WO1991013097A1 - Derives d'acide polyaminocarboxylique - Google Patents

Derives d'acide polyaminocarboxylique Download PDF

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Publication number
WO1991013097A1
WO1991013097A1 PCT/GB1991/000316 GB9100316W WO9113097A1 WO 1991013097 A1 WO1991013097 A1 WO 1991013097A1 GB 9100316 W GB9100316 W GB 9100316W WO 9113097 A1 WO9113097 A1 WO 9113097A1
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group
cho
compound according
value
integer
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PCT/GB1991/000316
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English (en)
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Robin Ewart Offord
Keith Rose
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Robin Ewart Offord
Keith Rose
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Publication of WO1991013097A1 publication Critical patent/WO1991013097A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/001—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof by chemical synthesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/107—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides
    • C07K1/1072—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups

Definitions

  • This invention relates to derivatives of polyaminocarboxylic acids, to processes for their preparation and to their use in the preparation of novel conjugates which are of use in medicine.
  • the conjugate generally comprises a protein, such as an antibody, to which is attached an effector or a reporter group, for example a cytotoxic agent or a group capable of being radioactively labelled.
  • site specific linkage by its very nature, means that few linking sites in the protein become coupled to the group of interest, it is difficult in practice to achieve a high degree of labelling.
  • R is a polyaminocarboxylic acid or a derivative thereof linked to the remainder of the molecule through its N-terminus;
  • X is a spacer group
  • n is zero or an integer of value 1; and R 1 is a reactive functional group;
  • R 1 is a group CHO, or
  • the -NH group shown in formula (1) is the residue of the N-terminal amino group of the polyaminocarboxylic acid or derivative thereof.
  • the polyaminocarboxylic acid represented by the group R may be for example polyglutamic acid, especially poly-L-glutamic acid, or polylysine, especially poly-L-lysine.
  • the polyaminocarboxylic acid may be of any size, for example up to a molecular weight of around 50KD, e.g. around 5-50KD.
  • Derivatives of polyaminocarboxylic acids include those wherein one or more side chain carboxyl or amino groups of the polyaminocarboxylic acid is each coupled to a reporter or effector group.
  • Reporter groups include any group or compound which is easily detectable by analytical means in vitro and/or in vivo and which confers this property to the compound of formula (1).
  • Effector groups include any group or compound which is capable of eliciting a change in, or a response from, a biological system and which also confers this property to the compounds of the invention.
  • Suitable reporter or effector molecules include chelated metals; carboranes and derivatives thereof; fluorescent compounds or compounds which may be detected by NMR or ESR spectroscopy; pharmacological agents, including cytotoxic compounds and toxins e.g. ricin and fragments thereof; enzymes; and hormones.
  • Chelated metals include chelates of monovalent metals, or. especially of di- or tripositive metals having a coordination number from 2 up to 8 inclusive.
  • Particular examples of such metals include technetium (Tc), rhenium (Re), cobalt (Co), copper (Cu), gold (Au), silver (Ag), lead (Pb), bismuth (Bi), indium (In), gallium (Ga), yttrium (Y), terbium (Tb), gadolinium (Gd), and Scandium (Sc).
  • the metal is preferably a radionuclide.
  • radionuclides include 99m Tc, 186 Re, 188 Re, 58 Co, 60 Co, 67 Cu, 195 AU, 199 Au, 110 Ag, 111 Ag, 203 pb, 206 Bi, 207 Bi, 111 In, 67 Ga, 68 Ga, 88 Y, 90 Y, 160 Tb, 153 Gd and 47 Sc.
  • the chelated metal may be for example one of the above types of metal chelated with any suitable polydentate chelating agent, for example acyclic or cyclic polyamines, polyethers, (e.g. crown ethers and derivatives thereof); polyamides; porphyrins; and carbocyclic derivatives.
  • chelating agent in general, the type of chelating agent will depend on the metal in use.
  • One particularly useful group of chelating agents in compounds according to the invention are acyclic and cyclic polyamines, especially polyaminocarboxylic acids, for example diethylenetriaminepentaacetic acid and derivatives thereof, and macrocyclic amines, e.g. cyclic tri-aza and tetra-aza derivatives; and polyamides , especially desf errioxamine (Desferal) and derivatives thereof.
  • Other compounds which may be coupled to the polyaminocarboxylic acid in compounds of formula (1) include carborane derivatives, for example derivatives of 1,2-dicarba-closo-decarborane, of value as radiosensitizers by capture of thermal neutrons.
  • any suitable pharmacological agent may be attached to the polyaminocarboxylic acid, providing of course that the resulting attached agent retains its activity, or is attached in a form which can be converted in vivo to the active agent, for example by the action of host or exogenous enzymes.
  • Cytotoxic compounds for use as effector molecules in compounds according to the invention include cytostatic compounds.
  • Particular compounds include for example, alkylating agents, such as nitrogen mustards (e.g. chlorambucil, melphalan, mechlorethamine, cyclophosphamide, or uracil mustard) and derivatives thereof, triethylenephosphoramide, triethylenethiophosphoramide, busulphan, or cisplatin, antimetabolites, such as methotrexate, fluorouracil and floxuridine, cytarabine. mercaptopurine. thioguanine, fluoroacetic acid or fluorocitric acid; antibiotics, such as bleomycins (e.g.
  • bleomycin sulphate doxorubicin, daunorubicin, mitomycins (e.g. mitomycin C), actinomycins (e.g. dactinomycin) or plicamycin, mitotic inhibitors, such as etoposide, and vinca alkaloids such as vincristine or vinblastine; ureas, such as hydroxyurea; hydrazines, such as procarbazine; or imidazoles, such as dacarbazine; calicheamicin, esperamicin or taxol.
  • Hormones include androgens (e.g. dromostanolone or testolactone), progestins (e.g. megestrol acetate or medroxyprogesterone acetate), estrogens (e.g. diethylstilbe ⁇ trol diphosphate, polyestradiol phosphate or estramustine phosphate) or antiestrogens (e.g. tamoxifen).
  • androgens e.g. dromostanolone or testolactone
  • progestins e.g. megestrol acetate or medroxyprogesterone acetate
  • estrogens e.g. diethylstilbe ⁇ trol diphosphate, polyestradiol phosphate or estramustine phosphate
  • antiestrogens e.g. tamoxifen
  • n is an integer of value 1
  • the spacer group represented by X in such compounds of may in general be an optionally substituted straight or branched aliphatic hydrocarbyl chain optionally interrupted by one or more heteroatoms selected from -O- or -S- or one or more -N(R 3 ) [e.g. -NH- or -N(CH 3 )-], -CON(R 3 ), -N(R 3 )CO-, cycloaliphatic (e.g. C 3-8 cycloalkylene such as cyclohexylene) or aromatic (e.g. C 6-12 arylene such as phenylene) groups.
  • cycloaliphatic e.g. C 3-8 cycloalkylene such as cyclohexylene
  • aromatic e.g. C 6-12 arylene such as phenylene
  • Particularly useful spacer groups represented by X are peptides, for example polyglycine [(-Gly-) p where Gly is glycine and p is an integer 2 or more], such as -Gly-Gly-, -Gly-Gly-Gly-Gly-Gly-, -Gly-Gly-Gly-Gly-Gly-, and especially -Gly-Gly-Gly-.
  • Reactive functional groups represented by R 1 include groups capable of reacting with any thiol, amino, carboxyl, hydroxyl, aldehyde, aromatic or heteroaromatic groups in a selective manner. Particular groups of these types include aldehyde-seeking or aldehydic groups, especially amino groups, including optionally substituted hydrazines and hydroxylamines, and optionally substituted aldehydes.
  • R 1 may especially be a group of formula -CHO or -(CH 2 ) m R 2 where m is an integer of value 1 or 2 and R 2 is a group -CHO, ONH 2 , -CONHNHCONHNH 2 or -CONHCH 2 CHO.
  • Compounds of formula (1) are useful for coupling to other molecules such as proteins, especially antibodies, peptides or carbohydrates to form conjugate compounds for use in diagnosis or therapy.
  • the compounds of formula (1) are preferably coupled to proteins or peptides, for example a plasma protein such as fibrinogen or an immunoglobulin or a fragment thereof, a hormone, such as insulin, a cytokine, such as tumour necrosis factor, or a therapeutically useful enzyme, such as tissue plasminogen acitvator.
  • proteins or peptides for example a plasma protein such as fibrinogen or an immunoglobulin or a fragment thereof, a hormone, such as insulin, a cytokine, such as tumour necrosis factor, or a therapeutically useful enzyme, such as tissue plasminogen acitvator.
  • the compounds of formula (1) are preferably coupled to an immunoglobulin or a fragment thereof.
  • the immunoglobulin or immunoglobulin fragment may in general belong to any immunoglubulin class. Thus, for example, it may be an antibody belonging to an immunoglobulin M class or, in particular, an antibody belonging to an immunoglobulin G class.
  • the antibody, or fragment thereof may be of animal, for example mammalian origin and may be for example of murine, rat or human origin. It may be a natural antibody or a fragment thereof, or, if desired, a recombinant antibody or antibody fragment, i.e. an antibody or antibody fragment which has been produced using recombinant DKA techniques.
  • Particular recombinant antibodies or antibody fragments include, (1) those having an antigen binding site at least part of which is derived from a different antibody, for example those in which the hypervariable or complementarity determining regions of one antibody have been grafted into the variable framework regions of a second, different antibody (as described in European Patent Specification No. 239400); (2) recombinant antibodies or fragments wherein non-Fv sequences have been substituted by non-Fv sequences from other, different antibodies (as described in European Patent Specifications Nos.
  • the antibody or antibody fragment may be of polyclonal, or, preferably, monoclonal origin. It may be specific for any number of antigenic determinants, but is preferably specific for one.
  • the antigenic determinant may be any hapten or an antigenic determinant associated with animals, e.g.
  • tumour cell-associated antigens for example oncofetal antigens such as carcinoembryonic antigen or alphafetoprotein, placental antigens such as chorionic gonadotropin and placental alkaline phosphatase, and prostate antigens such as prostatic acid phosphatase and prostate specific antigen
  • antigens associated with components of body fluids such as fibrin or platelets
  • viruses for example normal animal tissue or organ cell-associated antigens, tumour cell-associated antigens (for example oncofetal antigens such as carcinoembryonic antigen or alphafetoprotein, placental antigens such as chorionic gonadotropin and placental alkaline phosphatase, and prostate antigens such as prostatic acid phosphatase and prostate specific antigen) and antigens associated with components of body fluids such as fibrin or platelets], viruses, bacteria and fungi.
  • tumour cell-associated antigens for example oncofetal antigens such as carcinoe
  • Antibody fragments include for example fragments derived by proteolytic cleavage of a whole antibody, such as F(ab') 2 , Fab' or Fab fragments, or fragments obtained by recombinant DNA techniques, for example Fv fragments (as described in International Patent Application No. PCT/GB 88/00747).
  • the compounds of formula (1) may be coupled to proteins, peptides or carbohydrates using standard procedures, [for example as described in the following examples] depending on the nature of the functional group R 1 .
  • the protein, peptide or carbohydrate may need to be previously modified [for example by oxidation, to create e.g. an aldehyde group, or reduction, to create e.g. a thiol group or any other convenient reaction to create a reactive group] to allow the compound of formula (1) to react with it.
  • a compound of formula (1) may be prepared by condensing a polyaminocarboxylic acid R-[X] n -NH 2 and an acid R 1 CO 2 H or a reactive derivative thereof.
  • the reaction may generally be performed in a solvent, for example an inert organic solvent such as dimethylsulphoxide in the presence of a tertiary amine, for example 1-hydroxybenzotriazole or N-methylmorpholine at any suitable temperature, for example around room temperature.
  • a solvent for example an inert organic solvent such as dimethylsulphoxide
  • a tertiary amine for example 1-hydroxybenzotriazole or N-methylmorpholine
  • Reactive derivatives of the acid R 1 CO 2 H include for example esters, for example succinimide esters such as N-hydroxysuccinimide esters.
  • any reactive groups in the starting materials R-[X] n -NH 2 and, especially, R 1 CO 2 H which it is not desired to participate in the reaction will need to be in a protected state.
  • Conventional methods of protection may be used, and any protecting group may be removed once the desired reaction is complete using standard procedures.
  • intermediates R-[X] n -NH 2 and R 1 CO 2 H, and reactive derivatives thereof are generally either known compounds or may be prepared using methods analogous to those used for the preparation of the known compounds.
  • Intermediates of formula R-[X] n -NH 2 in which X is present i.e. where n is an integer of value 1
  • R-[X] n -NH 2 in which X is present may be prepared by reaction of a polyaminocarboxylic acid with a bifunctional reagent L-[X] n -R 3 (where L is a leaving group and R 3 is an amino or protected amino group), followed where necessary by deprotection, using standard procedures for reactions of this type.
  • Effector or reporter molecules may be coupled to the polyaminocarboxylic acid R at any suitable stage, for example by condensing polyaminocarboxylic acid side chain -CO 2 H or -NH 2 groups or reactive derivatives thereof, with an appropriate group or reactive derivative thereof on the effector or reporter molecule using standard procedures.
  • PG Poly-L-glutamic acid (Bachem, Switzerland) of molecular-weight range: 5,000-10,000 or 15,000-50,000.
  • ONSu in the following Examples is the residue of N-hydroxysuccinimide
  • DMSO dimethylsulphoxide
  • Boc tert-butyloxycarbonyl
  • Ferrioxamine is desferrioxamine (or 1-amino-6,17-dihydroxy-7,10,18,21-tetraoxo-27
  • Compound I is the following:
  • R 4 is -CH 2 CH 2 CHNHNCOCH( ⁇ NH 2 )CH 2 CH 2 CH 2 CH 2 NHCOCH(CH 3 )-NH-DTPA and DTPA is diethylenetriaminepentaacetic acid.
  • the ⁇ -NH 2 group provides the reactive amino group for the reaction described in Example 1(c). See Starkeman, C (1986) Thesis-Departement de Biochimie Medicale, University of Geneva.
  • DMSO redistilled 0.15ml
  • N-Ethylmorpholine Fluka. redistilled 0.02ml
  • Boc-NHOCH 2 CO-ONSu in DMSO 0.05ml made as in Example 16 of EP243929
  • 1-hydroxybenzotriazole 0.01ml: 3.5mg/0.02ml
  • Paper electrophoresis (Whatman 3MM paper) at pH 6.5 was used to check that the reaction had gone to completion.
  • the columns were equilibrated and run in 0.2% NH 4 HCO 3 and monitored at 206nm.
  • fractions 15-20, 21-23, 24-26 and 27-32 were pooled and freeze-dried separately in order to have PG derivatives with a narrower size range.
  • reaction mixture was diluted to 1.5ml with 0.2% NH 4 HCO 3 .
  • the solution was divided into two and each was separated on a column of Sephadex G-50 (53cm x 1cm 32.2ml) run in 0.2% NH 4 HCO 3 , monitoring at 206nm.
  • the desired product eluted in fractions 15-32 (0.7ml fractions). These fractions were pooled and freeze dried.
  • the amount of Glu was determined by acid hydrolysis and amino acid analysis of Sephadex G-50 isolated material as described below [Example 2(b)] using lie as an internal standard..
  • the amount of Glu in the Boc-NHOCH 2 CO-PG- (ferrioxamine) x product was determined by acid hydrolysis and amino acid analysis as desribed below [Example 2(b)] using lie as an internal standard.
  • the amount of ferrioxamine was determined from the absorbance at 425nm [see Example 2(b)].
  • the ratio ferrioxamine: Glu obtained in this way was 0.77 i.e. 77% of the PG carboxyls were substituted.
  • Example 1(e) To each appropriate ether precipitate of Example 1(e) and derived from Example 1(b)and 1(c) was added 0.08ml of 0.1M sodium acetate. After mixing 0.08ml of 0.1M acetic acid was added. The pH was 4.25. The solution was dried in a Speed Vac (lh) and taken up in 0.16ml of water. The pH was 5.2. The solution was stored frozen.
  • aldehydic monoclonal antibody has essentially the same amino acid composition as unreacted monoclonal antibody.
  • the aldehydic antibody which had been reacted with NH 2 -OCH 2 CO-PG(ferrioxamine) x showed a 27% increase in the proportion of Glu after acid hydrolysis, which corresponds to an incorporation of approximately 40 Glu per antibody.
  • the amino acid composition was otherwise unaltered.
  • the number of ferrioxamines per antibody was 31.
  • Aldehydic antibody which had been reacted with NH 2 -O-CH 2 CO-PG(5-10K)-(I) x showed a 64% increase in the proportion of Glu and a 48% increase in the proportion of Ala, which corresponds to an incorporation of approximately 90 Glu and 40 Ala per antibody.

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  • General Health & Medical Sciences (AREA)
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Abstract

La présente invention décrit des acides polyaminocarboxyliques dans lesquels le groupe amino à terminaison N est relié, par exemple par l'intermédiaire d'un groupe d'insertion, à un groupe fonctionnel réactif. Les composés peuvent coupler plus d'un groupe effecteur ou marqueur et peuvent aussi réagir aux protéines et à d'autres molécules de manière spécifique au site.
PCT/GB1991/000316 1990-02-28 1991-02-28 Derives d'acide polyaminocarboxylique WO1991013097A1 (fr)

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GB909004538A GB9004538D0 (en) 1990-02-28 1990-02-28 Chemical compounds
GB9004538.6 1990-02-28

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0525992A2 (fr) * 1991-07-01 1993-02-03 Eli Lilly And Company Groupe de conjugués de médicaments avec des anticorps
GR1001459B (el) * 1992-10-08 1993-12-30 Lilly Co Eli Σύμπλεγμα συζυγών φαρμάκων με αντισώματα.
WO1994025071A1 (fr) * 1993-05-05 1994-11-10 Keith Rose Composes de polyoximes et leur preparation
FR2727117A1 (fr) * 1994-11-18 1996-05-24 Geffard Michel Utilisation de conjugues de la polylysine pour la preparation de medicaments utiles dans le traitement des maladies neurodegeneratives et des affections degeneratives a caractere autoimmun
AU686153B2 (en) * 1993-05-05 1998-02-05 Robin E Offord Polyoxime compounds and their preparation
US6001364A (en) * 1993-05-05 1999-12-14 Gryphon Sciences Hetero-polyoxime compounds and their preparation by parallel assembly
US6174530B1 (en) 1993-05-05 2001-01-16 Gryphon Sciences Homogeneous polyoxime compositions and their preparation by parallel assembly

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0243929A2 (fr) * 1986-04-30 1987-11-04 Robin Ewart Offord Dérivés de polypeptides et de protéines et procédé pour leur préparation
EP0359428A1 (fr) * 1988-08-26 1990-03-21 Robin Ewart Offord Dérivés de protéines et leur procédé de préparation
EP0360433A1 (fr) * 1988-08-26 1990-03-28 Robin Ewart Offord Dérivés de protéines et procédé pour leur préparation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0243929A2 (fr) * 1986-04-30 1987-11-04 Robin Ewart Offord Dérivés de polypeptides et de protéines et procédé pour leur préparation
EP0359428A1 (fr) * 1988-08-26 1990-03-21 Robin Ewart Offord Dérivés de protéines et leur procédé de préparation
EP0360433A1 (fr) * 1988-08-26 1990-03-28 Robin Ewart Offord Dérivés de protéines et procédé pour leur préparation

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0525992A2 (fr) * 1991-07-01 1993-02-03 Eli Lilly And Company Groupe de conjugués de médicaments avec des anticorps
EP0525992A3 (fr) * 1991-07-01 1994-03-16 Lilly Co Eli
GR1001459B (el) * 1992-10-08 1993-12-30 Lilly Co Eli Σύμπλεγμα συζυγών φαρμάκων με αντισώματα.
AU686153B2 (en) * 1993-05-05 1998-02-05 Robin E Offord Polyoxime compounds and their preparation
WO1994025071A1 (fr) * 1993-05-05 1994-11-10 Keith Rose Composes de polyoximes et leur preparation
US6001364A (en) * 1993-05-05 1999-12-14 Gryphon Sciences Hetero-polyoxime compounds and their preparation by parallel assembly
US6174530B1 (en) 1993-05-05 2001-01-16 Gryphon Sciences Homogeneous polyoxime compositions and their preparation by parallel assembly
US6217873B1 (en) 1993-05-05 2001-04-17 Gryphon Sciences Polyoxime compounds and their preparation
US6663869B1 (en) 1993-05-05 2003-12-16 Gryphon Therapeutics, Inc. Polyoxime compounds and their preparation
FR2727117A1 (fr) * 1994-11-18 1996-05-24 Geffard Michel Utilisation de conjugues de la polylysine pour la preparation de medicaments utiles dans le traitement des maladies neurodegeneratives et des affections degeneratives a caractere autoimmun
WO1996015810A1 (fr) * 1994-11-18 1996-05-30 Michel Geffard Conjugues monofonctionnels et/ou polyfonctionnels de la polylysine
AU694825B2 (en) * 1994-11-18 1998-07-30 Michel Geffard Monofunctional and/or polyfunctional polylysine conjugates
US6114388A (en) * 1994-11-18 2000-09-05 Geffard; Michel Monofunctional and/or polyfunctional polylysine conjuages

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