Antibody-drug conjugates comprising branched linkers and methods related thereto

Abstract

The present invention relates to antibody-drug conjugates (ADCs) wherein a plurality of active agents are conjugated to an antibody through at least one branched linker. The branched linker may comprise a branching unit, and two active agents are coupled to the branching unit through a secondary linker and the branching unit is coupled to the antibody by a primary linker. The active agents may be the same or different. In certain such embodiments, two or more such branched linkers are conjugated to the antibody, e.g., 2-4 branched linkers, which may each be coupled to a different C-terminal cysteine of a heavy or light chain of the antibody. The branched linker may comprise one active agent coupled to the branching unit by a first branch and a second branch that comprises a polyethylene glycol moiety coupled to the branching unit. In certain such embodiments, two or more such branched linkers are conjugated to the antibody, e.g., 2-4 branched linkers, which may each be coupled to a different C-terminal cysteine of a heavy or light chain of the antibody.

Description

ANTIBODY-DRUG CONJUGATES COMPRISING BRANCHED LINKERS AND METHODS RELATED THERETO CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application Serial No. 62 / 260,006, filed November 25, 2015 BACKGROUND Antibody-drug conjugate (ADC) technology is a target-oriented technology, which allows for selective killing or inhibition of growth or division of cancer cells. Typically, ADCs function by targeting cancer cells using the antibody and then releasing a toxic material (i.e., the drug) in a cell, thereby triggering cell death. Since ADC technology allows a drug to be accurately delivered to a target cancer cell and released under specific conditions, while minimizing collateral damage to healthy cells, ADC technology increases the efficacy of a therapeutic antibody and decreases the risk of an adverse reaction. A basic structure of an antibody-drug conjugate is an "antibody-linker-low molecular drug (toxin)". The linker ideally allows the drug to exhibit an effect on a target cancer cell, e.g., after being separated from the antibody (for example, by enzyme-mediated hydrolysis), after the drug reaches a target cell. The linker also plays a functional role, by connecting the antibody and the drug. The efficacy and toxicity of the antibody-drug conjugate thereby depends, in part, on the stability of the linker, and thus, the linker plays an important role in drug safety. The linkers of antibody-drug conjugates may be roughly classified as non-cleavable or cleavable. Many non-cleavable linkers are attached to antibodies using a thioether, comprising a cysteine of the antibody. The pendant drug generally cannot dissociate from the antibody in vivo and reduced efficacy may be further encountered when ADC internalization is poor. In the case of the widely-used thiol-maleimide method, the antibody-drug conjugate is unstable, which may result in dissociation of the drug from the conjugate before or after it reaches a target cell. Instead of chemically labile linkers that have limited stability in physiological extracellular conditions, such as hydrazone and disulfide-based linkers, there is a need for linkers that are stable in physiological extracellular conditions. Furthermore, there is a need for linkers that have high plasma stability to improve therapeutic applicability, since the drug should be released only within the cell, which is targeted by the protein, to which the drug is linked, and not outside of the cell. Cleavable linkers may be hydrolyzed, for example, by a lysosomal enzyme. A cleavable linker may comprise a disulfide bond, e.g., including a cysteine of the antibody. A disulfide linker, which allows for dissociation via a thiol exchange reaction, relies in part on the uptake of an antibody-drug conjugate into a target cell and the exposure of the disulfide to the cytosol, which is a reducing environment. Since various types of thiols (for example, albumin, and glutathione) are present in the blood, however, a drug may dissociate from the antibody prior to reaching its target. Recently, a new approach to making antibody-drug conjugates has been described, using protein prenylation of a C-terminal amino acid sequence to install a modified isoprenoid unit that allows for attachment of a drug or other active agent to the antibody in a mild and site-specific manner (e.g., see U.S. Patent Publication No. 2012 / 0308584). Further refinement is possible. In light of the foregoing, improved linkers for antibody-drug conjugates are desirable. SUMMARY In some aspects, the invention relates to antibody-drug conjugates (ADCs) comprising an antibody, at least one branched linker covalently coupled to the antibody, and at least one or two active agents covalently coupled to the branched linker. A branched linker may comprise a branching unit, with at least one drug coupled to the branching unit through a secondary linker; the branching unit is coupled to the antibody by a primary linker. The primary and / or secondary linker may comprise at least one polyethylene glycol unit. In some embodiments, the invention relates to a ligand-drug conjugate, comprising a ligand and one or more branched linkers covalently coupled to the ligand, wherein i) each branched linker comprises a branching unit (BR) covalently coupled to the ligand by a primary linker (PL); ii) each branched linker comprises a first branch (B1), in which a first active agent is covalently coupled to the branching unit by a secondary linker (SL) and a cleavage group (CG); and iii) each branched linker further comprises a second branch (B2), in which either a) a second active agent is covalently coupled to the branching unit by a secondary linker (SL) and a cleavage group (CG) or b) a polyethylene glycol moiety is covalently coupled to the branching unit, wherein each cleavage group can be hydrolyzed to release the active agent from the ligand- drug conjugate. In some embodiments, the invention relates to a branched ligand-active agent compound, wherein i) the branched linker comprises a branching unit (BR) covalently coupled to a reactive moiety by a primary linker (PL); ii) the branching unit is covalently coupled to a first branch (B1), comprising a first active agent covalently coupled to a secondary linker (SL) and a cleavage group (CG); and iii) the branching unit is covalently coupled to a second branch (B2), comprising either a) a second active agent covalently coupled to a secondary linker (SL) and a cleavage group (CG) or b) a polyethylene glycol moiety, wherein each cleavage group can be hydrolyzed to release the active agent from the ligand-active agent compound. In some embodiments, the cleavage group has the formula: [Image disponible dans le document PDF, Image available in the PDF document] wherein: G represents a sugar, sugar acid, or modified sugar, preferably a sugar or sugar acid, most preferably glucuronic acid; W represents <com:Math><semantics>−C(O)<annotation encoding="application / x-tex">-C(O)< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(O)NR′<annotation encoding="application / x-tex">-C(O)NR'< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(O)O<annotation encoding="application / x-tex">-C(O)O< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(O)2NR′<annotation encoding="application / x-tex">-S(O)_2NR'< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−P(O)R″NR′<annotation encoding="application / x-tex">-P(O)R''NR'< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(O)NR′<annotation encoding="application / x-tex">-S(O)NR'< / annotation>< / semantics>< / com:Math>, or <com:Math><semantics>−<annotation encoding="application / x-tex">-< / annotation>< / semantics>< / com:Math> PO<com:Sub>2< / com:Sub>NR'-, in each case where the C(O), S, or P is preferably directly bound to the phenyl ring, and R' and R" are each independently hydrogen, (C<com:Sub>1< / com:Sub>-C<com:Sub>8< / com:Sub>)alkyl, mono- or di-carboxyl(<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C8<annotation encoding="application / x-tex">C_8< / annotation>< / semantics>< / com:Math>)alkyl, (<com:Math><semantics>C3<annotation encoding="application / x-tex">C_3< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C8<annotation encoding="application / x-tex">C_8< / annotation>< / semantics>< / com:Math>)cycloalkyl, (<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C8<annotation encoding="application / x-tex">C_8< / annotation>< / semantics>< / com:Math>)alkoxy, (<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C8<annotation encoding="application / x-tex">C_8< / annotation>< / semantics>< / com:Math>)alkylthio, mono- or di-<com:Math><semantics>(C1−C8)<annotation encoding="application / x-tex">(C_1-C_8)< / annotation>< / semantics>< / com:Math>alkylamino, <com:Math><semantics>(C3−C20)<annotation encoding="application / x-tex">(C_3-C_{20})< / annotation>< / semantics>< / com:Math>heteroaryl, or <com:Math><semantics>(C6−C20)<annotation encoding="application / x-tex">(C_6-C_{20})< / annotation>< / semantics>< / com:Math>aryl and W is coupled directly or indirectly to the branching unit; each Z independently represents hydrogen, (C<com:Sub>1< / com:Sub>-C<com:Sub>8< / com:Sub>)alkyl, or an electron-withdrawing group (such as an amide, carboxylic acid, carboxylic acid ester, halogen, cyano, or nitro), preferably a hydrogen, (C<com:Sub>1< / com:Sub>-C<com:Sub>8< / com:Sub>)alkyl, halogen, cyano, or nitro, most preferably hydrogen; n is an integer from 1 to 3; m is 0 or 1, preferably 1; and R<com:Sub>1< / com:Sub> and R<com:Sub>2< / com:Sub> are each independently hydrogen, (C<com:Sub>1< / com:Sub>-C<com:Sub>8< / com:Sub>)alkyl, or (C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub>)cycloalkyl, preferably hydrogen, or R<com:Sub>1< / com:Sub> and R<com:Sub>2< / com:Sub> taken together with the carbon atom to which they are attached form a (C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub>)cycloalkyl ring. In some embodiments, the active agent is coupled to the first branch through a cleavage group having the formula: [Image disponible dans le document PDF, Image available in the PDF document] or a pharmaceutically acceptable salt thereof, wherein G represents a sugar, sugar acid, or modified sugar, preferably a sugar or sugar acid, most preferably glucuronic acid; B is a unit covalently attached to the active agent, W represents <com:Math><semantics>−C(O)<annotation encoding="application / x-tex">-C(O)< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(O)NR′<annotation encoding="application / x-tex">-C(O)NR'< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(O)O<annotation encoding="application / x-tex">-C(O)O< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(O)2NR′<annotation encoding="application / x-tex">-S(O)_2NR'< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−P(O)R″NR′<annotation encoding="application / x-tex">-P(O)R''NR'< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(O)NR′<annotation encoding="application / x-tex">-S(O)NR'< / annotation>< / semantics>< / com:Math>, or <com:Math><semantics>−<annotation encoding="application / x-tex">-< / annotation>< / semantics>< / com:Math> PO<com:Sub>2< / com:Sub>NR'-, in each case where the C(O), S, or P is directly bound to the phenyl ring, and R' and R" are each independently hydrogen, (C<com:Sub>1< / com:Sub>-C<com:Sub>8< / com:Sub>)alkyl, (C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub>)cycloalkyl, <com:Math><semantics>(C1−C8)<annotation encoding="application / x-tex">(C_1-C_8)< / annotation>< / semantics>< / com:Math>alkoxy, <com:Math><semantics>(C1−C8)<annotation encoding="application / x-tex">(C_1-C_8)< / annotation>< / semantics>< / com:Math>alkylthio, mono- or di-<com:Math><semantics>(C1−C8)<annotation encoding="application / x-tex">(C_1-C_8)< / annotation>< / semantics>< / com:Math>alkylamino, <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math>alkylamino, <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math>alkylamino, <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math>alkylamino, <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math>alkylamino, <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math>alkylamino, <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math>alkylamino, <com:Math><semantics>(C3−C<annotation encoding="application / x-tex">(C_3-C< / annotation>< / semantics>< / com:Math> <com:Math><semantics>C20<annotation encoding="application / x-tex">C_{20}< / annotation>< / semantics>< / com:Math>)heteroaryl, or <com:Math><semantics>(C6−C20)<annotation encoding="application / x-tex">(C_6-C_{20})< / annotation>< / semantics>< / com:Math>aryl each Z independently represents hydrogen, (C<com:Sub>1< / com:Sub>-C<com:Sub>8< / com:Sub>)alkyl, or an electron-withdrawing group (such as an amide, carboxylic acid, carboxylic acid ester, halogen, cyano, or nitro), preferably a hydrogen, (C<com:Sub>1< / com:Sub>-C<com:Sub>8< / com:Sub>)alkyl, halogen, cyano, or nitro, most preferably hydrogen; n is an integer from 1 to 3, preferably 3; L represents a bond to a linker or a branching unit; <com:Math><semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R2<annotation encoding="application / x-tex">R_2< / annotation>< / semantics>< / com:Math> are each independently hydrogen, (<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C8<annotation encoding="application / x-tex">C_8< / annotation>< / semantics>< / com:Math>)alkyl, or (<com:Math><semantics>C3<annotation encoding="application / x-tex">C_3< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C8<annotation encoding="application / x-tex">C_8< / annotation>< / semantics>< / com:Math>)cycloalkyl, preferably hydrogen, or R<com:Sub>1< / com:Sub> and R<com:Sub>2< / com:Sub> taken together with the carbon atom to which they are attached form a (C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub>)cycloalkyl ring. In some embodiments, the sugar or sugar acid is a monosaccharide. In some embodiments, the sugar comprises: [Image disponible dans le document PDF, Image available in the PDF document] G is R<com:Sub>3< / com:Sub> is hydrogen or a carboxyl protecting group; and each R<com:Sub>4< / com:Sub> is independently hydrogen or a hydroxyl protecting group. In some embodiments, the primary or secondary linker has the structure - [Image disponible dans le document PDF, Image available in the PDF document] wherein: r is an integer from 0 to 10; p is an integer from 1 to 10; q is an integer from 1 to 20; V and Y are each independently a single bond, -O-, -S-, -NR<com:Sub>21< / com:Sub>-, -C(O)NR<com:Sub>22< / com:Sub>-, - <com:Math><semantics>NR23C(O)<annotation encoding="application / x-tex">NR_{23}C(O)< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>−NR24SO2<annotation encoding="application / x-tex">-NR_{24}SO_2< / annotation>< / semantics>< / com:Math>-, or <com:Math><semantics>−SO2NR25<annotation encoding="application / x-tex">-SO_2NR_{25}< / annotation>< / semantics>< / com:Math>-; and <com:Math><semantics>R21<annotation encoding="application / x-tex">R_{21}< / annotation>< / semantics>< / com:Math> to <com:Math><semantics>R25<annotation encoding="application / x-tex">R_{25}< / annotation>< / semantics>< / com:Math> are each independently hydrogen, <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math> alkyl <com:Math><semantics>(C6−C20)<annotation encoding="application / x-tex">(C_6-C_{20})< / annotation>< / semantics>< / com:Math> aryl or <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math>alkyl<com:Math><semantics>(C3−C20)<annotation encoding="application / x-tex">(C_3-C_{20})< / annotation>< / semantics>< / com:Math>heteroaryl. In some embodiments, the at least one branching unit has the structure [Image disponible dans le document PDF, Image available in the PDF document] - 1 wherein L<com:Sub>1< / com:Sub>, L<com:Sub>2< / com:Sub>, L<com:Sub>3< / com:Sub> is each independently a direct bond or -C<com:Sub>n< / com:Sub>H<com:Sub>2n< / com:Sub>- where n is a integer of 1 to 30, [Image disponible dans le document PDF, Image available in the PDF document] wherein <com:Math><semantics>G1<annotation encoding="application / x-tex">G_1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>G2<annotation encoding="application / x-tex">G_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>G3<annotation encoding="application / x-tex">G_3< / annotation>< / semantics>< / com:Math> is each independently a direct bond, 2 [Image disponible dans le document PDF, Image available in the PDF document] 7 wherein <com:Math><semantics>R3<annotation encoding="application / x-tex">R_3< / annotation>< / semantics>< / com:Math> is hydrogen or <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C30<annotation encoding="application / x-tex">C_{30}< / annotation>< / semantics>< / com:Math> alkyl; wherein <com:Math><semantics>R4<annotation encoding="application / x-tex">R_4< / annotation>< / semantics>< / com:Math> is hydrogen or <com:Math><semantics>−L4<annotation encoding="application / x-tex">-L_4< / annotation>< / semantics>< / com:Math>-COOR<com:Sub>5< / com:Sub>, wherein <com:Math><semantics>L4<annotation encoding="application / x-tex">L_4< / annotation>< / semantics>< / com:Math> is a direct bond or <com:Math><semantics>−CnH2n<annotation encoding="application / x-tex">-C_nH_{2n}< / annotation>< / semantics>< / com:Math>- wherein n is a integer of 1 to 10, and <com:Math><semantics>R5<annotation encoding="application / x-tex">R_5< / annotation>< / semantics>< / com:Math> is hydrogen or <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C30<annotation encoding="application / x-tex">C_{30}< / annotation>< / semantics>< / com:Math> alkyl. A secondary linker (e.g., linking an active agent to the branching unit) may comprise a binding unit formed by a 1,3-dipolar cycloaddition reaction, hetero-Diels-Alder reaction, nucleophilic substitution reaction, non-aldol type carbonyl reaction, addition to a carbon-carbon multiple bond, oxidation reaction, or click reaction. A binding unit may be formed by a reaction between an acetylene and azide, or a non-aldol type carbonyl reaction, such as a reaction between an aldehyde or ketone group and hydrazine or alkoxyamine, reactions which allow for mild coupling of active agents and / or cleavage groups to the branching unit. Such binding units may be represented by Formula (A), (B), (C), or (D). [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (A) (B) (C) (D) <com:Math><semantics>L1<annotation encoding="application / x-tex">L_1< / annotation>< / semantics>< / com:Math> is a single bond or alkylene having 1 to 30 carbon atoms, preferably 10, 11, 12, 13, 14, 15, or 16 carbon atoms; R<com:Sub>11< / com:Sub> is hydrogen or an alkyl having 1 to 10 carbon atoms, preferably methyl; and L<com:Sub>2< / com:Sub> is an alkylene having 1 to 30 carbon atoms, preferably 10, 11, 12, 13, 14, 15, or 16 carbon atoms. In some embodiments, the ligand-drug conjugate as described above comprises a ligand, a linker, and an active agent, and has the formula: [Image disponible dans le document PDF, Image available in the PDF document] wherein: G represents a sugar, sugar acid, or a modified sugar; A represents the ligand; B represents the active agent; W represents <com:Math><semantics>−C(O)<annotation encoding="application / x-tex">-C(O)< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(O)NR′<annotation encoding="application / x-tex">-C(O)NR'< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(O)O<annotation encoding="application / x-tex">-C(O)O< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(O)2NR′<annotation encoding="application / x-tex">-S(O)_2NR'< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−P(O)R″NR′<annotation encoding="application / x-tex">-P(O)R''NR'< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(O)NR′<annotation encoding="application / x-tex">-S(O)NR'< / annotation>< / semantics>< / com:Math>, or <com:Math><semantics>−<annotation encoding="application / x-tex">-< / annotation>< / semantics>< / com:Math> PO<com:Sub>2< / com:Sub>NR'-, in each case where the C(O), S, or P is directly bound to the phenyl ring, and R' and R" are each independently hydrogen, (C<com:Sub>1< / com:Sub>-C<com:Sub>8< / com:Sub>)alkyl, (C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub>)cycloalkyl, <com:Math><semantics>(C1−C8)<annotation encoding="application / x-tex">(C_1-C_8)< / annotation>< / semantics>< / com:Math>alkoxy, <com:Math><semantics>(C1−C8)<annotation encoding="application / x-tex">(C_1-C_8)< / annotation>< / semantics>< / com:Math>alkylthio, mono- or di-<com:Math><semantics>(C1−C8)<annotation encoding="application / x-tex">(C_1-C_8)< / annotation>< / semantics>< / com:Math>alkylamino, <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math>alkylamino, <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math>alkylamino, <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math>alkylamino, <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math>alkylamino, <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math>alkylamino, <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math>alkylamino, <com:Math><semantics>(C3−C<annotation encoding="application / x-tex">(C_3-C< / annotation>< / semantics>< / com:Math> <com:Math><semantics>C20<annotation encoding="application / x-tex">C_{20}< / annotation>< / semantics>< / com:Math>)heteroaryl, or <com:Math><semantics>(C6−C20)<annotation encoding="application / x-tex">(C_6-C_{20})< / annotation>< / semantics>< / com:Math>aryl each Z independently represents hydrogen, (C<com:Sub>1< / com:Sub>-C<com:Sub>8< / com:Sub>)alkyl, or an electron-withdrawing group (such as an amide, carboxylic acid, carboxylic acid ester, halogen, cyano, or nitro), preferably a hydrogen, (C<com:Sub>1< / com:Sub>-C<com:Sub>8< / com:Sub>)alkyl, halogen, cyano, or nitro, most preferably hydrogen; n is an integer from 1 to 3, preferably 3; m is 0 or 1, preferably 1; L is a linker that comprises at least one branching unit (BR) and at least one primary linker (PL); R<com:Sub>1< / com:Sub> and R<com:Sub>2< / com:Sub> are each independently hydrogen, (C<com:Sub>1< / com:Sub>-C<com:Sub>8< / com:Sub>)alkyl, or (C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub>)cycloalkyl, preferably hydrogen, or <com:Math><semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R2<annotation encoding="application / x-tex">R_2< / annotation>< / semantics>< / com:Math> taken together with the carbon atom to which they are attached form a (C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub>)cycloalkyl ring. In any of the embodiments disclosed herein, the ligand is preferably an antibody. In some embodiments, the invention relates to an antibody-drug conjugate, comprising an antibody; at least one branched linker covalently coupled to the antibody; and at least two active agents covalently coupled to the branched linker. Preferably, at least two branched linkers are coupled to the antibody, and each branched linker is coupled to at least two active agents. Three or even four such branched linkers may be coupled to the antibody. In some embodiments, exactly one branched linker is coupled to the antibody. In certain embodiments, each branched linker is coupled to exactly two active agents. In some embodiments, all of the active agents of the antibody-drug conjugate are the same. In other embodiments, the antibody-drug conjugate comprises at least two different active agents. In some such embodiments, at least one branched linker is coupled to two different active agents. In some embodiments, each active agent is coupled to a branched linker by a cleavable (e.g., hydrolysable) bond, such as via a self-immolative group, e.g., a cleavage group as described in greater detail below. In preferred embodiments, each branched linker comprises a branching unit, and each active agent is coupled to the branching unit through a secondary linker and the branching unit is coupled to the antibody by a primary linker. For example, the branching unit may comprise a nitrogen atom, e.g., of an amine or an amide. In embodiments wherein the branching unit is an amide, the primary linker may comprise the carbonyl of the amide, or a secondary linker may comprise the carbonyl of the amide. In certain preferred embodiments, the branching unit is an amine. In other preferred embodiments, the branching unit is a lysine unit, e.g., such that one secondary linker extends from the α- nitrogen and the other secondary linker extends from the backbone nitrogen. In some embodiments, one or more or even each active agent is coupled to the branched linker through a cleavage group having the formula: [Image disponible dans le document PDF, Image available in the PDF document] wherein: G represents a sugar or sugar acid, preferably glucuronic acid; B represents the active agent; W represents an electron-withdrawing group, preferably -C(O)NR'-, where C(O) is bonded to the phenyl ring and NR' (which may be the amino group of an amino acid, preferably a hydrophilic amino acid) is bonded to L; each Z independently represents hydrogen, (C<com:Sub>1< / com:Sub>-C<com:Sub>8< / com:Sub>)alkyl, or an electron-withdrawing group (such as an amide, carboxylic acid, carboxylic acid ester, halogen, cyano, or nitro), preferably a hydrogen, (C<com:Sub>1< / com:Sub>-C<com:Sub>8< / com:Sub>)alkyl, halogen, cyano, or nitro, most preferably hydrogen; n is an integer from 1 to 3; 9 L represents a linkage to the antibody; <com:Math><semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R2<annotation encoding="application / x-tex">R_2< / annotation>< / semantics>< / com:Math> are each independently hydrogen, (<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C8<annotation encoding="application / x-tex">C_8< / annotation>< / semantics>< / com:Math>)alkyl, or (<com:Math><semantics>C3<annotation encoding="application / x-tex">C_3< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C8<annotation encoding="application / x-tex">C_8< / annotation>< / semantics>< / com:Math>)cycloalkyl, preferably hydrogen, or R<com:Sub>1< / com:Sub> and R<com:Sub>2< / com:Sub> taken together with the carbon atom to which they are attached form a (C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub>)cycloalkyl ring. Alternative cleavage groups include valine-citrulline-p-aminobenzylcarbamate (VC- PABC). In some embodiments, W is <com:Math><semantics>−C(O)<annotation encoding="application / x-tex">-C(O)< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>−C(O)NR′<annotation encoding="application / x-tex">-C(O)NR'< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>−C(O)O<annotation encoding="application / x-tex">-C(O)O< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>−S(O)2NR′<annotation encoding="application / x-tex">-S(O)_2NR'< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>−<annotation encoding="application / x-tex">-< / annotation>< / semantics>< / com:Math> P(O)R''NR'-, -S(O)NR'-, or -PO<com:Sub>2< / com:Sub>NR'-, in each case where the C(O), S, or P is preferably directly bound to the phenyl ring, and R' and R' are each independently hydrogen, (<com:Math><semantics>C1<annotation encoding="application / x-tex">C_{1}< / annotation>< / semantics>< / com:Math>- <com:Math><semantics>C8<annotation encoding="application / x-tex">C_8< / annotation>< / semantics>< / com:Math>)alkyl, <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math>cycloalkyl, <com:Math><semantics>(C1−C8)<annotation encoding="application / x-tex">(C_1-C_8)< / annotation>< / semantics>< / com:Math>alkoxy, <com:Math><semantics>(C1−C8)<annotation encoding="application / x-tex">(C_1-C_8)< / annotation>< / semantics>< / com:Math>alkylthio, mono- or di-<com:Math><semantics>(C1−C8)<annotation encoding="application / x-tex">(C_1-C_8)< / annotation>< / semantics>< / com:Math>alkyl, <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math>cycloalkyl, <com:Math><semantics>(C1−C8)<annotation encoding="application / x-tex">(C_1-C_8)< / annotation>< / semantics>< / com:Math>alkoxy, <com:Math><semantics>(C1−C8)<annotation encoding="application / x-tex">(C_1-C_8)< / annotation>< / semantics>< / com:Math>alkylthio, mono- or di-<com:Math><semantics>(C1−C8)<annotation encoding="application / x-tex">(C_1-C_8)< / annotation>< / semantics>< / com:Math>alkyl C<com:Sub>8< / com:Sub>)alkylamino, (C<com:Sub>3< / com:Sub>-C<com:Sub>20< / com:Sub>)heteroaryl, or (C<com:Sub>6< / com:Sub>-C<com:Sub>20< / com:Sub>)aryl. In certain preferred embodiments, W represents -C(O)NR'-, and the nitrogen of W is a nitrogen of an amino acid, preferably a hydrophilic amino acid. In some embodiments, W is -C(O)NR'-, where C(O) is bonded to the phenyl ring and NR' is bonded to L. In some embodiments, the sugar or sugar acid is a monosaccharide. In some embodiments, the sugar comprises: [Image disponible dans le document PDF, Image available in the PDF document] G is • R<com:Sub>3< / com:Sub> is hydrogen or a carboxyl protecting group; and each R<com:Sub>4< / com:Sub> is independently hydrogen or a hydroxyl protecting group. In some such embodiments, <com:Math><semantics>R3<annotation encoding="application / x-tex">R_3< / annotation>< / semantics>< / com:Math> is hydrogen and each <com:Math><semantics>R4<annotation encoding="application / x-tex">R_4< / annotation>< / semantics>< / com:Math> is hydrogen. In some embodiments, each Z represents hydrogen and n is 3. In certain preferred embodiments: G is glucuronic acid; W is -C(O)NR'-, where C(O) is bonded to the phenyl ring and NR' is bonded to L; Z represents hydrogen; n is 3; and <com:Math><semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R2<annotation encoding="application / x-tex">R_2< / annotation>< / semantics>< / com:Math> each represent hydrogen. In some embodiments of the invention, the primary linker of the antibody-drug conjugate comprises an alkylene having 1 to 100, preferably 1-50, carbon atoms, and either: the alkylene includes at least one unsaturated bond; the alkylene includes at least one heteroarylene; a carbon atom of the alkylene is replaced by one or more heteroatoms selected from nitrogen (N), oxygen (O), and sulfur (S); or the alkylene is further substituted with one or more alkyls having 1 to 20 carbon atoms. In some such embodiments, the at least one carbon atom of the alkylene is replaced by a nitrogen, the primary linker comprises at least two atoms of a hydrophilic amino acid, and the nitrogen forms a peptide bond with the backbone carbonyl of the hydrophilic amino acid. The hydrophilic amino acid may be, for example, arginine, aspartate, asparagine, glutamate, glutamine, histidine, lysine, ornithine, proline, serine, or threonine. In some embodiments, the branched linker of the antibody-drug conjugate comprises an amino acid having a side chain with a moiety that bears a charge at neutral pH in aqueous solution, preferably an arginine, aspartate, glutamate, lysine, or ornithine. This amino acid may be present anywhere in the branched linker. For example, it may covalently link an oxime of the branched linker to a polyethylene glycol unit of the branched linker. Alternatively or additionally, such an amino acid may by present in a secondary linker, optionally in each secondary linker. In certain preferred embodiments, the branched linker of the antibody-drug conjugate is covalently bound to the antibody by a thioether bond, and the thioether bond comprises a sulfur atom of a cysteine of the antibody, most preferably a C-terminal cysteine, which may be part of amino acid motif that is recognized by an isoprenoid transferase. For example, the amino acid motif may be a sequence selected from CXX, CXC, XCXC, XXCC, and CYYX; C represents cysteine; Y, independently for each occurrence, represents an aliphatic amino acid; X, independently for each occurrence, represents glutamine, glutamate, serine, cysteine, methionine, alanine, or leucine; and the thioether bond comprises a sulfur atom of a cysteine of the amino acid motif. In some embodiments, the amino acid motif is: a sequence CYYX; and Y, independently for each occurrence, represents alanine, isoleucine, leucine, methionine, or valine. In certain preferred embodiments, the amino acid motif is a sequence CVIM or CVLL. In some embodiments, at least one of the seven amino acids preceding the amino acid motif is glycine. In some embodiments, at least three of the seven amino acids preceding the amino acid motif are each independently selected from glycine and proline. In some embodiments, one to ten amino acids immediately preceding the amino acid motif are glycine. In certain preferred embodiments, at least one, two, three, four, five, six, seven, eight, nine, or ten amino acids immediately preceding the amino acid motif are glycine, most preferably at least five. In certain preferred embodiments, each of the one, two, three, four, five, six, seven, eight, nine, or ten amino acids preceding the amino acid motif is glycine. In some embodiments, a C-terminus of the antibody comprises the amino acid sequence GGGGGGCVIM. In some embodiments, the above-described thioether bond comprises a carbon atom [Image disponible dans le document PDF, Image available in the PDF document] of at least one isoprenyl unit, represented by . In preferred embodiments, n is 1 or 2, most preferably 2. In some embodiments of the invention, the branched linker comprises an oxime, and the at least one isoprenyl unit covalently links the oxime to the antibody. In some embodiments, the branched linker comprises: [Image disponible dans le document PDF, Image available in the PDF document] In some embodiments, the linker may comprise [Image disponible dans le document PDF, Image available in the PDF document] In some embodiments of the invention, the primary linker and / or secondary linker (preferably each secondary linker) comprises at least one polyethylene glycol unit, [Image disponible dans le document PDF, Image available in the PDF document] represented by either . The polyethylene glycol unit may comprise 1 to 19 -OCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>- units, preferably 4 to 20 -OCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>- units. In some preferred embodiments, the linker may comprise 1 to 20 -OCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>- units. In certain preferred embodiments, the linker may comprise 1 to 12 -OCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>- units. In other preferred embodiments, the linker may comprise 3 to 12 -OCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>- units. In some embodiments, the linker comprises an oxime, and the at least one polyethylene glycol unit covalently links the oxime to the peptide. In some embodiments of the invention, the primary linker, the secondary linker (preferably each secondary linker), or both comprise a connection unit represented by - <com:Math><semantics>(CH2)r(V(CH2)p)q−<annotation encoding="application / x-tex">(CH_2)_r(V(CH_2)_p)_{q^-}< / annotation>< / semantics>< / com:Math>, wherein: r is an integer from 1 to 10, preferably 2; p is an integer from 0 to 12, preferably 2; q is an integer from 1 to 20; [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>R21<annotation encoding="application / x-tex">R_{21}< / annotation>< / semantics>< / com:Math> to <com:Math><semantics>R25<annotation encoding="application / x-tex">R_{25}< / annotation>< / semantics>< / com:Math> are each independently hydrogen, <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>(C6−C20)<annotation encoding="application / x-tex">(C_6-C_{20})< / annotation>< / semantics>< / com:Math> aryl, [Image disponible dans le document PDF, Image available in the PDF document] In some embodiments, the primary linker, the secondary linker (preferably each secondary linker), or both comprise a connection unit represented by <com:Math><semantics>−(CH2)r(V(CH2)p)q−<annotation encoding="application / x-tex">-(CH_2)_r(V(CH_2)_p)_{q^-}< / annotation>< / semantics>< / com:Math>, - [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] wherein: r is an integer from 0 to 10; p is an integer from 1 to 10; q is an integer from 1 to 20; V and Y are each independently a single bond, -O-, -S-, -NR<com:Sub>21< / com:Sub>-, -C(O)NR<com:Sub>22< / com:Sub>-, - [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] In some embodiments of these linkers, q is an integer from 4 to 20. In some embodiments of these linkers, q is an integer from 6 to 20. In certain preferred embodiments, q is an integer from 1 to 10. In other preferred embodiments, q is 2, 5, or 11. In some embodiments of these linkers, r is preferably 2. In some embodiments of these linkers, p is preferably 2. In some embodiments, V and Y are each independently -O-. In some embodiments of these linkers: r is 2; p is 2; q is 2, 5, or 11, and V is -O-. In some embodiments of the invention, the primary linker, the secondary linker (preferably each secondary linker), or both comprises a connection unit represented by - <com:Math><semantics>(CH2CH2X)w<annotation encoding="application / x-tex">(CH_2CH_2X)_{w}< / annotation>< / semantics>< / com:Math>-, wherein: X represents -O-, <com:Math><semantics>(C1−C8)<annotation encoding="application / x-tex">(C_1-C_8)< / annotation>< / semantics>< / com:Math>alkylene, or -NR<com:Sub>21< / com:Sub>-, preferably -O-; R<com:Sub>21< / com:Sub> represents hydrogen, (C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkyl, (C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkyl(C<com:Sub>6< / com:Sub>-C<com:Sub>20< / com:Sub>)aryl, or (C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkyl(C<com:Sub>3< / com:Sub>- C<com:Sub>20< / com:Sub>)heteroaryl, preferably hydrogen; and w is an integer from 1 to 12, preferably 1, 3, 6, or 12. In some embodiments X is -O- and w is an integer from 6 to 12. In some embodiments of the invention, the primary linker comprises a binding unit formed by a 1,3-dipolar cycloaddition reaction, hetero-Diels-Alder reaction, nucleophilic substitution reaction, non-aldol type carbonyl reaction, addition to carbon-carbon multiple bond, oxidation reaction, or click reaction. In some embodiments, the binding unit is formed by a reaction between acetylene and azide, or a reaction between an aldehyde or ketone group and a hydrazine or alkoxyamine. In some embodiments, the binding unit is represented by any one of Formulas A, B, C, or D, preferably D: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (A) (B) (C) (D) wherein: <com:Math><semantics>L1<annotation encoding="application / x-tex">L_1< / annotation>< / semantics>< / com:Math> is a single bond or alkylene having 1 to 30 carbon atoms, preferably 12; <com:Math><semantics>R11<annotation encoding="application / x-tex">R_{11}< / annotation>< / semantics>< / com:Math> is hydrogen or alkyl having 1 to 10 carbon atoms, preferably methyl; and <com:Math><semantics>L2<annotation encoding="application / x-tex">L_2< / annotation>< / semantics>< / com:Math> is alkylene having 1 to 30 carbon atoms, preferably 11. In some embodiments the primary linker comprises [Image disponible dans le document PDF, Image available in the PDF document] V is a single bond, -O-, -S-, -NR<com:Sub>21< / com:Sub>-, -C(O)NR<com:Sub>22< / com:Sub>-, -NR<com:Sub>23< / com:Sub>C(O)-, -NR<com:Sub>24< / com:Sub>SO<com:Sub>2< / com:Sub>-, or - SO<com:Sub>2< / com:Sub>NR<com:Sub>25< / com:Sub>-, preferably -O-; <com:Math><semantics>R21<annotation encoding="application / x-tex">R_{21}< / annotation>< / semantics>< / com:Math> to <com:Math><semantics>R25<annotation encoding="application / x-tex">R_{25}< / annotation>< / semantics>< / com:Math> are each independently hydrogen, (<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math>)alkyl, (<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math>)alkyl(<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C20<annotation encoding="application / x-tex">C_{20}< / annotation>< / semantics>< / com:Math>)aryl, or <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math>alkyl<com:Math><semantics>(C3−C20)<annotation encoding="application / x-tex">(C_3-C_{20})< / annotation>< / semantics>< / com:Math>heteroaryl; r is an integer of 1 to 10, preferably 2 or 3; p is an integer of 0 to 10, preferably 1 or 2; q is an integer of 1 to 20, preferably 1 to 6; and <com:Math><semantics>L1<annotation encoding="application / x-tex">L_1< / annotation>< / semantics>< / com:Math> is a single bond. In some embodiments of the invention, the branched linker comprises an O- substituted oxime; wherein a) the oxygen atom of the oxime is substituted with a group that covalently links the oxime to the active agent, e.g., via the branching unit; and the carbon atom of the oxime is substituted with a group that covalently links the oxime to the antibody; or b) the oxygen atom of the oxime is substituted with a group that covalently links the oxime to the antibody; and the carbon atom of the oxime is substituted with a group that covalently links the oxime to the active agent, e.g., via the branching unit. In some embodiments, the antibody-drug conjugate comprises the structure of Formula II: [Image disponible dans le document PDF, Image available in the PDF document] (II) wherein: B and B' represent active agents, which may be the same or different; n, independently for each occurrence, represents an integer from 0 to 30; f, independently for each occurrence, represents an integer from 0 to 30; and L represents a linkage to the antibody. In some embodiments, n is an integer from 1 to 10. In some embodiments, n is an integer from 4 to 20. In some embodiments, f is an integer from 1 to 10. In some embodiments, f is an integer from 4 to 20. Preferably n and f are selected such that n + f is less than 20, e.g., less than 15. In some embodiments, the linker comprises an oxime, and the at least one polyethylene glycol unit covalently links the oxime to the active agent. In some embodiments of the invention, the antibody is a monoclonal antibody, polyclonal antibody, antibody fragment, Fab, Fab', Fab'-SH, F(ab')<com:Sub>2< / com:Sub>, Fv, single chain Fv ("scFv"), diabody, linear antibody, bispecific antibody, multispecific antibody, chimeric antibody, humanized antibody, human antibody, or fusion protein comprising the antigen- binding portion of an antibody. In some embodiments of the invention, the antibody is selected from muromonab- CD3 abciximab, rituximab, daclizumab, palivizumab, infliximab, trastuzumab, etanercept, basiliximab, gemtuzumab, alemtuzumab, ibritumomab, adalimumab, alefacept, omalizumab, efalizumab, tositumomab, cetuximab, ABT-806, bevacizumab, natalizumab, ranibizumab, panitumumab, eculizumab, rilonacept, certolizumab, romiplostim, AMG-531, golimumab, ustekinumab, ABT-874, belatacept, belimumab, atacicept, an anti-CD20 antibody, canakinumab, tocilizumab, atlizumab, mepolizumab, pertuzumab, HuMax CD20, tremelimumab, ticilimumab, ipilimumab, IDEC-114, inotuzumab, HuMax EGFR, aflibercept, HuMax-CD4, teplizumab, otelixizumab, catumaxomab, the anti-EpCAM antibody IGN101, adecatumomab, oregovomab, dinutuximab, girentuximab, denosumab, bapineuzumab, motavizumab, efumgumab, raxibacumab, LY2469298, and veltuzumab. In some embodiments of the invention, the active agent is independently selected from chemotherapeutic agents and toxins. In some embodiments of the invention, the active agent is independently selected from: (a) erlotinib, bortezomib, fulvestrant, sutent, letrozole, imatinib mesylate, PTK787 / ZK 222584, oxaliplatin, 5-fluorouracil, leucovorin, rapamycin, lapatinib, lonafarnib, sorafenib, gefitinib, AG1478, AG1571, thiotepa, cyclophosphamide, busulfan, improsulfan, piposulfan, benzodopa, carboquone, meturedopa, uredopa, ethylenimine, altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide, trimethylolomelamine, bullatacin, bullatacinone, camptothecin, camptothecin derivatives and metabolites (SN-38), topotecan, bryostatin, callystatin, CC-1065, adozelesin, carzelesin, bizelesin, cryptophycin 1, cryptophycin 8, dolastatin, duocarmycin, KW-2189, CB1-TM1, eleutherobin, pancratistatin, sarcodictyin, spongistatin, chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard, carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimnustine, calicheamicin, calicheamicin gamma 1, calicheamicin omega 1, dynemicin, dynemicin A, clodronate, esperamicin, neocarzinostatin chromophore, aclacinomysins, actinomycin, antrmycin, azaserine, bleomycins, cactinomycin, carabicin, carninomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubucin, 6-diazo-5-oxo-L-norleucine, doxorubicin, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino- doxorubucin, liposomal doxorubicin, deoxydoxorubicin, epirubicin, esorubicin, marcellomycin, mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptomigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin, 5-fluorouracil, denopterin, methotrexate, pteropterin, trimetrexate, fludarabine, 6-mercaptopurine, thiamiprine, thiguanine, ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone, aminoglutethimide, mitotane, trilostane, folinic acid, aceglatone, aldophosphamide glycoside, aminolevulinic acid, eniluracil, amsacrine, bestrabucil, bisantrene, edatraxate, defofamine, demecolcine, diaziquone, elfornithine, elliptinium acetate, etoglucid, gallium nitrate, hydroxyurea, lentinan, lonidainine, maytansine, ansamitocins, mitoguazone, mitoxantrone, mopidanmol, nitraerine, pentostatin, phenamet, pirarubicin, losoxantrone, 2-ethylhydrazide, procarbazine, polysaccharide-k, razoxane, rhizoxin, sizofiran, spirogermanium, tenuazonic acid, triaziquone, 2,2',2"- trichlorotriethylamine, T-2 toxin, verracurin A, roridin A, and anguidine, urethane, vindesine, dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman, gacytosine, arabinoside, cyclophosphamide, thiotepa, paclitaxel, albumin-engineered nanoparticle formulation of paclitaxel, doxetaxel, chlorambucil, gemcitabine, 6-thioguanine, mercaptopurine, cisplatin, carboplatin, vinblastine, platinum, etoposide, ifosfamide, mitoxantrone, vincristine, vinorelbine, novantrone, teniposide, edatrexate, daunomycin, aminopterin, xeloda, ibandronate, CPT-11, topoisomerase inhibitor RFS 2000, difluoromethylornithine, retinoic acid, capecitabine, or pharmaceutically acceptable salts, solvates or acids of any of the foregoing; (b) monokine, a lymphokine, a traditional polypeptide hormone, parathyroid hormone, thyroxine, relaxin, prorelaxin, a glycoprotein hormone, follicle stimulating hormone, thyroid stimulating hormone, luteinizing hormone, hepatic growth factor fibroblast growth factor, prolactin, placental lactogen, tumor necrosis factor-α, tumor necrosis factor-β, mullerian-inhibiting substance, mouse gonadotropin-associated peptide, inhibin, activin, vascular endothelial growth factor, thrombopoietin, erythropoietin, an osteoinductive factor, an interferon, interferon-<com:Math><semantics>α<annotation encoding="application / x-tex">\alpha< / annotation>< / semantics>< / com:Math>, interferon-<com:Math><semantics>β<annotation encoding="application / x-tex">\beta< / annotation>< / semantics>< / com:Math>, interferon-<com:Math><semantics>γ<annotation encoding="application / x-tex">\gamma< / annotation>< / semantics>< / com:Math>, a colony stimulating factor ("CSF"), macrophage-CSF, granulocyte-macrophage-CSF, granulocyte- CSF, an interleukin ("IL"), IL-1, IL-1α, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL- 10, IL-11, IL-12, a tumor necrosis factor, TNF-α, TNF-β, a polypeptide factor, LIF, kit ligand, or a combination of any of the foregoing; (c) diphtheria toxin, botulium toxin, tetanus toxin, dysentery toxin, cholera toxin, amanitin, amanitin derivatives, <com:Math><semantics>α<annotation encoding="application / x-tex">\alpha< / annotation>< / semantics>< / com:Math>-amanitin, pyrrolobenzodiazepine, pyrrolobenzodiazepine derivatives, tetrodotoxin, brevetoxin, ciguatoxin, ricin, AM toxin, tubulysin, geldanamycin, maytansinoid, calicheamicin, daunomycin, doxorubicin, methotrexate, vindesine, SG2285, dolastatin, a dolastatin analog, auristatin, cryptophycin, camptothecin, camptothecin derivatives and metabolites (SN-38), rhizoxin, a rhizoxin derivative, CC-1065, a CC-1065 analogue or derivative, duocarmycin, an enediyne antibiotic, esperamicin, epothilone, azonafide, aplidine, a toxoid, or a combination of any of the foregoing; (d) an affinity ligand, wherein the affinity ligand is a substrate, an inhibitor, a stimulating agent, a neurotransmitter, a radioisotope, or a combination of any of the foregoing; (e) a radioactive label, <com:Sup>32< / com:Sup>P, <com:Sup>35< / com:Sup>S, a fluorescent dye, an electron dense reagent, an enzyme, biotin, streptavidin, dioxigenin, a hapten, an immunogenic protein, a nucleic acid molecule with a sequence complementary to a target, or a combination of any of the foregoing; (f) an immunomodulatory compound, an anti-cancer agent, an anti-viral agent, an anti-bacterial agent, an anti-fungal agent, and an anti-parasitic agent, or a combination of any of the foregoing; (g) tamoxifen, raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, or toremifene; (h) 4(5)-imidazoles, aminoglutethimide, megestrol acetate, exemestane, letrozole, or anastrozole; (i) flutamide, nilutamide, bicalutamide, leuprolide, goserelin, or troxacitabine; (j) an aromatase inhibitor; (k) a protein kinase inhibitor; (1) a lipid kinase inhibitor; (m) an antisense oligonucleotide; (n) a ribozyme; (o) a vaccine; and (p) an anti-angiogenic agent. In some embodiments of the invention, the active agent is amanitin, auristatin, calicheamicin, camptothecin, camptothecin derivatives and metabolites (SN-38), cryptophycin, daunomycin, dolastatin, doxorubicin, duocarmycin, epothilone, esperamicin, geldanamycin, maytansinoid, methotrexate, monomethyl auristatin E ("MMAE"), monomethyl auristatin F ("MMAF"), pyrrolobenzodiazepine, rhizoxin, SG2285, tubulysin, vindesine, toxoid, or a derivative of any one of the foregoing. In some embodiments, the active agent is amanitin, MMAE, or MMAF, or a derivative of any one of the foregoing. In some embodiments of the invention, the active agent is: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] - - - , [Image disponible dans le document PDF, Image available in the PDF document] , [Image disponible dans le document PDF, Image available in the PDF document] wherein y is an integer of 1 to 10. Structures and components of related antibody-drug conjugates are disclosed in PCT / KR2015 / 005299, in particular for the chemical formulae and generic structures of antibody-drug conjugates, their component parts (e.g., linkers, cleavage groups, etc.), and their preparation and use as disclosed therein. In certain preferred embodiments, the various conjugates and other aspects of the present invention specifically exclude the various structures and methods disclosed in PCT / KR2015 / 005299. In some embodiments, the invention provides a pharmaceutical composition comprising an antibody-drug conjugate as described herein. A pharmaceutical composition may further comprise a therapeutically effective amount of chemotherapeutic agent. In some embodiments, the invention provides a method of treating cancer in a subject, comprising administering such a pharmaceutical composition to the subject. In some embodiments, the subject is a mammal, e.g., selected from rodents, lagomorphs, felines, canines, porcines, ovines, bovines, equines, and primates. In some embodiments, the subject is preferably a human. In some embodiments, the invention provides a method for making an antibody- drug conjugate as described herein, comprising reacting a biomolecule with a prodrug, wherein: the biomolecule comprises an antibody and a ketone or aldehyde; the prodrug comprises an alkoxyamine; and the reaction produces an oxime, thereby covalently linking the antibody to the prodrug. In some embodiments, the method further comprises isoprenylating the antibody, thereby producing the biomolecule, wherein: the antibody comprises an isoprenylation sequence; isoprenylating the antibody comprises incubating the antibody with an isoprenoid transferase and an isoprenoid transferase substrate; and the substrate comprises the ketone or aldehyde. In some embodiments, the isoprenoid transferase is farnesyltransferase or geranylgeranyltransferase. In some embodiments, the invention provides a method for making a ligand-drug conjugate as described herein, comprising isoprenylating a ligand, wherein the ligand comprises an amino acid motif that is recognized by an isoprenoid transferase; isoprenylating the ligand comprises incubating the ligand with an isoprenoid transferase and an isoprenoid transferase substrate; and the substrate comprises the active agent. In some embodiments, the invention provides a method for making a ligand-drug conjugate as described herein, comprising isoprenylating a ligand, wherein the ligand comprises an amino acid motif that is recognized by an isoprenoid transferase; isoprenylating the ligand comprises incubating the ligand with an isoprenoid transferase and an isoprenoid transferase substrate; and the substrate comprises the active agent. In other embodiments, the invention relates to an antibody-drug conjugate, comprising an antibody; at least one branched linker covalently coupled to the antibody, the branched linker comprising a branching unit covalently coupled to the antibody by a primary linker; an active agent covalently coupled to the branching unit by a first branch; and a second branch that comprises a polyethylene glycol moiety covalently coupled to the branching unit. Preferably, at least two branched linkers are coupled to the antibody, each branched linker coupled to exactly one active agent. Three or even four such branched linkers may be coupled to the antibody. In some such embodiments, at least two different active agents are coupled to different branched linkers. In some embodiments, only one branched linker is coupled to the antibody. In certain preferred embodiments, each branched linker is coupled to exactly one active agent. In some embodiments, the active agent is coupled to the first branch by a cleavable (e.g., hydrolysable) bond, such as via a self-immolative group, e.g., a cleavage group as described in greater detail below. In some embodiments, the branching unit may comprise a nitrogen atom, e.g., of an amine or an amide. In certain preferred embodiments, the branching unit is an amine. In embodiments wherein the branching unit is an amide, the primary linker may comprise the carbonyl of the amide. In some embodiments wherein the branching unit is an amide and the first branch or the second branch may comprise the carbonyl of the amide. In other preferred embodiments, the branching unit is a lysine unit. In some embodiments, one or more or even each active agent is coupled to the first branch through a cleavage group having the formula: [Image disponible dans le document PDF, Image available in the PDF document] wherein: G represents a sugar or sugar acid, preferably glucuronic acid; B represents the active agent; W represents an electron-withdrawing group, preferably -C(O)NR'-, where C(O) is bonded to the phenyl ring and NR' (which may be the amino group of an amino acid, preferably a hydrophilic amino acid) is bonded to L; each Z independently represents hydrogen, <com:Math><semantics>(C1−C8)<annotation encoding="application / x-tex">(C_1-C_8)< / annotation>< / semantics>< / com:Math> alkyl, or an electron-withdrawing group (such as an amide, carboxylic acid, carboxylic acid ester, halogen, cyano, or nitro), preferably a hydrogen, (C<com:Sub>1< / com:Sub>-C<com:Sub>8< / com:Sub>)alkyl, halogen, cyano, or nitro, most preferably hydrogen; n is an integer from 1 to 3; L represents a linkage to the antibody; <com:Math><semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R2<annotation encoding="application / x-tex">R_2< / annotation>< / semantics>< / com:Math> are each independently hydrogen, <com:Math><semantics>(C1−C8)<annotation encoding="application / x-tex">(C_1-C_8)< / annotation>< / semantics>< / com:Math>alkyl, or <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math>cycloalkyl, preferably hydrogen, or R<com:Sub>1< / com:Sub> and R<com:Sub>2< / com:Sub> taken together with the carbon atom to which they are attached form a (C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub>)cycloalkyl ring. In some embodiments, the active agent is coupled to the first branch through a cleavage group having the formula: [Image disponible dans le document PDF, Image available in the PDF document] wherein: G represents a sugar, sugar acid, or modified sugar, preferably a sugar or sugar acid, most preferably glucuronic acid; W represents <com:Math><semantics>−C(O)<annotation encoding="application / x-tex">-C(O)< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(O)NR′<annotation encoding="application / x-tex">-C(O)NR'< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(O)O<annotation encoding="application / x-tex">-C(O)O< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(O)2NR′<annotation encoding="application / x-tex">-S(O)_2NR'< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−P(O)R″NR′<annotation encoding="application / x-tex">-P(O)R''NR'< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(O)NR′<annotation encoding="application / x-tex">-S(O)NR'< / annotation>< / semantics>< / com:Math>, or - <com:Math><semantics>PO2NR′<annotation encoding="application / x-tex">PO_2NR'< / annotation>< / semantics>< / com:Math>-, in each case where the <com:Math><semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>< / com:Math>, S, or P is preferably directly bound to the phenyl ring, and R' are each independently hydrogen, (C<com:Sub>1< / com:Sub>-C<com:Sub>8< / com:Sub>)alkyl, mono- or di-carboxyl(<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C8<annotation encoding="application / x-tex">C_8< / annotation>< / semantics>< / com:Math>)alkyl, (<com:Math><semantics>C3<annotation encoding="application / x-tex">C_3< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C8<annotation encoding="application / x-tex">C_8< / annotation>< / semantics>< / com:Math>)cycloalkyl, (<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C8<annotation encoding="application / x-tex">C_8< / annotation>< / semantics>< / com:Math>)alkoxy, (<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C8<annotation encoding="application / x-tex">C_8< / annotation>< / semantics>< / com:Math>)alkylthio, mono- or di-<com:Math><semantics>(C1−C8)<annotation encoding="application / x-tex">(C_1-C_8)< / annotation>< / semantics>< / com:Math>alkylamino, <com:Math><semantics>(C3−C20)<annotation encoding="application / x-tex">(C_3-C_{20})< / annotation>< / semantics>< / com:Math>heteroaryl, or <com:Math><semantics>(C6−C20)<annotation encoding="application / x-tex">(C_6-C_{20})< / annotation>< / semantics>< / com:Math>aryl and W is coupled directly or indirectly to the branching unit; each Z independently represents hydrogen, (C<com:Sub>1< / com:Sub>-C<com:Sub>8< / com:Sub>)alkyl, or an electron-withdrawing group (such as an amide, carboxylic acid, carboxylic acid ester, halogen, cyano, or nitro), preferably a hydrogen, (C<com:Sub>1< / com:Sub>-C<com:Sub>8< / com:Sub>)alkyl, halogen, cyano, or nitro, most preferably hydrogen; n is an integer from 1 to 3; m is 0 or 1, preferably 1; and <com:Math><semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R2<annotation encoding="application / x-tex">R_2< / annotation>< / semantics>< / com:Math> are each independently hydrogen, (<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C8<annotation encoding="application / x-tex">C_8< / annotation>< / semantics>< / com:Math>)alkyl, or (<com:Math><semantics>C3<annotation encoding="application / x-tex">C_3< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C8<annotation encoding="application / x-tex">C_8< / annotation>< / semantics>< / com:Math>)cycloalkyl, preferably hydrogen, or R<com:Sub>1< / com:Sub> and R<com:Sub>2< / com:Sub> taken together with the carbon atom to which they are attached form a (C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub>)cycloalkyl ring. In some embodiments, the active agent is coupled to the first branch through a cleavage group having the formula: [Image disponible dans le document PDF, Image available in the PDF document] or a pharmaceutically acceptable salt thereof, wherein G represents a sugar, sugar acid, or modified sugar, preferably a sugar or sugar acid, most preferably glucuronic acid; B is a unit covalently attached to the active agent, W represents <com:Math><semantics>−C(O)<annotation encoding="application / x-tex">-C(O)< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>−C(O)NR′<annotation encoding="application / x-tex">-C(O)NR'< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>−C(O)O<annotation encoding="application / x-tex">-C(O)O< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>−S(O)2NR′<annotation encoding="application / x-tex">-S(O)_2NR'< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>−P(O)R″NR′<annotation encoding="application / x-tex">-P(O)R''NR'< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>−S(O)NR′<annotation encoding="application / x-tex">-S(O)NR'< / annotation>< / semantics>< / com:Math>-, or <com:Math><semantics>−<annotation encoding="application / x-tex">-< / annotation>< / semantics>< / com:Math> <com:Math><semantics>PO2NR′<annotation encoding="application / x-tex">PO_2NR'< / annotation>< / semantics>< / com:Math>-, in each case where the C(O), S, or P is directly bound to the phenyl ring, and R' and R" are each independently hydrogen, (C<com:Sub>1< / com:Sub>-C<com:Sub>8< / com:Sub>)alkyl, (C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub>)cycloalkyl, <com:Math><semantics>(C1−C8)<annotation encoding="application / x-tex">(C_1-C_8)< / annotation>< / semantics>< / com:Math>alkoxy, <com:Math><semantics>(C1−C8)<annotation encoding="application / x-tex">(C_1-C_8)< / annotation>< / semantics>< / com:Math>alkylthio, mono- or di-<com:Math><semantics>(C1−C8)<annotation encoding="application / x-tex">(C_1-C_8)< / annotation>< / semantics>< / com:Math>alkylamino, <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math>alkylamino, <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math>alkylamino, <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math>alkylamino, <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math>alkylamino, <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math>alkylamino, <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math>alkylamino, <com:Math><semantics>(C3−C<annotation encoding="application / x-tex">(C_3-C< / annotation>< / semantics>< / com:Math> <com:Math><semantics>C20<annotation encoding="application / x-tex">C_{20}< / annotation>< / semantics>< / com:Math>)heteroaryl, or <com:Math><semantics>(C6−C20)<annotation encoding="application / x-tex">(C_6-C_{20})< / annotation>< / semantics>< / com:Math>aryl each Z independently represents hydrogen, <com:Math><semantics>(C1−C8)<annotation encoding="application / x-tex">(C_1-C_8)< / annotation>< / semantics>< / com:Math> alkyl, or an electron-withdrawing group (such as an amide, carboxylic acid, carboxylic acid ester, halogen, cyano, or nitro), preferably a hydrogen, <com:Math><semantics>(C1−C8)<annotation encoding="application / x-tex">(C_1-C_8)< / annotation>< / semantics>< / com:Math>alkyl, halogen, cyano, or nitro, most preferably hydrogen; n is an integer from 1 to 3, preferably 3; L represents a bond to a linker or a branching unit; <com:Math><semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R2<annotation encoding="application / x-tex">R_2< / annotation>< / semantics>< / com:Math> are each independently hydrogen, <com:Math><semantics>(C1−C8)<annotation encoding="application / x-tex">(C_1-C_8)< / annotation>< / semantics>< / com:Math>alkyl, or <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math>cycloalkyl, preferably hydrogen, or R<com:Sub>1< / com:Sub> and R<com:Sub>2< / com:Sub> taken together with the carbon atom to which they are attached form a (C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub>)cycloalkyl ring. In some embodiments, W is -C(O)-, -C(O)NR'-, -C(O)O-, -S(O)<com:Sub>2< / com:Sub>NR'-, - P(O)R''NR'-, -S(O)NR'-, or -PO<com:Sub>2< / com:Sub>NR'-, in each case where the C(O), S, or P is preferably directly bound to the phenyl ring, and R' and R" are each independently hydrogen, (C1- <com:Math><semantics>C8<annotation encoding="application / x-tex">C_8< / annotation>< / semantics>< / com:Math>)alkyl, <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math>cycloalkyl, <com:Math><semantics>(C1−C8)<annotation encoding="application / x-tex">(C_1-C_8)< / annotation>< / semantics>< / com:Math>alkoxy, <com:Math><semantics>(C1−C8)<annotation encoding="application / x-tex">(C_1-C_8)< / annotation>< / semantics>< / com:Math>alkylthio, mono- or di-<com:Math><semantics>(C1−C8)<annotation encoding="application / x-tex">(C_1-C_8)< / annotation>< / semantics>< / com:Math>alkyl, <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math>cycloalkyl, <com:Math><semantics>(C1−C8)<annotation encoding="application / x-tex">(C_1-C_8)< / annotation>< / semantics>< / com:Math>alkoxy, <com:Math><semantics>(C1−C8)<annotation encoding="application / x-tex">(C_1-C_8)< / annotation>< / semantics>< / com:Math>alkylthio, mono- or di-<com:Math><semantics>(C1−C8)<annotation encoding="application / x-tex">(C_1-C_8)< / annotation>< / semantics>< / com:Math>alkyl <com:Math><semantics>C8<annotation encoding="application / x-tex">C_8< / annotation>< / semantics>< / com:Math>)alkylamino, <com:Math><semantics>(C3−C20)<annotation encoding="application / x-tex">(C_3-C_{20})< / annotation>< / semantics>< / com:Math>heteroaryl, or <com:Math><semantics>(C6−C20)<annotation encoding="application / x-tex">(C_6-C_{20})< / annotation>< / semantics>< / com:Math>aryl, preferably hydrogen. In certain preferred embodiments, W represents -C(O)NR'-, and the nitrogen of W is a nitrogen of an amino acid, preferably a hydrophilic amino acid. In some embodiments, W is -C(O)NR'-, where C(O) is bonded to the phenyl ring and NR' is bonded to L. In some embodiments, the sugar or sugar acid is a monosaccharide. In some embodiments, the sugar comprises: [Image disponible dans le document PDF, Image available in the PDF document] G is R<com:Sub>3< / com:Sub> is hydrogen or a carboxyl protecting group; and each R<com:Sub>4< / com:Sub> is independently hydrogen or a hydroxyl protecting group. In some such embodiments, <com:Math><semantics>R3<annotation encoding="application / x-tex">R_3< / annotation>< / semantics>< / com:Math> is hydrogen and each <com:Math><semantics>R4<annotation encoding="application / x-tex">R_4< / annotation>< / semantics>< / com:Math> is hydrogen. In some embodiments, each Z represents hydrogen and n is 3. In certain preferred embodiments: G is glucuronic acid; W is -C(O)NR'-, where C(O) is bonded to the phenyl ring and NR' is bonded to L; Z represents hydrogen; n is 3; and <com:Math><semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R2<annotation encoding="application / x-tex">R_2< / annotation>< / semantics>< / com:Math> each represent hydrogen. In some embodiments of the invention, the primary linker of the antibody-drug conjugate comprises an alkylene having 1 to 100, preferably 1-50, carbon atoms, and either: the alkylene includes at least one unsaturated bond; the alkylene includes at least one heteroarylene; a carbon atom of the alkylene is replaced by one or more heteroatoms selected from nitrogen (N), oxygen (O), and sulfur (S); or the alkylene is further substituted with one or more alkyls having 1 to 20 carbon atoms. In some such embodiments, the at least one carbon atom of the alkylene is replaced by a nitrogen, the primary linker comprises at least two atoms of a hydrophilic amino acid, and the nitrogen forms a peptide bond with the backbone carbonyl of the hydrophilic amino acid. The hydrophilic amino acid is arginine, aspartate, asparagine, glutamate, glutamine, histidine, lysine, ornithine, proline, serine, or threonine. In some embodiments, the primary linker comprises an amino acid, and the amino acid comprises having a side chain with a moiety that bears a charge at neutral pH in aqueous solution, preferably an arginine, aspartate, glutamate, lysine, or ornithine. This amino acid may be present anywhere in the branched linker. For example, it may covalently link an oxime of the branched linker to a polyethylene glycol unit of the branched linker. Alternatively or additionally, such an amino acid may be present in the first branch. In certain preferred embodiments, the primary linker of the antibody-drug conjugate is covalently bound to the antibody by a thioether bond, and the thioether bond comprises a sulfur atom of a cysteine of the antibody, most preferably a C-terminal cysteine, which may be part of the amino acid motif that is recognized by an isoprenoid transferase. For example, the amino acid motif may be a sequence selected from CXX, CXC, XCXC, XXCC, and CYYX; C represents cysteine; Y, independently for each occurrence, represents an aliphatic amino acid; X, independently for each occurrence, represents glutamine, glutamate, serine, cysteine, methionine, alanine, or leucine; and the thioether bond comprises a sulfur atom of a cysteine of the amino acid motif. In some embodiments, the amino acid motif is: a sequence CYYX; and Y, independently for each occurrence, represents alanine, isoleucine, leucine, methionine, or valine. In certain preferred embodiments, the amino acid motif is a sequence CVIM or CVLL. In some embodiments, at least one of the seven amino acids preceding the amino acid motif is glycine. In some embodiments, the at least three of the seven amino acids preceding the amino acid motif are each independently selected from glycine and proline. In some embodiments, one to ten amino acids immediately preceding the amino acid motif are glycine. In certain preferred embodiments, at least one, two, three, four, five, six, seven, eight, nine, or ten amino acids immediately preceding the amino acid motif are glycine, most preferably at least five. In certain preferred embodiments, each of the one, two, three, four, five, six, seven, eight, nine, or ten amino acids preceding the amino acid motif is glycine. In some embodiments, a C-terminus of the antibody comprises the amino acid sequence GGGGGGCVIM. In some embodiments, the above described thioether bond comprises a carbon atom of at least one isoprenyl unit, represented by . In preferred embodiments, n is 1 or 2, most preferably 2. In some embodiments, the primary linker comprises an oxime, and the at least one isoprenyl unit covalently links the oxime to the antibody. In some embodiments, the linker comprises: or In some embodiments, the linker may comprise vvv( In some embodiments, the primary linker and / or the first branch comprises at least [Image disponible dans le document PDF, Image available in the PDF document] one polyethylene glycol unit, represented by either The polyethylene glycol unit may comprise 1 to 19 -OCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>- units, preferably 4 to 20 - OCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>- units. In some preferred embodiments, the linker may comprise 1 to 20 - OCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>- units. In certain preferred embodiments, the linker may comprise 1 to 12 - OCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>- units. In other preferred embodiments, the linker may comprise 3 to 12 - OCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>- units. In some embodiments, the linker comprises an oxime, and the at least one polyethylene glycol unit covalently links the oxime to the peptide. In some embodiments of the invention, the primary linker, the first branch, or both comprises a connection unit represented by <com:Math><semantics>−(CH2)r(V(CH2)p)q<annotation encoding="application / x-tex">-(CH_2)_r(V(CH_2)_p)_q< / annotation>< / semantics>< / com:Math>-, wherein: r is an integer from 1 to 10, preferably 2; p is an integer from 0 to 12, preferably 2; q is an integer from 1 to 20; [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>R21<annotation encoding="application / x-tex">R_{21}< / annotation>< / semantics>< / com:Math> to <com:Math><semantics>R25<annotation encoding="application / x-tex">R_{25}< / annotation>< / semantics>< / com:Math> are each independently hydrogen, <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>(C6−C20)<annotation encoding="application / x-tex">(C_6-C_{20})< / annotation>< / semantics>< / com:Math> aryl, [Image disponible dans le document PDF, Image available in the PDF document] In certain preferred embodiments, q is an integer from 1 to 10. In other preferred embodiments, q is 2, 5, or 11. In some embodiments of the invention, the primary linker, the first branch, or both comprises a connection unit represented by <com:Math><semantics>−(CH2)r(V(CH2)p)q<annotation encoding="application / x-tex">-(CH_2)_r(V(CH_2)_p)_q< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>−((CH2)pV)q<annotation encoding="application / x-tex">-((CH_2)_pV)_q< / annotation>< / semantics>< / com:Math>-, - [Image disponible dans le document PDF, Image available in the PDF document] wherein: r is an integer from 0 to 10; p is an integer from 1 to 10; q is an integer from 1 to 20; V and Y are each independently a single bond, -O-, -S-, -NR<com:Sub>21< / com:Sub>-, -C(O)NR<com:Sub>22< / com:Sub>-, - [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>R21<annotation encoding="application / x-tex">R_{21}< / annotation>< / semantics>< / com:Math> to <com:Math><semantics>R25<annotation encoding="application / x-tex">R_{25}< / annotation>< / semantics>< / com:Math> are each independently hydrogen, <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math> alkyl <com:Math><semantics>(C6−C20)<annotation encoding="application / x-tex">(C_6-C_{20})< / annotation>< / semantics>< / com:Math> aryl or [Image disponible dans le document PDF, Image available in the PDF document] In certain preferred embodiments of these linkers, q is an integer from 4 to 20. In some embodiments q is an integer from 6 to 20. In other preferred embodiments, q is an integer from 2 to 12. In some embodiments, q is 2, 5 or 11. In some embodiments of these linkers, r is preferably 2. In some embodiments of these linkers, p is preferably 2. In some embodiments of these linkers, q is an integer from 6 to 20. In some embodiments, V and Y are each independently -O-. In some embodiments: r is 2; p is 2; q is 2, 5, or 11, and V is -O-. In some embodiments of the invention, the at least one branching unit is [Image disponible dans le document PDF, Image available in the PDF document] ” wherein <com:Math><semantics>L1<annotation encoding="application / x-tex">L_1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>L2<annotation encoding="application / x-tex">L_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>L3<annotation encoding="application / x-tex">L_3< / annotation>< / semantics>< / com:Math> is each independently a direct bond or <com:Math><semantics>−CnH2n<annotation encoding="application / x-tex">-C_nH_{2n}< / annotation>< / semantics>< / com:Math>- where n is a integer of 1 to 30, [Image disponible dans le document PDF, Image available in the PDF document] wherein <com:Math><semantics>G1<annotation encoding="application / x-tex">G_1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>G2<annotation encoding="application / x-tex">G_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>G3<annotation encoding="application / x-tex">G_3< / annotation>< / semantics>< / com:Math> is each independently a direct bond, , [Image disponible dans le document PDF, Image available in the PDF document] , wherein <com:Math><semantics>R3<annotation encoding="application / x-tex">R_3< / annotation>< / semantics>< / com:Math> is hydrogen or <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C30<annotation encoding="application / x-tex">C_{30}< / annotation>< / semantics>< / com:Math> alkyl; wherein <com:Math><semantics>R4<annotation encoding="application / x-tex">R_4< / annotation>< / semantics>< / com:Math> is hydrogen or <com:Math><semantics>−L4<annotation encoding="application / x-tex">-L_4< / annotation>< / semantics>< / com:Math>-COOR<com:Sub>5< / com:Sub>, wherein <com:Math><semantics>L4<annotation encoding="application / x-tex">L_4< / annotation>< / semantics>< / com:Math> is a direct bond or <com:Math><semantics>−CnH2n<annotation encoding="application / x-tex">-C_nH_{2n}< / annotation>< / semantics>< / com:Math>- wherein n is a integer of 1 to 10, and <com:Math><semantics>R5<annotation encoding="application / x-tex">R_5< / annotation>< / semantics>< / com:Math> is hydrogen or <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C30<annotation encoding="application / x-tex">C_{30}< / annotation>< / semantics>< / com:Math> alkyl. A secondary linker (e.g., linking an active agent to the branching unit) may comprise a binding unit formed by a 1,3-dipolar cycloaddition reaction, hetero-Diels-Alder reaction, nucleophilic substitution reaction, non-aldol type carbonyl reaction, addition to a carbon-carbon multiple bond, oxidation reaction, or click reaction. A binding unit may be formed by a reaction between an acetylene and azide, or a non-aldol type carbonyl reaction, such as a reaction between an aldehyde or ketone group and hydrazine or alkoxyamine, reactions which allow for mild coupling of active agents and / or cleavage groups to the branching unit. Such binding units may be represented by Formula (A), (B), (C), or (D). [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (A) (B) (C) (D) <com:Math><semantics>L1<annotation encoding="application / x-tex">L_1< / annotation>< / semantics>< / com:Math> is a single bond or alkylene having 1 to 30 carbon atoms, preferably 10, 11, 12, 13, 14, 15, or 16 carbon atoms; <com:Math><semantics>R11<annotation encoding="application / x-tex">R_{11}< / annotation>< / semantics>< / com:Math> is hydrogen or an alkyl having 1 to 10 carbon atoms, preferably methyl; and L<com:Sub>2< / com:Sub> is an alkylene having 1 to 30 carbon atoms, preferably 10, 11, 12, 13, 14, 15, or 16 carbon atoms. In some embodiments of the invention, the primary linker, the first branch, or both comprises a connection unit represented by <com:Math><semantics>−(CH2CH2X)w<annotation encoding="application / x-tex">-(CH_2CH_2X)_w< / annotation>< / semantics>< / com:Math>-, wherein: X represents -O-, <com:Math><semantics>(C1−C8)<annotation encoding="application / x-tex">(C_1-C_8)< / annotation>< / semantics>< / com:Math>alkylene, or -NR<com:Sub>21< / com:Sub>-, preferably -O-; <com:Math><semantics>R21<annotation encoding="application / x-tex">R_{21}< / annotation>< / semantics>< / com:Math> represents hydrogen, <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math> alkyl<com:Math><semantics>(C6−C20)<annotation encoding="application / x-tex">(C_6-C_{20})< / annotation>< / semantics>< / com:Math> aryl, or <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math> alkyl<com:Math><semantics>(C3−C20)<annotation encoding="application / x-tex">(C_3-C_{20})< / annotation>< / semantics>< / com:Math> C<com:Sub>20< / com:Sub>)heteroaryl, preferably hydrogen; and w is an integer from 1 to 12, preferably 1, 3, 6, or 12. In some embodiments, X is -O- and w is an integer from 6 to 12. In some embodiments of the invention, the primary linker comprises a binding unit formed by a 1,3-dipolar cycloaddition reaction, hetero-Diels-Alder reaction, nucleophilic substitution reaction, non-aldol type carbonyl reaction, addition to carbon-carbon multiple bond, oxidation reaction, or click reaction. In some embodiments, the binding unit is formed by a reaction between acetylene and azide, or a reaction between an aldehyde or ketone group and a hydrazine or alkoxyamine. In some embodiments, the binding unit is represented by any one of Formulas A, B, C, or D, preferably D: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (A) (B) (C) (D) wherein: <com:Math><semantics>L1<annotation encoding="application / x-tex">L_1< / annotation>< / semantics>< / com:Math> is a single bond or alkylene having 1 to 30 carbon atoms, preferably 12; <com:Math><semantics>R11<annotation encoding="application / x-tex">R_{11}< / annotation>< / semantics>< / com:Math> is hydrogen or alkyl having 1 to 10 carbon atoms, preferably methyl; and <com:Math><semantics>L2<annotation encoding="application / x-tex">L_2< / annotation>< / semantics>< / com:Math> is alkylene having 1 to 30 carbon atoms, preferably 11. In some embodiments the primary linker comprises [Image disponible dans le document PDF, Image available in the PDF document] V is a single bond, <com:Math><semantics>−O−<annotation encoding="application / x-tex">-O_{-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S−<annotation encoding="application / x-tex">-S_{-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NR21<annotation encoding="application / x-tex">-NR_{21}< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>−C(O)NR22<annotation encoding="application / x-tex">-C(O)NR_{22}< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>−NR23C(O)<annotation encoding="application / x-tex">-NR_{23}C(O)< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>−NR24SO2<annotation encoding="application / x-tex">-NR_{24}SO_{2}< / annotation>< / semantics>< / com:Math>-, or <com:Math><semantics>−<annotation encoding="application / x-tex">-< / annotation>< / semantics>< / com:Math> SO<com:Sub>2< / com:Sub>NR<com:Sub>25< / com:Sub>-, preferably -O-; R<com:Sub>21< / com:Sub> to R<com:Sub>25< / com:Sub> are each independently hydrogen, (C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkyl, (C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkyl(C<com:Sub>6< / com:Sub>-C<com:Sub>20< / com:Sub>)aryl, or <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math>alkyl<com:Math><semantics>(C3−C20)<annotation encoding="application / x-tex">(C_3-C_{20})< / annotation>< / semantics>< / com:Math>heteroaryl; r is an integer of 1 to 10, preferably 2 or 3; p is an integer of 0 to 10, preferably 1 or 2; q is an integer of 1 to 20, preferably 1 to 6; and <com:Math><semantics>L1<annotation encoding="application / x-tex">L_1< / annotation>< / semantics>< / com:Math> is a single bond. In some embodiments, the primary linker comprises an O-substituted oxime; wherein a) the oxygen atom of the oxime is substituted with a group that covalently links the oxime to the active agent; e.g., via the branching unit; and the carbon atom of the oxime is substituted with a group that covalently links the oxime to the antibody; or b) the oxygen atom of the oxime is substituted with a group that covalently links the oxime to the antibody; and the carbon atom of the oxime is substituted with a group that covalently links the oxime to the active agent, e.g., via the branching unit. In some embodiments, the antibody-drug conjugate comprises the structure of Formula III: [Image disponible dans le document PDF, Image available in the PDF document] (III) wherein: B represents an active agent, x represents an integer from 1 to 3; y represents an integer from 0 to 20; z represents an integer from 1 to 20; and L represents a linkage to the antibody. In some embodiments, y and z independently represent an integer from 1 to 20. In other embodiments, y and z independently represent an integer from 2 and 20. In certain preferred embodiments, y and z independently represent an integer from 1 to 19, most preferably from 4 to 20. In certain preferred embodiments, y and z independently represent an integer less than or equal to 20. In some embodiments, the primary linker and / or the first branch comprises at least one polyethylene glycol moiety that comprises 1 to 20 -OCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>- units, preferably 4 to 20 -OCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>- units. In some preferred embodiments, the primary linker and / or the first branch comprises at least one polyethylene glycol moiety that comprises 3 to 12 - OCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>- units. In some embodiments, the polyethylene glycol moiety terminates with a hydroxyl moiety, an amino group, or an alkyl ether. In some embodiments of the invention, the antibody is a monoclonal antibody, polyclonal antibody, antibody fragment, Fab, Fab', Fab'-SH, F(ab')<com:Sub>2< / com:Sub>, Fv, single chain Fv ("scFv"), diabody, linear antibody, bispecific antibody, multispecific antibody, chimeric antibody, humanized antibody, human antibody, or fusion protein comprising the antigen- binding portion of an antibody. In some embodiments of the invention, the antibody is selected from muromonab- CD3 abciximab, rituximab, daclizumab, palivizumab, infliximab, trastuzumab, etanercept, basiliximab, gemtuzumab, alemtuzumab, ibritumomab, adalimumab, alefacept, omalizumab, efalizumab, tositumomab, cetuximab, ABT-806, bevacizumab, natalizumab, ranibizumab, panitumumab, eculizumab, rilonacept, certolizumab, romiplostim, AMG-531, golimumab, ustekinumab, ABT-874, belatacept, belimumab, atacicept, an anti-CD20 antibody, canakinumab, tocilizumab, atlizumab, mepolizumab, pertuzumab, HuMax CD20, tremelimumab, ticilimumab, ipilimumab, IDEC-114, inotuzumab, HuMax EGFR, aflibercept, HuMax-CD4, teplizumab, otelixizumab, catumaxomab, the anti-EpCAM antibody IGN101, adecatumomab, oregovomab, dinutuximab, girentuximab, denosumab, bapineuzumab, motavizumab, efumgumab, raxibacumab, LY2469298, and veltuzumab. In some embodiments, the one active agent is selected from chemotherapeutic agents and toxins. In some emboidments, the active agent is selected from: (a) erlotinib, bortezomib, fulvestrant, sutent, letrozole, imatinib mesylate, PTK787 / ZK 222584, oxaliplatin, 5-fluorouracil, leucovorin, rapamycin, lapatinib, lonafarnib, sorafenib, gefitinib, AG1478, AG1571, thiotepa, cyclophosphamide, busulfan, improsulfan, piposulfan, benzodopa, carboquone, meturedopa, uredopa, ethylenimine, altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide, trimethylolomelamine, bullatacin, bullatacinone, camptothecin, camptothecin derivatives and metabolites (SN-38), topotecan, bryostatin, callystatin, CC-1065, adozelesin, carzelesin, bizelesin, cryptophycin 1, cryptophycin 8, dolastatin, duocarmycin, KW-2189, CB1-TM1, eleutherobin, pancratistatin, sarcodictyin, spongistatin, chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard, carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimnustine, calicheamicin, calicheamicin gamma 1, calicheamicin omega 1, dynemicin, dynemicin A, clodronate, esperamicin, neocarzinostatin chromophore, aclacinomysins, actinomycin, antrmycin, azaserine, bleomycins, cactinomycin, carabicin, carninomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubucin, 6-diazo-5-oxo-L-norleucine, doxorubicin, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino- doxorubucin, liposomal doxorubicin, deoxydoxorubicin, epirubicin, esorubicin, marcellomycin, mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptomigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin, 5-fluorouracil, denopterin, methotrexate, pteropterin, trimetrexate, fludarabine, 6-mercaptopurine, thiamiprine, thiguanine, ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone, aminoglutethimide, mitotane, trilostane, folinic acid, aceglatone, aldophosphamide glycoside, aminolevulinic acid, eniluracil, amsacrine, bestrabucil, bisantrene, edatraxate, defofamine, demecolcine, diaziquone, elfornithine, elliptinium acetate, etoglucid, gallium nitrate, hydroxyurea, lentinan, lonidainine, maytansine, ansamitocins, mitoguazone, mitoxantrone, mopidanmol, nitraerine, pentostatin, phenamet, pirarubicin, losoxantrone, 2-ethylhydrazide, procarbazine, polysaccharide-k, razoxane, rhizoxin, sizofiran, spirogermanium, tenuazonic acid, triaziquone, 2,2',2"- trichlorotriethylamine, T-2 toxin, verracurin A, roridin A, and anguidine, urethane, vindesine, dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman, gacytosine, arabinoside, cyclophosphamide, thiotepa, paclitaxel, albumin-engineered nanoparticle formulation of paclitaxel, doxetaxel, chlorambucil, gemcitabine, 6-thioguanine, mercaptopurine, cisplatin, carboplatin, vinblastine, platinum, etoposide, ifosfamide, mitoxantrone, vincristine, vinorelbine, novantrone, teniposide, edatrexate, daunomycin, aminopterin, xeloda, ibandronate, CPT-11, topoisomerase inhibitor RFS 2000, difluoromethylornithine, retinoic acid, capecitabine, or pharmaceutically acceptable salts, solvates or acids of any of the foregoing; (b) monokine, a lymphokine, a traditional polypeptide hormone, parathyroid hormone, thyroxine, relaxin, prorelaxin, a glycoprotein hormone, follicle stimulating hormone, thyroid stimulating hormone, luteinizing hormone, hepatic growth factor fibroblast growth factor, prolactin, placental lactogen, tumor necrosis factor-α, tumor necrosis factor-β, mullerian-inhibiting substance, mouse gonadotropin-associated peptide, inhibin, activin, vascular endothelial growth factor, thrombopoietin, erythropoietin, an osteoinductive factor, an interferon, interferon-<com:Math><semantics>α<annotation encoding="application / x-tex">\alpha< / annotation>< / semantics>< / com:Math>, interferon-<com:Math><semantics>β<annotation encoding="application / x-tex">\beta< / annotation>< / semantics>< / com:Math>, interferon-<com:Math><semantics>γ<annotation encoding="application / x-tex">\gamma< / annotation>< / semantics>< / com:Math>, a colony stimulating factor ("CSF"), macrophage-CSF, granulocyte-macrophage-CSF, granulocyte- CSF, an interleukin ("IL"), IL-1, IL-1α, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL- 10, IL-11, IL-12, a tumor necrosis factor, TNF-α, TNF-β, a polypeptide factor, LIF, kit ligand, or a combination of any of the foregoing; (c) diphtheria toxin, botulium toxin, tetanus toxin, dysentery toxin, cholera toxin, amanitin, amanitin derivatives, <com:Math><semantics>α<annotation encoding="application / x-tex">\alpha< / annotation>< / semantics>< / com:Math>-amanitin, pyrrolobenzodiazepine, pyrrolobenzodiazepine derivatives, tetrodotoxin, brevetoxin, ciguatoxin, ricin, AM toxin, tubulysin, geldanamycin, maytansinoid, calicheamicin, daunomycin, doxorubicin, methotrexate, vindesine, SG2285, dolastatin, a dolastatin analog, auristatin, cryptophycin, camptothecin, camptothecin derivatives and metabolites (SN-38), rhizoxin, a rhizoxin derivative, CC-1065, a CC-1065 analogue or derivative, duocarmycin, an enediyne antibiotic, esperamicin, epothilone, azonafide, aplidine, a toxoid, or a combination of any of the foregoing; (d) an affinity ligand, wherein the affinity ligand is a substrate, an inhibitor, a stimulating agent, a neurotransmitter, a radioisotope, or a combination of any of the foregoing; (e) a radioactive label, <com:Sup>32< / com:Sup>P, <com:Sup>35< / com:Sup>S, a fluorescent dye, an electron dense reagent, an enzyme, biotin, streptavidin, dioxigenin, a hapten, an immunogenic protein, a nucleic acid molecule with a sequence complementary to a target, or a combination of any of the foregoing; (f) an immunomodulatory compound, an anti-cancer agent, an anti-viral agent, an anti-bacterial agent, an anti-fungal agent, and an anti-parasitic agent, or a combination of any of the foregoing; (g) tamoxifen, raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, or toremifene; (h) 4(5)-imidazoles, aminoglutethimide, megestrol acetate, exemestane, letrozole, or anastrozole; (i) flutamide, nilutamide, bicalutamide, leuprolide, goserelin, or troxacitabine; (j) an aromatase inhibitor; (k) a protein kinase inhibitor; (1) a lipid kinase inhibitor; (m) an antisense oligonucleotide; (n) a ribozyme; (o) a vaccine; and (p) an anti-angiogenic agent. In some embodiments, the least one active agent is taltobulin or azonafide. In some embodiments, the active agent is amanitin, auristatin, calicheamicin, camptothecin, camptothecin derivatives and metabolites (SN-38), cryptophycin, daunomycin, dolastatin, doxorubicin, duocarmycin, epothilone, esperamicin, geldanamycin, maytansinoid, methotrexate, monomethyl auristatin E ("MMAE"), monomethyl auristatin F ("MMAF"), pyrrolobenzodiazepine, rhizoxin, SG2285, tubulysin, vindesine, toxoid, or a derivative of any one of the foregoing. In certain embodiments, active agent is amanitin, MMAE, or MMAF, or a derivative of any one of the foregoing. In some embodiments, the conjugate comprises one or more branched linkers comprising a moiety selected from: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] ž ۲ [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] ł Λ [Image disponible dans le document PDF, Image available in the PDF document] • In some embodiments, the active agent is: [Image disponible dans le document PDF, Image available in the PDF document] ~ ¢¹ , [Image disponible dans le document PDF, Image available in the PDF document] • , 9 [Image disponible dans le document PDF, Image available in the PDF document] 1 wherein y is an integer of 1 to 10. In other embodiments, the invention relates to a linker compound, e.g., suitable for coupling to a ligand and one or more active agents to prepare a ligand-drug conjugate as disclosed herein, wherein i) the branched linker comprises a branching unit (BR) covalently coupled to the ligand by a primary linker (PL); ii) the branching unit is covalently coupled to a first branch (B1), in which a cleavage group (CG) is covalently coupled to a secondary linker (SL); and iii) the branching unit is covalently coupled to a second branch (B2), comprising either a) a second cleavage group (CG) covalently coupled to a secondary linker (SL) or b) a polyethylene glycol moiety. In some embodiments, the invention relates to a linker compound, e.g., suitable for coupling to a ligand and one or more active agents to prepare a linker-active agent conjugate as disclosed herein, wherein i) the branched linker comprises a branching unit (BR) covalently coupled to the ligand by a primary linker (PL); ii) the branching unit is covalently coupled to a first branch (B1), which has a terminal reactive group, capable of reacting with a cleavage group (CG), covalently coupled to a secondary linker (SL); and iii) the branching unit is covalently coupled to a second branch (B2), comprising either a) a second terminal reactive group, capable of reacting with a cleavage group (CG), covalently coupled to a secondary linker (SL) or b) a polyethylene glycol moiety. In certain embodiments of such linker compounds, the cleavage group has the formula: [Image disponible dans le document PDF, Image available in the PDF document] wherein: G represents a sugar, sugar acid, or modified sugar, preferably a sugar or sugar acid, most preferably glucuronic acid; W represents <com:Math><semantics>−C(O)<annotation encoding="application / x-tex">-C(O)< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(O)NR′<annotation encoding="application / x-tex">-C(O)NR'< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(O)O<annotation encoding="application / x-tex">-C(O)O< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(O)2NR′<annotation encoding="application / x-tex">-S(O)_2NR'< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−P(O)R″NR′<annotation encoding="application / x-tex">-P(O)R''NR'< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(O)NR′<annotation encoding="application / x-tex">-S(O)NR'< / annotation>< / semantics>< / com:Math>, or <com:Math><semantics>−<annotation encoding="application / x-tex">-< / annotation>< / semantics>< / com:Math> PO<com:Sub>2< / com:Sub>NR'-, in each case where the C(O), S, or P is preferably directly bound to the phenyl ring, and R' and R" are each independently hydrogen, (C<com:Sub>1< / com:Sub>-C<com:Sub>8< / com:Sub>)alkyl, mono- or di-carboxyl(<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C8<annotation encoding="application / x-tex">C_8< / annotation>< / semantics>< / com:Math>)alkyl, (<com:Math><semantics>C3<annotation encoding="application / x-tex">C_3< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C8<annotation encoding="application / x-tex">C_8< / annotation>< / semantics>< / com:Math>)cycloalkyl, (<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C8<annotation encoding="application / x-tex">C_8< / annotation>< / semantics>< / com:Math>)alkoxy, (<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C8<annotation encoding="application / x-tex">C_8< / annotation>< / semantics>< / com:Math>)alkylthio, mono- or di-<com:Math><semantics>(C1−C8)<annotation encoding="application / x-tex">(C_1-C_8)< / annotation>< / semantics>< / com:Math>alkylamino, <com:Math><semantics>(C3−C20)<annotation encoding="application / x-tex">(C_3-C_{20})< / annotation>< / semantics>< / com:Math>heteroaryl, or <com:Math><semantics>(C6−C20)<annotation encoding="application / x-tex">(C_6-C_{20})< / annotation>< / semantics>< / com:Math>aryl and W is coupled directly or indirectly to the branching unit; each Z independently represents hydrogen, (C<com:Sub>1< / com:Sub>-C<com:Sub>8< / com:Sub>)alkyl, or an electron-withdrawing group (such as an amide, carboxylic acid, carboxylic acid ester, halogen, cyano, or nitro), preferably a hydrogen, (C<com:Sub>1< / com:Sub>-C<com:Sub>8< / com:Sub>)alkyl, halogen, cyano, or nitro, most preferably hydrogen; n is an integer from 1 to 3; m is 0 or 1, preferably 1; and <com:Math><semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R2<annotation encoding="application / x-tex">R_2< / annotation>< / semantics>< / com:Math> are each independently hydrogen, <com:Math><semantics>(C1−C8)<annotation encoding="application / x-tex">(C_1-C_8)< / annotation>< / semantics>< / com:Math>alkyl, or <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math>cycloalkyl, preferably hydrogen, or R<com:Sub>1< / com:Sub> and R<com:Sub>2< / com:Sub> taken together with the carbon atom to which they are attached form a (C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub>)cycloalkyl ring. In other embodiments of such linker compounds, the cleavage group has the formula: [Image disponible dans le document PDF, Image available in the PDF document] wherein: G represents a sugar or sugar acid, preferably glucuronic acid; B represents a leaving group capable of being displaced an active agent, such as a halogen (esp. Cl or Br), or a unit comprising a reactive moiety capable of being coupled to an active agent, such as an isocyanate, an acid chloride, a chloroformate, etc.; W represents an electron-withdrawing group, preferably -C(O)NR'-, where C(O) is bonded to the phenyl ring and NR' (which may be the amino group of an amino acid, preferably a hydrophilic amino acid) is bonded to L; each Z independently represents hydrogen, (C<com:Sub>1< / com:Sub>-C<com:Sub>8< / com:Sub>)alkyl, or an electron-withdrawing group (such as an amide, carboxylic acid, carboxylic acid ester, halogen, cyano, or nitro), preferably a hydrogen, (C<com:Sub>1< / com:Sub>-C<com:Sub>8< / com:Sub>)alkyl, halogen, cyano, or nitro, most preferably hydrogen; n is an integer from 1 to 3; L represents a linkage to the branching unit; <com:Math><semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R2<annotation encoding="application / x-tex">R_2< / annotation>< / semantics>< / com:Math> are each independently hydrogen, (<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C8<annotation encoding="application / x-tex">C_8< / annotation>< / semantics>< / com:Math>)alkyl, or (<com:Math><semantics>C3<annotation encoding="application / x-tex">C_3< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C8<annotation encoding="application / x-tex">C_8< / annotation>< / semantics>< / com:Math>)cycloalkyl, preferably hydrogen, or R<com:Sub>1< / com:Sub> and R<com:Sub>2< / com:Sub> taken together with the carbon atom to which they are attached form a (C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub>)cycloalkyl ring. In still other embodiments of such linker compounds, the cleavage group has the formula: [Image disponible dans le document PDF, Image available in the PDF document] or a pharmaceutically acceptable salt thereof, wherein G represents a sugar, sugar acid, or modified sugar, preferably a sugar or sugar acid, most preferably glucuronic acid; B is a unit comprising a reactive moiety capable of being coupled to the active agent, W represents <com:Math><semantics>−C(O)<annotation encoding="application / x-tex">-C(O)< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(O)NR′<annotation encoding="application / x-tex">-C(O)NR'< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(O)O<annotation encoding="application / x-tex">-C(O)O< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(O)2NR′<annotation encoding="application / x-tex">-S(O)_2NR'< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−P(O)R″NR′<annotation encoding="application / x-tex">-P(O)R''NR'< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(O)NR′<annotation encoding="application / x-tex">-S(O)NR'< / annotation>< / semantics>< / com:Math>, or <com:Math><semantics>−<annotation encoding="application / x-tex">-< / annotation>< / semantics>< / com:Math> <com:Math><semantics>PO2NR′<annotation encoding="application / x-tex">PO_2NR'< / annotation>< / semantics>< / com:Math>-, in each case where the C(O), S, or P is directly bound to the phenyl ring, and R' and R" are each independently hydrogen, (C<com:Sub>1< / com:Sub>-C<com:Sub>8< / com:Sub>)alkyl, (C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub>)cycloalkyl, <com:Math><semantics>(C1−C8)<annotation encoding="application / x-tex">(C_1-C_8)< / annotation>< / semantics>< / com:Math>alkoxy, <com:Math><semantics>(C1−C8)<annotation encoding="application / x-tex">(C_1-C_8)< / annotation>< / semantics>< / com:Math>alkylthio, mono- or di-<com:Math><semantics>(C1−C8)<annotation encoding="application / x-tex">(C_1-C_8)< / annotation>< / semantics>< / com:Math>alkylamino, <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math>alkylamino, <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math>alkylamino, <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math>alkylamino, <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math>alkylamino, <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math>alkylamino, <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math>alkylamino, <com:Math><semantics>(C3−C<annotation encoding="application / x-tex">(C_3-C< / annotation>< / semantics>< / com:Math> <com:Math><semantics>C20<annotation encoding="application / x-tex">C_{20}< / annotation>< / semantics>< / com:Math>)heteroaryl, or <com:Math><semantics>(C6−C20)<annotation encoding="application / x-tex">(C_6-C_{20})< / annotation>< / semantics>< / com:Math>aryl each Z independently represents hydrogen, (C<com:Sub>1< / com:Sub>-C<com:Sub>8< / com:Sub>)alkyl, or an electron-withdrawing group (such as an amide, carboxylic acid, carboxylic acid ester, halogen, cyano, or nitro), preferably a hydrogen, (C<com:Sub>1< / com:Sub>-C<com:Sub>8< / com:Sub>)alkyl, halogen, cyano, or nitro, most preferably hydrogen; n is an integer from 1 to 3, preferably 3; L represents a bond to the branching unit; <com:Math><semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R2<annotation encoding="application / x-tex">R_2< / annotation>< / semantics>< / com:Math> are each independently hydrogen, (<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C8<annotation encoding="application / x-tex">C_8< / annotation>< / semantics>< / com:Math>)alkyl, or (<com:Math><semantics>C3<annotation encoding="application / x-tex">C_3< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C8<annotation encoding="application / x-tex">C_8< / annotation>< / semantics>< / com:Math>)cycloalkyl, preferably hydrogen, or R<com:Sub>1< / com:Sub> and R<com:Sub>2< / com:Sub> taken together with the carbon atom to which they are attached form a (C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub>)cycloalkyl ring. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 illustrates an active drug release mechanism from a <com:Math><semantics>β<annotation encoding="application / x-tex">\beta< / annotation>< / semantics>< / com:Math>-glucuronide based linker. Figure 2 is a graph depicting the hydrolysis of a linker by <com:Math><semantics>β<annotation encoding="application / x-tex">\beta< / annotation>< / semantics>< / com:Math>-glucuronidase from Experimental Example 1. Figure 3 is a graph depicting the plasma stability of two drug-linker conjugates from Experimental Example 2. Figure 4 is a graph depicting the plasma stability of compound 47a, described in Example 68. Figure 5 is a graph depicting the plasma stability of compound 49a, described in Example 70. Figure 6 is a graph depicting the plasma stability of compound 48a, described in Example 69. Figure 7 consists of two panels, Figure 7A and Figure 7B. Figure 7A displays a strategy for conjugating a drug to an antibody (DAR2). Figure 7B displays a strategy for conjugating a drug to an antibody (DAR4). Figure 8 shows relative in vitro activities of the DAR2 MMAE-conjugates, with varying PEG length in the linker, against JIMT-1 (HER2 positive) and MCF7 cells (HER2 negative). Figure 9 shows relative in vitro activities of the DAR4 MMAE-conjugates, which have a different PEG length in linker part, against JIMT-1 (HER2 positive) and MCF7 cells (HER2 negative). Figure 10 shows human beta-glucuronidase reactivity in DAR4 ADCs, which have the various linker types. 12 µM of ADCs were incubated with 0.01 µg of human beta- glucuronidase (R&D Systems) for 3 hours at 37°C. Figure 11 shows plasma stability of ADC2 and Kadcyla in mouse or human plasma. Figure 12 shows human plasma stability of ADC33 and ADC34 for 7 days. Figure 13 shows Rat PK profile of Herceptin and ADC2. Figure 14 shows Rat PK profile of ADC23 and ADC34. Figure 15 shows Rat PK profile improvement of MMAE-based ADCs by replacing linker-toxin from 2g to 11j. Figure 16 shows Rat PK profile improvement by branched linker unit. Figure 17 shows impact of polar amino acid on Rat PK profile in MMAE ADC. Figure 18 shows Rat PK profile improvement by branched linker-toxin with or without polar amino acid in ADC with DAR2. Figure 19 shows effects of Asp in linker-toxin unit on Rat PK profile of ADC with DAR4. Figure 20 shows effects of Glu in linker-toxin unit on Rat PK profile of ADC with DAR4. Figure 21 shows in vivo efficacy of representative amine type DAR4 ADC using MMAF (ADC23) or MMAE (ADC24). Figure 22 shows in vivo efficacy of representative amide type DAR4 ADC using MMAF (ADC34) or MMAE (ADC33). DETAILED DESCRIPTION The present invention relates to antibody-drug conjugates (ADCs) wherein a plurality of active agents are conjugated to an antibody through at least one branched linker. However, as one of skill in the art would recognize, the antibody portion of such conjugates can be replaced by any suitable ligand, and thus the invention relates in equal measure to ligand-drug conjugates. Accordingly, references to and discussions of antibody-drug conjugates herein should be understood, where not contradicted by context, as equally applicable to ligand-drug conjugates and their corresponding intermediates (e.g., ligand- linker conjugates). In all aspects related to the various ligand-drug conjugates disclosed herein, however, the ligand is preferably an antibody. The branched linker may comprise a branching unit, with two active agents coupled to the branching unit through a secondary linker, while the branching unit is coupled to the antibody by a primary linker. Two or more such branched linkers may be conjugated to an antibody, e.g., 2-4 branched linkers, which may each be coupled to a different C-terminal cysteine of a heavy or light chain of the antibody as described in greater detail herein. The active agents on any branched linker may be the same or different, and active agents may differ from one branched linker to another on the same antibody. One or more of the primary and / or secondary linkers, optionally all of the primary and secondary linkers, may comprise at least one polyethylene glycol unit. A branched linker may comprise one active agent coupled to the branching unit by a first branch and a second branch that comprises a polyethylene glycol moiety coupled to the branching unit. Two or more such branched linkers may be conjugated to an antibody, e.g., 2-4 branched linkers, which may each be coupled to a different C-terminal cysteine of a heavy or light chain of the antibody. Branched linkers coupled to different C-terminal cysteines of the heavy or light chain of an antibody may be the same or different. One may be a branched linker of the first type, with an active agent coupled to each branch, while another may be a branched linker of the second type, where one of the branches has a polyethylene glycol moiety but does not have an active agent. The active agents may be the same or different between different branched linkers or even within the same branched linker. For example, one branched linker comprising two active agents coupled to the branching unit may be coupled to the heavy chain of the antibody, and a second branched linker comprising one active agent coupled to the branching unit by a first branch and a second branch comprising a polyethylene glycol moiety may be coupled to the light chain of the antibody. Such combinations allow for 1 to 8 active agents, which may be the same or different, to be coupled to the antibody through a branched linker. This, in turn, allows delivery of a higher number of active agents to the target cells per antibody binding event. The branching unit of the branched linker may comprise an atom such as nitrogen. The branching unit may comprise any atom or group that permits three linkages, such as an amine, a tertiary amide, or a tertiary or quaternary carbon. In certain preferred embodiments, the branching unit is an amine or an amino acid having a side chain with a group capable of participating in an amide or ester (preferably amide) bond. In some embodiments, the branching unit comprises an amide. When the branching unit comprises an amide, the primary linker may comprise the carbonyl of the amide, or the carbonyl may be included in one of the other branches. For example, the branched linker may have two active agents, such that when the branching unit is an amide, the secondary linker comprises the carbonyl of the amide. The branching unit may have only one active agent, such that when the branching unit is an amide, either the first branch or the second branch comprises the carbonyl of the amide. In some embodiments, the branching unit is a lysine unit. The lysine unit may comprise modifications, such as methylation of the <com:Math><semantics>ε<annotation encoding="application / x-tex">\varepsilon< / annotation>< / semantics>< / com:Math>-amino group, giving methyl-, dimethyl-, and trimethyllysine and even acetylation, sumoylation, and / or ubiquitination. The branching unit may comprise many other amino acids in various embodiments of the invention. For example, an amino acid of the branching unit may be selected from lysine, 5- hydroxylysine, 4-oxalysine, 4-thialysine, 4-selenalysine, 4-thiahomolysine, 5,5- dimethyllysine, 5,5-difluorolysine, trans-4-dehydrolysine, 2,6-diamino-4-hexynoic acid, cis-4-dehydrolysine, 6-N-methyllysine, diaminopimelic acid, ornithine, 3-methylornithine, α-methylornithine, citrulline, and homocitrulline. The branching unit may comprise a L- amino acid or a D-amino acid. The branching unit may comprise an <com:Math><semantics>α<annotation encoding="application / x-tex">\alpha< / annotation>< / semantics>< / com:Math>-amino acid or a <com:Math><semantics>β<annotation encoding="application / x-tex">\beta< / annotation>< / semantics>< / com:Math>- amino acid. The branching unit may comprise a naturally-occurring amino acid or a non- naturally-occurring amino acid. The branching unit of the antibody-drug conjugate may comprise other amino acids instead of or in addition to lysine. Active agents may be coupled to a linker by cleavable or non-cleavable bonds, hydrolysable or non-hydrolyzable bonds. In certain preferred embodiments, the active agents are coupled to the branched linker by cleavable bonds. For example, an antibody- drug conjugate may comprise a self-immolative group, preferably a self-immolative group for each active agent, e.g., to release an active agent from the ADC, such a cleavage group having the formula: [Image disponible dans le document PDF, Image available in the PDF document] wherein G is a sugar or sugar acid, preferably glucuronic acid or a derivative thereof; B represents the active agent, such as a drug; W represents an electron-withdrawing group, preferably -C(O)NR'-, where C(O) is bonded to the phenyl ring and NR' is bonded to L; each Z independently represents <com:Math><semantics>(C1−C8)<annotation encoding="application / x-tex">(C_1-C_8)< / annotation>< / semantics>< / com:Math>alkyl, halogen, cyano, or nitro, preferably hydrogen; n is an integer from 1 to 3, preferably 3; L comprises a chain of 20 to 100 atoms that covalently links the antibody to W; and <com:Math><semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R2<annotation encoding="application / x-tex">R_2< / annotation>< / semantics>< / com:Math> are each independently hydrogen, (<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C8<annotation encoding="application / x-tex">C_8< / annotation>< / semantics>< / com:Math>)alkyl, or (<com:Math><semantics>C3<annotation encoding="application / x-tex">C_3< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C8<annotation encoding="application / x-tex">C_8< / annotation>< / semantics>< / com:Math>)cycloalkyl, preferably hydrogen, or R<com:Sub>1< / com:Sub> and R<com:Sub>2< / com:Sub> taken together with the carbon atom to which they are attached form a <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math>cycloalkyl ring. A cleavage group of any other formula disclosed herein can similarly be used in this fashion. In some embodiments, L and / or the branched linker comprises a hydrophilic amino acid, e.g., to increase the water solubility of the antibody-drug conjugate, linker, and / or precursors of the antibody-drug conjugate. The hydrophilic amino acid may be located proximal to the active agent, proximal to the antibody, or interposed anywhere along the branched linker, e.g., in the primary linker and / or a secondary linker, preferably each secondary linker. For example, a hydrophilic amino acid may covalently link an oxime of L and / or the primary linker to a polyethylene glycol unit of L and / or the primary linker. A peptide may covalently link an oxime of L and / or the primary linker to a polyethylene glycol unit of L and / or the primary linker. The electron withdrawing group W may be <com:Math><semantics>−C(O)<annotation encoding="application / x-tex">-C(O)< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>−C(O)NR′<annotation encoding="application / x-tex">-C(O)NR'< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>−C(O)O<annotation encoding="application / x-tex">-C(O)O< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>−SO2NR′<annotation encoding="application / x-tex">-SO_2NR'< / annotation>< / semantics>< / com:Math>-, -P(O)R''NR'-, -SONR'-, or -PO<com:Sub>2< / com:Sub>NR'-, preferably -C(O)NR'-, and R' and R" may be each independently hydrogen, <com:Math><semantics>(C1−C8)<annotation encoding="application / x-tex">(C_1-C_8)< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math> cycloalkyl, <com:Math><semantics>(C1−C8)<annotation encoding="application / x-tex">(C_1-C_8)< / annotation>< / semantics>< / com:Math> alkoxy, <com:Math><semantics>(C1−C8)<annotation encoding="application / x-tex">(C_1-C_8)< / annotation>< / semantics>< / com:Math> alkylthio, mono- or di-<com:Math><semantics>(C1−C8)<annotation encoding="application / x-tex">(C_1-C_8)< / annotation>< / semantics>< / com:Math>alkylamino, <com:Math><semantics>(C3−C20)<annotation encoding="application / x-tex">(C_3-C_{20})< / annotation>< / semantics>< / com:Math>heteroaryl, or <com:Math><semantics>(C6−C20)<annotation encoding="application / x-tex">(C_6-C_{20})< / annotation>< / semantics>< / com:Math>aryl, preferably hydrogen. In such embodiments, W is preferably oriented such that the carbonyl, phosphoryl, sulphonyl, or sulphinyl group is directly bound to the phenyl ring. Where Z represents an electron-withdrawing group, Z may represent any of the moieties described in this paragraph for W. W may represent -C(O)NR'-, and the nitrogen of W may be a nitrogen atom of a hydrophilic amino acid. The hydrophilic amino acid may be a naturally-occurring amino acid or a non-naturally-occurring amino acid. The hydrophilic amino acid may be an <com:Math><semantics>α<annotation encoding="application / x-tex">\alpha< / annotation>< / semantics>< / com:Math>- amino acid or a <com:Math><semantics>β<annotation encoding="application / x-tex">\beta< / annotation>< / semantics>< / com:Math>-amino acid. The hydrophilic amino acid may be arginine, aspartate, asparagine, glutamate, glutamine, histidine, lysine, ornithine, proline, serine, or threonine, and may be a D-amino acid or an L-amino acid. In certain preferred embodiments, the hydrophilic amino acid is aspartate or glutamate, such as L-aspartate or L-glutamate. In other preferred embodiments, the hydrophilic amino acid is lysine or ornithine, such as L- lysine or L-ornithine. In certain embodiments, the hydrophilic amino acid is arginine, such as L-arginine. In certain embodiments, the hydrophilic amino acid comprises a side chain having a moiety that bears a charge at neutral pH in aqueous solution (e.g., an amine, guanidine, or carboxyl moiety). The sugar or sugar acid of the cleavage group (i.e., G in the previous figure) is linked to the phenyl ring, e.g., by a bond susceptible to enzymatic cleavage, such as a glycosidic bond to an oxygen substituent on the phenyl ring. The sugar or sugar acid is preferably a monosaccharide, such as glucuronic acid or a derivative thereof, which is capable of being cleaved from the ADC by an enzyme, such as a <com:Math><semantics>β<annotation encoding="application / x-tex">\beta< / annotation>< / semantics>< / com:Math>-glucuronidase, e.g., an enzyme present in cells to be targeted by the conjugate. Glucuronic acid and derivatives thereof may be represented by the formula: [Image disponible dans le document PDF, Image available in the PDF document] wherein R<com:Sub>3< / com:Sub> is hydrogen or a carboxyl protecting group, preferably hydrogen, and each R<com:Sub>4< / com:Sub> is independently hydrogen or a hydroxyl protecting group, preferably hydrogen. A carboxyl protecting group may be any suitable protecting group for masking a carboxylic acid, e.g., in organic synthesis, such as methyl, methoxymethyl, methylthiomethyl, tetrahydropyranyl, benzyloxymethyl, phenacyl, N-phthalimidomethyl, 2,2,2-trichloroethyl, 2-haloethyl, 2-(p-toluenesulfonyl)ethyl, t-butyl, cinnamyl, benzyl, triphenylmethyl, bis(o-nitrophenyl)methyl, 9-anthrylmethyl, 2-(9,10-dioxo)anthrylmethyl, piperonyl, 2-trimethylsilylethyl, trimethylsilyl, or t-butyldimethylsilyl. In some embodiments, the entire moiety <com:Math><semantics>R3<annotation encoding="application / x-tex">R_3< / annotation>< / semantics>< / com:Math>-OC(=0)- is replaced by a carboxyl-masking moiety such as 2-alkyl-1,3-oxazolinyl. A hydroxyl protecting group may be any suitable protecting group suitable for masking a hydroxyl group, e.g., in organic synthesis, such as acetyl, methyl, ethoxyethyl, benzoyl, benzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, tetrahydropyranyl (THP), tetrahydrofuranyl (THF), tert-butyldimethylsilyl (TBDMS), trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldiphenylsilyl (TBDPS), tri- isopropylsilyloxymethyl (TOM), β-methoxyethoxymethyl (MEM), methoxymethyl (MOM), allyl, or trityl. L and / or the branched linker may comprise a substituted or unsubstituted alkylene having 1 to 100 carbon atoms, preferably 20 to 80 carbon atoms, and satisfy at least one, preferably at least two, of the following (i) to (iv): (i) the alkylene includes at least one unsaturated bond, preferably 3 or 4 double bonds and no triple bonds, (ii) the alkylene includes at least one heteroarylene, (iii) at least one carbon atom of the alkylene is replaced by one or more heteroatoms selected from nitrogen (N), oxygen (O), and sulfur (S), preferably at least one nitrogen and at least one oxygen (e.g., as in an oxime), and (iv) the alkylene is substituted with one or more alkyls having 1 to 20 carbon atoms, preferably 2 or 3 methyls. In preferred embodiments, a cysteine of the antibody, preferably at a C-terminus of a heavy or light chain of the antibody, forms a thioether bond with a carbon atom of an isoprenyl unit, thereby covalently linking the antibody to the branched linker, e.g., the primary linker. Thus, in some embodiments, L and / or the branched linker (e.g., the primary linker) may comprise at least one isoprenyl unit, preferably two isoprenyl units, each represented by the following formula, which is preferably recognizable by an isoprenoid transferase, e.g., as part of a product or substrate of the isoprenoid transferase. [Image disponible dans le document PDF, Image available in the PDF document] In certain such preferred embodiments, the antibody comprises an amino acid motif capable of being recognized by an isoprenoid transferase. For example, at least one C- terminus of the antibody may comprise an amino acid motif capable of being recognized by an isoprenoid transferase (e.g., as a substrate, for example, prior to forming the antibody- drug conjugate, or as a product of an isoprenoid transferase, for example, after forming the antibody-drug conjugate). The antibody may further comprise a spacer, such as an amino acid or a stretch of amino acids that links a peptide chain of the antibody to the amino acid motif. The spacer may consist of 1 to 20 consecutive amino acids, preferably 7 or more amino acids. Glycine and proline are preferred amino acids for the spacer, and may be used in any combination, such as a series of about 7 glycines. In some embodiments, the C- terminus of the antibody comprises the amino acid sequence GGGGGGCVIM. The antibody may comprise an addition or deletion at a carboxy terminus, e.g., relative to a form of the antibody not included in an ADC. Examples of isoprenoid transferases include farnesyl protein transferase (FTase) and geranylgeranyl transferase (GGTase), which can catalyze the transfer of a farnesyl or geranyl-geranyl group to at least one C-terminal cysteine of a target protein. A GGTase may be classified as either GGTase I or GGTase II. FTase and GGTase I may recognize a CAAX motif, and GGTase II may recognize a XXCC, XCXC, or CXX motif, wherein C represents cysteine, A represents an aliphatic amino acid (e.g., isoleucine, valine, methionine, leucine), and each X independently represents, for example, glutamine, glutamate, serine, cysteine, methionine, alanine, or leucine (see Nature Rev. Cancer, 5(5):405-12 (2005); Nature Chemical Biology 17:498-506 (2010); Lane KT, Bees LS, J. Lipid Research, 47:681-699 (2006); Kasey PJ, Seabra MC, J. Biological Chemistry, 271(10):5289-5292 (1996)). The antibody-drug conjugates according to the present invention may comprise an amino acid motif, such as CYYX, XXCC, XCXC, or CXX, preferably CYYX (wherein, C represents cysteine, Y represents an aliphatic amino acid, such as leucine, isoleucine, valine, and / or methionine, and X represents an amino acid that determines a substrate specificity of the isoprenoid transferase, such as glutamine, glutamate, serine, cysteine, methionine, alanine, and / or leucine). Isoprenoid transferases from various sources may be used. For example, the isoprenoid transferase may be obtained from a human, animal, plant, bacteria, virus, or other source. In some embodiments, a naturally occurring isoprenoid transferase is used. In some embodiments, a naturally-modified or artificially-modified isoprenoid transferase may be used. For example, the isoprenoid transferase may comprise one or more amino acid substitutions, additions, and / or deletions, and / or the isoprenoid transferase may be modified by the addition of at least one of Histidine-tag, GST, GFP, MBP, CBP, Isopeptag, BCCP, Myc-tag, Calmodulin-tag, FLAG-tag, HA-tag, Maltose binding protein-tag, Nus- tag, Glutathione-S-transferase-tag, Green fluorescent protein-tag, Thioredoxin-tag, S-tag, Softag 1, Softag 3, Strep-tag, SBP-tag, Ty-tag, and the like. Isoprenoid transferases recognize an isosubstrate and / or a substrate. The term isosubstrate refers to a substrate analog comprising a chemical modification. Isoprenoid transferases can alkylate a specific amino acid motif (for example, a CAAX motif) at the C- terminus of an antibody (see, e.g., Duckworth, BP et al., ChemBioChem, 8:98 (2007); Uyen TT et al., ChemBioChem, 8:408 (2007); Labadie, GR et al., J. Org. Chem., 72(24):9291 (2007); Wollack, JW et al., ChemBioChem, 10:2934 (2009)). A functionalized antibody may be produced using an isoprenoid transferase and an isosubstrate, which may alkylate a C-terminal cysteine. The isosubstrate may be, for example, the compound having the formula: [Image disponible dans le document PDF, Image available in the PDF document] The cysteine of a C-terminal CAAX motif may be bound to an isosubstrate using an isoprenoid transferase. In some embodiments, part of the motif, e.g., AAX, may subsequently be removed by a protease, e.g., leaving only the cysteine to which the isoprenoid is bound. The cysteine may optionally be methylated at the carboxyl terminus, e.g., by an enzyme (see, e.g., Bell, IM, J. Med. Chem., 47(8):1869 (2004)). L and / or the branched linker, e.g., the primary linker, may comprise a binding unit formed by a 1,3-dipolar cycloaddition reaction, hetero-Diels-Alder reaction, nucleophilic substitution reaction, non-aldol type carbonyl reaction, addition to a carbon-carbon multiple bond, oxidation reaction, or click reaction. A binding unit may be formed by a reaction between an acetylene and azide, or a non-aldol type carbonyl reaction, such as a reaction between an aldehyde or ketone group and hydrazine or alkoxyamine; such binding units may be represented by Formula (A), (B), (C), or (D). [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (A) (B) (C) (D) <com:Math><semantics>L1<annotation encoding="application / x-tex">L_1< / annotation>< / semantics>< / com:Math> is a single bond or alkylene having 1 to 30 carbon atoms, preferably 12 carbon atoms; <com:Math><semantics>R11<annotation encoding="application / x-tex">R_{11}< / annotation>< / semantics>< / com:Math> is hydrogen or an alkyl having 1 to 10 carbon atoms, preferably methyl; and L<com:Sub>2< / com:Sub> is an alkylene having 1 to 30 carbon atoms, e.g., 10 or 11, preferably 11 carbon atoms. In some embodiments, <com:Math><semantics>L1<annotation encoding="application / x-tex">L_1< / annotation>< / semantics>< / com:Math> and / or <com:Math><semantics>L2<annotation encoding="application / x-tex">L_2< / annotation>< / semantics>< / com:Math> may comprise at least one isoprenyl unit, preferably two isoprenyl units. L<com:Sub>2< / com:Sub> may consist of at least one isoprenyl unit, preferably two isoprenyl units. In preferred embodiments, a carbon atom of an isoprenyl unit forms a thioether bond with the sulfur atom of a cysteine of the antibody, most preferably at a C- terminus of a heavy or light chain, thereby covalently linking the antibody and the branched linker, e.g., the primary linker. An antibody-drug conjugate may comprise the binding unit represented by Formula (D) supra, wherein <com:Math><semantics>L2<annotation encoding="application / x-tex">L_2< / annotation>< / semantics>< / com:Math> consists of at least one isoprenyl unit, preferably two isoprenyl units. The binding unit may be an O-substituted oxime, i.e., the nitrogen of the binding unit may be covalently bound to a substituted oxygen. A carbon atom of an isoprenyl unit may form a thioether bond with the sulfur atom of a cysteine of the antibody, most preferably at a C- terminus of a heavy or light chain, thereby covalently linking the binding unit and the antibody. L and / or the branched linker, e.g., the primary linker, may comprise an isoprenyl group represented by [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] or , e.g., wherein a carbon atom of the isoprenyl group forms a thioether bond with a sulfur atom of a cysteine of the antibody, thereby covalently linking the isoprenyl group and the antibody. The nitrogen of the isoprenyl group may covalently link the isoprenyl group to a polyethylene glycol unit of L and / or the branched linker, e.g., the primary linker. L and / or the branched linker, e.g., the primary linker, may comprise an isoprenyl group represented by [Image disponible dans le document PDF, Image available in the PDF document] , e.g., wherein a carbon atom of the isoprenyl group forms a thioether bond with a sulfur atom of a cysteine of the antibody, thereby covalently linking the isoprenyl group and the antibody. The nitrogen of the isoprenyl group may covalently link the isoprenyl group to a polyethylene glycol unit of L and / or the branched linker, e.g., the primary linker. Click chemistry reactions may be carried out under mild conditions, which can be performed in the presence of an antibody without denaturing the antibody. A click chemistry reaction shows high reaction specificity. Therefore, even though antibodies have various functional groups (for example, amines, carboxyls, carboxamides, and guanidiniums), a click chemistry reaction may be performed, for example, without affecting the amino acid side chains of the antibody. A click chemistry reaction between an azide group and an acetylene group, for example, may occur in the presence of an antibody without modifying the amino acid side chain functional groups of the antibody. Further, a click chemistry reaction may precisely target a specific functional group, such as functional groups rarely found in nature, regardless of the nature of the reactants. In some cases, the reactants are selected to improve overall reaction efficiency. For example, an azide- acetylene click chemistry reaction may produce triazole with a high yield (see, e.g., Hia, RK et al., Chem. Rev., 109:5620 (2009); Meldal, M & Tornoe, CW, Chem Rev., 108:2952 (2008); Kolb, HC et al., Angew. Chemie Int. Ed. Engl., 40:2004 (2001), each of which is hereby incorporated by reference). Azide and acetylene functional groups do not exist in natural proteins. Thus, none of the amino acid side chains, N-terminal amines, or C-terminal carboxyls should be affected by a click chemistry reaction that utilizes these functional groups. The connection unit may be represented by <com:Math><semantics>−(CH2)r(V(CH2)p)q<annotation encoding="application / x-tex">-(CH_2)_r(V(CH_2)_p)_q< / annotation>< / semantics>< / com:Math> or <com:Math><semantics>−(CH2CH2X)w<annotation encoding="application / x-tex">-(CH_2CH_2X)_w< / annotation>< / semantics>< / com:Math>-, wherein V is a single bond, -O-, -S-, -NR<com:Sub>21< / com:Sub>-, -C(O)NR<com:Sub>22< / com:Sub>-, -NR<com:Sub>23< / com:Sub>C(O)-, -NR<com:Sub>24< / com:Sub>SO<com:Sub>2< / com:Sub>-, or -SO<com:Sub>2< / com:Sub>NR<com:Sub>25< / com:Sub>-, preferably -O-; X is <com:Math><semantics>−O<annotation encoding="application / x-tex">-O< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>(C1−C8)<annotation encoding="application / x-tex">(C_1-C_8)< / annotation>< / semantics>< / com:Math>alkylene, or <com:Math><semantics>−NR21<annotation encoding="application / x-tex">-NR_{21}< / annotation>< / semantics>< / com:Math>-, preferably <com:Math><semantics>−O<annotation encoding="application / x-tex">-O< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R21<annotation encoding="application / x-tex">R_{21}< / annotation>< / semantics>< / com:Math> to <com:Math><semantics>R25<annotation encoding="application / x-tex">R_{25}< / annotation>< / semantics>< / com:Math> are each independently hydrogen, <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math>alkyl, <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math>alkyl<com:Math><semantics>(C6−C20)<annotation encoding="application / x-tex">(C_6-C_{20})< / annotation>< / semantics>< / com:Math>aryl, or <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math> <com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math>)alkyl(<com:Math><semantics>C3<annotation encoding="application / x-tex">C_3< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C20<annotation encoding="application / x-tex">C_{20}< / annotation>< / semantics>< / com:Math>)heteroaryl, preferably hydrogen; r is an integer from 1 to 10, preferably 2 or 3; p is an integer from 0 to 12, preferably 1 or 2; q is an integer from 1 to 20; and w is an integer from 1 to 20, preferably 4 to 20. In some preferred embodiments, q is an integer from 2 to 12. In other preferred embodiments, q is an integer from 4 to 20. L and / or the branched linker, e.g., the primary linker, may comprise the binding unit represented by Formula (A), (B), (C), or (D) and the connection unit represented by - <com:Math><semantics>(CH2)r(V(CH2)p)q<annotation encoding="application / x-tex">(CH_2)_r(V(CH_2)_p)_q< / annotation>< / semantics>< / com:Math>- or <com:Math><semantics>−(CH2CH2X)w<annotation encoding="application / x-tex">-(CH_2CH_2X)_w< / annotation>< / semantics>< / com:Math>-. In preferred embodiments, L and / or the branched linker, e.g., the primary linker or the secondary linker, or a combination of both, comprise at least one polyethylene glycol [Image disponible dans le document PDF, Image available in the PDF document] unit represented by either . In certain embodiments, the antibody-drug conjugate may comprise from 1 to 20 -OCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>- units, e.g., from 1 to 19 -OCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>- units, such as 1 to 12 -OCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>- units, 5 to 12 -OCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>- units, 6 to 12 - OCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>- units, 5 to 20 -OCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>- units, 6 to 20 -OCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>- units, or 4 to 20 - OCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>- units. Such units may vary in number in the primary and secondary linkers. In embodiments wherein the primary linker comprises an oxime, a polyethylene glycol unit preferentially covalently links the oxime to the peptide, e.g., the N-terminus of the peptide, the C-terminus of the peptide, or a side chain of the peptide. L and / or the branched linker, e.g., the primary linker, preferably comprises a polyethylene glycol group represented by <com:Math><semantics>−(CH2CH2O)n<annotation encoding="application / x-tex">-(CH_2CH_2O)_n< / annotation>< / semantics>< / com:Math>, wherein n is 1 to 20, such as 1 to 12, 5 to 12, 6 to 12, 5 to 20, or 6 to 20. The secondary linker preferably comprises a polyethylene glycol group represented by -(CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>O)<com:Sub>n< / com:Sub>-, wherein n is 1 to 20, such as 1 to 12, 5 to 12, 6 to 12, 5 to 20, or 6 to 20. In embodiments wherein the primary linker comprises an oxime, a polyethylene glycol group preferentially covalently links the oxime to the peptide. In embodiments wherein the primary linker comprises an oxime, a polyethylene glycol group preferentially covalently links the oxime to W, e.g., wherein W is represented by represent -C(O)NR'-. A carbon of a polyethylene glycol group may form a covalent bond with an atom of W (e.g., the nitrogen of -C(O)NR'-) and / or an oxygen of a polyethylene glycol group may be the oxygen of an oxime. In some embodiments, the primary linker is preferably represented by one of the following two structures, and thus, the linker may comprise one of the following two structures: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] wherein n is an integer from 1 to 20, such as 4 to 20. [Image disponible dans le document PDF, Image available in the PDF document] L and / or the linker may comprise > [Image disponible dans le document PDF, Image available in the PDF document] V represents a single bond, -O-, -S-, -NR<com:Sub>21< / com:Sub>-, -C(O)NR<com:Sub>22< / com:Sub>-, -NR<com:Sub>23< / com:Sub>C(O)-, -NR<com:Sub>24< / com:Sub>SO<com:Sub>2< / com:Sub>-, or - SO<com:Sub>2< / com:Sub>NR<com:Sub>25< / com:Sub>-, preferably -O-; R<com:Sub>21< / com:Sub> to R<com:Sub>25< / com:Sub> represents each independently hydrogen, (C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkyl, (C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkyl(C<com:Sub>6< / com:Sub>-C<com:Sub>20< / com:Sub>)aryl, or <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math>alkyl<com:Math><semantics>(C3−C20)<annotation encoding="application / x-tex">(C_3-C_{20})< / annotation>< / semantics>< / com:Math>heteroaryl; r is an integer from 1 to 10, preferably 2 or 3; p is an integer from 0 to 10, preferably 1 or 2; q is an integer from 1 to 20, preferably 1 to 6; and <com:Math><semantics>L1<annotation encoding="application / x-tex">L_1< / annotation>< / semantics>< / com:Math> is a single bond. In some embodiments, the antibody-drug conjugate comprises the structure: [Image disponible dans le document PDF, Image available in the PDF document] wherein: B and B' represent active agents, which may be the same or different; n, independently for each occurrence, represents an integer from 0 to 30; f, independently for each occurrence, represents an integer from 0 to 30; and L represents a linkage to the antibody. In certain preferred embodiments, each n is an integer from 1-20, preferably from 1- 10. In certain preferred embodiments, f is an integer from 1-20, preferably from 1-10. Most preferably, each n and f is selected such that <com:Math><semantics>f+n<annotation encoding="application / x-tex">f + n< / annotation>< / semantics>< / com:Math> is less than 20, e.g., less than 15. In some embodiments, the antibody-drug conjugate comprises the structure: [Image disponible dans le document PDF, Image available in the PDF document] wherein: B represents an active agent, x represents an integer from 1 to 3; y represents an integer from 0 to 20; z represents an integer from 1 to 20; and L represents a linkage to the antibody. In some embodiments, y and z independently represent an integer from 2 and 20. In preferred embodiments, y and z independently represent an integer from 1 to 19, preferably from 4 to 20. In certain preferred embodiments, y and z independently represent an integer less than or equal to 20. The antibody-drug conjugates of the invention may be prepared using any method known in the art, including molecular biology and cell biology methods. For example, transient or stable transfection methods may be used. Genetic sequences encoding a specific amino acid motif capable of being recognized by an isoprenoid transferase may be inserted into a known plasmid vector using standard PCR and / or ligation technologies so as to express an antibody having the specific amino acid motif at a C-terminus thereof. An antibody having at least one amino acid motif capable of being recognized by the isoprenoid transferase may thus be expressed in a suitable host, e.g., a CHO cell or in E coli. The term "acyl" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-. The term "acylamino" is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbylC(O)NH-. The term "acyloxy" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-. The term "alkoxy" refers to an alkyl group, preferably a lower alkyl group, having an oxygen attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like. The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl. The term "alkenyl", as used herein, refers to an aliphatic group containing at least one double bond and is intended to include both "unsubstituted alkenyls" and "substituted alkenyls", the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the alkenyl group. Such substituents may occur on one or more carbons that are included or not included in one or more double bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed below, except where stability is prohibitive. For example, substitution of alkenyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated. An "alkyl" group or "alkane" is a straight chained or branched non-aromatic hydrocarbon which is completely saturated. Typically, a straight chained or branched alkyl group has from 1 to about 20 carbon atoms, preferably from 1 to about 10 unless otherwise defined. Examples of straight chained and branched alkyl groups include methyl, ethyl, n- propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl and octyl. A C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> straight chained or branched alkyl group is also referred to as a "lower alkyl" group. Moreover, the term "alkyl" (or "lower alkyl") as used throughout the specification, examples, and claims is intended to include both "unsubstituted alkyls" and "substituted alkyls", the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents, if not otherwise specified, can include, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. For instance, the substituents of a substituted alkyl may include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF<com:Sub>3< / com:Sub>, -CN and the like. Exemplary substituted alkyls are described below. Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted alkyls, -CF<com:Sub>3< / com:Sub>, -CN, and the like. The term "C<com:Sub>x-v< / com:Sub>" when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups that contain from x to y carbons in the chain. For example, the term "C<com:Sub>x-y< / com:Sub>alkyl" refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched- chain alkyl groups that contain from x to y carbons in the chain, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl, etc. <com:Math><semantics>C0<annotation encoding="application / x-tex">C_0< / annotation>< / semantics>< / com:Math> alkyl indicates a hydrogen where the group is in a terminal position, a bond if internal. The terms "<com:Math><semantics>C2−v<annotation encoding="application / x-tex">C_{2-v}< / annotation>< / semantics>< / com:Math>alkenyl" and "<com:Math><semantics>C2−v<annotation encoding="application / x-tex">C_{2-v}< / annotation>< / semantics>< / com:Math> valkynyl" refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively. The term "alkylamino", as used herein, refers to an amino group substituted with at least one alkyl group. The term "alkylthio", as used herein, refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-. The term "alkynyl", as used herein, refers to an aliphatic group containing at least one triple bond and is intended to include both "unsubstituted alkynyls" and "substituted alkynyls", the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the alkynyl group. Such substituents may occur on one or more carbons that are included or not included in one or more triple bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed above, except where stability is prohibitive. For example, substitution of alkynyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated. The term "amide", as used herein, refers to a group [Image disponible dans le document PDF, Image available in the PDF document] wherein each R<com:Sup>10< / com:Sup> independently represent a hydrogen or hydrocarbyl group, or two R<com:Sup>10< / com:Sup> are taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure. The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that can be represented by [Image disponible dans le document PDF, Image available in the PDF document] wherein each R<com:Sup>10< / com:Sup> independently represents a hydrogen or a hydrocarbyl group, or two R<com:Sup>10< / com:Sup> are taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure. The term "aminoalkyl", as used herein, refers to an alkyl group substituted with an amino group. The term "carboxy", as used herein, refers to a group represented by the formula -CO<com:Sub>2< / com:Sub>H. The terms "hetaralkyl" and "heteroaralkyl", as used herein, refers to an alkyl group substituted with a hetaryl group. The term "heteroalkyl", as used herein, refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom, wherein no two heteroatoms are adjacent. The terms "heteroaryl" and "hetaryl" include substituted or unsubstituted aromatic single ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6- membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms "heteroaryl" and "hetaryl" also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like. The term "heteroatom" as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur. The terms "heterocyclyl", "heterocycle", and "heterocyclic" refer to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms "heterocyclyl" and "heterocyclic" also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like. Heterocyclyl groups can also be substituted by oxo groups. For example, "heterocyclyl" encompasses both pyrrolidine and pyrrolidinone. The term "hydroxyalkyl", as used herein, refers to an alkyl group substituted with a hydroxy group. The term "substituted" refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that "substitution" or "substituted with" includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term "substituted" is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as "unsubstituted," references to chemical moieties herein are understood to include substituted variants. For example, reference to an "aryl" group or moiety implicitly includes both substituted and unsubstituted variants. The term "thioalkyl", as used herein, refers to an alkyl group substituted with a thiol group. The term "thioester", as used herein, refers to a group -C(O)SR<com:Sup>10< / com:Sup> or -SC(O)R<com:Sup>10< / com:Sup> wherein R<com:Sup>10< / com:Sup> represents a hydrocarbyl. The term "thioether", as used herein, is equivalent to an ether, wherein the oxygen is replaced with a sulfur. "Protecting group" refers to a group of atoms that, when attached to a reactive functional group in a molecule, mask, reduce or prevent the reactivity of the functional group. Typically, a protecting group may be selectively removed as desired during the course of a synthesis. Examples of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Chemistry, 3<com:Sup>rd< / com:Sup> Ed., 1999, John Wiley & Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1-8, 1971-1996, John Wiley & Sons, NY. Representative nitrogen protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2-trimethylsilyl-ethanesulfonyl ("TES"), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl ("FMOC"), nitro-veratryloxycarbonyl ("NVOC") and the like. Representative hydroxylprotecting groups include, but are not limited to, those where the hydroxyl group is either acylated (esterified) or alkylated such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPS groups), glycol ethers, such as ethylene glycol and propylene glycol derivatives and allyl ethers. "Covalently coupled" includes both direct bonding and indirect bonding (e.g., through an intervening series of atoms) of two chemical species. For example, an amino acid may be covalently coupled to polyethylene glycol directly, e.g., by forming an ester between the carboxyl of the amino acid and a hydroxyl of the polyethylene glycol, or indirectly, e.g., by reacting the polyethylene glycol with epichlorohydrin to form an epoxypropyl ether and reacting the resulting epoxide with the amino group of the amino acid, thereby covalently linking the amino acid and the polyethylene glycol through a 2- hydroxypropyl linker. Various moieties and reactions for coupling diverse moieties directly or indirectly are well known in the art. In certain preferred embodiments, unless otherwise indicated by the context, an indirect bonding involves only 1-10 intervening atoms (e.g., a methylene, a dibutyl ether, a tripeptide, etc.), most preferably 1-6 intervening atoms. As used herein, a therapeutic that "prevents" a disorder or condition refers to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample. The term "treating" includes prophylactic and / or therapeutic treatments. The term "prophylactic or therapeutic" treatment is art-recognized and includes administration to the host of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic (i.e., it protects the host against developing the unwanted condition), whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof). The term "prodrug" is intended to encompass compounds which, under physiologic conditions, are converted into the therapeutically active agents of the present invention. A common method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids) are preferred prodrugs. The term "antibody" refers to an immunoglobulin molecule that recognizes and specifically binds to a different molecule through at least one antigen recognition site within a variable region of the immunoglobulin molecule. As used herein, the term "antibody" includes intact polyclonal antibodies, intact monoclonal antibodies, antibody fragments (for example, Fab, Fab', F(ab')<com:Sub>2< / com:Sub>, Fd, and Fv fragments), single chain Fv (scFv) mutants, multispecific antibodies such as bispecific antibodies generated from two or more intact antibodies, chimeric antibodies, humanized antibodies, human antibodies, fusion proteins including an antigen determination portion of an antibody, and any other modified immunoglobulin molecule including an antigen recognition site. The antibody may be any of the five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, or subclasses (isotypes) thereof (for example, IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), based on the identity of its heavy chain constant domains, referred to as alpha, delta, epsilon, gamma, and mu, respectively. The different classes of immunoglobulins have different and well- known subunit structures and three-dimensional configurations. The term "antibody" does not refer to molecules that do not share homology with an immunoglobulin sequence. For example, the term "antibody" as used herein does not include "repebodies". The term "antibody fragment" refers to a portion of an intact antibody and refers to antigenic determining variable regions of an intact antibody. Examples of antibody fragments include Fab, Fab', F(ab')<com:Sub>2< / com:Sub>, Fd, and Fv fragments, linear antibodies, single chain antibodies, and multispecific antibodies formed from antibody fragments. The term "monoclonal antibody" refers to a homogeneous antibody population involved in the highly specific recognition and binding of a single antigenic determinant or epitope. This contrasts with polyclonal antibodies that typically include different antibodies directed against a variety of different antigenic determinants. The term "monoclonal antibody" includes antibody fragments (such as Fab, Fab', F(ab')2, Fd, Fv), single chain (scFv) mutants, fusion proteins including an antibody portion, and any other modified immunoglobulin molecule including an antigen recognition site as well as both intact and full-length monoclonal antibodies, but are not limited thereto. Additionally, "monoclonal antibody" refers to such antibodies made in any number of methods, including but not limited to hybridoma, phage selection, recombinant expression, and transgenic animals. The term "humanized antibody" refers to forms of non-human (e.g., murine) antibodies that are specific immunoglobulin chains, chimeric immunoglobulins, or fragments thereof that contain minimal non-human (e.g., murine) sequences. In general, humanized antibodies are human immunoglobulins in which residues from complementary determining region (CDR) are replaced by residues from CDR of a non-human species (e.g., mouse, rat, rabbit, and hamster) having the desired specificity, affinity, and capability (see, e.g., Jones et al., Nature, 321:522-525 (1986); Riechmann et al., Nature, 332:323-327 (1988); Verhoeyen et al., Science, 239:1534-1536 (1988)). In some instances, Fv framework region (FR) residues of a human immunoglobulin are replaced with the corresponding residues in an antibody from a non-human species having a desired specificity, affinity, and / or binding capability. The humanized antibody may be further modified by the substitution of additional residues either in the Fv framework region and / or within the replaced non-human residues to refine and optimize antibody specificity, affinity, and / or binding capability. In general, a humanized antibody includes substantially all of at least one, and typically two or three, variable domains containing all or substantially all of the CDRs that correspond to the non-human immunoglobulin whereas all or substantially all of the framework regions (FRs) have those of a human immunoglobulin consensus sequence. The humanized antibody may also include at least a portion of an immunoglobulin constant region or domain (Fc), typically that of a human immunoglobulin. Examples of methods used to generate humanized antibodies are described in U.S. Patent No. 5,225,539, The term "human antibody" as used herein refers to an antibody encoded by a human nucleotide sequence or an antibody having an amino acid sequence corresponding to an antibody produced by a human using any technique known in the art. This definition of the human antibody includes intact full-length antibodies and / or fragments thereof. The term "chimeric antibody" refers to an antibody wherein an amino acid sequence of an immunoglobulin molecule is derived from two or more species, one of which is preferably human. In general, variable regions of both light and heavy chains correspond to variable regions of antibodies derived from one species of mammals (e.g., mouse, rat, rabbit, etc) with the desired specificity, affinity, and capability, while constant regions are homologous to the sequences in antibodies derived from another species (usually human), e.g., to avoid eliciting an immune response in that species. The terms "epitope" and "antigenic determinant" are used interchangeably herein and refer to that portion of an antigen capable of being recognized and specifically bound by a particular antibody. When the antigen is or comprises a polypeptide or protein, epitopes may be formed from contiguous and / or non-contiguous amino acids, e.g., juxtaposed by secondary, tertiary, and / or quaternary folding of a protein. Epitopes formed from contiguous amino acids are typically retained upon protein denaturing, whereas epitopes formed by tertiary folding may be lost upon protein denaturing. An epitope typically includes 3 or more, 5 or more, or 8 to 10 or more amino acids in a unique spatial conformation. An antibody "specifically binds" to an epitope or antigenic molecule, which means that the antibody interacts or associates more frequently, more rapidly, with greater duration, with greater affinity, or with some combination of the foregoing to an epitope or antigenic molecule than alternative substances, including unrelated proteins. In specific embodiments, "specifically binds" means, for instance, that an antibody binds to a protein with a K<com:Sub>D< / com:Sub> of about 0.1 mM or less, but more usually, less than about 1 μM. In specific embodiments, "specifically binds" means that an antibody binds to a protein at times with a <com:Math><semantics>KD<annotation encoding="application / x-tex">K_D< / annotation>< / semantics>< / com:Math> of about 0.1 <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>M or less, and at other times, with a <com:Math><semantics>KD<annotation encoding="application / x-tex">K_D< / annotation>< / semantics>< / com:Math> of about 0.01 <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>M or less. Because of the sequence identity between homologous proteins in different species, specific binding may include an antibody recognizing a particular protein in more than one species. It is understood that an antibody or binding residue that specifically binds to a first target may or may not specifically bind to a second target. As described above, "specific binding" does not necessarily require (although it may include) exclusive binding, that is, binding to a single target. Generally, but not necessarily, the term binding used herein means specific binding. The antibodies, including fragments / derivatives thereof and monoclonal antibodies, may be obtained using methods known in the art (see, e.g., McCafferty et al., Nature 348:552-554 (1990); Clackson et al., Nature 352:624-628; Marks et al., J. Mol. Biol. 222:581-597 (1991); Marks et al., Bio / Technology 10:779-783 (1992); Waterhouse et al., Nucleic Acids Res. 21:2265-2266 (1993); Morimoto et al., J Biochemical & Biophysical Methods 24:107-117 (1992); Brennan et al., Science 229:81(1985); Carter et al., Bio / Technology 10:163-167 (1992); Kohler et al., Nature 256:495 (1975); Kilpatrick et al., Hybridoma 16(4):381-389 (1997); Wring et al., J. Pharm. Biomed. Anal. 19(5):695-707 (1999); Bynum et al., Hybridoma 18(5):407-411 (1999), Jakobovits et al., Proc. Natl. Acad. Sci. USA, 90:2551 (1993); Jakobovits et al., Nature, 362:255-258 (1993); Bruggemann et al., Year Immuno. 7:33 (1993); Barbas et al., Proc. Nat. Acad. Sci. USA 91:3809-3813 (1994); Schier et al., Gene 169:147-155 (1995); Yelton et al., J. Immunol. 155:1994-2004 (1995); Jackson et. al., J. Immunol. 154(7):3310-9 (1995); Hawkins et al., J. Mol. Biol. 226:889-896 (1992), U.S. Pat. Nos. 4,816,567, 5,514,548, 5,545,806, 5,569,825, 5,591,669, 5,545,807; PCT Patent Application Publication No. WO 97 / 17852). The antibody may be muromonab-CD3 abciximab, rituximab, daclizumab, palivizumab, infliximab, trastuzumab, etanercept, basiliximab, gemtuzumab, alemtuzumab, ibritumomab, adalimumab, alefacept, omalizumab, efalizumab, tositumomab, cetuximab, ABT-806, bevacizumab, natalizumab, ranibizumab, panitumumab, eculizumab, rilonacept, certolizumab, romiplostim, AMG-531, golimumab, ustekinumab, ABT-874, belatacept, belimumab, atacicept, an anti-CD20 antibody, canakinumab, tocilizumab, atlizumab, mepolizumab, pertuzumab, HuMax CD20, tremelimumab, ticilimumab, ipilimumab, IDEC- 114, inotuzumab, HuMax EGFR, aflibercept, HuMax-CD4, teplizumab, otelixizumab, catumaxomab, the anti-EpCAM antibody IGN101, adecatumomab, oregovomab, dinutuximab, girentuximab, denosumab, bapineuzumab, motavizumab, efumgumab, raxibacumab, LY2469298, and veltuzumab. When the antibody comprises at least one light chain and at least one heavy chain, at least one light chain of the antibody, or at least one heavy chain of the antibody, or both may comprise an amino acid region having an amino acid motif capable of being recognized by an isoprenoid transferase. As an antibody may comprise four polypeptide chains (e.g., two heavy chains and two light chains), an antibody may comprise four isoprenylation sequences, each of which can be used to conjugate an active agent to the antibody via a linker. Thus, an antibody-drug conjugate may comprise 4 linkers, each conjugated to an active agent. Accordingly, an antibody-drug conjugate may comprise at least one linker and at least one active agent. An antibody-drug conjugate may comprise at least two linkers, and an antibody-drug conjugate may comprise at least two active agents. An antibody-drug conjugate may comprise 1, 2, 3, or 4 linkers. An antibody-drug conjugate may comprise 1, 2, 3, or 4 active agents. The active agent may be a drug, toxin, affinity ligand, detection probe, or combination of any of the foregoing. The active agent may be selected from erlotinib; bortezomib; fulvestrant; sutent; letrozole; imatinib mesylate; PTK787 / ZK 222584; oxaliplatin; 5-fluorouracil; leucovorin; rapamycin (Sirolimus); lapatinib; lonafarnib; sorafenib; gefitinib; AG1478; AG1571; alkylating agents (for example, thiotepa or cyclophosphamide); alkyl sulfonate (for example, busulfan, improsulfan, or piposulfan); aziridine (for example, benzodopa, carboquone, meturedopa, or uredopa); ethyleneimine, methylmelamine, altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, trimethylolmelamine; acetogenins (for example, bullatacin or bullatacinone); camptothecin and camptothecin derivatives and metabolites (SN-38); topotecan; bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin, or bizelesin synthetic analogs); cryptophycins (for example, cryptophycin 1 or cryptophycin 8); dolastatin; duocarmycin (including synthetic analogs, e.g., KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictyin; spongistatin; nitrogen mustard (for example, chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, or uracil mustard); nitrousurea (for example, carmustine, chlorozotocin, fotemustine, lomustine, nimustine, or ranimnustine); antibiotics (for example, enedigne antibiotics such as calicheamicin selected from calicheamicin gamma 1I and calicheamicin omega 1I, or dynemicin including dynemicin A); bisphosphonate (for example, clodronate; esperamicin, neocarzinostatin chromophore, or related chromoprotein enediyne antibiotic chromophores, aclacinomysins, actinomycin, anthramycin, azaserine, bleomycins, cactinomycin, carabicin, carninomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubucin, 6- diazo-5-oxo-L-norleucine, doxorubicin (for example, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubucin, liposomal doxorubicin, or deoxydoxorubicin), epirubicin, esorubicin, marcellomycin, mitomycins (for example, mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptomigrin, streptozocin, tubercidin, ubenimex, zinostatin, or zorubicin); anti-metabolites (for example, 5-fluorouracil); folic acid analogs (for example, denopterin, methotrexate, pteropterin, or trimetrexate); purine analogs (for example, fludarabine, 6-mercaptopurine, thiamiprine, or thiguanine); pyrimidine analogs (for example, ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, or floxuridine); androgens (for example, calusterone, dromostanolone propionate, epitiostanol, mepitiostane), or testolactone); anti-adrenals (for example, aminoglutethimide, mitotane, or trilostane); folic acid replenisher (for example, folinic acid); aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfornithine; elliptinium acetate; epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids (for example, maytansine or ansamitocins); trichothecenes (particularly T-2 toxin, verracurin A, roridin A, or anguidine); mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; 2- ethylhydrazide; procarbazine; polysaccharide K complex; razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; trichothecenes (particularly, T-2 toxin, verracurin A, roridin A, and anguidine); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside; cyclophosphamide; thiotepa; taxoids (for example, paclitaxel), ABRAXANETM cremophor-free, albumin-engineered nanoparticle formulation of paclitaxel, doxetaxel; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; platinum analog (for example, cisplatin or carboplatin); vinblastine; platinum; etoposide, ifosfamide; mitoxantrone; vincristine; vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; CPT-11; topoisomerase inhibitor (RFS 2000); difluoromethylornithine; retinoid (for example, retinoic acid); capecitabine, and pharmaceutically acceptable salts, solvates, acids, or derivatives thereof, but is not necessarily limited thereto. The active agent may be selected from (i) anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators, including, for example, tamoxifen, raloxifene, droloxifene, 4- hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene; (ii) aromatase inhibitors that inhibit aromatase enzyme, which regulates estrogen production in the adrenal glands, for example, 4(5)-imidazoles, aminoglutethimide, megestrol acetate, exemestane, letrozole, and anastrozole; (iii) anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; as well as troxacitabine (a 1,3-dioxolane nucleoside cytosine analog); (iv) aromatase inhibitors; (v) protein kinase inhibitors; (vi) lipid kinase inhibitors; (vii) antisense oligonucleotides, particularly those that inhibit expression of genes in signaling pathways implicated in adherent cells, for example, PKC-alpha, Raf, H- Ras; (viii) ribozyme, for example, VEGF inhibitor such as ribozyme and HER2 expression inhibitors; (ix) vaccines such as a gene therapy vaccine; ALLOVECTIN® vaccine, LEUVECTIN vaccine, VAXID vaccine; PROLEUKIN®rlL-2; LURTOTECAN® topoisomerase 1 inhibitor; ABARELIX® rmRH; (x) an anti-angiogenic agent such as Bevacizumab; and (xi) pharmaceutically acceptable salts, solvates, acids, or derivatives thereof. In addition, cytokines may be used as the active agent. Cytokines are small cell- signaling protein molecules that are secreted by numerous cells and are a category of signaling molecules used extensively in intercellular communication. The cytokines include monokines, lymphokines, traditional polypeptide hormones, and the like. Examples of the cytokines include growth hormone (for example, human growth hormone, N- methionyl human growth hormone, or bovine growth hormone); parathyroid hormone; thyroxine; insulin; proinsulin; relaxin; prorelaxin; glycoprotein hormone (for example, follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), or luteinizing hormone (LH)); hepatic growth factor; fibroblast growth factor; prolactin; placental lactogen; tumor necrosis factor-α, tumor necrosis factor-β; mullerian-inhibiting substance; mouse gonadotropin-associated peptide; inhibin; activin; vascular endothelial growth factor; integrin, thrombopoietin (TPO); nerve growth factor (for example, NGF-β); platelet- growth factor; transforming growth factor (TGF) (for example, TGF-<com:Math><semantics>α<annotation encoding="application / x-tex">\alpha< / annotation>< / semantics>< / com:Math> or TGF-<com:Math><semantics>β<annotation encoding="application / x-tex">\beta< / annotation>< / semantics>< / com:Math>); insulin- like growth factor-I, insulin-like growth factor-II; erythropoietin (EPO); osteoinductive factor; interferon (for example, interferon-<com:Math><semantics>α<annotation encoding="application / x-tex">\alpha< / annotation>< / semantics>< / com:Math>, interferon-<com:Math><semantics>β<annotation encoding="application / x-tex">\beta< / annotation>< / semantics>< / com:Math>, or interferon-<com:Math><semantics>γ<annotation encoding="application / x-tex">\gamma< / annotation>< / semantics>< / com:Math>); colony stimulating factor (CSF) (for example, macrophage-CSF (M-CSF), granulocyte- macrophage-CSF (GM-CSF), or granulocyte-CSF (G-CSF)); interleukin (IL) (for example, IL-1, IL-1α, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, or IL-12); tumor necrosis factor (TNF) (for example, TNF-<com:Math><semantics>α<annotation encoding="application / x-tex">\alpha< / annotation>< / semantics>< / com:Math> or TNF-<com:Math><semantics>β<annotation encoding="application / x-tex">\beta< / annotation>< / semantics>< / com:Math>); and polypeptide factor (for example, LIF or kit ligand), but are not limited thereto. Further, the term "cytokine" also includes cytokines from natural sources or recombinant cell cultures and biologically active equivalents of the native sequence cytokines. The term "toxin" refers substances that are poisonous to living cells or organisms. Toxins may be small molecules, peptides or proteins capable of causing cell dysfunction or cell death after contact with or absorption by body tissue, e.g., through an interaction with one or more biological macromolecules such as enzymes or cell receptors. Toxins include plant toxins and animal toxins. Examples of animal toxins include diphtheria toxin, botulinum toxin, tetanus toxin, dysentery toxin, cholera toxin, tetrodotoxin, brevetoxin, and ciguatoxin, but are not limited thereto. Examples of plant toxins include ricin and AM- toxin, but are not limited thereto. Examples of small molecule toxins include auristatin, tubulysin, geldanamycin (Kerr et al., 1997, Bioconjugate Chem. 8(6):781-784), maytansinoid (EP 1391213, ACR 2008, 41, 98-107), calicheamicin (U.S. Patent Publication No. 2009 / 0105461, Cancer Res. 1993, 53, 3336-3342), daunomycin, doxorubicin, methotrexate, vindesine, SG2285 (Cancer Res. 2010, 70(17), 6849-6858), dolastatin, dolastatin analogs auristatin (U.S. Patent No. 5,635,483), cryptophycin, camptothecin, rhizoxin derivative, CC 1065 analog or derivative, duocarmycin, enediyne antibiotic, esperamicin, epothilone, pyrrolobenzodiazepine (PBD) derivatives, α-amanitin, and toxoid, but are not limited thereto. Toxins may exhibit cytotoxicity and cell growth-inhibiting activity by tubulin binding, DNA binding, topoisomerase suppression, and the like. The term "ligand" refers to a molecule capable of forming a complex with a target biomolecule. An example of the ligand is a molecule bound to a predetermined position of a target protein to transmit a signal. The ligand may be a substrate, an inhibitor, a stimulating agent, a neurotransmitter, or a radioisotope. "Detectable moiety" or a "label" refers to a composition detectable by spectroscopic, photochemical, biochemical, immunochemical, radioactive, or chemical means. For example, useful labels include 32P, 35S, fluorescent dyes, electron-dense reagents, enzymes (for example, enzymes commonly used in an ELISA), biotin- streptavidin, dioxigenin, haptens, and proteins for which antisera or monoclonal antibodies are available, or nucleic acid molecules with a sequence complementary to a target. The detectable moiety often generates a measurable signal, such as a radioactive, chromogenic, or fluorescent signal, that may be used to quantify the amount of bound detectable moiety in a sample. Quantitation of the signal may be achieved, for example, by scintillation counting, densitometry, flow cytometry, ELISA, or direct analysis by mass spectrometry of intact or subsequently digested peptides (one or more peptide may be assessed). The term "probe" as used herein refers to a material that may (i) provide a detectable signal, (ii) interact a first probe or a second probe to modify a detectable signal provided by the first or second probe, such as fluorescence resonance energy transfer (FRET), (iii) stabilize an interaction with an antigen or a ligand or increase binding affinity; (iv) affect electrophoresis mobility or cell-intruding activity by a physical parameter such as charge, hydrophobicity, etc., or (v) control ligand affinity, antigen-antibody binding, or ionic complex formation. The active agent may be an immunomodulatory compound, an anticancer agent, an antiviral agent, an antibacterial agent, an antifungal agent, an antiparasitic agent, or a combination thereof. An immunomodulatory compound may be selected from aminocaproic acid, azathioprine, bromocriptine, chlorambucil, chloroquine, cyclophosphamide, cyclosporine, cyclosporine A, danazol, dehydroepiandrosterone, dexamethasone, etanercept, hydrocortisone, hydroxychloroquine, infliximab, meloxicam, methotrexate, mycophenylate mofetil, prednisone, sirolimus, and tacrolimus. An anticancer agent may be selected from 1-methyl-4-phenylpyridinium ion, 5-ethynyl-1-beta-D-ribofuranosylimidazole-4- carboxamide (EICAR), 5-fluorouracil, 9-aminocamptothecin, actinomycin D, asparaginase, bicalutamide, bis-chloroethylnitrosourea (BCNU), bleomycin, bleomycin A2, bleomycin B2, busulfan, camptothecin, carboplatin, carmustine, CB1093, chlorambucil, cisplatin, crisnatol, cyclophosphamide, cytarabine, cytosine arabinoside, cytoxan, dacarbazine, dactinomycin, daunorubicin, decarbazine, deferoxamine, demethoxy-hypocrellin A, docetaxel, doxifluridine, doxorubicin, EB1089, epirubicin, etoposide, floxuridine, fludarabine, flutamide, gemcitabine, goserelin, hydroxyurea, idarubicin, ifosfamide, interferon-α, interferon-γ, irinotecan, KH1060, leuprolide acetate, lomustine, lovastatin, megestrol, melphalan, mercaptopurine, methotrexate, mitomycin, mitomycin C, mitoxantrone, mycophenolic acid, nitrogen mustard, nitrosourea, paclitaxel, peplomycin, photosensitizer Pe4, phthalocyanine, pirarubicin, plicamycin, procarbazine, raloxifene, raltitrexed, revlimid, ribavirin, staurosporine, tamoxifen, teniposide, thalomid, thapsigargin, thioguanine, tiazofurin, topotecan, treosulfan, trimetrexate, tumor necrosis factor, velcade, verapamil, verteporfin, vinblastine, vincristine, vinorelbine, and zorubicin. An antiviral agent may be selected from pencicyclovir, valacyclovir, gancicyclovir, foscarnet, ribavirin, idoxuridine, vidarabine, trifluridine, acyclovir, famcicyclovir, amantadine, rimantadine, cidofovir, antisense oligonucleotide, immunoglobulin, and interferon. An antibacterial agent may be selected from chloramphenicol, vancomycin, metronidazole, trimethoprin, sulfamethazole, quinupristin, dalfopristin, rifampin, spectinomycin, and nitrofurantoin. The antifungal agent may be selected from amphotericin B, candicidin, filipin, hamycin, natamycin, nystatin, rimocidin, bifonazole, butoconazole, clotrimazole, econazole, fenticonazole, isoconazole, ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole, sertaconazole, sulconazole, tioconazole, albaconazole, fluconazole, isavuconazole, itraconazole, posaconazole, ravuconazole, terconazole, voriconazole, abafungin, amorolfin, butenafine, naftifine, terbinafine, anidulafungin, caspofungin, micafungin, benzoic acid, ciclopirox, flucytosine, griseofulvin, haloprogin, tolnaftate, undecylenic acid, crystal violet, balsam of peru, ciclopirox olamine, piroctone olamine, zinc pyrithione, and selenium sulfide. An antiparasitic agent may be selected from mebendazole, pyrantel pamoate, thiabendazole, diethylcarbamazine, ivermectin, niclosamide, praziquantel, albendazole, rifampin, amphotericin B, melarsoprol, effornithine, metronidazole, tinidazole, and miltefosine. The antibody may comprise an amino acid motif selected from Ab-HC-(G)<com:Sub>z< / com:Sub>CVIM, Ab-HC-(G)<com:Sub>z< / com:Sub>CVLL, Ab-LC-(G)<com:Sub>z< / com:Sub>CVIM, and Ab-LC-(G)<com:Sub>z< / com:Sub>CVLL, wherein Ab represents an antibody, -HC- represents a heavy chain, -LC- represents a light chain, G represents a glycine, C represents cysteine, V represents valine, I represents isoleucine, M represents methionine, L represents leucine, and z is an integer from 0 to 20. The active agent of the antibody-drug conjugate may be selected from any one of the following structures: [Image disponible dans le document PDF, Image available in the PDF document] - کې , [Image disponible dans le document PDF, Image available in the PDF document] • , 9 [Image disponible dans le document PDF, Image available in the PDF document] 1( wherein y is an integer from 1 to 10. The antibody-drug conjugate may be used to transfer the active agent to a target cell of a subject to treat the subject using a method of preparing a composition known to those skilled in the art. In some aspects, the invention relates to a composition <com:Math><semantics>(e.g.,a)<annotation encoding="application / x-tex">(e.g., a)< / annotation>< / semantics>< / com:Math> pharmaceutical composition) comprising an antibody-drug conjugate as described herein. Compositions may be prepared in an injectable form, either as a liquid solution or as a suspension. Solid forms suitable for injection may also be prepared, e.g., as emulsions, or with the antibody-drug conjugate encapsulated in liposomes. Antibody-drug conjugates may be combined with a pharmaceutically acceptable carrier, which includes any carrier that does not induce the production of antibodies harmful to the subject receiving the carrier. Suitable carriers typically comprise large macromolecules that are slowly metabolized, for example, proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers, lipid aggregates, and the like. The compositions may also contain diluents, for example, water, saline, glycerol, and ethanol. Auxiliary substances, for example, wetting or emulsifying agents, pH buffering substances, and the like may also be present therein. The compositions may be parenterally administered by injection, wherein such injection may be either subcutaneous or intramuscular injection. In some embodiments, a composition may be administered into a tumor. The composition may be inserted (<com:Math><semantics>e.g.<annotation encoding="application / x-tex">e.g.< / annotation>< / semantics>< / com:Math>, injected) into a tumor. Additional formulations are suitable for other forms of administration, such as suppository or oral administration. Oral compositions may be administered as a solution, suspension, tablet, pill, capsule, or sustained release formulation. The compositions may be administered in a manner compatible with a dose and a formulation. The composition preferably comprises a therapeutically effective amount of the antibody-drug conjugate. The term "therapeutically effective amount" means a single dose or a composition administered in a multiple dose schedule that is effective for the treatment or prevention of a disease or disorder. A dose may vary, depending on the subject to be treated, the subject's health and physical conditions, a degree of protection to be desired, and other relevant factors. The exact amount of an active ingredient (e.g., the antibody-drug conjugate) may depend on the judgment of a doctor. For example, a therapeutically effective amount of the antibody-drug conjugate or composition containing the same may be administered to a patient suffering from a cancer or tumor to treat the cancer or tumor. The antibody-drug conjugate according to the present invention or the composition containing the same may be administered in the form of a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the antibody-drug conjugate according to the present invention or the composition containing the same may be administered with a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and / or a pharmaceutically acceptable additive. The effective amount and the type of the pharmaceutically acceptable salt or solvate, excipient and additive may be measured using standard methods (see, e.g., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18th Edition, 1990). The term "therapeutically effective amount" with regard to cancer or tumor means an amount that may decrease the number of cancer cells; decrease a size of cancer cells; inhibit cancer cells from intruding into peripheral systems or decrease the intrusion; inhibit cancer cells from spreading to other systems or decrease the spreading; inhibit cancer cells from growing; and / or ameliorate at least one symptom related to the cancer. In the treatment of cancer, the effectiveness of a drug may be assessed by time to tumor progression (TTP) and / or response rate (RR). The term "pharmaceutically acceptable salts" used herein includes organic salts and inorganic salts. Examples thereof include hydrochloride, hydrobromide, hydroiodide, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acidic phosphate, isonicotinate, lactate, salicylate, acidic citrate, tartrate, oleate, tannate, pantonate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucoronate, saccharate, formate, benzoate, glutamate, methane sulfonate, ethane sulfonate, benzene sulfonate, p-toluene sulfonate, and pamoate (that is, 1,1'-methylenebis-(2-hydroxy- 3-naphthoate)). The pharmaceutically acceptable salt may include another molecule (for example, acetate ions, succinate ions, and / or other counter ions). Exemplary solvates that may be used for pharmaceutically acceptable solvates of the antibody-drug conjugates described herein include water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and ethanol amine. In some embodiments, the invention relates to a method of treating cancer in a subject, comprising administering a pharmaceutical composition comprising an antibody- drug conjugate as described herein to the subject. A pharmaceutical composition may further comprise a therapeutically effective amount of chemotherapeutic agent. In preferred embodiments, the subject is a mammal. For example, the subject may be selected from rodents, lagomorphs, felines, canines, porcines, ovines, bovines, equines, and primates. In certain preferred embodiments, the subject is a human. EXEMPLIFICATION The table below lists the abbreviations used throughout the following Examples: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] Example 1. Preparation of Compound 1i PCT / IB2016 / 001811 [Image disponible dans le document PDF, Image available in the PDF document] Preparation of Compound 1b To a suspension of 5-formylsalicylic acid 1a (10.0 g, 60.1 mmol) in THF (30 mL) was added DIPEA (29.8 mL, 180 mmol) and benzyl bromide (7.15 mL, 60.1 mmol) at room temperature. Then the reaction mixture was heated under reflux. After 18 hours under reflux, the reaction mixture diluted with 2 N aq. HCl (100 mL). The resulting mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over anhydrous MgSO<com:Sub>4< / com:Sub>, filtered and concentrated. The residue was purified by column chromatography to produce the compound 1b (12.9 g, 83 %). <com:Sup>1< / com:Sup>H-NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 11.38 (s, 1H), 9.86 (s, 1H), 8.40 (s, 1H), 8.01 (d, <com:Math><semantics>J=8.8<annotation encoding="application / x-tex">J = 8.8< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.44 (m, 5H), 7.12 (d, <com:Math><semantics>J=8.8<annotation encoding="application / x-tex">J = 8.8< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.44 (m, 5H), 7.12 (d, <com:Math><semantics>J=8.8<annotation encoding="application / x-tex">J = 8.8< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.44 (m, 5H), 7.12 (d, <com:Math><semantics>J=8.8<annotation encoding="application / x-tex">J = 8.8< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.44 (m, 5H), 7.12 ( <com:Math><semantics>=8.0 Hz,1H,5.42 (s, 2H).<annotation encoding="application / x-tex">= 8.0 \text{ Hz}, 1\text{H}, 5.42 \text{ (s, 2H)}.< / annotation>< / semantics>< / com:Math> Preparation of Compound 1c To a solution of compound 1b (5.0 g, 19.5 mmol) and compound M (8.5 g, 21.4 mmol, see Example 66) in MeCN (100 mL) were added 4 Å molecular sieve (10 g) and Ag<com:Sub>2< / com:Sub>O (18.0 g, 78.0 mmol). After stirring at room temperature for 12 hours under N<com:Sub>2< / com:Sub>, the reaction mixture was concentrated. Then the concentrated reaction mixture was diluted with H<com:Sub>2< / com:Sub>O (100 mL) and extracted with EtOAc (2 x 200 mL). The combined organic layers were dried over anhydrous MgSO<com:Sub>4< / com:Sub>, filtered and concentrated. The residue was purified by column chromatography to produce the compound 1c (8.63 g, 77 %). <com:Sup>1< / com:Sup>H-NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 9.94 (s, 1H), 8.28 (s, 1H), 8.02 (d, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 8.8 Hz, 1H), 7.46-7.28 (m, 6H), 5.41-5.32 <com:Math><semantics>(m,6H),4.27(d,J=9.2Hz,1H),3.71(s,3H),2.05(m,9H).<annotation encoding="application / x-tex">(m, 6H), 4.27 (d, J = 9.2 Hz, 1H), 3.71 (s, 3H), 2.05 (m, 9H).< / annotation>< / semantics>< / com:Math> Preparation of Compound 1d To a solution of compound 1c (3.10 g, 5.41 mmol) in <com:Math><semantics>i<annotation encoding="application / x-tex">i< / annotation>< / semantics>< / com:Math>-PrOH / CHCl<com:Sub>3< / com:Sub> (9 mL / 45 mL) was added silica gel (3 g) and NaBH<com:Sub>4< / com:Sub> (0.41 g, 10.82 mmol) at 0 °C. After stirring at 0 °C for 2 hours under <com:Math><semantics>N2<annotation encoding="application / x-tex">N_2< / annotation>< / semantics>< / com:Math>, the reaction mixture was quenched with <com:Math><semantics>H2O<annotation encoding="application / x-tex">H_2O< / annotation>< / semantics>< / com:Math> (100 mL) and extracted with EtOAc (200 mL). The organic layer was dried over anhydrous MgSO<com:Sub>4< / com:Sub>, filtered and concentrated. The crude product was purified by column chromatography to produce the compound 1d (2.73 g, 87 %) as white solid. <com:Sup>1< / com:Sup>H-NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) δ 7.74 (s, 1H), 7.48-7.34 (m, 6H), 7.16 (d, <com:Math><semantics>J=8.8<annotation encoding="application / x-tex">J = 8.8< / annotation>< / semantics>< / com:Math> Hz, 1H), 5.35-5.26 (m, 5H), 5.15 (m, 1H), 4.17 (m, 1H), 3.73 (s, 3H), 2.04 (s, 9H), 1.73 (t, 1H). Preparation of Compound 1e To a solution of compound 1d (2.40 g, 4.17 mmol) in EtOH (150 mL) Pd / C (10 wt. %, 240 mg) was added. The reaction mixture was stirred at room temperature for 10 minutes under hydrogen. Then the reaction mixture was filtered through a celite pad and washed with EtOH (100 mL). The filtrate was concentrated to provide the crude product 1e as white solid (2.10 g), which was used without further purification. <com:Sup>1< / com:Sup>H-NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.06 (s, 1H) 7.61 (dd, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 8.8 Hz, 1H), 7.23 (d, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 8.0 Hz 1H), 5.43-5.29 (m, 5H), <com:Math><semantics>4.17<annotation encoding="application / x-tex">4.17< / annotation>< / semantics>< / com:Math> (s, 2H), <com:Math><semantics>4.32<annotation encoding="application / x-tex">4.32< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=8.4<annotation encoding="application / x-tex">J = 8.4< / annotation>< / semantics>< / com:Math> Hz, 1H) <com:Math><semantics>3.69<annotation encoding="application / x-tex">3.69< / annotation>< / semantics>< / com:Math> (s, 3H), <com:Math><semantics>2.11−2.08<annotation encoding="application / x-tex">2.11-2.08< / annotation>< / semantics>< / com:Math> (t, 9H), <com:Math><semantics>1.24<annotation encoding="application / x-tex">1.24< / annotation>< / semantics>< / com:Math> (t, 1H). Preparation of Compound 1f To a solution of the crude compound 1e (2.10 g, 4.33 mmol) in DMF (50 mL) were added K<com:Sub>2< / com:Sub>CO<com:Sub>3< / com:Sub> (1.79 g, 13.01 mmol) and allyl bromide (0.41 mL, 4.76 mmol) at room temperature. After stirring at room temperature for 3 hours, the reaction mixture was diluted with 2 N aq. HCl (100 mL). The resulting mixture was extracted with EtOAc (200 mL). The organic layer was dried over anhydrous MgSO<com:Sub>4< / com:Sub>, filtered and concentrated. The residue was purified by column chromatography to produce the compound 1f (1.55 g, 70 % for 2 steps). <com:Sup>1< / com:Sup>H-NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.74 (s, 1H), 7.45 (dd, <com:Math><semantics>J=8.0<annotation encoding="application / x-tex">J = 8.0< / annotation>< / semantics>< / com:Math> Hz, 2.0 Hz, 1H), <com:Math><semantics>7.16<annotation encoding="application / x-tex">7.16< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=8.8<annotation encoding="application / x-tex">J = 8.8< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>6.02<annotation encoding="application / x-tex">6.02< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>5.40−5.26<annotation encoding="application / x-tex">5.40-5.26< / annotation>< / semantics>< / com:Math> (m, 5H), <com:Math><semantics>5.16<annotation encoding="application / x-tex">5.16< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>4.76<annotation encoding="application / x-tex">4.76< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>4.66<annotation encoding="application / x-tex">4.66< / annotation>< / semantics>< / com:Math> (s, 2H), 4.19 (m, 1H), 3.73 (s, 3H), 2.07-2.05 (m, 9H), 1.68 (t, 1H). Preparation of Compound 1g To a solution of compound 1f (2.50 g, 4.77 mmol) in DMF (20 mL) were added bis(4-nitrophenyl)carbonate (1.30 g, 4.29 mmol) and DIPEA (0.80 mL 4.77 mmol) at 0 °C under N<com:Sub>2< / com:Sub>. The reaction mixture was stirred at 0 °C for 30 min and allowed to warm to room temperature for 1 hour. The reaction mixture was diluted with H<com:Sub>2< / com:Sub>O (100 mL) and extracted with EtOAc (200 mL). The organic layer was washed with brine (100 mL) and dried over anhydrous MgSO<com:Sub>4< / com:Sub>. After filtration and concentration under reduced pressure, the resulting crude product was purified by column chromatography to produce the compound 1g (2.80) g, 85 %). <com:Math><semantics>1<annotation encoding="application / x-tex">^{1}< / annotation>< / semantics>< / com:Math>H-NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.28 (d, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 15.2 Hz, 2H), 7.85 (d, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 2.4 Hz, 1H), 7.55 (dd, <com:Math><semantics>J=3.2<annotation encoding="application / x-tex">J = 3.2< / annotation>< / semantics>< / com:Math> Hz, 2.4 Hz, 1H), 7.38 (d, <com:Math><semantics>J=15.2<annotation encoding="application / x-tex">J = 15.2< / annotation>< / semantics>< / com:Math> Hz, 2H), 7.20 (d, <com:Math><semantics>J=8.8<annotation encoding="application / x-tex">J = 8.8< / annotation>< / semantics>< / com:Math> Hz, 1H) 6.03 (m, 1H), <com:Math><semantics>5.42−5.19<annotation encoding="application / x-tex">5.42-5.19< / annotation>< / semantics>< / com:Math> (m, 8H), <com:Math><semantics>4.78<annotation encoding="application / x-tex">4.78< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=5.2<annotation encoding="application / x-tex">J = 5.2< / annotation>< / semantics>< / com:Math> Hz, 2H), <com:Math><semantics>4.12<annotation encoding="application / x-tex">4.12< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=7.2<annotation encoding="application / x-tex">J = 7.2< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>3.74<annotation encoding="application / x-tex">3.74< / annotation>< / semantics>< / com:Math> (s, 3H). [Image disponible dans le document PDF, Image available in the PDF document] Preparation of Compound 1h Compound 1g (528 mg, 0.77 mmol), MMAE (500 mg, 0.7 mmol) and anhydrous HOBt (19 mg, 0.14 mmol) were dissolved in DMF (3 mL) at 0 °C. Then pyridine (0.7 mL) and DIPEA (0.24 mL, 1.39 mmol) were added. After stirring at room temperature for 24 hours under N<com:Sub>2< / com:Sub>, the reaction mixture was diluted with H<com:Sub>2< / com:Sub>O / saturated aqueous NH<com:Sub>4< / com:Sub>Cl solution (100 mL / 50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over anhydrous MgSO<com:Sub>4< / com:Sub>, filtered, and concentrated. The residue was purified by column chromatography to produce the compound 1h (600 mg, 67 %). EI-MS <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math>: <com:Math><semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>< / com:Math> 1269.5, <com:Math><semantics>[M+Na]+<annotation encoding="application / x-tex">[M+Na]^+< / annotation>< / semantics>< / com:Math> 1291.5. Preparation of Compound 1i To a solution of compound 1h (600 mg, 0.47 mmol) and triphenylphosphine (31 mg, 0.12 mmol) in DCM (10 mL) were added pyrrolidine (0.047 mL, 0.57 mmol) and Pd(PPh<com:Sub>3< / com:Sub>)<com:Sub>4< / com:Sub> (27 mg, 0.02 mmol) at room temperature. After stirring for 2 hours, the reaction mixture was diluted with <com:Math><semantics>H2O / 1<annotation encoding="application / x-tex">H_2O / 1< / annotation>< / semantics>< / com:Math> N aq. HCl (50 mL / 50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous MgSO<com:Sub>4< / com:Sub>, filtered, and concentrated. The residue was purified by column chromatography (Hex / EtOAc 1 / 1 to EtOAc) to produce the compound 1i (480 mg, 82 %) as a white solid. EI-MS m / z: [M+H]<com:Sup>+< / com:Sup> 1228.4, [M+Na]<com:Sup>+< / com:Sup> 1250.4. Example 2. Preparation of Compound 1j [Image disponible dans le document PDF, Image available in the PDF document] Compound 1j was prepared from MMAF-OMe by a similar method of preparing compound 1i in Example 1. Example 3. Preparation of Compound 2g [Image disponible dans le document PDF, Image available in the PDF document] Preparation of Compound 2a 2-(2-(2-Chloroethoxy)ethoxy)ethanol (10 g, 59.3 mmol) was dissolved in DMF (90 mL) at room temperature under nitrogen, and then NaN<com:Sub>3< / com:Sub> (5.78 g, 88.9 mmol) was added thereto. After stirring at 100 °C for 13 hours, chloroform (200 mL) and distilled water (300 mL) were added thereto to extract an organic layer, and the extracted organic layer was dried over anhydrous Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub> and concentrated under reduced pressure. The residue was subjected to column chromatography, which produced the compound 2a (10.3 g, 99 %). <com:Sup>1< / com:Sup>H- NMR (600 MHz, CDCl<com:Sub>3< / com:Sub>) δ 3.75-3.73 (m, 2H), 3.70-3.68 (m, 6H), 3.63-3.61 (m, 2H), 3.40 <com:Math><semantics>(t,J=5.4 Hz,2H),2.20(t,J=6.0 Hz,1H).<annotation encoding="application / x-tex">(t, J = 5.4 \text{ Hz}, 2H), 2.20 (t, J = 6.0 \text{ Hz}, 1H).< / annotation>< / semantics>< / com:Math> Preparation of Compound 2b CBr<com:Sub>4< / com:Sub> (21.4 g, 64.6 mmol) was dissolved in DCM (100 mL) at 0°C under nitrogen, and then triphenylphosphine (16.9 g, 64.6 mmol) in DCM (100 mL) and compound 2a (10.3 g, 58.7 mmol) were added thereto, and the mixture was stirred at room temperature for 13 hours. After the reaction was completed, DCM (300 mL) and distilled water (300 mL) were added thereto to extract an organic layer, and the extracted organic layer was dried over anhydrous Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub> and concentrated under reduced pressure. The residue was subjected to column chromatography, which produced the compound 2b (12 g, 85 %). <com:Sup>1< / com:Sup>H- NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 3.83 (t, <com:Math><semantics>J=6.4<annotation encoding="application / x-tex">J = 6.4< / annotation>< / semantics>< / com:Math> Hz, 2H), 3.72-3.67 (m, 6H), 3.48 (t, <com:Math><semantics>J=6.0<annotation encoding="application / x-tex">J = 6.0< / annotation>< / semantics>< / com:Math> Hz, 2H), 3.40 (t, <com:Math><semantics>J=4.8<annotation encoding="application / x-tex">J = 4.8< / annotation>< / semantics>< / com:Math> Hz, 2H) Preparation of Compound 2c Compound 2b (1g, 4.20 mmol) was dissolved in MeCN at room temperature under nitrogen, and then N-Boc-hydroxylamine (643 mg, 4.82 mmol) and DBU (0.66 mL, 4.41mmol) were added thereto. After stirring at 60 °C for 13 hours, DCM (300 mL) and distilled water (300 mL) were added thereto to extract an organic layer, and the extracted organic layer was dried over anhydrous Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub> and concentrated under reduced pressure. The residue was subjected to column chromatography, which produced the compound 2c (748 mg, 70 %). <com:Sup>1< / com:Sup>H-NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) δ 7.55 (s, 1H), 4.05-4.03 (m, 2H), 3.76-3.74 <com:Math><semantics>(m,2H),3.74−3.69(m,6H),3.42(t,J=4.8Hz,2H),1.49(s,9H).<annotation encoding="application / x-tex">(m, 2H), 3.74-3.69 (m, 6H), 3.42 (t, J = 4.8 Hz, 2H), 1.49 (s, 9H).< / annotation>< / semantics>< / com:Math> Preparation of Compound 2d Compound 2c (200 mg, 0.688 mmol) was dissolved in MeOH (5 mL), and then Pd / C (10% wt., 70 mg) was added thereto and stirred under hydrogen for 3 hours. After the reaction was completed, the reaction mixture was celite-filtered and concentrated under reduced pressure, which produced the compound 2d (180 mg, 98 %). <com:Sup>1< / com:Sup>H-NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 4.04-4.01 (m, 2H), 3.74-3.62 (m, 7H), 3.55 (t, <com:Math><semantics>J=5.2<annotation encoding="application / x-tex">J = 5.2< / annotation>< / semantics>< / com:Math> Hz, 1H), 2.88 (t, <com:Math><semantics>J=5.2<annotation encoding="application / x-tex">J = 5.2< / annotation>< / semantics>< / com:Math> Hz, 1H), 2.81 (t, <com:Math><semantics>J=5.2<annotation encoding="application / x-tex">J = 5.2< / annotation>< / semantics>< / com:Math> Hz, 1H), 1.64 (s, 2H), 1.48 (s, 9H). PCT / IB2016 / 001811 [Image disponible dans le document PDF, Image available in the PDF document] Preparation of Compound 2e DIPEA (0.042 mL, 0.32 mmol) and PyBOP (126 mg, 0.24 mmol) were added to a stirred mixture of compound 1i (200 mg, 0.16 mmol) and compound 2d (51 mg, 0.19 mmol) in DMF (4 mL). After stirring at room temperature for 4 hours under <com:Math><semantics>N2<annotation encoding="application / x-tex">N_2< / annotation>< / semantics>< / com:Math>, the reaction mixture was diluted with H<com:Sub>2< / com:Sub>O (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over anhydrous Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub>, filtered and concentrated. The resulting residue was purified by column chromatography to yield the compound 2e (142 mg, 60 %). EI-MS m / z: [M+H]<com:Sup>+< / com:Sup> 1474.7. Preparation of Compound 2f To a solution of compound 2e (142 mg, 0.096 mmol) in MeOH (2 mL) was added LiOH monohydrate (36 mg, 0.86 mmol) in H<com:Sub>2< / com:Sub>O (2 mL) at -20 °C. After stirred at 0 °C for 1 hour, the reaction mixture was diluted with <com:Math><semantics>H2O / 2<annotation encoding="application / x-tex">H_2O / 2< / annotation>< / semantics>< / com:Math> N aq. HCl solution (50 mL / 2 mL) and extracted with CHCl<com:Sub>3< / com:Sub> (2 x 100 mL). The combined organic layers were dried over anhydrous Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub>, filtered and concentrated to yield the crude compound 2f (128 mg), which was used without further purification. EI-MS m / z: [M+H]<com:Sup>+< / com:Sup> 1334.5. Preparation of Compound 2g To a solution of crude compound 2f (105 mg, 0.08 mmol) in DCM (3 mL) HCl (4 M in 1,4- dioxane, 1 mL) was added at 0 °C. After 1 hour, the solvent and excess HCl were removed by <com:Math><semantics>N2<annotation encoding="application / x-tex">N_2< / annotation>< / semantics>< / com:Math> flow and then the residue was purified by HPLC, which produced the compound <com:Math><semantics>2g<annotation encoding="application / x-tex">2g< / annotation>< / semantics>< / com:Math> (47 mg, 46 %) as white solid. EI-MS m / z: [M+H]<com:Sup>+< / com:Sup> 1234.4. Example 4. Preparation of Compound 2h [Image disponible dans le document PDF, Image available in the PDF document] Compound 2h was prepared from compound 1j and compound 2d by a similar method of preparing compound 2g in Example 3. EI-MS m / z: [M+H]<com:Sup>+< / com:Sup> 1248.9. Example 5. Preparation of Compound 3f [Image disponible dans le document PDF, Image available in the PDF document] Preparation of Compound 3a A mixture of hexaethylene glycol (1.0 g, 3.54 mmol), Ag<com:Sub>2< / com:Sub>O (1.23 g, 5.31 mmol) and KI (117 mg, 0.71 mmol) in DCM (10 mL) was sonicated for 15 min. The suspension was cooled to -30 °C and a solution of p-toluenesulfonyl chloride (688 mg, 3.61 mmol) in DCM (13 mL) was added dropwise. The mixture was then gradually warmed up to 0 °C and kept for 15 minutes at this temperature. Then the reaction mixture was dried over anhydrous MgSO<com:Sub>4< / com:Sub>, filtered and concentrated to produce the syrupy residue. Then, the syrupy residue was purified by column chromatography (EtOAc to EtOAc / MeOH 10 / 1). The pure fractions were evaporated in vacuo to yield the compound 3a (1.18 g, 77 %). <com:Sup>1< / com:Sup>H- NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.80 (d, <com:Math><semantics>J=8.4<annotation encoding="application / x-tex">J = 8.4< / annotation>< / semantics>< / com:Math> Hz, 2H), 7.34 (d, <com:Math><semantics>J=8.4<annotation encoding="application / x-tex">J = 8.4< / annotation>< / semantics>< / com:Math> Hz, 2H), 4.16 (m, 2H), 3.72-3.58 (m, 22H), 2.97 (br, 1H), 2.45 (s, 3H). Preparation of Compound 3b Compound 3a (1.18 g, 2.71 mmol) and NaN<com:Sub>3< / com:Sub> (264 mg, 4.07 mmol) were dissolved in DMF (3 mL). And then the reaction mixture was heated at 100 °C. After 15 hours at 100 °C, the reaction mixture was filtered and concentrated. The residue was purified by column chromatography (EtOAc to EtOAc / MeOH 10 / 1) to yield the compound 3b (728 mg, 87 %). <com:Sup>1< / com:Sup>H-NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) δ 3.75-3.70 (m, 2H), 3.69-3.63 (m, 18H), 3.62-3.60 (m, 2H), <com:Math><semantics>3.39(d,J=5.2Hz,2H),3.07(br,1H).<annotation encoding="application / x-tex">3.39 (d, J = 5.2 Hz, 2H), 3.07 (br, 1H).< / annotation>< / semantics>< / com:Math> Preparation of Compound 3c To a stirred solution of compound 3b (728 mg, 2.36 mmol) in THF (10 mL) at 0 °C were added triethylamine (0.73 mL, 5.21 mmol) and methanesulfonic anhydride (619 mg, 3.55 mmol). After 2 hours, LiBr (1.03 g, 11.8 mmol) was added to a stirred solution and the resulting reaction mixture was refluxed for 5 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc to EtOAc / MeOH 10 / 1) to yield the compound 3c (810 mg, 92 %). <com:Math><semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>< / com:Math>H-NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 3.81 (t, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 6.4 Hz, 2H), 3.69-3.65 (m, 18H), <com:Math><semantics>3.47<annotation encoding="application / x-tex">3.47< / annotation>< / semantics>< / com:Math> (t, <com:Math><semantics>J=6.4<annotation encoding="application / x-tex">J = 6.4< / annotation>< / semantics>< / com:Math> Hz, <com:Math><semantics>2H<annotation encoding="application / x-tex">2H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>3.39<annotation encoding="application / x-tex">3.39< / annotation>< / semantics>< / com:Math> (t, <com:Math><semantics>J=5.2<annotation encoding="application / x-tex">J = 5.2< / annotation>< / semantics>< / com:Math> Hz, <com:Math><semantics>2H<annotation encoding="application / x-tex">2H< / annotation>< / semantics>< / com:Math>). Preparation of Compound 3d NaH (60 % in oil, 564 mg, 12.9 mmol) was added to a stirred mixture of compound 3c (3.42 g, 9.24 mmol) and N,N-diBoc-hydroxylamine (2.80 g, 12.0 mmol, synthesized by the procedures in PCT publication No. WO2004 / 018466A2, hereby incorporated by reference) in DMF (20 mL) at 0 °C. The reaction mixture was warmed to room temperature and kept for 2 hours at this temperature. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (EtOAc / Hex 1 / 20 to 1 / 5), which produced the compound 3d (3.51 g, 73 %). <com:Math><semantics>1<annotation encoding="application / x-tex">^{1}< / annotation>< / semantics>< / com:Math>H-NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 4.08 (t, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> <com:Math><semantics>=4.8 Hz,2H<annotation encoding="application / x-tex">= 4.8 \text{ Hz}, 2\text{H}< / annotation>< / semantics>< / com:Math>), 3.73 (t, <com:Math><semantics>J=4.8 Hz,2H<annotation encoding="application / x-tex">J = 4.8 \text{ Hz}, 2\text{H}< / annotation>< / semantics>< / com:Math>), 3.69-3.62 (m, 18H), 3.39 (t, <com:Math><semantics>J=5.6 Hz,2H<annotation encoding="application / x-tex">J = 5.6 \text{ Hz}, 2\text{H}< / annotation>< / semantics>< / com:Math>), 1.53 (s, 18H). Preparation of Compound 3e To a stirred mixture of compound 3d (123 mg, 0.23 mmol), and Pd / C (10 wt. %, 25 mg) in MeOH (5 mL) at 0 °C was added HCl (4 N in 1,4-dioxane, 0.05 mL, 0.21 mmol). After stirring at room temperature for 5 hours under hydrogen, the reaction mixture was filtered through a celite pad and washed with MeOH (100 mL). The filtrate was concentrated to produce the compound 3e (118 mg, 95 %) as colorless oil, which was used without further purification. <com:Sup>1< / com:Sup>H-NMR (400 MHz, DMSO-d<com:Sub>6< / com:Sub>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 3.98 (t, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 4.4 Hz, 2H), 3.61-3.51 (m, 22H), 2.95 (br, 3H), 1.46 (s, 18H). EI-MS m / z: [M+H]<com:Sup>+< / com:Sup> 497.6. Preparation of Compound 3f [Image disponible dans le document PDF, Image available in the PDF document] Compound 3f was prepared from compound 1i and compound 3e by a similar method of preparing compound 2g in Example 3. EI-MS m / z: [M+H]<com:Sup>+< / com:Sup> 1366.6, [M+Na]<com:Sup>+< / com:Sup> 1389.6. Example 6. Preparation of Compound 3g [Image disponible dans le document PDF, Image available in the PDF document] Compound 3g was prepared from compound 1j and compound 3e by a similar method of preparing compound 2g in Example 3. EI-MS m / z: [M+H]<com:Sup>+< / com:Sup> 1380.6, [M+Na]<com:Sup>+< / com:Sup> 1403.6. Example 7. Preparation of Compound 4f [Image disponible dans le document PDF, Image available in the PDF document] Preparation of Compound 4a To a stirred solution of dodecaethylene glycol (1.8 g, 3.2 mmol) in DCM (18 mL) was added p-toluenesulfonyl chloride (656 mg, 3.4 mmol), Ag<com:Sub>2< / com:Sub>O (1.13 g, 4.9 mmol) and KI (108 mg, 0.65 mmol). After stirring at room temperature for 30 minutes, the reaction mixture was filtered through a celite pad and washed with DCM (50 mL). The filtrate was concentrated. The resulting residue was purified by column chromatography to produce the compound 4a (490 mg, 21 %) as light yellowish oil. <com:Sup>1< / com:Sup>H-NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) δ 7.81 (d, 2H), 7.35 (d, 2H), 4.16 (t, 2H), 3.72-3.58 (m, 46H), 2.82 (br s, 1H), 2.45 (s, 3H). Preparation of Compound 4b Compound 4a (490 mg, 0.69 mmol) and NaN<com:Sub>3< / com:Sub> (68 mg, 1.04 mmol) were dissolved in DMF (16 mL) and the reaction mixture was heated at 100 °C for 3 hours. The reaction mixture was filtered and concentrated. The crude product was purified by column chromatography to yield the compound 4b (267 mg, 67 %). <com:Sup>1< / com:Sup>H-NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) δ 3.72-3.60 (m, 46H), 3.39 (t, 2H), 2.84 (t, 1H), 3.40 (m, 2H). Preparation of Compound 4c To a stirred solution of compound 4b (265 mg, 0.46 mmol) in THF (10 mL) at 0 °C were added 4-methylmorpholine (0.066 mL, 0.60 mmol) and methanesulfonic anhydride (121 mg, 0.69 mmol). After 2 hours, LiBr (120 mg, 1.38 mmol) was added to a stirred solution and the resulting reaction mixture was refluxed for 6 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc to EtOAc / MeOH 10 / 1) to yield the compound 4c (178 mg, 60 %). <com:Sup>1< / com:Sup>H-NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) δ 3.81 (t, 2H), 3.65 (m, 42H), 3.47 (t, 2H), 3.39 (t, 2H). Preparation of Compound 4d NaH (60 % in oil, 14 mg, 0.33 mmol) was added to a stirred mixture of compound 4c (175 mg, 0.27 mmol), and N-Boc-hydroxylamine (47 mg, 0.35 mmol) in DMF (5 mL) at 0 °C. The reaction mixture was warmed up to room temperature and kept for 12 hours at this temperature. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (MeOH / CHCl<com:Sub>3< / com:Sub> 1 / 20 to 1.5 / 20), which produced the compound 4d (148 mg, 78 %). <com:Sup>1< / com:Sup>H-NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) δ 4.00 (t, 2H), 3.66 (m, 44H), 3.39 (t, 2H), 1.47 (d, 9H). Preparation of Compound 4e To a stirred mixture of compound 4d (148 mg, 0.21 mmol), and Pd / C (10 wt. %, 28 mg) in MeOH (5 mL) at 0 °C was added HCl (4 N in 1,4-dioxane, 0.053 mL, 0.21 mmol). After stirring at room temperature for 30 minutes under hydrogen, the reaction mixture was filtered through a celite pad and washed with MeOH (30 mL). The filtrate was concentrated to produce the compound 4e (142 mg, 96 %) as colorless oil, which was used without further purification. <com:Sup>1< / com:Sup>H-NMR (400 MHz, DMSO-d<com:Sub>6< / com:Sub>) δ 4.00 (t, 2H), 3.92 (t, 2H), 3.76-3.64 (m, 42H), 3.18 (t, 2H) 1.47 (s, 9H). Preparation of Compound 4f [Image disponible dans le document PDF, Image available in the PDF document] Compound 4f was prepared from compound 1i and compound 4e by a similar method of preparing compound 2g in Example 3. EI-MS m / z: [M+H]<com:Sup>+< / com:Sup> 1631.9. Example 8. Preparation of Compound 4g [Image disponible dans le document PDF, Image available in the PDF document] Compound 4g was prepared from compound 1j and compound 4e by a similar method of preparing compound 2g in Example 3. EI-MS m / z: EI-MS m / z [M+H]<com:Sup>+< / com:Sup> 1645.3. Example 9. Preparation of Compound 5e [Image disponible dans le document PDF, Image available in the PDF document] Preparation of Compound 5a To a solution of 2-aminoethanol (10 g, 164 mmol) in DCM (70 mL) were added triethylamine (3.9 mL, 28.1 mmol) and benzyl chloroformate (30 mL, 213 mmol) in DCM (30 mL) at 0 °C under N<com:Sub>2< / com:Sub>. After 24 hours, the reaction mixture was concentrated. The resulting residue was diluted with <com:Math><semantics>H2O<annotation encoding="application / x-tex">H_2O< / annotation>< / semantics>< / com:Math> (50 mL) and extracted with EtOAc (3 x 100 mL). The organic layers were combined, dried over anhydrous MgSO<com:Sub>4< / com:Sub>, filtered and concentrated. The crude product was purified by column chromatography to produce the compound 5a (17 g, 53 %). <com:Sup>1< / com:Sup>H-NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) δ 7.40-7.27 (m, 5H), 5.11 (s, 2H), 3.72 (s, 2H), 3.56 (s, 2H), 2.13 (br s, 1H). Preparation of Compound 5b To a solution of compound 5a (5.0 g, 25.6 mmol) in DCM (70 mL) triethylamine (3.9 mL, 28.1 mmol) were added DMAP (100 mg, 5.12 mmol) and p-toluenesulfonyl chloride (5.4 g, 28.1 mmol) in DCM (30 mL) at 0 °C under N<com:Sub>2< / com:Sub>. After 15 hours at 0 °C, the reaction mixture was diluted with saturated aq. NH<com:Sub>4< / com:Sub>Cl (100 mL) and extracted with DCM (2 x 100 mL). The organic layers were combined, dried over anhydrous MgSO<com:Sub>4< / com:Sub>, filtered and concentrated. The crude product was purified by column chromatography to produce the compound 5b (8.29 g, 92 %). <com:Sup>1< / com:Sup>H-NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.77 (d, <com:Math><semantics>J=7.6<annotation encoding="application / x-tex">J = 7.6< / annotation>< / semantics>< / com:Math> Hz, 2H), 7.40-7.28 (m, 7H), 5.07 (s, 3H), 4.09 (s, 2H), 3.45 (s, 2H), 2.43 (s, 3H). Preparation of Compound 5c To a solution of compound 5b (2.0 g, 7.23 mmol) in THF (20 mL) was added N,N- diBoc-hydroxylamine (1.7 g, 7.44 mmol) and NaH (300 mg, 6.86 mmol) at 0 °C under N<com:Sub>2< / com:Sub>. After stirring at room temperature for 17 hours, the reaction mixture was diluted with saturated aqueous NH<com:Sub>4< / com:Sub>Cl (50 mL) and extracted with EtOAc (3 x 50 mL). The organic layers were combined, dried over anhydrous MgSO<com:Sub>4< / com:Sub>, filtered and concentrated. The crude product was purified by column chromatography to produce the compound 5c (375 mg, 16 %). <com:Sup>1< / com:Sup>H-NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) δ 7.45-7.27 (m, 5H), 5.11 (s, 2H), 4.01 (br s, 2H), 3.44 (d, <com:Math><semantics>J=4.8 Hz,2H,1.52 (s, 18H). EI-MS m / z:[M+H]+410.7.<annotation encoding="application / x-tex">J = 4.8 \text{ Hz}, 2\text{H}, 1.52 \text{ (s, 18H)}. \text{ EI-MS m / z}: [\text{M+H}]^+ 410.7.< / annotation>< / semantics>< / com:Math> To a solution of compound 5c (187 mg, 0.45 mmol) in MeOH (20 mL) Pd / C (10 % wt. %, 20 mg) was added and then the reaction mixture was stirred at room temperature for 4 hours under hydrogen. The reaction mixture was filtered through a celite pad and washed with MeOH (20 mL). The filtrate was concentrated to produce the compound 5d (120 mg) as colorless oil, which was used without further purification. Preparation of Compound 5e [Image disponible dans le document PDF, Image available in the PDF document] Compound 5e was prepared from compound 1i and compound 5d by a similar method of preparing compound 2g in Example 3. EI-MS m / z: [M+H]<com:Sup>+< / com:Sup> 1146.4. Example 10. Preparation of Compound 5f [Image disponible dans le document PDF, Image available in the PDF document] Compound 5f was prepared from compound 1j and compound 5d by a similar method of preparing compound 2g in Example 3. EI-MS m / z: [M+H]<com:Sup>+< / com:Sup> 1160.3. Example 11. Preparation of Compound 6e [Image disponible dans le document PDF, Image available in the PDF document] Preparation of Compound 6a DIPEA (1.2 mL, 9.96 mmol) and HBTU (1.69 g, 6.22 mmol) were added to a stirred mixture of Z-Asp(OMe)-OH (500 mg, 1.78 mmol) and compound 2d (642 mg, 2.98 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature for 22 hours under <com:Math><semantics>N2<annotation encoding="application / x-tex">N_2< / annotation>< / semantics>< / com:Math>. The reaction mixture was diluted with <com:Math><semantics>H2O<annotation encoding="application / x-tex">H_2O< / annotation>< / semantics>< / com:Math> (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over anhydrous Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub>, filtered and concentrated. The resulting residue was purified by column chromatography to yield the compound 6a (368 mg, 40 %). <com:Sup>1< / com:Sup>H-NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) δ 7.85-7.70 (m, 1 H), 7.45-7.28 (m, 5H), 7.04 (s, 1H), 6.02 (d, <com:Math><semantics>J=8.4<annotation encoding="application / x-tex">J = 8.4< / annotation>< / semantics>< / com:Math> Hz, 1H), 5.11 (s, 2H), 4.65-4.50 (m, 1H), 4.00 (d, <com:Math><semantics>J=<annotation encoding="application / x-tex">J =< / annotation>< / semantics>< / com:Math> 3.6 Hz, 2H), 3.72-3.30 (m, 10H), 2.80 (dd, <com:Math><semantics>J=5.6<annotation encoding="application / x-tex">J = 5.6< / annotation>< / semantics>< / com:Math> Hz, 2H), 1.46 (s, 9H). Preparation of Compound 6b To a stirred mixture of compound 6a (150 mg, 0.28 mmol) and Pd / C (10 wt. %, 20 mg) in MeOH (5 mL) at 0 °C was added HCl (4 N in 1,4-dioxane, 0.07 mL, 0.28 mmol). After stirring at room temperature for 2 hours under hydrogen, the reaction mixture was filtered through a celite pad and washed with MeOH (20 mL). The filtrate was concentrated to produce the compound 6b (169 mg) as colorless oil, which was used without further purification. EI-MS m / z: <com:Math><semantics>[M+1]+<annotation encoding="application / x-tex">[M+1]^+< / annotation>< / semantics>< / com:Math> 393.7. [Image disponible dans le document PDF, Image available in the PDF document] Preparation of Compound 6c DIPEA (0.022 mL, 0.12 mmol) and HBTU (20 mg, 0.05 mmol) were added to a stirred mixture of compound 1i (50 mg, 0.04 mmol) and compound 6b (22 mg, 0.05 mmol) in DMF (1 mL). The reaction mixture was stirred at room temperature for 14 hours under <com:Math><semantics>N2<annotation encoding="application / x-tex">N_2< / annotation>< / semantics>< / com:Math>. Then, the reaction mixture was diluted with <com:Math><semantics>H2O<annotation encoding="application / x-tex">H_2O< / annotation>< / semantics>< / com:Math> (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were dried over anhydrous Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub>, filtered and concentrated. The resulting residue was purified by column chromatography to yield the compound 6c (38 mg, 60 %). EI-MS m / z: [M+H]<com:Sup>+< / com:Sup> 1604.5. Preparation of Compound 6d To a solution of compound 6c (38 mg, 0.023 mmol) in MeOH (1 mL) was added LiOH monohydrate (5 mg, 0.118 mmol) in H<com:Sub>2< / com:Sub>O (1 mL) at 0 °C. After 2 hours at 0 °C, the pH of the solution was adjusted with AcOH to 4~5 and concentrated under reduced pressure. The residue was dissolved in DMSO (1.5 mL) and purified by HPLC to produce the compound 6d (26 mg, 78 %). EI-MS m / z: [M+H]<com:Sup>+< / com:Sup> 1450.5. Preparation of Compound 6e TFA (0.3 mL) was added to a stirred solution of compound 6d (26 mg, 0.018 mmol) in DCM (1.5 mL). After stirring at 0 °C for 2 hours, the solvent and excess TFA were removed by N<com:Sub>2< / com:Sub> flow. Then the residue was dissolved in DMSO (1 mL) and purified by HPLC. Pure fractions with the same retention time were combined and lyophilized to produce the compound 6e (19.5 mg, 80 %) as white solid. EI-MS m / z: [M+H]<com:Sup>+< / com:Sup> 1350.6. Example 12. Preparation of Compound 7e [Image disponible dans le document PDF, Image available in the PDF document] Preparation of Compound 7a NaH (60 wt. %, 500 mg, 12.49 mmol) was added to a stirred mixture of compound 4c (6.10 g, 9.61 mmol) and N,N-diBoc-hydroxylamine (2.69 g, 11.53 mmol) in DMF (90 mL) at 0 °C. The reaction mixture was heated up to room temperature and kept for 12 hours at this temperature. The reaction mixture was evaporated under reduced pressure and the resulting residue was purified by column chromatography. Pure fractions were evaporated in vacuo to yield the compound 7a (5.70 g, 75 %). <com:Math><semantics>1<annotation encoding="application / x-tex">^{1}< / annotation>< / semantics>< / com:Math>H-NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 4.05 (t, 2H), 3.71 (t, 2H), 3.64 (m, 42H), 3.37 (t, 2H), 1.51 (d, 18H). Preparation of Compound 7b To a stirred mixture of compound 7a (5.70 g, 7.21 mmol), and Pd / C (10 wt. %, 570 mg) in MeOH (100 mL) at 0 °C was added HCl (4 N in 1,4-dioxane, 1.9 mL, 7.2 mmol). After stirring at room temperature for 30 minutes under hydrogen, the reaction mixture was filtered through a celite pad and washed with MeOH (30 mL). The filtrate was concentrated to produce the compound 7b (5.10 g, 87 %) as colorless oil, which was used without further purification. <com:Sup>1< / com:Sup>H-NMR (400 MHz, DMSO-d<com:Sub>6< / com:Sub>) δ 4.21 (t, 2H), 4.07 (s, 2H), 3.95-3.78 (m, 42H), 3.32 (s, 2H) 1.63 (s, 18H). [Image disponible dans le document PDF, Image available in the PDF document] Preparation of Compound 7c DIPEA (0.25 mL, 1.42 mmol) and HBTU (337g, 0.89mmol) were added to a stirred mixture of Z-Asp(OMe)-OH (100 mg, 0.36 mmol) and compound 7b (340 mg, 0.43 mmol) in DMF (10 mL). The reaction mixture was stirred at room temperature for 20 hours under <com:Math><semantics>N2<annotation encoding="application / x-tex">N_2< / annotation>< / semantics>< / com:Math>. Then, the reaction mixture was diluted with <com:Math><semantics>H2O<annotation encoding="application / x-tex">H_2O< / annotation>< / semantics>< / com:Math> (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over anhydrous Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub>, filtered and concentrated. The resulting residue was purified by column chromatography to yield the compound 7c (123 mg, 58 %). EI-MS m / z: [M+H]<com:Sup>+< / com:Sup> 1024.2. Preparation of Compound 7d To a stirred mixture of compound 7c (120 mg, 0.12 mmol) and Pd / C (10 wt. %, 20 mg) in MeOH (5 mL) at 0 °C was added HCl (4 N in 1,4-dioxane, 0.03 mL, 0.12 mmol). After stirring at room temperature for 2 hours under hydrogen, the reaction mixture was filtered through a celite pad and washed with MeOH (20 mL). The filtrate was concentrated to produce the compound 7d (120 mg) as colorless oil, which was used without further purification. Preparation of Compound 7e [Image disponible dans le document PDF, Image available in the PDF document] Compound 7e was prepared from compound 1i and compound 7d by a similar method of preparing compound 6e in Example 11. EI-MS m / z: [M+H]<com:Sup>+< / com:Sup> 1747.1. Example 13. Preparation of Compound 8f [Image disponible dans le document PDF, Image available in the PDF document] Preparation of Compound 8a To a solution of 2-(2-(2-chloroethoxy)ethoxy)ethanol (5.0 g, 29.6 mmol) in acetone (30 mL) was added NaI (13.3 g, 88.9 mmol). The reaction mixture was refluxed for 12 hours. After the reaction was completed, the reaction mixture was filtered and concentrated. The crude product was purified by column chromatography to produce the compound 8a (7.0 g, 91 %). <com:Sup>1< / com:Sup>H-NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) δ 3.80-3.73 (m, 4H), 3.72-3.65 (m, 4H), 3.63- 3.61 (m, 2H), 3.27 (t, <com:Math><semantics>J=6.4<annotation encoding="application / x-tex">J = 6.4< / annotation>< / semantics>< / com:Math> Hz, 2H). Preparation of Compound 8b NaH (500 mg, 12.49 mmol) was added to a stirred mixture of compound 8a (2.0 g, 7.69 mmol), and N,N-diBoc-hydroxylamine (2.33 g, 10.00 mmol) in DMF (20 mL) at 0 °C under N<com:Sub>2< / com:Sub>. After stirring at room temperature for 17 hours, the reaction mixture was diluted with saturated aq. NH<com:Sub>4< / com:Sub>Cl (50 mL) and extracted with EtOAc (3 x 50 mL). The organic layers were combined, dried over anhydrous MgSO<com:Sub>4< / com:Sub>, filtered and concentrated. The crude product was purified by column chromatography to produce the compound 8b (1.54 g, 54 %). <com:Sup>1< / com:Sup>H-NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) δ 7.45-7.27 (m, 5H), 5.11 (s, 2H), 4.01 (br s, 2H), 3.44 (d, <com:Math><semantics>J=4.8 Hz,2H,1.52 (s, 18H)<annotation encoding="application / x-tex">J = 4.8 \text{ Hz}, 2\text{H}, 1.52 \text{ (s, 18H)}< / annotation>< / semantics>< / com:Math>. EI-MS m / z: [M+H]<com:Sup>+< / com:Sup> 410.7. Preparation of Compound 8c To a stirred solution of the compound 8b (123 mg, 0.242 mmol) in DMSO (2 mL) and DCM (2 mL) were added SO<com:Sub>3< / com:Sub>.pyridine complex (116 mg, 0.726 mmol) and triethylamine (0.17mL, 1.21 mmol) at 0 °C under N<com:Sub>2< / com:Sub>. After 1 hour, the reaction mixture was diluted with saturated aq. NH<com:Sub>4< / com:Sub>Cl (10 mL) and extracted with DCM (2 x 10 mL). The organic layers were combined, dried over anhydrous MgSO<com:Sub>4< / com:Sub>, and filtered. Concentration under reduced pressure provided the compound 8c (88 mg), which was used without further purification. <com:Sup>1< / com:Sup>H-NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) δ 9.74 (s, 1H), 4.19 (s, 2H), 3.77-3.69 (m, 6H), 3.42 (m, 2H). [Image disponible dans le document PDF, Image available in the PDF document] Preparation of Compound 8d To a solution of □-glutamic acid (500 mg, 0.339 mmol) in MeOH (10 mL) was added thionyl chloride (0.148 mL, 2.04 mmol) at 0 °C under N<com:Sub>2< / com:Sub>. After 24 hours, the reaction mixture was concentrated to produce the compound 8d (697 mg), which was used without further purification. <com:Sup>1< / com:Sup>H-NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) δ 7.40-7.27 (m, 5H), 5.11 (s, 2H), 3.72 (s, 2H), 3.56 (s, 2H), 2.13 (br s, 1H). Preparation of Compound 8e To a solution of compound 8d (34 mg, 0.16 mmol) and compound 8c (88 mg, 0.24 mmol) in MeOH (5 mL) was added NaCNBH<com:Sub>3< / com:Sub> (10 mg, 0.16 mmol) at room temperature under N<com:Sub>2< / com:Sub>. After 3 hours, the reaction mixture was filtered and concentrated. The crude product was purified by column chromatography to produce the compound 8e (53 mg, 63 %). <com:Sup>1< / com:Sup>H-NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) δ 7.45-7.25 (m, 10H), 5.60 (br s, 2H), 5.03 (s, 4H), 3.80- 3.25 (m, 20H), 2.81 (s, 4H). Preparation of Compound 8f [Image disponible dans le document PDF, Image available in the PDF document] Compound 8f was prepared from compound 1i and compound 8e by a similar method of preparing compound 6e in Example 11. EI-MS m / z: [M+H]<com:Sup>+< / com:Sup> 1365.0. Example 14. Preparation of Compound 9j [Image disponible dans le document PDF, Image available in the PDF document] Preparation of Compound 9a To a solution of hexaethylene glycol (10.48 g, 37.12 mmol) in DCM (400 mL) was added imidazole (3.20 g, 44.54 mmol) at 0 °C under N<com:Sub>2< / com:Sub>. After 5 minutes, the reaction mixture was added dropwise to the solution of TBSCl (5.60 g, 37.12 mmol) in DCM (50 mL) at the same temperature under N<com:Sub>2< / com:Sub> atmosphere. The reaction mixture was stirred at 0 °C and warmed to room temperature for 21 hours under N<com:Sub>2< / com:Sub>. After the reaction was completed, the reaction mixture was diluted with water (200 mL) and extracted with DCM (2 x 100 mL). The organic layers were dried over anhydrous Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub> and concentrated under reduced pressure. The resulting residue was purified by column chromatography. The pure fractions were evaporated in vacuo to yield the compound 9a (6.70 g, 46 %). <com:Sup>1< / com:Sup>H-NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) δ 3.77-3.71 (m, 4H), 3.66-3.60 (m, 18H), 3.56-3.54 (t, 2H), 0.89 (s, 9H), 0.06 <com:Math><semantics>(s,6H)<annotation encoding="application / x-tex">(s, 6H)< / annotation>< / semantics>< / com:Math>. Preparation of Compound 9b To a solution of compound 9a (3.32 g, 8.37 mmol) in dry THF (40 mL) was added NaH (55 % in oil, 438 mg, 10.05 mmol) at 0 °C under N<com:Sub>2< / com:Sub>. After 30 minutes, MeI (0.78 mL, 12.56 mmol) was added to the reaction mixture at the same temperature under <com:Math><semantics>N2<annotation encoding="application / x-tex">N_2< / annotation>< / semantics>< / com:Math>. The reaction mixture was stirred and warmed to room temperature for 18 hours under N<com:Sub>2< / com:Sub>. After the reaction was completed, quenched with <com:Math><semantics>H2O<annotation encoding="application / x-tex">H_2O< / annotation>< / semantics>< / com:Math> (10 mL) and extracted with EA (3 x 10 mL). The organic layers were combined, washed with saturated aq. NH<com:Sub>4< / com:Sub>Cl (5 mL) and brine (10 mL), dried over anhydrous Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub> and evaporated under reduced pressure. The resulting residue was purified by column chromatography. Pure fractions were evaporated in vacuo to yield the compound 9b (3.16 g, 92 %). <com:Sup>1< / com:Sup>H-NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) δ 3.78-3.75 (t, 2H), 3.65 (s, 20H), 3.57-3.54 (t, 4H), 3.38 (s, 3H), 0.89 (s, 9H), 0.06 (s, 6H). Preparation of Compound 9c To a solution of compound 9b (3.16 g, 7.69 mmol) in acetone (100 mL) was added Jones reagent (10 mL) at 0 °C under N<com:Sub>2< / com:Sub>. The reaction mixture was stirred and warmed to room temperature for 17 hours under <com:Math><semantics>N2<annotation encoding="application / x-tex">N_2< / annotation>< / semantics>< / com:Math>. After the reaction was completed, the reaction mixture was filtered and evaporated under reduced pressure. The residue was diluted with H<com:Sub>2< / com:Sub>O (100 mL) and extracted with CHCl<com:Sub>3< / com:Sub> (3 x 50 mL). The organic layers were combined, dried over anhydrous Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub> and evaporated under reduced pressure. The resulting crude compound 9c (2.28 g, 95 %) was used without further purification. <com:Sup>1< / com:Sup>H-NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 4.16 (s, 2H), 3.76-3.75 (t, 2H), 3.69-3.67 (m, 16H), 3.57-3.55 (t, 2H), 3.38 (s, 3H). Preparation of Compound 9d DIPEA (3.8 mL, 22.03 mmol), HOBt (1.29 g, 9.55 mmol) and EDC·HCl (1.83 g, 9.55 mmol) were added to a stirred mixture of compound 9c (2.28 g, 7.34 mmol) and H- Lys(Z)-OMe hydrochloride (2.91 g, 8.81 mmol) in DMF (30 mL). After stirring at room temperature for 14 hours under <com:Math><semantics>N2<annotation encoding="application / x-tex">N_2< / annotation>< / semantics>< / com:Math>, the reaction mixture was concentrated. Purification by column chromatography gave the compound 9d (1.23 g, 72 %). <com:Sup>1< / com:Sup>H-NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) δ 7.38-7.31 (m, 5H), 5.10 (s, 2H), 5.00 (s, 1H) 4.68-4.62 (m, 1H), 4.03 (s, 2H), 3.75 (s, 3H), 3.68-3.64 (m, 16H), 3.56 (t, 2H), 3.39 (s, 3H), 3.20 (m, 2H), 1.89 (m, 1H), 1.74 (m, 1H), 1.55(m, 1H), 1.40 (m, 1H). EI-MS m / z: [M+H]<com:Sup>+< / com:Sup> 586.8, [M+Na]<com:Sup>+< / com:Sup> 608.9. Preparation of Compound 9e To a solution of compound 9d (2.16 g, 3.68 mmol) in THF / MeOH / H<com:Sub>2< / com:Sub>O (18 mL / 6 mL / 6 mL) was added LiOH monohydrate (307 mg, 7.31 mmol) at 0 °C under N<com:Sub>2< / com:Sub>. The reaction mixture was stirred for 1 hour at room temperature. Then the pH of the solution was adjusted to <com:Math><semantics>2∼3<annotation encoding="application / x-tex">2\sim3< / annotation>< / semantics>< / com:Math> with 1 N aq. HCl. The reaction mixture was poured into H<com:Sub>2< / com:Sub>O (20 mL) and extracted with DCM (3 x 50 mL). The organic layers were combined, dried over Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub>. Filtration and concentration produced the compound 9e (2.28 g, 99 %), which was used without further purification. <com:Sup>1< / com:Sup>H-NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) δ 7.34-7.30 (m, 5H), 5.08 (s, 2H), 4.66-4.60 (q, 1H), 4.01 (s, 2H), 3.67-3.55 (m, 18H), 3.37 (s, 3H), 3.20 (m, 2H), 1.87 (m, 1H), 1.72 (m, 1H), 1.53(m, 1H), 1.38 (m, 1H). Preparation of Compound 9f DIPEA (0.45 mL, 2.63 mmol), HOBt (154 mg, 0.11 mmol) and EDC·HCl (218 mg, 0.11 mmol) were added to a stirred mixture of compound 9e (502 mg, 0.88 mmol) and compound 7b (700 mg, 0.88 mmol) in DMF (8 mL). After stirring at room temperature for 14 hours under <com:Math><semantics>N2<annotation encoding="application / x-tex">N_2< / annotation>< / semantics>< / com:Math>, the reaction mixture was poured into <com:Math><semantics>H2O<annotation encoding="application / x-tex">H_2O< / annotation>< / semantics>< / com:Math> (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with aq. NaHCO<com:Sub>3< / com:Sub> (20 mL) and brine (20 mL) and dried over anhydrous Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub>. After filtration and concentration under reduced pressure, the resulting residue was purified by column chromatography to yield the compound 9f (499 mg, 43 %). <com:Sup>1< / com:Sup>H-NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) δ 7.35-7.30 (m, 5H), 6.83 (s, 1H), 5.15 (s, 1H), 5.08 (s, 2H), 4.43 (q, 1H) 4.07 (t, 1H), 3.65-3.60 (m, 54H), 3.55- 3.53 (m, 4H), 3.37 (s, 3H), 3.16 (m, 2H), 1.85 (m, 1H), 1.53-1.52 (d, 19H), 1.38(m, 2H). EI-MS m / z: [M+H]<com:Sup>+< / com:Sup> 1337.5. Preparation of Compound 9g To a stirred mixture of compound 9f (499 mg, 0.37 mmol) and Pd / C (10 wt. %, 50 mg) in MeOH (20 mL) at 0 °C was added HCl (4 N in 1,4-dioxane, 0.1 mL, 0.37 mmol). After stirring at room temperature for 90 minutes under hydrogen, the reaction mixture was filtered through a celite pad and washed with MeOH (10 mL). The filtrate was concentrated to produce the compound 9g (458 mg, 98 %) as colorless oil, which was used without further purification. EI-MS m / z: [M+H]<com:Sup>+< / com:Sup> 1218.6. [Image disponible dans le document PDF, Image available in the PDF document] Preparation of Compound 9h DIPEA (0.019 mL, 0.11 mmol) and HBTU (18 mg, 0.05 mmol) were added to a stirred mixture of compound 1i (45 mg, 0.04 mmol) and compound 9g (57 mg, 0.05 mmol) in DMF (0.5 mL). The reaction mixture was stirred at room temperature for 14 hours under <com:Math><semantics>N2<annotation encoding="application / x-tex">N_2< / annotation>< / semantics>< / com:Math>. The reaction mixture was diluted with <com:Math><semantics>H2O / DMSO<annotation encoding="application / x-tex">H_2O / DMSO< / annotation>< / semantics>< / com:Math> (1.5 mL / 1.5 mL) and purified by HPLC, which produced compound 9h (65 mg, 57 %). EI-MS m / z: 1 / 2[M+H]<com:Sup>+< / com:Sup> 1181.7. Preparation of Compound 9i To a solution of compound 9h (65 mg, 0.03 mmol) in MeOH (1.5 mL) was added LiOH monohydrate (10 mg, 0.24 mmol) in H<com:Sub>2< / com:Sub>O (1.5 mL) at 0 °C. After 1 hour at 0 °C, the pH of the solution was adjusted with AcOH to 4~5 and concentrated under reduced pressure. Then the reaction mixture was dissolved in H<com:Sub>2< / com:Sub>O / DMSO (1.5 mL / 1.5 mL) and purified by HPLC, which produced compound 9i (45 mg, 55 %). EI-MS m / z: 1 / 2[M+Na]<com:Sup>+< / com:Sup> 1098.7. Preparation of Compound 9i TFA (0.2 mL) was added to a stirred solution of compound 9i (45 mg, 0.02 mmol) in DCM (1 mL). After stirring at 0 °C for 30 minutes, the solvent and excess TFA were removed by <com:Math><semantics>N2<annotation encoding="application / x-tex">N_2< / annotation>< / semantics>< / com:Math> flow. Then the residue was dissolved in <com:Math><semantics>H2O / DMSO<annotation encoding="application / x-tex">H_2O / DMSO< / annotation>< / semantics>< / com:Math> (1 mL / 1 mL) and purified by HPLC. Pure fractions with the same retention time were combined and lyophilized to produce the compound 9j (14 mg, 32 %) as white solid. EI-MS m / z: <com:Math><semantics>1 / 2[M+H]+<annotation encoding="application / x-tex">1 / 2[M+H]^{+}< / annotation>< / semantics>< / com:Math> 1026.3. Example 15. Preparation of Compound 10c [Image disponible dans le document PDF, Image available in the PDF document] Preparation of Compound 10a DIPEA (0.03 mL, 0.17 mmol), HOBt (10 mg, 0.075 mmol) and EDC·HCl (14 mg, 0.075 mmol) were added to a stirred mixture of compound 9e (33 mg, 0.058 mmol) and compound 7d (54 mg, 0.058 mmol) in DMF (3 mL). After stirring at room temperature for 14 hours under <com:Math><semantics>N2<annotation encoding="application / x-tex">N_2< / annotation>< / semantics>< / com:Math>, the reaction mixture was poured into <com:Math><semantics>H2O<annotation encoding="application / x-tex">H_2O< / annotation>< / semantics>< / com:Math> (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with 1 N aq. HCl (8 mL), saturated aq. NaHCO<com:Sub>3< / com:Sub> (8 mL) and brine (8 mL), and dried over anhydrous Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub>. After filtration and concentration, the residue was purified by column chromatography, which produced the compound 10a (61 mg, 73 %). EI-MS m / z: [M+H]<com:Sup>+< / com:Sup> 1445.0, [M+H-Boc]<com:Sup>+< / com:Sup> 1344.9. Preparation of Compound 10b To a stirred mixture of compound 10a (60 mg, 0.04 mmol), and Pd / C (10 wt. %, 30 mg) in MeOH (10 mL) at 0 °C was added HCl (4 N in 1,4-dioxane, 0.01 mL, 0.01 mmol). After stirring at room temperature for 3 hours under hydrogen, the reaction mixture was filtered through a celite pad and washed with MeOH (40 mL). The filtrate was concentrated to produce the compound 10b (56 mg, 100 %) as colorless oil, which was used without further purification. EI-MS m / z: [M+H]<com:Sup>+< / com:Sup> 1311.0, [M+Na+]<com:Sup>+< / com:Sup> 1332.9. Preparation of Compound 10c [Image disponible dans le document PDF, Image available in the PDF document] Compound 10c was prepared from compound 1i and compound 10b by a similar method of preparing compound 9j in Example 14. EI-MS m / z: 1 / 2[M+H]<com:Sup>+< / com:Sup> 1083.8. Example 16. Preparation of Compound 10d [Image disponible dans le document PDF, Image available in the PDF document] Compound 10d was prepared from compound 1j and compound 10b by a similar method of preparing compound 9j in Example 14. EI-MS m / z: [M+H]<com:Sup>+< / com:Sup> 2181.3, 1 / 2[M+H]<com:Sup>+< / com:Sup> 1091.3. Example 17. Preparation of Compound 11j [Image disponible dans le document PDF, Image available in the PDF document] PCT / IB2016 / 001811 Preparation of Compound 11a To a solution of compound 3a (8.0 g, 18.3 mmol) in THF (50 mL) was added LiBr (7.9 g, 91.6 mmol) at room temperature. After stirring for 17 hours under reflux, the reaction mixture was filtered and concentrated. The crude product was purified by column chromatography to produce the compound 11a (3.2 g, 50 %). <com:Sup>1< / com:Sup>H-NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) δ 3.95-3.50 (m, 24H). Preparation of Compound 11b To a solution of compound 11a (3.2 g, 12.3 mmol) in acetone (20 mL) at 0 °C was added Jones reagent (20 mL). After 15 hours at 0 °C, the reaction mixture was filtered and concentrated. The residue was diluted with H<com:Sub>2< / com:Sub>O (50 mL) and extracted with EtOAc (2 x 100 mL). The organic layers were combined, dried over anhydrous MgSO<com:Sub>4< / com:Sub>, filtered and concentrated. The crude product was purified by column chromatography to produce the compound 11b (3.2 g, 72 %). <com:Sup>1< / com:Sup>H-NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) δ 4.16 (s, 2H), 3.95-3.30 (m, 20H). Preparation of Compound 11c To a solution of compound 11b (3.2 g, 8.90 mmol) in MeOH (30 mL) was added oxalyl chloride (1.15 mL, 13.3 mmol) at 0 °C under N<com:Sub>2< / com:Sub>. After 16 hours, the reaction mixture was concentrated and purified by column chromatography, which produced the compound 11c (2.7 g, 81 %). <com:Math><semantics>1<annotation encoding="application / x-tex">^{1}< / annotation>< / semantics>< / com:Math>H-NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 4.17 (s, 2H), 3.80-3.60 (m, 21H), 3.47 (t, <com:Math><semantics>J=6.4 Hz,2H<annotation encoding="application / x-tex">J = 6.4 \text{ Hz}, 2\text{H}< / annotation>< / semantics>< / com:Math>). Preparation of Compound 11d Compound 11c (1.0 g, 2.67 mmol) and NaN<com:Sub>3< / com:Sub> (261 mg, 4.01 mmol) were dissolved in DMF (3 mL). The reaction mixture was heated at 100 °C for 5 hours. After the reaction was completed, the reaction mixture was filtered and concentrated. The residue was purified by column chromatography (EtOAc to EtOAc / MeOH 10 / 1), which produced the compound 11d (854 mg, 95 %). <com:Sup>1< / com:Sup>H-NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) δ 4.17 (s, 2H), 3.76-3.64 (m, 21H), 3.39 (t, <com:Math><semantics>J=5.2<annotation encoding="application / x-tex">J = 5.2< / annotation>< / semantics>< / com:Math> Hz, 2H). Preparation of Compound 11e To a stirred solution of compound 11d (854 mg, 2.54 mmol) in MeOH (25 mL) at 0 °C was added 2 M aq. NaOH (6.3 mL, 12.64 mmol). The reaction mixture was stirred at room temperature for 3 hours. The solution was then concentrated under reduced pressure. The resulting suspension was acidified with aqueous 2 N HCl while cooling at 0 °C. The residue was extracted by CHCl<com:Sub>3< / com:Sub> (8 x 50 mL). The organic layers were combined, dried over Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub> and concentrated to produce the compound 11e (783 mg, 96 %). <com:Sup>1< / com:Sup>H-NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 4.16 (s, 2H), 3.76-3.65 (m, 18H), 3.40 (t, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 5.2 Hz, 2H). [Image disponible dans le document PDF, Image available in the PDF document] Preparation of Compound 11f DIPEA (0.47 mL, 2.72 mmol), HOBt (160 mg, 1.18 mmol) and EDC·HCl (226 mg, 1.18 mmol) were added to a stirred mixture of compound 9e (520 mg, 0.91 mmol) and compound 2d (270 mg, 0.91 mmol) in DMF (5 mL). After stirring at room temperature for 14 hours under <com:Math><semantics>N2<annotation encoding="application / x-tex">N_2< / annotation>< / semantics>< / com:Math>, the reaction mixture was poured into <com:Math><semantics>H2O<annotation encoding="application / x-tex">H_2O< / annotation>< / semantics>< / com:Math> (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with 1 N aq. HCl (15 mL), saturated aq. NaHCO<com:Sub>3< / com:Sub> (15 mL) and brine (15 mL), and dried over anhydrous Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub>. After filtration and concentration, the residue was purified by column chromatography, which produced the compound 11f (631 mg, 85 %). EI-MS m / z: [M+H]<com:Sup>+< / com:Sup>819.1, [M+H-Boc]<com:Sup>+< / com:Sup>719.1 [M+Na+]<com:Sup>+< / com:Sup>841.1. Preparation of Compound 11g To a stirred mixture of compound 11f (300 mg, 0.36 mmol), and Pd / C (10 wt. %, 70 mg) in MeOH (20 mL) at 0 °C was added HCl (4 N in 1,4-dioxane, 0.08 mL, 0.08 mmol). After stirring at room temperature for 3 hours under hydrogen, the reaction mixture was filtered through a celite pad and washed with MeOH (40 mL). The filtrate was concentrated to produce the compound 11g (200 mg, 99 %) as colorless oil, which was used without further purification. EI-MS m / z: [M+H]<com:Sup>+< / com:Sup> 685.1, [M+Na]<com:Sup>+< / com:Sup> 707.1. Preparation of Compound 11h DIPEA (0.024 mL, 0.41 mmol), HOBt (24 mg, 0.18 mmol) and EDC·HCl (34 mg, 0.18 mmol) were added to a stirred mixture of compound 11g (100 mg, 0.14 mmol) and compound 11e (44 mg, 0.14 mmol) in DMF (5 mL). After stirring at room temperature for 14 hours under <com:Math><semantics>N2<annotation encoding="application / x-tex">N_2< / annotation>< / semantics>< / com:Math>, the reaction mixture was poured into <com:Math><semantics>H2O<annotation encoding="application / x-tex">H_2O< / annotation>< / semantics>< / com:Math> (10 mL) and extracted with DCM (3 x 10 mL). The combined organic layers were dried over anhydrous Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub>. After filtration and concentration, the residue was purified by column chromatography, which produced the compound 11h (73 mg, 53 %). EI-MS m / z: [M+H]<com:Sup>+< / com:Sup> 988.4, [M+Na-Boc]<com:Sup>+< / com:Sup> 888.2, [M+Na]<com:Sup>+< / com:Sup> 1010.4. Preparation of Compound 11i To a stirred mixture of compound 11h (73 mg, 0.07 mmol), and Pd / C (10 wt. %, 10 mg) in MeOH (7 mL) at 0 °C was added HCl (4 N in 1,4-dioxane, 0.018 mL, 0.018 mmol). After stirring at room temperature for 2 hours under hydrogen, the reaction mixture was filtered through a celite pad and washed with MeOH (30 mL). The filtrate was concentrated to produce the compound 11i (72 mg, 99 %) as colorless oil, which was used without further purification. EI-MS m / z: [M+H]<com:Sup>+< / com:Sup> 962.4, [M+Na]<com:Sup>+< / com:Sup> 984.4. Preparation of Compound 11j [Image disponible dans le document PDF, Image available in the PDF document] Compound 11j was prepared from compound 1i and compound 11i by a similar method of preparing compound 9j in Example 14. EI-MS m / z: [M+H]<com:Sup>+< / com:Sup> 1932.5. Example 18. Preparation of Compound 11k [Image disponible dans le document PDF, Image available in the PDF document] Compound 11k was prepared from compound 1j and compound 11i by a similar method of preparing compound 9j in Example 14. EI-MS m / z: [M+H]<com:Sup>+< / com:Sup> 1947.1. Example 19. Preparation of Compound 12c 115 [Image disponible dans le document PDF, Image available in the PDF document] Preparation of Compound 12a DIPEA (0.13 mL, 0.77 mmol) and HBTU (110 mg, 0.35 mmol) were added to a stirred mixture of compound 9g (235 mg, 0.1929 mmol) and Z-Asp(OMe)-OH (54 mg, 0.212 mmol) in DMF (5 mL). After stirring at room temperature for 14 hours under N<com:Sub>2< / com:Sub>, the reaction mixture was poured into <com:Math><semantics>H2O<annotation encoding="application / x-tex">H_2O< / annotation>< / semantics>< / com:Math> (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with 1 N aq. HCl (7 mL), saturated aq. NaHCO<com:Sub>3< / com:Sub> (7 mL) and brine (7 mL), and dried over anhydrous Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub>. After filtration and concentration, the residue was purified by column chromatography, which produced the compound 12a (260 mg, 93 %). <com:Sup>1< / com:Sup>H-NMR (400 MHz, CDCl3) δ 8.07 (t, 1H), 7.62 (t, 1H), 7.54-7.52 (m, 1H), 5.73 (s, 2H), 4.27-4.25 (q, 1H), 3.96 (t, 2H), 3.88 (s, 2H), 3.82 (s, 2H), 3.58-3.48 (m, 52H), 3.19-3.18 (m, 3H), 3.04-3.03 (m, 3H), 1.44 (s, 18H), 1.39-1.37 (m, 3H), 1.21-1.19 <com:Math><semantics>(m,3H)<annotation encoding="application / x-tex">(m, 3H)< / annotation>< / semantics>< / com:Math>. EI-MS m / z: <com:Math><semantics>[M+H−2Boc]+<annotation encoding="application / x-tex">[M+H-2Boc]^+< / annotation>< / semantics>< / com:Math> 1031.6. Preparation of Compound 12b To a stirred mixture of compound 12a (260 mg, 0.179 mmol), and Pd / C (10 wt. %, 72 mg) in MeOH (20 mL) at 0 °C was added HCl (4 N in 1,4-dioxane, 0.040 mL, 0.179 mmol). After stirring at room temperature for 3 hours under hydrogen, the reaction mixture was filtered through a celite pad and washed with MeOH (40 mL). The filtrate was concentrated to produce the compound 12b (242 mg, 100 %) as colorless oil, which was used without further purification. EI-MS m / z: [M+H]<com:Sup>+< / com:Sup>625.0, [M+H-Boc]<com:Sup>+< / com:Sup>525.0, [M+H- <com:Math><semantics>2Boc]+424.9.<annotation encoding="application / x-tex">2Boc]^{+}424.9.< / annotation>< / semantics>< / com:Math> Preparation of Compound 12c 116 [Image disponible dans le document PDF, Image available in the PDF document] Compound 12c was prepared from compound 1i and compound 12b by a similar method of preparing compound 9j in Example 14. EI-MS m / z: 1 / 2[M+H]<com:Sup>+< / com:Sup> 1083.5. Example 20. Preparation of Compound 12d [Image disponible dans le document PDF, Image available in the PDF document] Compound 12d was prepared from compound 1j and compound 12b by a similar method of preparing compound 9j in Example 14. EI-MS m / z: 1 / 2[M+H]<com:Sup>+< / com:Sup> 1090.5. Example 21. Preparation of Compound 13e PCT / IB2016 / 001811 [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] Preparation of Compound 13a DIPEA (0.22 mL, 1.25 mmol) and HBTU (356 mg, 0.94 mmol) were added to a stirred mixture of Z-Glu(OMe)-OH (222 mg, 0.75 mmol) and compound 7b (500 mg, 0.62 mmol) in DMF (5.0 mL). The reaction mixture was stirred at room temperature for 14 hours under N<com:Sub>2< / com:Sub>. The reaction mixture was diluted with water (200 mL) and extracted with EA (3 x 100 mL). The organic layers were dried over anhydrous MgSO<com:Sub>4< / com:Sub>, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography to yield the compound 13a (370 mg, 57 %). <com:Sup>1< / com:Sup>H-NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) δ 7.34 (br, 5H), 6.73 (br, 1H), 5.72 (d, J=7.6Hz, 1H), 5.06 (br, 2H), 4.28-4.18 (m, 1H), 4.07 (t, J=4.4Hz, 2H), 3.76-3.71 (m, 2H), 3.70-3.50 (m, 45H), 3.48-3.42 (m, 2H), 2.53-2.36 (m, 2H), 2.20-2.08 (m, 1H), 2.00-1.88 (m, 1H), 1.53 (s, 18H). EI-MS m / z: [M+Na]<com:Sup>+< / com:Sup> 1061.2. Preparation of Compound 13b 4N HCl in 1,4-dioxane (0.08 mL, 0.32 mmol) was added to a stirred mixture of the compound 13a (370 mg, 0.35 mmol), and Pd / C (38 mg) in MeOH (8 mL) at 0 °C. After stirring at room temperature for 20 hours under hydrogen, the reaction mixture was filtered through a celite pad and washed with MeOH (400 mL). The filtrate was concentrated, producing compound 13b (301 mg, 90 %) as yellow liquid, which was used without further purification. <com:Sup>1< / com:Sup>H-NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) δ 8.41 (br, 1H), 8.09 (br, 3H), 4.13 (br, 1H), 3.85-3.56 (m, 51H), 2.55 (br, 2H), 2.38-2.18 (m, 2H), 1.53 (s, 18H). EI-MS m / z: [M+H]<com:Sup>+< / com:Sup> 905.0. Preparation of Compound 13c DIPEA (0.165 mL, 0.96 mmol) and HBTU (279 mg, 0.74 mmol) were added to a stirred mixture compound 13b (300 mg, 0.32 mmol) and compound 9e (366 mg, 0.64 mmol) in DMF (5.0 mL). The reaction mixture was stirred at room temperature for 14 hours under N<com:Sub>2< / com:Sub>. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (3 x 100 mL). The organic layers were dried over anhydrous MgSO<com:Sub>4< / com:Sub>, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography to yield the compound 13c (290 mg, 62 %). <com:Sup>1< / com:Sup>H-NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) δ 7.40-7.32 (m, 7H), 7.00 (br, 1H), 6.73 (br, 1H), 5.07 (br, 2H), 4.44-4.36 (m, 2H), 4.07 (t, J=4.8Hz, 2H), 4.02 (br, 2H), 3.73 (t, <com:Math><semantics>J=5.2<annotation encoding="application / x-tex">J = 5.2< / annotation>< / semantics>< / com:Math>Hz, 2H), 3.71-3.52 (m, 68H), 3.24-3.14 (m, 2H), 2.52-2.34 (m, 3H), 2.18-2.06 (m, 2H), 1.98-1.82 (m, 4H), 1.76-1.64 (m, 3H), 1.53 (s, 18H). EI-MS m / z: [M+H]<com:Sup>+< / com:Sup> 1459.7. Preparation of Compound 13d Pd / C (21 mg) was added to a stirred mixture of compound 13c (290 mg, 0.19 mmol) in MeOH (5 mL) at 0 °C. After stirring at room temperature for 20 hours under hydrogen, the reaction mixture was filtered through a celite pad and washed with MeOH (400mL). The filtrate was concentrated, producing compound 13c (247 mg, 94 %) as yellow liquid, which was used without further purification. <com:Math><semantics>1<annotation encoding="application / x-tex">^{1}< / annotation>< / semantics>< / com:Math>H-NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.20 (d, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 8.4 Hz, 1H), 7.74 (br, 1H), 7.30 (br, 1H), 4.66-4.48 (m, 2H), 4.07 (t, <com:Math><semantics>J=5.2<annotation encoding="application / x-tex">J = 5.2< / annotation>< / semantics>< / com:Math> Hz, 2H), 4.01 (br, 2H), 3.74-3.62 (m, 70H), 3.57-3.53 (m, 2H), 3.04-2.98 (m, 2H), 2.24-2.15 (m, 2H), 2.14- 2.06 (m, 2H), 1.99-1.86 (m, 4H), 1.84-1.74 (m, 2H), 1.53 (s, 18H). EI-MS m / z: [M+H]<com:Sup>+< / com:Sup> 1325.5. Preparation of Compound 13e 119 [Image disponible dans le document PDF, Image available in the PDF document] Compound 13e was prepared from compound 1i and compound 13d by a similar method of preparing compound 9j in Example 14. EI-MS m / z: [M+H]<com:Sup>+< / com:Sup> 2181.5. Example 22. Preparation of Compound 13f [Image disponible dans le document PDF, Image available in the PDF document] Compound 13f was prepared from compound 1j and compound 13d by a similar method of preparing compound 9j in Example 14. EI-MS m / z: [M+H]<com:Sup>+< / com:Sup> 2195.5. Example 23. Preparation of Compound 14m [Image disponible dans le document PDF, Image available in the PDF document] Preparation of Compound 14a To a solution of 6-amino-1-hexanol (5.0 g, 42.6 mmol) in DCM (30 mL) was added di-tert-butyl dicarbonate (9.3 g, 42.6 mmol) at room temperature. After stirring for 18 hours, triethylamine (8.7 mL, 63.9 mmol) and t-butyldimethylsilyl chloride (7.7 g, 51.2 mmol) were added to the reaction mixture at 0 °C. After 24 hours at room temperature, the reaction mixture diluted with saturated aq. NH<com:Sub>4< / com:Sub>Cl (200 mL). The resulting mixture was extracted with EtOAc (100 mL). The organic layer was washed with brine (100 mL) and dried over anhydrous MgSO<com:Sub>4< / com:Sub>, filtered and concentrated. The residue was purified by column chromatography to produce the compound 14a (12 g, 84 %). <com:Sup>1< / com:Sup>H-NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 4.50 (br s, 1H), 3.58 (t, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 6.8 Hz, 2H), 3.10 (d, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 6.4 Hz, 2H), 1.72-1.20 (m, 17H), 0.88 (s, 9H), 0.04 (s, 6H). Preparation of Compound 14b To a solution of compound 14a (6.0 g, 18.1 mmol) in THF (30 mL) were added NaH (60 % in oil, 2.4 g, 54.2 mmol) and methyl iodide (3.4 mL, 54.2 mmol) at 0 °C under <com:Math><semantics>N2<annotation encoding="application / x-tex">N_2< / annotation>< / semantics>< / com:Math>. After 14 hours, the reaction mixture was diluted with <com:Math><semantics>H2O<annotation encoding="application / x-tex">H_2O< / annotation>< / semantics>< / com:Math> (50 mL) and extracted with EtOAc (2 x 100 mL). The organic layers were combined, dried over anhydrous MgSO<com:Sub>4< / com:Sub>, filtered and concentrated. The crude product was purified by column chromatography to produce the compound 14b (4.3 g, 69 %). <com:Math><semantics>1<annotation encoding="application / x-tex">^{1}< / annotation>< / semantics>< / com:Math>H-NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 3.59 (t, <com:Math><semantics>J=6.4<annotation encoding="application / x-tex">J = 6.4< / annotation>< / semantics>< / com:Math> Hz, 2H), 3.17 (br s, 2H), 2.82 (s, 3H), 1.62-1.21 (m, 17H), 0.88 (s, 9H), 0.04 (s, 6H). Preparation of Compound 14c To a solution of compound 14b (4.3 g, 12.4 mmol) in THF (15 mL) was added TBAF (1 M in THF, 15 mL, 14.9 mmol) at 0 °C under N<com:Sub>2< / com:Sub>. After 5 hours, the reaction mixture was diluted with <com:Math><semantics>H2O<annotation encoding="application / x-tex">H_2O< / annotation>< / semantics>< / com:Math> (50 mL) and extracted with diethyl ether (2 x 100 mL). The organic layers were combined, dried over anhydrous MgSO<com:Sub>4< / com:Sub>, filtered and concentrated. The crude product was purified by column chromatography to produce the compound 14c (3.0) g, 98 %). <com:Sup>1< / com:Sup>H-NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) δ 3.63 (br s, 2H), 3.20 (br s, 2H), 2.82 (s, 3H), 1.65- 1.23 (m, 17H). Preparation of Compound 14d To a solution of compound 14c (3.0 g, 12.9 mmol) in THF (30 mL) was added carbon tetrabromide (6.4 g, 19.4 mmol) and triphenylphosphine (5.1 g, 19.4 mmol) at 0 °C under N<com:Sub>2< / com:Sub>. After 2 hours, the reaction mixture was filtered through silica gel and washed diethyl ether (100 mL). The filtrate was concentrated and purified by column chromatography to produce the compound 14d (3.3 g, 86 %). <com:Sup>1< / com:Sup>H-NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 3.40 (t, <com:Math><semantics>J=6.8<annotation encoding="application / x-tex">J = 6.8< / annotation>< / semantics>< / com:Math> Hz, 2H), 3.19 (br s, 2H), 2.83 (s, 3H), 1.90-1.70 (m, 2H), 1.65-1.40 (m, 13H), 1.38-1.25 (m, 2H). [Image disponible dans le document PDF, Image available in the PDF document] Preparation of Compound 14e DIPEA (53.0 mL, 302.5 mmol) and EDC.HCl (35.7 g, 186.2 mmol) were added to a stirred mixture of compound 2d (35.0 g, 116.4 mmol) and 5-formylsalicylic acid (21.3 g, 128.0 mmol) in DCM (1.6 L) at 0 °C. The reaction mixture was stirred at room temperature for 20 hours under N<com:Sub>2< / com:Sub>. The reaction mixture was diluted with saturated aq. NH<com:Sub>4< / com:Sub>Cl solution (1.5 L) and extracted DCM (2 x 1.5 L). The combined organic layers washed with brine (1.5 L) and dried anhydrous MgSO<com:Sub>4< / com:Sub>, filtered and concentrated. The crude product was purified by column chromatography to produce the compound 14e (28.2 g, 59 %). <com:Sup>1< / com:Sup>H-NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) δ 13.37 (br s, 1H), 9.86 (s, 1H), 8.20 (s, 1H), 8.07 (br s, 2H), 7.90 (d, J <com:Math><semantics>=8.4 Hz,1H,7.07 (d, J=8.4 Hz,1H),4.06−4.01 (m, 2H),3.79−3.66 (m, 10H),1.47 (s, 1.47 m)<annotation encoding="application / x-tex">= 8.4 \text{ Hz}, 1\text{H}, 7.07 \text{ (d, } J = 8.4 \text{ Hz}, 1\text{H}), 4.06-4.01 \text{ (m, 2H)}, 3.79-3.66 \text{ (m, 10H)}, 1.47 \text{ (s, 1.47 m)}< / annotation>< / semantics>< / com:Math> 9H). Preparation of Compound 14f To a solution of compound 14e (28.0 g, 67.9 mmol) in MeCN (500 mL) were added compound M (29.7 g, 74.7 mmol), 4 Å molecular sieve (30 g) and Ag<com:Sub>2< / com:Sub>O (62.9 g, 272 mmol). After stirring at room temperature for 12 hours under <com:Math><semantics>N2<annotation encoding="application / x-tex">N_2< / annotation>< / semantics>< / com:Math>, the reaction mixture was concentrated, diluted with H<com:Sub>2< / com:Sub>O (800 mL) and extracted with EtOAc (1 L). The combined organic layers were dried over anhydrous MgSO<com:Sub>4< / com:Sub>, filtered and concentrated. The residue was purified by column chromatography to produce the compound 14f (30.1 g, 61 %). <com:Sup>1< / com:Sup>H- NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 9.99 (s, 1H), 8.54 (s, 1H), 7.99 (d, <com:Math><semantics>J=8.8<annotation encoding="application / x-tex">J = 8.8< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.68 (s, 1H), 7.44 (br s, 1H), 7.18 (d, <com:Math><semantics>J=8.8<annotation encoding="application / x-tex">J = 8.8< / annotation>< / semantics>< / com:Math> Hz, 1H), 5.45-5.30 (m, 4H), 4.26 (d, <com:Math><semantics>J=9.2<annotation encoding="application / x-tex">J = 9.2< / annotation>< / semantics>< / com:Math> Hz, 1H), 4.02- 3.97 (m, 2H), 3.80-3.55 (m, 13H), 2.06 (s, 9H), 1.46 (s, 9H). Preparation of Compound 14g To a solution of compound 14f (29.0 g, 39.8 mmol) in i-PrOH / CHCl<com:Sub>3< / com:Sub> (90 mL / 450 mL) was added silica gel (16.7 g) and NaBH<com:Sub>4< / com:Sub> (3.70 g, 99.5 mmol) at 0 °C. After stirring at 0 °C for 2 hours under N<com:Sub>2< / com:Sub>, the reaction mixture was quenched with H<com:Sub>2< / com:Sub>O (500 mL) and extracted with EtOAc (1 L). The organic layer was dried over anhydrous MgSO<com:Sub>4< / com:Sub>, filtered and concentrated. The crude product was purified by column chromatography to produce the compound 14g (24.1 g, 83 %). <com:Sup>1< / com:Sup>H-NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) δ 7.98 (s, 1H), 7.72 (s, 1H), 7.46 (d, <com:Math><semantics>J=8.8<annotation encoding="application / x-tex">J = 8.8< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.41 (br, 1H), 7.04 (d, <com:Math><semantics>J=8.8<annotation encoding="application / x-tex">J = 8.8< / annotation>< / semantics>< / com:Math> Hz, 1H), 5.41-5.24 (m, 4H), 4.67 (d, <com:Math><semantics>J=6.6 Hz<annotation encoding="application / x-tex">J = 6.6 \text{ Hz}< / annotation>< / semantics>< / com:Math>, 2H), 4.19 (d, <com:Math><semantics>J=8.8 Hz<annotation encoding="application / x-tex">J = 8.8 \text{ Hz}< / annotation>< / semantics>< / com:Math>, 1H), 3.99-3.93 (m, 2H), 3.79-3.65 (m, 12H), 3.59-3.50 (m, 1H), 2.08-2.00 (m, 10H), 1.46 (s, 9H). Preparation of Compound 14h To a solution of compound 14g (23.7 g, 31.5 mmol) in DMF (50 mL) were added bis(4-nitrophenyl)carbonate (8.9 g, 29.3 mmol) and DIPEA (5.65 mL, 31.5 mmol) at 0 °C under N<com:Sub>2< / com:Sub>. The reaction mixture was stirred at 0 °C for 30 minutes and allowed to warm to room temperature for 1 hour. The reaction mixture was diluted with <com:Math><semantics>H2O<annotation encoding="application / x-tex">H_2O< / annotation>< / semantics>< / com:Math> (500 mL) and extracted with EtOAc (500 mL). The organic layer was washed with brine (2 x 200 mL), dried over anhydrous MgSO<com:Sub>4< / com:Sub>, filtered, and concentrated. The crude product was purified by column chromatography to produce the compound 14h (22.4 g, 77 %) as white foam. H- NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.28 (d, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 7.2 Hz, 2H), 8.13 (s, 1H...

Claims

1. A conjugate, comprising an antibody and a branched linker covalently coupled to the antibody, wherein said branched linker comprises: i) a branching unit covalently coupled to the antibody by a primary linker; ii) a first branch, comprising a first active agent covalently coupled to the branching unit by a first secondary linker and a first cleavage group; and iii) a second branch, comprising either: a) a second active agent covalently coupled to the branching unit by a second secondary linker and a second cleavage group; or b) a polyethylene glycol moiety covalently coupled to the branching unit; wherein the primary linker and the first secondary linker or the second secondary linker comprise an alkylene having 1 to 100 carbon atoms, and either: i) the alkylene includes at least one unsaturated bond; ii) the alkylene includes at least one heteroarylene; iii) a carbon atom of the alkylene is replaced by one or more heteroatoms selected from nitrogen (N), oxygen (O), and sulfur (S); or iv) the alkylene is further substituted with one or more alkyls having 1 to 20 carbon atoms; [Image disponible dans le document PDF, Image available in the PDF document] the branching unit has a structure represented by: , [Image disponible dans le document PDF, Image available in the PDF document] L 11 L_{11} , L 22 L_{22} , and L 33 L_{33} are each independently a bond or − C n H 2 n -C_nH_{2n} , where n is an integer of 1 to 30; [Image disponible dans le document PDF, Image available in the PDF document] G 1 G_1 , G 2 G_2 , and G 3 G_3 are each independently a bond, , [Image disponible dans le document PDF, Image available in the PDF document] R 33 R_{33} is hydrogen or C 1 C_1 - C 30 C_{30} alkyl; and R 44 is hydrogen or –L 4 -COOR 5 , wherein L 4 is a bond or -C n H 2n - wherein n is an integer of 1 to 10, and R 5 is hydrogen or C 1 -C 30 alkyl; and each cleavage group is independently selected from a group having the formula: [Image disponible dans le document PDF, Image available in the PDF document] wherein: B represents the first active agent or second active agent; [Image disponible dans le document PDF, Image available in the PDF document] G is W represents -C(O)NR'-, and in each case the C(O) is directly bound to the phenyl ring, and R' is hydrogen, (C 1 -C 8 )alkyl, mono- or di-carboxyl(C 1 -C 8 )alkyl, (C 3 - C 8 C_8 )cycloalkyl, ( C 1 C_1 - C 8 C_8 )alkoxy, ( C 1 C_1 - C 8 C_8 )alkylthio, mono- or di-( C 1 C_1 - C 8 C_8 )alkylamino, ( C 3 − C 20 ) (C_3-C_{20}) heteroaryl, or ( C 6 − C 20 ) (C_6-C_{20}) aryl; each Z independently represents hydrogen, (C 1 -C 8 )alkyl, an amide, carboxylic acid, carboxylic acid ester, halogen, cyano, or nitro; n is an integer from 1 to 3; m is 0 or 1; R 1 R_1 and R 2 R_2 are each independently hydrogen, ( C 1 − C 8 ) (C_1-C_8) alkyl, or ( C 3 − C 8 ) (C_3-C_8) cycloalkyl, or R 1 R_1 and R 2 taken together with the carbon atom to which they are attached form a (C 3 - C 8 )cycloalkyl ring; R 3 is hydrogen or a carboxyl protecting group; each R 4 is independently hydrogen or a hydroxyl protecting group; and is a bond to the first or second secondary linker.

2. The conjugate of claim 1, wherein each Z independently represents hydrogen, (C 1 - C 8 )alkyl, halogen, cyano, or nitro.

3. The conjugate of claim 1 or 2, wherein W represents -C(O)NR'- and the nitrogen of W is a nitrogen of an amino acid.

4. The conjugate of any one of claims 1-3, wherein R 3 and each R 4 is hydrogen.

5. The conjugate of any one of claims 1-4, wherein the primary linker comprises an alkylene having 1 to 100 carbon atoms, and either: i) the alkylene includes at least one heteroarylene; or ii) a carbon atom of the alkylene is replaced by one or more heteroatoms selected from nitrogen (N), oxygen (O), and sulfur (S).

6. The conjugate of claim 5, wherein the primary linker comprises a nitrogen (N).

7. The conjugate of any one of claims 1-6, wherein the primary linker comprises an amino acid, and the amino acid comprises a side chain having a moiety that bears a charge at neutral pH in aqueous solution.

8. The conjugate of any one of claims 1-7, wherein the first or second secondary linker comprises an alkylene having 1 to 100 carbon atoms, and either: i) the alkylene includes at least one heteroarylene; or ii) a carbon atom of the alkylene is replaced by one or more heteroatoms selected from nitrogen (N), oxygen (O), and sulfur (S).

9. The conjugate of claim 8, wherein at least one carbon atom of the alkylene is replaced by a nitrogen, the first or second secondary linker comprises at least two atoms of a hydrophilic amino acid, and the nitrogen forms a peptide bond with the backbone carbonyl of the hydrophilic amino acid.

10. The conjugate of any one of claims 1-9, wherein the first or second secondary linker comprises an amino acid, and the amino acid comprises a side chain having a moiety that bears a charge at neutral pH in aqueous solution.

11. The conjugate of any one of claims 1-10, wherein the branching unit is coupled to the primary linker by an amide moiety, and further wherein the primary linker comprises the carbonyl of the amide.

12. The conjugate of any one of claims 1-10, wherein the branching unit is coupled to the primary linker by an amide moiety and the first branch or the second branch comprises the carbonyl of the amide.

13. The conjugate of any one of claims 1-12, wherein at least one branching unit is a hydrophilic amino acid.

14. The conjugate of claim 13, wherein the hydrophilic amino acid is arginine, aspartate, asparagine, glutamate, glutamine, histidine, lysine, ornithine, proline, serine, or threonine.

15. The conjugate of any one of claims 1-14, wherein two, three, or four branched linkers are coupled to the antibody.

16. The conjugate of any one of claims 1-14, wherein two branched linkers are coupled to the antibody.

17. The conjugate of any one of claims 1-16, wherein each branched linker is coupled to one active agent.

18. The conjugate of any one of claims 1-17, wherein at least two different active agents are coupled to different branched linkers.

19. The conjugate of any one of claims 1-18, wherein the primary linker is covalently bound to the antibody by a thioether bond, and the thioether bond comprises a sulfur atom of a cysteine of the antibody.

20. The conjugate of claim 19, wherein: the antibody comprises an amino acid motif that is recognized by an isoprenoid transferase; and the thioether bond comprises a sulfur atom of a cysteine of the amino acid motif.

21. The conjugate of claim 20, wherein the amino acid motif is a CYYX; further wherein, C represents cysteine; each Y is an aliphatic amino acid; X is glutamine, glutamate, serine, cysteine, methionine, alanine, or leucine; and the thioether bond comprises a sulfur atom of a cysteine of the amino acid motif.

22. The conjugate of claim 20, wherein the amino acid motif is CysVallleMet or CysValLeuLeu.

23. The conjugate of any one of claims 19-22, wherein the thioether bond comprises a carbon [Image disponible dans le document PDF, Image available in the PDF document] atom of at least one isoprenyl unit, represented by and n is at least 2.

24. The conjugate of any one of claims 1-23, wherein the primary linker comprises: [Image disponible dans le document PDF, Image available in the PDF document]25. The conjugate of any one of claims 1-24, wherein the primary linker, the first branch, or both comprises a connection unit represented by − ( C H 2 ) r ( V ( C H 2 ) p ) q -(CH_2)_r(V(CH_2)_p)_q -, − ( ( C H 2 ) p V ) q -((CH_2)_pV)_q -, [Image disponible dans le document PDF, Image available in the PDF document] wherein: r is an integer from 0 to 10; p is an integer from 1 to 10; q is an integer from 1 to 20; V and Y are each independently a single bond, -O-, -S-, -NR 21 -, -C(O)NR 22 -, -NR 23 C(O)-, - [Image disponible dans le document PDF, Image available in the PDF document] R 21 to R 25 are each independently hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl(C 6 -C 20 )aryl or (C 1 - [Image disponible dans le document PDF, Image available in the PDF document]26. The conjugate of claim 25, wherein the connection unit is represented by − ( ( C H 2 ) p V ) q -((CH_2)_pV)_q -.

27. The conjugate of claim 25 or 26, wherein V and Y are each independently -O-.

28. The conjugate of any one of claims 25-27, wherein: r is 2; p is 2; q is 2, 5, or 11; and V is -O-.

29. The conjugate of any one of claims 1-28, wherein the primary linker further comprises a binding unit represented by Formula A, B, C, or D: [Image disponible dans le document PDF, Image available in the PDF document] wherein: L 1 L_1 is a single bond or alkylene having 1 to 30 carbon atoms; R 11 is hydrogen or alkyl having 1 to 10 carbon atoms; and L 2 is alkylene having 1 to 30 carbon atoms.

30. The conjugate of claim 29, wherein the primary linker comprises [Image disponible dans le document PDF, Image available in the PDF document] wherein, V is a single bond, -O-, -S-, -NR 21 -, -C(O)NR 22 -, -NR 23 C(O)-, -NR 24 SO 2 -, or -SO 2 NR 25 -; R 21 to R 25 are each independently hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl(C 6 -C 20 )aryl, or (C 1 - [Image disponible dans le document PDF, Image available in the PDF document] r is an integer of 1 to 10; p is an integer of 0 to 10; q is an integer of 1 to 20; and L 1 L_1 is a single bond.

31. The conjugate of any one of claims 1-30, wherein the primary linker comprises an O- substituted oxime, wherein either: i) the oxygen atom of the oxime is substituted with a group that covalently links the oxime to the active agent; and the carbon atom of the oxime is substituted with a group that covalently links the oxime to the antibody; or ii) the oxygen atom of the oxime is substituted with a group that covalently links the oxime to the antibody; and the carbon atom of the oxime is substituted with a group that covalently links the oxime to the active agent.

32. The conjugate of claim 1, wherein the conjugate has a structure represented by: [Image disponible dans le document PDF, Image available in the PDF document] wherein: B represents an active agent, x represents an integer from 1 to 3; y represents an integer from 0 to 20; z represents an integer from 1 to 20; and the wavy line represents a connection to the antibody.

33. The conjugate of any one of claims 1-32, wherein the antibody is a monoclonal antibody, polyclonal antibody, antibody fragment, Fab, Fab', Fab'-SH, F(ab') 2 , Fv, single chain Fv ("scFv"), diabody, linear antibody, bispecific antibody, multispecific antibody, chimeric antibody, humanized antibody, human antibody, or fusion protein comprising the antigen- binding portion of an antibody.

34. The conjugate of any one of claims 1-33, wherein the antibody is selected from the group consisting of: muromonab-CD3 abciximab, rituximab, daclizumab, palivizumab, infliximab, trastuzumab, etanercept, basiliximab, gemtuzumab, alemtuzumab, ibritumomab, adalimumab, alefacept, omalizumab, efalizumab, tositumomab, cetuximab, ABT-806, bevacizumab, natalizumab, ranibizumab, panitumumab, eculizumab, rilonacept, certolizumab, romiplostim, AMG-531, golimumab, ustekinumab, ABT-874, belatacept, belimumab, atacicept, an anti-CD20 antibody, canakinumab, tocilizumab, atlizumab, mepolizumab, pertuzumab, HuMax -CD20 TM , tremelimumab, ticilimumab, ipilimumab, IDEC-114, inotuzumab, HuMax-EGFR TM , aflibercept, HuMax-CD4 TM , teplizumab, otelixizumab, catumaxomab, the anti-EpCAM antibody IGN101, adecatumomab, oregovomab, dinutuximab, girentuximab, denosumab, bapineuzumab, motavizumab, efumgumab, raxibacumab, LY2469298, and veltuzumab.

35. The conjugate of any one of claims 1-34, wherein at least one active agent is selected from the group consisting of chemotherapeutic agents and toxins.

36. The conjugate of any one of claims 1-35, wherein at least one active agent is selected from the group consisting of: (a) erlotinib, bortezomib, fulvestrant, sunitinib, letrozole, imatinib mesylate, PTK787 / ZK 222584, oxaliplatin, 5-fluorouracil, leucovorin, rapamycin, lapatinib, lonafarnib, sorafenib, gefitinib, AG1478, AG1571, thiotepa, cyclophosphamide, busulfan, improsulfan, piposulfan, benzodopa, carboquone, meturedopa, uredopa, ethylenimine, altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, trimethylolmelamine, bullatacin, bullatacinone, camptothecin, topotecan, bryostatin, callystatin, CC-1065, adozelesin, carzelesin, bizelesin, cryptophycin 1, cryptophycin 8, dolastatin, duocarmycin, KW-2189, CB1- TM1, eleutherobin, pancratistatin, sarcodictyin, spongistatin, chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard, carmustine, chlorozotoxin, fotemustine, lomustine, nimustine, ranimustine, calicheamicin, calicheamicin gamma 1, calicheamicin omega 1, dynemicin, dynemicin A, clodronate, esperamicin, neocarzinostatin chromophore, aclacinomysins, actinomycin, antimycin, azaserine, bleomycins, cactinomycin, carabicin, carninomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubucin, liposomal doxorubicin, deoxydoxorubicin, epirubicin, esorubicin, marcellomycin, mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptomigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin, denopterin, methotrexate, pteropterin, trimetrexate, fludarabine, 6- mercaptopurine, thiamiprine, thioguanine, ancitabine, azacytidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone, aminoglutethimide, mitotane, trilostane, folinic acid, aceglatone, aldophosphamide glycoside, aminolevulinic acid, eniluracil, amsacrine, bestrabucil, bisantrene, edatrexate, democolcine, diaziquone, elfornithine, elliptinium acetate, etoglucid, gallium nitrate, hydroxyurea, lentinan, lonidainine, maytansine, ansamitocins, mitoguazone, mitoxantrone, mopidanmol, pentostatin, phenamet, pirarubicin, losoxantrone, 2-ethylhydrazide, procarbazine, polysaccharide-k, razoxane, rhizoxin, sizofiran, spirogermanium, tenuazonic acid, triaziquone, 2,2',2"-trichlorotriethylamine, T-2 toxin, verracurin A, roridin A, and anguidine, urethane, vindesine, dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman, arabinoside, paclitaxel, albumin-engineered nanoparticle formulation of paclitaxel, docetaxel, gemcitabine, 6-thioguanine, mercaptopurine, cisplatin, carboplatin, vinblastine, platinum, etoposide, vincristine, vinorelbine, novantrone, teniposide, daunomycin, aminopterin, ibandronate, CPT-11, topoisomerase inhibitor RFS 2000, difluoromethylornithine, retinoic acid, capecitabine, or pharmaceutically acceptable salts, solvates or acids of any of the foregoing; (b) monokine, a lymphokine, a traditional polypeptide hormone, parathyroid hormone, thyroxine, relaxin, prorelaxin, a glycoprotein hormone, follicle stimulating hormone, thyroid stimulating hormone, luteinizing hormone, hepatic growth factor fibroblast growth factor, prolactin, placental lactogen, tumor necrosis factor-α, tumor necrosis factor-β, Mullerian inhibiting substance, mouse gonadotropin associated peptide, inhibin, activin, vascular endothelial growth factor, thrombopoietin, erythropoietin, an osteoinductive factor, an interferon, interferon- α \alpha , interferon- β \beta , interferon- γ \gamma , a colony stimulating factor (CSF), macrophage-CSF, granulocyte-macrophage-CSF, granulocyte-CSF, an interleukin (IL), IL-1, IL-1α, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, a tumor necrosis factor, polypeptide factor, LIF, kit ligand, or a combination of any of the foregoing; (c) diphtheria toxin, botulinum toxin, tetanus toxin, dysentery toxin, cholera toxin, amanitin, α \alpha - amanitin, pyrrolobenzodiazepine, tetrodotoxin, brevetoxin, ciguatoxin, ricin, AM toxin, an auristatin, tubulysin, geldanamycin, maytansinoid, SG2285, cryptophycin, an enediyne antibiotic, epothilone, taltobulin, azonafide, a toxoid, or a combination of any of the foregoing; (d) an affinity ligand, wherein the affinity ligand is a substrate, an inhibitor, a stimulating agent, a neurotransmitter, a radioisotope, or a combination of any of the foregoing; (e) a radioactive label, 32 P, 35 S, a fluorescent dye, an electron dense reagent, an enzyme, biotin, streptavidin, digoxigenin, a hapten, an immunogenic protein, a nucleic acid molecule with a sequence complementary to a target, or a combination of any of the foregoing; (f) an immunomodulatory compound, an anti-cancer agent, an anti-viral agent, an anti-bacterial agent, an anti-fungal agent, and an anti-parasitic agent, or a combination of any of the foregoing; (g) tamoxifen, raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, LY117018, onapristone, or toremifene; (h) 4(5)-imidazoles, megestrol acetate, exemestane, or anastrozole; (i) flutamide, nilutamide, bicalutamide, leuprolide, goserelin, or troxacitabine; (j) an aromatase inhibitor; (k) a protein kinase inhibitor; (l) a lipid kinase inhibitor; (m) an antisense oligonucleotide; (n) a ribozyme; (o) a vaccine; and (p) an anti-angiogenic agent.

37. The conjugate of any one of claims 1-36, wherein at least one active agent is amanitin, auristatin, calicheamicin, camptothecin, cryptophycin, daunomycin, dolastatin, doxorubicin, duocarmycin, epothilone, esperamicin, geldanamycin, maytansinoid, methotrexate, monomethyl auristatin E ("MMAE"), monomethyl auristatin F ("MMAF"), pyrrolobenzodiazepine, rhizoxin, SG2285, tubulysin, vindesine, toxoid, and a derivative of any one of the foregoing.

38. The conjugate of any one of claims 1-36, wherein the conjugate has at least one branched [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] the wavy line represents a connection to the antibody.

39. The conjugate of any one of claims 1-38, wherein the active agent is: [Image disponible dans le document PDF, Image available in the PDF document] , [Image disponible dans le document PDF, Image available in the PDF document] , [Image disponible dans le document PDF, Image available in the PDF document] • [Image disponible dans le document PDF, Image available in the PDF document] wherein y is an integer of 1 to 10; and the wavy line represents a connection to the antibody.

40. A pharmaceutical composition comprising the conjugate of any one of claims 1-39 and at least one pharmaceutically acceptable excipient.

41. Use of the conjugate as defined in any one of claims 1-39, in the manufacture of a medicament for treating a disease or condition.

42. The use of claim 41, wherein the disease or condition is cancer.

43. The conjugate of any one of claims 1-39 for use in treating a disease or condition.

44. The conjugate for use of claim 43, wherein the disease or condition is cancer.