Therapeutic dendrimers

Abstract

The present invention provides a dendrimer comprising: a core unit; a fifth generation building block, the building block being a lysine residue or an analog thereof; a first terminal group, the first terminal group comprising a cabazitaxel residue covalently linked to a diethylene glycol-based linker; and a second terminal group, the second terminal group comprising a PEG group. Also provided herein are pharmaceutical compositions comprising the dendrimers, and methods and uses of the dendrimers in the treatment of conditions such as cancer. Also provided are processes for preparing the dendrimers and intermediates.

Description

Technical Field

[0001] The present invention generally relates to drug-dendrimer conjugates comprising a dendrimer, the dendrimer comprising a core and building blocks, the outermost building blocks comprising one or more pharmaceutically active agents linked via a cleavable linker. The present invention also relates to pharmaceutical compositions and methods of treatment comprising the drug-dendrimer conjugates, as well as processes and synthetic intermediates for preparing the drug-dendrimer conjugates. Background Art

[0002] The formulation and delivery of pharmaceutically active agents present many difficulties, including poor aqueous solubility, toxicity, low bioavailability, instability under biological conditions, lack of targeted sites of action, and rapid degradation in vivo.

[0003] To overcome some of these difficulties, the pharmaceutically active agent can be formulated with a solubilizing agent, which itself can cause side effects, such as hypersensitivity reactions, and may require pre-dosing to reduce these side effects. Alternative approaches include encapsulating the pharmaceutically active agent in liposomes, micelles, or polymer matrices, or attaching the pharmaceutically active agent to liposomes, micelles, and polymer matrices.

[0004] While these approaches may improve some of the problems associated with the formulation and delivery of pharmaceutically active agents, many approaches still have disadvantages.

[0005] Oncology drugs can be particularly difficult to formulate and have side effects that can limit the doses and regimens that can be used for treatment. This can lead to reduced efficacy of the treatment. For example, taxane drugs such as cabazitaxel have low water solubility but also have a relatively narrow therapeutic window, so increasing the concentration of the agent by, for example, using solubilizing excipients can lead to associated toxicity issues.

[0006] Liposomes, micelles and polymer matrices are used as carriers to encapsulate or attach pharmaceutically active agents, while allowing dissolution of the pharmaceutically active agent, and in some cases improving bioavailability and reducing toxicity, and there are difficulties associated with the release of the pharmaceutically active agent. In some cases, the carrier rapidly degrades and releases the pharmaceutically active agent before reaching the target organ. In other cases, the release of the pharmaceutically active agent from the carrier is slowed to the extent that the therapeutic dose of the drug cannot be reached in the body or in the target organ. In addition, such compositions can present stability and manufacturing challenges.

[0007] Therefore, alternative formulations and modes of delivery for delivering drugs are needed to reduce side effects, improve dosing regimens and improve therapeutic windows, which can lead to better patient compliance and efficacy of the drug, while being stable and practical to manufacture and having a substantially homogeneous composition. Summary of the invention

[0008] The subject matter of the present invention is based, in part, on the surprising discovery that cabazitaxel provides improved efficacy and / or pharmacokinetic properties of the drug when conjugated to dendrimers.

[0009] Thus, in a first aspect, there is provided a dendrimer comprising:

[0010] i) a core unit (C); and

[0011] ii) building units (BU), each building unit being a lysine residue or an analog thereof;

[0012] wherein the core unit is covalently linked to two building blocks via amide bonds, each amide bond being formed between a nitrogen atom present in the core unit and a carbon atom of an acyl group present in a building block;

[0013] The dendrimer is a five-generation building block dendrimer;

[0014] wherein the building blocks of different generations are covalently linked to each other via an amide bond formed between a nitrogen atom present in one building block and a carbon atom of an acyl group present in another building block;

[0015] The dendrimer further comprises:

[0016] ) a plurality of first terminal groups (T1), each first terminal group (T1) comprising a cabazitaxel residue covalently linked to a diethylene glycol-based linker; and

[0017] iv) a plurality of second terminal groups (T2), each second terminal group comprising a PEG group;

[0018] wherein at least one third of the nitrogen atoms present in the outer building blocks are each covalently attached to a first terminal group; and

[0019] At least one third of the nitrogen atoms present in the outer building blocks are each covalently linked to a second terminal group;

[0020] or a pharmaceutically acceptable salt thereof.

[0021] In some embodiments, the core is:

[0022]

[0023] In some embodiments, the building blocks are each:

[0024]

[0025] wherein the acyl group of each building block provides a covalent attachment point for linkage to the core or a previous generation building block; and wherein each nitrogen atom provides a covalent attachment point for linkage to a subsequent generation building block, a first terminal group, or a second terminal group.

[0026] In some embodiments, the building blocks are each:

[0027]

[0028] In some embodiments, the dendrimer has five complete generations of building blocks.

[0029] In some embodiments, each first terminal group (T1) is:

[0030]

[0031] In some embodiments, the second terminal group comprises a PEG group having an average molecular weight in the range of 1000 to 2500 Daltons.

[0032] In some embodiments, each of the second terminal groups comprises a covalent bond to the PEG linking group (L1) via an ether bond formed between a carbon atom present in the PEG group and an oxygen atom present in the PEG linking group, and each second terminal group is covalently linked to the building block via an amide bond formed between a nitrogen atom present in the building block and a carbon atom of the acyl group present in the PEG linking group.

[0033] In some embodiments, each of the second terminal groups is

[0034]

[0035] And the PEG group is a methoxy-terminated PEG having an average molecular weight in the range of about 1750 to 2500 Daltons.

[0036] In some embodiments, the dendrimer comprises a surface unit comprising an external building block attached to a first terminal group and a second terminal group, the surface unit having the following structure:

[0037]

[0038] And wherein the PEG group is a methoxy-terminated PEG having an average molecular weight in the range of about 1750 to 2500 Daltons.

[0039] In some embodiments, the dendrimers have 28 to 32 surface units, preferably 30 to 32 surface units.

[0040] In some embodiments, at least 40% of the nitrogen atoms present in the outer building blocks are each covalently linked to the first terminal group; and at least 40% of the nitrogen atoms present in the outer building blocks are each covalently linked to the second terminal group.

[0041] In some embodiments, the five-generation building block is a full generation, and wherein the building block of the outer generation provides 64 nitrogen atoms for covalent attachment to a first terminal group or a second terminal group, wherein 26 to 32 first terminal groups are covalently attached to one of the nitrogen atoms, and wherein 28 to 32 second terminal groups are each covalently attached to one of the nitrogen atoms.

[0042] In some embodiments, in terms of w / w %, the cabazitaxel residues comprise within the range of 23% w / w to 28% w / w of the dendrimer.

[0043] In some embodiments, the dendrimer is:

[0044]

[0045] Wherein T1′ represents the first terminal group as follows:

[0046] or T1′ represents H, wherein less than 5 T1′ are H; and T2′ represents the following second terminal group:

[0047]

[0048] wherein the PEG group is a methoxy-terminated PEG having an average molecular weight in the range of about 1750 to 2500 Daltons, or T2' represents H, and wherein less than 5 T2's are H.

[0049] In some embodiments, the in vitro half-life of cabazitaxel released from the dendrimer is in the range of 20 to 100 hours in PBS at pH 7.4 and 37°C.

[0050] In some embodiments, the in vitro half-life of cabazitaxel released from the dendrimer is in the range of 30 to 60 hours in PBS at pH 7.4 and 37°C.

[0051] In a second aspect, a composition comprising a plurality of dendrimers or pharmaceutically acceptable salts thereof,

[0052] wherein dendrimer is as defined herein,

[0053] The average number of first end groups per dendrimer in the composition is in the range of 24 to 32, and

[0054] The average number of second end groups per dendrimer in the composition is in the range of 24 to 32.

[0055] In some embodiments, in terms of w / w %, the cabazitaxel residues comprise within the range of 23% w / w to 28% w / w of the dendrimer.

[0056] In some embodiments, the composition is a pharmaceutical composition, and wherein the composition comprises a pharmaceutically acceptable excipient.

[0057] In a third aspect, a pharmaceutical composition is provided, comprising:

[0058] i) a dendrimer as defined herein, or a pharmaceutically acceptable salt thereof, and ii) a pharmaceutically acceptable excipient.

[0059] In some embodiments, the composition is a solid composition comprising a dendrimer as defined herein, a sugar and an acid, and wherein the composition is for reconstitution with a diluent.

[0060] In some embodiments, the sugar is trehalose and the acid is citric acid.

[0061] In some embodiments, upon reconstitution with a diluent, the pH of the reconstituted composition is in the range of 3.5 to 5.5.

[0062] In some embodiments, the composition comprises a dendrimer as defined herein, comprising a sugar and an acid, and a diluent.

[0063] In some embodiments, the composition is free or substantially free of polyethoxylated castor oil and polyethoxylated sorbitan monooleate.

[0064] In some embodiments, the composition is formulated for administration as an infusion over a period of up to 30 minutes, or wherein the composition is formulated for administration as a bolus over a period of up to 5 minutes.

[0065] In a fourth aspect, there is provided a dendrimer or a pharmaceutical composition as defined herein for use in therapy.

[0066] In some embodiments, the dendrimer or pharmaceutical composition is used to treat cancer.

[0067] Also provided is a method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a dendrimer or a pharmaceutical composition as defined herein.

[0068] Also provided is the use of a dendrimer or composition as defined herein in the preparation of a medicament for the treatment of cancer.

[0069] In some embodiments, the cancer is selected from pancreatic cancer, prostate cancer, breast cancer, and ovarian cancer.

[0070] In some embodiments, the cancer is metastatic castration-resistant prostate cancer (mCRPC).

[0071] In some embodiments, the therapeutically effective amount of the dendrimer is 10 to 100 mg / m 2 within the range of body surface area.

[0072] In some embodiments, the therapeutically effective amount of the dendrimer is between 20 and 50 mg / m 2 within the range of body surface area.

[0073] In some embodiments, the therapeutically effective amount of the dendrimer is 50 to 100 mg / m 2 within the range of body surface area.

[0074] In some embodiments, the composition is formulated for administration as an infusion over a period of up to 30 minutes, or wherein the composition is formulated for administration as a bolus over a period of up to 5 minutes.

[0075] In some embodiments, the dendrimers are administered in combination with an additional therapeutic agent.

[0076] In some embodiments, the dendrimers are administered in combination with additional anti-cancer drugs.

[0077] In some embodiments, the dendrimer is

[0078]

[0079] Wherein T1′ represents the first terminal group as follows:

[0080] or T1′ represents H, wherein less than 5 T1′ are H; and T2′ represents the following second terminal group:

[0081]

[0082] wherein the PEG group is a methoxy-terminated PEG having an average molecular weight in the range of about 1750 to 2500 Daltons, or T2' represents H, and wherein less than 5 T2's are H.

[0083] In some embodiments, administration of the dendrimer provides therapeutically effective plasma concentrations of cabazitaxel for a longer period of time compared to administration of an equivalent dose of free cabazitaxel.

[0084] In some embodiments, administration of the dendrimer provides a maximum concentration (Cmax) of cabazitaxel that is no more than 20% of the maximum concentration provided by administration of an equivalent dose of free cabazitaxel.

[0085] In some embodiments, administration of the dendrimer provides therapeutically effective plasma concentrations of cabazitaxel for a longer period of time compared to administration of an equivalent dose of free cabazitaxel.

[0086] In some embodiments, administration of the dendrimer provides reduced neutropenia, lymphopenia, anemia, and / or thrombocytopenia compared to administration of an equivalent dose of free cabazitaxel.

[0087] In some embodiments, administration of the dendrimer provides a greater AUC of total cabazitaxel compared to direct administration of an equal dose of free cabazitaxel.

[0088] In some embodiments, administration of the dendrimer provides therapeutically effective plasma concentrations of cabazitaxel for a longer period of time compared to administration of an equivalent dose of free cabazitaxel.

[0089] In some embodiments, 20 or 25 mg / m 2 Administration of a course of the dendrimer provided enhanced clinical efficacy compared to cabazitaxel.

[0090] In some embodiments, administration of the dendrimer provides reduced neutropenia, lymphopenia, anemia, and / or thrombocytopenia compared to administration of an equivalent dose of free cabazitaxel.

[0091] In some embodiments, 20 or 25 mg / m 2 Administration of the dendrimers provides reduced neutropenia, lymphopenia, anemia and / or thrombocytopenia compared to cabazitaxel.

[0092] In some embodiments, the subject matter of the present application provides a drug conjugated to a dendrimer, wherein the drug exhibits an improved pharmacokinetic profile of at least one of improved therapeutic exposure, lower maximum concentration (Cmax), and / or increased area under the curve (AUC) compared to the unconjugated drug.

[0093] In a fifth aspect, there is provided a process for producing a dendrimer as defined herein, comprising:

[0094] a) reacting a cabazitaxel intermediate with a dendrimer intermediate or a salt thereof under amide coupling conditions,

[0095] The cabazitaxel intermediate is:

[0096]

[0097] wherein X is -OH or a leaving group, or wherein X together with the C(O) group to which it is attached forms a carboxylic acid;

[0098] The dendrimer intermediate comprises:

[0099] i) a core unit (C); and

[0100] ii) building units (BU), each building unit being a lysine residue or an analog thereof;

[0101] wherein the core unit is covalently linked to two building blocks via amide bonds, each amide bond being formed between a nitrogen atom present in the core unit and a carbon atom of an acyl group present in a building block;

[0102] The dendrimer is a five-generation building block dendrimer;

[0103] wherein the building blocks of different generations are covalently linked to each other via an amide bond formed between a nitrogen atom present in one building block and a carbon atom of an acyl group present in another building block;

[0104] The dendrimer further comprises:

[0105] a plurality of second terminal groups (T2), each second terminal group comprising a PEG group;

[0106] wherein at least one third of the nitrogen atoms present in the outer building blocks are each covalently attached to a second terminal group;

[0107] and wherein at least one third of the nitrogen atoms present in said outer building block are unsubstituted and available for reaction with said first intermediate;

[0108] or

[0109] b) reacting the PEG intermediate with the dendrimer intermediate or a salt thereof under amide coupling conditions,

[0110] The PEG intermediate is:

[0111]

[0112] wherein the PEG group is a PEG-containing group, and

[0113] X is -OH or a leaving group, and X and the C(O) group to which it is attached together form a carboxylate;

[0114] The dendrimer intermediate comprises:

[0115] i) a core unit (C); and

[0116] ii) building units (BU), each building unit being a lysine residue or an analog thereof;

[0117] wherein the core unit is covalently linked to two building blocks via amide bonds, each amide bond being formed between a nitrogen atom present in the core unit and a carbon atom of an acyl group present in a building block;

[0118] The dendrimer is a five-generation building block dendrimer;

[0119] wherein the building blocks of different generations are covalently linked to each other via an amide bond formed between a nitrogen atom present in one building block and a carbon atom of an acyl group present in another building block;

[0120] The dendrimer further comprises:

[0121] a plurality of first terminal groups (T1), each first terminal group (T1) comprising a cabazitaxel residue covalently linked to a diethylene glycol-based linker;

[0122] wherein at least one third of the nitrogen atoms present in the outer building blocks are each covalently attached to a first terminal group;

[0123] and wherein at least one third of the nitrogen atoms present in said outer building unit are unsubstituted;

[0124] or

[0125] c) reacting the surface unit intermediate with the dendrimer intermediate or a salt thereof under amide coupling conditions,

[0126] The surface unit intermediate is:

[0127]

[0128] wherein the PEG group is a PEG-containing group, and

[0129] X is -OH or a leaving group, and X and the C(O) group to which it is attached together form a carboxylate;

[0130] The dendrimer intermediate comprises:

[0131] i) a core unit (C); and

[0132] ii) building units (BU), each building unit being a lysine residue or an analog thereof;

[0133] wherein the core unit is covalently linked to two building blocks via amide bonds, each amide bond being formed between a nitrogen atom present in the core unit and a carbon atom of an acyl group present in a building block;

[0134] The dendrimer intermediate is a fourth generation building block dendrimer intermediate;

[0135] wherein the building blocks of different generations are covalently linked to each other via an amide bond formed between a nitrogen atom present in one building block and a carbon atom of an acyl group present in another building block;

[0136] and wherein the nitrogen atoms present in said outer building blocks of said dendrimer intermediate are unsubstituted.

[0137] In a sixth aspect, there is provided an intermediate for producing a dendrimer, which is

[0138]

[0139] wherein X is -OH or a leaving group, or wherein X together with the C(O) group to which it is attached forms a carboxylate.

[0140] In a seventh aspect, there is provided an intermediate for producing a dendrimer, which is

[0141]

[0142] wherein the PEG group is a PEG-containing group, and

[0143] X is -OH or a leaving group, and X forms a carboxylate together with the C(O) group to which it is attached.

[0144] It should be understood that further aspects, embodiments and examples are described herein that may include one or more embodiments or features as described above. BRIEF DESCRIPTION OF THE DRAWINGS

[0145] Figure 1 The efficacy of the compounds of the invention (SPL9048) and comparative compounds (cabazitaxel, and SPL9005-comparator cabazitaxel-dendrimer compound) in SCID mice is shown as measured by mean tumor volume (TV) (mm 3 ) is expressed as a function of time.

[0146] Figure 2 Shown are mean body weight changes of SCID mice following administration of a compound of the invention (SPL9048) and comparative compounds (cabazitaxel, and SPL9005-comparator cabazitaxel-dendrimer compound) over time in a prostate cancer model study.

[0147] Figure 3The efficacy of the compound of the invention (SPL9048) and the comparative compound (cabazitaxel) in SCID mice is shown as measured by the mean tumor volume (TV) (mm 3 ) changes over time.

[0148] Figure 4 Shown are the mean body weight changes of SCID mice after administration of the compound of the present invention (SPL9048) and the comparative compound (cabazitaxel) over time in a breast cancer model study.

[0149] Figure 5 Shown are in vivo free-cabazitaxel (released) concentration levels over time following administration of a compound of the invention (SPL9048) and a comparator cabazitaxel-dendrimer compound (SPL9005) to rats.

[0150] Figure 6 The results show that after administration of the compound of the present invention (SPL9048) and the comparative compound ( Results of neutropenia toxicity study data in both male and female rats following administration of cabazitaxel (a brand of cabazitaxel).

[0151] Figure 7 The efficacy of the compound of the invention (SPL9048) when administered alone and in combination with gemcitabine is shown in female NOD-scid interleukin 2 receptor gamma chain null mice as measured by mean tumor volume (TV) (mm 3 ) is expressed as a function of time.

[0152] Figure 8 Shown are the levels of the prostate cancer biomarker PSA (μg / L) in prostate cancer patients over time.

[0153] Fig. 9 Shown are levels of the ovarian cancer biomarker CA-125 (μg / L) in ovarian cancer patients over time. DETAILED DESCRIPTION

[0154] General Definition

[0155] Unless explicitly defined otherwise, all technical and scientific terms used herein should be considered to have the same meanings as commonly understood by one of ordinary skill in the art (eg, chemistry, biochemistry, medicinal chemistry, polymer chemistry, etc.).

[0156] As used herein, the term "and / or", such as "X and / or Y", should be understood to mean "X and Y" or "X or Y", and should be construed to mean both or either of these meanings.

[0157] As used herein, unless otherwise indicated, the term "about" means + / - 20%, more preferably + / - 10% of the specified value.

[0158] As used herein, the singular forms "a," "an," and "the" include plural aspects unless the context clearly dictates otherwise.

[0159] Throughout the specification, the word "comprise" or variations such as "comprises" or "comprising" will be understood to imply the inclusion of stated elements, integers or steps, or groups of elements, integers or steps, but not the exclusion of any other elements, integers or steps, or groups of elements, integers or steps.

[0160] As used herein, the term "subject" refers to any organism susceptible to a disease or condition. In one embodiment, the disease or condition is cancer. For example, the subject can be a mammal, a primate, livestock (e.g., sheep, cattle, horses, pigs), a companion animal (e.g., dogs, cats), or a laboratory animal (e.g., mice, rabbits, rats, guinea pigs, hamsters). In one embodiment, the subject is a mammal. In one embodiment, the subject is a human.

[0161] As used herein, the term "treating" includes alleviating symptoms associated with a particular condition or disorder and eliminating the symptoms. For example, as used herein, the term "treating cancer" refers to alleviating symptoms associated with cancer and eliminating the symptoms. In one embodiment, the term "treating cancer" refers to a decrease in the size of a cancerous tumor. In one embodiment, the term "treating cancer" refers to an increase in progression-free survival. As used herein, the term "progression-free survival" refers to the length of time during and after treatment of cancer that a patient has the disease, i.e., cancer, but the disease does not recur or symptoms increase.

[0162] As used herein, the term "prevent" includes preventing a particular condition or disorder. For example, as used herein, the term "preventing cancer" refers to preventing the onset or duration of symptoms associated with cancer. In one embodiment, the term "preventing cancer" refers to slowing or stopping the progression of cancer. In one embodiment, the term "preventing cancer" refers to slowing or preventing metastasis.

[0163] As will be understood by those skilled in the art, the dendrimer will be administered in a therapeutically effective amount. The term "therapeutically effective amount" as used herein refers to a dendrimer administered in an amount sufficient to alleviate or prevent to some extent one or more symptoms of the condition or disorder being treated. The result may be a reduction and / or alleviation of the signs, symptoms or causes of the disease or disorder, or any other desired change in a biological system. In one embodiment, the term "therapeutically effective amount" refers to a dendrimer administered in an amount sufficient to cause a reduction in the size of a cancerous tumor. In one embodiment, the term "therapeutically effective amount" refers to a dendrimer administered in an amount sufficient to cause an increase in progression-free survival. The term "effective amount" as used herein refers to an amount of a dendrimer that is effective to achieve the desired pharmacological effect or therapeutic improvement without undue adverse side effects or to achieve the desired pharmacological effect or therapeutic improvement with a reduced side effect profile. By way of example only, a therapeutically effective amount may be determined by routine experimentation, including but not limited to a dose escalation clinical trial. The term "therapeutically effective amount" includes, for example, a prophylactic effective amount. In one embodiment, a prophylactic effective amount is an amount sufficient to prevent metastasis. It is understood that an "effective amount" or "therapeutically effective amount" may vary from subject to subject due to variations in the metabolism of the compound as well as any of the subject's age, weight, general condition, condition being treated, severity of the condition being treated, and the judgment of the prescribing physician. Thus, it is not always possible to specify an exact "effective amount". However, in any individual case, an appropriate "effective amount" may be determined by one of ordinary skill in the art using routine experimentation. When more than one therapeutic agent is used in combination, a "therapeutically effective amount" of each therapeutic agent may refer to an amount of the therapeutic agent that would be therapeutically effective when used alone, or may refer to a reduced amount that is therapeutically effective due to its combination with one or more additional therapeutic agents.

[0164] As used herein, the term "alkyl" refers to a straight chain (i.e., linear) or branched hydrocarbon, ranging in size from one to ten carbon atoms (i.e., C 1-10 Thus, alkyl moieties include, unless expressly limited to smaller groups, moieties ranging in size, for example, from about one to about six carbon atoms or larger, such as methyl, ethyl, n-propyl, isopropyl and / or butyl, pentyl, hexyl, and higher isomers. In one embodiment, the alkyl moiety has from one to 10 carbon atoms (i.e., C 1-10 In another embodiment, the alkyl moiety has 2 to 4 carbon atoms, preferably 4 carbon atoms.

[0165] As used herein, the term "alkylene" refers to a straight chain (i.e., linear) or branched hydrocarbon, ranging in size from 1 to 10 carbon atoms (i.e., C 1-10Thus, the alkylene moiety includes, for example, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH(CH3)-, -CH2CH2CH2CH2-, -CH2CH(CH3)CH2-, and the like.

[0166] Suitable salts of dendrimers include those formed with organic or inorganic acids or bases. As used herein, the phrase "pharmaceutically acceptable salts" refers to pharmaceutically acceptable organic or inorganic salts. Exemplary acid addition salts include, but are not limited to, sulfates, citrates, acetates, oxalates, chlorides, bromides, iodides, nitrates, bisulfates, phosphates, acid phosphates, isonicotinates, lactates, salicylates, citric acid, tartrates, oleates, tannates, pantothenates, bitartrates, ascorbates, succinates, maleates, gentisates, fumarates, gluconates, glucuronic acid, sucrose salts, formates, benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and pamoates (i.e., 1,1′-methylene-bis(2-hydroxy-3-naphthoate)) salts. Exemplary base addition salts include, but are not limited to, ammonium salts, alkali metal salts, such as those of potassium and sodium, alkaline earth metal salts, such as those of calcium and magnesium, and salts with organic bases, such as dicyclohexylamine, N-methyl-D-glucamine, morpholine, thiomorpholine, piperidine, pyrrolidine, mono-, di- or tri-lower alkylamines, such as ethyl-, tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethyl-propylamine, or mono-, di- or trihydroxy lower alkylamines, such as mono-, di- or triethanolamine. Pharmaceutically acceptable salts may involve the inclusion of another molecule, such as acetate ions, succinate ions or other counterions. Counterions may be any organic or inorganic moiety that stabilizes the charge on the parent compound. In addition, pharmaceutically acceptable salts may have more than one charged atom in their structure. Cases where multiple charged atoms are part of a pharmaceutically acceptable salt may have multiple counterions. Thus, a pharmaceutically acceptable salt may have one or more charged atoms and / or one or more counterions. It will also be understood that non-pharmaceutically acceptable salts also fall within the scope of the present invention, as these may be used as intermediates in the preparation of pharmaceutically acceptable salts or may be used during storage or transport.

[0167] Those skilled in the art of organic and / or medicinal chemistry will appreciate that many organic compounds can form complexes with solvents in which they react or from which they precipitate or crystallize. These complexes are referred to as "solvates". For example, complexes with water are referred to as "hydrates". As used herein, the phrase "pharmaceutically acceptable solvate" or "solvate" refers to the association of one or more solvent molecules with a compound of the invention. Examples of solvents that form pharmaceutically acceptable solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

[0168] As used herein, the term "dendrimer" refers to a molecule containing a core and a dendron attached to the core. Each dendron is composed of multiple generations of branching building blocks, resulting in a branched structure with an increasing number of branches with each generation of building blocks. "Dendrimers", including drug-dendrimer conjugates, may include pharmaceutically acceptable salts or solvates as defined above.

[0169] As used herein, the term "building block" refers to a branched molecule that is a lysine residue or its analog having three functional groups, one functional group for attachment to the core or the previous generation building block and at least two functional groups for attachment to the next generation building block or the surface of the dendrimer-forming molecule.

[0170] As used herein, the term "attached" refers to the connection between chemical components by covalent bonding. As used herein, the term "covalent bonding" refers to a chemical bond formed by sharing one or more electrons, especially electron pairs, between atoms. The term "covalent bonding" is used interchangeably with the term "covalently linked".

[0171] As used herein, the term "solubilizing excipient" refers to a formulation additive used to solubilize an insoluble or slightly soluble drug into an aqueous formulation. Examples include surfactants such as polyethoxylated castor oil, including Cremophor EL, Cremophor RH 40 and Cremophor RH 60, D-α-tocopherol-polyethylene glycol 1000 succinate, polysorbate 20, polysorbate 80, solutol HS15, sorbitan monooleate, poloxamer 407, Labrasol, and the like.

[0172] is manufactured by Sanofi (France) and is an example of free cabazitaxel used for comparison with dendrimers. Pharmacokinetic data (see, e.g., Mita AC, Denis LJ, Rowinsky EK, et al. Phase I and pharmacokinetic study of XRP6258 (RPR 116258A), a novel taxane, administered as a 1-hour infusion every 3 weeks in patients with advanced solid tumors. Clin Cancer Res. 2009; 15(2): 723-730).

[0173] In Mita, 25-mg / m 2 The dose was associated with a Cmax of 535 ± 305 mcg / L and an AUC concentration of 642 ± 320 mcg / L per hour. A three-phase model was used to describe the decreasing plasma concentrations of the drug. The plasma concentration pharmacokinetic activity was characterized by a rapid initial elimination phase (mean terminal half-life [t1 / 2] = 2.6 ± 1.4 minutes), followed by an intermediate elimination phase (mean t1 / 2 = 1.3 ± 0.6 hours) and a prolonged terminal elimination phase (mean t1 / 2 = 77.3 ± 45.5 hours). Approximately 80% of the dose was eliminated within 2 weeks. The volume of distribution at steady state was large and highly variable (2,034 ± 1,495 L / m2).

[0174] The major dose-limiting toxicity in this study was hematologic myelosuppression (i.e., leukopenia). Grade 4 neutropenia occurred in one patient (4%) and febrile neutropenia in a second patient (4%), both at the 25-mg / m2 dose. Nonhematologic toxicities also occurred. Two patients (8%) experienced flushing, dizziness, and chest tightness, which were identified as grade 1 allergic reactions. Other nonhematologic toxicities included diarrhea (14 patients; 56%), nausea (10 patients; 40%), fatigue (nine patients; 36%), neurotoxicity (nine patients; 36%), and vomiting (four patients; 16%).

[0175] In the Phase 3 TROCIC study of patients with metastatic prostate cancer (n=67 years), the mean Cmax was 226 ng / mL (coefficient of variation, CV 107%) and was reached at the end of a 1-hour infusion (Tmax). The mean AUC was 991 ng.h / mL (CV: 34%). Neutropenia (all grades) occurred in 94% of cabazitaxel patients, and 8% had grade 3 or 4 febrile neutropenia. In the TROPIC registration study of Jevtana, patients treated with 25 mg / m 21 hour after the IV administration of cabazitaxel (de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel ormitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: A randomised open-label trial. Lancet. 2010; 376(9747): 1147-1154.)

[0176] Dendrimer

[0177] In a first aspect, there is provided a dendrimer comprising:

[0178] i) a core unit (C); and

[0179] ii) building units (BU), each building unit being a lysine residue or an analog thereof;

[0180] wherein the core unit is covalently linked to two building blocks via amide bonds, each amide bond being formed between a nitrogen atom present in the core unit and a carbon atom of an acyl group present in a building block;

[0181] The dendrimer is a five-generation building block dendrimer;

[0182] wherein the building blocks of different generations are covalently linked to each other via an amide bond formed between a nitrogen atom present in one building block and a carbon atom of an acyl group present in another building block;

[0183] The dendrimer further comprises:

[0184] iii) a plurality of first terminal groups (T1), each first terminal group comprising a cabazitaxel residue covalently linked to a diethylene glycol-based linking group; and

[0185] iv) a plurality of second terminal groups (T2), each second terminal group comprising a PEG group;

[0186] wherein at least one third of the nitrogen atoms present in the outer building blocks are each covalently attached to the first terminal group; and

[0187] At least one third of the nitrogen atoms present in the outer building blocks are each covalently linked to a second terminal group;

[0188] or a pharmaceutically acceptable salt thereof.

[0189] The core unit (C) of the dendrimer is covalently linked to two building blocks via an amide bond, each amide bond being formed between a nitrogen atom present in the core unit and a carbon atom of an acyl group present in the building block. Thus, the core unit can be formed, for example, by a core unit precursor comprising two amino groups. Any suitable diamino-containing molecule can be used as a core unit precursor. In some embodiments, the core unit is:

[0190]

[0191] and can be formed, for example, from a nuclear unit precursor:

[0192]

[0193] Has two reactive (amino) nitrogens.

[0194] The building block (BU) is a lysine residue or an analog thereof and can be formed from a suitable building block precursor, such as lysine or a lysine analog containing an appropriate protecting group. A lysine analog has two amino nitrogen atoms for binding to subsequently generated building blocks and an acyl group for binding to previously generated building blocks or nuclei. Examples of suitable building blocks include

[0195]

[0196] wherein the acyl group of each building block provides a covalent attachment point for linkage to the core or a previous generation building block; and wherein each nitrogen atom provides a covalent attachment point for linkage to a subsequent generation building block, a first terminal group, or a second terminal group.

[0197] In some preferred embodiments, the building blocks are each:

[0198]

[0199] wherein the acyl group of each building block provides a covalent attachment point for linkage to the core or a previous generation building block; and wherein each nitrogen atom provides a covalent attachment point for linkage to a subsequent generation building block, a first terminal group, or a second terminal group.

[0200] In some preferred embodiments, the building blocks are each:

[0201]

[0202] wherein the acyl group of each building block provides a covalent attachment point for linkage to the core or a previous generation building block; and wherein each nitrogen atom provides a covalent attachment point for linkage to a subsequent generation building block, a first terminal group, or a second terminal group.

[0203] Outermost building unit (BU outer ) can be formed from lysine or lysine analog building blocks, as used for other generations of building blocks (BU) as described above. The outermost generation building block (BU outer ) is the outermost generation building block of the core of the dendrimer, i.e., in the outermost generation building block (BU outer ) has no building blocks from other generations attached to it.

[0204] It will be appreciated that the dendrons of the dendrimers can be synthesized to the desired number of generations, for example by linking the building blocks (BU) accordingly. In some embodiments, each generation of building blocks (BU) can be formed from the same building blocks, for example the building blocks of all generations can be lysine building blocks. In some other embodiments, one or more generations of building blocks can be formed from different building blocks than other generations of building blocks.

[0205] The dendrimer is a five-generation building block dendrimer. A five-generation building block dendrimer is a dendrimer having a structure comprising five building blocks covalently linked to each other, for example in the case where the building block is lysine, it may comprise the following substructures:

[0206]

[0207] In some embodiments, the dendrimer has five complete generations of building units. For a core with two reactive amine groups, such a dendrimer would contain 62 building units (i.e., core unit + 2BU + 4BU + 8BU + 16BU + 32BU). However, it should be understood that due to the nature of the synthetic method used to prepare the dendrimer, one or more reactions performed to prepare the dendrimer may not be fully completed. Therefore, in some embodiments, the dendrimer may contain incomplete generations of building units. For example, a population of dendrimers can be obtained in which the dendrimers have a distribution of the number of building units per dendrimer. In some embodiments, a population of dendrimers is obtained, wherein the average number of building units per dendrimer is at least 55 or at least 56 or at least 57 or at least 58 or at least 59 or at least 60. In some embodiments, a population of dendrimers is obtained in which at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% of the dendrimers have 55 or more building units. In some embodiments, a population of dendrimers is obtained wherein at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% of the dendrimers have 60 or more building blocks.

[0208] Each reactive (amino) group of the core represents a conjugation site for a dendron comprising one or more generations of building blocks. The core has two reactive (amino) groups and two dendrons for attaching each generation of building blocks.

[0209] In some embodiments, each generation of building blocks in each dendron (X) can be represented by the formula [BU]2(b-1), where b is the number of generations. A dendron (X) having five complete generations of building blocks is represented by [BU]1-[BU]2-[BU]4-[BU]8-[BU] 16 .

[0210] The dendrimer comprises a plurality of first terminal groups (T1), each of which comprises a cabazitaxel residue covalently linked to a diethylene glycol linking group. Each first terminal group (T1) is preferably:

[0211]

[0212] That is, the cabazitaxel residue is covalently linked to the diethylene glycol linker via an ester bond formed between an oxygen atom present as part of the cabazitaxel side chain and a carbon atom of an acyl group present as part of the diethylene glycol linker. The other acyl group of the diethylene glycol linker forms an amide bond with a nitrogen atom present in the outer building block. In such an embodiment, the cabazitaxel residue is:

[0213]

[0214] Upon in vivo administration, dendrimers typically release cabazitaxel as:

[0215]

[0216] The dendrimer comprises a plurality of second terminal groups (T2), each of which comprises a PEG group. The second terminal group T2 is a pharmacokinetic modifier. A pharmacokinetic modifier is an agent that can modify or regulate the pharmacokinetic properties of a dendrimer or a pharmaceutically active agent (i.e., cabazitaxel) delivered by the dendrimer. A pharmacokinetic modifier can regulate the absorption, distribution, metabolism, excretion, and / or toxicity of the dendrimer of the pharmaceutically active agent. A pharmacokinetic modifier (T2) can affect the release rate of the pharmaceutically active agent by slowing down or increasing the rate at which the active agent is released from the dendrimer by chemical (e.g., hydrolysis) or enzymatic degradation pathways. A pharmacokinetic modifier (T2) can change the solubility curve of the dendrimer, increasing or decreasing the solubility of the dendrimer in a pharmaceutically acceptable carrier. A pharmacokinetic modifier (T2) can help the dendrimer deliver the pharmaceutically active agent to a specific tissue (e.g., a tumor). Pharmacokinetic modifiers (T2) can prolong the half-life of the pharmaceutically active agent by reducing the clearance rate of the dendrimer.

[0217] A PEG group is a polyethylene glycol group, i.e., a group comprising repeating units of the formula -CH2CH2O-. The PEG material used to produce the dendrimers of the invention typically contains a mixture of PEGs with some variation in molecular weight (i.e., ±10%), so the molecular weight specified is typically an approximation of the average molecular weight of the PEG composition. For example, the term "PEG ～2100 ” refers to a polyethylene glycol (i.e., PEG) having an average molecular weight of about 2100 Daltons, i.e., ± about 10% 1900 To PEG 2300 ). Three methods are commonly used to calculate the MW average: number average molecular weight, weight average molecular weight, and z average molecular weight. As used herein, the phrase "molecular weight" refers to the weight average molecular weight that can be measured using techniques well known in the art, including but not limited to NMR, mass spectrometry, matrix-assisted laser desorption ionization time of flight (MALDI-TOF), gel permeation chromatography or other liquid chromatography techniques, light scattering techniques, ultracentrifugation, and viscometry.

[0218] In some embodiments, the second terminal group comprises a PEG group with an average molecular weight of about 200 to 5000 daltons. In some embodiments, the second terminal group comprises a PEG group with an average molecular weight of at least 750 daltons. In some embodiments, the second terminal group comprises a PEG group with an average molecular weight of 1000 to 2500 daltons. In some embodiments, the second terminal group comprises a PEG group with an average molecular weight of 1900 to 2300 daltons. In some embodiments, the second terminal group comprises a PEG group with an average molecular weight of 2000 to 2200 daltons. In some embodiments, the second terminal group comprises a PEG group with an average molecular weight of about 2100 daltons.

[0219] In some embodiments, the polydispersity index (PDI) of the PEG group is from about 1.00 to about 1.50, from about 1.00 to about 1.25, or from about 1.00 to about 1.10. In some embodiments, the PEG group has a polydispersity index (PDI) of about 1.05. The term "polydispersity index" refers to a measure of the distribution of molecular weights in a given polymer sample. The polydispersity index (PDI) is equal to the weight average molecular weight (M w ) divided by the number average molecular weight (M n ) and indicates the distribution of individual molecular masses in a batch of polymers. The polydispersity index (PDI) has values ​​equal to or greater than 1, but will be closer to 1 as the polymers approach uniform length and average molecular weight.

[0220] In some embodiments, the PEG group is a methoxy-terminated PEG.

[0221] The PEG group can be connected to the external building block via any suitable means. In some embodiments, the PEG linking group is used to connect the PEG group to the external building block. In some embodiments, each of the second terminal groups comprises an ether bond covalently connected to the PEG linking group (L1) via a carbon atom present in the PEG group and an oxygen atom present in the PEG linking group, and each second terminal group is covalently connected to the building block via an amide bond formed between a nitrogen atom present in the building block and a carbon atom of an acyl group present in the PEG linking group. In some embodiments, each of the second terminal groups is

[0222]

[0223] And wherein the PEG group is a methoxy-terminated PEG having an average molecular weight in the range of about 1750 to 2500 Daltons.

[0224] In the dendrimers of the invention, at least one third of the nitrogen atoms present in the outer building blocks are each covalently linked to the first terminal group; and

[0225] At least one third of the nitrogen atoms present in the outer building blocks are each covalently linked to the second terminal group.

[0226] In some embodiments, the dendrimer has a controlled stoichiometry and / or topology. For example, the dendrimer is typically prepared using a synthetic process that allows a high degree of control over the number and arrangement of first and second terminal groups present on the dendrimer. In some embodiments, each functionalized external building block contains a first terminal group and a second terminal group. In some embodiments, the dendrimer comprises a surface unit, the surface unit comprising an external building unit connected to a first terminal group and a second terminal group, the surface unit having the following structure:

[0227]

[0228] And wherein the PEG group is a methoxy-terminated PEG having an average molecular weight in the range of about 1750 to 2500 Daltons. In some embodiments, the dendrimer has 28 to 32 surface units. In some embodiments, the dendrimer has 30 to 32 surface units.

[0229] In some embodiments, at least 40% of the nitrogen atoms present in the outer building blocks are each covalently linked to the first terminal group. In some embodiments, at least 45% of the nitrogen atoms present in the outer building blocks are each covalently linked to the first terminal group. In some embodiments, about 50% of the nitrogen atoms present in the outer building blocks are each covalently linked to the first terminal group.

[0230] In some embodiments, at least 40% of the nitrogen atoms present in the outer building blocks are each covalently linked to the second terminal group. In some embodiments, at least 45% of the nitrogen atoms present in the outer building blocks are each covalently linked to the second terminal group. In some embodiments, about 50% of the nitrogen atoms present in the outer building blocks are each covalently linked to the second terminal group.

[0231] In some embodiments, at least 40% of the nitrogen atoms present in the outer building blocks are each covalently attached to the first terminal group; and at least 40% of the nitrogen atoms present in the outer building blocks are each covalently attached to the second terminal group. In some embodiments, at least 45% of the nitrogen atoms present in the outer building blocks are each covalently attached to the first terminal group; and at least 45% of the nitrogen atoms present in the outer building blocks are each covalently attached to the second terminal group. In some embodiments, about 50% of the nitrogen atoms present in the outer building blocks are each covalently attached to the first terminal group; and about 50% of the nitrogen atoms present in the outer building blocks are each covalently attached to the second terminal group.

[0232] In some embodiments, the five generations of building blocks are complete generations, and the building blocks of the outer generations provide 64 nitrogen atoms for covalent attachment to the first terminal group or the second terminal group, wherein 26 to 32 first terminal groups are covalently attached to one of the nitrogen atoms, and wherein 28 to 32 second terminal groups are each covalently attached to one of the nitrogen atoms. In some embodiments, 28 to 32 first terminal groups are each covalently attached to one of the nitrogen atoms. In some embodiments, 29 to 31 first terminal groups are each covalently attached to one of the nitrogen atoms.

[0233] In some embodiments, the cabazitaxel residues comprise at least 20% w / w dendrimers, at least 22% w / w dendrimers, or at least 24% w / w dendrimers. In some embodiments, the cabazitaxel residues comprise at most 30% w / w dendrimers, at most 28% w / w dendrimers, or at most 26% w / w dendrimers. In some embodiments, in terms of w / w%, the cabazitaxel residues comprise dendrimers in the range of 20% w / w to 30% w / w, or 23% w / w to 28% w / w, or 24% w / w to 26% w / w. The w / w% of dendrimers that are cabazitaxel residues can be determined by any suitable method. In some embodiments, the w / w% of dendrimers that are cabazitaxel residues can be determined by 1 H NMR determination.

[0234] In some embodiments, no more than one fourth of the nitrogen atoms present in the exo building unit are unsubstituted. In some embodiments, no more than one fifth of the nitrogen atoms present in the exo building unit are unsubstituted. In some embodiments, no more than one sixth of the nitrogen atoms present in the exo building unit are unsubstituted. In some embodiments, no more than one eighth of the nitrogen atoms present in the exo building unit are unsubstituted. In some embodiments, no more than one tenth of the nitrogen atoms present in the exo building unit are unsubstituted.

[0235] In some embodiments, no more than 20 nitrogen atoms present in an Exo building unit are unsubstituted. In some embodiments, no more than 10 nitrogen atoms present in an Exo building unit are unsubstituted. In some embodiments, no more than 5 nitrogen atoms present in an Exo building unit are unsubstituted. In some embodiments, no more than 3 nitrogen atoms present in an Exo building unit are unsubstituted. In some embodiments, no more than 2 nitrogen atoms present in an Exo building unit are unsubstituted. In some embodiments, no more than 1 nitrogen atom present in an Exo building unit is unsubstituted. In some embodiments, substantially all nitrogen atoms present in an Exo building unit are substituted.

[0236] In some embodiments, the dendrimer is:

[0237]

[0238] Wherein T1′ represents the first terminal group as follows:

[0239] or T1′ represents H, wherein less than 5 T1′ are H; and T2′ represents the following second terminal group:

[0240]

[0241] wherein the PEG group is a methoxy-terminated PEG having an average molecular weight in the range of about 1750 to 2500 Daltons, or T2' represents H, and wherein less than 5 T2's are H.

[0242] In some embodiments, the molecular weight of the dendrimer is in the range of 50 to 300 kDa. In some embodiments, the molecular weight of the dendrimer is in the range of 75 to 200 kDa. In one embodiment, the molecular weight of the dendrimer is in the range of 90 to 150 kDa.

[0243] In some embodiments, the in vitro half-life of cabazitaxel released from the dendrimer is in the range of 20 to 100 hours in PBS (phosphate buffered saline) at pH 7.4 and 37°C. In some embodiments, the in vitro half-life of cabazitaxel released from the dendrimer is in the range of 24 to 60 hours in PBS at pH 7.4 and 37°C. In some embodiments, the in vitro half-life of cabazitaxel released from the dendrimer is in the range of 30 to 60 hours in PBS at pH 7.4 and 37°C. In some embodiments, the in vitro half-life of cabazitaxel released from the dendrimer is in the range of 30 to 50 hours in PBS at pH 7.4 and 37°C.

[0244] Composition

[0245] In some embodiments, the dendrimer is presented as a composition, preferably a pharmaceutical composition.

[0246] It should be understood that due to the nature of the synthetic process used to produce the dendrimers, there may be some variation in the molecular composition between the dendrimers present in a given composition. For example, as described above, one or more of the synthetic steps used to prepare the dendrimers may not be carried out completely to completion, which may result in the presence of dendrimers that do not all contain the same number of first or second terminal groups, or contain incomplete generations of building blocks.

[0247] Thus, provided are compositions comprising a plurality of dendrimers or pharmaceutically acceptable salts thereof, wherein the dendrimers are as defined herein,

[0248] The average number of first end groups per dendrimer in the composition is in the range of 24 to 32, and

[0249] The average number of second end groups per dendrimer in the composition is in the range of 24 to 32. In some embodiments, the average number of first end groups per dendrimer is in the range of 26 to 32, and wherein the average number of second end groups per dendrimer is in the range of 28 to 32. In some embodiments, the average number of first end groups per dendrimer is in the range of 28 to 32, or in the range of 29 to 31. In some embodiments, the average number of second end groups per dendrimer is in the range of 29 to 31.

[0250] In some embodiments, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% of the dendrimers contain at least 24 first terminal groups. In some embodiments, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% of the dendrimers contain at least 26 first terminal groups. In some embodiments, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% of the dendrimers contain at least 28 first terminal groups.

[0251] In some embodiments, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% of the dendrimers contain at least 28 second terminal groups. In some embodiments, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% of the dendrimers contain at least 29 second terminal groups.

[0252] In some embodiments, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% of the dendrimers contain at least 24 first terminal groups and at least 28 second terminal groups. In some embodiments, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% of the dendrimers contain at least 26 first terminal groups and at least 29 second terminal groups.

[0253] In some embodiments, a composition comprising a plurality of dendrimers or pharmaceutically acceptable salts thereof comprises cabazitaxel residues in an amount of at least 20% w / w, at least 22% w / w, or at least 24% w / w of the dendrimers present in the composition. In some embodiments, a composition comprising a plurality of dendrimers or pharmaceutically acceptable salts thereof comprises cabazitaxel residues in an amount of at most 30% w / w of the dendrimers, at most 28% w / w of the dendrimers, or at most 26% w / w of the dendrimers. In some embodiments, a composition comprising a plurality of dendrimers or pharmaceutically acceptable salts thereof comprises cabazitaxel residues in an amount ranging from 20% w / w to 30% w / w, or from 23% w / w to 28% w / w, or from 24% w / w to 26% w / w. The w / w % of dendrimers that are cabazitaxel residues may be determined by any suitable method. In some embodiments, the w / w % of dendrimers that are cabazitaxel residues may be determined by 1 H NMR determination.

[0254] The present invention also provides pharmaceutical compositions for both veterinary and human medical use, comprising a dendrimer of the present invention or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable carriers, and optionally any other therapeutic ingredients, stabilizers, etc. The carrier must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and not overly harmful to the recipient thereof. In some embodiments, the composition is a pharmaceutical composition, and wherein the composition comprises a pharmaceutically acceptable excipient. The composition of the present invention may also include a polymeric excipient / additive or carrier, such as polyvinylpyrrolidone, derivatized cellulose, such as hydroxymethylcellulose, hydroxyethylcellulose and hydroxypropylmethylcellulose, Ficolls (a polymeric sugar), hydroxyethyl starch (HES), dextran (e.g., cyclodextrins, such as 2-hydroxypropyl-β-cyclodextrin and sulfobutyl ether-β-cyclodextrin), polyethylene glycol, and pectin. The composition may further include diluents, buffers, citrate, trehalose, binders, disintegrants, thickeners, lubricants, preservatives (including antioxidants, inorganic salts (e.g., sodium chloride), antimicrobials (e.g., benzalkonium chloride), sweeteners, antistatic agents, sorbitan esters, lipids (e.g., phospholipids such as lecithin and other phosphatidylcholines, phosphatidylethanolamines, fatty acids and fatty acid esters, steroids (e.g., cholesterol)), and chelating agents (e.g., EDTA, zinc and other such suitable cations). Other pharmaceutical excipients and / or additives suitable for use in the composition according to the present invention are listed in "Remington: The Science & Practice of Pharmacy", 19.sup.th ed., Williams & Williams, (1995)", and "Physician's Desk Reference", 52.sup.nd ed., Medical Economics, Montvale, NJ (1998), and "Handbook of Pharmaceutical Excipients", Third Ed., Ed. AHKibbe, Pharmaceutical Press, 2000".

[0255] In some embodiments, the composition is a solid composition suitable for reconstitution with a diluent. For example, the composition can be in the form of a powder or granules. Such a composition may be advantageous for transporting and / or storing the dendrimer prior to administration, for example, to help provide stability to the dendrimer.

[0256] In some embodiments, a stable composition is one in which the rate of release of cabazitaxel from the dendrimer is less than 1%, less than 0.5%, less than 0.2%, or less than 0.1% of the total cabazitaxel within 4 hours at room temperature, such as 25°C.

[0257] Excipients used with such solid compositions may include, for example, buffers or other pH control agents. If the solid composition is mixed with a diluent, the pH control agent may be used, for example, in the solid composition itself or in a subsequent reconstituted composition to maintain and / or preserve the chemical stability of the dendritic polymer. In some embodiments, an acid is used in the solid composition that can provide a pH of less than 6 after reconstitution with a diluent, or can provide a pH in the range of less than 5, or can provide a pH in the range of 3.5 to 5.5, or can provide a pH in the range of 4 to 5, or can provide a pH of about 4.5. In some embodiments, after reconstitution with a diluent, the pH of the reconstituted composition is in the range of less than 5, in the range of 3.5 to 5.5, in the range of 4 to 5, or about 4.5. In some embodiments, an acid having an acidic group with a pKa in the range of 4 to 5 is used. In some embodiments, an acid such as citric acid is included in the composition.

[0258] In some embodiments, the solid composition comprises a bulking agent, such as a non-reducing sugar. In some embodiments, the sugar is a disaccharide. In some embodiments, the sugar is trehalose, mannitol, sorbitol, or lactose.

[0259] In some embodiments, the solid composition comprises a sugar and an acid, and the composition is for reconstitution with a diluent. In some embodiments, the composition comprises trehalose and citric acid.

[0260] In some embodiments, the composition comprises a dendrimer and a sugar (preferably trehalose) in a weight ratio ranging from 1:1 to 1:3, or in a weight ratio of about 1:2. In some embodiments, the composition comprises a dendrimer and an acid (preferably citric acid) in a weight ratio ranging from 1:0.5 to 1:2, or about 1:1, or 1:0.96. In some embodiments, the weight ratio of dendrimer: sugar: acid is about 100:200:96. In some embodiments, the weight ratio of dendrimer: sugar: acid in the composition is about 100:200:96, and the composition comprises cabazitaxel residues in an amount of 23% w / w to 28% w / w of the dendrimer.

[0261] In some embodiments, the composition is prepared by freeze drying, i.e., it is a lyophilisate. In some embodiments, the composition is a solid lyophilisate comprising a dendrimer or a pharmaceutically acceptable salt thereof, a sugar and an acid. In some embodiments, the composition is a solid lyophilisate comprising a dendrimer or a pharmaceutically acceptable salt thereof, trehalose and citric acid.

[0262] In some embodiments, the composition is a liquid composition, such as a reconstituted composition, which is suitable for administration by, for example, injection or infusion. For example, the composition can be a reconstituted composition prepared by mixing the above solid composition with a diluent such as saline or WFI (water for injection).

[0263] In some embodiments, the liquid composition is a sufficiently stable reconstituted composition under ambient conditions (e.g., at about 25° C.) for up to 2 hours, up to 4 hours, up to 6 hours, up to 12 hours, or up to 24 hours, or up to 48 hours, or up to 1 week after reconstitution. In some embodiments, the liquid composition is a sufficiently stable reconstituted composition under refrigerated conditions (e.g., at about 4° C.) for up to 2 hours, up to 4 hours, up to 6 hours, up to 12 hours, or up to 24 hours, or up to 48 hours, or up to 1 week after reconstitution. In some embodiments, the liquid composition is a sufficiently stable reconstituted composition when protected from light for up to 2 hours, up to 4 hours, up to 6 hours, up to 12 hours, or up to 24 hours, or up to 48 hours, or up to 1 week after reconstitution.

[0264] It has been found that after reconstitution but before transfer into the infusion bag (saline infusion), the data show that the reconstituted solution according to the invention is stable (less than 0.1% cabazitaxel released) at room temperature for at least 4 hours (25±5°C).

[0265] In some embodiments, the liquid composition is a composition wherein the release rate of cabazitaxel from the dendrimer when present in the composition is less than 1%, less than 0.5%, less than 0.2% or less than 0.1% of the total cabazitaxel within 4 hours at room temperature, such as 25°C.

[0266] In some embodiments, the liquid composition is a reconstitution composition present in an infusion bag. In some embodiments, the liquid composition is a reconstitution composition present in a syringe.

[0267] It will be appreciated that the above compositions may be used with drug-dendrimer conjugates other than those described in the first aspect, for example with other drug-dendrimer conjugates in which the pharmaceutically active agent is linked to the dendrimer via a diethylene glycol-based linker through a hydroxyl group.

[0268] Thus, also provided herein is a pharmaceutical composition comprising a) a dendrimer comprising a core unit; a building unit; a plurality of first terminal groups (T1), each comprising a residue of a pharmaceutically active agent, the pharmaceutically active agent comprising a hydroxyl group covalently linked to a diethylene glycol-based linking group; and a plurality of second terminal groups (T2), each comprising a pharmacokinetic modifier; wherein the first and second terminal groups are covalently linked to an external building unit; and b) an acid. In some embodiments, the pharmaceutically active agent is an oncological agent, such as a taxane, such as docetaxel or cabazitaxel. In some embodiments, the pharmacokinetic modifier comprises a PEG or PEOX group. In some embodiments, the pharmacokinetic modifier comprises a PEG group. In some embodiments, the core is a BHALys group. In some embodiments, the building unit is a lysine residue or an analog thereof. In some embodiments, the dendrimer is a five-generation building unit dendrimer. In some embodiments, the acid is citric acid. In some embodiments, the composition comprises c) a sugar, such as a disaccharide, such as trehalose. In some embodiments, the composition is a solid composition. In some embodiments, the composition is prepared by lyophilization, that is, it is a solid lyophilisate. In some embodiments, the composition is used for reconstitution with a diluent. In some embodiments, the composition is a liquid composition, such as a reconstituted composition, which is suitable for administration by, for example, injection or infusion. For example, the composition can be a reconstituted composition produced by mixing a solid composition as discussed above with a diluent such as saline or WFI (water for injection). The dendrimer of the present invention can be present in a composition, including those suitable for inhalation into the lungs or parenteral administration (including intraperitoneal, intravenous, subcutaneous or intramuscular injection) by aerosol. The composition can be conveniently present in a unit dosage form and can be prepared by any method well known in the pharmaceutical field. All methods include the step of associating a dendrimer with a carrier constituting one or more auxiliary components. Typically, by associating a dendrimer with a liquid carrier to form a solution or suspension, or alternatively, by associating a dendrimer with a composition component suitable for forming a solid, optionally a granular product, and then, if guaranteed, the product is shaped into a desired delivery form to prepare the composition. When particles, the solid compositions of the invention will typically contain particles ranging in size from about 1 nanometer to about 500 microns. Typically, for solid compositions for intravenous administration, the diameter of the particles will typically be in the range of about 1 nm to about 10 microns. The composition may contain dendrimers of the invention, which are nanoparticles having a particle diameter below 1000 nm, for example between 5 and 1000 nm, particularly between 5 and 500 nm, more particularly between 5 and 400 nm, such as between 5 and 50 nm and particularly between 5 and 20 nm. In one embodiment, the composition contains dendrimers having an average size between 5 and 20 nm.In some embodiments, the dendrimers are polydisperse in the composition, with a PDI between 1.01 and 1.8, particularly between 1.01 and 1.5, more particularly between 1.01 and 1.2. In one example, the dendrimers are monodisperse in the composition.

[0269] In some preferred embodiments, the composition is for patent delivery. For example, in one embodiment, the composition can be a sterile lyophilized composition suitable for reconstitution in an aqueous vehicle prior to injection.

[0270] In one embodiment, compositions suitable for parenteral administration conveniently comprise a sterile aqueous preparation of the dendrimer, which may, for example, be made isotonic with the blood of the recipient.

[0271] Also provided are pharmaceutical compositions suitable for administration by inhalation as an aerosol. These compositions comprise a solution or suspension of the desired dendrimer or a salt thereof. The desired composition can be placed in a chamber and atomized. Atomization can be accomplished by compressed air or by ultrasonic energy to form a plurality of droplets or solid particles comprising the dendrimer or a salt thereof.

[0272] In some embodiments, the composition can be formulated for administration as an infusion. In some embodiments, the composition can be formulated for administration as a bolus injection. In some embodiments, the composition is formulated for administration as an infusion over a period of up to 30 minutes, or is formulated for administration as a bolus injection over a period of up to 5 minutes.

[0273] As described below, the dendrimers of the present invention can be administered, for example, in combination with one or more additional pharmaceutically active agents. Thus, in some embodiments, the composition comprises a dendrimer as defined herein or a pharmaceutically acceptable salt thereof, one or more pharmaceutically acceptable carriers and one or more additional pharmaceutically active agents, such as additional oncology agents, small molecule cytotoxic agents, checkpoint inhibitors, antibody therapy. In some embodiments, the composition comprises a dendrimer as defined herein or a pharmaceutically acceptable salt thereof, and an additional oncology agent, such as gemcitabine. Not only can the dendrimers of the present invention be administered with other chemotherapeutic drugs, but they can also be administered with other drugs, such as corticosteroids, antihistamines, analgesics, and drugs that help restore or prevent blood toxicity, such as cytokines.

[0274] In some embodiments, the composition is for parenteral infusion as part of a chemotherapy regimen. In these embodiments, the composition may, for example, be substantially free of or completely free of solubilizing excipients, particularly solubilizing excipients such as polyethoxylated castor oil (e.g., such as those sold under the trade name Sold or sold under the trade name ) or polyethoxylated sorbitan monooleate (such as those sold under the trade name polysorbate A solubilizing excipient is an additive that helps the dendrimer dissolve in one or more solvents. In one embodiment, the composition is substantially free of or completely free of polyethoxylated castor oil (e.g., such as sold under the trade name Sold or sold under the trade name Products sold in the market) and polyethoxylated sorbitan monooleate (such as polysorbate In one embodiment, the composition is substantially or completely free of solubilizing excipients. By avoiding the use of solubilizing excipients, the dendrimer composition is less likely to cause side effects, such as acute or delayed hypersensitivity reactions, including life-threatening anaphylaxis and / or severe fluid retention, and / or eliminates the need for steroid pretreatment.

[0275] How to use

[0276] The dendrimers of the invention may be used to treat or prevent any disease, condition or symptom that an unmodified pharmaceutically active agent may be used to treat or prevent. Thus, there is also provided a dendrimer or pharmaceutical composition as described herein for use in therapy.

[0277] In some embodiments, the dendrimer is used in a method of treating or preventing cancer, for example, for inhibiting the growth of a tumor. In some embodiments, the dendrimer is used to treat cancer. Also provided is a method of treating cancer, comprising administering a therapeutically effective amount of a dendrimer to a subject in need thereof. Also provided is the use of a dendrimer as defined herein or a composition as defined herein in the preparation of a medicament for treating cancer.

[0278] In some embodiments, the cancer is a solid tumor. The cancer can be a primary or metastatic tumor. In some embodiments, the cancer is a primary tumor. In some embodiments, the cancer is a metastatic tumor.

[0279] In some embodiments, the cancer is selected from the group consisting of breast cancer, ovarian cancer (e.g., recurrent ovarian cancer), pancreatic cancer, testicular cancer (e.g., cisplatin-resistant germ cell cancer), prostate cancer (e.g., bone metastatic prostate cancer, prostate tumors, hormone-refractory prostate cancer, castration-resistant prostate cancer, advanced prostate cancer), dedifferentiated liposarcoma, bladder urothelial cancer (e.g., urothelial transitional cell carcinoma (TCCU)), adrenocortical carcinoma, brain cancer (e.g., recurrent malignant glioma), AML (acute myeloid leukemia) and CLL (chronic lymphocytic leukemia). In some embodiments, the cancer is prostate cancer, pancreatic cancer, ovarian cancer, or breast cancer. In some embodiments, the cancer is prostate cancer, such as hormone-refractory prostate cancer, or, for example, metastatic castration-resistant prostate cancer (mCRPC). In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is a tumor of the sweat glands, such as papillary adenocarcinoma.

[0280] In some embodiments, a dendrimer for use in therapy (e.g., cancer therapy) has a core that is:

[0281]

[0282] In some embodiments, dendrimers for use in therapy (e.g., cancer therapy) have building blocks, each of which is:

[0283]

[0284] wherein the acyl group of each building block provides a covalent attachment point for linkage to the core or a previous generation building block; and wherein each nitrogen atom provides a covalent attachment point for linkage to a subsequent generation building block, a first terminal group, or a second terminal group.

[0285] In some embodiments, the dendrimers used for therapy (eg, cancer therapy) have first terminal groups (T1), each of which is:

[0286]

[0287] In some embodiments, the dendrimers used for therapy (e.g., cancer therapy) have second terminal groups, each of which is

[0288]

[0289] And wherein the PEG group is a methoxy-terminated PEG having an average molecular weight in the range of about 1750 to 2500 Daltons.

[0290] In some embodiments, dendrimers for use in therapy (eg, cancer therapy) have a first terminal group in the range of 26-32 and a second terminal group in the range of 28-32.

[0291] In some embodiments, the dendrimer used for therapy (e.g., cancer therapy) is

[0292]

[0293] Wherein T1′ represents the first terminal group as follows:

[0294]

[0295] or T1′ represents H, wherein less than 5 T1′ are H; and T2′ represents the following second terminal group:

[0296]

[0297] wherein the PEG group is a methoxy-terminated PEG having a molecular weight in the range of about 1750 to 2500 Daltons, or T2' represents H, and wherein less than 5 T2' are H.

[0298] In combined therapy, especially during chemotherapy, drugs are usually co-administered with other drugs. Therefore, in some embodiments, dendrimers are co-administered with one or more other therapeutic / pharmaceutical agents, such as one or more other anticancer agents. Dendrimers and one or more other therapeutic / pharmaceutical agents can be administered simultaneously, subsequently or separately. For example, they can be administered as part of the same composition, or administered by a separate composition. The one or more additional pharmaceutically active agents can be, for example, anticancer agents for the treatment of prostate cancer or breast cancer, or, for example, for the treatment of pancreatic cancer or ovarian cancer. Examples of other pharmaceutically active agents include chemotherapeutic agents and cytotoxic agents, immune-oncology agents (such as checkpoint inhibitors) and antibody therapies. Examples of other pharmaceutically active agents include paclitaxel, docetaxel, abraxane, clarithromycin, vinflunine, bavituximab, tocotrienols, gemcitabine, capecitabine, carboplatin, oxaliplatin, niraparib, folinic acid, 5-fluorouracil, irinotecan, tamsulosin, ADT, G-CSF, LHRH antagonists, bicalutamide, enzlutamide, clarithromycin, vinflunine, bacituximab, and bevacizumab.

[0299] Currently for The label of (free cabazitaxel) indicates that During treatment, it is administered as a one-hour intravenous infusion in combination with oral prednisone 10 mg administered daily. In addition, to reduce the risk and / or severity of hypersensitivity reactions, it is recommended that each dose Prophylactic medication was given at least 30 minutes before by intravenous injection of the following drugs: (i) antihistamine (dexclopramide 5 mg or diphenhydramine 25 mg or equivalent antihistamine), (ii) corticosteroid (dexamethasone 8 mg or equivalent steroid) and (iii) H2 antagonist (ranitidine 50 mg or equivalent H2 antagonist).

[0300] In some embodiments, the dendrimer or composition comprising the dendrimer is not used to deliver In some embodiments, the dendrimer or composition comprising the dendrimer is not administered as part of a regimen requiring prophylactic medication. In some embodiments, the dendrimer or composition comprising the dendrimer is not administered in combination with a drug that reduces the risk and / or severity of a hypersensitivity reaction, is not administered as part of a regimen requiring prophylactic medication with a drug that reduces the risk and / or severity of a hypersensitivity reaction, or is not administered as part of a regimen requiring treatment with a drug that reduces the risk and / or severity of a hypersensitivity reaction. In some embodiments, the dendrimer or composition comprising the dendrimer is not administered in combination with an antihistamine, a corticosteroid, or an H2 antagonist, and is not administered as part of a regimen requiring prophylactic medication with an antihistamine, a corticosteroid, or an H2 antagonist, and is not administered as part of a regimen requiring treatment with an antihistamine, a corticosteroid (e.g., prednisone, prednisolone), an immunosuppressant, or an H2 antagonist.

[0301] It is understood that a therapeutically effective amount refers to a dendrimer administered in an amount sufficient to alleviate or prevent to some extent one or more symptoms of the condition or disorder being treated. The therapeutically effective amount of a dendrimer can be based on, for example, the amount of dendrimer administered. Alternatively, it can be determined based on the amount of active agent (cabazitaxel) that the dendrimer can theoretically deliver, for example based on the loading of cabazitaxel on the dendrimer.

[0302] In some embodiments, the amount of dendrimer administered is sufficient to deliver between 5 and 100 mg of active agent / m 2 , between 10 and 100 mg active agent / m 2 , between 5 and 50 mg active agent / m 2 , between 5 and 40 mg active agent / m 2 , between 5 and 30 mg active agent / m 2 , between 5 and 25 mg active agent / m 2 , between 5 and 20 mg active agent / m 2 , between 10 and 50 mg active agent / m 2 , between 20 and 40 mg active agent / m 2 , between 15 and 35 mg active agent / m 2 , between 10 and 20 mg active agent / m 2 , between 20 and 30 mg active agent / m 2 , between 20 and 50 mg active agent / m 2 , between 25 and 50 mg active agent / m 2 , between 30 and 40 mg active agent / m 2 , between 25 and 35 mg active agent / m 2, between 50 and 100 mg active agent / m 2 , between 50 and 75 mg active agent / m 2 , or between 75 and 100 mg active agent / m 2 Cabazitaxel is suitable for 20-25mg / m 2 , and similar or slightly higher doses of the active agent have been shown to be effective with dendrimers in the comparative mouse studies below. A dose of 10 mg / kg of the active agent in mice should be approximately equivalent to 30 mg / m 2 Human dose (FDA Guidance 2005). (To convert human mg / kg doses to mg / m 2 , this number can be multiplied by 37, FDA Guidance 2005).

[0303] In some embodiments, the amount of dendrimer administered delivers an amount of cabazitaxel to the patient of 20-25 mg / m 2 In some embodiments, the amount of dendrimer administered delivers to the patient an amount of cabazitaxel that is 0.5 to 3 times the amount of free cabazitaxel delivered when 20-25 mg / m 2 In some embodiments, the amount of dendrimer administered delivers to the patient an amount of cabazitaxel that is 1 to 2 times the amount of free cabazitaxel delivered when 20-25 mg / m 2 In some embodiments, the amount of dendrimer administered delivers to the patient an amount of cabazitaxel that is 0.5 to less than 3 times the amount of free cabazitaxel delivered when 20-25 mg / m 2 In some embodiments, the amount of dendrimer administered delivers to the patient an amount of cabazitaxel that is 0.5 to 1.5 times the amount of free cabazitaxel delivered when 20-25 mg / m 2 The amount of dendrimer administered delivers to the patient an amount of cabazitaxel that is 0.8 to 1.2 times the amount of free cabazitaxel delivered when administered. ) is substantially equal to the amount of cabazitaxel delivered when administered. For example, as described above, the recommended dose level of cabazitaxel is 20-25 mg / m 2 In some embodiments, the amount of dendrimer administered can be substantially equivalent to administering 20-25 mg / m 2 The amount of free cabazitaxel delivered to the patient. The amount of dendrimer administered can be determined, for example, with reference to the amount of cabazitaxel that the dendrimer is capable of delivering (ie, the cabazitaxel loading).

[0304] In some embodiments, a therapeutically effective amount of a dendrimer is administered to a subject in need thereof at a predetermined frequency. In some embodiments, a dendrimer is administered to a subject in need thereof according to a dosing regimen in which the dendrimer is administered once every one to four weeks. In some embodiments, a dendrimer is administered to a subject in need thereof according to a dosing regimen in which the dendrimer is administered once every three to four weeks.

[0305] In some embodiments, the dendrimer or pharmaceutical composition is administered as a rapid infusion or as a bolus. In some embodiments, the infusion time is within a period of less than 1 hour, less than 30 minutes, or less than 20 minutes, for example, it can be administered within a period of about 20 minutes, 15 minutes, or 10 minutes. In some embodiments, the administration can be a bolus, for example, it can be administered within a period of time suitable for a bolus injection, such as a period of up to about 5 minutes, such as within the range of 5 seconds to 5 minutes.

[0306] It has surprisingly been found that the dendrimers of the present invention have increased efficacy compared to direct administration of the free drug.

[0307] The equivalent dose of free cabazitaxel is the equivalent amount of cabazitaxel contained (loaded) in the dendrimer to be administered.

[0308] As used herein, the term "free" refers to the drug, i.e., cabazitaxel, which has not been previously conjugated to a dendrimer. For example, direct administration of free cabazitaxel refers to direct administration of the cabazitaxel molecule that is administered without being conjugated to a dendrimer. An example of such a therapy is As used herein, the terms "unconjugated" and "released" refer to the drug, i.e., cabazitaxel, which has dissociated or cleaved from the dendrimer. Such dissociation or cleavage may occur in vivo following administration of the drug-dendrimer conjugate.

[0309] In some embodiments, administration of the dendrimer provides therapeutically effective plasma concentrations of cabazitaxel for a longer period of time compared to administration of an equivalent dose of free cabazitaxel.

[0310] In some embodiments, 20 or 25 mg / m 2 Administration of a course of the dendrimer provided enhanced clinical efficacy compared to cabazitaxel.

[0311] In some embodiments, in at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% of a patient population, administration of a dendrimer provides:

[0312] Reduce or eliminate cancer-related symptoms;

[0313] Reduce the size of cancerous tissue,

[0314] Increase progression-free survival, and / or

[0315] Slow down or prevent metastasis.

[0316] Oncology drugs often have significant side effects, which are attributed to off-target toxicities such as hematotoxicity, neurotoxicity, cardiotoxicity, hepatotoxicity, nephrotoxicity, ototoxicity, and cerebrotoxicity. For example, taxanes such as cabazitaxel can cause the following side effects: infection, neutropenia, anemia, febrile neutropenia, hypersensitivity reactions, thrombocytopenia, myelotoxicity, myelosuppression, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, fatigue, nonspecific neurocognitive problems, vertigo, encephalopathy, mucositis, alopecia, skin reactions, and myalgia.

[0317] In some embodiments, administration of a dendrimer provides reduced toxicity compared to administration of an equivalent dose of free cabazitaxel. The toxicity of a drug refers to the degree of damage caused to an organism and is measured by its effect on the target. In oncology, one such measure of toxicity in animal models is weight loss, which determines the maximum tolerated dose (MTD). In humans, toxicity is typically determined by specific adverse events (AE events), which typically include dose-limiting toxicities. It should be understood that, typically in oncology, there is a narrow therapeutic window and off-target toxicity is considered a normal side effect of killing tumor cells.

[0318] In some embodiments, administration of the dendrimer provides reduced toxicity compared to administration of an equivalent dose of free cabazitaxel when used in a method of treating cancer, e.g., in the treatment of cancers such as breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer, e.g., hormone-refractory prostate cancer, metastatic castration-resistant prostate cancer (mCRPC).

[0319] In some embodiments, 20 or 25 mg / m 2 Administration of dendrimers provided reduced toxicity compared to cabazitaxel.

[0320] In some embodiments, when used in a method of treating cancer, for example, in a cancer such as breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer, for example, hormone-refractory prostate cancer, metastatic castration-resistant prostate cancer (mCRPC), the dosage is comparable to that of 20 or 25 mg / m 2 Administration of dendrimers provided reduced toxicity compared to cabazitaxel.

[0321] In some embodiments, 20 or 25 mg / m 2 Compared with cabazitaxel, the course of treatment with dendrimers provided reduced toxicity.

[0322] In some embodiments, administration of a course of dendrimers provides reduced toxicity in at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% of a patient population.

[0323] Toxicology studies performed with the dendrimers of the invention indicate that the dendrimers may induce less neutropenia and therefore be less clinically toxic compared to administration of an equivalent dose of free cabazitaxel.

[0324] Thus, in some embodiments, administration of a dendrimer provides reduced bone marrow toxicity, e.g., in the form of reduced neutropenia, lymphopenia, anemia, and / or thrombocytopenia, compared to administration of an equivalent dose of free cabazitaxel. In some embodiments, administration of a dendrimer reduces neutropenia compared to administration of an equivalent dose of free cabazitaxel.

[0325] In some embodiments, 20 or 25 mg / m 2 Compared to cabazitaxel, treatment courses with dendrimers provided reduced neutropenia, lymphopenia, anemia, and / or thrombocytopenia.

[0326] In some embodiments, when used in a method of treating cancer, administration of the dendrimer provides reduced bone marrow toxicity, e.g., in the form of reduced neutropenia, lymphopenia, anemia, and / or thrombocytopenia, compared to administration of an equivalent dose of free cabazitaxel. In some embodiments, when used in a method of treating cancer, e.g., when used in a cancer, such as breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer, e.g., hormone-refractory prostate cancer, metastatic castration-resistant prostate cancer (mCRPC), administration of the dendrimer provides reduced neutropenia compared to administration of an equivalent dose of free cabazitaxel. In some embodiments, when used in a method of treating cancer, e.g., when used in a cancer, such as breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer, e.g., hormone-refractory prostate cancer, metastatic castration-resistant prostate cancer (mCRPC), administration of the dendrimer provides reduced neutropenia compared to administration of an equivalent dose of free cabazitaxel. 2 Administration of one course of dendrimers provided reduced neutropenia compared to cabazitaxel.

[0327] In some embodiments, the dendrimers provide at least a 10%, at least a 20%, at least a 30%, at least a 40%, at least a 50%, at least a 60%, at least a 70%, at least a 80%, or at least a 90% reduction in toxicity as measured by a specific AE, such as infections (cystitis, upper respiratory tract, herpes zoster, candidiasis, sepsis, influenza, UTI), fever, neutropenia, anemia, febrile neutropenia, thrombocytopenia, leukopenia, myelotoxicity, myelosuppression, neuropathy, hypersensitivity reactions, dysgeusia, gastrointestinal toxicity, dyspnea, cough, abdominal pain, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, fatigue, non-specific neurocognitive problems, headache, dizziness, back pain, arthralgia, encephalopathy, mucositis, alopecia, skin reactions, and myalgia, compared to directly administering an equivalent dose of the free pharmaceutically active agent. In one embodiment, administration of the dendrimer provides less than 95%, less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, or less than 10% toxicity compared to direct administration of an equivalent dose of free cabazitaxel.

[0328] The dendrimers of the present invention surprisingly achieve a sustained pharmacokinetic profile for unconjugated or released drugs. This sustained pharmacokinetic profile indicates that the drug will be present in vivo at therapeutically effective levels for a longer period of time. It should be understood that longer exposure to the drug is desirable because it can prolong the therapeutic effect of the drug and allow for reduced dosing frequency. In some embodiments, administration of the dendrimer provides a therapeutically effective plasma concentration of cabazitaxel for a longer period of time compared to administration of an equivalent dose of free cabazitaxel.

[0329] In addition to having a sustained in vivo pharmacokinetic profile providing relatively prolonged therapeutic levels of exposure, dendrimers also achieve relatively low Cmax levels when administered in vivo.

[0330] In some embodiments, administration of dendrimers provides a lower maximum concentration (Cmax) of unconjugated / released drug compared to direct administration of an equal dose of free drug. The maximum concentration (Cmax) of a drug is the maximum (or peak) serum concentration of the drug reached in a specified compartment or test area of ​​the body after the drug has been administered and before a second dose is administered. It should be understood that while it is important to be able to administer an agent at a level sufficient to achieve therapeutic concentration levels, if the maximum concentration level achieved is high, the risk of encountering certain off-target effects, side effects, and increased toxicity will increase. This is particularly a problem for compounds with short half-lives, because in these cases, in order to provide therapeutically effective levels of the active agent over an extended period of time, it may be necessary to increase the dose and therefore increase the Cmax, increasing the likelihood of side effects. Therefore, it is highly desirable to be able to deliver a pharmaceutical active agent in a form that provides a therapeutically effective level for a sustained period of time while avoiding administration at a level that achieves a very high maximum concentration (Cmax) in the body.

[0331] In some embodiments, the dendrimer has a lower maximum concentration (Cmax) of unconjugated / released cabazitaxel compared to directly administering an equivalent dose of free cabazitaxel. In some embodiments, when used, for example, in a method of treating cancer, such as breast cancer, ovarian cancer, pancreatic cancer or prostate cancer, such as hormone-refractory prostate cancer, metastatic castration-resistant prostate cancer, the dendrimer has a lower maximum concentration (Cmax) of released / unconjugated cabazitaxel compared to directly administering an equivalent dose of free cabazitaxel.

[0332] In some embodiments, direct administration of 20 or 25 mg / m 2 In some embodiments, when used, for example, in a method of treating cancer, such as breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer, such as hormone-refractory prostate cancer, metastatic castration-resistant prostate cancer (mCRPC), the dendrimer has a lower maximum concentration (Cmax) of unconjugated / released cabazitaxel compared to directly administering 20 or 25 mg / m 2 Compared with the free cabazitaxel at 1:1 dose, the dendrimers had a lower maximum concentration (Cmax) of released / unconjugated cabazitaxel.

[0333] In some embodiments, administration of the dendrimer provides a maximum concentration (Cmax) of drug (i.e., released / unconjugated cabazitaxel) that is less than 90%, 50%, 40%, 30%, 20%, 10% or 5% of the Cmax produced by direct administration of an equivalent dose of free cabazitaxel.

[0334] In some embodiments, dendrimers are administered in an amount sufficient to provide a maximum concentration (Cmax) of unconjugated cabazitaxel of less than 800, less than 500, less than 200, less than 100, less than 50, less than 25, or less than 20 ng / mL. In some embodiments, the amount of dendrimer administered provides a maximum concentration (Cmax) of unconjugated / released cabazitaxel of about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 80, about 95, or about 100 ng / mL.

[0335] AUC is the area under the curve of drug concentration in plasma versus time. AUC represents total drug exposure over time. It should be understood that AUC is generally proportional to the total amount of drug delivered to the body.

[0336] It is understood that following administration of the dendrimer, and when some cabazitaxel is released from the dendrimer, there will be unbound cabazitaxel and cabazitaxel still bound to the dendrimer in vivo.

[0337] In some embodiments, administration of a dendrimer provides a greater AUC of total cabazitaxel (ie, dendrimer-bound cabazitaxel and released cabazitaxel) compared to direct administration of an equal dose of free cabazitaxel.

[0338] In some embodiments, when used, for example, in a method of treating cancer, such as breast cancer, ovarian cancer, pancreatic cancer or prostate cancer, e.g., hormone-refractory prostate cancer, metastatic castration-resistant prostate cancer, administration of a dendrimer provides a greater AUC of total cabazitaxel (i.e., both dendrimer-bound cabazitaxel and released cabazitaxel) compared to direct administration of an equal dose of free cabazitaxel. In some embodiments, administration of a dendrimer provides at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, or at least 5-fold greater AUC of total cabazitaxel (i.e., dendrimer-bound cabazitaxel and released cabazitaxel) compared to direct administration of an equal dose of free cabazitaxel.

[0339] In some embodiments, when used, for example, in a method of treating cancer, such as breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer, such as hormone-refractory prostate cancer, metastatic castration-resistant prostate cancer (mCRPC), the amount of the drug administered is comparable to that of the drug administered directly at 20 or 25 mg / m 2 Administration of dendrimers provides greater AUC of total cabazitaxel (i.e., both dendrimer-bound cabazitaxel and released cabazitaxel) compared to direct administration of 20 or 25 mg / m 2Administration of the dendrimer provides at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, or at least 5-fold greater AUC of total cabazitaxel (i.e., dendrimer-bound cabazitaxel and released cabazitaxel) compared to a 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, or at least 5-fold greater dose of free cabazitaxel.

[0340] In some embodiments, the dendrimer is administered in an amount that provides an AUC of total cabazitaxel (i.e., both dendrimer-bound cabazitaxel and released cabazitaxel) of at least 100,000, at least 110,000, at least 120,000, at least 130,000, at least 140,000, at least 150,000, at least 160,000, at least 170,000, at least 180,000, at least 190,000, or at least 200,000 ng.h / mL. In some embodiments, the dendrimer is administered in an amount that provides an AUC of total cabazitaxel (i.e., both dendrimer-bound cabazitaxel and released cabazitaxel) of about 150,000, about 160,000, about 170,000, about 180,000, about 190,000, about 200,000, about 210,000, about 220,000, or about 230,000 ng.h / mL.

[0341] In some embodiments, administration of the dendrimer provides an equal or greater AUC of unconjugated / released cabazitaxel compared to direct administration of an equal dose of free cabazitaxel.

[0342] In some embodiments, administration of a dendrimer provides at least 1.1 fold, at least 1.2 fold, at least 1.3 fold, at least 1.4 fold, at least 1.5 fold, at least 1.6 fold, at least 1.7 fold, at least 1.8 fold, at least 1.9 fold, at least 2 fold, at least 2.5 fold, at least 3 fold, at least 3.5 fold, or at least 4 fold higher AUC of unconjugated / released cabazitaxel compared to direct administration of an equivalent dose of free cabazitaxel.

[0343] In some embodiments, administration of the dendrimer provides 0.8-fold to 1.2-fold higher AUC of unconjugated / released cabazitaxel compared to direct administration of an equal dose of free cabazitaxel.

[0344] In some embodiments, when used, for example, in a method of treating cancer, such as breast cancer, ovarian cancer, pancreatic cancer or prostate cancer, e.g., hormone-refractory prostate cancer, metastatic castration-resistant prostate cancer (mCRPC), administration of the dendrimer provides an equal or greater AUC of unconjugated / released cabazitaxel compared to direct administration of an equal dose of free cabazitaxel.

[0345] In some embodiments, direct administration of 20 or 25 mg / m 2Administration of dendrimers provided equal or greater AUC of unconjugated / released cabazitaxel compared to the 1:1 dose of cabazitaxel.

[0346] In some embodiments, direct administration of 20 or 25 mg / m 2 Administration of the dendrimer provides at least 1.1-fold, at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5-fold, at least 1.6-fold, at least 1.7-fold, at least 1.8-fold, at least 1.9-fold, at least 2-fold, at least 2.5-fold, at least 3-fold, at least 3.5-fold, or at least 4-fold higher AUC of unconjugated / released cabazitaxel compared to a 1:1 dose of cabazitaxel.

[0347] In some embodiments, 20 or 25 mg / m 2 Administration of dendrimers provided 0.8- to 1.2-fold higher AUC of unconjugated / released cabazitaxel compared to the 1:1 dose of cabazitaxel.

[0348] In some embodiments, when used, for example, in a method of treating cancer, such as breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer, such as hormone-refractory prostate cancer, metastatic castration-resistant prostate cancer (mCRPC), 20 or 25 mg / m is administered directly. 2 Administration of dendrimers provided equal or greater AUC of unconjugated / released cabazitaxel compared to the 1:1 dose of cabazitaxel.

[0349] In some embodiments, the dendrimer is administered in an amount to provide an AUC of at least 500, at least 600, at least 700, at least 800, at least 900, at least 1000, at least 1100, at least 1200, at least 1300, at least 1400, at least 1500, at least 1750, at least 2000, at least 2500, at least 3000, at least 3500, or at least 4000 ng.h / mL released / unconjugated cabazitaxel.

[0350] In some embodiments, the dendrimer is administered in an amount that provides an AUC of about 500, about 600, about 700, about 800, about 900, about 1000, about 1100, about 1200, about 1300, about 1400, about 1500, about 1600, about 1700, about 1800, about 2000, about 2500, about 3000, about 3500, or about 4000 g.h / mL released / unconjugated cabazitaxel.

[0351] Free cabazitaxel is characterized by a three-phase elimination profile with an initial phase half-life averaging 4 minutes, followed by an intermediate phase half-life of 2 hours, and an extended terminal phase half-life averaging 95 hours. In some embodiments, administration of the dendrimer provides a terminal phase half-life (t of unconjugated / released cabazitaxel of at least 12 hours, at least 24 hours, at least 30 hours, at least 40 hours, at least 48 hours, at least 50 hours, or at least 75 hours. 1 / 2 ).

[0352] It should be understood that any one or more of the above pharmacokinetic properties may provide better clinical efficacy compared to direct administration of the free drug. In some embodiments, administration of the dendrimer provides better drug efficacy compared to direct administration of an equal dose of the free drug. In some embodiments, the dendrimer provides improved efficacy properties selected from progression-free survival, time to progression, objective response rate (PR+CR), overall response rate, overall survival, and duration of response compared to direct administration of an equal dose of free cabazitaxel.

[0353] Dendrimer Synthesis

[0354] The dendrimers of the invention may be prepared by any suitable method, for example by reacting a precursor containing cabazitaxel with a dendritic intermediate already containing a PEG group to introduce the pharmaceutically active agent, by reacting a precursor containing PEG with a dendritic intermediate already containing a cabazitaxel residue, or by reacting an intermediate containing a residue of a lysine group, a cabazitaxel residue with a PEG group having a dendrimer intermediate. Thus, in a fifth aspect, there is provided a method for producing a dendrimer as defined herein, comprising:

[0355] a) reacting a cabazitaxel intermediate with a dendrimer intermediate or a salt thereof under amide coupling conditions,

[0356] The cabazitaxel intermediate is:

[0357]

[0358] wherein X is -OH or a leaving group, or wherein X together with the C(O) group to which it is attached forms a carboxylic acid;

[0359] The dendrimer intermediate comprises:

[0360] i) a core unit (C); and

[0361] ii) building units (BU), each building unit being a lysine residue or an analog thereof;

[0362] wherein the core unit is covalently linked to two building blocks via amide bonds, each amide bond being formed between a nitrogen atom present in the core unit and a carbon atom of an acyl group present in a building block;

[0363] The dendrimer is a five-generation building block dendrimer;

[0364] wherein the building blocks of different generations are covalently linked to each other via an amide bond formed between a nitrogen atom present in one building block and a carbon atom of an acyl group present in another building block;

[0365] The dendrimer further comprises:

[0366] a plurality of second terminal groups (T2), each second terminal group comprising a PEG group;

[0367] wherein at least one third of the nitrogen atoms present in the outer building blocks are each covalently attached to a second terminal group;

[0368] and wherein at least one third of the nitrogen atoms present in said outer building block are unsubstituted and available for reaction with said first intermediate;

[0369] or

[0370] b) reacting the PEG intermediate with the dendrimer intermediate or a salt thereof under amide coupling conditions,

[0371] The PEG intermediate is:

[0372]

[0373] wherein the PEG group is a PEG-containing group, and

[0374] X is -OH or a leaving group, and X and the C(O) group to which it is attached together form a carboxylate;

[0375] The dendrimer intermediate comprises:

[0376] i) a core unit (C); and

[0377] ii) building units (BU), each building unit being a lysine residue or an analog thereof;

[0378] wherein the core unit is covalently linked to two building blocks via amide bonds, each amide bond being formed between a nitrogen atom present in the core unit and a carbon atom of an acyl group present in a building block;

[0379] The dendrimer is a five-generation building block dendrimer;

[0380] wherein the building blocks of different generations are covalently linked to each other via an amide bond formed between a nitrogen atom present in one building block and a carbon atom of an acyl group present in another building block;

[0381] The dendrimer further comprises:

[0382] a plurality of first terminal groups (T1), each first terminal group (T1) comprising a cabazitaxel residue covalently linked to a diethylene glycol-based linker;

[0383] wherein at least one third of the nitrogen atoms present in the outer building blocks are each covalently attached to a first terminal group;

[0384] and wherein at least one third of the nitrogen atoms present in said outer building blocks are unsubstituted

[0385] or

[0386] c) reacting the surface unit intermediate with the dendrimer intermediate or a salt thereof under amide coupling conditions,

[0387] The surface unit intermediate is:

[0388]

[0389] wherein the PEG group is a PEG-containing group, and

[0390] X is -OH or a leaving group, and X and the C(O) group to which it is attached together form a carboxylate;

[0391] The dendrimer intermediate comprises:

[0392] i) a core unit (C); and

[0393] ii) building units (BU), each building unit being a lysine residue or an analog thereof;

[0394] wherein the core unit is covalently linked to two building blocks via amide bonds, each amide bond being formed between a nitrogen atom present in the core unit and a carbon atom of an acyl group present in a building block;

[0395] The dendrimer intermediate is a fourth generation building block dendrimer intermediate;

[0396] wherein the building blocks of different generations are covalently linked to each other via an amide bond formed between a nitrogen atom present in one building block and a carbon atom of an acyl group present in another building block;

[0397] and wherein the nitrogen atoms present in said outer building blocks of said dendrimer intermediate are unsubstituted.

[0398] Process variants a), b) and c) involve the formation of an amide bond by reaction of a -C(O)X group with an amine group present in the dendritic intermediate. Any suitable amide forming conditions may be used. Examples of typical conditions include the use of a suitable solvent (e.g. dimethylformamide), optionally a suitable base, and at a suitable temperature (e.g. ambient temperature, e.g. in the range of 15 to 30°C). Where X is a leaving group, any suitable leaving group may be used, e.g. an activated ester. Where X is a -OH group or where X forms a carboxylate together with the C(O) group to which it is attached, e.g. by using a suitable amide coupling agent, such as PyBOP, which group is typically converted to a suitable leaving group prior to reaction with the dendritic intermediate.

[0399] Any suitable separation and / or purification technique may be used, for example the dendrimer may be obtained by dissolution in a suitable solvent (eg THF) and precipitation by addition of an anti-solvent (eg MTBE).

[0400] The cabazitaxel intermediate for variant a) itself can be obtained, for example, by reacting cabazitaxel with diglycolic anhydride, for example in the presence of a suitable solvent such as dichloromethane and a suitable base such as triethylamine.

[0401] The surface unit intermediate used in variant c) can itself be obtained, for example, by the following steps:

[0402] i) reacting a PEG intermediate, wherein the PEG intermediate is:

[0403]

[0404] wherein the PEG group is a PEG-containing group, and

[0405] X is -OH or a leaving group, and X and the C(O) group to which it is attached together form a carboxylate;

[0406] and

[0407]

[0408] wherein PG1 is an amine protecting group (such as a Boc or Cbz group), and PG2 is an acid protecting group (such as a methyl ester or a benzyl ester);

[0409] ii) deprotecting PG1;

[0410] iii) reacting the product of step ii) with a cabazitaxel intermediate, said intermediate being:

[0411]

[0412] wherein X is -OH or a leaving group, or wherein X together with the C(O) group to which it is attached forms a carboxylic acid; and

[0413] iv) Deprotecting PG2.

[0414] The dendrimer intermediate used in variant a) can itself be obtained, for example, by a continuous process comprising the following steps:

[0415] i) reacting a core unit (C) containing an amino group with a building block, which is a protected lysine or an analog thereof, containing a -C(O)X group, wherein X is -OH or a leaving group or -C(O)X forms a carboxylate, and wherein the amino group present in the lysine or an analog thereof is protected, to form an amide bond between the core unit and the building block;

[0416] ii) deprotecting the protecting groups present on the building blocks;

[0417] iii) reacting a free amino group present on a building block with another building block, which is a protected lysine or an analog thereof, containing a -C(O)X group, wherein X is -OH or a leaving group or -C(O)X forms a carboxylate, and wherein the amino group present in lysine or an analog thereof is protected, to form an amide bond between building blocks of different generations;

[0418] iv) deprotecting the protecting groups present on the building blocks;

[0419] v) repeating steps iii) and iv) until four generations of building blocks are produced;

[0420] vi) reacting a free amino group present on a building block with, to form an amide bond therebetween,

[0421]

[0422] wherein PG is a protecting group, and wherein X is -OH or a leaving group, or wherein X together with the C(O) group to which it is attached forms a carboxylate; and

[0423] vii) Deprotecting the protecting group PG.

[0424] Alternatively, the dendrimer intermediate used in variant a) may be obtained, for example, by carrying out steps i) to v) as described above, and:

[0425] vi) reacting a free amino group present on a building block with another building block, which is a protected lysine or an analog thereof, containing a -C(O)X group, wherein X is -OH or a leaving group or -C(O)X forms a carboxylate, and wherein the amino group present in the lysine or an analog thereof is orthogonally protected, to form an amide bond between building blocks of different generations;

[0426] vii) deprotecting the first set of amino protecting groups;

[0427] viii) reacting a free amino group present on a building block with, to form an amide bond therebetween,

[0428]

[0429] wherein the PEG group is a PEG-containing group, and X is -OH or a leaving group, or wherein X together with the C(O) group to which it is attached forms a carboxylate;

[0430] vii) deprotecting the second set of amino protecting groups.

[0431] The dendrimer intermediate used in variant b) can itself be obtained, for example, by carrying out steps i) to v) as described above for variant a), and:

[0432] vi) reacting a free amino group present on a building block with, to form an amide bond therebetween,

[0433]

[0434] wherein PG is a protecting group, and wherein X is -OH or a leaving group, or wherein X together with the C(O) group to which it is attached forms a carboxylate; and

[0435] vii) Deprotecting the protecting group PG.

[0436] Alternatively, the dendrimer intermediate used in variant b) may be obtained, for example, by carrying out steps i) to v) as described above, and:

[0437] vi) reacting a free amino group present on a building block with another building block, which is a protected lysine or an analog thereof, containing a -C(O)X group, wherein X is -OH or a leaving group or -C(O)X forms a carboxylate, and wherein the amino group present in the lysine or an analog thereof is orthogonally protected, to form an amide bond between building blocks of different generations;

[0438] vii) deprotecting the first set of amino protecting groups;

[0439] viii) reacting a free amino group present on a building block with, to form an amide bond therebetween,

[0440]

[0441] wherein X is -OH or a leaving group, or wherein X together with the C(O) group to which it is attached forms a carboxylic acid;

[0442] vii) deprotecting the second set of amino protecting groups.

[0443] The dendrimer intermediate used in variant c) can itself be obtained, for example, by carrying out steps i) to v) as described above in relation to variant a).

[0444] The present invention also provides a synthetic intermediate for preparing dendrimers. Therefore, the present invention also provides an intermediate for preparing dendrimers, which is

[0445]

[0446] wherein X is -OH or a leaving group, or wherein X together with the C(O) group to which it is attached forms a carboxylate. Such intermediates can be prepared, for example, as described above.

[0447] Also provided are intermediates for producing dendrimers, which are

[0448]

[0449] wherein the PEG group is a PEG-containing group, and

[0450] X is -OH or a leaving group, X together with the C(O) group to which it is attached forms a carboxylate. Such intermediates can be prepared, for example, as described above.

[0451] The invention will now be described with reference to the following examples which illustrate some specific aspects of the invention. However, it should be understood that the particularity of the following description of the invention does not supersede the generality of the preceding description of the invention.

[0452] Example

[0453] Example 1: BHALys[Lys] 32 [α-NH2TFA] 32 [ε-PEG~2100] Synthesis and characterization of

[0454] The dendrimers represented in the following examples include cores and building blocks that are involved in the outermost generation of the dendrimer. Subsurface generations are not described. Dendrimer BHALys[Lys] 32Representative has the formula BHALys[Lys]2[Lys]4[Lys]8[Lys] 16 [Lys] 32 5 generations of dendrimers.

[0455] Involving available PEG ～2100 The theoretical number of ε surface amino groups on substituted dendrimers is given by 1 H NMR experimentally determined the attachment to BHALys[Lys] 32 PEG ～2100 The actual average number of groups (see the following section of this Example, entitled BHALys[Lys] 32 [α-NH2-TFA] 32 [ε-PEG ～2100 ] of characterization).

[0456] BHALys[Boc]2

[0457] Solid α, ε-(t-Boc) 2-(L)-lysine p-nitrophenolate (2.787 kg, 5.96 mol) was added to aminodiphenylmethane (benzylamine) (0.99 kg, 5.4 mol) in anhydrous acetonitrile (4.0 L) solution, DMF (1.0 L) and triethylamine (1.09 kg) for 15 min. The reaction mixture was stirred overnight at 20 ° C. The reaction mixture was then warmed to 35 ° C, and an aqueous sodium hydroxide solution (0.5 N, 10 L) was slowly added within 30 min. The mixture was stirred for another 30 min and then filtered. The solid filter cake was washed with water and dried to constant weight (2.76 kg, 5.4 mol), with a yield of 100%. 1 H NMR (CD3OD) δ7.3 (m, 10H, Ph calculated for 10H); 6.2 (s, 1H, CH-Ph2 calculated for 1H); 4.08 (m, α-CH, 1H), 3.18 (br, ε-CH2) and 2.99 (m, ε-CH22H); 1.7-1.2 (br, β, γ, δ-CH2) and 1.43 (s, tBu) β, γ, δ-CH2 and tBu, total 25H calculated for 24H. MS (ESI+ve) found 534.2 [M+Na] + , calculate the value C 29 H 41 N3O5Na[M+Na] + 534.7.

[0458] BHALys[HCl]2

[0459] A solution of concentrated HCl (1.5 L) in methanol (1.5 L) was slowly added to a stirred suspension of BHALys[Boc]2 (780.5 g, 1.52 mol) in methanol (1.5 L) in three portions at a rate that minimized excessive foaming. The reaction mixture was stirred for another 30 min and then concentrated under vacuum at 35 ° C. The residue was dissolved in water (3.4 L) and concentrated twice under vacuum at 35 ° C. and then stored under vacuum overnight. Acetonitrile (3.4 L) was then added, and the residue was concentrated under vacuum at 35 ° C. again to obtain BHALys[HCl]2 as a white solid (586 g, 1.52 mol), 100% yield. 1 H NMR (D2O) δ7.23 (br m, 10H, Ph calculated for 10H); 5.99 (s, 1H, CH-Ph2 calculated for 1H); 3.92 (t, J = 6.5 Hz, α-CH, 1H, calculated for 1H); 2.71 (t, J = 7.8 Hz, ε-CH2, 2H, calculated for 2H); 1.78 (m, β, γ, δ-CH2, 2H), 1.47 (m, β, γ, δ-CH2, 2H), and 1.17 (m, β, γ, δ-CH2, 2H, total 6H calculated for 6H). MS (ESI+ve) found 312 [M+H] + , calculate the value C 19 H 26 N3O[M+H] + 312.

[0460] BHALys[Lys]2[Boc]4

[0461] Triethylamine (1.08 kg) was slowly added to a suspension of BHALys[HCl]2 (586 g, 1.52 mmol) in anhydrous DMF (3.8 L) to maintain the reaction temperature below 30 ° C. Solid α, ε-(t-Boc)2-(L)-lysine p-nitrophenolate (1.49 kg) was slowly added in three portions, stirring for 2 hours between additions. The reaction was stirred overnight. Sodium hydroxide aqueous solution (0.5 M, 17 L) was slowly added to the well-stirred mixture, and stirring was maintained until the solid precipitate moved freely. The precipitate was collected by filtration, and the solid filter cake was washed with water (2×4 L) and then with acetone / water (1:4, 2×4 L). The solid was slurried with water again, then filtered and dried under vacuum overnight to obtain BHALys[Lys]2[Boc]4 (1.51 kg) in 100% yield. 1H NMR (CD3OD) δ7.3 (m, 10H, Ph calculated 10H); 6.2 (s, 1H, CH-Ph2 calculated 1H); 4.21 (m, α-CH), 4.02 (m, α-CH) and 3.93 (m, α-CH, 3H in total, calculated 3H); 3.15 (m, ε-CH2) and 3.00 (m, ε-CH2 6H in total, calculated 6H); 1.7-1.3 (br, β, γ, δ-CH2) and 1.43 (s, tBu) β, γ, δ-CH2 and tBu 57H in total, calculated 54H. MS (ESI+ve) found 868.6 [M-Boc] + ; 990.7[M+Na] + , calculate the value C 51 H 81 N7O 11 Na[M+Na] + 991.1.

[0462] BHALys[Lys]2[HCl]4

[0463] BHALys[Lys]2[Boc]4 (1.41 kg, 1.46 mol) was suspended in methanol (1.7 L) under stirring at 35°C. Hydrochloric acid (1.7 L) was mixed with methanol (1.7 L) and the resulting solution was added to the dendrimer suspension in four portions and stirred for 30 minutes. The solvent was removed under reduced pressure and treated with two consecutive strips of water (3.5 L) followed by two consecutive strips of acetonitrile (4 L) to give BHALys[Lys]2[HCl]4 (1.05 Kg, 1.46 mmol) in 102% yield. 1 H NMR (D2O) δ7.4 (br m, 10H, Ph calculated for 10H); 6.14 (s, 1H, CH-Ph2 calculated for 1H); 4.47 (t, J = 7.5 Hz, α-CH, 1H), 4.04 (t, J = 6.5 Hz, α-CH, 1H), 3.91 (t, J = 6.8 Hz, α-CH, 1H, total 3H, calculated for 3H); 3.21 (t, J = 7.4 Hz, ε-CH2, 2H) , 3.01 (t, J = 7.8 Hz, ε-CH2, 2H) and 2.74 (t, J = 7.8 Hz, ε-CH2, 2H, 6H in total, calculated 6H); 1.88 (m, β, γ, δ-CH2), 1.71 (m, β, γ, δ-CH2), 1.57 (m, β, γ, δ-CH2) and 1.35 (m, β, γ, δ-CH2, 19H in total, calculated 18H).

[0464] BHALys[Lys]4[Boc]8

[0465] BHALys[Lys]2[HCl]4 (1.05 Kg, 1.47 mol) was dissolved in DMF (5.6 L) and triethylamine (2.19 L). α,ε-(t-Boc)2-(L)-lysine p-nitrophenolate (2.35 kg, 5.03 mol) was added in three portions and the reaction was stirred overnight at 25 °C. NaOH (0.5 M, 22 L) solution was added, the resulting mixture was filtered, washed with water (42 L), and then air-dried. The solid was dried under vacuum at 45 °C to give BHALys[Lys]4[Boc]8 (2.09 kg, 1.11 mol) in 76% yield. 1 H NMR (CD3OD) δ7.3 (m, 10H, Ph calculated 10H); 6.2 (s, 1H, CH-Ph2 calculated 1H); 4.43 (m, α-CH), 4.34 (m, α-CH), 4.25 (m, α-CH) and 3.98 (br, α-CH, 7H in total, calculated 7H); 3.15 (br, ε-CH2) and 3.02 (br, ε-CH2 in total 14H, calculated 14H); 1.9-1.2 (br, β, γ, δ-CH2) and 1.44 (br s, tBu) β, γ, δ-CH2 and tBu in total 122H, calculated 144H.

[0466] BHALys[Lys]4[TFA]8

[0467] To a stirred suspension of BHALys[Lys]4[Boc]8 (4 g, 2.13 mmol) in DCM (18 mL) was added TFA (13 mL) at 0°C. The solid was dissolved and the solution was stirred overnight under an argon atmosphere. The solvent was removed in vacuo and residual TFA was removed by trituration with ether (100 mL). The product was redissolved in water and then freeze-dried to give BHALys[Lys]4[TFA]8 as an off-white solid (4.27 g, 2.14 mmol) in 101% yield. 1H NMR(D2O)δ7.21(br m, 10H, Ph calculated 10H); 5.91 (s, 1H, CH-Ph2 calculated 1H); 4.17 (t, J = 7.4Hz, α-CH, 1H), 4.09 (t, J = 7.1Hz, α-CH, 1H), 4. 02(t,J=7.2Hz,α-CH,1H,3.84(t,J=6.5Hz,α-CH,2H),3.73(t,J=6.7Hz,α-CH,1H),3.67(t,J=6.7Hz,α-CH , 1H, 7H in total, calculated 7H); 3.0 (m, ε-CH2), 2.93 (m, ε-CH2) and 2.79 (b, ε-CH2, 15H in total, calculated 14H); 1.7 (br, β, γ, δ-CH2), 1.5 (br, β, γ, δ-CH2), 1.57 (m, β, γ, δ-CH2) and 1.25 (br, β, γ, δ-CH2 45H in total, calculated 42H). MS (ESI+ve) found 541.4 [M+2H] 2+ ; Calculated value C 55 H 99 N 15 O7[M+2H] 2+ 541.2.

[0468] BHALys[Lys]8[Boc] 16

[0469] α,ε-(t-Boc)2-(L)-lysine p-nitrophenolate (1.89 g, 4.05 mmol) in DMF (25 mL) was added to a solution of BHALys[Lys]4[NH2TFA]8 (644 mg, 0.32 mmol) and triethylamine (0.72 mL, 5.2 mmol) in DMF (25 mL), and the reaction was stirred overnight under an argon atmosphere. The reaction mixture was poured onto ice / water (500 mL), then filtered and the collected solid was dried overnight under vacuum. The dried solid was thoroughly washed with acetonitrile to obtain BHALys[Lys]8[Boc] 16 , as an off-white solid (0.82 g, 0.22 mmol), 68% yield. 1H NMR (CD3OD) δ7.3 (m, 10H, Ph calculated 10H); 6.2 (br s, 1H, CH-Ph2 calculated 1H); 4.48 (br, α-CH), 4.30 (br, α-CH) and 4.05 (br, α-CH, total 16H calculated 15H); 3.18 (br, ε-CH2) and 3.02 (m, ε-CH2 total 31H, calculated 30H); 1.9-1.4 (br, β, γ, δ-CH2) and 1.47 (br s, tBu) β, γ, δ-CH2 and tBu total 240H, calculated 234H. MS (ESI+ve) found 3509 [M+H-(Boc)2] + , calculated value C 173 H 306 N 31 O 43 [M+H-(Boc)2] + 3508.5; 3408[M+H-(Boc)3] + , calculated value C 168 H 298 N 31 O 41 [M+H-(Boc)3] + 3408.4.

[0470] BHALys[Lys]8[TFA] 16

[0471] A solution of TFA / DCM (1:1, 19 mL) was slowly added to BHALys[Lys]8[Boc] 16 (800 mg, 0.22 mmol) was added to a stirred suspension in DCM (25 mL). The solid was dissolved and the solution was stirred overnight under an argon atmosphere. The solvent was removed under vacuum and the residual TFA was removed by repeated freeze drying of the residue to give BHALys[Lys]8[TFA] 16 , as off-white lyophilizate (848 mg, 0.22 mmol), 100% yield. 1H NMR (D2O) δ7.3 (br m, 10H, Ph calculated 10H); 6.08 (s, 1H, CH-Ph2 calculated 1H); 4.3 (m, α-CH), 4.18 (m, α-CH), 4.0 (m, α-CH) and 3.89 (m, α-CH, total 16H, calculated 15H); 3.18 (br, ε-CH2) and 2.94 (m, ε-CH2 total 32H, calculated 30H); 1.9 (m, β, γ, δ-CH2), 1.68 (m, β, γ, δ-CH2) and 1.4 (m, β, γ, δ-CH2 total 99H, calculated 90H). MS (ESI+ve) found 2106 [M+H] + , calculate the value C 103 H 194 N 31 O 15 [M+H] + 2106.9.

[0472] BHALys[Lys] 16 [Boc] 32

[0473] A solution of α,ε-(t-Boc)2-(L)-lysine p-nitrophenolate (1.89 g, 4.05 mmol) in DMF (25 mL) was added to BHALys[Lys]8[TFA] 16 (644 mg, 0.32 mmol) and triethylamine (0.72 mL, 5.2 mmol) in DMF (25 mL) and the reaction was stirred overnight under an argon atmosphere. The reaction was poured onto ice / water (500 mL) and then filtered and the collected solid was dried under vacuum overnight. The dried solid was washed thoroughly with acetonitrile to give BHALys[Lys] 16 [Boc] 32 , as an off-white solid (0.82 g, 0.22 mmol), 68% yield. 1 H NMR (CD3OD) δ7.28 (m, 9H, Ph calculated 10H); 6.2 (br s, 1H, CH-Ph2 calculated 1H); 4.53 (br, α-CH), 4.32 (br, α-CH) and 4.05 (br, α-CH, 35H in total, 31H calculated); 3.18 (br, ε-CH2) and 3.04 (m, ε-CH2 total 67H, 62H calculated); 1.9-1.5 (br, β, γ, δ-CH2) and 1.47 (br s, tBu) β, γ, δ-CH2 and tBu total 474H calculated, 474H. MS (ESI+ve) found 6963 [M+H-(Boc)4] + , calculated value C 339 H610 N 63 O 87 [M+H-(Boc)4] + 6960.9; 6862[M+H-(Boc)5] + , calculated value C 334 H 604 N 63 O 85 [M+H-(Boc)5] + 6860.8.

[0474] BHALys[Lys] 16 [TFA] 32

[0475] A solution of TFA / DCM (1:1, 19 mL) was slowly added to BHALys[Lys] 16 [Boc] 32 (800 mg, 0.11 mmol) was added to a stirred suspension in DCM (25 mL). The solid was dissolved and the solution was stirred overnight under an argon atmosphere. The solvent was removed under vacuum and the residual TFA was removed by repeated freeze drying of the residue to give BHALys[Lys] 16 [TFA] 32 , as off-white lyophilizate (847 mg, 0.11 mmol), 100% yield. 1 H NMR (D2O) δ7.3 (br m, 10H, Ph calculated 10H); 6.06 (s, 1H, CH-Ph2 calculated 1H); 4.3 (m, α-CH), 4.19 (m, α-CH), 4.0 (m, α-CH) and 3.88 (m, α-CH, total 35H, calculated 31H); 3.15 (br, ε-CH2) and 2.98 (m, ε-CH2 total 69H, calculated 62H); 1.88 (m, β, γ, δ-CH2), 1.7 (m, β, γ, δ-CH2) and 1.42 (m, β, γ, δ-CH2 total 215H, calculated 186H). MS (ESI+ve) found 4158 [M+H] + , calculate the value C 199 H 386 N 63 O 31 [M+H] + 4157.6

[0476] HO-Lys(α-BOC)(ε-PEG ～2100 )

[0477] DIPEA (0.37 mL, 2.10 mmol) was added to NHS-PEG ～2100(2.29 g, 1.05 mmol) (PEG ～2100 =( ... 2100 ). 1 H NMR (CD3OD) δ3.96-4.09(m,1H),3.34-3.87(m,188H);3.32(s,3H),3.15(q,J=6.0Hz,2H),2.40(t,J=6.2Hz,2H),1.28-1.88(m,6H),1.41(s,9H).

[0478] BHALys[Lys] 32 [α-BOC] 32 [ε-PEG ～2100 ]

[0479] To BHA Lys [Lys] 16 [TFA] 32 To a stirred mixture of PEG (0.19 g, 24 μmol) in DMF (20 mL) was added DIPEA (0.86 mL, 4.86 mmol). The mixture was then added dropwise to PyBOP (0.62 g, 1.20 mmol) and Lys(BOC) (PEG ～2100) (2.94 g, 1.20 mmol) in a stirred mixture of DMF (20 mL). The reaction mixture was stirred overnight and then diluted with water (200 mL). The aqueous mixture was centrifugally filtered (5K membrane, 20 L water). The retentate was freeze-dried to provide 1.27 g (73%) of the desired dendrimer. HPLC (C8 NMR (300MHz, D2O) δ (ppm): 1.10-2.10 (m, LysCH2 (β, χ, δ) and BOC, 666H), 3.02-3.36 (m, Lys CH2(ε),110H),3.40(s,PEG-OMe,98H),3.40-4.20(m,PEG-OCH2,5750H+Lys CH surface, 32H), 4.20-4.50 (m, Lys, CH internal 32H), 7.20-7.54 (m, BHA, 8H). 1 H NMR showed about 29 PEGs.

[0480] BHALys[Lys] 32 [α-NH2TFA] 32 [ε-PEG ～2100 ]

[0481] Add 1.27g (17.4μmol) BHALys[Lys] 32 [α-BOC] 32 [ε-PEG ～2100 ] 32 Stir overnight at room temperature in TFA / DCM (1:1, 20 mL). The volatiles were removed in vacuo and the residue was dissolved in water (30 mL). The mixture was then concentrated. The process was repeated two more times and then freeze-dried to provide 1.35 g (106%) of the desired product as a viscous colorless oil. HPLC (C8 XBridge, 3x 100 mm, gradient: 5% ACN (0-1 min), 5-80% ACN / H2O) (1-7 min), 80% ACN (7-12 min), 80-5% ACN (12-13 min), 5% ACN (13-15 min), 214 nm, 0.1% TFA) Rf (min) = 8.51. 1H-nmr ​​(300 MHz, D2O) δ (ppm): 1.22-2.08 (Lys CH2 ((β, χ, δ), 378H), 3.00-3.26 (LysCH2 (ε), 129H), 3.40 (PEG-OMe, 96H), 3.45-4.18 (PEG-OCH2, 5610H + Lys CH surface, 32H), 4.20-4.46 (Lys, CH interior, 33H), 7.24-7.48 (8H, BHA). 1 H NMR showed about 29 PEGs.

[0482] BHALys[Lys] 32 [α-NH2TFA] 32 [ε-PEG ～2100 ] Characterization

[0483] Table 1 shows the different batches of BHALys[Lys] synthesized. 32 [α-NH2TFA] 32 [ε-PEG ～2100 ] 32# The actual number of PEG chains on the dendrimer is also determined by 1 H NMR calculations.

[0484] Table 1. BHALys[Lys] from different batches 32 [α-NH2TFA] 32 [ε-PEG ～2100 ]

[0485]

[0486] *The amount of PEG was calculated from proton NMR. For batch 1: The amount of PEG = the number of protons in the PEG region of NMR (integrated) (3.4-4.2 ppm) / the average (mean) number of protons per PEG chain (CoA PEG / 44 Da x 4H)

[0487] =5706H / (2200 / 44×4)

[0488] =28.53 (about 29 PEG units)

[0489] **Molecular weight estimated by adding the MW of various components. For Batch 1:

[0490] Total MW = Mw of dendrimer + Mw of TFA + Mw of PEG

[0491] =BHALys[Lys] 32+32(TFA)+29(PEG)

[0492] =8,258+3,648+63800

[0493] =~75.7 kDa

[0494] Table 2. BHALys[Lys] from different batches 32 [α-NH2TFA] 32 [ε-PEG ～2100 ] of 1 H NMR data

[0495]

[0496] Example 2: Synthesis of Linker-Cabazitaxel, wherein the Linker is Diglycolic Acid (DGA) [DGA-Cabazitaxel]

[0497] To a solution of cabazitaxel (2.00 g, 2.39 mmol) in dichloromethane (30 mL, 15 vol) was added diglycolic anhydride (320.70 mg, 2.62 mmol, 1.1 eq, 95% purity). After stirring for 5 minutes, triethylamine (500 μL, 3.59 mmol, 1.5 eq) was added. The reaction mixture was stirred at room temperature for 1.5 h. LC-MS analysis (eluent: 40-80% acetonitrile in water, containing 0.1% 10 mM ammonium formate buffer) showed less than 1% of starting material. The reaction mixture was diluted with 30 mL of DCM and then washed twice with sodium chloride (5%) and sodium phosphate (1%) buffer at pH = 3 (30 mL). During the first wash, the pH rose to 6.0 and 1 M aqueous HCl (2.0 mL) was added to readjust the pH to 3.0. The layers were separated. The DCM extracts were dried over MgSO4 (3.2 g) and filtered through a glass sintered funnel. The funnel was washed with 5 mL (10 mL) of DCM. The filtrate was evaporated to give a white solid. Yield = 2.03 g, 88.5%. 1H NMR: DMSO-d6.δ(ppm):0.97(s,3H),0.99(s,3H),1.38(s,9H),1.46-1.60(m,5H),1.77-1.85(m,4H),2.23(s,3H),2.62-2.75(m, 1H),3.22(s,3H),3.29(s,3H),3.59(d,J=6Hz,1H),3.76(dd,J=6Hz and 12Hz,1H),4.02(s,2H),4.14(s,2H),4.31(d,J=18Hz,1H),4 .40(d,J=15Hz,1H),4.51(s,1H),4.71(s,1H),4.96(d,J=9Hz,1H),5.06(t,J=9Hz,1H),5.17(d,J=6Hz,1H),5.38(d,J=9Hz,1H), 5.82(t,J=9Hz,1H),7.19(t,J=9Hz,1H),7.35-7.46(m,4H),7.64-7.77(m,3H),7.88(d,J=9Hz,1H),7.98(d,J=6Hz,2H).LC-MS: C8 XBridge 3.0×100mm, 120A, 3.5μm. 40-80% ACN / H2O (1-7min), 80% ACN (7-9min), 80-40% ACN (9-11min), 40% ACN (11-15min), 0.1% 10mM ammonium formate Rf (min) = 5.76. ESI+(ve) found value [M+OH] + =969. Calculate C 49 H 61 NO 18 = 952.02 Da. In-process analysis: Dilute 25 μl aliquot with 1 ml acetonitrile. Isolation material: Approximately 1.0 mg / ml in acetonitrile.

[0498] Example 3: BHALys[Lys] 32 [α-DGA-Cabazitaxel] [ε-PEG ～2100 ] Synthesis of (SPL9048)

[0499]

[0500] PEG stands for -C(O)CH2-PEG ～2100 , where PEG ～2100 represents a methoxy-terminated PEG group having an average molecular weight of about 2100 Daltons (e.g., an average molecular weight in the range of about 1900 to 2300); and

[0501] ● represents the residue of cabazitaxel.

[0502] Note: The theoretical number of α-surface amino groups on the dendrimer that can be replaced with DGA-cabazitaxel is related to the number of α-surface amino groups on the dendrimer that can be replaced with DGA-cabazitaxel. 1 H NMR experimentally determined the presence of BHALys[Lys] 32 Actual average number of patients on the DGA-cabazitaxel group.

[0503] To a solution of DGA-cabazitaxel (2.020 g, 2.12 mmol, 1.2 eq / NH2) in DMF (20 mL, 4.8 vol) was added solid PyBOP (1.15 g, 2.21 mmol, 1.25 eq / NH2). After stirring at room temperature for 5 min, solid BHALys[Lys] 32 [α-NH2TFA] 32 [ε-PEG ～2100 ] (4.19 g, 55.25 μmol). The residual solid was rinsed from the vial with DMF (3 mL). The suspension was stirred at room temperature and the mixture became homogeneous within 15 min. NMM (0.97 mL, 8.84 mmol, 5 eq / NH2) was added. A light yellow solution was formed and stirred at room temperature for 24 h. The solution was diluted with ACN (24 mL) and filtered through a 0.45 μm filter. BHALys[Lys] 32 [α-DGA-Cabazitaxel] [ε-PEG ～2100 ] The filtrate was prepared by using 0.1 m 2 The retentate solution was concentrated in vacuo to give a yellow gum, which was dissolved in THF (60 mL) and filtered through a 0.45 μm filter. The filtrate was concentrated in vacuo to give a gum. The yellow gum was dissolved in THF (27.5 ml, 4.9 volumes based on 5.6 g BHALys[Lys] 32 [α-DGA-Cabazitaxel] [ε-PEG ～2100 ] The flask was stirred for 1 h at 4 °C for 2 h (theoretical yield) and added to vigorously stirred MTBE (110 mL, 20 volumes) via a dropping funnel over 1 h, cooled in an ice bath and under N2. A fine white suspension was formed with some lumps and some material sticking to the walls of the flask. Once the addition was complete, the suspension was stirred on ice for another 60 min. The flask was then removed from the ice bath and allowed to warm to room temperature with stirring. Most of the solids on the walls of the flask were removed with a spatula and the solids were collected by filtering on a P3 sintered funnel. The lumps were broken up using a metal spatula and the filtered solids were repeatedly washed with MTBE (2×28 mL). The wet cake was transferred to a vial and the residual MTBE was removed in vacuo at room temperature to give a fine white powder; 5.35 g, 94.9%. 1 H NMR: CD3OD-d4.δ(ppm):1.13-2.73(m,1225H),3.23-3.30(m,57H),3.37(s,99H),3.39-3.97(m,5720H),4.04-4.50(m,114H),5.003(br s,27H),5.39-5.6.15(m,108H),7.28-8.10(m,334H).3,4,5-Trichloropyridine was used as internal standard and the loading was calculated by comparing the aromatic signal of cabazitaxel with the signal of 3,4,5-trichloropyridine. Theoretical molecular weight of the conjugate: 102 kDa. 1 H NMR showed 29.8 CTX / dendrimer. The actual molecular weight was about 100 kDa (24.9% CTX by weight). Over 10 batches were produced, the loading of cabazitaxel was 24.2% to 26%. HPLC (C8 Phenomenex Kinetex 2.1 x 75 mm, 100A, 2.6 μm. Gradient of 5-45-90% ACN (with 0.1% TFA) in water (with 0.1% TFA): 5% (0-1 min), 5-45% ACN / H2O (1-2 min), 45% ACN (2-10 min), 45-90% (10-14 min), 90% (14-18 min), 90-5% ACN (18-18.1 min), 5% ACN (18.1-20 min) Rf (min) = 14.03. In-process analysis: 5 μL aliquots were diluted with 1 mL acetonitrile. Isolation material: Acetonitrile solution at approximately 3.0 mg / ml.

[0504] Example 4: Efficacy of dendrimer compounds in SCID mice

[0505] Example 4 compares the efficacy of dendrimer compounds in SCID mice.

[0506] In the following experiments and figures:

[0507] SPL9005 is BHALys[Lys] 32 [α-TDA-Cabazitaxel] [ε-PEG ～2100 ] and

[0508] SPL9048 is BHALys[Lys] 32 [α-DGA-Cabataxel] [ε-PEG ～2100 ]

[0509] SPL9005 differs from SPL9048 in that it contains a TDA (thiodiglycol) linker instead of a diglycol linker (ie -S- instead of the -O- present in the diglycol linker). SPL9005 is prepared by synthetic methods similar to those used to prepare SPL 9048.

[0510] The amount of dendrimer administered in mg / kg refers to the amount of cabazitaxel that could theoretically be released from the dendrimer.

[0511] Study on DU145 mouse xenograft prostate cancer model

[0512] A DU145 mouse xenograft prostate cancer model study was performed to evaluate the antitumor efficacy properties of SPL9048 relative to a comparator compound. The comparator compound was free cabazitaxel and SPL9005(BHALys[Lys] 32 [α-TDA-Cabazitaxel] [ε-PEG ～2100 ] ).

[0513] Dendrimer compounds were pre-weighed in glass vials and stored at 20°C until use and dissolved in saline immediately prior to dosing. Cabazitaxel was prepared fresh on each dosing day. Aliquots of cabazitaxel concentrate were removed under aseptic conditions and mixed with 13% ethanol diluent to make a 10 mg / ml working stock solution. Dosing solutions of 4.5 and 5.5 mg / mL were prepared from this working stock solution immediately prior to injection.

[0514] 3 × 10 6 Male SCID mice (7-8 weeks old) were inoculated subcutaneously with DU145 cells. The mice were weighed and tumors were measured 2-3 times per week using an electronic caliper. Tumor volume (mm 3 ) is calculated as length (mm) / 2×width (mm) 2On day 24 post-implantation (again referred to as day 1), tumors of similar size (mean tumor volume 105 mm 3 ) were randomly divided into 5 groups of 10 animals each. Treatment groups were administered saline, cabazitaxel (9 and 11 mg / kg), SPL-9048 (9 mg / kg), and SPL-9005 (25 mg / kg). Test compounds were administered intravenously at 0.1 ml / 10 g body weight by tail vein injection on days 1, 8, and 15. Cabazitaxel was administered at 0.05 ml / 10 g body weight. Mice received a small dish containing food supplement (mixed with food dust) every day. The experiment ended on day 126, or earlier if ethical endpoints were met. Survival curves were analyzed using the Mantel Cox log rank test.

[0515] Figure 1 The antitumor efficacy of the treatment against DU145 tumor xenografts is shown. Tumor volume was measured 2-3 times per week and is expressed as the mean tumor volume (± SEM). Each group initially consisted of 10 mice, and the graph is displayed until no fewer than 6 animals remained in the group. Figure 1 As shown, when the experiment was terminated, on day 126, SPL9048 was administered at a dose that induced complete tumor regression, with no regrowth observed in any of the animals.

[0516] Figure 2 Effects of saline, cabazitaxel, SPL-9005 and SPL-9048 on DU145 tumor-bearing body weight in male mice are shown. Drugs were administered intravenously on days 1, 8 and 15 (indicated by solid lines). Data represent the mean percent weight change from baseline (day 1) for each group; bars SEM. Graphs for each group are shown until fewer than 6 animals remain in each group.

[0517] like Figure 2 As shown, SPL9048 was generally well tolerated in mice (maximum weight loss of -10% on day 20; neutral weight loss / gain after day 40). SPL9048 was also better tolerated by male mice than SPL9005. For SPL9005, 8 / 10 male mice had >20% weight loss after the third dose administered around day 25, but 2 / 10 male mice recovered to +5 / 10% starting weight after day 40. However, in a separate study in female SCID mice, SPL9005 was better tolerated in female mice with a mean weight loss of less than 10% when dosed at 25 mg / kg cabazitaxel equivalents, suggesting possible sex-related differences for this compound.

[0518] Study on MDA-MB-231 Mouse Xenograft Breast Cancer Tumor Model

[0519] MDA-MB-231 (human breast cancer cell line) mouse xenograft breast cancer model studies were performed to evaluate the anti-tumor efficacy properties of SPL9048 against free cabazitaxel.

[0520] SPL-9048 was pre-weighed in glass bottles and stored at 20°C until use and dissolved in saline immediately prior to dosing. Cabazitaxel was prepared fresh on each dosing day. An aliquot of the Cabazitaxel concentrate was removed under aseptic conditions and mixed with 13% ethanol diluent to make a 10 mg / ml working stock solution. A 1.8 mg / mL dosing solution was prepared from this working stock solution immediately prior to injection.

[0521] Female Balb / c nude mice (7 weeks old) were treated with 3.5×10 6 MDA-MB-231 cells were inoculated subcutaneously on the flank:Matrigel (1:1 dilution). Mice were weighed and tumors were measured twice a week using an electronic caliper. Tumor volume (mm 3 ) is calculated as length (mm) / 2×width (mm) 2 On day 10 after implantation (again referred to as day 1), tumors of similar size (mean tumor volume 90 mm 3 ) were randomly divided into 4 groups of 10 animals each. Treatment groups were administered saline, cabazitaxel (9 mg / kg), SPL-9048 (9 mg / kg), and SPL-9048 (10 mg / kg). On days 1, 8, and 15, all compounds were administered by tail vein injection at 0.1 ml / 10 g body weight, except cabazitaxel, which was administered at 0.05 ml / 10 g body weight. Mice received a small dish containing food supplement (mixed with food dust) every day. The experiment ended on day 113 or earlier if ethical endpoints were met.

[0522] Figure 3 The antitumor efficacy of the treatment against MDA-MB-231 tumor xenografts is shown. Tumor volume was measured twice a week and expressed as mean tumor volume (± SEM). Each group initially consisted of 10 mice, and the graph was displayed until no less than 7 animals remained in the group. Figure 3 As shown, SPL9048 induced complete tumor regression. Tumor regrowth in the cabazitaxel group was evident on day 43, with 9 of 10 tumors reaching ethical tumor volume endpoints on day 98. Both doses of SPL-9048 significantly prolonged survival over cabazitaxel.

[0523] Figure 4Shown is the effect of saline, cabazitaxel, and SPL-9048 on body weight in mice bearing MDA-MB-231 tumors. Each group initially consisted of 10 mice. Drugs were administered intravenously on days 1, 8, and 15 (indicated by solid lines). Data represent the mean percent weight change from baseline (day 1) for each group; bars SEM. The graph for each group is shown until fewer than 7 animals remained in each group. Figure 4 As shown, SPL9048 was generally well tolerated, and the mean body weight loss in any group did not exceed 6%.

[0524] Example 5: Toxicokinetic / pharmacokinetic studies

[0525] Single-dose toxicokinetics of SPL-9048 and SPL-9005 were studied by intravenous bolus injection for 21 days. Prepare the control, 0.9% sodium chloride, and dispense on the day of dosing. Prepare appropriate concentrations of SPL-9048 and SPL-9005 to meet the dose level requirements. Prepare the dosing formulations and dispense on each day of dosing and use within 3 hours of preparation. Weigh out the required amount of test article and dissolve in an appropriate volume of normal saline with gentle swirling and record the pH. Prepare appropriate concentrations of cabazitaxel To meet the dosage level requirements. The required amount (1.5 ml) of Cabazitaxel concentrate (40 mg / ml) was aliquoted under sterile conditions and dissolved in an appropriate volume (4.5 mL) of 13% ethanol diluent between 15°C and 30°C to prepare a 10 mg / mL stock solution. The stock solution was further diluted with normal saline to produce the final dosing concentration within 30 minutes.

[0526] The animals used are male and female Sprague Dawley Crl:CD (SD) rats. The animals are 10 to 14 weeks old, males weigh between 327 and 565g, and females weigh between 212 and 316g. The animals were adapted to their designated enclosures for at least 4 days before the first day of administration. The animals were grouped by a stratified randomization scheme designed to achieve similar group average weights. Males and females were randomly grouped separately. Animals with poor health or extreme weight ranges were not grouped. Throughout the study, rodent food No.5CR4 certified by PMI Nutrition International was provided ad libitum, except during the specified procedures. A diet in the same food form was also provided as needed. After treatment by reverse osmosis and ultraviolet irradiation, each animal had free access to city tap water through an automatic watering system, except during the specified procedures. Water bottles were also provided as needed. Animals were socially housed for psychological / environmental enrichment, and items such as chews were provided to the animals, except when interrupted by research procedures / activities. Veterinary care was available throughout the study.

[0527] Test and control articles were administered to appropriate animals via a single intravenous (slow bolus) injection into the tail vein in the amounts shown in the table below. The amount of dendrimers SPL-9048 and SPL-9005 dosed in mg / kg refers to the amount of cabazitaxel that could theoretically be released from the dendrimers.

[0528] Animals were observed for 21 days after dosing. The dose volume for each animal was based on the most recent body weight measurement. Animals were temporarily restrained for dosing and were not sedated. Dosing was performed using a syringe with an attached needle. The first day of dosing for each group was designated as Day 1. During the dosing period, the comparison dose formulation ( Cabazitaxel) and the test article were maintained between 15 and 30°C.

[0529]

[0530] Toxicokinetic parameters were estimated using Phoenix Pharmacokinetics software. Parameter estimates were performed using a noncompartmental approach consistent with the intravenous route of administration. Whenever feasible, all parameters were calculated from SPL9048, SPL9005, and (cabazitaxel) complex concentrations in plasma.

[0531] table below and Figure 5 Provided are data on the effects of administration of SPL9048 (a cabazitaxel-containing dendrimer of the present invention) or a comparative compound, namely SPL9005 (a different cabazitaxel-containing dendrimer) and Details of the pharmacokinetic parameters of free cabazitaxel following administration of (cabazitaxel).

[0532]

[0533] Plasma distribution of free cabazitaxel in SPL9005 and SPL9048 Significantly different. The results showed that administration of SPL9048 at 2.5 mg / kg resulted in a Cmax value of 36.89 ng / mL, a Tmax value of 6 hours, and an area under the curve (AUC) of 1239.99 ng.h / mL. Administration of SPL9005 at 2.5 mg / kg resulted in a Cmax of 9.29 ng / mL, a Tmax of 2 hours, and an AUC of 548.96 ng.h / mL. Administration of SPL9048 at 2.5 mg / kg resulted in a Cmax of 36.89 ng / mL, a Tmax of 6 hours, and an AUC of 1239.99 ng.h / mL. This resulted in a Cmax value of 801.05 ng.h / mL, a Tmax of 2 min, and an AUC of 679.99 ng.h / mL. Group, cabazitaxel in the administration It is not measurable after more than 24 hours.

[0534] Therefore, due to the significantly lower Cmax, administration of SPL9048 resulted in Compared to sham-treated Compared to the control group, administration of SPL9048 also resulted in an increase in the total exposure of cabazitaxel, as shown by the AUC values ​​in the table above. The cabazitaxel Cmax of SPL-9048 and SPL-9005 was lower than that of the control group when the equivalent amount of cabazitaxel was administered. However, as demonstrated by AUC levels, the amount of free cabazitaxel delivered by SPL9048 over the time course studied was higher than the amount of free cabazitaxel delivered by a comparable dose of SPL9005 (i.e., an amount containing an equivalent amount of cabazitaxel) (see Tables and Figure 4 ). SPL9048 exhibits an excellent pharmacokinetic profile consistent with a reduced potential for side effects and increased efficacy at equivalent doses.

[0535] Example 6: Toxicology studies

[0536] Toxicology studies were conducted in rats comparing SPL9048 and free cabazitaxel role.

[0537] At 1mg / kg SPL9048 and Administration to rats, n=6 (3 males, 3 females). The amount of dendrimer administered in mg / kg refers to the amount of cabazitaxel that can theoretically be released from the dendrimer.

[0538] like Figure 6 As shown, the results showed that at this dose level (1 mg / kg) there was dissociation of neutropenia in both male and female rats, which could be This is evidenced by the decrease in values ​​observed with 1 mg / kg neutropenia (i.e., Cabazitaxel), and less / no decrease in values ​​observed after SPL9048 administration (especially see Day 7). As expected, the rebound after Day 7 appears to depend on the severity of neutropenia. (ie, free cabazitaxel) group, there was substantial rebound on day 14, whereas there was almost no rebound in the 1 mg / kg SPL9048 group (or control), consistent with the limited neutropenia in these groups. This suggests that SPL9048 may induce less neutropenia and therefore be less clinically toxic than administration of an equivalent dose of free cabazitaxel.

[0539] In the case of SPL9048 and Similar results were found in the study. Less neutropenia. Compared with cabazitaxel, SPL9048 showed reduced toxicity. Test article-related hematologic changes (leukocytes, neutrophils, lymphocytes, monocytes, eosinophils, platelets, and reticulocytes) were noted in males and females at 1:10 pm and remained at low levels until Day 7. The decreases in these parameters were generally greater in rats with

[0540] In the case of SPL9048 administered at 2.5 mg / kg and In animals receiving The severity of the bone marrow and thymus was generally higher in the treated rats.

[0541] Example 7: Comparative Linker Release Rates in PBS at 37°C and pH 7.4

[0542] A study was conducted to determine the release rate of Cabazitaxel from certain dendrimers in PBS (phosphate buffered saline) at 37°C and pH 7.4. The compounds tested were:

[0543] i) Compounds of the present invention, BHALys[Lys] 32 [α-DGA-Cabataxel] [ε-PEG ～1100 ] SPL9049 differs from SPL9048 in that it contains a lower molecular weight PEG group; and

[0544] ii) Comparators Cabazitaxel-containing dendrimers, SPL9005 and SPL9006 (SPL9006 differs from SPL9048 in that it contains a MIDA (methyliminodiacetyl) linker in place of the diglycol acyl linker (i.e. -N(Me)- in place of the -O- present in the diglycol acyl linker). SPL9006 was prepared by a synthetic method similar to that used to prepare SPL 9048.

[0545] The following table shows the results of two replicate experiments for the % of Cabazitaxel released at 24 hours, and the mean time to 50% release (or the mean time to 50% release estimated based on the data points):

[0546] % Cabazitaxel released in PBS at 37°C and pH 7.4:

[0547]

[0548] The data for SPL9048 and SPL9049 at other time points in Experiment #2 are also provided below:

[0549] % Cabazitaxel released in PBS at 37°C and pH 7.4:

[0550] Time (h) SPL9049 SPL9048 0 0.97 0.95 24 32.06 41.28 48 45.156 55.48 67 59.676 62.65 87 67.86 71.12

[0551] The results show the relative release rates of cabazitaxel from the dendrimers after administration. Comparator SPL9005 resulted in the release of approximately 12 to 15% of cabazitaxel in PBS at 37°C and pH 7.4 over 24 hours, comparator SPL9006 (MIDA linker) resulted in the release of approximately 8% of cabazitaxel in PBS at 37°C and pH 7.4 over the same period of time, the compound of the invention SPL9048 resulted in the release of approximately 40% of cabazitaxel in PBS at 37°C and pH 7.4 over 24 hours, and SPL9049 resulted in the release of approximately 30 to 50% of cabazitaxel under the same conditions.

[0552] It was also observed that SPL9048 had increased stability in solution (e.g., with respect to precipitation) compared to SPL9049, which may be attributed to the presence of PEG 2200 Groups other than PEG 1100 In addition to the excellent potency, toxicokinetics and pharmacokinetic properties observed for SPL9048, this property is a further advantage for this drug-dendrimer conjugate.

[0553] Example 8: Stability of Citric Acid Drug-Dendrimer Conjugates

[0554] Drug release studies of dendrimer molecules containing different drugs in 0.1 M citric acid at pH 3.5 to 6.5 identified the maximum stability at pH 4.5 over 7 days at room temperature and 4 degrees Celsius. The optimal range was 3.5 to 5.5 with less than 0.3% and 0.1% release at room temperature and 4C, respectively. Another study was conducted to evaluate 10 different drug release inhibitors on drug release from dendrimer molecules containing different drugs in dog, mouse and human plasma. Citric acid was found to be the most effective drug release inhibitor.

[0555] Example 9: SPL9048 and Comparison with gemcitabine

[0556] CAPAN-1 (human pancreatic adenocarcinoma cell line) mouse xenograft pancreatic cancer model studies were conducted to evaluate the efficacy of SPL9048 alone or in combination with gemcitabine. (albumin-bound paclitaxel) compared to the antitumor efficacy properties.

[0557] SPL9048 and cabazitaxel were prepared as described above. Gemcitabine and was obtained from the Peter MacCallum Cancer Centre Pharmacy and dissolved in saline solution immediately before administration.

[0558] Female NOD-SCID interleukin-2 receptor γ chain null mice (9 weeks old) were placed on the flank with 5×10 6 CAPAN-1 cells were inoculated subcutaneously. Mice were weighed and tumors were measured twice a week using an electronic caliper. Tumor volume (mm 3 ) is calculated as length (mm) / 2×width (mm) 2 On day 26 after implantation, tumors of similar size (average tumor volume 100 mm 3 ) were randomly divided into 8 groups, with 9 animals in each group.

[0559] Administer intravenously via tail vein and SPL9048, gemcitabine was administered by intraperitoneal injection. 0.1 ml / 10 g body weight was injected on days 1, 8, and 15. The experiment ended on day 107 or earlier if ethical endpoints were met. One mouse was injected on day 1 The patient died immediately due to an injection error. All other treatments were well tolerated with no weight loss. Tumor growth data were analyzed by ANOVA in GraphPad Prism followed by Dunnett's ad-hoc test. Dosing groups were as follows:

[0560] 1. Saline-solvent

[0561] 2. Gemcitabine (80 mg / kg, ip) - vehicle (saline)

[0562] 3. (40mg / kg, iv)-solvent

[0563] 4. (40 mg / kg, iv) + gemcitabine (80 mg / kg, ip)

[0564] 7.SPL9048 (7.5mg / kg, iv)-solvent

[0565] 8. SPL9048 (7.5 mg / kg, iv) + gemcitabine (80 mg / kg, ip)

[0566] Figure 7The antitumor efficacy of the treatment against CAPAN-1 tumor xenografts is shown. Tumor volumes were measured twice a week and are expressed as mean tumor volumes (± SEM). Figure 7 As shown, SPL9048, administered alone or in combination with gemcitabine, induced complete regression of CAPAN-1 tumors during the study period. None of them were effective in this model. More effectively inhibited CAPAN-1 tumor growth (P = 0.004, Relative to SPL-8732; P < 0.0001 Mantel Cox regression analysis of Kaplan-Meier survival curves).

[0567] Alone and in combination with gemcitabine SPL9048 significantly prolonged the duration of gemcitabine or Life span.

[0568]

[0569] Analysis was performed on Day 37, the last day that all vehicle-treated animals remained on the study.

[0570] Example 10: Phase 1 Clinical Study—PK and Biomarkers

[0571] A Phase 1 dose escalation study was conducted to determine the appropriate dose of SPL9048. Biomarkers, PK, and other data were collected from patients participating in the study. Patients were dosed every 3 weeks using an infusion pump over 1 hour. All patients had progressive metastatic disease. The patient population was heavily pretreated with a series of chemotherapeutic agents as described in the table below.

[0572]

[0573] Figure 8 and 9 Data from the study showed that biomarker responses occurred at as low as 10 mg / m 2 under the dose of SPL9048. Figure 8 It was shown that in patients with prostate cancer, multiple doses of 10 mg / m 2 and continued at 20 mg / m 2 PSA, a marker for prostate cancer, decreased after cabazitaxel-equivalent administration. Fig. 9 showed that CA-125, an ovarian cancer marker, was significantly increased at 15 mg / m 2 The dose dropped after two doses. These are important signs of efficacy.

[0574] The table below lists the patients in the study, many of whom showed signs of stable disease.

[0575]

[0576] The pharmacokinetic data related to free cabazitaxel from the study are shown in the table below. In summary, after administration of SPL9048, at an equivalent cabazitaxel dose of 20 mg / m 2 The Cmax of free cabazitaxel was The Cmax of cabazitaxel equivalent to 20 mg / ml was measured to be 53.6, 15.8 and 17.6 ng / ml in three patients.

[0577]

[0578] The pharmacokinetic data related to total cabazitaxel (i.e. free cabazitaxel and dendrimer-bound cabazitaxel) from the study are shown in the table below. In summary, at equivalent cabazitaxel doses, the AUCinf of total cabazitaxel after administration of SPL9048 was higher than About 2000 to 4000 times.

[0579]

[0580] Calculated using the model described in Ferron G., et al Cancer Chemo Pharma (2013) 71: 681-692 quantity.

Claims

1. A dendrimer comprising: i) nuclear unit, wherein the core unit is and ii) building blocks, wherein the building blocks are each wherein the acyl group of each building block provides a covalent attachment point for linking to the core unit or a previous generation building block; and wherein each nitrogen atom provides a covalent attachment point for linking to a subsequent generation building block, a first terminal group, or a second terminal group; wherein the core unit is covalently linked to two building blocks via amide bonds, each amide bond being formed between a nitrogen atom present in the core unit and a carbon atom of an acyl group present in a building block; The dendrimer is a five-generation building block dendrimer; wherein the building blocks of different generations are covalently linked to each other via an amide bond formed between a nitrogen atom present in one building block and a carbon atom of an acyl group present in another building block; The dendrimer further comprises: iii) a plurality of first terminal groups, each first terminal group comprising a cabazitaxel residue covalently linked to a diethylene glycol-based linking group, wherein each of the first terminal groups is: and iv) a plurality of second end groups, each second end group comprising a PEG group having an average molecular weight in the range of 1000 to 2500 Daltons; wherein at least one third of the nitrogen atoms present in the outer building blocks are each covalently attached to the first terminal group; and At least one third of the nitrogen atoms present in the outer building blocks are each covalently linked to the second terminal group; or a pharmaceutically acceptable salt thereof.

2. The dendrimer of claim 1, wherein each of said building blocks is:

3. The dendrimer of claim 1, wherein the dendrimer has five complete generations of building blocks.

4. The dendrimer of claim 1 , wherein each of the second terminal groups comprises a covalent bond to a PEG linking group via an ether bond formed between a carbon atom present in the PEG group and an oxygen atom present in the PEG linking group, and each second terminal group is covalently linked to a building block via an amide bond formed between a nitrogen atom present in the building block and a carbon atom of an acyl group present in the PEG linking group.

5. The dendrimer of claim 4, wherein each of the second terminal groups is And wherein the PEG group is a methoxy-terminated PEG having an average molecular weight in the range of 1750 to 2500 Daltons.

6. The dendrimer of claim 5, wherein the dendrimer comprises a surface unit comprising an external building block connected to a first terminal group and a second terminal group, the surface unit having the following structure: And wherein the PEG group is a methoxy-terminated PEG having an average molecular weight in the range of 1750 to 2500 Daltons.

7. The dendrimer of claim 6, wherein the dendrimer has 28 to 32 surface units.

8. The dendrimer of claim 7, wherein the dendrimer has 30 to 32 surface units.

9. The dendrimer of claim 1 , wherein at least 40% of the nitrogen atoms present in the outer building blocks are each covalently linked to a first terminal group; and at least 40% of the nitrogen atoms present in the outer building blocks are each covalently linked to a second terminal group.

10. The dendrimer of claim 1, wherein the fifth generation building blocks are full generation, and wherein the building blocks of the outer generation provide 64 nitrogen atoms for covalent attachment to the first terminal group or the second terminal group, wherein, 26 to 32 first terminal groups are covalently attached to one of the nitrogen atoms, and wherein 28 to 32 second terminal groups are each covalently attached to one of the nitrogen atoms.

11. The dendrimer of claim 1, wherein in w / w %, the cabazitaxel residues comprise in the range of 23% w / w to 28% w / w of the dendrimer.

12. The dendrimer of claim 1, wherein the dendrimer is: Wherein T1′ represents the first terminal group as follows: or T1′ represents H, wherein less than 5 T1′ are H; and T2' represents the second terminal group as follows: wherein the PEG group is a methoxy-terminated PEG having an average molecular weight in the range of 1750 to 2500 Daltons, or T2' represents H, and wherein less than 5 T2's are H.

13. The dendrimer of claim 1, wherein the in vitro half-life of cabazitaxel released from the dendrimer is in the range of 20 to 100 hours in PBS at pH 7.4 and 37°C.

14. The dendrimer of claim 13, wherein the in vitro half-life of cabazitaxel released from the dendrimer is in the range of 30 to 60 hours in PBS at pH 7.4 and 37°C.

15. A composition comprising a plurality of dendrimers or pharmaceutically acceptable salts thereof, wherein the dendrimer is as defined in claim 1, The average number of first end groups per dendrimer in the composition is in the range of 24 to 32, and The average number of second end groups per dendrimer in the composition is in the range of 24 to 32.

16. The composition of claim 15, wherein, in w / w %, the cabazitaxel residues comprise in the composition in the range of 23% w / w to 28% w / w of the dendrimer.

17. The composition of claim 16, wherein the composition is a pharmaceutical composition, and wherein the composition comprises a pharmaceutically acceptable excipient.

18. A pharmaceutical composition comprising: i) the dendrimer according to claim 1, or a pharmaceutically acceptable salt thereof, and ii) a pharmaceutically acceptable excipient.

19. The pharmaceutical composition of claim 18, wherein the composition is a solid composition comprising the dendrimer according to claim 1, a sugar and an acid, and wherein the composition is for reconstitution with a diluent.

20. The pharmaceutical composition of claim 19, wherein the sugar is trehalose and the acid is citric acid.

21. The pharmaceutical composition of claim 19, wherein after reconstitution with a diluent, the pH of the reconstituted composition is in the range of 3.5 to 5.

5.

22. The pharmaceutical composition of claim 18, wherein the composition is free of polyethoxylated castor oil and polyethoxylated sorbitan monooleate.

23. The pharmaceutical composition of claim 18, wherein the composition is formulated for administration as an infusion over a period of up to 30 minutes, or wherein the composition is formulated for administration as a bolus over a period of up to 5 minutes.

24. Use of a dendrimer as claimed in any one of claims 1 to 14, or a composition as claimed in any one of claims 17 to 23, in the manufacture of a medicament for the treatment of cancer.

25. The use of claim 24, wherein the cancer is selected from the group consisting of pancreatic cancer, prostate cancer, breast cancer and ovarian cancer.

26. The use of claim 25, wherein the cancer is metastatic castration-resistant prostate cancer (mCRPC).

27. The use according to claim 24, wherein the therapeutically effective amount of the dendrimer is in the range of 10 to 100 mg / m2 body surface area.

28. The use according to claim 27, wherein the therapeutically effective amount of the dendrimer is in the range of 20 to 50 mg / m2 body surface area.

29. The use according to claim 28, wherein the therapeutically effective amount of the dendrimer is in the range of 50 to 100 mg / m2 body surface area.

30. The use of claim 24, wherein the composition is for administration as an infusion over a period of up to 30 minutes, or wherein the composition is for administration as a bolus over a period of up to 5 minutes.

31. The use of claim 24, wherein the dendrimer is administered in combination with an additional therapeutic agent.

32. The use of claim 31 , wherein the additional therapeutic agent is an additional anti-cancer drug.

33. The use of claim 24, wherein the dendrimer is Wherein T1′ represents the first terminal group as follows: or T1′ represents H, wherein less than 5 T1′ are H; and T2′ represents the following second terminal group: wherein the PEG group is a methoxy-terminated PEG having an average molecular weight in the range of 1750 to 2500 Daltons, or T2' represents H, and wherein less than 5 T2's are H.

34. The use of claim 24, wherein administration of the dendrimer provides therapeutically effective plasma concentrations of cabazitaxel for a longer period of time compared to administration of an equivalent dose of free cabazitaxel.

35. The use of claim 24, wherein administration of the dendrimer provides a maximum concentration Cmax of cabazitaxel that is no more than 20% of the maximum concentration provided by administration of an equivalent dose of free cabazitaxel.

36. The use of claim 24, wherein administration of the dendrimer provides a greater AUC of total cabazitaxel compared to direct administration of an equal dose of free cabazitaxel.

37. The use of claim 24, wherein administration of the dendrimer provides enhanced clinical efficacy compared to administration of an equivalent dose of free cabazitaxel.

38. The method of claim 24, wherein the dosage is 20 or 25 mg / m 3 times per week. 2 Administration of a course of the dendrimer provided enhanced clinical efficacy compared to cabazitaxel.

39. The use of claim 24, wherein administration of the dendrimer provides reduced neutropenia, lymphopenia, anemia and / or thrombocytopenia compared to administration of an equivalent dose of free cabazitaxel.

40. The method of claim 24, wherein 20 or 25 mg / m is administered three times per week. 2 Administration of the dendrimers provides reduced neutropenia, lymphopenia, anemia and / or thrombocytopenia compared to cabazitaxel.

41. A process for producing a dendrimer as claimed in any one of claims 1 to 14, the process comprising: a) reacting a cabazitaxel intermediate with a dendrimer intermediate or a salt thereof under amide coupling conditions, The cabazitaxel intermediate is: wherein X is -OH or a leaving group, or wherein X together with the C(O) group to which it is attached forms a carboxylate; The dendrimer intermediate comprises: i) nuclear unit, wherein the core unit is and ii) building blocks, wherein the building blocks are each wherein the acyl group of each building block provides a covalent attachment point for linking to the core unit or a previous generation building block; and wherein each nitrogen atom provides a covalent attachment point for linking to a subsequent generation building block, a first terminal group, or a second terminal group; wherein the core unit is covalently linked to two building blocks via amide bonds, each amide bond being formed between a nitrogen atom present in the core unit and a carbon atom of an acyl group present in a building block; The dendrimer is a five-generation building block dendrimer; wherein the building blocks of different generations are covalently linked to each other via an amide bond formed between a nitrogen atom present in one building block and a carbon atom of an acyl group present in another building block; The dendrimer further comprises: a plurality of second end groups, each second end group comprising a PEG group having an average molecular weight in the range of 1000 to 2500 Daltons; wherein at least one third of the nitrogen atoms present in the outer building blocks are each covalently attached to a second terminal group; and wherein at least one third of the nitrogen atoms present in said external building blocks are unsubstituted and available for reaction with said cabazitaxel intermediate; or b) reacting the PEG intermediate with the dendrimer intermediate or a salt thereof under amide coupling conditions, The PEG intermediate is: wherein the PEG group is a PEG-containing group having an average molecular weight in the range of 1000 to 2500 Daltons, and X is -OH or a leaving group, or wherein X together with the C(O) group to which it is attached forms a carboxylate; The dendrimer intermediate comprises: i) nuclear unit, wherein the core unit is and ii) building blocks, wherein the building blocks are each wherein the acyl group of each building block provides a covalent attachment point for linking to the core unit or a previous generation building block; and wherein each nitrogen atom provides a covalent attachment point for linking to a subsequent generation building block, a first terminal group, or a second terminal group; wherein the core unit is covalently linked to two building blocks via amide bonds, each amide bond being formed between a nitrogen atom present in the core unit and a carbon atom of an acyl group present in a building block; The dendrimer is a five-generation building block dendrimer; wherein the building blocks of different generations are covalently linked to each other via an amide bond formed between a nitrogen atom present in one building block and a carbon atom of an acyl group present in another building block; The dendrimer further comprises: a plurality of first terminal groups, each first terminal group comprising a cabazitaxel residue covalently linked to a diethylene glycol-based linker, wherein each of the first terminal groups is: wherein at least one third of the nitrogen atoms present in the outer building blocks are each covalently attached to a first terminal group; and wherein at least one third of the nitrogen atoms present in said outer building unit are unsubstituted; or c) reacting the surface unit intermediate with the dendrimer intermediate or a salt thereof under amide coupling conditions, The surface unit intermediate is: wherein the PEG group is a PEG-containing group having an average molecular weight in the range of 1000 to 2500 Daltons, and X is -OH or a leaving group, or wherein X together with the C(O) group to which it is attached forms a carboxylate; The dendrimer intermediate comprises: i) nuclear unit, wherein the core unit is and ii) building blocks, wherein the building blocks are each wherein the acyl group of each building block provides a covalent attachment point for linking to the core unit or a previous generation building block; and wherein each nitrogen atom provides a covalent attachment point for linking to a subsequent generation building block, a first terminal group, or a second terminal group; wherein the core unit is covalently linked to two building blocks via amide bonds, each amide bond being formed between a nitrogen atom present in the core unit and a carbon atom of an acyl group present in a building block; The dendrimer intermediate is a fourth generation building block dendrimer intermediate; wherein the building blocks of different generations are covalently linked to each other via an amide bond formed between a nitrogen atom present in one building block and a carbon atom of an acyl group present in another building block; and wherein the nitrogen atoms present in said outer building blocks of said dendrimer intermediate are unsubstituted.

42. An intermediate for producing a dendrimer, which is wherein the PEG group is a PEG-containing group having an average molecular weight in the range of 1000 to 2500 Daltons, and X is -OH or a leaving group, or wherein X together with the C(O) group to which it is attached forms a carboxylate.

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