WO2005065717A2 - Formulations liquides de conjugues d'anticorps - Google Patents

Formulations liquides de conjugues d'anticorps Download PDF

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Publication number
WO2005065717A2
WO2005065717A2 PCT/EP2004/014589 EP2004014589W WO2005065717A2 WO 2005065717 A2 WO2005065717 A2 WO 2005065717A2 EP 2004014589 W EP2004014589 W EP 2004014589W WO 2005065717 A2 WO2005065717 A2 WO 2005065717A2
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WIPO (PCT)
Prior art keywords
antibody
cyclodextrin
antibodies
conjugate
cancer
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PCT/EP2004/014589
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German (de)
English (en)
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WO2005065717A3 (fr
Inventor
Patrick Garidel
Karoline Bechtold-Peters
Christian Berger
Stefan Bassarab
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Boehringer Ingelheim International Gmbh
Boehringer Ingelheim Pharma Gmbh & Co. Kg
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Publication of WO2005065717A2 publication Critical patent/WO2005065717A2/fr
Publication of WO2005065717A3 publication Critical patent/WO2005065717A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • 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
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/68033—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a maytansine
    • 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
    • A61K47/69—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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

Definitions

  • the present invention relates to pharmaceutical compositions of antibodies, preferably of antibodies, which are conjugated to an effector molecule.
  • the present invention relates to stable liquid formulations of Antikö ⁇ er-DM1 complexes.
  • Recombinant antibody molecules have been known for a long time in the prior art, for example humanized mouse antibodies (Shin et al, 1989; Güssow et Seemann, 1991), bispecific antibodies (Weiner et al, 1993; Goodwin, 1989), (scFv, Johnson et Bird, 1991), complete or fragmentary immunoglobulins (Coloma et al, 1992; Nesbit et al, 1992; Barbas et al, 1992) or antibodies generated by chain shuffling (Winter et al, 1994).
  • Fully human antibodies can be produced by, for example, "phage display” methods (Aujame et al., 1997; US 5,885,793; US
  • conjugates from antibodies with effector molecules are known, such as, for example, s77 ⁇ g / ec / «antibodies / toxin fusion proteins (Chaudhary et al, 1990; Friedman et al, 1993); Conjugates from antibodies with radioactive isotopes such as 131 I, n ⁇ In, 99m Tc or radioactive compounds (Larson et al, 1991; Thomas et al, 1989; Srivastava, 1988), enzymes such as peroxidase or alkaline phosphatase (Catty et Raykundalia, 1989) , with fluorescent dyes (Johnson, 1989) or biotin molecules (Guesdon et al, 1979); Toxins (Vitetta et ⁇ /., 1991; Vitetta et Tho ⁇ e, 1991; Kreitman et ⁇ /., 1993; Theuer et al, 1993), cytostatics (Schrappe et al, 1992), prod
  • CD44 is a protein that is expressed in various isoforms on a variety of cells (see e.g. for further information WO02 / 094879A1; WO02 / 094325 A2). However, the expression of the splice variants that contain the domain v6 (CD44v6) in the extracellular region is restricted to a part of epithelial tissue.
  • CD44v6 like other variant exons (CD44v3, CD44v5, CD44v7 / v8, CD44vlO), is a tumor-associated antigen with a favorable expression pattern in human tumors and normal tissue (Heider et al., 1995; Heider et al., 1996; Dali et al., 1996; Beham-Schmid et al., 1998; Tempfer et al, 1998; Wagner et al., 1998).
  • Antibodies are known in the prior art which are specific for certain splice variants of CD44 (CD44v, CD44var) which are only expressed on a subset of epithelial cells. Examples include the CD44v6-specific antibodies (WO02 / 094879A1), in particular also as conjugates with radioactive or cytotoxic substances, and in particular as conjugates with mantansinoids (WO02 / 094325A2).
  • the present invention encompasses pharmaceutical preparations of antibodies.
  • the stability of the product, preferably of antibodies which are conjugated to an effector molecule, can be increased by adding cyclodextrins and / or by lowering them increase the pH value.
  • the present invention relates to stable liquid
  • Figure 1 Influence of the pH value on the formation of free DM1 and its derivatives in liquid formulated antibody DMl complexes. Stress stability study over 8 weeks at 40 ° C. The difference between the content of the DM1 derivatives of the 4-week value at zero is shown, as well as the difference between the content of the DM1 derivatives of the 8-week value at zero.
  • Figure 2 Influence of the addition of various cyclodextrins in the weight ratios 1, 5 and 15% by weight on the formation of free DM1 and its derivatives in liquid-formulated antibody DMl complexes. Stress stability study over 8 weeks at 40 ° C. The difference between the content of the DM1 derivatives of the 4-week value and the zero value is shown, as well as the difference between the content of the DM1 derivatives of the 8-week value and the zero value.
  • the present invention relates to pharmaceutical compositions containing stable formulations of antibody-effector molecule conjugates and methods for producing stable antibody-effector molecule conjugates.
  • the effects according to the invention were surprisingly achieved by lowering the pH of the active ingredient solution to pH 5-6, preferably pH 5.5 ⁇ 0.2.
  • these advantages can be achieved by adding at least one cyclodextrin.
  • the. Invention a pharmaceutical composition containing a conjugate of an antibody and a maytansinoid in aqueous solution, which is characterized in that the solution has a pH of 5-6.
  • a pharmaceutical composition containing a conjugate of an antibody and a maytansinoid in aqueous solution, which is characterized in that it contains a cyclodextrin.
  • a composition comprising a mixture of an antibody conjugate, at least one cyclodextrin, and water.
  • a detergent is also advantageous.
  • an amphiphile can also be used, as described in more detail below.
  • the invention relates to formulations of antibody conjugates.
  • antibody and “antibody molecule” are synonymous.
  • Antibodies can be complete immunoglobulins containing two heavy and two light chains, fragments of such immunoglobulins such as Fab, Fab ', or F (ab) 2 fragments, recombinantly produced antibody molecules such as chimeric, humanized or completely human antibodies.
  • Antibody conjugate means a complex of antibodies and effector molecules. The effector molecule is preferably linked to the antibody by a covalent bond.
  • HER2 Antikö ⁇ er such as Herceptin ® (trastuzumab, Genentech, Inc.), VEGF specific antibodies such as bevacizumab (Genentech, Inc.); Rituxan (rituximab), anti
  • An antibody conjugate according to the invention can be obtained from one of the inventive
  • Antibodies and an effector molecule are produced, optionally in combination with a connecting molecule, a so-called linker.
  • effector molecules are: toxins, such as the maytansinoids preferred below, or the DM1 mentioned by way of example, radioactive isotopes such as 131 I, 1 "in, 99m Tc, enzymes such as peroxidase or alkaline phosphatase, fluorescent dyes or biotin molecules, cytostatics (doxorubicin , taxanes such as Taxotere ®, (EP 0253 738, US 4,814,470) docetaxel, daunorubicin, dactinomycin, plicamycin ,.
  • toxins such as the maytansinoids preferred below, or the DM1 mentioned by way of example, radioactive isotopes such as 131 I, 1 "in, 99m Tc
  • enzymes such as peroxidase or alkaline phosphatase
  • fluorescent dyes or biotin molecules fluorescent dyes or biotin molecules
  • cytostatics doxorubicin , taxanes such as Taxotere ®,
  • antibody conjugates according to the invention are the antibody conjugates AS 1406 (Antisoma); the humanized antibody HMFG1, which is bound to the enzyme RNase; Zevalin (ibritumomab tiuxetan); Bexxar (Corixa, iodine 1-131 tositumomab); or the maytansinoid or DM1 conjugates mentioned below.
  • conjugates of antibodies with maytansinoids in particular DM1.
  • C242 / CanAg-specific humanized monoclonal antibody-DMl conjugate canru-zumab-DMl (Liu et al., 1996; Lambert et al., 1998); the humanized monoclonal Antibody-DMl conjugate "huN901-DMl” specific for the CD56 antigen (Chari et al., 2000); the humanized monoclonal antibody-DMl conjugate My9-6-DMl specific for the CD33 antigen (Aventis); humanized monoclonal antibody-DMl conjugates specific for the IGF-1 receptor "anti-IGFl hu MAbs" (Mo ⁇ ho-Sys / IrnmunoGen); humanized monoclonal antibody-DMl conjugate anti-EGFRvIII-DMl with target molecule EGFR (Abgenix).
  • compositions of antibody conjugates as described in WO 02/094325 are particularly preferred. These are conjugates of the formula A (LB) “wherein
  • A is an antibody molecule
  • L is a linker substance
  • Antibody molecule A has a binding specificity for CD44, preferably variant CD44. “Specific for CD44” in this context means that the antibody binds specifically to an epitope in the CD44 region.
  • the antibody according to the invention preferably binds to an amino acid sequence which is encoded by the variant exon v6 of the human CD44 gene.
  • a preferred antibody molecule binds specifically to peptides containing or consisting of the sequence SEQ ID NO: 1 of the attached sequence listing, or an allelic variant of said sequence
  • the antibody molecule according to the invention specifically binds to the amino acid sequence SEQ ID NO: 2 or SEQ ID NO: 3.
  • Such antibodies can be prepared using methods from the prior art (WO 95/33771, WO 97/21104), for example by immunizing laboratory animals with chemically synthesized peptides of the abovementioned sequences.
  • the antibody is preferably the murine monoclonal antibody VFF-18, which is deposited by the hybridoma cell line (deposited according to the Budapest Treaty on June 7, 1994, accession number DSM ACC2174 at the DSM-Deutsche Sammlung für Mikro- Organismen und Zellkulturen GmbH, Mascheroder Weg lb, D-38124 Braunschweig,
  • CDR's complementarity determining regions
  • Regions have been introduced into human light and heavy chains of respiratory globulin genes. "Complementarity determining regions” are defined analogously to Kabat et al, 1991, in connection with Chothia and Lesk, 1987.
  • Antibody A is particularly preferably an antibody comprising the light chains with the amino acid sequence SEQ ID NO: 4 and the heavy chains with the amino acid sequence SEQ ID NO: 6. Likewise particularly preferred is the antibody A comprising the light chains with the Amino acid sequence SEQ ID NO: 8 and the heavy chains with the amino acid sequence SEQ ID NO: 6.
  • the production of the antibodies according to the invention can be carried out analogously to WO02 / 094879A1 and WO02 / 094325A2, in which the nucleotide sequences SEQ ID NO: 5 and SEQ ID NO: 7 and SEQ ID NO: 9 and SEQ ID NO: 7, respectively, are introduced into an expression vector and expressed in a suitable host cell.
  • the coupling to toxins according to the invention is also described in detail in WO02 / 094325A2.
  • the linker group L advantageously contains a chemical bond which can be split off within a cell, preferably a disulfide bond.
  • Toxic is a substance that inhibits or completely prevents the function of cells and / or causes cell destruction. Toxic substances as ligands can either act cytostatically or cytotoxically and lead to cell cycle arrest or cell death. These substances can enter the cell cycle at various points intervene, for example by interaction with nucleic acid synthesis, inactivation of nucleic acids or by tubulin binding.
  • the toxic compound B is preferably a maytansinoid, ie a derivative of maytansine (CAS 35846538). B is preferably a C-3 ester of maytansinol. Maytansinoids can be coupled to antibodies have been previously described (Chari et al., 1992; Liu et al., 1996; US Patent No. 5,208,020). These maytansinoids can be used in the present invention.
  • Preferred is the toxic compound BN -deacetyl- N - (3-mercapto-l-oxopropyl) - Maytansin
  • Said maytansinoid is preferably a maytansinol derivative that is coupled to the antibody with a disulfide bridge at the C-3 position of maytansinol.
  • the antibody / maytansinoid conjugate according to the invention is particularly preferably produced from a maytansinoid of the following formula
  • Ri represents H or SP, where ⁇ represents methyl, ethyl, linear alkyl, branched alkyl, cycloalkyl, simple or substituted aryl, or heterocyclic;
  • R 2 represents Cl or H
  • R 3 represents H or CH 3 ; and m represents 1, 2, or 3.
  • the compound of formula (I) is less toxic than the compounds B, B-X or B-L "-X, which are released after intracellular cleavage.
  • Antibodies / maytansinoid conjugates linked by means of disulfide bonds are preferred which can release maytansinoid molecules.
  • Such cell-binding conjugates are produced according to methods in the prior art (US 5,208,020; WO02 / 094325A2).
  • the conjugate consists of a CD44v6-specific antibody molecule and a maytansinoid.
  • CD44v6 specific means that the antibody has a specific binding affinity for an epitope which is preferably human CD44 in a peptide having the amino acid sequence encoded by the variant exon v6 of CD44.
  • a preferred antibody molecule of the invention specifically binds to peptides or Polypeptides comprising or precisely with the amino acid sequence SEQ ID NO: 1 or an allelic variant of said sequence.
  • Said antibody molecule preferably binds specifically to an epitope in this sequence.
  • the antibody molecule according to the invention specifically binds to the amino acid sequence SEQ ID NO: 2 or SEQ ID NO : 3.
  • the antibody molecule according to the invention in said conjugate is preferably the monoclonal antibody VFF-18 (DSM ACC2174) or a recombinant antibody with the complement binding regions (CDRs) of VFF-18.
  • the antibody molecule according to the invention particularly preferably contains the light chains with the amino acid sequence SEQ ID NO: 4 and the heavy chains with the amino acid sequence SEQ ID NO: 6.
  • the antibody molecule according to the invention particularly preferably contains the light chains with the amino acid sequence SEQ ID NO: 8 and heavy chains with the amino acid sequence SEQ ID NO: 6.
  • the maytansinoid is preferably coupled to the antibody via a disulfide bond and has the formula
  • the antibody molecule can be modified by a suitable linker, as shown in WO02 / 094325A2.
  • the maytansinoid to the antibody molecule is preferably by an S-CH 2 CH 2 -CO-, an -S-CH 2 CH 2 CH 2 CH 2 -CO-, or an -S-CH (CH 3 ) CH 2 CH 2 -CO- bound.
  • the sulfur atom in such a linker group forms the disulfide bond with the maytansinoid, whereas the carbonyl function can bind to an amine function, which can be present in an amino acid side chain.
  • a particularly preferred embodiment is a conjugate of a CD44v6-specific antibody molecule and a maytansinoid, in which the antibody molecule contains the light chains with the amino acid sequence SEQ ID NO: 4 and the heavy chains with the amino acid sequence SEQ ID NO: 6, and in which Maytansinoid the formula IV at and is coupled to the Antikö ⁇ er via a disulfide bond.
  • the linker group is preferably -S-CH 2 CH CH 2 CH 2 -CO- or -S- CH (CH 3 ) CH CH 2 -CO-, and the number of bound maytansinoid residues per antibody molecule is 3 to 4.
  • the concentration of the antibody conjugate complex according to the invention in solution is between 0.01 and 40 mg / ml, preferably between 0.1-20 mg / ml, in particular between 0.1-10 mg / ml. A concentration of 2-5 mg / ml is particularly suitable.
  • the cyclodextrins (CD) to be used according to the invention are cyclic oligosaccharides or cyclic polymers, the ring systems of which consist of six, seven or eight ⁇ -1,4-linked glucose units, and corresponding to their number of monomers as ⁇ -, ⁇ - or ⁇ -cyclodextrins.
  • Cyclodextrins are known to form inclusion complexes with various biomolecules, such as fatty acids or amino acids, or to incorporate them until they are saturated. can close.
  • the various available cyclodextrins differ primarily in their different ring sizes ( ⁇ -cyclodextrins, ⁇ -cyclodextrins, ⁇ -cyclodextrins).
  • Suitable cyclodextrins include, for example, substituted ⁇ -cyclodextrins (consisting of 7 glucopyranose units), hydroxypropyl- ⁇ -cyclodextrin (HP-ß-CD), sulfobutyl ether- ⁇ -cyclodextrin (SBE-ß-CD), ⁇ -cyclodextrin (consisting of 8 Glucopyranose units) and hydroxypropyl- ⁇ -cyclodextrin (HP- ⁇ -CD).
  • SAE-CD sulfoalkyl ether cyclodextrins
  • n 4, 5 or 6 - the radicals R 1, R 2 , R 3 , P, R 5 , R ⁇ , R 7 , R 8 and R each, independently, -O- or a -O- (C 2 - C 6 alkylene) -SO 3 group, in which at least one of the radicals Rj and R is independently a -O- (C 2 -C 6 alkylene) -SO 3 - group, preferably an -O- (CH 2 ) m SO Group in which m is 4 (for example -OCH 2 CH 2 CH 2 SO 3 - or -OCH 2 CH 2 CH 2 CH 2 SO 3 -); and
  • Si, S 2 , S 3 , S 4 , S 5 , S 6 , S 7 , S 8 and S are each independently a pharmaceutically acceptable cation comprising, for example, H +, alkali metals (for example Li + , Na + , K + ), Alkaline earth metals (eg, approx. "1 ⁇ , Mg " “ “ ), ammonium ions and amine cations such as the cations of (C1-C6) alkylamines, piperidine, pyrazine, (C1-C6) alkanolamine and (C4-C8) -
  • cyclodextrins are in particular gamma-cyclodextrin ( ⁇ -CD), hydroxypropyl-gamma-cyclodextrin (HP- ⁇ -CD), hydroxypropyl-beta-cyclodextrin (HP-ß-CD) or sulfobutyl ether-beta-cyclodextrin (SBE-ß- CD).
  • ⁇ -CD gamma-cyclodextrin
  • HP- ⁇ -CD hydroxypropyl-gamma-cyclodextrin
  • HP-ß-CD hydroxypropyl-beta-cyclodextrin
  • SBE-ß- CD sulfobutyl ether-beta-cyclodextrin
  • the cyclodextrin according to the invention is particularly preferably a cyclodextrin selected from the following table.
  • Table 1 Cyclodextrin abbreviation rest n cc-cyclodextrin ⁇ -CD H 4 ß-cyclodextrin ß-CD H 5 ⁇ -cyclodextrin ⁇ -CD H 6 carboxymethyl-ß-cyclodextrin CM-ß-CD CH 2 CO 2 H or H 5 carboxymethyl -ethyl-ß- CME-ß-CD CH 2 CO 2 H, CH 2 CH 3 5 cyclodextrin or H diethyl-ß-cyclodextrin DE-ß-CD CH 2 CH 3 or H 5 dimethyl-ß-cyclodextrin DM-ß- CD CH 3 or H 5 methyl-ß-cyclodextrin M-ß-CD CH 3 or H 5 random methyl-ß-RM-ß-CD CH 3 or H 5 cyclodextrin glucosyl-
  • a hydroxypropyl- ⁇ -cyclodextrin which can advantageously be used for the present invention and has a molar degree of substitution of 0.5 to 0.7 is commercially available, for example, from Wacker-Chemie GmbH, D-Burghausen, under the name "CAVASOL® W8 HP Pharma” Sulfobutyl ether beta-cyclodextrin (SBE-ß-CD), also commercially available under the name Captisol (company CyDex, USA), can also be used very well.
  • Cyclodextrin can be used in the formulations according to the invention in percentages by weight per volume (w%) from 0.001 to about 40 w%, preferably 0.1-20 w%, particularly preferably 0.1-10 w% or 1-5 w%.
  • the cyclodextrin according to the invention is very particularly preferably present in an amount of about 1, 5 or 15% by weight.
  • SBE-ß-CD is particularly preferably present in an amount of approximately 1, 5 or 15% by weight.
  • Another embodiment of the invention relates to the complexation of the antibody conjugate with cyclodextrins and hydroxy acids.
  • cyclodextrin can be reduced by the formation of a ternary complex consisting of the anti-body conjugate, the respective cyclodextrin and a hydroxy acid.
  • Suitable cyclodextrins include, for example, HP-ß-CD, SBE-ß-CD, ⁇ -CD and HP- ⁇ -CD.
  • the pharmaceutical compositions according to the invention intended for parenteral use can therefore contain hydroxy acids such as malic acid, lactic acid, tartaric acid, succinic acid or citric acid.
  • the molar ratio of active ingredient to cyclodextrin is between 1: 1 and 1: 3300.
  • the molar ratio of active ingredient to cyclodextrin is according to the invention as mentioned above.
  • Suitable amphiphiles that can be used instead of the cyclodextrins are, for example, choline derivatives (C6-C20), naturally occurring cholines (egg and soy lecithin), for example such as dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), dioleoylphosphatidylcholine (DOP) Ethanolamine derivatives (C6 to C20) naturally occurring ethanolamines (egg and soy
  • DMPC dimyristoylphosphatidylcholine
  • DPPC dipalmitoylphosphatidylcholine
  • DOP dioleoylphosphatidylcholine
  • Ethanolamines for example, such as dimyristoylphosphatidylethanolamine (DMPE), dipalmitoylphosphatidylethanolamine (DPPE), dioleoylphosphatidylethanolamine (DOPE), DOPE being particularly preferred.
  • DMPE dimyristoylphosphatidylethanolamine
  • DPPE dipalmitoylphosphatidylethanolamine
  • DOPE dioleoylphosphatidylethanolamine
  • DOPE dioleoylphosphatidylethanolamine
  • the corresponding glycerol derivatives (C6-C20) or phosphatidic acids (C6-C20) with saturated and unsaturated fatty acids can be used as further phospholipids.
  • Polyoxyethylene sorbitan monolaurate preferably n approx. 20, 60 or 80; polysorbate 20, 60 or 80, Tween 20 ® , Tween 60 ® , Tween 80 ® ) or also poloxamers (Pluronic ® ) in the concentration range of 0.01-5 percent by weight, preferably 0.01-0.1 percent by weight, particularly preferably 0.01-0.05 percent by weight can be used.
  • Preferred detergent concentrations are 0.01 +/- 0.01 percent by weight per 1 mg / ml antibody conjugate, for example 0, 0.01 or 0.02 percent by weight per 1 mg / ml antibody conjugate, particularly preferably 0.01 percent by weight per 1 mg / ml
  • the concentration is 0.01-0.05 weight percent polyoxyethylene sorbitan monolaurate (0.01, 0.02, 0.03, 0.04 or 0.05 weight percent).
  • compositions according to the invention also contain customary auxiliaries and excipients such as, for example, the isotonants glucose, mannitol or sodium chloride.
  • Formulations according to the invention can also contain a buffer, for example sodium acetate or sodium acetate trihydrate in combination with acetic acid, or a citric acid / phosphate buffer consisting, for example, of citric acid and disodium hydrogen phosphate or disodium hydrogen phosphate dihydrate.
  • a buffer for example sodium acetate or sodium acetate trihydrate in combination with acetic acid
  • a citric acid / phosphate buffer consisting, for example, of citric acid and disodium hydrogen phosphate or disodium hydrogen phosphate dihydrate.
  • Other buffer systems can also be used and are described below.
  • a succinate buffer eg using Na 2 succinate x 6 H 2 O
  • a concentration of 5-20 mmol / l has proven to be particularly suitable, preferably pH 5-6, in particular 5.5 ⁇ 0.2.
  • a Na K phosphate buffer in a concentration of 5-20 mmol / 1 at pH 6.5 can be used.
  • Water for injection is usually used as the solvent for the preparation of the solution.
  • the preparations can be filled into standard ampoules and stored at 2-8 ° C.
  • the pH can be lowered with the following agents: HC1, H 3 PO 4 and other derivatives of phosphoric acid, HNO 3 , H 2 SO 4 , CH 3 COOH, or all pharmaceutically acceptable acids known for this purpose, or selected by selection of suitable buffer systems from the group of buffer systems based on monobasic acids: acetic, benzoic, gluconic, glycerol, lactate; dibasic acids: aconite, adipine, Ascorbic, carbon, glutamine, apple, amber, tartrate; polybasic acids: citrate, phosphate, or bases: ammonia, diethanolamine, glycine, triethanolamine,
  • Tromethamine and its salts can be adjusted. If the pH value needs to be increased due to the pH being too low, the relevant known substances or solutions thereof, such as NaOH, KOH, ammonia solution, etc. come into question.
  • the pharmaceutical composition can also contain salts or salt solutions, in particular pharmaceutically acceptable salts, such as, for example, inorganic salts such as chlorides, sulfates, phosphates, di-phosphates, hydrobromides and / or nitrate salts.
  • pharmaceutically acceptable salts such as, for example, inorganic salts such as chlorides, sulfates, phosphates, di-phosphates, hydrobromides and / or nitrate salts.
  • the lipid suspension can also contain organic salts, e.g.
  • composition can also contain arginine, glycine or other amino acids.
  • polymers optionally contained in the pharmaceutical composition according to the invention include polyvinylpyrrolidones, derivatized celluloses such as e.g. Hydroxymethyl, hydroxyethyl or hydroxypropyl ethyl cellulose, polymeric sugars such as e.g. Ficoll or dextran, starch such as Hydroxyethyl or hydroxypropyl starch, dextrins such as e.g.
  • Cyclodextrins (2-hydroxypropyl-ß-cyclodextrin, sulfobutyl ether-ß-cyclodextrin), polyethylenes, glycols, chitosan, collagen, hyaluronic acid, polyacrylates, polyvinyl alcohols and / or pectins.
  • sugars optionally contained in the pharmaceutical composition according to the invention are mono-, di-, oligo- or polysaccharides or a combination thereof.
  • simple sugar are preferably the aldohexoses, ketohexoses and their derivatives and optical isomers, fructose, maltose, galactose, glucose, D-mannose, sorbose, D (+) - glucose, D (+) - mannose, D (+) - galactose , D (-) - fructose, D (+) - sorbose, and the like.
  • Double sugars are, for example, lactose, sucrose, sucrose, trehalose or cellobiose. Suitable as multiple sugar or polysaccharides NEN in particular raffinose, melezitose, dextrin, or starch: •
  • compositions according to the invention can be used for parenteral systemic, e.g. intravenous, intravascular, intramuscular, intraarterial, intraperitoneal, or intrathecal application can be used.
  • parenteral systemic e.g. intravenous, intravascular, intramuscular, intraarterial, intraperitoneal, or intrathecal application can be used.
  • compositions according to the invention can be administered subcutaneously, intracutaneously, intracardially, intralobal, intramedullary, intrapulmonary or directly in or near the organ to be treated (connective tissue, bone, muscle, nerve or epithelial tissue).
  • the invention relates to a treatment method for cancer, in that a pharmaceutical preparation according to the invention is administered to a patient in need in a therapeutically effective amount of the pharmaceutical preparation according to the invention.
  • the preparation contains an antibody which is specific for the antigen CD44v6 and is conjugated with a maytansinoid, in particular in the preferred embodiments described above.
  • the cancer is preferably squamous cell carcinoma (e.g.
  • SCC Head and Neck Squameous Cell Carcinoma
  • esophagus SCC esophagus SCC
  • lung SCC skin SCC
  • breast adenocarcinoma esophagus SCC
  • lung SCC skin SCC
  • breast adenocarcinoma esophagus SCC
  • lung adenocarcinoma cervix SCC
  • pancreatic adenocarcinoma pancreatic adenocarcinoma
  • colon adenocarcinoma gastric adenocarcinoma
  • the pharmaceutical preparation according to the invention is administered, for example, according to the following protocols, for example weekly for 1 to 6 weeks as an iv bolus or continuous infusion over 5 days.
  • the bolus dose can be administered in 50 to 100 ml of physiological saline, to which 5 to 10 ml of human serum albumin are added.
  • Continuous infusions can be administered in 250 to 500 ml of physiological saline per 24 hours, to which 25 to 50 ml of human serum albumin has been added.
  • the antibody conjugate dose is generally 10 mg to 400 mg / m 2 body surface area per application. The dose must be high enough on the one hand to be effective, but also below the so-called "dose limiting toxicity" (DLT).
  • DLT dose limiting toxicity
  • MTD maximum tolerated dose
  • the administration can take place in 5 daily doses followed by a break of several weeks, in which case the expected MTD is lower than 100 mg / m 2
  • the pharmaceutical preparation according to the invention can be administered as a single iv infusion at a rate of 3 mg / min every 21 days, up to 7 treatment cycles are used, and the doses used can also vary outside of the above Move areas when the clinical situation requires it.
  • a single dose can also be a higher dose than 400 mg / m, or the weekly dose higher than 200 mg / m 2 .
  • An embodiment of a parenteral composition of antibody conjugate according to the invention contains the active substance in doses of 1 mg / kg body weight to 40 mg / kg body weight daily, preferably in the range 3-15 mg / kg body weight. Dosages expressed in [mg / m 2 ] are also preferred: 10 [mg / m 2 ] to 200 [mg / m 2 ]; particularly preferably 20 to 100 [mg / m 2 ], very particularly preferably 10, 20, 40 or 50 mg / m 2 .
  • the application is carried out in a preferred embodiment via a continuous infusion over 0.5 to 24 hours or possibly over several days in order to maintain a steady-state plasma level.
  • a preferred embodiment of the invention is therefore the use of a formulation or pharmaceutical composition according to the invention for the production of a medicament for the treatment of cancer (for definitions see above).
  • the present preferred methods for producing stable Antikö ⁇ er- Maytansinoid or -DM1 complexes lead to a reduction in the formation of free Maytansinoid or DM1 and their derivatives during storage of the product. This enables the runtime of such a preparation (stored at 2-8 ° C) to be increased compared to conventional formulations.
  • a preferred formulation contains an antibody-DMl conjugate in which the antibody contains the light chains with the amino acid sequence SEQ ED NO: 4 or SEQ ID NO: 8 and the heavy chains with the amino acid sequence SEQ ID NO: 6, a phosphate buffer, Common salt, as well as Tween 20.
  • Particularly preferred is such a formulation containing 1-5 mg / ml conjugate, a phosphate buffer made of 1-1.9 mmol / 1 NaH 2 PO 4 x H 2 O; 4-5 mmol / 1 KH 2 PO 4 ; 3.5-4.5 mmol / 1 Na 2 HPO 4 , 30-100 mmol / 1 NaCl; 0.01 w% Tween 20 per mg / ml antibody conjugate, (ie 0.02 weight percent if the conjugate is present in a concentration of 2 mg / ml, 0.04 weight percent for a conjugate concentration of 4 mg / ml), at a pH from 5-6.
  • the pH is particularly preferred 5.5.
  • Another preferred formulation contains 1-2.5 mg / ml, preferably 1.8 to 2 mg / ml of a conjugate as described above, a phosphate buffer of approx. 1.45 nmol / 1 NaH 2 PO 4 x H 2 O, approx 4.19 mmol / 1 KH 2 PO 4 , approx. 3.91 mmol / 1 Na 2 HPO 4 , and approx. 60 mmol / 1 NaCl, as well as 0.02 w% Tween 20 ® at a pH of 5.5 ,
  • the preparation contains 4 mg / ml of a conjugate as described above, a phosphate buffer of approx. 1.45 mmol / 1 NaH 2 PO 4 ⁇ H 2 O, approx. 4.19 mmol / 1 KH 2 PO 4 , approx. 3.91 mmol / 1 Na 2 HPO 4 , and 0.04 w% Tween 20 ® at a pH of 5.5.
  • a phosphate buffer of approx. 1.45 mmol / 1 NaH 2 PO 4 ⁇ H 2 O, approx. 4.19 mmol / 1 KH 2 PO 4 , approx. 3.91 mmol / 1 Na 2 HPO 4 , and 0.04 w% Tween 20 ® at a pH of 5.5.
  • Another preferred formulation contains 1 mmol / 1 succinate buffer, for example
  • Further optional components of this particularly preferred pharmaceutical preparation are NaCl in the range from 30-100 mmol of 1 NaCl, preferably 60 mmol / 1 NaCl, and / or Tween 20 in the range of 0.01-0.05 w% Tween 20, preferably Tween 20 at 0.01, 0.02, 0.03, 0.04 or 0.05 percent by weight or 0.01 +/- 0.01 percent by weight of Tween 20 per 1 mg / ml antibody conjugate, i.e. 0, 0.01 or 0 , 02 percent by weight per mg / ml antibody conjugate, particularly preferably 0.01 percent by weight per 1 mg / ml antibody conjugate.
  • the pH is adjusted to 5-6, particularly preferably 5.5.
  • Another preferred formulation contains 5-20 mrnol / 1 succinate, examples play Natriumsuccinatpuffer, 2-5 mg / ml Antikö ⁇ erkonjugat, and 0.02 to 0.05 percent by weight Tween ® 20, an embodiment containing 4 mg / ml of conjugate, 10 mmol / 1 succinate (preferably the disodium salt), 0.4 g / 1 Tween ® (0.04% w) 20.
  • the Antikö ⁇ erkonjugat is preferably a conjugate of an CD44v6-specific antibody as described above and the maytansinoid DM1.
  • the pH is adjusted to 5-6 before, particularly preferably 5.5.
  • the excipients used meet the requirements for pharmaceutically approved excipients.
  • the auxiliaries used are summarized in Table 2.
  • WFI is water for injections.
  • HP hydroxypropyl SBE: sulfobutyl ether
  • CD cyclodextrin
  • the antibody-DMl complex used is a conjugate of a CD44v6-specific antibody molecule and the maytansinoid DM1, in which the antibody molecule contains the light chains with the amino acid sequence SEQ ID NO: 4 and the heavy chains with the amino acid sequence SEQ ID NO: 6, and in which the maytansinoid has the formula IV and is coupled to the antibody via a disulfide bond.
  • the starting solution is buffered in the new solutions to be tested (according to standard methods) or the appropriate auxiliary substances are added together.
  • the protein concentration can be increased to 4-5 mg / ml. The exact composition of these formulations is described in the examples.
  • the pH value, osmolality, appearance, color and clarity (AFK) are determined in accordance with the applicable PharmEu and USP regulations.
  • RP-HPLC reversed phase high performance liquid chromatography
  • Crimp cap Kombika / Alu-KU (West company, DE)
  • Crimp cap Kombika / Alu-KU (West company, DE)
  • the various formulations to be tested are sterile filtered through a sterile filter (0.22 micrometer, Millipore) and filled into the vials.
  • the filling volume is 20 ml for the liquid formulations, 10 ml for the lyophilization formulation.
  • the filled 10 ml lyophilization formulation is then freeze-dried.
  • the vials are closed with a stopper and crimp cap and stored overhead.
  • the storage temperature for the stress stability studies is 40 ° C.
  • the sampling times are: 0, 4 and 8 weeks.
  • Example 1 Influence of pH and lyophilization on the stability of antibody-DMl complexes
  • the protein concentration (antibody-DMl complex) is 1.8 mg / ml for all liquid formulations and 4.65 mg / ml for the lyophilization formulations.
  • the comparison formulation (Table 3) consists of the following auxiliaries:
  • the pH of the various formulations to be investigated was adjusted to pH 6.0 and 5.5 using 1 N phosphoric acid based on the comparison formulation (Table 3). 20 ml of the respective formulation were filled into a 20 R vial and the vials were stored upside down at 40 ° C.
  • the lyophilization formulation consists of (Table 4): Table 4:
  • Figure 1 shows the difference between free DM1 content. The difference of free DM1 between the zero value and the 4-week value is shown, and the difference between the zero value and the 8-week value.
  • the monomer content is 2-6% higher for pH 5.5 than for formulations at pH 6.5.
  • the pH reduction also has an advantageous influence on the AFK (appearance, color clarity) parameter (see Table 4). Over a period of 8 weeks (stored at 40 ° C) the monomer content decreases by 12% (formulation at pH 6.5).
  • Example 2 Influence of cyclodextrins on the stability of antibody-DMl complexes
  • the Gnmd formulation consists of the following auxiliaries (Table 6):
  • Figure 2 shows that the free DM1 content is lowest for Formulations D (Captisol).
  • the monomer contents of the various cyclodextrin formulations are comparable to the comparison formulation at pH 6.5 (Table 3).
  • the formulations with cyclodextrins, in particular captisol stabilize the antibody-DMl complex.
  • the term of the product can thus be extended compared to the comparison formulation.
  • Goldmacher et al. J Immunol 135: 3648-3651, 1985.
  • Goldmacher et al. J Cell Biol 102: 1312-1319, 1986.
  • glycoprotein CD44 confers metastatic potential to rat carcinoma cells.
  • Genomic structure of DNA encoding the lymphocyte homing receptor CD44 reveals at least 12 alternatively spliced exons. Proc. Natl. Acad. Be. U.S.A. 89: 12160-12164 (1992)
  • Vitetta E S Tho ⁇ e P E. Immunotoxins. In: DeVita V T, Hellman S, Rosenberg S A (ed.). Biologic therapy of cancer. JB Lippincott Comp., Philadelphia, 482-495 (1991 Vitetta ES, Stone M, Amlot P, Fay J, May R, Till M, Newman J, Clark P, Collins R, Cunningham D, Ghetie V, Uhr JW, Tho ⁇ e P E. Phase I immunotoxin trial in patients with B-cell lymphoma Cancer Res. 51: 4052-4058 (1991)

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Abstract

La présente invention concerne des compositions pharmaceutiques liquides d'anticorps, de préférence d'anticorps qui sont conjugués à un maytansinoïde. L'invention concerne notamment les formulations stables de complexes d'anticorps-DM1.
PCT/EP2004/014589 2003-12-24 2004-12-22 Formulations liquides de conjugues d'anticorps WO2005065717A2 (fr)

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WO2005065709A2 (fr) * 2003-12-24 2005-07-21 Boehringer Ingelheim International Gmbh Formulation lyophilisee de conjugues d'anticorps
EP2358395A1 (fr) * 2008-11-17 2011-08-24 F. Hoffmann-La Roche AG Procédé et formulation pour réduire l'agrégation d'une macromolécule dans des conditions physiologiques
US9114179B2 (en) 2005-08-03 2015-08-25 Immunogen, Inc. Immunoconjugate formulations
US9610361B2 (en) 2013-03-13 2017-04-04 Seattle Genetics, Inc. Cyclodextrin and antibody-drug conjugate formulations
US20170189536A1 (en) * 2015-12-30 2017-07-06 Genentech, Inc. Formulations with reduced degradation of polysorbate

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US8883979B2 (en) 2012-08-31 2014-11-11 Bayer Healthcare Llc Anti-prolactin receptor antibody formulations

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005065709A3 (fr) * 2003-12-24 2006-08-24 Boehringer Ingelheim Int Formulation lyophilisee de conjugues d'anticorps
WO2005065709A2 (fr) * 2003-12-24 2005-07-21 Boehringer Ingelheim International Gmbh Formulation lyophilisee de conjugues d'anticorps
US9114179B2 (en) 2005-08-03 2015-08-25 Immunogen, Inc. Immunoconjugate formulations
EP2358395A1 (fr) * 2008-11-17 2011-08-24 F. Hoffmann-La Roche AG Procédé et formulation pour réduire l'agrégation d'une macromolécule dans des conditions physiologiques
JP2012509269A (ja) * 2008-11-17 2012-04-19 ジェネンテック， インコーポレイテッド 生理的条件下での高分子の凝集を低減するための方法及び製剤
EP2358395A4 (fr) * 2008-11-17 2013-11-20 Hoffmann La Roche Procédé et formulation pour réduire l'agrégation d'une macromolécule dans des conditions physiologiques
US9987374B2 (en) 2013-03-13 2018-06-05 Seattle Genetics, Inc. Cyclodextrin and antibody-drug conjugate formulations
US9610361B2 (en) 2013-03-13 2017-04-04 Seattle Genetics, Inc. Cyclodextrin and antibody-drug conjugate formulations
US10391181B2 (en) 2013-03-13 2019-08-27 Seattle Genetics, Inc. Cyclodextrin and antibody-drug conjugate formulations
WO2017117311A1 (fr) * 2015-12-30 2017-07-06 Genentech, Inc. Formulations présentant une moindre dégradation des polysorbates
CN108472379A (zh) * 2015-12-30 2018-08-31 豪夫迈·罗氏有限公司 减少聚山梨酯降解的制剂
US20170189536A1 (en) * 2015-12-30 2017-07-06 Genentech, Inc. Formulations with reduced degradation of polysorbate
US10525137B2 (en) 2015-12-30 2020-01-07 Genentech, Inc. Formulations with reduced degradation of polysorbate
US10933141B2 (en) 2015-12-30 2021-03-02 Genentech, Inc. Formulations with reduced degradation of polysorbate
CN108472379B (zh) * 2015-12-30 2022-06-21 豪夫迈·罗氏有限公司 减少聚山梨酯降解的制剂
IL259646B2 (en) * 2015-12-30 2023-06-01 Genentech Inc Formulations with reduced polysorbate dissolution

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