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WO2005112999A2 - Traitement du cancer au moyen d'inhibiteurs de synthese du collagene - Google Patents

Traitement du cancer au moyen d'inhibiteurs de synthese du collagene Download PDF

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Publication number
WO2005112999A2
WO2005112999A2 PCT/US2005/017732 US2005017732W WO2005112999A2 WO 2005112999 A2 WO2005112999 A2 WO 2005112999A2 US 2005017732 W US2005017732 W US 2005017732W WO 2005112999 A2 WO2005112999 A2 WO 2005112999A2
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Prior art keywords
tumor
composition
agent
polymer
fibrotic
Prior art date
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Ceased
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PCT/US2005/017732
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English (en)
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WO2005112999A3 (fr
Inventor
Paul M. Simon
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Vectramed Inc
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Vectramed Inc
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Filing date
Publication date
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Publication of WO2005112999A2 publication Critical patent/WO2005112999A2/fr
Anticipated expiration legal-status Critical
Publication of WO2005112999A3 publication Critical patent/WO2005112999A3/fr
Ceased legal-status Critical Current

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    • 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
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • 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 generally to anti -tumor agents and, more
  • anti-tumor Mabs with the exception of HERCEPTIN ® and ERBITUX ® , available therapeutic Mabs target - tumor cells that reside in the vasculature or are well vascularized, or molecular targets that reside on vascular endothelial cells. Therefore, the promise of biological and other macromolecular therapeutic agents against solid
  • an anti-tumor composition for shrinking or retarding the growth of a tumor which may be a solid tumor, comprising: a biocompatible polymer matrix, an anti-tumor agent, and an anti-fibrotic agent, wherein the anti-
  • fibrotic agent is free or incorporated into and released from the polymer matrix by degradation of the matrix or diffusion of the agent out of the matrix over a period of time in an amount effective to shrink or retard growth of the tumor.
  • the anti-tumor agent may comprise an anti-tumor antibody, an anti- angiogenic agent, a monoclonal antibody, a micellar or liposomal preparation, a fusion protein, or a combination thereof.
  • the anti-tumor agent may further comprise a
  • the anti-tumor agent may further yet comprise a taxane, such as paclitaxel or docetaxel; and, the anti-fibrotic agent may comprise a proline analog or a lathyrogen.
  • the anti-fibrotic agent can be selected from the group consisting of ra-hydroxyproline, dehydroproline, thiaproline,
  • the polymer matrix may be biodegradable, formed of a polymer
  • compositions may further comprise additional biologically active compounds selected from the group consisting of chemotherapeutics, immunoglobulins, antibiotics, antivirals, antiinflammatories, cytokines,
  • immunotoxins anti-tumor antibodies, anti-angiogenic agents, anti-edema agents,
  • radiosensitizers monoclonal antibodies, cytokine receptors or their cognate ligands, toxins, nucleic acids, oligosaccharides, polysaccharides, synthetic polymers, lipids, micellar or liposomal preparations, chemical conjugates of the above with cytotoxic or
  • cytostatic or other drugs cytostatic or other drugs, fusion proteins, and combinations thereof.
  • a method of treating a patient in need of shrinking or retarding the growth of a tumor comprising: administering to the patient an effective amount of an anti-tumor agent and an effective amount of an anti-fibrotic agent, wherein the anti- fibrotic agent is incorporated into and released from a polymer matrix by degradation of the polymer matrix or diffusion of the anti-fibrotic agent out of the matrix over a
  • the anti-tumor agent may comprise an anti-tumor antibody, an anti- angiogenic agent, a monoclonal antibody, a micellar or liposomal preparation, a fusion protein, or a combination thereof.
  • the anti-tumor agent may further comprise a
  • the anti-tumor agent may further yet comprise a taxane, such as paclitaxel or docetaxel; and, the anti-fibrotic agent may
  • the anti-fibrotic agent can be selected
  • the anti-tumor agent may be administered systemically or locally delivered by direct infusion to the tumor, and/or the anti-fibrotic agent may be
  • the polymer matrix may be biodegradable, formed of a polymer selected from the group
  • the method may further comprise administering radiation in
  • the method may also comprise administering an additional biologically active compounds selected from the group consisting of chemotherapeutics, immunoglobulins, antibiotics, antivirals, anti-inflammatories, cytokines, immunotoxins, anti-tumor antibodies, anti-angiogenic agents, anti-edema agents, radiosensitizers, monoclonal antibodies, cytokine receptors or their cognate ligands, toxins, nucleic acids, oligosaccharides, polysaccharides, synthetic polymers, lipids, micellar or liposomal preparations, chemical conjugates of the above with cytotoxic or cytostatic or other drugs, fusion proteins, and combinations thereof.
  • an additional biologically active compounds selected from the group consisting of chemotherapeutics, immunoglobulins, antibiotics, antivirals, anti-inflammatories, cytokines, immunotoxins, anti-tumor antibodies, anti-angiogenic agents, anti-edema agents, radiosensitizers, monoclon
  • compositions may be in the form of micro-implants and may be administered by injection or infusion.
  • the method may involve the substantially
  • At least one of the anti-tumor agent and anti-fibrotic agent can be any one of the anti-tumor agent and anti-fibrotic agent.
  • a prodrug is administered intravenously, intraperitonealy, or intramuscularly, and in other embodiments, both of the anti-tumor agent and the anti-fibrotic agent is administered intravenously.
  • a prodrug is administered intravenously, intraperitonealy, or intramuscularly, and in other embodiments, both of the anti-tumor agent and the anti-fibrotic agent is administered intravenously.
  • composition comprising: at least one anti-fibrotic agent; at least one anti-
  • the hydrolysable bond may also include any enzyme-cleavable
  • the composition may further include a biodegradable polymer, and the biodegradable polymer may be coupled to the at least one anti- fibrotic agent and the at least one anti-tumor agent.
  • the prodrug composition may be
  • a method of treating a patient in need of shrinking or retarding the growth of tumors comprising: administering a prodrug composition comprising: at least one anti-fibrotic agent; at least one anti-tumor agent; and wherein the at least one anti-fibrotic agent
  • the hydrolysable bond may be selected from an ester, diester, urethane, amide, secondary or tertiary amine, and an ether bond.
  • the hydrolysable bond may also be selected from an ester, diester, urethane, amide, secondary or tertiary amine, and an ether bond.
  • the hydrolysable bond may also be selected from an ester, diester, urethane, amide, secondary or tertiary amine, and an ether bond.
  • the hydrolysable bond may also be selected from an ester, diester, urethane, amide, secondary or tertiary amine, and an ether bond.
  • the hydrolysable bond may also be selected from an ester, diester, urethane, amide, secondary or tertiary amine, and an ether bond.
  • the hydrolysable bond may also be selected from an ester, diester, urethane, amide, secondary or tertiary amine
  • enzyme-cleavable group such as a peptide bond, a phosphodiester bond,
  • composition may further include a biodegradable polymer, and the biodegradable polymer may be coupled to
  • the at least one anti-fibrotic agent and the at least one anti-tumor agent are the at least one anti-fibrotic agent and the at least one anti-tumor agent.
  • a drug- polymer composition having the general formula D1-X-P-Y-D2 wherein P is a polymer; wherein the drugs Dl and D2 are separately an anti-tumor agent and an
  • P may be a water-soluble polymer, optionally cross-linked to form an
  • insoluble gel and/or selected from the group consisting of poly(ethylene glycol),
  • X and Y may be individually an ester, diester, urethane, amide, secondary or tertiary amine or ether linking groups.
  • X any Y may also include any enzyme-cleavable group such as a peptide bond, a phosphodiester bond, oligosaccharide bonds, and other chemical groups.
  • a method of treating a patient in need of shrinking or retarding the growth of tumors comprising: administering a drug-polymer composition having the general formula D1-X-P-Y-D2, wherein P is a polymer; wherein the drugs Dl and D2 are separately an anti-tumor agent and an anti-fibrotic agent; and the drugs and polymer are linked by the covalent linkages X and Y.
  • P may be a water-soluble polymer, optionally cross-linked to form an insoluble gel, and/or selected from the group consisting of
  • X and Y may be individually an ester, diester, urethane, amide,
  • FIG. 1 is a graph depicting the molar therapeutic efficacy of free CHOP
  • the regression lines fit to the data have r 2 values of 0.55 for free CHOP and 0.92 for CHOP-PEG, and the half-maximal response intercepts occur at 170 mM for free CHOP and at 0.17 mM for conjugated CHOP-PEG.
  • FIG. 2 shows the treatment of Balb/c female mice bearing the mammary carcinoma EMT-6 s.c. with the polymer Pt prodrug VEO-063 in the presence and absence of the collagen inhibitory conjugate CHOP-PEG.
  • FIG. 3 depicts the survival curve of EMT-6 bearing mice treated with the regimen described in Fig. 1.
  • FIG. 4 is the treatment profile of Balb/c female mice bearing the mammary carcinoma EMT-6 s.c. with the polymer Pt prodrug VEO-067 in the presence and absence of the collagen inhibitory conjugate CHOP-PEG, and also in the presence of the control analog prodrug conjugate THOP-PEG.
  • FIG. 5 is a schematic of one preparation of poly(PEG2000-Lys-c/,s-
  • FIG. 6 is a schematic of one preparation of VEO-063. DETAILED DESCRIPTION
  • compositions and methods are provided for the treatment of tumors with a combination of anti-collagen agents and
  • Anti-tumor agents are defined herein broadly to encompass both
  • chemotherapeutics as well as so-called biologies, including, for example, antibodies, nucleic acids, proteins, lipids, and
  • agents and methods provided may be equally suitable for any and all applications where fibrosis is an impediment to therapy.
  • Such applications may include, without limitations to, inflammation therapy, such as, for example,
  • chemokine also has anti-inflammatory and anti-fibrotic effects.
  • thalidomide has anti-inflammatory and anti-collagen effects. Abs that inhibit
  • angiogenic factors also have anti-inflammatory activity and include anti-FGF ⁇ and
  • anti-VEGF are such Mabs that have been cited for anti-fibrotic effects.
  • Collagen a ubiquitous protein that provides the "glue” of most tissues, as well as many other biological functions, turns over rather slowly during normal tissue maintenance; but in fibrotic sites, such as in inflammation, wound healing, and also tumors, collagen turnover is relatively rapid.
  • one method of inhibiting collagen synthesis is by the use of proline analogues that interfere with the posttranslational processing of collagen
  • Proline analogs may be incorporated into
  • pro- ⁇ -collagen chains in lieu of endogenous proline and impair folding of pro- collagen into a stable triple helix by steric hindrance.
  • "flawed" collagen molecules i.e., molecules incorporating proline analogues
  • Cw-hydroxyproline (“CHOP”) is an analog of tr ⁇ -hydroxyproline, the natural form of the imino acid which is abundant in
  • CHOP can be limited by its very rapid renal elimination. Aggressive dosing has been used to overcome this problem, which in turn, has been shown to generate systemic toxic side effects.
  • conjugate can release free CHOP at fibrotic sites undergoing elevated collagen biosynthesis in a sustained manner.
  • the conjugate can be administered by any parenteral route, and even a single dose given subcutaneously (s.c.) or intravenously (i.v.). Administration of the conjugate provides about a week-long anti-fibrotic activity in animal models of
  • a partial list of polymer supports that may be used in conjugate or in conjunction with the aforementioned anti-fibrotic agents is listed in Table 1.
  • solubility 50 mg, or 382 ⁇ mol, in a 100 ⁇ l reservoir of a 7-day osmotic pump
  • carboxypeptidase (not yet identified) is upregulated at the site of inflammatory fibrosis and causes the local release of free CHOP from the carrier backbone.
  • the activity of a collagen-inhibitory agent can facilitate tumor
  • MMP extracellular matrix degrading metalloproteinases
  • anti-fibrosis treatment has been combined with the administration of an anti-tumor agent, which may result in enhanced anti-tumor activity.
  • the combination of agents suppressing collagen biosynthesis can enhance the therapeutic efficacy of anti-tumor agents, especially macromolecular ones, by facilitating their diffusional access to tumor cells.
  • Table 2 is a partial list of anti-cancer Mabs and other anti-tumor macromolecular agents that may be used in some embodiments of the inventive method.
  • SSSGPQG-IFGN peptide
  • Control animals received either agent alone or
  • mice treated with VEO-067 There was no net survival benefit for the mice treated with any of the drugs, when compared to vehicle control animals.
  • the anti-neoplastic agents used were two different constructs consisting of PEG-Lys copolymer backbones bearing repeating units of a Pt-chelate
  • the potentiating effect of the collagenolytic agent is likely to be useful in the treatment with other macromolecular therapeutic agents such as monoclonal antibodies, cytokines, toxins, and other proteins, and their various conjugates, fragments, constructs, and fusion proteins.
  • the Pt-containing polymer prodrugs used in this study had MW in the range of about 25 - about 35 kDa, which is sufficient to retard and concentrate them in the tumor milieu, according to the EPR effect (Greish K, et al., 2003, Clin Pharmacokinet 42:1089-1105).
  • poly(PEG-Lys-CHOP) polymer was synthesized as previously described (Greco MJ, et al., 1997, Am. J. Respir. Crit. Care. Med. 155:1391-1397). Briefly, Lys-CHOP dipeptides were synthesized, and chain extension was
  • This conjugate was prepared identically to CHOP-PEG but using Lys- THOP instead of Lys-CHOP.
  • M is a trifunctional monomer such as L-lysine
  • L is an enzymatically labile linker functions (in most cases a peptide)
  • D is a biologically active pharmaceutical agent
  • n is the number of repeating units of the co-polymer backbone.
  • the linker-monomer conjugates, M-L were assembled on an automated peptide synthesizer using Fmoc protected amino acids and standard coupling reagents.
  • L was SSSGPQG-IFGN
  • L was SSSLIPVS-LIS.
  • the presumptive MMP-2 cleavage site is indicated by " ⁇ " (Netzel-Arnet, et al. 1993, Biochemistry 32:6427-32; Turk, et al., 2001, Nat Biotechnol 19:661-7, respectively).
  • PEG 6w-( ⁇ -hydroxysuccinimidyl) carbonate was reacted with the M-L to give the regular repeating block co-polymer
  • D was Pt, added as PtC14, for chelation by the terminal Asp at the C-terminus of the L peptide group. It was stabilized as the diaminochclohexyl (DACH) adduct,
  • mice were implanted with l-2xl0 6 EMT-6 mammary
  • carcinoma cells obtained from the American Type Culture Collection
  • Tumor growth was monitored by measuring two orthogonal diameters of the s.c. mass with calipers. Tumor volume was calculated by the formula ab 2 /2, where a is the larger and b is the smaller tumor diameter in mm, and expressed as mg,
  • CHOP-PEG polyethylene glycol) polymethylmethacrylate polyamino acids oligosaccharides polysaccharides polyvinyl alcohol polylactic acid polyglycolic acid dehydroproline (DHP) none
  • VEO-063 VectraMed PEG Pt MMP-2 + VEO-0 ⁇ 7 VectraMed PEG Pt MMP-2 + VEO-020 VectraMed PEG Pt MMP-2 + VEO-035 VectraMed PEG Pt MMP-2 VEO-028 VectraMed PEG Pt MMP-2 VEO-061 VectraMed PEG Pt MMP-2 VEO-037 VectraMed PEG Pt plasmin VEO-039 VectraMed PEG Pt plasmin VEO-066 VectraMed PEG Pt uPA VEO-069 VectraMed PEG Doxorubicin MMP-2 VEO-002 VectraMed PEG 5FU Cathepsin B VEO-003 VectraMed PEG Doxorubicin Cathepsin B

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  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
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  • Epidemiology (AREA)
  • Oncology (AREA)
  • Biomedical Technology (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des compositions et des procédés pour le traitement de tumeurs au moyen d'une combinaison d'agents anticollagène et d'agents anticancéreux. Dans certains modes de réalisation, un ou plusieurs des agents anticollagène et des agents anticancéreux peuvent se présenter sous forme de matrice polymère biocompatible. L'invention concerne également des promédicaments comprenant des conjugués d'agents anticollagène et d'agents anticancéreux. Les compositions et les procédés de l'invention peuvent s'avérer utiles pour le rétrécissement ou la réduction de la taille d'une tumeur par suppression des barrières de diffusion de médicament qui résultent souvent de la matrice extracellulaire collagène de tumeurs solides.
PCT/US2005/017732 2004-05-20 2005-05-20 Traitement du cancer au moyen d'inhibiteurs de synthese du collagene Ceased WO2005112999A2 (fr)

Applications Claiming Priority (2)

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US57261104P 2004-05-20 2004-05-20
US60/572,611 2004-05-20

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WO2005112999A2 true WO2005112999A2 (fr) 2005-12-01
WO2005112999A3 WO2005112999A3 (fr) 2009-05-07

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8668703B2 (en) 2006-12-01 2014-03-11 Wake Forest University Health Sciences Medical devices incorporating collagen inhibitors

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4485088A (en) * 1982-03-26 1984-11-27 Bio-Products, Inc. Method of treatment of fibrotic lesions by topical administration of lathyrogenic drugs
US6193991B1 (en) * 1997-10-29 2001-02-27 Atul J. Shukla Biodegradable delivery systems of biologically active substances
US6719977B1 (en) * 1998-02-12 2004-04-13 The General Hospital Corporation Methods to potentiate cancer therapies

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8668703B2 (en) 2006-12-01 2014-03-11 Wake Forest University Health Sciences Medical devices incorporating collagen inhibitors
US8883190B2 (en) 2006-12-01 2014-11-11 Wake Forest University Health Sciences Urologic devices incorporating collagen inhibitors
US8883183B2 (en) 2006-12-01 2014-11-11 Wake Forest University Health Sciences Medical devices incorporating collagen inhibitors

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