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WO1998010651A1 - Conjugues utiles dans le traitement du cancer de la prostate - Google Patents

Conjugues utiles dans le traitement du cancer de la prostate Download PDF

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Publication number
WO1998010651A1
WO1998010651A1 PCT/US1997/016087 US9716087W WO9810651A1 WO 1998010651 A1 WO1998010651 A1 WO 1998010651A1 US 9716087 W US9716087 W US 9716087W WO 9810651 A1 WO9810651 A1 WO 9810651A1
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WIPO (PCT)
Prior art keywords
seq
serleu
dox
information
ser
Prior art date
Application number
PCT/US1997/016087
Other languages
English (en)
Inventor
Dong-Mei Feng
Victor M. Garsky
Raymond E. Jones
Allen I. Oliff
Jenny M. Wai
Original Assignee
Merck & Co., Inc.
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
Priority claimed from GBGB9624170.8A external-priority patent/GB9624170D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to CA002265476A priority Critical patent/CA2265476A1/fr
Priority to JP10513857A priority patent/JP2001501601A/ja
Priority to AU44123/97A priority patent/AU715632B2/en
Priority to US09/254,892 priority patent/US6391305B1/en
Priority to EP97942423A priority patent/EP0926955A4/fr
Publication of WO1998010651A1 publication Critical patent/WO1998010651A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • 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
    • A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1016—Tetrapeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • prostate cancer is the most frequently diagnosed malignancy (other than that of the skin) in U.S. men and the second leading cause of cancer-related deaths (behind lung cancer) in that group.
  • Prostate specific Antigen is a single chain 33 kDa glycoprotein that is produced almost exclusively by the human prostate epithelium and occurs at levels of 0.5 to 2.0 mg/ml in human seminal fluid (Nadji, M., Taber, S.Z., Castro, A., et al. ( 1981 ) Cancer 48: 1229; Papsidero, L., Kuriyama, M., Wang, M., et al. ( 1981 ). JNCI 66:37; Qui, S.D., Young, C.Y.F., Bihartz, D.L., et al. (1990), J. Urol.
  • PSA protease with chymotrypsin-like specificity (Christensson, A., Laureil, C.B., Lilja, H. (1990). Eur. J. Biochem. 194:755-763).
  • PSA is mainly responsible for dissolution of the gel structure formed at ejaculation by proteolysis of the major proteins in the sperm entrapping gel, Semenogelin I and Semenogelin II, and fibronectin (Lilja, H. ( 1985). J. Clin. Invest. 76: 1899; Lilja, H., Oldbring, J., Rannevik, G., et al. (1987). J. Clin. Invest. 80:281 ; McGee, R.S., Herr, J.C. (1988). Biol. Reprod. 39:499).
  • PSA proteolytically degrade IGFBP-3 (insulin-like growth factor binding protein 3) allowing IGF to stimulate specifically the growth of PSA secreting cells (Cohen et al., ( 1992) J. Clin. Endo.
  • PSA complexed to alpha 1 - antichymotrypsin is the predominant molecular form of serum PSA and may account for up to 95% of the detected serum PSA (Christensson, A., Bjork, T., Nilsson, O., et al. (1993). J. Urol. 150: 100- 105; Lilja, H., Christensson, A., Dahlen, U. (1991 ). Clin. Chem. 37: 1618- 1625; Stenman, U.H., Leinoven, J., Alfthan, H., et al. ( 1991 ). Cancer Res. 51 :222-226).
  • the prostatic tissue normal, benign hyperplastic, or malignant tissue
  • the prostatic tissue is implicated to predominantly release the mature, enzymatically active form of PSA, as this form is required for complex formation with alpha 1 - antichymotrypsin (Mast, A.E., Enghild, J.J., Pizzo, S.V., et al. ( 1991 ). Biochemistry 30: 1723- 1730; Perlmutter, D.H., Glover, G.I., Rivetna, M., et al. ( 1990). Proc. Natl. Acad. Sci. USA 87:3753-3757).
  • PSA in the microenvironment of prostatic PSA secreting cells the PSA is believed to be processed and secreted in its mature enzymatically active form not complexed to any inhibitory molecule.
  • PSA also forms stable complexes with alpha 2 - macroglobulin, but as this results in encapsulation of PSA and complete loss of the PSA epitopes, the in vivo significance of this complex formation is unclear.
  • a free, noncomplexed form of PSA constitutes a minor fraction of the serum PSA (Christensson, A., Bjork, T., Nilsson, O., et al. ( 1993). J. Urol. 150: 100- 105; Lilja, H., Christensson, A., Dahlen, U. ( 1991 ). Clin.
  • Serum measurements of PSA are useful for monitoring the treatment of adenocarcinoma of the prostate (Duffy, M.S. ( 1989). Ann. Clin. Biochem. 26:379-387; Brawer, M.K. and Lange, P.H. ( 1989). Urol. Suppl. 5: 1 1 - 16; Hara, M. and Kimura, H. ( 1989). J. Lab. Clin. Med. 1 13:541 -548), although above normal serum concentrations of PSA have also been reported in benign prostatic hyperplasia and subsequent to surgical trauma of the prostate (Lilja, H., Christensson, A., Dahlen, U. ( 1991 ). Clin. Chem. 37: 1618- 1625).
  • Prostate metastases are also known to secrete immunologically reactive PSA since serum PSA is detectable at high levels in prostatectomized patients showing widespread metatstatic prostate cancer (Ford, T.F., Butcher, D.N., Masters, R.W., et al. (1985). Brit. J. Urology 57:50-55). Therefore, a cytotoxic compound that could be activated by the proteolytic activity of PSA should be prostate cell specific as well as specific for PSA secreting prostate metastases.
  • Another object of this invention is to provide a method of treating prostate cancer which comprises administration of the novel anti-cancer composition.
  • the instant invention relates to novel anti-cancer compositions useful for the treatment of prostate cancer.
  • Such compositions comprise the oligopeptides covalently bonded directly, or through a chemical linker, to a cytotoxic agent.
  • the oligopeptides are chosen from oligomers that are selectively recognized by the free prostate specific antigen (PSA) and are capable of being proteolytically cleaved by the enzymatic activity of the free prostate specific antigen.
  • PSA prostate specific antigen
  • Such a combination of an oligopeptide and cytotoxic agent may be termed a conjugate.
  • the conjugates of the instant invention are further characterized by having a hydrophilic blocking group at the N-terminus of the oligopeptide which contributes to the aqueous solubility of the conjugate.
  • hydrophilic blocking groups include but are not limited to hydroxylated and polyhydroxylated alkanoyi moieties and alkanoyi moieties that incorporate ether functionalities.
  • the cytotoxic activity of the cytotoxic agent is greatly reduced or absent when the oligopeptide containing the PSA proteolytic cleavage site is bonded directly, or through a chemical linker, to the cytotoxic agent and is intact. Also ideally, the cytotoxic activity of the cytotoxic agent increases significantly or returns to the activity of the unmodified cytotoxic agent upon proteolytic cleavage of the attached oligopeptide at the cleavage site.
  • the oligopeptide is selected from oligopeptides that are not cleaved or are cleaved at a much slower rate in the presence of non-PSA proteolytic enzymes when compared to the cleavage of the oligopeptides in the presence of free enzymatically active PSA.
  • the oligopeptide may comprise a short peptide sequence, preferably less than ten amino acids. Most preferably the oligopeptide comprises seven or fewer amino acids. Because the conjugate preferably comprises a short amino acid sequence, the solubility of the conjugate may be influenced to a greater extent by the generally hydrophobic character of the cytotoxic agent component. Therefore, the hydrophilic blocking groups of the instant conjugates are selected to offset or diminish such a hydrophobic contribution by the cytotoxic agent.
  • a preferred embodiment of this invention is a conjugate wherein the oligopeptide, and the chemical linker if present, are detached from the cytotoxic agent by the proteolytic activity of the free PSA and any other native proteolytic enzymes present in the tissue proximity, thereby releasing unmodified cytotoxic agent into the physiological environment at the place of proteolytic cleavage.
  • the oligopeptide that is conjugated to the cytotoxic agent does not need to be the oligopeptide that has the greatest recognition by free PSA and is most readily proteolytically cleaved by free PSA.
  • the oligopeptide that is selected for incorporation in such an anti-cancer composition will be chosen both for its selective, proteolytic cleavage by free PSA and for the cytotoxic activity of the cytotoxic agent-proteolytic residue conjugate (or, in what is felt to be an ideal situation, the unmodified cytotoxic agent) which results from such a cleavage.
  • oligopeptide component of the instant invention is a prefered substrate of free PSA.
  • selective also indicates that the oligopeptide is proteolytically cleaved by free PSA between two specific amino acids in the oligopeptide.
  • oligopeptide components of the instant invention are selectively recognized by the free prostate specific antigen (PSA) and are capable of being proteolytically cleaved by the enzymatic activity of the free prostate specific antigen.
  • PSA prostate specific antigen
  • Such oligopeptides comprise an oligomer selected from: a) AsnLysIleSerTyrGln
  • hArg is homoarginine
  • Cha is cyclohexylalanine
  • Chg is cyclohexylglycine
  • the oligopeptide comprises an oligomer that is selected from:
  • the oligopeptide comprises an oligomer selected from:
  • SerLeu SEQ.ID.NO.: 41 );
  • GlySerSerChgGlnlSerLeu (SEQ.ID.NO.: 45);
  • hSerSerSerChgGInlSerLeu (SEQ.ID.NO.: 46); hArgSerSerChgGln
  • SerSerSerLeu SEQ.ID.NO.: 57
  • oligomers that comprise an amino acid sequence describes oligomers of from about 3 to about 100 amino acids residues which include in their amino acid sequence the specific amino acid sequence decribed and which are therefore proteolytically cleaved within the amino acid sequence described by free PSA.
  • the oligomer is from 5 to 10 amino acid residues.
  • the following oligomer hArgSerAlaChgGln
  • amino acids in a biologically active oligopeptide may be replaced by other homologous, isosteric and/or isoelectronic amino acids wherein the biological activity of the original oligopeptide has been conserved in the modified oligopeptide.
  • Certain unnatural and modified natural amino acids may also be utilized to replace the corresponding natural amino acid in the oligopeptides of the instant invention.
  • tyrosine may be replaced by 3-iodotyrosine, 2-methyltyrosine, 3-fluorotyrosine, 3-methyltyrosine and the like.
  • lysine may be replaced with N'-(2-imidazolyl)lysine and the like.
  • amino acid replacements is meant to be illustrative and is not limiting:
  • oligopeptides may be synthesized by techniques well known to persons of ordinary skill in the art and would be expected to be proteolytically cleaved by free PSA: AsnArgIleSerTyrGln
  • the compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention.
  • named amino acids are understood to have the natural "L" stereoconfiguration
  • hR or hArg homoarginine
  • hY or hTyr homotyrosine
  • DPL 2-(4,6-dimethylpyrimidinyl)lysine
  • O-Me-Y O-methyltyrosine TIC: tetrahydro-3-isoquinoline carboxylic acid
  • a A acetic acid
  • the conjugates of the instant invention comprise oligomers wherein the N-terminus amino acid is modified with a hydrophilic blocking group.
  • Such blocking groups are chosen based upon the presence of hydrophilic functionality. The presence of the hydrophilic functionality distinquishes the instant conjugates from conjugates previously disclosed that also had N-terminus blocking groups.
  • Such blocking of the terminal amino group may also reduce or eliminate the enzymatic degradation of such peptidyl therapeutic agents by the action of exogenous amino peptidases which are present in the blood plasma of warm blooded animals.
  • Blocking groups that increase the hydro- philicity of the conjugates and therefore increase the aqueous solubility of the conjugates include but are not limited to hydroylated alkanoyi, polyhydroxylated alkanoyi, polyethylene glycol, glycosylates, sugars and crown ethers.
  • the blocking group is selected from a)
  • R l and R ⁇ are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl,
  • CN N ⁇ 2, R 3 C(0)-, N3, -N(R3)2, or R4 ⁇ C(0)NR3-, c) unsubstituted C l -C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted Cj -C alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R3 ⁇ -, R4S(0) m NH, R3c(0)NR3-, (R3) 2 NC(0)-, R32N-C(NR3)-, CN, R3C(0)-, N3, -N(R3)2, and R4OC(0)-NR3- ; or
  • R 1 and R2 are combined to form - (CH2)s - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(0)m, -NC(O)-, NH and -N(COR )- ;
  • R is selected from: hydrogen, aryl, substituted aryl, heterocycle, substituted heterocycle, C1 -C6 alkyl and C3-C10 cycloalkyl;
  • R is selected from: aryl, substituted aryl, heterocycle, substituted heterocycle, C 1 -C alkyl and C3-C 10 cycloalkyl ;
  • the conjugates of the present invention may have asymmetric centers and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention.
  • any variable e.g. aryl, heterocycle, R3 etc.
  • its definition on each occurence is independent of every other occurence.
  • HO(CR 1 R2)2- represents HOCH2CH2-, HOCH2CH(OH)-, HOCH(CH3)CH(OH)-, etc.
  • substituents and/or variables are permissible only if such combinations result in stable compounds.
  • alkyl and the alkyl portion of aralkyl and similar terms, is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; “alkoxy” represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge.
  • cycloalkyl is intended to include non- aromatic cyclic hydrocarbon groups having the specified number of carbon atoms.
  • examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • alkenyl groups include those groups having the specified number of carbon atoms and having one or several double bonds. Examples of alkenyl groups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, isoprenyL farnesyl, geranyi, geranylgeranyl and the like.
  • Alkynyl groups include those groups having the specified number of carbon atoms and having one triple bonds. Examples of alkynyl groups include acetylene, 2-butynyl, 2-pentynyl, 3-pentynyl and the like.
  • Halogen or “halo” as used herein means fluoro, chloro, bromo and iodo.
  • aryl and the aryl portion of aralkyl and aroyl, is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromat ic. Examples of such aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.
  • heterocycle or heterocyclic represents a stable 5- to 7-membered monocyclic or stable 8- to 1 1 -membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and
  • heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
  • heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl.
  • substituted aryl and “substituted heterocycle” include moieties containing from 1 to 3 substituents in addition to the point of attachment to the rest of the compound. Such additional substituents are selected from F, Cl, Br, CF3, NH2, N(C ⁇ -C6 alkyl)2, NO2, CN, ( -C6 alkyl)0-, -OH, ( -C6 alkyl)S(0) m -, ( -C6 alkyl)C(0)NH-, H2N-C(NH)-, (C1 -C6 alkyl)C(O)-, (C1 -C6 alkyl)OC(O)-, N3, (C1 -C6 alkyl)OC(0)NH- and C1 -C20 alkyl.
  • the cyclic moieties and heteroatom-containing cyclic moieties so defined include, but are not limited to:
  • PEG represents certain polyethylene glycol containing substituents having the designated number of ethyleneoxy subunits.
  • PEG(2) represents
  • cytotoxic agent is not to be construed as limited to classical chemical therapeutic agents.
  • the cytotoxic agent may be a protein or polypeptide possessing a desired biological activity.
  • Such proteins may include, for example, a toxin such as abrin, ricin A, pseudomonas exotoxin, or diphtheria toxin; a protein such as tumor necrosis factor, -interferon, ⁇ - interferon, nerve growth factor, platelet derived growth factor, tissue plasminogen activator; or, biological response modifiers such as, for example, lymphokines, interleukin- 1 ("IL-1 "), interleukin-2 (“IL-2”), interleukin-6 (“IL-6”), granulocyte macrophage colony stimulating factor (“GM-CSF”), granulocyte colony stimulating factor (“G-CSF”), or other growth factors.
  • a toxin such as abrin, ricin A, pseudomonas exotoxin, or diphtheria toxin
  • a protein such as tumor necrosis factor, -interferon, ⁇ - interferon, nerve growth factor, platelet derived growth factor, tissue plasminogen activator
  • the preferred cytotoxic agents include, in general, alkylating agents, antiproliferative agents, tubulin binding agents and the like.
  • Preferred classes of cytotoxic agents include, for example, the anthracycline family of drugs, the vinca drugs, the mitomycins, the bleomycins, the cytotoxic nucleosides, the taxanes, the pteridine family of drugs, diynenes and the podophyllotoxins.
  • Particularly useful members of those classes include, for example, doxorubicin, carminomycin, daunorubicin, aminopterin, methotrexate, methopterin, dichloro-methotrexate, mitomycin C, porfiromycin, 5-fluorouracil, 6-mercaptopurine, cytosine arabinoside, podophyllotoxin, or podo- phyllotoxin derivatives such as etoposide or etoposide phosphate, melphalan, vinblastine, vincristine, leurosidine, vindesine, leurosine, taxol and the like.
  • Other useful cytotoxic agents include estramustine, cisplatin and cyclophosphamide.
  • One skilled in the art may make chemical modifications to the desired cytotoxic agent in order to make reactions of that compound more convenient for purposes of preparing conjugates of the invention.
  • cytotoxic agents for the present invention include drugs of the following formulae: THE METHOTREXATE GROUP OF FORMULA( l ):
  • R 12 i amino or hydroxy
  • R7 is hydrogen or methyl
  • R ⁇ is hydrogen, fluoro, chloro, bromo or iodo
  • R9 is hydroxy or a moiety which completes a salt of the carboxylic acid
  • R lO is hydrogen or methyl
  • R l 1 is hydroxy, amino, C1 -C3 alkylamino, di(C ⁇ -C3 alkyl)amino, C4-C6 polymethylene amino.
  • Rl3 is hydrogen or methyl
  • Rl4 is methyl or thienyl; or a phosphate salt thereof;
  • Rl5 is H, CH3 or CHO; when R 17 and Rl 8 are taken singly;
  • RlSis H and one of R*6 and Rl7 j s ethyl and the other is H or OH; when Rl? and Rl are taken together with the carbons to which they are attached, they form an oxirane ring in which case Rl6 i s ethyl;
  • Rl9 IS hydrogen, (C1-C3 alkyl)-CO, or chlorosubstituted (Cl-C3alkyl)-CO;
  • R21 is a base of one of the formulae:
  • R22 J S hydrogen, methyl, bromo, fluoro, chloro or iodo
  • R24 is hydrogen, bromo, chloro or iodo
  • Ra is -CH3, -CH20H, -CH2 ⁇ CO(CH2)3CH3, or
  • Rb is -OCH3, -OH or -H
  • R c is -NH2, -NHCOCF3, 4-mo ⁇ holinyl, 3-cyano-4- mo ⁇ holinyl, 1 -piperidinyl, 4-methoxy- l -piperidinyi, benzylamine, dibenzylamine, cyanomethylamine, or l -cyano-2-methoxyethyl amine
  • R5 is -OH -OTHP or -H
  • R 6 is -OH or -H provided that
  • R6 is not -OH when R5 is -OH or -OTHP.
  • the most highly preferred drugs are the anthracycline antiobiotic agents of Formula (10), described previously.
  • this structural formula includes compounds which are drugs, or are derivatives of drugs, which have acquired in the art different generic or trivial names.
  • Table 1 which follows, represents a number of anthracycline drugs and their generic or trivial names and which are especially preferred for use in the present invention.
  • daunomycin is an alternative name for daunorubicin
  • adriamycin is an alternative name for doxorubicin
  • cytotoxic agents are doxombicin, vinblastine and desacetyl- vinblastine.
  • Doxombicin (also referred to herein as "DOX") is that anthracycline of Formula ( 10) in which R a is -CH20H, R c is -OCH3, R4 is -NH2, R 5 is -OH, and R° is -H.
  • the blocked oligopeptide-cytotoxic agent conjugate of the instant invention wherein the cytotoxic agent is the preferred cytotoxic agent doxombicin may be described by the general formula I below:
  • oligopeptide is an oligopeptide which is selectively recognized by the free prostate specific antigen (PSA) and is capable of being proteolytically cleaved by the enzymatic activity of the free prostate specific antigen, and wherein the C-terminus carbonyl is covalently bound to the amine of doxombicin and the N-terminus amine is covalently bound to the carbonyl of the blocking group;
  • PSA prostate specific antigen
  • R is selected from
  • Rl and R ⁇ are independently selected from: hydrogen. OH, Cl-C6 alkyl, Cl-C6 alkoxy, Cl-C6 aralkyl and aryl; n is 1, 2, 3 or 4; p is zero or an integer between I and 100; q is 0 or 1, provided that if p is zero, q is 1;
  • R is selected from
  • Rl and R ⁇ are independently selected from: hydrogen, Cj-C6 alkyl and aryl; n is 1, 2, 3 or 4; n' is 0, 1,2 or 3; p is zero or an integer between 1 and 14; q is 0 or 1, provided that if p is zero, q is 1;
  • SerSerSerChgGlnSerLeu- (SEQ.ID.NO.: 61 ),
  • conjugates of an oligopeptide and doxombicin wherein the N-terminus of the oligopeptide is blocked by a hydrophilic moiety and the C-terminus of the oligopeptide is attached to the doxombicin at the 3'-amine are as follows: 2-hydroxyacetyl-hArgSerSerTyrGln-SerNle-DOX (3') (SEQ.ID.NO.:
  • oligopeptide-cytotoxic agent conjugate of the instant invention wherein the cytotoxic agent is the preferred cytotoxic agent vinblastine or desacetylvinblastine may be described by the general formula II below:
  • oligopeptide is an oligopeptide which is specifically recognized by the free prostate specific antigen (PSA) and is capable of being proteolytically cleaved by the enzymatic activity of the free prostate specific antigen;
  • PSA prostate specific antigen
  • XL is - NH - (CH2)r - NH -
  • R is selected from
  • R l and R2 are independently selected from: hydrogen, OH, -C6 alkyl, C1 -C6 alkoxy, C1 -C aralkyl and aryl;
  • R l9 is hydrogen, (C1 -C3 alkyl)-CO, or chlorosubstituted (Cl -C3 aIkyl)-CO;
  • p is zero or an integer between 1 and 100; q is 0 or 1 , provided that if p is zero, q is 1 ;
  • r is 1 , 2, 3, 4 or 5
  • oligopeptide is an oligopeptide which is specifically recognized by the free prostate specific antigen (PSA) and is capable of being proteolytically cleaved by the enzymatic activity of the free prostate specific antigen,
  • PSA prostate specific antigen
  • Rd and R e are independently selected from: hydrogen,
  • Rd and R e are not hydrogen or
  • Rd and R e are combined to form a -CH2CH2OCH2CH2- diradical
  • R l 9 is hydrogen, (C1 -C3 alkyl)-CO, or chlorosubstituted (Cl -C3 alkyl)-CO;
  • p is zero or an integer between 1 and 100; q is 0 or 1 , provided that if p is zero, q is 1 ;
  • oligopeptides, peptide subunits and peptide derivatives can be synthesized from their constituent amino acids by conventional peptide synthesis techniques, preferably by solid-phase technology.
  • the peptides are then purified by reverse-phase high performance liquid chromatography (HPLC).
  • the pharmaceutically acceptable salts of the compounds of this invention include the conventional non-toxic salts of the compounds of this invention as formed, e.g., from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like: and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenyl-acetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.
  • conjugates of the instant invention which comprise the oligopeptide containing the PSA cleavage site and a cytotoxic agent may similarly be synthesized by techniques well known in the medicinal chemistry art.
  • a free amine moiety on the cytotoxic agent may be covalently attached to the oligopeptide at the carboxyl terminus such that an amide bond is formed.
  • an amide bond may be formed by covalently coupling an amine moiety of the oligopeptide and a carboxyl moiety of the cytotoxic agent.
  • a reagent such as 2-(l H-benzotriazol- l-yl)-I ,3,3-tetramethyluronium hexafluoro- phosphate (known as HBTU) and 1 -hyroxybenzotriazole hydrate (known as HOBT), dicyclohexyl- carbodiimide (DCC), N-ethyl-N-(3-dimethyl- aminopropyl)- carbodiimide (EDC), diphenylphosphorylazide (DPPA), benzotriazol- 1 -y l-oxy-tris-(dimethy lamino)phosphonium hexafluoro- phosphate (BOP) and the like, used in combination or singularly, may be utilized.
  • DCC dicyclohexyl- carbodiimide
  • EDC N-ethyl-N-(3-dimethyl- aminopropyl)- carbodiimide
  • DPPA diphen
  • the instant conjugate may be formed by a non-peptidyl bond between the PSA cleavage site and a cytotoxic agent.
  • the cytotoxic agent may be covalently attached to the carboxyl terminus of the oligopeptide via a hydroxyl moiety on the cytotoxic agent, thereby forming an ester linkage.
  • a reagent such as a combination of HBTU and HOBT, a combination of BOP and imidazole, a combination of DCC and DMAP, and the like may be utilized.
  • the carboxylic acid may also be activated by forming the nitro-phenyl ester or the like and reacted in the presence of DBU (1 ,8-diazabicyclo[5,4,0]undec-7-ene.
  • the instant conjugate may also be formed by attachment of the oligopeptide to the cytotoxic agent via a linker unit.
  • linker units include, for example, a biscarbonyl alkyl diradical whereby an amine moiety on the cytotoxic agent is connected with the linker unit to form an amide bond and the amino terminus of the oligopeptide is connected with the other end of the linker unit also forming an amide bond.
  • a diaminoalkyl diradical linker unit whereby a carbonyl moiety on the cyctotoxic agent is covalently attacted to one of the amines of the linker unit while the other amine of the linker unit is covalently attached to the C terminus of the oligopeptide, may also be uselful.
  • Other such linker units which are stable to the physiological environment when not in the presence of free PSA, but are cleavable upon the cleavage of the PSA proteolytic cleavage site, are also envisioned.
  • linker units may be utilized that, upon cleavage of the PSA proteolytic cleavage site, remain attached to the cytotoxic agent but do not significantly decrease the cytotoxic activity of such a post-cleavage cytotoxic agent derivative when compared with an unmodified cytotoxic agent.
  • linker units may be utilized that, upon cleavage of the PSA proteolytic cleavage site, remain attached to the cytotoxic agent but do not significantly decrease the cytotoxic activity of such a post-cleavage cytotoxic agent derivative when compared with an unmodified cytotoxic agent.
  • useful amino-protecting groups may include, for example, C l - o alkanoyi groups such as formyl, acetyl, dichloroacetyl, propionyl, hexanoyl, 3,3-diethylhexanoyl, ⁇ -chlorobutryl, and the like; -C i o alkoxycarbonyl and C5-C 15 aryloxycarbonyl groups such as tert-butoxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl, 4-nitrobenzyloxycarbonyl, fluorenylmethyloxycarbonyl and cinnamoyloxycarbonyl; halo- (C ⁇ -C l ⁇ )-alkoxycarbonyl such as 2,2,2-trichloroethoxycarbonyl; and C 1-C15 arylalkyl and alkenyl group such as benzyl, phenethyl, allyl, tr
  • carboxy-protecting groups are those in the form of enamines prepared with ⁇ -keto-esters such as methyl or ethyl acetoacetate.
  • Useful carboxy-protecting groups may include, for example, Cj -ClO alkyl groups such as methyl, tert-butyl, decyl; halo- C l -C io alkyl such as 2,2,2-trichloroethyl, and 2-iodoethyl; C5- 5 arylalkyl such as benzyl, 4-methoxybenzyl, 4-nitrobenzyl, triphenyl- methyl, diphenyl-methyl; C l -ClO alkanoyloxymethyl such as acetoxy- methyl, propionoxymethyl and the like; and groups such as phenacyl, 4-halophenacyl, allyl, dimethylallyl, tri-(C ⁇ -C3 alkyl)silyl, such as trimethyl
  • useful hydroxy protecting groups may include, for example, the for yl group, the chloroacetyl group, the benzyl group, the benzhydryl group, the trityl group, the 4-nitrobenzyl group, the trimethylsilyl group, the phenacyl group, the tert-butyl group, the methoxymethyl group, the tetrahydropyranyl group, and the like.
  • the following Reaction Schemes illustrate the synthsis of the conjugates of the instant invention.
  • Reaction Scheme VI illustrates preparation of conjugates of the oligopeptides of the instant invention and the vinca alkaloid cytotoxic agent vinblastine wherein the attachment of vinblastine is at the C-terminus of the oligopeptide.
  • the use of the 1 ,3-diaminopropane linker is illustrative only; other spacer units between the carbonyl of vinblastine and the C-terminus of the oligopeptide are also envisioned.
  • Scheme VI illustrates a synthesis of conjugates wherein the C-4-position hydroxy moiety is reacetylated following the addition of the linker unit.
  • the desacetyl vinblastine conjugate is also efficacious and may be prepared by eliminating the steps shown in Reaction Scheme VI of protecting the primary amine of the linker and reacting the intermediate with acetic anhydride, followed by deprotection of the amine. Conjugation of the oligopeptide at other positions and functional groups of vinblastine may be readily accomplished by one of ordinary skill in the art and is also expected to provide compounds useful in the treatment of prostate cancer.
  • oligopeptide-cytotoxic agent conjugates of the invention are administered to the patient in the form of a pharmaceutical composition which comprises a conjugate of of the instant invention and a pharmaceutically acceptable carrier, excipient or diluent therefor.
  • pharmaceutically acceptable refers to those agents which are useful in the treatment or diagnosis of a warm-blooded animal including, for example, a human, equine, procine, bovine, murine, canine, feline, or other mammal, as well as an avian or other warmblooded animal.
  • the preferred mode of administration is parenterally, particularly by the intravenous, intramuscular, subcutaneous, intraperitoneal, or intralymphatic route.
  • compositions can be prepared using carriers, diluents or excipients familiar to one skilled in the art.
  • Sg£ eg. Remington's Pharmaceutical Sciences. 16th ed., 1980, Mack Publishing Company, edited by Osol et ah
  • Such compositions may include proteins, such as semm proteins, for example, human semm albumin, buffers or buffering substances such as phosphates, other salts, or electrolytes, and the like.
  • Suitable diluents may include, for example, sterile water, isotonic saline, dilute aqueous dextrose, a polyhydric alcohol or mixtures of such alcohols, for example, glycerin, propylene glycol, polyethylene glycol and the like.
  • the compositions may contain preservatives such as phenethyl alcohol, methyl and propyl parabens, thimerosal, and the like. If desired, the composition can include about 0.05 to about .20 percent by weight of an antioxidant such as sodium metabisulfite or sodium bisulfite.
  • composition is intended to encompass a product comprising the specified ingredients in the specific amounts, as well as any product which results, directly or indirectly, from combination of the specific ingredients in the specified amounts.
  • the composition preferably will be prepared so that the amount administered to the patient will be from about .01 to about 1 g of the conjugate.
  • the amount administered will be in the range of about .2 g to about 1 g of the conjugate.
  • the conjugates of the invention are effective over a wide dosage range depending on factors such as the disease state to be treated or the biological effect to be modified, the manner in which the conjugate is administered, the age, weight and condition of the patient as well as other factors to be determined by the treating physician.
  • Blocked oligopeptides were prepared by solid-phase synthesis, using a double coupling protocol for the introduction of amino acids on the Applied Biosystems model 430A automated peptide synthesizer. Deprotection and removal of the oligopeptide from the resin support were achieved by treatment with liquid hydrofluoric acid. The oligopeptides were purified by preparative high pressure liquid chromatography on reverse phase C18 silica columns using an aqueous 0.1 % trifluoroacetic acid/acetonitrile gradient. Identity and homogeneity of the oligopeptides were confirmed by amino acid composition analysis, high pressure liquid chromatography, and fast atom bombardment mass spectral analysis. The oligopeptides that were prepared by this method are shown in Table 2.
  • oligopeptides prepared as described in Example 1 were individually dissolved in PSA digestion buffer (12 mM tris(hydroxymethyl)-aminomethane pH8.0, 25 mM NaCl, 0.5 mM CaCl2) and the solution added to PSA at a molar ration of 100 to 1.
  • the reaction is quenched after various reaction times by the addition of trifluoroacetic acid (TFA) to a final 1 % (volume/volume).
  • TFA trifluoroacetic acid
  • the quenched reaction was analyzed by HPLC on a reversed-phase C18 column using an aqueous 0.1 %TFA/acetonitrile gradient. The results of the assessment are shown in Table 2.
  • Table 2 shows the amount of time (in minutes) required for 50% cleavage of the noted oligopeptides with enzymatically active free PSA.
  • Oligopeptides containing free amine moieties ie. comprising hArg, Om, Lys and or 3PAL
  • All other oligopeptides were tested as neutral compounds.
  • Step A 2-HO-Ac-Ser(Bzl)-Ser(Bzl)-Ser(Bzl)-Chg-Gln-Ser-Leu- PAM Resin (3-1 ).
  • Boc-Leu-PAM resin (Applied Biosystems Inc. - ABI)
  • the protected peptide was synthesized on a 430A ABI peptide synthesizer.
  • the protocol used a 4 fold excess (2 mmol) of each of the following protected amino acids: Boc-Ser(OBzl), Boc-Gln, Boc-Chg. Coupling was achieved using DCC and HOBT activation in methyl-2-pyrrolidinone. Removal of the Boc group was performed using 50% TFA in methylene chloride and the TFA salt neutralized with diisopropylethylamine. 2-Hydroxyacetic acid was used for the introduction of the N terminal blocking group, which was also carried out on the peptide synthesizer. At the completion of the synthesis, the peptide resin was dried to provide the title resin- peptide conjugate.
  • Step B 2-HO-Ac-Ser-Ser-Ser-Chg-Ser-Leu-OH (3-2).
  • Step C 2-HO-Ac-Ser-Ser-Ser-Chg-Ser-Leu-Dox (3-3)
  • Step A N-2(R)-2,3-dihydroxypropionyl-Ser(Bzl)-Ser(Bzl)-
  • Boc-Leu-PAM resin Starting with 0.5 mmol (0.67g) Boc-Leu-PAM resin, the protected peptide was synthesized on a 430A ABI peptide synthesizer. The protocol used a 4 fold excess (2 mmol) of each of the following protected amino acids: Boc-Ser(OBzl), Boc-Gln and Boc-Chg. Coupling was achieved using DCC and HOBT activation in methyl- 2-pyrrolidinone. Removal of the Boc group was performed using 50% TFA in methylene chloride and the TFA salt neutralized with diisopropylethylamine. D-Glyceric acid, which was converted from D-Glyceric acid calcium salt, was used for the introduction of the N terminal blocking group. At the completion of the synthesis, the peptide resin was dried to provide the title resin-peptide conjugate.
  • Boc-Ser(OBzl) Boc-Gln
  • Boc-Chg Coupling was achieved using DCC and HOBT activation in
  • Step B N-2(R)-2,3-dihydroxypropionyl-Ser-Ser-Ser-Chg-Gln-Ser-
  • Table 3 shows other blocked peptide-doxombicin conjugates that were prepared by the procedures described in Examples 3-6, but utilizing the appropriate amino acid residues and blocking group acylation.
  • the cells are resuspended in serum-free ⁇ -MEM and counted.
  • this solution containing the desired number of cells is then transferred to a conical centrifuge tube, centrifuged as before and resuspended in the appropriate volume of a cold 1 : 1 mixture of ⁇ -MEM-Matrigel.
  • the suspension is kept on ice until the animals are inoculated.
  • Harlan Sprague Dawley male nude mice (10-12 weeks old) are restrained without anesthesia and are inoculated with 0.5 mL of cell suspension on the left flank by subcutaneous injection using a
  • mice Following inoculation with the tumor cells the mice are treated under one of two protocols:
  • Protocol B 5-10 day intervals. At the end of 5.5 weeks the mice are sacrificed and weights of any tumors present are measured and semm PSA again determined. The animals' weights are determined at the beginning and end of the assay. Protocol B:
  • Step A Preparation of proteolytic tissue extracts
  • the pellet is respuspended in Buffer B (10 mM EDTA containing 1.15% KC1, pH 7.5) using the same volume used in step as used above with Buffer A.
  • the suspension is homogenized in a dounce homogenizer and the solution centrifuged at 100,000x g. The supernatant is discarded and the pellet resuspended in Buffer C (10 mM potassium phosphate buffer containing ⁇ .25 M sucrose, pH 7.4), using 1/2 the volume used above, and homogenized with a dounce homogenizer.
  • Protein content of the two solutions is determine using the Bradford assay. Assay aliquots are then removed and frozen in liquid N2- The aliquots are stored at -70°C.
  • Step B Proteolytic cleavage assay
  • MOLECULE TYPE peptide (xi ) SEQUENCE DESCRIPTION: SEQ ID NO : 6 :

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Abstract

La présente invention concerne des conjugués chimiques comprenant des oligopeptides dont les séquences d'acide aminé sont sélectivement coupées de façon protéolytique par un antigène prostate-spécifique libre, des groupes de blocage d'oligopeptides hydrophiles et des agents cytotoxiques connus. Ces conjugués sont utiles dans le traitement du cancer de la prostate et de l'hypertrophie prostatique bénigne.
PCT/US1997/016087 1996-09-12 1997-09-10 Conjugues utiles dans le traitement du cancer de la prostate WO1998010651A1 (fr)

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CA002265476A CA2265476A1 (fr) 1996-09-12 1997-09-10 Conjugues utiles dans le traitement du cancer de la prostate
JP10513857A JP2001501601A (ja) 1996-09-12 1997-09-10 前立腺ガンの治療において有用な共役体
AU44123/97A AU715632B2 (en) 1996-09-12 1997-09-10 Conjugates useful in the treatment of prostate cancer
US09/254,892 US6391305B1 (en) 1997-09-10 1997-09-10 Conjugates useful in the treatment of prostate cancer
EP97942423A EP0926955A4 (fr) 1996-09-12 1997-09-10 Conjugues utiles dans le traitement du cancer de la prostate

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US2601596P 1996-09-12 1996-09-12
US60/026,015 1996-09-12
GBGB9624170.8A GB9624170D0 (en) 1996-11-19 1996-11-19 Conjugates useful in the treatment of prostate cancer
GB9624170.8 1996-11-19

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Cited By (32)

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WO1999028345A1 (fr) * 1997-12-02 1999-06-10 Merck & Co., Inc. Conjugues utiles dans le traitement du cancer de la prostate
US6174858B1 (en) 1998-11-17 2001-01-16 Merck & Co., Inc. Conjugates useful in the treatment of prostate cancer
WO2001029065A1 (fr) * 1999-10-19 2001-04-26 Merck Sharp & Dohme Limited Procede de preparation d'intermediaires peptidiques
WO2002085908A1 (fr) * 2001-04-24 2002-10-31 Purdue Research Foundation Mimetiques de folate et ses conjugues de liaison aux recepteurs de folate
US6552166B1 (en) * 1999-10-19 2003-04-22 Merck & Co., Inc. Process for the preparation of conjugates useful in the treatment of prostate cancer
US6649587B1 (en) * 1999-04-30 2003-11-18 Slil Biomedical Corporation Polyamine analog conjugates and quinone conjugates as therapies for cancers and prostate diseases
US6713454B1 (en) 1999-09-13 2004-03-30 Nobex Corporation Prodrugs of etoposide and etoposide analogs
US6844318B2 (en) 2000-03-15 2005-01-18 Bristol Myers Squibb Pharma Company Peptidase-cleavable, targeted antineoplastic drugs and their therapeutic use
US7279502B2 (en) 1999-04-30 2007-10-09 Cellgate, Inc. Polyamine analog conjugates and quinone conjugates as therapies for cancers and prostate diseases
US7312244B2 (en) 1999-04-30 2007-12-25 Cellgate, Inc. Polyamine analog-amino acid conjugates useful as anticancer agents
CN100372862C (zh) * 2003-11-05 2008-03-05 天津和美生物技术有限公司 具有抗癌活性的阿霉素衍生物及其制备方法和应用
WO2008028934A1 (fr) 2006-09-06 2008-03-13 Aeterna Zentaris Gmbh Conjugués de disorazoles et leurs dérivés avec des molécules se fixant à des cellules, nouveaux dérivés de disorazole et procédés de fabrication et d'utilisation de ces conjugués et dérivés
US7442763B2 (en) * 1999-12-06 2008-10-28 Hopital Sainte-Justine Compositions for treating abnormalities in glomerular filtration, patent ductus arteriosus and osteoporosis
EP1144011B1 (fr) * 1998-12-11 2010-03-10 Coulter Pharmaceutical, Inc. Composes de promedicaments et procede de preparation
US7910594B2 (en) 2002-05-15 2011-03-22 Endocyte, Inc. Vitamin-mitomycin conjugates
US8044200B2 (en) 2005-03-16 2011-10-25 Endocyte, Inc. Synthesis and purification of pteroic acid and conjugates thereof
US8105568B2 (en) 2003-01-27 2012-01-31 Endocyte, Inc. Vitamin receptor binding drug delivery conjugates
US8288557B2 (en) 2004-07-23 2012-10-16 Endocyte, Inc. Bivalent linkers and conjugates thereof
US9138484B2 (en) 2007-06-25 2015-09-22 Endocyte, Inc. Conjugates containing hydrophilic spacer linkers
US9187521B2 (en) 2007-10-25 2015-11-17 Endocyte, Inc. Tubulysins and processes for preparing
US9358282B2 (en) 2011-03-17 2016-06-07 The University Of Birmingham Re-directed immunotherapy
US9505747B2 (en) 2012-03-29 2016-11-29 Endocyte, Inc. Processes for preparing tubulysin derivatives and conjugates thereof
US9555139B2 (en) 2007-03-14 2017-01-31 Endocyte, Inc. Binding ligand linked drug delivery conjugates of tubulysins
US9650445B2 (en) 2012-02-28 2017-05-16 The University Of Birmingham Immunotherapeutic molecules and uses
US9662402B2 (en) 2012-10-16 2017-05-30 Endocyte, Inc. Drug delivery conjugates containing unnatural amino acids and methods for using
US9877965B2 (en) 2007-06-25 2018-01-30 Endocyte, Inc. Vitamin receptor drug delivery conjugates for treating inflammation
US10035856B2 (en) 2015-11-19 2018-07-31 Revitope Limited Functional antibody fragment complementation for a two-components system for redirected killing of unwanted cells
US10080805B2 (en) 2012-02-24 2018-09-25 Purdue Research Foundation Cholecystokinin B receptor targeting for imaging and therapy
US10441649B2 (en) 2015-02-02 2019-10-15 The University Of Birmingham Targeting moiety peptide epitope complexes having a plurality of T-cell epitopes
US10947271B2 (en) 2014-02-10 2021-03-16 The University Of Queensland Antibacterial agents
WO2022136586A1 (fr) 2020-12-22 2022-06-30 Cobiores Nv Composés comprenant une fraction tétrapeptidique
WO2022167664A1 (fr) 2021-02-07 2022-08-11 Cobiores Nv Composés comprenant une fraction tétrapeptidique

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Cited By (48)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999028345A1 (fr) * 1997-12-02 1999-06-10 Merck & Co., Inc. Conjugues utiles dans le traitement du cancer de la prostate
US6174858B1 (en) 1998-11-17 2001-01-16 Merck & Co., Inc. Conjugates useful in the treatment of prostate cancer
EP1144011B1 (fr) * 1998-12-11 2010-03-10 Coulter Pharmaceutical, Inc. Composes de promedicaments et procede de preparation
US6649587B1 (en) * 1999-04-30 2003-11-18 Slil Biomedical Corporation Polyamine analog conjugates and quinone conjugates as therapies for cancers and prostate diseases
US7279502B2 (en) 1999-04-30 2007-10-09 Cellgate, Inc. Polyamine analog conjugates and quinone conjugates as therapies for cancers and prostate diseases
US7312244B2 (en) 1999-04-30 2007-12-25 Cellgate, Inc. Polyamine analog-amino acid conjugates useful as anticancer agents
US6713454B1 (en) 1999-09-13 2004-03-30 Nobex Corporation Prodrugs of etoposide and etoposide analogs
US7119074B2 (en) 1999-09-13 2006-10-10 Nobex Corporation Treatment of cancers, tumors and malignancies using amphiphilic prodrugs
WO2001029065A1 (fr) * 1999-10-19 2001-04-26 Merck Sharp & Dohme Limited Procede de preparation d'intermediaires peptidiques
US6552166B1 (en) * 1999-10-19 2003-04-22 Merck & Co., Inc. Process for the preparation of conjugates useful in the treatment of prostate cancer
US7262169B1 (en) 1999-10-19 2007-08-28 Merck & Co., Inc. Process for preparing peptide intermediates
US7442763B2 (en) * 1999-12-06 2008-10-28 Hopital Sainte-Justine Compositions for treating abnormalities in glomerular filtration, patent ductus arteriosus and osteoporosis
US6844318B2 (en) 2000-03-15 2005-01-18 Bristol Myers Squibb Pharma Company Peptidase-cleavable, targeted antineoplastic drugs and their therapeutic use
WO2002085908A1 (fr) * 2001-04-24 2002-10-31 Purdue Research Foundation Mimetiques de folate et ses conjugues de liaison aux recepteurs de folate
US7875612B2 (en) 2001-04-24 2011-01-25 Purdue Research Foundation Folate mimetics and folate-receptor binding conjugates thereof
US7910594B2 (en) 2002-05-15 2011-03-22 Endocyte, Inc. Vitamin-mitomycin conjugates
US8105568B2 (en) 2003-01-27 2012-01-31 Endocyte, Inc. Vitamin receptor binding drug delivery conjugates
CN100372862C (zh) * 2003-11-05 2008-03-05 天津和美生物技术有限公司 具有抗癌活性的阿霉素衍生物及其制备方法和应用
US9090563B2 (en) 2004-07-23 2015-07-28 Endocyte, Inc. Bivalent linkers and conjugates thereof
US8288557B2 (en) 2004-07-23 2012-10-16 Endocyte, Inc. Bivalent linkers and conjugates thereof
US10647676B2 (en) 2004-07-23 2020-05-12 Endocyte, Inc. Bivalent linkers and conjugates thereof
US9550734B2 (en) 2004-07-23 2017-01-24 Endocyte, Inc. Bivalent linkers and conjugates thereof
US8044200B2 (en) 2005-03-16 2011-10-25 Endocyte, Inc. Synthesis and purification of pteroic acid and conjugates thereof
WO2008028934A1 (fr) 2006-09-06 2008-03-13 Aeterna Zentaris Gmbh Conjugués de disorazoles et leurs dérivés avec des molécules se fixant à des cellules, nouveaux dérivés de disorazole et procédés de fabrication et d'utilisation de ces conjugués et dérivés
US9555139B2 (en) 2007-03-14 2017-01-31 Endocyte, Inc. Binding ligand linked drug delivery conjugates of tubulysins
US9138484B2 (en) 2007-06-25 2015-09-22 Endocyte, Inc. Conjugates containing hydrophilic spacer linkers
US10738086B2 (en) 2007-06-25 2020-08-11 Endocyte Inc. Conjugates containing hydrophilic spacer linkers
US10500204B2 (en) 2007-06-25 2019-12-10 Endocyte, Inc. Vitamin receptor drug delivery conjugates for treating inflammation
US9877965B2 (en) 2007-06-25 2018-01-30 Endocyte, Inc. Vitamin receptor drug delivery conjugates for treating inflammation
US9187521B2 (en) 2007-10-25 2015-11-17 Endocyte, Inc. Tubulysins and processes for preparing
US9745341B2 (en) 2007-10-25 2017-08-29 Endocyte, Inc. Tubulysins and processes for preparing
US9358282B2 (en) 2011-03-17 2016-06-07 The University Of Birmingham Re-directed immunotherapy
US9402916B2 (en) 2011-03-17 2016-08-02 The University Of Birmingham Re-directed immunotherapy
US11236131B2 (en) 2011-03-17 2022-02-01 The University Of Birmingham Re-directed immunotherapy
US10287321B2 (en) 2011-03-17 2019-05-14 The University Of Birmingham Re-directed immunotherapy
US11344623B2 (en) 2012-02-24 2022-05-31 Purdue Research Foundation Cholecystokinin B receptor targeting for imaging and therapy
US10080805B2 (en) 2012-02-24 2018-09-25 Purdue Research Foundation Cholecystokinin B receptor targeting for imaging and therapy
US10765756B2 (en) 2012-02-24 2020-09-08 Purdue Research Foundation Cholecystokinin B receptor targeting for imaging and therapy
US10106621B2 (en) 2012-02-28 2018-10-23 The University Of Birmingham Immunotherapeutic molecules and uses
US9650445B2 (en) 2012-02-28 2017-05-16 The University Of Birmingham Immunotherapeutic molecules and uses
US9822180B2 (en) 2012-02-28 2017-11-21 The University Of Birmingham Immunotherapeutic molecules and uses
US9505747B2 (en) 2012-03-29 2016-11-29 Endocyte, Inc. Processes for preparing tubulysin derivatives and conjugates thereof
US9662402B2 (en) 2012-10-16 2017-05-30 Endocyte, Inc. Drug delivery conjugates containing unnatural amino acids and methods for using
US10947271B2 (en) 2014-02-10 2021-03-16 The University Of Queensland Antibacterial agents
US10441649B2 (en) 2015-02-02 2019-10-15 The University Of Birmingham Targeting moiety peptide epitope complexes having a plurality of T-cell epitopes
US10035856B2 (en) 2015-11-19 2018-07-31 Revitope Limited Functional antibody fragment complementation for a two-components system for redirected killing of unwanted cells
WO2022136586A1 (fr) 2020-12-22 2022-06-30 Cobiores Nv Composés comprenant une fraction tétrapeptidique
WO2022167664A1 (fr) 2021-02-07 2022-08-11 Cobiores Nv Composés comprenant une fraction tétrapeptidique

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EP0926955A1 (fr) 1999-07-07
AU4412397A (en) 1998-04-02
EP0926955A4 (fr) 2003-05-07

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