WO2019150985A1 - Complexe anticorps-médicament et composition pharmaceutique le contenant - Google Patents

Complexe anticorps-médicament et composition pharmaceutique le contenant Download PDF

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WO2019150985A1
WO2019150985A1 PCT/JP2019/001431 JP2019001431W WO2019150985A1 WO 2019150985 A1 WO2019150985 A1 WO 2019150985A1 JP 2019001431 W JP2019001431 W JP 2019001431W WO 2019150985 A1 WO2019150985 A1 WO 2019150985A1
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antibody
carbon atoms
optionally substituted
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金井　求
幸之助 生長
隆史 石山
邦子 斎木
陽平 関
満田　勝
恵太 井口
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国立大学法人東京大学
株式会社カネカ
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/537—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines spiro-condensed or forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/46—Hybrid immunoglobulins

Definitions

  • the present invention relates to an antibody-drug conjugate (ADC).
  • ADC antibody-drug conjugate
  • An antibody-drug conjugate is a substance in which an antibody and a drug are bound via a linker, and has attracted attention in recent years because it can effectively act on a drug by utilizing high target cell selectivity by the antibody.
  • Patent Document 1 discloses an antibody drug complex in which an anti-HER2 antibody and a camptothecin fusion are bound by a linker having a succinimido-3-yl group
  • Patent Document 2 discloses an anti-ErbB2 antibody and a maytansinoid.
  • Antibody drug conjugates are disclosed wherein are linked by a linker such as N-succinimidyl-4- (2-pyridylthio) pentanoate (SPP).
  • Patent Document 3 describes that anti-amyloid ⁇ antibody and fluorescein methyl ester can be bound by a linker having an azabicyclo [3.3.1] nonane N-oxyl group.
  • the present invention has been made paying attention to the above-described circumstances, and an object of the present invention is to provide an antibody-drug conjugate that controls the binding between an antibody and a drug and exhibits an appropriate antitumor effect. .
  • the present invention is as follows. (1) A complex in which an IgG1 antibody and an antitumor compound are bound via a cross-linking agent-derived moiety having an N oxy radical group or an N hydroxy group, An antibody drug complex in which the N oxy radical group or N hydroxy group reacts with the tryptophan residue of the IgG1 antibody and is covalently bonded to the IgG1 antibody. (2) The antibody drug conjugate according to (1), wherein the antitumor compound is bound to the constant region of the IgG1 antibody.
  • the ratio of the antitumor compound bound in the constant region of the IgG1 antibody is 90% or more (on a molar basis) with respect to the total antitumor compound bound to the IgG1 antibody ( The antibody drug conjugate according to 1) or (2).
  • the number of tryptophan residues present in the constant region of the IgG1 antibody is 6 to 18 per antibody molecule before binding to the cross-linking agent, and the number of tryptophan residues present in the variable region is 4.
  • the carbon atom at the 3-position of the indole ring in the side chain of the tryptophan residue is a protein.
  • the antibody drug conjugate according to (6), wherein the anti-HER2 antibody is a humanized monoclonal antibody.
  • the antibody-drug conjugate according to any one of (1) to (7), wherein the antitumor compound is maytansinoid.
  • Ants with 6 to 30 carbon atoms An aryloxy group, an optionally substituted heteroaryloxy group having 4 to 30 carbon atoms, an optionally substituted aralkyloxy group having 7 to 30 carbon atoms, and an optionally substituted cycloalkyl having 3 to 30 carbon atoms
  • R 5 is not a halogen atom
  • E 1 and E 2 together may form an optionally substituted —CH (CH 2 ) m CH— group, m represents an integer from 0 to 12,
  • the antitumor compound is bound to at least one group of A 1 , B 1 , C 1 , D 1 , E 1 and E 2 directly or through an intermediate chain)
  • the bicyclo structure forms at least one of a bond represented by the following formula (B1), a bond represented by the following formula (B2), and a bond represented by the following formula (B3) with the tryptophan residue of
  • the bicyclo structure of the cross-linking agent and the antitumor compound comprise N-succinimidyl-4- (2-pyridylthio) pentanoate (SPP), N-succinimidyl-3- (2-pyridyldithio) propionate (SPDP) Succinimidyl-4- (N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC), iminothiolane (IT), dimethyl adipimidate HCL, disuccinimidyl suberate, glutaraldehyde, bis (p- Azidobenzoyl) hexanediamine, bis- (p-diazoniumbenzoyl) -ethylenediamine, or triene-2,6-diisocyanate, 1,5-di
  • an antibody-drug conjugate that can control the binding between an antibody and a drug and has an excellent drug effect.
  • FIG. 1 is a chart showing MALDI-TOF-MS measurement results of Herceptin * -TrpADC (DM1), which corresponds to an example of the present invention.
  • FIG. 2 is a chart showing MALDI-TOF-MS measurement results of Herceptin * , which corresponds to the prior art.
  • FIG. 3 is a graph showing the survival rate of SK-BR-3 cells in the presence of Herceptin * -TrpADC (DM1). *: Herceptin is Gentech inc. Is a registered trademark.
  • IgG1 Antibody The present invention is a complex in which an IgG1 antibody and an antitumor compound (also referred to as an anticancer compound) are bound via a cross-linking agent-derived moiety having an N oxy radical group or an N hydroxy group. It has been found by the present inventors that a cross-linking agent having an N oxy radical group or an N hydroxy group selectively reacts with a specific tryptophan residue among tryptophan residues of an IgG1 antibody. Therefore, if the cross-linking agent is used, the binding between the antitumor compound and the IgG1 antibody can be highly controlled, and the antitumor effect of the obtained antibody drug conjugate can be made more appropriate.
  • an antitumor compound also referred to as an anticancer compound
  • the IgG1 antibody one having a tryptophan residue in the variable region as well as the constant region can be used. According to the present invention, the binding between the antibody and the antitumor compound can be controlled, and even when the variable region has tryptophan, the antitumor compound can be bound preferentially in the constant region.
  • the number of tryptophan residues present in the constant region of the IgG1 antibody used in the present invention is, for example, 6-18 per antibody before binding with a cross-linking agent, preferably 8-16 per antibody. More preferably, 10 to 14 antibodies / molecule of antibody.
  • trastuzumab which will be described later, has heavy regions Ala121 to Gly449 (containing 5 tryptophan residues) and light chain Arg108 to Cys214 (containing 1 tryptophan residue) as constant regions, and tryptophan present in the constant regions.
  • the number of residues is 12 / molecule of antibody.
  • the number of tryptophan residues present in the variable region is, for example, 4 to 16 per antibody molecule, preferably 6 to 14 per antibody molecule, and more preferably 8 to 1 before binding to the cross-linking agent. 12 / one antibody molecule.
  • trastuzumab which will be described later, has a heavy chain Glu1 to Ser120 (containing 4 tryptophan residues) and a light chain Asp1 to Lys107 (containing 1 tryptophan residue), and the tryptophan present in the variable region.
  • the number of residues is 10 / molecule of antibody.
  • the number of tryptophan residues in the complementarity determining region is, for example, 10 / antibody molecule or less, preferably 6 / antibody molecule or less, and 2 / antibody. Most preferably, it is 1 molecule or less. The fewer tryptophan residues in the complementarity determining region, the more reliably the reaction of the cross-linking agent in the complementarity determining region can be prevented, and the production efficiency of the antibody drug conjugate can be increased.
  • trastuzumab described below includes heavy chain Asp31 to His35 (including 0 tryptophan residues), Arg50 to Gly66 (including 0 tryptophan residues), Trp99 to Tyr109 (including 1 tryptophan residue), and light chain Arg24 to Ala34 (including 0 tryptophan residues), Ser50 to Ser56 (including 0 tryptophan residues), Gln89 to Thr97 (including 0 tryptophan residues) are complementarity determining regions, and tryptophan in the complementarity determining region The number of residues is 2 / molecule of antibody.
  • the IgG1 antibody does not contain a tryptophan residue in the complementarity determining region and its vicinity (for example, within 3 residues before and after), and the IgG1 antibody is in the complementarity determining region and its vicinity (within 3 residues before and after).
  • a tryptophan residue is included, it is preferable that the carbon atom at the 3-position of the indole ring in the side chain of the tryptophan residue in the complementarity determining region and the vicinity thereof is buried in the protein molecule.
  • the carbon atom at the 3-position of the indole ring is a carbon atom numbered 3 in the formulas (B1) to (B3) described later.
  • the IgG1 antibody preferably does not contain a tryptophan residue in the variable region.
  • the tryptophan residue in the variable region also has an indole ring on its side chain.
  • the 3-position carbon atom is preferably buried inside the protein molecule. If the variable region contains multiple tryptophan residues, the carbon atom at the 3-position of the indole ring in the side chain of the tryptophan residues in all the variable regions need not be buried inside the protein molecule.
  • tryptophan residues for example, 40% or more, preferably 60% or more, more preferably 80% or more, and most preferably 100% of the carbon at the 3-position in the indole ring of the side chain. It suffices if atoms are buried inside the protein molecule.
  • Whether the carbon atom at the 3-position of the indole ring in the side chain of the tryptophan residue is buried in the protein molecule or exposed on the surface of the protein molecule can be determined based on the X-ray structural analysis of the antibody. As long as the three-dimensional structure of the protein molecule is not affected, the X-ray structural analysis result of a part of the antibody (such as Fab region), a modified antibody, or a part of the modified antibody may be used.
  • the X-ray structural analysis result is displayed using a molecular graphics tool such as PyMOL (https://pymol.org/2/) to display the 3D view, and the side chain to be determined is exposed. Based on whether or not the carbon atom at the 3-position of the indole ring of the side chain is exposed on the surface of the protein molecule or whether it is buried inside. In light of the above criteria, it is determined that the carbon atom at the 3-position of the indole ring in the side chain of all tryptophan residues in the variable region of trastuzumab is buried in the protein molecule.
  • PyMOL https://pymol.org/2/
  • the IgG1 antibody is preferably an antibody that specifically binds to a tumor cell, more preferably an antibody against the epidermal growth factor receptor family, and the anti-EGFR antibody (anti-ErbB antibody) is an anti-HER1 antibody (anti-ErbB antibody).
  • Anti-ErbB1 antibody anti-HER2 antibody (anti-ErbB2 antibody), anti-HER3 antibody (anti-ErbB3 antibody), anti-HER4 antibody (anti-ErbB4 antibody) and the like.
  • the anti-ErbB antibody and the antitumor compound By binding the anti-ErbB antibody and the antitumor compound, the effect of the antitumor compound can be appropriately exhibited.
  • HER2 is known to form heterodimers with homodimers or other EGF receptors HER1 (ErbB1), HER3 (ErbB3), HER4 (ErbB4), etc., and act on cell proliferation, differentiation and survival.
  • HER1 ErbB1
  • HER3 HER3
  • HER4 ErbB4
  • the drug effect of the anti-tumor compound can be caused to act on the tumor cells more efficiently.
  • the anti-HER2 antibody may be derived from any species, and preferably, mammals such as humans, rats, mice, and rabbits can be exemplified, and anti-HER2 antibodies derived from rats or mice are easily available. If the antibody is derived from a species other than human, it is preferably chimerized or humanized using well-known techniques.
  • chimeric antibody examples include antibodies in which the variable region and constant region of the antibody are derived from different species, for example, a chimeric antibody in which the variable region of a rat or mouse-derived antibody is joined to the constant region derived from human (Proc. Natl. Acad.Sci.U.S.A., 81, 6851-6855, (1984)).
  • a chimeric antibody of this invention The chimeric antibody containing the variable region of mouse
  • a humanized antibody an antibody in which only a complementarity determining region (CDR; complementarity determining region) is incorporated into a human-derived antibody (see Nature (1986) 321, p.522-525), a CDR sequence is obtained by CDR grafting.
  • CDR complementarity determining region
  • an antibody obtained by transplanting amino acid residues of some frameworks into a human antibody WO 90/07861
  • an antibody humanized using a gene conversion mutagenesis strategy US patent
  • Human antibodies are not limited to human-derived anti-HER2 antibodies as long as they have only human chromosome-derived antibody gene sequences, for example, human antibody production having human chromosome fragments including human antibody heavy and light chain genes
  • Method using mouse Tomizuka, K. et al., Nature Genetics (1997) 16, p. 133-143; Kuroiwa, Y. et. Al., Nucl. Acids Res. (1998) 26, p. 3447- 3448; Yoshida, H. et.al., Animal Cell Technology: Basic and Applied Aspects vol.10, p.69-73 (Kitagawa, Y., Matsuda, T. and Iijima, S.eds.). cademic Publishers, 1999; Tomizuka, K.et.al., Proc.Natl.Acad.Sci.USA (2000) 97, may be an antibody obtained by reference) to p.722-727 like..
  • the anti-HER2 antibody may be either a polyclonal antibody or a monoclonal antibody, and is preferably a monoclonal antibody, more preferably a human antibody or a humanized monoclonal antibody.
  • the anti-HER2 antibody includes Coussens L, et al. , Science. 1985; 230 (4730): 1132-1139, a transmembrane receptor protein having a tyrosine kinase domain with a molecular weight of 185 kDa (its DNA sequence and amino acid sequence have been published on public databases, for example, M11730 (Genbank ), And can be referred to by an accession number such as NP_004439.2 (NCBI)).
  • mouse anti-HER2 antibody 4D5 Fendly. Et al., Cancer Research 1990 (50): 1550- 1558, US Pat. No.
  • trastuzumab huMAb4D5-8, rhuMAb HER2, Herceptin (Genen), a recombinant humanized monoclonal antibody of the mouse anti-HER2 antibody 4D5 ech inc. registered trademark of)
  • pertuzumab Pajeta (a registered trademark of H.Hoffmann-La Roche AG)
  • the anti-HER2 antibody of the present invention can specifically bind to HER2, an amino acid residue in which a part of amino acid residues is substituted, deleted, or added to the specific examples of the anti-HER2 antibody shown above. It may have an array. Whether or not the binding is specific can be determined based on a dissociation constant (hereinafter referred to as a KD value).
  • the KD value for the HER2 protein of a suitable antibody is 1 ⁇ 10 ⁇ 5 M or less, more preferably 1 ⁇ 10 ⁇ 7 M or less, even more preferably 1 ⁇ 10 ⁇ 8 M or less, and most preferably 1 ⁇ 10 -9 M or less.
  • the binding between the HER2 protein and the antibody can be measured using a known method such as Surface Plasma Resonance method, ELISA method, or RIA method.
  • amino acid residue substitution is preferably a conservative amino acid substitution.
  • Conservative amino acid substitutions are those that take place within a group of amino acids that are related in their side chains.
  • Suitable amino acid groups are as follows: Acidic group: aspartic acid, glutamic acid Basic group: lysine, arginine, histidine
  • Nonpolar group alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan
  • Uncharged polar group glycine, asparagine, glutamine, cysteine, serine, Threonine, tyrosine
  • Aliphatic hydroxy group serine, threonine
  • Amide-containing group asparagine, glutamine Aliphatic group: alanine, valine, leucine, isoleucine
  • Aromatic group phenylalanine, tryptophan, tyrosine
  • the substitution, deletion, or addition of amino acid residues is performed so that the heavy chain amino acid sequence and the light chain amino acid sequence of the antibody have a sequence exhibiting high homology (identity). It is preferable that there is 80% or more homology, more preferably 90% or more, even more preferably 95% or more, and most preferably 99% or more.
  • Blast algorithm version 2.2.2 (Altschul, Stephen F., Thomas L. Madden, Alejandro A. Schaeffer, Jinghui Zhang, ZhangWebbhan, ZhangWebbhan. J. Lipman (1997), “Gapped BLAST and PSI-BLAST: a new generation of protein database search programs”, Nucleic Acids Res. 25: 3389-3402). Blast algorithm can also be used by accessing www.ncbi.nlm.nih.gov/blast on the Internet.
  • the IgG1 antibody used in the present invention is a modified antibody, for example, a chemical compound, as long as it can bind to a cross-linking agent-derived moiety having an N oxy radical group or an N hydroxy group, such as a tryptophan residue remaining. It may be modified chemically or biologically.
  • the chemical modification includes a modification with a compound capable of forming a covalent bond with the amino acid skeleton, for example, a modification with an N-linked or O-linked carbohydrate chain.
  • Biological modifications include post-translational modifications (eg, glycosylation to N- or O-links, N- or C-terminal processing, deamidation, aspartic acid isomerization, methionine oxidation) And those in which a methionine residue is added to the N-terminus by expression using a prokaryotic host cell.
  • Such modifications also include those labeled to enable detection or isolation of the antibody or antigen of the present invention, such as enzyme labels, fluorescent labels, and affinity labels.
  • the anti-tumor compound that binds to the IgG1 antibody can be a compound that has an anti-tumor effect and can bind to a cross-linking agent.
  • a maytansin analog maytansinoid
  • Exatecan ((1S, 9S) -1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H, 12H-benzo [de] pyrano [3 ′, 4 ': 6,7] Indolizino [1,2-b] quinoline-10,13 (9H, 15H) -dione) and other camptothecin derivatives; doxorubicin, daunorubicin, mitomycin C, bleomycin, cyclocytidine, vincristine, vinblastine, methotrexate , Platinum-based antitumor agents (cisplatin or derivatives thereof), paclitaxel (e
  • Maytansinoid refers to a compound group developed using maytansine represented by the following formula (2b) as a lead compound, and is characterized by having a group represented by the following formula (2c).
  • a compound represented by the following formula (2d) is preferable.
  • R is an alkanediyl group having 1 to 10 carbon atoms.
  • the carbon number of R is preferably 1 to 6, more preferably 1 to 3.
  • R is ethane-1 , 2-diyl is referred to as maytansinoid DM1, and R is 1,1-dimethylpropane-1,3-diyl (where SH is bonded to the 1-position) It is said to be maytansinoid DM4.)
  • the maytansinoid represented by the formula (2d) often reacts with a crosslinking agent at the SH portion.
  • crosslinking agent The IgG1 antibody and the antitumor compound are bound together by a crosslinking agent having an N oxy radical group or an N hydroxy group.
  • the N oxy radical group or N hydroxy group of the cross-linking agent reacts with the tryptophan residue of the IgG1 antibody to form a covalent bond.
  • the crosslinking agent having an N oxy radical group or an N hydroxy group preferably has a bicyclo structure (preferably an azabicyclononane (ABNO) structure) represented by the following formula (b1a) or the following formula (b1b).
  • ABNO azabicyclononane
  • Ants with 6 to 30 carbon atoms An aryloxy group, an optionally substituted heteroaryloxy group having 4 to 30 carbon atoms, an optionally substituted aralkyloxy group having 7 to 30 carbon atoms, and an optionally substituted cycloalkyl having 3 to 30 carbon atoms
  • R 5 is not a halogen atom
  • E 1 and E 2 together may form an optionally substituted —CH (CH 2 ) m CH— group, m represents an integer from 0 to 12,
  • the antitumor compound is bound to at least one group of A 1 , B 1 , C 1 , D 1 , E 1 and E 2 directly or through an intermediate chain)
  • hetero atom means a divalent or higher atom other than carbon and hydrogen.
  • heteroatom group means a substituent having a heteroatom as part of the group.
  • the number of carbon atoms of the alkyl group in R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 is preferably 1-20.
  • Specific examples of the alkyl group having 1 to 30 carbon atoms include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert, -Butyl group, n-pentyl group, n-hexyl group, n-octyl group, n-decyl group, n-dodecyl group, n-octadecyl group, n-icosyl group and the like.
  • the carbon number of the alkenyl group in R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 is preferably 2-15.
  • Preferred examples of the alkenyl group having 2 to 30 carbon atoms include a vinyl group, an allyl group, a 3-butenyl group, a 4-pentenyl group, a 5-hexenyl group, a 6-heptenyl group, and a 7-octenyl group.
  • the number of carbon atoms of the alkynyl group in R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 is preferably 2-15.
  • Preferred examples of the alkynyl group having 2 to 30 carbon atoms include ethynyl group, 2-propynyl group, 3-butynyl group, 4-pentynyl group, 5-hexynyl group, 6-heptynyl group, and 7-octynyl group. .
  • the number of carbon atoms of the aryl group in R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 is preferably 6-15.
  • Preferred examples of the aryl group having 6 to 30 carbon atoms include phenyl group, 1-naphthyl group, 2-naphthyl group and the like.
  • the heteroaryl group in R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 preferably has 4 to 15 carbon atoms.
  • Preferred examples of the heteroaryl group having 4 to 30 carbon atoms include 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2-thiophenyl group, 2-furyl group and the like.
  • the number of carbon atoms of the aralkyl group in R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 is preferably 7-15.
  • Preferred examples of the aralkyl group having 7 to 30 carbon atoms include benzyl group and 1-phenethyl group.
  • the number of carbon atoms of the cycloalkyl group in R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 is preferably 3-15.
  • Preferred examples of the cycloalkyl group having 3 to 30 carbon atoms include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
  • R 1, R 2, R 3, R 4, R 5, R 6, alkyl group in R 7 and R 8 alkenyloxy group, alkynyloxy group, an aryloxy group, heteroaryloxy group, an aralkyloxy group And an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, an aralkyl group and a cycloalkyl group which are part of the cycloalkyloxy group, R 1 , R 2 , R 3 , R 4 , R 5 ,
  • the alkyl group, alkenyl group, alkynyl group, aryl group, heteroaryl group, aralkyl group and cycloalkyl group in R 6 , R 7 and R 8 can be selected.
  • the polyalkyleneoxy group in R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 is preferably a polyethyleneoxy group, more preferably — (CH 2 CH 2 O )
  • a -group (a is an integer from 1 to 10), more preferably-(CH 2 CH 2 O) a -group (a is 4).
  • a hydrogen atom for example, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, or an optionally substituted aryl A group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group and an optionally substituted cycloalkyl group may be bonded.
  • Examples of the alkyl group, alkenyl group, alkynyl group, aryl group, heteroaryl group, aralkyl group and cycloalkyl group bonded to the free end of the polyoxyalkylene group include R 1 , R 2 , R 3 , R 4 , R 5 ,
  • the alkyl group, alkenyl group, alkynyl group, aryl group, heteroaryl group, aralkyl group and cycloalkyl group in R 6 , R 7 and R 8 can be selected.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 include a hydrogen atom; a halogen atom; a heteroatom group (preferably a hydroxyl group);
  • Preferred examples include a reactive functional group described below and a halogen Atoms.
  • the number of substitution groups and the substitution position are not particularly limited.
  • the reactive functional group as a group or a part of the group (substituent) in R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 is represented by the formula (b1a) or the formula It is preferable to select in consideration of imparting reactivity between the crosslinking agent having a bicyclo structure (b1b) and the antitumor compound or the compound forming the intermediate chain.
  • a person skilled in the art can make an appropriate selection based on the description of “Bioconjugate Techniques, third edition” by Hermanson.
  • Suitable examples of reactive functional groups include alcohol groups, epoxy groups, acetal groups, orthoester groups, ester groups, carbonyl groups, carboxyl groups, carboxylic anhydride groups, amide groups, imidate groups, amino groups, imino groups, Aziridine group, diazo group, azido group, amidino group, guanidyl group, hydrazyl group, hydrazone group, alkoxyamino group, oxime group, carbonate group, carbamate group, sulfhydryl group, ether group, imide group, thioester group, thioamide group, isothiocyano group Group, thioether group, disulfide group, halogen group, isocyano group, isocyanate group, oxazirine group, diaziridine group, sulfonyl group, sulfone group, sulfoxide group, sulfonimide group, seleno group, silyl group, boryl group
  • any one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 is an optionally substituted alkyl group having 1 to 30 carbon atoms.
  • an optionally substituted alkenyl group having 2 to 30 carbon atoms more preferably an n-butyl group, an n-pentyl group, an n-hexyl group, an allyl group, or a 3-butenyl group.
  • any one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 is a polyalkyleneoxy group whose free end may be an alkoxy group.
  • R 5 is a polyalkyleneoxy group whose free end may be an alkoxy group.
  • the polyalkyleneoxy group whose free end side may be an alkoxy group is preferably substituted.
  • Suitable examples of the substituent include an allyl group, a vinyl group, a phenyl group, a naphthyl group, and an azide group. , Pyridyl group, triazole group and the like.
  • a 1 , B 1 , C 1 and D 1 are each independently CR 1 R 2 , Is CH 2 or CHR 1 .
  • R 1 is a reactive functional group, more preferably an alcohol group, an epoxy group, an acetal group, an orthoester group, an ester group, Carbonyl group, carboxyl group, carboxylic anhydride group, amide group, imidate group, amino group, imino group, aziridine group, diazo group, azido group, amidino group, guanidyl group, hydrazyl group, hydrazone group, alkoxyamino group, oxime group , Carbonate group, carbamate group, sulfhydryl group, ether group, imide group, thioester group, thioamide group, isothiocyano group, thioether group, disulfide group, halogen group, isocyano group, isocyanate group, oxazirine group, diaziridine group, sulfonyl group, sulfone Group,
  • R 1 and R 5 are preferably polyoxyalkylene groups having an alkyl group having a reactive functional group on the free end side; or reaction More preferably, the reactive functional group is an alcohol group, epoxy group, acetal group, orthoester group, ester group, carbonyl group, carboxyl group, carboxylic anhydride group, amide group, imidate group, amino group.
  • E 1 and E 2 may be taken together to form a —CH (CH 2 ) m CH— group.
  • m is preferably an integer of 0 to 12, more preferably an integer of 0 to 9.
  • the —CH (CH 2 ) m CH— group may preferably have a substituent, and the substituent in the —CH (CH 2 ) m CH— group is preferably a reactive functional group.
  • a 1 , B 1 , C 1 and D 1 all represent CH 2
  • F 1 and G 1 both represent CH
  • at least one of E 1 and E 2 is CR 1 R 2 (R 1 , R 2 is at least one reactive functional group), C ⁇ O, C ⁇ S, C ⁇ NR 5 , NR 5 , SiR 6 R 7 , or E 1 and E 2 together , —CH (CH 2 ) m CH— group, and at least one hydrogen on the —CH (CH 2 ) m CH— group is preferably substituted with a reactive functional group.
  • crosslinking agent having the bicyclo structure of the formula (b1a) or the formula (b1b)
  • E 1 and E 2 are both CH 2 and F 1 and G 1 are both CH
  • a 1 , B 1 , C 1 and D 1 are preferably CHR 1 .
  • a 1 , B 1 , C 1 and D 1 all represent CH 2 and F 1 And G 1 both represent CH, one of E 1 and E 2 represents CH 2 or an oxygen atom, and the other represents C ⁇ O, CHNH 2 , CH (CO) NH 2, or C ⁇ NOH.
  • one of E 1 and E 2 preferably represents CH 2 .
  • the crosslinking agent having the bicyclo structure of the formula (b1a) or the formula (b1b) can be said to have the structure of the following formula (b2a) or the formula (b2b), and binds an antitumor compound or an intermediate chain.
  • a compound in which the structure of the formula (b2a) or the formula (b2b) is appropriately changed can be used.
  • the E 1 moiety (carbon atom) and Ex moiety (single bond or double bond) in formula (b2a) or formula (b2b) may be a part or all of C ⁇ O, amide, amine, oxime. Good.
  • cross-linking agent having a bicyclo structure represented by the formula (b1a) or the formula (b1b) examples include those described in Sonobe, T .; Oisaki, K .; Kanai, M .; Chem. Sci. 2012, 3, 1572-1576, Lauber, M.M. B. Stahl, S .; S. ACS Catal. 2013, 3, 2612-2616, Hayashi, M .; Sasano, Y .; Nagasawa, S .; Shibuya, M .; Iwabuchi, Y .; Chem. Pharm. Bull 2011, 59, 1570, Sasano, Y.B.
  • the cross-linking agent having the bicyclo structure of the formula (b1a) or the formula (b1b) is a tryptophan residue of an IgG1 antibody, a bond represented by the following formula (B1), a bond represented by the following formula (B2), and a formula (B3 It is preferable to form at least one of the bonds represented by (Wherein A 1 , B 1 , C 1 , D 1 , E 1 , E 2 , F 1 and G 1 have the same meaning as described above)
  • the number of bonds of the cross-linking agent per molecule of IgG1 antibody is, for example, 1 to 10 / antibody molecule, preferably 2 to 8 / antibody molecule, as an arithmetic average.
  • the cross-linking agent is preferably bound in the constant region of the IgG1 antibody, and the ratio of the cross-linking agent bound in the constant region of the IgG1 antibody is, for example, It is 90% or more (on a molar basis), preferably 95% or more (on a molar basis), more preferably 99% or more (on a molar basis), and may be 100% (on a molar basis).
  • the cross-linking agent is preferably bound in the constant region of IgG1 antibody. According to the combination of the antibody and the crosslinking agent of the present invention, the number of bonds of the crosslinking agent, its accuracy, the binding site, etc. can be controlled to a higher degree.
  • one antitumor compound binds to an antibody via one crosslinker. Therefore, the number of binding of the cross-linking agent per antibody molecule, its standard deviation, and the binding site are in the same range as the number of binding of the antitumor compound per antibody molecule, its standard deviation and binding site, respectively.
  • the cross-linking agent and the antitumor compound may be bonded directly or via an intermediate chain.
  • various compounds (bifunctional protein coupling agents) used as a linker between an antibody and a drug in conventional antibody-drug conjugates can be used, and N-succinimidyl-4- (2-pyridylthio) pentanoate (SPP), N-succinimidyl-3- (2-pyridyldithio) propionate (SPDP), succinimidyl-4- (N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC), iminothiolane (IT) ), Dimethyl adipimidate HCL, disuccinimidyl suberate, glutaraldehyde, bis (p-azidobenzoyl) hexanediamine, bis- (p-diazoniumbenzoyl) -ethylenediamine, or tri
  • the antibody drug complex of the present invention can be produced without applying a transition metal catalyst or non-biocompatible conditions. Specifically, an IgG1 antibody, a crosslinking agent having an N oxyradical group or an N hydroxy group, and an antitumor compound may be mixed in an appropriate order, and an IgG1 antibody-crosslinking agent bond and a crosslinking agent-antitumor may be mixed. The order of formation of the bond between the active compounds is not limited.
  • an anti-tumor compound may be bound to the cross-linking agent, and a cross-linking agent bound with an anti-tumor compound and An IgG1 antibody may be bound.
  • an antibody drug complex may be prepared by mixing an IgG1 antibody, a cross-linking agent having an N oxy radical group or an N hydroxy group, and an antitumor compound.
  • the order of formation of an IgG1 antibody-crosslinking agent bond, a crosslinking agent-intermediate chain-forming compound bond, and an intermediate chain-forming compound-antitumor compound bond is not limited.
  • the compound forming the intermediate chain was reacted with a cross-linking agent (which may be bound to the antibody or may be bound to the antibody). Later, it may be conjugated with an anti-tumor compound, and a compound that forms an intermediate chain is conjugated with an anti-tumor compound, and then a cross-linking agent (which may be conjugated with an antibody or conjugated with an antibody). Or a cross-linking agent (which may be bound to an antibody or may be bound to an antibody), a compound forming an intermediate chain, and an antitumor compound (Furthermore, antibodies may be mixed as necessary) to obtain these conjugates.
  • a cross-linking agent which may be bound to the antibody or may be bound to the antibody
  • an antitumor compound (Furthermore, antibodies may be mixed as necessary) to obtain these conjugates.
  • a product obtained by previously reacting an intermediate chain forming compound with a crosslinking agent having an N oxy radical group or an N hydroxy group (the product obtained by this reaction is hereinafter referred to as a composite linker) It is preferable to mix the IgG1 antibody and the antitumor compound in an appropriate order, and it is more preferable to react the composite linker with the IgG1 antibody and then react the antitumor compound.
  • the formation reaction of the IgG1 antibody-crosslinking agent bond can be performed, for example, in an aqueous solvent or a water-water-soluble organic solvent mixed solvent. From the viewpoint of convenience and safety, the reaction is performed in an aqueous solvent. Is preferred. Since the crosslinking agent having an N oxy radical group or an N hydroxy group has high solubility in water and can be used for a modification reaction in water, it is useful for a reaction excellent in biocompatibility.
  • water-soluble organic solvent examples include alcohol solvents, ketone solvents, ether solvents, nitrile solvents, amide solvents, and sulfoxide solvents.
  • these solvents include, but are not limited to, methanol, ethanol, propanol, ethylene glycol, acetone, dioxane, tetrahydrofuran, acetonitrile, dimethylformamide, dimethyl sulfoxide and the like.
  • nitrite for example, nitrite, Bronsted acid, metal catalyst, photocatalyst, peracid, oxygen, or the like is used as an activator / oxidant for generating active species.
  • nitrite is used.
  • nitrite is used in the reaction, it is preferably used in an amount of 0.6 to 3 equivalents per equivalent of the crosslinking agent.
  • a Bronsted acid it is preferably used in an amount such that the reaction solution has a pH of 2.0 to 4.5, more preferably in an amount such that the pH is 3.0 to 4.0.
  • a metal catalyst / photocatalyst it is preferably used in an amount of 1 equivalent or less that can function as a catalyst with respect to 1 equivalent of the crosslinking agent.
  • a peracid preferably 1 equivalent or more with respect to 1 equivalent of the cross-linking agent, and when using oxygen, it is preferably used at normal pressure.
  • the temperature and reaction time of the IgG1 antibody-crosslinking agent bond formation reaction may be appropriately adjusted by those skilled in the art depending on the type of catalyst, the amount of each reaction component, etc., but when nitrite is used in the reaction, The temperature is, for example, ⁇ 10 to 60 ° C., preferably 20 to 40 ° C.
  • the reaction time can be, for example, about 1 minute to 24 hours.
  • the cross-linking agent-antitumor compound bond forming reaction, the cross-linking agent-intermediate chain forming compound bond forming reaction, or the intermediate chain forming compound-anti-tumor compound bond forming reaction is the IgG1 antibody-crosslinking agent bond forming reaction.
  • the reaction is performed at the same timing as the above, or when the IgG1 antibody-crosslinking agent bond forming reaction is performed in one pot, it is preferably performed in the same solvent as the IgG1 antibody-crosslinking agent bond forming reaction.
  • the cross-linking agent-antitumor compound-binding reaction the cross-linking agent-intermediate-chain-forming compound bond-forming reaction, or the intermediate chain-forming compound-anti-tumor compound-binding, in addition to the IgG1 antibody-crosslinking agent-binding reaction.
  • the formation reaction it may be performed in the same solvent as the IgG1 antibody-crosslinking agent bond formation reaction, or in a solvent different from the IgG1 antibody-crosslinking agent bond formation reaction, for example, in an organic solvent,
  • the organic solvent may be water-soluble or water-insoluble.
  • water-soluble or water-insoluble organic solvent examples include alcohol solvents, ketone solvents, ether solvents, ester solvents, nitrile solvents, amide solvents, sulfoxide solvents, halogen solvents, hydrocarbon solvents, and the like.
  • methanol n-hexanol, t-butyl alcohol, ethylene glycol, acetone, methyl ethyl ketone, cyclohexanone, dioxane, tetrahydrofuran, diethyl ether, ethyl acetate, acetonitrile, methylformamide, dimethylformamide, dimethylacetamide,
  • Examples include dimethyl sulfoxide, methylene chloride, n-hexane, toluene, xylene and the like.
  • the antibody-drug conjugate of the present invention is purified to a predetermined purity, and then mixed with a pharmaceutically acceptable carrier and, if necessary, an excipient, a stabilizer, or the like.
  • the preservative dosage form may be a freeze-dried preparation, an aqueous solution, or the like. Carriers, excipients, stabilizers, etc.
  • buffers such as phosphates, citrates and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (octadecyldimethylbenzylammonium chloride, hexametho About 10 residues; such as nium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propylparaben; catechol, resorcinol, cyclohexanol; 3-pentanol and m-cresol)
  • proteins such as serum albumin, gelatin, or immunoglobulin
  • hydrophilic polymers such as polyvinylpyrrolidone
  • glycine, glutamine, asparagine, histidine, arginine or rigid Amino acids such as glucose; monosaccharides, disaccharides and other carbohydrates including glucose, mannose, or dextrin; chel
  • the pharmaceutical composition may be a sustained-release preparation.
  • Sustained release formulations include semi-permeable materials of solid hydrophobic polymers containing antibodies, which are preferably in the form of molded articles such as films or microcapsules.
  • formulation materials used in sustained release formulations include polyesters, hydrogels (eg, poly (2-hydroxyethyl-methacrylate) or poly (vinyl alcohol)), polylactides (US Pat. No. 3,773,919).
  • LUPRONDEPOT injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate
  • poly-D- And degradable lactic acid-glycolic acid copolymers such as ( ⁇ )-3-hydroxybutyric acid.
  • succinimidyl-4- (N-maleimidomethyl) cyclohexane-1-carboxylate SMCC, 250 mg, 0.75 mmol
  • triethylamine 207 ⁇ L, 1.5 mmol
  • dichloromethane 5 mL
  • Saturated ammonium chloride was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate.
  • DM1 Herceptin-TrpADC
  • Herceptin-TrpADC Herceptin-TrpADC
  • MALDI-TOF-MS manufactured by Shimadzu Corporation: AXIMA-TOF2, matrix: 3,5-dimethoxy-4-hydroxycinnamic acid.
  • FIG. 1 The result shown in FIG. 1 was obtained.
  • the peaks at 151 and 804 in FIG. 1 correspond to Herceptin-TrpADC (DM1).
  • the result of measuring MALDI-TOF-MS under the same conditions for Herceptin before the reaction is as shown in FIG. 2, and 149 and 202 in FIG. 2 correspond to Herceptin. From FIG. 1 and FIG. 2, it can be seen that in Herceptin-TrpADC (DM1), two molecules of ABNO-MCC-DM1 are introduced on average.
  • Herceptin registered trademark; Genentech Inc.
  • the remaining substrate and by-products are precipitated by centrifugation (10,000 rpm, 15 minutes), and the supernatant fraction is subjected to size exclusion chromatography (chromatography system AKTA pure M1 (F9-R, PC set) / GE).
  • the product was manufactured by Healthcare Japan Co., Ltd., and purified with column: Superdex 200 Increase 10/100 GL, eluent: PBS buffer (pH 7.4)).
  • the target product fraction was concentrated by ultrafiltration (Amicon (registered trademark) Ultra-15 Centrifugal Filter Devices (Ultracel (registered trademark) -50k)) to obtain the target compound, Herceptin-TrpADC (DM1).
  • the concentration of the target compound was quantified by absorbance at 280 nm and used in the subsequent experiments.
  • Herceptin-TrpADC DM1
  • the cytotoxic activity to HER2 antigen positive cells was evaluated with reference to Sliwowski Breast Cancer Res Treat (2011) 128: 347-356.
  • SK-BR-3 cells which are HER2 antigen-positive human breast cancer lines, were cultured, and 100 ⁇ L each was added to a 96-well microplate so as to be 5 ⁇ 10 3 cells / well 100 ⁇ L, followed by overnight culture.
  • the antibody-drug conjugate of the present invention is useful as a medicine for treating humans and animals (mammals).

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Abstract

L'invention concerne un complexe anticorps-médicament permettant de commander la liaison d'un anticorps et d'un médicament et qui présente un effet antitumoral approprié. Le complexe anticorps-médicament, selon la présente invention est un complexe dans lequel un anticorps IgG1 et un composé antitumoral sont liés par l'intermédiaire d'une partie dérivée d'un agent de réticulation ayant un groupe radical N oxy ou un groupe N hydroxy, et le groupe radical N oxy ou le groupe N hydroxy se lient de manière covalente avec l'anticorps IgG1 par réaction avec un résidu de tryptophane de l'anticorps IgG1.
PCT/JP2019/001431 2018-01-31 2019-01-18 Complexe anticorps-médicament et composition pharmaceutique le contenant WO2019150985A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003503365A (ja) * 1999-06-25 2003-01-28 ジェネンテック・インコーポレーテッド 抗−ＥｒｂＢ抗体−メイタンシノイド複合体を用いた治療方法
JP2007520450A (ja) * 2003-10-10 2007-07-26 イミュノジェン・インコーポレーテッド 非開裂リンカーを介して連結した細胞結合物質メイタンシノイド複合体を用いて特定の細胞集団を標的とする方法、前記複合体、および前記複合体の製造法
WO2017154997A1 (fr) * 2016-03-09 2017-09-14 国立大学法人 東京大学 Agent de réticulation sélective de structure indole et composite le comprenant

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003503365A (ja) * 1999-06-25 2003-01-28 ジェネンテック・インコーポレーテッド 抗−ＥｒｂＢ抗体−メイタンシノイド複合体を用いた治療方法
JP2007520450A (ja) * 2003-10-10 2007-07-26 イミュノジェン・インコーポレーテッド 非開裂リンカーを介して連結した細胞結合物質メイタンシノイド複合体を用いて特定の細胞集団を標的とする方法、前記複合体、および前記複合体の製造法
WO2017154997A1 (fr) * 2016-03-09 2017-09-14 国立大学法人 東京大学 Agent de réticulation sélective de structure indole et composite le comprenant

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SEKI, Y. ET AL.: "Transition metal-free tryptophan-selective bioconjugation of proteins", J. AM. CHEM. SOC., vol. 138, 2016, pages 10798 - 10801, XP055420898, doi:10.1021/jacs.6b06692 *

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