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EP1501535A1 - Antagonistes de megaline ou de cubiline destines a etre utilises dans la prevention de l'endommagement d'organes induit par des agents therapeutiques - Google Patents

Antagonistes de megaline ou de cubiline destines a etre utilises dans la prevention de l'endommagement d'organes induit par des agents therapeutiques

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Publication number
EP1501535A1
EP1501535A1 EP02807105A EP02807105A EP1501535A1 EP 1501535 A1 EP1501535 A1 EP 1501535A1 EP 02807105 A EP02807105 A EP 02807105A EP 02807105 A EP02807105 A EP 02807105A EP 1501535 A1 EP1501535 A1 EP 1501535A1
Authority
EP
European Patent Office
Prior art keywords
substance
receptor
amino acid
therapeutic agent
megalin
Prior art date
Legal status (The legal status 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 status listed.)
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Application number
EP02807105A
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German (de)
English (en)
Inventor
Thomas Willnow
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Publication of EP1501535A1 publication Critical patent/EP1501535A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • A61K38/57—Protease inhibitors from animals; from humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies

Definitions

  • the invention relates to agents for the prevention of organ damage, in particular of the kidneys and the inner ear, induced by the administration of therapeutic agents.
  • aminoglycosides are some of the most important antibiotics for the treatment of severe bacterial infections. They are the preferred agents against a 0 number of Gram-negative bacteria. Their annual market potential in Germany is about 500 million DM. At present, the market share of the aminoglycosides in the field of anti-infectious agents is even rapidly increasing. This is above all due to the general increase in the occurrence of pathological strain resistance to other classes of antibiotics. 5
  • aminoglycosides The main obstacle in the clinical use of aminoglycosides is their severe oto- and nephrotoxic side effects which especially lead to complete loss of hearing and to renal failure in the long term.
  • the use of aminoglycosides is thus not only associated with a high risk, but also entails high resulting costs. Their use is therefore restricted 0 to incidences of the most severe infections in the industrial countries. In the developing countries in which aminoglycosides are more often used because of their low production costs, these antibiotics account for 70% of all cases of acquired deafness.
  • aminoglycosides bind to the surface of cells in the kidneys and the inner ear and are taken up into the cells through unknown mechanisms. As aminoglycosides are only weakly degradable in the cells, they accumulate in large numbers and lead to destruction of the cell structures and thus to renal damage and loss of hearing. Various surface structures 0 or receptors have been made responsible for the binding and uptake of the antibiotics; however, a clear demonstration of the binding sites of aminoglycosides on the body cells has not yet been possible. Decorti et al.
  • LRP's found in the liver, but not in the kidneys.
  • aminoglycosides are only taken up into the organism in the kidneys and in the inner ear, the value of these in vitro experiments is unclear.
  • amikacin a semi-synthetic derivative of kanamycin (Begg, E.J. & Barclay, M.L. Br. J. Clin. Pharmac. 39, 597-603, 1995).
  • the use of amikacin reduced the rate of toxicity to 1-4%.
  • this use is also connected with a further increase in the therapy costs as amikacin (DM 180 per day) is clearly more expensive than usual gentamicin compositions (DM 35 per day).
  • DM 180 per day is clearly more expensive than usual gentamicin compositions (DM 35 per day).
  • the present invention relates to the use of a substance capable of binding to one or more of the following:
  • a therapeutic agent capable of binding to the megalin receptor and/or the cubilin receptor
  • Cubilin is a receptor colocalizing with megalin, that may facilititate the endocytic process of megalin by sequestering the therapeutic agent on the cellular surface before megalin-mediated intemalization of the cubilin-bound ligand.
  • the invention in another aspect relates to a method for treating side effects caused by a medical treatment with a therapeutic agent, comprising administering an effective amount of a substance, said substance being capable of binding to one or more of the following:
  • a therapeutic agent capable of binding to the megalin receptor and/or the cubilin receptor
  • the invention relates to a combinatorial medicament comprising a substance, said substance being capable of binding to one or more of the following:
  • a therapeutic agent capable of binding to the megalin receptor and/or the cubilin receptor, and said therapeutic agent, wherein said therapeutic agent is capable of causing side effects by intracellular accumulation.
  • the invention relates to a method for evaluating whether megalin is responsible for cell uptake of a test drug, comprising
  • the invention relates to a method for assessing a candidate substance for treating side effects of medical treatment, comprising
  • Fig. 1 Megalin is responsible for the uptake of aminoglycosides into the kid- neys.
  • Radioactively labelled aminoglycosides were injected into 26 normal (wildtype) and into 3 megalin-deficient mice (knockout). After 24 hours, the secretion of the aminoglycosides into the urine and their accumulation in the kidneys were determined. In wildtype mice, about 10% of the administered aminoglycosides are accumulated in the kidneys and 40% are secreted into the urine. In knockout mice, there is no accumulation of the aminoglycosides in the kidneys because of the receptor deficiency; 40% of the antibiotics are secreted into the urine.
  • Fig. 2 Megalin antagonists suppress the uptake of aminoglycosides into the kidneys.
  • polymyxin B a substance that binds with a high affinity to megalin and displaces gentamicin from the receptor.
  • the administration of polymyxin B reduces the uptake of aminoglycosides into the kidneys by more than 60%.
  • Fig. 3 BIAcore analysis demonstrating direct binding of gentamicin to megalin (panel A) and cubilin (panel B).
  • Binding to both receptors is not dependent on the native conformation of the receptors, since reduction of disulfide-bridges does not significantly interefere with ligand binding (cubilin may, however, be somewhat more sensitive to the native receptor conformation since reduction affects binding more). Moreover, the addition of EDTA, which depletes the receptors for calcium and affects receptor stability does not abolish binding, indicating that the interaction between receptors and gentamicin may depend on simple ionic interactions rather than the overall confirmation of the receptors.
  • RAP a protein ligand which is basic in structure but known to bind only the native conformation of the receptors
  • Fig. 5 Inhibition of uptake of radio-labeled gentamicin into mouse kidney
  • the drugs were administrated intravenously. Uptake of gentamicin can be inhibited by co-infusion with unlabeled gentamicin, polymyxin and poly-lysine. In contrast to the situation in cells, the C-terminal domain of RAP does not inhibit. This is most likely because infused RAP rapidly is cleared from the circulation by uptake into the liver.
  • the principle for the present invention is to reduce the side effects, in particular kid- ney and inner ear damages, caused by therapeutic agents, possibly due to the accumulation of the therapeutic agent in cells in the organs in question.
  • the invention is focused on inhibition of the accumulation in the cells of the therapeutic agent.
  • the invention is based on the surprising finding that it could be shown for the first time that contrary to previous hypotheses, only megalin-mediated processes are responsible for the accumulation of the antibiotics in the kidneys when various models for the uptake of aminoglycosides were tested.
  • Megalin is a 600 kDa endocytosis receptor of the low density lipoprotein (LDL) receptor gene family. Megalin is a multifunctional clearance receptor that binds and internalises a number of macromolecules.
  • LDL low density lipoprotein
  • cDNA U33837 gene: NT_002176
  • the present invention relates to the use of substances capable of inhibiting the intracellular accumulation. This may for example be done by inhibiting the binding of the therapeutic agent to the megalin receptor by either blocking a sufficient amount of binding sites on the megalin receptor and/or blocking the therapeu- tic agent so that it maintains the normal therapeutic effect, however is inhibited from binding to the receptor.
  • the invention relates to inhibiting of the cubilin receptor.
  • Cubilin a 460 kDa membrane-associated protein colocalizing with megalin, may facilititate the endocytic process by sequestering the therapeutic agent on the cellular surface before megalin-mediated intemalization of the cubilin-bound ligand.
  • the therapeutic agent may bind to cubilin as well as directly to megalin.
  • Cubilin appears not to be able to mediate endocytosis on its own but megalin can physically associate with cubilin and mediate its intemalization.
  • the sequence for the cubilin receptor is shown as:
  • cDNA XM_011904 gene: NT_008682 (Homo sapiens chromosome 10 working draft sequence segment)
  • classes of substances acting as antagonists have been provided; these classes of antagonists reducing the uptake of aminoglycosides into the organs and thereby suppressing the side effects of these antibiotics.
  • the substance according to the invention is capable of binding to either one or both of the receptors discussed above and/or to the therapeutic agent. In case of binding to the receptor(s) it is of importance that the binding is effective in respect of blocking binding of the therapeutic agent to the receptor.
  • the megalin receptor for example comprises 50-100 binding sites for the therapeutic agent gentamicin, and it is crucial for the effect of the treatment of this invention, that the substance is capable of blocking an effective amount of these binding sites.
  • Prior art has shown that the naturally occurring substance RAP only binds to a minority of the binding sites, and the inhibitory effect of RAP with respect to intracellular accumulation of a therapeutic agent is also too small to have a clinical significance.
  • the substance according to the invention may bind either the megalin receptor in order to inhibit endocytosis or the cubulin receptor in order to reduce sequestering and thereby inhibit or reduce endocytosis.
  • the substance is preferably either capable of binding to a sufficiently amount of binding sites on the receptor(s) or binding to the receptor and sterically hindering the binding of the therapeutic agent.
  • the substance according to the invention is capable of binding to cubilin, thereby inhibiting or reducing binding of the therapeutic agent to cubilin.
  • the substance has at least 3 positive charges in solution.
  • the substance exhibits at least 5 positive charges, such as at least 10 positive charges, such as at least 15 positive charges. It is preferred that the polybasic charge distribution is having the same charge distribution as aminoglycosides.
  • the substances are polybasic.
  • polybasic substances having at least 5 positive charges in solu- tion.
  • substances exhibiting the preferred positive charge distribution are polymyxin, structurally or functionally related molecules of polymyxin, aprotinin and polylysine, wherein polylysine is a sequence comprising the amino acid lysine, said sequence having at least 5 lysine residues.
  • the substance may be selected from organic molecules, peptides, polypeptides, proteins, antibodies, fragments of antibodies, antibody light chains, wherein the functional requirement being that they are able to bind to megalin and/or cubilin and by this binding inhibit the binding and subsequently uptake of the therapeutic agent into the cell presenting the megalin and/or cubilin receptor.
  • the substance is preferably not an immunogenic substance.
  • the substance is selected from peptides and/or proteins capable of binding the receptor(s) in question.
  • the peptide/protein has a length to fit into the various binding sites on the receptor(s).
  • the peptide/protein has at most 104 amino acids, preferably from 20 to 60 amino acids. In particular, they are minimal functional protein domains.
  • At least a part of said peptide or protein exhibits a positive charge distribution as described above.
  • the substance is preferably derived from naturally occurring RAP (receptor-associated protein), it is however preferred that the substance is capable of binding at least 25 % of the binding sites for the therapeutic agent on the megalin receptor and/or the cubilin receptor. Accordingly, it is preferred that the substance does not consist of full-length RAP.
  • RAP receptor-associated protein
  • RAP is a cellular protein comprising about 300 amino acids, in a preferred embodiment having the sequence shown in: XM_003315, Gene: AH006949, and known to bind to megalin to suppress the interaction of the receptor with ligands (cellular receptor antagonist) (Willnow et al., EMBO J. 15, 2632-2639, 1996). It has been possible to isolate minimal domains of RAP (peptides) that carry the minimal functional domains of the receptor binding and inhibition and thus also function as megalin antagonists.
  • the RAP derived substance is a peptide comprising a minimal functional domain having at most 104 amino acids, preferably from 20 to 60 amino acids.
  • they are minimal functional protein domains.
  • These peptides have at the most 104 amino acids, preferably from 20 to 60 amino acids.
  • a preferred domain is amino acid positions 219-323 of RAP.
  • the peptide/protein is a cubilin fragment, such as a domain capable of associating with the megalin receptor. Accordingly, such a peptide could competitively inhibit the association between the megalin receptor and the therapeutic agent or the cubilin co-receptor.
  • the peptide comprises or consists of fragments of the cubilin polypeptide sequence.
  • a fragment may comprise amino acid 1 to 50, such as amino acid 25 to 75, for example amino acid 50 to 100, such as amino acid 75 to 125, for example amino acid 100 to 150, such as amino acid 125 to 175, for example amino acid 150 to 200, such as amino acid 175 to 225, for example amino acid 200 to 250, such as amino acid 225 to 275, for example amino acid 250 to 300, such as amino acid 275 to 325, for example amino acid 300 to 350, such as amino acid 325 to 375, for example amino acid 350 to 400, such as amino acid 375 to 425, for example amino acid 400 to 450, such as amino acid 425 to 475, for example amino acid 450 to 500, such as amino acid 475 to 525, for example amino acid 500 to 550, such as amino acid 525 to 575, for example amino acid 550 to 600, such as amino acid 575 to 625, for example amino acid 600 to 650,
  • amino acid 1200 to 1250 such as amino acid 1225 to 1275
  • amino acid 1250 to 1300 such as amino acid 1275 to 1325
  • amino acid 1300 to 1350 such as amino acid 1325 to 1375
  • amino acid 1350 to 1400 such as amino acid 1375 to 1425
  • amino acid 1400 to 1450 such as amino acid 1425 to 1475
  • amino acid 1500 such as amino acid 1475 to 1525, for example amino acid 1500 to 1550, such as amino acid 1525 to 1575, for example amino acid 1550 to 1600, such as amino acid 1575 to 1625, for example amino acid 1600 to 1650, such as amino acid 1625 to 1675, for example amino acid 1650 to 1700, such as amino acid 1675 to 1725, for example amino acid 1700 to 1750, such as amino acid 1725 to 1775, for example amino acid 1750 to 1800, such as amino acid 1775 to 1825, for example amino acid 1800 to 1850, such as amino acid 1825 to 1875, for example amino acid 1850 to 1900, such as amino acid 1875 to 1925, for example amino acid 1900 to 1950, such as amino acid 1925 to 1975, for example amino acid 1950 to 2000, such as amino acid 1975 to 2025, amino acid 2001 to 2050, such as amino acid 2025 to 2075, for example amino acid 2050 to 2100, such as amino acid 2075 to 2125, for example amino acid 2100 to 2150, such as amino acid 2125 to 21
  • the peptide/protein is a megalin fragment, such as a domain capable of associating with the cubulin receptor. Accordingly, such a peptide could competitively inhibit the association between the megalin receptor and the thera- Treatmentic agent or the cubilin co-receptor.
  • the substance comprise or consists of fragments of the megalin polypeptide sequence.
  • a fragment may comprise amino acid 1 to 50, such as amino acid 25 to 75, for example amino acid 50 to 100, such as amino acid 75 to 125, for example amino acid 100 to 150, such as amino acid 125 to 175, for example amino acid 150 to 200, such as amino acid 175 to 225, for example amino acid 200 to 250, such as amino acid 225 to 275, for example amino acid 250 to 300, such as amino acid 275 to 325, for example amino acid 300 to 350, such as amino acid 325 to 375, for example amino acid 350 to 400, such as amino acid 375 to 425, for example amino acid 400 to 450, such as amino acid 425 to 475, for example amino acid 450 to 500, such as amino acid 475 to 525, for example amino acid 500 to 550, such as amino acid 525 to 575, for example amino acid 550 to 600, such as amino acid 575 to 625, for example amino acid 600 to 650,
  • amino acid 2050 such as amino acid 2025 to 2075, for example amino acid 2050 to 2100, such as amino acid 2075 to 2125, for example amino acid 2100 to 2150, such as amino acid 2125 to 2175, for example amino acid 2150 to 2200, such as amino acid 2175 to 2225, for example amino acid 2200 to 2250, such as amino acid 2225 to 2275, for example amino acid 2250 to 2300, such as amino acid 2275 to 2325, for example amino acid 2300 to 2350, such as amino acid 2325 to 2375, for example amino acid 2350 to 2400, such as amino acid 2375 to 2425, for example amino acid 2400 to 2450, such as amino acid 2425 to 2475, for example amino acid 2450 to 2500, such as amino acid 2475 to 2525, for example amino acid 2500 to 2550, such as amino acid 2525 to 2575, for example amino acid 2550 to 2600, such as amino acid 2575 to 2625, for example amino acid 2600 to 2650, such as amino acid 2625 to 2675,
  • amino acid 3200 such as amino acid 3175 to 3225, for example amino acid 3200 to 3250, such as amino acid 3225 to 3275, for example amino acid 3250 to 3300, such as amino acid 3275 to 3325, for example amino acid 3300 to 3350, such as amino acid 3325 to 3375, for example amino acid 3350 to 3400, such as amino acid 3375 to 3425, for example amino acid 3350 to 3400, such as amino acid 3375 to 3425, for example amino acid 3400 to 3450, such as amino acid 3425 to 3475, for example amino acid 3450 to 3500, such as amino acid 3475 to 3525, for example amino acid 3500 to 3550, such as amino acid 3525 to 3575, for example amino acid 3550 to 3600, such as amino acid 3575 to 3625, for example amino acid 3600 to 3650, such as amino acid 3625 to 3675, for example amino acid 3650 to 3700, such as amino acid 3675 to 3725, for example amino acid 3700 to 3750, such as amino acid 3725 to 3775,
  • amino acid 4350 such as amino acid 4325 to 4375, for example amino acid 4350 to 4400, such as amino acid 4375 to 4425, for example amino acid 4400 to 4450, such as amino acid 4425 to 4475, for example amino acid 4450 to 4500, such as amino acid 4475 to 4525, for example amino acid 4500 to 4550, such as amino acid 4525 to 4575, for example amino acid 4550 to 4600, such as amino acid 4575 to 4625, for example amino acid 4600 to 4655 of the megalin polypeptide sequence.
  • the peptide or protein comprises a high amount of positively charged amino acid residues, in particular a high amount of lysine residue.
  • the peptide is a polylysine sequence comprising substantially only lysine residues.
  • Polylysine sequences according to the invention preferably comprises from 5 to 300 lysine residues, more preferably from 10 to 200 lysine residues.
  • Functional homologues of the polypeptides of the present invention may be used as the substance.
  • Functional homologues of polypeptides according to the present invention is meant to comprise any polypeptide sequence which is capable of associating with a megalin and/or cubilin receptor and thereby prevents association between the therapeutic agent and the megalin and/or cubilin receptor.
  • Functional homologues comprise polypeptides with an amino acid sequence, which are sharing at least some homology with the predetermined polypeptide sequences as outlined herein above.
  • polypeptides are at least about 40 percent, such as at least about 50 percent ho- mologous, for example at least about 60 percent homologous, such as at least about 70 percent homologous, for example at least about 75 percent homologous, such as at least about 80 percent homologous, for example at least about 85 percent homologous, such as at least about 90 percent homologous, for example at least 92 percent homologous, such as at least 94 percent homologous, for example at least 95 percent homologous, such as at least 96 percent homologous, for example at least 97 percent homologous, such as at least 98 percent homologous, for example at least 99 percent homologous with the predetermined polypeptide sequences as outlined herein above.
  • the homology between amino acid sequences may be calculated using well known algorithms such as for example any one of BLOSUM 30, BLOSUM 40, BLOSUM 45, BLOSUM 50, BLOSUM 55, BLOSUM 60, BLOSUM 62, BLOSUM 65, BLOSUM 70, BLOSUM 75, BLOSUM 80, BLOSUM 85, and BLOSUM 90.
  • Functional homologues may comprise an amino acid sequence that comprises at least one substitution of one amino acid for any other amino acid.
  • a substitution may be a conservative amino acid substitution or it may be a non- conservative substitution.
  • a conservative amino acid substitution is a substitution of one amino acid within a predetermined group of amino acids for another amino acid within the same group, wherein the amino acids within a predetermined groups exhibit similar or substantially similar characteristics.
  • conservative amino acid substitution as applied herein, one amino acid may be substituted for another within groups of amino acids characterised by having
  • polar side chains (Asp, Glu, Lys, Arg, His, Asn, Gin, Ser, Thr, Tyr, and Cys,)
  • non-polar side chains (Gly, Ala, Val, Leu, lie, Phe, Trp, Pro, and Met)
  • amino acids being monoamino-dicarboxylic acids or monoamino- monocarboxylic-monoamidocarboxylic acids (Asp, Glu, Asn, Gin).
  • Non-conservative substitutions are any other substitutions.
  • a non-conservative substitution leading to the formation of a functional homologue would for example i) differ substantially in hydrophobicity, for example a hydrophobic residue (Val, lie, Leu, Phe or Met) substituted for a hydrophilic residue such as Arg, Lys, Trp or Asn, or a hydrophilic residue such as Thr, Ser, His, Gin, Asn, Lys, Asp, Glu or Trp substituted for a hydrophobic residue; and/or ii) differ substantially in its effect on polypeptide backbone orientation such as substitution of or for Pro or Gly by another residue; and/or iii) differ substantially in electric charge, for example substitution of a negatively charged residue such as Glu or Asp for a positively charged residue such as Lys, His or Arg (and vice versa); and/or iv) differ substantially in steric bulk, for ex- ample substitution of a bulky residue such as His, Trp, Phe or Tyr for
  • Functional homologues according to the present invention may comprise more than one such substitution, such as e.g. two amino acid substitutions, for example three or four amino acid substitutions, such as five or six amino acid substitutions, for example seven or eight amino acid substitutions, such as from 10 to 15 amino acid substitutions, for example from 15 to 25 amino acid substitution, such as from 25 to 30 amino acid substitutions, for example from 30 to 40 amino acid substitution, such as from 40 to 50 amino acid substitutions, for example from 50 to 75 amino acid substitution, such as from 75 to 100 amino acid substitutions, for example more than 100 amino acid substitutions.
  • substitutions such as e.g. two amino acid substitutions, for example three or four amino acid substitutions, such as five or six amino acid substitutions, for example seven or eight amino acid substitutions, such as from 10 to 15 amino acid substitutions, for example from 15 to 25 amino acid substitution, such as from 25 to 30 amino acid substitutions, for example from 30 to 40 amino acid substitution, such as from 40 to 50 amino acid substitutions, for example from 50 to 75 amino acid substitution,
  • the addition or deletion of an amino acid may be an addition or deletion of from 2 to 5 amino acids, such as from 5 to 10 amino acids, for example from 10 to 20 amino acids, such as from 20 to 50 amino acids.
  • additions or deletions of more than 50 amino acids, such as additions from 50 to 200 amino acids are also comprised within the present invention.
  • functional homologues may be capable of associating with antisera which are specific for the polypeptides according to the present invention.
  • the present invention relates to functional equivalents which comprise substituted amino acids having hydrophilic or hydropathic indices that are within +/-2.5, for example within +/- 2.3, such as within +/- 2.1 , for example within +/- 2.0, such as within +/- 1.8, for example within +/- 1.6, such as within +/- 1.5, for example within +/- 1.4, such as within +/- 1.3 for example within +/- 1.2, such as within +/- 1.1 , for example within +/- 1.0, such as within +/- 0.9, for example within +/- 0.8, such as within +/- 0.7, for example within +/- 0.6, such as within +/- 0.5, for example within +/- 0.4, such as within +/- 0.3, for example within +/- 0.25, such as within +/- 0.2 of the value of the amino acid it has substituted.
  • hydrophilic and hydropathic amino acid indices in conferring interactive biologic function on a protein is well understood in the art (Kyte & Doolit- tle, 1982 and Hopp, U.S. Pat. No. 4,554,101 , each incorporated herein by reference).
  • amino acid hydropathic index values as used herein are: isoleucine (+4.5); va- line (+4.2); leucine (+3.8); phenylalanine (+2.8); cysteine/cystine (+2.5); methionine (+1.9); alanine (+1.8); glycine (-0.4 ); threonine (-0.7 ); serine (-0.8 ); tryptophan (- 0.9); tyrosine (-1.3); proline (-1.6); histidine (-3.2); glutamate (-3.5); glutamine (-3.5); aspartate (-3.5); asparagine (-3.5); lysine (-3.9); and arginine (-4.5) (Kyte & Doolittle, 1982).
  • amino acid hydrophilicity values are: arginine (+3.0); lysine (+3.0); aspartate (+3.0.+-.1 ); glutamate (+3.0.+-.1); serine (+0.3); asparagine (+0.2); glutamine (+0.2); glycine (0); threonine (-0.4); proline (-0.5.+-.1); alanine (-0.5); histidine (-0.5); cys- teine (-1.0); methionine (-1.3); valine (-1.5); leucine (-1.8); isoleucine (-1.8); tyrosine
  • Substitution of amino acids can therefore in one embodiment be made based upon their hydrophobicity and hydrophilicity values and the relative similarity of the amino acid side-chain substituents, including charge, size, and the like.
  • Exemplary amino acid substitutions which take various of the foregoing characteristics into consideration are well known to those of skill in the art and include: arginine and lysine; glutamate and aspartate; serine and threonine; glutamine and asparagine; and valine, leucine and isoleucine.
  • sterically similar compounds may be formulated to mimic the key portions of the peptide structure and that such compounds may also be used in the same manner as the peptides of the invention. This may be achieved by techniques of modelling and chemical designing known to those of skill in the art. For example, esterification and other alkylations may be employed to modify the amino terminus of, e.g., a di-arginine peptide backbone, to mimic a tetra peptide structure. It will be understood that all such sterically similar constructs fall within the scope of the present invention.
  • Functional equivalents also comprise glycosyl- ated and covalent or aggregative conjugates, including dimers or unrelated chemical moieties. Such functional equivalents are prepared by linkage of functionalities to groups which are found in fragment including at any one or both of the N- and C- termini, by means known in the art.
  • Functional equivalents may thus comprise fragments conjugated to aliphatic or acyl esters or amides of the carboxyl terminus, alkylamines or residues containing car- boxyl side chains, e.g., conjugates to alkylamines at aspartic acid residues; O-acyl derivatives of hydroxyl group-containing residues and N-acyl derivatives of the amino terminal amino acid or amino-group containing residues, e.g. conjugates with Met-Leu-Phe.
  • Derivatives of the acyl groups are selected from the group of alkyl- moieties (including C3 to C10 normal alkyl), thereby forming alkanoyl species, and carbocyclic or heterocyclic compounds, thereby forming aroyl species.
  • the reactive groups preferably are difunctional compounds known per se for use in cross-linking proteins to insoluble matrices through reactive side groups.
  • peptides, polypeptides and proteins according to the invention may be produced by any suitable method known to the person skilled in the art, such as syn- thetically and recombinant.
  • the substance according to the invention relates to an anti- body or an antibody fragment directed to the megalin receptor or the cubilin receptor or to parts of the receptor(s).
  • the antibody fragments are for example IgG light chains or any other IgG fragment.
  • IgG light chains may bind unspecifi- cally to the cubilin receptor, and therefore in relation to binding to the cubilin receptor it is preferred that the substance is a IgG light chain.
  • the antibodies and antibody fragments according to the invention may be produced by any suitable method known to the person skilled in the art.
  • the invention relates to a method for testing the mechanism of side effects of various drugs, by testing the drug in question in an assay using an animal model. Accordingly, the invention relates to a method for evaluating whether megalin is responsible for cell uptake of a test drug, comprising
  • the animal model is a mouse model with an induced megalin gene defect (knockout mouse; Nykjaer, A. et al., Cell 96, 507-515).
  • the contribution of megalin and other receptor-mediated or receptor-independent processes to the drug uptake into the kidneys may be tested.
  • the amount of intracellular accumulation of the drug in question as compared to a control having sufficient megalin indicates whether the mechanism of side effects is intracellular accumulation through megalin binding or some other mechanism.
  • the animal model is a mouse model with an induced RAP gene defect (knockout mouse; Willnow T.E. et al (1995) Proc. Natl. Acad. Sci. 92:4537-4541).
  • the RAP knock out mouse is a 50 % deficient mouse with respect to megalin, thus capable of uptaking only 50 % of the therapeutic agent as compared to the megalin sufficient mouse.
  • the contribution of megalin and other receptor-mediated or receptor-independent processes to the drug uptake into the kidneys may be quantified.
  • the amount of intracellular accumulation of the drug in question as compared to a control having sufficient megalin indicates whether the mechanism of side effects is intracellular accumulation through megalin binding or some other mechanism.
  • the two animal models may also be combined.
  • the invention relates to a method for assessing a candidate substance for treating side effects of medical treatment, comprising
  • the method may for example be used for screening the substance in question in an assay as described below.
  • the substance according to the invention is preferably a substance capable of inhibiting uptake of labeled (e.g. by biotinylation) drugs, for examples aminoglycosides, such as gentamicin and/or kanamycin in the following ELISA-plate assay:
  • the uptake in this ELISA-plate assay is inhibited by at least 25 % as compared to the control, such as at least 30 % as compared to the control, such as at least 40 % as compared to the control, such as at least 50 % as compared to the control, such as at least 60 % as compared to the control, such as at least 70 % as compared to the control, such as at least 80 % as compared to the control, such as at least 90 % as compared to the control.
  • the therapeutic agent according to the invention may be any therapeutic agent capable of causing organ damages due to intracellular accumulation in cells in the organs.
  • the therapeutic agent is capable of accumulating in cells in the kidneys and/or inner ear, thus causing kidney damages as well as damages to the inner ear.
  • the therapeutic agent is selected from aminoglycosides, such as gen- tamicin and kanamycin, cisplatin, amphotericin B, ifosfomide, polymyxin B, cyclo- phosphomide, methotrexate, aprotinin and valproate.
  • the therapeutic agent is an aminoglycoside, such as gentamicin and kanamycin.
  • fusion proteins or fusion products used for medical treatment wherein one of the proteins is capable of binding the megalin or the cubilin receptor and the other protein/product cell toxic when accumulating in the cells.
  • fusion products wherein one part of the product is an antibody or IgG light chain, both capable of unspecifically binding to cubilin, and the other part of the product being cytotoxic, such as cancer treatment, may be co-administered with a substance according to the present invention, in order to reduce organ damage, in particular kidney damage.
  • the substance according to the invention preferably has at least 2 times greater affinity to the megalin receptor and/or the cubilin receptor than the therapeutic agent, in a preferred em- bodiment at least 5 times greater affinity, in a more preferred embodiment at least
  • the dosage of the substance according to the invention is depending on the substance in question, however the amount of substance is also closely related to the therapeutic agent co-administered with the substance as well as the dosage of said therapeutic agent.
  • the daily oral dosage regimen will preferably be from about 0.01 to about 80 mg/kg of total body weight.
  • the daily parenteral dosage regimen about 0.001 to about 80 mg/kg of total body weight.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human and animal individuals, each unit containing a predetermined quantity of a compound, alone or in combination with other agents, calculated in an amount sufficient to produce the desired effect in association with a pharmaceutically acceptable diluent, carrier, or vehicle.
  • the specifications for the unit dosage forms of the present invention depend on the particular compound or compounds employed and the effect to be achieved, as well as the pharmacody- namics associated with each compound in the host.
  • the dose administered should be an " effective amount” or an amount necessary to achieve an "effective level" in the individual patient.
  • the effective level is used as the preferred endpoint for dosing, the actual dose and schedule can vary, depending on inter-individual differences in pharmaco- kinetics, drug distribution, and metabolism.
  • the "effective level” can be defined, for example, as the blood or tissue level desired in the individual that corresponds to a concentration of one or more compounds according to the invention. Also, the effective level is depending on the therapeutic agent in question, and in particular on the concentration of the effective level in question.
  • the ratio of the substance administered to the therapeutic agent administered is in the interval of from 200:1 mokmol to 1 :200 mokmol, such as in the interval of from 100:1 mol:mol to 1 :50 mol:mol, such as in the interval of from 50:1 mol:mol to 1 :25 mokmol
  • the substance may be administered in any suitable dosage regime, but is preferably administered with the same intervals as the therapeutic agent, preferably either shortly before or during administration of the therapeutic agent.
  • therapeutic agents according to this invention are administered paren- terally, often intravenously.
  • the substance according to the invention may be ad- ministered in any suitable manner according to the formulation thereof, it is however often preferred that the substance is administered parenterally, such as intravenously as the therapeutic agent.
  • the present invention further relates to a combinatorial medicament comprising the substance according to the invention in combination with the therapeutic agent.
  • a combinatorial medicament com- prising a substance, said substance being capable of binding to one or more of the following:
  • a cubilin receptor 2) a cubilin receptor, and/or 3) a therapeutic agent, said therapeutic agent being capable of binding to the megalin receptor and/or the cubilin receptor,
  • said therapeutic agent is capable of causing side effects by intracellular accumulation.
  • the substance and the therapeutic agent may be administered simultaneously, either as separate formulations or combined in a unit dosage form, or administered sequentially.
  • the combinatorial medicament may be formulated by co-formulating the substance according to the invention with the therapeutic agent for simultaneous administration.
  • the combinatorial medicament is formulated as two separate medicament for either simultaneous or sequential administration.
  • the main routes of drug delivery according to the present invention are intravenous, oral, and topical, as will be described below.
  • Other drug-administration methods such as subcutaneous injection, which are effective to deliver the drug to a target site or to introduce the drug into the bloodstream, are also contemplated.
  • the mucosal membrane to which the pharmaceutical preparation of the invention is administered may be any mucosal membrane of the mammal to which the biologi- cally active substance is to be given, e.g. in the nose, vagina, eye, mouth, genital tract, lungs, gastrointestinal tract, or rectum.
  • Compounds of the invention may be administered parenterally, that is by intravenous, intramuscular, subcutaneous intranasal, intrarectal, intravaginal or in- traperitoneal administration.
  • the subcutaneous and intramuscular forms of paren- teral administration are generally preferred.
  • Appropriate dosage forms for such administration may be prepared by conventional techniques.
  • the compounds may also be administered by inhalation, that is by intranasal and oral inhalation administration.
  • the compounds according to the invention may be administered with at least one other compound.
  • the compounds may be administered simultaneously, either as separate formulations or combined in a unit dosage form, or administered sequentially.
  • the combinatorial medicament may be formulated by co-formulating the substance according to the invention with the therapeutic agent for simultaneous administration.
  • the combinatorial medicament is formulated as two separate medicament for either simultaneous or sequential administration.
  • compositions containing a compound of the present invention may be prepared by conventional techniques, e.g. as described in Remington: The Science and Practice of Pharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton, Pa.
  • the compositions may appear in conventional forms, for example capsules, tablets, aerosols, solutions, suspensions or topical applications.
  • the compounds of the present invention may be formulated for parenteral administration (e.g., by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative.
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol.
  • oily or nonaqueous carriers, diluents, solvents or vehicles examples include propylene glycol, poly- ethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilising and/or dispersing agents.
  • the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water.
  • parenteral formulations typically will contain from about 0.5 to about 25% by weight of the active ingredient in solution. Preservatives and buffers may be used. In order to minimise or eliminate irritation at the site of injection, such compositions may contain one or more nonionic surfactants having a hydrophile-lipophile balance
  • Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
  • the parenteral formulations can be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, for injections, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.

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Abstract

La présente invention concerne des agents destinés à la prévention de l'endommagement d'organes, notamment des reins et de l'oreille interne, induit par l'administration d'aminoglycosides. Les agents selon l'invention sont tous des substances qui sont antagonistes (inhibiteurs) de la mégaline et/ou de la cubiline. Lesdits agents sont notamment des molécules (composés) présentant des structures polybasiques qui se fixent à la mégaline et inhibent la fixation des aminoglycosides et des substances associées.
EP02807105A 2002-04-25 2002-04-25 Antagonistes de megaline ou de cubiline destines a etre utilises dans la prevention de l'endommagement d'organes induit par des agents therapeutiques Withdrawn EP1501535A1 (fr)

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WO2021117065A1 (fr) * 2019-12-14 2021-06-17 Manu Chaudhary Formulations de médicaments polybasiques pour réduire la toxicité d'organes multiples

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US7345018B2 (en) * 2002-04-25 2008-03-18 Reception Aps Method of treating side effects induced by therapeutic agents
CN100441175C (zh) * 2003-03-26 2008-12-10 里斯普蒂康公司 化合物用于制备预防药物诱导的细胞毒性药物的用途
WO2005063260A2 (fr) * 2003-12-22 2005-07-14 Oregon Health And Science University Procedes et composition pour prevenir des effets secondaires toxiques des medicaments a aminoglycosides
WO2005070965A2 (fr) * 2004-01-21 2005-08-04 Five Prime Therapeutics, Inc. Compositions pharmaceutiques contenant des antagonistes a lrp4, lrp8 ou a la megaline pour le traitement de maladies
EP1809381A2 (fr) * 2004-10-06 2007-07-25 Recepticon ApS Utilisation de composes pour la prevention d'une toxicite cellulaire induite par un medicament
AU2011269156A1 (en) * 2010-06-22 2013-01-10 Jjk Medical Ltd. New medium, devices and methods
WO2021078359A1 (fr) * 2019-10-21 2021-04-29 INSERM (Institut National de la Santé et de la Recherche Médicale) Utilisation d'inhibiteurs de la cubiline pour le traitement de maladies rénales chroniques
US20250090629A1 (en) * 2021-08-03 2025-03-20 The Trustees Of Indiana University Alleviating drug nephrotoxicity

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CA2319210A1 (fr) * 1998-01-22 1999-07-29 The Administrators Of The Tulane Educational Fund Proteine cubiline, sequences d'adn codant la cubiline, et utilisations correspondantes
AU6275800A (en) * 1999-07-16 2001-02-05 Mallinckrodt, Inc. Inhibition of renal uptake of molecules that are potentially damaging for the kidney
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WO2021117065A1 (fr) * 2019-12-14 2021-06-17 Manu Chaudhary Formulations de médicaments polybasiques pour réduire la toxicité d'organes multiples

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