EP1409026A1 - Trousse servant a l'administration par voie intraperitoneale et a l'elimination extracorporelle d'un medicament - Google Patents

Trousse servant a l'administration par voie intraperitoneale et a l'elimination extracorporelle d'un medicament

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Publication number
EP1409026A1
EP1409026A1 EP01976972A EP01976972A EP1409026A1 EP 1409026 A1 EP1409026 A1 EP 1409026A1 EP 01976972 A EP01976972 A EP 01976972A EP 01976972 A EP01976972 A EP 01976972A EP 1409026 A1 EP1409026 A1 EP 1409026A1
Authority
EP
European Patent Office
Prior art keywords
kit
antibody
affinity
molecule
cytotoxic
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP01976972A
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German (de)
English (en)
Inventor
Bengt E. B. Sandberg
Rune Nilsson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mitra Medical Technology AB
Original Assignee
Mitra Medical Technology AB
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Filing date
Publication date
Priority claimed from US09/689,421 external-priority patent/US6723318B1/en
Application filed by Mitra Medical Technology AB filed Critical Mitra Medical Technology AB
Publication of EP1409026A1 publication Critical patent/EP1409026A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • 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
    • A61K47/68—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 an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6891—Pre-targeting systems involving an antibody for targeting specific cells
    • A61K47/6897—Pre-targeting systems with two or three steps using antibody conjugates; Ligand-antiligand therapies
    • A61K47/6898—Pre-targeting systems with two or three steps using antibody conjugates; Ligand-antiligand therapies using avidin- or biotin-conjugated antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
    • A61K51/1093—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody conjugates with carriers being antibodies
    • A61K51/1096—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody conjugates with carriers being antibodies radioimmunotoxins, i.e. conjugates being structurally as defined in A61K51/1093, and including a radioactive nucleus for use in radiotherapeutic applications

Definitions

  • the present invention relates to improvements in the diagnosis and treatment of peritoneal cancers, including ovarian cancer. More specifically, the invention relates to a kit, whereby the tumour to non-tumour ratio of cytotoxic agents in the treatment of disseminated carcinomas, in particular ovarian carcinomas, can be improved by reducing the concentration of a cytotoxic agent in the blood circulation after intraperitoneal administration of the same, a higher dosage and a more effective treatment regime beeing achieved without vital organs being exposed to high tox- icities .
  • the invention also relates to the use of a compound comprising at least one affinity region for the preparation of a medicament for treatment of an intraperitoneal tumour.
  • Ovarian cancer is the sixth most common cancer among women, excluding non-melanoma skin cancers.
  • the American Cancer Society estimated that about 23,100 new cases of ovarian cancer had been diagnosed in the United States during 2000. Ovarian cancer accounts for 4% of all cancers in women. Ovarian cancer is also the fifth most common cause of cancer deaths among women, causing more deaths than any other cancer of the female reproductive system. It was estimated that there was about 14,000 deaths from ovarian cancer in the United States during 2000. If diagnosed, and treated while the cancer has not spread outside the ovary, the live-year survival rate is 95%. However, only 25% of all ovarian cancers are found at this early stage . Thus, most women having an intraperitoneal cancer are diagnosed far too late. Late diagnosis results in a non- effective treatment with no regression of the tumour. With the treatments used today, regression is obtained only in 40% of the patients.
  • the 5 -year survival rate refers to the percent of patients who survive at least 5 years after their cancer is diagnosed. Of course, 5-year survival rates are based on patients diagnosed and initially treated more than 5 years ago. Improvements in treatment often result in a more favorable outlook for recently diagnosed patients.
  • tumours There are many types of tumours that can start growing in the ovaries. Some are benign (non-cancerous) and never spread beyond the ovary. These patients can be cured by surgically removing one ovary or the part of an ovary containing the tumour. Other types of ovarian tumours are malignant (cancerous) and may spread to other parts of the body .
  • ovarian tumours are named according to the kind of cells the tumour started from and whether the tumour is benign or cancerous.
  • Epi thelial tumours start from the cells that cover the outer surface of the ovary.
  • Cancerous epithelial tumours are called carcinomas .
  • Germ cell tumours start from the cells that produce the eggs (ova) .
  • Stromal tumours start from connective tissue cells that hold the ovary together and produce the female hormones, oestrogen and progesterone.
  • EOC Epi thelial ovarian carcinomas
  • the cells of EOC may have several forms that can be recognized under the microscope.
  • EOCs are also given a grade and a stage .
  • the grade is on a scale of 1, 2, or 3.
  • Grade 1 EOC more closely resembles normal tissue 25 and tends to have a better prognosis.
  • Grade 3 EOC less closely resembles normal tissues and usually has a worse outlook.
  • the tumour stage describes how far the tumour has spread from where it started in the ovary.
  • Another area of investigation involves treatment with very high doses of anticancer drugs, and then "rescuing" the woman from the side effects with infusions of her own bone marrow stem cells or peripheral blood stem cells (immature blood cells that may be taken from the bone marrow or removed from the bloodstream by using a special filtering process) .
  • the bone marrow or peripheral blood stem cells are removed before a high dose of chemotherapy is administered and is returned to the woman (reinfused) after the high-dose treatment is complete. In that way, the side effect of suppressed blood cell production is overcome.
  • avidin or streptavidin is administered systemically after administration of the therapeutic or diagnostic antibody to which biotin has been attached, at a time when a sufficient amount of the antibody has been accumulated in the tumour.
  • Avidin or streptavidin will associate with the antibodies and the so formed immunocomplex will clear from the blood circulation via the reticuloendothelial system (RES) and be cleared from the patient via the liver.
  • RES reticuloendothelial system
  • RES reticuloendothelial system
  • anti-idiotypic antibodies is an alternative approach to the same end.
  • all these methods rely on the liver or kidney for blood clearance and thereby expose either or both of these vital organs as well as the urinary bladder to high dose of cytotoxicity.
  • Extracorporeal techniques for blood clearance are widely used in kidney dialysis, where toxic materials build up in the blood due to a lack of kidney function.
  • Other medical applications, whereby an extracorporeal apparatus can be used include: removal of radioactive materials; removal of toxic levels of metals; removal of toxins produced from bacteria or viruses; removal of toxic levels of drugs, and removal of whole cells (e.g. cancerous cells, specific haematopoietic cells - e.g. B, T, or NK cells) or removal of bacteria and viruses.
  • Radiolabeled antibodies can be obtained by using molecules that bind to the therapeutic antibody, such as other monoclonal antibodies directed towards the therapeutic antibody (Klibanov et al . , J. Nucl . Med . 29, 1951-1956, 1988; Marshall et al . Br . J. Cancer 69, 502-507, 1994; Sharkey et al . Biocon juga te Chem .
  • tumour specific monoclonal antibody carrying cell killing agents or radionuclides for tumour localization have been biotinylated and cleared by an avidin-based adsorbent on a column matrix.
  • a number of publications provide data showing that this technique is both efficient and practical for the clearance of biotinylated and radionuclide labeled tumour specific antibodies (Norrgren K, et al .
  • tumour specific monoclonal antibodies are used as a carrier (immunoconjugates) of various cytotoxic moieties used in prodrug protocols (Meyer et al . , Bioconjugate Chem . 6, 440-446; 1995; Houba et al . , Biocon jugate Chem. 7, 606-611, 1996; Blakey et al . , Cancer Res . 56, 3287-3292, 1996).
  • tumour-speci ic immunoconjugates are selectively bound to tumour cells
  • an initial high concentration of the cell-toxic immunocon ugate in the peritoneal fluid is necessary to reach a sufficiently high concentration in the target tissue.
  • the high concentration of cytotoxic material in the peritoneal fluid will gradually increase the level of the cell toxic material in the blood and other non-tumour tissues, in most cases leading to tissue damage and/or lesion formation in sensitive and vital tissues like the bone marrow .
  • the purpose of the invention is to produce a kit for controlled removal from a body fluid of a compound, or a part thereof, which previously has been given by means of intraperionteal administration, the above-mentioned problems being avoided.
  • the invention has obtained the characterizing features of claims 1 and 25, respectively.
  • the intraperitoneal tumours are formed as small protuberances from peritoneum. More specifically, they are localized on the inside of the membrane, from which they mainly grow inwards, and they can be reached by administrating a toxic drug to the peritoneal cavity.
  • the inventive kit is especially adapted for treating early tumours intraperitoneally of as an alternative for systemic administration of an anti-tumour agent.
  • peritoneal cancers including ovarian cancer
  • Other carcinomas are also contemplated, where intraperitoneal administration of cytotoxic agents is applicable, either alone, or in combination with intravenous administration. These include, but are not limited to, colon and/or rectal cancer.
  • peritoneal dialysis the peritoneum is used as a semipermeable membrane.
  • the clearance of the peritoneal liquid takes place via the lymph system, and will subsequently enter the blood stream via the lymph nodes .
  • cytotoxic agents or toxic immunoconjugates By using the inventive kit it is possible to reduce the level of cytotoxic agents or toxic immunoconjugates from the blood circulation after intraperitoneal injection of these compounds. Furthermore, by removing the circulating cytotoxic agent or immunoconj ugate, it is possible both to decrease the toxic side effect on other organs and at the same time increase the therapeutic dose by means of a single administration or through the administration of multiple doses, which results in an increased penetration of the tumour tissue by the cytotoxic agent or immunoconjugate .
  • a cytotoxic targeting biomolecule e.g. immunoconjugate
  • An improved target-to non-target ratio provides a better therapeutic index.
  • the bone marrow rescue can be avoided, which sometimes is used to circumvent potentially lethal effects. Such a rescue is both extremely costly and poses high risk for the patient .
  • the kit comprises (a) at least one compound comprising at least one affinity region; (b) a device for intraperitoneal administration of the at least one compound to a mammal; and (c) an apparatus to be connected to the mammal for extracorporeal removal of the at least one compound, or a part thereof, from a body fluid of the mammal by means of at least one receptor interacting with the at least one affinity region.
  • the compound accord- ing to the invention can also be used for the preparation of a medicament for treatment of an intraperitoneal tumour.
  • the compound can be a cytotoxic agent; a cytotoxic moiety conjugated to a targeting agent; and a cytotoxic moiety, the cytotoxic moiety being selected from the group consisting of a radionuclide, a chemotherapy drug, a synthetic or naturally occurring toxin, an immuno- suppressive, an immunostimulant , and a prodrug activating enzyme.
  • the biomolecule is the cytotoxic agent conjugated to a targeting agent, it is preferred that the affinity ligand be directly covalently bound to the cytotoxic agent.
  • the affinity ligand be directly covalently or coordinately bound to the radionuclide or directly covalently bound to the chemotherapy drug, the synthetic or naturally occurring toxin, the immunosuppressive, the immunostimulant , or the prodrug activating enzyme.
  • the treatment of intraperitoneal cancers in mammals can be improved by: (a) administering the compound intraperitoneally to said mammal; and (b) substantially reducing the level of the compound, or a part thereof, in a body fluid at suitable time intervals, whereby side effects associated with biomolecules or their cytotoxic fragments are reduced.
  • the body fluid can be blood and the reduction of the compound, or its cytotoxic fragmentary part, in the circulation is achieved by passing the blood or a component thereof through an apparatus to be connected to the mammal for extracorporeal removal of the compound, or a part thereof, by means of at least one receptor interacting with the at least one affinity region of the compound.
  • the blood component may be serum or plasma.
  • the extracorporeal apparatus can comprise a solid support with a receptor bound thereto; and the biomolecule or cytotoxic fragment is conjugated to an affinity ligand with a high affinity to the receptor.
  • the biomolecule or cytotoxic fragment has a high affinity to the receptor.
  • the part of the compound to be removed is a cytotoxic fragment, which can comprise a radionuclide or a toxic metabolite or structure derived from the cytotoxic agent, the chemotherapy drug, the synthetic or naturally occurring toxin, the immunosuppressant , the immunostimulant or the prodrug activating enzyme.
  • the inventive kit it is also possible to improve the treatment of intraperitoneal cancers in mammals by: (a) administering a conjugate of a biomolecule and an affinity ligand intraperitoneally to the mammal; and (b) substantially reducing the level of said biomolecule or cytotoxic fragment thereof in the blood circulation by passing at suitable time intervals the blood or a component thereof through an extracorporeal apparatus comprising a solid support having a receptor bound thereto, the affinity ligand having a high affinity to the receptor, whereby the level of biomolecule or cytotoxic fragment in the circula- tion is reduced.
  • the inventive kit can also comprises more than one compound for intraperitoneal administration. These can be administrated together or in sequence, with or without a time lag, and with or without interacting with each other.
  • the imaging of peritoneal cancers in mammals can be improved by means of the inventive kit by: (a) administering a conjugate of a radionuclide and a targeting agent intraperitoneally to the mammal, the targeting agent having a high affinity for the cancer; and (b) sub- stantially reducing the level of radionuclide in the body fluid at suitable time intervals, whereby side effects associated with circulating radionuclide are reduced or whereby imaging contrast is improved.
  • the reduction of radionuclide can be achieved by passing peritoneal liquid, blood, or a component thereof through an extracorporeal adsorption apparatus.
  • the extracorporeal apparatus comprises a solid support with a receptor bound thereto, and the conjugate of radionuclide and targeting agent, or a cytotoxic fragment thereof, is further conjugated to an affinity ligand with a high affinity to the receptor.
  • the receptors in the extracorporeal may have a high affinity to the targeting agent.
  • a radionuclide is directly covalently or coordinately bound to the affinity ligand, which is directly covalently bound to the targeting agent.
  • the invention can be illustrated with the simulation exemplified in Example 1.
  • FIG. 1 illustrate how treatment of the blood at selected time intervals after administration can significantly or substantially reduce the level of biomolecule in the blood, thereby substantially reducing side effects associated with the circulating biomolecule and enhancing the target to non- arget ratio for the biomolecule. This improved ratio can result in decreased side effects and/or improved contrast for imaging.
  • the present invention is described for application to human ovarian carcinoma it is also applicable to other types of human cancer diseases where intraperitoneal administration is deemed preferable.
  • the subject procedure is also suitable for the treatment of other mammalian species.
  • the clearance of the biomolecule from the blood is achieved by passing the patient's whole blood through an apparatus that specifically adsorbs the biomolecule.
  • the biomolecule is labeled with biotin and the blood clearance is achieved by passing the blood on-line through an apparatus coated with avidin or streptavidin.
  • an apparatus is described in EP0 5675 14 and exhibits the proper characteristics of the matrix and means of immobilizing the biotin-binding entity for processing of whole blood and obtaining excellent clearance in a reasonable time period.
  • Figure 1 illustrates a simulation of the effect of Mitradep ® treatments on blood levels of a conjugate of Y- HMFG-1 and biotin.
  • FIG. 1 shows the retention of antigen binding of
  • FIG. 3 illustrates the percent reduction in whole body (WB) radioactivity after intraperitoneal injection of X11 In-HMFG-l in rats.
  • Figure 4 illustrates the pharmacokinetics of bio- tm > ylated 111In-HMFG-1 followi * ng intraperi «toneal inj * ection in rats.
  • Figures 5A and 5B shows the radioactivity uptake in selected rat organs and tissues at selected times following
  • Figure 6 illustrates the reduction in blood radio- activity following extracorporeal treatment at 12 and 18 hours after intraperitoneal injection (ECIA is extracorporeal immunoadsorption) .
  • the compound of the inventive kit comprises at least one cytotoxic effector.
  • a "cytotoxic effector” means any compound which exhibits or results in a cytotoxic effect on a tumour cell .
  • the cytotoxic effector can be a chemotherapy drug, an immuno- suppressive drug, an immunostimulating drug, a synthetic toxin, a naturally occurring toxin, a radionuclide, or an enzyme .
  • cytotoxic agent includes all medical agents which, when administered intraperitoneally exert a cell toxic effect, are mainly transported to the blood circulation through the lymphatic route, and can be biotinylated or otherwise labeled with an affinity ligand without severely affecting the efficacy of the drug.
  • the at least one affinity region of the compound in the inventive kit is an affinity ligand.
  • Cytotoxic agents to be used in the treatment of ovarian cancer include cisplatin, carboplatin or taxenes like docetaxel or paclitaxel or analogues or derivatives thereof, bleomycin, anthracyclines and derivatives thereof, alkylating agents like cyclophosphamide, etoposide, anti- estrogen drugs like tamoxifen, GnRH analogues, topo- isomerase I inhibitors like Topotecan, as well as naturally occurring toxins like doxorubicin and derivatives thereof.
  • a “targeting agent” is an agent which specifically binds to a tumour cell.
  • the compound according to the invention may comprise, or compose, at least one targeting agent, which is a molecule having an adhesive region for a receptor or any cell surface structure on the tumour cell .
  • the targeting agent carryies a cytotoxic moiety that, contrary to common cytotoxic agents, binds specifically to tumour cell with a high affinity and which could be administered intraperitoneally to a mammal or human being.
  • the targeting agents are antibodies, which could be of different isotypes and could originate from any species. Of particular interest are the monoclonal antibodies and derivatives thereof.
  • the latter include fragments such as the F(ab') 2 , F(ab'), F(ab) and the like. They also include genetically engineered hybrids or chemically synthesized peptides based on the specificity of the antigen binding region of one or several target specific monoclonal antibodies e.g. chimeric or humanized antibodies, single chain antibodies etc.
  • bi-specific antibodies with high affinities for tumour cells as well as the cytostatic effector, e.g. cytostatic agents.
  • These bi-specific antibodies can be two antibodies, each having a specific affinity, which have fused Fc regions.
  • the bi-specific antibodies have different light chains of different affinity.
  • the compound according to the invention may also comprise, or compose, an immunoadhesin.
  • Such a molecule is a genetically engineered, disulphide-linked homodimer which is structurally similar to an antibody. Immunoadhesins bind to their target with high affinity and specificity because the binding capacity of their adhesin domain is identical to that of the receptor or ligand of interest.
  • the compound according to the invention may also comprise, or compose, a peptide of non-monoclonal origin, which specifically binds to a target cell, i.e. a tumour cell .
  • suitable peptides are hormone analogues of somatostatin and melanocyte stimulating hormone.
  • the compound may comprise, or compose, a carbohydrate that by means of lectin-carbo- hydrate interactions can target lectin domains of tumour cells.
  • any of these targeting agents can be modified by the coupling of various number of polyethylene glycol chains in order to optimize the half-life in body fluid and the retention of the antibody or antibody fragments or deriv- atives, in the tumour tissue.
  • the antibodies or antibody derivatives should allow for the attachment of a sufficient number of affinity ligands, e.g., biotin residues, to be used for extra- corporeal removal through interaction with immobilized receptors, e.g., avidin, without significantly diminishing the binding properties of the targeting agent.
  • the receptor can also be an antibody having affinity for the affinity region of the compound.
  • tumour specific targeting agents or monoclonal antibodies are used as carriers (immunoconjugates) to carry cytotoxic agents (as defined above) and various other cytotoxic moieties used in prodrug protocols.
  • cytotoxic agents as defined above
  • cytotoxic moieties used in prodrug protocols.
  • conjugates of targeting agents and cytotoxic agents or other cytotoxic moieties are referred to herein as "targeting agent conjugates” .
  • the cytotoxic effector is a radionuclide such as a gamma-emitter, e.g. iodine-131 or metal ion conjugate, where the metal is selected from a beta-particle emitter, such as yttrium or rhenium.
  • a radionuclide such as a gamma-emitter, e.g. iodine-131 or metal ion conjugate, where the metal is selected from a beta-particle emitter, such as yttrium or rhenium.
  • DTPA diethylene- triaminepentaacetic acid
  • the '509 patent is particularly directed to a purification technique for the removal of non-bonded and adventitiously bonded (non-chelated) metal from radiopharmaceuticals but is illustrative of art recognized protocols for preparation of radioisotopic pharmaceuticals.
  • an antibody specifically reactive with the target tissue associated antigen is reacted with a quantity of a selected bifunc- tional chelating agent having protein binding and metal binding functionalities to produce a chelator/antibody conjugate.
  • an excess of chelating agent is reacted with the antibodies, the specific ratio being dependent upon the nature of the reagents and the desired number of chelating agents per antibody.
  • radionuclides are bound by chelation (for metals) or covalent bonds in such a manner that they do not become separated from the biotinylation/radiolabeling compound under the conditions that the biomolecule conjugates is used (e.g. in patients) .
  • chelation for metals
  • covalent bonds in such a manner that they do not become separated from the biotinylation/radiolabeling compound under the conditions that the biomolecule conjugates is used (e.g. in patients) .
  • the most stable chelates or covalent bonding arrangements are preferred.
  • binding or bonding moieties are: aryl halides and vinyl halides for radionuclides of halogens; N 2 S 2 & and N 3 S chelates for Tc and Re radionuclides; amino-carboxy derivatives such as EDTA, DTPA, derivatives Me-DTPA and Cyclohexyl-DTPA, and cyclic amines such as NOTA (1, 4 , 7-triazacyclononane-l , 4 , 7- triacetic acid), DOTA (1 , 4 , 7 , 10-tetraazacyclododecane- N,N ' ,N " ,N " -tetraacetic acid), TETA (1, 4 , 8 , 11-tetraaza- cyclotetradecane-N,N ' ,N " ,N '” -tetraacetic acid) , CITC-DTPA (-DTPA), SCNBz DOTA (isothiocyanatobenzobenz
  • Beta radiation emitters which are useful as cyto- toxic moieties, include isotopes such as scandium-46, scandium-47, scandium-48, copper-67, gallium-72, gallium- 73, yttrium-90, ruthenium-97 , palladium-100 , rhodium-101, palladium-109 , samarium-153 , rhenium-186, rhenium-188, rhenium-189, gold-198, radium-212 and lead-212.
  • the most useful gamma emitters are iodine-131 and indium-mll4.
  • ra- dionuclide-labeled targeting agents are useful not only in treatment of peritoneal cancers, but also for imaging of such cancers .
  • at least one cytotoxic effector suitable for treatment of peritoneal cancer such as but not limited to ovarian cancer, is administered intraperitoneally to a mammal in need thereof .
  • the cytotoxic effector can either have a direct cytotoxic effect on tumour cells or assist in the therapeutic therapy.
  • Cytotoxic effectors assisting in the therapeutic treatment can include but are not limited to cytotoxic effectors which can convert a prodrug to an active drug.
  • cytotoxic effectors are chosen for their abilities to convert relatively non-cytotoxic prodrugs (drug precursors) into active cancer drugs.
  • the drugs thus formed can then exert their cytotoxic effects.
  • alkaline phosphatase conjugated to monoclonal antibodies, convert etoposide phosphate into the clinically approved anticancer drug etoposide.
  • Different carboxy- peptidases for example conjugated to a monoclonal F(ab') 2 fragment, hydrolyze ⁇ -peptidyl methotrexate derivatives to methotrexate .
  • Monoclonal antibody conjugates of penicillin- V amidase act on phenoxyacetamide derivatives of doxo- rubicin and melphalan, producing the cytotoxic drugs doxorubicin and melphalan, respectively.
  • 5-Fluorocytocine is a substrate for cytocine deaminase conjugated to an anti-cancer monoclonal antibody, the anti-cancer drug 5- fluorouracil being produced.
  • the inventive kit for administration and extracorporeal removal of compound (s), or part(s) thereof, from a body fluid of the mammal include the following components .
  • Intraperitoneal administration of medical agents can be achieved by utilizing various blood access devices, CD CD 0 CD CO O 0 X! CJ 4-> CQ Xl - ⁇ Xl
  • Blood access could be achieved through peripheral vein catheters or if higher blood flow is needed through central vein catheters such as but not limited to sub- clavian or femoral catheters .
  • peritoneal cancer cells can be treated with cytotoxic effectors (including cell-killing drugs) or conjugates of a targeting agent a cytotoxic effector.
  • cytotoxic effectors including cell-killing drugs
  • conjugates of a targeting agent a cytotoxic effector are referred to collectively herein as "biomolecules" .
  • the matrix may be of various shapes and chemical compositions. It may, for example, constitute a column house filled with particulate polymers, the latter of natural origin or artificially made.
  • the particles may be macroporous or their surface may be grafted, the latter in order to enlarge the surface area.
  • the particles may be spherical or granulated and be based on polysaccharides, ceramic material, glass, silica, plastic, or any combination of these or similar materials. A combination of these could, for example, be solid particles coated with a suitable polymer of natural origin or artificially made. Artificial membranes may also be used.
  • These may be flat sheet membranes made of cellulose, polyamide, polysulfone, polypropylene or other types of material which are sufficiently inert, biocompatible , nontoxic and to which the receptor could be immobilized either directly or after chemical modification of the membrane surface.
  • Capillary membranes like the hollow fibers made from cellulose, polypropylene or other materials suitable for this type of membranes may also be used.
  • a preferred embodiment is a particulate material based on agarose and suitable for extracorporeal applications.
  • the blood clearance is achieved by the use of a specific adsorption device.
  • a specific adsorption device could utilize immobilized anti-species antibodies for the removal of therapeutic antibodies of, e.g., murine origin, or immobilized anti-idiotypic antibodies for removal of therapeutic antibodies regardless of the species origin.
  • an affinity ligand is attached to the biomolecule and the adsorption device contains an immobilized receptor binding specifically to the affinity ligand.
  • affinity ligand/immob- ilized receptor combinations can be used in this connec- tion, provided that the they do not significantly interfere with the binding affinity and selectively of the biomolecule to the tumour, and provided that the affinity ligand-receptor interaction is not interfered with by blood or other body fluids or tissues being in contact with the biomolecule-affinity ligand conjugate and/or the receptor of the adsorption device .
  • the adsorbent device to which the receptor is immobilized may be of various shapes and chemical compositions. It may for example constitute a column house filled with particulate polymers, the latter of natural origin or artificially made.
  • the particles may be macroporous or their surface may be grafted, the latter in order to enlarge the surface area.
  • the particles may be spherical or granulated and be based on polysaccharides , ceramic material, glass, silica, plastic, or any combination of these or a like material . A combination of these could for example be solid particles coated with a suitable polymer of natural origin or artificially made. Artificial membranes may also be used.
  • These may be flat sheet membranes made of cellulose, polyamide, polysulfone, polypropen or other types of material which are sufficiently inert, biocompatible, non-toxic and to which the receptor could be immobilized either directly or after chemical modification of the membrane surface.
  • Capillary membranes like the hollow fibers made from cellulose, polypropen or other materials suitable for this type of membranes may also be used.
  • the receptor to which the affinity ligand has a high affinity may be immobilized to various types of solid supports.
  • the coupling method of choice will depend on the nature of the receptor as well as the nature of the immuno- sorbent support matrix.
  • functional groups such as hydroxyl-, amino-, carboxyl- or thiol-groups may be utilized.
  • Glycoproteins may be coupled to the matrix via their glycoresidues .
  • the solid support may also be activated to enable binding of the receptor by means in which the receptor forms linkages with the solid support through specific or non-specific reaction with the side-chains or the backbone structure of the receptor protein.
  • the linkage between the solid support and the receptor may also be of non-covalent nature, where electrostatic or hydrophobic forces are utilized.
  • affinity ligand and corresponding receptors can be used within the scope of this invention. The following list is by no means complete and will merely serve as examples of additional combinations of affinity ligands and their receptors .
  • Antibody/antigen e.g. anti-DNP antibodies/targeting molecules conjugated with DNP;
  • Lectins/saccharide residues e.g. Lectin from Sambueus nigra/beta-D-gal (1-4) -D-glc ;
  • Enzyme/enzyme inhibitors e.g. D-alanine carboxypeptidase from B . subtili s or E. coli/6-aminopenicillanic acid or p-aminobenzyl- penicillin/e . g . dehydrofolate reductase/aminopterin or amethopterin;
  • the affinity ligand/immobilized receptor combination is biotin or biotin derivatives thereof and biotin binding molecules.
  • the affinity ligand can be biotin or derivatives thereof and the immobilized receptor can be avidin or streptavidin or any other biotin binding molecule.
  • the affinity ligand pairs biotin/avidin and biotin/streptavidin are often used in other applications. The very strong interaction (i.e.
  • affinity ligand e.g. biotin moiety
  • an cytotoxic agent can be interconnected by means of a trifunctional cross-linking reagent to form a new type of reagent.
  • ⁇ ⁇ tr ⁇ ⁇ 3 S ⁇ 3 ⁇ fD tr ⁇ 0 rr ft ⁇ 3 ⁇ tr i o 3 tr o ⁇ - ft CD SD 3 ⁇ - rr tr H 3 SD Mi 3 ⁇ ⁇ -
  • the kit according to the invention it is possible to increase the dose of anti-tumour agent with up to a factor of 5 by utilizing two consecutive treatments with Mitradep ® . Additional Mitradep ® treatment will allow an even higher enhancement of the dose. This can be a tremendous advantage, especially in that bone marrow transplants can be avoided.
  • the cost for a bone marrow transplant is SEK 2-300 000.
  • patients having impaired or decreased bone marrow production resulting from medications will with advantage be treated with the inventive kit .
  • the inventive kit may not only be the choice when treating an intraperitoneal cancer, but also for diagnosing the same, since intraperitoneal administration is a safer choice.
  • small tumours ⁇ 2 mm
  • suitable dosages can be calculated for individual patients.
  • a cancer treatment with this kit is not only safer but also less expensive than previous treatments .
  • Example 1 illustrates how extracorporeal treatment can reduce the cytotoxicity associated with intraperitoneal injections of radiolabeled antibody directed to cancerous tissue.
  • Examples 2-5 illustrate the effectiveness of the subject invention in attenuating the patient's toxic exposure.
  • Examples 2-5 illustrate that a radiolabeled anti- ovarian cancer immunoconjugate can be biotinylated to a sufficient degree for extracorporeal depletion without significantly affecting the avidin-binding properties or the biodistribution in the blood and vital organs.
  • Example 5 shows that the biotinylated immunocon- j ugate can be efficiently cleared from the blood circulation.
  • Figure 1 illustrates the percentage of injected radioactivity in the blood after intraperitoneal adminis- tration of 90Y-HMFG-1 to patients with ovarian cancer as reported by Maraveyas A. et al . ( Cancer 73: 1067-1075, 1994) . These data were utilized to simulate the effects of two extracorporeal adsorptions with Mitradep ® (a blood filter having avidin immobilized to agarose particles approved for human use in Sweden) conducted at various or suitable times after administration of the conjugate of antibody and biotin.
  • Mitradep ® a blood filter having avidin immobilized to agarose particles approved for human use in Sweden
  • Each adsorption is assumed to remove 90 per cent of the circulating conjugate according to the specification of Mitradep ® . It is also assumed that the rate of transport of conjugate from the intraperitoneal volume to blood or the biological half-life of the conjugate in blood is not influenced by the extracorporeal adsorptions .
  • the calculations are under-estimations as data is available up to 90 hours only.
  • the AUC is generally con- sidered as directly correlated to the myelotoxic side effects seen in treatment with the radioimmunoconjugate .
  • the optimal post -injection extracorporeal treatment time can be calculated by calculating the AUC (without ECAT) /AUC (with ECAT) ratio. The greater this ratio, the less the cytotoxic (radioactive) exposure.
  • Example 2 Radiolabeling and biotinylation of HMFG-LCITC- DTPA.
  • Indium-Ill was used as a substitute for yttrium-90, because the former is a gamma-emitter and possesses less radiation hazard than yttrium-90.
  • DTPA diethylenetriamine pentaacetic acid
  • N-hydroxysuccinimide (NHS) -biotin (10 mg/ml DMSO) was added to a vial with 500 ⁇ l 1:L1 In-HMFG-l conjugate (2.25 mg/ml), followed by addition of DMSO to give a final DMSO concentration of 10%. The mixture was incubated for 4 hours at room temperature. Low molecular weight components were removed by gel filtration. The quality of the radio conjugate was determined by TLC and HPLC. The antigen-binding reactivity was analyzed after two separate biotinylation procedures conducted on non-radio- labeled HMFG-1 -CITC-DTPA. 40 ⁇ g of NHS-biotin was added per mg of antibody.
  • Rats of the Fl breeding of Brown Norway (BN) and Wistar Furth (WF) rats were injected intraperitoneally with approximately 150 ⁇ g of biotinylated HMFGl labeled with 5
  • Whole body (WB) imaging was performed using a scintillation camera (General Electric 400T, GE, Milwaukee, WI , USA) equipped with a medium-energy collimator. Images were stored and analyzed with Nuclear MAC 2.7 software. From the images, the total number of counts in the entire body were obtained. After radioactivity decay correction and background subtraction, the counts were used for the calculation of activity retention (%) in the body. See Figure 3.
  • Example 4 Biodistribution of Conjugates to Organs and Tissues .
  • Dissections of organs and tissues of interest were performed after 8, 24, 72, and 96 hours.
  • the organs and tissues were removed, weighed, and measured for activity content.
  • the radioactivity was measured in an automatic Nal (TI) scintillation well counter, and the counts were corrected for decay.
  • the distribution of the injected activity is shown in Figures 5A and 5B.
  • the rats underwent arterial and venous catherization for extracorporeal affinity adsorption treatment. Blood was pumped from the arterial catheter through an adsorbent with avidin-agarose at a flow rate of 0.5 ml/min. During a 3- hours treatment approximately 3 blood volumes were processed.
  • radiolabeled anti-ovarian cancer i >mmunoconj> ugate as exempli>fied wi'th 111In labeled HMFG-1- CITC-DTPA can be biotinylated to a sufficient degree for extracorporeal depletion without significantly affecting the binding properties or the biodistribution in the blood and vital organs. It has also been shown that the same biotinylated immunoconj ugate can efficiently be cleared from the blood circulation. It should be understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and the scope of the appended claims.

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Abstract

La présente invention concerne un moyen qui permet d'améliorer le traitement d'un cancer intrapéritonéal chez un mammifère, notamment le cancer de l'ovaire, par administration, par voie intrapéritonéale, d'agents médicaux cytotoxiques ou d'immunoconjugués. En réduisant sensiblement, par élimination extracorporelle, le niveau des agents médicaux cytotoxiques ou des immunoconjugués dans les liquides organiques, on réduit au minimum l'exposition de l'organe à des agents cytotoxiques circulants, ce qui permet d'utiliser des régimes de traitement à des doses plus effectives.
EP01976972A 2000-10-12 2001-10-12 Trousse servant a l'administration par voie intraperitoneale et a l'elimination extracorporelle d'un medicament Withdrawn EP1409026A1 (fr)

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US689421 1985-01-07
US09/689,421 US6723318B1 (en) 1991-01-17 2000-10-12 Targeting of biomolecules
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