WO1996040261A1 - Methods for the preparation of monomeric calicheamicin derivative/carrier conjugates - Google Patents

Methods for the preparation of monomeric calicheamicin derivative/carrier conjugates Download PDF

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WO1996040261A1
WO1996040261A1 PCT/US1996/006738 US9606738W WO9640261A1 WO 1996040261 A1 WO1996040261 A1 WO 1996040261A1 US 9606738 W US9606738 W US 9606738W WO 9640261 A1 WO9640261 A1 WO 9640261A1
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coor
conhr
radical
bond
trivalent
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PCT/US1996/006738
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English (en)
French (fr)
Inventor
Martin Paul Kunstmann
Irwin Jack Hollander
Philip Hamann
Arthur Kunz
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American Cyanamid Company
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Priority to MX9709316A priority Critical patent/MX9709316A/es
Priority to AU57423/96A priority patent/AU703862B2/en
Priority to EP96915718A priority patent/EP0837698B1/en
Priority to JP9500547A priority patent/JPH11508232A/ja
Priority to DE69614551T priority patent/DE69614551T2/de
Priority to HK98119234.9A priority patent/HK1016871B/xx
Priority to HU9901351A priority patent/HU221246B1/hu
Priority to KR1019970708934A priority patent/KR100499648B1/ko
Priority to DK96915718T priority patent/DK0837698T3/da
Priority to AT96915718T priority patent/ATE204180T1/de
Application filed by American Cyanamid Company filed Critical American Cyanamid Company
Priority to BR9608564A priority patent/BR9608564A/pt
Priority to NZ307926A priority patent/NZ307926A/en
Publication of WO1996040261A1 publication Critical patent/WO1996040261A1/en
Priority to BG102100A priority patent/BG63492B1/bg
Priority to NO19975706A priority patent/NO324609B1/no
Priority to GR20010401797T priority patent/GR3036930T3/el

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    • 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
    • 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
    • A61K47/6835—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 the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6881—Cluster-antibody conjugates, i.e. the modifying agent consists of a plurality of antibodies covalently linked to each other or of different antigen-binding fragments covalently linked to each other
    • 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
    • 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
    • A61K47/6807—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug or compound being a sugar, nucleoside, nucleotide, nucleic acid, e.g. RNA antisense
    • A61K47/6809—Antibiotics, e.g. antitumor antibiotics anthracyclins, adriamycin, doxorubicin or daunomycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to methods for producing monomeric calicheamicin derivative/carrier conjugates.
  • the potent family of antibacterial and antitumor agents known collectively as the calicheamicins or the LL-E33288 complex, are described in U.S. Pat. No..4,970, 198 (1990).
  • the most potent of the agents is designated ⁇ ,', which is herein referenced simply as gamma.
  • These compounds contain a methyltrisulfide that can be reacted with appropriate thiols to form disulfides, at the same time introducing a functional group such as a hydrazide or other functional group that is useful in attaching a calicheamicin derivative to a carrier. Examples of this reaction with the calicheamicins are given in U.S. Pat. No.
  • the amount of calicheamicin loaded on the carrier protein (the drug loading), the amount of aggregate that is formed in the conjugation reaction, and the yield of final purified monomeric conjugate that can be obtained are therefore all related. A compromise must therefore be made between higher drug loadings and the yield of the final monomer by adjusting the amount of the reactive calicheamicin derivative that is added to the conjugation reaction.
  • the tendency for calicheamicin conjugates to aggregate is especially problematic when the conjugation reactions are performed with the linkers described in European Patent Application No. 0689845. In this case, a large percentage of the conjugates produced are in an aggregated form that is quite difficult to purify further for therapeutic administration. For some carrier proteins, conjugates with even modest loadings are virtually impossible to make except on small scale.
  • the calicheamicin derivative/carrier conjugates of the present invention have the formula
  • Pr is a proteinaceous carrier
  • X is a linker that comprises a product of any reactive group that can react with a proteinaceous carrier
  • W is the calicheamicin radical formed by removal of the naturally occuring methyl trisulfide group; and m is a number from 0.5 to 15.
  • a method of the present invention for preparing monomeric calicheamicin derivative/carrier conjugates with higher drug loading/yield and decreased aggregation comprises the steps of:
  • An alternative embodiment of the method of the present invention for preparing monomeric calicheamicin derivative/carrier conjugates with higher drug loading/yield and decreased aggregation comprises the steps of:
  • the conjugates of the present invention include a therapeutic agent derivatized with a linker that includes any reactive group that reacts with a proteinaceous targeting carrier.
  • a linker that includes any reactive group that reacts with a proteinaceous targeting carrier.
  • the use of particular cosolvents and additives induces the monomeric form as opposed to the aggregate form of these conjugates and allows for higher drug loading/yield without excessive aggregation.
  • the monomeric form has therapeutic value.
  • the carriers of the present invention preferably are proteinaceous carriers. Included as carrier molecules are growth factors, antibodies, antibody fragments, and their genetically or enzymatically engineered counterparts, hereinafter referred to singularly or as a group as carriers.
  • the essential property of the carrier is its ability to recognize an antigen or receptor associated with undesired cells. Examples of carriers are given in U.S. Pat. No. 5,053,394, and such carriers are also appropriate in the present invention.
  • Preferred carriers for use in the present invention are human or humanized antibodies.
  • carriers which are exemplified herein are the antibodies P67.6, A33, CT-M-01 (also known as 7F11C7) and the "anti- Tac" antibody of Waldman. These antibodies are used herein in two forms: a murine form, designated by an “m” (e.g., m-P67.6), and a genetically engineered, humanized form, designated by an "h” (e.g., h-P67.6) whenever appropriate.
  • m e.g., m-P67.6
  • h e.g., h-P67.6
  • m-P67.6 is disclosed in I.D. Bernstein et al.. J. Clin. Invest. 79:1153 (1987) and I.D. Bernstein et al., ⁇ Immunol. 122:867-881 (1992) and recognizes the CD33 antigen which is prevalent on certain human myeloid tumors, especially acute non- lymphocytic leukemia (ANLL).
  • ANLL acute non- lymphocytic leukemia
  • Another antibody that can be used is MOPC-
  • the antibody m-CT-M-01 is disclosed in European Patent Application No. 86401482.4/0208615 and recognizes the polyepithelial mucin (PEM) antigen present on many human solid tumors, particularly breast, lung, and ovarian tumors.
  • the humanized version of this antibody, h-CT-M-01 is described in PCT Publication No. WO 93/06231 (1993).
  • the antibody m-A33 is disclosed in U.S. Patent Nos. 5,160,723 and 5,431,897 and is a murine antibody which recognizes a glycoprotein antigen present on colon cancer cells.
  • the humanized version of this antibody, h-A33 is disclosed in PCT Patent Publication No. WO94/13805 (June 23, 1994).
  • Anti-Tac is disclosed in T.A. Waldman et al.. J. Immunol. 126:1393 (1981), and is a murine antibody reactive with the IL-2 receptor that is found on activated and functionally mature T cells, including abnormally activated leukemia cells.
  • the therapeutic agents suitable for use in the present invention are cytotoxic antibiotics that bind to and disrupt DNA.
  • Preferred cytotoxic agents are the calicheamicins which are methyl trisulfide antitumor antibiotics.
  • Examples of calicheamicins suitable for use in the present invention are disclosed, for example, in U.S. Pat. No. 5,053,394. See also, U.S. Patent Nos. 4,671,958; 4,970,198; 5,037,651; and 5,079,233.
  • Preferred calicheamicins are gamma calicheamicin of N-acetyl gamma calicheamicins. The structure of N-acetyl gamma-calicheamicin in a conjugated form is illustrated below.
  • the conjugates of the present invention have the formula
  • Pr is a proteinaceous carrier
  • X is a linker that comprises a product of any reactive group that can react with a proteinaceous carrier
  • W is the calicheamicin radical formed by removal of the naturally occuring methyl trisulfide group; and m is a number from 0.5 to 15.
  • X has the formula Z-Sp wherein:
  • Sp is a straight or branched-chain divalent or trivalent (C,-C 18 ) radical, divalent or trivalent aryl or heteroaryl radical, divalent or trivalent (C 3 -C 18 ) cycloalkyi or heterocycloalkyi radical, divalent or trivalent aryl- or heteroaryl-aryl (C C 18 ) radical, divalent or trivalent cycloalkyi- or heterocycloalkyl-alkyl (C C 18 ) radical or divalent or trivalent (C 2 -C 18 ) unsaturated alkyl radical, wherein heteroaryl is preferably furyl, thienyl, N- methylpyrrolyl, pyridinyl, N-methylimidazolyl, oxazolyl, pyrimidinyl, quinolyl, isoquinolyl, N-methylcarbazoyl, aminocourmarinyl, or phenazinyl and wherein if Sp is a trivalent radical, Sp can be additionally substitute
  • Alk' and Alk 2 are independently a bond or branched or unbranched (C,-C 10 ) alkylene chain;
  • Ar is 1,2-, 1,3-, or 1 ,4-phenylene optionally substituted with one, two, or three groups of (C r C 6 ) alkyl, (C,-C 3 ) alkoxy, (C ⁇ C thioalkoxy, halogen, nitro, -COOR', -CONHR', -0(CH 2 ) n COOR', -S(CH 2 ) n COOR', -O(CH 2 ) n CONHR', or -S(CH 2 ) n CONHR' wherein n and R' are as hereinbefore defined or a 1 ,2-, 1 ,3-, 1,4-, 1 ,5-, 1 ,6-, 1,7-, 1 ,8-, 2,3-, 2,6-, or 2,7-naphthylidene or
  • each naphthylidene or phenothiazine optionally substituted with one, two, three, or four groups of (C,- ⁇ ) alkyl, (C C 5 ) alkoxy, (C r C 4 ) thioalkoxy, halogen, nitro, -COOR', -CONHR', -0(CH 2 ) n COOR', -S(CH 2 ) n COOR', or -S(CH 2 ) ⁇ CONHR' wherein n and R' are as defined above, with the proviso that when Ar is phenothiazine, Sp 1 is a bond only connected to nitrogen;
  • Sp 2 is a bond, -S-, or -0-, with the proviso that when Alk 2 is a bond, Sp 2 is a bond;
  • Z 1 is H, (C C 5 ) alkyl, or phenyl optionally substituted with one, two, or three groups of (C C 5 ) alkyl, alkoxy, (C C 4 ) thioalkoxy, halogen, nitro, -COOR', -CONHR', -0(CH 2 ) n COOR', -S(CH 2 ) n COOR',
  • Sp is a straight or branched-chain divalent or trivalent (0,-C ⁇ ) radical, divalent or trivalent aryl or heteroaryl radical, divalent or trivalent (C 3 -C 18 ) cycloalkyi or heterocycloalkyi radical, divalent or trivalent aryl- or heteroaryl-aryl (C C 1 ⁇ ) radical, divalent or trivalent cycloalkyi- or heterocycloalkyl-alkyl (C C 18 ) radical or divalent or trivalent (C 2 -C 18 ) unsaturated alkyl radical, wherein heteroaryl is preferably furyl, thienyl, N- methylpyrrolyl, pyridinyl, N-methylimidazolyl, oxazolyl, pyrimidinyl, quinolyl, isoquinolyl, N-methylcarbazoyl, aminocourmarinyl, or phenazinyl and wherein if Sp is a trivalent radical, Sp can be additionally substituted
  • Alk 1 is a branched or unbranched (C C 10 ) alkylene chain
  • Sp' is a bond, -S-, -0-, -CONH-, -NHCO-, or -NR' wherein R' is as hereinbefore defined, with the proviso that when Alk 1 is a bond, Sp 1 is a bond;
  • Ar is 1 ,2-, 1 ,3-, or 1 ,4-phenylene optionally substituted with one, two, or three groups of (C r C 6 ) alkyl, alkoxy, (C r C 4 ) thioalkoxy, halogen, nitro, -COOR', -CONHR', -0(CH 2 ) n COOR', -S(CH 2 ) n COOR', -0(CH 2 ) n CONHR', or -S(CH 2 ) ⁇ CONHR' wherein n and R' are as hereinbefore defined, or Ar is a 1,2-, 1,3-, 1 ,4-, 1 ,5-, 1,6-, 1,7-, 1 ,8-, 2,3-, 2,6-, or 2,7- naphthylidene each optionally substituted with one, two, three, or four groups of (C C 6 ) alkyl, (C 1 -C 5 ) alkoxy, (C C
  • Z 1 is (C C 5 ) alkyl, or phenyl optionally substituted with one, two, or three groups of (C ⁇ Cs) alkyl, (C C 4 ) alkoxy, (C ⁇ C thioalkoxy, halogen, nitro, -COOR', -CONHR', -0(CH 2 ) n COOR', -S(CH 2 ) n COOR ⁇
  • Calicheamicin derivatives can, for example, be attached to lysine residues of the antibody. Lysine attachment as disclosed in U.S. Pat.
  • U.S. Pat. No. 5,053,394 also discloses conjugates where a nucleophilic calicheamicin derivative, such as a hydrazide, is reacted with periodate oxidized carbohydrates on an antibody under mildly acidic conditions. This produces a Schiff base or derivative thereof, such as a hydrazone, which can be further reduced with, e.g., cyanoborohydride, if desired, to produce a hydrolytically stable conjugate.
  • a nucleophilic calicheamicin derivative such as a hydrazide
  • European Patent Application No. 0689845 discloses other linkers that can be used with nucleophilic derivatives, particularly hydrazides and related nucleophiles, prepared from the calicheamicins. These linkers are useful in those cases (e.g., P67.6), where better activity is obtained when the linkage formed between the drug and the linker is hydrolyzable. These linkers contain two functional groups. One group typically is a carboxylic acid that is utilized to react with the carrier. The acid functional group.when properly activated, can form an amide linkage with a free amine group of the carrier, such as, for example, the amine in the side chain of a lysine of a monoclonal antibody carrier.
  • the other functional group commonly is a carbonyl group, i.e., an aldehyde or a ketone, which will react with the appropriately modified therapeutic agent.
  • the carbonyl groups can react with a hydrazide group on the drug to form a hydrazone linkage. This linkage is hydrolyzable at the target cell to release the therapeutic agent from the conjugate.
  • a most preferred bifunctional linker for use in the present invention is 4-(4-acetylphenoxy) butanoic acid (AcBut), which results in a preferred product where the conjugate consists of gamma calicheamicin or N-acetyl gamma calicheamicin functionalized by reacting with the hydrazide of 3-mercapto-3-methyl butanoic acid, the linker 4-(4-acetylphenoxy)butanoic acid (AcBut), and a human or humanized monoclonal antibody targeting carrier.
  • AcBut 4-(4-acetylphenoxy) butanoic acid
  • humanized carriers including, but not limited to, proteins such as human or humanized monoclonal antibodies that are used to target the cytotoxic therapeutic agents herein, such as, for example, P67.6 and the other humanized monoclonal antibodies disclosed herein, use of a non- nucleophilic, protein-compatible, buffered solution containing (i) propylene glycol (PG) as a cosolvent and (ii) an additive comprising at least one C 6 -
  • C 18 carboxylic acid was found to produce monomeric calicheamicin derivative/carrier conjugates with higher drug loading/yield and decreased aggregation having excellent activity.
  • Preferred acids are C 7 to C 12 acids, and the most preferred acid is octanoic (caprylic) acid (CA).
  • Preferred buffered solutions for conjugates made from OSu esters or other comparably activated esters are phosphate-buffered saline (PBS) or N-2- hydroxyethyl piperazine-N'-2-ethane sulfonic acid (Hepes buffer), while preferred buffered solutions for conjugates made from the oxidized carbohydrates of antibodies is sodium acetate.
  • PBS phosphate-buffered saline
  • Hepes buffer N-2- hydroxyethyl piperazine-N'-2-ethane sulfonic acid
  • preferred buffered solutions for conjugates made from the oxidized carbohydrates of antibodies is sodium acetate.
  • Acceptable buffers for other types of conjugates can be readily determined by those who are skilled in the art.
  • the use of a non- nucleophilic, protein-compatible, buffered solution containing t-butanol without an additive was also found to produce monomeric calicheamicin derivative/carrier conjugates with higher drug loading/yield and decreased aggregation.
  • the amount of cosolvent used is a monomeric conjugating effective amount and can be determined by those of ordinary skill in the art without undue experimentation.
  • the amount of additive is a monomeric conjugation enhancing effective amount. This amount can also be determined by one of ordinary skill in the art without undue experimentation.
  • PG propylene glycol
  • Some or all of the PG cosolvent is used to transfer the drug into the conjugation mixture. When the cosolvent used for drug transfer amounts to 10% or less of the total volume of the conjugation mixture, it can optionally be substituted by ethanol or DMSO.
  • the concentration of the C 6 - C 18 carboxylic acid, preferably caprylic acid can be increased to 150-300 mM and the cosolvent dropped to 1-10% propylene glycol, ethanol, or DMSO, and is preferably
  • t-butanol at concentrations ranging from about 10% to about 25%, preferably about 15%, by volume of the total solution may be added to the conjugation reaction to produce monomeric calicheamicin derivative/carrier conjugates with higher drug loading/yield and decreased aggregation.
  • the concentration of MoAb ranges from about 1 to about 15 mg/ml and the concentration of the drug, e.g., AcBut calicheamicin, ranges from about 0.025 to about 1 mg/ml.
  • the reactions are performed in PBS or acetate buffer at a pH of from about 4.0 to about 8.5, depending on the type of conjugate being made, at a temperature ranging from about room temperature (25° C) to about 37° C for times ranging from about 15 minutes to about 24 hours.
  • the conjugates may be recovered and purified by conventional methods, for example, HPLC, FPLC or SEPHACRYL S-200TM.
  • the purified conjugates are monomeric and contain from about 2 to about 6 moles/mole drug/MoAb.
  • the addition of cosolvent and/or the additive may alter the pH of the buffered solution so that it may be necessary to adjust the pH of the solution to the preferred pH range of about 4.0 to 8.5.
  • the pH of the buffered solution containing the cosolvent and the additive will be about 7.0 to 8.5 for conjugates made from OSu esters, or about 4.0 to 6.5 for conjugates made from the oxidized carbohydrates of the antibody.
  • the pH of the buffered solution containing the cosolvent and the additive will be about 7.7 for conjugates made from OSu esters, or about 5.5 for conjugates made from the oxidized carbohydrates of the antibody.
  • Acceptable pH ranges for other types of conjugates can be readily determined by those who are skilled in the art.
  • the first set of experiments were performed with N-acetyl gamma calicheamicin functionalized by reacting with the hydrazide of 3- mercapto-3-methyl butanoic acid attached to the linker 4-(4- acetylphenoxy)butanoic acid and activated as the OSu ester (herein referred to as AcBut calicheamicin) on both murine and human P67.6 with variations in DMF concentrations, drug/protein ratio, and buffer.
  • IPA IPA
  • 25% t-butanol 25% PG + 80 mM CA. All were done with 3.25 mg/mL protein (final) in PBS, pH 7.4, and 6 moles drug per mole MoAb. All were compared to a control conjugation performed in 25% DMF while all the test solutions contained ⁇ 5% DMF from the drug stock. Conjugation was also done with 4 M/M drug in 25% PG or 25% DMF as control. All samples were incubated at room temperature overnight, exchanged into PBS on PD10 columns, and analyzed by spectrophotometry for protein recovery and drug loading. Samples were further analyzed by HPLC on ZorbaxTM and SuperoseTM. Following the conjugation reaction, the conjugates were purified on FPLC SuperoseTM. Results: All of these additives seemed beneficial except glycerol (low loading). PG + CA seemed best in terms of conjugate yield, drug loading and minimizing aggregate.
  • CA were incompatible at these concentrations, while IPA was not as good as PG in improving yield and decreasing aggregate.
  • CT-M-01 monoclonal antibody in the presence of 25% propylene glycol (PG) and 80% caprylic acid. The reaction was performed overnight
  • Example 9 AcBut-calicheamicin was conjugated to 36.6 mg hCT-M-01 monoclonal antibody in the presence of 30% PG and 60 mM CA. The reaction was performed for 2 hours at about 25°C. The product was analyzed by HPLC.
  • AcBut-calicheamicin was conjugated to 1 mg humanized A33 MoAb in the presence of 30% PG and 60 mM CA.
  • the pH was adjusted by addition of -10 mL NaOH/mL of solution to obtain a pH of 7.7-7.8.
  • the drug was then added and the solution mixed vigorously.
  • the solution was incubated at 25°C with shaking for 3 hours followed by filtration through Millex HV filters to remove insoluble material.
  • the conjugate was then purified by gel filtration on SEPHACRYL S-200TM in PBS (pH 7.4) using no more than a -1% load or, for small conjugations ⁇ 0.5 mL, SuperoseTM 12 FPLC in PBS was utilized.
  • Final monomeric ( ⁇ 4% dimer) conjugate was produced in >60% protein yield with a drug loading of >2.5 moles drug/mole protein.
  • Protein yields were modest, ranging from 20 to 40%.
  • final loading on monomer was only 1.1-1.3 M/M.
  • the anti-Tac conjugate, with a loading of 0.7 m/M, was reconjugated in the presence of 20% t-BuOH since that was the best backup additive. This increased loading to 2.0 M/M but in only 23% yield.
  • MOPC-21 was oxidized in pH 5.5 acetate buffer with 15 mM Nal0 4 at ambient temperature for 45 minutes. The buffered was then exchanged for fresh acetate buffer to remove the spent oxidation reagents. A portion of this oxidized antibody was treated with the disulfide resulting from the reaction of N-acetyl gamma-calicheamicin with the hydrazide of 3- mercapto-3-methyl butanoic acid (GAD) in the presence of 15% DMF. A second portion was treated with the same concentration of GAD in the presence of 5% DMF and 15% tBuOH. Both reactions were allowed to proceed at ambient temperature for 17 hours. Each reaction then had the buffer exchanged for pH 7.4 PBS.
  • GAD 3- mercapto-3-methyl butanoic acid

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PCT/US1996/006738 1995-06-07 1996-05-10 Methods for the preparation of monomeric calicheamicin derivative/carrier conjugates WO1996040261A1 (en)

Priority Applications (15)

Application Number Priority Date Filing Date Title
DK96915718T DK0837698T3 (da) 1995-06-07 1996-05-10 Fremgangsmåder til fremstilling af monomere calicheamicin-derivat/bærer-konjugater
EP96915718A EP0837698B1 (en) 1995-06-07 1996-05-10 Methods for the preparation of monomeric calicheamicin derivative/carrier conjugates
JP9500547A JPH11508232A (ja) 1995-06-07 1996-05-10 モノマー性カリキアミシン誘導体／キャリアー複合体の調製方法
DE69614551T DE69614551T2 (de) 1995-06-07 1996-05-10 Verfahren zur herstellung von monomeren calicheamicinderivaten/trägerkonjugaten
HK98119234.9A HK1016871B (en) 1995-06-07 1996-05-10 Methods for the preparation of monomeric calicheamicin derivative/carrier conjugates
HU9901351A HU221246B1 (en) 1995-06-07 1996-05-10 Methods for the preparation of monomeric calicheamicin derivative/carrier conjugates
KR1019970708934A KR100499648B1 (ko) 1995-06-07 1996-05-10 단량체칼리케아미신유도체/캐리어공액체의제조방법
MX9709316A MX9709316A (es) 1995-06-07 1996-05-10 Metodos para la preparacion de conjugados monomericos de derivado de caliqueamicina/portador.
AU57423/96A AU703862B2 (en) 1995-06-07 1996-05-10 Methods for the preparation of monomeric calicheamicin derivative/carrier conjugates
AT96915718T ATE204180T1 (de) 1995-06-07 1996-05-10 Verfahren zur herstellung von monomeren calicheamicinderivaten/trägerkonjugaten
BR9608564A BR9608564A (pt) 1995-06-07 1996-05-10 Processo para a preparação de conjugados de derivado de caliqueamicina/veículo monoméricos
NZ307926A NZ307926A (en) 1995-06-07 1996-05-10 Methods for the preparation of monomeric calicheamicin derivative/carrier conjuates
BG102100A BG63492B1 (bg) 1995-06-07 1997-12-03 Методи за получаване на мономерни конюгати калихеамициново производно/носител
NO19975706A NO324609B1 (no) 1995-06-07 1997-12-05 Fremgangsmater for fremstilling av monomere calicheamicin-derivat/baerer-konjugater
GR20010401797T GR3036930T3 (en) 1995-06-07 2001-10-18 Methods for the preparation of monomeric calicheamicin derivative/carrier conjugates

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