WO2014151030A1 - Inhibiteurs de la prolifération cellulaire et leurs conjugués - Google Patents
Inhibiteurs de la prolifération cellulaire et leurs conjugués Download PDFInfo
- Publication number
- WO2014151030A1 WO2014151030A1 PCT/US2014/024795 US2014024795W WO2014151030A1 WO 2014151030 A1 WO2014151030 A1 WO 2014151030A1 US 2014024795 W US2014024795 W US 2014024795W WO 2014151030 A1 WO2014151030 A1 WO 2014151030A1
- Authority
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- WIPO (PCT)
- Prior art keywords
- alkyl
- antibody
- compound
- formula
- immunoconjugate
- Prior art date
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
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- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
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- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
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Definitions
- the invention provides compounds that inhibit cell proliferation by inhibiting Eg5 activity, and are thus useful to treat cellular proliferative disorders associated with excessive Eg5 activity.
- the invention also includes conjugates that comprise an inhibitor of Eg5 linked to an antigen-binding moiety, and pharmaceutical compositions containing these conjugates. Also included are methods of using these compounds and conjugates to treat cell proliferation disorders, including cancers.
- ADCs antibody-drug conjugates
- the ADCs typically contain an antibody selected for its ability to bind to a cell targeted for therapeutic intervention, linked to a drug selected for its cytostatic or cytotoxic activity. Binding of the antibody to the targeted cell delivers the drug to the site where its therapeutic effect is needed and thus reduces off-target activities while improving the efficiency with which the payload compound is utilized.
- Antibody-Drug Conjugates the Next Generation of Moving Parts, A. Lash, Start-Up, Dec. 201 1 , 1-6. This suggests how difficult it is to identify a suitable class of drug compounds that make effective ADC payloads. Given the widely acknowledged value of ADCs as therapeutics, particularly for treating cancer, there thus remains a need for novel cell proliferation inhibitors suited for use as payloads in ADCs. SUMMARY OF THE INVENTION
- the invention includes novel inhibitors of Eg5, and methods of using Eg5 inhibitors either as small-molecule pharmaceuticals or as the drug component (payload) of an antibody-drug conjugate (ADC).
- ADC antibody-drug conjugate
- Eg5 also known as kinesin spindle protein or KSP, is a kinesin motor protein, involved in cross-linking of microtubules during mitosis, and is thus required for cell division.
- Inhibitors of Eg5 are known to be useful to treat cell proliferation disorders like cancer (Rath and Kozielski, Nature Rev. Cancer, vol. 12, 527-39 (2012); see also WO06/002236, WO2007/021794, WO2008/063912, WO2009/077448, WO201 1/128381 , WO201 1/128388, and WO2006/049835). While a number of different chemical families of Eg5 inhibitors are known, they have not heretofore been used in ADCs.
- the present invention includes use of Eg5 inhibitors as drug payloads for ADCs, and novel Eg5 inhibitors that are useful as ADC payloads and as small-molecule pharmaceuticals.
- the invention further includes methods and intermediates useful for incorporating certain Eg5 inhibitors into ADCs, and methods to use the novel compounds and conjugates to treat cell proliferation disorders.
- the present invention provides immunoconjugates (e.g., ADCs) containing inhibitors of Eg5 linked to an antigen binding moiety such as an antibody or antibody fragment.
- immunoconjugates e.g., ADCs
- conjugates comprising an Eg5 inhibitor are useful to treat cell proliferation disorders, particularly when the Eg5 inhibitor is linked to an antibody that recognizes cancer cells and thus promotes delivery of the Eg5 inhibitor to a cancer cell targeted for attack.
- the immunoconjugates are especially useful for treating certain cancers as further detailed herein. Data provided herein demonstrate that these immunoconjugates are effective inhibitors of cell proliferation and for treating some types of cancer; without being bound by theory, it is believed their activity is due to inhibition of Eg5 in cells.
- immunoconjugates of the invention include compounds of this formula: wherein Ab represents an antigen binding moiety;
- L represents a linking group that connects X to Ab
- n is an integer from 1 -4;
- n is an integer from 1 to 16;
- each L independently at each occurrence represents an inhibitor of Eg5.
- m is greater than 1
- each L is independently selected. In some embodiments, each L is the same.
- X can be a compound of Formula II as described herein, or any Eg5 inhibitor having an IC-50 below about 100 nM for inhibition of Eg5.
- Eg5 inhibitors including ispinesib, SB-743921 , AZD4877, ARQ621 , ARRY-520, LY2523355, MK-0731 , EMD534085, and GSK-923295, and Eg5 inhibitors described in WO06/002236, WO2007/021794, WO2008/063912, WO2009/077448, WO201 1/128381 , WO201 1/128388, and WO2006/049835.
- m is 1 or 2 in immunoconjugates of this formula, preferably 1 ; and n is 2-8, preferably about 2 to about 6, more preferable between 3 and 5.
- Ab can be any suitable antigen binding moiety, and is often an antibody. Suitable antibodies are well known in the art, and may be either native antibody sequence or they may be modified by, e.g., protein engineering techniques to improve their usefulness or activity.
- L can be any linker suitable for attaching one or more X groups to Ab; often L is attached to a lysine delta- amino group, or to a cysteine sulfhydryl of the antibody. These can be naturally-occurring residues, or they can be introduced at selected locations in the antibody sequence.
- Suitable options for X include compounds of Formula (II) disclosed herein, as well as monastrol (Ethyl 4-(3-hydroxyphenyl)-6-methyl-2-sulfanylidene-3,4-dihydro-1 H- pyrimidine-5-carboxylate); (2S)-4-(2,5-Difluorophenyl)-N-[(3R,4S)-3-fluoro-1 -methyl-4- piperidinyl]-2,5-dihydro-2-(hydroxymethyl)-/V-methyl-2-phenyl-1 H-pyrrole-1-carboxamide (MK-0731 , CAS 845256-65-7); Litronesib (LY2523355, CAS 910634-41 -2); and (2S)-2- (3-Aminopropyl)-5-(2,5-difluorophenyl)-/V-methoxy-/V-methyl-2-phenyl-1 ,3,4-thiadiazole- 3(2H
- the immunoconjugate is of Formula (I)
- Ab represents an antigen binding moiety such as an antibody or antibody fragment
- L represents a linking group that connects X to Ab by covalent or non-covalent bonding, which may optionally attach more than one X to Ab, and which may or may not be designed to facilitate in vivo cleavage;
- n is an integer from 1 to 16, preferably 2-8.
- each L can be independently selected. In some embodiments, each group L is the same.
- the invention provides methods for making ADCs using Eg5 inhibitors, particularly compounds of Formula (II) or (III), as the payload (drug) to be delivered, and methods to use these ADCs to treat cell proliferation disorders.
- the invention also provides modified compounds of Formula (II) that are described herein as Formula (IIA) and (MB) and (IIC): these are structures that comprise a compound of Formula (II) having a reactive functional group and optionally one or more linker components attached, to facilitate connecting the compound either directly or indirectly to an antibody or antigen binding fragment. These compounds are useful to make immunoconjugates.
- the invention provides compounds of Formula (IIA) and (MB) and (110):
- W comprises a reactive functional group that can be used to connect (IIA) or (MB) or (IIC) to a linker component, or directly to Ab, to provide an immunoconjugate of Formula (I), and methods to use these compounds for making ADCs.
- the invention provides novel Eg5 inhibitors of Formula (III) as described herein and pharmaceutically acceptable salts thereof.
- These compounds are novel inhibitors of Eg5 and possess anticancer activity as shown herein. They can be used as ADC payloads as demonstrated herein, or, like other inhibitors of Eg5, they can be used as small-molecule therapeutic agents for treatment of cell proliferation disorders.
- the invention provides pharmaceutical compositions comprising an immunoconjugate of Formula (I) or a compound of Formula (III) admixed with at least one pharmaceutically acceptable carrier or excipient, optionally admixed with two or more pharmaceutically acceptable carriers or excipients, and methods to use these
- compositions to treat cell proliferation disorders are provided.
- the invention provides a method to treat a condition
- characterized by excessive or undesired cell proliferation which comprises administering to a subject in need of such treatment an effective amount of an immunoconjugate of Formula (I) or a compound of Formula (III), or any subgenus thereof as described herein, or a pharmaceutical composition comprising such compound or immunoconjugate.
- the subject for treatment can be a mammal, and is preferably a human.
- Conditions treatable by the compounds and methods described herein include various forms of cancer, such as gastric, myeloid, colon, nasopharyngeal, esophageal, and prostate tumors, glioma, neuroblastoma, melanoma, breast cancer, lung cancer, ovarian cancer, colorectal cancer, thyroid cancer, leukemia (e.g., chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), T-lineage acute lymphoblastic leukemia or T-ALL), lymphoma (especially non-Hodgkin's), bladder, renal, gastric (e.g., gastrointestinal stromal tumors (GIST)), liver, and pancreatic cancer, and sarcoma.
- Other cell proliferation disorders that can be treated with these methods and compositions include diabetic retinopathy, liver and lung fibrosis, Sjogren's syndrome, and lupus erythematous.
- the invention includes compositions of Formulas (l)-(lll) and the subgenera thereof as described herein, and all stereoisomers (including diastereoisomers and enantiomers), tautomers and isotopically enriched versions thereof (including deuterium substitutions) as well as pharmaceutically acceptable salts of these compounds.
- compositions of the present invention also comprise polymorphs of Formula (l)-(lll) (or sub-formulas thereof) and salts, particularly pharmaceutically acceptable salts, thereof.
- the invention provides immunoconjugates comprising an improved linking group that connects an antibody with a payload such as a cytotoxin, including the Eg5 inhibitors described herein.
- These immunoconjugates comprise a linking group that comprises a group of the formula -C(0)NR - or -NR -C(O)-, which may be an amide or a carbamate, wherein R 21 is of the formula -(CH 2 )i-4-R 22 , R 22 is a polar group selected from -OH, -NH 2 , N(R 23 ) 2 , COOR 23 , CON(R 23 ) 2 , -(OCH 2 CH 2 0) k - OCH 2 CH 2 OR 23 , and -S0 2 R 23 , where k is 0 to 4 and each R 23 is independently H or C1-4 alkyl.
- These linking groups reduce aggregation of the immunoconjugate.
- FIG. 1A-1 B Determination of average drug loading (DAR, drug to antibody ratio) for an ADC based on heavy chain and light chain loading.
- DAR drug to antibody ratio
- FIG. 2A-2E Antiproliferative activity of various compounds of Formula (II) and (III) in cell cultures.
- FIG. 3A-3L Anti-proliferative activities of certain Eg5 inhibitors across a variety of cancer cell lines derived from different lineages.
- FIG. 4A-4V In vitro anti-proliferative activity of ADCs on a cell line engineered for high Her2 expression vs. matched parental (Her2-low) cell line.
- FIG. 5A - 5E In vitro anti-proliferative activity of ADCs on cell lines with endogenous Her2 expression.
- FIG. 6(A) Efficacy of a TBS-Cmpd 220 conjugate in HCC 1954 breast cancer xenografts.
- FIG. 7 (A) and (B) shows efficacy of a TBS-Cmpd 220 conjugate in SK-OV-3ip xenografts.
- FIG. 8 shows efficacy of a TBS-Cmpd 215 conjugate in SK-OV-3ip xenografts.
- FIG. 9 shows efficacy of a TBS-Cmpd 223 conjugate in SK-OV-3ip xenografts.
- FIG. 10(A) shows the degree of aggregation of construct referred to as ADC-1 10 as measured by size exclusion chromatography.
- the amount of aggregate detected is about 12% of the total detected conjugate.
- FIG. 10(B) shows the amount of aggregation of ADC-1 1 1 , which is about 2.4%.
- FIG. 10(C) shows the amount of aggregation of ADC-1 12, which is about 2.7%.
- FIG. 11 shows in vitro activity of ADC-1 10 and ADC-1 1 1 against various cell types.
- Fig. 12 shows activity of a series of immunoconjugates having different payloads (5A, 5B, 5C, 5D, 5E and 5F from Table 5) linked to antibody cKitA. All exhibit good to excellent activity in cell culture on SK-OV-3ip.
- Fig. 13 shows activity of selected payloads conjugated to trastuzumab (TBS) on various tumor cell lines, demonstrating that a variety of payloads of Formula I I are active against various cancer cell lines.
- TBS trastuzumab
- Fig. 14 shows a representative inhibitor of the invention compared to Eg5 inhibitors from other compound classes; compounds in Figure 14 are all linked to trastuzumab via a Val- Cit linker.
- Fig. 15 shows activity of trastuzumab immunoconjugates of the invention on Her2-high and Her2-low cell lines, compared to an immunoconjugate with a maytansine payload. An immunoconjugate with a non-Her2 antigen binder is included for comparison.
- Fig. 16 shows in vivo tumor growth inhibition results on mouse xenograft tumors (SK-OV- 3ip) treated with trastuzumab alone, trastuzumab conjugated with compound 5B (5 mg/kg dose and 10 mg/kg dose), and a control conjugate where the antigen binding group does not recognize tumor antigens.
- Fig. 17 shows in vivo tumor growth inhibition activity on mouse xenograft tumors
- SK_OV-3ip treated with immunoconjugates having Eg5 inhibitor payloads on trastuzumab (anti-Her2 antibody) compared to conjugates with maytansine payloads and with one control lacking payload and one control without a tumor binding antibody.
- Fig. 18 shows in vivo tumor growth inhibition activity on mouse xenograft tumors (H526) treated with immunoconjugates having Eg5 inhibitor payloads on cKitA (an anti- cKit antibody).
- Fig. 19 shows in vivo tumor growth inhibition activity on mouse xenograft tumors (H526) treated with immunoconjugates having Eg5 inhibitor payloads on cKitA (an anti-cKit antibody) compared with a cKitA conjugate containing a maytansine payload (DM1 ).
- Fig. 20 shows in vivo tumor growth inhibition activity on a mouse carrying two xenograft tumors (H526 and SK-OV-3ip) treated with immunoconjugates having Eg5 inhibitor payloads on a cKitA (an anti-cKit) antibody and on a trastuzumab antibody.
- Fig. 21 shows activity of a variety of Eg5 inhibitor immunoconjugates with trastuzumab antibody, tested on mouse xenograft SK-OV-3ip tumors. For comparison,
- immunoconjugates having the same antibody conjugated with an auristatin payload (MMAE) and a maytansine payload (DM 1 ).
- MMAE auristatin payload
- DM 1 a maytansine payload
- Fig. 22 shows in vivo activity of several immunoconjugates from Table 5 in mouse xenograft tumors, using Kadcyla® and the anti-Her2 antibody as comparators and vehicle-only as a control.
- Fig. 23 shows in vivo activity of several immunoconjugates from Tables 5 in mouse xenografts, using Kadcyla®, and a Compound 6U— anti-Her2 antibody conjugate, and an igG 1 kappa chain specific for a viral glycoprotein, gH , as comparators and vehicle-only as a control.
- Fig. 24 shows in vivo activity of several immunoconjugates from Tables 5 in mouse xenografts, using vehicle-only as a control.
- the immunoconjugates have anti-cKit antibodies conjugated to compounds from Table 5, and the cell line is sensitive to ckit antibodies.
- Fig. 25 shows in vivo activity of several immunoconjugates from Tables 5 in mouse xenografts, using vehicle-only as a control.
- the immunoconjugates have anti-cKit antibodies conjugated to compounds from Table 5.
- Fig. 26 shows in vivo activity of immunoconjugates having payload-linker Compound 5B in mouse xenografts, and three different anti-cKit antibodies.
- cKitA is the parent antibody;
- cKitB and cKitC are cysteine-engineered muteins of cKitA as described here. Results are shown at two different dosing levels, with vehicle-only as a control. At both doses, each of the cysteine-engineered mutant antibodies provided a more active immunoconjugate than the native antibody.
- Fig. 27 shows in vivo activity of an immunoconjugate comprising the antibody cKitA conjugated with compound 5B, with the cKitA antibody (unconjugated) and vehicle as controls.
- Fig. 28 includes graphs of in vitro (cell culture) activity of a wide range of
- amino acid refers to canonical, synthetic, and unnatural amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the canonical amino acids.
- Canonical amino acids are proteinogenous amino acids encoded by the genetic code and include alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline serine, threonine, tryptophan, tyrosine, valine, as well as selenocysteine, pyrrolysine and pyrroline-carboxy-lysine.
- Amino acid analogs refer to compounds that have the same basic chemical structure as a canonical amino acid, i.e., an a-carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium.
- Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a canonical amino acid.
- antigen binding moiety refers to a moiety capable of binding specifically to an antigen, and includes but is not limited to antibodies and antibody fragments.
- antibody refers to a polypeptide of the immunoglobulin family that is capable of binding a corresponding antigen non-covalently, reversibly, and in a specific manner.
- a naturally occurring IgG antibody is a tetramer comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds. Each heavy chain is comprised of a heavy chain variable region
- V H a heavy chain constant region
- the heavy chain constant region is comprised of three domains, CH1 , CH2 and CH3.
- Each light chain is comprised of a light chain variable region (abbreviated herein as V L ) and a light chain constant region.
- the light chain constant region is comprised of one domain, C L .
- the V H and V L regions can be further subdivided into regions of hyper variability, termed
- CDR complementarity determining regions
- FR framework regions
- Each V H and V L is composed of three CDRs and four FRs arranged from amino-terminus to carboxy-terminus in the following order: FR1 , CDR1 , FR2, CDR2, FR3, CDR3, and FR4.
- the variable regions of the heavy and light chains contain a binding domain that interacts with an antigen.
- the constant regions of the antibodies may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g. , effector cells) and the first component (Clq) of the classical complement system.
- antibody includes, but is not limited to, monoclonal antibodies, human antibodies, humanized antibodies, camelid antibodies, chimeric antibodies, and anti- idiotypic (anti-Id) antibodies (including, e.g. , anti-Id antibodies to antibodies of the invention).
- the antibodies can be of any isotype/class (e.g. , IgG, IgE, IgM, IgD, IgA and IgY), or subclass (e.g. , lgG 1 , lgG2, lgG3, lgG4, lgA1 and lgA2).
- variable domains of both the light (V L ) and heavy (V H ) chain portions determine antigen recognition and specificity.
- the constant domains of the light chain (C L ) and the heavy chain (CH 1 , CH2 or CH3) confer important biological properties such as secretion, transplacental mobility, Fc receptor binding, complement binding, and the like.
- the numbering of the constant region domains increases as they become more distal from the antigen binding site or amino- terminus of the antibody.
- the N-terminus is a variable region and at the C-terminus is a constant region; the CH3 and C L domains actually comprise the carboxy-terminal domains of the heavy and light chain, respectively.
- antigen binding fragment refers to one or more portions of an antibody that retain the ability to specifically interact with (e.g. , by binding, steric hindrance, stabilizing/destabilizing, spatial distribution) an epitope of an antigen.
- binding fragments include, but are not limited to, single-chain Fvs (scFv), disulfide-linked Fvs (sdFv), Fab fragments, F(ab') fragments, a monovalent fragment consisting of the VL, VH, CL and CH 1 domains; a F(ab)2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; a Fd fragment consisting of the VH and CH 1 domains; a Fv fragment consisting of the VL and VH domains of a single arm of an antibody; a dAb fragment (Ward et al. , Nature 341 :544- 546, 1989), which consists of a VH domain; and an isolated complementarity determining region (CDR), or other epitope-binding fragments of an antibody.
- scFv single-chain Fvs
- sdFv disulfide-linked Fvs
- Fab fragments F
- the two domains of the Fv fragment, VL and VH are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv ("scFv"); see, e.g. , Bird et al., Science 242:423-426, 1988; and Huston et al., Proc. Natl. Acad. Sci. 85:5879- 5883, 1988).
- single chain Fv single chain Fv
- Such single chain antibodies are also intended to be encompassed within the term "antigen binding fragment.”
- antigen binding fragments are obtained using conventional techniques known to those of skill in the art, and the fragments are screened for utility in the same manner as are intact antibodies.
- Antigen binding fragments can also be incorporated into single domain antibodies, maxibodies, minibodies, nanobodies, intrabodies, diabodies, triabodies, tetrabodies, v- NAR and bis-scFv (see, e.g., Hollinger and Hudson, Nature Biotechnology 23:1 126-1 136, 2005).
- Antigen binding fragments can be grafted into scaffolds based on polypeptides such as fibronectin type III (Fn3) (see U.S. Pat. No. 6,703,199, which describes fibronectin polypeptide monobodies).
- Fn3 fibronectin type III
- Antigen binding fragments can be incorporated into single chain molecules comprising a pair of tandem Fv segments (VH-CH1-VH-CH1 ) which, together with complementary light chain polypeptides, form a pair of antigen binding regions (Zapata et al., Protein Eng. 8:1057-1062, 1995; and U.S. Pat. No. 5,641 ,870).
- monoclonal antibody or “monoclonal antibody composition” as used herein refers to polypeptides, including antibodies and antigen binding fragments that have substantially identical amino acid sequence or are derived from the same genetic source. This term also includes preparations of antibody molecules of single molecular composition. A monoclonal antibody composition displays a single binding specificity and affinity for a particular epitope.
- human antibody includes antibodies having variable regions in which both the framework and CDR regions are derived from sequences of human origin. Furthermore, if the antibody contains a constant region, the constant region also is derived from such human sequences, e.g., human germline sequences, or mutated versions of human germline sequences or antibody containing consensus framework sequences derived from human framework sequences analysis, for example, as described in Knappik et al., J. Mol. Biol. 296:57-86, 2000).
- the human antibodies of the invention may include amino acid residues not encoded by human sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo, or a conservative substitution to promote stability or manufacturing).
- the term "humanized" antibody, as used herein, refers to an antibody that retains the reactivity of a non-human antibody while being less immunogenic in humans. This can be achieved, for instance, by retaining the non-human CDR regions and replacing the remaining parts of the antibody with their human counterparts. See, e.g., Morrison et al., Proc. Natl. Acad. Sci. USA, 81 :6851-6855 (1984); Morrison and Oi, Adv.
- an antigen e.g., a protein
- an antibody, antibody fragment, or antibody-derived binding agent refers to a binding reaction that is determinative of the presence of the antigen in a heterogeneous population of proteins and other biologies, e.g., in a biological sample, e.g., a blood, serum, plasma or tissue sample.
- a biological sample e.g., a blood, serum, plasma or tissue sample.
- the antibody or binding agents with a particular binding specificity bind to a particular antigen at least ten (10) times the background and do not substantially bind in a significant amount to other antigens present in the sample.
- Specific binding to an antibody or binding agent under such conditions may require the antibody or agent to have been selected for its specificity for a particular protein. As desired or appropriate, this selection may be achieved by subtracting out antibodies that cross-react with molecules from other species (e.g., mouse or rat) or other subtypes. Alternatively, in some embodiments, antibodies or antibody fragments are selected that cross-react with certain desired molecules.
- immunoassay formats may be used to select antibodies specifically immunoreactive with a particular protein.
- immunoassays are routinely used to select antibodies specifically immunoreactive with a protein (see, e.g., Harlow & Lane, Using Antibodies, A Laboratory Manual (1998), for a description of immunoassay formats and conditions that can be used to determine specific immunoreactivity).
- a specific or selective binding reaction will produce a signal at least twice over the background signal and more typically at least than 10 to 100 times over the background.
- affinity refers to the strength of interaction between antibody and antigen at single antigenic sites. Within each antigenic site, the variable region of the antibody "arm” interacts through weak non-covalent forces with antigen at numerous sites; the more interactions, the stronger the affinity.
- isolated antibody refers to an antibody that is substantially free of other antibodies having different antigenic specificities.
- An isolated antibody that specifically binds to one antigen may, however, have cross-reactivity to other antigens.
- an isolated antibody may be substantially free of other cellular material and/or chemicals.
- polypeptide and "protein” are used interchangeably herein to refer to a polymer of amino acid residues. The terms apply to canonical amino acid polymers as well as to non-canonical amino acid polymers. Unless otherwise indicated, a particular polypeptide sequence also implicitly encompasses conservatively modified variants thereof.
- immunoconjugate or "antibody conjugate” as used herein refers to the linkage of an antigen binding moiety such as an antibody or an antigen binding fragment thereof with another agent, such as a chemotherapeutic agent, a toxin, an
- the linkage can be covalent bonds, or non-covalent interactions, and can include chelation.
- Various linkers known in the art, can be employed in order to form the immunoconjugate.
- the immunoconjugate can be provided in the form of a fusion protein that may be expressed from a polynucleotide encoding the immunoconjugate.
- fusion protein refers to proteins created through the joining of two or more genes or gene fragments which originally coded for separate proteins (including peptides and polypeptides). Translation of the fusion gene results in a single protein with functional properties derived from each of the original proteins.
- cytotoxin refers to any agent that is detrimental to the growth and proliferation of cells and may act to reduce, inhibit, or destroy a cell or malignancy.
- anti-cancer agent refers to any agent that can be used to treat a cell proliferative disorder such as cancer, including but not limited to, cytotoxic agents, chemotherapeutic agents, radiotherapy and radiotherapeutic agents, targeted anti-cancer agents, and immunotherapeutic agents.
- drug moiety or “payload” as used herein, includes but is not limited to inhibitors of Eg5, refers to a chemical moiety that is or can be conjugated to the antibody or antigen binding fragment to form an immunoconjugate, and can include any moiety that is useful to attach to an antibody or antigen binding fragment.
- the immunoconjugates of the invention comprise an Eg5 inhibitor as a payload, for example, but may also include one or more other payloads.
- a drug moiety or payload can be an anticancer agent, an anti-inflammatory agent, an antifungal agent, an antibacterial agent, an anti-parasitic agent, an anti-viral agent, or an anesthetic agent.
- a drug moiety is selected from a V-ATPase inhibitor, a HSP90 inhibitor, an IAP inhibitor, an mTor inhibitor, a microtubule stabilizer, a microtubule destabilizer, an auristatin, a dolastatin, a maytansinoid, a MetAP (methionine aminopeptidase), an inhibitor of nuclear export of proteins CRM1 , a DPPIV inhibitor, an inhibitor of phosphoryl transfer reactions in mitochondria, a protein synthesis inhibitor, a kinase inhibitor, a CDK2 inhibitor, a CDK9 inhibitor, a proteasome inhibitor, a kinesin inhibitor, an HDAC inhibitor, a DNA damaging agent, a DNA alkylating agent, a DNA
- calicheamycins such as gamma-calicheamycin
- maytansinoids such as DM1 , DM3 and DM4.
- a payload can be a biophysical probe, a fluorophore, a spin label, an infrared probe, an affinity probe, a chelator, a spectroscopic probe, a radioactive probe, a lipid molecule, a polyethylene glycol, a polymer, a spin label, DNA, RNA, a protein, a peptide, a surface, an antibody, an antibody fragment, a nanoparticle, a quantum dot, a liposome, a PLGA particle, a saccharide or a polysaccharide, a reactive functional group such as those described herein, or a binding agent that can connect the conjugate to another moiety or surface, etc.
- Tumor refers to neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues.
- anti-tumor activity means a reduction in the rate of tumor cell proliferation, viability, or metastatic activity.
- a possible way of showing anti-tumor activity is to show a decline in growth rate of abnormal cells that arises during therapy or tumor size stability or reduction.
- Such activity can be assessed using accepted in vitro or in vivo tumor models, including but not limited to xenograft models, allograft models, MMTV models, and other known models known in the art to investigate anti-tumor activity.
- malignancy refers to a non-benign tumor or a cancer.
- cancer includes a malignancy characterized by deregulated or uncontrolled cell growth.
- Exemplary cancers include: carcinomas, sarcomas, leukemias, and lymphomas.
- cancer includes primary malignant tumors (e.g., those whose cells have not migrated to sites in the subject's body other than the site of the original tumor) and secondary malignant tumors (e.g., those arising from metastasis, the migration of tumor cells to secondary sites that are different from the site of the original tumor).
- primary malignant tumors e.g., those whose cells have not migrated to sites in the subject's body other than the site of the original tumor
- secondary malignant tumors e.g., those arising from metastasis, the migration of tumor cells to secondary sites that are different from the site of the original tumor.
- the term "pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.
- a therapeutically effective amount of a compound of the present invention refers to an amount of the compound of the present invention that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc.
- the term "a therapeutically effective amount” refers to the amount of the compound of the present invention that, when administered to a subject, is effective to at least partially alleviate, inhibit, prevent and/or ameliorate a condition, or a disorder or a disease.
- a therapeutically effective amount refers to the amount of the compound of the present invention that, when administered to a cell, or a tissue, or a non-cellular biological material, or a medium, is effective to at least partially reduce or inhibit the activity of Eg5.
- the term "subject” refers to an animal. Typically the animal is a mammal. A subject also refers to for example, primates (e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In specific embodiments, the subject is a human.
- the term “inhibit”, “inhibition” or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
- the term “treat”, “treating” or “treatment” of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof).
- “treat”, “treating” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
- “treat”, “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.
- “treat”, “treating” or “treatment” refers to preventing or delaying progression of the disease or disorder.
- a subject is "in need of” a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.
- the modified immunoconjugates of the invention are described according to an "X group-to-antibody" ratio of, e.g., 1 , 2, 3, 4, 5, 6, 7, or 8, or 12 or 16; this ratio corresponds to 'n' in Formula (I). While this ratio has an integer value for a specific conjugate molecule, it is understood that an average value is typically used to describe a sample containing many molecules, due to some degree of inhomogeneity within a sample of an immunoconjugate.
- the average loading for a sample of an immunoconjugate is referred to herein as the "drug to antibody ratio," or DAR.
- the DAR is between about 1 and about 16, and typically is about 1 , 2, 3, 4, 5, 6, 7, or 8.
- At least 50% of a sample by weight is compound having the average DAR plus or minus 2, and preferably at least 50% of the sample is a product that contains the average DAR plus or minus 1.5.
- Preferred embodiments include immunoconjugates wherein the DAR is about 2 to about 8, e.g., about 2, about 3, about 4, about 5, about 6, about 7, or about 8.
- a DAR of 'about q' means the measured value for DAR is within ⁇ 20% of q, or preferably within ⁇ 10% of q.
- an optical isomer or "a stereoisomer” refers to any of the various stereo isomeric configurations which may exist for a given compound of the present invention and includes geometric isomers. It is understood that a substituent may be attached at a chiral center of a carbon atom.
- the term “chiral” refers to molecules which have the property of non-superimposability on their mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner. Therefore, the invention includes enantiomers, diastereomers or racemates of the compound. "Enantiomers” are a pair of stereoisomers that are non- superimposable mirror images of each other.
- a 1 :1 mixture of a pair of enantiomers is a "racemic" mixture.
- the term is used to designate a racemic mixture where appropriate.
- "Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror- images of each other.
- the absolute stereochemistry is specified according to the Cahn- Ingold-Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S.
- Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line.
- Certain compounds described herein contain one or more asymmetric centers or axes and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-.
- the compounds can be present in the form of one of the possible isomers or as mixtures thereof, for example as pure optical isomers, or as isomer mixtures, such as racemates and diastereoisomer mixtures, depending on the number of asymmetric carbon atoms.
- the present invention is meant to include all such possible isomers, including racemic mixtures, diasteriomeric mixtures and optically pure forms, unless otherwise stated, e.g., where a specific isomer is identified.
- Optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
- the substituent may be E or Z configuration. If the compound contains a di-substituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration. All tautomeric forms are also intended to be included.
- salt refers to an acid addition or base addition salt of a compound of the invention.
- Salts include in particular “pharmaceutical acceptable salts”.
- pharmaceutically acceptable salts refers to salts that retain the biological effectiveness and properties of the compounds of this invention and, which typically are not biologically or otherwise undesirable.
- the compounds of the present invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
- Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate,
- bromide/hydrobromide bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlorotheophyllinate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate,
- polygalacturonate propionate, stearate, succinate, subsalicylate, tartrate, tosylate and trifluoroacetate salts.
- Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
- Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.
- Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
- Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table.
- the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.
- Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like.
- Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.
- the pharmaceutically acceptable salts of the present invention can be synthesized from a basic or acidic moiety, by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, use of non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable. Lists of additional suitable salts can be found, e.g., in "Remington's
- any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds.
- Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
- isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 F 31 P, 32 P, 35 S, 36 CI, 125 l respectively.
- the invention includes various isotopically labeled compounds as defined herein, for example those into which radioactive isotopes, such as 3 H and 14 C, or those into which non-radioactive isotopes, such as 2 H and 13 C are present.
- isotopically labeled compounds are useful in metabolic studies (with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), 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.
- PET positron emission tomography
- SPECT single- photon emission computed tomography
- an 18 F or labeled compound may be particularly desirable for PET or SPECT studies.
- Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the
- 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.
- concentration of such a heavier isotope, specifically deuterium may be defined by the isotopic enrichment factor.
- isotopic enrichment factor as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
- a substituent in a compound of this invention is denoted deuterium
- such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium
- 'thiol-maleimide' refers to a group formed by reaction of a thiol with maleimide, having this general formula
- Y and Z are groups to be connected via the thiol-maleimide linkage and can comprise linker components, antibodies or payloads.
- 'Cleavable' refers to a linking group or linker component that connects two moieties by covalent connections, but breaks down to sever the covalent connection between the moieties under physiologically relevant conditions, typically a cleavable linking group is severed in vivo more rapidly in an intracellular environment than when outside a cell, causing release of the payload to preferentially occur inside a targeted cell.
- Cleavage may be enzymatic or non-enzymatic, but generally releases a payload from an antibody without degrading the antibody. Cleavage may leave some portion of a linking group or linker component attached to the payload, or it may release the payload without any residue of the linking group.
- 'Pel' refers to pyrroline carboxy lysine, e.g.,
- R is H, which has the following formula when incorporated into a peptide:
- Non-cleavable' refers to a linking group or linker component that is not especially susceptible to breaking down under physiological conditions, e.g., it is at least as stable as the antibody or antigen binding fragment portion of the
- linking groups are sometimes referred to as 'stable', meaning they are sufficiently resistant to degradation to keep the payload connected to the antigen binding moiety Ab until Ab is itself at least partially degraded, i.e., the degradation of Ab precedes cleavage of the linking group in vivo.
- Degradation of the antibody portion of an ADC having a stable or non-cleavable linking group may leave some or all of the linking group, e.g., one or more amino acid groups from an antibody, attached to the payload or drug moiety that is delivered in vivo.
- halogen refers to fluorine, bromine, chlorine or iodine, in particular fluorine or chlorine.
- Halogen-substituted groups and moieties, such as alkyl substituted by halogen (haloalkyl) can be mono-, poly- or per-halogenated.
- hetero atoms refers to nitrogen (N), oxygen (O) or sulfur (S) atoms, in particular nitrogen or oxygen, unless otherwise provided.
- alkyl refers to a fully saturated branched or unbranched hydrocarbon moiety. Unless otherwise provided, alkyl refers to hydrocarbon moieties having 1 to 10 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms.
- alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2- dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like.
- a substituted alkyl is an alkyl group containing one or more substituents in place of hydrogen, such as one, two or three substituents, up to the number of hydrogens present on the unsubstituted alkyl group.
- Suitable substituents for alkyl groups may be selected from halogen, CN, oxo, hydroxy, Ci_ 4 alkoxy, substituted or unsubstituted C 3 .
- a Ci_ substituted alkyl has 1-3 substituents unless otherwise specified.
- alkylene refers to a divalent alkyl group having 1 to 10 carbon atoms, and two open valences to attach to other features. Unless otherwise provided, alkylene refers to moieties having 1 to 10 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms.
- alkylene examples include, but are not limited to, methylene, ethylene, n-propylene, iso-propylene, n-butylene, sec-butylene, iso-butylene, tert-butylene, n-pentylene, isopentylene, neopentylene, n-hexylene, 3-methylhexylene, 2,2- dimethylpentylene, 2,3-dimethylpentylene, n-heptylene, n-octylene, n-nonylene, n- decylene and the like.
- a substituted alkylene is an alkylene group containing one or more, such as one, two or three substituents; unless otherwise specified, suitable substituents are selected from the substituents listed above for alkyl groups.
- haloalkyl refers to an alkyl as defined herein, which is substituted by one or more halo groups as defined herein.
- the haloalkyl can be monohaloalkyl, dihaloalkyl, trihaloalkyl, or polyhaloalkyl including perhaloalkyl.
- a monohaloalkyl can have one iodo, bromo, chloro or fluoro within the alkyl group. Chloro and fluoro are preferred on alkyl or cycloalkyl groups; fluoro, chloro and bromo are often preferred on aryl or heteroaryl groups.
- DihaloalkyI and polyhaloalkyi groups can have two or more of the same halo atoms or a combination of different halo groups within the alkyi.
- the polyhaloalkyi contains up to 12, or 10, or 8, or 6, or 4, or 3, or 2 halo groups.
- Non-limiting examples of haloalkyi include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
- a perhalo-alkyl refers to an alkyi having all hydrogen atoms replaced with halo atoms, e.g, trifluoromethyl.
- alkoxy refers to alkyl-O-, wherein alkyi is defined above.
- Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, and the like.
- alkoxy groups typically have 1 -10, or 1 -6 carbons, more commonly 1 -4 carbon atoms.
- a “substituted alkoxy” is an alkoxy group containing one or more, such as one, two or three substituents on the alkyi portion of the alkoxy. Unless otherwise specified, suitable substituents are selected from the substituents listed above for alkyi groups, except that hydroxyl and amino are not normally present on the carbon that is directly attached to the oxygen of the substituted 'alkyl-O' group.
- alkyi part of other groups like “alkylaminocarbonyl”, “alkoxyalkyl”, “alkoxycarbonyl”, “alkoxy-carbonylalkyl”, “alkylsulfonyl”, “alkylsulfoxyl”, “alkylamino”, shall have the same meaning as described in the above-mentioned definition of "alkyi”.
- the alkyi group is often a 1 -4 carbon alkyi and is not further substituted by groups other than the component named.
- suitable substituents are those named above for alkyi groups unless otherwise specified.
- haloalkoxy refers to haloalkyl-O-, wherein haloalkyi is defined above.
- Representative examples of haloalkoxy include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, trichloromethoxy, 2-chloroethoxy, 2,2,2- trifluoroethoxy, 1 , 1 , 1 ,3,3,3-hexafluoro-2-propoxy, and the like.
- haloalkyi groups have 1 -4 carbon atoms.
- cycloalkyl refers to saturated or unsaturated non- aromatic monocyclic, bicyclic, tricyclic or spirocyclic hydrocarbon groups of 3-12 carbon atoms: the cycloalkyl group may be unsaturated, and may be fused to another ring that can be saturated, unsaturated or aromatic, provided the ring atom of the cycloalkyl group that is connected to the molecular formula of interest is not an aromatic ring carbon.
- cycloalkyi refers to cyclic hydrocarbon groups having between 3 and 9 ring carbon atoms or between 3 and 7 ring carbon atoms.
- cycloalkyi groups are saturated monocyclic rings having 3-7 ring atoms unless otherwise specified.
- a substituted cycloalkyi is a cycloalkyi group substituted by one, or two, or three, or more than three substituents, up to the number of hydrogens on the unsubstituted group.
- a substituted cycloalkyi will have 1 -4 or 1 -2 substituents.
- Suitable substituents are independently selected from the group consisting of halogen, hydroxyl, thiol, cyano, nitro, oxo, Ci.
- Ci_ 4 -alkylimino Ci_ 4 -alkoximino, hydroxyimino, Ci_ 4 -alkyl, C 2 -4-alkenyl, C 2 -4-alkynyl, Ci_ 4 -alkoxy, C 1 _ 4 -thioalkyl, C 2 _4- alkenyloxy, C2-4-alkynyloxy, Ci- 4 alkylcarbonyl, carboxy, Ci-4-alkoxycarbonyl, amino, C1-4- alkylamino, di- Ci_ 4 -alkylamino, Ci_ 4 -alkylaminocarbonyl, di- Ci_ 4 -alkylaminocarbonyl, C1-4- alkylcarbonylamino, Ci-4-alkylcarbonyl(Ci- 4 -alkyl)amino, Ci_ 4 -alkylsulfonyl, Ci_ 4 -alkylimino, Ci_ 4 -alkoximino, hydroxyi
- hydrocarbon groups e.g., alkyl, alkenyl, alkynyl, alkoxy residues
- hydrocarbon groups may be further substituted by one or more groups independently selected at each occurrence from the list of preferred substituents for 'alkyl' groups herein.
- Exemplary monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl and the like.
- Exemplary bicyclic hydrocarbon groups include bornyl, indyl, hexahydroindyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1 .1 ]hexyl, bicyclo[2.2.1 ]heptyl, bicyclo[2.2.1 Jheptenyl, 6,6-dimethylbicyclo[3.1 .1 Jheptyl, 2,6,6-trimethylbicyclo[3.1 .1 Jheptyl, bicyclo[2.2.2]octyl and the like.
- Exemplary tricyclic hydrocarbon groups include adamantyl and the like.
- cycloalkoxyalkyl shall have the same meaning as described in the above-mentioned definition of "cycloalkyi”.
- the cycloalkyi is typically a monocyclic 3-7 carbon ring that is unsubstituted or substituted with 1 -2 groups.
- the substituents are typically selected from C1-C4 alkyl and those set forth above as suitable for cycloalkyl groups.
- aryl refers to an aromatic hydrocarbon group having 6- 14 carbon atoms in the ring portion. Typically, aryl is monocyclic, bicyclic or tricyclic aryl having 6-14 carbon atoms, often 6-10 carbon atoms, e.g., phenyl or naphthyl.
- aryl refers to an aromatic substituent which can be a single aromatic ring, or multiple aromatic rings that are fused together.
- Non-limiting examples include phenyl, naphthyl and 1 ,2,3,4-tetrahydronaphthyl, provided the tetrahydronaphthyl is connected to the formula being described through a carbon of the aromatic ring of the tetrahydronaphthyl group.
- a substituted aryl is an aryl group substituted by 1-5 (such as one, or two, or three) substituents independently selected from the group consisting of hydroxyl, thiol, cyano, nitro, C-i-4-alkyl, C 2 -4-alkenyl, C 2 -4-alkynyl, Ci_ 4 alkoxy, Ci_ 4 -thioalkyl, C 2 -4-alkenyloxy, C2-4- alkynyloxy, halogen, C Ci-4-alkylcarbonyl, carboxy, Ci-4-alkoxycarbonyl, amino, C1-4- alkylamino, di- Ci_ 4 -alkylamino, Ci_ 4 alkylaminocarbonyl, di- Ci_ 4 -alkylaminocarbonyl, C1-4- alkylcarbonylamino, Ci- 4 alkylcarbonyl(Ci- 4 alkyl)amino, Ci_ 4 alkylsulfonyl, sul
- hydrocarbon groups may be further substituted by one or more groups independently selected at each occurrence from the groups listed above as preferred substituents for alkyl groups.
- aryloxycarbonyl "aryloxy-carbonylalkyl” shall have the same meaning as described in the above-mentioned definition of “aryl”.
- heterocyclyl refers to a heterocyclic radical that is saturated or partially unsaturated but not aromatic, and can be a monocyclic or a polycyclic ring (in case of a polycyclic ring particularly a bicyclic, tricyclic or spirocyclic ring); and has 3 to 14, more commonly 4 to 10, and most preferably 5 or 6 ring atoms; wherein one or more, preferably one to four, especially one or two ring atoms are heteroatoms independently selected from O, S and N (the remaining ring atoms therefore being carbon).
- a heterocycle contains at least one heteroatom as a ring atom and has the number of ring atoms stated, e.g. 5-6 in this example.
- a heterocyclyl group has one or two such heteroatoms as ring atoms, and preferably the heteroatoms are not directly connected to each other.
- the bonding ring i.e. the ring connecting to the Formula of interest
- the heterocyclic group can be fused to an aromatic ring, provided the atom of the heterocyclic group attached to the Formula of interest is not aromatic.
- the heterocyclic group can be attached to the Formula of interest via a heteroatom (typically nitrogen) or a carbon atom of the heterocyclic group.
- the heterocyclyl can include fused or bridged rings as well as spirocyclic rings, and only one ring of a polycyclic heterocyclic group needs to contain a heteroatom as a ring atom.
- heterocycles include tetrahydrofuran (THF), dihydrofuran, 1 ,4-dioxane, morpholine, 1 ,4-dithiane, piperazine, piperidine, 1 ,3-dioxolane, imidazolidine, imidazoline, pyrroline, pyrrolidine, tetrahydropyran, dihydropyran, oxathiolane, dithiolane, 1 ,3-dioxane, 1 ,3-dithiane, oxathiane, thiomorpholine, and the like.
- THF tetrahydrofuran
- dihydrofuran 1,4-dioxane
- morpholine 1 ,4-dithiane
- piperazine piperidine
- 1 ,3-dioxolane imidazolidine
- imidazoline imidazoline
- pyrroline pyrrolidine
- a substituted heterocyclyl is a heterocyclic group independently substituted by 1-5 (such as one, or two, or three) substituents selected from the substituents described above for a cycloalkyl group.
- heterocyclyl part of other groups like “heterocyclyloxy”,
- heterocyclyloxyalkyl "heterocyclyloxycarbonyl” shall have the same meaning as described in the above-mentioned definition of “heterocyclyl”.
- Cyclic ether refers to a heterocyclic ring containing 4-7 ring atoms unless otherwise specified, which contains an oxygen atom as a ring member, and optionally two non-adjacent oxygen atoms for rings of five or more atoms. Typical examples include oxetane, tetrahydrofuran, tetrahydropyran, oxepane, and 1 ,4-dioxane.
- heteroaryl refers to a 5-14 membered monocyclic- or bicyclic- or tricyclic-aromatic ring system, having 1 to 8 heteroatoms as ring members; the heteroatoms are selected from N, O and S.
- Heteroaryl and heterocyclic rings may be referred to herein as, e.g., C 5 . 6 heteroaryl or heterocyclic: it is understood when this description is used that 5-6 refers to the total number of ring atoms, including both carbon and heteroatoms; such rings may alternatively be referred to as 5-6 membered heteroaryl or heterocyclic groups.
- the heteroaryl is a 5-10 membered ring system, e.g., a
- heteroaryl groups include 2- or 3-thienyl, 2- or 3- furyl, 2- or 3-pyrrolyl, 2-, 4-, or 5-imidazolyl, 1-, 3-, 4-, or 5- pyrazolyl, 2-, 4-, or 5-thiazolyl,
- heteroaryl also refers to a group in which a heteroaromatic ring is fused to one or more aryl, cycloalkyl, or heterocyclyl rings, where the radical or point of attachment to the Formula of interest is on a heteroaromatic ring.
- Nonlimiting examples include 1-, 2-, 3-, 5-, 6-, 7-, or 8- indolizinyl, 1-, 3-, 4-, 5-, 6-, or 7-isoindolyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-indazolyl, 2-, 4-, 5-, 6-, 7-, or 8- purinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-quinolizinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinoliyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8- isoquinoliyl, 1-, 4-, 5-, 6-, 7-, or 8-phthalazinyl, 2-, 3-, 4-, 5-, or 6-naphthyridinyl, 2-, 3- , 5-,
- 6- , 7-, or 8-quinazolinyl 3-, 4-, 5-, 6-, 7-, or 8-cinnolinyl, 2-, 4-, 6-, or 7-pteridinyl, 1-, 2-, 3-,
- Typical fused heteroaryl groups include, but are not limited to 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-,
- a substituted heteroaryl is a heteroaryl group containing one or more substituents selected from the substituents described above as suitable for an aryl group.
- heteroaryloxyalkyl shall have the same meaning as described in the above-mentioned definition of “heteroaryl”.
- the invention provides immunoconjugates (e.g., ADCs) that comprise an inhibitor of Eg5 as the drug or payload, and compositions and methods using such immunoconjugates or ADCs to treat cell proliferation disorders.
- ADCs immunoconjugates
- Certain imidazole and triazole compounds are known in the art as inhibitors of Eg5 and as therapeutic agents to treat cell proliferation disorders, and can be used as ADC payloads; see for example WO2007/021794, WO2006/002236, WO2008/063912, WO2009/077448, WO201 1/128381 , and WO201 1/128388.
- Eg5 inhibitors known in the art that could be adapted for use as ADC payloads include, for example, compounds disclosed in WO2006/049835, U.S. Patent No. 7,504,405, U.S. Patent No. 7,939,539, and in Figure 3 of Rath and Kozielski, Nature Reviews: Cancer, vol. 12, 527-39 (Aug. 2012).
- Immunoconjugates that comprise an Eg5 inhibitor as payload (drug) include conjugates of Formula (I):
- Ab represents an antigen binding moiety such as an antibody or antibody fragment
- L represents a linking group that connects X to Ab by covalent or non-covalent bonding, which may optionally attach more than one X to Ab, and which may or may not contain a linker component that is cleavable;
- X represents an Eg5 inhibitor, such as a compound of Formula (II) or Formula (III) as described herein, or other inhibitors of Eg5 including compounds disclosed in Rath (Rath and Kozielski, Nature Rev. Cancer, vol. 12, 527-39 (2012)), including ispinesib, SB- 743921 , AZD4877, ARQ621 , ARRY-520, LY2523355, MK-0731 , EMD534085, and GSK- 923295, and Eg5 inhibitors described in WO06/002236, WO2007/021794,
- n is an integer from 1 to 16, preferably 2-8.
- Ab represents an antigen binding moiety
- L represents a linking group that connects X to Ab
- n is an integer from 1-4;
- n is an integer from 1 to 16;
- Ar 1 is phenyl optionally substituted with up to three groups selected from halo, C1-3 alkyl, and C1.3 haloalkyl;
- Ar 2 is phenyl or pyridinyl or a 4-6 atom cyclic ether, and Ar 2 is optionally substituted with up to two groups selected from halo, CN, C1.3 alkyl, hydroxyl, amino, and C1-3 haloalkyl; R 1 is C-i-6 alkyl, -(CH 2 )o-2-C 3 -6 cycloalkyl, or -(CH 2 )o-2-C 4 -7 heterocyclyl (a 4-7 membered heterocycle) containing up to two heteroatoms selected from N, O and S as ring members, wherein each Ci_ 6 alkyl, C 3 . 6 cycloalkyl, or C 4 .
- heterocyclyl is optionally substituted with up to three groups selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, hydroxyl, amino, oxo, hydroxyl-substituted Ci_ alkyl, amino-substituted C1.4 alkyl, Ci_ alkyl-amino, and COO(Ci_ alkyl); and further optionally including -C(0)-Ci_ 6 alkyl, -C(O)- NH-d.6 alkyl, and -C(0)0-Ci -6 alkyl;
- R 2 is H or Ci-4 alkyl
- T (CH 2 ) 1 . 3 ;
- Y is selected from C1.3 aminoalkyl, C . 6 heterocyclyl, and C 3 . 6 cycloalkyl, wherein C1-3 aminoalkyl, C 4 . 6 heterocyclyl, and C 3 . 6 cycloalkyl are each optionally substituted with up to two groups selected from amino, oxo, halo, hydroxyl, Ci_ alkyl, Ci_ alkoxy, hydroxyl- substituted C1-4 alkyl, amino-substituted C1-4 alkyl, COOH, COO-(Ci- 4 alkyl),
- alkyl alkyl
- alkyl alkyl
- A is NH, N(Ci- alkyl), or a bond between the carbonyl in Formula (II) and Q;
- Q is selected from Ci_ 4 alkyl, -0-Ci_ 4 alkyl, -(CH 2 ) 0 - 2 -C 4 . 6 heterocyclyl, -(CH 2 ) 0 . 2 -C 3 . ecycloalkyl, -(CH 2 ) 0 - 2 -C 5 - 6 heteroaryl, and -(CH 2 ) 0 .
- each R is Ci_ 6 alkyl optionally substituted with halo, -SH, -NH 2 , OMe, or -OH; in some embodiments, R can also be a C 3 -e cycloalkyl, or a 4-6 membered heterocycle containing N, O or S as a ring member, and each R is
- n is 2-8, preferably about 2 to about 4, or between 3 and 5.
- n 2, 4, 6 or 8. In some embodiments, where more than one L is present, each L is independently selected. In other embodiments, each L is the same.
- R 1 is Ci -6 alkyl, -(CH 2 ) 0 - 2 -C 3 . 6 cycloalkyl, or -(CH 2 ) 0 .
- each Ci -6 alkyl, C 3 . 6 cycloalkyl, or C 4 . 7 heterocyclyl is optionally substituted with up to three groups selected from halo, Ci_ alkyl, Ci_ haloalkyl, Ci_ alkoxy, hydroxyl, amino, oxo, hydroxyl-substituted Ci_ 4 alkyl, Ci_ 4 alkyl-amino, and COO(Ci_ 4 alkyl).
- each C1-6 alkyl, C3-6 cycloalkyl, or C4-7 heterocyclyl is substituted with up to two groups selected from halo, Ci_ 4 alkyl, C1.4 haloalkyl, Ci_ 4 alkoxy, hydroxyl, amino, and hydroxyl-substituted Ci_ 4 alkyl, with preferred substituents selected from F, hydroxy, methoxy, and amino.
- suitable R 1 groups include t-butyl, 2-
- linker L is attached to moiety A, by replacement of one of the hydrogen atoms of R 1 or A.
- R 1 include 4-tetrahydropyranyl
- A is -OH, -NH 2 , -COOH, -CONH 2 , -NHC(0)H, or -SH, and the dashed line indicates the point of attachment of each R 1 to Formula II.
- R 2 is H.
- A is a bond between the carbonyl and Q. In other embodiments, A is NH.
- T is CH 2 when Y is a heterocyclyl or cycloalkyl, and T is CH 2 or CH 2 CH 2 when Y is Ci_ 3 aminoalkyl.
- Q is Ci_ alkyl substituted with one or two groups selected from hydroxy, amino, thiol, amino-Ci_ 4 -alkyloxy or amino-Ci_ 4 - alkylthio.
- Q is a ring selected from morpholine, thiomorpholine, pyrrolidine, tetrahydrofuran, piperazine, phenyl and pyridine, where the ring is optionally substituted with up to two groups selected from Ci_ 4 alkyl, halo, CN, hydroxy, amino, Ci_ alkyl-amino, Ci_ alkylsulfonyl, and Ci_ alkoxy.
- Y is a pyrrolidine ring optionally substituted with up to two groups selected from halo, Ci_ alkyl, hydroxy, amino, hydroxy- Ci_4 alkyl, amino-Ci_ alkyl, Ci_ alkyl-amino, and Ci_ alkoxy.
- Preferred substituents for the pyrrolidine include F, methyl, hydroxy, and hydroxymethyl.
- Ar 1 is dihalophenyl.
- Ar 1 is 2,5-dihalophenyl, e.g., Ar 1 can be 2,5- difluorophenyl.
- Ar 2 can be phenyl, halophenyl, hydroxyphenyl, or aminopyridine e.g., phenyl, 3-fluorophenyl, 3-hydroxyphenyl, 3-amino-2-pyridinyl.
- L in Formula (I) is attached to Y, or to Q, or to R 1 in Formula (II).
- L is attached to an oxygen atom or amine nitrogen that is part of group Y or part of group Q.
- R 1 is an optionally substituted alkyl group.
- R 1 is a C 3 -e alkyl group of general formula -CMe 2 (CH 2 )o-2-G-[L], where [L] indicates the point where R 1 is attached to L, and G can be a bond, -0-, -NH-, - S-, -CONH-or -COO-.
- R 1 is -C(Me) 2 -(CH 2 )o-2-R 30 , wherein R 30 is hydroxy, carboxy, or amino.
- L is often attached to R 1 via the group R 30 .
- R 1 is .
- the tetrahydropyran ring can be substituted by one or two substituents selected from hydroxy, methyl, methoxy, and halo.
- Q in Formula (II) is Ci_ 4 alkyl substituted with one or two groups selected from hydroxyl and amino.
- A is NH or N(alkyl)
- Q is often -CH 2 OH, -CH 2 NH 2 , or C 2 _4 alkyl, substituted with one or two groups selected from -OH and -NH 2 .
- A is a bond
- Q can be Ci_ 3 alkyl, optionally substituted with -OH and/or NH 2 .
- a hydroxyl or amine of group Q can be used to attach the compound of Formula (II) to L in Formula (I).
- Y is pyrrolidine optionally substituted with one or two groups selected from fluoro, amino, hydroxyl, methoxy, and hydroxymethyl.
- the pyrrolidine ring NH, or an amino or hydroxyl on the pyrrolidine ring can be the point of attachment of the compound of Formula (II) to L in Formula (I).
- linking group is cleavable.
- Cleavable linking groups include a linker component such as a dipeptide that provides a site for enzymatic cleavage in cells (e.g., val-cit); a linker component such as a hydrazone or imine that is pH sensitive and prone to cleavage inside cells; a disulfide linker component that tends to cleave inside cells; or a linker component such as a dipeptide that provides a site for enzymatic cleavage in cells (e.g., val-cit); a linker component such as a hydrazone or imine that is pH sensitive and prone to cleavage inside cells; a disulfide linker component that tends to cleave inside cells; or a linker component such as a dipeptide that provides a site for enzymatic cleavage in cells (e.g., val-cit); a linker component such as a hydr
- glucuronidase-sensitive linker component such as a p-aminobenzyloxycarbonyl moiety having an-O-glucuronic acid group on the phenyl ring of the aminobenzyloxy group.
- Z is N or CH;
- Ar 1 is phenyl optionally substituted with up to three groups selected from halo, Ci_ 3 alkyl, and Ci_ 3 haloalkyl;
- Ar 2 is phenyl or pyridinyl, and is optionally substituted with up to two groups selected from halo, CN, Ci_ 3 alkyl, hydroxyl, amino, and Ci_ 3 haloalkyl;
- R 1 is -(CH 2 )o-2-C 4 -7 heterocyclyl or -(CH 2 )o-2-C 3 . 7 cycloalkyl, where the C 4 - 7 heterocyclyl is a 4-7 membered ring containing up to two heteroatoms selected from N, O and S as ring members, and C 4 . 7 heterocyclyl and C 3 . 7 cycloalkyl are each optionally substituted with up to three groups selected from halo, Ci_ 4 alkyl (e.g. , methyl), Ci_ haloalkyl (e.g.
- Ci_ alkoxy hydroxyl, amino, oxo, hydroxyl-substituted Ci_ alkyl, amino-substituted Ci_ alkyl, or COO(Ci_ alkyl); is optionally substituted with up to three groups selected from halo, d-4 alkyl, d-4 alkoxy, oxo, or -COO(d-4 alkyl);
- R 2 is H or d-4 alkyl
- T (CH 2 ) 1 . 3 ;
- Y is selected from Ci_ 2 aminoalkyl, C . 6 heterocyclyl, and C 3 . 6 cycloalkyl, wherein C1-2 aminoalkyl, C 4 . 6 heterocyclyl, and C 3 . 6 cycloalkyl are each optionally substituted with up to two groups selected from amino, oxo, halo, hydroxyl, Ci_ alkoxy, hydroxyl- substituted Ci-4 alkyl, amino-substituted d-4 alkyl, COOH, COO-(d-4 alkyl), and d-3 haloalkyl;
- A is NH, N(d_ alkyl), or a bond between the carbonyl in Formula (I I I) and Q;
- Q is selected from d-4 alkyl, -(CH 2 ) 0 - 2 -d- 6 heterocyclyl, -(CH 2 ) 0 - 2 -C 5 - 6 heteroaryl, and -(CH 2 ) 0 - 2 -phenyl, and Q is optionally substituted with up to three groups selected from halo, hydroxyl, amino, -SH, -R, -OR, -SR, -S0 2 R, -N 3 , -NHR, -O-glucuronate, and -NR 2 , where each R is Ci_ 6 alkyl optionally substituted with halo, -SH, -NH 2 , OMe, or -OH.
- R 1 is -(CH 2 ) 0 . 2 -C 3 -6 cycloalkyl, or - (CH 2 )o- 2 -C 4 -7 heterocyclyl containing up to two heteroatoms selected from N, O and S as ring members, wherein each C 3 . 6 cycloalkyl, or C -7 heterocyclyl is optionally substituted with up to three groups selected from halo, C 1 .
- d-e cycloalkyl, or C4-7 heterocyclyl is substituted with up to two groups selected from halo, d-4 alkyl, d-4 haloalkyl, d-4 alkoxy, hydroxyl, amino, and hydroxyl-substituted Ci_ 4 alkyl, with preferred substituents selected from F, hydroxy, methoxy, and amino.
- R 1 is selected from 4-tetrahydropyranyl and
- A is -OH, -NH 2 , -COOH, -CONH 2 , -NHC(0)H, or -SH and the dashed line indicates the point of attachment for each R 1 .
- R 2 is H.
- A is a bond between the carbonyl and Q.
- A is NH.
- T is CH 2 when Y is a heterocyclyl or cycloalkyi, and T is CH 2 or CH 2 CH 2 when Y is Ci_ 3 aminoalkyl.
- Q is Ci_ 4 alkyl substituted with one or two groups selected from hydroxy, amino, thiol, amino-Ci_ 4 -alkyloxy or amino- Ci- 4 -alkylthio.
- Q is a ring selected from morpholine,
- Ci_ alkyl thiomorpholine
- pyrrolidine tetrahydrofuran
- piperazine phenyl and pyridine
- the ring is optionally substituted with up to two groups selected from Ci_ alkyl, halo, CN, hydroxy, amino, Ci_ 4 alkyl-amino, Ci_ 4 alkylsulfonyl, and Ci_ alkoxy.
- Y is a pyrrolidine ring optionally substituted with up to two groups selected from halo, Ci_ alkyl, hydroxy, amino, hydroxy-Ci_ alkyl, amino-Ci_ alkyl, Ci_ alkyl-amino, and Ci_ alkoxy.
- Preferred substituents for the pyrrolidine include F, methyl, hydroxy, and hydroxymethyl.
- novel Eg5 inhibitors can be used to treat cancer as low-molecular weight drug compounds, or they can be incorporated into an ADC for targeted in vivo delivery.
- R 1 is tetrahydropyranyl; in some embodiments R 1 is tetrahydropyran-4-yl.
- Q * is selected from -CH 2 -, -CH(Me)-, -CH(Me)CH 2 -, -CH 2 CH 2 -, -CH 2 0-, -CH 2 S-, - CH 2 -NH-, -CH 2 -NMe-, -CH(Me)0-, -CH(OH)-CH 2 0-, -CH(0-)-CH 2 OH, -CH(OH)-CH 2 NH-, - CH(NH-)-CH 2 OH, -CH(0-)-CH 2 NH 2 , -CH(NH-)-CH 2 OH, -CH(Me)S-, -CH(Me)NH- , -CH 2 CH 2 0-, -CH 2 CH 2 NH-, -CH 2 CH 2 S-, -CH(Me)CH 2 0-, -CH(Me)CH 2 S- , -CH(Me)CH 2 NH-,
- Q * is selected from -CH 2 0-, -CH 2 S-, - CH 2 -NH-, -CH 2 -NMe-, -CH(Me)0-, -CH(OH)-CH 2 0-, -CH(0-)-CH 2 OH, - CH(OH)-CH 2 NH-, -CH(NH-)-CH 2 OH, -CH(0-)-CH 2 NH 2 , -CH(NH-)- CH 2 OH, -CH(Me)S-, -CH(Me)NH-, -CH 2 CH 2 0-, -CH 2 CH 2 NH-, -CH 2 CH 2 S-, - CH(Me)CH 2 0-, -CH(Me)CH 2 S-, -CH(Me)CH 2 NH-,
- Y* is selected from -CH(CH 2 F)NH-, -CH 2 NH-,
- R 10 and R 11 are independently H, Me, OMe, F, CH 2 F, CH 2 OH, COOH, COO(d_ 4 alkyl), CONH(d_ 4 alkyl), CON(C 1 _ 4 alkyl) 2 , or OH; and W is a linking moiety that comprises one or more linker components and a reactive functional group. Suitable linking moieties with reactive functional groups such as maleimide are disclosed herein, including
- X represents the compound of Formula (IIA) or (MB)
- LG is a leaving group suitable to provide an acylating agent, such as CI, -O-Benzotriazole (-OBt), -O- Azabenzotriazole (-OAt), -O-succinimide, substituted phenoxy, -OC(0)(phenyl or substituted phenyl), -OC(0)(Ci -6 alkyl), or -OC(0)0(Ci -6 alkyl).
- an acylating agent such as CI, -O-Benzotriazole (-OBt), -O- Azabenzotriazole (-OAt), -O-succinimide, substituted phenoxy, -OC(0)(phenyl or substituted phenyl), -OC(0)(Ci -6 alkyl), or -OC(0)0(Ci -6 alkyl).
- An alternative embodiment includes a compound of Formula (IIC):
- R is C3-6 alkyl optionally substituted with oxo, hydroxy, amino, or carboxy, e.g., R is -C(Me) 2 -(CH 2 )o-2-A, wherein A is amino, hydroxy, carboxy, CONH 2 , or -SH; and W is a linking moiety that comprises one or more linker components and a reactive functional group.
- W can be -L 1 -L 2 -L 3 -L 4 -L 5 -G, wherein G is the reactive functional group, and L 1 , L 2 , L 3 , L 4 and L 5 are linker components selected from those described herein.
- Suitable reactive functional groups (G) are ones having suitable reactivity to form a covalent linkage to an amino acid side chain of an amino acid in an antibody or antigen binding moiety, such as -SH or -NH 2 of a cysteine or lysine, respectively.
- Suitable reactive functional groups ABA, AAP and ABP include the following groups:
- Fc u is H or Me
- R is H, Me or Phenyl
- inventions of the invention are activated intermediates useful for the preparation of conjugates comprising an Eg5 inhibitor payload similar to the compounds of Formula (II) and (III) described above.
- the compounds comprise a reactive functional group positioned at a location that is well tolerated, even for use with non-cleavable linkers, e.g., the linking group attaches to an atom
- Particularly suitable groups include 2,5-difluorophenyl, 2-Fluoro-5-chlorophenyl and 2- chloro-5-fluorophenyl.
- R 2 is H.
- R 2 can be methyl.
- T is CH 2 or CH 2 CH 2 .
- T is CH 2 CH 2 when Y or Y* is an aminoalkyl such as -CH(CH 2 F)NH 2 or - CH 2 NH 2 ; and T is -CH 2 - when Y or Y * is an optionally substituted pyrrolidine, such as
- R 10 and R 11 are independently H, Me, OMe, F, CH 2 F, CH 2 OH, COOH, COO(d_ 4 alkyl), or OH.
- Y is selected from -CH(CH 2 F)NH 2 ,
- Preferred embodiments of Y * include
- [T] indicates the point of attachment of Y * to T in the formula
- [W] indicates where Y * attaches to W.
- Preferred embodiments of the combination -A-Q include -CH 2 OH, -CH(Me)OH, -NH-CH 2 -CHOH-CH 2 OH, -NH-CH 2 -CH 2 OH, and -NH-CHMe-CH 2 OH.
- -A-Q can be selected from
- a pharmaceutical composition comprising a compound of any of embodiments 15- 29 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.
- a combination comprising a therapeutically effective amount of a compound according to one of embodiments 14-15 or a pharmaceutically acceptable salt thereof and one or more therapeutically active co-agents.
- a method of treating a cell proliferation disorder comprising administering to a subject in need thereof a therapeutically effective amount of an immunoconjugate of any of embodiments 1 -13, or a compound of any of embodiments 14-15, or a
- the cancer is selected from gastric, myeloid, colon, nasopharyngeal, esophageal, and prostate tumors, glioma, neuroblastoma, melanoma, breast cancer, lung cancer, ovarian cancer, colorectal cancer, thyroid cancer, leukemia (e.g., chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), T-lineage acute lymphoblastic leukemia or T-ALL), lymphoma (especially non-Hodgkin's), bladder, renal, gastric (e.g., gastrointestinal stromal tumors (GIST)), liver, and pancreatic cancer, and sarcoma.
- CML chronic myeloid leukemia
- ALL acute lymphoblastic leukemia
- T-ALL T-lineage acute lymphoblastic leukemia or T-ALL
- lymphoma especially non-Hodgkin's
- bladder renal
- gastric e.g., gastrointestinal stromal tumor
- each R N is independently H or CH 2 CH 2 -R 30 , where R 30 is hydroxy, amino or carboxy, and R N is preferably H;
- R o is H or Me
- R 0U is H, Me or Phenyl
- the linking group L * comprises a group of the formula -C(0)NR 21 - or -NR 21 -C(0)- wherein R 21 is of the formula -(CH 2 )i-4-R 22 , where R 22 is a polar group selected from -OH, -IMH2, N(R 23 ) 2 , COOR 23 , CON(R 23 ) 2 , -(OCH 2 CH20)k-OCH2CH 2 OR 23 , and -S0 2 R 23 , where k is 0 to 4 and each R 23 is independently H or Ci_ 4 alkyl.
- X is an inhibitor of Eg5, including a compound of any of embodiments 14-29.
- Ab represents an antigen binding moiety
- L represents a linking group that connects X to Ab
- n is an integer from 1-4;
- n is an integer from 1 to 16;
- X independently at each occurrence represents an inhibitor of Eg5.
- X is a compound according to any of embodiments 14-29.
- X is a compound of this formula:
- R 4a is H, F or OH
- R is H or F; R is selected from
- Y is selected from
- linker L is attached to X at Y 4 , Q 4 , or R 1 .
- Preferred linkers L for these embodiments include, where [Ab] designates the point of attachment to the antibody:
- An immunoconjugate made by reaction of an antibody containing at least one free thiol group with a maleimide compound selected from the following group:
- the antibody is selected from anti- estrogen receptor antibody, anti-progesterone receptor antibody, anti-p53 antibody, anti- HER-2 antibody, anti-cKit antibody, anti-EGFR antibody, anti-cathepsin D antibody, andti-Bcl-2 antibody, anti-E-cadherin antibody, anti-CA125 antibody, anti-CA15-3 antibody, anti-CA19-9 antibody, anti-c-erbB-2 antibody, anti-P-glycoprotein antibody, anti- CEA antibody, anti-retinoblastoma protein antibody, anti-ras oncoprotein antibody, anti- Lewis X antibody, anti-Ki-67 antibody, anti-PCNA antibody, anti-CD3 antibody, anti-CD4 antibody, anti-CD5 antibody, anti-CD7 antibody, anti-CD8 antibody, anti-CD9/p24 antibody, anti-CD1- antibody, anti-CD1 1c antibody, anti-CD13 antibody, anti-CD14 antibody, anti-CD15 antibody, anti-CD19 antibody,
- These immunoconjugates may have a drug to antibody ratio (DAR) between 1 and 8, typically between 2 and 6, and preferably between 3 and 5.
- DAR drug to antibody ratio
- Ab can be any antigen binding moiety unless otherwise defined, and is preferably an antibody or antigen binding fragment that recognizes a cell surface marker such as those described herein that is characteristic of a targeted cell, such as a cancer cell.
- a tumor-associated antigen is especially suitable.
- X can be any compound of Formula (I I) or (II I), particularly any of the compounds disclosed in embodiments 1 -1 1 above or in embodiments 14-15, and including any of the species in Table 1 . In preferred implementations of embodiment 36, X is selected from:
- X is of the formula:
- Ab in any of the above embodiments can be any antigen binding moiety, typically one that recognizes an antigen characteristic of cells to be targeted for pharmaceutical intervention, such as cancer cells.
- antigen binding moiety typically one that recognizes an antigen characteristic of cells to be targeted for pharmaceutical intervention, such as cancer cells.
- Many suitable antigens are well known in the art; specific ones of special interest are described herein.
- Ab is an antibody, which may be isolated or constructed, and may be natural or modified (engineered), or an antibody fragment that retains antigen binding activity similar to the antibody.
- L in the above embodiments can be any linking group that connects Ab to one or more X groups, including a single bond directly connecting Ab to an atom of a compound of Formula (II).
- Suitable linkers for use in ADCs are well known in the art, and can be used in the conjugates of the invention.
- L can be attached to Ab at any suitable available position on Ab: typically, L is attached to an available amino nitrogen atom (i.e., a primary or secondary amine, rather than an amide) or a hydroxylic oxygen atom, or to an available sulfhydryl, such as on a cysteine.
- n is 1-10, commonly 1-8 or 1-6, and preferably n is 1 , 2, 3, 4, or 5.
- R 1 is or comprises a 3-6 membered cycloalkyi ring or a 4-6 membered heterocyclic group, and may be substituted as described in the various enumerated embodiments.
- R 1 is a 5-6 membered heterocyclic group that is unsubstituted.
- R 1 is a 5-6 membered heterocyclic group substituted by an amine or hydroxyl, either of which is optionally a point of attachment for the linking group.
- L can be comprised of up to six linker components, L 1 , L 2 , L 3 , L 4 , L 5 and L 6 , as further described herein.
- the immunoconjugate of Formula (I) can be of the Formula (IA):
- L 1 , L 2 , L 3 , L 4 , L 5 , and L 6 each independently represent a linker component; n is an integer from 1 to 16; and
- X represents an Eg5 inhibitor, e.g., a compound of Formula (II) or Formula (III) as described herein.
- Ab represents an antigen binding moiety
- L 1 , L 2 , L 3 , L 4 , L 5 , and L 6 each independently represent a linker component; n is an integer from 1 to 16; and Ar 1 , Ar 2 , R 1 , R 2 , T, Y, A, Q and Z are as defined for Formula (II) or Formula (III) herein.
- L 6 in this formula is attached to the chemical structure shown: -L 6 - can be considered a substituent of the group of Formula (II) or (III).
- L 6 is attached to an atom of Q, Y, or R 1 , often at an oxygen atom or nitrogen atom of Q, Y or R 1 or one of their substituents.
- each linker component can optionally be a bond joining the groups on either side of the linker component, so in some embodiments the compounds of Formula (I A) include 0, 1 , 2, 3, 4, 5, or 6 of the linker components L 1 , L 2 , L 3 , L 4 , L 5 , and L 6 connecting Ab to X.
- Suitable linker components for forming linking group L are known in the art, as are methods for constructing the linking group L. These components include the groups commonly used to attach a group to an amino acid, spacers such as alkylene groups and ethylene oxide oligomers, amino acids and short peptides up to about 4 amino acids in length; a bond; and carbonyl, carbamate, carbonate, urea, ester and amide linkages, and the like.
- L 1 is selected from groups formed upon reaction of a reactive functional group with one of the amino acid side chains commonly used for conjugation, e.g., the thiol of cysteine, or the free -NH 2 of lysine, or a Pel or Pyl group engineered into an antibody. See e.g., Ou, et al., PNAS 108(26), 10437- 42 (201 1 ). Suitable -L 1 - groups include, but are not limited to, a single bond,
- each p is 1 -10, and each R is independently H or Ci_ 4 alkyl (preferably methyl); and
- R is H or Me, and R is H, Me or Phenyl, for linking to a Pel or Pyl group, where the acyl group shown attaches to the lysine portion of a Pel or Pyl in an engineered antibody.
- R 20 is H or Me
- R 30 is H, Me or Phenyl, where each q is 0-10, preferably 0-6 or 1-6; each R, R 5 , and R 6 is independently H or Ci- 4 alkyl,
- R * is a side chain of a common amino acid such as gly, ala, trp tyr, phe, leu, val, asp, glu gin, asn, his, arg, lys, cys, met, ser, thr, phenylglycine, t-butylglycine;
- R 7 is independently selected from H, Ci_ 4 alkyl, phenyl, pyrimidine and
- R is independently selected from
- R 9 is independently selected from H, Ci_ 4 alkyl, and Ci_ 6 haloalkyl; and any or all of L 1 to L 6 can be absent, i.e., any or all of them can represent a bond between the two groups to which they are attached.
- R 22 is -(CH 2 ) 2 -OH or -(CH 2 ) 2 -COOH.
- the invention provides an immunoconjugate Ab-L*-X, comprising a payload (X) linked to an antibody (Ab), wherein the linking group L * comprises a group of the formula -C(0)NR 21 - or -NR 21 -C(0)- wherein R 21 is of the formula -(CH 2 )i- 4 -R 22 , where R 22 is a polar group selected from -OH, -NH 2 , N(R 23 ) 2 , COOR 23 , CON(R 23 ) 2 , -(OCH 2 CH 2 0) k -OCH 2 CH 2 OR 23 , and -S0 2 R 23 , where k is 0 to 4 and each R 23 is independently H or Ci -4 alkyl.
- the payload can be any suitable payload, such as a cytotoxin like a maytansinoid, auristatin, amatoxin or amanitin, or other known payloads having therapeutic utility in an ADC.
- a cytotoxin like a maytansinoid, auristatin, amatoxin or amanitin, or other known payloads having therapeutic utility in an ADC.
- X is an Eg5 inhibitor such as those as described herein.
- X in embodiments of Formula I can be any Eg5 inhibitor, but is preferably a compound of Formula II as described above, or any of the sub-classes of this Formula that are described in the enumerated embodiments, such as a compound of Formula (III) as described above.
- X is a compound selected from Table 1. While Formula (II) and (III) describe 'neutral' compounds, it is understood that in the context of the conjugates, X comprises one atom that is covalently attached to L or directly to Ab.
- X is attached to the linking group in the above formulas via any available position.
- X is attached to the linking group via one of the atoms of the group represented by Q, or the group represented by Y, or the group represented by R 1 in either Formula (II) or Formula (III).
- Ab can be any antigen binding moiety, including those described herein.
- Ab is an antibody, which may be modified; e.g., Ab can have other payloads attached in addition to at least one Eg5 inhibitor of the present invention.
- Ab is attached to a succinimide ring or to a -CH 2 - or -S- of the linking group L, it is typically connected via a sulfur atom of a cysteine of Ab; in embodiments where Ab is attached to the linking group at a carbonyl of the linking group, it is typically attached via a nitrogen atom, such as the amine of a lysine, in Ab.
- Eg5 inhibitor as a cytotoxic payload for immunoconjugates. It is illustrated with Eg5 inhibitors of Formula (II), but is not limited to these inhibitors, and has been demonstrated to work with other classes of Eg5 inhibitors.
- the Eg5 inhibitor is a compound of Formula (II) or (III), particularly including any of the compounds in Table 1.
- compounds of Formula (II) or (III), when they are part of an immunoconjugate, are covalently attached to a linking group L (or to a linker component that is part of L), or to Ab itself.
- the compounds of Formula (II) or (III) have an open valence whereby they are linked covalently to L (or directly linked to Ab), preferably tightly enough for in vivo delivery to cells targeted for inhibition or elimination.
- the link between the Eg5 inhibitor and Ab involves covalent connection of the antigen binding moiety Ab to the Eg5 inhibitor(s), often through a linking group comprising one or more linker components, such as those described herein.
- the Eg5 inhibitor In use, either before or, more typically, after an ADC reaches and binds to an antigen on a targeted cell, the Eg5 inhibitor will be released from Ab: preferably, the Eg5 inhibitor is released primarily within the targeted cell, after the ADC binds to a surface antigen and is then internalized into the targeted cell.
- the linking group L is designed to be cleavable, and the Eg5 inhibitor detaches from the ADC following internalization.
- the linking group is not designed to be cleavable, and release of the Eg5 inhibitor results when the antigen binding group (e.g., antibody) is degraded in vivo. Typically, degradation of Ab occurs inside a targeted cell, as by protease digestion.
- at least a portion of linking group L may remain attached to the Eg5 inhibitor X, provided the portion of linking group L that remains on X does not interfere with sub-micromolar affinity of the inhibitor X for inhibition of Eg5.
- linking groups for use in ADCs are known (see, e.g., Lash, Antibody-Drug Conjugates: the Next Generation of Moving Parts, Start-Up, Dec. 201 1 , 1 - 6), and can be used in conjugates within the scope of the invention.
- a linking group can be a single covalent bond between an atom of the Eg5 inhibitor and an atom of the antibody; for example, Q can be an alkyl group such as methyl and A can be absent in Formula (II), providing an Eg5 inhibitor of this formula:
- this inhibitor can be converted into a modified Eg5 inhibitor of the following formula, having an iodide (I) as a reactive functional group:
- the iodide compound an alpha-halo acetamide, can react directly with a free thiol group on an antibody, providing an immunoconjugate of this formula:
- S is the sulfur atom of a cysteine residue of the antibody
- linking group L in Formula (I) represents the covalent bond between CH 2 and S.
- L can be comprised of two, three, four, five, six, or more than six linker components, e.g., L 1 , L 2 , L 3 , L 4 , L 5 , and L 6 .
- linker components e.g., L 1 , L 2 , L 3 , L 4 , L 5 , and L 6 .
- Many linkers comprising multiple linker components are known in the art, and the various linker components can be selected and combined to provide operable immunoconjugates of the invention.
- the immunoconjugate is of the Formula (IA):
- L 1 , L 2 , L 3 , L 4 , L 5 , and L 6 represent linker components
- n is an integer from 1 to 16; and X represents an Eg5 inhibitor, e.g., a compound of Formula (II) or Formula (III) as described herein.
- L 1 is typically selected from groups formed upon reaction of a reactive functional group with one of the amino acid side chains commonly used for conjugation, e.g., the thiol of cysteine, or the free -NH 2 of lysine on an antibody, or a Pel or Pyl group engineered into an antibody. See e.g., Ou, et al., PNAS 108(26), 10437-42 (2011 ).
- Suitable -L 1 - groups include, but are not limited to, a single bond as described above,
- each n is 1-10, and each R is independently H or Ci_ 4 alkyl (preferably methyl).
- a bond a non-enzymatically cleavable linker, a non-cleavable linker, an enzymatically cleavable linker, a photo-stable linker, a photo-cleavable linker or a self-immolative spacer.
- each q is 0-10, preferably 0-6 or 1-6; each R, R 5 , and R 6 is independently H or C ⁇ alkyl,
- R 7 is independently selected from H, Ci_ 4 alkyl, phenyl, pyrimidine and pyridine;
- R 8 is independently selected from
- R is independently selected from H, Ci_ 4 alkyl, and Ci_ 6 haloalkyl; and each R * represents the side chain of an amino acid, which can be one of the amino acids encoded by the genetic code, or an alpha-amino acid analog such as citrulline, t-butyl glycine, phenyl glycine, homoserine, and the like; and any or all of these can be absent, i.e., they can represent a bond between the two groups to which they are attached.
- an amino acid which can be one of the amino acids encoded by the genetic code, or an alpha-amino acid analog such as citrulline, t-butyl glycine, phenyl glycine, homoserine, and the like; and any or all of these can be absent, i.e., they can represent a bond between the two groups to which they are attached.
- linker component L 6 include a covalent bond, carbonyl [
- G is an enzyme-cleavable group such as glucuronate
- n is 1 -10
- R is independently H or Ci_ 4 alkyl (preferably methyl).
- Another aspect of the invention provides linkers that reduce ADC aggregation and thus improve ADC function and properties. It is well known that aggregation of ADCs can be detrimental to their activity, and that aggregation depends on the characteristics of the payload as well as the linker. Certain hydrophilic linkers have been used to reduce aggregation.
- Example 4 illustrates novel linkers (e.g., linkers in ADC-1 1 1 and ADC-1 12) that reduce aggregation. These novel linkers comprise a linker component that is an N- substituted amide or carbamate of general formula -C(0)-NR 21 - or -NR 21 -C(0)- or -O-
- R 21 is an alkyl group substituted with a polar group such as hydroxy, amino, mono- or di-alkyl amine, carboxylate, carboxamide, or alkyl sulfonyl.
- a polar group such as hydroxy, amino, mono- or di-alkyl amine, carboxylate, carboxamide, or alkyl sulfonyl.
- antigens associated with cancer cells are known, and antibodies that bind to these antigens can be used in immunoconjugates within the scope of the invention.
- antibodies that bind to these antigens can be used in immunoconjugates within the scope of the invention.
- the clinical candidate ADCs reported in Lash utilize only four payload classes, they include at least 15 antigens associated with various targeted cells.
- Representative examples of the immunoconjugates of the invention are described herein, but the examples do not limit the scope of the invention or the claims.
- solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 0, d 6 - acetone, d 6 -DMSO, as well as solvates with non-enriched solvents.
- Compounds of the invention i.e. compounds of formula (I) that contain groups capable of acting as donors and/or acceptors for hydrogen bonds may be capable of forming co-crystals with suitable co-crystal formers.
- These co-crystals may be prepared from compounds of formula (I) by known co-crystal forming procedures. Such procedures include grinding, heating, co-subliming, co-melting, or contacting in solution compounds of formula (I) with the co-crystal former under crystallization conditions and isolating co- crystals thereby formed.
- Suitable co-crystal formers include those described in WO 2004/078163.
- the invention further provides co-crystals comprising a compound of formula (I).
- Any asymmetric atom (e.g., carbon or the like) of the compound(s) of the present invention can be present in racemic or enantiomerically enriched, for example the (R)-, (S)- or (R,S)- configuration.
- each asymmetric atom has at least 50 % enantiomeric excess, at least 60 % enantiomeric excess, at least 70 % enantiomeric excess, at least 80 % enantiomeric excess, at least 90 % enantiomeric excess, at least 95 % enantiomeric excess, or at least 99 % enantiomeric excess of either the (R)- or (S)- configuration; i.e., for optically active compounds, it is often preferred to use one enantiomer to the substantial exclusion of the other enantiomer.
- Substituents at atoms with unsaturated double bonds may, if possible, be present in cis- (Z)- or trans- (E)- form.
- a compound of the present invention can be in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof.
- substantially pure geometric cis or trans
- optical isomers antipodes
- racemates or mixtures thereof.
- 'Substantially pure' or 'substantially free of other isomers' as used herein means the product contains less than 5%, and preferably less than 2%, of other isomers relative to the amount of the preferred isomer, by weight.
- any resulting racemates of final products or intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound.
- a basic moiety may thus be employed to resolve the compounds of the present invention into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-0,0'-p-toluoyl tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid.
- Racemic products can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent.
- HPLC high pressure liquid chromatography
- the compounds of the present invention can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.
- the compounds of the present invention may inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, it is intended that the invention embrace both solvated and unsolvated forms.
- solvate refers to a molecular complex of a compound of the present invention (including pharmaceutically acceptable salts thereof) with one or more solvent molecules.
- solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to the recipient, e.g., water, ethanol, and the like.
- hydrate refers to the complex where the solvent molecule is water.
- the compounds of the present invention including salts, hydrates and solvates thereof, may inherently or by design form polymorphs.
- the ADCs of the invention can include any suitable Eg5 inhibitor, especially inhibitors having a molecular weight under 1000 Da, preferably under 700 Da.
- the Eg5 inhibitor has an IC-50 less than 1 micromolar; in preferred embodiments, an Eg5 inhibitor for use as a payload has an IC-50 less than 100 nanomolar (nM).
- IC50's for this purpose can be measured as described in
- Suitable Eg5 inhibitors include compounds disclosed in Rath (Rath and Kozielski, Nature Rev. Cancer, vol. 12, 527-39 (2012), including ispinesib, SB- 743921 , AZD4877, ARQ621 , ARRY-520, LY2523355, MK-0731 , EMD534085, and GSK- 923295, and Eg5 inhibitors described in WO06/002236, WO2007/021794,
- WO2006/049835 preferred payloads are compounds of Formula (II) and (III) described herein.
- MK-0731 SB-743921 ispinesib Eg5 inhibitors of Formula (II) or (III) for use as ADC payloads can be attached to linking group L (or directly to Ab) at various positions on the inhibitor; in some
- a compound of Formula (II) is attached to L via an atom of group Q or Y or R 1 .
- Any available valence on the compound of Formula (II) can be attached to L, but for convenient preparation of the conjugate or of modified Eg5 inhibitors of Formula (IIA) or (MB), attachment to L typically occurs at a heteroatom (N, O or S) of Q or Y.
- the compound of Formula (II) comprises a free -NH- or free -OH or free -SH, which is used to attach the compound of Formula (II) to linking group L.
- the free -NH-, -OH, or -SH is a portion of group Q or Y or R 1 in Formula (II).
- the free -NH- can be an amino group (-NH 2 ), cyclic amine (e.g., -NH- in a cyclic group such as pyrrolidone, piperidine, or morpholine), or a secondary acyclic amine; in each case, the -NH- group is preferably not part of an amide or conjugated to a carbonyl or to an aryl or heteroaryl ring, which would reduce its reactivity.
- a free primary or secondary amine or a hydroxyl group is conjugated by an acylation reaction, using a linker component that comprises an activated ester, such as an N-hydroxysuccinimide ester or sulfonate-substituted N- hydroxysuccinimide ester to form an ester or amide linkage.
- a linker component that comprises an activated ester, such as an N-hydroxysuccinimide ester or sulfonate-substituted N- hydroxysuccinimide ester to form an ester or amide linkage.
- an Eg5 inhibitor of Formula (III) is provided.
- the compounds of Formula III may be used as small-molecule therapeutic agents, or they may be incorporated as a payload in an ADC.
- Z is N or CH
- Ar 1 is phenyl optionally substituted with up to three groups selected from halo, Ci_ 3 alkyl, and Ci_ 3 haloalkyl;
- Ar 2 is phenyl or pyridinyl, optionally substituted with up to two groups selected from halo, CN, Ci_ 3 alkyl, hydroxyl, amino, and Ci_ 3 haloalkyl;
- R 1 is -(CH 2 )o-2-C 4 -7 heterocyclyl, where the C 4 - 7 heterocyclyl contains up to two heteroatoms selected from N, O and S as ring members and is optionally substituted with up to three groups selected from halo, d-4 alkoxy, hydroxyl, amino, oxo, hydroxyl- substituted Ci_ 4 alkyl, amino-substituted Ci_ alkyl, methyl, trifluoromethyl, or COO(Ci_ alkyl);is optionally substituted with up to three groups selected from halo, Ci_ alkyl, Ci_ alkoxy, oxo, or -COO(d-4 alkyl);
- R 2 is H or d_ 4 alkyl
- T (CH 2 ) 1 . 3 ;
- Y is selected from d-2 aminoalkyl, C . 6 heterocyclyl, and C 3 . 6 cycloalkyl, wherein C1-2 aminoalkyl, C 4 _e heterocyclyl, and d-e cycloalkyl are each optionally substituted with up to two groups selected from amino, oxo, halo, hydroxyl, Ci_ alkoxy, hydroxyl- substituted d-4 alkyl, amino-substituted d-4 alkyl, COOH, COO-(d-4 alkyl), and d_ 3 haloalkyl;
- A is NH, N(d_ alkyl), or a bond between the carbonyl in Formula (I I I) and Q;
- Q is selected from d-4 alkyl, -(CH 2 ) 0 -2-d-6heterocyclyl, -(CH 2 ) 0 -2-d-6heteroaryl, and -(CH 2 )o-2-phenyl, and Q is optionally substituted with up to three groups selected from halo, hydroxyl, amino, -SH, -R, -OR, -SR, -S0 2 R, -NHR, and -NR 2 , where each R is Ci -6 alkyl optionally substituted with halo, -SH, -NH 2 , OMe, or -OH.
- Additional embodiments include compounds of Formula (III) wherein or R 1 is C 3 . 5 alkyl substituted with -OH, -NH 2 , -COOH, -COO(Ci- 4 alkyl), -CONMe 2 , CONHMe, or - CONH 2 ; and all other features are as described above for Formula (III).
- Z can be CH or N; in many embodiments, Z is CH.
- Ar 1 can be a substituted phenyl as described above, typically a di-substituted phenyl such as dihalophenyl.
- Ar 1 is a 2,5- dihalophenyl such as 2,5-difluorophenyl, 2-chloro-5-fluorophenyl, or 2-fluoro-5- chlorophenyl.
- Ar 2 can be a substituted phenyl or pyridine as described above, or an optionally substituted cyclic either.
- Ar 2 is an unsubstituted or mono-substituted phenyl or pyridine.
- Suitable substituents for the substituted Ar 2 include halo, hydroxyl, and amino; the substituent can be at any position, e.g., it can be at the position meta to the position of Ar 2 that is attached to the imidazole / triazole ring in the Formula.
- R 2 can be H or Ci_ 4 alkyl, typically it is H or Me, preferably H.
- R 1 can be a substituted or unsubstituted heterocyclic group as described above; in some
- R 1 is a cyclic ether such as tetrahydropyran-4-yl, tetrahydropyran-3-yl, tetrahydrofuran-3-yl, or oxetan-3-yl.
- Tetrahydropyran-4-yl is sometimes preferred: when incorporated into an ADC, this moiety reduces aggregation of the conjugate that may occur when R 1 is a t-butyl, for example, so this moiety is especially advantageous for ADC purposes. Data demonstrating this advantage is included in Table 7 herein.
- T can be methylene, ethylene or propylene.
- T is methylene when Y is one of the heterocyclic or cycloalkyl groups described, and T is methylene or -CH 2 CH 2 - when Y is an aminoalkyl group within the scope of Formula (III).
- A can be a bond; in other embodiments, A is preferably -NH-.
- Y can be an aminoalkyi group or heterocyclic group as described above.
- Y is an aminoalkyi such as 1 -fluoro-2-amino-2-ethyl or 1 -amino-2-ethyl or 1 -methoxy-2-amino- 2-ethyl.
- Y is a pyrrolidine ring, e.g., pyrrolidin-3-yl, and may be substituted with F, CH 2 F, CF 3 , Me, or OH.
- Y is a 3-pyrrolidinyl substituted at position 4 with one of these groups (F, CH 2 F, CF 3 , Me, or OH).
- R 2 can be H or Ci_ 4 alkyl; in some embodiments R 2 is H or methyl, preferably H.
- Eg5 inhibitors for use in the immunoconjugates of the invention include any of the compounds in Table 1 , such as:
- R 1 is heterocyclic group such as a cyclic ether, e.g., a tetrahydropyranyl group (e.g. tetrahydropyran): a heterocyclic group at R 1 in the compounds of Formula (II) reduces aggregation when used as an ADC payload, as compared to conjugates having a t-butyl group as R 1 , thus these compounds exhibit an advantage over known inhibitors of Eg5.
- a cyclic ether e.g., a tetrahydropyranyl group (e.g. tetrahydropyran): a heterocyclic group at R 1 in the compounds of Formula (II) reduces aggregation when used as an ADC payload, as compared to conjugates having a t-butyl group as R 1 , thus these compounds exhibit an advantage over known inhibitors of Eg5.
- the linking group L in Formula (I) can be a bond directly connecting payload compound X to Ab (i.e., L or each linker component can represent a bond connecting the groups flanking it together), or it can be a linking moiety comprising one or more linker components L 2 , L 3 , L 4 , L 5 , L 6 , etc. Some preferred linking groups are depicted herein. Linking groups for ADCs commonly contain two or more linker components, which may be selected for convenience in assembly of the conjugate, or they may be selected to impact properties of the conjugate.
- Linker components include chemical groups that are readily formed when connecting Ab to X, such as thiol-maleimide groups, thioethers, amides, and esters; groups that are easily cleaved in vivo under conditions found in, on or around targeted cells, such as disulfides, hydrazones, dipeptides like Val-Cit, substituted benzyloxycarbonyl groups, and the like; spacers to orient X in a suitable position relative to Ab, such as phenyl, heteroaryl, cycloalkyl or heterocyclyl rings, and alkylene chains; and/or pharmacokinetic property-enhancing groups, such as alkylene substituted with one or more polar groups (carboxy, sulfonate, hydroxyl, amine, amino acid, saccharide), and alkylene chains containing one or more -NH- or -O- in place of methylene group(s), such as glycol ethers (-CH 2 CH 2 0-)p where p
- a linking group may be divalent, meaning it can link only one X group to Ab, or it can be trivalent (able to link two X groups to Ab), or it can be polyvalent. Trivalent, tetravalent, and polyvalent linking group can be used to increase the loading of drug on an antibody, increasing the drug to antibody ratio (DAR) without requiring additional sites on the antibody for attaching linking groups.
- DAR drug to antibody ratio
- Such linking groups are known in the art, see e.g., Bioconjugate Chem., 1999 Mar-Apr; 10(2):279-88; US6638499; Clin Cancer Res October 15, 2004 10; 7063; WO2012/1 13847A1.
- a linking group for use in the immunoconjugates of Formula (I) can be cleavable or non-cleavable.
- Cleavable linking groups such as those containing a hydrazone, a disulfide, the dipeptide Val-Cit, and ones containing a glucuronidase-cleavable p- aminobenzyloxycarbonyl moiety, are well known in the art, and can be used. See, e.g., Ducry, et al., Bioconjugate Chem., vol. 21 , 5-13 (2010).
- the linking group is substantially stable in vivo until the immunoconjugate binds to or enters a cell, at which point either intracellular enzymes or intracellular chemical conditions (pH, reduction capacity) cleave the linking group to free the Eg5 inhibitor.
- non-cleavable linking groups can be used in the immunoconjugates of Formula (I).
- Non-cleavable linkers lack structural components designed to degrade in cells, and thus their structures can vary substantially. See, e.g., Ducry, et al.,
- Formulas ( 11 A) and (MB) and (IIC) represent activated Eg5 inhibitors having a linking group attached at specific positions where it has been shown that residual parts of the linking group and/or antibody do not prevent inhibition of Eg5; thus attachment of a linking group at the positions represented by W in Formulas ( 11 A) and (MB) and (IIC) is preferred when a non- cleavable linking group is used.
- linking groups are those that reduce aggregation.
- Linking groups in Compounds 367 and 368 herein have been shown to have the effect of reducing aggregation when used with the Eg5 inhibitors described herein.
- R is of the formula -(CH 2 )i-4-R , where R is a polar group selected from -OH, -NH 2 , N(R 23 ) 2 , COOR 23 , CON(R 23 ) 2 , -(OCH 2 CH 2 0) k -OCH 2 CH 2 OR 23 , and - S0 2 R 23 , where k is 0 to 4 and each R 23 is independently H or Ci_ 4 alkyl; and j is an integer selected from 1 , 2, 3, and 4; and immunoconjugates Ab-L * -X, comprising a payload (X) linked to an antibody (Ab), wherein the linking group L * comprises a group of the formula -C(0)NR 21 - or -NR 21 -C(0)- , are also included in the invention.
- the linking group is of Formula (V).
- [PL] indicates the attachment point of the payload
- [Ab] indicates the point of attachment to an antibody.
- the antibody is typically connected to L * via a sulfur atom of a cysteine residue, which may be a cysteine from the native antibody sequence or a cysteine introduced by protein engineering.
- Preferred polar groups for these linkers include hydroxy and carboxy, j is typically 2, 3 or 4, and a R 21 is often -(CH 2 ) 2 - 3 -R 23 .
- the compounds of Formula (IIA) and (MB) and (IIC) comprise an Eg5 inhibitor attached to a reactive group and optionally one or more linker components connecting the Eg5 inhibitor to the reactive group.
- Table 2 depicts examples of these compounds, comprising an Eg5 inhibitor such as those shown in Table 1 plus a reactive functional group, and optionally one or more linker components.
- Entries 508 and 509 are provided as comparative examples, with Eg5 inhibitors known in the art but not within the scope of Formula II.
- the antigen-binding moiety in Formula (I) or (IA) can be any moiety that selectively binds to a cell-surface marker found on a targeted cell type.
- Ab is an antibody or antibody fragment (e.g., antigen binding fragment of an antibody) that specifically binds to an antigen predominantly or preferentially found on the surface of cancer cells, e.g., a tumor-associated antigen.
- Ab is an antibody or antibody fragment (e.g., antigen binding fragment) that specifically binds to a cell surface receptor protein or other cell surface molecules, a cell survival regulatory factor, a cell proliferation regulatory factor, a molecules associated with (for e.g., known or suspected to contribute functionally to) tissue development or differentiation, a lymphokine, a cytokine, a molecule involved in cell cycle regulation, a molecule involved in
- a tumor-associated antigen may be a cluster differentiation factor (i.e., a CD protein).
- the antigen binding moiety of the invention specifically binds to one antigen.
- the antigen binding moiety of the invention specifically binds to two or more antigens described herein, for example, the antigen binding moiety of the invention is a bispecific or multispecific antibody or antigen binding fragment thereof.
- antibodies or antigen binding fragments include but are not limited to anti-estrogen receptor antibody, anti-progesterone receptor antibody, anti-p53 antibody, anti-HER-2 antibody, anti-cKit antibody, anti-EGFR antibody, anti-cathepsin D antibody, andti-Bcl-2 antibody, anti-E-cadherin antibody, anti-CA125 antibody, anti-CA15-3 antibody, anti-CA19-9 antibody, anti-c-erbB-2 antibody, anti-P-glycoprotein antibody, anti- CEA antibody, anti-retinoblastoma protein antibody, anti-ras oncoprotein antibody, anti- Lewis X antibody, anti-Ki-67 antibody, anti-PCNA antibody, anti-CD3 antibody, anti-CD4 antibody, anti-CD5 antibody, anti-CD7 antibody, anti-CD8 antibody, anti-CD9/p24 antibody, anti-CD1- antibody, anti-CD1 1 c antibody, anti-CD13 antibody, anti-CD14 antibody, anti-CD15 antibody, anti-CD19 antibody,
- the antigen binding moiety of the antibody-drug conjugates (ADC) of Formula (I) or (IA) specifically binds to a receptor encoded by an ErbB gene.
- the antigen binding moiety may bind specifically to an ErbB receptor selected from EGFR, HER2, HER3 and HER4.
- the antigen binding moiety may be an antibody that will specifically bind to the extracellular domain (ECD) of the HER2 receptor and inhibit the growth of tumor cells which overexpress HER2 receptor.
- the antibody may be a monoclonal antibody, e.g. a murine monoclonal antibody, a chimeric antibody, or a humanized antibody.
- a humanized antibody may be huMAb4D5-1 , huMAb4D5-2, huMAb4D5-3, huMAb4D5-4, huMAb4D5-5, huMAb4D5-6, huMAb4D5-7 or huMAb4D5-8 (trastuzumab).
- the antibody may be an antibody fragment, e.g. a Fab fragment.
- the antibody used in the examples herein has the heavy chain and light chain sequences listed in Table 3.
- the sequences are the same as those for trastuzumab, and the antibody is referred to herein as "trastuzumab" or "TBS".
- Trastuzumab is thus one suitable antibody for use in the immunoconjugates of Formula (I) or (IA).
- Table 3 Sequence for antibody TBS used in the following Examples.
- Antigen-binding moieties in Formula I or IA include, but are not limited to, antibodies or antibody fragments (e.g., antigen binding fragments) against cell surface receptors and tumor-associated antigens.
- tumor-associated antigens are known in the art, and can be prepared for use in generating antibodies using methods and information which are well known in the art.
- researchers have sought to identify
- 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). Often, such 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.
- Antibodies and antibody fragments useful for the immunoconjugates of the invention include modified or engineered antibodies, such as an antibody modified to introduce a cysteine residue or lysine residue in place of at least one amino acid of the native sequence, thus providing a reactive site on the antibody or fragment for conjugation to an Eg5 inhibitor.
- the antibodies or antibody fragments can be modified to incorporate Pel or pyrrolysine (Noren et al., (1989) Science 14;244(4901 ): 182-188; Mendel et al., (1995) Annu Rev Biophvs Biomol Struct. 24:435- 462) as sites for conjugation to an Eg5 inhibitor.
- Methods for conjugating such antibodies with payloads or linker-payload combinations are known in the art.
- Antigen-binding moieties e.g., antibodies and antigen binding fragments
- Antigen-binding moieties may also have other modifications or be conjugated to other moieties, such as but not limited to polyethylene glycol tags, albumin, and other fusion polypeptide.
- the antibodies and antibody fragments (e.g., antigen binding fragments) of the invention can be produced by any means known in the art, including but not limited to, recombinant expression, chemical synthesis, and enzymatic digestion of antibody tetramers, whereas full-length monoclonal antibodies can be obtained by, e.g., hybridoma or recombinant production.
- Recombinant expression can be from any appropriate host cells known in the art, for example, mammalian host cells, bacterial host cells, yeast host cells, insect host cells, etc.
- the invention further provides polynucleotides encoding the antibodies described herein, e.g., polynucleotides encoding heavy or light chain variable regions or segments comprising the complementary determining regions as described herein.
- the polynucleotide sequences can be produced by de novo solid-phase DNA synthesis or by PCR mutagenesis of an existing sequence (e.g., sequences as described in the Examples below) encoding an antibody or its binding fragment.
- Direct chemical synthesis of nucleic acids can be accomplished by methods known in the art, such as the phosphotriester method of Narang et al., Meth. Enzymol. 68:90, 1979; the phosphodiester method of Brown et al., Meth. Enzymol. 68:109, 1979; the diethylphosphoramidite method of Beaucage et al., Tetra. Lett., 22:1859, 1981 ; and the solid support method of U.S. Patent No. 4,458,066.
- PCR Technology Principles and Applications for DNA Amplification, H.A. Eriich (Ed.), Freeman Press, NY, NY, 1992
- PCR PROTOCOLS A GUIDE TO METHODS AND APPLICATIONS, Innis et al. (Ed.), Academic Press, San Diego, CA, 1990
- Mattila et al. Nucleic Acids Res. 19:967, 1991
- Eckert et al. PCR Methods and Applications 1 :17, 1991.
- expression vectors and host cells for producing the antibodies or antibody fragments described above are also provided in the invention.
- Nonviral vectors and systems include plasmids, episomal vectors, typically with an expression cassette for expressing a protein or RNA, and human artificial chromosomes (see, e.g., Harrington et al., Nat Genet 15:345, 1997).
- nonviral vectors useful for expression of the polynucleotides and polypeptides in mammalian (e.g., human) cells include pThioHis A, B & C, pcDNA3.1/His, pEBVHis A, B & C (Invitrogen, San Diego, CA), MPSV vectors, and numerous other vectors known in the art for expressing other proteins.
- Useful viral vectors include vectors based on retroviruses, adenoviruses, adenoassociated viruses, herpes viruses, vectors based on SV40, papilloma virus, HBP Epstein Barr virus, vaccinia virus vectors and Semliki Forest virus (SFV). See, Smith, Annu. Rev. Microbiol. 49:807, 1995; and Rosenfeld et al., Cell 68:143, 1992.
- expression vector depends on the intended host cells in which the vector is to be expressed.
- the expression vectors contain a promoter and other regulatory sequences (e.g., enhancers) that are operably linked to the polynucleotides encoding an antibody chain or fragment of the invention.
- promoter e.g., enhancers
- an inducible promoter is employed to prevent expression of inserted sequences except under inducing conditions.
- Inducible promoters include, e.g., arabinose, lacZ,
- metallothionein promoter or a heat shock promoter.
- Cultures of transformed organisms can be expanded under noninducing conditions without biasing the population for coding sequences whose expression products are better tolerated by the host cells.
- other regulatory elements may also be required or desired for efficient expression of an antibody chain or fragment of the invention. These elements typically include an ATG initiation codon and adjacent ribosome binding site or other sequences.
- the efficiency of expression may be enhanced by the inclusion of enhancers appropriate to the cell system in use (see, e.g., Scharf et al., Results Probl. Cell Differ. 20:125, 1994; and Bittner et al.. Meth. Enzvmol.. 153:516. 1987).
- the SV40 enhancer or CMV enhancer may be used to increase expression in mammalian host cells.
- the expression vectors may also provide a secretion signal sequence position to form a fusion protein with polypeptides encoded by inserted antibody sequences. More often, the inserted antibody sequences are linked to a signal sequences before inclusion in the vector.
- Vectors to be used to receive sequences encoding antibody light and heavy chain variable domains sometimes also encode constant regions or parts thereof. Such vectors allow expression of the variable regions as fusion proteins with the constant regions thereby leading to production of intact antibodies or fragments thereof. Typically, such constant regions are human.
- the host cells for harboring and expressing the antibody chains of the invention can be either prokaryotic or eukaryotic.
- E. coli is one prokaryotic host useful for cloning and expressing the polynucleotides of the present invention.
- Other microbial hosts suitable for use include bacilli, such as Bacillus subtilis, and other enterobacteriaceae, such as Salmonella, Serratia, and various Pseudomonas species.
- bacilli such as Bacillus subtilis
- enterobacteriaceae such as Salmonella, Serratia, and various Pseudomonas species.
- expression vectors which typically contain expression control sequences compatible with the host cell (e.g., an origin of replication).
- any number of a variety of well-known promoters may be present, such as the lactose promoter system, a tryptophan (trp) promoter system, a beta-lactamase promoter system, or a promoter system from phage lambda.
- the promoters typically control expression, optionally with an operator sequence, and have ribosome binding site sequences and the like, for initiating and completing transcription and translation.
- Other microbes, such as yeast can also be employed to express the antibodies or antibody fragments of the invention. Insect cells in combination with baculovirus vectors can also be used.
- mammalian host cells are used to express and produce the antibodies and antibody fragments of the present invention.
- they can be either a hybridoma cell line expressing endogenous immunoglobulin genes (e.g., the myeloma hybridoma clones as described in the Examples) or a mammalian cell line harboring an exogenous expression vector.
- endogenous immunoglobulin genes e.g., the myeloma hybridoma clones as described in the Examples
- a mammalian cell line harboring an exogenous expression vector include any normal mortal or normal or abnormal immortal animal or human cell.
- suitable host cell lines capable of secreting intact immunoglobulins have been developed, including the CHO cell lines, various Cos cell lines, HeLa cells, myeloma cell lines, transformed B-cells and hybridomas.
- Expression vectors for mammalian host cells can include expression control sequences, such as an origin of replication, a promoter, and an enhancer (see, e.g., Queen et al., Immunol. Rev. 89:49-68, 1986), and necessary processing information sites, such as ribosome binding sites, RNA splice sites, polyadenylation sites, and
- transcriptional terminator sequences usually contain promoters derived from mammalian genes or from mammalian viruses. Suitable promoters may be constitutive, cell type-specific, stage-specific, and/or modulatable or regulatable. Useful promoters include, but are not limited to, the metallothionein promoter, the constitutive adenovirus major late promoter, the dexamethasone-inducible MMTV promoter, the SV40 promoter, the MRP poll 11 promoter, the constitutive MPSV promoter, the tetracycline-inducible CMV promoter (such as the human immediate-early CMV promoter), the constitutive CMV promoter, and promoter-enhancer combinations known in the art.
- promoters derived from mammalian genes or from mammalian viruses. Suitable promoters may be constitutive, cell type-specific, stage-specific, and/or modulatable or regulatable.
- Useful promoters include, but are not limited to, the metallothionein
- Methods for introducing expression vectors containing the polynucleotide sequences of interest vary depending on the type of cellular host. For example, calcium chloride transfection is commonly utilized for prokaryotic cells, whereas calcium
- phosphate treatment or electroporation may be used for other cellular hosts (see generally Sambrook et al., supra).
- Other methods include, e.g., electroporation, calcium phosphate treatment, liposome-mediated transformation, injection and microinjection, ballistic methods, virosomes, immunoliposomes, polycation:nucleic acid conjugates, naked DNA, artificial virions, fusion to the herpes virus structural protein VP22 (Elliot and O'Hare, Cell 88:223, 1997), agent-enhanced uptake of DNA, and ex vivo transduction. For long-term, high-yield production of recombinant proteins, stable expression will often be desired.
- cell lines which stably express antibody chains or binding fragments can be prepared using expression vectors of the invention which contain viral origins of replication or endogenous expression elements and a selectable marker gene. Following introduction of the vector, cells may be allowed to grow for 1 -2 days in an enriched media before they are switched to selective media.
- the purpose of the selectable marker is to confer resistance to selection, and its presence allows growth of cells which successfully express the introduced sequences in selective media. Resistant, stably transfected cells can be proliferated using tissue culture techniques appropriate to the cell type.
- the invention provides immunoconjugates comprising an Eg5 inhibitor linked to an antigen-binding moiety, such as an antibody or antibody fragment.
- an antigen-binding moiety such as an antibody or antibody fragment.
- immunoconjugates of the invention are those of Formula (I) or (IA) as described herein.
- Preferred immunoconjugates include those disclosed in Tables 5 and 6, and variations thereof having another antigen binding moiety instead of trastuzumab, particularly such conjugates where trastuzumab is replaced by an antibody selected from the following list: anti-estrogen receptor antibody, anti-progesterone receptor antibody, anti-p53 antibody, anti-HER-2 antibody, anti-cKit antibody, anti-EGFR antibody, anti-cathepsin D antibody, andti-Bcl-2 antibody, anti-E-cadherin antibody, anti-CA125 antibody, anti-CA15-3 antibody, anti-CA19-9 antibody, anti-c-erbB-2 antibody, anti-P-glycoprotein antibody, anti- CEA antibody, anti-retinoblastoma protein antibody, anti-ras oncoprotein antibody, anti- Lewis X antibody, anti-Ki-67 antibody, anti-PCNA antibody, anti-CD3 antibody, anti-CD4 antibody, anti-CD5 antibody, anti-
- an immunoconjugate of the invention comprises an antibody or antibody fragment Ab having antigen-binding activity, where the linking group L is attached to Ab at a cysteine sulfur atom of Ab:
- L and X are as defined for Formula (I), and R' and R" are side chains of amino acids adjacent to a cysteine in Ab.
- -S-L- often comprises a thiol- maleimide linkage, and L optionally comprises additional linker components.
- Preferred immunoconjugates include immunoconjugates comprising any of the payload compounds in the following tables (Tables 5 and 6) conjugated with an antibody (AntiB), where the conjugate has the structure shown in the Table, wherein AntiB— S- represents an antibody bonded to the maleimide ring via a sulfur atom (S in the structure) of a cysteine residue of the antibody.
- the antibody (AntiB) is an antibody that recognizes an antigen expressed on a cancer cell.
- Suitable antigens are disclosed herein, including anti-estrogen receptor antibody, anti-progesterone receptor antibody, anti-p53 antibody, anti-HER-2 antibody, anti-cKit antibody, anti-EGFR antibody, anti-cathepsin D antibody, andti-Bcl-2 antibody, anti-E-cadherin antibody, anti-CA125 antibody, anti-CA15-3 antibody, anti-CA19-9 antibody, anti-c-erbB-2 antibody, anti-P- glycoprotein antibody, anti-CEA antibody, anti-retinoblastoma protein antibody, anti-ras oncoprotein antibody, anti-Lewis X antibody, anti-Ki-67 antibody, anti-PCNA antibody, anti-CD3 antibody, anti-CD4 antibody, anti-CD5 antibody, anti-CD7 antibody, anti-CD8 antibody, anti-CD9/p24 antibody, anti-CD1- antibody, anti-CD1 1 c antibody, anti-CD13 antibody, anti-CD14 antibody, anti-CD15 antibody, anti-CD19 antibody, anti-CD
- the cysteine residue connecting the antibody to the maleimide compound may be naturally present in the native antibody, or it may have been introduced into the antibody by protein engineering methods known in the art.
- Antibodies engineered to contain a cysteine residue introduced by protein engineering are sometimes preferred.
- antibodies engineered to introduce cysteine in place of at least one of the following sites are particularly suited for use in the immunoconjugates of the invention: heavy chain sites K360, E152, and S375; and Light chain residue K107.
- the following sites are particularly suited for use in the immunoconjugates of the invention: heavy chain sites K360, E152, and S375; and Light chain residue K107.
- the antibody may contain more than one payload: in typical embodiments, the conjugate contains 2-6, preferably 3-5 payload compounds (Eg5 inhibitors) on an antibody that consists of two heavy chain and two light chain peptides.
- the conjugate contains 2-6, preferably 3-5 payload compounds (Eg5 inhibitors) on an antibody that consists of two heavy chain and two light chain peptides.
- AntiB is an antibody in preferred conjugates.
- AntiB represents a cysteine residue attached via its sulfur atom to the succinimide ring in the Conjugates.
- AntiB is an antibody in preferred immunoconjugates.
- AntiB represents a cysteine residue attached via its sulfur atom to the succinimide ring in these Conjugates.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
- the pharmaceutical composition can be formulated for particular routes of administration such as oral administration, parenteral administration, and rectal administration, and the like.
- the pharmaceutical compositions of the present invention can be made up in a solid form (including without limitation capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including without limitation solutions, suspensions or emulsions).
- compositions can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers and buffers, etc.
- the immunoconjugates of the invention are typically formulated as solutions or suspensions in aqueous buffer and/or isotonic aqueous solution. They are typically formulated and administered at a pH near neutral to protect the stability of the protein component, e.g. at pH between 6 and 8, and may include pharmaceutically acceptable salts. And/or buffers Because the protein components are typically produced from cells, they may contain counterions found in cells, e.g., phosphate, acetate, sodium, potassium, and the like, and such counterions if present are typically not specifically identified or characterized.
- immunoconjugates are typically isolated and handled in buffered solutions such as phosphate-buffered saline, and any counterions present are not expected to affect activity
- the immunoconjugates are typically administered parenterally, either by injection or by infusion. Methods for their formulation and administration are similar to those for formulation and administration of other biologic-based pharmaceuticals such as antibody therapeutics, and are known to those of skill in the art.
- Compounds of Formula (III) for use as small-molecule pharmaceuticals may be formulated for and administered by conventional routes, such as orally, topically, parenterally, buccally, by inhalation, or as suppositories.
- compositions for oral administration include an effective amount of a compound of the invention in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
- Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide
- Tablets may contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
- excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc.
- the tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
- a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.
- Formulations for oral use can be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
- compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions.
- Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances.
- Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1-75%, or contain about 1-50%, of the active ingredient.
- compositions for transdermal application include an effective amount of a compound of the invention with a suitable carrier.
- Carriers suitable for transdermal delivery include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host.
- transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound of the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
- compositions for topical application include aqueous solutions, suspensions, ointments, creams, gels or sprayable formulations, e.g., for delivery by aerosol or the like.
- topical delivery systems will in particular be appropriate for dermal application, e.g., for the treatment of skin cancer, e.g., for prophylactic use in sun creams, lotions, sprays and the like. They are thus particularly suited for use in topical, including cosmetic, formulations well-known in the art.
- Such may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
- a topical application may also pertain to an inhalation or to an intranasal application. They may be conveniently delivered in the form of a dry powder (either alone, as a mixture, for example a dry blend with lactose, or a mixed component particle, for example with phospholipids) from a dry powder inhaler or an aerosol spray presentation from a pressurized container, pump, spray, atomizer or nebulizer, with or without the use of a suitable propellant.
- a dry powder either alone, as a mixture, for example a dry blend with lactose, or a mixed component particle, for example with phospholipids
- the present invention further provides anhydrous pharmaceutical compositions and dosage forms comprising the compounds of the present invention as active ingredients, since water may facilitate the degradation of certain compounds.
- Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.
- An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous
- compositions are packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits.
- suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e. g., vials), blister packs, and strip packs.
- compositions and dosage forms that comprise one or more agents that reduce the rate by which the compound of the present invention as an active ingredient will decompose.
- agents which are referred to herein as “stabilizers,” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers, etc.
- the compounds (immunoconjugates) of formula I in free form or in salt form exhibit valuable pharmacological activities: as the data herein demonstrates, the compounds of Formula (II) and (III) inhibit growth of tumor cells, and are accordingly useful to treat cancers. As the data further demonstrate, these compounds can advantageously be delivered as the payload of an ADC.
- Such conjugates as demonstrated herein, exhibit substantial activity on targeted cells in vitro and on tumors in vivo, as demonstrated by potent growth inhibition of xenograft tumors representing different human cancers.
- the immunoconjugates of the invention comprising a payload of Formula (II) or (III) linked to an antigen binding moiety such as an antibody, are also useful to treat cancers, such as glioma, neuroblastoma, melanoma, breast cancer, lung cancer, ovarian cancer, colorectal cancer, thyroid cancer, leukemia (e.g., chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), T-lineage acute lymphoblastic leukemia or T-ALL), lymphoma (especially non-Hodgkin's), bladder, renal, gastric (e.g., gastrointestinal stromal tumors (GIST)), liver, and pancreatic cancer, and sarcoma.
- cancers such as glioma, neuroblastoma, melanoma, breast cancer, lung cancer, ovarian cancer, colorectal cancer, thyroid cancer, leukemia (e.g., chronic myeloid leukemia (CML), acute lymph
- the compounds and immunoconjugates of the invention are particularly useful for treating cancers known in the art to be inhibited by compounds active against Eg5, and those tumor types demonstrated herein to be susceptible to inhibition by the compounds and conjugates of the invention.
- Suitable indications for treatment include, but are not limited to, gastric, myeloid, colon, nasopharyngeal, esophageal, and prostate tumors, glioma, neuroblastoma, melanoma, breast cancer, lung cancer, ovarian cancer, colorectal cancer, thyroid cancer, leukemia (e.g., chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), T-lineage acute lymphoblastic leukemia or T-ALL), lymphoma (especially non-Hodgkin's), bladder, renal, gastric (e.g., gastrointestinal stromal tumors (GIST)), liver, and pancreatic cancer, and sarcoma.
- CML chronic myeloid leukemia
- the invention provides the use of a compound of formula (I) or (III) or any of the embodiments within the scope of Formula (I) and (III) as described herein, in therapy.
- the therapy is for a disease which may be treated by inhibition of Eg5.
- the compounds of the invention are useful to treat cancers, including but not limited to breast cancer, Hodgkin's lymphoma (HL), non-Hodgkin's lymphoma (NHL), leukemia, myelogenous leukemia, lymphocytic leukemia, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), hairy cell leukemia and multiple myeloma.
- HL Hodgkin's lymphoma
- NHL non-Hodgkin's lymphoma
- leukemia myelogenous leukemia
- lymphocytic leukemia acute myelogenous leukemia
- AML acute myelogenous leukemia
- CML chronic myelogenous leukemia
- ALL acute lymphocytic leukemia
- CLL chronic lympho
- the methods typically comprise administering an effective amount of a compound as described herein or a pharmaceutical composition comprising such compound to a subject in need of such treatment.
- the compound may be administered by any suitable method such as those described herein, and the administration may be repeated at intervals selected by a treating physician.
- the present invention provides the use of a compound of formula (I) or (III), or any of the embodiments of such compounds described herein, for the manufacture of a medicament.
- the medicament is for treatment of a disease which may be treated by inhibition of Eg5.
- the disease is selected from gastric, myeloid, colon, nasopharyngeal, esophageal, and prostate tumors, glioma, neuroblastoma, melanoma, breast cancer, lung cancer, ovarian cancer, colorectal cancer, thyroid cancer, leukemia (e.g., chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), T-lineage acute lymphoblastic leukemia or T-ALL), lymphoma (especially non-Hodgkin's), bladder, renal, gastric (e.g., gastrointestinal stromal tumors (GIST)), liver, and pancreatic cancer, and sarcoma.
- CML chronic myeloid leukemia
- ALL acute lymphoblastic leukemia
- T-ALL T-lineage acute lymphoblastic leukemia or T-ALL
- lymphoma especially non-Hodgkin's
- bladder renal
- gastric e.g., gastrointestinal stromal tumor
- the pharmaceutical composition or combination of the present invention can be in unit dosage of about 1-1000 mg of active ingredient(s) for a subject of about 50-70 kg, or about 1-500 mg or about 1-250 mg or about 1-150 mg or about 0.5-100 mg, or about 1-50 mg of active ingredients.
- the therapeutically effective dosage of a compound, the pharmaceutical composition, or the combinations thereof is dependent on the species of the subject, the body weight, age and individual condition, the disorder or disease or the severity thereof being treated. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease.
- a pharmaceutical combination refers to either a fixed combination in one dosage unit form, or a combined administration where a compound of the present invention and a combination partner (e.g. another drug as explained below, also referred to as
- therapeutic agent or “co-agent”
- the single components may be packaged in a kit or separately.
- One or both of the components e.g., powders or liquids
- co-administration or “combined administration” or the like as utilized herein are meant to encompass administration of the selected combination partner to a single subject in need thereof (e.g. a patient), and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
- pharmaceutical combination means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
- fixed combination means that the active ingredients, e.g. a compound of the present invention and a combination partner, are both administered to a patient simultaneously in the form of a single entity or dosage.
- non-fixed combination means that the active ingredients, e.g. a compound of the present invention and a combination partner, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides
- therapeutically effective levels of the two compounds in the body of the patient also applies to cocktail therapy, e.g. the administration of three or more active ingredients.
- the above-cited dosage properties are demonstrable in vitro and in vivo tests using advantageously mammals, e.g., mice, rats, dogs, monkeys or isolated organs, tissues and preparations thereof.
- the compounds of the present invention can be applied in vitro in the form of solutions, e.g., aqueous solutions, and in vivo either enterally, parenterally, advantageously intravenously, e.g., as a suspension or in aqueous solution.
- the dosage in vitro may range between about 10 3 molar and 10 "9 molar concentrations.
- a therapeutically effective amount in vivo may range depending on the route of administration, between about 0.1-500 mg/kg, or between about 1-100 mg/kg.
- the compound of the present invention may be administered either
- the compound of the present invention may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the co-agent(s).
- the invention provides a product comprising a compound of formula (I) and at least one other therapeutic co-agent as a combined preparation for simultaneous, separate or sequential use in therapy.
- the therapy is the treatment of a disease or condition mediated by Eg5, such as cancer.
- Products provided as a combined preparation include a composition comprising the compound of formula (I) or (III) and the other therapeutic co-agent(s) together in the same
- composition or the compound of formula (I) or (III) and the other therapeutic co-agent(s) in separate form, e.g. in the form of a kit.
- the invention provides a pharmaceutical composition comprising a compound of formula (I) or (III) and another therapeutic co-agent(s).
- the pharmaceutical composition may comprise a pharmaceutically acceptable carrier, as described above.
- Suitable co-agents for use with the compounds and conjugates of the invention include other anti-cancer agents, anti-allergic agents, anti-nausea agents (or anti-emetics), pain relievers, anti-inflammatory agents, cytoprotective agents, and combinations thereof.
- anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan (Myleran®), busulfan injection (Busulfex®), capecitabine (Xeloda®), N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin
- Dome® Dome®
- dactinomycin Actinomycin D, Cosmegan
- Hydrea® Idarubicin (Idamycin®), ifosfamide (IFEX®), irinotecan (Camptosar®), L- asparaginase (ELSPAR®), leucovorin calcium, melphalan (Alkeran®), 6-mercaptopurine (Purinethol®), methotrexate (Folex®), mitoxantrone (Novantrone®), mylotarg, paclitaxel (Taxol®), phoenix (Yttrium90/MX-DTPA), pentostatin, polifeprosan 20 with carmustine implant (Gliadel®), tamoxifen citrate (Nolvadex®), teniposide (Vumon®), 6-thioguanine, thiotepa, tirapazamine (Tirazone®), topotecan hydrochloride for injection (Hycamptin®), vinblastine (Velban®), vincristine
- Suitable anti-allergic agents include corticosteroids, such as dexamethasone (e.g., Decadron®), beclomethasone (e.g., Beclovent®), hydrocortisone (also known as cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate, and sold under the tradenames Ala-Cort®, hydrocortisone phosphate, Solu-Cortef®, Hydrocort Acetate® and Lanacort®), prednisolone (sold under the tradenames Delta-Cortel®, Orapred®, Pediapred® and Prelone®), prednisone (sold under the tradenames Deltasone®, Liquid Red®, Meticorten® and Orasone®), methylprednisol
- corticosteroids such as dexamethasone (e.g., Decadron®), beclomethasone (e.g., Beclovent®), hydrocortisone
- antiemetics are used in preventing nausea (upper stomach) and vomiting.
- Suitable antiemetics include aprepitant (Emend®), ondansetron (Zofran®), granisetron HCI (Kytril®), lorazepam (Ativan®, dexamethasone (Decadron®), prochlorperazine (Compazine®), casopitant (Rezonic® and Zunrisa®), and combinations thereof.
- Medication to alleviate the pain experienced during the treatment period is often prescribed to make the patient more comfortable.
- Common over-the-counter analgesics such Tylenol®, are often used.
- opioid analgesic drugs such as hydrocodone/paracetamol or hydrocodone/acetaminophen (e.g., Vicodin®), morphine (e.g., Astramorph® or Avinza®), oxycodone (e.g., OxyContin® or Percocet®), oxymorphone hydrochloride (Opana®), and fentanyl (e.g., Duragesic®) are also useful for moderate or severe pain.
- hydrocodone/paracetamol or hydrocodone/acetaminophen e.g., Vicodin®
- morphine e.g., Astramorph® or Avinza®
- oxycodone e.g., OxyContin® or Percocet®
- OxyContin® oxymorphone
- cytoprotective agents such as neuroprotectants, free-radical scavengers, cardio protectors, anthracycline extravasation neutralizers, nutrients and the like
- Suitable cytoprotective agents include Amifostine (Ethyol®), glutamine, dimesna (Tavocept®), mesna (Mesnex®), dexrazoxane (Zinecard® or Totect®), xaliproden (Xaprila®), and leucovorin (also known as calcium leucovorin, citrovorum factor and folinic acid).
- the invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (I) or (III).
- the kit comprises means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
- a container, divided bottle, or divided foil packet An example of such a kit is a blister pack, as typically used for the packaging of tablets, capsules and the like.
- the kit of the invention may be used for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another.
- the kit of the invention typically comprises directions for administration.
- the compound of the invention and the other therapeutic co-agent may be manufactured and/or formulated by the same or different manufacturers. Moreover, the compound of the invention and the other therapeutic may be brought together into a combination therapy: (i) prior to release of the combination product to physicians (e.g. in the case of a kit comprising the compound of the invention and the other therapeutic agent); (ii) by the physician themselves (or under the guidance of the physician) shortly before administration; (iii) in the patient themselves, e.g. during sequential administration of the compound of the invention and the other therapeutic agent.
- the invention provides the use of a compound of formula (I) or (III) for treating a disease or condition mediated by Eg5, wherein the medicament is prepared for administration with another therapeutic agent.
- the invention also provides the use of another therapeutic co-agent for treating a disease or condition, wherein the medicament is administered with a compound of formula (I) or (III).
- the invention also provides a compound of formula (I) or (III) for use in a method of treating a disease or condition mediated by Eg5, wherein the compound of formula (I) or (III) is prepared for administration with another therapeutic agent.
- the invention also provides another therapeutic co-agent for use in a method of treating a disease or condition mediated by Eg5, wherein the other therapeutic co-agent is prepared for administration with a compound of formula (I) or (III).
- the invention also provides a compound of formula (I) or (III) for use in a method of treating a disease or condition mediated by Eg5, wherein the compound of formula (I) or (III) is administered with another therapeutic co-agent.
- the invention also provides another therapeutic co-agent for use in a method of treating a disease or condition mediated by Eg5, wherein the other therapeutic co-agent is administered with a compound of formula (I) or (III).
- the invention also provides the use of a compound of formula (I) or (III) for treating a disease or condition mediated by Eg5, wherein the patient has previously (e.g. within 24 hours) been treated with another therapeutic agent.
- the invention also provides the use of another therapeutic agent for treating a disease or condition mediated by Eg5, wherein the patient has previously (e.g. within 24 hours) been treated with a compound of formula (I) or (III).
- All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts utilized to synthesize the compounds of the present invention are either commercially available or can be produced by organic synthesis methods known to one of ordinary skill in the art (see e.g., Houben-Weyl 4th Ed. 1952, Methods of Organic Synthesis, Thieme, Volume 21 ). Further, the compounds of the present invention can be produced by organic synthesis methods known to one of ordinary skill in the art in view of the following examples.
- Eg5 inhibitor compounds of formula (II) can be prepared according to methods known in the art, including methods disclosed in WO2007/021794,
- This process begins with the known protected chiral amino acid having a THP group at the alpha-carbon, and formation of an ester with an appropriate alpha-halo acetophenone to provide the desired Ar 1 group.
- Treatment with ammonium acetate provides the substituted imidazole with retention of chirality at the group on C-2 of the imidazole ring.
- the imidazole nitrogen can be alkylated with mild base to introduce
- the free amine can then be acylated with any suitable acylating agent to introduce appropriate -A-Q moieties using conventional methods known in the art.
- a chiral lactate derivative is used to introduce an acyl group in protected form, having a bond for the group A in Formula (I I) and (I I I), and a protected hydroxyalkyl group for group Q.
- Deprotection of the pyrrolidine ring nitrogen and of the hydroxyl group on Q provides a compound of Formula (I I I).
- Grignard reagent such as vinyl Grignard
- copper (I) bromide to provide a trans-disubstituted pyrrolidine. This can be used to make various pyrrolidine
- Scheme 3 illustrates synthesis of compounds wherein A is -NH-, beginning with an intermediate from Scheme 1.
- Phosgene in dichloromethane followed by introduction of a suitable amine provides the protected intermediate, and deprotection can be
- Scheme 3A illustrates a method to synthesize compounds of Formula (IIA), having a reactive functional group (maleimide, in this case) attached through the acyl group of the compound of Formula (II), i.e., L is attached to Q.
- the intermediate shown, from Scheme 2 is converted to an activated acylating agent using bis-(para-nitrophenol)carbonate, forming a mixed carbonate with a p-nitrophenoxy leaving group.
- the mixed carbonate is then allowed to react with a suitable amine, followed by deprotection of the pyrrolidine ring nitrogen to provide a compound of Formula (IIA), wherein W is a maleimide, suitable for reaction with a thiol on Ab, or on a linker component attached to Ab.
- the product in this example would be considered a non-cleavable linker, since none of the linker components present are designed for in vivo cleavage at a rate faster than the rate of degradation of an antibody to which the moiety would be attached in an ADC of Formula (I).
- Scheme 3B illustrates a method to prepare compounds of Formula (MB), using the product of Scheme 1.
- a mixed carbonate of the maleimide-containing linking group precursor is formed, using bis(para-nitrophenol)carbonate.
- the mixed carbonate is then used to acylate the pyrrolidine nitrogen of the Eg5 inhibitor, providing the compound of Formula (MB) shown above.
- the reactive functional group of W in Formula (MB) is a maleimide
- the linker components in group W include a cleavable linker (val-cit), so this compound exemplifies a conjugate having a cleavable linking group that is subject to cleavage by a cathepsin B.
- the para- aminobenzyloxycarbamate linker component functions as a self-immolative linker: once cathepsin B cleaves the val-cit dipeptide from the para-amino group, the benzyl carbamate spontaneously decomposes to release the Eg5 compound.
- the invention further includes any variant of the present processes, in which an intermediate product obtainable at any stage thereof is used as starting material and the remaining steps are carried out, or in which the starting materials are formed in situ under the reaction conditions, or in which the reaction components are used in the form of their salts or optically pure material.
- DIAD Diisopropyl azodicarboxylate
- DIPEA diisopropyl ethylamine
- LC/MS data were produced with a Waters Acquity UPLC/SQD system, using a photodiode array detector and a single quadrupole mass detector. The following conditions were utilized:
- Method A was used if retention time is under 1.5 minutes and Method B was used for retention times between 1.5 and 10 minutes.
- Preparative Reverse Phase Chromatography - PrepLC Method D System Waters Acquity Prep LC/MS with Waters SQ detector. Column: Sunfire Preparative C18, 5 ⁇ , 30 x 150 mm. Flow: 60 ml/min.
- tert-butyl (2-((tert-butyldimethylsilyl)oxy)ethyl)(2-(2,5-dioxo-2,5-dihydro-1 H- pyrrol-1-yl)ethyl)carbamate (220 mg, 0.552 mmol) was dissolved in 20 mL of DCM, and TFA (2.126 mL, 27.6 mmol) was added. Reaction mixture was stirred at room temperature for 2 h.
- a ethanolamine, 90% yield
- b di-tert-butyl dicarbonate, TEA, THF, 50% yield
- tert-Butyl 3-((2-hydroxyethyl)amino)propanoate (1304 mg, 6.89 mmol) was dissolved in 20 mL of THF, and triethylamine (0.960 mL, 6.89 mmol), followed by Boc- anhydride (1.600 mL, 6.89 mmol) were added. Reaction mixture was stirred at room temperature for 4 hr. Reaction mixture was concentrated in-vacuo and partitioned between ethyl acetate and brine. Organics dried with Na 2 S0 4 , filtered and absorbed onto Isolute.
- Reaction mixture was stirred at -10°C for 3 hr, then concentrated in-vacuo, redissolved in in a mixture of acetonitrile and water and freeze-dried to yield 1086 mg of the crude desired product (1.420 mmol, 60.1 % yield, about 50% pure as determined by purification of a small batch) as a yellow oil.
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Abstract
Priority Applications (3)
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JP2016501643A JP2016516035A (ja) | 2013-03-15 | 2014-03-12 | 細胞増殖阻害剤およびそれらのコンジュゲート |
EP14723916.4A EP2968591A1 (fr) | 2013-03-15 | 2014-03-12 | Inhibiteurs de la prolifération cellulaire et leurs conjugués |
CN201480028219.0A CN105451773A (zh) | 2013-03-15 | 2014-03-12 | 细胞增殖抑制剂及其缀合物 |
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JP (1) | JP2016516035A (fr) |
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EP2968591A1 (fr) | 2016-01-20 |
JP2016516035A (ja) | 2016-06-02 |
CN105451773A (zh) | 2016-03-30 |
UY35471A (es) | 2014-10-31 |
TW201512174A (zh) | 2015-04-01 |
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