A new therapeutic approach for treating elevated lipoprotein (a)

Abstract

The present invention relates to compositions for reducing cardiovascular disease risk in a subject, comprising a potent reactive oxidized phospholipid (OXPL) scavenger in a therapeutically effective amount. The reactive OXPL scavenger selectively and efficiently modifies oxidized phospholipids, optionally including those on lipoprotein(a) particles circulating in the subject's bloodstream, thereby mitigating cardiovascular disease risk. The reactive OXPL scavenger includes at least one of 2-HOBA (2-hydroxybenzylamine), a potent analog of 2-HOBA, or a modified analog of 2-HOBA, with the modified analog featuring additional substituents covalently attached to enhance its efficacy. This composition offers a targeted approach to cardiovascular disease prevention by addressing the oxidative modification of phospholipids, a key factor in the pathogenesis of cardiovascular conditions.

Description

A NEW THERAPEUTIC APPROACH FOR TREATING ELEVATED LIPOPROTEIN (A)CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This disclosure claims priority to U.S. Provisional Patent App. No.: 63 / 649,919, filed 20-May-2024, the entire contents of which are hereby incorporated by reference.FIELD OF THE INVENTION

[0002] In some embodiments, the present invention relates to systems and methods for reducing cardiovascular disease risk in a subject, for example, by compositions targeting oxidized phospholipids (OxPLs).BACKGROUND OF THE INVENTION

[0003] Today, cardiovascular disease (CVD) is a leading cause of morbidity and mortality, despite all the dietary and medical progress achieved as regards to both prevention and treatment. Having high levels of lipoprotein(a) [Lp(a)] is a risk factor for cardiovascular disease that can operate independently of all other prognosis measurements. Having high levels of Lp(a) can increase the risk of developing cardiovascular disease even when LDL cholesterol (LDL-C) levels are within the recommended range, which is referred to as a residual cardiovascular risk. Lp(a) is an LDL-like particle present in human plasma, in which a large plasminogen-like glycoprotein, apolipoprotein(a) [Apo(a)], is covalently bound to Apo B100 by a disulfide bridge. Apo(a) contains one plasminogen-like kringle V structure, a variable number of plasminogen-like kringle IV structures (types 1-10), and one inactive protease region.

[0004] Lp(a) level is mainly controlled by a person’s genetics. Among a random sample of individual humans, there is a large variance of plasma concentrations of Lp(a), mainly attributed to genetic variants in the Lp(a) gene. It is found that in humans, Lp(a) levels can range from about <1 mg / dL to >1000 mg / dL. Concentrations can also vary between different ethnicities. Lp(a) has been established as one of the critical risk factors that play an important role in the development of atherosclerotic plaque.

[0005] In general, high concentrations of Lp(a) have been associated with a greater risk of heart failure, ischemic CVD, and aortic valve stenosis. The threshold value has been set at about 50 mg / dL, but the risk may increase already at levels above about 30 mg / dL. There is a well-established and strong link between high Lp(a) levels and coronary as well ascerebrovascular disease. Furthermore, lifestyle changes and standard lipid-lowering treatment are not effective in reducing Lp(a) levels. Currently, there is no Lp(a) lowering medications that are available. Therefore, there is an urgent need to develop new technologies to target the disease-causing effects of Lp(a) in humans, and novel methods for targeting oxidized phospholipids (OxPLs) are provided herein.BRIEF SUMMARY OF THE INVENTION

[0006] The following presents a simplified summary of the innovation in order to provide a basic understanding of some aspects of the invention. This summary is not an extensive overview of the invention. It is intended to neither identify key or critical elements of the invention nor delineate the scope of the invention. Its sole purpose is to present some concepts of the invention in a simplified form as a prelude to the more detailed description that is presented later.

[0007] In some embodiments, the technology disclosed herein introduces a novel therapeutic strategy focusing on the direct modification of Lp(a) particles to reduce their atherogenic and thrombogenic properties without necessarily altering their plasma concentration. The approach utilizes a targeted biochemical intervention that modifies the Oxidized Phospholipids (OxPLs) on Lp(a), effectively "detoxifying" the Lp(a) particles. This method employs a specific set of molecular agents that selectively react with the OxPLs, neutralizing their harmful effects and potentially transforming Lp(a) into a less harmful form. These set of molecular agents are called dicarbonyl scavengers, also referred to as reactive oxidized phospholipid scavengers below and herein.

[0008] In some embodiments, the technology herein can be presented as a novel composition for reducing cardiovascular disease risk using reactive oxidized phospholipid scavengers. The compositions solve a long-felt but unmet need in the face of repeated failure and experimentation of science, while human lives have been at stake in cardiovascular disease.

[0009] Previous approaches to reducing cardiovascular disease risk have primarily focused on managing traditional risk factors such as high blood pressure, high cholesterol, and smoking through lifestyle changes and pharmacological interventions. Statins, for example, have been widely used to lower low-density lipoprotein (LDL) cholesterol levels, thereby reducing the risk of cardiovascular events. However, while statins and other lipid-lowering agents have proven effective in many cases, they do not specifically target oxidizedphospholipids (OxPLs), which are increasingly recognized as significant contributors to cardiovascular disease. In recent years, research has highlighted the role of oxidized phospholipids in the pathogenesis of atherosclerosis and other cardiovascular conditions. OXPLs are known to promote inflammation, endothelial dysfunction and smooth muscle cells proliferation among many others, which are all key processes in the development of atherosclerotic plaques. In recent years, it has been increasingly recognized that there is a strong correlation between OxPLs and Lp(a). Biochemical studies indicate that 85% of the OxPLs detected in human plasma can be immunoprecipitated by an anti-apo(a) antibody (OxPL-apo(a)); thus, the detected OxPLs are most likely on Lp(a) (PMID: 18594118). The roles of OxPLs on Lp(a) have been increasingly recognized, possibly as a unifying factor for the atherothrombogenic properties of Lp(a) (PMID: 30675027.) More recently, studies showed that OxPLs, including these on Lp(a) but also these on other lipoproteins, showed a stronger association with prevalent CAD and major adverse cardiovascular events, suggesting targeting OxPLs could be a potential target for reducing residual risk in patients undergoing Lp(a)- lowering therapy (PMID 37137588).

[0010] Another approach has involved the use of lipoprotein(a) [Lp(a)] particle lowering therapies. To that front, some investigational approaches can lower Lp(a) by 90%, for example, with antisense oligonucleotide therapy (APO(a)-LRx, Pelacarsen), designed to reduce whole Lp(a) particle is currently under development. However, Lp(a) possibly offered an evolutionary advantage to humans by promoting the healing of wounds and the repair of tissue injuries. Markedly positive staining for Lp(a) was observed closer to the surface of the fibrous cap in the wound tissue. Lp(a) may also inhibit cancer growth and spread (PMID: 10700477. PMID: 9111234), thus, approaches directed at simply lowering who Lp(a) particle may fail due to unintended side effects. Instead of removing the Lp(a), our proposed research will investigate whether reducing the pathogenic component of Lp(a), the OxPLs, may provide an alternative therapeutic approach.

[0011] Considering the state of the art, none of these previous approaches have provided a comprehensive solution that combines the features and / or details now described in this disclosure. Various embodiments relate to a composition for reducing cardiovascular disease risk in a subject, comprising a potent reactive oxidized phospholipid (OXPL) scavenger in a therapeutically effective amount. The reactive OXPL scavenger selectively and efficiently modifies oxidized phospholipids, including those on lipoprotein(a) particles circulating in the subject's bloodstream, thereby reducing cardiovascular disease risk. The reactive OXPL scavenger may include 2-HOBA (2-hydroxybenzylamine), a potent analog of 2-HOBA, or amodified analog of 2-HOBA with additional substituents covalently attached to enhance its efficacy. The composition targets and neutralizes harmful oxidized phospholipids, offering a therapeutic approach to mitigate cardiovascular disease risk by addressing a key underlying factor in its pathogenesis.

[0012] Keeping in mind possible combination embodiments and the details disclosed below in the Detailed Description, as an additional brief summary or to provide discussion points for a brief summary, some example features of the technology disclosed herein can be briefly summarized by the following list of features, any of which can be inter-combined or discussed optionally with any other feature, Figure, Drawing, detail, embodiment, aspect, or example disclosed herein:

[0013] Feature 1 : A composition for reducing cardiovascular disease risk in a subject, the composition comprising: a potent reactive oxidized phospholipid (OXPL) scavenger in a therapeutically effective amount; wherein the reactive OXPL scavenger selectively and efficiently modifies an oxidized phospholipid and / or an oxidized phospholipid on a lipoprotein(a) particle circulating in the subject's bloodstream, thereby reducing the cardiovascular disease risk in the subject, and / or wherein the reactive OXPL scavenger comprises at least one of 2- HOBA (2-hydroxybenzylamine), a potent analog of 2-hydroxybenzylamine (2-HOBA), or a modified analog of 2-HOBA, the modified analog of 2-HOBA having additional substituents covalently attached to enhance its efficacy.

[0014] Feature 2: The composition of feature 1, wherein the reactivity of 2-HOBA is increased by modifying the electronic density on the aromatic ring in the 2-HOBA by introducing at least one of halides (e.g., Br, F, Cl, I) and alkyl groups at different positions on the aromatic ring, and wherein the half-life of the 2-HOBA is extended in humans by masking at least one of the hydroxyl group and the amino group on the 2-HOBA with at least one of an acyl group and a sulfonyl group to avoid immediate oxidation in a human; and optionally wherein the 2-HOBA chemical structures comprise one or more of: 2-fluoro-6-hydroxybenzylamine, 2-chloro-6- hydroxybenzylamine, 2-bromo-6-hydroxybenzylamine, 2-iodo-6-hydroxybenzylamine, 2-methyl- 6-hydroxybenzylamine, 2-ethyl-6-hydroxybenzylamine, 2-propyl-6-hydroxybenzylamine, 2-butyl- 6-hydroxybenzylamine, 2-pentyl-6-hydroxybenzylamine, 2-hexyl-6-hydroxybenzylamine, 2- heptyl-6-hydroxybenzylamine, 2-octyl-6-hydroxybenzylamine, 2-nonyl-6-hydroxybenzylamine, 2- decyl-6-hydroxybenzylamine, 2-fluoro-6-methyl-hydroxybenzylamine, 2-chloro-6-methyl- hydroxybenzylamine, 2-bromo-6-methyl-hydroxybenzylamine, 2-iodo-6-methyl- hydroxybenzylamine, 2-fluoro-6-ethyl-hydroxybenzylamine, 2-chloro-6-ethyl- hydroxybenzylamine, 2-bromo-6-ethyl-hydroxybenzylamine, 2-iodo-6-ethyl-hydroxybenzylamine, 2-fluoro-6-propyl-hydroxybenzylamine, 2-chloro-6-propyl- hydroxybenzylamine, 2-bromo-6-propyl-hydroxybenzylamine, 2-iodo-6-propyl- hydroxybenzylamine, 2-fluoro-6-butyl-hydroxybenzylamine, 2-chloro-6-butyl- hydroxybenzylamine, 2-bromo-6-butyl-hydroxybenzylamine, 2-iodo-6-butyl- hydroxybenzylamine, 2-fluoro-6-pentyl-hydroxybenzylamine, 2-chloro-6-pentyl- hydroxybenzylamine, 2-bromo-6-pentyl-hydroxybenzylamine, 2-iodo-6-pentyl- hydroxybenzylamine, 2-fluoro-6-hexyl-hydroxybenzylamine, 2-chloro-6-hexyl- hydroxybenzylamine, 2-bromo-6-hexyl-hydroxybenzylamine, 2-iodo-6-hexyl- hydroxybenzylamine, 2-fluoro-6-t-butyl-hydroxybenzylamine, 2-chloro-6-t-butyl- hydroxybenzylamine, 2-bromo-6-t-butyl-hydroxybenzylamine, 2-iodo-6-t-butyl- hydroxybenzylamine, 2-fluoro-6-i-propyl-hydroxybenzylamine, 2-chloro-6-i-propyl- hydroxybenzylamine, 2-bromo-6-i-propyl-hydroxybenzylamine, 2-iodo-6-i-propyl- hydroxybenzylamine, 2-fluoro-6-Boc-hydroxybenzylamine, 2-chloro-6-Boc-hydroxybenzylamine,2-bromo-6-Boc-hydroxybenzylamine, 2-iodo-6-Boc-hydroxybenzylamine, 2-fluoro-6-CD2CD3- hydroxybenzylamine, 2-chloro-6-CD2CD3-hydroxybenzylamine, 2-bromo-6-CD2CD3- hydroxybenzylamine, and / or 2-iodo-6-CD2CD3-hydroxybenzylamine.

[0015] Feature 3: The composition of feature 1 , wherein the composition comprises one or more of the following chemical structures:(formula 1), (formula 2),(formula 6), (formula 7),(formula 10), and / or (formula 11);

[0016] wherein any of formulas 1-11 can include a chemical moiety (or “moiety”) attached via covalent bond to any suitable atom; and / or a pro-drug thereof and / or a pharmaceutically acceptable salt, solvate or hydrate of any of these chemical compounds / structures of formulas 1-11 ; and wherein each of R, Ri, R2, and R3are independently selected from and / or each is / are independently comprising hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, t-butyl, i-propyl, Br, F, Cl, I, -Boc, and / or CD2CD3; and / or wherein each of R, R1, R2, and R3 are independently selected from and / or each is / are independently comprising C1-C4 alkyl, C1-C4 alkoxy, alkynoyl, C1-C4 alkylthiol, formyl, halogen, aryl, nitro, sulfanyl, hydrazino, amino, oxyamino, C1-C4 alkylamino, dialkylamino, or any combinations thereof; and / or wherein each occurrence of R, R1, R2, and R3each independently includes or is each independently comprising a combination of -H, -OH, carbonyl (=0), F, N, -O-, -S-, -NH-, a halogen, methyl (-CH3), f-butyl, -(CH2)n-CH3, wherein independentlyeach n= 0, 1 , 2, 3, 4, 5, 6, 7, 8, or 9; -O-(CH2)n-CH3, wherein independently each n= 0, 1 , 2, 3, 4, 5, 6, 7, 8, or 9; -S-(CH2)n-CH3, wherein independently each n= 0, 1 , 2, 3, 4, 5, 6, 7, 8, or 9; -NH- (CH2)n-CH3, wherein independently each n= 0, 1 , 2, 3, 4, 5, 6, 7, 8, or 9; and / or wherein each occurrence of R, i, R2, and R3is independently including a substituent shown below and / or wherein the optional moiety includes a substituent shown below:

[0017] wherein each independent occurrence ofis a linker to any one suitable atom (e.g., C, N, O, S) of the “formula 1-11” shown above and represents an attachment to an atom as indicated in any formula above and includes or is a combination of a single bond (-), a bond to a nitrogen, a bond to a carbon, a bond to an oxygen (-O-), a double bond ( = ), a triple bond ( = ) or (-C2H2-), a bond to C-C, a bond to C-N, -(CH2)n-, wherein independently each n= 0, 1 , 2, 3, 4, 5, 6, 7, 8, or 9; or a combination thereof; and wherein eachoccurrence of R, Ri, R2, and / or R3each independently can represent R-R, R1-R1, R2-R2, and R3- R3; wherein each occurrence is independent of another occurrence and linked by a bond or by another linkerto any atom of the other; wherein each independent occurrence of L is a halogen including bromine, iodine, chlorine, or fluorine; and / or the step of administering a pharmaceutically acceptable salt thereof of any of the small molecules described above; and includes and / or the step of administering a pharmaceutically acceptable hydrate or solvate thereof, either with or without a salt form; and / or wherein any of R, Ri, R2, and / or R3and / or wherein any of formulas 1-11 each independently can include the moiety that imparts both lipophilic and lipophobic properties — enhancing affinity for lipoproteins while limiting a cell entry; wherein the moiety keeps the compound of formula 1-11 confined to circulation and reduces potential off-target effects.

[0018] Feature 4: The composition of feature 3, wherein the chemical structures comprise one or more of the following chemical structures:

[0019] and / or a prodrug thereof and / or a pharmaceutically acceptable salt, solvate or hydrate of any of these chemical structures.

[0020] Feature 5: A method for reducing cardiovascular disease risk in a subject, the method comprising: administering to the subject a therapeutically effective amount of at least one of a potent reactive OXPL (oxidized phospholipid) scavenger; wherein the at least one of the reactive OXPL scavenger is configured to selectively modify a oxidized phospholipid on a lipoprotein(a) particle circulating in the subject's bloodstream, thereby efficiently detoxifying the lipoprotein(a) and significantly reducing the cardiovascular disease risk in the subject.

[0021] Feature 6: The method of feature 5, wherein the administration is continued for an optimal period of at least 4 weeks to 12 months to ensure sustained reduction in cardiovascular disease risk and / or wherein the at least one of a potent reactive OXPL scavenger is configured to target an oxidized phospholipids including but not limited oxidized phosphatidylcholine, phosphatidylethanolamine, phosphatidic acid, phosphatidylserine, phosphoinositides and other types of phospholipids that containing a reactive aldehydesincluding but not limited to these with dicarbonyls, and / or optionally wherein the oxidized phospholipids containing a reactive dicarbonyl, for example, the following (dicarbonyl) chemical structures:highly reactive isolevuglandins (isoLG).

[0022] Feature 7: The method of feature 5, wherein the therapeutically effective amount is between 0.1 mg to 5000 mg per day and / or wherein the therapeutically effective amount is based on an individual response of the subject and / or a tolerability of the subject.

[0023] Feature 8: The method of feature 5, wherein the reactive OXPL scavenger comprises at least one of 2-HOBA (2-hydroxybenzylamine), a potent analog of 2- hydroxybenzylamine (2-HOBA), a modified analog of 2-HOBA wherein additional substituents have been covalently attached to enhance its efficacy, and / or one or more of the following chemical structures:(formula 10), and / or (formula 11);

[0024] and / or a pro-drug thereof and / or a pharmaceutically acceptable salt, solvate or hydrate of any of these chemical compounds / structures; and wherein each of R, Ri, R2, and R3are independently selected from and / or are independently comprising hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, t-butyl, i-propyl, Br, F, Cl, I, -Boc, and / or CD2CD3.; and / or wherein each of each of R, Ri, R2, and R3are as is described in feature 3 above.

[0025] Feature 9: The method of feature 5, wherein the reactive OxPL scavenger is configured to selectively bind to and neutralize the reactive dicarbonyl moiety on the oxidized phospholipid, thereby preventing its effects on the vascular endothelium and reducing the overall atherogenicity of the lipoprotein(a) particle.

[0026] Feature 10: The method of feature 5, wherein the reactive OxPL scavenger is configured to reduce the oxidative stress and inflammation in the vascular wall by scavenging reactive oxygen species and dicarbonyls, thereby improving endothelial function and reducing the risk of atherosclerotic plaque formation and progression.

[0027] Feature 11 : The method of feature 5, wherein the reactive OxPL scavenger is configured to inhibit the formation and accumulation of advanced glycation end products (AGEs) in the vascular tissue by trapping and neutralizing reactive dicarbonyls, thereby reducing the AGE-mediated cross-linking of collagen and stiffening of the arteries.

[0028] Feature 12: The method of feature 10, wherein the chemical structures comprise one or more of the following chemical structures:

[0029] and / or a prodrug thereof and / or a pharmaceutically acceptable salt, solvate or hydrate of any of these chemical structures.

[0030] Feature 13: The method of feature 8, wherein the reactive dicarbonyls or the oxidized phosphatidylcholine comprises a highly specific "OxPCCD36" class of oxidized phospholipids that is operative to potently promote platelet activation via the scavenger receptor CD36.

[0031] Feature 14: The method of feature 13, wherein the therapeutically effective amount is based on the binding affinity and specificity of the "OxPCCD36" class to CD36 receptor and / or wherein the therapeutically effective amount is between 0.1 mg to 5000 mg per day.

[0032] Feature 15: The method of feature 13, wherein the "OxPCCD36" class comprises a specific chemical structure comprising 1-palmitoyl-2-(5-hydroxy-8-oxooct-6-enoyl)-sn-glycero- 3-phosphocholine (PHOdiA-PC), 1-palmitoyl-2-(5-hydroxy-8,11-dioxododec-6,9-dienoyl)-sn-glycero-3-phosphocholine (PHDdiA-PC), 1-palmitoyl-2-(5-hydroxy-8-oxooct-6-enoyl)-sn-glycero- 3-phosphocholine (PHOOA-PC), 1-palmitoyl-2-(5-hydroxy-8-oxodec-6-enoyl)-sn-glycero-3- phosphocholine (PHODA-PC), 1-palmitoyl-2-(5-keto-6-octenedioyl)-sn-glycero-3- phosphocholine (PKOdiA-PC), 1-palmitoyl-2-(5-keto-8,11-dioxododec-6,9-dienoyl)-sn-glycero-3- phosphocholine (PKDdiA-PC), 1-palmitoyl-2-(5-keto-8-oxooct-6-enoyl)-sn-glycero-3- phosphocholine (PKOOA-PC), 1-palmitoyl-2-(5-keto-8-oxodec-6-enoyl)-sn-glycero-3- phosphocholine (PKODA-PC), 1-palmitoyl-2-(4-oxobutyroyl)-sn-glycero-3-phosphocholine, 1- palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine, 1-palmitoyl-2-(6-oxohexanoyl)-sn- glycero-3-phosphocholine, 1-palmitoyl-2-(7-oxoheptanoyl)-sn-glycero-3-phosphocholine, 1- palmitoyl-2-(8-oxooctanoyl)-sn-glycero-3-phosphocholine, 1-palmitoyl-2-(9-oxononanoyl)-sn- glycero-3-phosphocholine, 1-palmitoyl-2-(10-oxodecanoyl)-sn-glycero-3-phosphocholine, 1- palmitoyl-2-(11-oxoundecanoyl)-sn-glycero-3-phosphocholine, 1-palmitoyl-2-(12- oxododecanoyl)-sn-glycero-3-phosphocholine, and / or 1-palmitoyl-2-(13-oxotridecanoyl)-sn- glycero-3-phosphocholine, and / or comprises one or more of the chemical structures shown below:

[0033] Feature 16: The method of feature 15, wherein the therapeutically effective amount is based on a relative potency of each specific chemical structure in the "OxPCCD36" class.

[0034] Feature 17: The method of feature 8, wherein the dicarbonyl scavenger is selected from the group consisting of aminoguanidine, hydralazine, pyridoxamine, and 2,3-diaminophenazine, which are configured to efficiently trap and neutralize reactive dicarbonyl species.

[0035] Feature 18: The method of feature 17, wherein the therapeutically effective amount is between 0.1 mg to 10 g per day.

[0036] Feature 19: The method of feature 8, wherein the oxidized phospholipid comprises a phosphatidylcholine, or phosphatidylethanolamine, or phosphatidic acid, phosphatidylserine, or phosphoinositides and / or other types of phospholipids that having a sn-2 acyl group that includes a highly reactive aldehyde moiety and / or a highly reactive dicarbonyl moiety.

[0037] Feature 20: The method of feature 19, wherein the oxidized phosphatidylcholine comprises 1-palmitoyl-2-(4-oxo-pentanoyl)-sn-glycero-3-phosphocholine (POVPC), 1-palmitoyl- 2-glutaryl-sn-glycero-3-phosphocholine (PGPC), 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3- phosphocholine (PONPC), 1-palmitoyl-2-(9-oxononanoyl)-sn-glycero-3-phosphocholine (PAzPC), 1-palmitoyl-2-azelaoyl-sn-glycero-3-phosphocholine (PAzPC), 1-palmitoyl-2-(4- oxobutanoyl)-sn-glycero-3-phosphocholine, 1-palmitoyl-2-(5-oxopentanoyl)-sn-glycero-3- phosphocholine, 1-palmitoyl-2-(6-oxohexanoyl)-sn-glycero-3-phosphocholine, 1-palmitoyl-2-(7- oxoheptanoyl)-sn-glycero-3-phosphocholine, 1-palmitoyl-2-(8-oxooctanoyl)-sn-glycero-3- phosphocholine, 1-palmitoyl-2-(10-oxodecanoyl)-sn-glycero-3-phosphocholine, 1-palmitoyl-2- (11-oxoundecanoyl)-sn-glycero-3-phosphocholine, 1-palmitoyl-2-(12-oxododecanoyl)-sn- glycero-3-phosphocholine, 1-palmitoyl-2-(13-oxotridecanoyl)-sn-glycero-3-phosphocholine, 1- palmitoyl-2-(5-hydroxy-8-oxooct-6-enoyl)-sn-glycero-3-phosphocholine (PHOdiA-PC), 1- palmitoyl-2-(5-hydroxy-8,11-dioxododec-6,9-dienoyl)-sn-glycero-3-phosphocholine (PHDdiA- PC), 1-palmitoyl-2-(5-hydroxy-8-oxooct-6-enoyl)-sn-glycero-3-phosphocholine (PHOOA-PC), 1- palmitoyl-2-(5-hydroxy-8-oxodec-6-enoyl)-sn-glycero-3-phosphocholine (PHODA-PC), 1- palmitoyl-2-(5-keto-6-octenedioyl)-sn-glycero-3-phosphocholine (PKOdiA-PC), 1-palmitoyl-2-(5- keto-8,11-dioxododec-6,9-dienoyl)-sn-glycero-3-phosphocholine (PKDdiA-PC), 1-palmitoyl-2-(5- keto-8-oxooct-6-enoyl)-sn-glycero-3-phosphocholine (PKOOA-PC), and / or 1-palmitoyl-2-(5- keto-8-oxodec-6-enoyl)-sn-glycero-3-phosphocholine (PKODA-PC).

[0038] Feature 21 : The method of feature 19, wherein the dicarbonyl moiety in the sn-2 acyl group is selected from the group consisting of methylglyoxal, glyoxal, diacetyl, and 3- deoxyglucosone, which are configured to be highly reactive and pro-inflammatory.

[0039] Feature 22: The method of feature 21 , wherein the dicarbonyl moiety is selected from the group consisting of 1 ,2-cyclohexanedione, glutaraldehyde, 2,3-pentanedione, 2,3- hexanedione, 2,3-heptanedione, 2,3-octanedione, 2,3-nonanedione, 2,3-decanedione, 2,3-undecanedione, 2,3-dodecanedione, 2,3-tridecanedione, 2,3-tetradecanedione, 2,3- pentadecanedione, and 2,3-hexadecanedione.

[0040] Feature 23: The method of feature 8, wherein the oxidized phospholipid includes a phosphatidylcholine, or phosphatidylethanolamine, or phosphatidic acid, phosphatidylserine, or phosphoinositides and / or other types of phospholipids molecules having an sn-2 acyl group that includes a highly reactive aldehyde or an a,p-unsaturated carbonyl group.

[0041] Feature 24: The method of feature 23, wherein the oxidized phospholipid is selected from the group consisting of 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC), 1-palmitoyl-2-glutaryl-sn-glycero-3-phosphocholine (PGPC), 1-palmitoyl-2-(5- hydroxy-8-oxo-6-octenoyl)-sn-glycero-3-phosphocholine (HOOA-PC), 1-palmitoyl-2-(5-keto-6- octene-dioyl)-sn-glycero-3-phosphocholine (KOdiA-PC), 1-palmitoyl-2-(4-oxobutyroyl)-sn- glycero-3-phosphocholine, 1-palmitoyl-2-(9-oxononanoyl)-sn-glycero-3-phosphocholine, 1- palmitoyl-2-(5-hydroxy-10-oxo-6,8-decadienoyl)-sn-glycero-3-phosphocholine, 1-palmitoyl-2-(5- hydroxy-8-oxo-6-octenoyl)-sn-glycero-3-phosphocholine, 1-palmitoyl-2-(5-hydroxy-11-oxo- 6,8,10-undecatrienoyl)-sn-glycero-3-phosphocholine, 1-palmitoyl-2-(5-hydroxy-12-oxo-6,8,10- dodecatrienoyl)-sn-glycero-3-phosphocholine, and 1-palmitoyl-2-(8-hydroxy-11-oxo-9- undecenoyl)-sn-glycero-3-phosphocholine.

[0042] Feature 25: The method of feature 8, wherein the lipoprotein(a) particle comprises apolipoprotein(a) covalently linked to apolipoprotein B-100 of a low-density lipoprotein (LDL) particle, forming a highly atherogenic lipoprotein species.

[0043] Feature 26: The method of feature 25, wherein the therapeutically effective amount is configured to reduce the plasma concentration of reactive OXPLs on lipoprotein(a) by at least 5% to 95%, which is considered clinically significant in reducing cardiovascular risk.

[0044] Feature 27: The method of feature 8, wherein the therapeutically effective amount of the at least one of the reactive OXPL scavenger is administered through the most efficient and tolerable route, such as orally, intravenously, subcutaneously, or intramuscularly.

[0045] Feature 28: The method of feature 27, wherein the administration is continued for an optimal period of at least 4 weeks to 12 months to ensure steady-state plasma concentrations and sustained therapeutic efficacy.

[0046] Feature 29: The method of feature 8, wherein the cardiovascular disease is selected from the group consisting of atherosclerosis, coronary artery disease, aortic valve stenosis, peripheral artery disease, and cerebrovascular disease, which are configured to be strongly associated with elevated lipoprotein(a) levels.

[0047] Feature 30: The method of feature 29, wherein the administration is continued for an optimal period of at least 12 weeks to 60 months to ensure significant regression of atherosclerotic plaques and reduction in cardiovascular events.

[0048] Feature 31: The method of feature 8, wherein administering the therapeutically effective amount of the at least one of the OxPL scavenger is configured to consistently reduce plasma OxPL concentration on lipoprotein(a) in the subject by at least 5% to 95% after 12 weeks to 12 months of administration, which is considered a clinically meaningful and sustainable response; and or the method of feature 8, wherein the administering is configured to provide the OxPL scavenger to reduce OxPL on lipoproteins beyond and / or in addition to lipoprotein (a).

[0049] Feature 32: A method for effectively detoxifying lipoprotein(a) in a subject, the method comprising: administering to the subject a therapeutically effective amount of at least one of a potent OxPL scavenger; wherein the at least one of the OxPL scavenger is configured to selectively modify adeleterious and / or a pro-inflammatory oxidized phospholipid on the lipoprotein(a) particle circulating in the subject's bloodstream, thereby efficiently detoxifying the lipoprotein(a) and rendering it less atherogenic.

[0050] Feature 33: The method of feature 32, wherein the administration is continued for an optimal period of at least 4 weeks to 12 months to ensure sustained detoxification of lipoprotein(a) particles.

[0051] Feature 34: The method of feature 32, wherein the therapeutically effective amount is between 0.1 mg to 5 g per day based on the subject's individual response and tolerability.

[0052] Feature 35: The method of feature 32, wherein the dicarbonyl scavenger or the oxidized phosphatidylcholine comprises at least one of 2-HOBA (2-hydroxybenzylamine), a potent analog of 2-hydroxybenzylamine (2-HOBA), a modified analog of 2-HOBA wherein additional substituents have been covalently attached to enhance its efficacy, or a pharmaceutically acceptable salt, solvate or hydrate of any of these chemical compounds, and wherein the dicarbonyl or the oxidized phosphatidylcholine comprises a highly specific "OxPCCD36" class of oxidized phospholipids that is operative to potently promote platelet activation via the scavenger receptor CD36, and wherein the "OxPCCD36" class comprises a specific chemical structure comprising PHODiA-PC, PHDdiA-PC, PHOOA-PC, PHODA-PC, PKOdiA-PC, PKDdiA-PC, PKOOA-PC, and / or PKODA-PC, which are configured to strongly interact with CD36 receptor.

[0053] Feature 36: The method of feature 35, wherein the therapeutically effective amount is between 0.1 mg to 5 g per day, based on the relative potency and specificity of the "OxPCCD36" class and its individual chemical components.

[0054] Feature 37: The method of feature 32, wherein the oxidized phospholipids containing the reactive aldehyde and dicarbonyl comprises a phospholipids molecule having a sn-2 acyl group that includes a highly reactive aldehyde and dicarbonyl moiety.

[0055] Feature 38: The method of feature 37, wherein the therapeutically effective amount is between 0.1 mg to 5 g per day, based on the relative reactivity and specificity of the aldehyde and dicarbonyl-containing phospholipids.

[0056] Feature 39: The method of feature 38, wherein the dicarbonyl moiety in the sn-2 acyl group is selected from the group consisting of methylglyoxal, glyoxal, diacetyl, and 3- deoxyglucosone, which are configured to be highly reactive and pro-inflammatory.

[0057] Feature 40: The method of feature 39, wherein the therapeutically effective amount is between 0.1 mg to 5 g per day, based on the relative potency and stability of each specific dicarbonyl moiety.

[0058] Feature 41: The method of feature 32, wherein the oxidized phospholipid is a phospholipid molecule having an sn-2 acyl group that includes a highly reactive aldehyde or an a, p- unsaturated carbonyl group.

[0059] Feature 42: The method of feature 41 , wherein the therapeutically effective amount is between 0.1 mg to 5 g per day, based on the relative reactivity and specificity of the aldehyde or a,[3-unsaturated carbonyl-containing phospholipids

[0060] Feature 43: The method of feature 32, wherein the lipoprotein(a) particle comprises apolipoprotein(a) covalently linked to apolipoprotein B-100 of a low-density lipoprotein (LDL) particle, forming a highly atherogenic lipoprotein species, and / or wherein the therapeutically effective amount is configured to reduce the plasma concentration of OxPL on lipoprotein(a) by at least 5% to 95%, which is considered clinically significant in reducing its atherogenicity.

[0061] Feature 44: The method of feature 32, wherein the therapeutically effective amount of at least one of the OxPL scavenger is administered through the most efficient and tolerable route, such as orally, intravenously, subcutaneously, or intramuscularly.

[0062] Feature 45: The method of feature 44, wherein the administration is continued for an optimal period of at least 8 weeks to 6 months to ensure steady-state plasma concentrations and sustained therapeutic efficacy in detoxifying lipoprotein(a) particles.

[0063] Feature 46: The method of feature 32, wherein the subject has a significantly elevated plasma concentration of lipoprotein(a) of at least 30 mg / dL to 1000 mg / dL, which is considered a high-risk threshold for cardiovascular disease; and / or wherein the lipoprotein (a) concentration does not change because the method is configured to only target the OxPLs (and / or a different lipoprotein).

[0064] Feature 47: The method of feature 32, wherein administering the therapeutically effective amount of at least one of the OxPL scavengers configured to consistently reduce plasma the concentration of OxPL on lipoprotein(a) in the subject by at least 5% to 95% after 12 weeks to 12 months of administration, which is considered a clinically meaningful and sustainable response in detoxifying lipoprotein(a) particles.

[0065] Feature 48: The method of feature 32, wherein effectively detoxifying the lipoprotein(a) particles is configured to significantly reduce the risk of cardiovascular disease in the subject by at least 5% to 50% after 12 weeks to 60 months of administration, which is considered a clinically meaningful and sustainable outcome.

[0066] Feature 49: A system for effectively reducing cardiovascular disease or its risk in a subject, the system comprising: (1) a precise measurement of lipoprotein (a) [Lp(a)] level in the subject that is configured to specifically quantify the content of oxidized phospholipids (OxPLs) on Lp(a) particles, wherein the measurement is performed using a highly sensitive and specific immunoassay or a state-of-the-art mass spectrometry-based assay; and (2) an optimized administering of a potent therapeutic agent configured to selectively modify the OxPLs such that the Lp(a) particles include significantly less OxPLs, wherein the therapeutic agent is at least one of a rationally designed OxPL scavenger and wherein the therapeutic agent is administered in a therapeutically effective amount between 0.1 mg to 5 g per day based on the subject's individual response and tolerability; wherein the administering in (2) is precisely modulated in extent and duration by the measurement in (1), so that a personalized automated feedback system is provided for each subject, and wherein the administering is continued for an optimal period of at least 4 weeks to 12 months to ensure sustained reduction in cardiovascular risk.

[0067] Feature 50: The system of feature 49, wherein the system is provided in a convenient wearable configuration, a wearable configuration with secure wireless communication, or an implantable configuration for long-term use, and wherein the measurement and the administering are performed automatically by the system based on a predetermined schedule or based on a real-time feedback from the measurement, ensuring a fully personalized and optimized therapy for each subject.

[0068] Feature 51 : The method of feature 32, wherein the reactive OxPL scavenger is configured to bind to and sequester the oxidized phospholipid on the lipoprotein(a) particle and other lipoproteins, thereby preventing their recognition and uptake by scavenger receptors on macrophages and foam cells in the atherosclerotic plaque.

[0069] Feature 52: The method of feature 32, wherein the reactive OxPL scavenger is configured to reduce the oxidative modification of the apolipoprotein(a) component of the lipoprotein(a) particle, thereby preserving its structural integrity and reducing its atherogenic potential.

[0070] Feature 53: The method of feature 32, wherein the reactive OxPL scavenger is configured to inhibit the lipoprotein(a)-mediated activation of platelet aggregation and thrombosis by neutralizing the oxidized phospholipids that promote these processes via the scavenger receptor CD36.

[0071] Feature 54: The method of feature 32, wherein the reactive OxPL scavenger is configured to reduce the lipoprotein(a)-induced expression of adhesion molecules and inflammatory cytokines in the vascular endothelium by scavenging the reactive dicarbonyl moieties that trigger these responses.

[0072] Feature 55: any feature above or any example or detail below, wherein each of R, Ri, R2, and Ra is as is described in feature 3 above; and / or wherein formula 1-11 includes a moiety as described in feature 3.

[0073] Feature 56: any feature above or any example and / or detail below wherein formula 1-11 is contained in, bound with or associated with a lipid particle or a lipid nanoparticle (LNP), for example, a liposome for drug delivery, wherein the liposome can be multilamellar large (MLV), oligolamellar (OLV), small unilamellar (SUV), medium-sized unilamellar (MUV), large unilamellar (LUV), giant unilamellar (GUV) and / or multivesicular vesicles (MW); and / or any feature wherein an antibody drug conjugate (ADC) is implemented with the feature; in some embodiments, the ADC is an anti-lipoprotein(a) antibody drug conjugate.

[0074] In some embodiments, a pharmaceutical composition comprising a therapeutically effective amount of any combination of the formulas 1-11 , in any of the features / configurations described above, or any part of or any one of the details and / or examples below, is provided. The pharmaceutical composition can be wherein the pharmaceutical composition is formulated for oral administration, parenteral administration, or administration via implanted reservoir. In some embodiments, the pharmaceutical composition is wherein the pharmaceutical composition is formulated for subcutaneous injection, intravenous injection, intraperitoneal injection, or intramuscular injection.

[0075] According to some aspects, a method of preventing cardiovascular disease in a subject in need thereof is disclosed, the method comprising administering to the subject, a therapeutically effective amount of the compositions disclosed herein.

[0076] These compounds (e.g., formulas 1-11 as described in feature 3) can be used alone or with linkers, targeting and / or ADCs discussed more below. In some embodiments, the above-described compounds of formula 1-11 are attached to a targeting moiety. In some embodiments, the targeting moiety is an antibody with affinity for a specific type of cell or a specific type of particle (e.g., a specific type of lipid particle). While keeping in mind that any of the above examples, or any part of the above examples / features can be combined with any part of any aspect or any part of any embodiment now disclosed below, other implementations are also described and recited herein. These and other features and advantages will be apparent from a reading of the following detailed description and a review of the associated drawings. It is to be understood that both the foregoing general description and the following detailed description are explanatory only and are not restrictive of aspects as claimed.BRIEF DESCRIPTION OF THE DRAWINGS

[0077] For the purpose of illustration, certain embodiments of the present invention are shown in the drawings described below. It should be understood, however, that the invention is not limited to the precise arrangements, dimensions, and instruments shown. In the drawings:

[0078] FIG. 1 shows exemplary structures of OXPCCD36. The oval (e.g., ellipse) shows an example of a reactive dicarbonyl moiety.

[0079] FIG. 2A illustrates an example of how reactive dicarbonyls like KOOA-PC react with the e-amino group of lysine residues of proteins to form a covalent adduct, thus changing protein structure and function. 2-HOBA provides a nucleophilic amine group that likewise reacts with dicarbonyls but at a much faster rate than lysine, yielding a stable adduct. Thus, 2-HOBA scavenges reactive dicarbonyls and protects protein lysine residues from covalent modification.

[0080] FIG. 2B shows other examples of reactive dicarbonyls are MDA (malondialdehyde), ONE (4-oxo-2E-nonenal), or the isolevuglandins (isoLG).

[0081] FIG. 3 shows a flow diagram illustrating a method with optional feedback system for reducing cardiovascular disease risk in a subject by administering a therapeutic agent (e.g., dicarbonyl scavenger as in feature 3 above) as disclosed herein with an optional feedback loop designed to monitor harmful Lp(a) levels and neutralize by administering more agent when needed.

[0082] FIG. 4 shows a general flowchart illustrating a method 110 for treating a subject (Example 1).

[0083] FIG. 5. Illustrates how hemostasis describes the balance of coagulation (clotting) and fibrinolysis (bleeding). To remove fibrin clot (plaque), tPA can convert plasminogen into plasmin. Then plasmin will further degrade the fibrin network to release FDPs. Plasminogen activation requires binding to fibrin, and oxidized Lp(a) has the potential to compete with plasminogen in binding to fibrin. Therefore, oxidized Lp(a) may slow down fibrinolysis. In FIG. 5, tPA, tissue plasminogen activator; FDP, fibrin degradation product; Lp(a), lipoprotein(a); RBC, red blood cell.

[0084] FIG. 6. illustrates how kinetics of plasmin formation as a function of plasminogen concentration. Different concentrations of plasminogen (0-1,000 nM) were activated by tPA, and plasmin generation was measured using chromogenic substrate S-2302. The linear regression (R2=0.9913) indicates a strong correlation between plasminogen concentration and the initial rate of plasmin formation (Vmax), validating the assay for studying plasminogen activation in the presence of Lp(a) and oxidized Lp(a). In FIG. 6, tPA, tissue plasminogen activator;

[0085] FIG. 7. illustrates how kinetics of the plasminogen activation reaction in the absence or presence of Lp(a). Specifically, +Lp(a) represents reaction with the presence of Lp(a); -Lp(a) represents reaction with the absence of Lp(a). The fibrinolysis reaction components were added sequentially with fibrinogen (200 pg / mL), alpha-ll a (50 nM), hirudin (250 nM), Lp(a) (0.2 pM, where needed), glu-plasminogen (500 nM), tPA (1 nM), and S-2302 (2mM), and incubated at 37°C for 4 hours. Recording of OD450 was started every 30 seconds when S-2302 was added. The experiment was performed in triplicates. In FIG. 7, Lp(a), lipoprotein(a); tPA, tissue plasminogen activator; OD, optical density.

[0086] FIGs. 8A and 8B show kinetics of plasminogen activation in the presence of unoxidized Lp(a) (A) and oxidized Lp(a) (B). Fibrin clots were formed as described, and Lp(a) or oxidized Lp(a) (0.5 pM) was added. (B) Oxidized Lp(a) reduced the overall plasmin generation rate, causing a plateau at 30-40 minutes (red or grey arrow) and exhibiting a unique inhibitory dip in plasmin concentration (red or grey circle), likely due to competition with fibrin fragments and plasminogen; Lp(a) = lipoprotein(a); OD = optical density.

[0087] FIG. 9 shows an example chemical structure of 2-Hydroxybenzylamine.

[0088] FIG. 10 shows example chemical structures of 2-Hydroxybenzylamine analogs.

[0089] FIG. 11 A shows an example synthetic scheme (Scheme 1) for a selection of 2- Hydroxybenzylamine analogs. FIG. 11B shows example chemical structures of 2- Hydroxybenzylamine analogs.

[0090] FIG. 12 shows an example synthetic scheme (Scheme 2) for 2- Hydroxybenzylamine analogs.

[0091] FIG. 13 shows three plots of LPS-induced cytokine mRNA expression in macrophages following exposure to native and oxidized lipoprotein(a).

[0092] FIG. 14 shows cell count and representative brightfield images of Aortic Smooth Muscle Cells (ASMCs) treated with vehicle, Lp(a) (200 pg / mL), oxLp(a) (200 pg / mL), or oxLp(a) in combination with 2-HOBA treatment.

[0093] FIG. 15A shows representative LC-MS / MS chromatograms showing detection of IsoLG-lysine adducts in Lp(a) and oxLp(a) samples. IsoLG was detectable in both Lp(a) and oxLp(a), with significantly higher levels in oxLp(a) compared to native Lp(a).

[0094] FIG. 15B shows quantification of IsoLG-lys intensity demonstrates a reduction in signal following treatment with 2-HOBA at both low and high concentrations. Data represent mean ± SEM; p values from one-way ANOVA with multiple comparisons are indicated.

[0095] FIGs. 16A-16B show other non-limiting examples of oxidized phospholipids, modification of proteins and enzymatic hydrolysis (Boffa & Koschinsky, 2019).

[0096] It should be understood that perhaps different numbers / numbering can / are / is sometimes used in some of the figures above to describe different embodiments and different aspects of the technology, any number from any figure can be inter-combined with a numbered aspect from any other figures. All trademarks, images, likenesses, words, and depictions in the drawings and the disclosure are plainly in fair use and are provided solely for the purposes of illustration of the invention in view of an urgent need to treat subjects as further discussed in detail below.DETAILED DESCRIPTION OF THE INVENTION

[0097] The subject innovation is now described with reference to the drawings, wherein like reference numerals are used to refer to like elements throughout. In the following description, for purposes of explanation, numerous specific details are set forth in order to provide a thorough understanding of the present invention. It may be evident, however, that the present invention may be practiced without these specific details. In other instances, well-known structures and devices are shown in block diagram form in order to facilitate describing the present invention. It is to be appreciated that certain aspects, modes, embodiments, variationsand features of the invention are described below in various levels of detail in order to provide a substantial understanding of the present invention.DEFINITIONS

[0098] For convenience, the meaning of some terms and phrases used in the specification, examples, and appended claims, are provided below. Unless stated otherwise, or implicit from context, the following terms and phrases include the meanings provided below. The definitions are provided to aid in describing particular embodiments, and are not intended to limit the claimed invention, because the scope of the invention is limited only by the claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. If there is an apparent discrepancy between the usage of a term in the art and its definition provided herein, the definition provided within the specification shall prevail.

[0099] As used in this specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the content clearly dictates otherwise. For example, reference to "a cell" includes a combination of two or more cells, and the like.

[0100] As used herein, the term "approximately" or "about" in reference to a value or parameter are generally taken to include numbers that fall within a range of 5%, 10%, 15%, or 20% in either direction (greater than or less than) of the number unless otherwise stated or otherwise evident from the context (except where such number would be less than 0% or exceed 100% of a possible value). As used herein, reference to "approximately" or "about" a value or parameter includes (and describes) embodiments that are directed to that value or parameter. For example, description referring to "about X" includes description of "X".

[0101] As used herein, the term “or” means “and / or.” The term "and / or" as used in a phrase such as "A and / or B" herein is intended to include both A and B; A or B; A (alone); and B (alone). Likewise, the term "and / or" as used in a phrase such as "A, B, and / or C" is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0102] As used herein, the term "comprising" means that other elements can also be present in addition to the defined elements presented. The use of "comprising" indicates inclusion rather than limitation.

[0103] The term "consisting of" refers to compositions, methods, and respective components thereof as described herein, which are exclusive of any element not recited in that description of the embodiment.

[0104] As used herein the term "consisting essentially of' refers to those elements required for a given embodiment. The term permits the presence of additional elements that do not materially affect the basic and novel or functional characteristic(s) of that embodiment of the invention.

[0105] The term "statistically significant" or "significantly" refers to statistical significance and generally means a two standard deviation (2SD) or greater difference.

[0106] As used herein, the term "subject" refers to a mammal, including but not limited to a dog, cat, horse, cow, pig, sheep, goat, chicken, rodent, or primate. Subjects can be house pets (e.g., dogs, cats), agricultural stock animals (e.g., cows, horses, pigs, chickens, etc.), laboratory animals (e.g., mice, rats, rabbits, etc.), but are not so limited. Subjects include human subjects. The human subject may be a pediatric, adult, or a geriatric subject. The human subject may be of either sex.

[0107] As used herein, the terms "effective amount" and “therapeutically-effective amount’’ include an amount sufficient to prevent or ameliorate a manifestation of disease or medical condition, such as cardiovascular disease. It will be appreciated that there will be many ways known in the art to determine the effective amount for a given application. For example, the pharmacological methods for dosage determination may be used in the therapeutic context. In the context of therapeutic or prophylactic applications, the amount of a composition administered to the subject will depend on the type and severity of the disease and on the characteristics of the individual, such as general health, age, sex, body weight and tolerance to drugs. It will also depend on the degree, severity and type of disease. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. The compositions can also be administered in combination with one or more additional therapeutic compounds.

[0108] As used herein, the terms “treat,” “treatment,” “treating,” or “amelioration” when used in reference to a disease, disorder or medical condition, refer to therapeutic treatments for a condition, wherein the object is to reverse, alleviate, ameliorate, inhibit, slow down or stop the progression or severity of a symptom or condition. The term “treating” includes reducing or alleviating at least one adverse effect or symptom of a condition. Treatment is generally “effective” if one or more symptoms or clinical markers are reduced. Alternatively, treatment is “effective” if the progression of a condition is reduced or halted. That is, “treatment” includes not just the improvement of symptoms or markers, but also a cessation or at least slowing of progress or worsening of symptoms that would be expected in the absence of treatment. Beneficial or desired clinical results include, but are not limited to, alleviation of one or more symptom(s), diminishment of extent of the deficit, stabilized ( / .e., not worsening) state of a tumoror malignancy, delay or slowing of tumor growth and / or metastasis, and an increased lifespan as compared to that expected in the absence of treatment.

[0109] As used herein, the term "long-term" administration means that the therapeutic agent or drug is administered for a period of at least 12 weeks. This includes that the therapeutic agent or drug is administered such that it is effective over, or for, a period of at least 12 weeks and does not necessarily imply that the administration itself takes place for 12 weeks, e.g., if sustained release compositions or long-acting therapeutic agent or drug is used. Thus, the subject is treated for a period of at least 12 weeks. In many cases, long-term administration is for at least 4, 5, 6, 7, 8, 9 months or more, or for at least 1, 2, 3, 5, 7 or 10 years, or more.

[0110] The administration of the compositions contemplated herein may be carried out in any convenient manner, including by aerosol inhalation, injection, ingestion, transfusion, implantation or transplantation. In a some embodiments, compositions are administered parenterally. The phrases “parenteral administration” and “administered parenterally” as used herein refers to modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravascular, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intratumoral, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion. In one embodiment, the compositions contemplated herein are administered to a subject by direct injection into a tumor, lymph node, or site of infection.

[0111] The terms “decrease”, “reduced”, “reduction”, or “inhibit” are all used herein to mean a decrease by a statistically significant amount. In some embodiments, “reduce,” “reduction" or “decrease" or “inhibit” typically means a decrease by at least 10% as compared to a reference level (e.g., the absence of a given treatment or agent) and can include, for example, a decrease by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99% , or more. As used herein, “reduction” or “inhibition” does not encompass a complete inhibition or reduction as compared to a reference level. “Complete inhibition” is a 100% inhibition as compared to a reference level. A decrease can be preferably down to a level accepted as within the range of normal for an individual without a given disorder.

[0112] The terms “increased”, “increase”, “enhance”, or “activate” are all used herein to mean an increase by a statically significant amount. In some embodiments, the terms“increased”, “increase”, “enhance”, or “activate” can mean an increase of at least 10% as compared to a reference level, for example an increase of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% increase or any increase between 10-100% as compared to a reference level, or at least about a 2-fold, or at least about a 3-fold, or at least about a 4-fold, or at least about a 5-fold or at least about a 10- fold increase, or any increase between 2-fold and 10-fold or greater as compared to a reference level. In the context of a marker or symptom, a “increase” is a statistically significant increase in such level.Antibody-Related or Antibody-Drug-Conjugate Related Definitions:

[0113] Any of the compounds or compositions of the present invention can be linked to an antibody with specific affinity for an epitope on a target cell or particle (e.g., lipid nanoparticle or LNP). The resulting antibody-drug conjugate (ADC) can thus deliver compounds with greater specificity.

[0114] As used herein, an “epitope” can be formed on a polypeptide both from contiguous amino acids, or noncontiguous amino acids juxtaposed by tertiary folding of a protein. Epitopes formed from contiguous amino acids are typically retained on exposure to denaturing solvents, whereas epitopes formed by tertiary folding are typically lost on treatment with denaturing solvents. An epitope typically includes at least 3, and more usually, at least 5, about 9, or about 8-10 amino acids in a unique spatial conformation. An “epitope” includes the unit of structure conventionally bound by an immunoglobulin VH / VL pair. Epitopes define the minimum binding site for an antibody, and thus represent the target of specificity of an antibody. In the case of a single domain antibody, an epitope represents the unit of structure bound by a variable domain in isolation. The terms “antigenic determinant” and “epitope” can also be used interchangeably herein. In certain embodiments, epitope determinants include chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl, or sulfonyl, and, in certain embodiments, may have specific three-dimensional structural characteristics, and / or specific charge characteristics.

[0115] As used herein, the term “antibody” refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, / .e., molecules that contain an antigen binding site that immunospecifically binds an antigen. The term also refers to antibodies comprised of two immunoglobulin heavy chains and two immunoglobulin light chains as well as a variety of forms including full length antibodies and antigen-binding portions thereof; including,for example, an immunoglobulin molecule, a monoclonal antibody, a chimeric antibody, a CDR- grafted antibody, a humanized antibody, a Fab, a Fab', a F(ab')2, a Fv, a disulfide linked Fv, a scFv, a single domain antibody (dAb), a diabody, a multispecific antibody, a dual specific antibody, an anti-idiotypic antibody, a bispecific antibody, a functionally active epitope-binding portion thereof, and / or bifunctional hybrid antibodies.

[0116] Each heavy chain is composed of a variable region of said heavy chain (abbreviated here as HCVR or VH) and a constant region of said heavy chain. The heavy chain constant region consists of three domains CH1 , CH2 and CH3. Each light chain is composed of a variable region of said light chain (abbreviated here as LCVR or VL) and a constant region of said light chain. The light chain constant region consists of a CL domain. The VH and VL regions may be further divided into hypervariable regions referred to as complementaritydetermining regions (CDRs) and interspersed with conserved regions referred to as framework regions (FR). Each VH and VL region thus consists of three CDRs and four FRs which are arranged from the N terminus to the C terminus in the following order: FR1, CDR1 , FR2, CDR2, FR3, CDR3, FR4. This structure is well known to those skilled in the art.

[0117] As used herein, the term “CDR” refers to the complementarity determining regions within antibody variable sequences. There are three CDRs in each of the variable regions of the heavy chain and of the light chain, which are designated CDR1 , CDR2 and CDR3, for each of the variable regions. The exact boundaries of these CDRs have been defined differently according to different systems. The system described by Kabat et al. (1987 and 1991)1not only provides an unambiguous residue numbering system applicable to any variable region of an antibody, but also provides precise residue boundaries defining the three CDRs. These CDRs may be referred to as Kabat CDRs. Other boundaries defining CDRs overlapping with the Kabat CDRs have been described by Padlan (1995),2MacCallum (1996),3Chothia and Lesk (1987),4and Chothia et al. (1989).5Still other CDR boundary definitions may not strictly follow one of the above systems, but will nonetheless overlap with the Kabat CDRs, although they may be shortened or lengthened in light of prediction or experimental findings that particular residues or groups of residues or even entire CDRs do not significantly impact antigen binding. The methods used herein may utilize CDRs defined according to any of these systems, although preferred embodiments use Kabat defined CDRs.

[0118] The term “antigen-binding portion” of an antibody refers to one or more portions of an antibody as described herein, said portions) still having the binding affinities as defined above herein. Portions of a complete antibody have been shown to be able to carry out the antigen-binding function of an antibody. In accordance with the term “antigen-binding portion” ofan antibody, examples of binding portions include (i) an Fab portion, i.e., a monovalent portion composed of the VL, VH, CL and CH1 domains; (ii) an F(ab')2 portion, i.e., a bivalent portion comprising two Fab portions linked to one another in the hinge region via a disulfide bridge;(iii) an Fd portion composed of the VH and CH1 domains; (iv) an Fv portion composed of the FL and VH domains of a single arm of an antibody; and (v) a dAb portion consisting of a VH domain or of VH, CH1, CH2, DH3, or VH, CH2, CH3 (dAbs, or single domain antibodies, comprising only VLdomains have also been shown to specifically bind to target epitopes). Although the two domains of the Fv portion, namely VL and VH, are encoded by separate genes, they may further be linked to one another using a synthetic linker, e.g., a poly-G4S amino acid sequence (‘G4S’ disclosed as SEQ ID NO: 29 in U.S. Patent No. 10,253,111 , which is incorporated by reference herein in its entirety as if fully printed here), and recombinant methods, making it possible to prepare them as a single protein chain in which the VL and VH regions combine in order to form monovalent molecules (known as single chain Fv (ScFv)). The term “antigen-binding portion” of an antibody is also intended to comprise such single chain antibodies. Other forms of single chain antibodies such as “diabodies” are likewise included here. Diabodies are bivalent, bispecific antibodies in which VH and VL domains are expressed on a single polypeptide chain, but using a linker which is too short for the two domains being able to combine on the same chain, thereby forcing said domains to pair with complementary domains of a different chain and to form two antigen-binding sites. An immunoglobulin constant domain refers to a heavy or light chain constant domain. Human IgG heavy chain and light chain constant domain amino acid sequences are known in the art.

[0119] As used herein, the term “antibody reagent" refers to a polypeptide that includes at least one immunoglobulin variable domain or immunoglobulin variable domain sequence and which specifically binds a given antigen. An antibody reagent can comprise an antibody or a polypeptide comprising an antigen-binding domain of an antibody. In some embodiments, an antibody reagent can comprise a monoclonal antibody or a polypeptide comprising an antigenbinding domain of a monoclonal antibody. For example, an antibody can include a heavy (H) chain variable region (abbreviated herein as VH), and a light (L) chain variable region (abbreviated herein as VL). In another example, an antibody includes two heavy (H) chain variable regions and two light (L) chain variable regions. The term "antibody reagent" encompasses antigen-binding fragments of antibodies (e.g., single chain antibodies, Fab and sFab fragments, F(ab')2, Fd fragments, Fv fragments, scFv, and domain antibodies (dAb) fragments as well as complete antibodies.

[0120] An antibody can have the structural features of IgA, IgG, IgE, IgD, IgM (as well as subtypes and combinations thereof). Antibodies can be from any source, including mouse, rabbit, pig, rat, and primate (human and non-human primate) and primatized antibodies. Antibodies also include midibodies, humanized antibodies, chimeric antibodies, and the like.

[0121] Furthermore, an antibody, antigen-binding portion thereof, or CAR as described herein may be part of a larger immunoadhesion molecule formed by covalent or noncovalent association of said antibody or antibody portion with one or more further proteins or peptides. Relevant to such immunoadhesion molecules are the use of the streptavidin core region in order to prepare a tetrameric scFv molecule and the use of a cysteine residue, a marker peptide and a C-terminal polyhistidinyl, e.g., hexahistidinyl tag (‘hexahistidinyl tag’ disclosed as SEQ ID NO: 30 in U.S. Patent No. 10,253,111) in order to produce bivalent and biotinylated scFv molecules.

[0122] In some embodiments, the antibody, antibody reagent, antigen-binding portion thereof, or CAR described herein can be an immunoglobulin molecule, a monoclonal antibody, a chimeric antibody, a CDR-grafted antibody, a humanized antibody, a Fab, a Fab', a F(ab')2, a Fv, a disulfide linked Fv, a scFv, a single domain antibody, a diabody, a multispecific antibody, a dual specific antibody, an anti-idiotypic antibody, a bispecific antibody, and a functionally active epitope-binding portion thereof.

[0123] In some embodiments, the antibody or antigen-binding portion thereof is a fully human antibody. In some embodiments, the antibody, antigen-binding portion thereof, is a humanized antibody or antibody reagent. In some embodiments, the antibody, antigen-binding portion thereof, is a fully humanized antibody or antibody reagent. In some embodiments, the antibody or antigen-binding portion thereof, is a chimeric antibody or antibody reagent. In some embodiments, the antibody, antigen-binding portion thereof, is a recombinant polypeptide. In some embodiments, the CAR comprises an extracellular domain that binds a specific epitope on the targeted particles and / or cells in the subject, wherein the extracellular domain comprises a humanized or chimeric antibody or antigen-binding portion thereof.

[0124] The term “human antibody” refers to antibodies whose variable and constant regions correspond to or are derived from immunoglobulin sequences of the human germ line, as described, for example, by Kabat, et al. (1991).6However, the human antibodies can contain amino acid residues not encoded by human germ line immunoglobulin sequences (for example mutations which have been introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example in the CDRs, and in particular in CDR3. Recombinant human antibodies as described herein have variable regions and may also contain constantregions derived from immunoglobulin sequences of the human germ line (see Kabat, et al. (1991).7According to particular embodiments, however, such recombinant human antibodies are subjected to in vitro mutagenesis (or to a somatic in vivo mutagenesis, if an animal is used which is transgenic due to human Ig sequences) so that the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences which although related to or derived from VH and VL sequences of the human germ line, do not naturally exist in vivo within the human antibody germ line repertoire. According to particular embodiments, recombinant antibodies of this kind are the result of selective mutagenesis or back mutation or of both. Preferably, mutagenesis leads to an affinity to the target which is greater, and / or an affinity to non-target structures which is smaller than that of the parent antibody. Generating a humanized antibody from the sequences and information provided herein can be practiced by those of ordinary skill in the art without undue experimentation. In one approach, there are four general steps employed to humanize a monoclonal antibody, see, e.g., U.S. Patent Nos. 5,585,089; 6,835,823; and 6,824,989. These are: (1) determining the nucleotide and predicted amino acid sequence of the starting antibody light and heavy variable domains; (2) designing the humanized antibody, i.e., deciding which antibody framework region to use during the humanizing process; (3) the actual humanizing methodologies / techniques; and (4) the transfection and expression of the humanized antibody.

[0125] In some embodiments, the antibody, antibody reagent, antigen-binding portion thereof, and / or CAR as described herein can be a variant of a sequence described herein, e.g., a conservative substitution variant of an antibody polypeptide. In some embodiments, the variant is a conservatively modified variant. Conservative substitution variants can be obtained by mutations of native nucleotide sequences, for example. A “variant,” as referred to herein, is a polypeptide substantially homologous to a native or reference polypeptide, but which has an amino acid sequence different from that of the native or reference polypeptide because of one or a plurality of deletions, insertions or substitutions. Variant polypeptide-encoding DNA sequences encompass sequences that comprise one or more additions, deletions, or substitutions of nucleotides when compared to a native or reference DNA sequence, but that encode a variant protein or portion thereof that retains activity, e.g., antigen-specific binding activity for the relevant target polypeptide, e.g., a specific epitope on a particle or on a cell. A wide variety of PCR-based site-specific mutagenesis approaches are also known in the art and can be applied by the ordinarily skilled artisan.

[0126] Usually, the CDR regions in humanized antibodies and human antibody variants are substantially identical, and more usually, identical to the corresponding CDR regions in themouse or human antibody from which they were derived. In some embodiments, it is possible to make one or more conservative amino acid substitutions of CDR residues without appreciably affecting the binding affinity of the resulting humanized immunoglobulin or human antibody variant. In some embodiments, substitutions of CDR regions can enhance binding affinity.

[0127] The term “chimeric antibody” refers to antibodies which contain sequences for the variable region of the heavy and light chains from one species and constant region sequences from another species, such as antibodies having murine heavy and light chain variable regions linked to human constant regions. Humanized antibodies have variable region framework residues substantially from a human antibody (termed an acceptor antibody) and complementarity determining regions substantially from a non-human antibody, e.g., a mouseantibody, (referred to as the donor immunoglobulin). The constant region(s), if present, are also substantially or entirely from a human immunoglobulin. The human variable domains are usually chosen from human antibodies whose framework sequences exhibit a high degree of sequence identity with the (murine) variable region domains from which the CDRs were derived. The heavy and light chain variable region framework residues can be substantially similar to a region of the same or different human antibody sequences. The human antibody sequences can be the sequences of naturally occurring human antibodies or can be consensus sequences of several human antibodies.

[0128] In addition, techniques developed for the production of “chimeric antibodies” by splicing genes from a mouse, or other species, antibody molecule of appropriate antigen specificity together with genes from a human antibody molecule of appropriate biological activity can be used. The variable segments of chimeric antibodies are typically linked to at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. Human constant region DNA sequences can be isolated in accordance with well-known procedures from a variety of human cells, such as immortalized B-cells. The antibody can contain both light chain and heavy chain constant regions. The heavy chain constant region can include CH1 , hinge, CH2, CH3, and, sometimes, CH4 regions. For therapeutic purposes, the CH2 domain can be deleted or omitted.

[0129] Additionally, and as described herein, a recombinant humanized antibody can be further optimized to decrease potential immunogenicity, while maintaining functional activity, for therapy in humans. In this regard, functional activity means a polypeptide capable of displaying one or more known functional activities associated with a recombinant antibody, antigen-binding portion thereof, or CAR as described herein. Such functional activities include binding to a particle in circulation, to a cell and / or a particle in the subject. Additionally, a polypeptide havingfunctional activity means the polypeptide exhibits activity similar, but not necessarily identical to, an activity of a reference antibody, antigen-binding portion thereof, or CAR as described herein, including mature forms, as measured in a particular assay, such as, for example, a biological assay, with or without dose dependency. In the case where dose dependency does exist, it need not be identical to that of the reference antibody, antigen-binding portion thereof, or CAR, but rather substantially similar to the dose-dependence in a given activity as compared to the reference antibody, antigen-binding portion thereof, or CAR as described herein ( / .e., the candidate polypeptide will exhibit greater activity, or not more than about 25-fold less, about 10- fold less, or about 3-fold less activity relative to the antibodies, antigen-binding portions, and / or CARs described herein).

[0130] In some embodiments, the antibody reagents (e.g., antibodies or CARs) described herein are not naturally-occurring biomolecules. For example, a murine antibody raised against an antigen of human origin would not occur in nature absent human intervention and manipulation, e.g., manufacturing steps carried out by a human. Chimeric antibodies are also not naturally-occurring biomolecules, e.g., in that they comprise sequences obtained from multiple species and assembled into a recombinant molecule. In certain particular embodiments, the human antibody reagents described herein are not naturally-occurring biomolecules, e.g., fully human antibodies directed against a human antigen would be subject to negative selection in nature and are not naturally found in the human body.

[0131] In some embodiments, the antibody, antibody reagent, antigen-binding portion thereof, and / or CAR is an isolated polypeptide. In some embodiments, the antibody, antibody reagent, antigen-binding portion thereof, and / or CAR is a purified polypeptide. In some embodiments, the antibody, antibody reagent, antigen-binding portion thereof, and / or CAR is an engineered polypeptide.

[0132] “Avidity” is the measure of the strength of binding between an antigen-binding molecule (such as an antibody or antigen-binding portion thereof described herein) and the pertinent antigen. Avidity is related to both the affinity between an antigenic determinant and its antigen binding site on the antigen-binding molecule, and the number of pertinent binding sites present on the antigen-binding molecule. Typically, antigen-binding proteins (such as an antibody or portion of an antibody as described herein) will bind to their cognate or specific antigen with a dissociation constant (KDof 10’5to 10’12moles / liter or less, such as 10’7to 10’12moles / liter or less, or 10"8to 10"12moles / liter ( / .e., with an association constant (KA) of 105to 1012liter / moles or more, such as 107to 1012liter / moles or 108to 1012liter / moles). Any KDvalue greater than 10"4mol / liter (or any KA value lower than 104M’1) is generally considered toindicate non-specific binding. The KD for biological interactions which are considered meaningful (e.g., specific) are typically in the range of 10’10M (0.1 nM) to 10"5M (10000 nM). The stronger an interaction, the lower is its KD. For example, a binding site on an antibody or portion thereof described herein will bind to the desired antigen with an affinity less than 500 nM, such as less than 200 nM, or less than 10 nM, such as less than 500 pM. Specific binding of an antigenbinding protein to an antigen or antigenic determinant can be determined in any suitable manner known perse, including, for example, Scatchard analysis and / or competitive binding assays, such as radioimmunoassays (RIA), enzyme immunoassays (EIA) and sandwich competition assays, and the different variants thereof known perse in the art; as well as other techniques as mentioned herein.

[0133] Accordingly, as used herein, “selectively binds” or “specifically binds” refers to the ability of a peptide (e.g., an antibody, CAR, or portion thereof) described herein to bind to a target, such as an antigen present on the cell-surface of a cell or a particle in the subject, with a KD 10“5M (10000 nM) or less, e.g., 10’6M, 10’7M, 1Q-8M, 10’9M, 1Q-10M, 10’11M, 10’12M, or less. Specific binding can be influenced by, for example, the affinity and avidity of the polypeptide agent and the concentration of polypeptide agent. The person of ordinary skill in the art can determine appropriate conditions under which the polypeptide agents described herein selectively bind the targets using any suitable methods, such as titration of a polypeptide agent in a suitable cell binding assay. A polypeptide specifically bound to a target is not displaced by a non-similar competitor. In certain embodiments, an antibody, antigen-binding portion thereof, or CAR is said to specifically bind an antigen when it preferentially recognizes its target antigen in a complex mixture of proteins and / or macromolecules.

[0134] In some embodiments, an antibody, antigen-binding portion thereof, or CAR, as described herein, binds to, e.g., a specific epitope on a cell and / or a particle in the subject with a dissociation constant (KD) of 10'5M (10000 nM) or less, e.g., 10‘6M, 10'7M, 10'8M, 10’9M, 10'10M, 10-11M, 10-12M, or less. In some embodiments, an antibody, antigen-binding portion thereof, or CAR, as described herein, binds to the specific epitope with a dissociation constant (KD) of from about 10-5M to 10'6M. In some embodiments, an antibody, antigen-binding portion thereof, or CAR, as described herein, binds to the specific epitope with a dissociation constant (KD) of from about 10‘6M to 10’7M. In some embodiments, an antibody, antigen-binding portion thereof, or CAR, as described herein, binds to the specific epitope with a dissociation constant (KD) of from about 10'7M to 10'8M. In some embodiments, an antibody, antigen-binding portion thereof, or CAR, as described herein, binds to the specific epitope with a dissociation constant (KD) of from about 10-8M to 10-9M. In some embodiments, an antibody, antigen-binding portion thereof,or CAR, as described herein, binds to the specific epitope with a dissociation constant (KD) of from about 10'9M to 10-10M. In some embodiments, an antibody, antigen-binding portion thereof, or CAR, as described herein, binds to the specific epitope with a dissociation constant (KD) of from about 10'10M to 10’11M. In some embodiments, an antibody, antigen-binding portion thereof, or CAR, as described herein, binds to the specific epitope with a dissociation constant (KD) of from about 10’11M to 10‘12M. In some embodiments, an antibody, antigenbinding portion thereof, or CAR, as described herein, binds to the specific epitope with a dissociation constant (KD) of less than 10'12M.

[0135] As used herein, “drug to antibody ratio” or “DAR” refers to the number of the azonafide-based compounds of the present invention linked to an ADC, an antibody, antigenbinding portion thereof, or CAR, as described herein. In some embodiments, the DAR is from 1 to about 30. In some embodiments, the DAR is from 1 to about 20. In some embodiments, the DAR is from 1 to about 15. In some embodiments, the DAR is from 1 to about 12. In some embodiments, the DAR is from 1 to about 10. In some embodiments, the DAR is from 1 to about 9. In some embodiments, the DAR is from 1 to about 8. In some embodiments, the DAR is from 1 to about 7. In some embodiments, the DAR is from 1 to about 6. In some embodiments, the DAR is from 1 to about 5. In some embodiments, the DAR is from 1 to about 4. In some embodiments, the DAR is from 1 to about 3. In some embodiments, the DAR is from 1 to about 2. In some embodiments, the DAR is 1.PHARMACEUTICAL COMPOSITIONS

[0136] The compositions and methods of the present invention may be utilized to treat an individual in need thereof. In certain embodiments, the individual is a mammal such as a human, or a non-human mammal. When administered to an animal, such as a human, the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the invention and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In some embodiments, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration ( .e., routes, such as injection or implantation, that circumvent transport or diffusion through an epithelial barrier), the aqueous solution is pyrogen-free, or substantially pyrogen-free. The excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in dosage unit form such as tablet, capsule (includingsprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like. The composition can also be present in a transdermal delivery system, e.g., a skin patch. The composition can also be present in a solution suitable for topical administration, such as a lotion, cream, or ointment.

[0137] A pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a compound of the invention. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a self-emulsifying drug delivery system or a self-micro emulsifying drug delivery system. The pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention. Liposomes, for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.

[0138] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0139] The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc;(8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol;(12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such asmagnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water;(17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0140] A pharmaceutical composition (preparation) can be administered to a subject by any of a number of routes of administration including, for example, orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually); subcutaneously; transdermally (for example as a patch applied to the skin); and topically (for example, as a cream, ointment or spray applied to the skin). The compound may also be formulated for inhalation. In certain embodiments, a compound may be simply dissolved or suspended in sterile water. Details of appropriate routes of administration and compositions suitable for same can be found in, for example, U.S. Patent Nos. 6,110,973, 5,763,493, 5,731 ,000, 5,541 ,231 , 5,427,798, 5,358,970 and 4,172,896, as well as in patents cited therein.

[0141] The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.

[0142] Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the invention, with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0143] Formulations of the invention suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), lyophile, powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such asgelatin and glycerin, or sucrose and acacia) and / or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. Compositions or compounds may also be administered as a bolus, electuary or paste.

[0144] To prepare solid dosage forms for oral administration (capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate;(5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; (10) complexing agents, such as, modified and unmodified cyclodextrins; and (11) coloring agents. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0145] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropyl methyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surfaceactive or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0146] The tablets, and other solid dosage forms of the pharmaceutical compositions, such as dragees, capsules (including sprinkle capsules and gelatin capsules), pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropyl methyl cellulose in varying proportions to provide the desired releaseprofile, other polymer matrices, liposomes and / or microspheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

[0147] Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophiles for reconstitution, micro-emulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

[0148] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0149] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0150] Dosage forms for the topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.

[0151] The ointments, pastes, creams and gels may contain, in addition to an active compound, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0152] Powders and sprays can contain, in addition to an active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0153] Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the active compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

[0154] The phrases "parenteral administration" and "administered parenterally" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intraocular (such as intravitreal), intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion. Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0155] Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Proper fluidity can bemaintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0156] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.

[0157] In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[0158] Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.

[0159] For use in the methods of this invention, active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically-acceptable carrier.

[0160] Methods of introduction may also be provided by rechargeable or biodegradable devices. Various slow-release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinaceous biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form an implant for the sustained release of a compound at a particular target site.

[0161] Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve thedesired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0162] The selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

[0163] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the pharmaceutical composition or compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. By “therapeutically effective amount” is meant the concentration of a compound that is sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the weight, sex, age, and medical history of the subject. Other factors which influence the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent being administered with the compound of the invention. A larger total dose can be delivered by multiple administrations of the agent. Methods to determine efficacy and dosage are known to those skilled in the art. See, e.g., Isselbacher et al. (1996).8

[0164] In general, a suitable daily dose of an active compound used in the compositions and methods of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.

[0165] If desired, the effective daily dose of the active compound may be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. In certain embodiments of the present invention, the active compound may be administered two or three times daily. In other embodiments, the active compound will be administered once daily.

[0166] The patient receiving this treatment is any animal in need, including primates, in particular humans; and other mammals such as equines bovine, porcine, sheep, feline, and canine; poultry; and pets in general.

[0167] In certain embodiments, compounds of the invention may be used alone or conjointly administered with another type of therapeutic agent.

[0168] The present disclosure includes the use of pharmaceutically acceptable salts of compounds of the invention in the compositions and methods of the present invention. In certain embodiments, contemplated salts of the invention include, but are not limited to, alkyl, dialkyl, trialkyl or tetra-alkyl ammonium salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1 H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2- hydroxyethyljpyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, Na, Ca, K, Mg, Zn or other metal salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, l-ascorbic acid, l-aspartic acid, benzenesulfonic acid, benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1 ,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, d-glucoheptonic acid, d-gluconic acid, d-glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, l-malic acid, malonic acid, mandelic acid, methanesulfonic acid , naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, l-pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, l-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, and undecylenic acid salts.

[0169] The pharmaceutically acceptable acid addition salts can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared. The source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.

[0170] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening,flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0171] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alphatocopherol, and the like; and (3) metal-chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0172] Unless otherwise defined herein, scientific and technical terms used in connection with the present application shall have the meanings that are commonly understood by those of ordinary skill in the art to which this disclosure belongs. It should be understood that this invention is not limited to the particular methodology, protocols, and reagents, etc., described herein and as such can vary. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention, which is defined solely by the claims. Definitions of common terms in immunology and molecular biology can be found in The Merck Manual of Diagnosis and Therapy;9The Encyclopedia of Molecular Cell Biology and Molecular Medicine;10Molecular Biology and Biotechnology: a Comprehensive Desk Reference;11Immunology;12Janeway's Immunobiology;13Lewin's Genes XI;14Molecular Cloning: A Laboratory Manual.;15Basic Methods in Molecular Biology;16Laboratory Methods in Enzymology;17Current Protocols in Molecular Biology (CPMB);18Current Protocols in Protein Science (CPPS);19and Current Protocols in Immunology (CPI).20

[0173] In some embodiments of any of the aspects, the disclosure described herein does not concern a process for cloning human beings, processes for modifying the germ line genetic identity of human beings, uses of human embryos for industrial or commercial purposes or processes for modifying the genetic identity of animals which are likely to cause them suffering without any substantial medical benefit to man or animal, and also animals resulting from such processes.

[0174] Other terms are defined herein within the description of the various aspects of the invention.A NEW THERAPEUTIC APPROACH FOR TREATING ELEVATED LIPOPROTEIN (A)

[0175] According to the Centers for Disease Control and Prevention (CDC), high levels of lipoprotein (a) increase your likelihood of having a heart attack, a stroke, and aortic stenosis, especially if you have familial hypercholesterolemia or signs of coronary heart disease.

[0176] The CDC has made it clear that like LDL-cholesterol, Lp(a)-cholesterol can build up in the walls of human blood vessels. In general, the higher a person’s Lp(a) level is, the more likely this is to happen. These cholesterol deposits, called plaques, can decrease blood flow to the heart, brain, kidneys, lungs, legs, and other parts of the body. Plaques can grow over time or suddenly rupture, blocking blood vessels and leading to heart attacks or strokes.

[0177] Lp(a) can cause increased clotting, which can lead to rapidly formed blockages in blood vessels, and Lp(a) promotes inflammation which increases the likelihood that plaques will rupture.

[0178] High Lp(a) can also lead to narrowing of the aortic valve, called aortic stenosis, because of its role in inflammation. Chronic inflammation leads to calcium build up on the valve, causing stiffness. This can result in reduced blood flow if the valve is unable to open completely. In some cases, people with aortic stenosis need surgery or a procedure to replace the aortic valve.

[0179] There is clearly a current Treatment Gap: Despite advancements in cardiovascular disease (CVD) treatment, elevated Lipoprotein(a) or Lp(a) remains a significant risk factor that is not adequately addressed by current therapies. Elevated Lp(a) levels are associated with increased risks of atherosclerosis and thrombosis, independent of other lipid levels. An estimated 20-30% of the world's population is believed to have elevated levels. Lp(a) levels are genetically determined, with little to no influence from environmental or lifestyle factors.

[0180] Currently, there are no treatments to effectively and specifically lowering Lp(a). Non-Limiting Example of How the Technology Herein Works: This invention introduces a novel therapeutic strategy focusing on the direct modification of Lp(a) particles to reduce their atherogenic and thrombogenic properties without necessarily altering their plasma concentration. The approach utilizes a targeted biochemical intervention that modifies the Oxidized Phospholipids (OxPLs) on Lp(a), effectively "detoxifying" the Lp(a) particles. This method employs a specific set of molecular agents that selectively react with the OxPLs, neutralizing their harmful effects and potentially transforming Lp(a) into a less harmful form. These set of molecular agents are called reactive aldehyde or dicarbonyl scavengers.

[0181] OxPLs and Lipoprotein (a): Almost all acute coronary syndromes feature thrombotic complications of atherosclerotic diseases; Lp(a) could contribute to the former or latter processes, or both. Lp(a) is an apoB containing cholesterol-enriched lipoprotein, so Lp(a) possesses many atherosclerotic properties similar to LDL particles. However, compared toregular LDL particles, Lp(a) has been profoundly linked with in vivo thrombosis events, traditionally attributed to its similarity to plasminogen, but more recently, the OxPL content.

[0182] Oxidative stress is a critical event in the development of atherothrombosis. Peroxidation of membranes and lipoproteins converts "inert" phospholipids (PL) into a plethora of OxPLs that can act as signaling molecules or as reactive biochemical agents resulting in the covalent modification of proteins. Enhanced activation of platelets was observed in human plasmas containing the highest amounts of OxPLs.

[0183] There are different OxPLs species. One example is the oxidized phosphatidylcholine, “OxPCCD36” class of OxPLs that promote platelet activation via the CD36 receptor. Prominent members of the OxPCCD36 family include those with an y-oxo -a,p- unsaturated-cu-aldehyde sn-2 moiety (e.g. KOOA-PC and KODA-PC) and these can further oxidize to form oxPL with y-oxo -a,p-unsaturated-w-carboxylate sn-2 moieties (e.g. KOdiA-PC and KDdiA-PC) (FIG. 1).

[0184] FIG. 1 shows exemplary (non-limiting) structures of OxPCCD36. The oval (e.g., circle or red circle) shows reactive dicarbonyl moiety. Furthermore, there are several other dicarbonyl containing OxPLs that also exhibit strong platelet activation properties, such as malondialdehyde (MDA), isolevuglandins (IsoLG), and 4-oxo-2-nonenal (ONE), (illustrated in Fig 2). These dicarbonyl containing OxPLs modified lipoproteins are strong activators of platelets. Research focusing on these compounds has been pioneered by several groups at Vanderbilt and others over the last couple of decades. We show that dicarbonyl scavengers will react with these dicarbonyl OxPLs, thereby reducing their levels and blocking their atherothrombogenic effects.

[0185] In recent years, it has been increasingly recognized that there is a strong correlation between OxPLs and Lp(a). Very interestingly, it was found that most circulating OxPLs are associated with Lp(a); only small amounts are found on LDL and HDL. Biochemical studies indicate that 85% of the OxPLs detected in human plasma can be immunoprecipitated by an anti-apo(a) antibody; thus, the detected OxPLs are most likely on Lp(a). This was established by a murine monoclonal IgM antibody E06, that specifically detects OxPLs. In patients with higher Lp(a) levels and smaller isoform sizes, the correlation between OxPL / apoB and Lp(a) is stronger. Some Lp(a)-associated OxPLs are covalently adduct to apo(a), primarily to its KIV10 domain. Approximately 50% of the E06-reactive OxPLs on Lp(a) can be extracted with organic solvents and, therefore, are not covalently bound to protein but are present in the lipid phase of Lp(a).

[0186] The association between the risk of OxPLs levels and the risk of CVD can be explained by its correlation with Lp(a) levels. In a prospective study, plasma levels of OxPLs and Lp(a) predicted the risk of 10-year CVD rates independently of traditional risk factors, but not independent of each other. In contrast, another study showed that, in individuals with the lowest quartile of Lp(a) levels, the OxPLs levels were not positively correlated with the risk of coronary artery disease events. These suggest that circulating OxPLs on Lp(a) are those that really matter.

[0187] Interestingly, recent data also suggest that Lipoprotein (a) contributed to Cardiac allograft vasculopathy (CAV). The mechanism is likely mediated by smooth muscle proliferation that is triggered by OxPLs on lipoprotein (a). It is plausible and OxPLs, the pathogenic component of Lp(a), mediate this effect. Therefore, our claim should also cover for this rare disease prevention in this population. CAV is the top cause for orthostatic heart transplant recipients and currently there is no specific treatment for CAV.

[0188] Dicarbonyl Scavengers: Dietary supplementation of antioxidants, e.g., vitamins C and E, failed to prevent atherosclerosis in human clinical trials. However, lipid peroxidation generates both protective (e.g., resolvins) and highly deleterious (e.g., reactive dicarbonyls) products. Thus, approaches that reduce all lipoxidation products may be far less beneficial than a targeted approach that selectively inhibits pathogenic peroxidation products, such as reactive dicarbonyls, without changing levels of non-reactive (potentially beneficial) peroxidation products such as resolvins. Therefore, dicarbonyl scavengers are mechanistically very different from antioxidants. They work by blocking the formation of deleterious dicarbonyl-protein adducts, rather than blocking the formation of all lipid peroxidation products. Vitamins C and E do not scavenge reactive dicarbonyls.

[0189] 2-Hydroxybenzylamine (2-HOBA), which is naturally found in buckwheat, is an orally bioavailable selective dicarbonyl scavenger due to its 2-aminomethylphenols (2 -AMP) moiety. Therefore, 2-HOBA can protect proteins from being modified by dicarbonyl electrophiles. We aim to use 2-HOBA as the prodrug to test our hypothesis. We will also work on modify the structure of 2-HOBA to make improved compounds with improved efficacy, pharmacokinetics and pharmacodynamics. Dicarbonyls react with 2-HOBA at a rate three orders of magnitude faster than they react with cellular nucleophiles, resulting in scavenging of the dicarbonyls. The mechanism for the reaction of 2-HOBA is illustrated in FIG. 2A.0003] FIG. 2A illustrates how reactive dicarbonyls like KOOA-PC react with the e-amino group of lysine residues of proteins to form a covalent adduct, thus changing protein structure and function. 2-HOBA provides a nucleophilic amine group that likewise reacts with dicarbonyls but atmuch faster rate than lysine, yielding a stable adduct. Thus, 2-HOBA scavenges reactive dicarbonyls and protects protein lysine residues from covalent modification.

[0004] FIG. 2B shows other reactive dicarbonyls are MDA (malondialdehyde), ONE (4-oxo-2E- nonenal), or the isolevuglandins (isoLG).

[0190] Lp(a) is the major OxPL carrier in the circulation rather than HDL or LDL. Therefore, OxPLs on the Lp(a) will be the major target for 2-HOBA in individuals with elevated Lp(a). 2-HOBA will very likely reduce the dicarbonyl oxidized phospholipid formation on the Lp(a), either as dicarbonyl adduct to the apo(a), or on the lipid phase of the lipoprotein.

[0191] It must be noted that 2-HOBA does not scavenge all types of OxPLs. It can scavenge reactive dicarbonyl OxPLs with exceptionally high affinity. Therefore, 2-HOBA is mostly effective in scavenging MDA, IsoLG, ONE, 5-keto-8-oxo-6-octenoic acid esters of 2-lyso- PC (KOOA-PC) and the 9-keto-12-oxo-10-dodecenoic acid (KODA-PC). However, KOOA-PC and KODA-PC also serve as precursors for 5-keto-6-octendioic acid esters of 2-lyso-PC (KOdiA-PC) and the 9-keto-10-dodecendioic acid (KDdiA-PC) respectively (FIG. 1), as they undergo oxidation to form these other compounds. Therefore, dicarbonyl scavengers should theoretically also reduce levels of these two dicarbonyl OxPLs (KOdiA-PC and KDdiA-PC).However, the KOdiA-PC and KDdiA-PC are not as reactive as KOOA-PC and KODA-PC in term of their ability to adduct protein because of the hydroxyl group. Therefore, KOdiA-PC and KDdiA-PC are not expected to form protein adducts. While OxPLs with an aldehyde but not dicarbonyl such as 5-hydroxy-8-oxo-6-octenoic acid esters of 2-lyso-PC (HOOA-PC), 5-hydroxy- 8-oxo-6-octenedioic acid esters of 2-lyso-PC (HOdiA-PC) and the 9-hydroxy-12-oxo-10- dodecenoic acid (HODA-PC), the 9-hydroxy-10-dodecenedioic acid (HDdiA-PC) are only very poorly scavenged by 2-HOBA. Therefore, they cannot form protein adducts, nor will their abundance be affected by dicarbonyl scavengers. However, 2-HOBA and analogs (and all other structures we proposed above) may also be scavenging other OxPLs with other types of reactive aldehydes in addition to the dicarbonyl structures that are outlined at examples in this application.

[0192] Advantages and Improvements Over Existing Methods: For example, the proposed methods offer several key advantages over existing therapies:

[0193] First-in-class: This strategy will be first in class strategy for reducing the pathogenicity of lipoprotein particles rather than lowering the absolute lipoprotein quantity.

[0194] Targeted Action: Unlike broad-spectrum lipid-lowering drugs, this method specifically targets the pathogenic components of Lp(a), minimizing unintended effects on other lipid profiles and reducing the risk of disrupting beneficial lipid functions.

[0195] Reduced Side Effects: By focusing on modifying the properties of Lp(a) rather than reducing its quantity, the therapy avoids the side effects associated with drastic changes in Lp(a) levels, such as potential interference with wound healing or tumor suppression.

[0196] Compatibility with Existing Therapies: This approach can be used in conjunction with existing lipid-lowering therapies, providing an additional layer of protection against cardiovascular events in patients with high Lp(a) levels.

[0197] Cost advantage: There are two drugs are currently being developed by big pharma for lowering Lp(a), both using RNA technologies. The cost of these strategy would significantly higher than oral pills. Given the extremely large patient population (25% of whole population), there are tremendous need for oral medications.

[0198] This invention introduces a novel therapeutic approach specifically designed for individuals with elevated Lipoprotein(a) levels, a critical risk factor for cardiovascular diseases such as atherosclerosis and thrombosis. By targeting and modifying the oxidized phospholipids on Lp(a) particles, the therapy effectively reduces their atherogenic and thrombogenic properties, thereby lowering the risk of cardiovascular events. This innovative treatment complements existing lipid-lowering therapies by specifically addressing the unique challenges posed by elevated Lp(a).

[0199] In some embodiments, the primary users of this therapy will be for these who have elevated Lp(a) by providing a targeted treatment option that addresses the underlying cause of their elevated cardiovascular risk.

[0200] An estimated 20-25% of the world's population is believed to have elevated levels. Lp(a) levels are genetically determined, with little to no influence from environmental or lifestyle factors. This represents tremendous opportunities for novel treatment. Currently, there is no medicines that are approved to treat elevated Lp(a).

[0201] Even at this early stage, we have some preliminary data showing dicarbonyl scavengers can reduce the oxidized phospholipids that are carried by lipoprotein (a) and subsequently reduces the pathogenicity of Lp(a) in ex vivo cellular models systems such as smooth muscle proliferation, inflammation and platelet aggregations.

[0202] Feedback systems can be utilized to administer the therapeutic agents disclosed herein. In FIG. 3, step 300 involves a method where a subject receives a specific amount of a dicarbonyl scavenger. This process is conducted by a healthcare provider or the subject underguidance, aiming to administer a quantity of dicarbonyl scavenger that is determined to be sufficient to achieve a desired therapeutic effect. Oxidized phosphatidylcholine is a phospholipid that has undergone a chemical change due to oxidation and includes a dicarbonyl group, which consists of two carbonyl (C=O) groups.

[0203] In 302, the administered dicarbonyl scavenger interacts chemically with lipoprotein(a) in the subject's blood. Lipoprotein(a) is a blood particle that carries cholesterol and is associated with the development of cardiovascular diseases. The interaction between the dicarbonyl scavenger and lipoprotein(a) results in a modification of the lipoprotein(a), potentially through scavengering the dicarbonyl group on the oxidized phospholipid component of lipoprotein(a).

[0204] In some embodiments, 302 describes the outcome of the modification process after 300, which is the detoxification of lipoprotein(a). Detoxification refers to the reduction of any potential harmful effects or toxicity of lipoprotein(a). The modified lipoprotein(a) is expected to have a reduced association with cardiovascular diseases, leading to a decrease in the risk of such diseases for the subject.

[0205] Overall, step 300 and its outcomes describe a method where a specific phospholipid is administered to a subject, followed by a biochemical interaction with a blood component, resulting in a modification that reduces the component's association with cardiovascular diseases, thereby aiming to decrease the risk of these diseases for the subject.

[0206] Step 302 involves the administration of dicarbonyl scavenger. The dicarbonyl group is a chemical structure with two carbonyl (C=O) groups, which is known to react with specific biomolecules, altering their structure and function.

[0207] The detoxifying action of the dicarbonyl scavenger within Step 302 refers to the chemical interaction of the administered compound with lipoprotein(a). This compound is designed to have this chemical structure to ensure that it can effectively engage with the oxidized phospholipid on lipoprotein(a), which is associated with cardiovascular disease risk.

[0208] The action of "detoxify" associated with Step 302 indicates that the compound with a dicarbonyl group will interact with the lipoprotein(a) in the blood. This interaction aims to alter the lipoprotein(a) to reduce its potential to contribute to cardiovascular disease, effectively reducing its harmful effects.

[0209] The compound is administered to the subject with the goal of it encountering and reacting with the lipoprotein(a). The outcome sought is a chemical modification of the lipoprotein(a) that leads to its reduced harmful effects, thereby reducing the cardiovasculardisease risk in the subject. This process is a targeted intervention aimed at mitigating a specific risk factor for cardiovascular disease.

[0210] In some aspects, the techniques described herein relate to a system for reducing cardiovascular disease or a risk of cardiovascular disease in a subject, the system including: (1) a measurement of a lipoprotein (a) [Lp(a)] level in the subject that includes oxidized phospholipids (OxPLs) on the Lp(a); (2) an administering of a therapeutic agent to modify the OxPLs such that the Lp(a) includes less OxPLs; wherein the administering in (2) is modulated in extent by the measurement in (1), so that an automated feedback system is provided.TARGETED COMPOUNDS OF THE PRESENT INVENTION

[0211] In some embodiments, the present invention provides a targeted compound (TAC) comprising:wherein:R4comprises a targeting moiety including an antibody, an antibody fragment, a peptide, an oligonucleotide or an aptamer, or a combination thereof; each instance of BA independently comprises a coupling moiety or a bond (-) operative to bond to R4each instance of Sp independently comprises -CH2-, -(O)CH2-CH2-, -C(O)CH2-, -CH2-CH2-O-, -O-, -, or a hydrophilic polymer and / or monomer;-(LL)I-3- comprises a cleavable linker, wherein each instance of LL independently comprises at least one of the following linkers:a naturally or non-naturally occurring amino acid, a nucleoside or nucleotide, a tertiary amine, -(CH2)I-6-, -(CH2)I-6-NH-, -(C3-C6branched alkyl)-, -NH-, -CH(=O)NH-, -NHC(=O)-, -O-, -OCH2-, -CH2O-, -P-, -S-, or -SO2-;each instance of PA independently comprises a payload residue (PA) including any of (or one or more of) the chemical structures in Features 1-4 above.

[0212] In some embodiments, a self-cleaving linker is used, and / or a cleavable linker is disclosed herein, wherein the cleavable linker comprises at least one of linkers shown above; and / or a naturally or non-naturally occurring amino acid, a nucleoside or nucleotide, a tertiary amine, -(CH2)I-6-, -(CH2)I-6-NH-, -(C3-C6branched alkyl)-, -NH-, -CH(=O)NH-, -NHC(=O)-, -O-, -OCH2-, -CH2O-, -P-, -S-, or -SO2-

[0213] While contemplating (and disclosing) the technology herein, in a discussion, study or a reading of the details, features, embodiments, aspects, any figure or any part of any figure, and / or examples of the technology disclosed herein, any of the features, embodiments, aspects, and / or examples herein can be optionally inter-combined (or inter-discussed) with the example details listed below, and any portion (or aspect) of any detail below can be intercombined with any portion (even the smallest detail) of any feature or example disclosed herein:

[0214] Detail 1 : A composition for reducing cardiovascular disease risk in a subject, the composition comprising: a potent reactive oxidized phospholipid (OXPL) scavenger in a therapeutically effective amount; wherein the reactive OXPL scavenger selectively and efficiently modifies an oxidized phospholipid and / or an oxidized phospholipid on a lipoprotein(a) particle circulating in the subject's bloodstream, thereby reducing the cardiovascular disease risk in the subject, and / or wherein the reactive OXPL scavenger comprises at least one of 2- HOBA (2-hydroxybenzylamine), a potent analog of 2-hydroxybenzylamine (2-HOBA), or a modified analog of 2-HOBA, the modified analog of 2-HOBA having additional substituents covalently attached to enhance its efficacy.

[0215] Detail 2: The composition of detail 1, wherein the reactivity of 2-HOBA is increased by modifying the electronic density on the aromatic ring in the 2-HOBA by introducing at least one of halides (Br, F, Cl, I) and alkyl groups at different positions on the aromatic ring, and wherein the half-life of the 2-HOBA is optionally extended in humans by masking at least one of the hydroxyl group and the amino group on the 2-HOBA with at least one of an acyl group and a sulfonyl group to avoid immediate oxidation in a human.

[0216] Detail 3: The composition of detail 1, wherein the composition further comprises an amphipathic moiety that imparts both lipophilic and lipophobic properties to the reactive OXPL scavenger, thereby enhancing the affinity of the reactive OXPL scavenger for lipoproteins while limiting cellular uptake of the reactive OXPL scavenger, thus confining the reactive OXPL scavenger to the subject's circulation and reducing potential off-target effects.

[0217] Detail 4: The composition of detail 3, wherein the therapeutically effective amount is an optimal dosage for reducing the cardiovascular disease risk in the subject, and wherein the oxidized phospholipid is selected from the group consisting of 1-palmitoyl-2-arachidonoyl-sn- glycero-3-phosphocholine (PAPC), 1-palmitoyl-2-oxovaleroyl-sn-glycero-3-phosphocholine (POVPC), 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine (PGPC), 1-palmitoyl-2-(5- oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC), 1-palmitoyl-2-(9-oxononanoyl)-sn-glycero- 3-phosphocholine (PONPC), 1-palmitoyl-2-azelaoyl-sn-glycero-3-phosphocholine (PAzPC), 1- palmitoyl-2-(5-hydroxy-8-oxo-6-octenoyl)-sn-glycero-3-phosphocholine (HOOA-PC), 1-stearoyl- 2-arachidonoyl-sn-glycero-3-phosphocholine (SAPC), 1-stearoyl-2-oxovaleroyl-sn-glycero-3- phosphocholine (SOVPC), 1-stearoyl-2-glutaroyl-sn-glycero-3-phosphocholine (SGPC), 1- stearoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (SOVPC), 1-stearoyl-2-(9- oxononanoyl)-sn-glycero-3-phosphocholine (SON PC), 1-stearoyl-2-azelaoyl-sn-glycero-3- phosphocholine (SAzPC), 1-stearoyl-2-(5-hydroxy-8-oxo-6-octenoyl)-sn-glycero-3- phosphocholine (HOOA-PC), and combinations thereof.

[0218] Detail 5: The composition of detail 1, wherein the modified analog of 2-HOBA has additional substituents covalently attached to enhance its efficacy and increase its lifetime in the human bloodstream, the additional substituents optionally selected from the group consisting of polyethylene glycol (PEG), polysaccharides, peptides, proteins, and combinations thereof, and wherein the additional substituents are optionally chemically bonded moieties that improve the performance of the modified analog of 2-HOBA, and wherein the modified analog of 2-HOBA optionally has a molecular weight ranging from about 200 Da to about 10,000 Da, and wherein the modified analog of 2-HOBA is optionally administered orally, intravenously, subcutaneously, intramuscularly, or intranasally, and wherein the modified analog of 2-HOBA optionally has an extended half-life in the human bloodstream ranging from about 1 hour to about 1 week.

[0219] Detail 6: The composition of detail 5, wherein the additional substituents are chemically bonded moieties that improve the performance of the modified analog of 2-HOBA, and wherein the chemically bonded moieties optionally increase the solubility, bioavailability, or stability of the modified analog of 2-HOBA, and wherein the chemically bonded moieties optionally reduce the toxicity or immunogenicity of the modified analog of 2-HOBA, and wherein the chemically bonded moieties optionally target the modified analog of 2-HOBA to specific tissues or cell types, and wherein the chemically bonded moieties optionally enhance the binding affinity of the modified analog of 2-HOBA for oxidized phospholipids or lipoprotein(a) particles.

[0220] Detail 7: A method for reducing cardiovascular disease risk in a subject, the method comprising: administering to the subject a composition comprising a potent reactive oxidized phospholipid (OXPL) scavenger in a therapeutically effective amount; wherein the reactive OXPL scavenger selectively and efficiently modifies an oxidized phospholipid and / or an oxidized phospholipid on a lipoprotein(a) particle circulating in the subject's bloodstream, thereby reducing the cardiovascular disease risk in the subject.

[0221] Detail 8: The method of detail 7, wherein the reactive OXPL scavenger comprises at least one of 2-HOBA (2-hydroxybenzylamine), a potent analog of 2- hydroxybenzylamine (2-HOBA), or a modified analog of 2-HOBA, and wherein the reactive OXPL scavenger optionally has a binding affinity for oxidized phospholipids or lipoprotein (a) particles with a dissociation constant (Kd) ranging from about 1 nM to about 1 pM, and wherein the reactive OXPL scavenger optionally has a reaction rate constant with oxidized phospholipids or lipoprotein(a) particles ranging from about 1 M-1s-1 to about 1010 M-1s-1 , and wherein the reactive OXPL scavenger optionally has a selectivity for oxidized phospholipids over nonoxidized phospholipids of at least 10-fold, and wherein the reactive OXPL scavenger optionally reduces the plasma concentration of oxidized phospholipids or lipoprotein(a) particles by at least 10% in the subject.

[0222] Detail 9: The method of detail 8, wherein the reactivity of 2-HOBA is increased by modifying the electronic density on the aromatic ring in the 2-HOBA by introducing at least one of halides (Br, F, Cl, I) and alkyl groups at different positions on the aromatic ring, and wherein the half-life of the 2-HOBA is optionally extended in humans by masking at least one of the hydroxyl group and the amino group on the 2-HOBA with at least one of an acyl group and a sulfonyl group to avoid immediate oxidation in a human, and wherein the 2-HOBA optionally has a bioavailability of at least 50% when administered orally to the subject, and wherein the 2- HOBA optionally has a plasma half-life of at least 1 hour in the subject, and wherein the 2- HOBA optionally has a volume of distribution of at least 0.5 L / kg in the subject, and wherein the 2-HOBA optionally is metabolized by cytochrome P450 enzymes in the subject.

[0223] Detail 10: The method of detail 8, wherein the modified analog of 2-HOBA has additional substituents covalently attached to enhance its efficacy and increase its lifetime in the human bloodstream, the additional substituents optionally selected from the group consisting of polyethylene glycol (PEG), polysaccharides, peptides, proteins, and combinations thereof, and wherein the additional substituents are optionally chemically bonded moieties that improve the performance of the modified analog of 2-HOBA, and wherein the modified analog of 2-HOBA optionally has a molecular weight ranging from about 200 Da to about 10,000 Da, and whereinthe modified analog of 2-HOBA is optionally administered orally, intravenously, subcutaneously, intramuscularly, or intranasally, and wherein the modified analog of 2-HOBA optionally has an extended half-life in the human bloodstream ranging from about 1 hour to about 1 week.

[0224] Detail 11 : The method of detail 7, wherein the composition further comprises an amphipathic moiety that imparts both lipophilic and lipophobic properties to the reactive OXPL scavenger, thereby enhancing the affinity of the reactive OXPL scavenger for lipoproteins while limiting cellular uptake of the reactive OXPL scavenger, thus confining the reactive OXPL scavenger to the subject's circulation and reducing potential off-target effects, and wherein the amphipathic moiety optionally comprises a phospholipid, a fatty acid, a steroid, or a combination thereof, and wherein the amphipathic moiety optionally has a molecular weight ranging from about 100 Da to about 2,000 Da, and wherein the amphipathic moiety is optionally covalently attached to the reactive OXPL scavenger via an ester, amide, or disulfide bond, and wherein the amphipathic moiety optionally increases the partition coefficient (LogP) of the reactive OXPL scavenger by at least 1 unit, and wherein the amphipathic moiety optionally reduces the cellular uptake of the reactive OXPL scavenger by at least 50% in vitro.

[0225] Detail 12: The method of detail 11 , wherein the therapeutically effective amount is an optimal dosage for reducing the cardiovascular disease risk in the subject, and wherein the oxidized phospholipid is selected from the group consisting of 1-palmitoyl-2-arachidonoyl-sn- glycero-3-phosphocholine (PAPC), 1-palmitoyl-2-oxovaleroyl-sn-glycero-3-phosphocholine (POVPC), 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine (PGPC), 1-palmitoyl-2-(5- oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC), 1-palmitoyl-2-(9-oxononanoyl)-sn-glycero- 3-phosphocholine (PONPC), 1-palmitoyl-2-azelaoyl-sn-glycero-3-phosphocholine (PAzPC), 1- palmitoyl-2-(5-hydroxy-8-oxo-6-octenoyl)-sn-glycero-3-phosphocholine (HOOA-PC), 1-stearoyl- 2-arachidonoyl-sn-glycero-3-phosphocholine (SAPC), 1-stearoyl-2-oxovaleroyl-sn-glycero-3- phosphocholine (SOVPC), 1-stearoyl-2-glutaroyl-sn-glycero-3-phosphocholine (SGPC), 1- stearoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (SOVPC), 1-stearoyl-2-(9- oxononanoyl)-sn-glycero-3-phosphocholine (SON PC), 1-stearoyl-2-azelaoyl-sn-glycero-3- phosphocholine (SAzPC), 1-stearoyl-2-(5-hydroxy-8-oxo-6-octenoyl)-sn-glycero-3- phosphocholine (HOOA-PC), and combinations thereof, and wherein the therapeutically effective amount optionally ranges from about 0.1 mg / kg to about 100 mg / kg of the subject's body weight per day, and wherein the therapeutically effective amount is optionally administered in a single dose or in divided doses, and wherein the therapeutically effective amount is optionally administered once daily, twice daily, or three times daily, and wherein thetherapeutically effective amount is optionally administered orally, intravenously, subcutaneously, intramuscularly, or intranasally.

[0226] Detail 13: The method of detail 10, wherein the additional substituents are chemically bonded moieties that improve the performance of the modified analog of 2-HOBA, and wherein the chemically bonded moieties optionally increase the solubility, bioavailability, or stability of the modified analog of 2-HOBA, and wherein the chemically bonded moieties optionally reduce the toxicity or immunogenicity of the modified analog of 2-HOBA, and wherein the chemically bonded moieties optionally target the modified analog of 2-HOBA to specific tissues or cell types, and wherein the chemically bonded moieties optionally enhance the binding affinity of the modified analog of 2-HOBA for oxidized phospholipids or lipoprotein(a) particles, and wherein the chemically bonded moieties optionally have a molecular weight ranging from about 50 Da to about 5,000 Da, and wherein the chemically bonded moieties are optionally selected from the group consisting of polyethylene glycol (PEG), polysaccharides, peptides, proteins, aptamers, antibodies, and combinations thereof.

[0227] Detail 14: The method of detail 7, further comprising wherein the method is operative for patients with elevated Lp(a) and / or wherein the method is operative as a preventative method for patients wherein in either instance administering the composition to the subject reduces the cardiovascular disease risk in the subject by at least 10%, and wherein the cardiovascular disease risk is associated with atherosclerosis, coronary artery disease, peripheral artery disease, or cerebrovascular disease, and wherein the subject optionally has a history of myocardial infarction, stroke, or transient ischemic attack, and wherein the subject optionally has a Framingham Risk Score of at least 10%, and wherein the subject optionally has a coronary artery calcium score of at least 100, and wherein the subject optionally has a carotid intima-media thickness of at least 0.8 mm, and wherein the subject optionally has an ankle- brachial index of less than 0.9.

[0228] Detail 15: The method of detail 7, wherein administering the composition to the subject reduces the cardiovascular disease risk in the subject by at least 5%, and wherein the cardiovascular disease risk is associated with hypertension, dyslipidemia, or diabetes, and wherein the subject optionally has a systolic blood pressure of at least 140 mmHg or a diastolic blood pressure of at least 90 mmHg, and wherein the subject optionally has a total cholesterol level of at least 240 mg / dL, a low-density lipoprotein (LDL) cholesterol level of at least 160 mg / dL, a high-density lipoprotein (HDL) cholesterol level of less than 40 mg / dL, or a triglyceride level of at least 200 mg / dL, and wherein the subject optionally has a fasting blood glucose level of at least 126 mg / dL or a hemoglobin A1c level of at least 6.5%.

[0229] Detail 16: The method of detail 7, wherein administering the composition to the subject reduces the cardiovascular disease risk in the subject by at least 5%, and wherein the cardiovascular disease risk is associated with smoking, obesity, or physical inactivity, and wherein the subject optionally smokes at least 10 cigarettes per day, and wherein the subject optionally has a body mass index (BMI) of at least 30 kg / m2 or a waist circumference of at least 40 inches for men or 35 inches for women, and wherein the subject optionally engages in less than 150 minutes of moderate-intensity aerobic exercise or 75 minutes of vigorous-intensity aerobic exercise per week.

[0230] Detail 17: The method of detail 7, wherein administering the composition to the subject reduces the cardiovascular disease risk in the subject by at Ieast5%, and wherein the cardiovascular disease risk is associated with a family history of premature heart disease or a personal history of heart disease, and wherein the subject optionally has a first-degree relative who developed heart disease before age 55 for men or age 65 for women, and wherein the subject optionally has a personal history of myocardial infarction, stroke, or transient ischemic attack.

[0231] Detail 18: The method of detail 7, wherein administering the composition to the subject reduces the cardiovascular disease risk in the subject by at least 5%, and wherein the cardiovascular disease risk is associated with elevated levels of inflammatory markers, such as C-reactive protein or interleukin-6, and wherein the subject optionally has a C-reactive protein level of at least 2 mg / L or an interleukin-6 level of at least 2 pg / mL, and wherein the subject optionally has a history of chronic inflammatory conditions, such as rheumatoid arthritis, psoriasis, or inflammatory bowel disease.

[0232] Detail 19: The method of detail 7, wherein administering the composition to the subject reduces the cardiovascular disease risk in the subject by at least 5%, and wherein the cardiovascular disease risk is associated with elevated levels of lipoprotein(a) or oxidized phospholipids on apolipoprotein B-containing lipoproteins, and wherein the subject optionally has a lipoprotein(a) level of at least 50 mg / dL or an oxidized phospholipid on apolipoprotein B level of at least 5 nmol / L, and wherein the subject optionally has a history of familial hypercholesterolemia or familial defective apolipoprotein B-100.

[0233] Detail 20: The method of detail 7, wherein administering the composition to the subject reduces the cardiovascular disease risk in the subject by modifying the oxidized phospholipids on lipoprotein(a) particles, thereby reducing the pro-inflammatory and pro- atherogenic effects of lipoprotein(a), and wherein modifying the oxidized phospholipids optionally comprises scavenging, neutralizing, or reducing the oxidized phospholipids, andwherein modifying the oxidized phospholipids optionally comprises inhibiting the formation or accumulation of oxidized phospholipids on lipoprotein(a) particles, and wherein modifying the oxidized phospholipids optionally comprises enhancing the clearance or catabolism of oxidized phospholipids on lipoprotein(a) particles, and wherein modifying the oxidized phospholipids optionally comprises blocking the interaction of oxidized phospholipids with cellular receptors or proteins.

[0234] Detail 21 : The method of detail 7, wherein administering the composition to the subject reduces the cardiovascular disease risk in the subject by scavenging the oxidized phospholipids in the subject's bloodstream, thereby reducing the oxidative stress and endothelial dysfunction associated with cardiovascular disease, and wherein scavenging the oxidized phospholipids optionally comprises binding, sequestering, or inactivating the oxidized phospholipids, and wherein scavenging the oxidized phospholipids optionally comprises reducing the plasma concentration or bioactivity of the oxidized phospholipids, and wherein scavenging the oxidized phospholipids optionally comprises preventing the oxidized phospholipids from inducing pro-inflammatory or pro-atherogenic responses in vascular cells, and wherein scavenging the oxidized phospholipids optionally comprises enhancing the antioxidant or anti-inflammatory defenses in the subject's bloodstream.

[0235] Detail 22: The method of detail 7, wherein administering the composition to the subject reduces the cardiovascular disease risk in the subject by at least 5%, and wherein the cardiovascular disease risk is optionally associated with elevated levels of lipoprotein- associated phospholipase A2 (Lp-PLA2) or secretory phospholipase A2 (sPLA2), and wherein the subject optionally has an Lp-PLA2 level of at least 200 ng / mL or an sPLA2 level of at least 5 ng / mL, and wherein administering the composition optionally reduces the Lp-PLA2 or sPLA2 level in the subject by at least 10%.

[0236] Detail 23: The method of detail 7, wherein administering the composition to the subject reduces the cardiovascular disease risk in the subject by at least 2%, by at least 5%, or optionally by at least 10%, by at least 20%, by at least 30%, by at least 40%, by at least 50%, by at least 60%, by at least 70%, by at least 80%, or optionally by at least 90%, and wherein the cardiovascular disease risk is optionally associated with elevated levels of malondialdehyde (MDA) or 4-hydroxynonenal (4-HNE), and wherein the subject optionally has an MDA level of at least 2 pM or a 4-HNE level of at least 1 pM, and wherein administering the composition optionally reduces the MDA or 4-HNE level in the subject by at least 2%, by at least 5%, or optionally by at least 10%, by at least 20%, by at least 30%, by at least 40%, by at least 50%, by at least 60%, by at least 70%, by at least 80%, or optionally by at least 90%.

[0237] Detail 24: The method of detail 7, wherein administering the composition to the subject reduces the cardiovascular disease risk in the subject optionally by at least 2%, by at least 5%, by at least 10%, by at least 20%, by at least 30%, by at least 40%, by at least 50%, by at least 60%, by at least 70%, by at least 80%, or optionally by at least 90%, and wherein the cardiovascular disease risk is optionally associated with elevated levels of oxidized low-density lipoprotein (oxLDL) or oxidized high-density lipoprotein (oxHDL), and wherein the subject optionally has an oxLDL level of at least 50 U / L or an oxHDL level of at least 20 U / L, and wherein administering the composition optionally reduces the oxLDL or oxHDL level in the subject by at least 2%, by at least 5%, or optionally by at least 10%, by at least 20%, by at least 30%, by at least 40%, by at least 50%, by at least 60%, by at least 70%, by at least 80%, or optionally by at least 90%.

[0238] Detail 25: The method of detail 7, wherein administering the composition to the subject reduces the cardiovascular disease risk in the subject by improving the subject's lipid profile, and wherein improving the subject's lipid profile optionally comprises reducing the subject's total cholesterol level by at least 10%, reducing the subject's LDL cholesterol level by at least 15%, increasing the subject's HDL cholesterol level by at least 5%, or reducing the subject's triglyceride level by at least 20%, and wherein improving the subject's lipid profile optionally comprises increasing the subject's ratio of HDL cholesterol to LDL cholesterol by at least 25%.

[0239] Detail 26: The method of detail 7, wherein administering the composition to the subject reduces the cardiovascular disease risk in the subject by improving the subject's vascular function, and wherein improving the subject's vascular function optionally comprises increasing the subject's brachial artery flow-mediated dilation by at least 2%, reducing the subject's carotid intima-media thickness by at least 0.1 mm, increasing the subject's ankle- brachial index by at least 0.1 , or reducing the subject's pulse wave velocity by at least 1 m / s, and wherein improving the subject's vascular function optionally comprises reducing the subject's systolic blood pressure by at least 5 mmHg or reducing the subject's diastolic blood pressure by at least 3 mmHg.

[0240] Detail 27: The method of detail 7, wherein administering the composition to the subject reduces the cardiovascular disease risk in the subject by improving the subject's glucose metabolism, and wherein improving the subject's glucose metabolism optionally comprises reducing the subject's fasting blood glucose level by at least 10 mg / dL, reducing the subject's hemoglobin A1c level by at least 0.5%, increasing the subject's insulin sensitivity index by at least 25%, or reducing the subject's homeostatic model assessment of insulin resistance(HOMA-IR) score by at least 20%, and wherein improving the subject's glucose metabolism optionally comprises increasing the subject's glucose disposal rate by at least 10% during a hyperinsulinemic-euglycemic clamp.

[0241] Detail 28: The method of detail 7, wherein administering the composition to the subject reduces the cardiovascular disease risk in the subject by improving the subject's body weight or composition, and wherein improving the subject's body weight or composition optionally comprises reducing the subject's body weight by at least 5%, reducing the subject's body mass index by at least 3%, reducing the subject's waist circumference by at least 2 inches, or reducing the subject's body fat percentage by at least 3%, and wherein improving the subject's body weight or composition optionally comprises increasing the subject's lean body mass by at least 2% or increasing the subject's muscle-to-fat ratio by at least 10%.

[0242] Detail 29: The method of detail 7, wherein administering the composition to the subject reduces the cardiovascular disease risk in the subject by improving the subject's exercise capacity or physical function, and wherein improving the subject's exercise capacity or physical function optionally comprises increasing the subject's maximal oxygen uptake (VO2max) by at least 10%, increasing the subject's anaerobic threshold by at least 20%, increasing the subject's six-minute walk distance by at least 50 meters, or reducing the subject's time to complete a 400-meter walk by at least 20 seconds, and wherein improving the subject's exercise capacity or physical function optionally comprises increasing the subject's muscle strength by at least 15% or increasing the subject's gait speed by at least 0.2 meters per second.

[0243] Detail 30: The method of detail 7, wherein administering the composition to the subject reduces the cardiovascular disease risk in the subject by improving the subject's quality of life or mental health, and wherein improving the subject's quality of life or mental health optionally comprises increasing the subject's score on a cardiovascular disease-specific quality of life questionnaire by at least 10 points, reducing the subject's score on a depression or anxiety scale by at least 20%, increasing the subject's score on a mental well-being or vitality scale by at least 15%, or reducing the subject's score on a fatigue or sleep disturbance scale by at least 25%, and wherein improving the subject's quality of life or mental health optionally comprises reducing the subject's risk of developing major adverse cardiovascular events, such as myocardial infarction, stroke, and / or cardiovascular death, optionally by at least 2%, by at least 5%, by at least 10%, by at least 20%, by at least 30%, by at least 40%, by at least 50%, by at least 60%, by at least 70%, by at least 80%, or optionally by at least 90%.

[0244] Detail 31 : A composition comprising a potent reactive oxidized phospholipid (OXPL) scavenger in a therapeutically effective amount that selectively and efficiently modifies an oxidized phospholipid on a lipoprotein(a) particle circulating in a subject's bloodstream, wherein the reactive OXPL scavenger comprises at least one of 2-HOBA (2- hydroxybenzylamine), a potent analog of 2-HOBA, or a modified analog of 2-HOBA having additional substituents covalently attached to enhance its efficacy, and wherein the reactive OXPL scavenger has a molecular weight ranging from about 100 to about 500 Daltons and a partition coefficient (log P) between about 1 and about 5.

[0245] Detail 32: The composition of detail 31 , wherein the composition reduces cardiovascular disease risk in the subject by at least 10% compared to a control subject not receiving the composition.

[0246] Detail 33: The composition of detail 31 , wherein the potent analog of 2-HOBA comprises structural modifications to 2-HOBA selected from the group consisting of substitution of one or more hydrogen atoms with alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyl, amino, thiol, halo, nitro, cyano, carboxyl, ester, ether, or amide groups; addition of one or more rings; and combinations thereof.

[0247] Detail 34: The composition of detail 31 , wherein the modified analog of 2-HOBA comprises additional functional groups attached to 2-HOBA, the additional functional groups selected to increase water solubility, enhance bioavailability, improve metabolic stability, or reduce toxicity compared to unmodified 2-HOBA.

[0248] Detail 35: The composition of detail 34, wherein the additional functional groups are selected from the group consisting of polyethylene glycol (PEG), amino acids, peptides, carbohydrates, hydroxyl groups, amino groups, carboxyl groups, and combinations thereof.

[0249] Detail 36: The composition of detail 31 , wherein the composition is formulated for oral administration and is designed to release the OXPL scavenger in the small intestine for optimal absorption.

[0250] Detail 37: The composition of detail 31 , wherein the composition is formulated as an enteric-coated tablet, a sustained-release capsule, a lipid nanoparticle / LNP formulation, a nanoparticle formulation, or a liposomal formulation to enhance bioavailability and reduce dosing frequency.

[0251] Detail 38: The composition of detail 31 , wherein the therapeutically effective amount of the OXPL scavenger ranges from about 0.1 mg to about 5000 mg per day, and is determined based on the subject's body weight, age, and severity of oxidized phospholipid accumulation.

[0252] Detail 39: The composition of detail 31, wherein the composition further comprises one or more pharmaceutically acceptable carriers, excipients, or diluents selected to enhance stability, improve palatability, or modify release characteristics of the OXPL scavenger.

[0253] Detail 40: The composition of detail 31, wherein the composition is administered to the subject daily, weekly, or monthly, with the dosing regimen adjusted based on monitoring of the subject's oxidized phospholipid levels and cardiovascular health.

[0254] Detail 41 : A method of reducing cardiovascular disease risk in a subject, the method comprising administering to the subject the composition of detail 31 , wherein the composition is administered orally, subcutaneously, intramuscularly, or intravenously.

[0255] Detail 42: The method of detail 41 , wherein the subject has elevated levels of oxidized phospholipids on lipoprotein(a) particles, as determined by an enzyme-linked immunosorbent assay (ELISA) or a liquid chromatography-mass spectrometry (LC-MS) assay.

[0256] Detail 43: The method of detail 41 , wherein the subject has a history of cardiovascular disease and the composition is administered as a secondary prevention measure to reduce the risk of recurrent cardiovascular events.

[0257] Detail 44: The method of detail 41 , wherein the subject is at risk of developing cardiovascular disease due to one or more risk factors selected from the group consisting of hypertension, hyperlipidemia, diabetes, obesity, smoking, family history, and sedentary lifestyle, and the composition is administered as a primary prevention measure.

[0258] Detail 45: The method of detail 41 , wherein the cardiovascular disease is selected from the group consisting of atherosclerosis, coronary artery disease, peripheral artery disease, and stroke, and the composition is administered to slow the progression or induce regression of atherosclerotic plaques.

[0259] Detail 46: The method of detail 41 , wherein the composition is administered orally in a dosage form selected from the group consisting of tablets, capsules, powders, liquids, gels, and chewable forms, with the dosage form selected based on patient preference and compliance.

[0260] Detail 47: The method of detail 41 , wherein the composition is administered daily, weekly, or monthly, with the dosing frequency determined based on the pharmacokinetic and pharmacodynamic properties of the specific OXPL scavenger and the subject's response to treatment.

[0261] Detail 48: The method of detail 41 , wherein the composition is administered in a therapeutically effective amount ranging from about 0.1 mg to about 5000 mg per day, and thedose is titrated based on monitoring of the subject's oxidized phospholipid levels and cardiovascular health markers, such as lipid profile, blood pressure, and inflammatory markers.

[0262] Detail 49: The method of detail 41 , wherein the composition is administered in combination with one or more additional therapeutic agents for treating or preventing cardiovascular disease, the additional therapeutic agents selected to target complementary pathways involved in cardiovascular disease pathogenesis.

[0263] Detail 50: The method of detail 49, wherein the one or more additional therapeutic agents are selected from the group consisting of statins, aspirin, beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, PCSK9 inhibitors, ezetimibe, niacin, bile acid sequestrants, other lp(a) whole particle lowering agents that are under development, and / or omega-3 fatty acids, and the choice of additional therapeutic agents is based on the subject's specific cardiovascular risk factors and comorbidities.

[0264] Detail 51: The composition of detail 31 , wherein the reactive OXPL scavenger is conjugated to a targeting moiety selected from the group consisting of antibodies, peptides, aptamers, and small molecules, to enhance delivery to specific tissues or cell types involved in cardiovascular disease.

[0265] Detail 52: The composition of detail 51 , wherein the targeting moiety is an antibody or antibody fragment that specifically binds to oxidized phospholipids, lipoprotein(a), or a receptor expressed on vascular endothelial cells or macrophages.

[0266] Detail 53: The composition of detail 31 , wherein the reactive OXPL scavenger is encapsulated in a nanoparticle or liposome delivery system to improve stability, prolong circulation time, and enhance uptake by target tissues.

[0267] Detail 54: The composition of detail 53, wherein the nanoparticle or liposome delivery system comprises a biodegradable polymer, such as poly(lactic-co-glycolic acid) (PLGA), or a lipid bilayer composed of phospholipids and cholesterol.

[0268] Detail 55: The composition of detail 31 , wherein the reactive OXPL scavenger is co-administered with an antioxidant or anti-inflammatory agent to provide synergistic cardiovascular protection.

[0269] Detail 56: The composition of detail 55, wherein the antioxidant is selected from the group consisting of vitamin C, vitamin E, coenzyme Q10, N-acetylcysteine, and polyphenols, and the anti-inflammatory agent is selected from the group consisting of curcumin, resveratrol, omega-3 fatty acids, and low-dose methotrexate.

[0270] Detail 57: A method of monitoring the efficacy of the composition of detail 31 in reducing cardiovascular disease risk, the method comprising: (a) measuring baseline levels ofoxidized phospholipids, lipoprotein(a), and one or more cardiovascular health markers in a subject prior to administration of the composition; (b) administering the composition to the subject; and (c) measuring levels of oxidized phospholipids, lipoprotein(a), and the one or more cardiovascular health markers in the subject at one or more time points after administration of the composition to determine the extent of reduction in oxidized phospholipids, lipoprotein(a), and improvement in cardiovascular health markers compared to baseline levels.

[0271] Detail 58: The method of detail 57, wherein the one or more cardiovascular health markers are selected from the group consisting of lipid profile, blood pressure, C-reactive protein, interleukin-6, and plasminogen activator inhibitor-1.

[0272] Detail 59: The method of detail 57, wherein the levels of oxidized phospholipids and lipoprotein(a) are measured using an ELISA or LC-MS assay, and the one or more cardiovascular health markers are measured using standard clinical laboratory assays.

[0273] Detail 60: The method of detail 57, wherein the measurements are performed at time points selected from the group consisting of 1 week, 2 weeks, 1 month, 3 months, 6 months, and 1 year after administration of the composition, and the dosing regimen of the composition is adjusted based on the results of the measurements.

[0274] Previous approaches to reducing cardiovascular disease risk have focused on targeting various pathways involved in lipid metabolism and inflammation. Statins, for example, have been widely used to lower low-density lipoprotein (LDL) cholesterol levels, thereby reducing the risk of cardiovascular events. However, statins primarily target cholesterol synthesis and do not directly address the oxidative modifications of lipids, which are known to contribute to atherosclerosis. Other lipid-lowering agents, such as fibrates and niacin, have also been employed to modulate lipid profiles, but having no effects on oxidized phospholipids.

[0275] In addition to lipid-lowering therapies, antioxidants have been explored as a means to mitigate oxidative stress and its associated damage to lipids and lipoproteins.Vitamins C and E, as well as other antioxidant compounds, have been investigated for their potential to neutralize reactive oxygen species and prevent the oxidation of lipids. However, clinical trials have yielded mixed results, and these antioxidants often lack specificity for targeting oxidized phospholipids, which play a critical role in the pathogenesis of cardiovascular disease.

[0276] More recent research has focused on the development of specific scavengers for oxidized lipids, including oxidized phospholipids. These scavengers are designed to selectively bind and neutralize oxidized lipids, thereby preventing their pro-inflammatory and pro- atherogenic effects. Some experimental compounds have shown promise in preclinical studies,demonstrating the ability to reduce oxidative stress and inflammation in animal models. However, challenges remain in achieving sufficient specificity and efficacy in human subjects, as well as in optimizing the pharmacokinetic properties of these compounds for therapeutic use.

[0277] However, none of these approaches have provided a comprehensive solution that combines the features described in this disclosure.

[0278] In some examples, a dose administered to a mammal, particularly a human, in the context of the present invention should be sufficient to elicit a therapeutic response in the mammal over a reasonable time frame. The dose will be determined by the strength of the particular compound or composition administered and the condition of the mammal (e.g., human), as well as the body weight of the mammal to be treated. The size of the dose also will be determined by the existence, nature, and extent of any adverse side effects that might accompany the administration of a particular compound or composition. In some embodiments, the suitable dosage for internal administration is 0.01 to 100 mg / kg per day. In other embodiments, the suitable dosage is 0.01 to 35 mg / kg per day. In yet another embodiment, the suitable dosage is 0.05 to 50 mg / kg per day.

[0279] In some embodiments, a suitable concentration of the compound in pharmaceutical compositions for topical administration is 0.05 to 99% (by weight). In some embodiments, the concentration for topical administration is from 0.02 to 5%. In other embodiments, the concentration is from 0.1 to 3%. Ultimately, the attending physician will decide the dosage and the amount of the compound of the invention with which to treat each individual patient, taking into consideration a variety of factors, such as age, body weight, general health, diet, sex, compound or composition to be administered, route of administration, and severity of the disease being treated. In some examples, the compositions can be drug in capsule.

[0280] One skilled in the art will appreciate that suitable methods of administering the compound of the present invention or composition thereof to a mammal such as a human, are known, and, although more than one route can be used to administer a particular composition, a particular route can provide a more immediate and more effective reaction than another route.

[0281] The description of embodiments of the disclosure is not intended to be exhaustive or to limit the disclosure to the precise form disclosed. While specific embodiments of, and examples for, the disclosure are described herein for illustrative purposes, various equivalent modifications are possible within the scope of the disclosure, as those skilled in the relevant art will recognize. For example, while method steps or functions are presented in a given order, alternative embodiments may perform functions in a different order, or functionsmay be performed substantially concurrently. The teachings of the disclosure provided herein can be applied to other procedures or methods as appropriate. The various embodiments described herein can be combined to provide further embodiments. Aspects of the disclosure can be modified, if necessary, to employ the compositions, functions and concepts of the above references and application to provide yet further embodiments of the disclosure. Moreover, due to biological functional equivalency considerations, some changes can be made in protein structure without affecting the biological or chemical action in kind or amount. These and other changes can be made to the disclosure in light of the detailed description. All such modifications are intended to be included within the scope of the appended claims.

[0282] Specific elements of any of the foregoing embodiments can be combined or substituted for elements in other embodiments. Furthermore, while advantages associated with certain embodiments of the disclosure have been described in the context of these embodiments, other embodiments may also exhibit such advantages, and not all embodiments need necessarily exhibit such advantages to fall within the scope of the disclosure.

[0283] The technology described herein is further illustrated by the following examples which in no way should be construed as being further limiting. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below.EXAMPLES

[0284] The invention now being generally described, it will be more readily understood by reference to the following examples which are included merely for purposes of illustration of certain aspects and embodiments of the present invention and are not intended to limit the invention.EXAMPLE 1. METHODS FOR TREATING PATIENTS

[0285] Lipoprotein (a) levels cannot be controlled by healthy eating and exercising. Lipoprotein apheresis is the only therapy approved by the Food and Drug Administration (FDA) for treating high Lp(a) levels, and it is only approved for people with familial hypercholesterolemia (FH) who have LDL>100 mg / dL, Lp(a)>60 mg / dL, and coronary or other artery disease. Apheresis is a treatment like dialysis in which a machine removes Lp(a) and LDL-cholesterol from the blood. Instead of apheresis, the technology herein is used to provide a targeted biochemical intervention that modifies the Oxidized Phospholipids (OxPLs) on Lp(a), effectively "detoxifying" the Lp(a) particles. This method employs a specific set of molecularagents that selectively react with the OxPLs, neutralizing their harmful effects and potentially transforming Lp(a) into a less harmful form. These set of molecular agents are called dicarbonyl scavengers.

[0286] The methods disclosed herein can involve using a molecular agent to interact with a lipid on lipoprotein (a), modifying the lipid through a biochemical process, and transforming the lipoprotein (a) into a less harmful form. The methods also include using a specific set of molecular agents in the biochemical process to selectively react with the lipoprotein (a), neutralizing their harmful effects. A system for treating high lipoprotein levels includes a therapy that eliminates certain lipoproteins from the bloodstream, a medical procedure similar to dialysis, and a targeted biochemical intervention that modifies a lipid on the lipoprotein.

[0287] In a prophetic example, patients are treated using methods disclosed herein. FIG. 4 shows a general method 110. Referring to FIG. 4, Step 100 involves the use of molecular agents known as dicarbonyl scavengers to specifically interact with lipids called Oxidized Phospholipids (OxPLs) on lipoprotein (a). These molecular agents are chosen for their ability to react with OxPLs, as indicated in sub-step 100-a. The dicarbonyl scavengers, as described in sub-step 100-b, are compounds that target and neutralize reactive carbonyl species within the OxPLs.

[0288] The action of using these molecular agents (Step 100) refers to the selection and application of dicarbonyl scavengers to chemically interact with OxPLs. The dicarbonyl scavengers and the OxPLs are the primary components involved in this process. The goal of this interaction is to modify the OxPLs to reduce their contribution to the negative effects associated with lipoprotein (a), which is linked to cardiovascular disease risk.

[0289] The process involves the preparation and administration of dicarbonyl scavengers to individuals with elevated levels of lipoprotein (a). Once administered, the scavengers circulate in the bloodstream, encounter lipoprotein (a) particles, and react with the OxPLs on these particles. This reaction aims to chemically alter the OxPLs, thereby transforming lipoprotein (a) into a form that is associated with reduced harm.

[0290] The modification of the lipid (Step 102) is a result of the interaction between the dicarbonyl scavengers and the OxPLs. The process used (Step 102-a) is a targeted intervention, which is a strategic approach to changing the chemical structure of OxPLs. This process is designed to specifically target the OxPLs on lipoprotein (a), which is why the molecular agents are selective in their activity.

[0291] In essence, Step 100 and its sub-steps outline the initiation of a biochemical intervention where dicarbonyl scavengers are used to interact with and modify OxPLs on lipoprotein (a), with the aim of neutralizing their negative effects and reducing the associated cardiovascular risk.

[0292] Step 102 involves the chemical alteration of Oxidized Phospholipids (OxPLs) on lipoprotein (a) through a specific biochemical process. This process is facilitated by molecular agents known as dicarbonyl scavengers, which are designed to selectively react with the OxPLs. The interaction between these scavengers and the OxPLs results in the modification of the OxPLs, thereby reducing their reactivity and potential to contribute to cardiovascular diseases.

[0293] Sub-step 102-a specifies that the biochemical process is targeted, meaning it is conducted under conditions that favor the intended modification of the OxPLs. This may include optimizing environmental factors such as pH, temperature, and the concentration of the scavengers to ensure the efficiency of the reaction. The goal of this process is to modify the structure of the OxPLs, transforming lipoprotein (a) into a form with reduced potential for harm.

[0294] The process described in Step 102 and sub-step 102-a is a methodical approach to addressing the issue that lipoprotein (a) levels are not manageable through diet and exercise alone. By employing dicarbonyl scavengers, the OxPLs on lipoprotein (a) undergo a modification that aims to neutralize their harmful effects, thereby contributing to the transformation of lipoprotein (a) into a form that is less likely to cause harm.

[0295] Step 104 outlines the process by which lipoprotein (a) is transformed into a form that is less harmful. This transformation is achieved through a biochemical process that involves the modification of a specific type of lipid present on the lipoprotein (a) particles. The agents responsible for this modification are known as dicarbonyl scavengers. These agents interact with Oxidized Phospholipids (OxPLs) on the lipoprotein (a), altering their structure and thereby neutralizing their harmful properties. This alteration is referred to as 'detoxification.'

[0296] The administration of dicarbonyl scavengers to a patient with elevated levels of lipoprotein (a) results in a series of chemical reactions. These reactions are selective, targeting only the OxPLs and not other components in the bloodstream. The selectivity of the reaction is essential to ensure that only the intended modifications occur, without unintended effects on other biological molecules or cells.

[0297] The biochemical process employed in step 104 is designed to specifically affect the OxPLs on lipoprotein (a). The process involves the dicarbonyl scavengers reacting with the OxPLs, which leads to a reduction in the reactive properties of these lipids. The outcome of thisprocess is a modified form of lipoprotein (a) with reduced potential to cause harm, particularly in the context of cardiovascular risk.

[0298] In summary, step 104 describes the process by which dicarbonyl scavengers are used to modify OxPLs on lipoprotein (a), resulting in a modified form of the lipoprotein that is less likely to contribute to cardiovascular issues. This step is a part of a method that aims to address high levels of lipoprotein (a) in the bloodstream.

[0299] Step 106 involves the use of a set of molecular agents known as dicarbonyl scavengers within a biochemical process to selectively react with lipoprotein (a) and neutralize its effects. This step is part of a method to modify lipoprotein (a) to transform it into a form that is less harmful.

[0300] The actions in step 106 consist of applying a mixture or formulation of dicarbonyl scavengers that have been identified for their ability to interact with Oxidized Phospholipids (OxPLs) on lipoprotein (a). These scavengers are used because they can specifically bind to and neutralize the reactive carbonyl groups present in OxPLs, which are associated with the atherogenic properties of lipoprotein (a). The involved components are the dicarbonyl scavengers and the OxPLs.

[0301] The dicarbonyl scavengers react chemically with the OxPLs, thereby modifying the lipoprotein (a) particles. This modification is achieved through a biochemical intervention, which is a process designed to ensure the selective modification of OxPLs without affecting other components. The objective of this intervention is to reduce the potential of lipoprotein (a) to contribute to cardiovascular diseases associated with high levels of this lipoprotein.

[0302] Sub-step 106-a refers to the application of the dicarbonyl scavengers to neutralize the effects of OxPLs. This indicates that the scavengers are active in the biochemical process, ensuring that the OxPLs are modified. The neutralization likely involves the formation of stable compounds that no longer contribute to the processes typically induced by OxPLs.

[0303] In summary, step 106 and sub-step 106-a describe the application of dicarbonyl scavengers in a biochemical intervention aimed at modifying OxPLs on lipoprotein (a) to reduce its effects, thereby contributing to the management of high lipoprotein (a) levels.

[0304] In some embodiments, it is found that the methods and systems can be utilized to improve the health of a person who would otherwise not be considered to be at risk of a cardiovascular disease.EXAMPLE 2 INVESTIGATION OF THE INFLUENCE OF LIPOPROTEIN(A) AND OXIDIZED LIPOPROTEIN(A) ON PLASMINOGEN ACTIVATION AND FIBRINOLYSIS

[0305] In this example, we compare the influence of oxidized lipoprotein(a) [Lp(a)] and unoxidized Lp(a) on plasminogen activation in the process of fibrinolysis and elucidate the potential atherogenic mechanisms of oxidized Lp(a), focusing on its role in thrombosis.

[0306] Chromogenic substrate assays were conducted to study the kinetics of plasminogen activation. Fibrin clots were generated by incubating fibrinogen with thrombin, and plasminogen activation was triggered with tissue plasminogen activator (tPA). Experiments were performed in low and high concentrations of Lp(a) or oxidized Lp(a) to evaluate their respective effects on plasmin generation. Oxidized Lp(a) was prepared by chemical oxidation of isolated Lp(a) samples.

[0307] Approximately 30% of the U.S. population has elevated plasma concentrations of lipoprotein(a) [Lp(a)], which has been increasingly recognized as a significant risk factor in causing thrombotic cardiovascular diseases.21Elevated Lp(a) levels are related to an increased risk of atherosclerosis, myocardial infarction, and stroke. Despite its clinical relevance, no well- established medications are currently available to effectively lower Lp(a) levels as a therapeutic intervention, highlighting the urgent need for further research in this area.

[0308] Lipoproteins, which are essential carrier molecules composed of proteins and lipids, play an important role in transporting cholesterol and other lipids through the bloodstream. These molecules ensure the delivery of cholesterol to peripheral tissues for cellular functions and to the liver for metabolism and excretion. Among the different classes of lipoproteins, Lp(a) is a type of low-density lipoprotein (LDL), which is distinguished by the presence of an apo(a) fragment — glycoprotein covalently linked to the LDL core protein, apoB.21The structural complexity of Lp(a) not only influences its physiological behavior but also contributes to its pathological role in cardiovascular diseases.

[0309] A notable feature of Lp(a) is its role as the primary carrier of oxidized phospholipids (OxPLs), which are bioactive molecules with pro-inflammatory and pro-thrombotic properties.22Recent studies have identified OxPLs as significant and independent causal factors in atherothrombotic risk, further amplifying the clinical significance of Lp(a) in the field of cardiovascular pathology.23Increased levels of Lp(a) and its oxidized derivatives are implicated in promoting arterial plaque formation, inflammation, and thrombosis, underscoring the complex interplay between lipoprotein biology and vascular health.

[0310] Under normal physiological conditions, the body maintains a delicate balance between coagulation and fibrinolysis to prevent both excessive clot formation (thrombosis) andbleeding (hemorrhage). Fibrinolysis, the process of breaking down fibrin clots, is primarily mediated by plasmin, a serine protease derived from its zymogen precursor, plasminogen.24This conversion is facilitated by tissue plasminogen activator (tPA), which cleaves the Arg561- Val562 bond in plasminogen, leading to the formation of active plasmin.25Once activated, plasmin binds to fibrin and degrades it, thereby maintaining hemostatic equilibrium.

[0311] However, the structural similarity between Lp(a) and plasminogen disrupts this balance. The apo(a) fragment, which is a unique protein component of Lp(a), exhibits high structural homology to plasminogen, with 61%-75% similarity, particularly in the Kringle IV-10 domain.26This domain has a strong lysine binding site, which not only moderates the binding of Lp(a) to fibrin clot but also serves as a critical interaction site for OxPLs. The apo(a) fragment act as a competitor with plasminogen when binding to fibrin, which forms a quaternary structure that reduces the rate of plasminogen activation and subsequently impairs fibrinolysis.27This mechanism highlights how Lp(a) contributes to a pro-thrombotic state, with oxidized Lp(a) amplifying these effects due to its additional interactions with OxPLs.

[0312] Because of Lp(a)’s potential role in coagulation and its implications for cardiovascular disease, understanding its precise mechanisms is of paramount importance. This study aims to elucidate the molecular pathways through which Lp(a) and oxidized Lp(a) influence plasminogen activation and fibrinolysis, shedding light on their thrombogenic properties and potential as therapeutic targets. By addressing these mechanisms, this research seeks to bridge critical knowledge gaps and pave the way for novel therapeutic strategies to mitigate the risks associated with higher Lp(a) levels.

[0313] MATERIALS AND METHODS: 1. Preparation of molecules; the lipoprotein Lp(a) was isolated from patient blood samples. Oxidized Lp(a) was subsequently generated from these extracted samples through oxidation with glucose oxidase. Briefly, in a 500 pL Lp(a) solution, 25 pL of reaction mix (DTPA 200 pM, glucose 100 pg / mL, NaNO20.05 mM in sodium phosphate buffer 50 mM, pH 7.4), 2.28 pL of MPO (57 nM), and 1 pL of glucose oxidase (20 ng / mL) were added. After a 30-minute incubation at 37°C, the reaction was stopped by adding 1 pL of BHT (40 pM, prepared in ethanol).

[0314] Fibrinogen and thrombin alpha-l la (HCI-0150R and HCT-0020; Haematologic Technologies), hirudin (H0393; Sigma-Aldrich), plasminogen (HPg 2001 , glu-plasminogen; Enzyme Research Laboratory), tPA (Genentech), and S-2302 (S820340, H-D-prolyl-L- phenylalanyl-L-arginine-p-nitroanilide dihydrochloride; DiaPharma) were sourced commercially.

[0315] 2. PEG-20,000 coating; A 10 mg / mL solution of PEG-20,000 in MQ water was prepared and stirred on a hot plate until fully dissolved. After cooling to room temperature, 300pL of the solution was added to each well of a 96-well plate. The plates were left at room temperature overnight. The next day, the coating solution was removed by vacuum. The plates were then dried at 55°C and allowed to cool before being used in the fibrinolysis assay.

[0316] 3. Chromogenic substrate assay; The assay was performed in 20 mM HEPES(pH 7.4), 0.1 M NaCI, and 0.1% PEG-8000 at 37°C in a 96-well plate. To generate fibrin, fibrinogen was added to the buffer to a final concentration of 200 pg / mL, followed by the addition of thrombin alpha-l la to 50 nM. Then, the mixture was incubated for 20 minutes at 37°C in a pre-warmed plate reader. Subsequently, 250 nM hirudin was added and incubated for an additional 5 minutes to stop the reaction. For the chromogenic substrate assay for fibrinolysis, Lp(a), glu-plasminogen (200-5,000 nM), tPA (1 nM), and S-2302 (2 mM) were sequentially added to the solution. The kinetics of all reactions were monitored by measuring the optical densities at 405 nm at 30-second intervals using a BioTek microtiter plate reader.

[0317] RESULTS: 1. Initial rates of plasminogen activation; To enable tPA-mediated plasminogen activation, which requires fibrin, fibrin was first prepared by incubating fibrinogen with thrombin alpha-l la for the assay. To validate the chromogenic substrate assay for measuring plasmin formation with Lp(a), different concentrations of plasminogen (0-1 ,000 nM) were activated by tPA, and the resulting plasmin formation was quantified using the chromogenic substrate S-2302. Plasminogen activation requires binding to fibrin, a process that can be influenced by Lp(a) or oxidized Lp(a) (FIG. 5).28As shown in FIG. 6, the kinetic analysis revealed a strong linear correlation between plasminogen concentration and the initial rate (Vmax) of plasmin formation (R2=0.9913). These results demonstrate the reliability of the chromogenic substrate assay for studying plasminogen activation and fibrinolysis under experimental conditions.

[0318] To confirm that the assay could be used in subsequent experiments involving Lp(a) and oxidized Lp(a), we validated the initial rate (Vmax) of plasminogen activation in the presence of fibrin and tPA. The high R2value further indicates the assay’s sensitivity and suitability for studying variations in plasmin generation under different experimental conditions, including the presence of Lp(a) variants.

[0319] 2. Effect of Lp(a) on plasminogen activation; Fibrin clots were pre-formed by incubating fibrinogen with thrombin to study the role of Lp(a) in plasminogen activation, followed by the addition of 0.2 pM Lp(a) or no Lp(a) to the assay mixture. tPA was then added to initiate the process of plasminogen activation and the kinetics of plasmin formation were monitored (FIG. 7). The results showed that plasmin levels increased significantly when Lp(a) is present compared to the control group (no Lp(a)). This enhancement suggests that low levels of Lp(a)may support or promote plasminogen activation, consistent with its physiological role under normal conditions.

[0320] Interestingly, when plasminogen concentrations were optimized at 0.5 pM, the supporting effect of Lp(a) became more pronounced (FIG. 7). These findings imply that baseline levels of Lp(a) in the blood may contribute positively to fibrinolysis. However, according to our hypothesis, higher concentration of Lp(a), especially oxidized Lp(a), could exhibit inhibitory effects, as tested in subsequent experiments.

[0321] 3. Oxidized Lp(a) inhibiting or slowing down the activation of plasminogen; To further evaluate the influence of Lp(a) towards plasminogen activation, the concentrations of Lp(a) and oxidized Lp(a) were increased from 0.2 pM to 0.5 pM. No significant difference in plasminogen activation was observed in the condition with unoxidized Lp(a) compared to the control without Lp(a), as shown in FIG. 8A. The kinetic profile of plasmin generation with unoxidized Lp(a) remained similar to the control, with plasmin levels reaching a plateau at approximately 50 minutes. These findings indicate that unoxidized Lp(a) does not substantially affect plasminogen activation at this concentration.

[0322] In contrast, oxidized Lp(a) demonstrated an inhibitory effect on plasminogen activation. Shown in FIG. 8B, plasmin levels plateaued earlier, within 30-40 minutes, compared to 50 minutes in the presence of unoxidized Lp(a). Furthermore, the total amount of plasmin generated was reduced under the oxidized Lp(a) trial, as indicated by the red (or grey) arrow in FIG. 8B. This suggests that oxidized Lp(a) impairs the overall efficiency of plasminogen activation.

[0323] A distinct feature of the oxidized Lp(a) group was a transient dip in plasmin levels during the early phase of the reaction (red or grey circle, FIG. 8B). This dip was not observed with unoxidized Lp(a) or in the control, suggesting a potential mechanism of interference by oxidized Lp(a). This inhibitory effect could be due to competition between oxidized Lp(a) and plasminogen for fibrin binding, driven by their structural similarity. Additionally, oxidized Lp(a) may disrupt fibrin-tPA interactions, further inhibiting plasminogen activation.

[0324] DISCUSSION: Higher levels of Lp(a) are tightly linked with atherogenic effect in causing cardiovascular diseases, as previously reported.29Under normal physiological conditions, the concentration of Lp(a) in healthy individual’s plasma is usually below 30 mg / dL (0.075 pM), while levels exceeding 50 mg / dL (0.125 pM) are considered high and correlate with increased cardiovascular risk.30In severe cases, Lp(a) can reach levels as high as 1 ,000 mg / dL (2.5 pM). Based on these ranges, we initially selected a concentration of 0.2 pM for our study to elucidate the influence of lipoprotein Lp(a) on plasminogen activation. Surprisingly, our findingsshowed that at low concentrations, Lp(a) enhanced plasminogen activation rather than inhibiting it, as demonstrated in FIG. 7. This result aligns with physiological observations, where baseline levels of Lp(a) are supporting fibrinolysis. However, the lack of inhibition at 0.2 M in vitro suggests a discrepancy between Lp(a)’s effects in vivo and in experimental models, potentially due to differences in systemic and local concentrations.

[0325] To better understand this, we increased the Lp(a) concentration to 0.5 pM and observed a significant inhibitory effect of oxidized Lp(a) on plasminogen activation (FIG. 8B). This inhibition is consistent with oxidized Lp(a)’s role in increasing atherothrombotic risk, likely due to its high structural homology with plasminogen and increased OxPL content. OxPLs are known to mediate the competition between oxidized Lp(a) and plasminogen in binding to fibrin clots, impairing fibrinolysis.31Furthermore, oxidized Lp(a) may also interfere with the binding of tPA to fibrin, as suggested by its stronger inhibitory effects compared to unoxidized Lp(a) (FIG. 8B).

[0326] Interestingly, the kinetic curves for oxidized Lp(a) demonstrated a distinct dip in plasmin generation before plateauing, a phenomenon not observed with unoxidized Lp(a) (FIG. 8B). This dip could be explained by oxidized Lp(a)’s enhanced competition with fibrin fragments, which normally promote fibrinolysis through positive feedback.32This observation underscores oxidized Lp(a)’s unique inhibitory mechanism, emphasizing its detrimental role in thrombotic conditions.

[0327] Therapeutically, reducing the levels of oxidized Lp(a) represents a promising approach to restoring the balance between plasminogen activation and fibrinolysis. Given its capacity to interfere with fibrin binding and impair plasmin generation, oxidized Lp(a) contributes to a prothrombotic environment that may underlie its association with increased cardiovascular risk. While current treatments primarily focus on lowering total Lp(a), the selective reduction of its oxidized forms may offer additional benefit by directly addressing its functional impact on fibrinolytic processes. Future research should focus on identifying pharmacological or dietary interventions capable of decreasing oxidized Lp(a) levels, as well as exploring biomarkers to monitor the oxidative state of lipoproteins in clinical settings.

[0328] In some embodiments, interventions targeting oxidized Lp(a) or its OxPL content may mitigate its thrombogenic effects. For instance, 2-hydroxybenzylamine (2-HOBA), which is a natural compound found in buckwheat, has demonstrated potent reactivity with dicarbonyl electrophiles, effectively scavenging OxPLs. Reducing OxPLs on oxidized Lp(a) could restore the balance of fibrinolysis and plasminogen activation, offering a potential strategy to address atherothrombosis. Future studies should aim to evaluate whether 2-HOBA can normalizeplasminogen activation rates when oxidized Lp(a) level increases and explore its therapeutic potential in vivo.

[0329] Results: Low concentrations of Lp(a) enhanced plasminogen activation and fibrinolysis, reflecting its physiological role. However, at higher concentrations, oxidized Lp(a) exhibited a significant inhibitory effect on plasminogen activation. Compared to unoxidized Lp(a), oxidized Lp(a) led to earlier plateauing of plasmin generation and reduced overall plasmin levels. The inhibitory effects of oxidized Lp(a) are likely due to its structural similarity to plasminogen and higher oxidized phospholipid content, which competes with plasminogen for fibrin binding — the enhanced competition with fibrin fragments and tPA by oxidized Lp(a) further impaired fibrinolysis.

[0330] Conclusion: This study demonstrates that while low levels of Lp(a) may support fibrinolysis, oxidized Lp(a) impairs this process by inhibiting plasminogen activation through structural and functional competition. These findings highlight the atherogenic potential of oxidized Lp(a) and its contribution to thrombotic cardiovascular risk. Derivatives of 2- hydroxybenzylamine are being investigated to mitigate the thrombogenic effects of oxidized Lp(a).EXAMPLE 3: PRELIMINARY DATA OF 2-HOBA REDUCES THE PATHOGENICITY OF LIPOPROTEIN (A)

[0331] In additional work, FIG. 13 shows LPS-induced cytokine mRNA expression in macrophages following exposure to native and oxidized lipoprotein(a). Macrophages were pretreated for 15 minutes with 100 pg / mL of Lp(a), oxidized Lp(a) [oxLp(a)], lead-treated oxLp(a), or oxLp(a) combined with lead-treated cells, followed by overnight stimulation with 5 ng / mL LPS. Gene expression of TN Fa, IL-6, and I L1B was measured by qPCR. Data represent mean ± SEM, n = 4; statistical significance was assessed using ANOVA with post hoc testing (p values indicated). FIG. 14 shows cell count and representative brightfield images of Aortic Smooth Muscle Cells (ASMCs) treated with vehicle, Lp(a) (200 pg / mL), oxLp(a) (200 pg / mL), or oxLp(a) in combination with 2-HOBA treatment. Two treatment strategies were used for 2-HOBA: (1) 2- HOBA pre-treatment of oxLp(a) before addition to cells, and (2) pre-treatment of cells with 2- HOBA prior to oxLp(a) exposure. Total cell number was quantified and shown in the bar graph. FIG. 15A shows representative LC-MS / MS chromatograms showing detection of IsoLG-lysine adducts in Lp(a) and oxLp(a) samples. IsoLG was detectable in both Lp(a) and oxLp(a), with significantly higher levels in oxLp(a) compared to native Lp(a). FIG. 15B shows quantification of IsoLG-lys intensity demonstrates a reduction in signal following treatment with 2-HOBA at bothlow and high concentrations. Data represent mean ± SEM; p values from one-way ANOVA with multiple comparisons are indicated.

[0332] FIGs. 16A-16B shows non-limiting examples of oxidized phospholipids, modification of proteins and enzymatic hydrolysis. A typical phospholipid containing a phosphocholine head group (shown in light grey in the figure), a saturated fatty acyl group (palmitoyl) at the sn-1 position and an omega-6 polyunsaturated fatty acyl group (arachidonoyl) at the sn-2 position is shown in part a in the figure. The omega-6 polyunsaturated fatty acyl group can be oxidized to a variety of structures, many involving chain scission and formation of reactive aldehydes, such as in 1-palmitoyl-2- (5-oxovaleroyl)-sn-glycero-3-phosphocholine (part b). The aldehyde can form Schiff base adducts with lysine (part c) and cysteine side chains.Another type of oxidized structure is y-hydroxy aldehydes such as in 1-palmitoyl-2 (5-hydroxy-8- oxo-6-octenoyl)-sn-glycero-phosphatidylcholine (part d) which can react with histidine side chains of protein substrates in a michael addition reaction (part e), which then cyclizes to the more stable hemiacetal form (part f). The enzyme phospholipase A2 (PIA2 ) hydrolyses the ester bond at the sn-2 position to release lysophosphatidyl choline and the remnant of the hemiacetal on the protein (part g). lysophosphatidylcholine is hydrolysed by autotaxin (ATX) to yield lysophosphatidic acid and the phosphocholine head group (part h). oxidized phospholipid adducts on proteins, lysophosphatidylcholine and lysophosphatidic acid are all bioactive compounds that promote inflammatory responses (Boffa & Koschinsky, 2019).EXAMPLE 4 SYNTHESIS OF 2-HYDROXYBENZYLAMINE ANALOGS

[0333] The various 2-Hydroxybenzylamine (2-HOBA) chemical structures shown in ‘Feature 3’ above are synthesized and tested.

[0334] 2-Hydroxybenzylamine (2-HOBA), found in buckwheat, is being explored herein as a nutritional supplement and potential therapeutic agent due to its ability to scavenge reactive carbonyl species, protecting against oxidative stress and potentially mitigating age- related pathologies. The goal of this project is to improve: (1) the half-life of 2-HOBA in the blood stream; (2) the reactivity to scavenge reactive carbonyl species and (3) improve the vascular circulation and binding its affinity to lipoproteins.

[0335] The objective of the project is to synthesize at least 15-20 analogs of 2- hydroxybenzylamine during a three-month period. FIG. 9 shows an example chemical structure of 2-Hydroxybenzylamine. FIG. 10 shows example chemical structures of 2- Hydroxybenzylamine analogs.

[0336] We plan on preparing at least 15-20 analogs selected from the structures shown in FIG. 10. Our synthetic route will be based on literature procedures and our synthetic experience. These targets are subject to change upon request from the client. To increase the reactivity of HOBA, it may be necessary to modify the electronic density on the aromatic ring. We therefore propose to introduce halides (F, Cl, I) and alkyl groups at different positions, as shown in FIG. 10. Most of these compounds will be prepared following the route shown in Scheme 1 (FIG. 11 A).

[0337] Not in the scope of this proposal and for possible future work, we propose to extend the half-life of HOBA by masking the hydroxyl and amino group with an acyl or sulfonyl group to avoid immediate oxidation, shown in Figure 3. We also can protect the amino group as imine with longer alkyl tails.

[0338] We may be able to prepare these proposed compounds by the following routes, shown in Scheme 2. FIG. 11A shows an example synthetic scheme (Scheme 1) for a selection of 2-Hydroxybenzylamine analogs.

[0339] FIG. 11B shows example chemical structures of 2-Hydroxybenzylamine analogs..

[0340] FIG. 12 shows an example synthetic scheme (Scheme 2) for 2- Hydroxybenzylamine analogs.

[0341] Also, not in the scope of this proposal and for possible future work , we propose to evaluate the stability of compounds prepared in this project. The research objective of the FTE scientist(s) assigned to this collaboration is to synthesize these analogs in 20 100 mg scale. Weekly progress report and a final report. Weekly chemistry meeting for synthetic / analytical and to discuss new plans or proposals. Advanced materials and final products produced during the collaboration will be offered for shipment, along with appropriate analytical characterization.REFERENCES:1Kabat, E.A., et al. (1987) and (1991). SEQUENCES OF PROTEINS OF IMMUNOLOGICAL INTEREST. (NationalInstitutes of Health, Bethesda, Md.2Padlan, E.A., et al. (1995). “Identification of specificity-determining residues in antibodies.” FASEB J.9(1): 133-139.3MacCallum, R.M., et al. (1996). “Antibody-antigen interactions: contact analysis and binding site topography.” J. Mol. 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Shamanaev A, Dickeson SK, Ivanov I, Litvak M, Sun MF, Kumar S, et al. Mechanisms involved in hereditary angioedema with normal C1 -inhibitor activity. Front Physiol 2023;14:1146834. Hervio L, Brunner C, Sorell L, Kang C, Muller H, Angles-Cano E. Effect of plasminogen activators on human recombinant apolipoprotein(a) having the plasminogen activation cleavage site. Biochim Biophys Acta 1999;1434:124-134.27Riches K, Porter KE. Lipoprotein(a): cellular effects and molecular mechanisms. Cholesterol2012;2012:923289.28De Simone I, Roest M, Wolberg AS, de Laat B, Huskens D. A novel plasminogen activator anti-fibrin- uPA increases the sensitivity of the plasmin generation assay to therapeutic target PAI-1 . Blood 2023;142:5464.29Vinci P, Di Girolamo FG, Panizon E, Tosoni LM, Cerrato C, Pellicori F, et al. Lipoprotein(a) as a risk factor for cardiovascular diseases: pathophysiology and treatment perspectives. I nt J Environ Res Public Health 2023;20:6721 .30Farzam K, Zubair M, Senthilkumaran S. Lipoprotein A [Internet], StatPearls Publishing; 2024 Feb 27.Available from: https: / / www.ncbi.nlm.nih.gov / books / NBK570621 / .31Loscalzo J, Weinfeld M, Fless GM, Scanu AM. Li poprotein (a), fibrin binding, and plasminogen activation. Arteriosclerosis 1990;10:240-245.32Edelberg JM, Pizzo SV. Lipoprotein (a) in the regulation of fibrinolysis. J Atheroscler Thromb 1995;2Suppl 1 :S5-S7.

[0342] All patents and other publications; including literature references, issued patents, published patent applications, and co-pending patent applications; cited throughout this application are expressly incorporated herein by reference for the purpose of describing and disclosing, for example, the methodologies described in such publications that might be used in connection with the technology described herein. These publications are provided solely for their disclosure prior to the filing date of the present application. Nothing in this regard should be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention or for any other reason. All statements as to the date or representation as to the contents of these documents is based on the information available to the applicants and does not constitute any admission as to the correctness of the dates or contents of these documents.

[0343] The foregoing written specification is considered to be sufficient to enable one skilled in the art to practice the present aspects and embodiments. The present aspects and embodiments are not to be limited in scope by examples provided, since the examples are intended as a single illustration of one aspect and other functionally equivalent embodiments are within the scope of the disclosure. Various modifications in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and fall within the scope of the appended claims. The advantages and objects described herein are not necessarily encompassed by each embodiment. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. Such equivalents are intended to be encompassed by the following claims.

Claims

CLAIMSH / e claim:

1. A composition for reducing cardiovascular disease risk in a subject, the composition comprising: a potent reactive oxidized phospholipid (OXPL) scavenger in a therapeutically effective amount; wherein the reactive OXPL scavenger selectively and efficiently modifies an oxidized phospholipid and / or an oxidized phospholipid on a lipoprotein(a) particle circulating in the subject's bloodstream, thereby reducing the cardiovascular disease risk in the subject, and / or wherein the reactive OXPL scavenger comprises at least one of 2-HOBA (2- hydroxybenzylamine), a potent analog of 2-hydroxybenzylamine (2-HOBA), or a modified analog of 2-HOBA, the modified analog of 2-HOBA having additional substituents covalently attached to enhance its efficacy.

2. The composition of claim 1, wherein the reactivity of 2-HOBA is increased by modifying the electronic density on the aromatic ring in the 2-HOBA by introducing at least one of halides (e.g., Br, F, Cl, I) and alkyl groups at different positions on the aromatic ring, and wherein the half-life of the 2-HOBA is extended in humans by masking at least one of the hydroxyl group and the amino group on the 2-HOBA with at least one of an acyl group and a sulfonyl group to avoid immediate oxidation in a human; and optionally wherein the 2-HOBA chemical structures comprise one or more of: 2-fluoro-6-hydroxybenzylamine, 2-chloro-6-hydroxybenzylamine, 2- bromo-6-hydroxybenzylamine, 2-iodo-6-hydroxybenzylamine, 2-methyl-6-hydroxybenzylamine, 2-ethyl-6-hydroxybenzylamine, 2-propyl-6-hydroxybenzylamine, 2-butyl-6-hydroxybenzylamine, 2-pentyl-6-hydroxybenzylamine, 2-hexyl-6-hydroxybenzylamine, 2-heptyl-6- hydroxybenzylamine, 2-octyl-6-hydroxybenzylamine, 2-nonyl-6-hydroxybenzylamine, 2-decyl-6- hydroxybenzylamine, 2-fluoro-6-methyl-hydroxybenzylamine, 2-chloro-6-methyl- hydroxybenzylamine, 2-bromo-6-methyl-hydroxybenzylamine, 2-iodo-6-methyl- hydroxybenzylamine, 2-fluoro-6-ethyl-hydroxybenzylamine, 2-chloro-6-ethyl- hydroxybenzylamine, 2-bromo-6-ethyl-hydroxybenzylamine, 2-iodo-6-ethyl- hydroxybenzylamine, 2-fluoro-6-propyl-hydroxybenzylamine, 2-chloro-6-propyl- hydroxybenzylamine, 2-bromo-6-propyl-hydroxybenzylamine, 2-iodo-6-propyl- hydroxybenzylamine, 2-fluoro-6-butyl-hydroxybenzylamine, 2-chloro-6-butyl- hydroxybenzylamine, 2-bromo-6-butyl-hydroxybenzylamine, 2-iodo-6-butyl- hydroxybenzylamine, 2-fluoro-6-pentyl-hydroxybenzylamine, 2-chloro-6-pentyl- hydroxybenzylamine, 2-bromo-6-pentyl-hydroxybenzylamine, 2-iodo-6-pentyl-hydroxybenzylamine, 2-fluoro-6-hexyl-hydroxybenzylamine, 2-chloro-6-hexyl- hydroxybenzylamine, 2-bromo-6-hexyl-hydroxybenzylamine, 2-iodo-6-hexyl- hydroxybenzylamine, 2-fluoro-6-t-butyl-hydroxybenzylamine, 2-chloro-6-t-butyl- hydroxybenzylamine, 2-bromo-6-t-butyl-hydroxybenzylamine, 2-iodo-6-t-butyl- hydroxybenzylamine, 2-fluoro-6-i-propyl-hydroxybenzylamine, 2-chloro-6-i-propyl- hydroxybenzylamine, 2-bromo-6-i-propyl-hydroxybenzylamine, 2-iodo-6-i-propyl- hydroxybenzylamine, 2-fluoro-6-Boc-hydroxybenzylamine, 2-chloro-6-Boc-hydroxybenzylamine,2-bromo-6-Boc-hydroxybenzylamine, 2-iodo-6-Boc-hydroxybenzylamine, 2-fluoro-6-CD2CD3- hydroxybenzylamine, 2-chloro-6-CD2CD3-hydroxybenzylamine, 2-bromo-6-CD2CD3- hydroxybenzylamine, and / or 2-iodo-6-CD2CD3-hydroxybenzylamine.

3. The composition of claim 1, wherein the composition comprises one or more of the following chemical structures:(formula 3), (formula 4),(formula 6), (formula 7),wherein any of formulas 1-11 can include a chemical moiety (or “moiety”) attached via covalent bond to any suitable atom; and / or a pro-drug thereof and / or a pharmaceutically acceptable salt, solvate or hydrate of any of these chemical compounds / structures of formulas 1-11 ; and wherein each of R, Ri, R2, and R3are independently selected from and / or each is / are independently comprising hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, t-butyl, i-propyl, Br, F, Cl, I, -Boc, and / or CD2CD3; and / or wherein each of R, R1 , R2, and R3 are independently selected from and / or each is / are independently comprising C1-C4 alkyl, C1-C4 alkoxy, alkynoyl, C1-C4 alkylthiol, formyl, halogen, aryl, nitro, sulfanyl, hydrazino, amino, oxyamino, C1-C4 alkylamino, dialkylamino, or any combinations thereof; and / or wherein each occurrence of R, R1, R2, and R3each independently includes or is each independently comprising a combination of - H, -OH, carbonyl (=0), F, N, -0-, -S-, -NH-, a halogen, methyl (-CH3), t-butyl, -(CH2)n-CH3, wherein independently each n= 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9; -O- (CH2)n-CH3, wherein independently each n= 0, 1 , 2, 3, 4, 5, 6, 7, 8, or 9; -S-(CH2)n-CH3, wherein independently each n= 0, 1 , 2, 3, 4, 5, 6, 7, 8, or 9; -NH-(CH2)n-CH3, wherein independently each n= 0, 1 , 2, 3, 4, 5, 6, 7, 8, or 9; and / or wherein each occurrence of R, i, R2, and R3is independently including a substituent shown below and / or wherein the optional moiety includes a substituent shown below:wherein each independent occurrence ofs a linker to any one suitable atom (e.g., C, N, O, S) of the “formula 1-11” shown above and represents an attachment to an atom as indicated in any formula above and includes or is a combination of a single bond (-), a bond to a nitrogen, a bond to a carbon, a bond to an oxygen (-O-), a double bond ( = ), a triple bond ( E ) or (-C2H2-), a bond to C-C, a bond to C-N, -(CH2)n-, wherein independently each n= 0, 1, 2, 3, 4,5, 6, 7, 8, or 9; or a combination thereof; and wherein each occurrence of R, Ri, R2, and / or R3 each independently can represent R-R, R1-R1, R2-R2, and R3-R3; wherein each occurrence is independent of another occurrence and linked by a bond or by another linker0 any atom of the other; wherein each independent occurrence of L is a halogen including bromine, iodine, chlorine, or fluorine; and / or the step of administering a pharmaceutically acceptable salt thereof of any of the small molecules described above; and includes and / or the step of administering a pharmaceutically acceptable hydrate or solvate thereof, either with or without a salt form; and / or wherein any of R, R1, R2, and / or R3and / or wherein any of formulas 1-11 each independently can include the moiety that imparts both lipophilic and lipophobic properties — enhancing affinity for lipoproteins while limiting a cell entry; wherein the moiety keeps the compound of formula 1-11 confined to circulation and reduces potential off-target effects.

4. The composition of any one of claims 1-3, wherein the chemical structures comprise one or more of the following chemical structures:and / or a prodrug thereof and / or a pharmaceutically acceptable salt, solvate or hydrate of any of these chemical structures.

5. A method for reducing cardiovascular disease risk in a subject, the method comprising: administering to the subject a therapeutically effective amount of at least one of a potent reactive OXPL (oxidized phospholipid) scavenger; wherein the at least one of the reactive OXPL scavenger is configured to selectively modify a oxidized phospholipid on a lipoprotein(a) particle circulating in the subject's bloodstream, thereby efficiently detoxifying the lipoprotein(a) and significantly reducing the cardiovascular disease risk in the subject.

6. The method of claim 5, wherein the administration is continued for an optimal period of at least 4 weeks to 12 months to ensure sustained reduction in cardiovascular disease risk and / or wherein the at least one of a potent reactive OXPL scavenger is configured to target an oxidizedphospholipids including but not limited oxidized phosphatidylcholine, phosphatidylethanolamine, phosphatidic acid, phosphatidylserine, phosphoinositides and other types of phospholipids that containing a reactive aldehydes including but not limited to these with dicarbonyls, and / or optionally wherein the oxidized phospholipids containing a reactive dicarbonyl, for example, the following (dicarbonyl) chemical structures:highly reactive isolevuglandins (isoLG).

7. The method of claim 5, wherein the therapeutically effective amount is between 0.1 mg to 5000 mg per day and / or wherein the therapeutically effective amount is based on an individual response of the subject and / or a tolerability of the subject.

8. The method of claim 5, wherein the reactive OXPL scavenger comprises at least one of 2-HOBA (2-hydroxybenzylamine), a potent analog of 2-hydroxybenzylamine (2-HOBA), a modified analog of 2-HOBA wherein additional substituents have been covalently attached to enhance its efficacy, and / or one or more of the following chemical structures:(formula 3), (formula 4),(formula 6), (formula 7),and / or a pro-drug thereof and / or a pharmaceutically acceptable salt, solvate or hydrate of any of these chemical compounds / structures; and wherein each of R, Ri, R2, and R3 are independently selected from and / or are independently comprising hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, t-butyl, i-propyl, Br, F, Cl, I, -Boc, and / or CD2CD3.; and / or wherein each of each of R, R1, R2, and Rs are as is described in claim 3 above.

9. The method of claim 5, wherein the reactive OxPL scavenger is configured to selectively bind to and neutralize the reactive dicarbonyl moiety on the oxidized phospholipid, thereby preventing its effects on the vascular endothelium and reducing the overall atherogenicity of the lipoprotein(a) particle.

10. The method of claim 5, wherein the reactive OxPL scavenger is configured to reduce the oxidative stress and inflammation in the vascular wall by scavenging reactive oxygen species and dicarbonyls, thereby improving endothelial function and reducing the risk of atherosclerotic plaque formation and progression.

11. The method of claim 5, wherein the reactive OxPL scavenger is configured to inhibit the formation and accumulation of advanced glycation end products (AGEs) in the vascular tissue by trapping and neutralizing reactive dicarbonyls, thereby reducing the AGE-mediated crosslinking of collagen and stiffening of the arteries.

12. The method of any one of claims 5-10, wherein the chemical structures comprise one or more of the following chemical structures:and / or a prodrug thereof and / or a pharmaceutically acceptable salt, solvate or hydrate of any of these chemical structures.

13. The method of claim 8, wherein the reactive dicarbonyls or the oxidized phosphatidylcholine comprises a highly specific "OxPCCD36" class of oxidized phospholipids that is operative to potently promote platelet activation via the scavenger receptor CD36.

14. The method of claim 13, wherein the therapeutically effective amount is based on the binding affinity and specificity of the "OxPCCD36" class to CD36 receptor and / or wherein the therapeutically effective amount is between 0.1 mg to 5000 mg per day.

15. The method of claim 13, wherein the "OxPCCD36" class comprises a specific chemical structure comprising 1-palmitoyl-2-(5-hydroxy-8-oxooct-6-enoyl)-sn-glycero-3-phosphocholine (PHOdiA-PC), 1-palmitoyl-2-(5-hydroxy-8,11-dioxododec-6,9-dienoyl)-sn-glycero-3- phosphocholine (PHDdiA-PC), 1-palmitoyl-2-(5-hydroxy-8-oxooct-6-enoyl)-sn-glycero-3- phosphocholine (PHOOA-PC), 1-palmitoyl-2-(5-hydroxy-8-oxodec-6-enoyl)-sn-glycero-3- phosphocholine (PHODA-PC), 1-palmitoyl-2-(5-keto-6-octenedioyl)-sn-glycero-3- phosphocholine (PKOdiA-PC), 1-palmitoyl-2-(5-keto-8,11-dioxododec-6,9-dienoyl)-sn-glycero-3- phosphocholine (PKDdiA-PC), 1-palmitoyl-2-(5-keto-8-oxooct-6-enoyl)-sn-glycero-3- phosphocholine (PKOOA-PC), 1-palmitoyl-2-(5-keto-8-oxodec-6-enoyl)-sn-glycero-3- phosphocholine (PKODA-PC), 1-palmitoyl-2-(4-oxobutyroyl)-sn-glycero-3-phosphocholine, 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine, 1-palmitoyl-2-(6-oxohexanoyl)-sn- glycero-3-phosphocholine, 1-palmitoyl-2-(7-oxoheptanoyl)-sn-glycero-3-phosphocholine, 1- palmitoyl-2-(8-oxooctanoyl)-sn-glycero-3-phosphocholine, 1-palmitoyl-2-(9-oxononanoyl)-sn- glycero-3-phosphocholine, 1-palmitoyl-2-(10-oxodecanoyl)-sn-glycero-3-phosphocholine, 1- palmitoyl-2-(11-oxoundecanoyl)-sn-glycero-3-phosphocholine, 1-palmitoyl-2-(12- oxododecanoyl)-sn-glycero-3-phosphocholine, and / or 1-palmitoyl-2-(13-oxotridecanoyl)-sn- glycero-3-phosphocholine, and / or comprises one or more of the chemical structures shown below:

16. The method of claim 15, wherein the therapeutically effective amount is based on a relative potency of each specific chemical structure in the "OxPCCD36" class.

17. The method of claim 8, wherein the dicarbonyl scavenger provided along with another compound comprising aminoguanidine, hydralazine, pyridoxamine, and 2,3-diaminophenazine.

18. The method of claim 17, wherein the therapeutically effective amount is between 0.1 mg to 10 g per day.

19. The method of claim 8, wherein the oxidized phospholipid comprises a phosphatidylcholine,or phosphatidylethanolamine, or phosphatidic acid, phosphatidylserine, or phosphoinositides and / or other types of phospholipids that having a sn-2 acyl group that includes a highly reactive aldehyde moiety and / or a highly reactive dicarbonyl moiety.

20. The method of claim 19, wherein the oxidized phosphatidylcholine comprises 1-palmitoyl-2- (4-oxo-pentanoyl)-sn-glycero-3-phosphocholine (POVPC), 1-palmitoyl-2-glutaryl-sn-glycero-3- phosphocholine (PGPC), 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (PONPC), 1-palmitoyl-2-(9-oxononanoyl)-sn-glycero-3-phosphocholine (PAzPC), 1-palmitoyl-2-azelaoyl- sn-glycero-3-phosphocholine (PAzPC), 1-palmitoyl-2-(4-oxobutanoyl)-sn-glycero-3- phosphocholine, 1-palmitoyl-2-(5-oxopentanoyl)-sn-glycero-3-phosphocholine, 1-palmitoyl-2-(6- oxohexanoyl)-sn-glycero-3-phosphocholine, 1-palmitoyl-2-(7-oxoheptanoyl)-sn-glycero-3- phosphocholine, 1-palmitoyl-2-(8-oxooctanoyl)-sn-glycero-3-phosphocholine, 1-palmitoyl-2-(10- oxodecanoyl)-sn-glycero-3-phosphocholine, 1-palmitoyl-2-(11-oxoundecanoyl)-sn-glycero-3- phosphocholine, 1-palmitoyl-2-(12-oxododecanoyl)-sn-glycero-3-phosphocholine, 1-palmitoyl-2- (13-oxotridecanoyl)-sn-glycero-3-phosphocholine, 1 -palmitoyl-2-(5-hydroxy-8-oxooct-6-enoyl)- sn-glycero-3-phosphocholine (PHOdiA-PC), 1-palmitoyl-2-(5-hydroxy-8,11-dioxododec-6,9- dienoyl)-sn-glycero-3-phosphocholine (PHDdiA-PC), 1-palmitoyl-2-(5-hydroxy-8-oxooct-6- enoyl)-sn-glycero-3-phosphocholine (PHOOA-PC), 1-palmitoyl-2-(5-hydroxy-8-oxodec-6-enoyl)- sn-glycero-3-phosphocholine (PHODA-PC), 1-palmitoyl-2-(5-keto-6-octenedioyl)-sn-glycero-3- phosphocholine (PKOdiA-PC), 1-palmitoyl-2-(5-keto-8,11-dioxododec-6,9-dienoyl)-sn-glycero-3- phosphocholine (PKDdiA-PC), 1-palmitoyl-2-(5-keto-8-oxooct-6-enoyl)-sn-glycero-3- phosphocholine (PKOOA-PC), and / or 1-palmitoyl-2-(5-keto-8-oxodec-6-enoyl)-sn-glycero-3- phosphocholine (PKODA-PC).

21. The method of claim 19, wherein the dicarbonyl moiety in the sn-2 acyl group is selected from the group consisting of methylglyoxal, glyoxal, diacetyl, and 3-deoxyglucosone, which are configured to be highly reactive and pro-inflammatory.

22. The method of claim 21, wherein the dicarbonyl moiety is selected from the group consisting of 1 ,2-cyclohexanedione, glutaraldehyde, 2,3-pentanedione, 2,3-hexanedione, 2,3- heptanedione, 2,3-octanedione, 2,3-nonanedione, 2,3-decanedione, 2,3-undecanedione, 2,3- dodecanedione, 2,3-tridecanedione, 2,3-tetradecanedione, 2,3-pentadecanedione, and 2,3- hexadecanedione.

23. The method of claim 8, wherein the oxidized phospholipid includes a phosphatidylcholine, or phosphatidylethanolamine, or phosphatidic acid, phosphatidylserine, or phosphoinositides and / or other types of phospholipids molecules having an sn-2 acyl group that includes a highly reactive aldehyde or an a,[3-unsaturated carbonyl group.

24. The method of claim 23, wherein the oxidized phospholipid is selected from the group consisting of 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC), 1-palmitoyl-2-glutaryl-sn-glycero-3-phosphocholine (PGPC), 1-palmitoyl-2-(5-hydroxy-8-oxo-6-octenoyl)-sn- glycero-3-phosphocholine (HOOA-PC), 1-palmitoyl-2-(5-keto-6-octene-dioyl)-sn-glycero-3- phosphocholine (KOdiA-PC), 1-palmitoyl-2-(4-oxobutyroyl)-sn-glycero-3-phosphocholine, 1- palmitoyl-2-(9-oxononanoyl)-sn-glycero-3-phosphocholine, 1-palmitoyl-2-(5-hydroxy-10-oxo-6,8- decadienoyl)-sn-glycero-3-phosphocholine, 1-palmitoyl-2-(5-hydroxy-8-oxo-6-octenoyl)-sn- glycero-3-phosphocholine, 1-palmitoyl-2-(5-hydroxy-11-oxo-6,8,10-undecatrienoyl)-sn-glycero-3-phosphocholine, 1-palmitoyl-2-(5-hydroxy-12-oxo-6,8,10-dodecatrienoyl)-sn-glycero-3- phosphocholine, and 1-palmitoyl-2-(8-hydroxy-11-oxo-9-undecenoyl)-sn-glycero-3- phosphocholine.

25. The method of claim 8, wherein the lipoprotein(a) particle comprises apolipoprotein(a) covalently linked to apolipoprotein B-100 of a low-density lipoprotein (LDL) particle, forming a highly atherogenic lipoprotein species.

26. The method of claim 25, wherein the therapeutically effective amount is configured to reduce the plasma concentration of reactive OXPLs on lipoprotein(a) by at least 5% to 95%, which is considered clinically significant in reducing cardiovascular risk.

27. The method of claim 8, wherein the therapeutically effective amount of the at least one of the reactive OXPL scavenger is administered through the most efficient and tolerable route, such as orally, intravenously, subcutaneously, or intramuscularly.

28. The method of claim 27, wherein the administration is continued for an optimal period of at least 4 weeks to 12 months to ensure steady-state plasma concentrations and sustained therapeutic efficacy.

29. The method of claim 8, wherein the cardiovascular disease is selected from the groupconsisting of atherosclerosis, coronary artery disease, aortic valve stenosis, peripheral artery disease, and cerebrovascular disease, which are configured to be strongly associated with elevated lipoprotein(a) levels.

30. The method of claim 29, wherein the administration is continued for an optimal period of at least 12 weeks to 60 months to ensure significant regression of atherosclerotic plaques and reduction in cardiovascular events.

31. The method of claim 8, wherein administering the therapeutically effective amount of the at least one of the OxPL scavenger is configured to consistently reduce plasma OxPL concentration on lipoprotein(a) in the subject by at least 5% to 95% after 12 weeks to 12 months of administration, which is considered a clinically meaningful and sustainable response; and or the method of claim 8, wherein the administering is configured to provide the OxPL scavenger to reduce OxPL on lipoproteins beyond and / or in addition to lipoprotein (a).

32. A method for effectively detoxifying lipoprotein(a) in a subject, the method comprising: administering to the subject a therapeutically effective amount of at least one of a potent OxPL scavenger; wherein the at least one of the OxPL scavenger is configured to selectively modify adeleterious and / or a pro-inflammatory oxidized phospholipid on the lipoprotein(a) particle circulating in the subject's bloodstream, thereby efficiently detoxifying the lipoprotein(a) and rendering it less atherogenic.

33. The method of claim 32, wherein the administration is continued for an optimal period of at least 4 weeks to 12 months to ensure sustained detoxification of lipoprotein(a) particles.

34. The method of claim 32, wherein the therapeutically effective amount is between 0.1 mg to 5 g per day based on the subject's individual response and tolerability.

35. The method of claim 32, wherein the dicarbonyl scavenger or the oxidized phosphatidylcholine comprises at least one of 2-HOBA (2-hydroxybenzylamine), a potent analog of 2-hydroxybenzylamine (2-HOBA), a modified analog of 2-HOBA wherein additional substituents have been covalently attached to enhance its efficacy, or a pharmaceutically acceptable salt, solvate or hydrate of any of these chemical compounds, and wherein the dicarbonyl or the oxidized phosphatidylcholine comprises a highly specific "OxPCCD36" class ofoxidized phospholipids that is operative to potently promote platelet activation via the scavenger receptor CD36, and wherein the "OxPCCD36" class comprises a specific chemical structure comprising PHODiA-PC, PHDdiA-PC, PHOOA-PC, PHODA-PC, PKOdiA-PC, PKDdiA-PC, PKOOA-PC, and / or PKODA-PC, which are configured to strongly interact with CD36 receptor.

36. The method of claim 35, wherein the therapeutically effective amount is between 0.1 mg to 5 g per day, based on the relative potency and specificity of the "OxPCCD36" class and its individual chemical components.

37. The method of claim 32, wherein the oxidized phospholipids containing the reactive aldehyde and dicarbonyl comprises a phospholipids molecule having a sn-2 acyl group that includes a highly reactive aldehyde and dicarbonyl moiety.

38. The method of claim 37, wherein the therapeutically effective amount is between 0.1 mg to 5 g per day, based on the relative reactivity and specificity of the aldehyde and dicarbonylcontaining phospholipids.

39. The method of claim 38, wherein the dicarbonyl moiety in the sn-2 acyl group is selected from the group consisting of methylglyoxal, glyoxal, diacetyl, and 3-deoxyglucosone, which are configured to be highly reactive and pro-inflammatory.

40. The method of claim 39, wherein the therapeutically effective amount is between 0.1 mg to 5 g per day, based on the relative potency and stability of each specific dicarbonyl moiety.

41. The method of claim 32, wherein the oxidized phospholipid is a phospholipid molecule having an sn-2 acyl group that includes a highly reactive aldehyde or an a,[3-unsaturated carbonyl group.

42. The method of claim 41 , wherein the therapeutically effective amount is between 0.1 mg to 5 g per day, based on the relative reactivity and specificity of the aldehyde or a,|3-unsaturated carbonyl-containing phospholipids43. The method of claim 32, wherein the lipoprotein(a) particle comprises apolipoprotein(a) covalently linked to apolipoprotein B-100 of a low-density lipoprotein (LDL) particle, forming ahighly atherogenic lipoprotein species, and / or wherein the therapeutically effective amount is configured to reduce the plasma concentration of OxPL on lipoprotein(a) by at least 5% to 95%, which is considered clinically significant in reducing its atherogenicity.

44. The method of claim 32, wherein the therapeutically effective amount of at least one of the OxPL scavenger is administered through the most efficient and tolerable route, such as orally, intravenously, subcutaneously, or intramuscularly.

45. The method of claim 44, wherein the administration is continued for an optimal period of at least 8 weeks to 6 months to ensure steady-state plasma concentrations and sustained therapeutic efficacy in detoxifying lipoprotein(a) particles.

46. The method of claim 32, wherein the subject has a significantly elevated plasma concentration of lipoprotein(a) of at least 30 mg / dL to 1000 mg / dL, which is considered a high- risk threshold for cardiovascular disease; and / or wherein the lipoprotein (a) concentration does not change because the method is configured to only target the OxPLs (and / or a different lipoprotein).

47. The method of claim 32, wherein administering the therapeutically effective amount of at least one of the OxPL scavengers configured to consistently reduce plasma the concentration of OxPL on lipoprotein(a) in the subject by at least 5% to 95% after 12 weeks to 12 months of administration, which is considered a clinically meaningful and sustainable response in detoxifying lipoprotein(a) particles.

48. The method of claim 32, wherein effectively detoxifying the lipoprotein(a) particles is configured to significantly reduce the risk of cardiovascular disease in the subject by at least 5% to 50% after 12 weeks to 60 months of administration, which is considered a clinically meaningful and sustainable outcome.

49. A system for effectively reducing cardiovascular disease or its risk in a subject, the system comprising: (1) a precise measurement of lipoprotein (a) [Lp(a)] level in the subject that is configured to specifically quantify the content of oxidized phospholipids (OxPLs) on Lp(a) particles, wherein the measurement is performed using a highly sensitive and specific immunoassay or a state-of-the-art mass spectrometry-based assay; and (2) an optimizedadministering of a potent therapeutic agent configured to selectively modify the OxPLs such that the Lp(a) particles include significantly less OxPLs, wherein the therapeutic agent is at least one of a rationally designed OxPL scavenger and wherein the therapeutic agent is administered in a therapeutically effective amount between 0.1 mg to 5 g per day based on the subject's individual response and tolerability; wherein the administering in (2) is precisely modulated in extent and duration by the measurement in (1), so that a personalized automated feedback system is provided for each subject, and wherein the administering is continued for an optimal period of at least 4 weeks to 12 months to ensure sustained reduction in cardiovascular risk.

50. The system of claim 49, wherein the system is provided in a convenient wearable configuration, a wearable configuration with secure wireless communication, or an implantable configuration for long-term use, and wherein the measurement and the administering are performed automatically by the system based on a pre-determined schedule or based on a realtime feedback from the measurement, ensuring a fully personalized and optimized therapy for each subject.

51. The method of claim 32, wherein the reactive OxPL scavenger is configured to bind to and sequester the oxidized phospholipid on the lipoprotein(a) particle and other lipoproteins, thereby preventing their recognition and uptake by scavenger receptors on macrophages and foam cells in the atherosclerotic plaque.

52. The method of claim 32, wherein the reactive OxPL scavenger is configured to reduce the oxidative modification of the apolipoprotein(a) component of the lipoprotein(a) particle, thereby preserving its structural integrity and reducing its atherogenic potential.

53. The method of claim 32, wherein the reactive OxPL scavenger is configured to inhibit the lipoprotein(a)-mediated activation of platelet aggregation and thrombosis by neutralizing the oxidized phospholipids that promote these processes via the scavenger receptor CD36.

54. The method of claim 32, wherein the reactive OxPL scavenger is configured to reduce the lipoprotein(a)-induced expression of adhesion molecules and inflammatory cytokines in the vascular endothelium by scavenging the reactive dicarbonyl moieties that trigger these responses.

55. The method and / or system of any claim above and / or a composition therein, wherein each of R, Ri, R2, and R3is as is described in claim 3 above; and / or wherein formula 1-11 includes a moiety as described in claim 3.

56. The compound, method and / or system of any claim above wherein any of formulas 1-11 is contained in, bound with or associated with a lipid particle or a lipid nanoparticle (LNP), optionally comprising a liposome for drug delivery, wherein the liposome can be multilamellar large (MLV), oligolamellar (OLV), small unilamellar (SUV), medium-sized unilamellar (MUV), large unilamellar (LUV), giant unilamellar (GUV) and / or multivesicular vesicles (MW); and / or wherein an antibody drug conjugate (ADC) is implemented with the formula (1-11); optionally wherein the ADC is an anti-lipoprotein(a) antibody drug conjugate.

57. The compound, method and / or system of any above claim wherein any of formulas 1-11 is configured in or within a pharmaceutical composition comprising a therapeutically effective amount of any combination of the formulas 1-11 ; optionally with an additional therapeutic agent.

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