WO2016044560A1 - Pyrrolobenzodiazepines and antibody disulfide conjugates thereof - Google Patents
Pyrrolobenzodiazepines and antibody disulfide conjugates thereof Download PDFInfo
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- WO2016044560A1 WO2016044560A1 PCT/US2015/050634 US2015050634W WO2016044560A1 WO 2016044560 A1 WO2016044560 A1 WO 2016044560A1 US 2015050634 W US2015050634 W US 2015050634W WO 2016044560 A1 WO2016044560 A1 WO 2016044560A1
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- 0 C[C@](CC(C1)=C*)N1C(C)=O Chemical compound C[C@](CC(C1)=C*)N1C(C)=O 0.000 description 7
- GOOQBNKSFNCUIP-HLYGARRCSA-N C[C@H](CCC(N([C@H]([C@H](CC(C1)=C)N1C(c1c2)=O)O)c1cc(OCCCCCOc(c(OC)c1)cc(N=C[C@H](C3)N4CC3=C)c1C4=O)c2OC)=O)SSc(nccc1)c1[N+]([O-])=O Chemical compound C[C@H](CCC(N([C@H]([C@H](CC(C1)=C)N1C(c1c2)=O)O)c1cc(OCCCCCOc(c(OC)c1)cc(N=C[C@H](C3)N4CC3=C)c1C4=O)c2OC)=O)SSc(nccc1)c1[N+]([O-])=O GOOQBNKSFNCUIP-HLYGARRCSA-N 0.000 description 1
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- 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
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- 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
- A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
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- 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
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- 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
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
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- 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
- C07K16/2851—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the lectin superfamily, e.g. CD23, CD72
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- 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
- C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
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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
- 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
- A61K47/6851—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 the antibody targeting a determinant of a tumour cell
- A61K47/6855—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 the antibody targeting a determinant of a tumour cell the tumour determinant being from breast cancer cell
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- C—CHEMISTRY; METALLURGY
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- C07K2317/522—CH1 domain
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- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/567—Framework region [FR]
Definitions
- the present invention relates to pyrrolobenzodiazepines (PBDs), in particular
- pyrrolobenzodiazepines having a labile N10 protecting group, suitable to form a linker to a cell binding agent.
- the present invention also relates to certain conjugates made from these PBDs.
- PBDs pyrrolobenzodiazepines
- Family members include abbeymycin (Hochlowski, et al., J. Antibiotics, 40, 145-148 (1987)), chicamycin (Konishi, et al., J. Antibiotics, 37, 200-206 (1984)), DC-81 (Japanese Patent 58-180 487; Thurston, et al., Chem. Brit, 26, 767-772 (1990); Bose, et al., Tetrahedron, 48, 751-758
- PBDs are of the general structure:
- a particularly advantageous pyrrolobenzodiazepine compound is described by Gregson et al. (Chem. Commun. 1999, 797-798) as compound 1 , and by Gregson et al. ⁇ J. Med. Chem. 2001 , 44, 1161-1174) as compound 4a.
- This compound also known as SJG-136, is shown below:
- ADC antibody-drug conjugates
- cytotoxic or cytostatic agents i.e. drugs to kill or inhibit tumor cells in the treatment of cancer
- cytotoxic or cytostatic agents i.e. drugs to kill or inhibit tumor cells in the treatment of cancer
- systemic administration of these unconjugated drug agents may result in unacceptable levels of toxicity to normal cells as well as the tumor cells sought to be eliminated
- Drug moieties may impart their cytotoxic and cytostatic effects by mechanisms including tubulin binding, DNA binding, or topoisomerase inhibition. Some cytotoxic drugs tend to be inactive or less active when conjugated to large antibodies or protein receptor ligands.
- WO 2013/055987 discloses conjugates comprising a PBD dimer compound connected through the N10 position via a specific sulfur linker to a cell binding agent, having a general formula A:
- conjugates were exemplified with A118C cysteine-engineered antibody mutants (THIOMABTM).
- Drug linkers of formul D were disclosed as useful in the preparation of such conjugates:
- the present inventors have developed further drug linkers, which are useful in the synthesis of the conjugate compounds disclosed in WO 2013/055987.
- the present invention provides drug linker compounds useful in the preparation of conjugates, the drug linkers comprising a PBD dimer compound connected through the N10 position via a specific sulfur linker to a nitro-pyridyl group, and methods of using the drug linker compounds to prepare conjugates.
- the present invention provides compounds of formula I:
- R D is independently selected from R, C0 2 R, COR, CHO, C0 2 H, and halo
- R 6 and R 9 are independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR', N0 2 , Me 3 Sn and halo;
- R 7 is independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR', N0 2 , Me 3 Sn and halo;
- Y is selected from a single bond, and a group of formulae A1 or A2:
- N shows where the group binds to the N10 of the PBD moiety
- R L1 and R L2 are independently selected from H and methyl, or together with the carbon atom to which they are bound form a cyclopropylene group;
- Q is independently selected from O, S and NH;
- R 11 is either H, or R or, where Q is O, S0 3 M, where M is a metal cation;
- R and R' are each independently selected from optionally substituted C1-12 alkyl, C 3 - 2 o heterocyclyl and C 5 . 2 o aryl groups, and optionally in relation to the group NRR', R and R' together with the nitrogen atom to which they are attached form an optionally substituted 4-, 5-, 6- or 7-membered heterocyclic ring;
- R 12 , R 16 , R 19 and R 17 are as defined for R 2 , R 6 , R 9 and R 7 respectively;
- R" is a C 3 _i 2 alkylene group, which chain may be interrupted by one or more heteroatoms, e.g. O, S, N(H), NMe and/or aromatic rings, e.g. benzene or pyridine, which rings are optionally substituted; and
- X and X' are independently selected from O, S and N(H).
- the present invention provides compounds of formula II:
- the resent invention provides novel compounds of formula III:
- nitro group on the pyridyl ring of formula I compounds provides an electron- withdrawing effect which accelerates reaction with a cysteine thiol of a cysteine-engineered antibody.
- the cysteine thiol has been introduced at a hindered or less-reactive site on the antibody, the compounds of formula I provide more efficient conjugation relative to a corresponding unsubstituted pyridyl analog of a compound of formula I.
- the present invention provides methods of making conjugate compounds of formula A from drug linkers of the first aspect of the invention, by reacting a compound of the first aspect of the invention with a cell binding agent, wherein formula A is:
- CBA represents a cell binding agent
- ring selected from:
- V and W are each selected from (CH 2 ) n , O, S, NR, CHR, and CRR' where n is 1 , 2 or 3, except that V is C when R 1 and R 2 , together with the carbon atoms of the C ring to which they are attached, form an optionally substituted benzene ring, and W is C when R 3 and R 2 , together with the carbon atoms of the C ring to which they are attached, form an optionally substituted benzene ring; and
- T is selected from CH 2 , NR, CO, BH, SO, and S0 2 ;
- U is selected from CH 2 , NR, O and S;
- Y is (CH 2 ) n , where n is 1 , 2, 3 or 4;
- T, U and Y are not all CH 2 .
- a third aspect of the present invention provides conjugates of formula A1 :
- Ab represents a cysteine-engineered antibody mutant (THIOMABTM) selected from the group consisiting of:
- a fourth aspect of the present invention provides the use of a conjugate of the first aspect of the invention in a method of medical treatment.
- the fourth aspect also provides a pharmaceutical composition comprising a conjugate of the first aspect, and a
- a fifth aspect of the present invention provides a conjugate of the first aspect of the invention or a pharmaceutical composition of the fourth aspect of the invention for use in a method of treatment of a proliferative disease.
- the fifth aspect also provides the use of a conjugate of the first aspect in a method of manufacture of a medicament for the treatment of a proliferative disease, and a method of treating a mammal having a proliferative disease, comprising administering an effective amount of a conjugate of the first aspect or a pharmaceutical composition of the fourth aspect.
- the present invention provides a compound (drug-linker) comprising a PBD dimer connected through the N 10 position on one of the PBD moieties via the specified linker to leaving group, wherein the pyridine ring is substituted with a nitro group.
- the present invention also provides a method of preparing a conjugate from drug-linker compounds, the method comprising the step of reacting a cell binding agent with a drug- linker compound.
- the cell binding agent is an antibody.
- the conjugates so formed can deliver a PBD compound to a preferred site in a subject.
- the conjugate allows the release of an active PBD compound that does not retain any part of the linker. There is no stub present that could affect the reactivity of the PBD compound. Preferences
- the present invention provides dug linkers for use in the preparation of the conjugate compounds described herein.
- the compound is a dimer wherein each of the monomers has a C2 aryl group i.e. each R 2 is optionally substituted C5-20 aryl, and there is a double bond between C2 and C3 in each PBD moiety.
- n 0;
- n 1 ;
- R E is H
- R E is R D , where R D is optionally substituted alkyl; R E is R D , where R D is methyl;
- R L1 and R L2 are H;
- R L1 and R L2 are Me.
- the com ound is:
- Ar 1 and Ar 2 are each independently optionally substituted C 5 . 2 o aryl, and n is 0 or 1 .
- Ar 1 and Ar 2 may be the same or different.
- Ar 1 and Ar 2 in each of the embodiments above are each independently selected from optionally substituted phenyl, furanyl, thiophenyl and pyridyl.
- Ar 1 and Ar 2 in each of the embodiments above is optionally substituted phenyl. In one embodiment, Ar 1 and Ar 2 in each of the embodiments above is optionally substituted thien-2-yl or thien-3-yl.
- Ar 1 and Ar 2 in each of the embodiments above is optionally substituted quinolinyl or isoquinolinyl.
- the quinolinyl or isoquinolinyl group may be bound to the PBD core through any available ring position.
- the quinolinyl may be quinolin-2-yl, quinolin-3-yl, quinolin-4yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl and quinolin-8-yl. Of these quinolin-3-yl and quinolin-6-yl may be preferred.
- the isoquinolinyl may be isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl and isoquinolin-8-yl. Of these isoquinolin-3-yl and isoquinolin-6-yl may be preferred.
- the com ound is:
- R V1 and R V2 may be the same or different.
- R V1 and R V2 may be independently selected from H, phenyl, and 4-fluorophenyl.
- the pyridyl ring is monosubstituted in the 3-position with -N0 2 (meta relative to the disulfide). In some of the above embodiments, the pyridyl ring is monosubstituted in the 5-position with -N0 2 (para relative to the disulfide).
- the first aspect of the present invention provides compounds of formula (D) comprising a 2- mercaptopyridine leaving group.
- the pyridine ring of the leaving group is substituted at one or more positions with a nitro group.
- the conjugates are produced more efficiently from intermediates which have a nitro-substituted pyridyl compared to corresponding
- a nitro substituent is particularly effective at providing the enhanced reactivity of the intermediates required to more efficiently prepare the antibody- drug conjugates.
- the ring is mono-substituted at the 5-position with -N0 2 (para- to the disulfide), for example as in the following compound:
- the ring is mono-substituted at the 3-position with -N0 2 (meta- to the disulfide), for exam le as in the following compound:
- the ring is poly-substituted with nitro groups.
- the dotted lines indicate the optional presence of a double bond between C2 and C3, as shown below:
- a double bond is present between C2 and C3 when R 2 is C 5 . 2 o aryl or C-i-12 alkyl.
- the dotted lines indicate the optional presence of a double bond between C1 and C2, as shown below:
- a double bond is present between C1 and C2 when R 2 is C 5 . 2 o aryl or C-i-12 alkyl.
- R 2 is independently H.
- the configuration is configuration (I).
- R is independently R.
- R 2 is independently optionally substituted C5-20 aryl.
- R 2 is independently optionally substituted C1-12 alkyl.
- R 2 is independently optionally substituted C5-20 aryl
- R 2 is independently optionally substituted C 5 . 7 aryl.
- R 2 is independently optionally substituted C 8- io aryl
- R 2 is independently optionally substituted phenyl.
- R 2 is independently optionally substituted thienyl.
- R 2 is independently optionally substituted naphthyl.
- R 2 is independently optionally substituted pyridyl. In one embodiment, R 2 is independently optionally substituted quinolinyl or isoquinolinyl.
- R 2 bears one to three substituent groups, with 1 and 2 being more preferred, and singly substituted groups being most preferred.
- the substituents may be position.
- R 2 is a C 5 . 7 aryl group
- a single substituent is preferably on a ring atom that is not adjacent the bond to the remainder of the compound, i.e. it is preferably ⁇ or ⁇ to the bond to the remainder of the compound. Therefore, where the C 5 . 7 aryl group is phenyl, the substituent is preferably in the meta- or para- positions, and more preferably is in the para- position.
- R 2 is selected from:
- R 2 is a C 8 -io aryl group, for example quinolinyl or isoquinolinyl, it may bear any number of substituents at any position of the quinoline or isoquinoline rings. In some embodiments, it bears one, two or three substituents, and these may be on either the proximal and distal rings or both (if more than one substituent).
- R 2 is optionally substituted
- the substituents are selected from those substituents given in the substituent section below.
- R is optionally substituted
- the substituents are preferably selected from:
- R or R 2 is optionally substituted
- the substituents are selected from the group consisting of R, OR, SR, NRR', N0 2 , halo, C0 2 R, COR, CONH 2 , CONHR, and CONRR'.
- R 2 is 0 1-12 alkyl
- the optional substituent may additionally include C 3 . 2 o heterocyclyl and C 5 - 2 o aryl groups.
- R 2 is C 3 . 2 o heterocyclyl
- the optional substituent may additionally include 0 1-12 alkyl and C5-20 aryl groups.
- R 2 is C5-20 aryl groups
- the optional substituent may additionally include
- alkyl encompasses the sub-classes alkenyl and alkynyl as well as cycloalkyl.
- R 2 is optionally substituted C1-12 alkyl
- the alkyl group optionally contains one or more carbon-carbon double or triple bonds, which may form part of a conjugated system.
- the optionally substituted C1-12 alkyl group contains at least one carbon-carbon double or triple bond, and this bond is conjugated with a double bond present between C1 and C2, or C2 and C3.
- the C1-12 alkyl group is a group selected from saturated C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl and C3-12 cycloalkyl. If a substituent on R 2 is halo, it is preferably F or CI, more preferably F.
- a substituent on R 2 is ether, it may in some embodiments be an alkoxy group, for example, a C1-7 alkoxy group (e.g. methoxy, ethoxy) or it may in some embodiments be a C 5 . 7 aryloxy group (e.g. phenoxy, pyridyloxy, furanyloxy).
- a substituent on R 2 is Ci -7 alkyl, it may preferably be a Ci_ 4 alkyl group (e.g. methyl, ethyl, propyl, butyl).
- a substituent on R 2 is C3-7 heterocyclyl, it may in some embodiments be Ce nitrogen containing heterocyclyl group, e.g. morpholino, thiomorpholino, piperidinyl, piperazinyl.
- These groups may be bound to the rest of the PBD moiety via the nitrogen atom. These groups may be further substituted, for example, by Ci_ 4 alkyl groups.
- R 2 is bis-oxy-Ci_ 3 alkylene, this is preferably bis-oxy-methylene or bis-oxy- ethylene.
- R 2 Particularly preferred substituents for R 2 include methoxy, ethoxy, fluoro, chloro, cyano, bis- oxy-methylene, methyl-piperazinyl, morpholino and methyl-thienyl.
- Particularly preferred substituted R 2 groups include, but are not limited to, 4-methoxy-phenyl, 3-methoxyphenyl, 4-ethoxy-phenyl, 3-ethoxy-phenyl, 4-methyl-phenyl, 4-fluoro-phenyl, 4- chloro-phenyl, 3,4-bisoxymethylene-phenyl, 4-methylthienyl, 4-cyanophenyl, 4- phenoxyphenyl, quinolin-3-yl and quinolin-6-yl, isoquinolin-3-yl and isoquinolin-6-yl, 2-thienyl, 2-furanyl, methoxynaphthyl, and naphthyl.
- R 2 is halo or dihalo.
- R D is independently selected from R, C0 2 R, COR, CHO, C0 2 H, and halo.
- R D is independently R.
- R D is independently halo.
- R 6 is independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR', N0 2 , Me 3 Sn- and Halo.
- R 6 is independently selected from H, OH, OR, SH, NH 2 , N0 2 and Halo. In one embodiment, R 6 is independently selected from H and Halo.
- R 6 is independently H.
- R 6 and R 7 together form a group -0-(CH 2 ) p -0-, where p is 1 or 2.
- R 7 is independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR', N0 2 , Me 3 Sn and halo. In one embodiment, R 7 is independently OR.
- R 7 is independently OR 7A , where R 7A is independently optionally substituted Ci- 6 alkyl.
- R 7A is independently optionally substituted saturated Ci_ 6 alkyl.
- R 7A is independently optionally substituted C 2 . 4 alkenyl.
- R 7A is independently Me.
- R 7A is independently CH 2 Ph.
- R 7A is independently allyl.
- R 9 is independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR', N0 2 , Me 3 Sn- and Halo.
- R 9 is independently H.
- R 9 is independently R or OR.
- the linking group is removable from the N10 position of the PBD moiety in the conjugate of formula A to leave an N10-C1 1 imine bond, a carbinolamine, a substituted carbinolamine, where QR 11 is OS0 3 M, a bisulfite adduct, a thiocarbinolamine, a substituted
- the linking group is removable from the N10 position of the PBD moi to leave an N10-C1 1 imine bond.
- the specified link between the PBD dimer and the cell binding agent, e.g. antibody, in the present invention is preferably stable extracellularly.
- the antibody-drug conjugate (ADC) is preferably stable and remains intact, i.e. the antibody remains linked to the drug moiety.
- the linkers are stable outside the target cell and may be cleaved at some efficacious rate inside the cell.
- An effective linker will: (i) maintain the specific binding properties of the antibody; (ii) allow intracellular delivery of the conjugate or drug moiety; (iii) remain stable and intact, i.e.
- Stability of the ADC may be measured by standard analytical techniques such as mass spectroscopy, HPLC, and the
- PBD compounds Delivery of the PBD compounds is achieved at the desited activation site of the conjugates of formula A by the action of an enzyme on the linking group.
- the S of the conjugate of formula A is linked by a disulfide bond to a free S (active thiol) on the cell binding agent.
- the linking group may be cleavable by the action of an enzyme.
- the enzyme is a thio reductase.
- Certain antibodies have reducible interchain disulfides, i.e. cysteine bridges.
- Antibodies may be made reactive for conjugation with linker reagents by treatment with a reducing agent such as DTT (dithiothreitol).
- a reducing agent such as DTT (dithiothreitol).
- DTT dithiothreitol
- Each cysteine bridge will thus form, theoretically, two reactive thiol nucleophiles.
- Additional nucleophilic groups can be introduced into antibodies through the reaction of lysines with 2-iminothiolane (Traut's reagent) resulting in conversion of an amine into a thiol.
- Reactive thiol groups may be introduced into the antibody (or fragment thereof) by introducing one, two, three, four, or more cysteine residues (e.g., preparing mutant antibodies comprising one or more non-native cysteine amino acid residues).
- US 7521541 teaches engineering antibodies by introduction of reactive cysteine amino acids.
- R L1 and R L2 are selected from H and methyl, or together with the carbon atom to which they are bound form a cyclopropylene group. In some embodiments, both are H. In other embodiment, both are methyl. In further embodiments, one is H and the other is methyl; in these embodiments, the carbon atom to which they are bound is a chiral centre.
- Y is a single bond. In other embodiments, Y is
- Y is
- Q is selected from O, S, or N(H).
- Q is O.
- R 11 is either H, or R or, where Q is O, S0 3 M, where M is a metal cation. In one embodiment, R 11 is H.
- R 11 is R.
- R 11 is S0 3 M, where M is a metal cation.
- the cation may be Na + .
- the compounds of the first aspect of the invention are useful for reaction with a cell binding agent to produce a conjugate compound.
- the method of the second aspect of the present invention involves the reaction of a cell binding agent with a compound of the first aspect.
- a cell binding agent may be of any kind, and include peptides and non-peptides. These can include antibodies or a fragment of an antibody that contains at least one binding site, lymphokines, hormones, growth factors, nutrient-transport molecules, or any other cell binding molecule or substance.
- antibody herein is used in the broadest sense and specifically covers monoclonal antibodies, polyclonal antibodies, dimers, multimers, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, so long as they exhibit the desired biological activity (Miller et al (2003) Jour, of Immunology 170:4854-4861 ).
- Antibodies may be murine, human, humanized, chimeric, or derived from other species.
- An antibody is a protein generated by the immune system that is capable of recognizing and binding to a specific antigen. (Janeway, C, Travers, P., Walport, M., Shlomchik (2001 ) Immuno Biology, 5th Ed., Garland Publishing, New York).
- a target antigen generally has numerous binding sites, also called epitopes, recognized by CDRs on multiple antibodies. Each antibody that specifically binds to a different epitope has a different structure. Thus, one antigen may have more than one corresponding antibody.
- An antibody includes a full-length immunoglobulin molecule or an immunologically active portion of a full-length immunoglobulin molecule, i.e., a molecule that contains an antigen binding site that immunospecifically binds an antigen of a target of interest or part thereof, such targets including but not limited to, cancer cell or cells that produce autoimmune antibodies associated with an autoimmune disease.
- immunoglobulin can be of any type (e.g. IgG, IgE, IgM, IgD, and IgA), class (e.g. lgG1 , lgG2, lgG3, lgG4, lgA1 and lgA2) or subclass of immunoglobulin molecule.
- the immunoglobulins can be derived from any species, including human, murine, or rabbit origin.
- Antibody fragments comprise a portion of a full length antibody, generally the antigen binding or variable region thereof.
- Examples of antibody fragments include Fab, Fab', F(ab') 2 , and Fv fragments; diabodies; linear antibodies; fragments produced by a Fab expression library, anti-idiotypic (anti-Id) antibodies, CDR (complementary determining region), and epitope-binding fragments of any of the above which immunospecifically bind to cancer cell antigens, viral antigens or microbial antigens, single-chain antibody molecules; and multispecific antibodies formed from antibody fragments.
- monoclonal antibody refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e. the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site. Furthermore, in contrast to polyclonal antibody preparations which include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. In addition to their specificity, the monoclonal antibodies are advantageous in that they may be synthesized uncontaminated by other antibodies.
- the modifier "monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.
- the monoclonal antibodies to be used in accordance with the present invention may be made by the hybridoma method first described by Kohler et al (1975) Nature 256:495, or may be made by recombinant DNA methods (see, US 4816567).
- the monoclonal antibodies may also be isolated from phage antibody libraries using the techniques described in Clackson et al (1991 ) Nature, 352:624-628; Marks et al (1991 ) J. Mol. Biol., 222:581-597.
- the monoclonal antibodies herein specifically include "chimeric" antibodies in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (US 4816567; and Morrison et al (1984) Proc. Natl. Acad. Sci. USA, 81 :6851-6855).
- Chimeric antibodies include "primatized” antibodies comprising variable domain antigen-binding sequences derived from a non- human primate (e.g. Old World Monkey or Ape) and human constant region sequences.
- an “intact antibody” herein is one comprising a VL and VH domains, as well as a light chain constant domain (CL) and heavy chain constant domains, CH1 , CH2 and CH3.
- the constant domains may be native sequence constant domains (e.g. human native sequence constant domains) or amino acid sequence variant thereof.
- the intact antibody may have one or more "effector functions" which refer to those biological activities attributable to the Fc region (a native sequence Fc region or amino acid sequence variant Fc region) of an antibody. Examples of antibody effector functions include C1q binding; complement dependent cytotoxicity; Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; and down regulation of cell surface receptors such as B cell receptor and BCR.
- intact antibodies can be assigned to different "classes.” There are five major classes of intact antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into “subclasses” (isotypes), e.g., lgG1 , lgG2, lgG3, lgG4, IgA, and lgA2.
- the heavy-chain constant domains that correspond to the different classes of antibodies are called ⁇ , ⁇ , ⁇ , ⁇ , and ⁇ , respectively.
- the subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known.
- cell binding agents include those agents described for use in WO 2007/085930, which is incorporated herein.
- the cell binding agent may be, or comprise, a polypeptide.
- the polypeptide may be a cyclic polypeptide.
- the cell binding agent may be antibody.
- the method of the present invention provides an antibody-drug conjugate (ADC).
- ADC antibody-drug conjugate
- the drug loading is the average number of PBD drugs per antibody.
- Drug loading may range from 1 to 8 drugs (D) per antibody (Ab), i.e. where 1 , 2, 3, 4, 5, 6, 7, and 8 drug moieties are covalently attached to the antibody.
- Compositions of ADC include collections of antibodies conjugated with a range of drugs, from 1 to 8.
- the average number of drugs per antibody in preparations of ADC from conjugation reactions may be characterized by conventional means such as mass spectroscopy, ELISA assay, electrophoresis, and HPLC.
- the quantitative distribution of ADC in terms of p may also be determined.
- ELISA the averaged value of p in a particular preparation of ADC may be determined (Hamblett et al (2004) Clin. Cancer Res.
- p drug
- ELISA assay for detection of antibody-drug conjugates does not determine where the drug moieties are attached to the antibody, such as the heavy chain or light chain fragments, or the particular amino acid residues.
- separation, purification, and characterization of homogeneous ADC where p is a certain value from ADC with other drug loadings may be achieved by means such as reverse phase HPLC or electrophoresis.
- p may be limited by the number of attachment sites on the antibody.
- an antibody may have only one or several cysteine thiol groups, or may have only one or several sufficiently reactive thiol groups through which a linker may be attached.
- Higher drug loading, e.g. p >5, may cause aggregation, insolubility, toxicity, or loss of cellular permeability of certain antibody-drug conjugates.
- an antibody may contain, for example, many lysine residues that do not react with the drug-linker intermediate (D-L) or linker reagent. Only the most reactive lysine groups may react with an amine-reactive linker reagent. Also, only the most reactive cysteine thiol groups may react with a thiol-reactive linker reagent. Generally, antibodies do not contain many, if any, free and reactive cysteine thiol groups which may be linked to a drug moiety.
- cysteine thiol residues in the antibodies of the compounds exist as disulfide bridges and must be reduced with a reducing agent such as dithiothreitol (DTT) or TCEP, under partial or total reducing conditions.
- DTT dithiothreitol
- TCEP TCEP
- the loading (drug/antibody ratio) of an ADC may be controlled in several different manners, including: (i) limiting the molar excess of drug-linker intermediate (D-L) or linker reagent relative to antibody, (ii) limiting the conjugation reaction time or temperature, and (iii) partial or limiting reductive conditions for cysteine thiol modification.
- Cysteine amino acids may be engineered at reactive sites in an antibody and which do not form intrachain or intermolecular disulfide linkages (Junutula, et al., 2008b Nature Biotech., 26(8):925-932; Dornan et al (2009) Blood 1 14(13):2721 -2729; US 7521541 ; US 7723485; WO2009/052249, Shen et al (2012) Nature Biotech., 30(2):184-191 ; Junutula et al (2008) Jour of Immun. Methods 332:41-52).
- the engineered cysteine thiols may react with linker reagents or the drug-linker reagents of the present invention which have thiol-reactive, electrophilic groups such as maleimide or alpha-halo amides to form ADC with cysteine engineered antibodies (THIOMABTM) and the PBD drug moieties.
- the location of the drug moiety can thus be designed, controlled, and known.
- the drug loading can be controlled since the engineered cysteine thiol groups typically react with thiol-reactive linker reagents or drug-linker reagents in high yield.
- Engineering an IgG antibody to introduce a cysteine amino acid by substitution at a single site on the heavy or light chain gives two new cysteines on the symmetrical antibody.
- a drug loading near 2 can be achieved and near homogeneity of the conjugation product ADC.
- the resulting product is a mixture of ADC compounds with a distribution of drug moieties attached to an antibody, e.g. 1 , 2, 3, etc.
- Liquid chromatography methods such as polymeric reverse phase (PLRP) and hydrophobic interaction (HIC) may separate compounds in the mixture by drug loading value.
- Preparations of ADC with a single drug loading value (p) may be isolated, however, these single loading value ADCs may still be heterogeneous mixtures because the drug moieties may be attached, via the linker, at different sites on the antibody.
- the antibody-drug conjugate compositions described herein include mixtures of antibody-drug conjugate compounds where the antibody has one or more PBD drug moieties and where the drug moieties may be attached to the antibody at various amino acid residues.
- the average number of dimer pyrrolobenzodiazepine groups per cell binding agent is in the range 1 to 20. In some embodiments the range is selected from 1 to 8, 2 to 8, 2 to 6, 2 to 4, and 4 to 8. In some embodiments, there is one dimer pyrrolobenzodiazepine groups per cell binding agent.
- Cysteine-engineered antibody mutants are described in WO 2006/034488 and WO 201 1/156328, which are herein incorporated by reference.
- K149C mutant is also described in WO 2013/093809 and US 2013/0066054.
- the LC K149C cysteine-engineered antibody mutant comprises a CA polypeptide, or portion thereof, comprising the amino acid substitution K149C according to the numbering of Kabat.
- Figure 1 a shows an example sequence in which the mutated residue (in bold & underlined) is shown in context of the five preceding and subsequent amino acids.
- the LC V205C cysteine-engineered antibody mutant comprises a CA polypeptide, or portion thereof, comprising the amino acid substitution V205C according to the numbering of Kabat.
- Figure 1 b shows an example sequence in which the mutated residue (in bold & underlined) is shown in context of the five preceding and subsequent amino acids.
- HC A140C cysteine-engineered antibody mutant (THIOMABTM)
- the HC 140C cysteine-engineered antibody mutant comprises a Cy polypeptide, or portion thereof, comprising the amino acid substitution A140C according to the EU index of Kabat.
- Figure 1 c shows an example sequence in which the mutated residue (in bold & underlined) is shown in context of the five preceding and subsequent amino acids.
- the HC S239C cysteine-engineered antibody mutant comprises a Cy polypeptide, or portion thereof, comprising the amino acid substitution S239C according to the EU index of Kabat.
- Figure 1d shows an example sequence in which the mutated residue (in bold & underlined) is shown in context of the five preceding and subsequent amino acids.
- the cell binding agent is a linear or cyclic peptide comprising 4-20, preferably 6-20, contiguous amino acid residues. In this embodiment, it is preferred that one cell binding agent is linked to one monomer or dimer pyrrolobenzodiazepine compound.
- the cell binding agent comprises a peptide that binds integrin ⁇ ⁇ ⁇ 6 .
- the peptide may be selective for ⁇ ⁇ ⁇ 6 over XYS.
- the cell binding agent comprises the A20FMDV-Cys polypeptide.
- the A20FMDV-Cys has the sequence: NAVPNLRGDLQVLAQKVARTC [SEQ ID NO:5].
- the antibody is a monoclonal antibody; chimeric antibody; humanized antibody; fully human antibody; or a single chain antibody.
- the antibody is a fragment of one of these antibodies having biological activity. Examples of such fragments include Fab, Fab', F(ab') 2 and Fv fragments.
- each antibody may be linked to one or several dimer pyrrolobenzodiazepine groups. The preferred ratios of pyrrolobenzodiazepine to cell binding agent are given above.
- the antibody may be a domain antibody (DAB).
- the antibody is a monoclonal antibody.
- Antibodies for use in the method of the present invention include those antibodies described in WO 2005/082023 which is incorporated herein. Particularly preferred are those antibodies for tumour-associated antigens. Examples of those antigens known in the art include, but are not limited to, those tumour-associated antigens set out in WO 2005/082023. See, for instance, pages 41-55.
- the conjugates described herein are designed to target tumour cells via their cell surface antigens.
- the antigens are usually normal cell surface antigens which are either over- expressed or expressed at abnormal times. Ideally the target antigen is expressed only on proliferative cells (preferably tumour cells), however this is rarely observed in practice. As a result, target antigens are usually selected on the basis of differential expression between proliferative and healthy tissue.
- Antibodies have been raised to target specific tumour related antigens including:
- Tumor-associated antigens are known in the art, and can prepared for use in generating antibodies using methods and information which are well known in the art.
- TAA Tumor-associated antigens
- researchers have sought to identify transmembrane or otherwise tumor-associated polypeptides that are specifically expressed on the surface of one or more particular type(s) of cancer cell as compared to on one or more normal non-cancerous cell(s).
- tumor-associated polypeptides are more abundantly expressed on the surface of the cancer cells as compared to on the surface of the non-cancerous cells.
- the identification of such tumor-associated cell surface antigen polypeptides has given rise to the ability to specifically target cancer cells for destruction via antibody-based therapies.
- TAA examples include, but are not limited to, TAA (1 )-(53) listed below.
- TAA (1 )-(53) listed below.
- information relating to these antigens, all of which are known in the art, is listed below and includes names, alternative names, Genbank accession numbers and primary reference(s), following nucleic acid and protein sequence identification conventions of the National Center for Biotechnology Information (NCBI).
- NCBI National Center for Biotechnology Information
- Nucleic acid and protein sequences corresponding to TAA (1 )-(53) are available in public databases such as GenBank.
- Tumor-associated antigens targeted by antibodies include all amino acid sequence variants and isoforms possessing at least about 70%, 80%, 85%, 90%, or 95% sequence identity relative to the sequences identified in the cited references, or which exhibit substantially the same biological properties or characteristics as a TAA having a sequence found in the cited references.
- a TAA having a variant sequence generally is able to bind specifically to an antibody that binds specifically to the TAA with the corresponding sequence listed.
- BMPR1 B bone morphogenetic protein receptor-type IB, Genbank accession no.
- WO2004/032842 (Example IV); WO2003/042661 (Claim 12); WO2003/016475 (Claim 1 ); WO2002/78524 (Example 2); WO2002/99074 (Claim 19; Page 127-129); WO2002/86443 (Claim 27; Pages 222, 393); WO2003/003906 (Claim 10; Page 293); WO2002/64798 (Claim 33; Page 93-95); WO2000/14228 (Claim 5; Page 133-136); US2003/224454 (Fig 3);
- WO2002/89747 (Example 5; Page 618-619); WO2003/022995 (Example 9; Fig 13A, Example 53; Page 173, Example 2; Fig 2A); NP_036581 six transmembrane epithelial antigen of the prostate; Cross-references: MIM:604415; NP_036581 .1 ; NM_012449_1
- MPF MPF, MSLN, SMR, megakaryocyte potentiating factor, mesothelin, Genbank accession no. NM_005823
- Yamaguchi N., et al Biol. Chem. 269 (2), 805-808 (1994), Proc. Natl. Acad. Sci. U.S.A. 96 (20): 1 1531 -1 1536 (1999), Proc. Natl. Acad. Sci. U.S.A. 93
- Napi3b (NAPI-3B, NPTIIb, SLC34A2, solute carrier family 34 (sodium phosphate), member 2, type II sodium-dependent phosphate transporter 3b, Genbank accession no. NM_006424) J. Biol. Chem. 277 (22): 19665-19672 (2002), Genomics 62 (2):281 -284 (1999), Feild, J.A., et al (1999) Biochem. Biophys. Res. Commun. 258 (3):578-582);
- WO2004/022778 (Claim 2); EP1394274 (Example 1 1 ); WO2002/102235 (Claim 13; Page 326); EP0875569 (Claim 1 ; Page 17-19); WO2001/57188 (Claim 20; Page 329);
- WO2004/032842 (Example IV); WO2001/75177 (Claim 24; Page 139-140); Cross- references: MIM:604217; NP_006415.1 ; NM_006424_1 (7) Sema 5b (FLJ 10372, KIAA1445, Mm.42015, SEMA5B, SEMAG, Semaphorin 5b Hlog, sema domain, seven thrombospondin repeats (type 1 and type 1 -like), transmembrane domain (TM) and short cytoplasmic domain, (semaphorin) 5B, Genbank accession no. AB040878); Nagase T., et al (2000) DNA Res.
- PSCA hlg (2700050C12Rik, C530008O16Rik, RIKEN cDNA 2700050C12, RIKEN cDNA 2700050C12 gene, Genbank accession no. AY358628); Ross et al (2002) Cancer Res.
- ETBR Endothelin type B receptor, Genbank accession no. AY275463
- Nakamuta M. et al Biochem. Biophys. Res. Commun. 177, 34-39, 1991
- Ogawa Y. et al Biochem. Biophys.
- WO2004/048938 Example 2; WO2004/040000 (Claim 151 ); WO2003/087768 (Claim 1 ); WO2003/016475 (Claim 1 ); WO2003/016475 (Claim 1 ); WO2002/61087 (Fig 1 );
- STEAP2 (HGNC_8639, IPCA-1 , PCANAP1 , STAMP1 , STEAP2, STMP, prostate cancer associated gene 1 , prostate cancer associated protein 1 , six transmembrane epithelial antigen of prostate 2, six transmembrane prostate protein, Genbank accession no.
- TrpM4 (BR22450, FLJ20041 , TRPM4, TRPM4B, transient receptor potential cation channel, subfamily M, member 4, Genbank accession no. NM_017636); Xu, X.Z., et al Proc.
- CRIPTO (CR, CR1 , CRGF, CRIPTO, TDGF1 , teratocarcinoma-derived growth factor, Genbank accession no. NP_003203 or NM_003212); Ciccodicola, A., et al EMBO J. 8 (7): 1987-1991 (1989), Am. J. Hum. Genet.
- Example 1 WO2003/062401 (Claim 9); WO2004/045520 (Example 4); WO91/02536 (Fig 9.1 -9.9); WO2004/020595 (Claim 1 ); Accession: P20023; Q13866; Q14212; EMBL; M26004; AAA35786.1 .
- CD79b (CD79B, CD79p, IGb (immunoglobulin-associated beta), B29, Genbank accession no. NM_000626 or 1 1038674); Proc. Natl. Acad. Sci. U.S.A. (2003) 100 (7):4126- 4131 , Blood (2002) 100 (9):3068-3076, Muller et al (1992) Eur. J. Immunol.
- FcRH2 (IFGP4, IRTA4, SPAP1A (SH2 domain containing phosphatase anchor protein 1 a), SPAP1 B, SPAP1 C, Genbank accession no. NM_030764, AY358130); Genome Res. 13 (10):2265-2270 (2003), Immunogenetics 54 (2):87-95 (2002), Blood 99 (8):2662-2669 (2002), Proc. Natl. Acad. Sci. U.S.A. 98 (17):9772-9777 (2001 ), Xu, M.J., et al (2001 ) Biochem. Biophys. Res. Commun.
- HER2 ErbB2, Genbank accession no. M1 1730
- Coussens L et al Science (1985) 230(4730): 1 132-1 139
- Yamamoto T. et al Nature 319, 230-234, 1986
- Semba K. et al Proc. Natl. Acad. Sci. U.S.A. 82, 6497-6501 , 1985
- Swiercz J.M. et al J. Cell Biol. 165, 869-880, 2004
- Kuhns J.J. et al J. Biol. Chem. 27 '4, 36422-36427, 1999
- WO2003/055439 (Claim 29; Fig 1A-B); WO2003/025228 (Claim 37; Fig 5C); WO2002/22636 (Example 13; Page 95-107); WO2002/12341 (Claim 68; Fig 7); WO2002/13847 (Page 71 - 74); WO2002/14503 (Page 1 14-1 17); WO2001/53463 (Claim 2; Page 41 -46);
- WO2001/41787 (Page 15); WO2000/44899 (Claim 52; Fig 7); WO2000/20579 (Claim 3; Fig 2); US5869445 (Claim 3; Col 31 -38); WO9630514 (Claim 2; Page 56-61 ); EP1439393 (Claim 7); WO2004/043361 (Claim 7); WO2004/022709; WO2001/00244 (Example 3; Fig 4); Accession: P04626; EMBL; M1 1767; AAA35808.1 . EMBL; M1 1761 ; AAA35808.1 (18) NCA (CEACAM6, Genbank accession no.
- WO2002/60317 (Claim 2); Accession: P40199; Q14920; EMBL; M29541 ; AAA59915.1 .
- MDP DPEP1 , Genbank accession no. BC017023); Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899-16903 (2002)); WO2003/016475 (Claim 1 ); WO2002/64798 (Claim 33; Page 85- 87); JP05003790 (Fig 6-8); W099/46284 (Fig 9); Cross-references: MIM: 179780;
- IL20Ra (IL20Ra, ZCYTOR7, Genbank accession no. AF184971 ); Clark H.F., et al Genome Res. 13, 2265-2270, 2003; Mungall A.J., et al Nature 425, 805-81 1 , 2003;
- EP1394274 (Example 1 1 ); US2004/005320 (Example 5); WO2003/029262 (Page 74-75); WO2003/002717 (Claim 2; Page 63); WO2002/22153 (Page 45-47); US2002/042366 (Page 20-21 ); WO2001/46261 (Page 57-59); WO2001/46232 (Page 63-65); W098/37193 (Claim 1 ; Page 55-59); Accession: Q9UHF4; Q6UWA9; Q96SH8; EMBL; AF184971 ; AAF01320.1 .
- EphB2R (DRT, ERK, Hek5, EPHT3, Tyro5, Genbank accession no. NM_004442); Chan, J. and Watt, V.M., Oncogene 6 (6), 1057-1061 (1991 ) Oncogene 10 (5):897-905 (1995), Annu. Rev. Neurosci. 21 :309-345 (1998), Int. Rev. Cytol. 196: 177-244 (2000));
- WO2003042661 (Claim 12); WO200053216 (Claim 1 ; Page 41 ); WO2004065576 (Claim 1 ); WO2004020583 (Claim 9); WO2003004529 (Page 128-132); WO200053216 (Claim 1 ; Page 42); Cross-references: M I M: 600997; NP_004433.2; NM_004442_1
- WO2002/71928 (Page 468-469); WO2002/02587 (Example 1 ; Fig 1 ); WO2001/40269
- WO2003/000842 (Claim 1 ); WO2003/023013 (Example 3, Claim 20); US2003/194704 (Claim 45); Cross-references: Gl:30102449; AAP14954.1 ; AY260763_1
- BAFF-R B cell -activating factor receptor, BLyS receptor 3, BR3, Genbank accession No. AF1 16456
- BAFF receptor /pid NP_443177.1 - Homo sapiens: Thompson, J.S., et al
- WO2003/035846 (Claim 70; Page 615-616); WO2002/94852 (Col 136-137); WO2002/38766 (Claim 3; Page 133); WO2002/24909 (Example 3; Fig 3); Cross-references: M I M: 606269; NP_443177.1 ; NM_052945_1 ; AF132600 (27) CD22 (B-cell receptor CD22-B isoform, BL-CAM, Lyb-8, Lyb8, SIGLEC-2, FLJ22814, Genbank accession No. AK026467); Wilson et al (1991 ) J. Exp. Med. 173: 137-146;
- CD79a (CD79A, CD79a, immunoglobulin-associated alpha, a B cell-specific protein that covalently interacts with Ig beta (CD79B) and forms a complex on the surface with Ig M molecules, transduces a signal involved in B-cell differentiation), pi: 4.84, MW: 25028 TM: 2 [P] Gene Chromosome: 19q13.2, Genbank accession No. NP_001774.10); WO2003/088808, US2003/0228319; WO2003/062401 (claim 9); US2002/150573 (claim 4, pages 13-14);
- CXCR5 Bokitt's lymphoma receptor 1 , a G protein-coupled receptor that is activated by the CXCL13 chemokine, functions in lymphocyte migration and humoral defense, plays a role in HIV-2 infection and perhaps development of AIDS, lymphoma, myeloma, and leukemia); 372 aa, pi: 8.54 MW: 41959 TM: 7 [P] Gene Chromosome: 1 1 q23.3, Genbank accession No. NP_001707.1 ); WO2004/040000; WO2004/015426; US2003/105292
- Example 2 US6555339 (Example 2); WO2002/61087 (Fig 1 ); WO2001/57188 (Claim 20, page 269); WO2001/72830 (pages 12-13); WO2000/22129 (Example 1 , pages 152-153, Example 2, pages 254-256); W099/28468 (claim 1 , page 38); US5440021 (Example 2, col 49-52); W094/28931 (pages 56-58); W092/17497 (claim 7, Fig 5); Dobner et al (1992) Eur. J. Immunol. 22:2795-2799; Barella et al (1995) Biochem. J. 309:773-779
- HLA-DOB Beta subunit of MHC class II molecule (la antigen) that binds peptides and presents them to CD4+ T lymphocytes); 273 aa, pi: 6.56, MW: 30820.TM: 1 [P] Gene Chromosome: 6p21 .3, Genbank accession No. NP_0021 1 1 .1 ); Tonnelle et a/ (1985) EMBO J. 4(1 1 ):2839-2847; Jonsson et a/ (1989) Immunogenetics 29(6):41 1 -413; Beck et a/ (1992) J. Mol. Biol. 228:433-441 ; Strausberg et al (2002) Proc.
- P2X5 Purinergic receptor P2X ligand-gated ion channel 5, an ion channel gated by extracellular ATP, may be involved in synaptic transmission and neurogenesis, deficiency may contribute to the pathophysiology of idiopathic detrusor instability
- 422 aa pi: 7.63, MW: 47206 TM: 1
- Gene Chromosome 17p13.3, Genbank accession No. NP_002552.2
- Le et al (1997) FEBS Lett. 418(1 -2): 195-199; WO2004/047749; WO2003/072035 (claim 10); Touchman et al (2000) Genome Res. 10: 165-173; WO2002/22660 (claim 20);
- CD72 B-cell differentiation antigen CD72, Lyb-2
- LY64 Lymphocyte antigen 64 (RP105), type I membrane protein of the leucine rich repeat (LRR) family, regulates B-cell activation and apoptosis, loss of function is associated with increased disease activity in patients with systemic lupus erythematosis); 661 aa, pi: 6.20, MW: 74147 TM: 1 [P] Gene Chromosome: 5q12, Genbank accession No.
- NP_005573.1 US2002/193567; WO97/07198 (claim 1 1 , pages 39-42); Miura et al (1996) Genomics 38(3):299-304; Miura et al (1998) Blood 92:2815-2822; WO2003/083047;
- FcRH1 Fc receptor-like protein 1 , a putative receptor for the immunoglobulin Fc domain that contains C2 type Ig-like and ITAM domains, may have a role in B-lymphocyte differentiation
- IRTA2 Immunoglobulin superfamily receptor translocation associated 2, a putative immunoreceptor with possible roles in B cell development and lymphomagenesis
- TENB2 (TMEFF2, tomoregulin, TPEF, HPP1 , TR, putative transmembrane
- proteoglycan related to the EGF/heregulin family of growth factors and follistatin
- 374 aa NCBI Accession: AAD55776, AAF91397, AAG49451 , NCBI RefSeq: NP_057276; NCBI Gene: 23671 ; OMIM: 605734; SwissProt Q9UIK5; Genbank accession No. AF179274;
- PMEL17 (silver homoiog; SILV; D12S53E; PMEL17; SI; SIL); ME20; gp100) BC001414; BT007202; M32295; M77348; NM_006928; McGlinchey, R.P. et al (2009) Proc. Natl. Acad. Sci. U.S.A. 106 (33), 13731-13736; Kummer, M.P. et al (2009) J. Biol. Chem. 284 (4), 2296- 2306;
- TMEFF1 transmembrane protein with EGF-like and two follistatin-like domains 1 ;
- Tomoregulin-1 H7365; C9orf2; C90RF2; U19878; X83961 ; NM_080655; NM_003692; Harms, P.W. (2003) Genes Dev. 17 (21 ), 2624-2629; Gery, S. et al (2003) Oncogene 22 (18):2723-2727;
- GDNF-Ra1 GDNF family receptor alpha 1 ; GFRA1 ; GDNFR; GDNFRA; RETL1 ;
- Ly6E lymphocyte antigen 6 complex, locus E; Ly67,RIG-E,SCA-2,TSA-1 );
- LGR5 (!eucine-rich repeat-containing G protein-coupled receptor 5; GPR49, GPR67); NP_003658.1 ; NM_003667.2; Salanti, G. et al (2009) Am. J. Epidemiol. 170 (5):537-545;
- RET ret proto-oncogene
- MEN2A proto-oncogene
- HSCR1 HSCR1
- MEN2B MTC1 ; PTC; CDHF12; Hs.1681 14; RET51 ; RET-ELE1
- NP_066124.1 NM_020975.4
- LY6K lymphocyte antigen 6 complex, locus K; LY6K; HSJ001348; FLJ35226;
- GPR19 G protein-coupled receptor 19; Mm.4787; NP_006134.1 ; NM_006143.2;
- ASPHD1 aspartate beta-hydroxyiase domain containing 1 ; LOC253982; NP_859069.2; NM_181718.3; Gerhard, D.S. et al (2004) Genome Res. 14 (10B):2121-2127;
- Tyrosinase (TYR; OCAIA; OCA1A; tyrosinase; SHEP3); NP_000363.1 ; NM_000372.4; Bishop, D.T. et al (2009) Nat. Genet. 41 (8):920-925; Nan, H. et al (2009) Int. J. Cancer 125 (4):909-917; (50) TMEM1 18 (ring finger protein, transmembrane 2; RNFT2; FLJ14627); NP_001 103373.1 ; NM_001 109903.1 ; Clark, H.F. et al (2003) Genome Res. 13 (10):2265-2270; Scherer, S.E. et al (2006) Nature 440 (7082):346-351 (51 ) GPR172A (G protein-coupled receptor 172A; GPCR41 ; FLJ1 1856; D15Ertd747e);
- NP_078807.1 NM_024531.3; Ericsson, T.A. et al (2003) Proc. Natl. Acad. Sci. U.S.A. 100 (1 1 ):6759-6764; Takeda, S. et al (2002) FEBS Lett. 520 (1-3):97-101.
- CD33 a member of the sialic acid binding, immunoglobulin-like lectin family, is a 67- kDa glycosylated transmembrane protein. CD33is expressed on most myeloid and monocytic leukemia cells in addition to committed myelomonocytic and erythroid progenitor cells. It is not seen on the earliest pluripotent stem cells, mature granulocytes, lymphoid cells, or nonhematopoietic cells (Sabbath et al., (1985) J. Clin. Invest. 75:756-56; Andrews et al., (1986) Blood 68:1030-5). CD33 contains two tyrosine residues on its cytoplasmic tail, each of which is followed by hydrophobic residues similar to the immunoreceptor tyrosine-based inhibitory motif (ITIM) seen in many inhibitory receptors.
- ITIM immunoreceptor tyrosine-based inhibitory motif
- CLL-1 (CLEC12A, MICL, and DCAL2)
- CTL/CTLD C-type lectin-like domain
- CLL-1 has been shown to be a type II transmembrane receptor comprising a single C-type lectin-like domain (which is not predicted to bind either calcium or sugar), a stalk region, a transmembrane domain and a short cytoplasmic tail containing an ITIM motif.
- the parent antibody may also be a fusion protein comprising an albumin-binding peptide (ABP) sequence (Dennis et al. (2002) “Albumin Binding As A General Strategy For
- Antibodies of the invention include fusion proteins with ABP sequences taught by: (i) Dennis ef al (2002) J Biol Chem. 277:35035-35043 at Tables III and IV, page 35038; (ii) US 2004/0001827 at [0076]; and (iii) WO 01/45746 at pages 12-13, and all of which are incorporated herein by reference.
- the antibody has been raised to target specific the tumour related antigen ⁇ ⁇ ⁇ 6 .
- the ADCs of the present invention comprise anti-HER2 antibodies.
- an anti-HER2 antibody of an ADC of the invention comprises a humanized anti-HER2 antibody, e.g., huMAb4D5-1 , huMAb4D5-2, huMAb4D5- 3, huMAb4D5-4, huMAb4D5-5, huMAb4D5-6, huMAb4D5-7 and huMAb4D5-8, as described in Table 3 of US 5821337.
- Those antibodies contain human framework regions with the complementarity-determining regions of a murine antibody (4D5) that binds to HER2.
- the humanized antibody huMAb4D5-8 is also referred to as trastuzumab, commercially available as HERCEPTIN®.
- an anti-HER2 antibody of an ADC of the invention comprises a humanized anti-HER2 antibody, e.g., humanized 2C4, as described in US7862817.
- An exemplary humanized 2C4 antibody is pertuzumab, commercially available as PERJETA®.
- an anti-HER2 antibody of an ADC of the invention comprises a humanized anti-HER2 antibody is 7C2.
- the cysteine-engineered THIOMABTM antibodies have a cysteine residue introduced at the 149-lysine site of the light chain (LC K149C) according to the numbering of Kabat.
- cysteine-engineered THIOMABTM antibodies have a cysteine residue introduced at the 205-valine site of the light chain (LC V205C) according to the numbering of Kabat.
- the cysteine-engineered THIOMABTM antibodies have a cysteine residue introduced at the 1 18-alanine site (EU numbering) of the heavy chain (HC A1 18C). This site is alternatively numbered 121 by Sequential numbering or 1 14 by Kabat numbering. In other embodiments, the cysteine-engineered THIOMABTM antibodies have a cysteine residue introduced at the 140-alanine site (EU numbering) of the heavy chain (HC A140C). This site is alternatively numbered 143 by Sequential numbering or 136 by Kabat numbering.
- the cysteine-engineered THIOMABTM antibodies have a cysteine residue introduced at the 239-serine site (EU numbering) of the heavy chain (HC S239C). This site is alternatively numbered 242 by Sequential numbering or 235 by Kabat numbering.
- the cell binding agent may be labelled, for example to aid detection or purification of the agent either prior to incorporation as a conjugate, or as part of the conjugate.
- the label may be a biotin label.
- the cell binding agent may be labelled with a radioisotope.
- R is independently selected from optionally substituted 0 1-12 alkyl
- R is independently optionally substituted C1-12 alkyl.
- R is independently optionally substituted C 3 . 2 o heterocyclyl.
- R is independently optionally substituted C 5 . 2 o aryl.
- R is independently optionally substituted C1-12 alkyl.
- R 2 Described above in relation to R 2 are various embodiments relating to preferred alkyl and aryl groups and the identity and number of optional substituents.
- the preferences set out for R 2 as it applies to R are applicable, where appropriate, to all other groups R, for examples where R 6 , R 7 , R 8 or R 9 is R.
- a compound having a substituent group -NRR' having a substituent group -NRR'.
- R and R' together with the nitrogen atom to which they are attached form an optionally substituted 4-, 5-, 6- or 7-membered heterocyclic ring.
- the ring may contain a further heteroatom, for example N, O or S.
- the heterocyclic ring is itself substituted with a group R. Where a further N heteroatom is present, the substituent may be on the N heteroatom. R"
- R" is a C3-12 alkylene group, which chain may be interrupted by one or more heteroatoms, e.g. O, S, N(H), NMe and/or aromatic rings, e.g. benzene or pyridine, which rings are optionally substituted.
- heteroatoms e.g. O, S, N(H), NMe and/or aromatic rings, e.g. benzene or pyridine, which rings are optionally substituted.
- R" is a C3.12 alkylene group, which chain may be interrupted by one or more heteroatoms and/or aromatic rings, e.g. benzene or pyridine.
- the alkylene group is optionally interrupted by one or more heteroatoms selected from O, S, and NMe and/or aromatic rings, which rings are optionally substituted.
- the aromatic ring is a C 5 . 2 o arylene group, where arylene pertains to a divalent moiety obtained by removing two hydrogen atoms from two aromatic ring atoms of an aromatic compound, which moiety has from 5 to 20 ring atoms.
- R" is a C3.12 alkylene group, which chain may be interrupted by one or more heteroatoms, e.g. O, S, N(H), NMe and/or aromatic rings, e.g. benzene or pyridine, which rings are optionally substituted by NH 2 .
- heteroatoms e.g. O, S, N(H), NMe and/or aromatic rings, e.g. benzene or pyridine, which rings are optionally substituted by NH 2 .
- R" is a C3.12 alkylene group.
- R" is selected from a C 3 , C 5 , C 7 , C 9 and a Cn alkylene group.
- R" is selected from a C 3 , C 5 and a C 7 alkylene group.
- R" is selected from a C 3 and a C 5 alkylene group.
- R" is a C 3 alkylene group.
- R" is a C 5 alkylene group.
- alkylene groups listed above may be optionally interrupted by one or more heteroatoms and/or aromatic rings, e.g. benzene or pyridine, which rings are optionally substituted.
- alkylene groups listed above may be optionally interrupted by one or more heteroatoms and/or aromatic rings, e.g. benzene or pyridine.
- alkylene groups listed above may be unsubstituted linear aliphatic alkylene groups.
- X is selected from O, S, or N(H).
- X is O.
- the compounds where one or both C rings is replaced by a ring of formula E have a group R 2 which with either of R 1 or R 3 , together with carbon atoms of the C ring to which they are attached, form an optionally substituted benzene ring.
- the optionally substituted benzene ring may be regarded as fused to the C ring of the pyrrolobenzodiazepine.
- the fused benzene ring may be referred to as the D ring.
- the structure of the fused ring is illustrated below:
- the benzene ring is unsubstituted.
- the benzene ring is optionally substituted with one, two, three of four groups selected from OH, CN, R, OR, 0-S0 2 -R, C0 2 R, COR, SH, SR, NH 2 , NHR, NRR', N0 2 , Me 3 Sn and halo.
- the benzene ring is monosubstituted.
- the monosubstituent may be any one of D 1 , D 2 , D 3 or D 4 (the rest being H).
- the benzene ring is substituted at D 2 , and D 1 , D 3 and D 4 are each H.
- the benzene ring is substituted at D 3 , and D 1 , D 2 and D 4 are each H.
- R 2 with R 1 together with carbon atoms of the C ring to which they are attached, form an optionally substituted benzene ring.
- U is CH 2 when T is NR, BH, SO, or S0 2 .
- T is CH 2 or CO when U is NR, O or S.
- T is selected from CH 2 and CO.
- U is selected from NR, O and S.
- Y is (CH 2 ) n , where n is 1 or 2.
- the C ring of the compound A-B has a structure selected from those shown below:
- V and W are each selected from (CH 2 ) n , O, S, NR, CHR, and CRR' where n is 2,3 or 4, except that V is C when R 1 and R 2 , together with carbon atoms of the C ring to which they are attached, form an optionally substituted benzene ring, and W is C when R 3 and R 2 , together with carbon atoms of the C ring to which they are attached, form an optionally substituted benzene ring.
- the other of V and W is selected from CH 2 and NR.
- V and W when one of V and W is C, the other of V and W is CH 2 .
- the method of the second aspect of the present invention prepares conjugate compounds from the reaction between a cell binding agent and an intermediate compound of the present invention.
- the cell binding agent may be an antibody.
- conjugates with LC K149C, LC V205C, HC A140C, or HC S239C cysteine-engineered antibody mutant (THIOMABTM), where CBA below represents Ab as defined above.
- LC K149C cysteine-engineered antibody mutant THIOMABTM
- THIOMABTM cysteine-engineered antibody mutant
- CBA is a cell binding agent such as an antibody or a cyclic or linear peptide, and n is 0 or 1 .
- Y, R L1 and R L2 are as previously defined, and R E and R E " are each independently selected from H or R D .
- C2 Aryl is a cell binding agent such as an antibody or a cyclic or linear peptide, and n is 0 or 1 .
- CBA is a cell binding agent such as an antibody or a cyclic or linear peptide
- Y, R L1 and R L2 are as previously defined
- Ar 1 and Ar 2 are each independently optionally substituted C 5 . 2 o aryl, and n is 0 or 1 .
- Ar 1 and Ar 2 may be the same or different.
- Ar 1 and Ar 2 in each of the embodiments above are each independently selected from optionally substituted phenyl, furanyl, thiophenyl and pyridyl.
- Ar 1 and Ar 2 in each of the embodiments above is optionally substituted phenyl.
- Ar 1 and Ar 2 in each of the embodiments above is optionally substituted thien-2-yl or thien-3-yl. In one embodiment, Ar 1 and Ar 2 in each of the embodiments above is optionally substituted quinolinyl or isoquinolinyl.
- the quinolinyl or isoquinolinyl group may be bound to the PBD core through any available ring position.
- the quinolinyl may be quinolin-2-yl, quinolin-3-yl, quinolin-4yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl and quinolin-8-yl. Of these quinolin-3-yl and quinolin-6-yl may be preferred.
- the isoquinolinyl may be isoquinolin-1 -yl, isoquinolin-3-yl, isoquinolin-4yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl and isoquinolin-8-yl. Of these isoquinolin-3-yl and isoquinolin-6-yl may be preferred.
- CBA is a cell binding agent such as an antibody or a cyclic or linear peptide
- Y, R L1 and R L2 are as previously defined
- R V1 and R V2 are independently selected from H, methyl, ethyl and phenyl (which phenyl may be optionally substituted with fluoro, particularly in the 4 position) and C 5 . 6 heterocyclyl
- n is 0 or 1.
- R V1 and R V2 may be the same or different.
- R V1 and R V2 may be independently selected from H, phenyl, and 4-fluorophenyl.
- n 0;
- n 1 ;
- R E is H
- R E is R D , where R D is optionally substituted alkyl
- R E is R D , where R D is methyl
- CBA is an antibody, in particular a LC K149C, LC V205C, HC A140C, or HC S239C cysteine-engineered antibody mutant (THIOMABTM);
- CBA is a cyclic peptide
- R L1 and R L2 are H;
- R L1 and R L2 are Me.
- substituted refers to a parent group which bears one or more substituents.
- substituted is used herein in the conventional sense and refers to a chemical moiety which is covalently attached to, or if appropriate, fused to, a parent group.
- substituents are well known, and methods for their formation and introduction into a variety of parent groups are also well known.
- the substituents described herein are limited to those groups that are not reactive to a cell binding agent.
- the link to the cell binding agent in the present case is formed from the N10 position of the PBD compound through a linker group (comprising, for example, L 1 , L 2 and A) to the cell binding agent.
- a linker group comprising, for example, L 1 , L 2 and A
- Reactive functional groups located at other parts of the PBD structure may be capable of forming additional bonds to the cell binding agent (this may be referred to as crosslinking). These additional bonds may alter transport and biological activity of the conjugate. Therefore, in some embodiment, the additional substituents are limited to those lacking reactive functionality.
- the substituents are selected from the group consisting of R, OR, SR, NRR', N0 2 , halo, C0 2 R, COR, CONH 2 , CONHR, and CONRR'.
- the substituents are selected from the group consisting of R, OR, SR, NRR', N0 2 , C0 2 R, COR, CONH 2 , CONHR, and CONRR'.
- the substituents are selected from the group consisting of R, OR, SR, NRR', N0 2 , and halo.
- the substituents are selected from the group consisting of R, OR, SR, NRR', and N0 2 .
- any one of the embodiment mentioned above may be applied to any one of the substituents described herein.
- the substituents may be selected from one or more of the groups listed below.
- C-i-12 alkyl The term "Ci_i 2 alkyl” as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a hydrocarbon compound having from 1 to 12 carbon atoms, which may be aliphatic or alicyclic, and which may be saturated or unsaturated (e.g. partially unsaturated, fully unsaturated).
- alkyl includes the sub-classes alkenyl, alkynyl, cycloalkyl, etc., discussed below.
- saturated alkyl groups include, but are not limited to, methyl (Ci ), ethyl (C 2 ), propyl (C 3 ), butyl (C 4 ), pentyl (C 5 ), hexyl (C 6 ) and heptyl (C 7 ).
- saturated linear alkyl groups include, but are not limited to, methyl (Ci), ethyl (C 2 ), n-propyl (C 3 ), n-butyl (C 4 ), n-pentyl (amyl) (C 5 ), n-hexyl (C 6 ) and n-heptyl (C 7 ).
- saturated branched alkyl groups include iso-propyl (C 3 ), iso-butyl (C 4 ), sec-butyl (C 4 ), tert-butyl (C 4 ), iso-pentyl (C 5 ), and neo-pentyl (C 5 ).
- C 2 - 20 Heteroalkyi The term "C 2 - 12 heteroalkyi" as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a hydrocarbon compound having from 2 to 12 carbon atoms, and one or more heteroatoms selected from O, N(H) and S, preferably O and S.
- heteroalkyi groups include, but are not limited to those comprising one or more ethylene glycol units of the type -(OCH 2 CH 2 )-.
- the terminal of a heteroalkyi group may be the primary form of a heteroatom, e.g. -OH, -SH or -NH 2 . In a preferred embodiment, the terminal is -CH 3 .
- C 2 - 12 Alkenyl The term "C 2 - 12 alkenyl” as used herein, pertains to an alkyl group having one or more carbon-carbon double bonds.
- unsaturated alkenyl groups include, but are not limited to, ethenyl
- C 2 -i 2 alkynyl The term "C 2 - 12 alkynyl" as used herein, pertains to an alkyl group having one or more carbon-carbon triple bonds.
- unsaturated alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH) and 2-propynyl (propargyl, -CH 2 -C ⁇ CH).
- C 3 -i 2 cycloalkyl refers to an alkyl group which is also a cyclyl group; that is, a monovalent moiety obtained by removing a hydrogen atom from an alicyclic ring atom of a cyclic hydrocarbon (carbocyclic) compound, which moiety has from 3 to 7 carbon atoms, including from 3 to 7 ring atoms.
- cycloalkyl groups include, but are not limited to, those derived from:
- unsaturated monocyclic hydrocarbon compounds cyclopropene (C 3 ), cyclobutene (C 4 ), cyclopentene (C 5 ), cyclohexene (C 6 ), methylcyclopropene (C 4 ), dimethylcyclopropene (C 5 ), methylcyclobutene (C 5 ),
- C3-20 heterocyclyl refers to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound, which moiety has from 3 to 20 ring atoms, of which from 1 to 10 are ring heteroatoms.
- each ring has from 3 to 7 ring atoms, of which from 1 to 4 are ring heteroatoms.
- the prefixes e.g. C 3 . 2 o, C 3 . 7 , C 5 . 6 , etc.
- the prefixes denote the number of ring atoms, or range of number of ring atoms, whether carbon atoms or heteroatoms.
- the term "Cs-eheterocyclyl”, as used herein, pertains to a heterocyclyl group having 5 or 6 ring atoms.
- monocyclic heterocyclyl groups include, but are not limited to, those derived from:
- N 2 imidazolidine (C 5 ), pyrazolidine (diazolidine) (C 5 ), imidazoline (C 5 ), pyrazoline
- N1O1 tetrahydrooxazole (C 5 ), dihydrooxazole (C 5 ), tetrahydroisoxazole (C 5 ),
- N1S1 thiazoline (C 5 ), thiazolidine (C 5 ), thiomorpholine (C 6 );
- O1S1 oxathiole (C 5 ) and oxathiane (thioxane) (C 6 ); and, N1O1 S1 : oxathiazine (C 6 ).
- substituted monocyclic heterocyclyl groups include those derived from saccharides, in cyclic form, for example, furanoses (C 5 ), such as arabinofuranose, lyxofuranose, ribofuranose, and xylofuranse, and pyranoses (C 6 ), such as allopyranose, altropyranose, glucopyranose, mannopyranose, gulopyranose, idopyranose,
- C5-20 aryl The term "C 5 . 2 o aryl", as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound, which moiety has from 3 to 20 ring atoms. Preferably, each ring has from 5 to 7 ring atoms.
- the prefixes e.g. C 3 . 2 o, C 5 . 7 , C 5 . 6 , etc.
- the prefixes denote the number of ring atoms, or range of number of ring atoms, whether carbon atoms or heteroatoms.
- the term "C 5 . 6 aryl” as used herein, pertains to an aryl group having 5 or 6 ring atoms.
- the ring atoms may be all carbon atoms, as in "carboaryl groups".
- carboaryl groups include, but are not limited to, those derived from benzene (i.e. phenyl) (C 6 ), naphthalene (C10), azulene (C10), anthracene (C14), phenanthrene (CM), naphthacene (Ci 8 ), and pyrene (C-
- aryl groups which comprise fused rings include, but are not limited to, groups derived from indane (e.g. 2,3-dihydro-1 H-indene) (C 9 ), indene (C 9 ), isoindene (C 9 ), tetraline (1 ,2,3,4-tetrahydronaphthalene (C10),
- indane e.g. 2,3-dihydro-1 H-indene
- indene C 9
- isoindene C 9
- tetraline (1 ,2,3,4-tetrahydronaphthalene (C10)
- the ring atoms may include one or more heteroatoms, as in "heteroaryl groups".
- monocyclic heteroaryl groups include, but are not limited to, those derived from: Ni : pyrrole (azole) (C 5 ), pyridine (azine) (C 6 );
- N1O1 oxazole (C 5 ), isoxazole (C 5 ), isoxazine (C 6 );
- N3O1 oxatriazole (C 5 );
- N1S1 thiazole (C 5 ), isothiazole (C 5 );
- N 2 imidazole (1 ,3-diazole) (C 5 ), pyrazole (1 ,2-diazole) (C 5 ), pyridazine (1 ,2-diazine) (C 6 ), pyrimidine (1 ,3-diazine) (C 6 ) (e.g., cytosine, thymine, uracil), pyrazine (1 ,4-diazine) (C 6 );
- N 3 triazole (C 5 ), triazine (C 6 ); and,
- heteroaryl which comprise fused rings, include, but are not limited to:
- Cio (with 2 fused rings) derived from chromene (Oi ), isochromene (Oi ), chroman (Oi ), isochroman (Oi ), benzodioxan (0 2 ), quinoline (N-i ), isoquinoline (N-i ), quinolizine (N-i ), benzoxazine (N-
- Ci 3 (with 3 fused rings) derived from carbazole (N-i ), dibenzofuran (Oi ), dibenzothiophene (Si ), carboline (N 2 ), perimidine (N 2 ), pyridoindole (N 2 ); and,
- Ci 4 (with 3 fused rings) derived from acridine (N-i ), xanthene (Oi ), thioxanthene (Si ), oxanthrene (0 2 ), phenoxathiin (O1S1 ), phenazine (N 2 ), phenoxazine (N-
- Halo -F, -CI, -Br, and -I .
- Ether -OR, wherein R is an ether substituent, for example, a Ci_ 7 alkyl group (also referred to as a C-i-7 alkoxy group, discussed below), a C 3 . 20 heterocyclyl group (also referred to as a C 3 . 20 heterocyclyloxy group), or a C 5 . 2 o aryl group (also referred to as a C 5 . 2 o aryloxy group), preferably a Ci_ 7 alkyl group.
- Alkoxy -OR, wherein R is an alkyl group, for example, a Ci_ 7 alkyl group.
- Ci -7 alkoxy groups include, but are not limited to, -OMe (methoxy), -OEt (ethoxy), -O(nPr) (n- propoxy), -O(iPr) (isopropoxy), -O(nBu) (n-butoxy), -O(sBu) (sec-butoxy), -O(iBu) (isobutoxy), and -O(tBu) (tert-butoxy).
- Acetal -CH(OR 1 )(OR 2 ), wherein R 1 and R 2 are independently acetal substituents, for example, a Ci -7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group, preferably a Ci -7 alkyl group, or, in the case of a "cyclic" acetal group, R 1 and R 2 , taken together with the two oxygen atoms to which they are attached, and the carbon atoms to which they are attached, form a heterocyclic ring having from 4 to 8 ring atoms.
- acetal groups include, but are not limited to, -CH(OMe) 2 , -CH(OEt) 2 , and -CH(OMe)(OEt).
- Hemiacetal -CH(OH)(OR 1 ), wherein R 1 is a hemiacetal substituent, for example, a C1.7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group, preferably a Ci -7 alkyl group.
- hemiacetal groups include, but are not limited to, -CH(OH)(OMe) and - CH(OH)(OEt).
- Ketal -CR(OR 1 )(OR 2 ), where R 1 and R 2 are as defined for acetals, and R is a ketal substituent other than hydrogen, for example, a Ci_ 7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group, preferably a Ci -7 alkyl group.
- ketal groups include, but are not limited to, -C(Me)(OMe) 2 , -C(Me)(OEt) 2 , -C(Me)(OMe)(OEt), -C(Et)(OMe) 2 , -C(Et)(OEt) 2 , and -C(Et)(OMe)(OEt).
- R 1 is as defined for hemiacetals, and R is a hemiketal substituent other than hydrogen, for example, a Ci -7 alkyl group, a C3-20 heterocyclyl group, or a C 5 -2o aryl group, preferably a C 1-7 alkyl group.
- hemiacetal groups include, but are not limited to, -C(Me)(OH)(OMe), -C(Et)(OH)(OMe), -C(Me)(OH)(OEt),
- Imino (imine): NR, wherein R is an imino substituent, for example, hydrogen, Ci_ 7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group, preferably hydrogen or a Ci -7 alkyl group.
- R is an acyl substituent, for example, a Ci_ 7 alkyl group (also referred to as Ci -7 alkylacyl or Ci -7 alkanoyl), a C3-20 heterocyclyl group (also referred to as C3-20 heterocyclylacyl), or a C 5 -2o aryl group (also referred to as C 5 -2o arylacyl), preferably a Ci_7 alkyl group.
- a Ci_ 7 alkyl group also referred to as Ci -7 alkylacyl or Ci -7 alkanoyl
- C3-20 heterocyclylacyl also referred to as C3-20 heterocyclylacyl
- C 5 -2o aryl group also referred to as C 5 -2o arylacyl
- Carboxy (carboxylic acid): -C( 0)OH.
- Thiocarboxy (thiocarboxylic acid): -C( S)SH.
- Ester (carboxylate, carboxylic acid ester, oxycarbonyl): -C( 0)OR, wherein R is an ester substituent, for example, a Ci -7 alkyl group, a C 3 . 2 o heterocyclyl group, or a C5-20 aryl group, preferably a Ci -7 alkyl group.
- R is an acyloxy substituent, for example, a Ci -7 alkyl group, a C 3 . 2 o heterocyclyl group, or a C 5 -2o aryl group, preferably a Ci_ 7 alkyl group.
- Oxycarboyloxy: -OC( 0)OR, wherein R is an ester substituent, for example, a Ci -7 alkyl group, a C 3 . 2 o heterocyclyl group, or a C5-20 aryl group, preferably a Ci -7 alkyl group.
- ester groups include, but are not limited
- R 1 and R 2 are independently amino substituents, for example, hydrogen, a Ci -7 alkyl group (also referred to as Ci -7 alkylamino or di-Ci_ 7 alkylamino), a C 3 . 2 o heterocyclyl group, or a C5-20 aryl group, preferably H or a Ci -7 alkyl group, or, in the case of a "cyclic" amino group, R 1 and R 2 , taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 8 ring atoms.
- a Ci -7 alkyl group also referred to as Ci -7 alkylamino or di-Ci_ 7 alkylamino
- C 3 . 2 o heterocyclyl group or a C5-20 aryl group, preferably H or a Ci -7 alkyl group, or, in the case of a "cyclic" amino group, R 1 and R 2 , taken together with the nitrogen atom to which they
- Amino groups may be primary (-NH 2 ), secondary (-NHR 1 ), or tertiary (-NHR 1 R 2 ), and in cationic form, may be quaternary (- + NR 1 R 2 R 3 ).
- Examples of amino groups include, but are not limited
- cyclic amino groups include, but are not limited to, aziridino, azetidino, pyrrolidino, piperidino, piperazino, morpholino, and thiomorpholino.
- Amido (carbamoyl, carbamyl, aminocarbonyl, carboxamide): -C( 0)NR 1 R 2 , wherein R 1 and R 2 are independently amino substituents, as defined for amino groups.
- amido groups include, but are not limited
- R 1 and R 2 together with the nitrogen atom to which they are attached, form a heterocyclic structure as in, for example, piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl, and piperazinocarbonyl.
- Thioamido (thiocarbamyl): -C( S)NR 1 R 2 , wherein R 1 and R 2 are independently amino substituents, as defined for amino groups.
- Acylamido (acylamino): -NR 1 C( 0)R 2 , wherein R 1 is an amide substituent, for example, hydrogen, a Ci_ 7 alkyl group, a C 3 . 20 heterocyclyl group, or a C 5 . 2 o aryl group, preferably hydrogen or a C 1-7 alkyl group, and R 2 is an acyl substituent, for example, a C 1-7 alkyl group, a C 3 . 20 heterocyclyl group, or a C 5 . 2 oaryl group, preferably hydrogen or a Ci -7 alkyl group.
- acylamide groups include, but are not limited
- R 1 and R 2 may together form a cyclic structure, as in, for example, succinimidyl, maleimidyl, and phthalimidyl:
- R 2 and R 3 are independently amino substituents, as defined for amino groups, and R 1 is a ureido substituent, for example, hydrogen, a Ci_ 7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group, preferably hydrogen or a Ci -7 alkyl group.
- ureido groups include, but are not limited to, -NHCONH 2 , - NHCONHMe, -NHCONHEt, -NHCONMe 2 , -NHCONEt 2 , -NMeCONH 2 , - NMeCONHMe, -NMeCONHEt, -NMeCONMe 2 , and -NMeCONEt 2 .
- Tetrazolyl a five membered aromatic ring having four nitrogen atoms and one carbon atom
- Imino: NR, wherein R is an imino substituent, for example, for example, hydrogen, a Ci -7 alkyl group, a C 3 . 2 o heterocyclyl group, or a C 5 . 2 o aryl group, preferably H or a Ci_ 7 alkyl group.
- R is an amidine substituent, for example, hydrogen, a Ci_ 7 alkyl group, a C 3 . 2 o heterocyclyl group, or a C 5 . 2 o aryl group, preferably H or a Ci -7 alkyl group.
- amidine groups include, but are not limited
- Isocyano -NC. Cyanato: -OCN. Isocyanato: -NCO.
- a Ci_ 7 alkyl group also referred to as a Ci_ 7 alkylthio group
- C3-20 heterocyclyl group or a C5-20 aryl group, preferably a C1.7 alkyl group.
- C1.7 alkylthio groups include, but are not limited
- Disulfide -SS-R, wherein R is a disulfide substituent, for example, a Ci_ 7 alkyl group, a C 3 . 2 o heterocyclyl group, or a C5-20 aryl group, preferably a Ci_ 7 alkyl group (also referred to herein as C1-7 alkyl disulfide).
- Ci_ 7 alkyl disulfide groups include, but are not limited to, -SSCH3 and -SSCH2CH3.
- Sulfine (sulfinyl, sulfoxide): -S( 0)R, wherein R is a sulfine substituent, for example, a Ci_ 7 alkyl group, a C3-20 heterocyclyl group, or a C 5 -2o aryl group, preferably a Ci_ 7 alkyl group.
- R is a sulfine substituent, for example, a Ci_ 7 alkyl group, a C3-20 heterocyclyl group, or a C 5 -2o aryl group, preferably a Ci_ 7 alkyl group.
- R is a sulfone substituent, for example, a Ci_ 7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group, preferably a Ci_ 7 alkyl group, including, for example, a fluorinated or perfluorinated Ci_ 7 alkyl group.
- Sulfonic acid sulfo
- Sulfinate sulfinic acid ester
- R is a sulfinate substituent, for example, a C ⁇ - 7 alkyl group, a C 3 . 20 heterocyclyl group, or a C 5 . 2 o aryl group, preferably a Ci -7 alkyl group.
- Sulfonate (sulfonic acid ester): -S( 0) 2 OR, wherein R is a sulfonate substituent, for example, a Ci-7 alkyl group, a C 3 . 20 heterocyclyl group, or a C 5 - 2 o aryl group, preferably a Ci -7 alkyl group.
- R is a sulfinyloxy substituent, for example, a Ci_ 7 alkyl group, a C 3 . 20 heterocyclyl group, or a C 5 . 2 o aryl group, preferably a Ci -7 alkyl group.
- R is a sulfonyloxy substituent, for example, a Ci_ 7 alkyl group, a C 3 . 20 heterocyclyl group, or a C 5 . 2 o aryl group, preferably a Ci -7 alkyl group.
- R is a sulfate substituent, for example, a Ci_ 7 alkyl group, a C 3 . 20 heterocyclyl group, or a C 5 . 2 o aryl group, preferably a Ci -7 alkyl group.
- R 1 and R 2 are independently amino substituents, as defined for amino groups.
- R 1 and R 2 are independently amino substituents, as defined for amino groups.
- Examples of sulfonamido groups include, but are not limited
- R 1 is an amino substituent, as defined for amino groups
- R is a sulfonamino substituent, for example, a C 1-7 alkyl group, a C 3 . 20 heterocyclyl group, or a C 5 - 2 o aryl group, preferably a Ci_ 7 alkyl group.
- R 1 is an amino substituent, as defined for amino groups
- R is a sulfinamino substituent, for example, a Ci -7 alkyl group, a C 3 . 20 heterocyclyl group, or a C 5 - 2 o aryl group, preferably a Ci -7 alkyl group.
- R is a phosphino substituent, for example, -H, a Ci -7 alkyl group, a C 3 . 20 heterocyclyl group, or a C 5 . 2 o aryl group, preferably -H, a Ci -7 alkyl group, or a C 5 - 2 o aryl group.
- Examples of phosphino groups include, but are not limited
- R is a phosphinyl substituent, for example, a Ci -7 alkyl group, a C 3 . 20 heterocyclyl group, or a C 5 . 2 o aryl group, preferably a Ci -7 alkyl group or a C 5 . 2 o aryl group.
- Phosphonic acid phosphono
- Phosphonate phosphono ester
- R is a phosphonate substituent, for example, -H, a Ci -7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group, preferably -H, a C1-7 alkyl group, or a C5-20 aryl group.
- Phosphorous acid -OP(OH) 2 .
- Phosphite -OP(OR) 2 , where R is a phosphite substituent, for example, -H, a Ci_ 7 alkyl group, a C 3 . 20 heterocyclyl group, or a C 5 . 2 o aryl group, preferably -H, a Ci -7 alkyl group, or a C 5 . 2 o aryl group.
- R is a phosphite substituent, for example, -H, a Ci_ 7 alkyl group, a C 3 . 20 heterocyclyl group, or a C 5 . 2 o aryl group, preferably -H, a Ci -7 alkyl group, or a C 5 . 2 o aryl group.
- phosphite groups include, but are not limited
- Phosphoramidite -OP(OR 1 )-NR 2 2 , where R 1 and R 2 are phosphoramidite substituents, for example, -H, a (optionally substituted) Ci -7 alkyl group, a C 3 . 20 heterocyclyl group, or a C 5 . 2 o aryl group, preferably -H, a Ci -7 alkyl group, or a C 5 . 2 o aryl group. Examples of
- phosphoramidite groups include, but are not limited to, -OP(OCH 2 CH 3 )- N(CH 3 ) 2 , -OP(OCH 2 CH 3 )-N(i-Pr) 2 , and -OP(OCH 2 CH 2 CN)-N(i-Pr) 2 .
- C 3 -i 2 alkylene refers to a bidentate moiety obtained by removing two hydrogen atoms, either both from the same carbon atom, or one from each of two different carbon atoms, of a hydrocarbon compound having from 3 to 12 carbon atoms (unless otherwise specified), which may be aliphatic or alicyclic, and which may be saturated, partially unsaturated, or fully unsaturated.
- alkylene includes the sub-classes alkenylene, alkynylene, cycloalkylene, etc., discussed below.
- linear saturated C 3 .i 2 alkylene groups include, but are not limited to, -(CH 2 ) n - where n is an integer from 3 to 12, for example, -CH 2 CH 2 CH2- (propylene), -CH2CH2CH2CH2- (butylene), -CH2CH2CH2CH2CH2- (pentylene)
- branched saturated C3.12 alkylene groups include, but are not limited to, -CH(CH 3 )CH 2 -, -CH(CH 3 )CH 2 CH 2 -, -CH(CH3)CH 2 CH 2 CH2-, -CH 2 CH(CH 3 )CH 2 -, -CH 2 CH(C H 3 )CH 2 CH 2 -, -CH(CH 2 CH 3 )-, -CH(CH 2 CH 3 )CH 2 -, and -CH 2 CH(CH 2 CH 3 )CH 2 -.
- alicyclic saturated C 3 _i 2 alkylene groups include, but are not limited to, cyclopentylene (e.g. cyclopent-1 ,3-ylene), and cyclohexylene
- C3-12 cycloalkylenes examples include, but are not limited to, cyclopentenylene (e.g. 4-cyclopenten-1 ,3-ylene),
- cyclohexenylene e.g. 2-cyclohexen-1 ,4-ylene; 3-cyclohexen-1 ,2-ylene; 2,5-cyclohexadien- 1 ,4-ylene).
- a reference to carboxylic acid (-COOH) also includes the anionic (carboxylate) form (-COO ), a salt or solvate thereof, as well as conventional protected forms.
- a reference to an amino group includes the protonated form (-N + HR 1 R 2 ), a salt or solvate of the amino group, for example, a
- hydrochloride salt as well as conventional protected forms of an amino group.
- a reference to a hydroxyl group also includes the anionic form (-0 ), a salt or solvate thereof, as well as conventional protected forms.
- a corresponding salt of the drug linker compound for example, a pharmaceutically-acceptable salt.
- a pharmaceutically-acceptable salt examples are discussed in Berge, et al., J. Pharm. Sci., 66, 1-19 (1977).
- a salt may be formed with a suitable cation.
- suitable inorganic cations include, but are not limited to, alkali metal ions such as Na + and K + , alkaline earth cations such as Ca 2+ and Mg 2+ , and other cations such as Af 3 .
- suitable organic cations include, but are not limited to, ammonium ion (i.e. NH 4 + ) and substituted ammonium ions (e.g. NH 3 R + , NH 2 R2 + , NHR 3 + , NR 4 + ).
- suitable substituted ammonium ions are those derived from: ethylamine, diethylamine,
- a common quaternary ammonium ion is N(CH 3 ) 4 + .
- a salt may be formed with a suitable anion.
- suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids:
- hydrochloric hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous.
- Suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic,
- Suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose. Solvates
- solvate is used herein in the conventional sense to refer to a complex of solute (e.g. active compound, salt of active compound) and solvent. If the solvent is water, the solvate may be conveniently referred to as a hydrate, for example, a mono-hydrate, a di-hydrate, a tri-hydrate, etc.
- the invention includes compounds where a solvent adds across the imine bond of the PBD moiety, which is illustrated below where the solvent is water or an alcohol (R A OH, where R A
- carbinolamine and carbinolamine ether forms of the PBD can be called the carbinolamine and carbinolamine ether forms of the PBD (as described in the section relating to R 10 above).
- the balance of these equilibria depend on the conditions in which the compounds are found, as well as the nature of the moiety itself. These particular compounds may be isolated in solid form, for example, by lyophilisation.
- Certain compounds of the invention may exist in one or more particular geometric, optical, enantiomeric, diasteriomeric, epimeric, atropic, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, and r- forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d- and l-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; a- and ⁇ -forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and combinations thereof, hereinafter collectively referred to as "isomers” (or "isomeric forms").
- stereoisomers refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
- Diastereomer refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography. “Enantiomers” refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.
- the compounds of the invention may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention.
- a specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
- a 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.
- the terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.
- isomers are structural (or constitutional) isomers (i.e. isomers which differ in the connections between atoms rather than merely by the position of atoms in space).
- a reference to a methoxy group, -OCH 3 is not to be construed as a reference to its structural isomer, a hydroxymethyl group, -CH 2 OH.
- a reference to ortho-chlorophenyl is not to be construed as a reference to its structural isomer, meta- chlorophenyl.
- a reference to a class of structures may well include structurally isomeric forms falling within that class (e.g. C ⁇ alkyl includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para- methoxyphenyl).
- C ⁇ alkyl includes n-propyl and iso-propyl
- butyl includes n-, iso-, sec-, and tert-butyl
- methoxyphenyl includes ortho-, meta-, and para- methoxyphenyl
- keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, N-nitroso/hyroxyazo, and nitro/aci-nitro.
- tautomer or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier.
- proton tautomers also known as prototropic tautomers
- Valence tautomers include interconversions by reorganization of some of the bonding electrons.
- H may be in any isotopic form, including 1 H, 2 H (D), and 3 H (T); C may be in any isotopic form, including 12 C, 13 C, and 14 C; O may be in any isotopic form, including 16 0 and 18 0; and the like.
- isotopes examples include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as, but not limited to 2 H (deuterium, D), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 CI, and 125 l.
- isotopically labeled compounds of the present invention for example those into which radioactive isotopes such as 3H, 13C, and 14C are incorporated.
- Such isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
- Deuterium labelled or substituted therapeutic compounds of the invention may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
- An 18F labeled compound may be useful for PET or SPECT studies.
- Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
- substitution with heavier isotopes, particularly deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index. It is understood that deuterium in this context is regarded as a substituent.
- the concentration of such a heavier isotope, specifically deuterium may be defined by an isotopic enrichment factor.
- any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom.
- a reference to a particular compound includes all such isomeric forms, including (wholly or partially) racemic and other mixtures thereof.
- Methods for the preparation (e.g. asymmetric synthesis) and separation (e.g. fractional crystallisation and chromatographic means) of such isomeric forms are either known in the art or are readily obtained by adapting the methods taught herein, or known methods, in a known manner.
- Exemplary drug linker compounds of formula I include: (1 1 S,1 1 aS)-((R)-2-((3-nitropyridin-2- yl)disulfanyl)propyl) 1 1-hydroxy-7- methoxy-8-(5-((S)-7-methoxy-2- methylene-5-oxo-2,3,5, 1 1 a-tetrahydro-
- the cytotoxic or cytostatic activity of an antibody-drug conjugate is measured by: exposing mammalian cells having receptor proteins, e.g. HER2, to the antibody of the ADC in a cell culture medium; culturing the cells for a period from about 6 hours to about 5 days; and measuring cell viability.
- Cell-based in vitro assays are used to measure viability (proliferation), cytotoxicity, and induction of apoptosis (caspase activation) of an ADC of the invention.
- the in vitro potency of antibody-drug conjugates can be measured by a cell proliferation assay.
- the CellTiter-Glo ® Luminescent Cell Viability Assay is a commercially available (Promega Corp., Madison, Wl), homogeneous assay method based on the recombinant expression of Coleoptera luciferase (US Patent Nos. 5583024; 5674713 and 5700670).
- This cell proliferation assay determines the number of viable cells in culture based on quantitation of the ATP present, an indicator of metabolically active cells (Crouch et al (1993) J. Immunol. Meth. 160:81-88; US 6602677).
- the CellTiter-Glo ® Assay is conducted in 96 well format, making it amenable to automated high-throughput screening (HTS) (Cree et al (1995) Anticancer Drugs 6:398-404).
- the homogeneous assay procedure involves adding the single reagent (CellTiter-Glo ® Reagent) directly to cells cultured in serum-supplemented medium. Cell washing, removal of medium and multiple pipetting steps are not required.
- the system detects as few as 15 cells/well in a 384-well format in 10 minutes after adding reagent and mixing.
- the cells may be treated continuously with ADC, or they may be treated and separated from ADC. Generally, cells treated briefly, i.e. 3 hours, showed the same potency effects as continuously treated cells.
- the homogeneous "add-mix-measure” format results in cell lysis and generation of a luminescent signal proportional to the amount of ATP present.
- the amount of ATP is directly proportional to the number of cells present in culture.
- the CellTiter-Glo ® Assay generates a "glow-type" luminescent signal, produced by the luciferase reaction, which has a half-life generally greater than five hours, depending on cell type and medium used. Viable cells are reflected in relative luminescence units (RLU).
- the substrate, Beetle Luciferin is oxidatively decarboxylated by recombinant firefly luciferase with concomitant conversion of ATP to AMP and generation of photons.
- the in vivo efficacy of antibody-drug conjugates (ADC) of the invention can be measured by tumor xenograft studies in mice.
- ADC antibody-drug conjugates
- an anti-HER2 ADC of the invention can be measured by a high expressing HER2 transgenic explant mouse model.
- An allograft is propagated from the Fo5 mmtv transgenic mouse which does not respond to, or responds poorly to, HERCEPTIN® therapy.
- Subjects can be treated once with ADC at certain dose levels (mg/kg) and PBD drug exposure ⁇ g/m 2 ); and placebo buffer control (Vehicle) and monitored over two weeks or more to measure the time to tumor doubling, log cell kill, and tumor shrinkage.
- the conjugates described herein may be used to provide a PBD compound at a target location.
- the target location is preferably a proliferative cell population.
- the antibody is an antibody for an antigen present in a proliferative cell population.
- the antigen is absent or present at a reduced level in a non-proliferative cell population compared to the amount of antigen present in the proliferative cell population, for example a tumour cell population.
- the linker may be cleaved by an enzyme present at the target location.
- the target location may be in vitro, in vivo or ex vivo.
- the antibody-drug conjugate (ADC) compounds described herein include those with utility for anticancer activity.
- the compounds include an antibody conjugated, i.e. covalently attached by a linker, to a PBD drug moiety, i.e. toxin.
- the PBD drug has a cytotoxic effect.
- the biological activity of the PBD drug moiety is thus modulated by conjugation to an antibody.
- the antibody-drug conjugates (ADC) of the invention selectively deliver an effective dose of a cytotoxic agent to tumor tissue whereby greater selectivity, i.e. a lower efficacious dose, may be achieved.
- conjugate compound for use in therapy is also described herein.
- conjugate compound for use in the treatment of a proliferative disease is also described herein.
- use of a conjugate compound in the manufacture of a medicament for treating a proliferative disease is also described herein.
- proliferative disease pertains to an unwanted or uncontrolled cellular proliferation of excessive or abnormal cells which is undesired, such as, neoplastic or hyperplastic growth, whether in vitro or in vivo.
- proliferative conditions include, but are not limited to, benign, pre-malignant, and malignant cellular proliferation, including but not limited to, neoplasms and tumours (e.g. histocytoma, glioma, astrocyoma, osteoma), cancers (e.g. lung cancer, small cell lung cancer, gastrointestinal cancer, bowel cancer, colon cancer, breast carcinoma, ovarian carcinoma, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreas cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, melanoma), leukemias, psoriasis, bone diseases, fibroproliferative disorders (e.g. of connective tissues), and atherosclerosis.
- Cancers of particular interest include, but are not limited to, leukemias and ovarian cancers.
- Any type of cell may be treated, including but not limited to, lung, gastrointestinal (including, e.g. bowel, colon), breast (mammary), ovarian, prostate, liver (hepatic), kidney (renal), bladder, pancreas, brain, and skin.
- gastrointestinal including, e.g. bowel, colon
- breast mammary
- ovarian prostate
- liver hepatic
- kidney renal
- bladder pancreas
- brain and skin.
- the treatment is of a pancreatic cancer.
- the treatment is of a tumour having ⁇ ⁇ ⁇ 6 integrin on the surface of the cell.
- the antibody-drug conjugates (ADC) described herein may be used to treat various diseases or disorders, e.g. characterized by the overexpression of a tumor antigen.
- exemplary conditions or hyperproliferative disorders include benign or malignant tumors; leukemia, haematological, and lymphoid malignancies.
- Others include neuronal, glial, astrocytal, hypothalamic, glandular, macrophagal, epithelial, stromal, blastocoelic, inflammatory, angiogenic and immunologic, including autoimmune, disorders.
- the disease or disorder to be treated is a hyperproliferative disease such as cancer.
- cancer to be treated herein include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More particular examples of such cancers include squamous cell cancer (e.g.
- lung cancer including small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, as well as head and neck cancer.
- lung cancer including small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer,
- Autoimmune diseases for which the ADC compounds may be used in treatment include rheumatologic disorders (such as, for example, rheumatoid arthritis, Sjogren's syndrome, scleroderma, lupus such as SLE and lupus nephritis, polymyositis/dermatomyositis, cryoglobulinemia, anti-phospholipid antibody syndrome, and psoriatic arthritis), osteoarthritis, autoimmune gastrointestinal and liver disorders (such as, for example, inflammatory bowel diseases (e.g.
- autoimmune gastritis and pernicious anemia autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, and celiac disease
- vasculitis such as, for example, ANCA-associated vasculitis, including Churg-Strauss vasculitis, Wegener's granulomatosis, and polyarteriitis
- autoimmune neurological disorders such as, for example, multiple sclerosis, opsoclonus myoclonus syndrome, myasthenia gravis, neuromyelitis optica, Parkinson's disease, Alzheimer's disease, and autoimmune polyneuropathies
- renal disorders such as, for example, glomerulonephritis, Goodpasture's syndrome, and Berger's disease
- autoimmune dermatologic disorders such as, for example, psoriasis, urticaria, hives, pemphigus vulgaris, bullous pemphigoid,
- Graves' disease and thyroiditis More preferred such diseases include, for example, rheumatoid arthritis, ulcerative colitis, ANCA-associated vasculitis, lupus, multiple sclerosis, Sjogren's syndrome, Graves' disease, IDDM, pernicious anemia, thyroiditis, and
- conjugates described herein may be used in a method of therapy. Also provided is a method of treatment, comprising administering to a subject in need of treatment a
- therapeutically-effective amount of a conjugate compound described herein.
- therapeutically effective amount is an amount sufficient to show benefit to a patient. Such benefit may be at least amelioration of at least one symptom.
- the actual amount is an amount sufficient to show benefit to a patient. Such benefit may be at least amelioration of at least one symptom.
- a compound may be administered alone or in combination with other treatments, either simultaneously or sequentially dependent upon the condition to be treated.
- treatments and therapies include, but are not limited to, chemotherapy (the administration of active agents, including, e.g. drugs, such as chemotherapeutics); surgery; and radiation therapy.
- chemotherapeutic agent is a chemical compound useful in the treatment of cancer, regardless of mechanism of action.
- Classes of chemotherapeutic agents include, but are not limited to: alkylating agents, antimetabolites, spindle poison plant alkaloids,
- Chemotherapeutic agents include compounds used in "targeted therapy” and conventional chemotherapy.
- chemotherapeutic agents include: erlotinib (TARCEVA®, Genentech/OSI Pharm.), docetaxel (TAXOTERE®, Sanofi-Aventis), 5-FU (fluorouracil, 5-fluorouracil, CAS No. 51-21-8), gemcitabine (GEMZAR®, Lilly), PD-0325901 (CAS No. 391210-10-9, Pfizer), cisplatin (cis-diamine, dichloroplatinum(ll), CAS No. 15663-27-1 ), carboplatin (CAS No.
- paclitaxel TAXOL®, Bristol-Myers Squibb Oncology, Princeton, N.J.
- trastuzumab HERCEPTIN®, Genentech
- temozolomide 4-methyl-5-oxo- 2,3,4,6,8- pentazabicycio [4.3.0] nona-2,7,9-triene- 9-carboxamide, CAS No.
- doxorubicin 85622-93-1 , TEMODAR®, TEMODAL®, Schering Plough), tamoxifen ((Z)-2-[4-(1 ,2-diphenylbut-1-enyl)phenoxy]-/V,/V- dimethylethanamine, NOLVADEX®, ISTUBAL®, VALODEX®), and doxorubicin
- chemotherapeutic agents include: oxaliplatin (ELOXATIN®, Sanofi), bortezomib (VELCADE®, Millennium Pharm.), sutent (SUNITINIB®, SU1 1248, Pfizer), letrozole (FEMARA®, Novartis), imatinib mesylate (GLEEVEC®, Novartis), XL-518 (Mek inhibitor, Exelixis, WO 2007/044515), ARRY-886 (Mek inhibitor, AZD6244, Array BioPharma, Astra Zeneca), SF-1 126 (PI3K inhibitor, Semafore Pharmaceuticals), BEZ-235 (PI3K inhibitor, Novartis), XL-147 (PI3K inhibitor, Exelixis), PTK787/ZK 222584 (Novartis), fulvestrant (FASLODEX®, AstraZeneca), leucovorin (folinic acid), rapamycin (si
- alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analog topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogs); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolast
- calicheamicin calicheamicin gammal l, calicheamicin omegaH (Angew Chem. Intl. Ed. Engl. (1994) 33: 183-186); dynemicin, dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, morpholino-doxorubicin,
- cyanomorpholino-doxorubicin 2-pyrrolino-doxorubicin and deoxydoxorubicin
- epirubicin esorubicin, idarubicin, nemorubicin, marcellomycin
- mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin
- anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-aza
- etoglucid gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine;
- pentostatin phenamet
- pirarubicin losoxantrone
- podophyllinic acid 2-ethylhydrazide
- PSK® polysaccharide complex JHS Natural Products, Eugene, OR
- razoxane rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2, 2', 2"- trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol;
- pipobroman gacytosine; arabinoside ("Ara-C”); cyclophosphamide; thiotepa; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin;
- vinblastine etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; vinorelbine
- NAVELBINE® novantrone
- teniposide edatrexate
- daunomycin aminopterin
- capecitabine XELODA®, Roche
- ibandronate CPT-1 1 ; topoisomerase inhibitor RFS 2000;
- DMFO difluoromethylornithine
- retinoids such as retinoic acid
- pharmaceutically acceptable salts, acids and derivatives of any of the above DMFO
- DMFO difluoromethylornithine
- chemotherapeutic agent include: (i) anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including
- aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE®
- anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; as well as troxacitabine (a 1 ,3-dioxolane nucleoside cytosine analog);
- protein kinase inhibitors such as MEK inhibitors (WO 2007/044515);
- antisense oligonucleotides particularly those which inhibit expression of genes in signaling pathways implicated in aberrant cell proliferation, for example, PKC-alpha, Raf and H-Ras, such as oblimersen (GENA
- chemotherapeutic agent therapeutic antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen personal), pertuzumab (OMNITARGTM, 2C4, Genentech), trastuzumab (HERCEPTIN®,
- Humanized monoclonal antibodies with therapeutic potential as chemotherapeutic agents in combination with the conjugates of the invention include: alemtuzumab, apolizumab, aselizumab, atlizumab, bapineuzumab, bevacizumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin,
- tacatuzumab tetraxetan tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab, trastuzumab, tucotuzumab celmoleukin, tucusituzumab, umavizumab, urtoxazumab, and visilizumab.
- compositions described herein, and for use as described herein may comprise, in addition to the active ingredient, i.e. a conjugate compound, a pharmaceutically acceptable excipient, carrier, buffer, stabiliser or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient.
- the precise nature of the carrier or other material will depend on the route of administration, which may be oral, or by injection, e.g. cutaneous, subcutaneous, or intravenous.
- Pharmaceutical compositions for oral administration may be in tablet, capsule, powder or liquid form.
- a tablet may comprise a solid carrier or an adjuvant.
- Liquid pharmaceutical compositions generally comprise a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol may be included.
- a capsule may comprise a solid carrier such a gelatin.
- the active ingredient will be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability.
- a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability.
- isotonic vehicles such as Sodium Chloride Injection, Ringer's Injection, Lactated Ringer's Injection.
- Preservatives, stabilisers, buffers, antioxidants and/or other additives may be included, as required.
- conjugate compound While it is possible for the conjugate compound to be used (e.g., administered) alone, it is often preferable to present it as a composition or formulation.
- the composition is a pharmaceutical composition (e.g., formulation, preparation, medicament) comprising a conjugate compound, as described herein, and a pharmaceutically acceptable carrier, diluent, or excipient.
- a pharmaceutical composition e.g., formulation, preparation, medicament
- a pharmaceutically acceptable carrier e.g., diluent, or excipient.
- the composition is a pharmaceutical composition comprising at least one conjugate compound, as described herein, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, including, but not limited to, pharmaceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, anti-oxidants, lubricants, stabilisers, solubilisers, surfactants (e.g., wetting agents), masking agents, colouring agents, flavouring agents, and sweetening agents.
- pharmaceutically acceptable carriers diluents, excipients, adjuvants, fillers, buffers, preservatives, anti-oxidants, lubricants, stabilisers, solubilisers, surfactants (e.g., wetting agents), masking agents, colouring agents, flavouring agents, and sweetening agents.
- the composition further comprises other active agents, for example, other therapeutic or prophylactic agents.
- Suitable carriers, diluents, excipients, etc. can be found in standard pharmaceutical texts. See, for example, Handbook of Pharmaceutical Additives, 2nd Edition (eds. M. Ash and I. Ash), 2001 (Synapse Information Resources, Inc., Endicott, New York, USA), Remington's Pharmaceutical Sciences, 20th edition, pub. Lippincott, Williams & Wilkins, 2000; and
- compositions comprising admixing at least one [ 11 C]-radiolabelled conjugate or conjugate-like compound, as defined herein, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, e.g., carriers, diluents, excipients, etc. If formulated as discrete units (e.g., tablets, etc.), each unit contains a predetermined amount (dosage) of the active compound.
- pharmaceutically acceptable pertains to compounds, ingredients, materials, compositions, dosage forms, etc., which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of the subject in question (e.g., human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
- Each carrier, diluent, excipient, etc. must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.
- the formulations may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the active compound with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active compound with carriers (e.g., liquid carriers, finely divided solid carrier, etc.), and then shaping the product, if necessary.
- carriers e.g., liquid carriers, finely divided solid carrier, etc.
- the formulation may be prepared to provide for rapid or slow release; immediate, delayed, timed, or sustained release; or a combination thereof.
- Formulations suitable for parenteral administration include aqueous or non-aqueous, isotonic, pyrogen-free, sterile liquids (e.g., solutions, suspensions), in which the active ingredient is dissolved, suspended, or otherwise provided (e.g., in a liposome or other microparticulate).
- sterile liquids e.g., solutions, suspensions
- Such liquids may additional contain other pharmaceutically acceptable ingredients, such as anti-oxidants, buffers, preservatives, stabilisers,
- bacteriostats suspending agents, thickening agents, and solutes which render the formulation isotonic with the blood (or other relevant bodily fluid) of the intended recipient.
- excipients include, for example, water, alcohols, polyols, glycerol, vegetable oils, and the like.
- suitable isotonic carriers for use in such formulations include Sodium Chloride Injection, Ringer's Solution, or Lactated Ringer's Injection.
- concentration of the active ingredient in the liquid is from about 1 ng/ml to about 10 ⁇ g/ml, for example from about 10 ng/ml to about 1 ⁇ g/ml.
- the formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
- sterile liquid carrier for example water for injections, immediately prior to use.
- Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.
- appropriate dosages of the conjugate compound, and compositions comprising the conjugate compound can vary from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects.
- the selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds, and/or materials used in combination, the severity of the condition, and the species, sex, age, weight, condition, general health, and prior medical history of the patient.
- the amount of compound and route of administration will ultimately be at the discretion of the physician, veterinarian, or clinician, although generally the dosage will be selected to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects.
- Administration can be effected in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell(s) being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician, veterinarian, or clinician.
- a suitable dose of the active compound is in the range of about 100 ng to about 25 mg (more typically about 1 ⁇ g to about 10 mg) per kilogram body weight of the subject per day.
- the active compound is a salt, an ester, an amide, a prodrug, or the like
- the amount administered is calculated on the basis of the parent compound and so the actual weight to be used is increased proportionately.
- the active compound is administered to a human patient according to the following dosage regime: about 100 mg, 3 times daily.
- the active compound is administered to a human patient according to the following dosage regime: about 150 mg, 2 times daily. In one embodiment, the active compound is administered to a human patient according to the following dosage regime: about 200 mg, 2 times daily.
- the conjugate compound is administered to a human patient according to the following dosage regime: about 50 or about 75 mg, 3 or 4 times daily.
- the conjugate compound is administered to a human patient according to the following dosage regime: about 100 or about 125 mg, 2 times daily.
- the dosage amounts described above may apply to the conjugate (including the PBD moiety and the linker to the antibody) or to the effective amount of PBD compound provided, for example the amount of compound that is releasable after cleavage of the linker.
- an ADC of the invention will depend on the type of disease to be treated, as defined above, the severity and course of the disease, whether the molecule is administered for preventive or therapeutic purposes, previous therapy, the patient's clinical history and response to the antibody, and the discretion of the attending physician.
- the molecule is suitably
- a typical daily dosage might range from about 1 ⁇ g kg to 100 mg/kg or more, depending on the factors mentioned above.
- An exemplary dosage of ADC to be administered to a patient is in the range of about 0.1 to about 10 mg/kg of patient weight. For repeated administrations over several days or longer, depending on the condition, the treatment is sustained until a desired suppression of disease symptoms occurs.
- An exemplary dosing regimen comprises a course of administering an initial loading dose of about 4 mg/kg, followed by additional doses every week, two weeks, or three weeks of an ADC. Other dosage regimens may be useful. The progress of this therapy is easily monitored by conventional techniques and assays. Treatment
- treatment pertains generally to treatment and therapy, whether of a human or an animal (e.g., in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, regression of the condition, amelioration of the condition, and cure of the condition.
- Treatment as a prophylactic measure i.e., prophylaxis, prevention is also included.
- terapéuticaally-effective amount refers to that amount of an active compound, or a material, composition or dosage from comprising an active compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio, when administered in accordance with a desired treatment regimen.
- prophylactically-effective amount pertains to that amount of an active compound, or a material, composition or dosage from comprising an active compound, which is effective for producing some desired prophylactic effect, commensurate with a reasonable benefit/risk ratio, when administered in accordance with a desired treatment regimen.
- the second aspect of the present invention relates to a method of preparing a conjugate, comprising the step of reacting a cell binding agent with a drug linker compound of the present invention, such as a formula I compound.
- Antibody drug conjugates may be prepared by several routes, employing organic chemistry reactions, conditions, and reagents known to those skilled in the art, including: (1 ) reaction of a nucleophilic group of an antibody with a bivalent linker reagent, to form antibody-linker intermediate Ab-L, via a covalent bond, followed by reaction with an activated drug moiety reagent ; and (2) reaction of a drug moiety reagent with a linker reagent, to form drug-linker reagent D-L, via a covalent bond, followed by reaction with the nucleophilic group of an antibody.
- conjugation method (2) may be employed with a variety of antibodies and linkers to prepare the antibody-drug conjugates described herein.
- Nucleophilic groups on antibodies include, but are not limited to side chain thiol groups, e.g. cysteine.
- Thiol groups are nucleophilic and capable of reacting to form covalent bonds with electrophilic groups on linker moieties such as those of the present invention.
- Certain antibodies have reducible interchain disulfides, i.e. cysteine bridges.
- Antibodies may be made reactive for conjugation with linker reagents by treatment with a reducing agent such as DTT (Cleland's reagent, dithiothreitol) or TCEP (tris(2-carboxyethyl)phosphine hydrochloride; Getz et al (1999) Anal. Biochem.
- Each cysteine disulfide bridge will thus form, theoretically, two reactive thiol nucleophiles. Additional nucleophilic groups can be introduced into antibodies through the reaction of lysines with 2-iminothiolane (Traut's reagent) resulting in conversion of an amine into a thiol.
- unsymmetrical dimers with respect to their N 10-C1 1 bonds, may be prepared by treating bis-amino compounds of formula IV with one equivalent of a commercially available (or readily prepared) chloroformate reagent in order to break the symmetry of the molecules. The remaining free amine can then be functionalised independently to introduce the linking group precursor (R L ). Further functional group manipulation to close the PBD B-ring, remove protecting groups affords the target molecule.
- Compounds of formula IV are typically prepared by coupling a suitably functionalised C-ring fragment (I) to an A-ring containing dimer core of formula II.
- C-ring fragments may be prepared from known carbamate protected methyl 4-oxoprolinate building blocks.
- Olefination under Wittig or Horner-Emmons conditions can be employed to furnish endo- or exo-unsatu rated alkenes.
- C-ring and A-ring fragments can be coupled under standard conditions in the presence of triethylamine, using acid chloride derivatives of the A-ring fragments to give molecules of formula III. Symmetry may also be broken at this stage by introducing different C-rings.
- Compounds of type III can be reduced, without affecting endo or exo C-ring unsaturation, with zinc in acetic or formic acid to afford molecules of formula IV.
- a suitable 4-hydroxy pyrrolidine building block may be coupled to a dimer core of formula I I .
- the hydroxyl groups can be oxidized to ketones and then converted to enol triflates. Suzuki coupling can be used to introduce the pro C2 substituents (e.g. aryl, alkenyl etc).
- the nitro groups can then be reduced to amines, one amine is protected leaving the other free to bear the linker group.
- Unsymmetrical carbamates of type VI can be prepared by treating bis-amines of type IV with a single equivalent of a commercially available (or readily prepared) chloroformates in the presence of pyridine or triethylamine.
- Chloroformates may be selected to afford appropriate carbamate based nitrogen protecting groups (Prot N ) which are orthogonal to those used in the pro-linker group (R L ).
- the R L carbamate may be introduced by converting the remaining amino group to an isocyanate and quenching it with the R L alcohol.
- the R L alcohol can be converted to a chloroformate or functional equivalent (fluoroformate, p-nitrocarbonate, pentafluorocarbonate or hydroxybenzotriazole carbonate).
- the remaining amino group can be converted to a reactive p-nitrocarbamate,
- Molecules of formula VII can be prepared from molecules of formula VI by removing the silyl protecting groups, with, for example, aqueous acetic acid. Oxidation with Dess-Martin periodinane (or alternatively TPAP/NMO, PDC or under Swern conditions) affords the ring closed product.
- Conjugates of formula V may be prepared from molecules of formula VII by removal of the carbamate based nitrogen protection group.
- dimer compound (15) shown in paragraph [164] may be used as compound III in Scheme I above. This, and further adaptations, would be apparent to one of skill in the art.
- TLC thin-layer chromatography
- Merck Kieselgel 60 F254 silica gel with fluorescent indicator on aluminium plates. Visualisation of TLC was achieved with UV light or iodine vapour unless otherwise stated.
- Flash chromatography was performed using VWR silica gel for flash chromatography. Extraction and chromatography solvents were bought and used without further purification from Fisher Scientific, U.K. All fine chemicals were purchased from Sigma-Aldrich or TCI Europe unless otherwise stated.
- the analytical LC/MS conditions were as follows: Positive mode electrospray mass spectrometry was performed using a Shimadzu Nexera®/Prominence® LCMS-2020. Mobile phases used were solvent A (H 2 0 with 0.1 % formic acid) and solvent B (CH 3 CN with 0.1 % formic acid). Gradient for routine 3-minute run: Initial composition 5% B held over 0.25 minutes, then increased from 5% B to 100% B over a 2 minute period. The composition was held for 0.50 minutes at 100% B, then returned to 5% B in 0.05 minutes and held there for 0.05 minutes. The total duration of the gradient run was 3.0 minutes. Gradient for 15-minute run: Initial composition 5% B held over 1 minute, then increased from 5% B to 100% B over a 10 minute period.
- the composition was held for 2 minutes at 100% B, then returned to 5% B in 0.1 minute and held there for 2.9 minutes.
- the total duration of the gradient run was 15.0 minutes.
- Flow rate was 0.8 mL/minute and 0.6 mL/minute (for 15-minute run). Detection was at 214 and 254 nm.
- reaction mixture was heated to 40°C and after 5 minutes a sample was treated with methanol and analysed by LCMS as the methyl carbamate.
- reaction mixture was allowed to stir under an argon atmosphere for 2.5 hours at which point analysis by LC/MS revealed substantial product formation at retention time 2.42 minutes (ES+) m/z 1226 ⁇ [M+ H] + , -20% relative intensity), 1248 ⁇ [M+ Na] + , -60% relative intensity).
- the mixture was diluted with DCM (20 mL) and treated with Si0 2 and the solvent removed by evaporation in vacuo.
- reaction mixture was allowed to stir for 16 hours at which point analysis by LC/MS revealed reaction completion with desired product observed at retention time 1 .82 minutes (ES+) m/z 997 ([M+ H] + , -100% relative intensity), 1019 ⁇ [M+ Na] + , -45% relative intensity).
- the reaction mixture was added drop- wise to a chilled (0-5°C) saturated solution of NaHC0 3 (400 ml_).
- the neutral solution was allowed to warm to room temperature and extracted with EtOAc (4 x 100 ml_), the combined organic layers were washed with H 2 0 (80 ml_), brine (100 ml_), dried (MgS0 4 ), filtered and evaporated in vacuo to give the crude product. Purification by flash chromatography
- reaction mixture was treated drop-wise with a solution of TEA (476 ⁇ _, 342 mg, 3.42 mmol) in dry DCM (7.5 mL).
- TEA 476 ⁇ _, 342 mg, 3.42 mmol
- the reaction mixture was allowed to warm to room temperature over a period of 1.5 hours and diluted with DCM (50 mL) then washed with saturated NH 4 CI (15 mL), saturated NaHC0 3 (15 mL), brine (15 mL), dried (MgS0 4 ), filtered and evaporated in vacuo to give the crude product. Purification by flash
- TCEP tris(2-carboxyethyl)phosphine hydrochloride or DTT (dithiothreitol) in 50 mM Tris pH 7.5 with 2 mM EDTA for 3 hrs at 37°C or overnight at room temperature.
- TCEP tris(2-carboxyethyl)phosphine hydrochloride or DTT (dithiothreitol) in 50 mM Tris pH 7.5 with 2 mM EDTA for 3 hrs at 37°C or overnight at room temperature.
- TCEP tris(2-carboxyethyl)phosphine hydrochloride or DTT (dithiothreitol) in 50 mM Tris pH 7.5 with 2 mM EDTA for 3 hrs at 37°C or overnight at room temperature.
- THIOMABTM The reduced cysteine-engineered antibody mutants (THIOMABTM) were diluted and loaded onto a HiTrap S® column in 10
- the antibody was acidified by addition of 1/20 th volume of 10% acetic acid, diluted with 10 mM succinate pH 5, loaded onto the column and then washed with 10 column volumes of succinate buffer.
- the column was eluted with 50 mM Tris pH7.5, 2 mM EDTA.
- the eluted reduced cysteine-engineered antibody mutants (THIOMABTM) was treated with 15 fold molar excess of DHAA (dehydroascorbic acid) or 200 nM aqueous copper sulfate (CUSCM). Oxidation of the interchain disulfide bonds was complete in about three hours or more. Ambient air oxidation was also effective.
- the re-oxidized antibody was dialyzed into 20 mM sodium succinate pH 5, 150 mM NaCI, 2 mM EDTA and stored frozen at -20°C.
- the crude antibody-drug conjugates were then applied to a cation exchange column after dilution with 20 mM sodium succinate, pH 5.
- the column was washed with at least 10 column volumes of 20 mM sodium succinate, pH 5, and the antibody was eluted with PBS.
- the antibody drug conjugates were formulated into 20 mM His/acetate, pH 5, with 240 mM sucrose using gel filtration columns.
- the antibody-drug conjugates were characterized by UV spectroscopy to determine protein concentration, analytical SEC (size-exclusion chromatography) for aggregation analysis and LC-MS before and after treatment with Lysine C endopeptidase.
- Size exclusion chromatography was performed using a Shodex KW802.5 column in 0.2M potassium phosphate pH 6.2 with 0.25 mM potassium chloride and 15% IPA at a flow rate of 0.75 ml/min. Aggregation state of the conjugate was determined by integration of eluted peak area absorbance at 280 nm.
- LC-MS analysis was performed using an Agilent QTOF 6520 ESI instrument.
- an antibody-drug conjugate generated using this chemistry was treated with 1 :500 w/w Endoproteinase Lys C (Promega) in Tris, pH 7.5, for 30 min at 37°C.
- the resulting cleavage fragments were loaded onto a 1000A, 8 urn PLRP-S column heated to 80°C and eluted with a gradient of 30% B to 40% B in 5 minutes.
- Mobile phase A was H 2 0 with 0.05% TFA and mobile phase B was acetonitrile with 0.04% TFA.
- the flow rate was 0.5ml/min.
- Protein elution was monitored by UV absorbance detection at 280nm prior to electrospray ionization and MS analysis. Chromatographic resolution of the unconjugated Fc fragment, residual unconjugated Fab and drugged Fab was usually achieved. The obtained m/z spectra were deconvoluted using Mass HunterTM software (Agilent Technologies) to calculate the mass of the antibody fragments.
- Efficacy of ADC were measured by a cell proliferation assay employing the following protocol (CellTiter Glo® Luminescent Cell Viability Assay, Promega Corp. Technical Bulletin TB288; Mendoza et al (2002) Cancer Res. 62:5485-5488). All cell lines were obtained from
- Control wells were prepared containing medium and without cells.
- ADC was added to the experimental wells and incubated for 3-5 days.
- the plate was incubated at room temperature for 10 minutes to stabilize the luminescence signal.
- Certain cells are seeded at 1000-2000/well or 2000-3000/well in a 96-well plate, 50 uL/well.
- ADC are added in 50 ⁇ _ volumes to final concentration of 9000, 3000, 1000, 333, 1 1 1 , 37, 12.4, 4.1 , or 1 .4 ng/mL, with "no ADC" control wells receiving medium alone.
- Conditions are in duplicate or triplicate
- 100 ⁇ ⁇ Cell TiterGlo II is added (luciferase-based assay; proliferation measured by ATP levels) and cell counts are determined using a luminometer. Data are plotted as the mean of luminescence for each set of replicates, with standard deviation error bars.
- the protocol is a modification of the
- ADC is serially diluted 1 :3 in media beginning at working concentration 18 ⁇ g/ml (this results in a final concentration of 9 ⁇ g/ml).
- 50 ⁇ _ of diluted ADC is added to the 50 ⁇ _ of cells and media already in the well.
- Antibody-drug conjugates Thio Hu anti-Her2 7C2 HC A1 18C-8 (101 ), Thio Hu anti-CD33 15G15.3 HC A1 18C-8 (103), Thio Hu anti-Her2 7C2 LC K149C-15 (105), Thio Hu anti-CD33 15G15.3 LC K149C-15 (106) were tested against SK-BR-3 (Levenson et al (1997) Cancer Res.
- SK-BR-3 cells are HER2+ expressing. Both 101 and 105 were active against these cells, whereas both 103 and 106 were effectively inactive.
- EOL1 and HL-60 Levenson et al (1997) Cancer Res. 57(15):3071 -3078) cells to measure in vitro cell viability in five day studies.
- EOL1 and HL-60 cells are CD33 expressing. Both 103 and 106 were active against these cells, whereas both 101 and 105 were effectively inactive.
- conjugates 101 , 103, 105 and 106 exhibit targeted cell killing.
- Antibody-drug conjugates Thio Hu anti-Her2 7C2 LC K149C-15 (105), Thio Hu anti-Her2 7C2 LC K149C-15 (117), Thio anti-Her2 7C2 LC K149C-20 (127), and Thio anti-Her2 7C2 LC K149C-26 (128) were also tested against SK-BR-3 (Levenson et al (1997) Cancer Res. 57(15):3071 -3078) cells to measure in vitro cell viability in five day studies. SK-BR-3 cells are HER2+ expressing.
- Conjugates of the invention were tested in appropriate in vivo models and shown to be active. Appropriate in vivo assays are described in Phillips et al (2008J Cancer Res. 68(22):9280-9290.
- Bzl benzyl where Bzl-OMe is methoxybenzyl and Bzl-Me is methylbenzene
Abstract
Description
Claims
Priority Applications (13)
Application Number | Priority Date | Filing Date | Title |
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EP15772143.2A EP3194400A1 (en) | 2014-09-17 | 2015-09-17 | Pyrrolobenzodiazepines and antibody disulfide conjugates thereof |
BR112017005393A BR112017005393A2 (en) | 2014-09-17 | 2015-09-17 | compound of formula I, method of preparing a conjugate of formula a, conjugate of formula a1, composition comprising a mixture of antibody-drug conjugate compounds, pharmaceutical composition, and use of a conjugate or composition |
EA201790359A EA201790359A1 (en) | 2014-09-17 | 2015-09-17 | Pyrrolobenzodiazepines and their conjugates associated with disulfide binding to antibodies |
JP2017514845A JP2017533887A (en) | 2014-09-17 | 2015-09-17 | Pyrrolobenzodiazepines and their antibody disulfide conjugates |
KR1020177009849A KR20170067771A (en) | 2014-09-17 | 2015-09-17 | Pyrrolobenzodiazepines and antibody disulfide conjugates thereof |
CA2959689A CA2959689A1 (en) | 2014-09-17 | 2015-09-17 | Pyrrolobenzodiazepines and antibody disulfide conjugates thereof |
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Publication number | Publication date |
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PH12017500518A1 (en) | 2017-08-07 |
CN107073136A (en) | 2017-08-18 |
MX2017003523A (en) | 2017-11-08 |
SG11201702079UA (en) | 2017-04-27 |
EP3235820A1 (en) | 2017-10-25 |
US20180362644A1 (en) | 2018-12-20 |
BR112017005393A2 (en) | 2017-12-05 |
US20160074527A1 (en) | 2016-03-17 |
KR20170067771A (en) | 2017-06-16 |
CR20170099A (en) | 2017-07-19 |
EP3194400A1 (en) | 2017-07-26 |
PE20170905A1 (en) | 2017-07-12 |
JP2017533887A (en) | 2017-11-16 |
MA40575A (en) | 2016-03-24 |
AU2015317653A1 (en) | 2017-04-06 |
EA201790359A1 (en) | 2017-08-31 |
IL250819A0 (en) | 2017-04-30 |
CA2959689A1 (en) | 2016-03-24 |
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