WO1989011299A1 - Procede d'acheminement d'agents therapeutiques a des tissus cibles du cerveau a l'aide de conjugues d'anticorps monoclonaux - Google Patents

Procede d'acheminement d'agents therapeutiques a des tissus cibles du cerveau a l'aide de conjugues d'anticorps monoclonaux Download PDF

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Publication number
WO1989011299A1
WO1989011299A1 PCT/US1989/002110 US8902110W WO8911299A1 WO 1989011299 A1 WO1989011299 A1 WO 1989011299A1 US 8902110 W US8902110 W US 8902110W WO 8911299 A1 WO8911299 A1 WO 8911299A1
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Prior art keywords
brain
conjugate
bbb
permeability
blood
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PCT/US1989/002110
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English (en)
Inventor
Edward A. Neuwelt
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State Of Oregon Acting By And Through The State Bo
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Publication of WO1989011299A1 publication Critical patent/WO1989011299A1/fr

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    • 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
    • A61K47/6893—Pre-targeting systems involving an antibody for targeting specific cells clearing therapy or enhanced clearance, i.e. using an antibody clearing agents in addition to T-A and D-M
    • 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
    • A61K47/6899—Antibody-Directed Enzyme Prodrug Therapy [ADEPT]

Definitions

  • the present invention generally relates to the treatment of brain tissue disorders, and more particularly to a method for treating such disorders using monoclonal antibody technology.
  • the BBB is a capillary barrier comprising a continuous layer of tightly bound endothelial cells. These cells permit a low degree of transendothelial transport, and exclude molecules in the blood from entering the brain on the basis of molecular weight and lipid solubility, as described in Neuwelt, E.A. , "Is There A Therapeutic Role For Blood-Brain Barrier Disruption", Ann. Int. Med. 93:137-139, 1980.
  • the BBB normally excludes molecules with a molecular weight greater than 180 daltons.
  • the lipid solubility of molecules is a major controlling factor in BBB passage.
  • BBB permeability characterisics in terms of lipid solubility, ionization fraction, protein binding and/or the molecular weight of foreign molecules.
  • the function of the BBB is to maintain the ho eostasis of the neuronal environment.
  • BBB enables the cerebrocapillary endothelium to act like a plasma membrane.
  • Small molecules (m.w. ⁇ 200 daltons) having a high degree of lipid solubility and low ionization at physiological pH are freely passed through the BBB.
  • the BBB allows water to move in either direction in order to maintain equal osmotic concentrations of solutes in the extracellular cerebral fluid.
  • the permeability characteristics of the BBB must be considered in treating central nervous system disorders. While the interendothelial junctions between the cells of the BBB are normally designed to keep potentially noxious substances away from the brain, chemicals exist which may osmotically disrupt the BBB, thereby increasing its permeability. Exemplary materials for this purpose include hypertonic solutions of mannitol, arabinose and/or glycerol. Chemical disruption of the BBB has been characterized in a variety of articles, including Neuwelt, E. A., et al, "Osmotic Blood-Brain Barrier Opening to IgM Monoclonal Antibody in the Rat", Am. J. Phvsiol.. 250:R875-883, 1986.
  • BBB permeability may change upon the formation of brain abscesses, inflammation, and/or tumors. Under. these conditions, BBB permeability has been shown to increase. This increase frequently allows the greater influx of molecules having a relatively small molecular weight ( ⁇ 1,000 daltons) which would nonetheless be excluded under normal BBB conditions. For example, experimental allergic encephalomyelitis (EAE) may cause an immune reaction which increases BBB permeability. Alvoode, E.C. et al, "Experimental Allergic Encephalomyelitis: A Useful Model For Multiple Sclerosis", Prog. Clin. Biol. Res.. Vol. 146, Alan R. Liss Co., N.Y., 1984.
  • Brain lipids are rich in arachidonic acid which may be released by brain tissue in response to trauma, neoplastic invasion or ischemia.
  • arachidonic acid and leukotrienes can increase BBB permeability when injected directly into the rat brain.
  • Leukotriene content of the brain tissue correlates significantly with the amount of edema surrounding various CNS neoplasms, and it is conceivable that leukotrienes released from the damaged brain contribute to BBB disruption and vasogenic edema in CNS neoplasia.
  • a method for the delivery of therapeutic agents across the BBB which uses monoclonal antibody technology in combination with chemical modification of the BBB.
  • a chemical composition is first administered which increases BBB permeability.
  • a chemical conjugate consisting of a monoclonal antibody in combination with an enzyme is administered.
  • the conjugate passes through the BBB and binds to neoplastic tissue in the brain or other disease- affected areas.
  • the BBB permeability is allowed to return to pre-treatment levels, wherein residual circulating amounts of the conjugate in the subject outside of the BBB are removed through renal clearance or other mechanisms.
  • a selected prodrug is administered to the subject having a molecular weight sufficiently small to pass through the BBB which, in many CNS lesions, is differentially permeable to smaller molecules as opposed to the high molecular weight conjugates described herein.
  • the conjugate enzyme acts on the prodrug to form a therapeutically effective drug useful in treating the brain lesions of concern.
  • the present invention involves a method for treating brain lesions.
  • the term "lesions” shall encompass malignant tumors, CNS infections, brain abscesses, cerebro-vascular disorders, and even degernative disorders such as Parkinson's disease and Alzheimer's disease. These disorders have many causes, including bacterial/viral infection or problems of genetic origin.
  • Blood brain barrier (BBB) permeability in a warm blooded subject is first modified through the administration of a suitable chemical agent.
  • BBB shall also encompass the vascular barrier associated with any brain tumors/lesions, otherwise known as the "blood-brain lesion barrier.”
  • Chemical agents useful for this purpose include hypertonic solutions of mannitol, arabinose, glycerol, and others known in the art.
  • Administration is generally accomplished by intra-arterial infusion techniques known in the art.
  • BBB permeability will be greatly increased.
  • a normal, unmodified BBB will prevent molecules larger than 180 daltons from entering the brain.
  • the BBB will permit the passage of molecules having a molecular weight of 1,000,000 daltons.
  • Preliminary studies indicate that even viral particles can be delivered across the BBB in this way.
  • Increased BBB permeability enables administration of therapeutic agents or drugs which would not normally pass through the BBB.
  • a chemical conjugate is administered consisting of a monoclonal. antibody in combination with a selected enzyme.
  • a selected monoclonal antibody is combined with an enzyme to form a conjugate of relatively high molecular weight which is administered to the subject following BBB modification.
  • the high molecular weight conjugate would not readily pass through an unmodified BBB.
  • entry of the conjugate into the brain is possible when BBB permeability is modified as described above.
  • the conjugate Upon administration of the conjugate and passage thereof through the modified BBB, the conjugate binds to the surface of antigen positive lesion/tumor cells within the brain. Thereafter, the BBB is allowed to return to pre-modification levels as the effects of the previously-delivered chemical agent completely reverse. Typically this will occur spontaneously in about thirty minutes.
  • a selected prodrug is administered intra-arterially or by other parenteral routes.
  • a prodrug is defined as an active drug linked to a moiety which is then metabolized to the active agent in vitro and/or in vivo.
  • the prodrug will preferably have a molecular weight small enough (i.e. 250 - 1,000 daltons) to pass through an unmodified differentially permeable blood-brain or blood-brain lesion barrier.
  • ambient (i.e., pre-treatment) BBB permeability is somewhat higher during the manifestation of brain lesions and similar conditions. This enables certain prodrugs to more readily pass through the BBB.
  • the prodrug is chemically altered by the enzyme in the conjugate.
  • the prodrug is enzymatically modified to produce a therapeutically effective drug which is capable of diminishing or controlling tumor development or other brain tissue disorders.
  • L6 was combined with the enzyme alkaline phosphatase (A.P.) .
  • A.P. enzyme alkaline phosphatase
  • the resulting conjugate is capable of converting the prodrug etoposide phosphate (E.P.) into, -etoposide.
  • Etoposide (4 '-Demethyl- epipodophyllotoxin 9-[4 , 6-0- (R) -ethylidene-Beta-D -glucopyranoside]
  • conjugate was specifically prepared by modifying the L6 monoclonal antibody with i inothiolane (0.5mM) in order to add a single thiol group onto the L6 molecule.
  • the A.P. used to form the conjugate was obtained from calf intestine having a molecular weight of 140kDa. Prior to conjugate formation, the A.P. was modified with succini idyl- 4(N-maleimidomethyl) cyclo-hexane-1-carboxylate. The A.P. and L6 were then combined and the resulting conjugate products purified by gel filtration on S-300 Sephacryl.
  • the E.P. prodrug was prepared by the phosphorylation of etoposide (obtained from the Bristol-Meyers Co.) using an equimolar amount of phosphoryl chloride and acetonitrile and N,N-diisopropyl ethyl amine.
  • the intermediate product was then hydrolyzed with aqueous NaHC0 3 and purified on a C-18 silica gel column. The column was washed with water, and the product eluted with 20% methanol in water. The completed conjugate was tested using mice.
  • H3347 a cell line designated "H3347" which was obtained from the Oncogen Company. This cell line was established from a etastatic human colon carcinoma.
  • IMDM incomplete modified Delbecco's medium
  • fetal calf serum 10% fetal calf serum was maintained at 4°C for a one-hour period in combination with 5ug/ml of the L6-A.P. conjugate.
  • the cells were washed twice with the IMDM, resuspended, and plated into 96-well microtiter plates (10,000 cells/well). The E.P.
  • mice With respect to the in vivo studies, Balb C nu/nu female mice (four to six weeks old) were injected with 10 7 H3347 cells subcutaneously in the left and right flanks.
  • the tumor cells used in these experiments were obtained from in vitro cultures previously suspended by treatment for two minutes with trypsin (0.5 g/1) and EDTA (0.2 g/1) .
  • the L6-A.P. conjugates (0.1 ml containing
  • mice 300ug monoclonal antibody in PBS
  • etoposide phosphate 0.2 ml containing 2 mg E.P. in water
  • the L6 A.P. was given 18-24 hours prior to treatment with the E.P.
  • Tumor growth in the mice was compared to growth in untreated mice and mice treated with maximum tolerated doses of etoposide or etoposide phosphate alone.
  • the E.P. was less toxic to the animals and exhibited a greater antitumor effect than treatment with etoposide alone.
  • the BBB would first be opened by administration of a hypertonic solution capable of increasing BBB permeability.
  • exemplary solutions for this purpose would include hypertonic mannitol, glycerol, and/or arabinose as previously discussed.
  • a conjugate consisting of IgG 2a monoclonal antibody in combination with alkaline phosphatase would be injected into the subject.
  • the conjugate would pass through the modified BBB and bind to the lesion/tumor tissues.
  • Sufficient time would then be allowed for the BBB to return to pre-treatment permeability levels.
  • Any remaining conjugate outside the BBB would be cleared from the subject either renally, or through other mechanisms. For example, clearance could occur via the reticulo-endothelial system, or through the addition of antibodies designed to enhance clearance, as is generally discussed in Sharkey, R.M. et al, "Factors Influencing
  • the foregoing process offers numerous benefits. It is capable of selectively delivering high-molecular-weight materials across the BBB which may be used to convert a prodrug into an active therapeutic agent. Furthermore, the therapeutic agent would be delivered directly to the site of the lesion/tumor proliferation. It would not be necessary for the monoclonal antibody conjugate to bind to every lesion or tumor cell, since the resulting drug formed through enzyme prodrug conversion could diffuse directly to adjacent cells.

Abstract

On a mis au point un procédé d'acheminement d'agents thérapeutiques dans le cerveau. On injecte d'abord dans le sang d'un sujet un agent chimique sélectionné, dans le sang d'un sujet afin d'augmenter la perméabilité de la barrière hématoencéphalique (BBB). Ensuite on administre un conjugué chimique consistant en un anticorps monoclonal sélectionné, en combinaison avec une enzyme. Ledit conjugué passe à travers la BBB et se lie sélectivement au tissu du cerveau présentant une lésion ou une tumeur. On laisse ensuite la BBB retourner à ses niveaux de perméabilité ambiants, après quoi les quantités circulantes résiduelles du conjugué se trouvant dans le sujet sont éliminées par les mécanismes d'élimination rénaux ou autres. Puis on administre un promédicament sélectionné ayant un poids moléculaire suffisamment faible pour passer à travers la BBB. On fait réagir le promédicament au moyen de l'enzyme afin de former un médicament thérapeutique, cette formation intervenant directement sur le site de la lésion ou de prolifération de la tumeur du cerveau.
PCT/US1989/002110 1988-05-18 1989-05-16 Procede d'acheminement d'agents therapeutiques a des tissus cibles du cerveau a l'aide de conjugues d'anticorps monoclonaux WO1989011299A1 (fr)

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US19596988A 1988-05-18 1988-05-18
US195,969 1988-05-18

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5827819A (en) * 1990-11-01 1998-10-27 Oregon Health Sciences University Covalent polar lipid conjugates with neurologically active compounds for targeting
US6063759A (en) * 1990-11-01 2000-05-16 Oregon Health Sciences University Conjugate of biologically active compound and polar lipid conjugated to a microparticle for biological targeting
WO2002011666A2 (fr) 2000-08-03 2002-02-14 D-Pharm Ltd. Derives de molecules lipophiles ramifiees et utilisations correspondantes
US7045543B2 (en) 2001-11-05 2006-05-16 Enzrel Inc. Covalent conjugates of biologically-active compounds with amino acids and amino acid derivatives for targeting to physiologically-protected sites
WO2009141329A1 (fr) 2008-05-20 2009-11-26 Consorzio Per Il Centro Di Biomedicina Molecolare Scrl Nanoparticules d'or encapsulées par polyélectrolyte capables de traverser la barrière hémato-encéphalique
WO2010035261A2 (fr) 2008-09-29 2010-04-01 Ben Gurion University Of The Negev Research And Development Authority Beta-peptides amyloides et procédés d'utilisation associés
US8835654B2 (en) 2004-12-22 2014-09-16 Bhi Limited Partnership Method and compositions for treating amyloid-related diseases
US9499480B2 (en) 2006-10-12 2016-11-22 Bhi Limited Partnership Methods, compounds, compositions and vehicles for delivering 3-amino-1-propanesulfonic acid
US10401363B2 (en) 2014-12-19 2019-09-03 Althia Health, S.L. Monoclonal antibody for the diagnosis, treatment and/or prevention of brain tumors and brain lesions
WO2021113512A1 (fr) 2019-12-04 2021-06-10 The Board Of Trustees Of The Leland Stanford Junior University Amélioration du transport de médicament à travers la barrière hémato-encéphalique par ciblage de régulateurs endogènes

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4479932A (en) * 1982-05-18 1984-10-30 University Of Florida Brain-specific drug delivery

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4479932A (en) * 1982-05-18 1984-10-30 University Of Florida Brain-specific drug delivery

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
AMERICAN JOURNAL OF PHYSIOLOGY, Vol. 250, issued 1986, NEUWELT et al., "Osmotic Blood-Brain Barrier opening to IgM Monoclonal Antibody in the Rat", pages R875-R883, see abstract. *
CHEMICAL ABSTRACTS, Vol. 107, No. 19, issued 9 November 1987, pages 328, abstract No. 171555s, BLASBERG et al., "Regional Localization of a Glioma-Associated antigen defined by Monoclonal Antibody 8IC6...", see whole abstract. *
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCE USA, Vol. 76, No. 1, issued January 1979, BARRANGER et al., "Modification of the Blood-Brain Barrier...", pages 481-485, see abstract, page 481, column 1, paragraph 2; page 484 column 2, three full paragraphs. *

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6024977A (en) * 1990-11-01 2000-02-15 Oregon Health Sciences University Covalent polar lipid conjugates with neurologically active compounds for targeting
US6063759A (en) * 1990-11-01 2000-05-16 Oregon Health Sciences University Conjugate of biologically active compound and polar lipid conjugated to a microparticle for biological targeting
US6339060B1 (en) 1990-11-01 2002-01-15 Oregon Health & Science University Conjugate of biologically active compound and polar lipid conjugated to a microparticle for biological targeting
US5827819A (en) * 1990-11-01 1998-10-27 Oregon Health Sciences University Covalent polar lipid conjugates with neurologically active compounds for targeting
US6436437B1 (en) 1990-11-01 2002-08-20 Oregon Health And Science University Covalent polar lipid conjugates with neurologically active compounds for targeting
US6858582B2 (en) 1990-11-01 2005-02-22 Oregon Health And Sciences University Composition containing porous microparticle impregnated with biologically-active compound for treatment of infection
US7423010B2 (en) 1994-05-19 2008-09-09 Oregon Health & Science University Nonporous microparticle-prodrug conjugates for treatment of infection
WO2002011666A2 (fr) 2000-08-03 2002-02-14 D-Pharm Ltd. Derives de molecules lipophiles ramifiees et utilisations correspondantes
US7045543B2 (en) 2001-11-05 2006-05-16 Enzrel Inc. Covalent conjugates of biologically-active compounds with amino acids and amino acid derivatives for targeting to physiologically-protected sites
US8835654B2 (en) 2004-12-22 2014-09-16 Bhi Limited Partnership Method and compositions for treating amyloid-related diseases
US9499480B2 (en) 2006-10-12 2016-11-22 Bhi Limited Partnership Methods, compounds, compositions and vehicles for delivering 3-amino-1-propanesulfonic acid
US10238611B2 (en) 2006-10-12 2019-03-26 Bellus Health Inc. Methods, compounds, compositions and vehicles for delivering 3-amino-1-propanesulfonic acid
US10857109B2 (en) 2006-10-12 2020-12-08 Bellus Health, Inc. Methods, compounds, compositions and vehicles for delivering 3-amino-1-propanesulfonic acid
US11020360B2 (en) 2006-10-12 2021-06-01 Bellus Health Inc. Methods, compounds, compositions and vehicles for delivering 3-amino-1-propanesulfonic acid
WO2009141329A1 (fr) 2008-05-20 2009-11-26 Consorzio Per Il Centro Di Biomedicina Molecolare Scrl Nanoparticules d'or encapsulées par polyélectrolyte capables de traverser la barrière hémato-encéphalique
WO2010035261A2 (fr) 2008-09-29 2010-04-01 Ben Gurion University Of The Negev Research And Development Authority Beta-peptides amyloides et procédés d'utilisation associés
US10401363B2 (en) 2014-12-19 2019-09-03 Althia Health, S.L. Monoclonal antibody for the diagnosis, treatment and/or prevention of brain tumors and brain lesions
WO2021113512A1 (fr) 2019-12-04 2021-06-10 The Board Of Trustees Of The Leland Stanford Junior University Amélioration du transport de médicament à travers la barrière hémato-encéphalique par ciblage de régulateurs endogènes
EP4069368A4 (fr) * 2019-12-04 2023-08-09 The Board of Trustees of the Leland Stanford Junior University Amélioration du transport de médicament à travers la barrière hémato-encéphalique par ciblage de régulateurs endogènes

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