WO2024028192A1 - Utilisation de conjugués d'albumine sérique humaine et de phosphocholine pour bloquer une protéine c-réactive - Google Patents

Utilisation de conjugués d'albumine sérique humaine et de phosphocholine pour bloquer une protéine c-réactive Download PDF

Info

Publication number
WO2024028192A1
WO2024028192A1 PCT/EP2023/070776 EP2023070776W WO2024028192A1 WO 2024028192 A1 WO2024028192 A1 WO 2024028192A1 EP 2023070776 W EP2023070776 W EP 2023070776W WO 2024028192 A1 WO2024028192 A1 WO 2024028192A1
Authority
WO
WIPO (PCT)
Prior art keywords
reactive protein
diseases
pharmaceutical composition
binding
crp
Prior art date
Application number
PCT/EP2023/070776
Other languages
German (de)
English (en)
Inventor
Ahmed Sheriff
Birgit Vogt
Rudolf Kunze
Original Assignee
Pentracor Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pentracor Gmbh filed Critical Pentracor Gmbh
Publication of WO2024028192A1 publication Critical patent/WO2024028192A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/643—Albumins, e.g. HSA, BSA, ovalbumin or a Keyhole Limpet Hemocyanin [KHL]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to CRP-binding phosphocholine-human serum albumin conjugates and their use for binding and/or neutralizing CRP in the bloodstream.
  • the phosphocholine-HSA conjugates according to the invention are particularly useful for the treatment and/or prevention of acute or chronic diseases that are associated with and/or caused by an increased CRP level.
  • CRP C-reactive protein
  • Elevated CRP blood levels are particularly observed in inflammations of various causes. CRP is therefore one of the most important indicators of inflammatory disease processes. The production of CRP takes place in the liver.
  • CRP Crepons kinase kinase kinase
  • CRP is a phylogenetically ancient molecule and widespread in the animal kingdom. It was first discovered in 1930 in the blood of people with acute bacterial infections. The physiologically dominant form is a pentamer made up of identical subunits that are not covalently linked. With a molecular weight of approximately 125,000 Da, it is one of the larger plasma molecules. Concentrations of 0.2-3 mg/L blood are considered the normal range.
  • CRP In the local microenvironment, in the presence of low pH and oxidative stress species (ROX), CRP undergoes a conformational change that allows complement binding (C1q), as well as the dissociation of the pentameric form (pCRP) into its monomers (mCRP). Both enable or increase local inflammatory processes.
  • the dissociation of the pentamer is a localized event, which is said to be promoted by lyso-phosphocholine.
  • the monomeric CRP is said to play a special role in destroying the blood-retinal barrier (Mollins et al. Front. Immunol.2018, 9:808). According to the authors, moderately elevated pCRP levels are in balance with the locally pathologically more active mCRP. In an animal model (rat, ischemia model).
  • PEN-P04423WO07 Patent application (final).docx by Braig et al. (Nat Commun; 2017, 8: 14188) and Thiele et al. (Front Immunol; 2018, 9: art.6) showed that in capillary vessels of muscle tissue, leukocyte rolling and adherence are increased by mCRP, but not by pCRP. The local molecular inflammatory cascade is probably enhanced with the formation of mCRP.
  • the authors assume that the conformational change of CRP is the key to understanding vascular inflammatory pathomechanisms, representative of diseases whose triggers are vascular narrowing or occlusion (e.g. heart attack, stroke).
  • CRP is one of the few plasma molecules whose concentration can increase more than a hundredfold.
  • the CRP concentration increases after one of the above-mentioned events with a delay of several hours. For example, a peak is observed around 48 hours after a heart attack, while in the days afterwards the CRP level drops continuously.
  • the individual CRP responder rate, extent and duration vary greatly.
  • PEN-P04423WO07 Patent application final.docx Cell death or necrosis, and it probably depends on the amount of CRP on site how high the proportion of reversibly damaged cells is that reaches the “point of no return”.
  • the natural ligand of CRP lyso-phosphatidylcholine (LPC)
  • LPC lyso-phosphatidylcholine
  • LPC is practically not present in vital cells as a component of the cell membrane.
  • LPC is produced on the cell surface by a special phospholipase, another acute phase protein. This is the secretory phospholipase A2 type IIa (sPLA2 IIa).
  • sPLA2 IIa secretory phospholipase A2 type IIa
  • CRP Crepons kinase kinase
  • the normal value for CRP in the blood of people varies from person to person, with the median being around 0.8 mg CRP per liter of blood, but can be significantly higher in the case of acute or chronic inflammatory reactions (e.g. bacterial infections, or after a heart attack). 100 mg of CRP per liter of blood increases. Since the half-life of CRP in the blood (approx. 19 hours) is constant and therefore independent of the patient's health condition, only the synthesis rate of CRP is responsible for the regulation of the CRP level in the blood (Pepys & Hirschfield, J. Clin. Invest ., 2003, 111: 1805-1812).
  • the oligonucleotide is not suitable for lowering acute CRP concentrations, such as those that can occur in the event of a heart attack or stroke.
  • CRP can be eliminated from the bloodstream or blood plasma using selective apheresis using a CRP adsorber.
  • the practicality and efficiency of a CRP apheresis system for acute inflammation has previously been demonstrated in a porcine infarction model (Sheriff et al., Journal of Clinical Apheresis 2015; 30: 15-21. doi.org/10.1002/jca.21344).
  • Using a CRP adsorber the amount of CRP in the animals' blood was reduced after the infarction had been triggered.
  • the specific CRP adsorber can in principle be used as a medical product where, in the course of a preferably acute inflammation or illness with high CRP levels.
  • PEN-P04423WO07 Patent application (final).docx Reflect elimination of CRP is of therapeutic benefit.
  • the procedure cannot always be used where the reduction of functionally active CRP or CRP blood levels is desired.
  • the use of extracorporeal apheresis procedures such as CRP apheresis, immunoadsorption or lipid apheresis requires considerable medical technology effort. This represents a certain technical limitation in the practicability of the process.
  • Pharmacological blockade of CRP is the third therapeutic option to limit the effects of CRP on previously damaged cells or tissues, as is known from heart attacks or strokes.
  • the active ingredient 1,6-bis(phosphocholine)-hexane blocks CRP in vivo.
  • the conjugates contain snail hemocyanin (KLH), bovine serum albumin (BSA) or HSA carrier proteins and are used to bind to IgM antibodies.
  • KLH snail hemocyanin
  • BSA bovine serum albumin
  • HSA carrier proteins A connection between the CRP level, the anti-phosphocholine antibodies or the intima-media thickness, which is used to determine the progression of atherosclerosis, could not be observed in the experimental examples.
  • the object of the present invention is therefore to provide a medicament for binding and/or neutralizing CRP in vivo, especially in the bloodstream, in particular for the treatment and/or prevention of acute or chronic diseases that are associated with an increased CRP level and/ or caused. This object is solved by the technical teaching of the independent claims of the present invention. Further advantageous embodiments of the invention
  • PEN-P04423WO07 Patent application (final).docx result from the dependent claims, the description and the examples.
  • the inventor has surprisingly found that a C-reactive protein-binding phosphocholine conjugate or a pharmaceutical composition thereof is suitable for binding and/or neutralizing C-reactive protein in the blood, the C-reactive protein-binding phosphocholine conjugate being covalently attached Human serum albumin-bound phosphocholine or phosphocholine derivative includes.
  • the said conjugate or a pharmaceutical formulation thereof is therefore particularly suitable for the treatment and/or prevention of acute or chronic diseases that are associated with and/or caused by an increased CRP level.
  • the present invention relates to a C-reactive protein-binding phosphocholine conjugate or a pharmaceutical composition thereof for use as a medicament for binding and/or neutralizing C-reactive protein in the blood, wherein the C-reactive protein-binding phosphocholine conjugate is a human - serum albumin (HSA) includes covalently bound 4-aminophenylphosphocholine (APPC).
  • HSA human - serum albumin
  • APPC 4-aminophenylphosphocholine
  • the APPC-HSA conjugates described herein are suitable for the treatment and/or prevention of diseases caused by and/or associated with a C-reactive protein blood level of >>5 mg/L.
  • a particular advantage of the CRP-binding APPC conjugate according to the invention is its rapid distribution in the bloodstream and in the interstitial spaces, which makes the said conjugate particularly suitable for the acute treatment of diseases such as infarctions or strokes.
  • the APPC-HSA conjugates of the present invention comprise a 4-aminophenyl-phosphocholine that binds to CRP under physiological conditions so that the
  • the APPC-HSA conjugates of the present invention bind monomeric CRP and/or pentameric CRP.
  • the APPC-HSA conjugates according to the invention have the structure of the general formula (I): where L represents a bond or linker; m comprises a number between 1 and 100; and HSA stands for human serum albumin.
  • a further aspect of the present invention relates to a pharmaceutical composition comprising the APPC-HSA conjugate according to the invention, a pharmaceutically acceptable carrier, an excipient and/or a diluent.
  • the APPC-HSA conjugate according to the invention or the pharmaceutical composition thereof can be used in combination with extracorporeal methods for lowering CRP levels, such as dialysis or apheresis.
  • the APPC-HSA conjugate according to the invention or the pharmaceutical composition thereof can be used in combination with at least one complement blocker for the treatment of diseases associated and/or caused by an increased CRP level.
  • the term "linker" as used herein includes molecular fragments capable of linking the 4-aminophenylphosphocholine at the aromatic amino group to the human serum albumin as a carrier molecule. More accurate
  • the linker connects the 4-aminophenylphosphocholine to the human serum albumin in such a way that the phosphocholine group is terminal and is therefore able to bind the CRP.
  • the function of the linker is to create, maintain and/or bridge a specific distance between the phosphocholine and the HSA carrier molecule.
  • human serum albumin or "HSA” or “human albumin” as used herein includes the human form of the globular blood protein albumin.
  • the human serum albumin used in the conjugates of the present invention may be of natural origin or synthetically produced.
  • physiological conditions refers to a temperature, a pH, an osmotic pressure, an osmolality, oxidative stress, an electrolyte concentration, a concentration of a small organic molecule such as glucose, lactic acid, pyruvate, Nutrient components, other metabolites and the like, a concentration of another molecule such as oxygen, carbonate, phosphate and carbon dioxide, and cell types and nutrient availability considered to be within a normal range at the site of administration or at the tissue or organ at the site of effect on a subject would.
  • the physiological conditions preferably relate to the conditions prevailing in the human organism at a temperature of 37 ° C, including pathophysiological conditions such as fever (temperature 37.5 ° C - 42 ° C), a pH value of 7.4, including a local one Variation from 5.0 to 8.5, such as in a wound or disease, and an osmotic pressure of approximately 300 mosmol/kg.
  • pathophysiological conditions such as fever (temperature 37.5 ° C - 42 ° C), a pH value of 7.4, including a local one Variation from 5.0 to 8.5, such as in a wound or disease, and an osmotic pressure of approximately 300 mosmol/kg.
  • biological fluid refers to aqueous solutions occurring in mammals, and preferably humans, containing CRP, such as cerebrospinal fluid, peritoneal fluid, pleural fluid, ascitic fluid, blood, blood plasma, liver extracts, and Interstitial fluid.
  • CRP-binding means that the APPC-HSA conjugates described herein are capable of reacting with and/or binding to C-reactive protein via their terminal phosphocholine group and /or to form a complex with the CRP.
  • neutralization refers to the prevention of the proinflammatory effects of CRP as well as activation of the complement system and/or interaction with immunocompetent cells. Neutralization can thus be achieved by suppressing the binding of CRP to phosphocholine and/or phospholipid components of destroyed endogenous cells, or by preventing complement activation, or by preventing binding to phagocytes.
  • complement blocker or “complement inhibitor” as used herein refers to drugs that reduce and/or inhibit the activity of individual components of the complement system or the entire complement system.
  • Complement blockers or complement inhibitors therefore bind to plasma proteins, such as the C3 and/or the C5 plasma protein, at molecularly defined locations and thus prevent complement activation.
  • plasma proteins such as the C3 and/or the C5 plasma protein
  • postoperative condition refers to the condition of a patient following a surgical procedure (invasive intervention into the patient's body performed by a surgeon), including vasoconstrictions, thromboembolic diseases and sequelae of muscular and musculoskeletal injuries .
  • the present invention relates to a C-reactive protein-binding phosphocholine conjugate or a pharmaceutical composition thereof for use as a medicament for binding and/or neutralizing C-reactive protein in the blood, the C-reactive protein-binding phosphocholine conjugate being bound to human serum albumin covalently bound 4-aminophenylphosphocholine.
  • the 4-aminophenylphosphocholine is covalently bound to the human serum albumin in such a way that a terminal phosphocholine group is formed with the structure shown below, where the dashed line represents the covalent bond to the HSA.
  • the 4-aminophenylphosphocholine is attached to a carboxylic acid group of a side chain of an amino acid, glutamic acid or aspartic acid, of HSA
  • the present invention relates to a C-reactive protein-binding phosphocholine conjugate or a pharmaceutical composition thereof for use as a medicament for binding and/or neutralizing C-reactive protein in the blood, wherein the C-reactive protein-binding phosphocholine conjugate is a Carboxylic acid residue of human serum albumin comprises covalently bound 4-aminophenylphosphocholine.
  • the 4-aminophenylphosphocholine can be bound to the HSA either directly or via a linker.
  • the present invention therefore also relates to a C-reactive protein-binding phosphocholine conjugate or a pharmaceutical composition thereof for use as a medication for binding and/or neutralizing C-reactive protein in the blood, wherein the C-reactive protein-binding phosphocholine conjugate is a direct 4-aminophenylphosphocholine covalently bound to human serum albumin.
  • the present invention relates to a C-reactive protein-binding phosphocholine conjugate or a pharmaceutical composition thereof for use as a medicament for binding and/or neutralizing C-reactive protein in the blood, wherein the C-reactive protein-binding phosphocholine conjugate has the structure of the general formula (I): where L represents a bond or linker; m comprises a number between 1 and 100; and HSA stands for human serum albumin.
  • L represents a bond or linker
  • m comprises a number between 1 and 100
  • HSA stands for human serum albumin.
  • the linker -L- is bound to the aromatic amine and to the carbonyl group of human serum albumin or forms a peptidic bond between the aromatic amine and the carbonyl group of human serum albumin.
  • -L- is a linker
  • at least two carbon atoms of the linker are located between the aromatic amine and the carbonyl group of the HSA.
  • the linker can be a PEN-P04423WO07 patent application (final).docx be an aliphatic chain, wherein the aliphatic chain optionally contains an inserted aromatic chain, or the aliphatic chain optionally contains 0 to 10 heteroatoms.
  • the linker preferably contains 2 to 40 carbon atoms (including the carbon atoms of the optional side chains), more preferably 2 to 30, more preferably 2 to 20, more preferably 2 to 14, more preferably 2 to 12 and even more preferably 2 to 10 carbon atoms.
  • the shortest atom chain between the aromatic amine and the HSA preferably consists of 2 to 14 atoms, more preferably 2 to 12 atoms, more preferably 2 to 10 atoms, and even more preferably 2 to 8 atoms. If the shortest chain (shortest possible connection between the aromatic amine and the HSA) consists of 2 to 6 atoms, these are preferably carbon atoms.
  • the shortest chain consists of 4 to 8 atoms, the chain may contain 1, 2, or 3 heteroatoms selected from O, N, and S. If the shortest chain consists of 9 to 14 atoms, the chain may contain 1, 2, Contain 3, 4, 5 or 6 heteroatoms selected from O, N and S. Also preferred is a linker -L- or a shortest atom chain that is completely or partially fluorinated.
  • the linker -L- can have a 3-membered or a 4-membered or a 5-membered or a 6-membered saturated carbocycle or a 5-membered partially unsaturated (and non-aromatic) carbocycle or a 4-membered or a 5-membered or contain a 6-membered saturated oxygen heterocycle or a 4-membered or a 5-membered or a 6-membered saturated nitrogen heterocycle or a 6-membered aromatic carbocycle.
  • the linker can also contain amide (-NH-CO-, -CO-NH-) and/or urea residues and preferably only one amide or only one urea residue.
  • the linker can also contain substituents, preferably two substituents, such as R 10 and R 11 , or four substituents, such as R 10 , R 11 , R 15 and R 14 , which have the meaning described here and are preferably selected from: -F, –Cl, –CH3, –C2H5, –C3H7, –C5H9, –C6H13, –OCH3, –OC2H5, –CH2F, –CHF2, –CF3, –C(O)–NH2, –SCH3, –SC2H5, –NHC( O)CH3, –N(CH3)2, and –N(C2H5)2; If the linker -L- is fluorinated, then more than two F substituents are preferred.
  • the linker is preferably selected from: -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2) 7–, –(CH2)8–, –(CH2)9–, –(CH2)10–, –CF2–, –(CF2)2–, –(CF2)3–, –(CF2)4–, – (CF2)5–, –(CF2)6–, –(CF2)7–, –(CF2)8–, –(CF2)9–, –(CF2)10–, –(CH2)2–O–( CH2)2–, –CH2–O–(CH2)3–, –(CH2)3–O–CH2–, –CH2–O–(CH2)2–, –(CH2)2–O–CH2–, – (CH2)3–O–CH2–, –(CH2)3–O–CH2
  • a linker -L- selected from: , where a is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, b is an integer selected from 1, 2, 3 and 4.
  • the present invention relates to a C-reactive protein-binding phosphocholine conjugate or a pharmaceutical composition thereof for use as a medicament for binding and/or neutralizing C-reactive protein in the blood, wherein the C-reactive protein-binding phosphocholine conjugate Conjugate has the structure of the general formula (II): where m comprises a number between 1 and 100; and HSA stands for human serum albumin.
  • the inventor has surprisingly discovered that the molecular ratio m of 4-aminophenylphosphocholine to human serum albumin is crucial for the binding of the APPC-HSA conjugate to CRP and the inhibition and/or blocking of the APPC-HSA conjugate-CRP complex to the complement protein C1q.
  • the APPC-HSA conjugates described herein are able to bind to the CRP in such a way that subsequent complexation with the complement protein C1q no longer occurs or only occurs to a lesser extent. This stops, reduces or even suspends the proedematous and pronecrotic effects of CRP in diseases such as heart attacks and strokes. Ultimately, this can stop the spread of damage and scars in the ischemic tissue and reduce or completely prevent an infarction scar after a heart attack.
  • the molecular ratio m of 4-aminophenylphosphocholine to human serum albumin in the conjugates of the general formula (I) and (II) is preferably between 1 and 100, more preferably between 1 and 50, more preferably between 1 and 30, even more preferably between 1 and 20, more preferably between 2 and 15 and most preferably between 5 and 10.
  • the molecular ratio m of 4-aminophenylphosphocholine to human serum albumin in the conjugates of the general formula (I) and (II) is between 35 and 40 more preferably between 30 and 35, even more preferably between 25 and 30, even more preferably between 20 and 25, even more preferably between 15 and 20, even more preferably between 10 and 15, even more preferably between 5 and 10 and most preferably between 1 and 5.
  • the molecular ratio m of 4-aminophenylphosphocholine to human serum albumin in the conjugates of the general formula (I) and (II) is approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
  • the molecular ratio m of 4-aminophenylphosphocholine to human serum albumin in the APPC -HSA conjugate in the conjugates of general formula (I) and (II) preferably not greater than 3, more preferably not greater than 4, nor PEN-P04423WO07 patent application (final).docx more preferably not greater than 5, more preferably not greater than 6, more preferably not greater than 7, even more preferably not greater than 8, even more preferably not greater than 9, even more preferably not greater than 10.
  • the APPC-HSA conjugates described herein can from phosphocholine and human serum albumin using the methods known from the prior art for the synthesis of peptide conjugates.
  • Human serum albumin has a large number of functional groups known to those skilled in the art, via which the phosphocholine can be covalently bound. This functional group can be, among other things, a primary amino group of a lysine residue that reacts with an active ester, a carboxyl group of a glutamate or aspartate residue or a thiol group of a cysteine residue.
  • peptide coupling reagents such as carbodiimides (including dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)), phosphonium salts (including BOP reagent, PyBOP, PyBrOP and PyOxime), immonium salts (including BOMI and BDMP), Aminium salts (including HBTU, TBTU, HATU, HCTU and TATU), Uronium salts (including TNTU, TPTU, TOTU, TDBTU, COMU, COMBU, TOMBU and TSTU), Imidazolium salts (including CBMIT, BOI, CIP, CIB and CMBI) or carbonyldiimidazole are suitable for the covalent binding of the APPC to a functional group of the amino acid side chain of the HSA.
  • Active esters are also suitable for coupling APPC to HSA.
  • Preferred active esters are N-( ⁇ -maleimidobutyryloxy) sulfosuccinimide ester (sulfo-GMBS), succinimidyl (4-iodoacetyl) aminobenzoate (sulfo-SIAB), succinimidyl 3-(bromocetamido) propionate (SBAP), disuccinimidyl glutarate (DSG), disuccinimidyl adipate (DSA), 2-pyridyldithiol-tetraoxatetradecane-N-hydroxysuccinimide (PEG-4-SPDP), bis-(4-nitrophenyl) adipate and bis-(4-nitrophenyl) succinate.
  • sulfo-GMBS N-( ⁇ -maleimidobutyryloxy) sulfosuccinimide ester
  • the 4-aminophenylphosphocholine can be covalently linked directly to a carboxyl group of a glutamate or aspartate residue using a peptide coupling reagent.
  • a linker a functional group of the HSA (carboxylate) or the aromatic amine of the APPC can first be activated with a peptide coupling reagent or active ester and then reacted with the linker.
  • HSA carboxyl group of a glutamate or aspartate residue
  • a linker a functional group of the HSA (carboxylate) or the aromatic amine of the APPC can first be activated with a peptide coupling reagent or active ester and then reacted with the linker.
  • the inventor has discovered that the APPC-HSA conjugates described herein efficiently bind CRP in the bloodstream and are therefore particularly relevant to PEN-P04423WO07 patent application (final).docx Suitable for the treatment of diseases associated and/or caused by elevated CRP levels
  • An elevated CRP level herein means a C-reactive protein blood level of preferably >5 mg/L, more preferably >10 mg/L, even more preferably >15 mg/L, even more preferably >20 mg/L, still more preferably from >25 mg/L, even more preferably from >30 mg/L, even more preferably from >50 mg/L, even more preferably from >75 mg/L, even more preferably from >100 mg/L, even more preferably from >150 mg /L and most preferably >200 mg/L at any time during the disease.
  • the present invention relates to a C-reactive protein binding phosphocholine conjugate or a pharmaceutical composition thereof for use in the treatment and/or prevention of diseases caused and/or by a C-reactive protein blood level of >5 mg/L are associated, the C-reactive protein binding phosphocholine conjugate comprising a 4-aminophenylphosphocholine covalently bound to human serum albumin (HSA).
  • HSA human serum albumin
  • the C-reactive protein binding phosphocholine conjugate or the pharmaceutical composition thereof for use in the treatment and/or prevention of diseases caused by a C-reactive protein blood level of >5 mg/L and/or are associated, the structure of the general formula (I), where L and m have the meanings described herein.
  • L is a linker selected from: , where a is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, b is an integer selected from 1, 2, 3 and 4.
  • m is between 1 and 100, more preferably between 1 and 50, even more preferably between 1 and 30, even more preferably between 1 and 20, even more preferably between 2 and 15 and most preferably between 5 and 10. It is also preferred if m is between 35 and 40, more preferably between 30 and 35, more preferably between 25 and 30, more preferably between 20 and PEN-P04423WO07 patent application (final).docx 25, more preferably between 15 and 20, more preferably between 10 and 15, more preferably between 5 and 10 and most preferably between 1 and 5.
  • m is approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20. Furthermore, it is preferred if m is not larger than 3, more preferably not larger than 4, even more preferably not larger than 5, even more preferably not larger than 6, even more preferably not larger than 7, even more preferably not larger than 8, even more preferably not larger than 9, more preferably not greater than 10.
  • the C-reactive protein binding phosphocholine conjugate or the pharmaceutical composition thereof for use in the treatment and/or prevention of diseases caused by a C-reactive protein blood level of >5 mg/L and/or are associated, the structure of the general formula (II), where m has the meaning described herein.
  • m is between 1 and 100, more preferably between 1 and 50, even more preferably between 1 and 30, even more preferably between 1 and 20, even more preferably between 2 and 15 and most preferably between 5 and 10. It is also preferred if m is between 35 and 40, more preferably between 30 and 35, more preferably between 25 and 30, more preferably between 20 and 25, more preferably between 15 and 20, more preferably between 10 and 15, more preferably between 5 and 10 and most preferably between 1 and 5 lies. It is also preferred if m is approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
  • m is not larger than 3, more preferably not larger than 4, even more preferably not larger than 5, even more preferably not larger than 6, even more preferably not larger than 7, even more preferably not larger than 8, even more preferably not larger than 9, more preferably not greater than 10.
  • the diseases associated and/or caused by elevated CRP levels do not include atherosclerosis. In atherosclerosis, an elevated CRP level of >20 mg/L in the blood is not regularly observed.
  • the present invention relates to a C-reactive protein binding phosphocholine conjugate or a pharmaceutical composition thereof for use in the treatment and/or prevention of diseases caused by a C-reactive protein blood level of >20 mg/L and/or are associated, the C-reactive protein binding phosphocholine conjugate being a PEN-P04423WO07 patent application (final).docx Human serum albumin (HSA) comprises covalently bound 4-aminophenylphosphocholine, the disease not being atherosclerosis.
  • HSA Human serum albumin
  • the C-reactive protein binding phosphocholine conjugate or the pharmaceutical composition thereof for use in the treatment and/or prevention of diseases caused by a C-reactive protein blood level of >20 mg/L and/or are associated, the structure of the general formula (I), where L and m have the meanings described herein.
  • L is a linker selected from: , where a is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, b is an integer selected from 1, 2, 3 and 4.
  • m is between 1 and 100, more preferably between 1 and 50, even more preferably between 1 and 30, even more preferably between 1 and 20, even more preferably between 2 and 15 and most preferably between 5 and 10.
  • m is between 35 and 40, more preferably between 30 and 35, more preferably between 25 and 30, more preferably between 20 and 25, more preferably between 15 and 20, more preferably between 10 and 15, more preferably between 5 and 10 and most preferably between 1 and 5 lies. It is also preferred if m is approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20. Furthermore, it is preferred if m is not larger than 3, more preferably not larger than 4, even more preferably not larger than 5, even more preferably not larger than 6, even more preferably not larger than 7, even more preferably not larger than 8, even more preferably not larger than 9, more preferably not greater than 10.
  • the C-reactive protein binding phosphocholine conjugate or the pharmaceutical composition thereof for use in the treatment and/or prevention of diseases caused by a C-reactive protein blood level of >20 mg/L and/or associated PEN-P04423WO07 patent application (final).docx are, the structure of the general formula (II), where m has the meaning described herein.
  • m is between 1 and 100, more preferably between 1 and 50, even more preferably between 1 and 30, even more preferably between 1 and 20, even more preferably between 2 and 15 and most preferably between 5 and 10.
  • m is between 35 and 40, more preferably between 30 and 35, more preferably between 25 and 30, more preferably between 20 and 25, more preferably between 15 and 20, more preferably between 10 and 15, more preferably between 5 and 10 and most preferably between 1 and 5 lies. It is also preferred if m is approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20. Furthermore, it is preferred if m is not larger than 3, more preferably not larger than 4, even more preferably not larger than 5, even more preferably not larger than 6, even more preferably not larger than 7, even more preferably not larger than 8, even more preferably not larger than 9, more preferably not greater than 10.
  • the diseases that are associated and/or caused by an increased CRP level are preferably acute diseases in which an increased CRP level (as described here) is observable in the patient within 1 to 5 days .
  • these diseases are associated and/or caused by an increase in CRP levels of >20 mg/L within 1 to 5 days.
  • these diseases are associated and/or caused by an increase in CRP levels of >20 mg/L within 1 to 4 days.
  • these diseases are associated and/or caused by an increase in CRP levels of >20 mg/L within 1 to 3 days.
  • these diseases are associated and/or caused by an increase in CRP levels of >20 mg/L within 1 to 2 days.
  • the present invention relates to a C-reactive protein binding phosphocholine conjugate or a pharmaceutical composition thereof for use in the treatment and/or prevention of diseases caused by an acute increase in C-reactive protein blood levels of >20 mg/L and/or associated, wherein the C-reactive protein-binding phosphocholine conjugate comprises a 4-aminophenylphosphocholine covalently bound to human serum albumin (HSA).
  • HSA human serum albumin
  • the C-reactive protein binding phosphocholine conjugate or pharmaceutical composition thereof is for use in the treatment and/or prevention of diseases caused by an acute increase in C-reactive protein blood levels of >20 mg/L and/or associated, the structure of the general formula (I), where L and m have the meanings described herein.
  • L is a linker selected from: , where a is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, b is an integer selected from 1, 2, 3 and 4.
  • m is between 1 and 100, more preferably between 1 and 50, even more preferably between 1 and 30, even more preferably between 1 and 20, even more preferably between 2 and 15 and most preferably between 5 and 10. It is also preferred if m is between 35 and 40, more preferably between 30 and 35, more preferably between 25 and 30, more preferably between 20 and 25, more preferably between 15 and 20, more preferably between 10 and 15, more preferably between 5 and 10 and most preferably between 1 and 5 lies. It is also preferred if m is approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
  • the C-reactive protein binding phosphocholine conjugate or pharmaceutical composition thereof is for use in the treatment and/or prevention of diseases caused by an acute increase in C-reactive protein blood levels of >20 mg/L and/or associated, the structure of the general formula (II), where m has the meaning described herein.
  • m is between 1 and 100, more preferably between 1 and 50, even more preferably between 1 and 30, even more preferably between 1 and 20, even more preferably between 2 and 15 and most preferably between 5 and 10. It is also preferred if m is between 35 and 40, more preferably between 30 and 35, more preferably between 25 and 30, more preferably between 20 and 25, more preferably between 15 and 20, more preferably between 10 and 15, more preferably between 5 and 10 and most preferably between 1 and 5 lies. It is also preferred if m is approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
  • m is not larger than 3, more preferably not larger than 4, even more preferably not larger than 5, even more preferably not larger than 6, even more preferably not larger than 7, even more preferably not larger than 8, even more preferably not larger than 9, more preferably not greater than 10.
  • the diseases that are associated with and/or caused by an increased CRP level include, among others, tumor diseases, inflammatory diseases, metabolic diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, postoperative conditions and infectious diseases.
  • the present invention therefore relates to a C-reactive protein-binding phosphocholine conjugate or a pharmaceutical composition thereof for use in the treatment and/or prevention of diseases selected from tumor diseases, inflammatory diseases, metabolic diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, and postoperative conditions and infectious diseases, wherein the C-reactive protein binding phosphocholine conjugate comprises a 4-aminophenylphosphocholine covalently bound to human serum albumin (HSA).
  • HSA human serum albumin
  • the present invention also relates to a method for the treatment and/or prevention of diseases selected from tumor diseases, inflammatory diseases, metabolic diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, postoperative conditions and infectious diseases in a patient, wherein the patient is provided with a C-reactive protein binding Phosphocholine conjugate or a pharmaceutical composition thereof is administered to lower the CRP level in the patient's blood.
  • diseases selected from tumor diseases, inflammatory diseases, metabolic diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, postoperative conditions and infectious diseases in a patient, wherein the patient is provided with a C-reactive protein binding Phosphocholine conjugate or a pharmaceutical composition thereof is administered to lower the CRP level in the patient's blood.
  • PEN-P04423WO07 Patent application (final).docx The treatment and prevention of cardiovascular diseases such as heart attack, cardiac arrest and stroke are preferred.
  • the C-reactive protein binding phosphocholine conjugate or the pharmaceutical composition thereof for use in the treatment and/or prevention of diseases selected from tumor diseases, inflammatory diseases, metabolic diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, postoperative conditions and infectious diseases, the structure of general formula (I), where L and m have the meanings described herein.
  • L is a linker selected from: , where a is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, b is an integer selected from 1, 2, 3 and 4.
  • m is between 1 and 100, more preferably between 1 and 50, even more preferably between 1 and 30, even more preferably between 1 and 20, even more preferably between 2 and 15 and most preferably between 5 and 10.
  • m is between 35 and 40, more preferably between 30 and 35, more preferably between 25 and 30, more preferably between 20 and 25, more preferably between 15 and 20, more preferably between 10 and 15, more preferably between 5 and 10 and most preferably between 1 and 5 lies. It is also preferred if m is approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20. Furthermore, it is preferred if m is not larger than 3, more preferably not larger than 4, even more preferably not larger than 5, even more preferably not larger than 6, even more preferably not larger than 7, even more preferably not larger than 8, even more preferably not larger than 9, more preferably not greater than 10.
  • the C-reactive protein binding phosphocholine conjugate or the pharmaceutical composition thereof has the PEN-P04423WO07 patent application (final).docx Use in the treatment and/or prevention of diseases selected from tumor diseases, inflammatory diseases, metabolic diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, postoperative conditions and infectious diseases, the structure of the general formula (II), where m has the meaning described herein.
  • m is between 1 and 100, more preferably between 1 and 50, even more preferably between 1 and 30, even more preferably between 1 and 20, even more preferably between 2 and 15 and most preferably between 5 and 10.
  • m is between 35 and 40, more preferably between 30 and 35, more preferably between 25 and 30, more preferably between 20 and 25, more preferably between 15 and 20, more preferably between 10 and 15, more preferably between 5 and 10 and most preferably between 1 and 5 lies. It is also preferred if m is approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20. Furthermore, it is preferred if m is not larger than 3, more preferably not larger than 4, even more preferably not larger than 5, even more preferably not larger than 6, even more preferably not larger than 7, even more preferably not larger than 8, even more preferably not larger than 9, more preferably not greater than 10.
  • the C-reactive protein binding phosphocholine conjugate described herein or the pharmaceutical composition thereof relates to the treatment and/or prevention of tumor diseases selected from adenocarcinoma, choroidal melanoma, acute leukemia, acoustic neuroma, ampullary carcinoma, anal carcinoma, astrocytoma, basal cell carcinoma, pancreatic cancer, Desmoid tumor, bladder cancer, bronchial carcinoma, breast cancer, Burkitt lymphoma, corpus cancer, CUP syndrome (carcinoma of unknown origin), colon cancer, small intestinal cancer, small intestinal tumors, ovarian cancer, endometrial carcinoma, ependymoma, epithelial cancers, Ewing tumors, gastrointestinal tumors, stomach cancer, Gallbladder cancer, gallbladder carcinomas, uterine cancer, cervical cancer, cervix, glioblastomas, gynecological tumors, ear, nose and throat tumors, hematological neoplasms,
  • the C-reactive protein binding phosphocholine conjugate described herein or the pharmaceutical composition thereof relates to the treatment and/or prevention of autoimmune diseases selected from asthma, diabetes, rheumatic diseases, AIDS, rejection of transplanted organs and tissues, rhinitis, chronic obstructive pulmonary diseases, Osteoporosis, ulcerative colitis, sinusitis, lupus erythematosus, recurrent infections, atopic dermatitis/eczema and occupational allergies, food allergies, drug allergies, severe anaphylactic reactions, anaphylaxis, manifestations of allergic diseases, primary immunodeficiency, antibody deficiency states, cell-mediated immunodeficiency, severe combined immunodeficiency, DiGeorge syndrome, hyper-IgE syndrome, Wiskott-Aldrich syndrome, ataxia telangiectasia, immune-mediated cancers, leukocyte defects, autoimmune diseases, systemic lupus erythematosus, rheuma
  • the C-reactive protein binding phosphocholine conjugate described herein or the pharmaceutical composition thereof relates to the treatment and/or prevention of infectious diseases selected from AIDS, PEN-P04423WO07 patent application (final).docx alveolar echinococcosis (AHD, echinococcosis), amebiasis (Entamoeba histolytica infection), angiostrongylus infection, anisakiasis, anthrax, babesiosis (Babesia infection), Balantidium infection (balantidiosis), Baylisascaris infection (raccoon roundworm), schistosomiasis, schistosomiasis, Blastocystis hominis infection (blastomycosis), Lyme disease, botulism, Brainerd's diarrhea, brucellosis, BSE (Bovine Spongiform Encephalopathy), candidiasis, capillariasis (Capillaria infection), CFS (
  • the C-reactive protein binding phosphocholine conjugate described herein or the pharmaceutical composition thereof relates to the treatment and/or prevention of inflammatory diseases selected from inflammatory diseases of the central nervous system (CNS), inflammatory rheumatic diseases, inflammatory diseases of the blood vessels, inflammatory diseases of the middle ear , inflammatory bowel disease, inflammatory skin disease, inflammatory disease uveitis and inflammatory disease of the larynx.
  • inflammatory diseases selected from inflammatory diseases of the central nervous system (CNS), inflammatory rheumatic diseases, inflammatory diseases of the blood vessels, inflammatory diseases of the middle ear , inflammatory bowel disease, inflammatory skin disease, inflammatory disease uveitis and inflammatory disease of the larynx.
  • the C-reactive protein binding phosphocholine conjugate described herein or the pharmaceutical composition thereof relates to the treatment and/or prevention of respiratory diseases selected from bronchial asthma, pediatric asthma, severe asthma, acute asthma attack, chronic bronchitis, COPD (chronic obstructive pulmonary disease) and interstitial lung diseases such as pneumonia, radiation-induced pneumonitis or fibrosis, collagen diseases such as lupus erythematosus, systemic scleroderma or sarcoidosis, granulomatosis such as Boeck's disease, idiopathic interstitial pneumonia or idiopathic pulmonary fibrosis (IPF).
  • respiratory diseases selected from bronchial asthma, pediatric asthma, severe asthma, acute asthma attack, chronic bronchitis, COPD (chronic obstructive pulmonary disease) and interstitial lung diseases such as pneumonia, radiation-induced pneumonitis or fibrosis, collagen diseases such as lupus erythematosus, systemic scler
  • the C-reactive protein binding phosphocholine conjugate described herein or the pharmaceutical composition thereof relates to the treatment and/or prevention of metabolic diseases selected from adrenogenital syndrome, alkaptonuria, alpha-1-antitrypsin deficiency, diabetes mellitus (diabetes), erythropoietic protoporphyria (disease from the group of porphyrias), galactosemia, hypophosphatasia (Rathbuin syndrome), hypothyroidism (underactive thyroid), ketoacidosis, ketosis (acetonemia, acetonuria), Lesch-Nyhan syndrome (hyperuricemia syndrome or hyperuricosis), methylmalonic aciduria (MMA), myoadenylate deaminase deficiency (MADD), Addison's disease (hypadrenocorticism), Conn's disease (hyperaldosteronism), Cushing's disease, Fabry's disease, Gaucher'
  • the C-reactive protein binding phosphocholine conjugate described herein or the pharmaceutical composition thereof relates to the treatment and/or prevention of the condition after operations, after organ and tissue and bone marrow transplants, after plastic surgical operations, in particular those with systemic anesthesia, after therapeutic irradiation with different external physical sources (such as ⁇ -, ß-, ⁇ -, positrons) as well as diagnostics and therapy with radionuclide drugs administered in vivo.
  • the present invention relates to a C-reactive protein binding phosphocholine conjugate or a pharmaceutical composition thereof for use in the treatment of ischemia. Ischemia hinders or stops cellular metabolism.
  • the C-reactive protein binding phosphocholine conjugate or pharmaceutical composition thereof for use in the treatment and/or prevention of ischemia has the structure of the general formula (I), where L and m have the meanings described herein.
  • L is a linker selected from: , where a is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, b is an integer selected from 1, 2, 3 and 4.
  • m is between 1 and 100, more preferably between 1 and 50, more preferably between 1 and 30, more preferably between 1 and 20, more preferably between 2 and 15 and most preferably between 5 and 10.
  • PEN-P04423WO07 Patent application (final) .docx It is also preferred if m is between 35 and 40, even more preferably between 30 and 35, even more preferably between 25 and 30, even more preferably between 20 and 25, even more preferably between 15 and 20, even more preferably between 10 and 15, even more preferably between 5 and 10 and most preferably between 1 and 5. It is also preferred if m is approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
  • the C-reactive protein binding phosphocholine conjugate or the pharmaceutical composition thereof for use in the treatment and/or prevention of ischemia has the structure of the general formula (II), where m has the meaning described herein.
  • m is between 1 and 100, more preferably between 1 and 50, even more preferably between 1 and 30, even more preferably between 1 and 20, even more preferably between 2 and 15 and most preferably between 5 and 10.
  • m is between 35 and 40, more preferably between 30 and 35, more preferably between 25 and 30, more preferably between 20 and 25, more preferably between 15 and 20, more preferably between 10 and 15, more preferably between 5 and 10 and most preferably between 1 and 5 lies. It is also preferred if m is approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20. Furthermore, it is preferred if m is not larger than 3, more preferably not larger than 4, even more preferably not larger than 5, even more preferably not larger than 6, even more preferably not larger than 7, even more preferably not larger than 8, even more preferably not larger than 9, more preferably not greater than 10.
  • the C-reactive protein binding phosphocholine conjugate or the pharmaceutical composition thereof for use in the treatment and/or prevention of diseases selected from cardiovascular arrest, stroke and pancreatitis has the structure of the general formula (I) , where L and m have the meanings described herein.
  • L is a linker selected from: PEN-P04423WO07 Patent application (final).docx , where a is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, b is an integer selected from 1, 2, 3 and 4.
  • m is between 1 and 100, more preferably between 1 and 50, even more preferably between 1 and 30, even more preferably between 1 and 20, even more preferably between 2 and 15 and most preferably between 5 and 10.
  • m is between 35 and 40, more preferably between 30 and 35, more preferably between 25 and 30, more preferably between 20 and 25, more preferably between 15 and 20, more preferably between 10 and 15, more preferably between 5 and 10 and most preferably between 1 and 5 lies. It is also preferred if m is approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20. Furthermore, it is preferred if m is not larger than 3, more preferably not larger than 4, even more preferably not larger than 5, even more preferably not larger than 6, even more preferably not larger than 7, even more preferably not larger than 8, even more preferably not larger than 9, more preferably not greater than 10.
  • the C-reactive protein binding phosphocholine conjugate or the pharmaceutical composition thereof for use in the treatment and/or prevention of diseases selected from cardiovascular arrest, stroke and pancreatitis has the structure of the general formula (II) , where m has the meaning described herein.
  • m is between 1 and 100, more preferably between 1 and 50, even more preferably between 1 and 30, even more preferably between 1 and 20, even more preferably between 2 and 15 and most preferably between 5 and 10. It is also preferred if m is between 35 and 40, more preferably between 30 and 35, more preferably between 25 and 30, more preferably between 20 and 25, more preferably between 15 and 20, more preferably between 10 and 15, more preferably between 5 and 10 and most preferably between 1 and 5 lies.
  • m is approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20. Furthermore, it is preferred if m is not greater than 3, more preferably not greater than 4, more preferably not greater than 5, more preferably not greater than 6, even more preferably not greater than 7, nor PEN-P04423WO07 patent application (final).docx more preferably not greater than 8, more preferably not greater than 9, even more preferably not greater than 10.
  • the present invention relates to a C-reactive protein binding phosphocholine conjugate or a pharmaceutical composition thereof for use in the treatment and/or prevention of autoimmune diseases
  • the autoimmune disease being selected from rheumatoid arthritis, inflammatory bowel disease, lupus, asthma , diabetes, rheumatic diseases, AIDS, rejection of transplanted organs and tissues, rhinitis, chronic obstructive pulmonary diseases, osteoporosis, ulcerative colitis, sinusitis, lupus erythematosus, recurrent infections, atopic dermatitis / eczema and occupational allergies, food allergies, drug allergies, severe anaphylactic reactions, Anaphylaxis, manifestations of allergic diseases, primary immune deficiency, antibody deficiency states, cell-mediated immune deficiency, severe combined immune deficiency, DiGeorge syndrome, hyper-IgE syndrome, Wiskott-Aldrich syndrome, ataxia telangiectasia
  • the C-reactive protein-binding phosphocholine conjugate or the pharmaceutical composition thereof for use in the treatment and/or prevention of diseases of infectious diseases, the infectious diseases caused by bacteria, viruses, prions, parasites, fungi, induced, initiated and/or amplified and/or triggered by irritant, traumatic, metabolic, allergic, autoimmunological or idiopathic causes, the structure of the general formula (I), where L and m have the meanings described herein.
  • L is a linker selected from: PEN-P04423WO07 patent application (final).docx , where a is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, b is an integer selected from 1, 2, 3 and 4.
  • m is between 1 and 100, more preferably between 1 and 50, even more preferably between 1 and 30, even more preferably between 1 and 20, even more preferably between 2 and 15 and most preferably between 5 and 10. It is also preferred if m is between 35 and 40, more preferably between 30 and 35, more preferably between 25 and 30, more preferably between 20 and 25, more preferably between 15 and 20, more preferably between 10 and 15, more preferably between 5 and 10 and most preferably between 1 and 5 lies. It is also preferred if m is approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
  • the C-reactive protein binding phosphocholine conjugate or the pharmaceutical composition thereof for use in the treatment and/or prevention of infectious diseases, wherein the infectious diseases are caused, induced, initiated and caused by bacteria, viruses, prions, parasites, fungi /or aggravated and/or triggered by irritant, traumatic, metabolic, allergic, autoimmunological or idiopathic causes, the structure of the general formula (II), where m has the meaning described herein.
  • m is between 1 and 100, more preferably between 1 and 50, even more preferably between 1 and 30, even more preferably between 1 and 20, even more preferably between 2 and 15 and most preferably between 5 and 10. It is also preferred if m is between 35 and 40, more preferably between 30 and 35, more preferably between 25 and 30, more preferably between 20 and 25, more preferably between 15 and 20, more preferably between 10 and 15, PEN-P04423WO07 patent application (final).docx more preferably between 5 and 10 and most preferably between 1 and 5. It is also preferred if m is approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
  • the C-reactive protein-binding phosphocholine conjugate or the pharmaceutical composition thereof for use in the treatment and/or prevention of infectious diseases being a disease triggered by coronaviruses, in particular SARS-CoV-2, the structure of the general formula (I), where L and m have the meanings described herein.
  • L is a linker selected from: , where a is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, b is an integer selected from 1, 2, 3 and 4.
  • m is between 1 and 100, more preferably between 1 and 50, even more preferably between 1 and 30, even more preferably between 1 and 20, even more preferably between 2 and 15 and most preferably between 5 and 10. It is also preferred if m is between 35 and 40, more preferably between 30 and 35, more preferably between 25 and 30, more preferably between 20 and 25, more preferably between 15 and 20, more preferably between 10 and 15, more preferably between 5 and 10 and most preferably between 1 and 5 lies.
  • m is approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20. Furthermore, it is preferred if m is not larger than 3, more preferably not larger than 4, even more preferably not larger than 5, even more preferably not larger than 6, even more preferably not larger than 7, even more preferably not larger than 8, even more preferably not larger than 9, more preferably not greater than 10.
  • the C-reactive protein-binding phosphocholine conjugate or the pharmaceutical composition thereof for use in the treatment and/or prevention of infectious diseases has the structure the general formula (II), where m has the meaning described herein.
  • m is between 1 and 100, more preferably between 1 and 50, even more preferably between 1 and 30, even more preferably between 1 and 20, even more preferably between 2 and 15 and most preferably between 5 and 10.
  • m is between 35 and 40, more preferably between 30 and 35, more preferably between 25 and 30, more preferably between 20 and 25, more preferably between 15 and 20, more preferably between 10 and 15, more preferably between 5 and 10 and most preferably between 1 and 5 lies. It is also preferred if m is approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20. Furthermore, it is preferred if m is not larger than 3, more preferably not larger than 4, even more preferably not larger than 5, even more preferably not larger than 6, even more preferably not larger than 7, even more preferably not larger than 8, even more preferably not larger than 9, more preferably not greater than 10.
  • CRP levels 20 mg/L and more (eg 20 mg/L to 100 mg/L)
  • the inventors have already scientifically proven in previous publications that lowering the CRP level in the blood through apheresis treatment can be used for the prophylaxis and treatment of the indications described herein.
  • the present patent application now scientifically proves that the disclosed 4-aminophenylphosphocholine-human serum albumin conjugates (APPC-HSA conjugates) reduce CRP levels and can therefore be used for the prophylaxis and/or treatment of the diseases described herein.
  • APPC-HSA conjugates 4-aminophenylphosphocholine-human serum albumin conjugates
  • Example 6 the human system was recreated using human blood plasma and binding of the APPC-HSA conjugates disclosed herein was demonstrated.
  • Figure 5 clearly shows the CRP binding to the APPC-HSA conjugates according to the invention in a concentration-dependent manner. The binding of CRP in the blood plasma and thus the blockade of CPR in the blood increases reproducibly with the concentration of APPC-HSA conjugate as well as with the number of APPC molecules in an APPC-HSA conjugate.
  • the APPC-HSA conjugate described herein or the pharmaceutical composition thereof may be used in combination with extracorporeal procedures to lower CRP levels, such as dialysis or apheresis.
  • the CRP is removed from blood plasma using affinity chromatographic columns loaded with CRP-binding material. The combination is useful for treating particularly high CRP levels of over 550 mg/L.
  • the present invention relates to a C-reactive protein binding phosphocholine conjugate or a pharmaceutical composition thereof for use as a medicament for binding and/or neutralizing C-reactive protein in the blood in combination with an apheresis or dialysis procedure to lower C-reactive Protein level, wherein the C-reactive protein binding phosphocholine conjugate comprises a 4-aminophenylphosphocholine covalently bound to human serum albumin (HSA).
  • HSA human serum albumin
  • the C-reactive protein binding phosphocholine conjugate or the pharmaceutical composition thereof has for use as a medicament for binding and/or neutralizing C-reactive PEN-P04423WO07 patent application (final).docx Protein in the blood in combination with an apheresis or dialysis procedure to reduce the C-reactive protein level has the structure of the general formula (I), where L and m have the meanings described herein.
  • L is a linker selected from: , where a is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, b is an integer selected from 1, 2, 3 and 4.
  • m is between 1 and 100, more preferably between 1 and 50, even more preferably between 1 and 30, even more preferably between 1 and 20, even more preferably between 2 and 15 and most preferably between 5 and 10. It is also preferred if m is between 35 and 40, more preferably between 30 and 35, more preferably between 25 and 30, more preferably between 20 and 25, more preferably between 15 and 20, more preferably between 10 and 15, more preferably between 5 and 10 and most preferably between 1 and 5 lies. It is also preferred if m is approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
  • the C-reactive protein binding phosphocholine conjugate or pharmaceutical composition thereof is for use as a medicament for binding and/or neutralizing C-reactive protein in the blood in combination with an apheresis or dialysis procedure to lower C-reactive Protein mirror has the structure of the general formula (II), where m has the meaning described herein.
  • m is between 1 and 100, more preferably between 1 and 50, even more preferably between 1 and 30, even more preferably between 1 and 20, even more preferably between 2 and 15 and most preferably between 5 and 10. It is also preferred if m is between 35 and 40, more preferably between 30 PEN-P04423WO07 patent application (final).docx and 35, more preferably between 25 and 30, more preferably between 20 and 25, more preferably between 15 and 20, more preferably between 10 and 15, more preferably between 5 and 10 and most preferably between 1 and 5. It is also preferred if m is approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
  • a further aspect of the present invention relates to pharmaceutical compositions for use as a medicament for binding and/or neutralizing C-reactive protein in the blood comprising a C-reactive protein binding phosphocholine-HSA conjugate, wherein the C-reactive protein binding phosphocholine conjugate 4-aminophenylphosphocholine covalently bound to human serum albumin (HSA).
  • HSA human serum albumin
  • the pharmaceutical formulation may further comprise pharmaceutically acceptable carriers, excipients and/or diluents.
  • the pharmaceutical compositions described herein may be prepared in a conventional solid or liquid carrier or diluent and a conventional pharmaceutically prepared excipient in appropriate dosage in a known manner.
  • the pharmaceutical compositions described herein are typically administered in conjunction with suitable acceptable carriers selected with respect to the intended form of administration, for example, as powders for constitution, gels, elixirs, dispersible granules, syrups, suspensions and the like, and in accordance with conventional pharmaceutical practices . Also included are preparations in solid form intended to be converted into a liquid form shortly before use.
  • liquid forms include solutions, suspensions and emulsions.
  • the pharmaceutical compositions described herein may be administered subcutaneously, by spray, by injection, intramuscularly, as a suppository or trans(epi)dermally.
  • PEN-P04423WO07 Patent application (final).docx The C-reactive protein-binding phosphocholine conjugates described herein and the pharmaceutical compositions thereof described herein are preferably intended for the treatment of humans but can also be used in animals and in particular in horses and preferably riding and dressage horses.
  • the C-reactive protein binding APPC-HSA conjugate contained in the pharmaceutical composition described herein is in a range of 1 mg/kg to 100 mg/kg, preferably 2 mg/kg to 100 mg/kg, preferably 5 mg/kg to 100 mg/kg, preferably 10 mg/kg to 100 mg/kg per body weight per day.
  • the pharmaceutical composition for the treatment and/or prevention of diseases associated and/or caused by an elevated CRP level comprises the C-reactive protein binding phosphocholine conjugate having the structure of the general formula (I), wherein L and m have the meanings described herein and the C-reactive protein binding APPC-HSA conjugate in a range of 1 mg/kg to 100 mg/kg, preferably 2 mg/kg to 100 mg/kg, preferably 5 mg/kg up to 100 mg/kg, preferably 10 mg/kg to 100 mg/kg per body weight per day.
  • L is a linker selected from: , where a is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, b is an integer selected from 1, 2, 3 and 4.
  • m is between 1 and 100, more preferably between 1 and 50, even more preferably between 1 and 30, even more preferably between 1 and 20, even more preferably between 2 and 15 and most preferably between 5 and 10. It is also preferred if m is between 35 and 40, more preferably between 30 PEN-P04423WO07 patent application (final).docx and 35, more preferably between 25 and 30, more preferably between 20 and 25, more preferably between 15 and 20, more preferably between 10 and 15, more preferably between 5 and 10 and most preferably between 1 and 5. It is also preferred if m is approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
  • m is not larger than 3, more preferably not larger than 4, even more preferably not larger than 5, even more preferably not larger than 6, even more preferably not larger than 7, even more preferably not larger than 8, even more preferably not larger than 9, more preferably not greater than 10.
  • the pharmaceutical composition for the treatment and/or prevention of diseases associated and/or caused by an elevated CRP level comprises the C-reactive protein binding phosphocholine conjugate having the structure of the general formula (II), wherein m has the meaning described herein and the C-reactive protein-binding APPC-HSA conjugate in a range from 1 mg/kg to 100 mg/kg, preferably 2 mg/kg to 100 mg/kg, preferably 5 mg/kg to 100 mg/kg, preferably 10 mg/kg to 100 mg/kg per body weight per day.
  • m is between 1 and 100, more preferably between 1 and 50, even more preferably between 1 and 30, even more preferably between 1 and 20, even more preferably between 2 and 15 and most preferably between 5 and 10.
  • m is between 35 and 40, more preferably between 30 and 35, more preferably between 25 and 30, more preferably between 20 and 25, more preferably between 15 and 20, more preferably between 10 and 15, more preferably between 5 and 10 and most preferably between 1 and 5 lies. It is also preferred if m is approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20. Furthermore, it is preferred if m is not larger than 3, more preferably not larger than 4, even more preferably not larger than 5, even more preferably not larger than 6, even more preferably not larger than 7, even more preferably not larger than 8, even more preferably not larger than 9, more preferably not greater than 10.
  • the APPC-HSA conjugate described herein or the pharmaceutical composition thereof can be used in combination with at least one complement blocker to bind and/or neutralize C-reactive protein in the blood.
  • the complement blocker inhibits the complement protein(s) C3 and/or C5 by acting on PEN-P04423WO07 patent application (final).docx binds an active site of the complement protein(s) C3 and/or C5.
  • the complement blocker also prevents complement activation, which stops the spread of damage and scarring in the ischemic tissue and reduces or completely prevents an infarction scar after a heart attack.
  • the present invention therefore also relates to a C-reactive protein-binding phosphocholine conjugate or a pharmaceutical formulation for use as a medicament for binding and/or neutralizing C-reactive protein in the blood, comprising a C-reactive protein-binding phosphocholine conjugate, wherein the C - Reactive protein-binding phosphocholine conjugate comprises a 4-aminophenylphosphocholine covalently bound to human serum albumin, in combination with at least one complement blocker.
  • the C-reactive protein-binding phosphocholine conjugate or the pharmaceutical composition thereof for use as a medicament for binding and/or neutralizing C-reactive protein in the blood in combination with at least one complement blocker has the structure of the general formula (I) , where L and m have the meanings described herein.
  • L is a linker selected from: , where a is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, b is an integer selected from 1, 2, 3 and 4.
  • m is between 1 and 100, more preferably between 1 and 50, even more preferably between 1 and 30, even more preferably between 1 and 20, even more preferably between 2 and 15 and most preferably between 5 and 10.
  • m is between 35 and 40, more preferably between 30 and 35, more preferably between 25 and 30, more preferably between 20 and 25, more preferably between 15 and 20, more preferably between 10 and 15, more preferably between 5 and 10 and most preferably between 1 and 5 lies. It is also preferred if m is approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20. Furthermore, it is preferred if m is not greater than 3, PEN-P04423WO07 patent application (final).docx more preferably not greater than 4, more preferably not greater than 5, more preferably not greater than 6, more preferably not greater than 7, more preferably not greater than 8, more preferably not greater than 9, even more preferably not greater than 10.
  • the C-reactive protein-binding phosphocholine conjugate or the pharmaceutical composition thereof for use as a medicament for binding and/or neutralizing C-reactive protein in the blood in combination with at least one complement blocker has the structure of the general formula (II) , where m has the meaning described herein.
  • m is between 1 and 100, more preferably between 1 and 50, even more preferably between 1 and 30, even more preferably between 1 and 20, even more preferably between 2 and 15 and most preferably between 5 and 10.
  • m is between 35 and 40, more preferably between 30 and 35, more preferably between 25 and 30, more preferably between 20 and 25, more preferably between 15 and 20, more preferably between 10 and 15, more preferably between 5 and 10 and most preferably between 1 and 5 lies. It is also preferred if m is approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20. Furthermore, it is preferred if m is not larger than 3, more preferably not larger than 4, even more preferably not larger than 5, even more preferably not larger than 6, even more preferably not larger than 7, even more preferably not larger than 8, even more preferably not larger than 9, more preferably not greater than 10.
  • PEN-P04423WO07 Patent application final).docx Examples
  • BSA Bovine serum albumin
  • CRP C reactive protein
  • ELISA Enzyme-Linked Immuno Sorbent Assay
  • APPC- HSA human serum albumin, coupled with APPC IgG: immunoglobulin G Cav.: Cavity MAK.
  • CRP-containing samples (plasma or sera) were diluted appropriately in assay buffer and incubated for 1 hour at room temperature. CRP standard solutions with a defined concentration were prepared and used to create the binding curve (see Table 1). The plates were then washed again with PBS and the bound CRP was detected by incubation with biotinylated monoclonal antibody 5G4 against human CRP (diluted in assay buffer for 60 min). The wells were subsequently incubated with polymerized peroxidase dissolved in veronal buffer and the peroxidase activity was visualized with 3,3',5,5'-tetramethylbenzidine. The reaction was stopped after 10 minutes by adding 2 molar sulfuric acid and the absorbance was measured at 450 nm with a plate reader.
  • Tab.1 Protocol for HSA-APPC and binding of CRP PEN-P04423WO07 Patent application (final).docx Tab.2: Optical density (OD) of the CRP quantity. The OD was measured using a standard MTP reader (96 well) immediately after step 6. The MW from two individual measurements are shown.
  • Example 4 This example shows how the test substances (HSA-APPC constructs or acetylated HSA-APPC constructs with different amounts of APPC per HSA molecule) block the binding of huCRP to the fixed BSA-APPC matrix.
  • the BSA-APPC matrix fixed to the wall of microtiter plates simulates the apoptotic-looking state of ischemic cells in which the natural phosphocholine molecules ready for CRP binding are accessible on the cell surface. Only in this state are the cells vulnerable to CRP.
  • PEN-P04423WO07 Patent application (final).docx The coupling of APPC to HSA or acHSA was carried out according to Example 1 with different and increasing concentrations of APPC. The result of the synthesis was then test substances with ratios of HSA to APPC: 1:5, 1:20, 1:40 and 1:80 (the latter not shown).
  • HSA-APPC matrix Figure 2
  • Table 4A Experiments with acetylated HSA-APPC matrix
  • Table 4B Experiments with acetylated HSA-APPC matrix
  • Figure 3 PEN-P04423WO07 patent application (final).docx
  • Example 5 HSA was coupled with various amounts of APPC. The following table shows the average number of APPC molecules per HSA molecule. The constructs were loaded onto an SDS gel. The increase in size caused by the APPC can be clearly seen (see Fig. 4).
  • Example 6 In another approach, HSA was coupled with various amounts of APPC. The number of APPC molecules per HSA molecule was 5, 20, 40 and 80.
  • human blood plasma was used in the following experiment. All relevant blood factors are found in the human blood plasma, which closely replicates the human in vivo situation.
  • the BSA-APPC fixed to the bottom of the microtiter plate simulates the cell surface of the damaged cell.
  • the blockade of CRP binding by the constructs is measured. The experiment was carried out three times. Human blood plasma containing 100 ng/mL CRP was mixed with different amounts of these HSA-APPC constructs 1:1 (vol:vol) and used in a BSA-APPC ELISA.
  • CRP without additive and CRP mixed with HSA was used as control PEN-P04423WO07 patent application (final).docx used.
  • Blocking CRP binding without additive was used as a starting point to calculate the blocking effect of the constructs. As Figure 5 shows, the blockade is concentration dependent.
  • Table 6 PEN-P04423WO07 Patent application (final).docx

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne des conjugués phosphocholine-ASH liant la CRP et leur utilisation pour lier et/ou neutraliser la CRP dans le flux sanguin. Les conjugués phosphocholine-ASH selon l'invention sont spécifiquement utiles dans le traitement et/ou la prévention de maladies aiguës ou chroniques associées à des taux élevés de CRP et/ou provoquées par des taux élevés de CRP.
PCT/EP2023/070776 2022-08-04 2023-07-26 Utilisation de conjugués d'albumine sérique humaine et de phosphocholine pour bloquer une protéine c-réactive WO2024028192A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP22188898 2022-08-04
EP22188898.5 2022-08-04
EP23168306 2023-04-17
EP23168306.1 2023-04-17

Publications (1)

Publication Number Publication Date
WO2024028192A1 true WO2024028192A1 (fr) 2024-02-08

Family

ID=87551069

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2023/070776 WO2024028192A1 (fr) 2022-08-04 2023-07-26 Utilisation de conjugués d'albumine sérique humaine et de phosphocholine pour bloquer une protéine c-réactive

Country Status (1)

Country Link
WO (1) WO2024028192A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160131661A1 (en) 2004-04-15 2016-05-12 Athera Biotechnologies Ab Phosphorylcholine conjugates and corresponding antibodies
EP4169577A1 (fr) * 2021-10-19 2023-04-26 Pentracor GmbH Composés de 4-aminophénylphosphorylcholine destinés au blocage de la protéine c-réactive

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160131661A1 (en) 2004-04-15 2016-05-12 Athera Biotechnologies Ab Phosphorylcholine conjugates and corresponding antibodies
EP4169577A1 (fr) * 2021-10-19 2023-04-26 Pentracor GmbH Composés de 4-aminophénylphosphorylcholine destinés au blocage de la protéine c-réactive

Non-Patent Citations (15)

* Cited by examiner, † Cited by third party
Title
BARRETT ET AL., J PHARMACOL EXP THER, vol. 303, no. 3, 2002, pages 1007 - 1013
GILL ET AL., J CEREB BLOOD FLOW METAB, vol. 24, no. 11, 2004, pages 1214 - 1218
GRISELLI ET AL., J EXP MED, vol. 190, no. 12, 1999, pages 1733 - 1740
JOURNAL OF IMMUNOLOGICAL METHODS, vol. 293, 2004, pages 1 - 11
MOLLINS ET AL., FRONT. IMMUNOL., vol. 9, 2018, pages 808
NIUBEL DIAZ PADILLA ET AL: "Levels of natural IgM antibodies against phophorylcholine in healthy individuals and in patients undergoing isolated limb perfusion", JOURNAL OF IMMUNOLOGICAL METHODS, ELSEVIER SCIENCE PUBLISHERS B.V.,AMSTERDAM, NL, vol. 293, 1 January 2004 (2004-01-01), pages 1 - 11, XP002467949, ISSN: 0022-1759, DOI: 10.1016/J.JIM.2004.06.011 *
NOVECK ET AL., J AM HEART ASSOC, 2014
PAUL ANTONI ET AL: "C-Reactive Protein Accelerates the Progression of Atherosclerosis in Apolipoprotein E-Deficient Mice", CIRCULATION, vol. 109, no. 5, 10 February 2004 (2004-02-10), US, pages 647 - 655, XP093094735, ISSN: 0009-7322, DOI: 10.1161/01.CIR.0000114526.50618.24 *
PEPYS ET AL., NATURE, vol. 440, no. 7088, 2006, pages 1217 - 1221
PEPYS M B ET AL: "Targeting C-reactive protein for the treatment of cardiovascular disease", CLEO: APPLICATIONS AND TECHNOLOGY 2019 SAN JOSE, CALIFORNIA UNITED STATES 5-10 MAY 2019, OPTICA, vol. 440, no. 7088, 27 April 2006 (2006-04-27), pages 1217 - 1221, XP002603932, DOI: 10.1038/NATURE04672 *
PEPYSHIRSCHFIELD, J. CLIN. INVEST., vol. 111, 2003, pages 1805 - 1812
RIES ET AL.: "C-reactive protein apheresis as anti-inflammatory therapy in acute myocardial infarction: Results of the CAMI-1 study", FRONT CARDIOVASC MED, vol. 8, 2021, pages 591741
SHERIFF ET AL., JOURNAL OF CLINICAL APHERESIS, vol. 30, 2015, pages 15 - 21
THIELE ET AL., FRONT IMMUNOL, vol. 9, 2018
VON BRAIG ET AL., NAT COMMUN, vol. 8, 2017, pages 14188

Similar Documents

Publication Publication Date Title
JP7101413B2 (ja) 真菌感染症の治療方法
DE69424560T2 (de) Verwendung von stickstoffoxid freisetzenden verbindungen zur herstellung eines arzneimittels zum schutz gegen die ischämischen reperfusionsschäden
DE69526934T2 (de) Medikamente zur behandlung von restenosis, enthaltend stickstoff freisetzende polymere
DE69732049T2 (de) Pharmazeutische zubereitungen, enthaltend salze von hyaluronsäure und lokalanästhetika
TWI446911B (zh) 含美西特田（ｍａｃｉｔｅｎｔａｎ）之治療組合物
US20040152745A1 (en) Dipeptidyl peptidase IV inhibitors and methods of making and using dipeptidyl peptidase IV inhibitors
Riaz et al. An overview of biomedical applications of choline geranate (CAGE): a major breakthrough in drug delivery
EP0708640A1 (fr) Preparations pharmaceutiques avec un principe actif contenant des groupes amidine modifies
US20220160701A1 (en) Methods of treatment and pharmaceutical compositions using bcn057 or bcn512
DE69506686T2 (de) Verwendung von bis (amidinobenzidazolen) zur herstellung eines medikamentes für die hemmung der retroviral integrase
DE69104362T2 (de) Autobiotika sowie deren verwendung bei der in vivo eliminierung körperfremder zellen.
DE69427130T2 (de) Ssi tyrphostine und pharmazeutische zusammensetzungen
EP4419208A1 (fr) Composés de 4-aminophénylphosphorylcholine pour le blocage de la protéine c-réactive
DE102014008685A1 (de) Freisetzungssystem für therapeutisches Gas
DE69808475T2 (de) Aminosäurederivate zur behandlung von schlaganfall
WO2021198504A1 (fr) Principes actifs à usage médical
CN111840561B (zh) S100a9抑制剂在制备治疗胰腺炎的药物中的应用
WO2024028192A1 (fr) Utilisation de conjugués d'albumine sérique humaine et de phosphocholine pour bloquer une protéine c-réactive
CN105769756B (zh) 一种富马酸西他沙星注射剂及其制备方法
DE69426316T2 (de) Verwendung von Beta-Naphthochinonderivaten zur Beschleunigung der Proliferation der Endothelzellen und Inhibierung der NO-Synthasen
EP1435914B1 (fr) Preparation pharmaceutique lyophilisee galenique stable de polypeptides de recombinaison liant les hydrocarbures
TW201615694A (zh) 主鏈型聚胺類
DE60203890T2 (de) Apfelsäureadditionssalze von terbinafin
CN109730988A (zh) 1，3-丙二磺酸或其药学上可接受的盐用于治疗肉样瘤病的用途
US20050148519A1 (en) Salts of pharmacologically active compounds

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23748763

Country of ref document: EP

Kind code of ref document: A1