WO2017048728A1 - Conjugués ciblés - Google Patents

Conjugués ciblés Download PDF

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Publication number
WO2017048728A1
WO2017048728A1 PCT/US2016/051546 US2016051546W WO2017048728A1 WO 2017048728 A1 WO2017048728 A1 WO 2017048728A1 US 2016051546 W US2016051546 W US 2016051546W WO 2017048728 A1 WO2017048728 A1 WO 2017048728A1
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Prior art keywords
alkyl
residue
targeted conjugate
bioagent
conjugate
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PCT/US2016/051546
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English (en)
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Lawrence Joseph Williams
Hong Zhao
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Rutgers, The State University Of New Jersey
Onco-Link Design Therapeutics
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Publication of WO2017048728A1 publication Critical patent/WO2017048728A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—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 a protein, peptide or polyamino acid
    • A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers

Definitions

  • ADCs Antibody drug conjugates
  • Adcetris® from SeattleGenetics to treat Hodgkin lymphoma (HL) and a rare lymphoma known as systemic anaplastic large cell lymphoma (ALCL), and Kydcyla® from Genentech/Immunogen to treat patients with HER2 -positive, late-stage (metastatic) breast cancer.
  • ADC As targeted therapy, ADC has the advantages of outstanding anticancer efficacy and minimal side effects (Eric L. Sievers and Peter D. Senter (2013). "Antibody-Drug Conjugates in Cancer Therapy”. Annual Review of Medicine 64: 15-29. Vol. 64: 15-29).
  • the toxin suitable for ADC applications is highly potent (often with a half maximal inhibitory concentration (IC50) in the range of picomoles), it is critically important to prevent premature release of the drug before the ADC compound reaches target tissue.
  • the ADC should release the payload quickly and efficiently in order to achieve an optimal cancer cell killing. It is essential that linkers used to conjugate the payload to the antibody have these properties in order to ensure efficacy and minimal off-target activity.
  • the first ADC to enter the market was Mylotarg®, developed by Wyeth Co. It used a plasma-sensitive hydrazone linkage to conjugate the toxin with the antibody (Hamann, Philip R.; Berger, Mark S. (2002). "Mylotarg” Tumor Targeting in Cancer Therapy, Cancer Drug
  • Kydcyla® another approved ADC, has a permanent linker, succinimidyl-4-(N- maleimidomethyl)cyclohexane-l-carboxylate (SMCC), that connects the drug to the remainder of the construct.
  • SMCC succinimidyl-4-(N- maleimidomethyl)cyclohexane-l-carboxylate
  • Maytansinoid DM1 The structure and activity of Maytansinoid DM1 is such that the modification, which is extensive, does not ablate the potency of the drag despite the presence of a residual lysine and SMCC linker appendage.
  • this strategy is not general and works in this case because the toxin maintains its anticancer activity despite modification.
  • the biological activity of small molecule drugs is highly sensitive to modification.
  • Adcetris® employs a linker system with two parts: valine-citrulline dipeptide and aniline-based p-aminobenzyloxycarbonyl (PABC) (Senter, Peter D.; Sievers, Eric L. (2012). "The discovery and development of brentuximab vedotin for use in relapsed Hodgkin lymphoma and systemic anaplastic large cell lymphoma”. Nature Biotechnology, 30(7): 631-637 ).
  • PABC aniline-based p-aminobenzyloxycarbonyl
  • Valine-citrulline is a substrate for the lysosomal enzyme cathepsin B.
  • 1 ,6-benzyl elimination of the PABC system will release the amine containing drag molecule.
  • the drag molecule can keep its integrity during circulation and transportation within the body, and it will release the toxin payload monomethyl auristatin E (MMAE) inside the lysosome when the valine-citrulline dipeptide is cleaved by cathepsin B and trigger the PABC linker to regenerate the intact amino containing toxin molecule.
  • MMAE monomethyl auristatin E
  • the PABS moiety is aromatic and hydrophobic, it may hinder and slow down the approach of cathepsin B enzyme and reduce the rate of valine-citrulline cleavage.
  • Slow release of toxin inside the cancer cell may not produce a high enough concentration of toxin molecules required to kill the cancer cell, may prolong the survival of cancer, and thereby provides a mechanism by which the cancer cell can generate drag resistance.
  • resistance can emerge as a function of ADC properties and cancer type.
  • this system is only applicable to amino containing toxins. Many drug molecules lack an amino group, or even a nitrogen atom. Current technologies are not applicable as a releasing agent to these drag molecules.
  • Adcetris® Adcetris®. However, this system has some serious limitations. There is a critical and unmet need for new linker systems that have all the desired features required for broadly applicable ADCs.
  • the present invention provides a targeted conjugate suitable for targeting a bioagent (e.g., an imaging agent or a therapeutic agent such as drag) to a target location (e.g., a target cell) using a targeting element (e.g., an antibody).
  • a targeting element e.g., an antibody
  • the conjugate comprises a targeting element, a cleavable linker comprising an activation element, a releasable linker comprising a residue of a substituted or unsubstituted amino methyl moiety and a residue of a bioagent.
  • the activation element masks the amino methyl moiety (releasable linker).
  • the activation element is cleaved (e.g., enzymatically cleaved) from the amino methyl releasable linker resulting in the degradation of the amino methyl moiety by spontaneous collapse which liberates the bioagent.
  • the targeted conjugates described herein are stable under physiological conditions such as in plasma, and activate inside the targeted location such as a cell (for example, a cancer cell).
  • one embodiment provides a targeted conjugate comprising a targeting element, an activation element, a residue of a substituted or unsubstituted amino methyl moiety and a residue of a bioagent.
  • One embodiment provides a pharmaceutical composition
  • a pharmaceutical composition comprising a targeted conjugate as described herein and a pharmaceutically acceptable carrier.
  • One embodiment provides a method to deliver a bioagent to an animal (e.g., a mammal such as a human) comprising administering a targeted conjugate described herein to the animal.
  • an animal e.g., a mammal such as a human
  • One embodiment provides a method to treat or diagnose a disease in an animal (e.g., a mammal such as a human) comprising administering a targeted conjugate as described herein to the animal.
  • an animal e.g., a mammal such as a human
  • One embodiment provides a method to treat or diagnose cancer in an animal (e.g., a mammal such as a human) comprising administering a targeted conjugate as described herein to the animal.
  • an animal e.g., a mammal such as a human
  • One embodiment provides a method to treat cancer in an animal (e.g., a mammal such as a human) comprising administering a targeted conjugate as described herein to the animal.
  • an animal e.g., a mammal such as a human
  • One embodiment provides a method to treat cancer in an animal (e.g., a mammal such as a human) in need thereof comprising administering to the animal a targeted conjugate as described herein.
  • an animal e.g., a mammal such as a human
  • One embodiment provides a targeted conjugate as described in herein for medical therapy or medical diagnosis.
  • One embodiment provides a targeted conjugate as described herein for the therapeutic treatment of cancer.
  • One embodiment provides the use of a targeted conjugate as described herein for the preparation of a medicament to treat a disease such as cancer.
  • Figure 1 is an exemplary antibody-drug-conjugate synthesized which can be prepared by the methods of Example 1 and which demonstrates a new releasing linker.
  • the exemplary releasing linker is outlined with a box on the structural formula.
  • Figure 2 shows an exemplary ADC incorporating a releasing linker according to the present invention. Adjacent to the Figure is a schematic showing the mechanism of toxin cleavage from the releasing linker.
  • FIG. 3 A is a schematic illustrating the branched conjugate according to an embodiment of the present invention.
  • the targeting element here an antibody
  • the releasing linker a residue of a substituted or unsubstituted amino methyl moiety.
  • the activation element and the residue of a bioagent are also directly attached to the releasing linker.
  • Figure 3B is a schematic illustrating a linear conjugate.
  • the targeting element, activation element, releasing linker (a residue of a substituted or unsubstituted amino methyl moiety) and a residue of a bioagent are connected in series).
  • Figure 4 shows natural products.
  • SeattleGenetics developed the first effective ADC: anti-CD30 Ab-Valine- citriline-PABC-MMAE (Adcetris).
  • the drug was granted accelerated approval by the FDA on August 19, 2011 for relapsed Hodgkin's lymphoma (HL) and relapsed or refractory systemic anaplastic large cell lymphoma (sALCL).
  • the Adcetris technology has many limitations.
  • the construct that SeattleGenetics has successfully assembled is a linear array of antibody attached to a linker system that is then attached to the drug, which may not be ideal.
  • the linker system has two parts: valine-citrulline dipeptide and aniline-based p-aminobenzyloxycarbonyl (PABC) system.
  • Valine-citriline is a protease substrate, e.g. for the lysosomal enzyme cathepsin B.
  • PABC is an aromatic moiety that does not mimic native peptides and may attenuate protease activity. The construct is not ideal because of the ADC conjugate structure, the cleavage mechanism, and the activation process.
  • the PABC 1,6- elimnation is not easily tuned while maintaining enzyme substrate viability.
  • the present invention provides a targeted conjugate comprising a targeting agent, an activation element, a releasing linker and a bioagent.
  • the releasing linker comprises a residue of a substituted or unsubstituted amino methyl moiety.
  • the targeting agent (such as an antibody) is used to target the bioagent (e.g., drug) to a specific cell type.
  • the targeting agent recognizes a particular molecule on the cell, such as a receptor, and the conjugate is subsequently internalized into the cell.
  • the releasing linker is masked by an activation element until the conjugate reaches a target cell.
  • the activation element is enzymatically cleaved away from the releasing linker and the releasing linker is subsequently degraded by spontaneous intramolecular collapse releasing the drug inside the target cell.
  • the targeted conjugate may be an antibody-drug-conjugate (ADC).
  • the cleavable linker described herein is superior to PABC, including tunable activity to proteases (e.g., cathepsin B), as well as tunable, fast release of the drug following proteolysis, the highly enabling flexibility to be attached to oxygen, as well as other atoms other than nitrogen, but including nitrogen, and a construct structure that can be branched or linear.
  • proteases e.g., cathepsin B
  • fast release of the drug following proteolysis the highly enabling flexibility to be attached to oxygen, as well as other atoms other than nitrogen, but including nitrogen, and a construct structure that can be branched or linear.
  • protease hydrolysis of a dipeptide (activation element) attached to the releasing linker, which is attached in turn to a drug (bioagent), would release the drug so it is free to act on the cell.
  • This activation preferably takes place in a cellular compartment, such as the lysosome or endosome of a target cell.
  • Liberation of the amino group by proteolysis triggers a cascade that results in disintegration of the new linker and releases the drug molecules within the cell.
  • linker systems are stable under physiological conditions such as in plasma, and only activate inside the targeted cells (for example, cancer cells). They are therefore especially suitable to be incorporated in antibody drug conjugates (ADCs).
  • alkyl refers to a straight or branched saturated hydrocarbon.
  • alkenyl refers to a straight or branched hydrocarbon comprising one or more double bonds.
  • alkynyl refers to a straight or branched hydrocarbon comprising one or more triple bonds.
  • chains include any branched or unbranched arrangement of atoms that are bonded together but are not cyclic.
  • chains include by way of example but are not limited to alkyl, alkenyl, alkynyl and heteroalkyl groups.
  • a heteroalkyl group can comprise a straight or branched arrangement of atoms such as a hydrocarbon wherein one or more of the carbon atoms has been replaced by a heteroatom selected from nitrogen, oxygen and sulfur.
  • halo or “halogen” as used herein refers to fluoro, chloro, bromo and iodo.
  • carbocycle or “carbocyclyl” refers to a single saturated (i.e., cycloalkyl) or a single partially unsaturated (e.g., cycloalkenyl, cycloalkadienyl, etc.) all carbon ring having 3 to 7 carbon atoms (i.e. (C 3 -C 7 )carbocycle).
  • Carbocyclene refers to an carbocycle group having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of the carbocycle.
  • heterocyclyl or “heterocycle” as used herein refers to a single saturated or partially unsaturated ring that has at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur.
  • the term includes 3, 4, 5, 6, 7 or 8-membered single saturated or partially unsaturated rings from about 1 to 7 carbon atoms and from about 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring.
  • the ring may be substituted with one or more (e.g., 1, 2 or 3) oxo groups and the sulfur and nitrogen atoms may also be present in their oxidized forms.
  • Such rings include but are not limited to azetidinyl, tetrahydrofuranyl or piperidinyl.
  • heteroaryl refers to a single aromatic ring that has at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur.
  • the term includes 5 and 6-membered single aromatic rings from about 1 to 5 carbon atoms and from about 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring.
  • the sulfur and nitrogen atoms may be present in their oxidized forms provided the ring is aromatic.
  • Such rings include but are not limited to pyridine, tetrazole and triazole.
  • cyclic group includes any arrangement of atoms that are bonded together that form a cyclic structure.
  • cyclic groups include by way of example but are not limited to carbocycle, phenyl, heteroaryl and heterocycle.
  • aryl refers to a phenyl or an ortho-fused bicyclic carbocyclic having about nine to ten ring atoms in which at least one ring is aromatic. In one embodiment the aryl is phenyl.
  • the releasable linker described herein is a residue of a substituted or unsubstituted amino methyl moiety which is connected (bonded) to both an activation element and a residue of a bioagent.
  • residue of a substituted or unsubstituted amino methyl moiety is separated from the activation element such as by cleavage of the bond connecting the two, the amino methyl moiety readily degrades to release the bioagent.
  • the amino methyl moiety, through substitution can be tuned in terms of both sterics and electronics. This feature allows easy access of potential proteases (for example) to cleave the activation element which enables rapid disintegration of the amino methyl moiety to release the bioagent (e.g., a hydroxyl containing bioagent).
  • the activation element Once the activation element has been cleaved from the residue of the substituted or unsubstituted amino methyl moiety (releasable linker) it disintegrates spontaneously and rapidly within the cellular environment because of very low enthalpic barriers and highly favorable entropic gains. This is in contrast to previously known linkers that require de-aromatization, a large enthalpic barrier, or the formation of intermediates that are slow to liberate the drug.
  • R 1 is H or (Ci-C )alkyl wherein (C]-C 6 )alkyl is optionally substituted with one or more halogen
  • R 2 is H, (Ci-C 6 )alkyl, -0(C r C 6 )alkyl, aryl or aryl(C r C 6 )alkyl wherein any(C C 6 )alkyl or -0(CrC )alkyl of R is optionally substituted independently with one or more
  • halogen -0(C 1 -C 3 )alkyl or -OH, and wherein any aryl or aryl(Ci-C6)alkyl of R 2 is optionally substituted independently with one or more halogen, (Cj-C )alkyl , -0(CrC 3 )alkyl or -OH;
  • R 3 is H, (Cj-C 6 )alkyl, -0(CrC 6 )alkyl, aryl or aryl(C 1 -C 6 )alkyl wherein any(C 1 -C 6 )alkyl or -0(C ! -C 6 )alkyl of R is optionally substituted independently with one or more
  • halogen -0(C!-C3)alkyl or -OH
  • any aryl or a y ⁇ C C ⁇ alkyl of R 3 is optionally substituted independently with one or more halogen, (Cj-C )alkyl , -0(Cj-C 3 )alkyl or -OH.
  • the activation element is bonded to the nitrogen atom attached to R 1 of the residue of formula I.
  • the term "residue of the substituted or unsubstituted amino methyl moiety” means that open valences have be created by removal of one or more atoms (e.g., hydrogen atoms) from the corresponding substituted or unsubstituted amino methyl moiety to allow for bonding between the moiety and various elements of the conjugate (e.g., activation element, residue of a bioagent, targeting element).
  • the residue of the substituted or unsubstituted amino methyl moiety is part of a second bioagent.
  • aldehyde and ketone and imine containing bioagents can be included into the residue of the substituted or unsubstituted amino methyl moiety.
  • part of the functional group (e.g., aldehyde and ketone and imine) of the second bioagent would become part of the linker itself.
  • the aminomethyl functionality can decompose to provide the second bioagent in addition to the first bioagent (e.g., H-W).
  • the residue of the second bioagent depicted by formula la is derivable from a bioagent the comprises one or more groups selected from ketone, aldehyde and imine.
  • residue of the second bioagent depicted by formula la is derivable from a bioagent the comprises one or more groups selected from ketone, aldehyde and imine. In one embodiment the residue of the second bioagent depicted by formula la is derived from a bioagent the comprises one or more groups selected from ketone, aldehyde and imine.
  • Y is O or N Ry' ; Ry' is H or (C 1 -C 6 )alkyl; and R 2 and R 3 together with the remainder of the compound of formula lb is a bioagent.
  • the residue of the second bioagent depicted by formula la is derived from a bioagent of formula lb.
  • bioagents include but are not limited to zaleplon, famciclovir, cetirizine, and peptides and peptide analogues, which contain or could be made to contain this functionality.
  • the activation element is a masking (protective) group which masks the releasing linker. Cleavage of the activation element from the releasing linker results in a reactive releasing linker intermediate which is capable of undergoing spontaneous disintegration to release the bioagent.
  • the activation element may be any element (e.g., molecular structure) that stabilizes (e.g., protects) the releasing linker (the substituted or unsubstituted amino methyl moiety) from disintegration and release of the bioagent until it is desirable to the release the bioagent.
  • the activation element once activated (e.g., through contact with an enzyme), results in the release of the bioagent (e.g., through breaking of the bond (cleavage) linking the activation element to the substituted or unsubstituted amino methyl moiety which moiety subsequently disintegrates to release the bioagent).
  • the activation element is cleavable from the substituted or unsubstituted amino methyl moiety by an enzyme; the cleavage can take place at any appropriate location including but not limited to inside a cell, outside a cell or proximal to a cell (e.g., a cell such as a target cell).
  • the activation element is cleaved from the substituted or unsubstituted amino methyl moiety by an enzyme; the cleavage can take place at any appropriate location including but not limited to inside a cell, outside a cell or proximal to a cell (e.g., a cell such as a target cell).
  • the activation element may comprise any molecular structure that functions in this manner such as amino acid, peptide, polypeptide or protein (e.g., a complete or partial protein or any variant thereof).
  • the activation element may comprise or consist of a polypeptide of 2-3, 2-5, 2-10 or 2-20 amino acids in length.
  • the activation element may comprise or consist 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19 or 20 amino acids in length (e.g., polypeptide, amino acid).
  • the activation element may comprise or consist of an amino acid.
  • the activation element is cleaved within a target such as a cellular compartment (e.g., a lysosome or endosome of a target cell).
  • the activation element is cleaved by an enzyme located within the target cell.
  • the enzyme may be cathepsin B.
  • the cleavage may be proteolysis.
  • the activation element is cleavable within a target such as a cellular compartment (e.g., a lysosome or endosome of a target cell).
  • the activation element is cleaved by an enzyme located within the target cell.
  • the activation element is cleavable by an enzyme located within the target cell.
  • the enzyme may be a proteolytic enzyme.
  • the cleavage may be proteolysis.
  • the enzyme may be cathepsin (e.g., cathepsin B).
  • the activation element is an amino acid or polypeptide.
  • the activation element is a polypeptide.
  • the activation element is a polypeptide comprising 2-10 amino acids. In one embodiment the activation element is a polypeptide comprising 2-5 amino acids. In one embodiment the activation element is a polypeptide comprising 2 amino acids. In one embodiment the activation element is a polypeptide comprising valine and citrulline.
  • the targeting element can be any element suitable for the targeting a bioagent; for example, to a specific cell or tissue, or to a specific location such as a location in a cell.
  • the targeting element may specifically bind an antigen on a target cell, for example, a tumor antigen on a cancer cell.
  • the targeting element can be subsequently absorbed or internalized into the target cell, thus delivering the targeted conjugate into the target cell.
  • Suitable targeting elements include polypeptides, linear or cyclic, such as an antibody (e.g., monoclonal antibodies), single chain antibody, Fab, small molecules (such as folate), or other binding scaffolds, such as centyrin, darpin, and small protein and peptide structures, or oligonucleotides, such as aptamers, that can be varied such that they can be made to target cells.
  • polypeptides linear or cyclic
  • an antibody e.g., monoclonal antibodies
  • single chain antibody Fab
  • small molecules such as folate
  • binding scaffolds such as centyrin, darpin, and small protein and peptide structures
  • oligonucleotides such as aptamers
  • Antibodies are excellent and selective cellular recognition elements that, due to their innate structure and function, have good stability and pharmacokinetic profiles.
  • the targeting agent is an antibody.
  • An antibody as discussed herein may be a whole antibody or antigen-binding fragment thereof including Fab and scFv fragments.
  • the antibody may be a monoclonal antibody (mAb).
  • Monoclonal antibodies that target a cell specific antigen include bevacizumab (humanized monoclonal antibody with a circulatory system target (VEGF- A)); cetuximab (chimeric monoclonal antibody with a tumor target (EGFR)); ipilimumab (fully human antibody with an immune system target (CTLA-4)); rituximab (targets CD20 on B cells); trastuzumab (targets the Her2/neu (ErbB2) receptor).
  • VEGF- A humanized monoclonal antibody with a circulatory system target
  • cetuximab chimeric monoclonal antibody with a tumor target (EGFR)
  • ipilimumab fully human antibody with an immune system target (CTLA-4)
  • rituximab targets CD20 on B cells
  • trastuzumab targets the Her2/neu (ErbB2) receptor
  • Other monoclonal antibodies are known in the art and may be used as targeting elements.
  • HER1/ERBB1 HER1/ERBB1
  • VEGF vascular endothelial growth factor
  • CD30 CD20
  • Other target antigens are known in the art.
  • the targeting element Since the function of the targeting element is independent of its point of attachment, this element can be connected to the targeted conjugate at any point that does not attenuate other modules of the construct.
  • the targeting agent is directly connected to the activation element.
  • the targeting agent is directly connected to the releasing linker.
  • bioagent includes therapeutic agents that are useful for the treatment of a disease or a physiological condition in an animal (e.g., a mammal such as a human) and thus includes known drugs.
  • bioagent includes “therapeutic agent” which includes but is not limited to known drugs and/or drugs that have been approved for sale in the United States.
  • therapeutic agents include but are not limited to chemotherapeutic
  • bioagent also includes imaging agents (detectable agents) that are useful for example in diagnosing diseases.
  • the bioagent can be bonded to the remainder of the targeted conjugate as described herein by the removal of an atom such as a hydrogen atom from the bioagent (e.g., a residue of a bioactive agent). Removal of the atom (e.g., hydrogen) provides the open valency to be connected to the remainder of the targeted conjugate.
  • the bioagent comprises one or more hydroxyl, thiol, or amine (primary or secondary) groups which can be bonded to the conjugate.
  • W is the residue of a bioagent and the corresponding group H-W is the corresponding bioagent.
  • the group -Z-W a is a residue of a bioagent and the corresponding group H-Z-W 3 is the
  • the Z of -Z-W a is an oxygen atom, sulfur atom, NH or NR (R can be any group such as alkyl).
  • bioagents comprising one or more hydroxyl (-OH), thiol (-SH) or amine (e.g., primary (-NH 2 ) or secondary (-NH-, -NH(C C 6 )alkyl) groups which groups can be connected to remainder of the targeted conjugate as described herein.
  • the residue of the bioagent is derivable from a bioagent that comprises one or more groups selected from hydroxyl (OH), thiol (SH), primary amine (NH 2 ) and secondary amine (NH).
  • the residue of the bioagent is derivable from a bioagent that comprises one or more hydroxyl (OH). In one embodiment the residue of the bioagent is derived from a bioagent that comprises one or more groups selected from hydroxyl (OH), thiol (SH), primary amine (NH 2 ) and secondary amine (NH). In one embodiment the residue of the bioagent is derived from a bioagent that comprises one or more hydroxyl (OH).
  • the bioagent is a therapeutic agent such as a chemotherapeutic agent, an antibiotic agent, an antifungal agent, an antiparasitic agent or an antiviral agent or a prodrug thereof.
  • the bioagent has one or more hydroxyl or thiol groups.
  • the bioagent has at least one hydroxyl group.
  • the bioagent has at least one hydroxyl group and is bonded to the residue of the substituted or unsubstituted amino methyl moiety through the oxygen atom of said hydroxyl group.
  • bioagents include but are not limited to the dolastatins, pyrrolobenzodiazepines and structures of the formula:
  • the bioagent described herein may be a therapeutic agent (drug) such as cell toxin or cytotoxin.
  • Suitable therapeutic agents are known in the art and include monomethyl auristatin E (MMAE) toxin, auristatin and maytansinoids.
  • the bioagent may also be selected from other natural products ( Figure 4).
  • existing amino containing bioagents such as auristatin and maytansinoids can be incorporated using the linker system described herein in their native form - without the need to remove a methyl group and reveal a derivatizable nitrogen in the case of auristatin and without the modification of an additional appendage in the case of the maytansinoids.
  • the native drug molecule will be regenerated to achieve fully biological efficacy.
  • suitable bioagents include:
  • R (CH 3 ) 2 CHCH 2 -
  • the bioagent may be an imaging agent (detectable agent).
  • imaging agents are known and include fluorescent or luminescent labels and radioactive isotopes such as 99m Tc and 1 1 'in.
  • Other examples of suitable imaging agents include for example FITC, biotin and
  • a targeted conjugate as described herein may comprise one or bioagents, which may be the same or different.
  • a targeted conjugate may comprise one, two, three, or more bioagents.
  • the targeted conjugate may be a multi-toxin conjugate which comprises two different types of therapeutic agents.
  • the targeted conjugate may comprise a bioagent which is a therapeutic agent and a bioagent which is an imaging agent.
  • Methods for linking a bioagent to a conjugate include for example a linkage via a hydroxyl group as demonstrated in Example 1.
  • the targeting element can be bonded (connected) to the remainder of the targeted conjugate agent through an optional linker.
  • the linker is absent (e.g., the targeting element can be bonded (connected) directly to the remainder of the targeted conjugate).
  • the linker can be variable provided the targeting conjugate functions as described herein.
  • the linker can vary in length and atom composition and for example can be branched or non-branched or cyclic or a combination thereof.
  • the linker may also modulate the properties of the targeted conjugate such as but not limited to solubility, stability and aggregation.
  • linkers used in the targeted conjugates e.g., linkers comprising polyethylene glycol (PEG)
  • PEG polyethylene glycol
  • the linker comprises about 3-5000 atoms. In one embodiment the linker comprises about 3-4000 atoms. In one embodiment the linker comprises about 3-2000 atoms. In one embodiment the linker comprises about 3-1000 atoms. In one embodiment the linker comprises about 3-750 atoms. In one embodiment the linker comprises about 3-500 atoms. In one embodiment the linker comprises about 3-250 atoms. In one embodiment the linker comprises about 3-100 atoms. In one embodiment the linker comprises about 3-50atoms. In one embodiment the linker comprises about 3-25 atoms.
  • the linker comprises about 10-5000 atoms. In one embodiment the linker comprises about 10-4000 atoms. In one embodiment the linker comprises about 10-2000 atoms. In one embodiment the linker comprises about 10-1000 atoms. In one embodiment the linker comprises about 10-750 atoms. In one embodiment the linker comprises about 10-500 atoms. In one embodiment the linker comprises about 10-250 atoms. In one embodiment the linker comprises about 10-100 atoms. In one embodiment the linker comprises about 10- 50atoms. In one embodiment the linker comprises about 10-25 atoms.
  • the linker comprises atoms selected from H, C, N, S and O.
  • the linker comprises atoms selected from H, C, N, S, P and O.
  • the linker comprises a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to 1000 (or 1 -750, 1 -500, 1-250, 1-100, 1 - 50, 1 -25, 1 -10, 1 -5, 5-1000, 5-750, 5-500, 5-250, 5-100, 5-50, 5-25, 5-10 or 2-5 carbon atoms) wherein one or more of the carbon atoms is optionally replaced independently
  • the linker comprises a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to 1000 (or 1 - 750, 1-500, 1 -250, 1 -100, 1 -50, 1 -25, 1 -10, 1-5, 5-1000, 5-750, 5-500, 5-250, 5-100, 5-50, 5-25, 5-10 or 2-5 carbon atoms) wherein one or more of the carbon atoms is optionally replaced independently by -0-, -S, -N(R a )-, , wherein each R a is independently H or (C 1 -C 6 )alkyl.
  • the linker comprises a polyethylene glycol. In one embodiment the linker comprises a polyethylene glycol linked to the remainder of the targeted conjugate by a carbonyl group. In one embodiment the polyethylene glycol comprises about 1 to about 500 or about 5 to about 500 or about 3 to about 100 repeat (e.g., -CH 2 CH 2 0-) units (Greenwald, R.B., et al., Poly (ethylene glycol) Prodrugs: Altered Pharmacokinetics and Pharmacodynamics,
  • the linker may be used to modulate the properties of the targeted conjugate such as but not limited to solubility, stability and aggregation.
  • solubility such as but not limited to solubility, stability and aggregation.
  • capped linker refers to a linker as described herein above that is capped with an atom or functional group for instance a hydrogen atom.
  • the capped linker comprises a polyethylene glycol.
  • the capped linker comprises a polyethylene glycol linked to the remainder of the targeted conjugate by a carbonyl group.
  • the polyethylene glycol comprises about 1 to about 500 or about 5 to about 500 or about 3 to about 100 repeat (e.g., -CH 2 CH 2 0-) units.
  • polyethylene glycol is capped with a hydrogen, ethyl, methyl, ethoxy or methoxy group.
  • the targeting element e.g. antibody
  • activation element e.g. activation element
  • releasing linker e.g. drug or label
  • targeted bioagent e.g. drug or label
  • a conjugate comprising a releasing linker as described herein may comprise a targeting element, activation element, releasing linker and bioagent that are connected in series, (i.e. in a linear arrangement).
  • one embodiment provides a targeted conjugate comprising a targeting element, bioagent, releasing linker and activation element which are configured in a branched (parallel) arrangement.
  • the targeting element can be connected to the construct at any point that does not attenuate the activation element, releasing linker or bioagent and which results in the conjugate having a branched/parallel configuration.
  • the targeting agent may be directly connected to the activation element, releasing linker or bioagent.
  • Targeted conjugates of the present invention also have tunable properties which can be modified as desired.
  • solubilizing/aggregation-suppressing elements can be added onto the activation element and/or between the targeting agent (e.g. antibody) and the releasing linker.
  • the linker may also comprise solubilizing/aggregation-suppressing elements such as but not limited to polysorbate 80, 20, or polyethylene glycol chains of varying lengths such as PEG200, 300, or 400.
  • a conjugate as described herein may further comprise one or more solubilizing elements and/or aggregation-suppressing elements. Additional Embodiments.
  • the activation element is bonded to the substituted or unsubstituted amino methyl moiety.
  • the residue of the substituted or unsubstituted amino methyl moiety is bonded to the residue of the bioagent.
  • the targeting element is bonded to the activation element through an optional linker, or the targeting element is bonded to the residue of the substituted or
  • the targeting element is bonded to the activation element through an optional linker.
  • the targeting element is bonded to the residue of the substituted or unsubstituted amino methyl moiety through an optional linker.
  • One embodiment provides a targeted conjugate comprising a targeting element, an activation element, a residue of a substituted or unsubstituted amino methyl moiety and a residue of a bioagent wherein:
  • the activation element is bonded to the residue of the substituted or unsubstituted amino methyl moiety
  • the targeting element is bonded to the activation element through an optional linker, or the targeting element is bonded to the residue of the substituted or unsubstituted amino methyl moiety through an optional linker.
  • One embodiment provides a targeted conjugate comprising a targeting element, an activation element, a residue of a substituted or unsubstituted amino methyl moiety and a residue of a bioagent wherein:
  • the activation element is bonded to the residue of the substituted or unsubstituted amino methyl moiety
  • the targeting element is bonded to the activation element through an optional linker.
  • a targeted conjugate comprising a targeting element, an activation element, a residue of a substituted or unsubstituted amino methyl moiety and a residue of a bioagent wherein:
  • the activation element is bonded to the residue of the substituted or unsubstituted amino methyl moiety
  • the targeting element is bonded to the activation element through a linker.
  • a targeted conjugate comprising a targeting element, an activation element, a residue of a substituted or unsubstituted amino methyl moiety and a residue of a bioagent wherein:
  • the activation element is bonded to the residue of the substituted or unsubstituted amino methyl moiety
  • the targeting element is bonded to the residue of the substituted or
  • One embodiment provides a targeted conjugate comprising a targeting element, an activation element, a residue of a substituted or unsubstituted amino methyl moiety and a residue of a bioagent wherein:
  • the activation element is bonded to the residue of the substituted or unsubstituted amino methyl moiety
  • the targeting element is bonded to the residue of the substituted or
  • the residue of the substituted or unsubstituted amino methyl moiety is capable of releasing the bioagent from the targeted conjugate.
  • the residue of the substituted or unsubstituted amino methyl moiety releases the bioagent from the targeted conjugate.
  • the residue of the substituted or unsubstituted amino methyl moiety releases the bioagent from the targeted conjugate when the targeted conjugate is contacted with an enzyme.
  • the enzyme interacts with the activation element.
  • the enzyme contact results in the activation element being separated from the residue of the substituted or unsubstituted amino methyl moiety.
  • the enzyme contact breaks a bond connecting the activation element and the residue of the substituted or unsubstituted amino methyl moiety.
  • the enzyme contact breaks an amide bond connecting the activation element and the residue of the substituted or unsubstituted amino methyl moiety.
  • the enzyme is capable of cleaving amide bonds.
  • the enzyme is a proteolytic enzyme.
  • the enzyme is a cathepsin.
  • the enzyme is a cathepsin B.
  • the residue of the substituted or unsubstituted amino methyl moiety is capable of releasing the bioagent from the targeted conjugate when the targeted conjugate is contacted with an enzyme.
  • an enzyme is capable of interacting with the activation element of the targeted conjugate.
  • an enzyme is capable of separating the activation element from the residue of the substituted or unsubstituted amino methyl moiety of the targeted conjugate.
  • an enzyme is capable of breaking a bond connecting the activation element and the residue of the substituted or unsubstituted amino methyl moiety of the targeted conjugate.
  • an enzyme is capable of breaking an amide bond connecting the activation element and the residue of the substituted or unsubstituted amino methyl moiety of the targeted conjugate.
  • One embodiment provides a targeted conjugate comprising a targeting element, an activation element, a residue of a substituted or unsubstituted amino methyl moiety and a residue of a bioagent wherein, the residue of the substituted or unsubstituted amino methyl moiety is a residue of formula I:
  • R 1 is H or (Ci-C )alkyl wherein (Ci-C )alkyl is optionally substituted with one or more halogen
  • R 2 is H, (C C 6 )alkyl, -0(Ci-C 6 )alkyl, aryl or aryl(C,-C 6 )alkyl wherein any(C 1 -C 6 )alkyl or -0(C 1 -C 6 )alkyl of R 2 is optionally substituted independently with one or more
  • halogen -0(Ci-C 3 )alkyl or -OH, and wherein any aryl or aryl(C ! -C 6 )alkyl of R 2 is optionally substituted independently with one or more halogen, (Q-Ce ⁇ lkyl , -0(C C 3 )alkyl or -OH;
  • R 3 is H, (C,-C 6 )alkyl, -0(Ci-C 6 )alkyl, aryl or aryl(Ci-C 6 )alkyl wherein any(Ci-C 6 )alkyl or -0(C 1 -C )alkyl of R is optionally substituted independently with one or more
  • any aryl or aryl(d-C 6 )alkyl of R 3 is optionally substituted independently with one or more halogen, (Ci-C6)alkyl , -0(C r C 3 )alkyl or -OH.
  • the activation element is bonded to the nitrogen atom attached to R 1 of the residue of formula I.
  • the residue of the bioagent is bonded to the carbon atom attached to R and R of the residue of formula I.
  • the targeting element is bonded to the activation element through an optional linker.
  • the targeting element is bonded, through an optional linker, to R , R , or the carbon atom attached to R and R of formula I or formula II or the nitrogen attached to R ] of formula I or formula II.
  • R 1 is H or (Ci-C6)alkyl wherein (C]-C )alkyl is optionally substituted with one or more halogen;
  • R 2 is H, (Ci-C 6 )alkyl, -0(Ci-C 6 )alkyl, aryl or aryl(C ! -C 6 )alkyl wherein any(d-C 6 )alkyl or -0(Ci-C 6 )alkyl of R is optionally substituted independently with one or more
  • halogen -0(CrC 3 )alkyl or -OH
  • any aryl or aryl(C C6)alkyl of R 2 is optionally substituted independently with one or more halogen, (Cj-C )alkyl , -0(Ci-C 3 )alkyl or -OH;
  • R 3 is H, (C C 6 )alkyl, -0(d-C 6 )alkyl, aryl or aryl(C 1 -C 6 )alkyl wherein any(Ci-C 6 )alkyl or -0(CrC 6 )alkyl of R is optionally substituted independently with one or more
  • halogen -0(CrC 3 )alkyl or -OH
  • any aryl or aryl(C 1 -C 6 )alkyl of R 3 is optionally substituted independently with one or more halogen, (Ci-C 6 )alkyl , -0(C]-C 3 )alkyl or -OH;
  • B is an activation element
  • W is a residue of a bioagent.
  • R 1 is H or (C 1 -C6)alkyl wherein (CrC ⁇ alkyl is optionally substituted with one or more halogen;
  • R 2 is H, (C r C 6 )alkyl, -0(Ci-C 6 )alkyl, aryl or aryl(Ci-C 6 )alkyl wherein any(d-C 6 )alkyl or -0(C]-C )alkyl of R 2 is optionally substituted independently with one or more
  • halogen -0(Ci-C 3 )alkyl or -OH
  • any aryl or aryl(C)-C 6 )alkyl of R 2 is optionally substituted independently with one or more halogen, (C ! -C 6 )alkyl , -0(Ci-C 3 )alkyl or -OH;
  • R 3 is H, (d-C 6 )alkyl, -0(C 1 -C 6 )alkyl, aryl or aryl(C 1 -C 6 )alkyl wherein any(C r C 6 )alkyl or -0(C 1 -C 6 )alkyl of R is optionally substituted independently with one or more
  • halogen -0(C 1 -C 3 )alkyl or -OH
  • any aryl or aryl(Ci-C )alkyl of R is optionally substituted independently with one or more halogen, (CrC 6 )alkyl , -0(Ci-C 3 )alkyl or -OH;
  • A is the targeting element
  • L is absent or a linker
  • B is an activation element
  • W is a residue of a bioagent.
  • R 1 is H or (C r C 6 )alkyl wherein (Cj-C )alkyl is optionally substituted with one or more halogen;
  • R 2 is H, (C C 6 )alkyl, -OCQ-Ce ⁇ lkyl, aryl or aryl(Ci-C 6 )alkyl wherein any(d-C 6 )alkyl or -0(C 1 -C 6 )alkyl of R is optionally substituted independently with one or more
  • halogen -0(Ci-C 3 )alkyl or -OH
  • any aryl or aryl(C C 6 )alkyl of R 2 is optionally substituted independently with one or more halogen, (d-C ⁇ alkyl , -0(Ci-C 3 )alkyl or -OH;
  • A is the targeting element
  • L is absent or a linker
  • L' is absent or a capped linker
  • B is an activation element
  • W is a residue of a bioagent.
  • R 1 is H or (C 1 -C )alkyl wherein (Ci-C6)alkyl is optionally substituted with one or more halogen;
  • R 2 is H, (C 1 -C 6 )alkyl, -0(C r C 6 )alkyl, aryl or aryl(Ci-C 6 )alkyl wherein any(C C 6 )alkyl or -0(C 1 -C 6 )alkyl of R is optionally substituted independently with one or more
  • halogen -0(CrC 3 )alkyl or -OH
  • any aryl or aryl(Ci-C 6 )alkyl of R is optionally substituted independently with one or more halogen, (C ! -C )alkyl , -0(Ci-C3)alkyl or -OH;
  • A is the targeting element
  • L is absent or a linker
  • B is an activation element
  • W is a residue of a bioagent.
  • R is H.
  • R 3 is H or (C]-C 6 )alkyl.
  • R 3 is H.
  • R 2 is H or (Ci-C 6 )alkyl.
  • R 2 is H.
  • One embodiment provides a targeted conjugate of formula Ilia':
  • One embodiment provides a targeted conjugate of formula IVa':
  • One embodiment provides a targeted conjugate of formula IVb':
  • One embodiment provides a targeted conjugate of formula Ilia":
  • One embodiment provides a targeted conjugate of formula IVa"
  • One embodiment provides a targeted conjugate of formula IVb'
  • One embodiment provides a targeted conjugate of formula Ilia*:
  • One embodiment provides a targeted conjugate of formula IVa*
  • One embodiment provides a targeted conjugate of formula IVb* :
  • One embodiment provides a salt or pharmaceutically acceptable salt of any targeted conjugate described herein (e.g., a salt or pharmaceutically acceptable salt of any targeted conjugate of any formula (e.g., Ill, IV or any subformula thereof)).
  • a salt or pharmaceutically acceptable salt of any targeted conjugate described herein e.g., a salt or pharmaceutically acceptable salt of any targeted conjugate of any formula (e.g., Ill, IV or any subformula thereof)).
  • the method of administering the targeted conjugate to the desired area for treatment and the dosage may be varied as needed.
  • Some methods of administration include intravascular injection, intravenous injection, intraperitoneal injection, subcutaneous injection, and intramuscular injection.
  • the n targeted conjugates may be formulated in an injectable format (e.g., suspension, emulsion) in a medium such as, for example, water, saline, Ringer's solution, dextrose, dimethylsulfoxide, albumin solution, and oils.
  • the targeted conjugate may also be administered to the patient through topical application via a salve or lotion, transdermally through a patch, orally ingested as a pill or capsule or suspended in a liquid or rectally inserted in suppository form.
  • Targeted conjugates may also be suspended in an aerosol or pre-aerosol formulation suitable for inhalation via the mouth or nose.
  • the targeted conjugates may also be delivered to the patient using other methods.
  • the targeted conjugate may be administered to the patient orally, or may be administered rectally.
  • the targeted conjugate described herein may also be useful in diagnostics as well as studies in cells, tissues and animals.
  • the targeted conjugates may also me in the form of a salt such as a pharmaceutically acceptable salt. Medical use
  • a targeted conjugate as described herein may be used in the treatment or prevention of a disease in a subject such as an animal (e.g., a mammal such as human).
  • the present invention provides a targeted conjugate as described herein for use in therapy.
  • the present invention provides a targeted conjugate as described herein for use in the treatment or prevention of cancer.
  • the cancer may be a solid tumor or blood malignancy such as carcinomas of the bladder, breast, colon and rectal, endometrial, kidney, leukemia, lung, melanoma, non- hodgkin lymphoma, pancreatic, prostate, or thyroid.
  • Example 1 Synthesis of a construct containing a novel releasing linker (i.e., residue of a substituted or unsubstituted amino methyl moiety.
  • the following compound has all the key features of the design of a linear construct, including a site for targeting element (e.g., an antibody) which can be conjugated through the azido (left), the activation element (e.g., a site for proteolysis (dipeptide, middle), the aminomethoxy unit (middle right), and a moiety that, once released, is an alcohol containing compound that represents a bioagent attached to the linker system by a hydroxyl group.
  • a site for targeting element e.g., an antibody
  • the activation element e.g., a site for proteolysis (dipeptide, middle)
  • aminomethoxy unit middle right
  • This construct is also shown in Figure 1 which highlights the releasing linker.
  • the targeted conjugates described herein have considerably expand the scope of bioagents that can be potentially delivered because bioagents (including therapeutic agents and therapeutic agent candidates drug candidates) that have hydroxyl, thiol and amine functional groups as well as aldehyde, ketone, imine, and functional groups can serve as point of attachment point of the bioactive to the remainder of the targeted conjugate. This is very significant as numerous bioactive agents contain such groups.
  • the targeted conjugates provided herein have broad applications for the design of therapeutic agents and imaging agents that can benefit from targeted delivery (e.g., antibody targeted delivery).

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Abstract

L'invention concerne des conjugués ciblés et leurs procédés d'utilisation. Le conjugué comprend un élément de ciblage, un lieur clivable comprenant un élément d'activation, un lieur libérable comprenant un résidu d'un fragment amino méthyle substitué ou non substitué et un résidu d'un agent biologique.
PCT/US2016/051546 2015-09-14 2016-09-13 Conjugués ciblés WO2017048728A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060182750A1 (en) * 2005-02-11 2006-08-17 Immunogen, Inc. Process for preparing stable drug conjugates
US20100145036A1 (en) * 2006-12-28 2010-06-10 Medarex, Inc. Chemical linkers and cleavable substrates and conjugates thereof
US20110150908A1 (en) * 2003-02-20 2011-06-23 Seattle Genetics, Inc. Anti-cd70 antibody-drug conjugates and their use for the treatment and prevention of cancer and immune disorders

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110150908A1 (en) * 2003-02-20 2011-06-23 Seattle Genetics, Inc. Anti-cd70 antibody-drug conjugates and their use for the treatment and prevention of cancer and immune disorders
US20060182750A1 (en) * 2005-02-11 2006-08-17 Immunogen, Inc. Process for preparing stable drug conjugates
US20100145036A1 (en) * 2006-12-28 2010-06-10 Medarex, Inc. Chemical linkers and cleavable substrates and conjugates thereof

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