including whole blood, isolated primary monocytes (e.g., PBMCs), or monocyte cell lines, and (2) the ELISA readouts, including IL-6, IL-1β, and TNF-α. All of them mimic the human pyrogen response in vitro.

[0250] For further details regarding means and methods for evaluating the toxicity and / or pyrogenity of LPS molecular species, see Chapters 5.1.10 and 2.6.30 of the European Pharmacopoeia.

[0251] In one embodiment, the modified LPS isoform has endotoxin activity of less than 5000 endotoxin equivalent units (EEU) / μg, preferably less than 4000, 3000, 2000, 1500, or 1000 EEU / μg, which can be evaluated, for example, by a monocyte activation test (MAT) based on peripheral blood mononuclear cells (PBMCs) and IL-6 response.

[0252] In one embodiment, the modified LPS molecular species according to the present invention may be modified by any means and methods known to those skilled in the art, including but not limited to chemical, enzymatic, physical, or genetic means.

[0253] In one embodiment, the modified LPS molecular species according to the present invention is a chemically modified LPS molecular species.

[0254] In one embodiment, modified LPS molecular species can be obtained by acidic hydrolysis of naturally occurring LPS molecular species.

[0255] In one embodiment, modified LPS molecular species can be obtained by acid hydrolysis of naturally occurring LPS molecular species at temperatures ranging from approximately 4°C to approximately 85°C.

[0256] In one embodiment, modified LPS molecular species can be obtained by acidic hydrolysis of naturally occurring LPS molecular species in the presence of alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, 1-pentanol, 3-methyl-1-butanol, 2,2-dimethyl-1-propanol, cyclopentanol, 1-hexanol, cyclohexanol, 1-heptanol, 1-octanol, 1-nonanol, 1-decanol, 2-propen-1-ol, phenylmethanol, diphenylmethanol, triphenylmethanol, etc.

[0257] In one embodiment, modified LPS molecular species can be obtained by acidic hydrolysis of naturally occurring LPS molecular species at a temperature in the range of about 4°C to about 85°C in the presence of alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 1-pentanol, 3-methyl-1-butanol, 2,2-dimethyl-1-propanol, cyclopentanol, 1-hexanol, cyclohexanol, 1-heptanol, 1-octanol, 1-nonanol, 1-decanol, 2-propen-1-ol, phenylmethanol, diphenylmethanol, triphenylmethanol, etc.

[0258] In one embodiment, modified LPS molecular species can be obtained by acidic hydrolysis followed by alkaline hydrolysis of naturally occurring LPS molecular species. In a preferred embodiment, modified LPS molecular species can be obtained by alkaline hydrolysis followed by acidic hydrolysis of naturally occurring LPS molecular species.

[0259] In one embodiment, modified LPS molecular species can be obtained by acidic hydrolysis followed by alkaline hydrolysis of naturally occurring LPS molecular species. According to this embodiment, it may be desirable to reduce the disaccharide of the lipid A domain, particularly glucosamine, with sodium borohydride before alkaline hydrolysis. For example, the reduction can be carried out at 52°C for 12 hours at pH 8 in the presence of 0.5 M NaBH (final concentration).

[0260] The present invention also relates to a method for obtaining modified LPS molecular species according to the present invention.

[0261] The innovative process involves dephosphorylation targeting lipid A glycoside-type phosphate, which is removed in situ in the complete LPS molecular species without splitting into its lipid A and polysaccharide moieties.

[0262] In particular, the present invention is i. The lipid A domain lacks a phosphate group at the C1 position of the reducing end, and is substituted with a monosaccharide, oligosaccharide, or polysaccharide moiety at the C6' position of the non-reducing end, and / or ii. The lipid A domain lacks a phosphate group at the non-reducing C4' position, and the non-reducing C6' position of the lipid A domain is substituted with a monosaccharide, oligosaccharide, or polysaccharide moiety. Furthermore iii. Compared to a classic (i.e., unmodified) E. coli or Salmonella enterica LPS molecule, it contains fewer or more fatty acid chains, with 6 fatty acid chains consisting of 4 primary fatty acid chains and 2 secondary fatty acid chains, and / or iv. Four primary 3-OH-C 14 Fatty acid chain, one secondary carbon 14 Fatty acid chain and one secondary C 12 It contains shorter and / or longer fatty acid chains compared to classical (i.e., unmodified) E. coli or Salmonella enterica LPS molecules that contain fatty acid chains.

[0263] In one embodiment, this method includes a preliminary step of extracting naturally occurring LPS molecular species.

[0264] In one embodiment, naturally occurring LPS molecular species are extracted from bacterial cultures. All methods of bacterial growth can be used. Examples of bacterial cultures include, but are not limited to, fermentation-based bacterial cultures, flask cultures, solid medium cultures (e.g., agar cultures), biofilm cultures grown at solid-liquid or liquid-gas interfaces, and any other methods known in the art. In one embodiment, naturally occurring LPS molecular species are extracted from bacterial pellets, culture concentrates, culture supernatants, concentrated membrane fractions, and / or outer membrane vesicle (OMV) fractions.

[0265] In one embodiment, naturally occurring LPS molecular species are extracted from naturally occurring biomass samples, such as marine plankton or microbial communities.

[0266] Any LPS extraction method can be used that utilizes solvents, reagents, and procedures suitable for the production of the pharmacological product. Following LPS extraction, an LPS purification step is preferentially followed to reduce bacteria and other contaminants associated with the production process, such as biomass production, to acceptable levels.

[0267] Methods for extracting naturally occurring LPS molecular species are well known in the art. Dozens of suitable methods for LPS extraction are described in the literature; see, for example, the overview by Wang et al., 2010 (Purification and characterization of lipopolysaccharides. In Wang & Quinn (Eds.), Endotoxins: structure, function and recognition. 53:27-51. Springer). Other methods are described in U.S. Patent No. 8,137,935. In one embodiment, LPS is extracted according to the method described in U.S. Patent No. 8,137,935. According to this method, bacterial pellets, culture concentrates, culture supernatants, concentrated membrane fractions, and / or outer membrane vesicle (OMV) fractions are suspended in a mixture of solvents comprising a solvent selected from linear or branched fatty acids containing about 10–90% of 3–6 carbon atoms, and a basic aqueous solution of an aliphatic amine containing about 90–10% of 0–12 carbon atoms. The entire mixture is stirred to produce a suspension of bacterial LPS in a mixture of solvents containing bacterial cell debris. The LPS extracts are recovered from the suspension by centrifugation and / or filtration in the form of supernatant and / or filtrate, respectively. Particles in the suspension are separated and discarded in the form of pellets and / or retaining solutions, respectively. Finally, the solvent is removed from the supernatant and / or filtrate, and the naturally occurring LPS molecular species are typically freeze-dried. Other preservation methods may be used, including, but not limited to, the dried form and suspension in a suitable solvent.

[0268] In one embodiment, the method includes a step of purifying naturally occurring LPS molecular species to reduce bacterial and process-related contaminants to acceptable levels, as described, for example, Tirsoaga et al., 2007 (Appl Environ Microbiol. 73(6):1803-8), as well as ensuring the TLR-grade purity of the final product (TLR4 ligand).

[0269] In one embodiment, this method includes the step of treating naturally occurring LPS molecular species by acidic hydrolysis.

[0270] The hydrolysis conditions known in the art and used to remove lipid A phosphate at the C1 position of the reducing end of the lipid A domain ultimately result in the cleavage of the ketoside bond at the C6' position of the non-reducing end of the lipid A domain, between lipid A and the sugar moiety (position R3 of formula A or formula B).

[0271] In one embodiment, the step of treating a naturally occurring LPS molecular species by acidic hydrolysis is carried out under acidic hydrolysis conditions that allow for the removal of glycoside phosphate without cleaving the ketoside bond at the C6' position of the non-reducing end of the lipid A domain.

[0272] In one embodiment, acidic hydrolysis is carried out at a temperature below 85°C, preferably in the range of about 4°C to about 85°C. Both inorganic and organic acids can be used, with or without additional reagents, such as salts. Acidic hydrolysis can be carried out in both aqueous solutions and organic solutions. Actual results can be obtained with hydrolysis durations ranging from a few minutes to several tens of hours, preferably 1 to 10 hours.

[0273] In one embodiment, acidic hydrolysis is carried out in the presence of an alcohol, such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, 1-pentanol, 3-methyl-1-butanol, 2,2-dimethyl-1-propanol, cyclopentanol, 1-hexanol, cyclohexanol, 1-heptanol, 1-octanol, 1-nonanol, 1-decanol, 2-propen-1-ol, phenylmethanol, diphenylmethanol, triphenylmethanol, etc.

[0274] In one embodiment, acidic hydrolysis is carried out at a temperature below 85°C, preferably in the range of about 4°C to about 85°C, in the presence of an alcohol such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 1-pentanol, 3-methyl-1-butanol, 2,2-dimethyl-1-propanol, cyclopentanol, 1-hexanol, cyclohexanol, 1-heptanol, 1-octanol, 1-nonanol, 1-decanol, 2-propen-1-ol, phenylmethanol, diphenylmethanol, or triphenylmethanol.

[0275] In one embodiment, acidic hydrolysis also partially removes one or more secondary fatty acid residues, thus amplifying the degree of LPS detoxification.

[0276] In one embodiment, the method includes an additional step of treating naturally occurring LPS molecular species by alkaline hydrolysis to remove one or more esterified fatty acid residues and thus amplify the degree of LPS detoxification. In certain initial structures of naturally occurring LPS molecular species, such as those containing a phosphate group at the C4' position of the non-reducing end of their lipid A domain substituted with an amino sugar (e.g., glucosamine, galactosamine, muramic acid, etc.), alkaline hydrolysis can result in at least partial removal of the phosphate at the C4' position.

[0277] In one embodiment, the steps of treatment by acidic hydrolysis and treatment by alkaline hydrolysis can be carried out in any order.

[0278] In one embodiment, the acid hydrolysis treatment step is performed before the alkaline hydrolysis treatment step. Alternatively, the alkaline hydrolysis treatment step is performed before the acid hydrolysis treatment step.

[0279] In a preferred embodiment, the alkaline hydrolysis treatment step is performed before the acid hydrolysis treatment step.

[0280] In one embodiment, the acidic hydrolysis step is performed before the alkaline hydrolysis step. According to this embodiment, it may be desirable to reduce the lipid A domain disaccharide, particularly glucosamine, with sodium borohydride before the alkaline hydrolysis step. For example, the reduction can be carried out at 52°C for 12 hours at pH 8 in the presence of 0.5 M NaBH (final concentration).

[0281] Those skilled in the art will readily recognize that, depending on the intended use, the LPS molecular species should be purified to a certain degree of purity (e.g., to GMP grade for intended human use, or to a lower purity for veterinary use). In particular for veterinary use, the method for obtaining modified LPS molecular species according to the present invention may not involve a step of purifying naturally occurring LPS molecular species; that is, the method may include a step of directly processing naturally occurring LPS from bacterial pellets, culture concentrates, culture supernatants, concentrated membrane fractions and / or outer membrane vesicle (OMV) fractions.

[0282] The present invention also relates to a composition comprising at least one LPS molecular species.

[0283] In one embodiment, at least one LPS molecular species is a modified LPS molecular species according to the present invention.

[0284] In one embodiment, the composition comprises at least one modified LPS molecular species of formula A as described herein.

[0285] In one embodiment, the composition comprises a mixture of modified LPS molecular species of formula A as described herein.

[0286] In one embodiment, the composition comprises an enriched population of modified LPS molecular species of formula A as described herein.

[0287] In one embodiment, the composition comprises at least one modified LPS molecular species of formula B as described herein.

[0288] In one embodiment, the composition comprises a mixture of modified LPS molecular species of formula B as described herein.

[0289] In one embodiment, the composition comprises an enriched population of modified LPS molecular species of formula B as described herein.

[0290] In one embodiment, the composition comprises a mixture of modified LPS molecular species as described herein, comprising at least 10%, at least 25%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, and at least 99% of the total amount of LPS molecular species in the population.

[0291] The mortgage shall also be defined as (I)(1)(a)(I)(1)(b)(I)(1)(c)(I)(1)(d)(e)(1)(1)(1) )、(I)(1)(f)、(I)(2)(a)、(I)(2)(b)、(I)(2)(c)、(I)(3)(a) (I)(3)(c)、(I)(5)(a)、(I)(5)(b)、(I)(6)(a)、(I)(6)(b)、(I)(7)(a)、(I )(7)(b)、(I)(7)(c)、(I)(7)(d)、(I)(8)(a)、(I)(8)(b)、(I)(8)(c)、(I)(9 )(a)、(I)(9)(b)、(I)(9)(c)、(I)(9)(d)、(I)(9)(e)、(I)(9)(f)、(II)(1) (a)、(II)(1)(b)、(II)(1)(c)、(II)(1)(d)、(II)(2)(a)、(II)(2)(b)、(II )(2)(c)、(II)(2)(d)、(III)(1)(a)、(III)(1)(b)、(III)(1)(c)、(III)(1 )(d)、(IV)(1)(a)、(IV)(1)(b)、(IV)(1)(c)、(V)(1)(a)、(V)(1)(b)、(V)(1 )(c)、(V)(1)(d)、(V)(1)(e)、(V)(1)(f)、(V)(1)(g)、(V)(1)(h)、(V)(1)( i)、(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)、(VI)(2)(a)、 (VI)(2)(b)、(VI)(2)(c)、(VII)(1)(a)、(VII)(1)(b)、(VII)(1)(c)、(VIII )(1)(a)、(VIII)(1)(b)、(VIII)(1)(c)、(VIII)(1)(d)、(IX)(1)(a)、(IX) (1)(b)、(IX)(1)(c)、(IX)(1)(d)、(X)(1)(a)、(X)(1)(b)、(X)(1)(c)、(X) (1)(d)、(XI)(1)(a)、(XI)(1)(b)、(XI)(1)(c)、(XI)(1)(d)、(XII)(1)、(X (III)(2)(a)、(XIII)(2)(b)、(XIII)(3)(a)、(XIII)(3)(b)、(XIII)(4)(a)、(XIII)(4)(b), (XIII)(5)(a), (XIII)(5)(b), (XIII)(5)(c), (XIII)(5)(d), (XIII)(6)(a), (XIII)(6)(b), (XIII)(6)(c), (XIII)(6)(d), (XII I)(6)(e), (XIII)(6)(f), (XIII)(7)(a), (XIII)(7)(b), (XIII)(7)(c), (XIII)(7)(d), (XIII)(7)(e), (XIII)(7)(f), (XIII)(8)(a), (XIII)(8) (b), (XIII)(8)(c), (XIII)(8)(d), (XIII)(8)(e), (XIII)(8)(f), (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), (XIII)(9)(j) LPS molecular species and combinations thereof, or mixtures of modified LPS molecular species selected from the group consisting of them.

[0292] In one embodiment, the composition is of formula (I)(1)(a), (I)(1)(b), (I)(1)(c), (I)(1)(d), (I)(1)(e), (I)(1)(f), (I)(2)(a), (I)(2)(b), (I)(2)(c), (I)(3)(a), (I)(3)(b), (I)(3)(c), (I)(5)(a), (I)(5)(b), (I)(6)(a), (I)(6)(b), (I)(7)(a), (I)(7)(b), (I)(7)(c), (I)(7)(d), (I)(8)(a), (I)(8)(b), (I)(8)(c), (I)(9)(a), (I)(9)(b), (I)(9)(c), (I)(9)(d), (I)(9)(e), (I)(9)(f), (II)(2)(a), (II)(2)(b), (II)(2)(c), (II)(2)(d), (III)(1)(a), (III)(1)(b), (III)(1)(c), (III)(1)(d), (IV)(1)(a), (IV)(1)(b), (IV)(1)(c), (V)(1)(a), (V)(1)(b), (V)(1)(c), (V)(1)(d), (V)(1)(e), (V)(1)(f), (V)(1)(g), (V)(1)(h), (V)(1)(i), (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), (VI)(2)(a), (VI)(2)(b), (VI)(2)(c), (VII)(1)(a), (VII)(1)(b), (VII)(1)(c), (VIII)(1)(a), (VIII)(1)(b), (VIII)(1)(c), (VIII)(1)(d), (IX)(1)(a), (IX)(1)(b), (IX)(1)(c), (IX)(1)(d), (X)(1)(a), (X)(1)(b), (X)(1)(c), (X)(1)(d), (XI)(1)(a), (XI)(1)(b), (XI)(1)(c), (XI)(1)(d), (XIII)(2)(a), (XIII)(2)(b), (XIII)(3)(a), (XIII)(3)(b), (XIII)(4)(a), (XIII)(4)(b), (XIII)(5)(a), (XIII)(5)(b), (XIII)(5)(c),(XIII)(5)(d), (XIII)(6)(a), (XIII)(6)(b), (XIII)(6)(c), (XIII)(6)(d), (XIII)(6)(e), (XIII)(6)(f), (XIII)(7)(a), (XII I)(7)(b), (XIII)(7)(c), (XIII)(7)(d), (XIII)(7)(e), (XIII)(7)(f), (XIII)(8)(a), (XIII)(8)(b), (XIII)(8)(c), (XIII)(8) (d), (XIII)(8)(e), (XIII)(8)(f), (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), (XIII)(9)(j) LPS molecular species and combinations thereof, or mixtures of modified LPS molecular species selected from the group consisting of them.

[0293] The mortgage shall also be defined as (I)(1)(a)(I)(1)(b)(I)(1)(c)(I)(1)(d)(e)(1)(1)(1) )、(I)(1)(f)、(I)(2)(a)、(I)(2)(b)、(I)(2)(c)、(I)(3)(a) (I)(3)(c)、(I)(5)(a)、(I)(5)(b)、(I)(6)(a)、(I)(6)(b)、(I)(7)(a)、(I )(7)(b)、(I)(7)(c)、(I)(7)(d)、(I)(8)(a)、(I)(8)(b)、(I)(8)(c)、(I)(9 )(a)、(I)(9)(b)、(I)(9)(c)、(I)(9)(d)、(I)(9)(e)、(I)(9)(f)、(II)(1) (a)、(II)(1)(b)、(II)(1)(c)、(II)(1)(d)、(II)(2)(a)、(II)(2)(b)、(II )(2)(c)、(II)(2)(d)、(III)(1)(a)、(III)(1)(b)、(III)(1)(c)、(III)(1 )(d)、(IV)(1)(a)、(IV)(1)(b)、(IV)(1)(c)、(V)(1)(a)、(V)(1)(b)、(V)(1 )(c)、(V)(1)(d)、(V)(1)(e)、(V)(1)(f)、(V)(1)(g)、(V)(1)(h)、(V)(1)( i)、(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)、(VI)(2)(a)、 (VI)(2)(b)、(VI)(2)(c)、(VII)(1)(a)、(VII)(1)(b)、(VII)(1)(c)、(VIII )(1)(a)、(VIII)(1)(b)、(VIII)(1)(c)、(VIII)(1)(d)、(IX)(1)(a)、(IX) (1)(b)、(IX)(1)(c)、(IX)(1)(d)、(X)(1)(a)、(X)(1)(b)、(X)(1)(c)、(X) (1)(d)、(XI)(1)(a)、(XI)(1)(b)、(XI)(1)(c)、(XI)(1)(d)、(XII)(1)、(X (III)(2)(a)、(XIII)(2)(b)、(XIII)(3)(a)、(XIII)(3)(b)、(XIII)(4)(a)、(XIII)(4)(b), (XIII)(5)(a), (XIII)(5)(b), (XIII)(5)(c), (XIII)(5)(d), (XIII)(6)(a), (XIII)(6)(b), (XIII)(6)(c), (XIII)(6)(d), (XIII)(6)(e), (XIII) (6)(f), (XIII)(7)(a), (XIII)(7)(b), (XIII)(7)(c), (XIII)(7)(d), (XIII)(7)(e), (XIII)(7)(f), (XIII)(8)(a), (XIII)(8)(b), (XIII)(8)(c), (XIII)(8)(d) , (XIII)(8)(e), (XIII)(8)(f), (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), (XIII)(9)(j) and combinations thereof, or a mixture of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 or more modified LPS molecular species selected from the group consisting of them.

[0294] In one embodiment, the composition is of formula (I)(1)(a), (I)(1)(b), (I)(1)(c), (I)(1)(d), (I)(1)(e), (I)(1)(f), (I)(2)(a), (I)(2)(b), (I)(2)(c), (I)(3)(a), (I)(3)(b), (I)(3)(c), (I)(5)(a), (I)(5)(b), (I)(6)(a), (I)(6)(b), (I)(7)(a), (I)(7)(b), (I)(7)(c), (I)(7)(d), (I)(8)(a), (I)(8)(b), (I)(8)(c), (I)(9)(a), (I)(9)(b), (I)(9)(c), (I)(9)(d), (I)(9)(e), (I)(9)(f), (II)(2)(a), (II)(2)(b), (II)(2)(c), (II)(2)(d), (III)(1)(a), (III)(1)(b), (III)(1)(c), (III)(1)(d), (IV)(1)(a), (IV)(1)(b), (IV)(1)(c), (V)(1)(a), (V)(1)(b), (V)(1)(c), (V)(1)(d), (V)(1)(e), (V)(1)(f), (V)(1)(g), (V)(1)(h), (V)(1)(i), (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), (VI)(2)(a), (VI)(2)(b), (VI)(2)(c), (VII)(1)(a), (VII)(1)(b), (VII)(1)(c), (VIII)(1)(a), (VIII)(1)(b), (VIII)(1)(c), (VIII)(1)(d), (IX)(1)(a), (IX)(1)(b), (IX)(1)(c), (IX)(1)(d), (X)(1)(a), (X)(1)(b), (X)(1)(c), (X)(1)(d), (XI)(1)(a), (XI)(1)(b), (XI)(1)(c), (XI)(1)(d), (XIII)(2)(a), (XIII)(2)(b), (XIII)(3)(a), (XIII)(3)(b), (XIII)(4)(a), (XIII)(4)(b), (XIII)(5)(a), (XIII)(5)(b), (XIII)(5)(c),(XIII)(5)(d), (XIII)(6)(a), (XIII)(6)(b), (XIII)(6)(c), (XIII)(6)(d), (XIII)(6)(e), (XIII)(6)(f), (XIII)(7)(a), (XIII)(7)(b), (XIII) (7)(c), (XIII)(7)(d), (XIII)(7)(e), (XIII)(7)(f), (XIII)(8)(a), (XIII)(8)(b), (XIII)(8)(c), (XIII)(8)(d), (XIII)(8)(e), (XIII)(8)(f) It includes the LPS molecular species (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), (XIII)(9)(j) and combinations thereof, or a mixture of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 or more modified LPS molecular species selected from the group consisting of them.

[0295] In one embodiment, a simple formula is (I)(1)(a), (I)(1)(b), (I)(1)(c), (I)(1)(d), (I)(1)(e), (I)(1)(f), (I)(2)(a), (I)(2)(b), (I)(2)(c), (I)(3)(a), (I)(3)(b), (I)(3)(c), (II)(1)(a), (II)(1)(b), (II)(1)(c), (II)(1)(d), (II)(2)(a), (II)(2)(b), (II) (2)(c), (II)(2)(d), (III)(1)(a), (III)(1)(b), (III)(1)(c), (III)(1)(d), (IV)(1)(a), (IV)(1)(b), (IV)(1)(c), (V) (1)(a), (V)(1)(b), (V)(1)(c), (V)(1)(d), (V)(1)(e), (V)(1)(f), (V)(1)(g), (V)(1)(h), (V)(1)(i), (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), (VI)(2)( a), (VI)(2)(b), (VI)(2)(c), (VII)(1)(a), (VII)(1)(b), (VII)(1)(c), (VIII)(1)(a), (VIII)(1)(b), (VIII)(1)(c), (V The LPS molecular species of III)(1)(d), (IX)(1)(a), (IX)(1)(b), (IX)(1)(c), (IX)(1)(d), (X)(1)(a), (X)(1)(b), (X)(1)(c), (X)(1)(d), (XI)(1)(a), (XI)(1)(b), (XI)(1)(c), (XI)(1)(d), (XII)(1) include combinations thereof, or mixtures of modified LPS molecular species selected from the group consisting of them.

[0296] In one embodiment, a simple formula is (I)(1)(a), (I)(1)(b), (I)(1)(c), (I)(1)(d), (I)(1)(e), (I)(1)(f), (I)(2)(a), (I)(2)(b), (I)(2)(c), (I)(3)(a), (I)(3)(b), (I)(3)(c), (II)(2)(a), (II)(2)(b), (II)(2)(c), (II)(2)(d), (III)(1)(a), ( III)(1)(b), (III)(1)(c), (III)(1)(d), (IV)(1)(a), (IV)(1)(b), (IV)(1)(c), (V)(1)(a), (V)(1)(b), (V)(1)( c), (V)(1)(d), (V)(1)(e), (V)(1)(f), (V)(1)(g), (V)(1)(h), (V)(1)(i), (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), (VI)(2)(a), (VI)(2) (b), (VI)(2)(c), (VII)(1)(a), (VII)(1)(b), (VII)(1)(c), (VIII)(1)(a), (VIII)(1)(b), (VIII)(1)(c), (VIII) The product includes the LPS molecular species (1)(d), (IX)(1)(a), (IX)(1)(b), (IX)(1)(c), (IX)(1)(d), (X)(1)(a), (X)(1)(b), (X)(1)(c), (X)(1)(d), (XI)(1)(a), (XI)(1)(b), (XI)(1)(c), (XI)(1)(d) and combinations thereof, or a mixture of modified LPS molecular species selected from the group consisting of them.

[0297] In one embodiment, the formulas (I)(1)(a), (I)(1)(b), (I)(1)(c), (I)(1)(d), (I)(1)(e), (I)(1)(f), (I)(2)(a), (I)(2)(b), (I)(2)(c), (I)(3)(a), (I)(3)(b), (I)(3)(c), (II)(1)(a), (II)(1)(b), (II)(1)(c), (II)(1)(d), (II)(2)(a), (II)(2)(b), (II)(2)(c), (II)(2)( d), (III)(1)(a), (III)(1)(b), (III)(1)(c), (III)(1)(d), (IV)(1)(a), (IV)(1)(b), (IV)(1)(c), (V)(1)(a), (V)(1)(b), (V)(1 )(c), (V)(1)(d), (V)(1)(e), (V)(1)(f), (V)(1)(g), (V)(1)(h), (V)(1)(i), (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), (VI)(2)(a), (VI)(2)(b), (VI)(2)(c), (VII)(1)(a) , (VII)(1)(b), (VII)(1)(c), (VIII)(1)(a), (VIII)(1)(b), (VIII)(1)(c), (VIII)(1)(d), (IX)(1)(a), (IX)(1)(b), (IX)(1)(c), (IX)(1)(d), (X)(1)(a), (X)(1)(b), (X)(1)(c), (X)(1)(d), (XI)(1)(a), (XI)(1)(b), (XI)(1)(c), (XI)(1)(d), (XII)(1) includes the LPS molecular species and combinations thereof, or includes a mixture of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 or more modified LPS molecular species selected from the group consisting of them.

[0298] In one embodiment, the simplest formulas are (I)(1)(a), (I)(1)(b), (I)(1)(c), (I)(1)(d), (I)(1)(e), (I)(1)(f), (I)(2)(a), (I)(2)(b), (I)(2)(c), (I)(3)(a), (I)(3)(b), (I)(3)(c), (II)(2)(a), (II)(2)(b), (II)(2)(c), (II)(2)(d), (III)(1)(a), (III)(1)(b), (III )(1)(c), (III)(1)(d), (IV)(1)(a), (IV)(1)(b), (IV)(1)(c), (V)(1)(a), (V)(1)(b), (V)(1)(c), (V)(1)(d), (V)(1)(e), (V)(1)(f), (V)(1)(g), (V)(1)(h), (V)(1)(i), (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), (VI)(2)(a), (VI)(2)(b), (VI)(2)(c), (VII)(1)(a), (VII)(1)(b) , (VII)(1)(c), (VIII)(1)(a), (VIII)(1)(b), (VIII)(1)(c), (VIII)(1)(d), (IX)(1)(a), (IX)(1)(b), (IX)(1)(c), (IX)( The mixture includes the LPS molecular species and combinations thereof of 1)(d), (X)(1)(a), (X)(1)(b), (X)(1)(c), (X)(1)(d), (XI)(1)(a), (XI)(1)(b), (XI)(1)(c), and (XI)(1)(d), or a mixture of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 or more modified LPS molecular species selected from the group consisting of them.

[0299] In one embodiment, the composition has the formula (I)(1)(a), (I)(1)(b), (I)(1)(c), (I)(1)(d), (I)(1)(e), (I)(1)(f), (I)(2)(a), (I)(2) (b), (I)(2)(c), (I)(3)(a), (I)(3)(b), (I)(3)(c), (I)(5)(a), (I)(5)(b), (I)(6)(a), (I)(6)(b), (I)(7) The product includes the LPS molecular species (a), (I)(7)(b), (I)(7)(c), (I)(7)(d), (I)(8)(a), (I)(8)(b), (I)(8)(c), (I)(9)(a), (I)(9)(b), (I)(9)(c), (I)(9)(d), (I)(9)(e), (I)(9)(f) and combinations thereof, or a mixture of modified LPS molecular species selected from the group consisting of them.

[0300] In one embodiment, the composition has the formula (I)(1)(a), (I)(1)(b), (I)(1)(c), (I)(1)(d), (I)(1)(e), (I)(1)(f), (I)(2)(a), (I)(2)(b), (I)(2)(c), (I)(3)( a), (I)(3)(b), (I)(3)(c), (I)(5)(a), (I)(5)(b), (I)(6)(a), (I)(6)(b), (I)(7)(a), (I)(7)(b), (I)(7)(c), (I)(7)(d), (I)(8)(a (I)(8)(b), (I)(8)(c), (I)(9)(a), (I)(9)(b), (I)(9)(c), (I)(9)(d), (I)(9)(e), (I)(9)(f) and combinations thereof, or a mixture of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 or 29 modified LPS molecular species selected from the group consisting of them.

[0301] In one embodiment, the composition comprises LPS molecular species of formula (I)(1)(a), (I)(1)(b), (I)(1)(c), (I)(1)(d), (I)(1)(e), (I)(1)(f), (I)(2)(a), (I)(2)(b), (I)(2)(c), (I)(3)(a), (I)(3)(b), (I)(3)(c) and combinations thereof, or a mixture of modified LPS molecular species selected from the group consisting of them.

[0302] In one embodiment, the composition comprises LPS molecular species of formula (I)(1)(a), (I)(1)(b), (I)(1)(c), (I)(1)(d), (I)(1)(e), (I)(1)(f), (I)(2)(a), (I)(2)(b), (I)(2)(c), (I)(3)(a), (I)(3)(b), (I)(3)(c) and combinations thereof, or a mixture of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 modified LPS molecular species selected from the group consisting of them.

[0303] In one embodiment, the composition comprises LPS molecular species of formula (I)(1)(a), (I)(1)(b), (I)(1)(c), (I)(1)(d), (I)(1)(e), (I)(1)(f) and combinations thereof, or a mixture of modified LPS molecular species selected from the group consisting of them.

[0304] In one embodiment, the composition comprises LPS molecular species of formula (I)(1)(a), (I)(1)(b), (I)(1)(c), (I)(1)(d), (I)(1)(e), (I)(1)(f) and combinations thereof, or comprises a mixture of at least 2, 3, 4, 5, or 6 modified LPS molecular species selected from the group consisting of them.

[0305] In one embodiment, the composition comprises at least one LPS molecular species of formula (I)(1)(a), at least one LPS molecular species of formula (I)(1)(b), at least one LPS molecular species of formula (I)(1)(c), at least one LPS molecular species of formula (I)(1)(d), at least one LPS molecular species of formula (I)(1)(e), and at least one LPS molecular species of formula (I)(1)(f), or comprises a mixture of modified LPS molecular species consisting of these.

[0306] In one embodiment, the composition comprises LPS molecular species of formula (I)(2)(a), (I)(2)(b), (I)(2)(c) and combinations thereof, or a mixture of modified LPS molecular species selected from the group consisting of them.

[0307] In one embodiment, the composition comprises LPS molecular species of formula (I)(2)(a), (I)(2)(b), (I)(2)(c) and combinations thereof, or a mixture of at least two or three modified LPS molecular species selected from the group consisting of those.

[0308] In one embodiment, the composition comprises at least one LPS molecular species of formula (I)(2)(a), at least one LPS molecular species of formula (I)(2)(b), and at least one LPS molecular species of formula (I)(2)(c), or comprises a mixture of modified LPS molecular species consisting of these.

[0309] In one embodiment, the composition comprises LPS molecular species of formula (I)(3)(a), (I)(3)(b), (I)(3)(c), and combinations thereof, or a mixture of modified LPS molecular species selected from the group consisting of them.

[0310] In one embodiment, the composition comprises LPS molecular species of formula (I)(3)(a), (I)(3)(b), (I)(3)(c), and combinations thereof, or a mixture of at least two or three modified LPS molecular species selected from the group consisting of them.

[0311] In one embodiment, the composition comprises at least one LPS molecular species of formula (I)(3)(a), at least one LPS molecular species of formula (I)(3)(b), and at least one LPS molecular species of formula (I)(3)(c), or comprises a mixture of modified LPS molecular species consisting of these.

[0312] In one embodiment, the composition comprises LPS molecular species of formula (I)(5)(a), (I)(5)(b), and combinations thereof, or a mixture of modified LPS molecular species selected from the group consisting of them.

[0313] In one embodiment, the composition comprises LPS molecular species of formula (I)(5)(a), (I)(5)(b), and combinations thereof, or a mixture of two modified LPS molecular species selected from the group consisting of them.

[0314] In one embodiment, the composition comprises a mixture of a modified LPS molecular species comprising at least one LPS molecular species of formula (I)(5)(a) or a modified LPS molecular species comprising at least one LPS molecular species of formula (I)(5)(b).

[0315] In one embodiment, the composition comprises LPS molecular species of formula (I)(6)(a), (I)(6)(b), and combinations thereof, or a mixture of modified LPS molecular species selected from the group consisting of them.

[0316] In one embodiment, the composition comprises LPS molecular species of formula (I)(6)(a), (I)(6)(b), and combinations thereof, or a mixture of two modified LPS molecular species selected from the group consisting of them.

[0317] In one embodiment, the composition comprises at least one LPS molecular species of formula (I)(6)(a) and at least one LPS molecular species of formula (I)(6)(b), or a mixture of modified LPS molecular species comprising them.

[0318] In one embodiment, the composition comprises LPS molecular species of formula (I)(7)(a), (I)(7)(b), (I)(7)(c), (I)(7)(d), and combinations thereof, or a mixture of modified LPS molecular species selected from the group consisting of them.

[0319] In one embodiment, the composition includes LPS molecular species of formula (I)(7)(a), (I)(7)(b), (I)(7)(c), (I)(7)(d), and combinations thereof, or a mixture of at least two, three, or four modified LPS molecular species selected from the group consisting of them.

[0320] In one embodiment, the composition comprises at least one LPS molecular species of formula (I)(7)(a), at least one LPS molecular species of formula (I)(7)(b), at least one LPS molecular species of formula (I)(7)(c), and at least one LPS molecular species of formula (I)(7)(d), or comprises a mixture of modified LPS molecular species consisting of these.

[0321] In one embodiment, the composition comprises LPS molecular species of formula (I)(8)(a), (I)(8)(b), (I)(8)(c), and combinations thereof, or a mixture of modified LPS molecular species selected from the group consisting of them.

[0322] In one embodiment, the composition comprises LPS molecular species of formula (I)(8)(a), (I)(8)(b), (I)(8)(c), and combinations thereof, or a mixture of at least two or three modified LPS molecular species selected from the group consisting of them.

[0323] In one embodiment, the composition comprises at least one LPS molecular species of formula (I)(8)(a), at least one LPS molecular species of formula (I)(8)(b), and at least one LPS molecular species of formula (I)(8)(c), or comprises a mixture of modified LPS molecular species consisting of these.

[0324] In one embodiment, the composition comprises LPS molecular species of formula (I)(9)(a), (I)(9)(b), (I)(9)(c), (I)(9)(d), (I)(9)(e), (I)(9)(f), and combinations thereof, or a mixture of modified LPS molecular species selected from the group consisting of them.

[0325] In one embodiment, the composition includes LPS molecular species of formula (I)(9)(a), (I)(9)(b), (I)(9)(c), (I)(9)(d), (I)(9)(e), (I)(9)(f), and combinations thereof, or a mixture of at least 2, 3, 4, 5, or 6 modified LPS molecular species selected from the group consisting of them.

[0326] In one embodiment, the composition comprises at least one LPS molecular species of formula (I)(9)(a), at least one LPS molecular species of formula (I)(9)(b), at least one LPS molecular species of formula (I)(9)(c), at least one LPS molecular species of formula (I)(9)(d), at least one LPS molecular species of formula (I)(9)(e), and at least one LPS molecular species of formula (I)(9)(f), or comprises a mixture of modified LPS molecular species consisting of these.

[0327] In one embodiment, the composition comprises LPS molecular species of formula (II)(1)(a), (II)(1)(b), (II)(1)(c), (II)(1)(d), (II)(2)(a), (II)(2)(b), (II)(2)(c), (II)(2)(d), and combinations thereof, or mixtures of modified LPS molecular species selected from the group consisting of them.

[0328] In one embodiment, the composition includes LPS molecular species of formula (II)(1)(a), (II)(1)(b), (II)(1)(c), (II)(1)(d), (II)(2)(a), (II)(2)(b), (II)(2)(c), (II)(2)(d), and combinations thereof, or a mixture of at least 2, 3, 4, 5, 6, 7, or 8 modified LPS molecular species selected from the group consisting of these.

[0329] In one embodiment, the composition comprises LPS molecular species of formula (II)(1)(a), (II)(1)(b), (II)(1)(c), (II)(1)(d), and combinations thereof, or a mixture of modified LPS molecular species selected from the group consisting of them.

[0330] In one embodiment, the composition includes LPS molecular species of formula (II)(1)(a), (II)(1)(b), (II)(1)(c), (II)(1)(d), and combinations thereof, or a mixture of at least two, three, or four modified LPS molecular species selected from the group consisting of them.

[0331] In one embodiment, the composition comprises at least one LPS molecular species of formula (II)(1)(a), at least one LPS molecular species of formula (II)(1)(b), at least one LPS molecular species of formula (II)(1)(c), and at least one LPS molecular species of formula (II)(1)(d), or comprises a mixture of modified LPS molecular species consisting of these.

[0332] In one embodiment, the composition comprises LPS molecular species of formula (II)(2)(a), (II)(2)(b), (II)(2)(c), (II)(2)(d), and combinations thereof, or a mixture of modified LPS molecular species selected from the group consisting of them.

[0333] In one embodiment, the composition includes LPS molecular species of formula (II)(2)(a), (II)(2)(b), (II)(2)(c), (II)(2)(d), and combinations thereof, or a mixture of at least two, three, or four modified LPS molecular species selected from the group consisting of them.

[0334] In one embodiment, the composition comprises at least one LPS molecular species of formula (II)(2)(a), at least one LPS molecular species of formula (II)(2)(b), at least one LPS molecular species of formula (II)(2)(c), and at least one LPS molecular species of formula (II)(2)(d), or comprises a mixture of modified LPS molecular species consisting of these.

[0335] In one embodiment, the composition comprises a mixture of modified LPS molecular species of formula (XII)(1).

[0336] In one embodiment, the composition comprises LPS molecular species of formula (III)(1)(a), (III)(1)(b), (III)(1)(c), (III)(1)(d), and combinations thereof, or a mixture of modified LPS molecular species selected from the group consisting of them.

[0337] In one embodiment, the composition includes LPS molecular species of formula (III)(1)(a), (III)(1)(b), (III)(1)(c), (III)(1)(d), and combinations thereof, or a mixture of at least two, three, or four modified LPS molecular species selected from the group consisting of them.

[0338] In one embodiment, the composition comprises at least one LPS molecular species of formula (III)(1)(a), at least one LPS molecular species of formula (III)(1)(b), at least one LPS molecular species of formula (III)(1)(c), and at least one LPS molecular species of formula (III)(1)(d), or comprises a mixture of modified LPS molecular species consisting of these.

[0339] In one embodiment, the composition comprises LPS molecular species of formula (XII)(1) and combinations thereof, or a mixture of modified LPS molecular species selected from the group comprising them.

[0340] In one embodiment, the composition comprises LPS molecular species of formula (IV)(1)(a), (IV)(1)(b), (IV)(1)(c), and combinations thereof, or a mixture of modified LPS molecular species selected from the group consisting of them.

[0341] In one embodiment, the composition comprises LPS molecular species of formula (IV)(1)(a), (IV)(1)(b), (IV)(1)(c), and combinations thereof, or a mixture of at least two or three modified LPS molecular species selected from the group consisting of them. In one embodiment, the composition comprises at least one LPS molecular species of formula (IV)(1)(a), at least one LPS molecular species of formula (IV)(1)(b), and at least one LPS molecular species of formula (IV)(1)(c), or comprises a mixture of modified LPS molecular species consisting of these. In one embodiment, the composition includes LPS molecular species of formula (V)(1)(a), (V)(1)(b), (V)(1)(c), (V)(1)(d), (V)(1)(e), (V)(1)(f), (V)(1)(g), (V)(1)(h), (V)(1)(i), and combinations thereof, or mixtures of modified LPS molecular species selected from the group consisting of them. In one embodiment, the composition includes LPS molecular species of formula (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), and combinations thereof, or a mixture of at least 2, 3, 4, 5, 6, 7, 8, or 9 modified LPS molecular species selected from the group consisting of them. In one embodiment, the composition comprises at least one LPS molecular species of formula (V)(1)(a), at least one LPS molecular species of formula (V)(1)(b), at least one LPS molecular species of formula (V)(1)(c), at least one LPS molecular species of formula (V)(1)(d), at least one LPS molecular species of formula (V)(1)(e), at least one LPS molecular species of formula (V)(1)(f), at least one LPS molecular species of formula (V)(1)(g), at least one LPS molecular species of formula (V)(1)(h), and at least one molecular species of formula (V)(1)(i), or comprises a mixture of modified LPS molecular species consisting of these.

[0342] In one embodiment, the composition comprises 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), (VI)(1)(j), (VI)(2)(a), (VI)(2)(b), (VI)(2)(c), and combinations thereof, or mixtures of modified LPS molecular species selected from the group consisting of them. In one embodiment, the composition comprises 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), (VI)(1)(j), (VI)(2)(a), (VI)(2)(b), (VI)(2)(c), and combinations thereof, or a mixture of at least 2, 3, 4, 5, 6, 7, or 8 modified LPS molecular species selected from the group consisting of them. In one embodiment, the composition comprises 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), (VI)(1)(j), and combinations thereof, or mixtures of modified LPS molecular species selected from the group consisting of them. In one embodiment, the composition includes 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), (VI)(1)(j), and combinations thereof, or a mixture of at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 modified LPS molecular species selected from the group consisting of them. In one embodiment, the composition comprises at least one LPS molecular species of formula (VI)(1)(a), at least one LPS molecular species of formula (VI)(1)(b), at least one LPS molecular species of formula (VI)(1)(c), at least one LPS molecular species of formula (VI)(1)(d), at least one LPS molecular species of formula (VI)(1)(e), at least one LPS molecular species of formula (VI)(1)(f), at least one LPS molecular species of formula (VI)(1)(g), at least one LPS molecular species of formula (VI)(1)(h), at least one LPS molecular species of formula (VI)(1)(i), and at least one LPS molecular species of formula (VI)(1)(j), or comprises a mixture of modified LPS molecular species consisting of these.

[0343] In one embodiment, the composition comprises LPS molecular species of formula (VI)(2)(a), (VI)(2)(b), (VI)(2)(c), and combinations thereof, or a mixture of modified LPS molecular species selected from the group consisting of them. In one embodiment, the composition comprises LPS molecular species of formula (VI)(2)(a), (VI)(2)(b), (VI)(2)(c), and combinations thereof, or a mixture of at least two or three modified LPS molecular species selected from the group consisting of them. In one embodiment, the composition comprises at least one LPS molecular species of formula (VI)(2)(a), at least one LPS molecular species of formula (VI)(2)(b), and at least one LPS molecular species of formula (VI)(2)(c), or a mixture of modified LPS molecular species comprising these. In one embodiment, the composition comprises LPS molecular species of formula (VII)(1)(a), (VII)(1)(b), (VII)(1)(c), and combinations thereof, or a mixture of modified LPS molecular species selected from the group consisting of them. In one embodiment, the composition comprises LPS molecular species of formula (VII)(1)(a), (VII)(1)(b), (VII)(1)(c), and combinations thereof, or a mixture of at least two or three modified LPS molecular species selected from the group consisting of them. In one embodiment, the composition comprises at least one LPS molecular species of formula (VII)(1)(a), at least one LPS molecular species of formula (VII)(1)(b), and at least one LPS molecular species of formula (VII)(1)(c), or comprises a mixture of modified LPS molecular species consisting of these.

[0344] In one embodiment, the composition comprises LPS molecular species of formula (VIII)(1)(a), (VIII)(1)(b), (VIII)(1)(c), (VIII)(1)(d), and combinations thereof, or a mixture of modified LPS molecular species selected from the group consisting of them. In one embodiment, the composition includes LPS molecular species of formula (VIII)(1)(a), (VIII)(1)(b), (VIII)(1)(c), (VIII)(1)(d), and combinations thereof, or a mixture of at least two, three, or four modified LPS molecular species selected from the group consisting of them. In one embodiment, the composition comprises at least one LPS molecular species of formula (VIII)(1)(a), at least one LPS molecular species of formula (VIII)(1)(b), at least one LPS molecular species of formula (VIII)(1)(c), and at least one LPS molecular species of formula (VIII)(1)(d), or comprises a mixture of modified LPS molecular species consisting of these. In one embodiment, the composition comprises LPS molecular species of formula (IX)(1)(a), (IX)(1)(b), (IX)(1)(c), (IX)(1)(d), and combinations thereof, or a mixture of modified LPS molecular species selected from the group consisting of them. In one embodiment, the composition includes LPS molecular species of formula (IX)(1)(a), (IX)(1)(b), (IX)(1)(c), (IX)(1)(d), and combinations thereof, or a mixture of at least two, three, or four modified LPS molecular species selected from the group consisting of them.

[0345] In one embodiment, the composition comprises at least one LPS molecular species of formula (IX)(1)(a), at least one LPS molecular species of formula (IX)(1)(b), at least one LPS molecular species of formula (IX)(1)(c), and at least one LPS molecular species of formula (IX)(1)(d), or comprises a mixture of modified LPS molecular species consisting of these. In one embodiment, the composition comprises LPS molecular species of formula (X)(1)(a), (X)(1)(b), (X)(1)(c), (X)(1)(d), and combinations thereof, or a mixture of modified LPS molecular species selected from the group consisting of them. In one embodiment, the composition includes LPS molecular species of formula (X)(1)(a), (X)(1)(b), (X)(1)(c), (X)(1)(d), and combinations thereof, or a mixture of at least two, three, or four modified LPS molecular species selected from the group consisting of them. In one embodiment, the composition comprises at least one LPS molecular species of formula (X)(1)(a), at least one LPS molecular species of formula (X)(1)(b), at least one LPS molecular species of formula (X)(1)(c), and at least one LPS molecular species of formula (X)(1)(d), or comprises a mixture of modified LPS molecular species consisting of these. In one embodiment, the composition comprises LPS molecular species of formula (XI)(1)(a), (XI)(1)(b), (XI)(1)(c), (XI)(1)(d), and combinations thereof, or a mixture of modified LPS molecular species selected from the group consisting of them. In one embodiment, the composition includes LPS molecular species of formula (XI)(1)(a), (XI)(1)(b), (XI)(1)(c), (XI)(1)(d), and combinations thereof, or a mixture of at least two, three, or four modified LPS molecular species selected from the group consisting of them.

[0346] In one embodiment, the composition comprises at least one LPS molecular species of formula (XI)(1)(a), at least one LPS molecular species of formula (XI)(1)(b), at least one LPS molecular species of formula (XI)(1)(c), and at least one LPS molecular species of formula (XI)(1)(d), or comprises a mixture of modified LPS molecular species consisting of these.

[0347] In one embodiment, the composition has formulas (XIII)(2)(a), (XIII)(2)(b), (XIII)(3)(a), (XIII)(3)(b), (XII I)(4)(a), (XIII)(4)(b), (XIII)(5)(a), (XIII)(5)(b), (XIII)(5)(c), (XIII)(5)( d), (XIII)(6)(a), (XIII)(6)(b), (XIII)(6)(c), (XIII)(6)(d), (XIII)(6)(e), (XI II)(6)(f), (XIII)(7)(a), (XIII)(7)(b), (XIII)(7)(c), (XIII)(7)(d), (XIII)(7) The LPS molecular species (e), (XIII)(7)(f), (XIII)(8)(a), (XIII)(8)(b), (XIII)(8)(c), (XIII)(8)(d), (XIII)(8)(e), (XIII)(8)(f), (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), (XIII)(9)(j) and combinations thereof, or mixtures of modified LPS molecular species selected from the group consisting of them.

[0348] In one embodiment, a simplified version of formula (XIII)(2)(a), (XIII)(2)(b), (XIII)(3)(a), (XIII)(3)(b), (XIII)(4)(a), (XIII)(4)(b), (XIII)(5)(a), (XIII)(5)(b), (XIII)(5)(c), (XIII)(5)(d), (XIII)(6)(a), (XIII)(6)(b) , (XIII)(6)(c), (XIII)(6)(d), (XIII)(6)(e), (XIII)(6)(f), (XIII)(7)(a), (XIII)(7)(b), (XIII )(7)(c), (XIII)(7)(d), (XIII)(7)(e), (XIII)(7)(f), (XIII)(8)(a), (XIII)(8)(b), (XIII)(8)(c) , (XIII)(8)(d), (XIII)(8)(e), (XIII)(8)(f), (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), (XIII)(9)(j) The mixture includes LPS molecular species and combinations thereof, or at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, or 38 modified LPS molecular species selected from the group consisting of them.

[0349] In one embodiment, the composition comprises LPS molecular species of formula (XIII)(2)(a), (XIII)(2)(b), and combinations thereof, or a mixture of modified LPS molecular species selected from the group consisting of them. In one embodiment, the composition comprises LPS molecular species of formula (XIII)(2)(a), (XIII)(2)(b), and combinations thereof, or a mixture of two modified LPS molecular species selected from the group consisting of them. In one embodiment, the composition comprises at least one LPS molecular species of formula (XIII)(2)(a) and at least one LPS molecular species of formula (XIII)(2)(b), or a mixture of modified LPS molecular species comprising them. In one embodiment, the composition comprises LPS molecular species of formula (XIII)(3)(a), (XIII)(3)(b), and combinations thereof, or a mixture of modified LPS molecular species selected from the group consisting of them. In one embodiment, the composition comprises LPS molecular species of formula (XIII)(3)(a), (XIII)(3)(b), and combinations thereof, or a mixture of two modified LPS molecular species selected from the group consisting of them. In one embodiment, the composition comprises at least one LPS molecular species of formula (XIII)(3)(a) and at least one LPS molecular species of formula (XIII)(3)(b), or a mixture of modified LPS molecular species comprising them.

[0350] In one embodiment, the composition comprises LPS molecular species of formula (XIII)(4)(a), (XIII)(4)(b), and combinations thereof, or a mixture of modified LPS molecular species selected from the group consisting of them. In one embodiment, the composition comprises LPS molecular species of formula (XIII)(4)(a), (XIII)(4)(b), and combinations thereof, or a mixture of two modified LPS molecular species selected from the group consisting of them. In one embodiment, the composition comprises at least one LPS molecular species of formula (XIII)(4)(a) and at least one LPS molecular species of formula (XIII)(4)(b), or a mixture of modified LPS molecular species comprising the same.

[0351] In one embodiment, the composition comprises LPS molecular species of formula (XIII)(5)(a), (XIII)(5)(b), (XIII)(5)(c), (XIII)(5)(d), and combinations thereof, or a mixture of modified LPS molecular species selected from the group consisting of them. In one embodiment, the composition comprises LPS molecular species of formula (XIII)(5)(a), (XIII)(5)(b), (XIII)(5)(c), (XIII)(5)(d), and combinations thereof, or a mixture of two modified LPS molecular species selected from the group consisting of them. In one embodiment, the composition comprises at least one LPS molecular species of formula (XIII)(5)(a), at least one LPS molecular species of formula (XIII)(5)(b), at least one LPS molecular species of formula (XIII)(5)(c), and at least one LPS molecular species of formula (XIII)(5)(d), or comprises a mixture of modified LPS molecular species consisting of these.

[0352] In one embodiment, the composition comprises LPS molecular species of formula (XIII)(6)(a), (XIII)(6)(b), (XIII)(6)(c), (XIII)(6)(d), (XIII)(6)(e), (XIII)(6)(f), and combinations thereof, or a mixture of modified LPS molecular species selected from the group consisting of them. In one embodiment, the composition comprises LPS molecular species of formula (XIII)(6)(a), (XIII)(6)(b), (XIII)(6)(c), (XIII)(6)(d), (XIII)(6)(e), (XIII)(6)(f), and combinations thereof, or a mixture of two modified LPS molecular species selected from the group consisting of them. In one embodiment, the composition comprises at least one LPS molecular species of formula (XIII)(6)(a), at least one LPS molecular species of formula (XIII)(6)(b), at least one LPS molecular species of formula (XIII)(6)(c), at least one LPS molecular species of formula (XIII)(6)(d), at least one LPS molecular species of formula (XIII)(6)(e), and at least one LPS molecular species of formula (XIII)(6)(f), or comprises a mixture of modified LPS molecular species consisting of these.

[0353] In one embodiment, the composition comprises LPS molecular species of formula (XIII)(7)(a), (XIII)(7)(b), (XIII)(7)(c), (XIII)(7)(d), (XIII)(7)(e), (XIII)(7)(f), and combinations thereof, or a mixture of modified LPS molecular species selected from the group consisting of them. In one embodiment, the composition comprises LPS molecular species of formula (XIII)(7)(a), (XIII)(7)(b), (XIII)(7)(c), (XIII)(7)(d), (XIII)(7)(e), (XIII)(7)(f), and combinations thereof, or a mixture of two modified LPS molecular species selected from the group consisting of them. In one embodiment, the composition comprises at least one LPS molecular species of formula (XIII)(7)(a), at least one LPS molecular species of formula (XIII)(7)(b), at least one LPS molecular species of formula (XIII)(7)(c), at least one LPS molecular species of formula (XIII)(7)(d), at least one LPS molecular species of formula (XIII)(7)(e), and at least one LPS molecular species of formula (XIII)(7)(f), or comprises a mixture of modified LPS molecular species consisting of these.

[0354] In one embodiment, the composition comprises LPS molecular species of formula (XIII)(8)(a), (XIII)(8)(b), (XIII)(8)(c), (XIII)(8)(d), (XIII)(8)(e), (XIII)(8)(f), and combinations thereof, or a mixture of modified LPS molecular species selected from the group consisting of them. In one embodiment, the composition comprises LPS molecular species of formulas (XIII)(8)(a), (XIII)(8)(b), (XIII)(8)(c), (XIII)(8)(d), (XIII)(8)(e), (XIII)(8)(f), and combinations thereof, or a mixture of two modified LPS molecular species selected from the group consisting of them. In one embodiment, the composition comprises at least one LPS molecular species of formula (XIII)(8)(a), at least one LPS molecular species of formula (XIII)(8)(b), at least one LPS molecular species of formula (XIII)(8)(c), at least one LPS molecular species of formula (XIII)(8)(d), at least one LPS molecular species of formula (XIII)(8)(e), and at least one LPS molecular species of formula (XIII)(8)(f), or comprises a mixture of modified LPS molecular species consisting of these.

[0355] In one embodiment, the composition comprises LPS molecular species of 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), (XIII)(9)(j), and combinations thereof, or a mixture of modified LPS molecular species selected from the group consisting of them. In one embodiment, the composition comprises LPS molecular species of 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), (XIII)(9)(j), and combinations thereof, or a mixture of two modified LPS molecular species selected from the group consisting of them. In one embodiment, the composition comprises at least one LPS molecular species of formula (XIII)(9)(a), at least one LPS molecular species of formula (XIII)(9)(b), at least one LPS molecular species of formula (XIII)(9)(c), at least one LPS molecular species of formula (XIII)(9)(d), at least one LPS molecular species of formula (XIII)(9)(e), at least one LPS molecular species of formula (XIII)(9)(f), at least one LPS molecular species of formula (XIII)(9)(g), at least one LPS molecular species of formula (XIII)(9)(h), at least one LPS molecular species of formula (XIII)(9)(i), and at least one LPS molecular species of formula (XIII)(9)(j), or comprises a mixture of modified LPS molecular species consisting of these.

[0356] In one embodiment, at least one LPS molecular species is a naturally occurring LPS molecular species. In one embodiment, the naturally occurring LPS molecular species is nontoxic.

[0357] In one embodiment, naturally occurring LPS molecular species have endotoxin activity of less than 5000 endotoxin equivalent units (EEU) / μg, preferably less than 4000, 3000, 2000, 1500, or 1000 EEU / μg, as can be evaluated by, for example, peripheral blood mononuclear cells (PBMCs) and a monocyte activation test (MAT) based on the IL-6 response.

[0358] Because bacteria existed on Earth long before humans, the latter co-evolved in the state where bacteria reside primarily in the gut microbiota, as well as on the skin and the entire body surface. Escherichia coli (E. coli) lives in symbiosis with humans, providing the host with vitamins and aiding digestion. Therefore, it is not surprising that the TLR4 LPS receptor present on the surface of different human cells accurately recognizes the structure of E. coli LPS molecular species, much like a glove does with a hand. As a result, LPS molecular species are distinguished from classical (i.e., unmodified) E. coli LPS molecules by fewer or more fatty acid chains, as well as / or shorter and / or longer fatty acid chains. Differentiation can also occur at the level of phosphate groups at the C1 position of the reducing end and / or the C4' position of the non-reducing end of the lipid A domain, either being absent or substituted for the neutralization of the negative charge.

[0359] In this regard, some of these post-differentiated LPS molecular species are not recognized by receptors and classical E. coli LPS molecules, and therefore do not induce cytokine release that leads to high inflammation.

[0360] Among the naturally occurring LPS molecular species that are non-toxic, i. The lipid A domains contain at least one, for example, one or zero, unsubstituted phosphate groups at the C1 position of the reducing end and / or the C4' position of the non-reducing end, and / or ii. Compared to toxic LPS molecular species such as the E. coli or Salmonella enterica LPS molecule, which contains 6 fatty acid chains with 4 primary fatty acid chains and 2 secondary fatty acid chains, it contains fewer or more fatty acid chains, and / or iii. Four primary 3-OH-C 14 Fatty acid chain, one secondary carbon 14 Fatty acid chain and one secondary C 12 This may include, but is not limited to, LPS molecular species containing shorter and / or longer fatty acid chains compared to toxic LPS molecular species such as E. coli or Salmonella enterica LPS molecules that contain fatty acid chains.

[0361] In one embodiment, non-toxic, naturally occurring LPS molecular species have two secondary fatty acids C2' and C3' simultaneously present at the C2' and C3' positions of their lipid A domain. 12 and / or C 14 It does not contain fatty acid chains. In one embodiment, naturally occurring LPS molecular species that are non-toxic have two secondary fatty acids C simultaneously present at the C2' and C3' positions of their lipid A domain. 12 It does not contain fatty acid chains. In one embodiment, naturally occurring LPS molecular species that are non-toxic have two secondary fatty acids C simultaneously present at the C2' and C3' positions of their lipid A domain. 14 It does not contain fatty acid chains. In one embodiment, a non-toxic, naturally occurring LPS molecular species has a single secondary fatty acid C simultaneously present at the C2' and C3' positions of its lipid A domain. 12 Fatty acid chain and one secondary fatty acid C 14 It does not contain fatty acid chains.

[0362] In one embodiment, non-toxic, naturally occurring LPS molecular species have four primary 3-OH-C molecules simultaneously present at the C2' and C3' positions of their lipid A domain. 14 The fatty acid chain also consists of two secondary fatty acids C 12 and / or C 14 It does not contain fatty acid chains. In one embodiment, non-toxic, naturally occurring LPS molecular species have four primary 3-OH-C molecules simultaneously present at the C2' and C3' positions of their lipid A domain. 14 The fatty acid chain also consists of two secondary fatty acids C 12 It does not contain fatty acid chains. In one embodiment, non-toxic, naturally occurring LPS molecular species have four primary 3-OH-C molecules simultaneously present at the C2' and C3' positions of their lipid A domain. 14 The fatty acid chain also consists of two secondary fatty acids C 14 It does not contain fatty acid chains. In one embodiment, non-toxic, naturally occurring LPS molecular species have four primary 3-OH-C molecules simultaneously present at the C2' and C3' positions of their lipid A domain. 14 The fatty acid chain also consists of one secondary fatty acid C 14 Fatty acid chain and one secondary fatty acid C 12It does not contain fatty acid chains.

[0363] In one embodiment, a non-toxic, naturally occurring LPS molecular species does not contain a phosphate group at either the C1 position of the reducing end of its lipid A domain, the C4' position of the non-reducing end of its lipid A domain, or both.

[0364] In one embodiment, the non-toxic, naturally occurring LPS molecular species includes a lipid A domain containing a disaccharide, such as a β-1,6-glucosamine [GlcN] disaccharide, a β-1,6-diaminoglucose [DAG] disaccharide, or a β-1,6-disaccharide containing one GlcN residue and one DAG residue.

[0365] However, naturally occurring, non-toxic LPS molecular species also include LPS molecular species that have a lipid A domain containing only one sugar, such as glucosamine, aminoglucose, or diaminohexose. These LPS molecular species are also included in the present invention.

[0366] Examples of non-toxic, naturally occurring LPS molecular species include LPS molecular species derived from Bordetella (e.g., LPS molecules from Bordetella pertussis), LPS molecular species derived from Vitreostilla (e.g., LPS molecules from Vitreostilla filiformis), LPS molecular species derived from Neisseria (e.g., LPS molecules from Neisseria meningitidis), LPS molecular species derived from Vibrio (e.g., LPS molecules from Vibrio cholera), and LPS molecular species derived from Helicobacter (e.g., LPS molecules from Helicobacter pylori). This includes, but is not limited to, LPS molecular species derived from species (such as seeds), LPS molecular species derived from Porphyromonas, LPS molecular species derived from Leptospira (e.g., Leptospira interrogans), LPS molecular species derived from Flavobacterium meningosepticum (e.g., Flavobacterium meningosepticum), LPS molecular species derived from Rhodobacter, LPS molecular species derived from Rhizobium, LPS molecular species derived from Bacteroides, and LPS molecular species derived from Prevotella.

[0367] In one embodiment, the non-toxic LPS molecular species derived from Bordetella contains 4 or fewer C14 Fatty acid chain and one C 10 Contains fatty acid chains. In one embodiment, the non-toxic LPS molecular species derived from Vitreostila contains two C 12 Fatty acid chains and 4 or fewer C atoms 10 Contains fatty acid chains. In one embodiment, a non-toxic LPS molecular species derived from Neisseria contains two C 14 Fatty acid chain and 4 C 12 Contains fatty acid chains. In one embodiment, the non-toxic LPS molecular species derived from Vibrio contains 3 C 14 Fatty acid chain and 3 C 12 Contains fatty acid chains. In one embodiment, a non-toxic LPS molecular species derived from Helicobacter is composed of one C 16 Fatty acid chain and 3 C 18 Contains fatty acid chains.

[0368] Other examples of naturally occurring, non-toxic LPS molecular species include, but are not limited to, the compounds of formula (I)(0)(a) and (I)(0)(b) shown in Figure 1, the compounds of formula (II)(0) shown in Figure 5, the compounds of formula (XIII)(0)(a) and (XIII)(0)(b) shown in Figure 34, and LPS molecular species selected from combinations thereof. Other examples of naturally occurring, non-toxic LPS molecular species include, but are not limited to, the compounds of formula (I)(0)(a) and (I)(0)(b) shown in Figure 1, the compounds of formula (II)(0) shown in Figure 5, and LPS molecular species selected from combinations thereof. In one embodiment, the composition includes LPS molecular species of formula (I)(1)(a), (I)(1)(b), and combinations thereof, or naturally occurring LPS molecular species selected from the group consisting of them. In one embodiment, the composition comprises LPS molecular species of formula (I)(1)(a), (I)(1)(b), and combinations thereof, or a mixture of at least two naturally occurring LPS molecular species selected from the group consisting of them. In one embodiment, the composition comprises at least one LPS molecular species of formula (I)(1)(a) and at least one LPS molecular species of formula (I)(1)(b), or a mixture of naturally occurring LPS molecular species comprising them. In one embodiment, the composition contains a naturally occurring LPS molecular species of formula (II)(0). In one embodiment, the composition according to the present invention comprises at least one modified LPS molecular species and at least one naturally occurring LPS molecular species. In one embodiment, the composition according to the present invention comprises a mixture of the modified LPS molecular species described herein and naturally occurring LPS molecular species.

[0369] In one embodiment, the composition according to the present invention comprises an LPS molecular species monodisperse in an aqueous solution, preferably in water and / or PBS, so that it can be evaluated, for example, by DLS measurement, preferably at a scattering angle Θ=90°, incident laser wavelength λ=633nm, and temperature 25°C.

[0370] As used herein, the term “monodisperse” with respect to LPS molecular species means that they are substantially uniform in size in an aqueous solution (e.g., water and / or PBS).

[0371] "Substantially uniform" means that the LPS molecular species have a narrow size distribution around their average size. In one embodiment, the LPS molecular species in water and / or PBS have a size that is less than 20% of their average size, for example, with a standard deviation of less than 10% or less than 5%.

[0372] In one embodiment, the composition according to the present invention comprises an LPS molecular species formulated as a liposome. According to this embodiment, the liposome may contain, substantially consist of, or exclusively consist of the LPS molecular species according to the present invention.

[0373] As used herein, “liposome” refers to a vesicle in which a lipid phase containing a bilayer of amphiphilic molecules, such as phospholipids or cholesterol, encapsulates an internal aqueous phase. Liposomes may be monolayer (i.e., containing a single lipid bilayer) or multilayer (i.e., containing at least two or more concentric lipid bilayers). Phospholipids are lipids that contain a phosphate group. They consist of a polar, hydrophilic "head" and two aliphatic, hydrophobic "tails." Examples of phospholipids include, but are not limited to, phosphatidic acid and phosphoglycerides. Liposomes can be prepared by various means and methods known in the art.

[0374] In one embodiment, an LPS molecular species formulated as a liposome in the sense of the present invention may be in the form of (1) a liposome composed of any suitable amphiphilic molecule according to the present invention and encapsulating an LPS molecular species, or (2) a liposome substantially composed of or consisting solely of an LPS molecular species according to the present invention. In one embodiment, the composition according to the present invention comprises an LPS molecular species formulated as a liposome, and further comprises at least one additional therapeutic agent which is either not conjugated to or conjugated to the LPS molecular species. In one embodiment, the composition according to the present invention comprises an LPS molecular species formulated as a liposome, and further comprises at least one additional therapeutic agent which is either encapsulated in the liposome or not encapsulated. Suitable examples of additional therapeutic agents include, but are not limited to, chemotherapeutic agents, targeted therapies, cytotoxic agents, antibiotics, antivirals, 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. Detailed examples of these therapeutic agents are described herein as agents suitable for conjugation at positions Z, R1 and / or R2 of formulas A and B. However, those skilled in the art will readily understand that these therapeutic agents may be provided additionally or alternatively, not conjugated in the compositions according to the present invention. In one embodiment, the additional therapeutic agent is a targeted therapeutic agent as defined above herein, preferably an anti-CD20 monoclonal antibody or its antigen-binding fragment. In one embodiment, the anti-CD20 monoclonal antibody includes or is selected from the group consisting of ibritumomab, obinutuzumab, ocrelizumab, ofatumumab, rituximab, tocitumomab, or their antigen-binding fragments, preferably the anti-CD20 monoclonal antibody is rituximab or its antigen-binding fragment. In one embodiment, the additional therapeutic agent is an immunostimulant as defined above herein, and preferably, the additional therapeutic agent is an immune checkpoint inhibitor. In one embodiment, the immune checkpoint inhibitor includes or is selected from the group consisting of inhibitors of CTLA4, PD-1, PD-L1, LAG-3, B7-H3, B7-H4, TIM3, A2AR, GITR, CD47, TNFR2, CD19, and / or IDO. In one embodiment, the immune checkpoint inhibitor includes, or is selected from, nivolumab, pembrolizumab, semiprimab, pizilizumab, AMP-224, AMP-514, MPDL3280A, MDX-1105, MEDI-4736, allerumab, ipilimumab, tremelimumab, pizilizumab, IMP321, MGA271, BMS-986016, lirirumab, urerumab, PF-05082566, IPH2101, MEDI-6469, CP-870, 893, mogamulizumab, valilumab, galiximab, AUNP12, indoximod, NLG-919, and INCB024360. In one embodiment, the immune checkpoint inhibitor is an inhibitor of PD-1 or PD-L1. Examples of PD-1 inhibitors include, but are not limited to, nivolumab, pembrolizumab, cemiprimab, spartalizumab, canrelizumab, cintilimab, tislerizumab, tripalimab, AMP-224, and AMP-514. Examples of PD-L1 inhibitors include, but are not limited to, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, and BMS-986189.

[0375] In one embodiment, the composition according to the present invention is a pharmaceutical composition further comprising at least one pharmaceutically acceptable excipient. As used herein, the term “pharmaceutically acceptable excipients” refers, rather than to the active ingredient, to solid, semi-solid, or liquid components of a pharmaceutical or vaccine composition that do not cause adverse allergic or other undesirable reactions when administered to animals, preferably humans. Most of these pharmaceutically acceptable excipients are described in detail, for example, Allen (ed.), 2017. Ansel's pharmaceutical dosage forms and drug delivery systems (11th edition). Philadelphia, PA: Wolters Kluwer; Remington, Allen & Adeboye (eds.), 2013. Remington: The science and practice of pharmacy (22nd edition). London: Pharmaceutical Press; and Sheskey, Cook & Cable (eds.), 2017. Handbook of pharmaceutical excipients (8th edition). London: Pharmaceutical Press; each of which is incorporated herein by reference in whole. Pharmaceutically acceptable excipients include, but are not limited to, water, physiological saline, Ringer's solution, dextrose solution, and solutions of ethanol, glucose, sucrose, dextran, mannose, mannitol, sorbitol, polyethylene glycol (PEG), phosphates, acetates, gelatin, collagen, Carbopol®, and vegetable oils. Pharmaceutically acceptable excipients may further include suitable preservatives, stabilizers, antioxidants, antimicrobial agents, and buffers, such as BHA, BHT, citric acid, ascorbic acid, and tetracycline. Other examples of pharmaceutically acceptable excipients that may be used in the compositions of the present invention include, but are not limited to, ion exchangers, alum, e.g., aluminum phosphate or aluminum hydroxide, alumina, aluminum stearate, lecithin, serum proteins, e.g., human serum albumin, buffering substances, e.g., phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin. In addition, several pharmaceutically acceptable excipients include surfactants (e.g., hydroxypropylcellulose); suitable carriers, such as water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and solvents and dispersion media containing vegetable oils, such as peanut oil and sesame oil; isotonic agents, such as sugars or sodium chloride; coating agents, such as lecithin; absorption-delaying agents, such as aluminum monostearate and gelatin; preservatives, such as benzalkonium chloride, benzethonium chloride, chlorobutanol, and thimerosal; buffers, such as boric acid, sodium bicarbonate and potassium bicarbonate, sodium borate and potassium borate, sodium carbonate and potassium carbonate. This may include: sodium ammonium compounds, sodium acetate, sodium diphosphate, etc.; isotonic agents, such as dextran 40, dextran 70, dextrose, glycerin, potassium chloride, propylene glycol, sodium chloride, etc.; antioxidants and stabilizers, such as sodium bisulfite, sodium metabisulfite, sodium thiosulfite, thiourea, etc.; nonionic wetting agents or clarifying agents, such as polysorbate 80, polysorbate 20, poloxamer 282, and tyroxapole, etc.; viscosity modifiers, such as dextran 40, dextran 70, gelatin, glycerin, hydroxyethylcellulose, hydroxymethylpropylcellulose, lanolin, methylcellulose, petrolatum, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose, etc.

[0376] In one embodiment, the composition according to the present invention is a vaccine composition. As used herein, the term “vaccine composition” means a composition comprising, in pharmaceutically acceptable excipients, at least one antigen or immunogen and optionally an adjuvant, which is useful for inducing an immune response in a subject at time of administration. As used herein, the terms “antigen” or “immunogen” refer to any substance that, after any incubation period (typically several days to several weeks in humans), induces a state of susceptibility and / or immune response and reacts in a demonstrable manner with antibodies and / or immune cells of a sensitized subject in vivo or in vitro. As used herein, the term “adjuvant” refers to a substance that, upon administration, enhances, increases, and / or strengthens the immune response to an antigen in a subject. Examples of adjuvants include, but are not limited to, helper peptides, aluminum salts (e.g., aluminum hydroxide gel (also known as alum), aluminum phosphate, etc.), Freund's incomplete adjuvant, Freund's complete adjuvant, saponins, Merck adjuvant 65, Smith-Kline Beecham adjuvant AS-2, Aquilla adjuvant QS-21, MPL® immunostimulant, 3d-MPL, LEIF, calcium salts, iron salts, zinc salts, acylated tyrosine, acylated sugars, cation-derivative polysaccharides, anion-derivative polysaccharides, polyphosphazenes, biodegradable microspheres, monophosphoryl lipid A, muramyl tripeptide phosphatidylethanolamine, cytokines (e.g., interleukin-2, interleukin-12, interleukin-4, interleukin-7, etc.), CpG-containing oligonucleotides, and combinations thereof. In one embodiment, the vaccine composition according to the present invention comprises at least one LPS molecular species described herein that acts as both a primary antigen and a primary adjuvant. In fact, an LPS molecular species comprising a core oligosaccharide domain which may be substituted with an antigen domain such as an O antigen domain and / or a capping antigen exhibits antigenicity and immunogenicity against the bacterial species from which the LPS molecular species is derived. In one embodiment, the vaccine composition according to the present invention comprises at least one LPS molecular species described herein that acts as a primary antigen, and at least one LPS molecular species other than the LPS molecular species described herein that acts as an adjuvant-secondary adjuvant. In one embodiment, the vaccine composition according to the present invention comprises at least one LPS molecular species described herein acting as a primary adjuvant, and at least one LPS molecular species other than the LPS molecular species described herein acting as an antigen-secondary antigen. In this embodiment, the at least one antigen may be an antigen derived from the same bacterial species as the LPS molecular species for a combined antigenic effect against the bacterial species. Alternatively, the at least one antigen may be an antigen not derived from the same bacterial species as the LPS molecular species (i.e., an antigen derived from another bacterial species, or any other antigen such as a pathogen-associated antigen, autoantigen, allergen-associated antigen, neoantigen, or others). In one embodiment, the vaccine composition is a subunit vaccine. In one embodiment, the vaccine composition is a protein vaccine. In one embodiment, the vaccine composition is a cell-based vaccine. Preferred examples of antigens include, but are not limited to, pathogen-associated antigens (e.g., antigens of viruses, fungi, or bacteria, or immunogenic molecules derived therefrom), autoantigens (e.g., cellular antigens including cells containing normal transplant antigens and / or tumor-associated antigens, RR-Rh antigens, and antigens characteristic of or specific to certain cells, tissues, or bodily fluids), allergen-associated antigens (e.g., those related to environmental allergens including plants, pollen, mold, dust, insects, dandruff, and venom; occupational allergens including latex, dandruff, urethane, epoxy resins, etc.; foods including shellfish, peanuts, eggs, dairy products, etc.; and drugs including antibiotics and anesthetics), neoantigens, and vaccines. Suitable examples of pathogen-associated antigens include vaccinia, aviipoxvirus, turkey influenza virus, bovine leukemia virus, feline leukemia virus, avian influenza, avian pneumonia virus, canine parvovirus, equine influenza, FHV, Newcastle disease virus (NDV), avian / Pennsylvania / 1 / 83 influenza virus, infectious bronchitis virus, dengue virus, measles virus, rubella virus, pseudorabies, Epstein-Barr virus, HIV, SIV, EHV, BHV, HCMV, Hantaan, C. tetani, mumps, morbillivirus, herpesvirus type 1, and herpes simplex virus. Antigens derived from, but not limited to, pesvirus type 2, human cytomegalovirus, hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis E virus, respiratory syncytial virus, human papillomavirus, influenza virus, Bordetella, Vitreostilla, Salmonella, Neisseria, Borrelia, Chlamydia, malaria parasite, Toxoplasma, Cryptococcus, Streptococcus, Staphylococcus, Haemophilus, Dipteria, Tetanus, Escherichia coli, Candida, Aspergillus, Actinomycetes, Burkholderia, Moraxella, Pseudomonas, Vibrio, Enteramoeba, Giardia, and Trypanasoma. Suitable examples of autoantigens include lupus autoantigen, Smith, Ro, La, U1-RNP, fibrillin, nuclear antigen, histone, glycoprotein gp70, ribosomal protein, pyruvate dehydrogenase, dehydrolipoamide acetyltransferase (PCD-E2), hair follicle antigen, human tropomyosin isoform 5 (hTM5), proinsulin, insulin, IA2, GAD65, type II collagen, human cartilage gp39 (HCgp39), gp130-RAPS, dnaJp1, citrullinated proteins and peptides (citrullinated type II). This includes, but is not limited to, collagen (including citrullinated vimentin and citrullinated fibrinogen), myelin basic proteins, proteolipidoproteins (PLPs), myelin oligodendrocyte glycoproteins (MOGs), thyroid-stimulating factor receptors (TSH-Rs), acetylcholine receptors (AchRs), gliadins, PLPs, glucose-6-phosphate isomerase, thyroglobulins, thyroid globulins, various tRNA synthetases, proteinase-3s, and myeloperoxidases (including their fragments). Suitable examples of tumor-associated antigens include MART-1 / Melan-A, gplOO, dipeptidyl peptidase IV (DPPIV), adenosine deaminase-binding protein (ADAbp), cyclophyllin b, colorectal-associated antigen (CRC)-C017-1A / GA733, carcinoembryonic antigen (CEA) and its immunogenic epitopes CAP-1 and CAP-2, etv6, amll, prostate-specific antigen (PSA) and its immunogenic epitopes PSA-1, PSA-2, and PSA-3, prostate-specific membrane antigen (PSMA), T cell receptor / CD3-zeta chain, and the MAGE family of tumor antigens (e.g., MAGE-A1, MAGE-A2, MAGE-A3, MAGE-A4, MAGE-A5, MAGE-A6, MAGE-A7, MAGE-A8, MAGE-A9, MAGE-A10, MAGE-A1 1. MAGE-A12, MAGE-Xp2 (MAGE-B2), MAGE-Xp3 (MAGE-B3), MAGE-Xp4 (MAGE-B4), MAGE-C1, MAGE-C2, MAGE-C3, MAGE-C4, MAGE-C5), GAGE ​​family of tumor antigens (e.g., GAGE-1, GAGE-2, GAGE-3, GAGE-4, GAGE-5, GAGE-6, GAGE-7, GAGE -8, GAGE-9), BAGE, RAGE, LAGE-1, NAG, GnT-V, MUM-1, CDK4, tyrosinase, p53, MUC family (e.g., MUC1, MUC16, etc.), HER2 / neu, p21ras, RCAS1, alpha-fetoprotein, E-cadherin, alpha-catenin, beta-catenin and gamma-catenin, pl20ctn, gpl00.sup.This includes, but is not limited to, Pmelll7, PRAME, NY-ESO-1, cdc27, adenomatous adenomatous polyposis protein (APC), fodrin, connexin 37, Ig-idiotype, pl5, gp75, GM2 and GD2 gangliosides, cancer antigens such as Smad family brain glycogen phosphorylases, SSX-1, SSX-2 (HOM-MEL-40), SSX-1, SSX-4, SSX-5, SCP-1 and CT-7, c-erbB-2, and viral antigens such as HPV-16 and HPV-18 E6 and E7 antigens, as well as nuclear antigen (EBNA)-1 encoded by EBV (including their fragments). Further examples of tumor-associated antigens are described, for example, in Li et al., 2004. Cancer Immunol Immunother. 53(3):139-43; and Novellino et al., 2005. Cancer Immunol Immunother. 54(3):187-20, which are incorporated herein by reference in their entirety. In one embodiment, the antigen may be conjugated to an LPS molecular species, for example, at positions Z, R1 and / or R2 of a modified LPS molecular species of formula A or formula B as described herein.

[0377] In one embodiment, the composition according to the present invention is a pharmaceutical product. As used herein, the term “medicine” should be understood to refer to various types of pharmacological materials intended to be applied to or delivered to any of the various patients, whether human or otherwise, through various delivery mechanisms.

[0378] In one embodiment, the composition, pharmaceutical composition, pharmaceutical or vaccine composition according to the present invention is formulated for administration to a subject. In one embodiment, the composition, pharmaceutical composition, pharmaceutical or vaccine composition according to the present invention is formulated for systemic or topical administration to a subject. In one embodiment, the composition, pharmaceutical composition, pharmaceutical or vaccine composition according to the present invention is formulated for administration by injection, oral administration, topical administration, nasal administration, buccal administration, rectal administration, vaginal administration, intratracheal administration, endoscopic administration, transmucosal administration, transdermal administration, or intratumor administration. In one embodiment, the composition, pharmaceutical composition, pharmaceutical or vaccine composition according to the present invention is formulated for administration by injection, preferably by systemic injection. Examples of formulations suitable for injection include, but are not limited to, solutions such as sterile aqueous solutions, gels, dispersions, emulsions, and suspensions, and solid forms suitable for use in preparing solutions or suspensions when liquid is added before use, such as powders, liposomes, and outer membrane vesicles (OMVs). Systemic injections include, but are not limited to, intravenous (IV), subcutaneous (SQ), intradermal (ID), intramuscular (IM), intraarterial, intracorneal, intranodal, intralymphatic, intraperitoneal (IP), intracranial, intracardiac, intralesional, intraprostatic, intravaginal, intrarectal, intrathecal, intranasal, intratumoral (IT), intravesical, and perfusion.

[0379] In one embodiment, when injected, the composition, pharmaceutical composition, pharmaceutical or vaccine composition according to the present invention is sterile. Methods for obtaining a sterile composition include, but are not limited to, GMP synthesis (GMP stands for "Good Manufacturing Practices"). The sterile injection form of the composition may be aqueous or oily. These suspensions may be formulated according to techniques known in the art using suitable dispersants or wetting agents and suspending agents. Sterile injection preparations may also be sterile injection solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixative oils have conventionally been used as solvents or suspension media. For this purpose, any non-irritating fixative oil, including synthetic monoglycerides or diglycerides, may be used. Fatty acids, such as oleic acid and its glyceride derivatives, as well as natural pharmaceutically acceptable oils such as olive oil or castor oil, especially their polyoxyethylated versions, are useful in the preparation of injections. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose or similar dispersants commonly used in formulations of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tween, Spans, biosurfactants, and other emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solids, liquids, or other dosage forms, may also be used for formulation purposes. In this invention, other suitable routes of administration are also considered, and it should be understood that the mode of administration will ultimately be determined by the attending physician within the bounds of sound medical judgment. In one embodiment, the composition, pharmaceutical composition, pharmaceutical or vaccine composition according to the present invention is formulated with at least one additional therapeutic agent which is either not conjugated to or conjugated to an LPS molecular species.

[0380] In one embodiment, the composition, pharmaceutical composition, pharmaceutical or vaccine composition according to the present invention should be administered to a subject requiring it before, simultaneously with, or after the administration of at least one additional therapeutic agent. Suitable examples of therapeutic agents include, but are not limited to, chemotherapeutic agents, targeted therapies, cytotoxic agents, antibiotics, antivirals, 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. Preferred examples of cell therapies include, but are not limited to, adoptive cell therapy, CAR-T cell therapy, allogeneic cell therapy, embryonic stem cell therapy, neural stem cell therapy, mesenchymal stem cell therapy, and hematopoietic stem cell transplantation. Further detailed examples of these therapeutic agents are described herein as agents suitable for conjugation at positions Z, R1 and / or R2 of formulas A and B. However, those skilled in the art will readily understand that these therapeutic agents may be provided additionally or alternatively as unconjugated compositions, pharmaceutical compositions, pharmaceutical or vaccine compositions according to the present invention. In one embodiment, the additional therapeutic agent is a targeted therapeutic agent as defined above herein, preferably an anti-CD20 monoclonal antibody or its antigen-binding fragment. In one embodiment, the anti-CD20 monoclonal antibody includes or is selected from the group consisting of ibritumomab, obinutuzumab, ocrelizumab, ofatumumab, rituximab, tocitumomab, or their antigen-binding fragments, preferably the anti-CD20 monoclonal antibody is rituximab or its antigen-binding fragment. In one embodiment, the additional therapeutic agent is an immunostimulant as defined above herein, and preferably, the additional therapeutic agent is an immune checkpoint inhibitor. In one embodiment, the immune checkpoint inhibitor includes or is selected from the group consisting of inhibitors of CTLA4, PD-1, PD-L1, LAG-3, B7-H3, B7-H4, TIM3, A2AR, GITR, CD47, TNFR2, CD19, and / or IDO. In one embodiment, the immune checkpoint inhibitor includes, or is selected from, nivolumab, pembrolizumab, semiprimab, pizilizumab, AMP-224, AMP-514, MPDL3280A, MDX-1105, MEDI-4736, allerumab, ipilimumab, tremelimumab, pizilizumab, IMP321, MGA271, BMS-986016, lirirumab, urerumab, PF-05082566, IPH2101, MEDI-6469, CP-870, 893, mogamulizumab, valilumab, galiximab, AUNP12, indoximod, NLG-919, and INCB024360. In one embodiment, the immune checkpoint inhibitor is an inhibitor of PD-1 or PD-L1. Examples of PD-1 inhibitors include, but are not limited to, nivolumab, pembrolizumab, cemiprimab, spartalizumab, canrelizumab, cintilimab, tislerizumab, tripalimab, AMP-224, and AMP-514. Examples of PD-L1 inhibitors include, but are not limited to, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, and BMS-986189.

[0381] As will be further detailed below, compositions, pharmaceutical compositions, pharmaceuticals or vaccine compositions according to the present invention, formulated with a modified LPS molecular species and optionally at least one additional therapeutic agent that is either not conjugated to or conjugated to the LPS molecular species, are useful for a wide range of therapeutic, vaccine, and immunostimulatory purposes.

[0382] The present invention relates to a modified LPS molecular species, composition, pharmaceutical composition, pharmaceutical or vaccine composition according to the present invention, for use as a drug. In particular, the present invention relates to modified LPS molecular species, compositions, pharmaceutical compositions, pharmaceuticals or vaccine compositions according to the present invention for use in subjects that require them to treat and / or prevent cancer, inflammatory diseases or infections, or to stimulate an immune response or to vaccinate. The present invention also relates to a method for treating and / or preventing cancer in a subject requiring such treatment, comprising administering, or comprising, a modified LPS molecular species, composition, pharmaceutical composition, pharmaceutical or vaccine composition according to the present invention to the subject. The present invention also relates to modified LPS molecular species, compositions, pharmaceutical compositions, pharmaceutical or vaccine compositions according to the present invention for use in subjects that require them to treat and / or prevent cancer.

[0383] Examples of cancer include those listed in the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD) under blocks C00–D48 of Chapter II. Further examples of cancer include, but are not limited to, recurrent, metastatic, or multidrug-resistant cancers. Further examples of cancer include adenofibrilloma, adenoma, aplastic myelometaplasia, AIDS-related malignancies, ameloblastoma, anal cancer, angiofollicular mediastinal lymphadenopathy, angioteratoma, angioplasia with eosinophilia, hemangiomatosis, anhidrotic ectodermal dysplasia, anterior facial dysplasia, apocrine metaplasia, apdoma, asphyxiated thoracic dysplasia, astrocytoma (including, e.g., cerebellar astrocytoma and cerebral astrocytoma), latal dysplasia, atypical melanocyte hyperplasia, atypical metaplasia, autologous parenchymal metaplasia, basal cell hyperplasia, benign giant lymphadenopathy. Bile duct cancer (including, e.g., extrahepatic cholangiocarcinoma), bladder cancer, bone cancer, brain tumors (including, e.g., brainstem glioma, cerebellar astrocytoma glioma, malignant glioma, supratentorial primitive neuroectodermal tumor, visual pathway and hypothalamic glioma, ependymoma, medulloblastoma, gestational choriocarcinoma glioma, and paraganglioma), branchionia, female breast cancer, male breast cancer, adenoma / carcinoid, bronchopulmonary dysplasia, cancerous growth of epithelial cells, precancerous growth of epithelial cells, metastatic growth of epithelial cells, carcinoid heart disease, Carcinoid tumors (e.g., including gastrointestinal carcinoid tumors), carcinomas (e.g., carcinoma of unknown primary origin, adrenocortical carcinoma, islet cell carcinoma, adenocarcinoma, adenocortical carcinoma, basal cell carcinoma, basal squamous cell carcinoma, bronchiolar carcinoma, Brown-Pierce carcinoma, cystadenocarcinoma, ductal carcinoma, hepatocellular carcinoma, Krebs carcinoma, papillary carcinoma, oat cell carcinoma, small cell lung carcinoma, non-small cell lung carcinoma, squamous cell carcinoma, transitional cell carcinoma, Walker carcinoma, Merkel cell carcinoma, and cutaneous carcinoma), cementoma, cementum carcinoma Formation, brain dysplasia, cervical cancer, cervical dysplasia, cholangiomas, cholesteatoma, chondroblastoma, chondroectoderm dysplasia, chordoma, spondylolysis, chondroma, cleistocranial dysplasia, colon cancer, colorectal cancer, locally metastatic colorectal cancer, congenital adrenal hyperplasia, congenital ectoderm dysplasia, congenital sebaceous hyperplasia, connective tissue metaplasia, craniocaracal and tarsal dysplasia, craniosynostosis, craniopharyngioma, cystadenoma, cystic hyperplasia (including cystic hyperplasia of the breast), epilobar cyssarcoma phyllodes), dentin dysplasia, denture hyperplasia, diaphysis dysplasia, mammary ductal hyperplasia, dysplasia, epiphyseal dysplasia, pleomorphic dysplasia, punctate dysplasia, ectodermal dysplasia, Ehrlich tumor, enamel dysplasia, cerebroocular dysplasia, endometrial cancer (including, e.g., ependymoma and endometrial hyperplasia), ependymoma, epithelial carcinoma, epithelial dysplasia, epithelial metaplasia, esophageal cancer, Ewing tumor family (e.g.,(including Ewing's sarcoma), extrahepatic cholangiocarcinoma, ocular cancer (e.g., including intraocular melanoma and retinoblastoma), dysplasia of the face, fingers, and toes, familial fibrous dysplasia of the jaw, familial dysplasia of the white folds, fibroma, fibromuscular dysplasia, fibromuscular hyperplasia, fibrous dysplasia of bone, hematopoietic dysplasia, focal epithelial hyperplasia, gallbladder cancer, ganglioneuroma, gastric cancer (e.g., including gastric cancer), gastrointestinal carcinoid tumors, gastrointestinal cancers, gastrointestinal tumors, Gaucher disease, germ cell tumors (e.g., including extracranial germ cell tumors, extragonadal germ cell tumors, and ovarian germ cell tumors), giant cell tumors, gingival hyperplasia, glioblastoma, glomus vessels tumor, granulosa cell tumor, male and female germinoma, hamartoma, head and neck cancer, hemangioendothelioma, hemangioma, hemangiopericytoma, hepatocellular carcinoma, liver cancer, hereditary renal retinal dysplasia, hidrotic ectodermal dysplasia, histiocytosis, histiocytosis, hypergammaglobulinemia, hypohidrotic ectodermal dysplasia, hypopharyngeal cancer, inflammatory fibrotic hyperplasia, inflammatory breast cancer Capitate hyperplasia, intestinal cancer, intestinal metaplasia, intestinal polyps, intraocular melanoma, intravascular papillary endothelial hyperplasia, renal cancer, laryngeal cancer, leiomyoma, leukemia (e.g., acute lymphoblastic leukemia, acute lymphocytic leukemia, acute myeloid leukemia, acute myeloid leukemia, acute hairy cell leukemia, acute B-cell leukemia, This includes T-cell leukemia, acute HTLV leukemia, chronic lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloid leukemia, chronic hairy cell leukemia, chronic B-cell leukemia, chronic T-cell leukemia, and chronic HTLV leukemia), Leydig cell tumors, lip and oral cancers, lipomas, liver cancers, lung cancers (including small cell lung cancer and non-small cell lung cancer), lymphangiomyomas, lymphangiomas, and lymphomas (e.g., AIDS-associated lymphoma, central nervous system lymphoma, primary central nervous system lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, Hodgkin lymphoma during pregnancy, and non-Hodgkin lymphoma during pregnancy). Lymphoma, mast cell lymphoma, B cell lymphoma, adenolymphoma, Burkitt lymphoma, cutaneous T cell lymphoma, large cell lymphoma and small cell lymphoma), lymphopenic thymic dysplasia, lymphoproliferative disorders, macroglobulinemia (e.g., Waldenström macroglobulinemia), malignant carcinoid syndrome, malignant mesothelioma, malignant thymoma, mammary dysplasia, mandibular-facial dysplasia, medulloblastoma, meningioma, mesenchymal dysplasia, mesonephroma, mesothelioma (e.g., malignant mesothelioma), diaphysis dysplasia, dysplastic anemia, metaplastic osteogenesis, metaplastic polyps, metastatic squamous cell carcinoma of the neck (e.g.,(including metastatic squamous cell carcinoma of unknown primary origin), Mondini dysplasia, monosticular fibrous dysplasia, mucosal epithelial dysplasia, multiple endocrine neoplastic syndromes, multiple extraskeletal dysplasias, multiple myeloma / plasmacytic neoplasms, mycosis fungoides, myelodysplastic syndromes, myelogenesis, myeloproliferative disorders, chronic myeloproliferative disorders, myoblastoma, fibroids, myxoma, nasal cavity and paranasal sinus cancers, nasopharyngeal cancers, prostate neoplasms, colon neoplasms, abdominal neoplasms, nasal bone neoplasms, breast neoplasms, gastrointestinal neoplasms, liver neoplasms, pancreatic neoplasms, peritoneal neoplasms, endocrine gland neoplasms (e.g., adrenal neoplasms, parathyroid neoplasms, pituitary neoplasms, testicular neoplasms, ovarian neoplasms) Neoplasms of the ophthalmos (including thymic neoplasms and thyroid neoplasms), ocular neoplasms, head and neck neoplasms, nervous system neoplasms (e.g., central nervous system neoplasms and peripheral nervous system neoplasms), lymphatic system neoplasms, pelvic neoplasms, skin neoplasms, soft tissue neoplasms, splenic neoplasms, thoracic neoplasms, urogenital neoplasms, schwannomas, neuroblastomas, neuroepitheliomas, neurofibromas, neurofibromatosis, neuromas, nodular hyperplasia of the prostate, nodular regenerative hyperplasia, oculoauricular spinal dysplasia, oculodentofibularodontogenic dysplasia, odontoma, fundus glandular dysplasia, oropharyngeal cancer, osteoma, ovarian cancer (e.g., ovarian epithelial carcinoma and low-grade ovarian tumors) **Placentroid cancers (including, for example, islet cell carcinoma and exocrine pancreatic carcinoma),** **Papillomas,** **Paragangliomas,** **Nonchromaffin paragangliomas,** **Sinus and nasal cavity cancers,** **Paraproteinemia,** **Parathyroid cancer,** **Periapical cementum dysplasia,** **Pheochromocytomas (including, for example, penile cancer),** **Primary neuroectodermal tumors of the pineal gland and supratentorial gland,** **Pineal tumors,** **Pituitary tumors,** **Plasma cell neoplasms / multiple myeloma,** **Plasma cell tumors,** **Pleuroblastoma,** **Polyostotic fibrous dysplasia,** **Polypse,** **Pre-neoplastic disorders (e.g., benign tumors, fibrocystic conditions, histiotrophy, intestinal polyps, colon polyps, esophageal dysplasia, leukoplakia, keratosis)** , including benign dysproliferative disorders such as Bowen's disease, farmer's skin, solar cheilitis and actinic keratosis), primary hepatocellular carcinoma, primary liver cancer, primary myelodysplasia, prostate cancer, pseudochondroplastic vertebral epiphyseal dysplasia, pseudoepitheliomatous hyperplasia, purpura, rectal cancer, renal cancer (e.g., kidney cancer, renal pelvis, ureteral cancer, transitional cell carcinoma of the renal pelvis and ureter), reticuloendotheliosis, retinal dysplasia, retinoblastoma, salivary gland cancer, sarcoma (e.g., uterine sarcoma, soft tissue sarcoma, carcinosarcoma, chondrosarcoma, fibrosarcoma, angiosarcoma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, myosarcoma, myxosarcoma, rhabdomyosarcoma, sarcoidosis sarcoma, osteosarcoma,This includes, but is not limited to, Ewing's sarcoma, malignant fibromatosis of bone and clear cell sarcoma of the tendon sheath, sclerosing hemangioma, secondary myelodysplasia, senile sebaceous hyperplasia, septal optical dysplasia, Sertoli cell tumor, Sézary syndrome, skin cancer (e.g., melanoma and non-melanoma skin cancer), small intestine cancer, vertebral epiphyseal dysplasia, squamous metaplasia (e.g., amniotic squamous metaplasia), gastric cancer, supratentorial primitive neuroectoderm and pineal gland tumors, supratentorial primitive neuroectoderm tumors, symptomatic myelometaplasia, teratomas, testicular cancer, follicular cell tumors, thymoma (e.g., malignant thymoma), thyroid cancer, trophoblastic tumors (e.g., gestational choriocarcinoma), ureteral cancer, urethral cancer, uterine cancer, vaginal cancer, ventricular radiodysplasia, verrucous hyperplasia, vulvar cancer, Waldenström macroglobulinemia, and Wilms' tumor. In one embodiment, cancer includes or is selected from the group consisting of osteosarcoma, colorectal cancer, lymphoma (e.g., B-cell lymphoma), chondrosarcoma, bladder cancer, and breast cancer. In one embodiment, cancer includes or is selected from the group consisting of osteosarcoma, chondrosarcoma, lymphoma (e.g., B-cell lymphoma), bladder cancer, and breast cancer. In one embodiment, the cancer includes or is selected from the group consisting of osteosarcoma, colorectal cancer, and lymphoma (such as B-cell lymphoma). In one embodiment, treating cancer in a subject requiring it further includes administering to the subject, either before, simultaneously with, or after, at least one additional therapeutic agent as defined above herein. In one embodiment, the additional therapeutic agent is a targeted therapeutic agent as defined above herein, preferably an anti-CD20 monoclonal antibody or its antigen-binding fragment. In one embodiment, the anti-CD20 monoclonal antibody includes or is selected from the group consisting of ibritumomab, obinutuzumab, ocrelizumab, ofatumumab, rituximab, tocitumomab, or their antigen-binding fragments, preferably the anti-CD20 monoclonal antibody is rituximab. In one embodiment, the additional therapeutic agent is an immunostimulant as defined above herein, and preferably, the additional therapeutic agent is an immune checkpoint inhibitor. In one embodiment, the immune checkpoint inhibitor includes or is selected from the group consisting of inhibitors of CTLA4, PD-1, PD-L1, LAG-3, B7-H3, B7-H4, TIM3, A2AR, GITR, CD47, TNFR2, CD19, and / or IDO. In one embodiment, the immune checkpoint inhibitor includes, or is selected from, nivolumab, pembrolizumab, semiprimab, pizilizumab, AMP-224, AMP-514, MPDL3280A, MDX-1105, MEDI-4736, allerumab, ipilimumab, tremelimumab, pizilizumab, IMP321, MGA271, BMS-986016, lirirumab, urerumab, PF-05082566, IPH2101, MEDI-6469, CP-870, 893, mogamulizumab, valilumab, galiximab, AUNP12, indoximod, NLG-919, and INCB024360. In one embodiment, the immune checkpoint inhibitor is an inhibitor of PD-1 or PD-L1. Examples of PD-1 inhibitors include, but are not limited to, nivolumab, pembrolizumab, cemiprimab, spartalizumab, canrelizumab, cintilimab, tislerizumab, tripalimab, AMP-224, and AMP-514. Examples of PD-L1 inhibitors include, but are not limited to, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, and BMS-986189.

[0384] The present invention also relates to a method for treating and / or preventing inflammatory diseases in a subject requiring such treatment, comprising administering, or otherwise administering, a modified LPS molecular species, composition, pharmaceutical composition, pharmaceutical or vaccine composition according to the present invention to the subject. The present invention also relates to modified LPS molecular species, compositions, pharmaceutical compositions, pharmaceutical or vaccine compositions according to the present invention for use in subjects that require them to treat and / or prevent inflammatory diseases. As used herein, the term “inflammatory disease” is used to define any disease that is caused by or leads to inflammation in question. This term may include, but is not limited to, (1) inflammatory and / or allergic diseases, (2) autoimmune diseases, (3) graft rejection, and (4) other diseases in which an undesirable inflammatory response is inhibited. Examples of inflammatory disorders include abdominal aortic aneurysm (AAA), acne, acute disseminated encephalomyelitis, acute leukocytosis-mediated lung injury, Addison's disease, adult respiratory distress syndrome, AIDS dementia, allergic asthma, allergic conjunctivitis, allergic contact dermatitis, allergic rhinitis, allergic sinusitis, allergies, allograft rejection, alopecia areata, Alzheimer's disease, anaphylaxis, angioedema, ankylosing spondylitis, antiphospholipid syndrome, asthma, atherosclerosis, atopic dermatitis, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, Behçet's syndrome, and eyelid disease. Inflammation, bronchitis, bullous pemphigoid, chronic inflammatory disease, chronic obstructive pulmonary disease, cirrhosis, closed head injury, coagulative necrosis, celiac disease, collagenous colitis, conjunctivitis, contact dermatitis, coronary heart disease, dermatofibrosis, cystic fibrosis, dermatitis, dermatomyositis, polymyositis cutaneously, type 1 diabetes, type 2 diabetes, distal proctitis, vasoconstrictive colitis, drug allergy, dry eye, eczema, encephalitis, endometriosis, endotoxin shock, epilepsy, erythema multiforme, erythema nodosum, fibrinoid necrosis, fibromyalgia, giant cell arteritis (also known as Horton's disease), glomerulonephritis, Goodpasture disease Syndrome, gout, gouty arthritis, graft-versus-host disease (e.g., acute graft-versus-host disease, chronic graft-versus-host disease, etc.), Graves' disease, Guillain-Barré syndrome, Hashimoto's disease, hay fever, hyperacute graft rejection, hyperlipidemia, hypersensitivity lung disease, idiopathic thrombocytopenic purpura, atypical colitis, inflammatory bowel disease (IBD) (e.g., Crohn's disease, ulcerative colitis, colitis, cystitis, ileitis, enteritis, etc.), inflammatory liver disease, insect bite dermatitis, insect bite allergy, interstitial cystitis, iritis, ischemic colitis, lichen planus, liquefaction necrosis, lupus, lupus erythematous, lymphocytic colitis, meningitis, metabolic syndrome Multiple sclerosis, multiple traumatic myasthenia gravis, myocarditis, myositis, narcolepsy, nephritis, obesity, osteoarthritis, osteoporosis, otitis, pancreatitis, Parkinson's disease, pemphigus vulgaris, periodontitis, periodontitis, pernicious anemia, polymyalgia rheumatica, polymyositis, postmenopausal-induced metabolic syndrome, primary biliary cirrhosis, psoriasis, psoriatic arthritis, radiation poisoning, radiation syndrome, relapsing polychondritis, retinitis, rheumatoid arthritis, rheumatoid spondylitis, rhinoconjunctivitis, sarcoidosis, scleroderma, septic shock, herpes zoster, sinusitis, Sjögren's syndrome, smooth muscle hypertrophy, photodermatitis,This includes, but is not limited to, spondyloarthritis, steatosis, stroke, systemic lupus erythematosus, urticaria, uveitis, vaginitis, vasculitis, vitiligo, and Wegener's granulomatosis. In one embodiment, treating an inflammatory disease in a subject requiring it further includes administering to the subject, either before, simultaneously with, or after, at least one additional therapeutic agent as defined above herein.

[0385] The present invention also relates to a method for treating and / or preventing an infection in a subject requiring such treatment, comprising administering or comprising administering a modified LPS molecular species, composition, pharmaceutical composition, pharmaceutical or vaccine composition according to the present invention to the subject. The present invention also relates to modified LPS molecular species, compositions, pharmaceutical compositions, pharmaceutical or vaccine compositions according to the present invention for use in subjects that require them to treat and / or prevent infectious diseases. As used herein, the term “infection” is used to define any disease caused by the invasion of an object by an infectious agent (or pathogen), their proliferation, and the response of the object's tissue to these infectious agents and the toxins they produce. This term may include, but is not limited to, (1) bacterial infections, (2) viral infections, (3) fungal infections, and (4) parasitic infections. Examples of infectious diseases include Acinetobacter infection, actinomycosis, African sleeping sickness (also known as African trypanosomiasis), AIDS (acquired immunodeficiency syndrome), amoebiasis, anaplasmosis, vasostonic disease, anisakiasis, anthrax, Arcanobacterium haemolyticum infection, argentine hemorrhagic fever, roundworm infection, aspergillosis, astrovirus infection, babesiosis, Bacillus cereus infection, bacterial meningitis, bacterial pneumonia, bacterial vaginosis, Bacteroides infection, balantidiosis, bartonellosis, Baylisaccharis infection, BK virus infection, and black pirate. Edra disease, blastocytosis, blastomycosis, Bolivian hemorrhagic fever, botulism, botulism, Brazilian hemorrhagic fever, brucellosis, bubonic plague, Burkholderia infection, brulic ulcer, calicivirus infection, campylobacteria infection, candidiasis, trichocarcinoma, Callion's disease, cat scratch disease, cellulitis, Chagas disease (also known as American trypanosomiasis), chancroid, varicella, chikungunya, chlamydia, Klebsiella pneumonia, cholera, cromoblastomycosis, citridiomycosis, clonorchikas infection, Clostridium difficile colitis, coccidia Geoidomycosis, Colorado tick fever, common cold (also known as acute viral nasopharyngitis or acute coryza), Creutzfeldt-Jakob disease, Crimean-Congo hemorrhagic fever, cryptococcosis, cryptosporidiosis, cutaneous larval migrans, cyclosporiasis, cysticercosis, cytomegalovirus infection, dengue fever, desmodesmus infection, dienthamoebicus, diphtheria, diphyllobothriasis, drakuncleasis, Ebola hemorrhagic fever, echinococcosis, ehrlichiosis, enterobacteriasis, enterococcal infection, enterovirus infection, typhus, erythema infectiosum, erythema infectiosum, rash subacute formitis Items, muscle relaxation, myofascial amblyopia, fatal familial insomnia, filariasis, Clostridium perfringens poisoning, free-living amoebiasis, Fusobacterium infection, gas gangrene, geotrichumosis, Gerstmann-Straussler-Shainker syndrome, giardiasis, glandular glandworm, gnathostomiasis, gonorrhea, granuloma groin, group A streptococcal infection, group B streptococcal infection, Haemophilus influenzae infection, hand, foot, and mouth disease, hantavirus pulmonary syndrome, Heartland virus disease, Helicobacter pylori infection, hemolytic uremic syndrome, hemorrhagic fever with renal syndrome, Hendra virus infection, hepatitis A, hepatitis B, hepatitis C,Hepatitis D, Hepatitis E, Herpes simplex, Histoplasmosis, Hookworm infection, Human bocavirus infection, Human ehrlichiosis, Human granulocytic anaplasmosis, Human metapneumovirus infection, Human monocytic ehrlichiosis, Human papillomavirus infection, Human parainfluenza virus infection, Hymenorepiasis, Infant botulism, Infectious mononucleosis, Influenza (also called flu), Isosporidemia, Kawasaki disease, Keratitis, Kingella infection, Kuru, Lassa fever, Legionnaires' disease, Leishmaniasis, Hansen's disease, Leptospirosis, Lister Lyme disease, Lymphatic filariasis, Lymphocytic choriomeningitis, Malaria, Marburg hemorrhagic fever, Measles, Middle East Respiratory Syndrome (MERS), Meloid rhinitis (also known as Whitmore's disease), Meningitis, Meningococcal disease, Metagonimiasis, Microsporidia, Molluscum contagiosum, Monkeypox, Mumps, Typhi, Mycoplasma pneumonia, Mycoplasma genitalium infection, Mycomas, Mycosis, Neonatal conjunctivitis, Nippa virus infection, Nocardiosis, Onchocerciasis (also known as river blindness), Ophthalmitis, Paracoccidioidomycosis (also known as South American blastomycosis) Paramonimiosis, Pasteurellosis, Head lice infestation, Body lice infestation, Pubic lice infestation, Pelvic inflammatory disease, Pertussis (also called pertussis), Plague, Pneumococcal infection, Pneumocystis pneumonia, Pneumonia, Poliomyelitis, Prevotella infection, Primary amoebic meningoencephalitis, Progressive multifocal leukoencephalopathy, Psittacosis, Q fever, Rabies, Relapsing fever, Respiratory syncytial virus infection, Rhinosporidium disease, Rhinovirus infection, Rickettsial infection, Rickettsial pox, Rift Valley fever, Rocky Mountain spotted fever, Rotavirus infection, Rubella, Salmonellosis, Scabies, Scarlet fever, Schistosomiasis Parasitic infections, sepsis, severe acute respiratory syndrome (including SARS-CoV-2, also known as SARS), dysentery, herpes zoster, smallpox (also known as variola), sporotrichosis, staphylococcal food poisoning, staphylococcal infection, stromgilus infection, subacute sclerosing encephalitis, syphilis, tapeworm infection, tetanus, tinea folliculitis, tinea, tinea capitis, tinea corporis, tinea cruris, tinea manuum, tinea pedis, onychomycosis, tinea versicolor, toxocariasis, toxoplasmosis, trachomatis, trichinellosis, trichomoniasis, flagellosis, tuberculosis, tularemia, typhoid fever, typhus fever, Ureaplasma urealyticum infection, Barre fever,This includes, but is not limited to, Venezuelan encephalitis, Venezuelan hemorrhagic fever, Vibrio vulnificus infection, Vibrio parahaemolyticus colitis, viral pneumonia, West Nile fever, Yersinia pseudotuberculosis infection, Yersiniasis, yellow fever, Supora fever, Zika fever, and zygomycosis. In one embodiment, treating an infectious disease in a subject requiring it further includes administering to the subject, either before, simultaneously with, or after, at least one additional therapeutic agent as defined above herein.

[0386] The present invention also relates to a method for stimulating an immune response in a subject requiring such treatment, comprising administering or otherwise administering a modified LPS molecular species, composition, pharmaceutical composition, pharmaceutical or vaccine composition according to the present invention to the subject. The present invention also relates to modified LPS molecular species, compositions, pharmaceutical compositions, pharmaceutical or vaccine compositions according to the present invention for use in subjects that require the stimulation of an immune response. The present invention also relates to the use of modified LPS molecular species, compositions, pharmaceutical compositions, pharmaceuticals, or vaccine compositions according to the present invention as immunostimulants. In one embodiment, stimulating an immune response in a subject requiring it further includes administering to the subject, either before, simultaneously with, or after, at least one additional therapeutic agent as defined above herein. In a preferred embodiment, the at least one additional therapeutic agent is an antigen as defined above herein. In one embodiment, where the antigen is an autoantigen (e.g., a cellular antigen including cells containing normal transplant antigens and / or tumor-associated antigens, an RR-Rh antigen, or an antigen characteristic or specific to a particular cell, tissue, or fluid), stimulating an immune response in a subject requiring it does not involve administering at least one additional antigen to the subject. Alternatively, if the antigen is an autoantigen, stimulating an immune response in a subject requiring it may involve administering at least one additional antigen, which is either the same autoantigen or a different antigen, to the subject before, simultaneously with, or after.

[0387] The present invention also relates to a method for vaccinating a subject in need of such a modification, comprising administering to the subject a modified LPS molecular species, composition, pharmaceutical composition, pharmaceutical or vaccine composition according to the present invention, or comprising administering to the subject a modified LPS molecular species, composition, pharmaceutical or vaccine composition according to the present invention.

[0388] The present invention also relates to modified LPS molecular species, compositions, pharmaceutical compositions, pharmaceutical or vaccine compositions according to the present invention for use in subjects requiring vaccination.

[0389] In one embodiment, vaccinating a subject in need further includes administering to the subject at least one additional therapeutic agent as defined above. In a preferred embodiment, the at least one additional therapeutic agent is an antigen as defined above herein.

[0390] In one embodiment, where the antigen is an autoantigen (e.g., a cellular antigen including cells containing normal transplant antigens and / or tumor-associated antigens, an RR-Rh antigen, or an antigen characteristic of or specific to certain cells, tissues, or fluids containing neoantigens), vaccination of a subject requiring it does not involve administering at least one additional antigen to the subject. Alternatively, if the antigen is an autoantigen, vaccination of a subject requiring it may involve administering at least one additional antigen, which is either the same autoantigen or a different antigen, to the subject before, simultaneously with, or after.

[0391] It is readily apparent that the therapeutic, vaccine, and immunostimulatory purposes disclosed herein above are applicable to non-human animals or other subjects requiring such purposes. Accordingly, compositions, pharmaceutical compositions, pharmaceuticals, or vaccine compositions according to the present invention, formulated with a modified LPS molecular species and optionally at least one additional therapeutic agent which is either unconjugated to or conjugated to the LPS molecular species, are useful for a wide range of therapeutic, vaccine, and immunostimulatory purposes in the field of veterinary medicine.

[0392] As described above in this specification, those skilled in the art will readily recognize that LPS molecular species should be purified to different degrees depending on their intended use, and that for veterinary applications, LPS molecular species may be purified to a lower degree, or even not purified at all. In this case, naturally occurring LPS molecular species and / or modified LPS molecular species can be formulated directly from bacterial pellets, culture concentrates, culture supernatants, concentrated membrane fractions and / or outer membrane vesicle (OMV) fractions with little or no purification steps.

[0393] In one embodiment, a composition comprising at least one LPS molecular species useful for veterinary applications may be the same as those described herein, or may comprise LPS molecular species of formula (XII)(1) and combinations thereof, or a mixture of modified LPS molecular species selected from the group comprising them.

[0394] In one embodiment, the subject requiring it is an animal. Examples of animals include, but are not limited to, mammals, birds, reptiles, amphibians, fish, insects, and mollusks.

[0395] In one embodiment, the subject requiring it is livestock—or animals of agricultural value (e.g., cattle, dairy cows, bison, pigs, wild boars, sheep, goats, horses, donkeys, alpacas, llamas, deer, moose, ostriches, emes, ducks, geese, chickens, partridges, quail, pheasants, mink, salmon, cod, catfish, herring, trout, bass, perch, flounder, sharks, tuna, geese, lobsters, crayfish) Non-human animals include, but are not limited to, crabs, snails, bivalves, oysters, etc., companion animals (e.g., dogs, cats, rabbits, rodents, fish, snakes, etc.), and non-human primates (e.g., great apes including chimpanzees, gorillas, and orangutans; great apes including gibbons; Old World monkeys; New World monkeys; and prosimians including tarsiers, lemurs, and lorises).

[0396] In one embodiment, the subject requiring it is a human being.

[0397] In one embodiment, the subjects requiring it are adults (e.g., subjects over 18 years of age or subjects who have reached reproductive capacity). In another embodiment, the subjects requiring it are children (e.g., subjects under 18 years of age or subjects who have not yet reached reproductive capacity).

[0398] In one embodiment, the person who needs it is male. In another embodiment, the person who needs it is female.

[0399] In one embodiment, the subject requiring it is diagnosed with / has been diagnosed with cancer, inflammatory disease, and / or infectious disease. In one embodiment, the subject requiring it is at risk of developing cancer, inflammatory disease, and / or infectious disease.

[0400] The present invention i. Modified LPS molecular species, compositions, pharmaceutical compositions, pharmaceutical or vaccine compositions, and ii. Regarding parts kits, including additional therapeutic agents. The term “parts kit” is also referred to as “package,” “commercial package,” or “pharmaceutical package,” and encompasses physically separated constituent entities that are intended for individual storage and / or use but are functionally related to one another. In particular, the term “parts kit” encompasses physically separated components (e.g., on the one hand, modified LPS molecular species, compositions, pharmaceutical compositions, pharmaceutical or vaccine compositions, etc. according to the present invention, and on the other hand, additional therapeutic agents) that are used or administered separately, or simultaneously, as an immediate formulation, or individually within a time interval of up to a few seconds to a few minutes, in any order and at a given time interval, typically but not necessarily, ranging from several hours to several days or several weeks or more. Suitable examples of additional therapeutic agents include, but are not limited to, chemotherapeutic agents, targeted therapies, cytotoxic agents, antibiotics, antivirals, 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. Detailed examples of these additional therapeutic agents are described herein as agents suitable for conjugation at positions Z, R1 and / or R2 of formulas A and B. However, those skilled in the art will readily understand that these additional therapeutic agents may be provided separately or alternatively, not conjugated in the parts kit according to the present invention. In one embodiment, the additional therapeutic agent is a targeted therapeutic agent as defined above herein, preferably an anti-CD20 monoclonal antibody or its antigen-binding fragment. In one embodiment, the anti-CD20 monoclonal antibody includes or is selected from the group consisting of ibritumomab, obinutuzumab, ocrelizumab, ofatumumab, rituximab, tocitumomab, or their antigen-binding fragments, preferably the anti-CD20 monoclonal antibody is rituximab. In one embodiment, the additional therapeutic agent is an immunostimulant as defined above herein, and preferably, the additional therapeutic agent is an immune checkpoint inhibitor. In one embodiment, the immune checkpoint inhibitor includes or is selected from the group consisting of inhibitors of CTLA4, PD-1, PD-L1, LAG-3, B7-H3, B7-H4, TIM3, A2AR, GITR, CD47, TNFR2, CD19, and / or IDO. In one embodiment, the immune checkpoint inhibitor includes, or is selected from, nivolumab, pembrolizumab, semiprimab, pizilizumab, AMP-224, AMP-514, MPDL3280A, MDX-1105, MEDI-4736, allerumab, ipilimumab, tremelimumab, pizilizumab, IMP321, MGA271, BMS-986016, lirirumab, urerumab, PF-05082566, IPH2101, MEDI-6469, CP-870, 893, mogamulizumab, valilumab, galiximab, AUNP12, indoximod, NLG-919, and INCB024360. In one embodiment, the immune checkpoint inhibitor is an inhibitor of PD-1 or PD-L1. Examples of PD-1 inhibitors include, but are not limited to, nivolumab, pembrolizumab, cemiprimab, spartalizumab, canrelizumab, cintilimab, tislerizumab, tripalimab, AMP-224, and AMP-514. Examples of PD-L1 inhibitors include, but are not limited to, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, and BMS-986189.

[0401] In one embodiment, the additional therapeutic agent is the antigen described herein.

[0402] Modified lipopolysaccharide (LPS) molecular species are disclosed herein, and said LPS molecular species are - The lipid A domain lacks a phosphate group at the C1 position of the reducing end and / or the C4' position of the non-reducing end, and -The lipid A domain is substituted at the C6' position of the non-reducing end with a hydrophilic moiety, however, the hydrophilic moiety is not a hydroxyl group, but preferably substituted at the C6' position of the non-reducing end with a monosaccharide, oligosaccharide, or polysaccharide moiety.

[0403] In one embodiment, the modified LPS molecular species is of general formula B [ka] 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 must not be a phosphate group (-OPO3H2), and R2 is a phosphate group (-OPO3H2) or a hydroxyl group (-OH) and may be substituted, or R1 is a phosphate group (-OPO3H2) or a hydroxyl group (-OH), and may be substituted. R2 is a hydroxyl group (-OH), and may be substituted, however, if substituted, the substitution must not be from a phosphate group (-OPO3H2). -R3 is a monosaccharide, oligosaccharide, or polysaccharide moiety, which may be substituted, and preferably R3 is a core oligosaccharide which may be substituted with an antigen domain, preferably an O antigen domain and / or a capping antigen. -R4 and R6 are independently fatty acid residues and may be substituted. -R5 and R7 are independently hydrogen or fatty acid residues and may be substituted.

[0404] In one embodiment, the modified LPS molecular species is one of the following formulas as shown in Figures 2-4, 7-17 and 27: (I)(1)(a), (I)(1)(b), (I)(1)(c), (I)(1)(d), (I)(1)(e), (I)(1)(f), (I)(2)(a), (I)(2)(b), (I)(2)(c), (I)(3)(a), (I)(3)(b), (I)(3)(c), (II)(2)(a), (II)(2)(b), (II)(2)(c), (II)(2)(d), (III)( 1)(a), (III)(1)(b), (III)(1)(c), (III)(1)(d), (IV)(1)(a), (IV)(1)(b), (IV)(1)(c), (V)(1)(a), (V)(1)(b), (V)(1)(c), (V )(1)(d), (V)(1)(e), (V)(1)(f), (V)(1)(g), (V)(1)(h), (V)(1)(i), (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), (VI)(2)(a), (VI)(2)(b), (VI)(2)(c), (VII)(1)(a), (V II)(1)(b), (VII)(1)(c), (VIII)(1)(a), (VIII)(1)(b), (VIII)(1)(c), (VIII)(1)(d), (IX)(1)(a), (IX)(1)(b), (IX)(1)(c), ( Selected from the group including the LPS molecular species of IX)(1)(d), (X)(1)(a), (X)(1)(b), (X)(1)(c), (X)(1)(d), (XI)(1)(a), (XI)(1)(b), (XI)(1)(c), (XI)(1)(d), (XII)(1), and combinations thereof, wherein the R at the C6' position is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and optionally an antigen domain, preferably an O antigen domain and / or a capping antigen.

[0405] A concentrated population of modified LPS molecular species is also disclosed herein, the concentrated population of LPS molecular species comprising at least 10%, preferably at least 50%, of the modified LPS molecular species according to the present invention.

[0406] In one embodiment, the concentrated population of modified LPS molecular species forms particles in an aqueous solution having an average size of less than approximately 200 nm in diameter, preferably less than approximately 150 nm in diameter, which can be evaluated by dynamic light scattering (DLS) at 25°C.

[0407] A composition comprising at least one modified LPS molecular species according to the present invention, or an enriched population of modified LPS molecular species according to the present invention, is also disclosed herein.

[0408] In one embodiment, the composition is - A mixture of at least two 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), preferably a mixture of six modified LPS molecular species, or - A mixture of at least two modified LPS molecular species of formula (I)(2)(a), (I)(2)(b), and (I)(2)(c), preferably a mixture of three modified LPS molecular species, or - A mixture of at least two modified LPS molecular species of formula (I)(3)(a), (I)(3)(b), and (I)(3)(c), preferably a mixture of three modified LPS molecular species, or - A mixture of at least two modified LPS molecular species of formula (II)(2)(a), (II)(2)(b), (II)(2)(c), and (II)(2)(d), preferably a mixture of four modified LPS molecular species, or - A mixture of at least two modified LPS molecular species of formula (III)(1)(a), (III)(1)(b), (III)(1)(c), and (III)(1)(d), preferably a mixture of four modified LPS molecular species, or - A mixture of at least two modified LPS molecular species of formula (IV)(1)(a), (IV)(1)(b), and (IV)(1)(c), preferably a mixture of three modified LPS molecular species, or - A mixture of at least two modified LPS molecular species of formula (V)(1)(a), (V)(1)(b), (V)(1)(c), (V)(1)(d), (V)(1)(e), (V)(1)(f), (V)(1)(g), (V)(1)(h), (V)(1)(i), preferably a mixture of nine modified LPS molecular species, or - A mixture of at least two 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), (VI)(1)(j), preferably a mixture of 10 modified LPS molecular species, or - A mixture of at least two modified LPS molecular species of formula (VI)(2)(a), (VI)(2)(b), and (VI)(2)(c), preferably a mixture of three modified LPS molecular species, or - A mixture of at least two modified LPS molecular species of formula (VII)(1)(a), (VII)(1)(b), and (VII)(1)(c), preferably a mixture of three modified LPS molecular species, or - A mixture of at least two modified LPS molecular species of formula (VIII)(1)(a), (VIII)(1)(b), (VIII)(1)(c), and (VIII)(1)(d), preferably a mixture of four modified LPS molecular species, or - A mixture of at least two modified LPS molecular species of formula (IX)(1)(a), (IX)(1)(b), (IX)(1)(c), and (IX)(1)(d), preferably a mixture of four modified LPS molecular species, or - A mixture of at least two modified LPS molecular species of formula (X)(1)(a), (X)(1)(b), (X)(1)(c), and (X)(1)(d), preferably a mixture of four modified LPS molecular species. - A mixture of at least two modified LPS molecular species of formula (XI)(1)(a), (XI)(1)(b), (XI)(1)(c), and (XI)(1)(d), preferably a mixture of four modified LPS molecular species, or -Includes a mixture of modified LPS molecular species of formula (XII)(1). In one embodiment, the composition is a pharmaceutical composition or a vaccine composition, further comprising at least one pharmaceutically acceptable excipient. - For use in subjects who need it to treat and / or prevent cancer, - For use in subjects who need it to treat and / or prevent inflammatory diseases, - For use in those who need it to treat and / or prevent infectious diseases, - To stimulate an immune response, for use in subjects that require it, and / or - To vaccinate, for use in those who need it, Naturally occurring non-toxic LPS molecular species and / or modified LPS molecular species, or compositions containing them, are also disclosed herein. The aforementioned naturally occurring non-toxic LPS molecular species and / or modified LPS molecular species, or compositions containing them, - Modified LPS molecular species according to the present invention, concentrated population of modified LPS molecular species according to the present invention, or composition according to the present invention, -2 secondary carbons 12 and / or C 14 The LPS molecular species are selected from those that do not contain fatty acid chains and / or do not contain phosphate groups at either the C1 position of the reducing end of its lipid A domain or the C4' position of the non-reducing end of its lipid A domain.

[0409] In one embodiment, the LPS molecular species or composition is - An LPS molecular species selected from the group containing the LPS molecular species of formulas (I)(0)(a), (I)(0)(b), (II)(0), (II)(1)(a), (II)(1)(b), (II)(1)(c), and (II)(1)(d) shown in Figures 1 to 6. - A mixture of LPS molecular species of formulas (I)(0)(a) and (I)(0)(b) shown in Figure 1, - A mixture of at least two LPS molecular species of formula (II)(0) shown in Figure 5, - A mixture of at least two LPS molecular species of formulas (II)(1)(a), (II)(1)(b), (II)(1)(c), and (II)(1)(d) shown in Figure 6, - A composition according to the present invention comprising a mixture of modified LPS molecular species of formulas (I)(1)(a), (I)(1)(b), (I)(1)(c), (I)(1)(d), (I)(1)(e) and (I)(1)(f), - A composition according to the present invention comprising a mixture of modified LPS molecular species of formula (I)(2)(a), (I)(2)(b) and (I)(2)(c), or -Selected from compositions according to the present invention, comprising a mixture of modified LPS molecular species of 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), and (VI)(1)(j).

[0410] In one embodiment, treating and / or preventing cancer, inflammatory diseases, or infectious diseases preferably further comprises administering to the subject at least one additional therapeutic agent selected from the group including chemotherapeutic agents, targeted therapeutic 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.

[0411] In one embodiment, at least one additional therapeutic agent is a targeted therapy agent, preferably an anti-CD20 antibody or its antigen-binding fragment.

[0412] In one embodiment, at least one additional therapeutic agent is an immunostimulant, preferably an immune checkpoint inhibitor, more preferably selected from the group consisting of CTLA4, PD-1, PD-L1, LAG-3, B7-H3, B7-H4, TIM3, A2AR, GITR, CD47, TNFR2, CD19, and IDO inhibitors, and most preferably at least one additional therapeutic agent is a PD-1 or PD-L1 inhibitor.

[0413] In one embodiment, vaccinating a subject in need of such vaccination further includes, preferably, administering to the subject at least one antigen selected from the group consisting of pathogen-related antigens, autoantigens, allergen-related antigens, and neoantigens.

[0414] In one embodiment, 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 or composition containing it are selected from the LPS molecular species of formula (XII)(1) as shown in Figure 27.

[0415] This specification includes, - Modified LPS molecular species according to the present invention, concentrated population of modified LPS molecular species according to the present invention, composition according to the present invention, or two secondary C 12 and / or C 14 LPS molecular species that do not contain fatty acid chains and / or that do not contain phosphate groups at both the C1 position of the reducing end of its lipid A domain and the C4' position of the non-reducing end of its lipid A domain, and A parts kit is also disclosed which preferably includes additional therapeutic agents selected from the group comprising chemotherapeutic agents, targeted therapy agents, cytotoxic agents, antibiotics, antiviral drugs, 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. [Brief explanation of the drawing]

[0416] [Figure 1] Figure 1 shows the structures of two naturally occurring LPS molecular species "LPS B2 0.0" derived from Bordetella pertussis, having formulas (I)(0)(a) and (I)(0)(b). The disaccharide of the lipid A domain is substituted with R at the non-reducing C6' position, where R is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and, optionally, an antigen domain such as an O antigen domain and / or a capping antigen. [Figure 2]Figure 2 shows the structures of six chemically modified LPS molecular species "LPS B2 0.1" derived from Bordetella pertussis, having formulas (I)(1)(a) to (I)(1)(f). The disaccharide of the lipid A domain is substituted with R at the non-reducing C6' position, where R is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and, optionally, an antigen domain such as an O antigen domain and / or a capping antigen. [Figure 3] Figure 3 shows the structures of three chemically modified LPS molecular species "LPS B2 1.1" derived from Bordetella pertussis, having formulas (I)(2)(a) to (I)(2)(c). The disaccharide of the lipid A domain is substituted with R at the non-reducing C6' position, where R is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and, optionally, an antigen domain such as an O antigen domain and / or a capping antigen. [Figure 4] Figure 4 shows the structures of three chemically modified LPS molecular species "LPS B2 1.2" derived from Bordetella pertussis, having formulas (I)(3)(a) to (I)(3)(c). The disaccharide of the lipid A domain is substituted with R at the non-reducing C6' position, where R is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and, optionally, an antigen domain such as an O antigen domain and / or a capping antigen. [Figure 5] Figure 5 shows the structure of the naturally occurring LPS molecular species "LPS W1 0.0" derived from Vitreostila filiformis, which has formula (II)(0). The disaccharide of the lipid A domain is substituted with R at the non-reducing C6' position, where R is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and, optionally, an antigen domain such as an O antigen domain and / or a capping antigen. The phosphorylethanolamine (PEA) residues shown in parentheses at the reducing C1 position and the non-reducing C4' position of the lipid A domain are either present or absent. [Figure 6]Figure 6 shows the structures of four chemically modified LPS molecular species "LPS W1 1.0" derived from Vitreostila filiformis having formulas (II)(1)(a) to (II)(1)(d). The disaccharide of the lipid A domain is substituted with R at the non-reducing C6' position, where R is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and, optionally, an antigen domain such as an O antigen domain and / or a capping antigen. [Figure 7] Figure 7 shows the structures of four chemically modified LPS molecular species "LPS W1 1.2" derived from Vitreostila filiformis having formulas (II)(2)(a) to (II)(2)(d). The disaccharide of the lipid A domain is substituted with R at the non-reducing C6' position, where R is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and, optionally, an antigen domain such as an O antigen domain and / or a capping antigen. [Figure 8-1] Figure 8 shows the structures of four chemically modified LPS molecular species "LPS SM1 1.2" derived from Salmonella enterica serotype Minnesota R595, having formulas (III)(1)(a) to (III)(1)(d). The disaccharide of the lipid A domain is substituted with R at the non-reducing C6' position, where R is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and, optionally, an antigen domain such as an O antigen domain and / or a capping antigen. The phosphate group shown in parentheses at the non-reducing C4' position of the lipid A domain is either present or absent. [Figure 8-2] Same as above. [Figure 9]Figure 9 shows the structures of three chemically modified LPS molecular isoforms "LPS ST1 1.2" derived from Salmonella enterica serotype Typhimurium Ra, or "LPS E2 1.2" derived from Escherichia coli K12, or "LPS V1 1.2" derived from Vibrio ficheri (all three having the same lipid A domain), having formulas (IV)(1)(a) to (IV)(1)(c). The disaccharide of the lipid A domain is substituted with R at the non-reducing C6' position, where R is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and, optionally, an antigen domain such as an O antigen domain and / or a capping antigen. [Figure 10] Figure 10 shows the structures of nine chemically modified LPS molecular species "LPS E1 0.1" derived from Escherichia coli J5 having formulas (V)(1)(a) to (V)(1)(i). The disaccharide of the lipid A domain is substituted with R at the non-reducing C6' position, where R is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and, optionally, an antigen domain such as an O antigen domain and / or a capping antigen. [Figure 11] Figure 11 shows the structures of 10 chemically modified LPS molecular species "LPS A1 0.1" derived from Actinobacillus pluprneumonier having formulas (VI)(1)(a) to (VI)(1)(j). The disaccharide of the lipid A domain is substituted with R at the non-reducing C6' position, where R is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and, optionally, an antigen domain such as an O antigen domain and / or a capping antigen. [Figure 12] Figure 12 shows the structures of three chemically modified LPS molecular species "LPS A1 1.2" derived from Actinobacillus pluprneumonier having formulas (VI)(2)(a) to (VI)(2)(c). The disaccharide of the lipid A domain is substituted with R at the non-reducing C6' position, where R is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and, optionally, an antigen domain such as an O antigen domain and / or a capping antigen. [Figure 13]Figure 13 shows the structures of three chemically modified LPS molecular species "LPS K1 1.2" derived from Burkholderia pseudomalley having formulas (VII)(1)(a) to (VII)(1)(c). The disaccharide of the lipid A domain is substituted with R at the non-reducing C6' position, where R is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and, optionally, an antigen domain such as an O antigen domain and / or a capping antigen. The phosphate group shown in parentheses at the non-reducing C4' position of the lipid A domain is either present or absent. [Figure 14] Figure 14 shows the structures of four chemically modified LPS molecular species "LPS M1 1.2" derived from Moraxella catarrhalis, having formulas (VIII)(1)(a) to (VIII)(1)(d). The disaccharide of the lipid A domain is substituted with R at the non-reducing C6' position, where R is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and, optionally, an antigen domain such as an O antigen domain and / or a capping antigen. [Figure 15] Figure 15 shows the structures of four chemically modified LPS molecular species "LPS N1 1.2" derived from Neisseria sicca, having formulas (IX)(1)(a) to (IX)(1)(d). The disaccharide of the lipid A domain is substituted with R at the non-reducing C6' position, where R is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and, optionally, an antigen domain such as an O antigen domain and / or a capping antigen. [Figure 16-1]Figure 16 shows the structures of four chemically modified LPS molecular species "LPS P1 1.2" from Pseudomonas aeruginosa or "LPS P2 1.2" from Pseudomonas fluorescent bacteria (both having the same lipid A domain) having formulas (X)(1)(a) to (X)(1)(d). The disaccharide of the lipid A domain is substituted with R at the non-reducing C6' position, where R is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and, optionally, an antigen domain such as an O antigen domain and / or a capping antigen. The phosphate group shown in parentheses at the non-reducing C4' position of the lipid A domain, and the hydroxyl group at C2 of the secondary fatty acid, are either present or absent. [Figure 16-2] Same as above. [Figure 17-1] Figure 17 shows the structures of four chemically modified LPS molecular species "LPS I1 1.2" from Bordetella hingii or "LPS T1 1.2" from Bordetella trematum (both having the same lipid A domain), having formulas (XI)(1)(a) to (XI)(1)(d). The disaccharide of the lipid A domain is substituted with R at the non-reducing C6' position, where R is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and, optionally, an antigen domain such as an O antigen domain and / or a capping antigen. The phosphate group shown in parentheses at the non-reducing C4' position of the lipid A domain, as well as the hydroxyl group at C2 of the secondary fatty acid, are either present or absent. [Figure 17-2] Same as above. [Figure 18-1]Figures 18A-D are a set of four graphs showing DLS measurements of LPS B2 0.0, LPS B2 0.1, LPS B2 1.1, and synthetic GLA (PHAD®, Avanti® Polar Lipids, Inc.) in water [H2O]. Triple DLS measurements for each suspension are shown. The average particle size (nm) is shown for each measurement, and the average of the three average particle size values ​​is shown in parentheses. Figure 18A: Triple DLS measurements of LPS B2 0.0 in water. Figure 18B: Triple DLS measurements of LPS B2 0.1 in water. Figure 18C: Triple DLS measurements of LPS B2 1.1 in water. Figure 18D: Triple DLS measurements of GLA in water. [Figure 18-2] Same as above. [Figure 19-1] Figures 19A-D are a set of four graphs showing DLS measurements for LPS B2 0.0, LPS B2 0.1, LPS B2 1.1, and synthetic GLA (PHAD®, Avanti® Polar Lipids, Inc.) in PBS suspension. Triple DLS measurements are shown for each suspension. The average particle size (nm) is shown for each measurement, and the average of the three average particle size values ​​is shown in parentheses. Figure 19A: Triple DLS measurements for LPS B2 0.0 in PBS suspension. Figure 19B: Triple DLS measurements for LPS B2 0.1 in PBS suspension. Figure 19C: Triple DLS measurements for LPS B2 1.1 in PBS suspension. Figure 19D: Triple DLS measurements for GLA in PBS suspension. [Figure 19-2] Same as above. [Figure 20] Figure 20 is a graph showing the average particle size (nm) of LPS B2 0.0, LPS B2 0.1, LPS B2 1.1, and synthetic GLA (PHAD®, Avanti® Polar Lipids, Inc.) in water [H2O] and PBS [PBS] suspensions. [Figure 21]Figure 21 shows a set of four MALDI spectra of MPL and candidate Salmonella enterica and E. coli (LPS SM1 1.2, LPS ST1 1.2, and LPS E1 1.2), showing the signal intensity on the y axis versus the mass-to-charge ratio (m / z) on the x axis. MPL (monophosphoryl lipid A) is a natural LPS derivative derived from Salmonella enterica serotype Minnesota R595, from which the phosphate group at the C1 position of the reducing end of its lipid A domain is cleaved by acidic hydrolysis along with the core portion of the LPS molecular species. Therefore, unlike the modified LPS molecular species of the present invention, it also lacks a core oligosaccharide domain at the C6' position of the non-reducing end of its lipid A domain. This sample gives a peak in the lower mass region of the mass spectrum, and the molecular species represents only the lipid A portion. [Figure 22] Figure 22 shows a set of four MALDI spectra of Bordetella pertussis candidates (LPS B2 0.0, LPS B2 0.1, LPS B2 1.1, and LPS B2 1.2), with signal intensity on the y-axis versus mass-to-charge ratio (m / z) on the x-axis. [Figure 23] Figure 23 shows a set of three MALDI spectra of candidate Vitreostila filiformis (LPS W1 0.0, LPS W1 1.0, and LPS W1 1.2), with signal intensity on the y-axis versus mass-to-charge ratio (m / z) on the x-axis. [Figure 24-1]Figures 24A-B are a set of two graphs showing the therapeutic efficacy of native (LPS B2 0.0 and LPS W1 0.0) LPS isoforms, alone or in combination with rituximab, in CB17-SCID mice transplanted with an established human B lymphoma tumor model (RL cells) and subsequently immunized. Figure 24A: Tracking tumor volume in a cohort of CB17-SCID mice transplanted with RL cells and subsequently immunized with native (LPS B2 0.0 or LPS W1 0.0) LPS, alone or in combination with rituximab ["+Ritux"]. Groups of mice treated with GLA were included for comparison, administered intravenously (not shown) or intraperitoneally, alone [GLA] or in combination with rituximab [GLA+Ritux]. Tumor-bearing mice injected with rituximab [Rituximab] or PBS alone [control] were used as controls. The data shown are the median ± SEM (n=6 mice / group) tumor body (mm3) over time for all mice in a cohort of one experiment. *P<0.05, **P<0.01, ns: not significant. Figure 24B: Tracking of tumor volume in each group of mice, expressed as the percentage of complete tumor regression at D54 after tumor loading. [Figure 24-2] Same as above. [Figure 25-1]Figures 25A-B are a set of two graphs showing the therapeutic efficacy of chemically modified (LPS B2 0.1 and LPS B2 1.1) LPS alone or in combination with rituximab in CB17-SCID mice transplanted with established human B lymphoma tumor models (RL cells) and subsequently immunized. PBS was used as a negative control. Figure 25A: Tracking tumor volume in a cohort of CB17-SCID mice transplanted with RL cells and subsequently immunized with chemically modified (LPS B2 0.1 or LPS B2 1.1) LPS alone or in combination with rituximab ["+Ritux"]. A group of mice treated with GLA, administered intravenously (not shown) or intraperitoneally, alone [GLA] or in combination with rituximab [GLA+Ritux], was included for comparison. Tumor-bearing mice injected with rirituximab [Rituximab] or PBS alone [control] were used as controls. The data shown are the median + / - SEM (n=6 mice / group) tumor volume (mm3) over time for all mice in a cohort of one experiment. *P<0.05, **P<0.01, ns: not significant. Figure 25B: Tracking of tumor vol...

Claims

1. A concentrated 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' position of the lipid A domain is substituted with a hydrophilic moiety, however, the hydrophilic moiety is not a hydroxyl group, but preferably a monosaccharide, oligosaccharide, or polysaccharide moiety at the C6' position of the non-reducing end of the lipid A domain. A concentrated population of modified LPS molecular species.

2. The modified LPS molecular species is, General formula A 【Chemistry 1】 (In the formula, -Y is -O- or -NH-, -R ２ is a phosphate group (-OPO ３ H ２ ) or a hydroxyl group (-OH), which may be substituted. -R ３ is a monosaccharide, oligosaccharide, or polysaccharide, and may be substituted, preferably R ３ This is a core oligosaccharide (i.e., inner core, or inner core and outer core) which may be substituted with an O antigen domain. -R ６ This is a fatty acid residue, and may be substituted. -R ７ is a hydrogen atom or a fatty acid residue, and may be substituted. -Z is a hydroxyl group (-OH), which may be substituted, provided that when it is substituted, the substitution does not consist of a phosphate group (-OPO ３ H ２ ), or Z is, 【Chemistry 2】 And here, -X is -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 ４ This is a fatty acid residue, and may be substituted. -R ５ (wherein this is a hydrogen atom or a fatty acid residue, and may be substituted.) The enriched population of modified LPS molecular species according to claim 1.

3. The modified LPS molecular species is, 【Transformation 3】 (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 just R ２ is a phosphate group (-OPO ３ H ２ ) or a hydroxyl group (-OH), which may be substituted, -R ３ is a monosaccharide, oligosaccharide, or polysaccharide moiety, which may be substituted, preferably R ３ This is a core oligosaccharide which may be substituted with an antigen domain, preferably an O antigen domain and / or a capping antigen. -R ４ and R ６ These are fatty acid residues, which are independent of each other and may be substituted. -R ５ and R ７ (These are, independently of each other, hydrogen atoms or fatty acid residues, and may be substituted.) An enriched population of modified LPS molecular species according to claim 1 or 2.

4. As shown in FIGS. 2 to 4, FIGS. 7 to 17, FIGS. 29 to 33, and FIGS. 36 to 43, the modified LPS molecular species are of formula (I)(1)(a), (I)(1)(b), (I)(1)(c), (I)(1)(d), (I)(1)(e), (I)(1)(f), (I)(2)(a), (I)(2)(b), (I)(2)(c), (I)(3)(a), (I)(3)(b), (I)(3)(c), (I)(5)(a), (I)(5)(b), (I)(6)(a), (I)(6)(b), (I)(7)(a), (I)(7)(b), (I)(7)(c), (I)(7)(d), (I)(8)(a), (I)(8)(b), (I)(8)(c), (I)(9)(a), (I)(9)(b), (I)(9)(c), (I)(9)(d), (I)(9)(e), (I)(9)(f), (II)(2)(a), (II)(2)(b), (II)(2)(c), (II)(2)(d), (III)(1)(a), (III)(1)(b), (III)(1)(c), (III)(1)(d), (IV)(1)(a), (IV)(1)(b), (IV)(1)(c), (V)(1)(a), (V)(1)(b), (V)(1)(c), (V)(1)(d), (V)(1)(e), (V)(1)(f), (V)(1)(g), (V)(1)(h), (V)(1)(i), (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), (VI)(2)(a), (VI)(2)(b), (VI)(2)(c), (VII)(1)(a), (VII)(1)(b), (VII)(1)(c), (VIII)(1)(a), (VIII)(1)(b), (VIII)(1)(c), (VIII)(1)(d), (IX)(1)(a), (IX)(1)(b), (IX)(1)(c), (IX)(1)(d), (X)(1)(a), (X)(1)(b), (X)(1)(c), (X)(1)(d), (XI)(1)(a), (XI)(1)(b), (XI)(1)(c), (XI)(1)(d), (XIII)(2)(a), (XIII)(2)(b), (XIII)(3)(a), (XIII)(3)(b), (XIII)(4)(a), (XIII)(4)(b),(XIII) (5) (a), (XIII) (5) (b), (XIII) (5) (c), (XIII) (5) (d), (XIII) (6) (a), (XIII) (6) (b), (XIII) (6) (c), (XIII) (6) (d), (XIII) (6) (e), (XIII) (6) (f), (XIII) (7) (a), (XIII) (7) (b), (XIII) (7) (c), (XIII) (7) (d), (XIII) (7) (e), (XIII) (7) (f), (XIII) (8) (a), (XIII) (8) (b), (XIII) (8) (c), (XIII) (8) (d), (XIII) (8) (e), (XIII) (8) (f), A concentrated population of modified LPS molecular species according to any one of claims 1 to 3, selected from the group comprising the LPS molecular species and combinations thereof of (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), (XIII)(9)(j), wherein the R at the C6' position is a monosaccharide, oligosaccharide, or polysaccharide moiety containing a core oligosaccharide domain and optionally an antigen domain such as an O antigen domain and / or a capping antigen, and the X at the C1 position is an ethyl moiety.

5. The enriched population of modified LPS molecular species according to any one of claims 1 to 4, wherein the modified LPS molecular species form particles having an average size of less than approximately 200 nm in diameter, preferably less than approximately 150 nm, in an aqueous solution, so that they can be evaluated by dynamic light scattering (DLS) at 25°C.

6. A composition comprising an enriched population of modified LPS molecular species according to any one of claims 1 to 5.

7. The composition is i. A concentrated population comprising a mixture of at least two 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), preferably a mixture of six modified LPS molecular species, or ii. A concentrated population comprising a mixture of at least two modified LPS molecular species of formula (I)(2)(a), (I)(2)(b), and (I)(2)(c), preferably a mixture of three modified LPS molecular species, or iii. A concentrated population comprising a mixture of at least two modified LPS molecular species of formula (I)(3)(a), (I)(3)(b), and (I)(3)(c), preferably a mixture of three modified LPS molecular species, or iv. A mixture of at least two modified LPS molecular species of formula (I)(5)(a) and (I)(5)(b), preferably an enriched population containing a mixture of two modified LPS molecular species, or v. A mixture of at least two modified LPS molecular species of formula (I)(6)(a) and (I)(6)(b), preferably an enriched population containing a mixture of two modified LPS molecular species, or vi. A concentrated population comprising a mixture of at least two modified LPS molecular species of formula (I)(7)(a), (I)(7)(b), (I)(7)(c), and (I)(7)(d), preferably a mixture of four modified LPS molecular species, or vii. A concentrated population comprising a mixture of at least two modified LPS molecular species of formula (I)(8)(a), (I)(8)(b), and (I)(8)(c), preferably a mixture of three modified LPS molecular species, or viiii. A concentrated population comprising a mixture of at least two modified LPS molecular species of formula (I)(9)(a), (I)(9)(b), (I)(9)(c), (I)(9)(d), (I)(9)(e), and (I)(9)(f), preferably a mixture of six modified LPS molecular species, or ix. A concentrated population comprising a mixture of at least two modified LPS molecular species of formula (II)(2)(a), (II)(2)(b), (II)(2)(c), and (II)(2)(d), preferably a mixture of four modified LPS molecular species, or x. A concentrated population comprising a mixture of at least two modified LPS molecular species of formula (III)(1)(a), (III)(1)(b), (III)(1)(c), and (III)(1)(d), preferably a mixture of four modified LPS molecular species, or xi. A concentrated population comprising a mixture of at least two modified LPS molecular species of formula (IV)(1)(a), (IV)(1)(b), and (IV)(1)(c), preferably a mixture of three modified LPS molecular species, or xi. A concentrated population comprising a mixture of at least two modified LPS molecular species of formula (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), preferably a mixture of nine modified LPS molecular species, or xiiii. A concentrated population comprising a mixture of at least two 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), preferably a mixture of 10 modified LPS molecular species, or xiv. A concentrated population comprising a mixture of at least two modified LPS molecular species of formula (VI)(2)(a), (VI)(2)(b), and (VI)(2)(c), preferably a mixture of three modified LPS molecular species, or xv. A concentrated population comprising a mixture of at least two modified LPS molecular species of formula (VII)(1)(a), (VII)(1)(b), and (VII)(1)(c), preferably a mixture of three modified LPS molecular species, or xvi. A concentrated population comprising a mixture of at least two modified LPS molecular species of formula (VIII)(1)(a), (VIII)(1)(b), (VIII)(1)(c), and (VIII)(1)(d), preferably a mixture of four modified LPS molecular species, or xvii. A concentrated population comprising a mixture of at least two modified LPS molecular species of formula (IX)(1)(a), (IX)(1)(b), (IX)(1)(c), and (IX)(1)(d), preferably a mixture of four modified LPS molecular species, or xviiii. A concentrated population comprising a mixture of at least two modified LPS molecular species of formula (X)(1)(a), (X)(1)(b), (X)(1)(c), and (X)(1)(d), preferably a mixture of four modified LPS molecular species, or xix. A concentrated population comprising a mixture of at least two modified LPS molecular species of formula (XI)(1)(a), (XI)(1)(b), (XI)(1)(c), and (XI)(1)(d), preferably a mixture of four modified LPS molecular species, or xx. A mixture of at least two modified LPS molecular species of formula (XIII)(2)(a) and (XIII)(2)(b), preferably an enriched population containing a mixture of two modified LPS molecular species, or xxi. A mixture of at least two modified LPS molecular species of formula (XIII)(3)(a) and (XIII)(3)(b), preferably an enriched population containing a mixture of two modified LPS molecular species, or xxii. A mixture of at least two modified LPS molecular species of formula (XIII)(4)(a) and (XIII)(4)(b), preferably an enriched population containing a mixture of two modified LPS molecular species, or xxiii. A concentrated population comprising a mixture of at least two modified LPS molecular species of formula (XIII)(5)(a), (XIII)(5)(b), (XIII)(5)(c), and (XIII)(5)(d), preferably a mixture of four modified LPS molecular species, or xxiv. A mixture of at least two modified LPS molecular species of formula (XIII)(6)(a), (XIII)(6)(b), (XIII)(6)(c), (XIII)(6)(d), (XIII)(6)(e), and (XIII)(6)(f), preferably an enriched population containing a mixture of six modified LPS molecular species, or xxv. A mixture of at least two modified LPS molecular species of formula (XIII)(7)(a), (XIII)(7)(b), (XIII)(7)(c), (XIII)(7)(d), (XIII)(7)(e) and (XIII)(7)(f), preferably an enriched population comprising a mixture of six modified LPS molecular species, or xxvi. A concentrated population comprising a mixture of at least two modified LPS molecular species of formula (XIII)(8)(a), (XIII)(8)(b), (XIII)(8)(c), (XIII)(8)(d), (XIII)(8)(e) and (XIII)(8)(f), preferably a mixture of six modified LPS molecular species, or xxvii. A concentrated population comprising a mixture of at least two modified LPS molecular species of 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), preferably a mixture of 10 modified LPS molecular species. The composition according to claim 6, comprising:

8. The composition according to claim 6 or 7, which is a pharmaceutical composition or vaccine composition, further comprising at least one pharmaceutically acceptable excipient.

9. A concentrated population of naturally occurring, non-toxic LPS molecular species and / or modified LPS molecular species, or a composition containing the same, for use in subjects where it is needed to treat and / or prevent cancer, inflammatory diseases, or infectious diseases, The aforementioned concentrated population of naturally occurring non-toxic LPS molecular species and / or modified LPS molecular species, or a composition containing them, - A concentrated population of modified LPS molecular species according to any one of claims 1 to 5, or a composition according to any one of claims 6 to 8, - Two secondary Cs simultaneously present at the C2' and C3' positions of those lipid A domains １２ and / or C １４ LPS molecular species that do not contain fatty acid chains, A concentrated population of naturally occurring, non-toxic LPS molecular species and / or modified LPS molecular species selected from, or a composition containing the same.

10. A concentrated population of naturally occurring, non-toxic LPS molecular species and / or modified LPS molecular species, or a composition containing them, for use in subjects requiring the stimulation of an immune response, The aforementioned concentrated population of naturally occurring non-toxic LPS molecular species and / or modified LPS molecular species, or a composition containing them, - A concentrated population of modified LPS molecular species according to any one of claims 1 to 5, or a composition according to any one of claims 6 to 8, - Two secondary Cs simultaneously present at the C2' and C3' positions of those lipid A domains １２ and / or C １４ LPS molecular species that do not contain fatty acid chains, A concentrated population of naturally occurring, non-toxic LPS molecular species and / or modified LPS molecular species selected from, or a composition containing the same.

11. A concentrated population of naturally occurring, non-toxic LPS molecular species and / or modified LPS molecular species, or a composition containing the same, for use in subjects requiring vaccination, The aforementioned concentrated population of naturally occurring non-toxic LPS molecular species and / or modified LPS molecular species, or a composition containing them, - A concentrated population of modified LPS molecular species according to any one of claims 1 to 5, or a composition according to any one of claims 6 to 8, Two secondary carbon atoms are simultaneously present at the C2' and C3' positions of the lipid A domain. １２ and / or C １４ Selected from LPS molecular species that do not contain fatty acid chains, A concentrated population of naturally occurring non-toxic LPS molecular species and / or modified LPS molecular species, or a composition containing such species.

12. The LPS molecular species or composition - An LPS molecular species selected from the group including the LPS molecular species of formulas (I)(0)(a), (I)(0)(b), (II)(0), (II)(1)(a), (II)(1)(b), (II)(1)(c), and (II)(1)(d) shown in Figures 1, 5, and 6. - A mixture of LPS molecular species of formulas (I)(0)(a) and (I)(0)(b) shown in Figure 1, - A mixture of at least two LPS molecular species of formula (II)(0) shown in Figure 5, - A mixture of at least two LPS molecular species of formulas (II)(1)(a), (II)(1)(b), (II)(1)(c), and (II)(1)(d) shown in Figure 6, - A composition according to any one of claims 6 to 8, comprising 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), - A composition according to any one of claims 6 to 8, comprising a mixture of modified LPS molecular species of formula (I)(2)(a), (I)(2)(b), and (I)(2)(c), - A composition according to any one of claims 6 to 8, comprising 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), or - A composition according to any one of claims 6 to 8, comprising a mixture of modified LPS molecular species of formula (I)(8)(a), (I)(8)(b), and (I)(8)(c). A concentrated population of naturally occurring non-toxic LPS molecular species and / or modified LPS molecular species, selected from, for use according to any one of claims 9 to 11, or a composition comprising the same.

13. A naturally occurring non-toxic LPS molecular species and / or modified LPS molecular species, or a composition containing the same, for use according to claim 9 or 12, preferably comprising administering to the subject at least one additional therapeutic agent 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, for use according to claim 9 or 12.

14. The at least one additional therapeutic agent is a targeted therapeutic agent, preferably an anti-CD20 antibody or its antigen-binding fragment, a naturally occurring non-toxic LPS molecular species and / or a modified LPS molecular species for use according to claim 13, or a composition comprising the same.

15. The anti-CD20 antibody is rituximab or its antigen-binding fragment, the naturally occurring non-toxic LPS molecular species and / or the modified LPS molecular species for use according to claim 14, or a composition comprising the same.

16. The at least one additional therapeutic agent is an immunostimulant, preferably an immune checkpoint inhibitor, more preferably selected from the group consisting of CTLA4, PD-1, PD-L1, LAG-3, B7-H3, B7-H4, TIM3, A2AR, GITR, CD47, TNFR2, CD19, and IDO inhibitors, and most preferably the at least one additional therapeutic agent is a PD-1 inhibitor or a PD-L1 inhibitor, a naturally occurring non-toxic LPS molecular species and / or a modified LPS molecular species for use according to claim 13, or a composition comprising the same.

17. The immune checkpoint inhibitor is a PD-1 inhibitor, preferably an anti-PD-1 antibody or its antigen-binding fragment, a naturally occurring non-toxic LPS molecular species and / or a modified LPS molecular species for use according to claim 16, or a composition comprising the same.

18. A naturally occurring non-toxic LPS molecular species and / or a modified LPS molecular species, or a composition containing the same, for use according to any one of claims 10 to 12, further comprising vaccinating or stimulating an immune response in a subject requiring the same, preferably administering to the subject at least one antigen selected from the group consisting of pathogen-related antigens, autoantigens, allergen-related antigens and neoantigens.

19. The subject requiring the said is an animal other than a human, and the said naturally occurring non-toxic LPS molecular species and / or modified LPS molecular species, or a composition containing the said, is selected from the LPS molecular species of formula (XII)(1) shown in Figure 27, wherein the said naturally occurring non-toxic LPS molecular species and / or modified LPS molecular species, or a composition containing the said, for use according to any one of claims 9 to 18.

20. It is a parts kit, - A concentrated population of modified LPS molecular species according to any one of claims 1 to 5, a composition according to any one of claims 6 to 8, or two secondary Cs simultaneously present at the C2' and C3' positions of their lipid A domains １２ and / or C １４ LPS molecular species that do not contain fatty acid chains, - An additional therapeutic agent preferably selected from the group comprising chemotherapeutic agents, targeted therapy agents, cytotoxic agents, antibiotics, antiviral drugs, 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, A parts kit that includes this.

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