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WO2001051075A1 - Amelioration du developpement des canaux lymphatiques, et traitement des maladies lymphatiques obstructives - Google Patents

Amelioration du developpement des canaux lymphatiques, et traitement des maladies lymphatiques obstructives Download PDF

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WO2001051075A1
WO2001051075A1 PCT/US2001/000545 US0100545W WO0151075A1 WO 2001051075 A1 WO2001051075 A1 WO 2001051075A1 US 0100545 W US0100545 W US 0100545W WO 0151075 A1 WO0151075 A1 WO 0151075A1
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vegf
stimulates
expression
development
lymphangiogenesis
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Stephen E. Epstein
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Priority to AU2001227717A priority Critical patent/AU2001227717A1/en
Priority to US10/169,838 priority patent/US20030211988A1/en
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    • 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
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1858—Platelet-derived growth factor [PDGF]
    • A61K38/1866—Vascular endothelial growth factor [VEGF]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy

Definitions

  • lymphatic channels for instance, in individuals with obstructed lymph channels (lymphedema).
  • lymphangiogenesis The process by which the enhancement of the development of lymphatic channels occurs is herein termed lymphangiogenesis.
  • the protein(s) can either be injected into the affected site directly as protein(s), or as a vector containing the gene encoding the relevant protein or proteins.
  • the protein(s) can be delivered either directly, or in a vehicle (such as Hposomes) that can facilitate delivery of the protein to the target site.
  • the vector containing the gene can be a naked plasmid DNA vector, or in any other suitable vector that contains the gene.
  • the resulting new or enlarged lymphatic channels enhance lymph conduction around the obstructed channels, thereby alleviating the lymphedema of the tissue drained by the obstructed lymphatics.
  • the present invention relates to compositions and methods for the preventing and/or treatment of lymphedema.
  • the present invention further relates to compositions and methods for producing a lymphangiogenic effect and/or for developing or enhancing the development of lymphatic channels, especially in individuals with obstructed lymph channels.
  • Lymphedema can be caused be various therapies or can occur spontaneously; and thus, the present invention relates to compositions and methods for inhibiting or preventing or controlling lymphedema; for instance, by producing a lymphangiogenic effect and/or for developing or enhancing the development of lymphatic channels, especially in individuals with obstructed lymph channels.
  • the present invention further relates to compositions and methods containing or employing agents having lymphangiogenic effects, such as VEGF-C or other agents which enhance the development of lymphatic channels.
  • the agent can be a protein or a gene; for instance a gene which expresses a protein in vivo; the gene could be delivered by a vector, e.g., plasmid or viral vector.
  • the present invention also relates to methods and compositions for administering an agent which induces lymphangiogenesis, and which thereby may inhibit lymphedema.
  • the present invention yet further relates to methods and compositions for administering an agent which inhibits lymphedema or that induces lymphangiogenesis, such as VEGF-C, or a vector expressing VEGF-C.
  • the administration can be sequential, simultaneous, or separated by a desired time period and can be by any suitable means.
  • the present invention relates to protein delivery, including by in vivo expression methods, to prevent or treat lymphedema.
  • the present invention relates to such protein delivery to induce lymphangiogenesis.
  • the present invention relates to such protein delivery for anti-lymphedema, e.g., to enhance development of lymph channels.
  • Lymphedema involving either the legs or arms is caused by obstruction of the lymphatic channels and is a common problem affecting tens of thousands of individuals throughout the world.
  • lymphatic obstruction derives from several types of therapeutic interventions. For example, during the course of treatment of cancers, extensive dissection in regions containing the lymphatic channels that drain a limb can seriously compromise lymphatic drainage and ultimately lead to lymphedema. In particular, axillary dissections can lead to arm lymphedema and groin dissections can lead to leg lymphedema.
  • lymph nodes are removed to test for the presence of cancerous cells. This diagnostic procedure further compromises lymphatic drainage. In addition, it often is deemed essential to radiate lymph nodes to eliminate remaining cancerous cells. Radiation seriously compromises the capacity of the lymphatic channels to drain the relevant limb, often resulting in lymphedema.
  • Lymphedema can also occur when non-cancer surgery is performed in a region in which lymphatics converge as they drain their relevant limb. A compromise in lymphatic drainage can occur during surgery of the shoulder or of the groin.
  • lymphatic obstruction can occur spontaneously with no known precipitating cause and lead to lymphedema of the effected limb or limbs.
  • VEGF-C VEGF-2 vascular endothelial growth factor C
  • Cao et al., PNAS USA 95(24): 14389-94 pertains to vascular endothelial growth factor C inducing angiogenesis in vivo.
  • U.S. Patent No. 5,919,459 concerns compositions and methods for treating cancer.
  • U.S. Patent Nos. 5,914,268 and 5,874,301 are directed to embryonic cell populations.
  • U.S. Patent No. 5,891 ,468 provides fusogenic liposome compositions.
  • U.S. Patent No. 5,877,289 involves tissue factor compositions for the coagulation of vasculature.
  • U.S. Patent Nos. 5,863,538, 5,776,427, and 5,855,866 concern compositions and methods for targeting the vasculature of solid tumors and to methods for treating the vasculature of solid tumors, respectively.
  • U.S. Patent No. 5,855,610 pertains to engineering of strong, pliable tissue.
  • U.S. Patent No. 5,776,755 is directed to FLT4, a receptor tyrosine kinase.
  • U.S. Patent No. 5,700,822 provides treatment of platelet derived growth factor related disorders such as cancer.
  • U.S. Patent No. 5,660,827 relates to antibodies that bind to endoglin.
  • Lymboussake et al., Am J Pathol 153(2):395-403 involves expression of the vascular endothelial growth factor C receptor VEGFR-3 in lymphatic endothelium of the skin and in vascular tumors.
  • Ristimaki et al., J Biol Chem 273(14):8413-8 (1998) relates to proinflammatory cytokines regulating expression of the lymphatic endothelial mitogen vascular endothelial growth factor-C.
  • the present invention thus provides methods and compositions for the prophylaxis of and/or therapy for lymphedema.
  • the present invention further provides such methods and compositions for prophylaxis and/or therapy which comprise an agent that enhances the development of lymphatic channels or lymphangiogenesis, such as VEGF-C, and/or that which stimulates VEGF-C expression and/or that which stimulates its interaction with its receptor (VEGF-C is a specific hgand for the VEGF receptor-3, or VEGFR-3, which is a specific marker for lymphatic endothelial cells) and/or an isoform of VEGF-C and/or a molecule having structural or functional homology to VEGF-C and/or a molecule that stimulates expression of VEGF-C and/or a molecule that participates in the signal transduction pathway of VEGF-C and/or in the signal transduction pathway of other molecules that stimulate the development of lymphatic channels or lymphangiogenesis and/or a molecule that activates other pathways to so stimulate the development of lymphatic channels or lymphangiogenesis and/or a portion or fragment of such a molecule that is active
  • nucleic acid molecules or sequences useful for expressing VEGF-C and/or that which stimulates VEGF-C expression and/or that which stimulates its interaction with its receptor and/or an isoform of VEGF-C and/or a molecule having structural or functional homology to VEGF-C and/or a molecule that stimulates expression of VEGF-C and/or a molecule that participates in the signal transduction pathway of VEGF-C and/or in the signal transduction pathway of other molecules that stimulate development of lymphatic channels or lymphangiogenesis and/or other molecules that activate other pathways to so stimulate the development of lymphatic channels or lymphangiogenesis and/or an active fragment or portion thereof, they can include nucleic acid sequences that are capable of hybridizing under high stringency conditions or those having a high homology with nucleic acid molecules encoding VEGF-C, and/or that which stimulates VEGF-C expression and/or that which stimulates its interaction with its receptor and/or an isoform of
  • Nucleotide sequence homology can be determined using the "Align” program of Myers and Miller, ("Optimal Alignments in Linear Space", CABIOS 4, 1 1-17, 1988, incorporated herein by reference) and available at NCBI.
  • the term “homology” or “identity”, for instance, with respect to a nucleotide or amino acid sequence can indicate a quantitative measure of homology between two sequences.
  • the percent sequence homology can be calculated as (N ⁇ ef - Nd, f )* 100 N re , wherein N .r is the total number of non-identical residues in the two sequences when aligned and wherein N ⁇ ef is the number of residues in one of the sequences.
  • "homology" or “identity” with respect to sequences can refer to the number of positions with identical nucleotides or amino acids divided by the number of nucleotides or amino acids in the shorter of the two sequences wherein alignment of the two sequences can be determined in accordance with the Wilbur and Lipman algorithm (Wilbur and Lipman, 1983 PNAS USA 80:726, incorporated herein by reference), for instance, using a window size of 20 nucleotides, a word length of 4 nucleotides, and a gap penalty of 4, and computer-assisted analysis and interpretation of the sequence data including alignment can be conveniently performed using commercially available programs (e.g., IntelligeneticsTM Suite, Intelligenetics Inc.
  • RNA sequences are said to be similar, or have a degree of sequence identity or homology with DNA sequences, thymidine (T) in the DNA sequence is considered equal to uracil (U) in the RNA sequence.
  • RNA sequences within the scope of the invention can be de ⁇ ved from DNA sequences, by thymidine (T) in the DNA sequence being considered equal to uracil (U) in RNA sequences.
  • amino acid sequence similarity or identity or homology can be determined using the BlastP program (Altschul et al, Nucl. Acids Res. 25, 3389-3402, incorporated herein by reference) and available at NCBI.
  • ClusterW improving the sensitivity of progressive multiple sequence alignment through sequence weighing, positions-specific gap penalties and weight matrix choice, Nucleic Acid Res., 22:4673-480 (1994); and, Devereux J, Haeberlie P and Smithies O, "A comprehensive set of sequence analysis program for the VAX.” Nucl. Acids Res., 12: 387-395 (1984).
  • Homology can also refer to a similar function, even in the complete absence of structural homology.
  • the invention comprehends the use of any molecule that promotes lymphangiogenesis, even if it bears no sequence homology to VEGF-C.
  • nucleic acid molecules used in this invention e.g., as in herein cited documents
  • the invention comprehends the use of codon equivalent nucleic acid molecules.
  • X codon equivalent nucleic acid molecules.
  • the invention comprehends "X" protein (e.g., Cp7 and/or Cp23 and/or Cpl 5/60) having amino acid sequence "A” and encoded by nucleic acid molecule "N”
  • the invention comprehends nucleic acid molecules that also encode protein X via one or more different codons than in nucleic acid molecule N.
  • the invention is not limited to VEGF-C, and it emcompasses that which stimulates VEGF-C expression and/or that which stimulates its interaction with its receptor and/or isoforrns of VEGF-C and/or molecules homologous to VEGF-C, and/or molecules that stimulate expression of VEGF-C and/or molecules that participate in the signal transduction pathway of VEGF-C and/or a molecule that participates in the signal transduction pathway of VEGF-C and/or in the signal transduction pathway of other molecules causing lymphangiogenesis or lymphatic channel development and/or that activates other pathways to so stimulate the development of lymphatic channels or lymphangiogenesis and/or an active fragment or portion of any of the foregoing; and, nucleic acid molecules encoding any or all of the foregoing, and nucleic acid molecules having homology with nucleic acid molecules encoding any or all of the foregoing, and molecules that promotes lymphangiogenesis even in the absence of sequence homology to VEGF-
  • the present invention still further provides such methods and compositions from in vitro and/or in vivo expression from plasmid DNA, or a vector system, such as a recombinant viral and/or DNA expression system; or from isolation from other sources, or from the administration of the protein itself.
  • the administration can be after cancer treatment or in conjunction with it (e.g., at points during chemotherapy, radiation therapy, and the like, or after there has been surgery or removal of lymph nodes) or after or in conjunction with non-cancer surgery performed in a region in which lymphatics converge as they drain their relevant limb.
  • the invention provides a therapeutic method for use with treatment of cancer or in conjunction with non- cancer surgery performed in a region in which lymphatics converge as they drain their relevant limb.
  • compositions of the invention can be administered before, during, or after any type of cancer treatment or therapy procedure (especially dissections, therapy such as radiation and/or chemotherapy, lymph node removal, etc.), or non-cancer surgery performed in a region in which lymphatics converge as they drain their relevant limb; e.g., before, to prevent, i.e., as a prophylaxis against, lymphedema; and during and after to prevent and/or control and/or treat lymphedema, for instance to prevent the development or progression of lymphedema.
  • cancer treatment or therapy procedure especially dissections, therapy such as radiation and/or chemotherapy, lymph node removal, etc.
  • non-cancer surgery performed in a region in which lymphatics converge as they drain their relevant limb; e.g., before, to prevent, i.e., as a prophylaxis against, lymphedema; and during and after to prevent and/or control and/or treat lymphedema, for instance to prevent the development or progression of lymphedem
  • Recombinant viral vectors such as replication incompetent adenovirus, expressing the agent that induces development of lymphatic channels or lymphangiogenesis, e.g., VEGF-C and/or that which stimulates VEGF-C expression and/or that which stimulates VEGF-C expression or that which stimulates its interaction with its receptor or that which stimulates along any point of or any molecules involved in its signal transduction pathway can be administered in an amount of about 10 7 pfu; thus, the inventive compositions can contain, and the inventive methods involve, administering a composition containing recombinant(s), at least this amount; more preferably about 10 4 pfu to about 10 10 pfu, e.g., about 10 5 pfu to about 10 9 pfu, for instance about 10 6 pfu to about 10 8 pfu.
  • each recombinant can be administered in these amounts; or, each recombinant can be administered such that there is, in combination, a sum of recombinants comprising these amounts.
  • the dosage should be a sufficient amount of naked DNA or DNA plasmid to elicit a response analogous to compositions containing the agent that induces development of lymphatic channels or lymphangiogenesis, e.g., VEGF-C and/or that which stimulates VEGE-C expression and/or that which stimulates VEGF-C expression or that which stimulates its interaction or that which stimulates along any point of or any molecules involved in its signal transduction pathway; or to have expression analogous to dosages in such compositions; or to have expression analogous to expression obtained in vivo by other, e.g., viral, recombinant compositions.
  • the agent that induces development of lymphatic channels or lymphangiogenesis e.g., VEGF-C and/or that which stimulates VEGE-C expression and/or that which stimulates VEGF-C expression or that which stimulates its interaction or that which stimulates along any point of or any molecules involved in its signal transduction pathway
  • VEGF-C e.g., VEGF-
  • suitable quantities of naked DNA or plasmid DNA in naked DNA or DNA plasmid compositions can be 1 ug to 100 mg, preferably 0.1 to 10 mg, e.g., 500 ug, but lower levels such as 0.1 to 2 mg or even 1 -10 ug, may be employed.
  • each recombinant and/or DNA system can be administered in these amounts; or, each recombinant and/or DNA system can be administered such that there is, in combination, a sum of recombinants and/or DNA comprising these amounts.
  • the dosage should be a sufficient amount of the agent that induces development of lymphatic channels or lymphangiogenesis, e.g., VEGF-C and/or that which stimulates VEGF-C expression and/or that which stimulates VEGF-C expression or that which stimulates its interaction or activates other pathways to so stimulate the development of lymphatic channels or lymphangiogenesis or that which stimulates along any point of or any molecules involved in the signal transduction pathway of VEGF-C or in the signal transduction pathway of other molecules causing lymphatic channel development or lymphangiogenesis; for instance, suitable quantities of protein can be 1 ug to 100 mg, preferably 0.1 to 10 mg, e.g., 500 ug, but lower levels such as 0.1 to 2 mg or even 1-10 ug, may be employed.
  • suitable quantities of protein can be 1 ug to 100 mg, preferably 0.1 to 10 mg, e.g., 500 ug, but lower levels such as 0.1 to 2 mg or even 1-10 ug, may be employed.
  • each protein can be administered in these amounts; or, each protein can be administered such that there is, in combination, a sum of proteins comprising these amounts.
  • Subcutaneous, intradermal or intramuscular administration are presently preferred.
  • the protein can be administered in a suitable carrier or diluent; and, it can be in the form of hposomes or other carriers designed to efficiently deliver a protein or prolong protein half-life.
  • the invention further comprehends methods for preparing the compositions of the invention, as well as kits for compositions and methods of the invention.
  • the invention comprehends a kit comprising an agent that induces development of lymphatic channels or lymphangiogenesis, e.g., VEGF-C and/or that which stimulates VEGF-C expression and/or that which stimulates VEGF-C expression or that which stimulates VEGF-C interaction or that which stimulates along any point of or any molecules involved in the signal transduction pathway of VEGF-C or in the signal transduction pathway of other molecules causing lymphatic channel development or lymphangiogenesis or activates other pathways to so stimulate the development of lymphatic channels or lymphangiogenesis; the agents, if there is two or more, and/or the agent(s) and any carrier or diluent can be in separate containers; the agent(s)/carrier/diluent can be in separate containers contained in a package; and, the kit can optionally include instructions for the storage and/or use and/or admixture and/or administration of the agent(s)/carrier/diluent.
  • Angiogenesis is a therapeutic target that has gained considerable interest over the past several years to treat ischemic syndromes of the heart and of the leg.
  • One of the primary strategies for growing new blood vessels is the use of growth factors that stimulate the proliferation, migration, and tube formation of vascular endothelial cells. These strategies employ such angiogenic factors as vascular endothelial growth factor 165 (VEGF 1 6 5 ) and its various isoforms (such as VEGFj 2 ⁇ ) and homologous molecules such as VEGF-2, the FGF family of proteins, and several additional angiogenic factors.
  • VEGF 1 6 5 vascular endothelial growth factor 165
  • VEGFj 2 ⁇ various isoforms
  • homologous molecules such as VEGF-2, the FGF family of proteins, and several additional angiogenic factors.
  • VEGF receptor-3 (VEGFR-3) has been shown to be a specific marker for lymphatic endothelial cells in the human skin, and that VEGF-C (also called VEGF-2) is a specific ligand for this receptor (1).
  • VEGFR-3 was also shown to be expressed in human saphenous vein and internal mammary artery (2).
  • the activity of VEGF-C is regulated by proinflamxnatory cytokines.
  • IL-1B causes a concentration-dependant increase in VEGF-C mRNA.
  • TNFoc and IL-oc also elevate VEGF-C mRNA steady-state levels.
  • hypoxia which is an important inducer of VEGF 165 and VEGF ⁇ 2 ⁇ expression, has no effect on VEGF-C mRNA levels (3).
  • VEGF avian chorioallantoic membrane
  • VEGF-C lymphangiogenic potential of VEGF-C was determined in a transgenic mouse model.
  • VEGF-C over-expression caused lymphatic, but not vascular, endothelial cell proliferation and vessel enlargement.
  • the authors concluded that VEGF-C induces selective hyperplasia of the lymphatic vasculature (5).
  • Murine VEGF-C was cloned by Kukk et al (6).
  • Murine VEGF-C is a dimer 85% homologous with the human VEGF-C amino acid sequence. Using the cloned murine gene, they found that VEGF-C mRNA was expressed in mesenchymal cells in regions where lymphatic vessels undergo sprouting, and in developing mesenterium, which is rich in lymphatic vessels.
  • Prophylactic/Therapeutic & Enhancing Strategy The strategy employed by this invention is based on the concept that specific lymphangiogenesis interventions will cause the development of functioning lymphatic channels that can supplement the impaired functioning of lymphatic beds that have been decreased either by spontaneous disease or iatrogenically. The approach has the benefit of reducing the lymphedema of limbs supplied by these impaired lymphatic channels.
  • This invention is designed to employ gene therapy or protein delivery to prevent or treat lymphedema by enhancing the development of lymph channels or by stimulating lymphangiogenesis.
  • the invention uses various strategies to suppress lymphedema such as the administration of an agent or a vector expressing an agent that induces development of lymphatic channels or lymphangiogenesis, e.g., VEGF-C and/or that which stimulates VEGF- C expression and/or that which stimulates VEGF-C expression or that which stimulates its interaction or that which, stimulates other pathways to so stimulate the development of lymphatic channels or lymphangiogenesis or that which stimulates along any point of or any molecules involved in the signal transduction pathway leading to lymphangiogenesis or lymphatic channel development.
  • an agent e.g., VEGF-C and/or that which stimulates VEGF- C expression and/or that which stimulates VEGF-C expression or that which stimulates its interaction or that which, stimulates other pathways to so stimulate the development of lymphatic channels or lymphangiogenesis or that which stimulates along any point of or
  • the agent could be in the form of a protein, or of a gene which expresses the protein.
  • the gene could be delivered to the patient in a plasmid, or in any other vector, including a viral vector. Delivery to patient will vary depending on the clinical situation; but, the time and amount and route or method of delivery can be determined by this disclosure and the knowledge in the art, without undue experimentation.
  • the present invention includes compositions and methods for preventing or treating lymphedema.
  • the present invention includes compositions comprising an agent that induces development of lymphatic channels or lymphangiogenesis, e.g., VEGF-C and/or that which stimulates VEGF-C expression and/or that which stimulates VEGF-C expression or that which stimulates its interaction or that which stimulates other pathways to so stimulate the development of lymphatic channels or lymphangiogenesis or that which stimulates along any point of or any molecules involved in the signal transduction pathway leading to lymphangiogenesis or lymphatic channel development; as well as methods comprising the administration of such agent(s), e g , individually, or separately, or sequentially or the like or in conjunction with other treatment or therapy such as cancer treatment or therapy or therapy or treatment involving non-cancer surgery in a region which lymphatics converge as they drain their relevant hmb Any or all of these agents can be present in the composition by way of a vector which expresses the agent in vivo
  • VEGF-C As to cloning and expression VEGF-C or VEGF-2, it is noted that Kukk et al (6) cloned munne VEGF-C (see also Parast et al Biochemistry 37(47) 16788-801 (November 1998) (VEGFR2 TK catalytic domain has been cloned and expressed via a baculovirus expression system), Pepper et al J Cell Physiol 177(3) 439-52 (December 1998) (VEGF-C has a potent synergistic effect on the induction of angiogenesis and VEGE, bFGF and VEGF-C are capable of alte ⁇ ng endothelial cell extracellular proteolytic activity))
  • agents that induces development of lymphatic channels or lymphangiogenesis e g , VEGF-C and/or that which stimulates VEGF-C expression and/or that which stimulates VEGF-C expression or that which stimulates its interaction or that which stimulates other pathways to so stimulate the development of lymphatic channels or lymphangiogenesis or that which stimulates along any point of or any molecules involved in the signal transduction pathway leading to lymphangiogenesis or lymph channel development
  • VEGF-C and/or that which stimulates VEGF-C expression and/or that which stimulates VEGF-C expression or that w hich stimulates its interaction or that which stimulates other pathways to so stimulate the development of lymphatic channels or lymphangiogenesis or that which stimulates along any point of or any molecules involved in the signal transduction pathway leading to lymnphangiogenesis or lymph channel development can be obtained by purification from natural sources or from purification from recombinant sources, and, techniques for such purifications or for protein purification are generally known and require no undue experimentation by the skilled artisan
  • the methods for making and/or administering a vector or recombinant for expression of such agents either in viva or in vitro can be by or analogous to the methods disclosed in: U.S.
  • the expression product generated b ⁇ vectors or recombinants in this invention can also be isolated from infected or transfected cells and used to prepare compositions for administration to patients
  • compositions for use in the invention can be prepared m accordance with standard techniques well known to those skilled in the pharmaceutical or medical arts Such compositions can be administered in dosages and by techniques well known to those skilled in the medical ads taking into consideration such factors as the age, sex, weight, and condition of the particular patient, and the route of administration
  • the compositions can be administered alone, or can be co-administered or sequentially administered with other compositions of the invention or with other piophylactic or therapeutic compositions
  • compositions of the m ⁇ ention include liquid preparations for orifice, eg , oral, nasal, anal, genital (e g , vaginal), vascular and/or SMC, etc , administration such as suspensions, syrups or elixirs, and, preparations for parenteral, subcutaneous, intradermal, intramuscular, intravenous, intraarte ⁇ al (e g , at site region deficient in or having obstructed lymphatic channels), mtralymphatic, or mtrape ⁇ toneal administration (e g , injectable administration) such as sterile suspensions or emulsions
  • the active agent be in admixture with a suitable earner diluent, or excipient such as sterile water, physiological salme, glucose or the like
  • the vector or protein can be in the form of hposomes or other earners designed to more efficiently deliver the protein or vector or to prolong its half-hfe
  • compositions of the invention may be packaged in a single dosage form for immunization by parenteral (I e , intramuscular, intradermal or subcutaneous) administration or orifice administration, e g , perhngual (i e , oral), mtragast ⁇ c, mucosal including intraoral, intraanal, travaginal, intravenous, mphat ⁇ c, lntraarte ⁇ al (e g , at site of deficiency or obstruction m lymphatic channels), mti apentoneal, and the like administration
  • parenteral I e , intramuscular, intradermal or subcutaneous
  • mtragast ⁇ c mucosal including intraoral, intraanal, travaginal, intravenous, mphat ⁇ c, lntraarte ⁇ al (e g , at site of deficiency or obstruction m lymphatic channels), mti apentoneal, and the like administration
  • parenteral I e
  • Dosages of each active agent can range from a few to a few hundred micrograms, e g , 5 to 500 mg
  • the inventive vector or recombinant can be administered to a patient or infected or transfected into cells in an amount of about at least 10 3 pfu, more preferably about 10 4 pfu to about 10 10 pfu, e g , about 10 5 pfu to about 10 9 pfu, for instance
  • the dosage should be a sufficient amount of plasmid to elicit a response analogous to compositions wherein the agent or agents ai e directly present, or to have expression analogous to dosages in such compositions, or to have expression analogous to expression obtained in vivo by recombinant compositions
  • suitable quantities of plasmid DNA in plasmid compositions can be 1 ug to 100 mg, preferably 0 1 to 10 mg, e g , 500 micrograms, but lower levels such as 0 1 to 2 mg or preferably 1 -10 ug may be employed
  • Documents cited herein, for instance, regarding vector expression and/or DNA plasmid vectors may, be consulted for the skilled artisan to ascertain other suitable dosages for expression vector and/or DNA plasmid vector compositions of the invention, without undue experimentation
  • the compositions compnsing an agent that induces development of lymphatic channels or lymphangiogenesis e g , VEGF-C and/or that which stimulates VEGF-C expression and/or that which stimulates VEGF-C expression or that which stimulates its interaction or that which stimulates other pathways to so stimulate the development of lymphatic channels oi lymphangiogenesis and/or that which stimulates any along any point of or any molecules invok ed m the signal transduction pathway leading to lymphangiogenesis or lymph channel development (and/or vector(s) expressing one or more of these agent(s)), alone or with other treatment (e g , cancer treatment therapy and/or non-cancer surgery in a region in which lymphatics converge and/or treatment, therapy for such non- cancer surgery), may be administered as desired by the skilled medical practitioner, from this disclosure and knowledge in the art, e g , at the first signs or symptoms of the condition for which the other treatment is being adm istei ed,
  • the compositions may be administered at the first indication of the patient being prone to lymphedema (e g , detection, treatment of cancer or of administration of treatment/procedure that can induce lymphedema such as non-cancer surgery in region in which lymphatics converge), or as soon thereafter as desired by the skilled medical practitioner, e g , within six months prior to, immediately prior to, or at or dunng treatment/proceduie that can induce lymphedema (e g , cancer treatment/therapy/procedure(s) and non-cancer treatment/therapy/procedure(s) such as those alluded to elsewhere herein), in any desired regimen such as a single administration or multiple administrations or in a regimen as desired, e g , monthly, bi-monthly, biannually, or within a year after, or annually or regularly or any combination thereof, for such time as is necessary to prevent lymphedema or symptoms or signs thereof, without any undue experimentation required
  • compositions of the invention can be administered before, during or immediately after a cancer treatment/therapy/procedure or non-cancer treatment/therapy/procedure prone to inducing lymphedema to induce maximal responses at that time, since process that may lead to lymphedema can happen quickly.
  • mice and/or pigs are subjected to lymphedema causing treatment/procedure/therapy, e.g., non-cancer surgery in region(s) in which lymphatics converge, as well as cancer treatment/therapy/procedure(s), e.g., radiation, lymph node removal, dissection in regions containing lymphatic channels, chemotherapy (with such mice or pigs either cancer-free or having tumor(s) such as tumor(s) commonly induced in such animals) Certain of those animals are given "treatment” (an agent that induces development of lymphatic channels or lymphangiogenesis, e.g., VEGF-C and/or that which stimulates VEGF-C expression and/or that which stimulates VEGF-C expression and/or that which stimulates its interaction or that which stimulates other pathways to so stimulate the development of lymphatic channels or lymphangiogenesis and/or that which stimulates along any point of or any molecules involved in the signal transduction pathway leading to lymphangiogenesis or lymph channel development (and/or vector(s)
  • Protocol in a first set of such animals treatment is administered in the form of either a protein or a vector expressing a nucleic acid molecule or gene encoding the protein, during and after the lymphedema causing event; in a second set of such animals no treatment is administered prior to, during or after the lymphedema causing event.
  • the treatment comprises an.
  • agent that induces development of lymphatic channels or lymphangiogenesis e.g., VEGF- C and/or that which stimulates VEGF-C expression and/or that which stimulates VEGF-C expression or that which stimulates its interaction or that which stimulates other pathways to so stimulate the development of lymphatic channels or lymnphangiogenesis or that which stimulates along any point of or any molecules involved in the signal transduction pathway leading to lymphangiogenesis or lymph channel development and/or vector(s) expressing one or more of these agent(s)) such as adenoviral vectors.
  • Tissue is obtained from each of 2 treated, and each of 2 untreated animals sacrificed 2 h, 6h, 24 h, and 14 days after injury and analysed for one or more or any or all of
  • VEGF-C protein by immunohistochemistry and/or by Western analysis
  • lymphatic channels Regard amount thereof and possible blackage/obstruction or lack thereof
  • Lymphatics are injected w ith dye each of 8 treated, and each of 8 untreated animals sacnficed at 28 days after injury and analyzed and observation of lymphatic channels regarding amount thereof and possible blockage/obstruction or lack thereof
  • Results confirm that administration of a VEGF-C and/or vector expressing it can prevent, treat and/or control lymphedema
  • the agent that induces development of lymphatic channels or lymphangiogenesis e g , VEGF-C and or that which stimulates VEGF-C expression and/or that which stimulates VEGF-C expression or that which stimulates its interaction or that which stimulates other pathways to so stimulate the development of lymphatic channels or lymphangiogenesis or that which stimulates along any point of or any molecules involved m the signal transduction pathway leading to lymphangiogenesis or lymph channel development (and/or vector(s) expressing one or more of these agent(s)) are admixed with earner, diluent etc and optionally, pnor thereto can be formulated into hposomes or other forms that enhance the half- life of the protem(s) and/or vector(s), as herein described in amounts as herein descnbed to obtain formulations DNA encoding an agent that induces development of lymphatic channels or lymphangio genesis, e g , ⁇ 'EGF-C and or that which stimulates VEGF-C expression and/or

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Abstract

L'invention concerne des compositions et des méthodes permettant de traiter ou de prévenir un lymphoedème. Ces compositions peuvent comprendre un agent, tel que VEGF-C, induisant le développement de canaux lymphatiques (lymphangiogénèse), et/ou stimulant l'expression de VEGF-C, et/ou stimulant l'expression de VEGF-C et son interaction avec un récepteur, ou stimulant d'autres chemins de façon à stimuler le développement desdits canaux lymphatiques ou de la lymphangiogénèse, ou stimulant un fragment de molécules impliquées dans le chemin de transduction de signal, ce qui permet la lymphangiogénèse ou le développement des canaux lymphatiques (et/ou vecteur(s) exprimant au moins l'un de ces agent(s)). Selon d'autres modes de réalisation, l'invention concerne des kits.
PCT/US2001/000545 2000-01-11 2001-01-09 Amelioration du developpement des canaux lymphatiques, et traitement des maladies lymphatiques obstructives Ceased WO2001051075A1 (fr)

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AU2001227717A AU2001227717A1 (en) 2000-01-11 2001-01-09 Enhancing lymph channel development and treatment of lymphatic obstructive disease
US10/169,838 US20030211988A1 (en) 2001-01-09 2001-01-09 Enhancing lymph channel development and treatment of lymphatic obstructive disease

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US60/175,393 2000-01-11

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Cited By (3)

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US6764820B2 (en) 1999-03-26 2004-07-20 Ludwig Institute For Cancer Research Screening for lymphatic disorders involving the FLT4 receptor tyrosine kinase (VEGFR-3)
US7829536B2 (en) 1999-03-26 2010-11-09 Vegenics Limited Method of treating lymphedema comprising administering VEGF-D
CN116036106A (zh) * 2021-10-28 2023-05-02 上海中医药大学附属龙华医院 一种治疗淋巴水肿的药物运用

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WO2000058511A1 (fr) * 1999-03-26 2000-10-05 Ludwig Institute For Cancer Research Dosage et therapie pour les troubles lymphatiques impliquant la tyrosine kinase flt4 (vegfr-3)

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WO1999033485A1 (fr) * 1997-12-24 1999-07-08 Ludwig Institute For Cancer Research Vecteurs d'expression et lignees cellulaires exprimant le facteur de croissance endothelial vasculaire d, et procede de traitement des melanomes
WO2000058511A1 (fr) * 1999-03-26 2000-10-05 Ludwig Institute For Cancer Research Dosage et therapie pour les troubles lymphatiques impliquant la tyrosine kinase flt4 (vegfr-3)

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KARKKAINEN ET AL.: "Vascular endothelial growth factor receptors in the regulation of angiogenesis and lymphangiogenesis", ONCOGENE, vol. 19, November 2000 (2000-11-01), pages 5598 - 5605, XP002939449 *
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6764820B2 (en) 1999-03-26 2004-07-20 Ludwig Institute For Cancer Research Screening for lymphatic disorders involving the FLT4 receptor tyrosine kinase (VEGFR-3)
US7829536B2 (en) 1999-03-26 2010-11-09 Vegenics Limited Method of treating lymphedema comprising administering VEGF-D
US8357669B2 (en) 1999-03-26 2013-01-22 Vegenics Pty Limited Method of treatment for lymphedema comprising administering a polynucleotide encoding VEGF-D
CN116036106A (zh) * 2021-10-28 2023-05-02 上海中医药大学附属龙华医院 一种治疗淋巴水肿的药物运用

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