Interleukin-13 receptor subunit alpha-2 antibody-drug conjugates and uses thereof

Abstract

The present disclosure provides interleukin-13 receptor subunit alpha-2 antibody drug conjugate structures. The antibody-drug conjugate structures include a branched linker, where two or more payloads per branched linker are attached to an antibody. In addition, the disclosure also encompasses compounds and methods for production of such conjugates. In addition, the disclosure also encompasses methods of using the conjugates.

Description

INTERLEUKIN-13 RECEPTOR SUBUNIT ALPHA-2 ANTIBODY-DRUGCONJUGATES AND USES THEREOF1. CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 514,794, filed July 20, 2023, the disclosure of which is incorporated by reference herein in its entirety.2. SEQUENCE LISTING

[0002] This application contains an electronic Sequence Listing which has been submitted in XML file format with this application, the entire content of which is incorporated by reference herein in its entirety. The Sequence Listing XML file submitted with this application is entitled “14529-145-228_SEQ_LISTING.xml”, was created on July 17, 2024, and is 265,790 bytes in size.3. FIELD

[0003] The present disclosure relates generally to antibody-drug conjugates (ADCs) that bind to interleukin- 13 receptor subunit alpha-2 (IL13Ra2, e.g., human IL13Ra2) and methods of their use.4. BACKGROUND

[0004] Interleukin- 13 receptor subunit alpha-2 (IL-13Ra2 or IL13Ra2), also known as CD213A2 (cluster of differentiation 213 A2), is a membrane-bound protein that in humans is encoded by the IL13Ra2 gene. IL13Ra2 is a high-affinity membrane receptor for the antiinflammatory cytokine interleukin 13 (IL-13). IL- 13 -mediated IL13Ra2 signaling occurs via STAT6-independent pathways, involving activation of activator protein 1 (AP-1) and extracellular signal-related kinase (ERK), promoting tumor invasion, metastasis, and production of transforming growth factor beta (TGFP). IL13Ra2 has been found to be overexpressed in a variety of cancers, including pancreatic, ovarian, melanomas, and malignant gliomas.

[0005] There remains a need in the art for ADCs that can target IL13Ra2 to treat, prevent, or alleviate IL 13Ra2 -mediated diseases, disorders, or conditions, such as cancer.5. SUMMARY

[0006] The present disclosure provides ADCs comprising an antibody that binds interleukin- 13 receptor subunit alpha-2 (“IL13Ra2-ADC”). Such IL13Ra2-ADCs, in some embodiments, bind to the same epitope of human IL13Ra2 as an antibody comprising a heavy chain variable region (VH) and a light chain variable region (VL) described herein.

[0007] The present disclosure also provides pharmaceutical compositions comprising an IL13Ra2-ADC that comprises an antibody or fragment thereof that binds to IL13Ra2 (“IL13Roc2 antibody”) and a drug conjugated (directly or indirectly) thereto. Such pharmaceutical compositions, in some embodiments, include IL13Ra2-ADCs comprising an antibody or fragment thereof that binds to essentially the same epitope of human IL I 3Ra2 as an antibody comprising a VH and a VL described herein.

[0008] The present disclosure also provides methods of treating, preventing, or alleviating an IL 13Ra2 -mediated disease, disorder, or condition, such as alleviating one or more symptoms of the IL 13Ra2 -mediated disease, disorder, or condition with an IL13Ra2-ADC.

[0009] More specifically, the present disclosure provides an IL13Ra2-ADC comprising (a) an IL13Ra2 antibody and (b) one or more pyridazine-pyrrolo coupling moi eties comprising a drug conjugated to the pyridazine-pyrrolo coupling moiety through a linker, for example, using the Hydrazino- / .w-Pictet-Spengler (HIPS) conjugation method.

[0010] Traditionally, the HIPS conjugation method has been used to produce conjugates carrying one payload per HIPS moiety per aldehyde tag, which produces antibody conjugates with DAR values of up to 4. In some embodiments, an IL13Ra2-ADC as disclosed herein comprises branched HIPS linkers that carry two (or more) molecules of the same or different payload per one HIPS moiety and are therefore capable of conjugating two (or more) small molecule payloads per one aldehyde group in a protein in a single conjugation step. Consequently, the usage of such branched linkers allows the generation of higher DAR sitespecific conjugates (e.g., DAR up to 8) with controlled payload placement, which in the context of therapeutic ADCs would result in larger quantities of pharmaceutical agent delivered to the targeted tissue.

[0011] The present disclosure provides IL13Ra2-ADC structures, each of which comprises (a) an antibody that binds to interleukin- 13 receptor subunit alpha-2 (IL13Ra2), (b) an unbranched or branched HIPS linker, and (c) a drug. The disclosure also encompasses compounds and methods for production of such conjugates, as well as methods of using the conjugates.

[0012] Aspects of the present disclosure include an IL13Ra2-ADC comprising (a) an IL13Ra2 antibody; and (b) one or more pyridazine-pyrrolo coupling moieties comprising one or more drugs conjugated to the pyridazine-pyrrolo coupling moiety via one or more linkers.

[0013] In some embodiments, provided is an ADC of Formula (A):wherein:Ab represents an antibody that binds to IL13Ra2 and Ab comprises any one or more of (i)-(iii): (i) a heavy chain variable region (VH) complementarity determining region 1 (CDR1), a VH complementarity determining region 2 (CDR2), and a VH complementarity determining region 3 (CDR3) as set forth in a VH comprising the amino acid sequence of SEQ ID NO:25 and a light chain variable region (VL) CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:26; or (ii) a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:48 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:49; or (iii) a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:73 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 74;L represents a linker; s is an integer from 1 to 10; andW1represents a drug.

[0014] In further embodiments, L comprises a pyridazine-pyrrolo coupling moiety, such as a hydrazinyl-indolyl or a hydrazinyl-pyrrolo-pyridinyl compound, or a derivative of each thereof.

[0015] In yet further embodiments, L comprises linker (L-I’):(L-E) wherein:t is 0 or 1;•~wrepresents the point of attachment to Ab;# represents the point of attachment to W1;Z1, Z2, Z3, and Z4are each independently selected from CR4, N, and C-LB-$, and $ represents the point of attachment to a second drug W2;R1, R2, R3, and R4are each selected from hydrogen and alkyl;LAis a first linker comprising: -(T1-V1)a-(T2-V2)b-(T3-V3)c-(T4-V4)d-(T5-V5)e-(T6-V6)f-, wherein: a, b, c, d, e, and f are each independently 0 or 1, provided at least one of a, b, c, d, e, and f are 1 ;T1, T2, T3, T4, T5and T6are each independently selected from a covalent bond, (Ci-Ci2)alkyl, substituted (Ci-Ci2)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, (EDA)w, (PEG)n, (AA)P, -(CR13OH)X-, 4-amino-piperidine (4AP), meta-amino-benzyloxy (MABO), meta-amino-benzyloxycarbonyl (MABC), para-amino-benzyloxy (PABO), para-amino-benzyloxycarbonyl (PABC), para-aminobenzyl (PAB), para-amino- benzylamino (PAB A), para-amino-phenyl (PAP), para-hydroxy-phenyl (PHP), an acetal group, a hydrazine, a disulfide, and an ester, wherein EDA is an ethylene diamine moiety, PEG is a polyethylene glycol, and AA is an amino acid residue or an amino acid analog, wherein each w is an integer from 1 to 20, each n is an integer from 1 to 30, each p is an integer from 1 to 20, and each x is an integer from 1 to 12;V1, V2, V3, V4, V5and V6are each independently selected from the group consisting of a covalent bond, -CO-, -NR15-, -NR15(CH2)q-, -NR15(CeH4)-, -CONR15-, -NR15CO-, -C(O)O-, -OC(O)-, -O-, -S-, -S(O)-, -SO2-, -SO2NR15-, -NR15SO2- and -P(O)OH-, wherein each q is an integer from 1 to 6; each R13is independently selected from hydrogen, an alkyl, a substituted alkyl, an aryl, and a substituted aryl; and each R15is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, carboxyl, carboxyl ester, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl;LBis a second linker comprising: -(T7-V7)g-(T8-V8)h-(T9-V9)i-(T10-V10)j-(T11-V11)k-(T12-V12)i-(T13-V13)m-,wherein: g, h, i, j, k, 1, and m are each independently 0 or 1, provided that at least one of g, h, i, j, k, 1, and m is 1;T7, T8, T9, T10, T11, T12and T13are each independently selected from a covalent bond, (Ci-Ci2)alkyl, substituted (Ci-Ci2)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, (EDA)w, (PEG)n, (AA)P, -(CR13OH)X-, 4-amino-piperidine (4AP), meta-amino-benzyloxy (MABO), meta-amino-benzyloxycarbonyl (MABC), para-amino-benzyloxy (PABO), para-amino-benzyloxycarbonyl (PABC), para-aminobenzyl (PAB), para-amino- benzylamino (PAB A), para-amino-phenyl (PAP), para-hydroxy-phenyl (PHP), an acetal group, a hydrazine, a disulfide, and an ester, wherein EDA is an ethylene diamine moiety, PEG is a polyethylene glycol, and AA is an amino acid residue or an amino acid analog, wherein each w is an integer from 1 to 20, each n is an integer from 1 to 30, each p is an integer from 1 to 20, and each x is an integer from 1 to 12;V7, V8, V9, V10, V11, V12and V13are each independently selected from the group consisting of a covalent bond, -CO-, -NR15-, -NR15(CH2)q-, -NR15(CeH4)-, -CONR15-, - NR15CO-, -C(O)O-, -OC(O)-, -O-, -S-, -S(O)-, -SO2-, -SO2NR15-, -NR15SO2- and - P(O)OH-, wherein each q is an integer from 1 to 6; each R13is independently selected from hydrogen, an alkyl, a substituted alkyl, an aryl, and a substituted aryl; and each R15is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, carboxyl, carboxyl ester, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl.

[0016] Additionally or alternatively, at least one of Z1, Z2, Z3, and Z4is C-LB-$, and $ represents the point of attachment to a second drug W2. In further embodiments, Z3is C-LB-$. Additionally or alternatively, W2comprises: (i) a camptothecin or an analog thereof, such as belotecan; or (ii) an auristatin or an analog thereof, such as MMAE. In yet further embodiments, W2comprises belotecan. In other embodiments, W2comprises MMAE. Additionally or alternatively, W1and W2are the same. In other embodiments, W1and W2are different.

[0017] In some embodiments, an IL13Ra2-ADC is represented by Formula (I):wherein:Ab represents an antibody that binds to IL13Ra2;Z1, Z2, and Z4are each independently CR4;Z3is C-LB-W2;R1, R2, R3, and R4are each selected from hydrogen and alkyl;LAis a first linker comprising:-(T1-V1)a-(T2-V2)b-(T3-V3)c-(T4-V4)d-(T5-V5)e-(T6-V6)f-, wherein: a, b, c, d, e, and f are each independently 0 or 1, provided at least one of a, b, c, d, e, and f are 1 ;T1, T2, T3, T4, T5and T6are each independently selected from a covalent bond, (Ci-Ci2)alkyl, substituted (Ci-Ci2)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, (EDA)w, (PEG)n, (AA)P, -(CR13OH)X-, 4-amino-piperidine (4AP), meta-amino-benzyloxy (MABO), meta-amino-benzyloxycarbonyl (MABC), para-amino-benzyloxy (PABO), para-amino-benzyloxycarbonyl (PABC), para-aminobenzyl (PAB), para-amino- benzylamino (PAB A), para-amino-phenyl (PAP), para-hydroxy-phenyl (PHP), an acetal group, a hydrazine, a disulfide, and an ester, wherein EDA is an ethylene diamine moiety, PEG is a polyethylene glycol, and AA is an amino acid residue or an amino acid analog, wherein each w is an integer from 1 to 20, each n is an integer from 1 to 30, each p is an integer from 1 to 20, and each x is an integer from 1 to 12;V1, V2, V3, V4, V5and V6are each independently selected from the group consisting of a covalent bond, -CO-, -NR15-, -NR15(CH2)q-, -NR15(CeH4)-, -CONR15-, -NR15CO-, -C(O)O-, -OC(O)-, -O-, -S-, -S(O)-, -SO2-, -SO2NR15-, -NR15SO2- and - P(O)OH-, wherein each q is an integer from 1 to 6;each R13is independently selected from hydrogen, an alkyl, a substituted alkyl, an aryl, and a substituted aryl; and each R15is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, carboxyl, carboxyl ester, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl;LBis a second linker comprising: -(T7-V7)g-(T8-V8)h-(T9-V9)i-(T10-V10)j-(T11-V11)k-(T12-V12)i-(T13-V13)m-, wherein: g, h, i, j, k, 1, and m are each independently 0 or 1, provided that at least one of g, h, i, j, k, 1, and m is 1;T7, T8, T9, T10, T11, T12and T13are each independently selected from a covalent bond, (Ci-Ci2)alkyl, substituted (Ci-Ci2)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, (EDA)w, (PEG)n, (AA)P, -(CR13OH)X-, 4-amino-piperidine (4AP), meta-amino-benzyloxy (MABO), meta-amino-benzyloxycarbonyl (MABC), para-amino-benzyloxy (PABO), para-amino-benzyloxycarbonyl (PABC), para-aminobenzyl (PAB), para-amino- benzylamino (PAB A), para-amino-phenyl (PAP), para-hydroxy-phenyl (PHP), an acetal group, a hydrazine, a disulfide, and an ester, wherein EDA is an ethylene diamine moiety, PEG is a polyethylene glycol, and AA is an amino acid residue or an amino acid analog, wherein each w is an integer from 1 to 20, each n is an integer from 1 to 30, each p is an integer from 1 to 20, and each x is an integer from 1 to 12;V7, V8, V9, V10, V11, V12and V13are each independently selected from the group consisting of a covalent bond, -CO-, -NR15-, -NR15(CH2)q-, -NR15(CeH4)-, -CONR15-, -NR15CO-, -C(O)O-, -OC(O)-, -O-, -S-, -S(O)-, -SO2-, -SO2NR15-, -NR15SO2- and -P(O)OH-, wherein each q is an integer from 1 to 6; each R13is independently selected from hydrogen, an alkyl, a substituted alkyl, an aryl, and a substituted aryl; and each R15is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, carboxyl, carboxyl ester, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl; s is an integer from 1 to 10;W1is a first drug; andW2is a second drug.

[0018] In further embodiments, the IL13Ra2-ADC comprises (a), an antibody that binds to interleukin- 13 receptor subunit alpha-2 (IL13Ra2); and (b). two or more drugs conjugated to a pyridazine-pyrrolo coupling moiety, each via a linker.

[0019] In further embodiments, provided is an IL13Ra2-ADC represented by Formula (II):Ab represents an antibody that binds to IL13Ra2; and s is an integer from 1 to 10.

[0020] Additionally or alternatively, s is an integer from 1 to 8. In some embodiments, s is 2. In some embodiments, s is 4.

[0021] In some embodiments, an IL13Ra2-ADC is represented by Formula (III):wherein:Ab represents the antibody that binds to IL13Ra2;W1is the drug; s is an integer from 1 to 10; t is 0 or 1;R2and R3are each independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acyl amino, amino acyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl; or R2and R3are cyclically linked to form a 5- or 6-membered heterocyclyl;X1, X2, X3, and X4are each independently selected from the group consisting of C, N, O and S;Y1, Y2, Y3, and Y4are each independently selected from the group consisting of hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acyl amino, amino acyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl substituted heterocyclyl, and absent when adjacent to N; or Y1and Y2, Y2and Y3, or Y3and Y4are cyclically linked;wherein: represents attachment to the nitrogen of the pyridazine-pyrrolo coupling moiety;* represents attachment to W1; each R5is independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, or substituted heterocyclyl; each R6is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl;R7is a cleavable moiety; k is an integer from 1 to 10;Llacomprises -(T1-V1)a-(T2-V2)b-(T3-V3)c-(T4-V4)d-;L2acomprises -(T5-V5)e-(T6-V6)f-(T7-V7)g-(T8-V8)h-; each of a, b, c, d, e, f, g, and h are independently 1 or 0;T1, T2, T3T4, T5, T6, T7, and T8are each independently selected from the group consisting of a covalent bond, C1-C12 alkyl, substituted C1-C12 alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, (EDA)W, (PEG)n, (AA)P, -(CR13OH)m-, P4A-R12, acetal, a hydrazine, a disulfide, and an ester; each w is an integer from 1 to 20; each n is an integer from 1 to 30; each p is an integer from 1 to 20; each m is an integer from 1 to 12;V1, V2, V3, V4, V5, V6, V7, and V8are each independently selected from the group consisting of a covalent bond, -CO-, -NR15-, -NR15(CH2)q-, -NR15(CeH4)-, -CONR15-, - NR15CO-, -C(O)O-, -OC(O)-, -O-, -S-, -S(O)-, -SO2-, -SO2NR15-, -NR15SO2-, and -P(O)OH-; each q is an integer from 1 to 6;R12is selected from the group consisting of hydrogen, alkyl, substituted alkyl, a polyethylene glycol moiety, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acylamino, amino acyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl; each R13is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, and substituted aryl; and each R15is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, carboxyl, carboxyl ester, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl.In further embodiments, the IL13Ra2-ADC comprises: (a), an antibody that binds to IL13Ra2; and (b). two or more drugs conjugated to a pyridazine-pyrrolo coupling moiety, each via a linker.

[0022] In further embodiments, s is an integer from 1 to 8. In some embodiments, s is 2. In some embodiments, s is 4.

[0023] In further embodiments, an IL13Ra2-ADC is represented by Formula (V-3):

[0024] In further embodiments, an IL13Ra2-ADC is represented by Formula (IV-5):(IV-5),wherein R6and R6are each independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, or substituted heterocyclyl.

[0025] In further embodiments, an IL13Ra2-ADC is represented by Formula (V-5):(V-5), wherein R6and R6are each independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, or substituted heterocyclyl.

[0026] In further embodiments, an IL13Ra2-ADC is represented by Formula (V-6):

[0027] In further embodiments, an IL13Ra2-ADC is represented by Formula (V-7):

[0028] In further embodiments, an IL13Ra2-ADC is represented by Formula (Vb-82):(Vb-82).

[0029] In further embodiments, an IL13Ra2-ADC is represented by Formula (Vb-82-1):(Vb-82-1).

[0030] In some embodiments, an IL13Ra2-ADC is represented by any one or more of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (FV-5), Formula (V), Formula (V-3), Formula (V-5), Formula (V-6), Formula (V-7), Formula (A), or Formula (Vb- 82), wherein s is an integer from 1 to 8. In some embodiments, s is 2. In further embodiments, an IL13Ra2-ADC is represented by Formula (Vb-82-1). In some embodiments, s is 4.

[0031] In some embodiments, an IL13Ra2-ADC is represented by any one or more of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (FV-5), Formula (V), Formula (V-3), Formula (V-5), Formula (V-6), Formula (V-7), or Formula (A), wherein W1comprises: (i) a camptothecin or an analog thereof, such as belotecan; or (ii) an auristatin or an analog thereof, such as MMAE. In further embodiments, W1comprises belotecan. In other embodiments, W1comprises MMAE.

[0032] In some embodiments, an IL13Ra2-ADC is represented by any one or more of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (FV-5), Formula (V), Formula (V-3), Formula (V-5), Formula (V-6), Formula (V-7), Formula (A), Formula (Vb- 82), or Formula (Vb-82-1), wherein the antibody (Ab) comprises any one or more of (i)-(ii):(i) a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:25 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:26; or(ii) a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:48 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:49; or(iii) a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:73 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:74.

[0033] In some embodiments, an IL13Ra2-ADC is represented by any one or more of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (IV-5), Formula (V), Formula (V-3), Formula (V-5), Formula (V-6), Formula (V-7), Formula (A), Formula (Vb- 82), or Formula (Vb-82-1), wherein the antibody (Ab) comprises:(a) a VH comprising:(1) a VH CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1, 2, 3, 4, and 5;(2) a VH CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 6, 7, 8, 9, and 10; and(3) a VH CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 11, 12, 13, and 14; and(b) a VL comprising:(1) a VL CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 15, 16, 17, and 18;(2) a VL CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 19, 20, and 21; and(3) a VL CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22, 23, and 24.

[0034] In some embodiments, an IL13Ra2-ADC is represented by any one or more of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (IV-5), Formula (V), Formula (V-3), Formula (V-5), Formula (V-6), Formula (V-7), Formula (A), Formula (Vb- 82), or Formula (Vb-82-1), wherein the antibody (Ab) comprises:(a) a VH comprising:(1) a VH CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 27, 28, 29, 30, and 31;(2) a VH CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 32, 33, 34, 35, and 36; and(3) a VH CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 37, 38, 39, and 40; and(b) a VL comprising:(1) a VL CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 41, 42, 43, and 44;(2) a VL CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 19, 20, and 21; and(3) a VL CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 45, 46, and 47.

[0035] In some embodiments, an IL13Ra2-ADC is represented by any one or more of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (IV-5), Formula (V), Formula (V-3), Formula (V-5), Formula (V-6), Formula (V-7), Formula (A), Formula (Vb- 82), or Formula (Vb-82-1), wherein the antibody (Ab) comprises:(a) a VH comprising:(1) a VH CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 50, 51, 52, 53, and 54;(2) a VH CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 55, 56, 57, 58, and 59; and(3) a VH CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 60, 61, 62, and 63; and(b) a VL comprising:(1) a VL CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 64, 65, 66, and 67;(2) a VL CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 68, 20, and 69; and(3) a VL CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 70, 71, and 72.

[0036] In some embodiments, an IL13Ra2-ADC is represented by any one or more of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (IV-5), Formula (V),Formula (V-3), Formula (V-5), Formula (V-6), Formula (V-7), Formula (A), Formula (Vb- 82), or Formula (Vb-82-1), wherein Ab comprises a framework 1 (FR1), a framework 2 (FR2), a framework 3 (FR3) and / or a framework 4 (FR4) sequence, for example, as set forth in any one of SEQ ID NOs: 25, 26, 48, 49, 73 and 74.

[0037] In some embodiments, an IL13Ra2-ADC is represented by any one or more of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (IV-5), Formula (V), Formula (V-3), Formula (V-5), Formula (V-6), Formula (V-7), Formula (A), Formula (Vb- 82), or Formula (Vb-82-1), wherein Ab comprises human framework sequences.

[0038] In some embodiments, an IL13Ra2-ADC is represented by any one or more of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (IV-5), Formula (V), Formula (V-3), Formula (V-5), Formula (V-6), Formula (V-7), Formula (A), Formula (Vb- 82), or Formula (Vb-82-1), wherein Ab comprises:(i) a VH comprising the amino acid sequence of SEQ ID NO:48 and a VL comprising the amino acid sequence of SEQ ID NO:49; or(ii) a VH comprising the amino acid sequence of SEQ ID NO:73 and a VL comprising the amino acid sequence of SEQ ID NO:74; or(iii) a VH comprising the amino acid sequence of SEQ ID NO:25 and a VL comprising the amino acid sequence of SEQ ID NO:26.

[0039] Additionally or alternatively, an IL13Ra2-ADC is represented by any one or more of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (IV-5), Formula (V), Formula (V-3), Formula (V-5), Formula (V-6), Formula (V-7), Formula (A), Formula (Vb- 82), or Formula (Vb-82-1), wherein Ab further comprises a sequence of Formula (X)X'(fGly’)X2Z20X3Z0(X) wherein: fGly’ is the amino acid residue coupled to the drug through a linker;Z20is either a proline (P) or alanine (A) residue;Z30is a basic amino acid residue optionally selected from the group consisting of: arginine (R), lysine (K), and histidine (H), or an aliphatic amino acid residue optionally selected from the group consisting of: alanine (A), glycine (G), leucine (L), valine (V), isoleucine (I), and proline (P);X1is present or absent and, when present, can be any amino acid residue, with the proviso that when the sequence of Formula (X) is at the N-terminus of the antibody Ab, X1is present; andX2and X3independently is any amino acid residue.

[0040] In further embodiments, the sequence of Formula (X) is selected from the group consisting of: L(fGly’)TPSR (SEQ ID NO: 146), M(fGly’)TPSR (SEQ ID NO: 147), V(fGly’)TPSR (SEQ ID NO: 148), L(fGly’)SPSR (SEQ ID NO: 149), L(fGly’)APSR (SEQ ID NO: 150), L(fGly’)VPSR (SEQ ID NO: 151), L(fGly’)GPSR (SEQ ID NO: 152), I(fGly’)TPAR (SEQ ID NO: 153), L(fGly’)TPSK (SEQ ID NO: 154), M(fGly’)TPSK (SEQ ID NO: 155), V(fGly’)TPSK (SEQ ID NO: 156), L(fGly’)SPSK (SEQ ID NO: 157), L(fGly’)APSK (SEQ ID NO: 158), L(fGly’)VPSK (SEQ ID NO: 159), L(fGly’)GPSK (SEQ ID NO: 160), L(fGly’)TPSA (SEQ ID NO: 161), I(fGly’)TPAA (SEQ ID NO: 162), M(fGly’)TPSA (SEQ ID NO: 163), V(fGly’)TPSA (SEQ ID NO: 164), L(fGly’)SPSA (SEQ ID NO: 165), L(fGly’)APSA (SEQ ID NO: 166), L(fGly’)VPSA (SEQ ID NO: 167), and L(fGly’)GPSA (SEQ ID NO: 168). In yet further embodiments, the sequence of Formula (X) comprises L(fGly’)TPSR (SEQ ID NO: 146).

[0041] In some embodiments, an IL13Ra2-ADC is represented by any one or more of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (IV-5), Formula (V), Formula (V-3), Formula (V-5), Formula (V-6), Formula (V-7), Formula (A), Formula (Vb- 82), or Formula (Vb-82-1), wherein Ab comprises:(i) a heavy chain comprising the amino acid sequence of any one of SEQ ID NO:201, or SEQ ID NO:203, or SEQ ID NO:205, and a light chain comprising the amino acid sequence of SEQ ID NO:76; or(ii) a heavy chain comprising the amino acid sequence of any one of SEQ ID NO:208, or SEQ ID NO:211, or SEQ ID NO:214, and a light chain comprising the amino acid sequence of SEQ ID NO: 80; or(iii) a heavy chain comprising the amino acid sequence of any one of SEQ ID NO:217, or SEQ ID NO:220, or SEQ ID NO:223, and a light chain comprising the amino acid sequence of SEQ ID NO:82.

[0042] In some embodiments, an IL13Ra2-ADC is represented by Formula (II), wherein s is 4, and wherein Ab comprises:(i) a heavy chain comprising the amino acid sequence of SEQ ID NO:201, and a light chain comprising the amino acid sequence of SEQ ID NO:76; or(ii) a heavy chain comprising the amino acid sequence of SEQ ID NO:208, and a light chain comprising the amino acid sequence of SEQ ID NO:80; or(iii) a heavy chain comprising the amino acid sequence of SEQ ID NO:217, and a light chain comprising the amino acid sequence of SEQ ID NO:82.

[0043] In some embodiments, an IL13Ra2-ADC is represented by Formula (Vb-82), and wherein Ab comprises:(i) a heavy chain comprising the amino acid sequence of SEQ ID NO:203, and a light chain comprising the amino acid sequence of SEQ ID NO:76; or(ii) a heavy chain comprising the amino acid sequence of SEQ ID NO:211, and a light chain comprising the amino acid sequence of SEQ ID NO:80; or(iii) a heavy chain comprising the amino acid sequence of SEQ ID NO:220, and a light chain comprising the amino acid sequence of SEQ ID NO:82.

[0044] In some embodiments, an IL13Ra2-ADC is represented by Formula (Vb-82), wherein s is 2 and wherein Ab comprises:(i) a heavy chain comprising the amino acid sequence of SEQ ID NO:205, and a light chain comprising the amino acid sequence of SEQ ID NO:76; or(ii) a heavy chain comprising the amino acid sequence of SEQ ID NO:214, and a light chain comprising the amino acid sequence of SEQ ID NO:80; or(iii) a heavy chain comprising the amino acid sequence of SEQ ID NO:223, and a light chain comprising the amino acid sequence of SEQ ID NO:82.

[0045] The present disclosure also provides a pharmaceutical composition comprising an IL13Ra2-ADC, wherein the IL13Ra2-ADC is represented by any one or more of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (FV-5), Formula (V), Formula (V-3), Formula (V-5), Formula (V-6), Formula (V-7), Formula (A), Formula (Vb-82), or Formula (Vb-82- 1), and a pharmaceutically acceptable excipient, wherein the IL13Ra2 antibody (IL13Ra2 Ab or Ab) is as described in any embodiment described herein. In some embodiments, such a pharmaceutical composition has a drug-to-antibody ratio (DAR) of the IL13Ra2-ADC of about 1 to about 20, for example, a DAR of about 2 to about 8, about 1 to about 4, about 2 to about 4, about 3 to about 4, about 4, about 1 to about 8, about 2 to about 8, about 3 to about 8, about 4 to about 8, about 5 to about 8, about 6 to about 8, about 6.5 to about 8, about 6 to about 7, about 6.5 to about 7.5, about 7 to about 8, about 6.5, about 7, about 7.5, or about 8.

[0046] The present disclosure also provides a method for treating a cancer or a tumor in a subject comprising administering to the subject the IL13Ra2-ADC, wherein the IL I 3Ra2- ADC is represented by any one or more of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (IV-5), Formula (V), Formula (V-3), Formula (V-5), Formula (V-6), Formula (V-7), Formula (A), Formula (Vb-82), or Formula (Vb-82-1) or a pharmaceutical compositioncomprising an IL13Roc2-ADC of any one or more of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (IV-5), Formula (V), Formula (V-3), Formula (V-5), Formula (V-6), Formula (V-7), Formula (A), Formula (Vb-82), or Formula (Vb-82-1) and a pharmaceutically acceptable excipient, wherein the IL13Ra2 antibody is as described in any embodiment herein.

[0047] Provided herein is a kit comprising the antibody-drug conjugate as disclosed herein or the pharmaceutical composition as disclosed herein, and instructions for use.6. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] FIGs. 1A-1E provide exemplary monovalent Kd results of A22 (FIG. 1A), A33 (FIG. IB), A52 (FIG. 1C), benchmark antibody 1 (FIG. ID), and benchmark antibody 2 (FIG. IE), as further illustrated in Example 2.

[0049] FIGs. 2A-2E provide exemplary SEC results of A22 (FIG. 2A), A33 (FIG. 2B), A52 (FIG. 2C), benchmark antibody 1 (FIG. 2D), and benchmark antibody 2 (FIG. 2E), as further illustrated in Example 4.

[0050] FIGs. 3A-3E provide exemplary SCX results of A22 (FIG. 3A), A33 (FIG. 3B), A52 (FIG. 3C), benchmark antibody 1 (FIG. 3D), and benchmark antibody 2 (FIG. 3E), as further illustrated in Example 4.

[0051] FIGs. 4A-4E provide exemplary SMAC results of A22 (FIG. 4A), A33 (FIG. 4B), A52 (FIG. 4C), benchmark antibody 1 (FIG. 4D), and benchmark antibody 2 (FIG. 4E), as further illustrated in Example 4.

[0052] FIGs. 5A-5E provide exemplary HIC results of A22 (FIG. 5A), A33 (FIG. 5B), A52 (FIG. 5C), benchmark antibody 1 (FIG. 5D), and benchmark antibody 2 (FIG. 5E), as further illustrated in Example 4.

[0053] FIGs. 6A-6E provide exemplary binding results of A22 (FIG. 6A), A33 (FIG. 6B), A52 (FIG. 6C), benchmark antibody 1 (FIG. 6D), and benchmark antibody 2 (FIG. 6E), to IL13Ra2 endogenously expressed on A375 cells, as further illustrated in Example 5.

[0054] FIGs. 7A-7E provide exemplary binding results of A22 (FIG. 7A), A33 (FIG. 7B), A52 (FIG. 7C), benchmark antibody 1 (FIG. 7D), and benchmark antibody 2 (FIG. 7E), to human IL13Ra2 expressed on HEK cells, as further illustrated in Example 5.

[0055] FIGs. 8A-8E provide exemplary binding results of A22 (FIG. 8A), A33 (FIG. 8B), A52 (FIG. 8C), benchmark antibody 1 (FIG. 8D), and benchmark antibody 2 (FIG. 8E), to cyno IL13Ra2 expressed on HEK cells, as further illustrated in Example 5.

[0056] FIGs. 9A-9E provide exemplary binding results of A22 (FIG. 9A), A33 (FIG. 9B), A52 (FIG. 9C), benchmark antibody 1 (FIG. 9D), and benchmark antibody 2 (FIG. 9E), to IL13Ra2 endogenously expressed on A375 cells pretreated with human IL13, as further illustrated in Example 5.

[0057] FIGs. 10A-10E provide exemplary binding results of A22 (FIG. 10A), A33 (FIG. 10B), A52 (FIG. 10C), benchmark antibody 1 (FIG. 10D), and benchmark antibody 2 (FIG. 10E), to human IL13Ra2 expressed on HEK cells pretreated with human IL13, as further illustrated in Example 5.

[0058] FIGs. 11A-11E provide exemplary ADC piggy-back assay results of A22 (FIG.11 A), A33 (FIG. 11B), A52 (FIG. 11C), benchmark antibody 1 (FIG. 11D), and benchmark antibody 2 (FIG. HE), in A375 cells endogenously expressing IL13Ra2, as further illustrated in Example 6.

[0059] FIGs. 12A-12E provide exemplary ADC piggy-back assay results of A22 (FIG. 12A), A33 (FIG. 12B), A52 (FIG. 12C), benchmark antibody 1 (FIG. 12D), and benchmark antibody 2 (FIG. 12E), in A375 cells endogenously expressing IL13Ra2 and pretreated with human IL 13, as further illustrated in Example 6.

[0060] FIGs. 13A-13E provide exemplary ADC piggy-back assay results of A22 (FIG. 13A), A33 (FIG. 13B), A52 (FIG. 13C), benchmark antibody 1 (FIG. 13D), and benchmark antibody 2 (FIG. 13E), in HEK cells expressing cyno IL13Ra2, as further illustrated in Example 6.

[0061] FIGs. 14A-14E provide exemplary binding results of A22 (FIG. 14A), A33 (FIG. 14B), A52 (FIG. 14C), benchmark antibody 1 (FIG. 14D), and benchmark antibody 2 (FIG. 14E), to human IL13Ral expressed on HEK cells, as further illustrated in Example 5.

[0062] FIGs. 15A-15E provide exemplary ADC piggy-back assay results of A22 (FIG. 15A), A33 (FIG. 15B), A52 (FIG. 15C), benchmark antibody 1 (FIG. 15D), and benchmark antibody 2 (FIG. 15E), in HEK cells expressing human IL13Ral, as further illustrated in Example 6.

[0063] FIGs. 16A-16E provide exemplary SDS-PAGE results of A22 (FIG. 16A), A33 (FIG. 16B), A52 (FIG. 16C), benchmark antibody 1 (FIG. 16D), and benchmark antibody 2 (FIG. 16E), as further illustrated in Example 4.

[0064] FIGs. 17A-17B illustrate analysis results comparing the ECsos between to free IL13Ra2 on A375 cells vs. to IL13Ra2: lL-13 on A375 cells. FIG. 17A plots all ECsos in the y axis, while FIG. 17B plots the ECsos of IL13Ra2 along the y axis and the ECsos of IL13Ra2: lL-13 along the x axis.

[0065] FIG. 18 illustrates analysis results comparing the ECsos between to free human IL13Ra2 on A375 vs. to free cyno IL13Ra2 on cyno IL13Ra2 over-expressing cells.

[0066] FIGs. 19A-19B compares the BmaxS of indicated groups. FIG. 19A illustrates analysis results comparing the BmaxS between to free IL13Ra2 on A375 vs. IL-13 bound IL13Ra2 on A375. FIG. 19B illustrates analysis results comparing the BmaxS between to free human IL13Ra2 on A375 vs. to free cyno IL13Ra2 on cyno IL13Ra2 over-expressing cells.

[0067] FIGs. 20A-20B illustrates analysis results comparing the cytotoxicity ICsos between to free IL13Ra2 on A375 cells vs. to IL13Ra2: lL-13 on A375 cells. FIG. 20A plots all ICsos in the y axis, while FIG. 20B plots the ICsos of IL13Ra2 along the y axis and the ICsos of IL13Ra2: lL-13 along the x axis.

[0068] FIGs. 21A-21B compares cell binding vs. cytotoxicity capability. FIG. 21A illustrates analysis results between the cell binding ECsos vs. the cytotoxicity ICsos, both of which are to the free IL13Ra2 on A375 cells. FIG. 21B illustrates analysis results between the cell binding ECsos vs. the cytotoxicity ICsos, both of which are to the IL 13 bound IL13Ra2 on A375 cells.

[0069] FIGs. 22A-22B illustrate analysis results comparing the ICsos between to free human IL13Ra2 on A375 vs. to free cyno IL13Ra2 on cyno IL13Ra2 over-expressing cells (FIG. 22A), and between the cell binding ECsos vs. the cytotoxicity ICsos, both of which are to free cyno IL13Ra2 on cyno IL13Ra2 over-expressing cells (FIG. 22B).

[0070] FIGs. 23A-23B illustrate analysis results between A375 cell binding ECsos vs. Kd affinity of binding to free human IL13Ra2. FIG. 23A plots both ECsos and Kd in the y axis, while FIG. 23B plots the Kd along the y axis and the ECsos along the x axis.

[0071] FIGs. 24A-24B illustrate analysis results between ECsos of binding to IL13-treated A375 cells vs. Kd affinity of binding to human IL13Ra2:IL13 complex. FIG. 24A plots both ECsos and Kd in the y axis, while FIG. 24B plots the Kd along the y axis and the ECsos along the x axis.

[0072] FIGs. 25A-25B illustrate analysis results between ECsos of binding to cyno IL13Ra2 over-expressed on HEK cells vs. Kd affinity of binding to free cyno IL13Ra2. FIG. 25A plots both ECsos and Kd in the y axis, while FIG. 25B plots the Kd along the y axis and the ECsos along the x axis.

[0073] FIG. 26 provides an exemplary FACS result assessing the binding of the indicated antibodies and ADCs to A375 (the left bar for each group) and HEK293-IL13Ra2 (the right bar for each group) cells as further illustrated in Example 11.

[0074] FIGs. 27A-27B provide exemplary in vitro cytotoxicity results of the tested ADCs against A375 cells as further illustrated in Example 12. FIG. 27A plots cells’ survival percentages, while FIG. 27B is a table listing the calculated ICsos.

[0075] FIGs. 28A-28B provide exemplary in vitro cytotoxicity results of the tested ADCs against Hl 792 cells as further illustrated in Example 12. FIG. 28A plots the data obtained from the indicated MMAE ADCs, while FIG. 28B plots the data obtained from the indicated belotecan ADCs.

[0076] FIGs. 29A-29B provide exemplary in vitro cytotoxicity results of the tested ADCs against H2228 cells as further illustrated in Example 12. FIG. 29A plots the data obtained from the indicated MMAE ADCs, while FIG. 29B plots the data obtained from the indicated belotecan ADCs.

[0077] FIGs. 30A-30B provide exemplary in vitro cytotoxicity results of the tested ADCs against SK-MES-1 cells as further illustrated in Example 12. FIG. 30A plots the data obtained from the indicated MMAE ADCs, while FIG. 30B plots the data obtained from the indicated belotecan ADCs.

[0078] FIGs. 31A-31C compare in vitro cytotoxicity results of the tested ADCs against A375 vs human primary corneal epithelial cells (HCE) as further illustrated in Example 12. FIG. 31A plots the data obtained from the indicated MMAE ADCs, while FIG. 31B plots the data obtained from the indicated belotecan ADCs. FIG. 31C compares data from HCE, IL13Roc2 knock-out A375 (A375 KO), A375, and HEK overexpressing IL13Ra2 (HEK IL13Ra2).

[0079] FIGs. 32A-32B provide exemplary in vitro cytotoxicity results of the tested ADCs against HCE cells as further illustrated in Example 12. FIG. 32A plots the data obtained from the indicated MMAE ADCs, while FIG. 32B plots the data obtained from the indicated belotecan ADCs.

[0080] FIGs. 33A-33C provide exemplary off-target toxicity results in erythroid (FIG. 33A), CFU-GM (FIG. 33B), and neutrophil (FIG. 33C) as further illustrated in Example 12.

[0081] FIGs. 34A-34F provide exemplary in vivo efficacy results of IL13Ra2 MMAE ADCs at a single dose of 10 mg / kg as further illustrated in Example 13. FIG. 34A plots body weights, while FIG. 34B plots tumor volumes of all animals. FIGs. 34C-34F plot tumor volumes of each of the animals in the treatment groups of ADC FITC-2, ADC 22-2, ADC 33- 2, and ADC 52-2, respectively.

[0082] FIGs. 35A-35F provide exemplary in vivo efficacy results of IL13Ra2 belotecan ADCs at a single dose of 10 mg / kg as further illustrated in Example 13. FIG. 35A plots body weights, while FIG. 35B plots tumor volumes of all animals. FIGs. 35C-35F plot tumor volumes of each of the animals in the treatment groups of ADC FITC-8, ADC 22-8, ADC 33- 8, and ADC 52-8, respectively.

[0083] FIG. 36 compares in vivo efficacy of all ADCs, including IL13Ra2 MMAE and belotecan ones.

[0084] FIGs. 37A-37B provide exemplary in vivo efficacy results of IL13Ra2 ADCs at a lower dose (3 mg / kg) in the A375 CDX model as further illustrated in Example 13. FIG. 37A plots body weights, while FIG. 37B plots tumor volumes of all animals.

[0085] FIGs. 38A-38D provide exemplary rat pharmacokinetics results of IL13Ra2 MMAE ADCs as further illustrated in Example 14. FIG. 38A plots total antibody and total ADC concentrations in plasma. FIG. 38B plots total exposure. FIG. 38C plots clearance. FIG. 38D plots terminal half-lives (HL).

[0086] FIGs. 39A-39D provide exemplary rat pharmacokinetics results of IL13Ra2 belotecan ADCs as further illustrated in Example 14. FIG. 39A plots total antibody and total ADC concentrations in plasma. FIG. 39B plots total exposure. FIG. 39C plots clearance. FIG. 39D plots terminal half-lives (HL).

[0087] FIGs. 40A-40F provide exemplary in vivo efficacy results of IL13Ra2 ADCs in the SK-MES-1 CDX model as further illustrated in Example 15. FIGs. 40A, 40C, and 40E plot body weights, while FIGs. 40B, 40D, and 40F plot tumor volumes of all animals. Further, FIGs. 40A-40B provide data obtained with a single dose of 10 mg / kg, while FIGs. 40C-40F compare data with a single dose of 10 mg / kg, 6 mg / kg, 3 mg / kg, or 1 mg / kg (FIGs. 40C-40D: MMAE ADCs; FIGs. 40E-40F belotecan ADCs).

[0088] FIGs. 41A-41B provide exemplary in vivo efficacy results of IL13Ra2 ADCs at a single dose of 10 mg / kg in the H2228 CDX model as further illustrated in Example 16. FIG. 41A plots body weights, while FIG. 41B plots tumor volumes of all animals.

[0089] FIGs. 42A-42B provide exemplary in vivo efficacy results of IL13Ra2 ADCs at a single dose of 10 mg / kg in the Hl 792 CDX model as further illustrated in Example 17. FIG. 42A plots body weights, while FIG. 42B plots tumor volumes of all animals.

[0090] FIGs. 43A-43C provide exemplary in vivo efficacy results of IL13Ra2 ADC 33-8 at a single dose of 10 mg / kg or 5 mg / kg in the PDX models as further illustrated in Example 18. FIG. 43A plots data from an NSCLC PDX model, while FIGs. 43B-43C plot data from two HNSCC PDX models.7. DETAILED DESCRIPTION

[0091] The present disclosure provides antibody-drug conjugates (ADCs) that bind to IL13Ra2 (or an IL13Ra2:IL13 complex) and a drug conjugated (directly or indirectly) thereto. Such IL13Ra2-ADCs are useful in compositions and in methods of treating, preventing, or alleviating an IL13Ra2-mediated disease, disorder, or condition, including one or more symptoms of the disease, disorder, or condition. IL13Ra2-mediated diseases, disorders, and conditions include a variety of cancers, including, but not limited to, any cancer wherein the tumor cells express or overexpress IL13Ra2. In addition, IL13Ra2-ADCs are useful for the killing and / or removal of tumor cells. IL13Ra2-ADCs described herein are useful in compositions and in methods for treating cancer.7.1 Definitions

[0092] The following terms have the following meanings unless otherwise indicated. Any undefined terms have their art-recognized meanings.

[0093] Techniques and procedures described or referenced herein include those that are generally well understood and / or commonly employed using conventional methodology by those skilled in the art, such as, for example, the widely utilized methodologies described in Sambrook et cd.. Molecular Cloning: A Laboratory Manual (3d ed. 2001); Current Protocols in Molecular Biology (Ausubel et al. eds., 2003); Therapeutic Monoclonal Antibodies: From Bench to Clinic (An ed. 2009); Monoclonal Antibodies: Methods and Protocols (Albitar ed. 2010); and Antibody Engineering Vols 1 and 2 (Kontermann and Diibel eds., 2d ed. 2010). Unless otherwise defined herein, technical and scientific terms used in the present description have the meanings that are commonly understood by those of ordinary skill in the art. For purposes of interpreting this specification, the following description of terms will apply and whenever appropriate, terms used in the singular will also include the plural and vice versa. In the event that any description of a term set forth conflicts with any document incorporated herein by reference, the description of the term set forth below shall control.

[0094] The term “IL13Ra2” refers to a polypeptide (“polypeptide” and “protein” are used interchangeably herein) or any native IL13Ra2 from any vertebrate source, including mammals such as primates (e.g., humans, cynomolgus monkey (cyno)), dogs, and rodents (e.g., mice and rats), unless otherwise indicated. An exemplary amino acid sequence of human IL13Ra2 is provided below: MAFVCLAIGCLYTFLISTTFGCTSSSDTEIKVNPPQDFEIVDPGYLGYLYLQWQPPLSL DHFKECTVEYELKYRNIGSETWKTIITKNLHYKDGFDLNKGIEAKIHTLLPWQCTNGSEVQSSWAETTYWISPQGIPETKVQDMDCVYYNWQYLLCSWKPGIGVLLDTNYNLFY WYEGLDHALQCVDYIKADGQNIGCRFPYLEASDYKDFYICVNGSSENKPIRSSYFTFQ LQNIVKPLPPVYLTFTRESSCEIKLKWSIPLGPIPARCFDYEIEIREDDTTLVTATVENET YTLKTTNETRQLCFVVRSKVNIYCSDDGIWSEWSDKQCWEGEDLSKKTLLRFWLPFG FILILVIFVTGLLLRKPNTYPKMIPEFFCDT (SEQ ID NO:83, UniProt: Q14627). In some embodiments, an exemplary amino acid sequence of human IL13Ra2 is amino acid (aa) 27 to aa 380 of SEQ ID NO:83. In some embodiments, the extracellular domain (ECD) of human IL13Ra2 is aa 1 to aa 343 of SEQ ID NO:83. In some embodiments, the ECD of human IL13Ra2 is aa 27 to aa 343 of SEQ ID NO:83.

[0095] An exemplary amino acid sequence of extracellular domain of cynomolgus monkey (cyno) IL13Ra2 (which is identical to a rhesus macaque IL13Ra2) is provided below:MDF VYL AIRCLCTFLISTTFGYTS S SDTEIKVNPPQDFEIVDPGYLGYLYLQWQPPLSL DNFKECTVEYELKYRNIGSETWTTIITKNLHYKDGFDLNKGIEAKIHTLLPWQCTNGS EVQSSWAEATYWISPQGIPETKVQDMDCVYYNWQYLLCSWKPGIGVLLDTNYNLFY WYEGLDRALQCVDYIKVDGQNIGCRFPYLESSDYKDFYICVNGSSETKPIRSSYFTFQ LQNIVKPLPPVCLTCTQESLYEIKLKWSIPLGPIPARCFVYEIEIREDDTTLVTTTVENET YTLKITNETRQLCFVVRSKVNIYCSDDGIWSEWSDKQCWEVEELLKKTLLLFLLPFGF ILILVIFVTGLLLCKRDSYPKMNFSVIDEDFPYQETWY (SEQ ID NO:84, UniProt: F6Z890). In some embodiments, an exemplary amino acid sequence of cyno / rhesus IL13Ra2 is aa 26 to aa 388 of SEQ ID NO:84. In some embodiments, the extracellular domain (ECD) of cyno / rhesus IL13Ra2 is aa 1 to aa 340 of SEQ ID NO:84. In some embodiments, the ECD of cyno / rhesus IL13Ra2 is aa 26 to aa 340 of SEQ ID NO:84.

[0096] An exemplary amino acid sequence of mouse (ms) IL13Ra2 is provided below: MAFVHIRCLCFILLCTITGYSLEIKVNPPQDFEILDPGLLGYLYLQWKPPVVIEKFKGCT LEYELKYRNVDSDSWKTIITRNLIYKDGFDLNKGIEGKIRTHLSEHCTNGSEVQSPWIE ASYGISDEGSLETKIQDMKCIYYNWQYLVCSWKPGKTVYSDTNYTMFFWYEGLDHA LQCADYLQHDEKNVGCKLSNLDSSDYKDFFICVNGSSKLEPIRSSYTVFQLQNIVKPL PPEFLHISVENSIDIRMKWSTPGGPIPPRCYTYEIVIREDDISWESATDKNDMKLKRRA NESEDLCFFVRCKVNIYCADDGIWSEWSEEECWEGYTGPDSKIIFIVPVCLFFIFLLLLL CLIVEKEEPEPTLSLHVDLNKEVCAYEDTLC (SEQ ID NO:85, UniProt: 088786). In some embodiments, an exemplary amino acid sequence of mouse IL13Ra2 is aa 21 to aa 383 of SEQ ID NO:85. In some embodiments, an exemplary amino acid sequence of mouse IL13Ra2 is aa 22 to aa 383 of SEQ ID NO:85. In some embodiments, the ECD of mouse IL13Ra2 is aa 1 to aa 334 of SEQ ID NO:85. In some embodiments, the ECD of mouseIL13Ra2 is aa 21 to aa 334 of SEQ ID NO:85. In some embodiments, the ECD of mouse IL13Ra2 is aa 22 to aa 334 of SEQ ID NO:85. In some embodiments, the ECD of mouse IL13Ra2 is aa 1 to aa 344 of SEQ ID NO:85. In some embodiments, the ECD of mouse IL13Ra2 is aa 21 to aa 344 of SEQ ID NO:85. In some embodiments, the ECD of mouse IL13Ra2 is aa 22 to aa 344 of SEQ ID NO:85.

[0097] An exemplary amino acid sequence of extracellular domain of rat (rt) IL13Ra2 is provided below: MALMAVNTRCLCLFLLCTITGHSLEIKVNPPQDFEILDPGLLGYLYLQWKPPVVMDN FKECKLEYELKYRNVDSDSWKTIITRNLIYKDGFDLNKGIEGKIRTHLSEHCTNGSEV QSPWTEASYGIADEGSLGTKIQDMKCIYYNWQYLVCSWKPGKTVHSDTNYTMFFW YEGLDHALQCADYLQDNEKNVGCKLSNLDSSDYKDFFIRVNGSSKLEPIRSSYMVFQ LQNIVKPLPPEFLHISVENSIDIRMKWSTPGGPIPPSCYTYEIVVREDDISWESATDKND MKLKRRANESEDLCFFVRCKINIYCADDGIWSEWSEEECWEGYTGPDSKIVFIVPVCL FFIFLLLLLCLIVEKEDPEPTLSLHVDLNKEMYAYEETLC (SEQ ID NO:86, UniProt: Q8VHK6). In some embodiments, an exemplary amino acid sequence of rat IL13Ra2 is aa 24 to aa 385 of SEQ ID NO:86. In some embodiments, the ECD of rat IL13Ra2 is aa 1 to aa 336 of SEQ ID NO:86. In some embodiments, the ECD of rat IL13Ra2 is aa 24 to aa 336 of SEQ ID NO:86.

[0098] IL13Ra2 is a single-pass type I transmembrane protein comprising three fibronectin type III (FNIII)-like domains (101, 97, and 94 aa), a single transmembrane (TM) domain (20 aa), and a short cytoplasmic domain (17 aa). There is one natural variant W111R. Four N- linked glycosylation sites are predicted, including: N115, N215, N290, and N299. IL13Ra2 is primarily tumor-restricted with protein expression in normal spermatocytes. It is also upregulated in malignant melanomas, malignant gliomas, pancreatic, ovarian, breast, liver, head and neck, and renal cancers. Its soluble form is detected in human and mouse serum / plasma (ng / mL), but conflicting reports are found on detection in human. Its soluble form is produced in mice by alternative splicing and MMP-8 cleavage, while in humans only by MMP-8 cleavage. IL13Ra2 is a high affinity (fM) Th2 cytokine receptor for IL-13, has been thought to be a decoy receptor, inhibits IL- 13 signaling, regulates serum and tissues levels of IL-13, and can mediate biological effects such as tumor proliferation, cell survival, cell adhesion and metastasis. The classic pathway for IL- 13 activation is JAK / STAT via binding heterodimer of IL13Ral and IL-4Ra (Type II complex), not IL13Ra2. In other words, IL13Ra2 binds IL-13 with extremely high affinity (< 10'15M), although it does not bind IL-4.It can act as a negative regulator of IL-4, but not IL- 13 induced signaling through the Type II IL-4R, but unclear how.

[0099] In some embodiments, the term IL13Ra2 as used herein refers to an IL13Ra2 epitope. In further embodiments, the term IL13Ra2 as used herein refers to an epitope of the ECD of IL13Ra2. In some embodiments, the term IL13Ra2 as used herein refers to a complex comprising IL13Ra2 and IL13. In further embodiments, the term IL13Ra2 as used herein refers to a complex comprising the ECD of IL13Ra2 and IL13. In yet further embodiments, the term IL13Ra2 as used herein refers to an epitope of a complex comprising the ECD of IL13Ra2 and IL13.

[0100] IL13Ral belongs to the same family as IL13Ra2 but shares a low sequence identity (20%). An exemplary amino acid sequence of human IL13Ral is provided below: MEWPARLCGLWALLLCAGGGGGGGGAAPTETQPPVTNLSVSVENLCTVIWTWNPPE GASSNCSLWYFSHFGDKQDKKIAPETRRSIEVPLNERICLQVGSQCSTNESEKPSILVE KCISPPEGDPESAVTELQCIWHNLSYMKCSWLPGRNTSPDTNYTLYYWHRSLEKIHQ CENIFREGQYFGCSFDLTKVKDSSFEQHSVQIMVKDNAGKIKPSFNIVPLTSRVKPDPP HIKNLSFHNDDLYVQWENPQNFISRCLFYEVEVNNSQTETHNVFYVQEAKCENPEFE RNVENTSCFMVPGVLPDTLNTVRIRVKTNKLCYEDDKLWSNWSQEMSIGKKRNSTL YITMLLIVPVIVAGAIIVLLLYLKRLKIIIFPPIPDPGKIFKEMFGDQNDDTLHWKKYDIY EKQTKEETDSVVLIENLKKASQ (SEQ ID NO:87, UniProt: P78552). In some embodiments, an exemplary amino acid sequence of human IL13Ral is aa 22 to aa 427 of SEQ ID NO:87. In some embodiments, an exemplary amino acid sequence of the ECD of human IL13Ral is aa 1 to aa 343 of SEQ ID NO:87. In some embodiments, an exemplary amino acid sequence of the ECD of human IL13Ral is aa 22 to aa 343 of SEQ ID NO:87], In some embodiments, the term IL13Ral as used herein refers to an IL13Ral epitope. In yet further embodiments, the term IL13Ral as used herein refers to the ECD of IL13Ral. In yet further embodiments, the term IL13Ral as used herein refers to an epitope of the ECD of IL13Ral.

[0101] An exemplary amino acid sequence of human IL13 is provided below: MHPLLNPLLLALGLMALLLTTVIALTCLGGFASPGPVPPSTALRELIEELVNITQNQKA PLCNGSMVWSINLT AGMYC AALESLINVSGC S AIEKTQRMLSGFCPHKVS AGQF S SL HVRDTKIEVAQFVKDLLLHLKKLFREGRFN (SEQ ID NO:88, UniProt: P35225). In some embodiments, an exemplary amino acid sequence of human IL13 is aa 25 to aa 146 of SEQ ID NO:88.

[0102] In some embodiments, an exemplary amino acid sequence of human IL 13 is provided below: MALLLTTVIALTCLGGFASPGPVPPSTALRELIEELVNITQNQKAPLCNGSMVWSINLT AGMYCAALESLINVSGCSAIEKTQRMLSGFCPHKVSAGQFSSLHVRDTKIEVAQFVK DLLLHLKKLFREGRFN (SEQ ID NO:89, GenBank: AAK53823.1).

[0103] An exemplary amino acid sequence of cyno IL 13 is provided below: MALLLTMVIALTCLGGFASPSPVPPSTALKELIEELVNITQNQKAPLCNGSMVWSINLT AGVYCAALESLINVSGCSAIEKTQRMLNGFCPHKVSAGQFSSLRVRDTKIEVAQFVK DLLVHLKKLFREGQFN (SEQ ID NO:90, GenBank: BG75889.1).

[0104] As used herein, the term “binding agent” or a grammatical equivalent thereof refers to a molecule (e.g., antibody) with one or more antigen-binding sites that binds an antigen. In some embodiments, an IL13Ra2 binding agent as described herein is an antibody (including an antibody fragment, such as an antigen-binding fragment or an epitope-binding fragment) or other peptide-based molecule as well as a conjugate of an antibody, antibody fragment, or peptide-based molecule (e.g., an antibody-drug conjugate) that binds to IL13Ra2, such as human IL13Ra2.

[0105] The terms “antibody,” “immunoglobulin,” and “Ig” are used interchangeably herein, and are used in the broadest sense and specifically cover, for example polyclonal antibodies, monoclonal antibodies (including agonist, antagonist, neutralizing antibodies, full- length monoclonal antibodies), antibody compositions with polyepitopic or monoepitopic specificity, recombinantly produced antibodies, single domain (e.g., VHH) antibodies, monospecific antibodies, multispecific antibodies (including bispecific antibodies), synthetic antibodies, chimeric antibodies, humanized antibodies, or human versions of antibodies having full-length heavy and / or light chains. “VHH,” as used herein, refers to a domain antibody derived from a variable region of a heavy chain only antibody. Exemplary single domain antibodies include, but are not limited to, antibodies naturally devoid of light chains such as those from Camelidae species (e.g., llama), single domain antibodies derived from conventional 4-chain antibodies, engineered antibodies, and single domain scaffolds other than those derived from antibodies. Single domain antibodies may be derived from any species including, but not limited to mouse, human, camel, llama, goat, rabbit, and bovine. VHH can also be derived from other species besides Camelidae that may produce heavy chain antibodies naturally devoid of light chain. Antibodies also include antibody fragments (and / or polypeptides that comprise antibody fragments) that retain IL13Ra2 binding characteristics. Non-limiting examples of antibody fragments include antigen-binding regions and / or effectorregions of the antibody, e.g., Fab, Fab’, F(ab’)2, Fv, scFv, (scFv)2, single chain antibody molecule, dual variable domain antibody, single variable domain, linear antibody, V region, a multispecific antibody formed from antibody fragments, F(ab)2, Fd, Fc, diabody, di-diabody, disulfide-linked Fvs (dsFv), single-domain antibody (e.g., nanobody) or other fragments e.g., fragments consisting of the variable regions of the heavy and light chains that are non- covalently coupled). In general terms, a variable (V) region domain may be any suitable arrangement of immunoglobulin heavy (VH) and / or light (VL) variable domains. For example, antibodies also include tetrameric antibodies comprising two heavy chain and two light chain molecules, an antibody light chain monomer, and an antibody heavy chain monomer. Thus, for example, the V region domain may be dimeric and contain VHH-VHH, VH-VH, VH-VL, or VL-VL dimers that bind IL13Ra2. If desired, the VH and VL may be covalently coupled either directly or through a linker to form a single chain Fv (scFv). For ease of reference, scFv proteins are referred to herein as included in the category “antibody fragments.” Another form of an antibody fragment is a peptide comprising one or more complementarity determining regions (CDRs) of an antibody. CDRs (also termed “minimal recognition units” or “hypervariable regions”) can be obtained by constructing polynucleotides that encode one or more CDRs of interest. Such polynucleotides are prepared, for example, by using the polymerase chain reaction to synthesize the variable region using mRNA of antibody-producing cells as a template (see, for example, Larrick et al., Methods: A Companion to Methods in Enzymology, 2:106 (1991); Courtenay-Luck, “Genetic Manipulation of Monoclonal Antibodies,” in Monoclonal Antibodies Production, Engineering and Clinical Application, Ritter et al. (eds.), page 166, Cambridge University Press (1995); and Ward et al., “Genetic Manipulation and Expression of Antibodies,” in Monoclonal Antibodies: Principles and Applications, Birch et al., (eds.), page 137, Wiley-Liss, Inc.(1995)). Antibody fragments may be incorporated, for example, into single domain antibodies, maxibodies, minibodies, intrabodies, diabodies, triabodies, tetrabodies, variable domains of new antigen receptors (v-NAR), and bis-single chain Fv regions (see, e.g., Hollinger and Hudson, Nature Biotechnology, 23(9): 1126-1136, 2005). In some embodiments, antibodies comprising a VH and / or VL further contain a light chain and / or a heavy chain constant region, such as one or more constant regions, including one or more IgGl, IgG2, IgG3 and / or IgG4 constant regions. In some embodiments, antibodies can include epitope-binding fragments of any of the above. The antibodies described herein can be of any class (e.g., IgG, IgE, IgM, IgD, and IgA) or any subclass (e.g., IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2) of immunoglobulin molecule.

[0106] The term “humanized antibody” or “humanized immunoglobulin” refers to a nonhuman (e.g., mouse or rabbit) antibody containing one or more amino acids (in a framework region, a constant region or a CDR, for example) that have been substituted with a correspondingly positioned amino acid from a human antibody. In general, humanized antibodies produce a reduced immune response in a human host, as compared to a nonhumanized version of the same antibody. Antibodies can be humanized using a variety of techniques known in the art including, for example, CDR-grafting (EP 239,400; PCT publication WO 91 / 09967; U.S. Pat. Nos. 5,225,539; 5,530,101; and 5,585,089), veneering or resurfacing (EP 592,106; EP 519,596; Padlan, Molecular Immunology 28(4 / 5):489-498 (1991); Studnicka et al., Protein Engineering 7(6):805-814 (1994); Roguska. et al., PNAS 91 :969-973 (1994)), and chain shuffling (U.S. Pat. No. 5,565,332). In certain embodiments, framework substitutions are identified by modeling of the interactions of the CDR and framework residues to identify framework residues important for antigen binding and sequence comparison to identify unusual framework residues at particular positions (see, e.g., U.S. Pat. No. 5,585,089; Riechmann et al., Nature 332:323 (1988)). Additional methods for humanizing antibodies contemplated for use in the present invention are described in U.S. Pat. Nos. 5,750,078; 5,502,167; 5,705,154; 5,770,403; 5,698,417; 5,693,493; 5,558,864;4,935,496; and 4,816,567, and PCT publications WO 98 / 45331 and WO 98 / 45332. In particular embodiments, a subject rabbit antibody may be humanized according to the methods set forth in US20040086979 and US20050033031. Accordingly, the antibodies described above may be humanized using methods that are well known in the art.

[0107] The term “chimeric antibodies” refer to antibodies whose light and heavy chain genes have been constructed, typically by genetic engineering, from antibody variable and constant region genes belonging to different species. For example, the variable segments of the genes from a mouse monoclonal antibody may be joined to human constant segments, such as gamma 1 and gamma 3. An example of a therapeutic chimeric antibody is a hybrid protein composed of the variable or antigen-binding domain from a mouse antibody and the constant or effector domain from a human antibody, although domains from other mammalian species may be used.

[0108] The term “monospecific” when used in reference to a binding agent (e.g., an antibody) as used herein denotes a binding agent that has one or more binding sites each of which binds to the same epitope of the same antigen.

[0109] The term “multispecific” when used in reference to a binding agent (e.g., an antibody) means that the binding agent is able to specifically bind to at least two distinctepitopes, for example two binding sites each formed by a pair of an antibody heavy chain variable domain (VH) and an antibody light chain variable domain (VL) or each formed by a pair of VHH domains binding to different antigens or to different epitopes on the same antigen. Such a bispecific binding agent (e.g., an antibody) may have a 1+1 format (comprising one binding site for a first antigen or epitope and one binding site for a second antigen or epitope). Other bispecific binding agent (e.g., an antibody) formats may be 2+1 or 1+2 formats (comprising two binding sites for a first antigen or epitope and one binding site for a second antigen or epitope) or 2+2 format (comprising two binding sites for a first antigen or epitope and two binding sites for a second antigen or epitope). When a bispecific binding agent (e.g., an antibody) comprises two antigen-binding sites, each may bind to a different epitope. Such a bispecific binding agent (e.g., an antibody) may bind to two different epitopes on the same antigen (e.g., epitopes on IL13Ra2).

[0110] The terms “identical” or percent “identity” in the context of two or more nucleic acids or polypeptides, refer to two or more sequences or subsequences that are the same or have a specified percentage of nucleotides or amino acid residues that are the same, when compared and aligned (introducing gaps, if necessary) for maximum correspondence, not considering any conservative amino acid substitutions as part of the sequence identity. The percent identity can be measured using sequence comparison software or algorithms or by visual inspection. Various algorithms and software that can be used to obtain alignments of amino acid or nucleotide sequences are well-known in the art. These include, but are not limited to, BLAST, ALIGN, Megalign, BestFit, GCG Wisconsin Package, and variants thereof. In some embodiments, two nucleic acids or polypeptides are substantially identical, meaning they have at least 70%, at least 75%, at least 80%, at least 85%, or at least 90%, and in some embodiments at least 95%, 96%, 97%, 98%, or 99% nucleotide or amino acid residue identity, when compared and aligned for maximum correspondence, as measured using a sequence comparison algorithm or by visual inspection. In some embodiments, identity exists over a region of the amino acid sequences that is at least about 10 residues, at least about 20 residues, at least about 40-60 residues, at least about 60-80 residues in length or any integral value there between. In some embodiments, identity exists over a longer region than 60-80 residues, such as at least about 80-100 residues, and in some embodiments the sequences are substantially identical over the full length of the sequences being compared, such as the coding region of a target protein or an antibody. In some embodiments, identity exists over a region of the nucleotide sequences that is at least about 10 bases, at least about 20 bases, at least about 40-60 bases, at least about 60-80 bases in length or any integral value therebetween. In some embodiments, identity exists over a longer region than 60-80 bases, such as at least about 80-1000 bases or more, and in some embodiments the sequences are substantially identical over the full-length of the sequences being compared, such as a nucleotide sequence encoding a protein of interest.

[0111] A “conservative amino acid substitution” is one in which one amino acid residue is replaced with another amino acid residue having a side chain with similar chemical characteristics. Families of amino acid residues having similar side chains have been generally defined in the art, including basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), betabranched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). For example, substitution of a phenylalanine for a tyrosine is a conservative substitution. Generally, conservative substitutions in the sequences of the polypeptides, soluble proteins, and / or antibodies of the disclosure do not abrogate the binding of the polypeptide, soluble protein, or antibody containing the amino acid sequence, to the target binding site. Methods of identifying amino acid conservative substitutions which do not eliminate binding are well-known in the art.

[0112] The term “polypeptide” refers to polymers of amino acids of any length. The polymer can be linear or branched, it can comprise modified amino acids, and it can include (e.g., be interrupted by) non-amino acids. The terms also encompass an amino acid polymer that has been modified naturally or by intervention; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification, such as linkage to or conjugation with (directly or indirectly) a moiety such as a labeling component or a drug (e.g., toxin). Also included within the definition are, for example, polypeptides containing one or more analogs of an amino acid (including, for example, unnatural amino acids), as well as other modifications known in the art. It is understood that, because the polypeptides of this disclosure can be based upon antibodies or other members of the immunoglobulin superfamily, in some embodiments, the polypeptides can occur as single chains or dimers of single chains.

[0113] As used herein, an “antigen” is a moiety or molecule that contains an epitope to which a binding agent (e.g., an antibody) can bind. As such, an antigen can be bound by an antibody. In some embodiments, the antigen, to which a binding agent (e.g., an antibody)described herein binds, is IL13Ra2 (e.g., human IL13Ra2), or a fragment thereof, including a fragment that comprises one or more domains of IL13Ra2.

[0114] As used herein, an “epitope” is a term in the art and refers to a localized region of an antigen to which an antibody can bind. An epitope can be a linear epitope or a conformational, non-linear, or discontinuous, epitope. In the case of a polypeptide antigen, for example, an epitope can be contiguous amino acids of the polypeptide (a “linear” epitope), or an epitope can comprise amino acids from two or more non-contiguous regions of the polypeptide (a “conformational,” “non-linear” or “discontinuous” epitope), e.g., human IL13Ra2. It will be appreciated by one of skill in the art that, in general, a linear epitope may or may not be dependent on secondary, tertiary, or quaternary structure. For example, in some embodiments, an antibody binds to a group of amino acids regardless of whether they are folded in a natural three-dimensional protein structure. In other embodiments, an antibody requires amino acid residues making up the epitope to exhibit a particular conformation (e.g., bend, twist, turn or fold) in order to recognize and bind the epitope.

[0115] An antibody binds “an epitope” or “essentially the same epitope” or “the same epitope” as a reference antibody, when the two antibodies recognize identical, overlapping, or adjacent epitopes in a three-dimensional space. The most widely used and rapid methods for determining whether two antibodies bind to identical, overlapping, or adjacent epitopes in a three-dimensional space are competition assays, which can be configured in a number of different formats, for example, using either labeled antigen or labeled antibody. In some assays, the antigen is immobilized on a 96-well plate, or expressed on a cell surface, and the ability of unlabeled antibodies to block the binding of labeled antibodies is measured using radioactive, fluorescent or enzyme labels.

[0116] “Epitope binning” is the process of grouping antibodies based on the epitopes they recognize. More particularly, epitope binning comprises methods and systems for discriminating the epitope recognition properties of different antibodies, using competition assays combined with computational processes for clustering antibodies based on their epitope recognition properties and identifying antibodies having distinct binding specificities.

[0117] As used herein, the terms “specifically binds,” “specifically recognizes,” “immunospecifically binds,” “selectively binds,” “immunospecifically recognizes” and “immunospecific” are analogous terms in the context of antibodies and refer to molecules that bind to an antigen (e.g., epitope) as such binding is understood by one skilled in the art. In some embodiments, “specifically binds” means, for instance that a polypeptide or molecule interacts more frequently, more rapidly, with greater duration, with greater affinity, or withsome combination of the above to the epitope, protein, or target molecule than with alternative substances, including related and unrelated proteins. For example, a molecule that specifically binds to an antigen may bind to other peptides or polypeptides, generally with lower affinity as determined by, e.g., immunoassays, BIACORE™, KinExA 3000 instrument (Sapidyne Instruments, Boise, ID), the OctetQK384 system (ForteBio, Menlo Park, CA), or other assays known in the art. In some embodiments, an antibody or antigen-binding domain binds to or specifically binds to an antigen when it binds to the antigen with higher affinity than to any cross-reactive antigen as determined using experimental techniques, such as radioimmunoassays (RIAs) and enzyme linked immunosorbent assays (ELISAs). Typically, a specific or selective reaction will be at least twice background signal or noise and may be more than 10 times background. See, e.g., Fundamental Immunology 332-36 (Paul ed., 2d ed. 1989) for a discussion regarding binding specificity. In some embodiments, the extent of binding of an antibody or antigen-binding domain to a “non-targef ’ protein is less than about 10% of the binding of the antibody or antigen-binding domain to its particular target antigen, for example, as determined by fluorescence activated cell sorting (FACS) analysis or RIAs. In some embodiments, molecules that specifically bind to an antigen bind to the antigen with a Ka that is at least 2 logs, 2.5 logs, 3 logs, 4 logs or greater than the Ka when the molecules bind to another antigen. In some embodiments, molecules that specifically bind to an antigen do not cross react with other proteins. In another specific embodiment, molecules that specifically bind to an antigen do not cross react with other non-IL13Ra2 proteins. In some embodiments “specifically binds” means, for instance, that a polypeptide or molecule binds a protein or target with a Ka of about 0.1 mM or less, but more usually less than about 1 pM. In some embodiments, “specifically binds” means that a polypeptide or molecule binds a target with a Ka of at least about 0.1 pM or less, at least about 0.01 pM or less, or at least about 1 nM or less. Because of the sequence identity between homologous proteins in different species, specific binding can include a polypeptide or molecule that recognizes a protein or target in more than one species. Likewise, because of homology within certain regions of polypeptide sequences of different proteins, specific binding can include a polypeptide or molecule that recognizes more than one protein or target. It is understood that, in some embodiments, a polypeptide or molecule that specifically binds a first target may or may not specifically bind a second target. As such, “specific binding” does not necessarily require (although it can include) exclusive binding, e.g., binding to a single target. Thus, a polypeptide or molecule can, in some embodiments, specifically bind more than one target. In some embodiments, multiple targets can be bound by the same antigen-binding site on thepolypeptide or molecule. For example, an antibody can, in certain instances, comprise two identical antigen-binding sites, each of which specifically binds the same epitope on two or more proteins. In certain alternative embodiments, an antibody can be bispecific and comprise at least two antigen-binding sites with differing specificities. Generally, but not necessarily, reference to “binding” means “specific binding.”

[0118] “Binding affinity” generally refers to the strength of the sum total of noncovalent interactions between a single binding site of a molecule (e.g., a binding agent such as an antibody) and its binding partner (e.g., an antigen such as IL13Ra2). Unless indicated otherwise, as used herein, “binding affinity” refers to intrinsic binding affinity which reflects a 1 : 1 interaction between members of a binding pair (c.g, antibody and antigen). The affinity of a binding molecule X for its binding partner Y can generally be represented by the dissociation constant (Kd). Affinity can be measured by common methods known in the art, including those described herein. Low-affinity antibodies generally bind antigen slowly and tend to dissociate readily, whereas high-affinity antibodies generally bind antigen faster and tend to remain bound longer. A variety of methods of measuring binding affinity are known in the art, any of which can be used for purposes of the present disclosure. In one embodiment, the “Kd” or “Kd value” may be measured by biolayer interferometry (BLI) using, for example, the OctetQK384 system (ForteBio, Menlo Park, CA). Alternatively, the Kd may also be measured in a radiolabeled antigen-binding assay (RIA), for example, performed with the Fab version of an antibody of interest and its antigen (Chen, et al.. (1999) J. Mol Biol 293:865- 881) or using surface plasmon resonance (SPR) assays by BIACORE™, using, for example, a BIACORE™-2000 or a BIACORE™-3000 (BIACORE™, Inc., Piscataway, NJ). An “on- rate” or “rate of association” or “association rate” or “kon,” as well as an “off-rate” or “rate of dissociation” or “dissociation rate” or “koir,” can also be determined with the same SPR or BLI techniques described above using, for example, the OctetQK384 system (ForteBio, Menlo Park, CA) or a BIACORE™-2000 or a BIACORE™-3000 (BIACORE™, Inc., Piscataway, NJ), respectively.

[0119] The term “compete” or any grammatical variation thereof when used in the context of IL13Ra2 binding agents (e.g., antibodies) means binding agents that compete for the same epitope or binding site on a target, which includes competition between such binding agents as determined by an assay in which the binding agent under study prevents or inhibits the specific binding of a reference molecule (e.g., a reference ligand, or reference antigen-binding protein, such as a reference antibody) to a common antigen (e.g., IL13Ra2). Numerous types of competitive binding assays can be used to determine if a test binding agent competes with areference molecule for binding to IL13Ra2 (e.g., human IL13Ra2). Examples of assays that can be employed include solid phase direct or indirect radioimmunoassay (RIA); solid phase direct or indirect enzyme immunoassay (EIA), sandwich competition assay (see, e.g., Stahli et al., (1983) Methods in Enzymology 9:242-253); solid phase direct biotin-avidin EIA (see, e.g., Kirkland et al., (1986) J. Immunol. 137:3614-3619 or Cheung, et al, (1990) Virology 176:546-552); solid phase direct labeled assay; solid phase direct labeled sandwich assay (see, e.g., Harlow and Lane, (1988) Antibodies, A Laboratory Manual, Cold Spring Harbor Press); solid phase direct label RIA using 1-125 label (see, e.g., Morel et al., (1988) Molec. Immunol. 25:7-15); and direct labeled RIA (Moldenhauer et al., (1990) Scand. J. Immunol. 32:77-82). Typically, such an assay involves the use of a purified antigen (e.g., IL13Ra2, such as human IL13Ra2) bound to a solid surface or cells bearing either of an unlabeled test antigen-binding protein (e.g., test IL13Ra2 antibody) or a labeled reference antigen-binding protein (e.g., reference IL13Ra2 antibody). Competitive inhibition may be measured by determining the amount of label bound to the solid surface or cells in the presence of the test antigen-binding protein. Usually, the test antigen-binding protein is present in excess. Antibodies identified by competition assay (competing antibodies) include antibodies binding to the same epitope as the reference antibody and / or antibodies binding to an adjacent epitope sufficiently proximal to the epitope bound by the reference for antibodies steric hindrance to occur (e.g., similar epitope or overlapping epitope). Usually, when a competing antibody is present in excess, it will inhibit specific binding of a reference antibody to a common antigen by at least 20%, for example, at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70% or 75%. In some instance, binding is inhibited by at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more.

[0120] As used herein, the term “constant region” or “constant domain” is a well-known antibody term of art and refers to an antibody portion, for example, a carboxyl terminal portion of a light and / or heavy chain which is not directly involved in binding of an antibody to an antigen, but which can exhibit various effector functions, such as interaction with an Fc receptor. The term includes the portion of an immunoglobulin molecule having a generally more conserved amino acid sequence relative to an immunoglobulin variable domain.

[0121] Antibody “effector functions” refer to those biological activities attributable to the Fc region (e.g., a native sequence Fc region or amino acid sequence variant Fc region) of an antibody and vary with the antibody isotype. Examples of antibody effector functions include: Clq binding and complement dependent cytotoxicity; Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; down regulation of cell surface receptors (e.g., B cell receptor); and B cell activation.

[0122] The term “Fc region” herein is used to define a C-terminal region of an immunoglobulin heavy chain, including, for example, native sequence Fc regions, recombinant Fc regions, and variant Fc regions. Although the boundaries of the Fc region of an immunoglobulin heavy chain might vary, the human IgG heavy chain Fc region is often defined to stretch from an amino acid residue at position Cys226 (according to the EU numbering system), or from Pro230 (according to the EU numbering system) to the carboxylterminus thereof. The C-terminal lysine (residue 447 according to the EU numbering system) of the Fc region may be removed, for example, during production or purification of the antibody, or by recombinantly engineering the nucleic acid encoding a heavy chain of the antibody. An exemplary Fc region sequence is provided below (CH2 domain = bold text with amino acid changes underlined; CH3 domain = underline text):CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGOPREPQVYTLPPSREEMTKNOVSLTCLVKGFYPSDIAVEWESNGOPENN YKTTPPVLDSDGSFFLYSKLTVDKSRWOOGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:97).

[0123] A “functional Fc region” possesses an “effector function” of a native sequence Fc region. Exemplary “effector functions” include Clq binding; complement dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis (such as antibody-dependent cellular phagocytosis, e.g., ADCP); down regulation of cell surface receptors (e.g., B cell receptor; BCR), etc. Such effector functions generally require the Fc region to be combined with a binding region or binding domain (e.g., an antibody variable region or domain) and can be assessed using various assays as disclosed.

[0124] A “native sequence Fc region” comprises an amino acid sequence identical to the amino acid sequence of an Fc region found in nature, and not manipulated, modified, and / or changed (e.g., isolated, purified, selected, including or combining with other sequences such as variable region sequences) by a human. Native sequence human Fc regions include a native sequence human IgGl Fc region (non-A and A allotypes); native sequence human IgG2 Fc region; native sequence human IgG3 Fc region; and native sequence human IgG4 Fc region as well as naturally occurring variants thereof.

[0125] A “variant Fc region” comprises an amino acid sequence which differs from that of a native sequence Fc region by virtue of at least one amino acid modification (e.g.,substituting, addition, or deletion), for example, one or more amino acid substitution(s). In some embodiments, the variant Fc region has at least one amino acid substitution compared to a native sequence Fc region or to the Fc region of a parent polypeptide, for example, from about one to about ten amino acid substitutions, or from about one to about five amino acid substitutions in a native sequence Fc region or in the Fc region of the parent polypeptide. The variant Fc region described herein can possess at least about 80% homology with a native sequence Fc region and / or with an Fc region of a parent polypeptide, or at least about 90% homology therewith, for example, at least about 95% homology therewith. The variant Fc region herein described herein may have a loss of an effector function (e.g., silent F c(also referred to herein as “sFc”)).

[0126] In some embodiments, a sFc comprises an alanine (Ala, A) residue at position Leu234 (L234) according to the EU numbering system, an alanine (Ala, A) residue at position Leu235 (L235) according to the EU numbering system, and a lysine (Lys, K) residue at position Pro329 (P329) according to the EU numbering system (also referred to herein as “LALAPK” or “L234A / L235A / P329K”).

[0127] An exemplary variant Fc region (“silent Fc”) sequence is provided below (CH2 domain = bold text with amino acid changes underlined; CH3 domain = underline text): CPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALKAPIE KTISKAKGOPREPQVYTLPPSREEMTKNOVSLTCLVKGFYPSDIAVEWESNGOPENN YKTTPPVLDSDGSFFLYSKLTVDKSRWOOGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:98).

[0128] Additionally or alternatively, a variant Fc region has a reduced potential immunogenicity. In further embodiments, a variant Fc region comprises a glutamic acid (Glu, E) residue at position Asp356 (D356) according to the EU numbering system, a glutamic acid (Glu, E) residue at position Glu357 (E357) according to the EU numbering system, and a methionine (Met, M) residue position Leu358 (L358) according to the EU numbering system (also referred to herein as “EEM” or “D356E / E357E / L358M”).

[0129] Additionally or alternatively, a variant Fc region has a reduced potential immunogenicity. In further embodiments, a variant Fc region comprises a glutamic acid (Glu, E) residue at position Asp356 (D356) of the EU numbering system, a glutamic acid (Glu, E) residue at position Glu357 (E357) of the EU numbering system, and a methionine (Met, M) residue position Leu358 (L358) of the EU numbering system (also referred to herein as “EEM” or “D356E / E357E / L358M”).

[0130] As used herein, the term “heavy chain” when used in reference to an antibody refers to a polypeptide chain of about 50-70 kDa, wherein the amino-terminal portion includes a variable region of about 120 to 130 or more amino acids, and a carboxy -terminal portion includes one or more constant regions. The “heavy chain” can refer to any distinct types, e.g., for example, alpha (a), delta (5), epsilon (a), gamma (y) and mu (p), based on the amino acid sequence of the constant domain, which give rise to IgA, IgD, IgE, IgG and IgM classes of antibodies, respectively, including subclasses of IgG, e.g., IgGl, IgG2, IgG3 and IgG4.

[0131] As used herein, the term “light chain” when used in reference to an antibody can refer to a polypeptide chain of about 25 kDa, wherein the amino-terminal portion includes a variable region of about 100 to about 110 or more amino acids, and a carboxy -terminal portion includes a constant region. The approximate length of a light chain is 211 to 217 amino acids. There are two distinct types, e.g., kappa (K) or lambda (X) based on the amino acid sequence of the constant domains. Light chain amino acid sequences are well known in the art.

[0132] The terms “antigen-binding fragment,” “antigen-binding domain,” “antigen-binding region,” and similar terms refer to that portion of an antibody, which comprises the amino acid residues that interact with an antigen and confer on the binding fragment, domain, or region its specificity and affinity for the antigen (e.g., the CDRs). “Antigen-binding fragment” as used herein includes “antibody fragment,” which comprises a portion of an antibody including one or more CDRs, such as the antigen-binding or variable region of the antibody.

[0133] Antibodies described herein include, but are not limited to, synthetic antibodies, monoclonal antibodies, recombinantly produced antibodies, multispecific antibodies (e.g., bispecific antibodies), human antibodies, humanized antibodies, chimeric antibodies, intrabodies, single-chain Fvs (scFv) (e.g., including monospecific, bispecific, etc.), camelized antibodies, Fab fragments, F(ab’) fragments, disulfide-linked Fvs (sdFv), anti -idiotypic (anti- id) antibodies, and epitope-binding fragments of any of the above.

[0134] In some embodiments, antibodies described herein include immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, including molecules that contain one or more antigen-binding sites that bind to an IL13Ra2 antigen.

[0135] Antibodies can be of any type (e.g., IgG, IgE, IgM, IgD, IgA or IgY), any class (e.g., IgGl, IgG2, IgG3, IgG4, IgAl or IgA2), or any subclass (e.g., IgG2a or IgG2b) of immunoglobulin molecule. In some embodiments, antibodies described herein are IgG antibodies (e.g., human IgG), or a class (e.g., human IgGl, IgG2, IgG3 or IgG4) or a subclass thereof.

[0136] In some embodiments, an antibody is a 4-chain antibody unit comprising two heavy (H) chain / light (L) chain pairs. In further embodiments, the amino acid sequences of the H chains are identical and the amino acid sequences of the L chains are identical. In other embodiments, the amino acid sequences of the H chains are different from each other.Additionally or alternatively, the amino acid sequences of the L chains are different from each other. For example, an antibody comprises a first H / L chain pair and a second H / L chain pair, wherein the first H / L chain pair binds to an IL13Ra2 antigen and the second H / L chain pair binds to another IL13Ra2 antigen or a non-IL13Ra2 antigen. In some embodiments, an antibody is a 2-chain antibody unit comprising a VHH-VHH pair. In further embodiments, the amino acid sequences of the VHH are identical. In other embodiments, the amino acid sequence of the VHH is different from each other. For example, an antibody comprises a first VHH and a second VHH, wherein the first VHH binds to an IL13Ra2 antigen and the second VHH binds to another IL13Ra2 antigen or a non-IL13Ra2 antigen. In some embodiments, the H and / or L chains comprise constant regions, for example, human constant regions. In some embodiments, the L chain constant region of such antibodies is a kappa or lambda light chain constant region, for example, a human kappa or lambda light chain constant region. In some embodiments, the H chain constant region of such antibodies comprises a gamma heavy chain constant region, for example, a human gamma heavy chain constant region. In some embodiments, such antibodies comprise IgG constant regions, for example, human IgG constant regions (e.g., IgGl, IgG2, IgG3, and / or IgG4 constant regions).

[0137] An antibody or fragment thereof may preferentially bind to IL13Ra2 (or an IL13Ra2:IL13 complex), such as human IL13Ra2, meaning that the antibody or fragment thereof binds IL13Ra2 with greater affinity than it binds to a control protein (e.g., unrelated control proteins such as hen egg white lysozyme) and / or binds human IL13Ra2 with greater affinity than it binds to an unrelated control protein. For example, the antibody or fragment thereof may specifically recognize and bind IL13Ra2 or a portion thereof. “Specific binding” means that the antibody or fragment thereof binds to IL13Ra2 with an affinity that is at least 5, 10, 15, 20, 25, 50, 100, 250, 500, 1000, or 10,000 times greater than the affinity for an unrelated control protein (e.g., hen egg white lysozyme). In some embodiments, the antibody or fragment thereof may bind IL13Ra2 substantially exclusively (e.g., is able to distinguish IL13Ra2 from other known polypeptides, for example, by virtue of measurable differences in binding affinity). In some embodiments, an IL13Ra2 binding agent (e.g., an antibody) may react with IL13Ra2 sequences other than human IL13Ra2 sequences (e.g., cynomolgusmonkey IL13Ra2 sequences). In other embodiments, an IL13Ra2 binding agent (e.g., an antibody) does not react with non-human (such as cynomolgus monkey).

[0138] The term “variable region” or “variable domain” refers to a portion of the light or heavy chains of an antibody that is generally located at the amino-terminal of the light or heavy chain, has a length of about 120 to 130 amino acids in the heavy chain and about 100 to 110 amino acids in the light chain, and is used in the binding and specificity of each particular antibody for its particular antigen. The variable region of the heavy chain may be referred to as “VH .” The variable region of the light chain may be referred to as “VL.” The term “variable” refers to the fact that certain segments of the variable regions differ extensively in sequence among antibodies. The V region mediates antigen binding and defines specificity of a particular antibody for its particular antigen. However, the variability is not evenly distributed across the 110-amino acid span of the variable regions. Instead, the V regions consist of less variable (e.g., relatively invariant) stretches called framework regions (FRs) of about 15-30 amino acids separated by shorter regions of greater variability (e.g., extreme variability) called “hypervariable regions” or alternatively called “complementarity determining regions (CDRs) ” The variable regions of heavy and light chains each comprise four frameworks (FR1, FR2, FR3 and FR4), largely adopting a P sheet configuration, connected by three hypervariable regions, which form loops connecting, and in some cases forming part of, the P sheet structure. The hypervariable regions in each chain are held together in close proximity by the frameworks and, with the hypervariable regions from the other chain, contribute to the formation of the antigen-binding site of antibodies (see, e.g., Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, (1991)). The constant regions are not involved directly in binding an antibody to an antigen, but exhibit various effector functions, such as participation of the antibody in antibody dependent cellular cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC). The variable regions differ extensively in sequence between different antibodies. The variability in sequence is concentrated in the CDRs while the less variable portions in the variable region are referred to as framework regions (FR). The CDRs of the light and heavy chains are primarily responsible for the interaction of the antibody with its antigen. In specific embodiments, the variable region is a human variable region.

[0139] The term “hypervariable region,” “HVR,” “HV,” “complementarity determining region,” or “CDR” when used herein refers to the regions of an antibody variable region that are hypervariable in sequence and / or form structurally defined loops. Generally, antibodiescomprise six hypervariable regions: three in the VH (Hl or VH CDR1, H2 or VH CDR2, and H3 or VH CDR3), and three in the VL (LI or VL CDR1, L2 or VL CDR2, and L3 or VL CDR3). A number of hypervariable region delineations are in use and are encompassed herein. The Kabat CDRs are based on sequence variability and are the most commonly used (see, e.g., Kabat etal., Sequences of Proteins of Immunological Intercst, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991)). Chothia refers instead to the location of the structural loops (see, e.g., Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)). The end of the Chothia CDR-H1 loop when numbered using the Kabat numbering convention varies between H32 and H34 depending on the length of the loop (this is because the Kabat numbering scheme places the insertions at H35A and H35B; if neither 35 A nor 35B is present, the loop ends at 32; if only 35A is present, the loop ends at 33; if both 35A and 35B are present, the loop ends at 34). The AbM hypervariable regions represent a compromise between the Kabat CDRs and Chothia structural loops and are used by Oxford Molecular’s AbM antibody modeling software (see, e.g., Martin, in Antibody Engineering, Vol. 2, Chapter 3, Springer Verlag). The “contact” hypervariable regions are based on an analysis of the available complex crystal structures. The residues from each of these hypervariable regions or CDRs are noted below.

[0140] A universal numbering system has been developed and widely adopted, ImMunoGeneTics (IMGT®) Information System (Lefranc et al., Dev. Comp. Immunol. 27(l):55-77 (2003)). IMGT is an integrated information system specializing in immunoglobulins (IG), T cell receptors (TR) and major histocompatibility complex (MHC) of human and other vertebrates. Herein, the CDRs are referred to in terms of both the amino acid sequence and the location within the light or heavy chain. As the “location” of the CDRs within the structure of the immunoglobulin variable domain is conserved between species and present in structures called loops, by using numbering systems that align variable domain sequences according to structural features, CDR and framework residues and are readily identified. This information can be used in grafting and replacement of CDR residues from immunoglobulins of one species into an acceptor framework from, typically, a human antibody. An additional numbering system (AHon) has been developed by Honegger and Pliickthun, J. Mol. Biol. 309: 657-670 (2001). Correspondence between the numbering system, including, for example, the Kabat numbering and the IMGT unique numbering system, is well known to one skilled in the art (see, e.g., Kabat, supra, Chothia and Lesk, supra, Martin, supra, Lefranc et al., supra) and is also illustrated below. Various systems known in the art or described herein represent different ways of delineating CDRs, and whenthey are used to define the same antibody, they are often considered equivalent. An Exemplary system, shown herein, combines Kabat and Chothia. The residues from each of these hypervariable regions or CDRs are exemplified in the table below.Exemplary CDRs According to Various Numbering Systems

[0141] Hypervariable regions may comprise “extended hypervariable regions” as follows: 24-36 or 24-34 (LI), 46-56 or 50-56 (L2) and 89-97 or 89-96 (L3) in the VL and 26-35 or 26- 35A (Hl), 50-65 or 49-65 (H2) and 93-102, 94-102, or 95-102 (H3) in the VH. As used herein, the terms “hypervariable region,” “HVR,” “HV,” “complementarity determining region,” or “CDR” are used interchangeably.

[0142] As used herein the term “isolated” is meant to describe a compound of interest that is in an environment different from that in which the compound naturally occurs. “Isolated” is meant to include compounds that are within samples that are substantially enriched for the compound of interest and / or in which the compound of interest is partially or substantially purified.

[0143] “Polynucleotide” or “nucleic acid,” as used interchangeably herein, refers to polymers of nucleotides of any length and includes DNA and RNA. The nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides, or bases, and / or their analogs, or any substrate that can be incorporated into a polymer by DNA or RNA polymerase or by a synthetic reaction. A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and their analogs. A cell that produces a binding molecule of the present disclosure may include a parent hybridoma cell, as well as bacterial and eukaryotic host cells into which nucleic acids encoding the antibodies have been introduced. Unless specified otherwise, the left-hand end of any single-stranded polynucleotide sequence disclosed herein is the 5’ end; the left-hand direction of double-stranded polynucleotide sequences is referred to as the 5’ direction. The direction of 5’ to 3’ addition of nascent RNA transcripts is referred to as the transcription direction; sequence regions on the DNA strand having the same sequence as the RNA transcript that are 5’ to the 5’ end of the RNA transcript are referred to as “upstream sequences”; sequence regions on the DNA strand having the same sequence asthe RNA transcript that are 3 ’ to the 3 ’ end of the RNA transcript are referred to as “downstream sequences.”

[0144] The term “vector” refers to a substance that is used to carry or include a nucleic acid sequence, including for example, in order to introduce a nucleic acid sequence into a host cell. Vectors applicable for use include, for example, expression vectors, plasmids, phage vectors, viral vectors, episomes and artificial chromosomes, which can include selection sequences or markers operable for stable integration into a host cell’s chromosome. Additionally, the vectors can include one or more selectable marker genes and appropriate expression control sequences. Selectable marker genes that can be included, for example, provide resistance to antibiotics or toxins, complement auxotrophic deficiencies, or supply critical nutrients not in the culture media. Expression control sequences can include constitutive and / or inducible promoters, transcription enhancers, transcription terminators, and the like which are well known in the art. When two or more nucleic acid molecules are to be co-expressed (e.g., both an antibody heavy and light chain or an antibody VH and VL) both nucleic acid molecules can be inserted, for example, into a single expression vector or in separate expression vectors. For single vector expression, the encoding nucleic acids can be operationally linked to one common expression control sequence or linked to different expression control sequences, such as one inducible promoter and one constitutive promoter. The introduction of nucleic acid molecules into a host cell can be confirmed using methods well known in the art. Such methods include, for example, nucleic acid analysis such as Northern blots or polymerase chain reaction (PCR) amplification of mRNA, or immunoblotting for expression of gene products, or other suitable analytical methods to test the expression of an introduced nucleic acid sequence or its corresponding gene product. It is understood by those skilled in the art that the nucleic acid molecules are expressed in a sufficient amount to produce a desired product (e.g., an IL13Ra2 binding agent as described herein), and it is further understood that expression levels can be optimized to obtain sufficient expression using methods well known in the art.

[0145] The term “pharmaceutically acceptable” as used herein means being approved by a regulatory agency of the federal or a state government, or listed in the U.S. Pharmacopeia, European Pharmacopeia or other generally recognized Pharmacopeia for use in animals, and more particularly in humans.

[0146] “Excipient” means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. Excipients include, for example, encapsulating materials or additives such as absorption accelerators,antioxidants, binders, buffers, carriers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents and mixtures thereof. The term “excipient” can also refer to a diluent, adjuvant (e.g., Freunds’ adjuvant (complete or incomplete)) or vehicle. In some embodiments, excipients are pharmaceutically acceptable excipients. Examples of pharmaceutically acceptable excipients include buffers, such as phosphate, citrate, and other organic acids; antioxidants, including ascorbic acid; low molecular weight (e.g., fewer than about 10 amino acid residues) polypeptide; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine, asparagine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrins; chelating agents, such as EDTA; sugar alcohols, such as mannitol or sorbitol; salt-forming counterions, such as sodium; and / or nonionic surfactants, such as TWEEN™, polyethylene glycol (PEG), and PLURONICS™. Other examples of pharmaceutically acceptable excipients are described in Remington and Gennaro, Remington’s Pharmaceutical Sclences (18th ed. 1990). In one embodiment, each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit / risk ratio. See, e.g., Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Exclpients, 6th ed.; Rowe etal., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formi'lation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009. In some embodiments, pharmaceutically acceptable excipients are nontoxic to the cell or mammal being exposed thereto at the dosages and concentrations employed. In some embodiments, a pharmaceutically acceptable excipient is an aqueous pH buffered solution. In some embodiments, excipients are sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water is an exemplary excipient when a composition (e.g., a pharmaceutical composition) is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, particularly for injectable solutions. An excipient can also include starch, glucose, lactose, sucrose, gelatin,malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, and the like. The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. Compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations, and the like. Oral compositions, including formulations, can include standard excipients such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Compositions, including pharmaceutical compounds, may contain a prophylactically or therapeutically effective amount of an IL13Ra2 binding agent (e.g., an antibody), for example, in isolated or purified form, together with a suitable amount of excipient so as to provide the form for proper administration to the subject (e.g., patient). The formulation should suit the mode of administration.

[0147] An “effective amount” is generally an amount sufficient to reduce the severity and / or frequency of symptoms, eliminate the symptoms and / or underlying cause, prevent or delay the occurrence of symptoms and / or their underlying cause, and / or improve or remediate the damage that results from or is associated with a disease, disorder, or condition. In some embodiments, the effective amount is a therapeutically effective amount or a prophylactically effective amount.

[0148] The term “therapeutically effective amount” as used herein refers to the amount of an agent (e.g., an antibody described herein or any other agent described herein) that is sufficient to reduce and / or ameliorate the severity and / or duration of a given disease, disorder, or condition, and / or a symptom related thereto. A therapeutically effective amount of an agent, including a therapeutic agent, can be an amount necessary for (i) reduction, delay or amelioration of the advancement or progression of a given disease, disorder, or condition, (ii) reduction, delay or amelioration of the recurrence, development or onset of a given disease, disorder or conditions, and / or (iii) to improve or enhance the prophylactic or therapeutic effect of another therapy (e.g, a therapy other than the administration of an agent described herein). A “therapeutically effective amount” of a substance / molecule / agent of the present disclosure (e.g, an IL13Ra2 antibody) may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the substance / molecule / agent, to elicit a desired response in the individual. A therapeutically effective amount encompasses an amount in which any toxic or detrimental effects of the substance / molecule / agent are outweighed by the therapeutically beneficial effects. In certain embodiments, the term “therapeuticallyeffective amount” refers to an amount of an agent effective to “treat” a disease, disorder, or condition, in a subject or mammal.

[0149] A “prophylactically effective amount” is an amount of a pharmaceutical composition that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of a disease, disorder or condition, or reducing the likelihood of the onset (or reoccurrence) of a disease, disorder, or condition or associated symptom(s).

[0150] The full therapeutic or prophylactic effect does not necessarily occur by administration of one dose and may occur only after administration of a series of doses. Thus, a therapeutically or prophylactically effective amount may be administered in one or more administrations.

[0151] The terms “about” and “approximately” mean within 20%, within 15%, within 10%, within 9%, within 8%, within 7%, within 6%, within 5%, within 4%, within 3%, within 2%, within 1%, or less variation of a given value or range.

[0152] As used herein, comparative terms as used herein, such as reduce, decrease, increase, or any grammatical variation thereof, can refer to certain variation from the reference. In some embodiments, such variation can refer to about 10%, or about 20%, or about 30%, or about 40%, or about 50%, or about 60%, or about 70%, or about 80%, or about 90%, or about 1 fold, or about 2 fold, or about 3 fold, or about 4 fold, or about 5 fold, or about 10 fold, or about 20 fold, or about 30 fold, or about 40 fold, or about 100 fold or higher than the reference. In some embodiments, such variation can refer to about 1%, or about 2%, or about 3%, or about 4%, or about 5%, or about 6%, or about 7%, or about 8%, or about 9%, or about 10%, or about 20%, or about 30%, or about 40%, or about 50%, or about 60%, or about 70%, or about 80%, or about 90%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99% of the reference.

[0153] As used in the present disclosure and claims, the singular forms “a,” “an” and “the” include plural forms unless the context clearly dictates otherwise.

[0154] In some embodiments, the terms “first,” “second,” “third,” “fourth” and similar in a component name are used to distinguish and identify more than one component sharing certain identity in their names. For example, “first antibody” and “second antibody” are used to distinguish two antibodies.

[0155] It is understood that wherever embodiments are described herein with the term “comprising” otherwise analogous embodiments described in terms of “consisting of’ and / or “consisting essentially of’ are also provided. It is also understood that wherever embodimentsare described herein with the phrase “consisting essentially of’ otherwise analogous embodiments described in terms of “consisting of’ are also provided.

[0156] The term “between” as used in a phrase as such “between A and B” or “between A- B” refers to a range including both A and B.

[0157] The term “and / or” as used in a phrase such as “A and / or B” herein is intended to include both A and B; A or B; A (alone); and B (alone). Likewise, the term “and / or” as used in a phrase such as “A, B, and / or C” is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0158] The term “optional” or “optionally” means that the subsequently described circumstance may or may not occur, so that the description includes instances wherein the circumstance occurs, and the instances wherein the circumstance does not occur.

[0159] “Alkyl” refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms and such as 1 to 6 carbon atoms, or 1 to 5, or 1 to 4, or 1 to 3 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), t-butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CJfc^CCTfc-).

[0160] The term “substituted alkyl” refers to an alkyl group as defined herein wherein one or more carbon atoms in the alkyl chain (except the Ci carbon atom) have been optionally replaced with a heteroatom such as -O-, -N-, -S-, -S(O)n- (where n is 0 to 2), -NR- (where R is hydrogen or alkyl) and having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SCh-alkyl, -SCh-aryl, -SCh-heteroaryl, and -NRaRb, wherein R and R may be the same or different and are chosen from hydrogen, optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic.

[0161] In one embodiment, a substituted alkyl includes an alkyl group substituted with SO3H.

[0162] “Alkylene” refers to divalent aliphatic hydrocarbyl groups having from 1 to 6, or 1 to 3 carbon atoms that are either straight-chained or branched, and which are optionallyinterrupted with one or more groups selected from -O-, -NR10-, -NR10C(O)-, -C(O)NR10- and the like. This term includes, by way of example, methylene (-CH2-), ethylene (-CH2CH2-), n- propylene (-CH2CH2CH2-), iso-propylene (-CH2CH(CH3)-), (-C(CH3)2CH2CH2-), (-C(CH3)2CH2C(O)-), (-C(CH3)2CH2C(O)NH-), (-CH(CH3)CH2-), and the like.

[0163] “ Substituted alkylene” refers to an alkylene group having from 1 to 3 hydrogens replaced with substituents as described for carbons in the definition of “substituted” below.

[0164] The term “alkane” refers to alkyl group and alkylene group, as defined herein.

[0165] The term “alkylaminoalkyl,” “alkylaminoalkenyl” and “alkylaminoalkynyl” refers to the groups R’NHR”- where R’ is alkyl group as defined herein and R” is alkylene, alkenylene or alkynylene group as defined herein.

[0166] The term “alkaryl” or “aralkyl” refers to the groups -alkylene-aryl and -substituted alkylene-aryl where alkylene, substituted alkylene and aryl are defined herein.

[0167] “Alkoxy” refers to the group -O-alkyl, wherein alkyl is as defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, n-pentoxy, and the like. The term “alkoxy” also refers to alkenyl-O-, cycloalkyl- O-, cycloalkenyl-O-, and alkynyl-O-, where alkenyl, cycloalkyl, cycloalkenyl, and alkynyl are as defined herein.

[0168] The term “substituted alkoxy” refers to the groups substituted alkyl-O-, substituted alkenyl-O-, substituted cycloalkyl-O-, substituted cycloalkenyl-O-, and substituted alkynyl-O- where substituted alkyl, substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyl and substituted alkynyl are as defined herein.

[0169] The term “alkoxyamino” refers to the group -NH-alkoxy, wherein alkoxy is defined herein.

[0170] The term “haloalkoxy” refers to alkyl-O- wherein one or more hydrogen atoms on the alkyl group have been substituted with a halo group and include, by way of examples, groups such as trifluoromethoxy, and the like.

[0171] The term “haloalkyl” refers to a substituted alkyl group as described above, wherein one or more hydrogen atoms on the alkyl group have been substituted with a halo group. Examples of such groups include, without limitation, fluoroalkyl groups, such as trifluoromethyl, difluoromethyl, trifluoroethyl and the like.

[0172] The term “alkylalkoxy” refers to the groups -alkylene-O-alkyl, alkylene-O- substituted alkyl, substituted alkylene-O-alkyl, and substituted alkylene-O-substituted alkyl wherein alkyl, substituted alkyl, alkylene and substituted alkylene are as defined herein.

[0173] The term “alkylthioalkoxy” refers to the group -alkylene-S-alkyl, alkylene-S- substituted alkyl, substituted alkylene-S-alkyl and substituted alkylene-S-substituted alkyl wherein alkyl, substituted alkyl, alkylene and substituted alkylene are as defined herein.

[0174] “Alkenyl” refers to straight chain or branched hydrocarbyl groups having from 2 to 6 carbon atoms, or 2 to 4 carbon atoms and having at least 1 or from 1 to 2 sites of double bond unsaturation. This term includes, by way of example, bi-vinyl, allyl, and but-3-en-l-yl. Included within this term are the cis and trans isomers or mixtures of these isomers.

[0175] The term “substituted alkenyl” refers to an alkenyl group as defined herein having from 1 to 5 substituents, or from 1 to 3 substituents, selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SCh-alkyl, -SCh-substituted alkyl, -SCh-aryl and -SCh-heteroaryl.

[0176] “Alkynyl” refers to straight or branched monovalent hydrocarbyl groups having from 2 to 6 carbon atoms, or 2 to 3 carbon atoms, and having at least 1, or from 1 to 2 sites of triple bond unsaturation. Examples of such alkynyl groups include acetylenyl (-C=CH), and propargyl (-CH2OCH).

[0177] The term “substituted alkynyl” refers to an alkynyl group as defined herein having from 1 to 5 substituents, or from 1 to 3 substituents, selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, and -SO2-heteroaryl.

[0178] “Alkynyloxy” refers to the group -O-alkynyl, wherein alkynyl is as defined herein. Alkynyloxy includes, by way of example, ethynyloxy, propynyloxy, and the like.

[0179] “Acyl” refers to the groups H-C(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl- C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, cycloalkenyl-C(O)-, substituted cycloalkenyl-C(O)-, aryl-C(O)-,substituted aryl-C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O)-, heterocyclyl-C(O)-, and substituted heterocyclyl-C(O)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. For example, acyl includes the “acetyl” group CH3C(0)-.

[0180] “Acylamino” refers to the groups -NR20C(O)alkyl, -NR20C(O)substituted alkyl, NR20C(O)cycloalkyl, -NR20C(O) substituted cycloalkyl, -NR20C(O)cycloalkenyl, -NR20C(O)substituted cycloalkenyl, -NR20C(O)alkenyl, -NR20C(O)substituted alkenyl, -NR20C(O)alkynyl, -NR20C(O)substituted alkynyl, -NR20C(O)aryl, -NR20C(O)substituted aryl, -NR20C(O)heteroaryl, -NR20C(O)substituted heteroaryl, -NR20C(O)heterocyclic, and -NR20C(O) substituted heterocyclic, wherein R20is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0181] “Aminocarbonyl” or the term “aminoacyl” refers to the group -C(O)NR21R22, wherein R21and R22independently are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R21and R22are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0182] “Aminocarbonylamino” refers to the group -NR21C(O)NR22R23where R21, R22, and R23are independently selected from hydrogen, alkyl, aryl or cycloalkyl, or where two R groups are joined to form a heterocyclyl group.

[0183] The term “alkoxycarbonylamino” refers to the group -NRC(O)OR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclyl wherein alkyl, substituted alkyl, aryl, heteroaryl, and heterocyclyl are as defined herein.

[0184] The term “acyloxy” refers to the groups alkyl-C(O)O-, substituted alkyl-C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)O-, aryl-C(O)O-, heteroaryl-C(O)O-, andheterocyclyl-C(O)O- wherein alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, and heterocyclyl are as defined herein.

[0185] “Aminosulfonyl” refers to the group -SO2NR21R22, wherein R21and R22independently are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and where R21and R22are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group and alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[0186] “Sulfonylamino” refers to the group -NR21SO2R22, wherein R21and R22independently are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R21and R22are optionally joined together with the atoms bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0187] “Aryl” or “Ar” refers to a monovalent aromatic carbocyclic group of from 6 to 18 carbon atoms having a single ring (such as is present in a phenyl group) or a ring system that has multiple condensed rings (examples of such aromatic ring systems include naphthyl, anthryl and indanyl) which condensed rings may or may not be aromatic, provided that the point of attachment is through an atom of an aromatic ring. This term includes, by way of example, phenyl and naphthyl. Unless otherwise constrained by the definition for the aryl substituent, such aryl groups can optionally be substituted with from 1 to 5 substituents, or from 1 to 3 substituents, selected from acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamino,thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SCh-alkyl, -SCh-substituted alkyl, -SCh-aryl, -SCh-heteroaryl and trihalom ethyl.

[0188] “Aryloxy” refers to the group -O-aryl, wherein aryl is as defined herein, including, by way of example, phenoxy, naphthoxy, and the like, including optionally substituted aryl groups as also defined herein.

[0189] “Amino” refers to the group -NH2.

[0190] The term “substituted amino” refers to the group -NRR where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, and heterocyclyl provided that at least one R is not hydrogen.

[0191] The term “azido” refers to the group -N3.

[0192] “Carboxyl,” “carboxy” or “carboxylate” refers to -CO2H or salts thereof.

[0193] “Carboxyl ester” or “carboxy ester” or the terms “carboxyalkyl” or “carboxylalkyl” refers to the groups -C(O)O-alkyl, -C(O)O-substituted alkyl, -C(O)O-alkenyl, -C(O)O-substituted alkenyl, -C(O)O-alkynyl, -C(O)O-substituted alkynyl, -C(O)O-aryl, -C(O)O-substituted aryl, -C(O)O-cycloalkyl, -C(O)O-substituted cycloalkyl, -C(O)O-cycloalkenyl, -C(O)O-substituted cycloalkenyl, -C(O)O-heteroaryl, -C(O)O-substituted heteroaryl, -C(O)O-heterocyclic, and -C(O)O-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0194] “(Carboxyl ester)oxy” or “carbonate” refers to the groups -O-C(O)O- alkyl, -O-C(O)O-substituted alkyl, -O-C(O)O-alkenyl, -O-C(O)O-substituted alkenyl, -O- C(O)O-alkynyl, -O-C(O)O-substituted alkynyl, -O-C(O)O-aryl, -O-C(O)O-substituted aryl, -O-C(O)O-cycloalkyl, -O-C(O)O-substituted cycloalkyl, -O-C(O)O-cycloalkenyl, -O-C(O)O- substituted cycloalkenyl, -O-C(O)O-heteroaryl, -O-C(O)O-substituted heteroaryl, -O-C(O)O- heterocyclic, and -O-C(O)O-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0195] “Cyano” or “nitrile” refers to the group -CN.

[0196] “Cycloalkyl” refers to cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple cyclic rings including fused, bridged, and spiro ring systems. Examples of suitable cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl and the like. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like.

[0197] The term “substituted cycloalkyl” refers to cycloalkyl groups having from 1 to 5 substituents, or from 1 to 3 substituents, selected from alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SCh-alkyl, -SCh-substituted alkyl, -SCh-aryl and -SCh-heteroaryl.

[0198] “Cycloalkenyl” refers to non-aromatic cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple rings and having at least one double bond, or from 1 to 2 double bonds.

[0199] The term “substituted cycloalkenyl” refers to cycloalkenyl groups having from 1 to 5 substituents, or from 1 to 3 substituents, selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO- alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl and -SO2-heteroaryl.

[0200] “Cycloalkynyl” refers to non-aromatic cycloalkyl groups of from 5 to 10 carbon atoms having single or multiple rings and having at least one triple bond.

[0201] “Cycloalkoxy” refers to -O-cycloalkyl.

[0202] “Cycloalkenyloxy” refers to -O-cycloalkenyl.

[0203] “Halo” or “halogen” refers to fluoro, chloro, bromo, and iodo.

[0204] “Hydroxy” or “hydroxyl” refers to the group -OH.

[0205] “Heteroaryl” refers to an aromatic group of from 1 to 15 carbon atoms, such as from 1 to 10 carbon atoms and 1 to 10 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur within the ring. Such heteroaryl groups can have a single ring (such as, pyridinyl, imidazolyl or furyl) or multiple condensed rings in a ring system (for example as in groups such as, indolizinyl, quinolinyl, benzofuran, benzimidazolyl or benzothienyl), wherein at least one ring within the ring system is aromatic. To satisfy valence requirements, any heteroatoms in such heteroaryl rings may or may not be bonded to H or a substituent group, e.g., an alkyl group or other substituent as described herein. In certain embodiments, the nitrogen and / or sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N— >0), sulfinyl, or sulfonyl moieties. This term includes, by way of example, pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl. Unless otherwise constrained by the definition for the heteroaryl substituent, such heteroaryl groups can be optionally substituted with 1 to 5 substituents, or from 1 to 3 substituents, selected from acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO- heteroaryl, -SCh-alkyl, -SCh-substituted alkyl, -SCh-aryl and -SCh-heteroaryl, and trihalom ethyl.

[0206] The term “heteroaralkyl” refers to the groups -alkylene-heteroaryl where alkylene and heteroaryl are defined herein. This term includes, by way of example, pyridylmethyl, pyridylethyl, indolylmethyl, and the like.

[0207] “Heteroaryl oxy” refers to -O-heteroaryl.

[0208] “Heterocycle,” “heterocyclic,” “heterocycloalkyl,” and “heterocyclyl” refer to a saturated or unsaturated group having a single ring or multiple condensed rings, including fused bridged and spiro ring systems, and having from 3 to 20 ring atoms, including 1 to 10 hetero atoms. These ring atoms are selected from nitrogen, sulfur, or oxygen, where, in fused ring systems, one or more of the rings can be cycloalkyl, aryl, or heteroaryl, provided that the point of attachment is through the non-aromatic ring. In certain embodiments, the nitrogen and / or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N- oxide, -S(O)-, or -SO2- moieties. To satisfy valence requirements, any heteroatoms in suchheterocyclic rings may or may not be bonded to one or more H or one or more substituent group(s), e.g., an alkyl group or other substituent as described herein.

[0209] Examples of heterocycles and heteroaryls include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholinyl, thiomorpholinyl (also referred to as thiamorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidine, tetrahydrofuranyl, and the like.

[0210] Unless otherwise constrained by the definition for the heterocyclic substituent, such heterocyclic groups can be optionally substituted with 1 to 5, or from 1 to 3 substituents, selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO- heteroaryl, -SCh-alkyl, -SCh-substituted alkyl, -SCh-aryl, -SCh-heteroaryl, and fused heterocycle.

[0211] “Heterocyclyloxy” refers to the group -O-heterocyclyl.

[0212] The term “heterocyclylthio” refers to the group heterocyclic-S-.

[0213] The term “heterocyclene” refers to the diradical group formed from a heterocycle, as defined herein.

[0214] The term “hydroxyamino” refers to the group -NHOH.

[0215] “Nitro” refers to the group -NO2.

[0216] “ Oxo” refers to the atom (=0).

[0217] “Sulfonyl” refers to the group -SO2-alkyl, -SO2-substituted alkyl, -SO2-alkenyl, -SO2-substituted alkenyl, -SO2-cycloalkyl, -SO2-substituted cylcoalkyl, -SO2-cycloalkenyl, -SO2-substituted cylcoalkenyl, -SO2-aryl, -SO2-substituted aryl, -SO2-heteroaryl, -SO2- substituted heteroaryl, -SO2-heterocyclic, and -SO2-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. Sulfonyl includes, by way of example, methyl-SCh-, phenyl-SCh-, and 4- methylphenyl-SCh-.

[0218] “Sulfonyloxy” refers to the group -OSCh-alkyl, -OSCh-substituted alkyl, -OSO2- alkenyl, -OSCh-substituted alkenyl, -OSCh-cycloalkyl, -OSCh-substituted cylcoalkyl, -OSO2- cycloalkenyl, -OSCh-substituted cylcoalkenyl, -OSO2-aryl, -OSO2-substituted aryl, -OSO2- heteroaryl, -OSO2-substituted heteroaryl, -OSO2-heterocyclic, and -OSO2-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0219] “Sulfate” or “sulfate ester” refers the group -O-SO2-OH, -O-SO2-O-alkyl, -O-SO2- O-substituted alkyl, -O-SO2-O-alkenyl, -O-SO2-O-substituted alkenyl, -O-SO2-O-cycloalkyl, -O-SO2-O-substituted cylcoalkyl, -O-SO2-O-cycloalkenyl, -O-SO2-O-substituted cylcoalkenyl, -O-SO2-O-aryl, -O-SO2-O-substituted aryl, -O-SO2-O-heteroaryl, -O-SO2-O- substituted heteroaryl, -O-SO2-O-heterocyclic, and -O-SO2-O-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0220] The term “aminocarbonyloxy” refers to the group -0C(0)NRR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.

[0221] “ Thiol” refers to the group -SH.

[0222] “ Thioxo” or the term “thioketo” refers to the atom (=S).

[0223] “Alkylthio” or the term “thioalkoxy” refers to the group -S-alkyl, wherein alkyl is as defined herein. In certain embodiments, sulfur may be oxidized to -S(O)-. The sulfoxide may exist as one or more stereoisomers.

[0224] The term “substituted thioalkoxy” refers to the group -S-substituted alkyl.

[0225] The term “thioaryloxy” refers to the group aryl-S- wherein the aryl group is as defined herein including optionally substituted aryl groups also defined herein.

[0226] The term “thioheteroaryloxy” refers to the group heteroaryl-S- wherein the heteroaryl group is as defined herein including optionally substituted aryl groups as also defined herein.

[0227] The term “thioheterocyclooxy” refers to the group heterocyclyl-S- wherein the heterocyclyl group is as defined herein including optionally substituted heterocyclyl groups as also defined herein.

[0228] In the disclosure herein, the term “substituted,” when used to modify a specified group or radical, can also mean that one or more hydrogen atoms of the specified group or radical are each, independently of one another, replaced with the same or different substituent groups as defined below.

[0229] In addition to the groups disclosed with respect to the individual terms herein, substituent groups for substituting for one or more hydrogens (any two hydrogens on a single carbon can be replaced with =0, =NR70, =N-OR70, =N2 or =S) on saturated carbon atoms in the specified group or radical are, unless otherwise specified, -R60, halo, =0, -OR70, -SR70, -NR80R80, trihalomethyl, -CN, -OCN, -SCN, -NO, -NO2, =N2, -N3, -SO2R70, -SO2O M+, -SO2OR70, -OSO2R70, -OSO2O M+, -OSO2OR70, -P(O)(O )2(M+)2, -P(O)(OR70)O M+, -P(O)(OR70)2,-C(O)R70, -C(S)R70, -C(NR70)R70, -C(O)O M+, -C(O)OR70, -C(S)OR70, -C(O)NR80R80, -C(NR70)NR80R80, -OC(O)R70, -OC(S)R70, -0C(0)0 M+, -OC(O)OR70, -OC(S)OR70, -NR70C( O)R70, -NR70C(S)R70, -NR70C02 M+, -NR70CO2R70, -NR70C(S)OR70, -NR70C(O)NR80R80, -NR70C(NR70)R70and -NR70C(NR70)NR80R80, where R60is selected from the group consisting of optionally substituted alkyl, cycloalkyl, heteroalkyl, heterocycloalkylalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, each R70is independently hydrogen or R60; each R80is independently R70or alternatively, two R80s, taken together with the nitrogen atom to which they are bonded, form a 5-, 6- or 7-membered heterocycloalkyl which may optionally include from 1 to 4 of the same or different additional heteroatoms selected from the group consisting of O, N and S, of which N may have -H or C1-C3 alkyl substitution; and each M+is a counter ion with a net single positive charge. Each M+may independently be, for example, an alkali ion, such as K+, Na+, Li+; an ammonium ion, such as+N(R60)4; or an alkaline earth ion, such as [Ca2+]o.s, [Mg2+]o.s, or [Ba2+]o.s (“subscript 0.5 means that one of the counter ions for such divalent alkali earth ions can be an ionized form of a compound of the invention and the other a typical counter ion such as chloride, or two ionized compounds disclosed herein can serve as counter ions for such divalent alkali earth ions, or a doubly ionized compound of the invention can serve as the counter ion for such divalent alkali earthions). As specific examples, -NR80R80is meant to include -NH2,-NH-alkyl, 7V-pyrrolidinyl, 7V-piperazinyl, 47V-methyl-piperazin-l-yl and TV-morpholinyl.

[0230] In addition to the disclosure herein, substituent groups for hydrogens on unsaturated carbon atoms in “substituted” alkene, alkyne, aryl and heteroaryl groups are, unless otherwise specified, -R60, halo, -O M+, -OR70, -SR70, -S M+, -NR80R80, trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO2, -N3, -SO2R70, -SO3M+, -SO3R70, -OSO2R70, -OSO3 M+, -OSO3R70, -PO3-2(M+)2, -P(O)(OR70)O M+, -P(O)(OR70)2, -C(O)R70, -C(S)R70, -C(NR70)R70, -CO2 M+, -CO2R70, -C(S)OR70, -C(O)NR80R80, -C(NR70)NR80R80, -OC(O)R70, -OC(S)R70, -OCO2 M+, -OCO2R70, -OC(S)OR70, -NR70C(O)R70, -NR70C(S)R70, -NR70C02 M+, -NR70CO2R70, -NR70C(S)OR70, -NR70C(O)NR80R80, -NR70C(NR70)R70and -NR70C(NR70)NR80R80, where R60, R70, R80and M+are as previously defined, provided that in case of substituted alkene or alkyne, the substituents are not -O M+, -OR70, -SR70, or -S M .

[0231] In addition to the groups disclosed with respect to the individual terms herein, substituent groups for hydrogens on nitrogen atoms in “substituted” heteroalkyl and cycloheteroalkyl groups are, unless otherwise specified, -R60, -O M+, -OR70, -SR70, -S'M+, -NR80R80, trihalomethyl, -CF3, -CN, -NO, -NO2, -S(O)2R70, -S(O)2O-M+, -S(O)2OR70, -OS(O)2R70, -OS(O)2O M+, -OS(O)2OR70, -P(O)(O )2(M+)2, -P(O)(OR70)O M+, -P(O)(OR70)(OR70), -C(O)R70, -C(S)R70, -C(NR7O)R70, -C(O)OR70, -C(S)OR70, -C(O)NR80R80, -C(NR70)NR80R80, -OC(O)R70, -OC(S)R70, -OC(O)OR70, -OC(S)OR70, -NR70C(O)R70, -NR7OC(S)R70, -NR70C(0)OR70, -NR70C(S)OR70, -NR70C(O)NR80R80, -NR70C(NR70)R70and -NR70C( R70)NR80R80, where R60, R70, R80and M+are as previously defined.

[0232] In addition to the disclosure herein, in a certain embodiment, a group that is substituted has 1, 2, 3, or 4 substituents, 1, 2, or 3 substituents, 1 or 2 substituents, or 1 substituent.

[0233] It is understood that in all substituted groups defined above, polymers arrived at by defining substituents with further substituents to themselves (e.g., substituted aryl having a substituted aryl group as a substituent which is itself substituted with a substituted aryl group, which is further substituted by a substituted aryl group, etc.) are not intended for inclusion herein. In such cases, the maximum number of such substitutions is three. For example, serial substitutions of substituted aryl groups specifically contemplated herein are limited to substituted aryl-(substituted aryl)-substituted aryl.

[0234] Unless indicated otherwise, the nomenclature of substituents that are not explicitly defined herein are arrived at by naming the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment. For example, the substituent “arylalkyloxycarbonyl” refers to the group (aryl)-(alkyl)-O-C(O)-.

[0235] As to any of the groups disclosed herein which contain one or more substituents, it is understood, of course, that such groups do not contain any substitution or substitution patterns which are sterically impractical and / or synthetically non-feasible. In addition, the subject compounds include all stereochemical isomers arising from the substitution of these compounds.

[0236] The term “pharmaceutically acceptable salt” means a salt which is acceptable for administration to a patient, such as a mammal (salts with counterions having acceptable mammalian safety for a given dosage regime). Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids. “Pharmaceutically acceptable salt” refers to pharmaceutically acceptable salts of a compound, which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, formate, tartrate, besylate, mesylate, acetate, maleate, oxalate, and the like.

[0237] The term “salt thereof’ means a compound formed when a proton of an acid is replaced by a cation, such as a metal cation or an organic cation and the like. Where applicable, the salt is a pharmaceutically acceptable salt, although this is not required for salts of intermediate compounds that are not intended for administration to a patient. By way of example, salts of the present compounds include those wherein the compound is protonated by an inorganic or organic acid to form a cation, with the conjugate base of the inorganic or organic acid as the anionic component of the salt.

[0238] “ Solvate” refers to a complex formed by combination of solvent molecules with molecules or ions of the solute. The solvent can be an organic compound, an inorganic compound, or a mixture of both. Some examples of solvents include, but are not limited to, methanol, A,r-di methyl form am ide, tetrahydrofuran, dimethylsulfoxide, and water. When the solvent is water, the solvate formed is a hydrate.

[0239] “ Stereoisomer” and “stereoisomers” refer to compounds that have same atomic connectivity but different atomic arrangement in space. Stereoisomers include cis-trans isomers, E and Z isomers, enantiomers, and diastereomers.

[0240] “ Tautomer” refers to alternate forms of a molecule that differ only in electronic bonding of atoms and / or in the position of a proton, such as enol-keto and imine-enamine tautomers, or the tautomeric forms of heteroaryl groups containing a -N=C(H)-NH- ring atom arrangement, such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles. A person of ordinary skill in the art would recognize that other tautomeric ring atom arrangements are possible.

[0241] It will be appreciated that the term “or a salt or solvate or stereoisomer thereof’ is intended to include all permutations of salts, solvates and stereoisomers, such as a solvate of a pharmaceutically acceptable salt of a stereoisomer of subject compound.

[0242] “Pharmaceutically effective amount” and “therapeutically effective amount” refer to an amount of a compound sufficient to treat a specified disorder or disease or one or more of its symptoms and / or to prevent the occurrence of the disease or disorder. In reference to tumorigenic proliferative disorders, a pharmaceutically or therapeutically effective amount comprises an amount sufficient to, among other things, cause the tumor to shrink or decrease the growth rate of the tumor.

[0243] “Patient” refers to human and non-human subjects, especially mammalian subjects.

[0244] As used herein, the term “substantially purified” refers to a compound that is removed from its natural environment and is at least 60% free, at least 75% free, at least 80% free, at least 85% free, at least 90% free, at least 95% free, at least 98% free, or more than 98% free, from other components with which it is naturally associated.

[0245] The term “physiological conditions” is meant to encompass those conditions compatible with living cells, e.g., predominantly aqueous conditions of a temperature, pH, salinity, etc. that are compatible with living cells.

[0246] By “reactive partner” is meant a molecule or molecular moiety that specifically reacts with another reactive partner to produce a reaction product. Exemplary reactive partners include a cysteine or serine of a sulfatase motif and Formylglycine Generating Enzyme (FGE), which react to form a reaction product of a converted aldehyde tag containing a formylglycine (fGly) in lieu of cysteine or serine in the motif. Other exemplary reactive partners include an aldehyde of an fGly residue of a converted aldehyde tag (e.g., a reactive aldehyde group) and an “aldehyde-reactive reactive partner,” which comprises an aldehydereactive group and a moiety of interest, and which reacts to form a reaction product of apolypeptide having the moiety of interest conjugated to the polypeptide through the fGly residue.

[0247] The term “subject” refers to human and non-human subjects, especially mammalian subjects.

[0248] The term “treating” or “treatment” as used herein means the treating or treatment of a disease or medical condition in a subject, such as a mammal (particularly a human) that includes: (a) preventing the disease or medical condition from occurring, such as, prophylactic treatment of a subject; (b) ameliorating the disease or medical condition, such as, eliminating or causing regression of the disease or medical condition in a subject; (c) suppressing the disease or medical condition, for example by, slowing or arresting the development of the disease or medical condition in a subject; or (d) alleviating a symptom of the disease or medical condition in a subject. In some embodiments, the term “treating,” or “treatment” excludes a prophylactic treatment.

[0249] The terms “interleukin- 13 receptor subunit alpha-2,” and “IL13Ra2,” are used interchangeably herein to refer to IL13Ra2, or any variants (e.g., splice variants and allelic variants), isoforms, and species homologs of IL13Ra2 that are naturally expressed by cells, or that are expressed by cells transfected with an IL13Ra2 gene. In some aspects, the IL13Ra2 protein is an IL13Ra2 protein naturally expressed by a primate (e.g., a monkey or a human), a rodent (e.g., a mouse or a rat), a dog, a camel, a cat, a cow, a goat, a horse, a pig, or a sheep.

[0250] The terms “IL13Ra2-mediated disease,” “IL13Ra2-mediated disorder,” and “IL13Ra2-mediated condition” are used interchangeably and refer to any disease, disorder or condition associated with or characterized by IL13Ra2-expressing cells, such as IL13Ra2- expressing tumor cells. AN IL 13Ra2 -mediated disease includes a cancer including, but not limited to, cancers that express or overexpress IL13Ra2.

[0251] The term “tumor,” in any embodiment herein, refers to any neoplastic cell growth or proliferation, whether malignant or benign, and to all pre-cancerous and cancerous cells and tissues.

[0252] The terms “cancer” and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.

[0253] The term “ADC” refers to an antibody-drug conjugate, which in the context of the present invention refers to an IL13Ra2 antibody, which is coupled to another moiety which includes a drug, as described herein.

[0254] As used herein, “drug” refers to a compound that has biological activity, such as a cytotoxic compound (e.g., a cytotoxic small molecule, a cytotoxic synthetic peptide, and the like).

[0255] Examples of drugs include small molecule drugs, such as a cancer chemotherapeutic agent. For example, where the polypeptide is an antibody (or fragment thereof) that has specificity for a tumor cell, the antibody can be modified as described herein to include a modified amino acid, which can be subsequently conjugated to a cancer chemotherapeutic agent. Cancer chemotherapeutic agents include non-peptidic (e.g., non- proteinaceous) compounds that reduce proliferation of cancer cells and encompass cytotoxic agents and cytostatic agents. Non-limiting examples of chemotherapeutic agents include alkylating agents, nitrosoureas, antimetabolites, antitumor antibiotics, plant (vinca) alkaloids, and steroid hormones. Peptidic compounds can also be used.

[0256] Suitable cancer chemotherapeutic agents include dolastatin and active analogs and derivatives thereof; and auristatin and active analogs and derivatives thereof (e.g., Monomethyl auristatin D (MMAD), monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), and the like). See, e.g., WO 96 / 33212, WO 96 / 14856, and U.S. 6,323,315. For example, dolastatin 10 or auristatin PE can be included in an IL13Ra2-ADC of the present disclosure. Suitable cancer chemotherapeutic agents also include maytansinoids and active analogs and derivatives thereof (see, e.g, EP 1391213; and Liu et al (1996) Proc. Natl. Acad. Set. USA 93:8618-8623); duocarmycins and active analogs and derivatives thereof (e.g, including the synthetic analogues, KW-2189 and CB 1-TM1); and benzodiazepines and active analogs and derivatives thereof (e.g., pyrrol obenzodiazepine (PBD)).

[0257] Agents that act to reduce cellular proliferation are known in the art and widely used. Such agents include alkylating agents, such as nitrogen mustards, nitrosoureas, ethylenimine derivatives, alkyl sulfonates, and triazenes, including, but not limited to, mechlorethamine, cyclophosphamide (CYNOTAN™), melphalan (L-sarcolysin), carmustine (BCNU), lomustine (CCNU), semustine (methyl-CCNU), streptozocin, chlorozotocin, uracil mustard, chlormethine, ifosfamide, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, dacarbazine, and temozolomide.

[0258] Antimetabolite agents include folic acid analogs, pyrimidine analogs, purine analogs, and adenosine deaminase inhibitors, including, but not limited to, cytarabine (CYTOSAR-U®), cytosine arabinoside, fluorouracil (5-FU), floxuridine (FudR), 6- thioguanine, 6-mercaptopurine (6-MP), pentostatin, 5 -fluorouracil (5-FU), methotrexate, 10-propargyl-5,8-dideazafolate (PDDF, CB3717), 5,8-dideazatetrahydrofolic acid (DDATHF), leucovorin, fludarabine phosphate, pentostatin, and gemcitabine.

[0259] Suitable natural products and their derivatives, (e.g., vinca alkaloids, antitumor antibiotics, enzymes, lymphokines, and epipodophyllotoxins), include, but are not limited to, Ara-C, paclitaxel (TAXOL®), docetaxel (TAXOTERE®), deoxycoformycin, mitomycin-C, L- asparaginase, azathioprine; brequinar; alkaloids, e.g. vincristine, vinblastine, vinorelbine, vindesine, and the like; podophyllotoxins, e.g. etoposide, teniposide, and the like; antibiotics, e.g. anthracycline, daunorubicin hydrochloride (daunomycin, rubidomycin, cerubidine), idarubicin, doxorubicin, epirubicin and morpholino derivatives, and the like; phenoxizone biscyclopeptides, e.g. dactinomycin; basic glycopeptides, e.g. bleomycin; anthraquinone glycosides, e.g. plicamycin (mithramycin); anthracenediones, e.g. mitoxantrone; azirinopyrrolo indolediones, e.g. mitomycin; macrocyclic immunosuppressants, e.g. cyclosporine, FK-506 (tacrolimus, prograf), rapamycin, and the like; and the like.

[0260] Other anti -proliferative cytotoxic agents are navelbene, CPT-11, anastrazole, letrazole, capecitabine, reloxafine, cyclophosphamide, ifosamide, and droloxafine.

[0261] Microtubule affecting agents that have antiproliferative activity are also suitable for use and include, but are not limited to, allocolchicine (NSC 406042), Halichondrin B (NSC 609395), colchicine (NSC 757), colchicine derivatives (e.g., NSC 33410), dolstatin 10 (NSC 376128), maytansine (NSC 153858), rhizoxin (NSC 332598), paclitaxel (TAXOL®), TAXOL® derivatives, docetaxel (TAXOTERE®), thiocolchicine (NSC 361792), trityl cysterin, vinblastine sulfate, vincristine sulfate, natural and synthetic epothilones including but not limited to, eopthilone A, epothilone B, discodermolide; estramustine, nocodazole, and the like.

[0262] Hormone modulators and steroids (including synthetic analogs) that are suitable for use include, but are not limited to, adrenocorticosteroids, e.g. prednisone, dexamethasone, and the like; estrogens and pregestins, e.g. hydroxyprogesterone caproate, medroxyprogesterone acetate, megestrol acetate, estradiol, clomiphene, tamoxifen; and the like; adrenocortical suppressants, e.g. aminoglutethimide; 17a-ethinylestradiol; di ethylstilbestrol, testosterone, fluoxymesterone, dromostanolone propionate, testolactone, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide, flutamide (DROGENIL®), toremifene (FARESTON®), and goserelin (ZOLADEX®), and the like. Estrogens stimulate proliferation and differentiation; therefore, compounds that bind to theestrogen receptor are used to block this activity. Corticosteroids can inhibit T cell proliferation.

[0263] Other suitable chemotherapeutic agents include metal complexes, e.g. cisplatin (cis- DDP), carboplatin, and the like; ureas, e.g. hydroxyurea; hydrazines, e.g. N-methylhydrazine; epidophyllotoxin; a topoisomerase inhibitor; procarbazine; mitoxantrone; leucovorin; tegafur; and the like Other anti-proliferative agents of interest include immunosuppressants, e.g. mycophenolic acid, thalidomide, desoxyspergualin, azasporine, leflunomide, mizoribine, azaspirane (SKF 105685); gefitinib (IRESSA®, ZD 1839, 4-(3-chloro-4-fluorophenylamino)- 7-methoxy-6-(3-(4-morpholinyl)propoxy)quinazoline); and the like.

[0264] Taxanes are suitable for use. “Taxanes” include paclitaxel, as well as any active taxane derivative or pro-drug. “Paclitaxel” (which should be understood herein to include analogues, formulations, and derivatives such as, for example, docetaxel, TAXOL®, TAXOTERE® (a formulation of docetaxel), 10-desacetyl analogs of paclitaxel and 3’N- desbenzoyl-3’N-t-butoxycarbonyl analogs of paclitaxel) can be readily prepared utilizing techniques known to those skilled in the art (see also WO 94 / 07882, WO 94 / 07881, WO 94 / 07880, WO 94 / 07876, WO 93 / 23555, WO 93 / 10076; U.S. Pat. Nos. 5,294,637; 5,283,253; 5,279,949; 5,274,137; 5,202,448; 5,200,534; 5,229,529; and EP 590,267), or obtained from a variety of commercial sources, including for example, Sigma Chemical Co., St. Louis, Mo. (T7402 from Taxus brevifolia or T-1912 from Taxus yannanensis). Paclitaxel should be understood to refer to not only the common chemically available form of paclitaxel, but analogs and derivatives (e.g., TAXOTERE® docetaxel, as noted herein) and paclitaxel conjugates (e.g., paclitaxel-PEG, paclitaxel-dextran, or paclitaxel -xylose).

[0265] Also included within the term “taxane” are a variety of known derivatives, including both hydrophilic derivatives, and hydrophobic derivatives. Taxane derivatives include, but are not limited to, galactose and mannose derivatives described in International Patent Application No. WO 99 / 18113; piperazino and other derivatives described in WO 99 / 14209; taxane derivatives described in WO 99 / 09021, WO 98 / 22451, and U.S. Patent No. 5,869,680; 6-thio derivatives described in WO 98 / 28288; sulfenamide derivatives described in U.S. Patent No. 5,821,263; and taxol derivative described in U.S. Patent No. 5,415,869. It further includes prodrugs of paclitaxel including, but not limited to, those described in WO 98 / 58927; WO 98 / 13059; and U.S. Patent No. 5,824,701.

[0266] Biological response modifiers suitable for use include, but are not limited to, (1) inhibitors of tyrosine kinase (RTK) activity; (2) inhibitors of serine / threonine kinase activity; (3) tumor-associated antigen antagonists, such as antibodies that bind specifically to a tumorantigen; (4) apoptosis receptor agonists; (5) interleukin-2; (6) IFN-a; (7) IFN-y; (8) colonystimulating factors; and (9) inhibitors of angiogenesis.

[0267] In some embodiments, the drug is a microtubule affecting agent that has antiproliferative activity, such as a maytansinoid. In some embodiments, the drug is an antimitotic agent, such as an auristatin or an active auristatin analog or derivative thereof. In some embodiments, the drug is a DNA alkylating agent.

[0268] The term “pharmaceutically acceptable” as used herein means being approved by a regulatory agency of the federal or a state government, or listed in the U.S. Pharmacopeia, European Pharmacopeia, or other generally recognized Pharmacopeia for use in animals, and more particularly in humans.

[0269] “Excipients” include carriers, excipients, preservatives, or stabilizers that are nontoxic to the cell or mammal being exposed thereto at the dosages and concentrations employed and can be included, for example, to affect stability, bulk up formulations, or to confer a therapeutic enhancement on the active ingredient in the final dosage form (e.g., facilitating absorption, reducing viscosity, enhancing solubility). An "excipient" can be an organic or inorganic ingredient, natural or synthetic with which the active ingredient is combined to facilitate the use of the active ingredient, e.g., the administration of the active ingredient to a subject. Examples of excipients include buffers such as phosphate, citrate, and other organic acids; antioxidants such as ascorbic acid; low molecular weight (e.g., less than about ten amino acid residues) polypeptide; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates such as glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and / or nonionic surfactants such as TWEEN™, polyethylene glycol (PEG), and PLURONICS™. The term “excipient” can also refer to a diluent, adjuvant (e.g., Freund’s adjuvant (complete or incomplete)), excipient, or vehicle with which the therapeutic is administered. Such excipients can be sterile liquids, such as water and oils, such as those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water is an exemplary excipient when a composition (e.g., a pharmaceutical composition) is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, particularly for injectable solutions. Suitable excipients (e.g., pharmaceutical excipients) include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, driedskim milk, glycerol, propylene, glycol, water, ethanol, and the like. The composition, in any embodiment, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. Compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations, and the like. Oral compositions, such as formulations, can include standard excipients such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, and the like. Examples of suitable excipients are described in Remington: The Science and Practice of Pharmacy (2020) (Elsevier Science, Amsterdam, Netherlands), including pharmaceutical compounds, can contain an effective amount or therapeutically effective amount of an IL13Ra2-ADC, for example, in isolated or purified form, together with a suitable amount of excipient to provide the form for proper administration to the subject. The formulation should suit the mode of administration.

[0270] Before the present invention is further described, it is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0271] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

[0272] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination. All combinations of the embodiments pertaining to the invention are specifically embraced by the present invention and are disclosed herein just as if each and every combination was individually and explicitly disclosed, to the extent that such combinations embrace subject matter that are, for example, compounds that are stable compounds (e.g., compounds that can be made, isolated, characterized, and tested forbiological activity). In addition, all sub-combinations of the various embodiments and elements thereof (e.g., elements of the chemical groups listed in the embodiments describing such variables) are also specifically embraced by the present invention and are disclosed herein just as if each and every such sub-combination was individually and explicitly disclosed herein.

[0273] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited.

[0274] It must be noted that as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the recitation of claim elements, or use of a “negative” limitation.

[0275] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination.

[0276] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.7.2 IL13Ra2-ADCs

[0277] An antibody that binds to interleukin- 13 receptor subunit alpha-2 (IL13Ra2) (also referred to herein as “IL13Ra2 antibody,” “anti-IL13Ra2 antibody,” “IL13Ra2 Ab,” “Ab” or “antibody”) and a drug can be linked directly or indirectly to each other via a pyridazine- pyrrolo coupling moiety to form an IL13Ra2-ADC as described herein. In certainembodiments, the IL13Ra2 antibody and the two or more drugs or active agents are bound to each other through one or more functional groups and covalent bonds. For example, the one or more functional groups and covalent bonds can include a branched linker as described herein.

[0278] Moi eties of interest (e.g., drugs or active agents) can be conjugated to the IL13Ra2 antibody at any desired site of the antibody. Thus, the present disclosure provides, for example, an IL13Ra2 antibody that has moieties conjugated at two or more sites on the antibody, such as a site at or near the C-terminus of the antibody, a position at or near the N- terminus of the antibody, and a position between the C-terminus and the N-terminus of the antibody (e.g., at an internal site of the antibody). Combinations of the above conjugation sites are also possible.

[0279] In certain embodiments, a conjugate of the present disclosure includes one (or more, such as two) drugs or active agents conjugated to an amino acid residue of an IL13Ra2 antibody at the a-carbon of an amino acid residue. Stated another way, a conjugate includes an IL13Ra2 antibody where the side chain of an amino acid residue in the antibody has been modified and attached to one (or more, such as two) drugs or active agents (e.g., attached to two drugs or active agents through a branched linker as described herein). For example, a conjugate includes an IL13Ra2 antibody where the a-carbon of an amino acid residue in the antibody has been modified and attached to one or two drugs or active agents (e.g., attached to two drugs or active agents through a branched linker as described herein).

[0280] Embodiments of the present disclosure include conjugates where an IL13Ra2 antibody is conjugated to two or more moieties, such as 2 moieties, 3 moieties, 4 moieties, 5 moieties, 6 moieties, 7 moieties, 8 moieties, 9 moieties, 10 moieties, 11 moieties, 12 moieties, 13 moieties, 14 moieties, 15 moieties, 16 moieties, 17 moieties, 18 moieties, 19 moieties, or 20 or more moieties. The moieties may be conjugated to the IL13Ra2 antibody at multiple sites in the antibody. In some embodiments, two moieties may be conjugated to a single amino acid residue of the IL13Ra2 antibody. For instance, two moieties may be conjugated to the same amino acid residue of the IL13Ra2 antibody. In other embodiments, two moieties are conjugated to a first amino acid residue of the IL13Ra2 antibody, and two other moieties are conjugated to a second amino acid residue of the IL13Ra2 antibody. For example, an IL13Ra2 antibody can be conjugated to first and second moieties at a first amino acid residue and conjugated to third and fourth moieties at a second amino acid residue, etc. In some cases, two or more amino acid residues in the IL13Ra2 antibody are each conjugated to a pair of moieties (e.g., two moieties), where each pair of moieties is conjugated to the IL13Ra2 antibody through a branched linker as described herein. In some cases, 1 amino acid residue inthe IL13Ra2 antibody is conjugated to a pair of moi eties through a branched linker as described herein. In other instances, 2 or more amino acid residues, such as 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid residues in the IL13Ra2 antibody are each conjugated to a pair of moieties through a branched linker as described herein.

[0281] In certain embodiments, one moiety may be conjugated to a single amino acid residue of the IL13Ra2 antibody.

[0282] The one or more amino acid residues of the IL13Ra2 antibody that are conjugated to the moieties of interest may be naturally occurring amino acids, unnatural amino acids, or combinations thereof. For instance, the conjugate may include moieties of interest (e.g., drugs or active agents) conjugated to a naturally occurring amino acid residue of the IL13Ra2 antibody. In other instances, the conjugate may include moieties of interest conjugated to an unnatural amino acid residue of the IL13Ra2 antibody. The moieties of interest may be conjugated to the IL13Ra2 antibody at a single natural or unnatural amino acid residue as described above. One or more natural or unnatural amino acid residues in the IL13Ra2 antibody may be conjugated to the moieties of interest as described herein. For example, two (or more) amino acid residues (e.g., natural or unnatural amino acid residues) in the IL13Ra2 antibody may each be conjugated to two moieties through a branched linker, such that multiple sites in the IL13Ra2 antibody are conjugated to the moieties of interest.

[0283] As described herein, an IL13Ra2 antibody may be conjugated to two or more moieties of interest. In certain embodiments, the moiety of interest is a payload, for instance, a chemical entity, such as a drug, an active agent, or a detectable label. For example, drugs (or active agents, such as cytokines) may be conjugated to the IL13Ra2 antibody, or in other embodiments, detectable labels may be conjugated to the IL13Ra2 antibody. In other embodiments, combinations of different payloads may be conjugated to the IL13Ra2 antibody. Thus, for instance, embodiments of the present disclosure include, but are not limited to, the following: a conjugate of an IL13Ra2 antibody and two or more drugs; a conjugate of an IL13Ra2 antibody and two or more active agents, such as cytokines; a conjugate of an IL13Ra2 antibody and two or more detectable labels; and combinations thereof.

[0284] In certain embodiments, the IL13Ra2 antibody and the moieties of interest (e.g., drugs or active agents) are conjugated through a conjugation moiety. For example, the IL13Ra2 antibody and the moieties of interest may each be bound (e.g., covalently bonded) to the conjugation moiety, thus indirectly binding the IL13Ra2 antibody and the moieties of interest together through the conjugation moiety. In some cases, the conjugation moietyincludes a hydrazinyl-indolyl or a hydrazinyl-pyrrolo-pyridinyl compound, or a derivative of a hydrazinyl-indolyl or a hydrazinyl-pyrrolo-pyridinyl compound. For instance, a general scheme for coupling moi eties of interest to an IL13Ra2 antibody through a hydrazinyl-indolyl or a hydrazinyl-pyrrolo-pyridinyl conjugation moiety is shown in the general reaction scheme below. Hydrazinyl-indolyl and hydrazinyl-pyrrolo-pyridinyl conjugation moieties are also referred to herein as a hydrazino- / .w-Pictet-Spengler (HIPS) conjugation moiety and an aza- hydrazino- / .w-Pictet-Spengler (azaHIPS) conjugation moiety, respectively.

[0285] In the reaction scheme above, each R independently includes a moiety of interest (e.g., drug or active agent) that is conjugated to the IL13Ra2 antibody (e.g., conjugated to the IL13Ra2 antibody through a linker as described herein), where n is an integer from 1 to 4. As shown in the reaction scheme above, a conjugation moiety (e.g., a hydrazinyl-indolyl or a hydrazinyl-pyrrolo-pyridinyl conjugation moiety) is attached to two or more drugs or active agents, R. An IL13Ra2 antibody that includes a 2-formylglycine residue (fGly) is reacted with the conjugation moiety to produce an IL13Ra2 antibody conjugate, thus attaching the two or more drugs or active agents to the IL13Ra2 antibody through the conjugation moiety. The reacted fGly residue in the produced conjugate is referred to herein as fGly’.

[0286] As described herein, the moieties can be any of a variety of moieties such as, but not limited to, chemical entities, such as detectable labels, or drugs or active agents. R’ and R” may each independently be any desired substituent, such as, but not limited to, hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acyl amino, amino acyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl. Z may be CR21, NR22, N, O or S, where R21and R22are each independently selected from any of the substituents described for R’ and R” above.

[0287] Other hydrazinyl-indolyl or hydrazinyl-pyrrolo-pyridinyl conjugation moieties are also possible, as shown in the conjugates and compounds described herein. For example, the hydrazinyl-indolyl or hydrazinyl-pyrrolo-pyridinyl conjugation moieties may be attached (e.g., covalently attached) to two or more linkers. As such, embodiments of the presentdisclosure include a hydrazinyl-indolyl or hydrazinyl-pyrrolo-pyridinyl conjugation moiety attached to two or more drugs or active agents each through a corresponding linker. Thus, conjugates of the present disclosure may include two or more linkers, where each linker attaches a corresponding drug or active agent to the hydrazinyl-indolyl or hydrazinyl-pyrrolo- pyridinyl conjugation moiety. Accordingly, the hydrazinyl-indolyl or hydrazinyl-pyrrolo- pyridinyl conjugation moiety and two or more linkers may be viewed overall as a “branched linker,” where the hydrazinyl-indolyl or hydrazinyl-pyrrolo-pyridinyl conjugation moiety is attached to two of more “branches,” where each branch includes a linker attached to a drug or active agent.

[0288] Combinations of the same or different payloads may be conjugated to the IL13Ra2 antibody through the branched linker. In certain embodiments, the two payloads (e.g., drugs, active agents, or detectable labels) attached to the branched linker are the same payload (e.g., drug, active agent, or detectable label). For example, a first branch of a branched linker may be attached to a payload (e.g., drug, active agent, or detectable label) and a second branch of the branched linker may be attached to the same payload (e.g., drug, active agent, or detectable label) as the first branch.

[0289] In other embodiments, the two payloads (e.g., drugs, active agents, or detectable labels) attached to the branched linker are different payloads (e.g, drugs, active agents, or detectable labels). For example, a first branch of a branched linker may be attached to a first payload (e.g, a first drug, active agent, or detectable label) and a second branch of the branched linker may be attached to a second payload (e.g., a second drug, active agent or detectable label) different from the first payload (e.g., the first drug, active agent or detectable label) attached to the first branch.

[0290] In some embodiments, where two different drugs or active agents are attached to the branched linker, the drugs or active agents may be selected from drugs and active agents that have a synergistic therapeutic effect. By “synergistic,” “synergism” or “synergy” is meant a therapeutic effect that is greater than the sum of the effects of the drugs or active agents taken separately. For example, in some instances, the use of two different drugs or active agents attached to the branched linker may provide a lower therapeutically effective concentration at which both payloads act, thereby increasing overall potency of the ADC.

[0291] In some embodiments, where two different drugs or active agents are attached to the branched linker, the drugs or active agents may be selected from drugs and active agents that provide an enhanced therapeutic benefit as compared to the use of the drugs or active agents separately, For example, the drugs or active agents may provide an increased effect ondrug delivery of the ADC e.g., some payloads, such as the iRGD peptide, can increase extravasation into tissues and augment tumor penetration).

[0292] In some embodiments, where two different drugs or active agents are attached to the branched linker, the drugs or active agents may be selected from drugs and active agents that use different mechanisms of action. In some cases, this may provide a decrease in tumor drug resistance by targeting multiple pathways. Examples of payload combinations can include, but are not limited to, cytotoxic drugs, immunomodulatory molecules to activate or inhibit immune cell populations, cytokines, hormones, chelating agents loaded with radioisotopes, and the like.

[0293] In some embodiments, where two different payloads are attached to the branched linker, the payloads may be selected from combinations of drugs or active agents and detectable labels. For example, a first payload may be a detectable label that is used as an imaging agent or tracer to detect the location of the ADC in vivo, while a second payload may be a drug or active agent that provides a therapeutic activity.

[0294] Various embodiments of the linkers that may couple the hydrazinyl-indolyl or hydrazinyl-pyrrolo-pyridinyl conjugation moiety to the drugs or active agents are described in detail herein. For example, in some instances, the linker is a cleavable linker, such as a cleavable linker as described herein.

[0295] In certain embodiments, the IL13Ra2 antibody may be conjugated to two or more moieties of interest, where one or more amino acids of the IL13Ra2 antibody are modified before conjugation to the moieties of interest. Modification of one or more amino acids of the IL13Ra2 antibody may produce an IL13Ra2 antibody that contains one or more reactive groups suitable for conjugation to the moieties of interest. In some cases, the IL13Ra2 antibody may include one or more modified amino acid residues to provide one or more reactive groups suitable for conjugation to the moieties of interest (e.g., where two or more moieties are attached to a conjugation moiety, such as a hydrazinyl-indolyl or a hydrazinyl- pyrrolo-pyridinyl conjugation moiety as described above). For example, an amino acid of the IL13Ra2 antibody may be modified to include a reactive aldehyde group (e.g., a reactive aldehyde). A reactive aldehyde may be included in an “aldehyde tag” or “aid-tag”, which, as used herein, refers to an amino acid sequence derived from a sulfatase motif (e.g., L(C / S)TPSR, SEQ ID NO:99) that has been converted by action of a formylglycine generating enzyme (FGE) to contain a 2-formylglycine residue (referred to herein as “fGly”). The fGly residue generated by an FGE may also be referred to as a “formylglycine.” Stated differently, the term “aldehyde tag” is used herein to refer to an amino acid sequence thatincludes a “converted” sulfatase motif (e.g., a sulfatase motif in which a cysteine or serine residue has been converted to fGly by action of an FGE, e.g., L(fGly)TPSR, SEQ ID NO: 123). A converted sulfatase motif may be produced from an amino acid sequence that includes an “unconverted” sulfatase motif (e.g., a sulfatase motif in which the cysteine or serine residue has not been converted to fGly by an FGE, but is capable of being converted, e.g., an unconverted sulfatase motif with the sequence: LCTPSR, SEQ ID NO: 100). By “conversion” as used in the context of action of a formylglycine generating enzyme (FGE) on a sulfatase motif refers to biochemical modification of a cysteine or serine residue in a sulfatase motif to a formylglycine (fGly) residue (e.g., Cys to fGly, or Ser to fGly). Additional aspects of aldehyde tags and uses thereof in site-specific protein modification are described in U.S. Patent No. 7,985,783 and U.S. Patent No. 8,729,232, the disclosures of each of which are incorporated herein by reference.

[0296] In some cases, to produce the conjugate, the IL13Ra2 antibody containing the fGly residue may be conjugated to the moieties of interest by reaction of the fGly with a compound (e.g., a compound containing a hydrazinyl-indolyl or a hydrazinyl-pyrrolo-pyridinyl conjugation moiety, as described above). For example, an fGly-containing IL13Ra2 antibody may be contacted with a reactive partner under conditions suitable to provide for conjugation of two or more drugs to the IL13Ra2 antibody. In some instances, the reactive partner may include a hydrazinyl-indolyl or a hydrazinyl-pyrrolo-pyridinyl conjugation moiety as described above. For example, two or more drugs or active agents may be attached to a hydrazinyl-indolyl or a hydrazinyl-pyrrolo-pyridinyl conjugation moiety. In some cases, the drugs or active agents are attached to a hydrazinyl-indolyl or a hydrazinyl-pyrrolo-pyridinyl conjugation moiety, such as covalently attached to a hydrazinyl-indolyl or a hydrazinyl- pyrrolo-pyridinyl, where each drug or active agent is attached through a corresponding linker to the hydrazinyl-indolyl or a hydrazinyl-pyrrolo-pyridinyl conjugation moiety. Accordingly, the fGly residue conjugated to the moieties of interest after the reaction is referred to herein as fGly’.

[0297] In certain embodiments, a conjugate of the present disclosure includes an IL13Ra2 antibody having at least one amino acid residue that has been attached to two or more moieties of interest (e.g., drugs or active agents). In order to make the conjugate, an amino acid residue of the IL13Ra2 antibody may be modified and then coupled to two or more drugs or active agents attached to a hydrazinyl-indolyl or a hydrazinyl-pyrrolo-pyridinyl conjugation moiety as described above. In certain embodiments, an amino acid residue of the IL13Ra2 antibody is a cysteine or serine residue that is modified to an fGly residue, as described above.In certain embodiments, the modified amino acid residue (e.g., fGly residue) is conjugated to two or more drugs or active agents containing a hydrazinyl-indolyl or a hydrazinyl-pyrrolo- pyridinyl conjugation moiety as described above to provide a conjugate of the present disclosure where the two or more drugs or active agents are conjugated to the IL13Ra2 antibody through the hydrazinyl-indolyl or hydrazinyl-pyrrolo-pyridinyl conjugation moiety. As used herein, the term fGly’ refers to the amino acid residue of the IL13Ra2 antibody that is coupled to the moieties of interest (e.g., drugs or active agents).

[0298] In certain embodiments, a conjugate of the present disclosure includes an IL13Ra2 antibody having at least one amino acid residue that has been attached to one or more (such as two) moieties of interest (e.g., drugs or active agents). In order to make the conjugate, an amino acid residue of the IL13Ra2 antibody may be modified and then coupled to one or more drugs or active agents (such as two) attached to a hydrazinyl-indolyl or a hydrazinyl- pyrrolo-pyridinyl conjugation moiety as described above. In certain embodiments, an IL13Ra2 antibody is modified to comprise an unconverted sulfatase motif, which in turn comprises a cysteine or serine residue that can be modified to an fGly residue, as described above. In certain embodiments, an amino acid residue of the IL13Ra2 antibody is a cysteine or serine residue that is modified to an fGly residue, as described above. In certain embodiments, the modified amino acid residue (e.g., fGly residue) is conjugated to two or more drugs or active agents containing a hydrazinyl-indolyl or a hydrazinyl-pyrrolo-pyridinyl conjugation moiety as described above to provide a conjugate of the present disclosure where the two or more drugs or active agents are conjugated to the IL13Ra2 antibody through the hydrazinyl-indolyl or hydrazinyl-pyrrolo-pyridinyl conjugation moiety. As used herein, the term fGly’ refers to the amino acid residue of the IL13Ra2 antibody that is coupled to the moieties of interest (e.g., drugs or active agents).

[0299] In certain embodiments, the conjugate includes an IL13Ra2 antibody having at least one amino acid residue attached to a branched linker as described herein, which in turn is attached to two or more drugs or active agents. For instance, the conjugate may include an IL13Ra2 antibody having at least one amino acid residue (fGly’) that is conjugated to the moieties of interest (e.g., drugs or active agents) as described above.

[0300] In certain embodiments, the conjugate includes an IL13Ra2 antibody having at least one amino acid residue attached to a branched linker as described herein, which in turn is attached to one or more drugs or active agents (such as two). For instance, the conjugate may include an IL13Ra2 antibody having at least one amino acid residue (fGly’) that is conjugated to the moieties of interest (e.g., drugs or active agents) as described above.7.2.1 Antibody Drug Conjugates (ADCs)

[0301] In some embodiments, provided herein is an IL13Ra2-ADC of Formula (A):wherein Ab represents an antibody that binds to interleukin- 13 receptor subunit alpha-2 (IL13Ra2); L represents a linker; s is an integer from 1 to 20; and W1represents a drug.

[0286] In further embodiments, Ab comprises any one or more of (i)-(iii): (i) a heavy chain variable region (VH) complementarity determining region 1 (CDR1), a VH complementarity determining region 2 (CDR2), and a VH complementarity determining region 3 (CDR3) as set forth in a VH comprising the amino acid sequence of SEQ ID NO:25 and a light chain variable region (VL) CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:26; or (ii) a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:48 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:49; or (iii) a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:73 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:74. In yet further embodiments, Ab is an IL13Ra2 antibody as disclosed herein. For example, see the descriptions and embodiments relating to an IL13Ra2 antibody detailed below in Sections 7.3 and 7.4.

[0287] Additionally or alternatively, s is an integer from 1 to 10, for example 1 to 8. In some embodiments, s is 2. In some embodiments, s is 4.

[0288] Additionally or alternatively, L comprises a conjugation moiety as disclosed herein. In some embodiments, L comprises a pyridazine-pyrrolo coupling moiety. In some embodiments, the conjugation moiety is a pyridazine-pyrrolo coupling moiety. In some embodiments, the conjugation moiety is a hydrazinyl-indolyl compound or a derivative thereof. In some embodiments, the conjugation moiety is a hydrazinyl-pyrrolo-pyridinyl compound, or a derivative thereof. In further embodiments, L comprises linker (L-I’):(L-E) wherein represents the point of attachment to Ab; and# represents the point of attachment to W1. In yet further embodiments, t is 0 or 1. In some embodiments, Z1, Z2, Z3, and Z4are each independently selected from CR4, N, OR4, SR4, and C-LB-$, and $ represents the point of attachment to a second drug W2. In some embodiments, Z1, Z2, Z3, and Z4are each independently selected from CR4, N, and C-LB-$, and $ represents the point of attachment to a second drug W2. In some embodiments, R1, R2, R3, and R4are each selected from hydrogen and alkyl. In some embodiments, LAis a first linker comprising:-(T1-V1)a-(T2-V2)b-(T3-V3)c-(T4-V4)d-(T5-V5)e-(T6-V6)f-, wherein: a, b, c, d, e, and f are each independently 0 or 1, provided at least one of a, b, c, d, e, and f are 1 ;T1, T2, T3, T4, T5and T6are each independently selected from a covalent bond, (Ci-Ci2)alkyl, substituted (Ci-Ci2)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, (EDA)w, (PEG)n, (AA)P, -(CR13OH)X-, 4-amino-piperidine (4AP), meta-amino-benzyloxy (MABO), meta-amino-benzyloxycarbonyl (MABC), para-amino-benzyloxy (PABO), para-amino-benzyloxycarbonyl (PABC), para-aminobenzyl (PAB), para-amino- benzylamino (PAB A), para-amino-phenyl (PAP), para-hydroxy-phenyl (PHP), an acetal group, a hydrazine, a disulfide, and an ester, wherein EDA is an ethylene diamine moiety, PEG is a polyethylene glycol, and AA is an amino acid residue or an amino acid analog, wherein each w is an integer from 1 to 20, each n is an integer from 1 to 30, each p is an integer from 1 to 20, and each x is an integer from 1 to 12;V1, V2, V3, V4, V5and V6are each independently selected from the group consisting of a covalent bond, -CO-, -NR15-, -NR15(CH2)q-, -NR15(CeH4)-, -CONR15-,-NR15CO-, -C(0)0-, -0C(0)-, -0-, -S-, -S(0)-, -SO2-, -SO2NR15-, -NR15SO2- and -P(O)OH-, wherein each q is an integer from 1 to 6; each R13is independently selected from hydrogen, an alkyl, a substituted alkyl, an aryl, and a substituted aryl; and each R15is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, carboxyl, carboxyl ester, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl.In some embodiments, LBis a second linker comprising:-(T7-V7)g-(T8-V8)h-(T9-V9)i-(T10-V10)j-(T11-V11)k-(T12-V12)i-(T13-V13)m-, wherein: g, h, i, j, k, 1, and m are each independently 0 or 1, provided that at least one of g, h, i, j, k, 1, and m is 1;T7, T8, T9, T10, T11, T12and T13are each independently selected from a covalent bond, (Ci-Ci2)alkyl, substituted (Ci-Ci2)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, (EDA)w, (PEG)n, (AA)P, -(CR13OH)X-, 4-amino-piperidine (4AP), meta-amino-benzyloxy (MABO), meta-amino-benzyloxycarbonyl (MABC), para-amino-benzyloxy (PABO), para-amino-benzyloxycarbonyl (PABC), para-aminobenzyl (PAB), para-amino- benzylamino (PAB A), para-amino-phenyl (PAP), para-hydroxy-phenyl (PHP), an acetal group, a hydrazine, a disulfide, and an ester, wherein EDA is an ethylene diamine moiety, PEG is a polyethylene glycol, and AA is an amino acid residue or an amino acid analog, wherein each w is an integer from 1 to 20, each n is an integer from 1 to 30, each p is an integer from 1 to 20, and each x is an integer from 1 to 12;V7, V8, V9, V10, V11, V12and V13are each independently selected from the group consisting of a covalent bond, -CO-, -NR15-, -NR15(CH2)q-, -NR15(CeH4)-, -CONR15-, - NR15CO-, -C(O)O-, -OC(O)-, -O-, -S-, -S(O)-, -SO2-, -SO2NR15-, -NR15SO2- and - P(O)OH-, wherein each q is an integer from 1 to 6; each R13is independently selected from hydrogen, an alkyl, a substituted alkyl, an aryl, and a substituted aryl; and each R15is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, carboxyl, carboxyl ester, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl.

[0302] In further embodiments, at least one of Z1, Z2, Z3, and Z4is C-LB-$, and $ represents the point of attachment to a second drug W2. In yet further embodiments, Z3is C- LB-$. In some embodiments, t is 1. In further embodiments, Z1, Z2, and Z4are each independently CR4. In yet further embodiments, Z3is C-LB-W2. In some embodiments, L comprises a conjugation moiety as described herein, such as a hydrazinyl-indolyl compound or a derivative thereof.

[0303] Accordingly, in some embodiments, L comprises Linker (L-I):

[0304] In further embodiments, one or more of the components (such as R1, R2, R3, Z1, Z2, Z3, Z4, LA, W1, LB, or W2) of an ADC which is represented by Formula (A) and comprises an L represented by Formula (L-I) are further detailed below in Section 7.2.2, For example, see the descriptions and embodiments relating to Formula (I).

[0305] In some embodiments, Z1is X^Y1, Z2is X2-Y2, Z3is X3-Y3, and Z4is X4-Y4, wherein each of X1, X2, X3, and X4represents an atom in the ring of Formula (L-F). In further embodiments, R1is hydrogen. Accordingly, in some embodiments, L comprises Linker (L- III):(L-III).

[0306] In further embodiments, one or more of the components (such as R2, R3, X1, X2, X3, X4, Y1, Y2, Y3, Y4, LA, W1) of an ADC which is represented by Formula (A) and comprises an L represented by Formula (L-III) are further detailed below in Section 7.2.3, For example, see the descriptions and embodiments relating to Formula (III). In some embodiments, L comprises a conjugation moiety as described herein, such as a hydrazinyl-pyrrolo-pyridinyl compound, or a derivative of each thereof.

[0307] In some embodiments, W1comprises: (i) a camptothecin or an analog thereof, such as belotecan; or (ii) an auristatin or an analog thereof, such as MMAE. In further embodiments, W1comprises belotecan. In other embodiments, W1comprises MMAE.

[0308] In some embodiments, W2comprises: (i) a camptothecin or an analog thereof, such as belotecan; or (ii) an auristatin or an analog thereof, such as MMAE. In yet further embodiments, W2comprises belotecan. In other embodiments, W2comprises MMAE. Additionally or alternatively, W1and W2are the same. In other embodiments, W1and W2are different.7.2.2 Dual Drug Linker Payloads

[0309] In one embodiment, the present disclosure provides an IL13Ra2-ADC of Formula (I):wherein:Ab represents the antibody that binds to IL13Ra2;Z1, Z2, Z3and Z4are each independently selected from CR4, N and C-LB-W2, wherein at least one of Z1, Z2, Z3and Z4is C-LB-W2;R1is selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl;R2and R3are each independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acyl amino, amino acyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, or R2and R3are optionally cyclically linked to form a 5 or 6-membered heterocyclyl; each R4is independently selected from hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acyl amino, amino acyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl;LAis a first linker;LBis a second linker; s is an integer from 1 to 10;W1is a first drug; andW2is a second drug.

[0310] The substituents related to conjugates of Formula (I) are described in more detail below.

[0311] In certain embodiments, Z1, Z2, Z3and Z4are each independently selected from CR4, N and C-LB-W2, wherein at least one of Z1, Z2, Z3and Z4is C-LB-W2. In certain embodiments, Z1is CR4. In certain embodiments, Z1is N. In certain embodiments, Z1is C- LB-W2. In certain embodiments, Z2is CR4. In certain embodiments, Z2is N. In certain embodiments, Z2is C-LB-W2. In certain embodiments, Z3is CR4. In certain embodiments, Z3is N. In certain embodiments, Z3is C-LB-W2. In certain embodiments, Z4is CR4. In certain embodiments, Z4is N. In certain embodiments, Z4is C-LB-W2. In some embodiments, each of Z1, Z3, and Z4is CR4. In some embodiments, Z3is C-LB-W2.

[0312] Combinations of various Z1, Z2, Z3and Z4are possible. For example, in some instances, Z1is C-LB-W2, Z2is CR4, Z3is CR4, and Z4is CR4. In some instances, Z1is CR4, Z2is C-LB-W2, Z3is CR4, and Z4is CR4. In some instances, Z1is CR4, Z2is CR4, Z3is C-LB-W2, and Z4is CR4. In some instances, Z1is CR4, Z2is CR4, Z3is CR4, and Z4is C-LB-W2.

[0313] In certain embodiments, R1is selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl. In certain embodiments, R1is hydrogen. In certain embodiments, R1is alkyl or substituted alkyl, such as Ci-6 alkyl or Ci-6 substituted alkyl, or Ci-4 alkyl or Ci-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl. In certain embodiments, R1is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl. In certain embodiments, R1is alkynyl or substituted alkynyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl. In certain embodiments, R1is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a Cs aryl or Cs substituted aryl, or a Ce aryl or Ce substituted aryl. In certain embodiments, R1is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a Cs heteroaryl or Cs substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl. In certain embodiments, R1is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl. In certain embodiments, R1is heterocyclyl or substituted heterocyclyl, such as C3-8 heterocyclyl or C3-8 substituted heterocyclyl, such as a C3-6 heterocyclyl or C3-6 substituted heterocyclyl, or a C3-5 heterocyclyl or C3-5 substituted heterocyclyl.

[0314] In certain embodiments, R2and R3are each independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acyl amino, amino acyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, or R2and R3are optionally cyclically linked to form a 5 or 6-membered heterocyclyl.

[0315] In certain embodiments, R2is selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acyl amino, amino acyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl. In certain embodiments, R2is hydrogen. In certain embodiments, R2is alkyl or substituted alkyl, such as Ci-6 alkyl or Ci-6 substituted alkyl, or Ci-4 alkyl or Ci-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl. In certain embodiments, R2is methyl. In certain embodiments, R2is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl. In certain embodiments, R2is alkynyl or substituted alkynyl. In certain embodiments, R2is alkoxy or substituted alkoxy. In certain embodiments, R2is amino or substituted amino. In certain embodiments, R2is carboxyl or carboxyl ester. In certain embodiments, R2is acyl or acyloxy. In certain embodiments, R2is acyl amino or amino acyl. In certain embodiments, R2is alkylamide or substituted alkylamide. In certain embodiments, R2is sulfonyl. In certain embodiments, R2is thioalkoxy or substituted thioalkoxy. In certain embodiments, R2is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a Cs aryl or Cs substituted aryl, or a Ce aryl or Ce substituted aryl. In certain embodiments, R2is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a Cs heteroaryl or Cs substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl. In certain embodiments, R2is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl. In certain embodiments, R2is heterocyclyl or substituted heterocyclyl, such as a C3-6 heterocyclyl or C3-6 substituted heterocyclyl, or a C3-5 heterocyclyl or C3-5 substituted heterocyclyl.

[0316] In certain embodiments, R3is selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino,substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acyl amino, amino acyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl. In certain embodiments, R3is hydrogen. In certain embodiments, R3is alkyl or substituted alkyl, such as Ci-6 alkyl or Ci-6 substituted alkyl, or Ci-4 alkyl or Ci-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl. In certain embodiments, R3is methyl. In certain embodiments, R3is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl. In certain embodiments, R3is alkynyl or substituted alkynyl. In certain embodiments, R3is alkoxy or substituted alkoxy. In certain embodiments, R3is amino or substituted amino. In certain embodiments, R3is carboxyl or carboxyl ester. In certain embodiments, R3is acyl or acyloxy. In certain embodiments, R3is acyl amino or amino acyl. In certain embodiments, R3is alkylamide or substituted alkylamide. In certain embodiments, R3is sulfonyl. In certain embodiments, R3is thioalkoxy or substituted thioalkoxy. In certain embodiments, R3is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a Cs aryl or Cs substituted aryl, or a Ce aryl or Ce substituted aryl. In certain embodiments, R3is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a Cs heteroaryl or Cs substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl. In certain embodiments, R3is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl. In certain embodiments, R3is heterocyclyl or substituted heterocyclyl, such as C3-8 heterocyclyl or C3-8 substituted heterocyclyl, such as a C3-6 heterocyclyl or C3-6 substituted heterocyclyl, or a C3-5 heterocyclyl or C3-5 substituted heterocyclyl.

[0317] In certain embodiments, both R2and R3are methyl.

[0318] In certain embodiments, R2and R3are optionally cyclically linked to form a 5 or 6- membered heterocyclyl. In certain embodiments, R2and R3are cyclically linked to form a 5 or 6-membered heterocyclyl. In certain embodiments, R2and R3are cyclically linked to form a 5-membered heterocyclyl. In certain embodiments, R2and R3are cyclically linked to form a 6-membered heterocyclyl.

[0319] In certain embodiments, each R4is independently selected from hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acyl amino, amino acyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substitutedthioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl.

[0320] The various possibilities for each R4are described in more detail as follows. In certain embodiments, R4is hydrogen. In certain embodiments, each R4is hydrogen. In certain embodiments, R4is halogen, such as F, Cl, Br, or I. In certain embodiments, R4is F. In certain embodiments, R4is Cl. In certain embodiments, R4is Br. In certain embodiments, R4is I. In certain embodiments, R4is alkyl or substituted alkyl, such as Ci-6 alkyl or Ci-6 substituted alkyl, or Ci-4 alkyl or Ci-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl. In certain embodiments, R4is methyl. In certain embodiments, R4is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl. In certain embodiments, R4is alkynyl or substituted alkynyl. In certain embodiments, R4is alkoxy or substituted alkoxy. In certain embodiments, R4is amino or substituted amino. In certain embodiments, R4is carboxyl or carboxyl ester. In certain embodiments, R4is acyl or acyloxy. In certain embodiments, R4is acyl amino or amino acyl. In certain embodiments, R4is alkylamide or substituted alkylamide. In certain embodiments, R4is sulfonyl. In certain embodiments, R4is thioalkoxy or substituted thioalkoxy. In certain embodiments, R4is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a Cs aryl or Cs substituted aryl, or a Ce aryl or Ce substituted aryl (e.g., phenyl or substituted phenyl). In certain embodiments, R4is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a Cs heteroaryl or Cs substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl. In certain embodiments, R4is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl. In certain embodiments, R4is heterocyclyl or substituted heterocyclyl, such as C3-8 heterocyclyl or C3-8 substituted heterocyclyl, such as a C3-6 heterocyclyl or C3-6 substituted heterocyclyl, or a C3-5 heterocyclyl or C3-5 substituted heterocyclyl.

[0321] In certain embodiments, LAis a first linker. Examples of linkers that can be used in the conjugates of the present disclosure are described in more detail below.

[0322] In certain embodiments, LBis a second linker. Examples of linkers that can be used in the conjugates of the present disclosure are described in more detail below.

[0323] In certain embodiments, W1is a first drug (or a first active agent). Examples of drugs and active agents that can be used in the conjugates of the present disclosure are described in more detail below.

[0324] In certain embodiments, W2is a second drug (or a second active agent). Examples of drugs and active agents that can be used in the conjugates of the present disclosure are described in more detail below.

[0325] In certain embodiments, Ab represents an antibody that binds to IL13Ra2 (“IL13Ra2 antibody”). In certain embodiments, Ab comprises one or more fGly’ residues as described herein. In certain embodiments, the IL13Ra2 antibody is attached to the rest of the conjugate through an fGly’ residue as described herein. Examples of IL13Ra2 antibodies that can be used in the conjugates of the present disclosure are described in more detail below.

[0326] In certain embodiments, the conjugate of Formula (I) includes a first linker, LA. The first linker, LA, may be utilized to bind a first moiety of interest (e.g., a first drug or active agent) to an IL13Ra2 antibody through a conjugation moiety. The first linker, LA, may be bound (e.g., covalently bonded) to the conjugation moiety (e.g., as described herein). For example, the first linker, LA, may attach a hydrazinyl-indolyl or a hydrazinyl-pyrrolo- pyridinyl conjugation moiety to a first drug. The hydrazinyl-indolyl or hydrazinyl-pyrrolo- pyridinyl conjugation moiety may be used to conjugate the first linker, LA, (and thus the first drug) to an IL13Ra2 antibody.

[0327] For example, as shown in Formula (I) above, LAis attached to Ab through a conjugation moiety, and thus Ab is indirectly bonded to the linker LAthrough the hydrazinyl- indolyl or a hydrazinyl-pyrrolo-pyridinyl conjugation moiety. As described above, Ab is an IL13Ra2 antibody, and thus LAis attached through the hydrazinyl-indolyl or a hydrazinyl- pyrrolo-pyridinyl conjugation moiety to the IL13Ra2 antibody, e.g, the linker LAis indirectly bonded to the IL13Ra2 antibody through the hydrazinyl-indolyl or a hydrazinyl-pyrrolo- pyridinyl conjugation moiety.

[0328] Any convenient linker may be utilized for the first linker LAin the subject conjugates and compounds. In certain embodiments, the first linker LAmay include a group selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl amino, alkylamide, substituted alkylamide, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl. In certain embodiments, the first linker LAmay include an alkyl or substituted alkyl group. In certain embodiments, the first linker LAmay include an alkenyl or substituted alkenyl group. In certain embodiments, the first linker LAmay include an alkynyl or substituted alkynyl group. In certain embodiments, the first linker LAmay include an alkoxy or substituted alkoxy group. In certain embodiments, the first linker LAmay include an amino or substituted aminogroup. In certain embodiments, the first linker LAmay include a carboxyl or carboxyl ester group. In certain embodiments, the first linker LAmay include an acyl amino group. In certain embodiments, the first linker LAmay include an alkylamide or substituted alkylamide group. In certain embodiments, the first linker LAmay include an aryl or substituted aryl group. In certain embodiments, the first linker LAmay include a heteroaryl or substituted heteroaryl group. In certain embodiments, the first linker LAmay include a cycloalkyl or substituted cycloalkyl group. In certain embodiments, the first linker LAmay include a heterocyclyl or substituted heterocyclyl group.

[0329] In certain embodiments, the first linker LAmay include a polymer. For example, the polymer may include a polyalkylene glycol and derivatives thereof, including polyethylene glycol, methoxypolyethylene glycol, polyethylene glycol homopolymers, polypropylene glycol homopolymers, copolymers of ethylene glycol with propylene glycol (e.g., where the homopolymers and copolymers are unsubstituted or substituted at one end with an alkyl group), polyvinyl alcohol, polyvinyl ethyl ethers, polyvinylpyrrolidone, combinations thereof, and the like. In certain embodiments, the polymer is a polyalkylene glycol. In certain embodiments, the polymer is a polyethylene glycol. Other linkers are also possible, as shown in the conjugates and compounds described in more detail below.

[0330] In some embodiments, LAis a first linker described by the formula:wherein L1, L2, L3, L4, L5and L6are each independently a linker subunit, and a, b, c, d, e, and f are each independently 0 or 1, provided that at least one of a, b, c, d, e, and f is 1.

[0331] In certain embodiments, the sum of a, b, c, d, e, and f is 1 to 6. In certain embodiments, the sum of a, b, c, d, e, and f is 1. In certain embodiments, the sum of a, b, c, d, e, and f is 2. In certain embodiments, the sum of a, b, c, d, e, and f is 3. In certain embodiments, the sum of a, b, c, d, e, and f is 4. In certain embodiments, the sum of a, b, c, d, e, and f is 5. In certain embodiments, the sum of a, b, c, d, e, and f is 6. In certain embodiments, a, b, c, d, e, and f are each 1. In certain embodiments, a, b, c, d, and e are each 1 and f is 0. In certain embodiments, a, b, c, and d are each 1 and e and f are each 0. In certain embodiments, a, b, and c are each 1 and d, e and f are each 0. In certain embodiments, a and b are each 1 and c, d, e, and f are each 0. In certain embodiments, a is 1 and b, c, d, e, and f are each 0.

[0332] In certain embodiments, the linker subunit L1is attached to the hydrazinyl-indolyl or a hydrazinyl-pyrrolo-pyridinyl conjugation moiety (e.g., as shown in Formula (I) above). In certain embodiments, the linker subunit L2, if present, is attached to the first drug or activeagent W1. In certain embodiments, the linker subunit L3, if present, is attached to the first drug or active agent W1. In certain embodiments, the linker subunit L4, if present, is attached to the first drug or active agent W1. In certain embodiments, the linker subunit L5, if present, is attached to the first drug or active agent W1. In certain embodiments, the linker subunit L6, if present, is attached to the first drug or active agent W1.

[0333] Any convenient linker subunits may be utilized in the first linker LA. Linker subunits of interest include, but are not limited to, units of polymers such as polyethylene glycols, polyethylenes and polyacrylates, amino acid residue(s), carbohydrate-based polymers or carbohydrate residues and derivatives thereof, polynucleotides, alkyl groups, aryl groups, heterocyclic groups, combinations thereof, and substituted versions thereof. In some embodiments, each of L1, L2, L3, L4, L5and L6(if present) comprise one or more groups independently selected from a polyethylene glycol, a modified polyethylene glycol, an amino acid residue, an alkyl group, a substituted alkyl, an aryl group, a substituted aryl group, and a diamine (e.g., a linking group that includes an alkylene diamine).

[0334] In some embodiments, L1(if present) comprises a polyethylene glycol, a modified polyethylene glycol, an amino acid residue, an alkyl group, a substituted alkyl, an aryl group, a substituted aryl group, or a diamine. In some embodiments, L1comprises a polyethylene glycol. In some embodiments, L1comprises a modified polyethylene glycol. In some embodiments, L1comprises an amino acid residue. In some embodiments, L1comprises an alkyl group or a substituted alkyl. In some embodiments, L1comprises an aryl group or a substituted aryl group. In some embodiments, L1comprises a diamine (e.g., a linking group comprising an alkylene diamine).

[0335] In some embodiments, L2(if present) comprises a polyethylene glycol, a modified polyethylene glycol, an amino acid residue, an alkyl group, a substituted alkyl, an aryl group, a substituted aryl group, or a diamine. In some embodiments, L2comprises a polyethylene glycol. In some embodiments, L2comprises a modified polyethylene glycol. In some embodiments, L2comprises an amino acid residue. In some embodiments, L2comprises an alkyl group or a substituted alkyl. In some embodiments, L2comprises an aryl group or a substituted aryl group. In some embodiments, L2comprises a diamine (e.g., a linking group comprising an alkylene diamine).

[0336] In some embodiments, L3(if present) comprises a polyethylene glycol, a modified polyethylene glycol, an amino acid residue, an alkyl group, a substituted alkyl, an aryl group, a substituted aryl group, or a diamine. In some embodiments, L3comprises a polyethylene glycol. In some embodiments, L3comprises a modified polyethylene glycol. In someembodiments, L3comprises an amino acid residue. In some embodiments, L3comprises an alkyl group or a substituted alkyl. In some embodiments, L3comprises an aryl group or a substituted aryl group. In some embodiments, L3comprises a diamine (e.g., a linking group comprising an alkylene diamine).

[0337] In some embodiments, L4(if present) comprises a polyethylene glycol, a modified polyethylene glycol, an amino acid residue, an alkyl group, a substituted alkyl, an aryl group, a substituted aryl group, or a diamine. In some embodiments, L4comprises a polyethylene glycol. In some embodiments, L4comprises a modified polyethylene glycol. In some embodiments, L4comprises an amino acid residue. In some embodiments, L4comprises an alkyl group or a substituted alkyl. In some embodiments, L4comprises an aryl group or a substituted aryl group. In some embodiments, L4comprises a diamine (e.g., a linking group comprising an alkylene diamine).

[0338] In some embodiments, L5(if present) comprises a polyethylene glycol, a modified polyethylene glycol, an amino acid residue, an alkyl group, a substituted alkyl, an aryl group, a substituted aryl group, or a diamine. In some embodiments, L5comprises a polyethylene glycol. In some embodiments, L5comprises a modified polyethylene glycol. In some embodiments, L5comprises an amino acid residue. In some embodiments, L5comprises an alkyl group or a substituted alkyl. In some embodiments, L5comprises an aryl group or a substituted aryl group. In some embodiments, L5comprises a diamine (e.g., a linking group comprising an alkylene diamine).

[0339] In some embodiments, L6(if present) comprises a polyethylene glycol, a modified polyethylene glycol, an amino acid residue, an alkyl group, a substituted alkyl, an aryl group, a substituted aryl group, or a diamine. In some embodiments, L6comprises a polyethylene glycol. In some embodiments, L6comprises a modified polyethylene glycol. In some embodiments, L6comprises an amino acid residue. In some embodiments, L6comprises an alkyl group or a substituted alkyl. In some embodiments, L6comprises an aryl group or a substituted aryl group. In some embodiments, L6comprises a diamine (e.g., a linking group comprising an alkylene diamine).

[0340] In some embodiments, LAis a first linker comprising: -(L1)a-(L2)b-(L3)c-(L4)d-(L5)e-(L6)f-, wherein:-(L3)c- is -(T3-V3)C-;-(L4)d- is -(T4-V4)d-;-(L5)e- is -(T5-V5)e-; and -(L6)f- is -(T6-V6)f-, wherein:T1, T2, T3, T4, T5and T6, if present, are tether groups;V1, V2, V3, V4, V5and V6, if present, are covalent bonds or linking functional groups; and a, b, c, d, e, and f are each independently 0 or 1, provided that at least one of a, b, c, d, e, and f is 1.

[0341] In certain embodiments, the sum of a, b, c, d, e, and f is 1 to 6. In certain embodiments, the sum of a, b, c, d, e, and f is 1. In certain embodiments, the sum of a, b, c, d, e, and f is 2. In certain embodiments, the sum of a, b, c, d, e, and f is 3. In certain embodiments, the sum of a, b, c, d, e, and f is 4. In certain embodiments, the sum of a, b, c, d, e, and f is 5. In certain embodiments, the sum of a, b, c, d, e, and f is 6. In certain embodiments, a, b, c, d, e, and f are each 1. In certain embodiments, a, b, c, d, and e are each 1 and f is 0. In certain embodiments, a, b, c, and d are each 1 and e and f are each 0. In certain embodiments, a, b, and c are each 1 and d, e and f are each 0. In certain embodiments, a and b are each 1 and c, d, e, and f are each 0. In certain embodiments, a is 1 and b, c, d, e, and f are each 0.

[0342] As described above, in certain embodiments, L1is attached to the hydrazinyl- indolyl or a hydrazinyl-pyrrolo-pyridinyl conjugation moiety (e.g., as shown in Formula (I) above). As such, in certain embodiments, T1is attached to the hydrazinyl-indolyl or a hydrazinyl-pyrrolo-pyridinyl conjugation moiety (e.g., as shown in Formula (I) above). In certain embodiments, V1is attached to the first drug or active agent. In certain embodiments, L2, if present, is attached to the first drug or active agent. As such, in certain embodiments, T2, if present, is attached to the first drug or active agent, or V2, if present, is attached to the first drug or active agent. In certain embodiments, L3, if present, is attached to the first drug or active agent. As such, in certain embodiments, T3, if present, is attached to the first drug or active agent, or V3, if present, is attached to the first drug or active agent. In certain embodiments, L4, if present, is attached to the first drug or active agent. As such, in certain embodiments, T4, if present, is attached to the first drug or active agent, or V4, if present, is attached to the first drug or active agent. In certain embodiments, L5, if present, is attached to the first drug or active agent. As such, in certain embodiments, T5, if present, is attached to the first drug or active agent, or V5, if present, is attached to the first drug or active agent. Incertain embodiments, L6, if present, is attached to the first drug or active agent. As such, in certain embodiments, T6, if present, is attached to the first drug or active agent, or V6, if present, is attached to the first drug or active agent.

[0343] In certain embodiments, the conjugate of Formula (I) includes a second linker, LB. The second linker, LB, may be utilized to bind a second moiety of interest (e.g., a second drug or active agent) to an IL13Ra2 antibody through a conjugation moiety. The second linker, LB, may be bound (e.g., covalently bonded) to the conjugation moiety (e.g., as described herein). For example, the second linker, LB, may attach a hydrazinyl-indolyl or a hydrazinyl-pyrrolo- pyridinyl conjugation moiety to a second drug. The hydrazinyl-indolyl or hydrazinyl-pyrrolo- pyridinyl conjugation moiety may be used to conjugate the second linker, LB, (and thus the second drug) to an IL13Ra2 antibody.

[0344] For example, as shown in Formula (I) above, LBis attached to Ab through a conjugation moiety, and thus Ab is indirectly bonded to the second linker LBthrough the hydrazinyl-indolyl or a hydrazinyl-pyrrolo-pyridinyl conjugation moiety. As described above, Ab is an IL13Ra2 antibody, and thus LBis attached through the hydrazinyl-indolyl or a hydrazinyl-pyrrolo-pyridinyl conjugation moiety to the IL13Ra2 antibody, e.g., the linker LBis indirectly bonded to the IL13Ra2 antibody through the hydrazinyl-indolyl or a hydrazinyl- pyrrolo-pyridinyl conjugation moiety.

[0345] Any convenient linker may be utilized for the second linker LBin the subject conjugates and compounds. In certain embodiments, the second linker LBmay include a group selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl amino, alkylamide, substituted alkylamide, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl. In certain embodiments, the second linker LBmay include an alkyl or substituted alkyl group. In certain embodiments, the second linker LBmay include an alkenyl or substituted alkenyl group. In certain embodiments, the second linker LBmay include an alkynyl or substituted alkynyl group. In certain embodiments, the second linker LBmay include an alkoxy or substituted alkoxy group. In certain embodiments, the second linker LBmay include an amino or substituted amino group. In certain embodiments, the second linker LBmay include a carboxyl or carboxyl ester group. In certain embodiments, the second linker LBmay include an acyl amino group. In certain embodiments, the second linker LBmay include an alkylamide or substituted alkylamide group. In certain embodiments, the second linker LBmay include an aryl or substituted aryl group. In certain embodiments, the second linker LBmay include aheteroaryl or substituted heteroaryl group. In certain embodiments, the second linker LBmay include a cycloalkyl or substituted cycloalkyl group. In certain embodiments, the second linker LBmay include a heterocyclyl or substituted heterocyclyl group.

[0346] In certain embodiments, the second linker LBmay include a polymer. For example, the polymer may include a polyalkylene glycol and derivatives thereof, including polyethylene glycol, methoxypolyethylene glycol, polyethylene glycol homopolymers, polypropylene glycol homopolymers, copolymers of ethylene glycol with propylene glycol (e.g., where the homopolymers and copolymers are unsubstituted or substituted at one end with an alkyl group), polyvinyl alcohol, polyvinyl ethyl ethers, polyvinylpyrrolidone, combinations thereof, and the like. In certain embodiments, the polymer is a polyalkylene glycol. In certain embodiments, the polymer is a polyethylene glycol. Other linkers are also possible, as shown in the conjugates and compounds described in more detail below.

[0347] In some embodiments, LBis a second linker described by the formula:wherein L7, L8, L9, L10, L11, L12and L13are each independently a linker subunit, and g, h, i, j, k, 1, and m are each independently 0 or 1, provided at least one of g, h, i, j, k, 1, and m is 1.

[0348] In certain embodiments, the sum of g, h, i, j, k, 1, and m is 1 to 7. In certain embodiments, the sum of g, h, i, j, k, 1, and m is 1. In certain embodiments, the sum of g, h, i, j, k, 1, and m is 2. In certain embodiments, the sum of g, h, i, j, k, 1, and m is 3. In certain embodiments, the sum of g, h, i, j, k, 1, and m is 4. In certain embodiments, the sum of g, h, i, j, k, 1, and m is 5. In certain embodiments, the sum of g, h, i, j, k, 1, and m is 6. In certain embodiments, the sum of g, h, i, j, k, 1, and m is 7. In certain embodiments, g, h, i, j, k, 1, and m are each 1. In certain embodiments, g, h, i, j, k and 1 are each 1 and m is 0. In certain embodiments, g, h, i, j and k are each 1 and 1 and m are each 0. In certain embodiments, g, h, i and j are each 1 and k, 1 and m are each 0. In certain embodiments, g, h, and i are each 1 and j, k, 1, and m are each 0. In certain embodiments, g and h are each 1 and i, j, k, 1, and m are each 0. In certain embodiments, g is 1 and h, i, j, k, 1, and m are each 0. In certain embodiments, g, h, i, j, k, 1, and m are each 0.

[0349] In certain embodiments, the linker subunit L7is attached to the hydrazinyl-indolyl or a hydrazinyl-pyrrolo-pyridinyl conjugation moiety (e.g., as shown in Formula (I) above). In certain embodiments, the linker subunit L8, if present, is attached to the second drug or active agent W2. In certain embodiments, the linker subunit L9, if present, is attached to the second drug or active agent W2. In certain embodiments, the linker subunit L10, if present, is attached to the second drug or active agent W2. In certain embodiments, the linker subunit L11, ifpresent, is attached to the second drug or active agent W2. In certain embodiments, the linker subunit L12, if present, is attached to the second drug or active agent W2. In certain embodiments, the linker subunit L13, if present, is attached to the second drug or active agent W2.

[0350] Any convenient linker subunits may be utilized in the second linker LB. Linker subunits of interest include, but are not limited to, units of polymers such as polyethylene glycols, polyethylenes and polyacrylates, amino acid residue(s), carbohydrate-based polymers or carbohydrate residues and derivatives thereof, polynucleotides, alkyl groups, aryl groups, heterocyclic groups, combinations thereof, and substituted versions thereof. In some embodiments, each of L7, L8, L9, L10, L11, L12and L13(if present) comprise one or more groups independently selected from a polyethylene glycol, a modified polyethylene glycol, an amino acid residue, an alkyl group, a substituted alkyl, an aryl group, a substituted aryl group, and a diamine (e.g., a linking group that includes an alkylene diamine).

[0351] In some embodiments, L7(if present) comprises a polyethylene glycol, a modified polyethylene glycol, an amino acid residue, an alkyl group, a substituted alkyl, an aryl group, a substituted aryl group, or a diamine. In some embodiments, L7comprises a polyethylene glycol. In some embodiments, L7comprises a modified polyethylene glycol. In some embodiments, L7comprises an amino acid residue. In some embodiments, L7comprises an alkyl group or a substituted alkyl. In some embodiments, L7comprises an aryl group or a substituted aryl group. In some embodiments, L7comprises a diamine (e.g., a linking group comprising an alkylene diamine).

[0352] In some embodiments, L8(if present) comprises a polyethylene glycol, a modified polyethylene glycol, an amino acid residue, an alkyl group, a substituted alkyl, an aryl group, a substituted aryl group, or a diamine. In some embodiments, L8comprises a polyethylene glycol. In some embodiments, L8comprises a modified polyethylene glycol. In some embodiments, L8comprises an amino acid residue. In some embodiments, L8comprises an alkyl group or a substituted alkyl. In some embodiments, L8comprises an aryl group or a substituted aryl group. In some embodiments, L8comprises a diamine (e.g., a linking group comprising an alkylene diamine).

[0353] In some embodiments, L9(if present) comprises a polyethylene glycol, a modified polyethylene glycol, an amino acid residue, an alkyl group, a substituted alkyl, an aryl group, a substituted aryl group, or a diamine. In some embodiments, L9comprises a polyethylene glycol. In some embodiments, L9comprises a modified polyethylene glycol. In some embodiments, L9comprises an amino acid residue. In some embodiments, L9comprises analkyl group or a substituted alkyl. In some embodiments, L9comprises an aryl group or a substituted aryl group. In some embodiments, L9comprises a diamine (e.g., a linking group comprising an alkylene diamine).

[0354] In some embodiments, L10(if present) comprises a polyethylene glycol, a modified polyethylene glycol, an amino acid residue, an alkyl group, a substituted alkyl, an aryl group, a substituted aryl group, or a diamine. In some embodiments, L10comprises a polyethylene glycol. In some embodiments, L10comprises a modified polyethylene glycol. In some embodiments, L10comprises an amino acid residue. In some embodiments, L10comprises an alkyl group or a substituted alkyl. In some embodiments, L10comprises an aryl group or a substituted aryl group. In some embodiments, L10comprises a diamine (e.g., a linking group comprising an alkylene diamine).

[0355] In some embodiments, L11(if present) comprises a polyethylene glycol, a modified polyethylene glycol, an amino acid residue, an alkyl group, a substituted alkyl, an aryl group, a substituted aryl group, or a diamine. In some embodiments, L11comprises a polyethylene glycol. In some embodiments, L11comprises a modified polyethylene glycol. In some embodiments, L11comprises an amino acid residue. In some embodiments, L11comprises an alkyl group or a substituted alkyl. In some embodiments, L11comprises an aryl group or a substituted aryl group. In some embodiments, L11comprises a diamine (e.g., a linking group comprising an alkylene diamine).

[0356] In some embodiments, L12(if present) comprises a polyethylene glycol, a modified polyethylene glycol, an amino acid residue, an alkyl group, a substituted alkyl, an aryl group, a substituted aryl group, or a diamine. In some embodiments, L12comprises a polyethylene glycol. In some embodiments, L12comprises a modified polyethylene glycol. In some embodiments, L12comprises an amino acid residue. In some embodiments, L12comprises an alkyl group or a substituted alkyl. In some embodiments, L12comprises an aryl group or a substituted aryl group. In some embodiments, L12comprises a diamine (e.g., a linking group comprising an alkylene diamine).

[0357] In some embodiments, L13(if present) comprises a polyethylene glycol, a modified polyethylene glycol, an amino acid residue, an alkyl group, a substituted alkyl, an aryl group, a substituted aryl group, or a diamine. In some embodiments, L13comprises a polyethylene glycol. In some embodiments, L13comprises a modified polyethylene glycol. In some embodiments, L13comprises an amino acid residue. In some embodiments, L13comprises an alkyl group or a substituted alkyl. In some embodiments, L13comprises an aryl group or asubstituted aryl group. In some embodiments, L13comprises a diamine (e.g., a linking group comprising an alkylene diamine).

[0358] In some embodiments, LBis a second linker comprising:wherein:-(L7)g- is -(T7-V7)g-;-(L8)h- is -(T8-V8)h-;-(L9)i- is -(T9-V9)i-;-(L10)j- is -(T10-V10)j-;wherein:T7, T8, T9, T10, T11, T12and T13if present, are tether groups;V7, V8, V9, V10, V11, V12and V13, if present, are covalent bonds or linking functional groups; and g, h, i, j, k, 1, and m are each independently 0 or 1, provided at least one of g, h, i, j, k, 1, and m is 1.

[0359] In certain embodiments, the sum of g, h, i, j, k, 1, and m is 1 to 7. In certain embodiments, the sum of g, h, i, j, k, 1, and m is 1. In certain embodiments, the sum of g, h, i, j, k, 1, and m is 2. In certain embodiments, the sum of g, h, i, j, k, 1, and m is 3. In certain embodiments, the sum of g, h, i, j, k, 1, and m is 4. In certain embodiments, the sum of g, h, i, j, k, 1, and m is 5. In certain embodiments, the sum of g, h, i, j, k, 1, and m is 6. In certain embodiments, the sum of g, h, i, j, k, 1, and m is 7. In certain embodiments, g, h, i, j, k, 1, and m are each 1. In certain embodiments, g, h, i, j, k and 1 are each 1 and m is 0. In certain embodiments, g, h, i, j and k are each 1 and 1 and m are each 0. In certain embodiments, g, h, i and j are each 1 and k, 1 and m are each 0. In certain embodiments, g, h, and i are each 1 and j, k, 1, and m are each 0. In certain embodiments, g and h are each 1 and i, j, k, 1, and m are each 0. In certain embodiments, g is 1 and h, i, j, k, 1, and m are each 0. In certain embodiments, g, h, i, j, k, 1, and m are each 0.

[0360] As described above, in certain embodiments, L7is attached to the hydrazinyl- indolyl or a hydrazinyl-pyrrolo-pyridinyl conjugation moiety (e.g., as shown in Formula (I) above). As such, in certain embodiments, T7is attached to the hydrazinyl-indolyl or a hydrazinyl-pyrrolo-pyridinyl conjugation moiety (e.g., as shown in Formula (I) above). Incertain embodiments, V7is attached to the second drug or active agent. In certain embodiments, L8, if present, is attached to the second drug or active agent. As such, in certain embodiments, T8, if present, is attached to the second drug or active agent, or V8, if present, is attached to the second drug or active agent. In certain embodiments, L9, if present, is attached to the second drug or active agent. As such, in certain embodiments, T9, if present, is attached to the second drug or active agent, or V9, if present, is attached to the second drug or active agent. In certain embodiments, L10, if present, is attached to the second drug or active agent. As such, in certain embodiments, T10, if present, is attached to the second drug or active agent, or VI 04, if present, is attached to the second drug or active agent. In certain embodiments, L11, if present, is attached to the second drug or active agent. As such, in certain embodiments, T11, if present, is attached to the second drug or active agent, or V11, if present, is attached to the second drug or active agent. In certain embodiments, L12, if present, is attached to the second drug or active agent. As such, in certain embodiments, T12, if present, is attached to the second drug or active agent, or V12, if present, is attached to the second drug or active agent. In certain embodiments, L13, if present, is attached to the second drug or active agent. As such, in certain embodiments, T13, if present, is attached to the second drug or active agent, or V13, if present, is attached to the second drug or active agent.

[0361] Regarding the tether groups, T1, T2, T3, T4, T5, T6, T7, T8, T9, T10, T11, T12and T13, any convenient tether groups may be utilized in the subject linkers. In some embodiments, T1, T2, T3, T4, T5, T6, T7, T8, T9, T10, T11, T12and T13each comprise one or more groups independently selected from a covalent bond, a (Ci-Cnjalkyl, a substituted (Ci-Cnjalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, (EDA)W, (PEG)n, (AA)P, -(CR13OH)X-, 4-amino- piperidine (4AP), meta-amino-benzyloxy (MABO), meta-amino-benzyloxycarbonyl (MABC), para-amino-benzyloxy (PABO), para-amino-benzyloxycarbonyl (PABC), para-aminobenzyl (PAB), para-amino-benzylamino (PABA), para-amino-phenyl (PAP), para-hydroxy-phenyl (PHP), an acetal group, a hydrazine, a disulfide, and an ester, where each w is an integer from 1 to 20, each n is an integer from 1 to 30, each p is an integer from 1 to 20, and each x is an integer from 1 to 12.

[0362] In certain embodiments, the tether group (e.g., T1, T2, T3, T4, T5, T6, T7, T8, T9, T10, T11, T12and / or T13) includes a (Ci-Ci2)alkyl or a substituted (Ci-Ci2)alkyl. In certain embodiments, (Ci-Ci2)alkyl is a straight chain or branched alkyl group that includes from 1 to 12 carbon atoms, such as 1 to 10 carbon atoms, or 1 to 8 carbon atoms, or 1 to 6 carbon atoms, or 1 to 5 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms. In some instances, (Ci-Cn)alkyl may be an alkyl or substituted alkyl, such as C1-C12 alkyl, or C1-C10 alkyl, or Ci-Ce alkyl, or C1-C3 alkyl. In some instances, (Ci-Ci2)alkyl is a C2-alkyl. For example, (Ci- Cn)alkyl may be an alkylene or substituted alkylene, such as C1-C12 alkylene, or C1-C10 alkylene, or Ci-Ce alkylene, or C1-C3 alkylene. In some instances, (Ci-Ci2)alkyl is a Ci- alkylene (e.g., CH2). In some instances, (Ci-Ci2)alkyl is a C2-alkylene (e.g., CH2CH2). In some instances, (Ci-Ci2)alkyl is a C3-alkylene (e.g., CH2CH2CH2).

[0363] In certain embodiments, substituted (Ci-Ci2)alkyl is a straight chain or branched substituted alkyl group that includes from 1 to 12 carbon atoms, such as 1 to 10 carbon atoms, or 1 to 8 carbon atoms, or 1 to 6 carbon atoms, or 1 to 5 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms. In some instances, substituted (Ci-Ci2)alkyl may be a substituted alkyl, such as substituted C1-C12 alkyl, or substituted C1-C10 alkyl, or substituted Ci-Ce alkyl, or substituted C1-C3 alkyl. In some instances, substituted (Ci-Ci2)alkyl is a substituted C2- alkyl. For example, substituted (Ci-Ci2)alkyl may be a substituted alkylene, such as substituted C1-C12 alkylene, or substituted C1-C10 alkylene, or substituted Ci-Ce alkylene, or substituted C1-C3 alkylene. In some instances, substituted (Ci-Ci2)alkyl is a substituted Ci- alkylene (e.g., Ci-alkylene substituted with -SO3H). In some instances, substituted (Ci- Cn)alkyl is a substituted C2-alkylene. In some instances, substituted (Ci-Ci2)alkyl is a substituted C3-alkylene. For example, substituted (Ci-Ci2)alkyl may include C1-C12 alkylene (e.g., C3-alkylene or Cs-alkylene) substituted with a (PEG)ki group as described herein (e.g., - CONH(PEG)ki, such as -CONH(PEG)3or -CONH(PEG)5; or -NHCO(PEG)ki, such as - NHCO(PEG)?), or may include C1-C12 alkylene (e.g., C3-alkylene) substituted with a - CONHCH2CH2SO3H group, or may include C1-C12 alkylene (e.g, Cs-alkylene) substituted with a -NHCOCH2SO3H group.

[0364] In some embodiments, substituted (Ci-Ci2)alkyl may include C1-C12 alkylene (e.g, C3-alkylene or Cs-alkylene) substituted with a (PEG)k’ group as described herein (e.g.,-NHCO(PEG)k’, wherein (integer), such as-NHCO(CH2CH2O)3CH3 or -NHCO(CH2CH2O)5CH3 or -NHCO(CH2CH2O)8CH3.

[0365] In certain embodiments, the tether group (e.g., T1, T2, T3, T4, T5, T6, T7, T8, T9, T10, T11, T12and / or T13) includes an aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, or substituted heterocyclyl. In some instances, the tether group (e.g., T1, T2, T3, T4, T5, T6, T7, T8, T9, T10, T11, T12and / or T13) includes an aryl or substituted aryl. For example, the aryl can be phenyl. In some cases, the substitutedaryl is a substituted phenyl. The substituted phenyl can be substituted with one or more substituents selected from (Ci-Ci2)alkyl, a substituted (Ci-Ci2)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl. In some instances, the substituted aryl is a substituted phenyl, where the substituent includes a cleavable moiety as described herein (e.g., an enzymatically cleavable moiety, such as a glycoside or glycoside derivative).

[0366] In some instances, the tether group (e.g., T1, T2, T3, T4, T5, T6, T7, T8, T9, T10, T11, T12and / or T13) includes a heteroaryl or substituted heteroaryl, such triazolyl (e.g., 1,2,3- triazolyl). In some instances, the tether group (e.g., T1, T2, T3, T4, T5, T6, T7, T8, T9, T10, T11, T12and / or T13) includes a cycloalkyl or substituted cycloalkyl. In some instances, the tether group (e.g., T1, T2, T3, T4, T5, T6, T7, T8, T9, T10, T11, T12and / or T13) includes a heterocyclyl or substituted heterocyclyl. In some instances, the substituent on the substituted heteroaryl, substituted cycloalkyl or substituted heterocyclyl includes a cleavable moiety as described herein (e.g., an enzymatically cleavable moiety, such as a glycoside or glycoside derivative).

[0367] In certain embodiments, the tether group (e.g., T1, T2, T3, T4, T5, T6, T7, T8, T9, T10, T11, T12and / or T13) includes an ethylene diamine (EDA) moiety, e.g., an EDA containing tether group. In certain embodiments, (EDA)Wincludes one or more EDA moieties, such as where w is an integer from 1 to 50, such as from 1 to 40, from 1 to 30, from 1 to 20, from 1 to 12 or from 1 to 6, such as 1, 2, 3, 4, 5 or 6). The linked ethylene diamine (EDA) moieties may optionally be substituted at one or more convenient positions with any convenient substituents, e.g, with an alkyl, a substituted alkyl, an acyl, a substituted acyl, an aryl, or a substituted aryl. In certain embodiments, the EDA moiety is described by the structure:where y is an integer from 1 to 6, r is 0 or 1, and each R12is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acyl amino, amino acyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl. In certain embodiments, y is 1, 2, 3, 4, 5 or 6. In certain embodiments, y is 1 and r is 0. In certain embodiments, y is 1 and r is 1. In certain embodiments, y is 2 and r is 0. In certain embodiments, y is 2 and r is 1. In certainembodiments, each R12is independently selected from hydrogen, an alkyl, a substituted alkyl, an aryl, and a substituted aryl. In certain embodiments, any two adjacent R12groups of the EDA may be cyclically linked, e.g., to form a piperazinyl ring. In certain embodiments, y is 1 and the two adjacent R12groups are an alkyl group, cyclically linked to form a piperazinyl ring. In certain embodiments, y is 1 and the adjacent R12groups are selected from hydrogen, an alkyl (e.g., methyl) and a substituted alkyl (e.g., lower alkyl-OH, such as ethyl-OH or propyl-OH).

[0368] In certain embodiments, the tether group (e.g., T1, T2, T3, T4, T5, T6, T7, T8, T9, T10, T11, T12and / or T13) includes a 4-amino-piperidine (4AP) moiety (also referred to herein as piperidin-4-amino, P4A). The 4AP moiety may optionally be substituted at one or more convenient positions with any convenient substituents, e.g., with an alkyl, a substituted alkyl, a polyethylene glycol moiety, an acyl, a substituted acyl, an aryl, or a substituted aryl. In certain embodiments, the 4AP moiety is described by the structure:wherein R12is selected from hydrogen, alkyl, substituted alkyl, a polyethylene glycol moiety (e.g., a polyethylene glycol or a modified polyethylene glycol), alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acyl amino, amino acyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl. In certain embodiments, R12is a polyethylene glycol moiety. In certain embodiments, R12is a carboxy modified polyethylene glycol.

[0369] In certain embodiments, R12includes a polyethylene glycol moiety described by the formula: (PEG)ki, which may be represented by the structure:where kl is an integer from 1 to 20, such as from 1 to 18, or from 1 to 16, or from 1 to 14, or from 1 to 12, or from 1 to 10, or from 1 to 8, or from 1 to 6, or from 1 to 4, or 1 or 2, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20. In some instances, kl is 2. In certain embodiments, R17is selected from OH, COOH, OR, or COOR, where R is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl,heterocyclyl, and substituted heterocyclyl. In certain embodiments, R17is COOH. In certain embodiments, R17is OH. In certain embodiments, R17is OCH3.

[0370] In certain embodiments, (PEG)ki is (PEG)k’ having the following structure:wherein k’ is an integer from 2 to 10. In certain embodiments, k’ is 8.

[0371] In certain embodiments, a tether group (e.g., T1, T2, T3, T4, T5, T6, T7, T8, T9, T10, T11, T12and / or T13) includes (PEG)n, where (PEG)n is a polyethylene glycol or a modified polyethylene glycol linking unit. In certain embodiments, (PEG)n is described by the structure:where n is an integer from 1 to 50, such as from 1 to 40, from 1 to 30, from 1 to 20, from 1 to 12 or from I to 6, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20. In some instances, n is 2. In some instances, n is 3. In some instances, n is 6. In some instances, n is 12.

[0372] In certain embodiments, a tether group (e.g, T1, T2, T3, T4, T5, T6, T7, T8, T9, T10, T11, T12and / or T13) includes (AA)P, where AA is an amino acid residue. Any convenient amino acids may be utilized. Amino acids of interest include but are not limited to, L- and D- amino acids, naturally occurring amino acids such as any of the 20 primary alpha-amino acids and beta-alanine, non-naturally occurring amino acids (e.g, amino acid analogs), such as a non-naturally occurring alpha-amino acid or a non-naturally occurring beta-amino acid, etc. In certain embodiments, p is an integer from 1 to 50, such as from 1 to 40, from 1 to 30, from 1 to 20, from 1 to 12 or from 1 to 6, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20. In certain embodiments, p is 1. In certain embodiments, p is 2.

[0373] In further embodiments, (AA)Pcomprises a dipeptide of valine-alanine. In some embodiments, the two amino acids of (AA)2 are valine and citrulline.

[0374] In certain embodiments, a tether group (e.g., T1, T2, T3, T4, T5, T6, T7, T8, T9, T10, T11, T12and / or T13) includes an amino acid analog. Amino acid analogs include compounds that are similar in structure and / or overall shape to one or more amino acids commonly found in naturally occurring proteins (e.g., Ala or A, Cys or C, Asp or D, Glu or E, Phe or F, Gly or G, His or H, He or I, Lys or K, Leu or L, Met or M, Asn or N, Pro or P, Gin or Q, Arg or R, Ser or S, Thr or T, Vai or V, Trp or W, Tyr or Y). Amino acid analogs also include naturalamino acids with modified side chains or backbones. Amino acid analogs also include amino acid analogs with the same stereochemistry as in the naturally occurring D-form, as well as the L-form of amino acid analogs. In some instances, the amino acid analogs share backbone structures, and / or the side chain structures of one or more natural amino acids, with difference(s) being one or more modified groups in the molecule. Such modification may include, but is not limited to, substitution of an atom (such as N) for a related atom (such as S), addition of a group (such as methyl, or hydroxyl, etc.) or an atom (such as Cl or Br, etc.), deletion of a group, substitution of a covalent bond (single bond for double bond, etc.), or combinations thereof. For example, amino acid analogs may include a-hydroxy acids, and a- amino acids, and the like. Examples of amino acid analogs include, but are not limited to, sulfoalanine, and the like.

[0375] In certain embodiments, a tether group (e.g., T1, T2, T3, T4, T5, T6, T7, T8, T9, T10, T11, T12and / or T13) includes a moiety described by the formula -(CR13OH)X-, where x is 0 or x is an integer from 1 to 50, such as from 1 to 40, from 1 to 30, from 1 to 20, from 1 to 12 or from 1 to 6, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12. In certain embodiments, x is 1. In certain embodiments, x is 2. In certain embodiments, R13is selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acyl amino, amino acyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl. In certain embodiments, R13is hydrogen. In certain embodiments, R13is alkyl or substituted alkyl, such as Ci-6 alkyl or Ci-6 substituted alkyl, or Ci-4 alkyl or Ci-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl. In certain embodiments, R13is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl. In certain embodiments, R13is alkynyl or substituted alkynyl. In certain embodiments, R13is alkoxy or substituted alkoxy. In certain embodiments, R13is amino or substituted amino. In certain embodiments, R13is carboxyl or carboxyl ester. In certain embodiments, R13is acyl or acyloxy. In certain embodiments, R13is acyl amino or amino acyl. In certain embodiments, R13is alkylamide or substituted alkylamide. In certain embodiments, R13is sulfonyl. In certain embodiments, R13is thioalkoxy or substituted thioalkoxy. In certain embodiments, R13is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a Cs aryl or Cs substituted aryl, or a Ce aryl or Ce substituted aryl. In certain embodiments, R13is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a Csheteroaryl or Cs substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl. In certain embodiments, R13is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3- 8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl. In certain embodiments, R13is heterocyclyl or substituted heterocyclyl, such as C3-8 heterocyclyl or C3-8 substituted heterocyclyl, such as a C3-6 heterocyclyl or C3-6 substituted heterocyclyl, or a C3-5 heterocyclyl or C3-5 substituted heterocyclyl.

[0376] In certain embodiments, R13is selected from hydrogen, alkyl, substituted alkyl, aryl, and substituted aryl. In these embodiments, alkyl, substituted alkyl, aryl, and substituted aryl are as described above for R13.

[0377] In certain embodiments, the tether group (e.g., T1, T2, T3, T4, T5, T6, T7, T8, T9, T10, T11, T12and / or T13) includes an acetal group, a disulfide, a hydrazine, or an ester. In some embodiments, the tether group includes an acetal group. In some embodiments, the tether group includes a hydrazine. In some embodiments, the tether group includes a disulfide. In some embodiments, the tether group includes an ester.

[0378] In certain embodiments, a tether group (e.g., T1, T2, T3, T4, T5, T6, T7, T8, T9, T10, T11, T12and / or T13) includes a meta-amino-benzyloxy (MABO), meta-amino- benzyloxycarbonyl (MABC), para-amino-benzyloxy (PABO), para-amino-benzyloxycarbonyl (PABC), para-aminobenzyl (PAB), para-amino-benzylamino (PABA), para-amino-phenyl (PAP), or para-hydroxy-phenyl (PHP).

[0379] In some embodiments, a tether group includes a MABO group described by the following structure:

[0380] In some embodiments, a tether group includes a MABC group described by the following structure:

[0381] In some embodiments, a tether group includes a PABO group described by the following structure:

[0382] In some embodiments, a tether group includes a PABC group described by the following structure:

[0383] In some embodiments, a tether group includes a PAB group described by the following structure:

[0384] In some embodiments, a tether group includes a PAB A group described by the following structure:

[0385] In some embodiments, a tether group includes a PAP group described by the following structure:

[0386] In some embodiments, a tether group includes a PHP group described by the following structure:

[0387] In certain embodiments, each R14is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acyl amino, amino acyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl,substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl.

[0388] In certain embodiments, R14is hydrogen. In certain embodiments, each R14is hydrogen. In certain embodiments, R14is alkyl or substituted alkyl, such as Ci-6 alkyl or Ci-6 substituted alkyl, or Ci-4 alkyl or Ci-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl. In certain embodiments, R14is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl. In certain embodiments, R14is alkynyl or substituted alkynyl. In certain embodiments, R14is alkoxy or substituted alkoxy. In certain embodiments, R14is amino or substituted amino. In certain embodiments, R14is carboxyl or carboxyl ester. In certain embodiments, R14is acyl or acyloxy. In certain embodiments, R14is acyl amino or amino acyl. In certain embodiments, R14is alkylamide or substituted alkylamide. In certain embodiments, R14is sulfonyl. In certain embodiments, R14is thioalkoxy or substituted thioalkoxy. In certain embodiments, R14is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a Cs aryl or Cs substituted aryl, or a Ce aryl or Ce substituted aryl. In certain embodiments, R14is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a Cs heteroaryl or Cs substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl. In certain embodiments, R14is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl. In certain embodiments, R14is heterocyclyl or substituted heterocyclyl, such as C3-8 heterocyclyl or C3-8 substituted heterocyclyl, such as a C3-6 heterocyclyl or C3-6 substituted heterocyclyl, or a C3-5 heterocyclyl or C3-5 substituted heterocyclyl.

[0389] In some embodiments of the MABO, MABC, PABO, PABC, PAB, PAB A, PAP, and PHP tether structures shown above, the phenyl ring may be substituted with one or more additional groups selected from halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acyl amino, amino acyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl.

[0390] In certain embodiments, one or more of the tether groups T1, T2, T3, T4, T5, T6, T7, T8, T9, T10, T11, T12and / or T13is each optionally substituted with a glycoside or glycoside derivative. For example, in some instances, T1, T2, T3, T4, T5and T6are each optionally substituted with a glycoside. In some instances, T7, T8, T9, T10, T11, T12and T13are eachoptionally substituted with a glycoside. In certain embodiments, the glycoside or glycoside derivative is selected from a glucuronide, a galactoside, a glucoside, a mannoside, a fucoside, O-GlcNAc, and O-GalNAc.

[0391] In certain embodiments, the MABO, MABC, PABO, PABC, PAB, PABA, PAP, and PHP tether structures shown above may be substituted with one or more additional groups selected from a glycoside and a glycoside derivative. For example, in some embodiments of the MABO, MABC, PABO, PABC, PAB, PABA, PAP, and PHP tether structures shown above, the phenyl ring may be substituted with one or more additional groups selected from a glycoside and a glycoside derivative. In certain embodiments, the glycoside or glycoside derivative is selected from a glucuronide, a galactoside, a glucoside, a mannoside, a fucoside, O-GlcNAc, and O-GalNAc. In some embodiments, the PABC is substituted with a glycoside, for example, a hydrogen of PABC is replaced with a glycoside, such as a glucuronide, a galactoside, a glucoside, a mannoside, a fucoside, O-GlcNAc, and O-GalNAc.

[0392] For example, in some embodiments, the glycoside or glycoside derivative is selected from the following structures:

[0393] Regarding the linking functional groups, V1, V2, V3, V4, V5, V6, V7, V8, V9, V10, V11, V12and V13any convenient linking functional groups may be utilized in the subject linkers. Linking functional groups of interest include, but are not limited to, amino, carbonyl, amido, oxycarbonyl, carboxy, sulfonyl, sulfoxide, sulfonylamino, aminosulfonyl, thio, oxy, phospho, phosphoramidate, thiophosphoraidate, and the like. In some embodiments, V1, V2, V3, V4, V5, V6, V7, V8, V9, V10, V11, V12and V13are each independently selected from a covalent bond, -CO-, -NR15-, -NR15(CH2)q-, -NR15(C6H4)-, -CONR15-, -NR15CO-, -C(O)O-, -OC(O)-, -O-, -S-, -S(O)-, -SO2-, -SO2NR15-, -NR15SO2- and -P(O)OH-, where q is an integer from 1 to 6. In certain embodiments, q is an integer from 1 to 6 (e.g., 1, 2, 3, 4, 5 or 6). In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, q is 3. Incertain embodiments, q is 4. In certain embodiments, q is 5. In certain embodiments, q is 6. In some embodiments, each R15is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acyl amino, amino acyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl.

[0395] In certain embodiments, R15is hydrogen. In certain embodiments, each R15is hydrogen. In certain embodiments, R15is alkyl or substituted alkyl, such as Ci-6 alkyl or Ci-6 substituted alkyl, or Ci-4 alkyl or Ci-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl. In certain embodiments, R15is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl. In certain embodiments, R15is alkynyl or substituted alkynyl. In certain embodiments, R15is alkoxy or substituted alkoxy. In certain embodiments, R15is amino or substituted amino. In certain embodiments, R15is carboxyl or carboxyl ester. In certain embodiments, R15is acyl or acyloxy. In certain embodiments, R15is acyl amino or amino acyl. In certain embodiments, R15is alkylamide or substituted alkylamide. In certain embodiments, R15is sulfonyl. In certain embodiments, R15is thioalkoxy or substituted thioalkoxy. In certain embodiments, R15is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a Cs aryl or Cs substituted aryl, or a Ce aryl or Ce substituted aryl. In certain embodiments, R15is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a Cs heteroaryl or Cs substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl. In certain embodiments, R15is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl. In certain embodiments, R15is heterocyclyl or substituted heterocyclyl, such as C3-8 heterocyclyl or C3-8 substituted heterocyclyl, such as a C3-6 heterocyclyl or C3-6 substituted heterocyclyl, or a C3-5 heterocyclyl or C3-5 substituted heterocyclyl.

[0396] In certain embodiments, each R15is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, carboxyl, carboxyl ester, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl. In these embodiments, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, carboxyl, carboxylester, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl are as described above for R15.

[0397] As described above, in some embodiments, LAis a first linker comprising: -(T1-V1)a-(T2-V2)b-(T3-V3)c-(T4-V4)d-(T5-V5)e-(T6-V6)f-, where a, b, c, d, e, and f are each independently 0 or 1, provided at least one of a, b, c, d, e, and f is 1.

[0398] In some embodiments, in the first linker LA:T1is selected from a (Ci-Cnjalkyl and a substituted (Ci-Ci2)alkyl;T2, T3, T4, T5and T6are each independently selected from (Ci-Ci2)alkyl, substituted (Ci-Ci2)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, (EDA)W, (PEG)n, (AA)P, -(CR13OH)X-, 4-amino-piperidine (4AP), MABO, MABC, PABO, PABC, PAB, PABA, PAP, PHP, an acetal group, a disulfide, a hydrazine, and an ester; andV1, V2, V3, V4, V5and V6are each independently selected from a covalent bond, -CO-, -NR15-, -NR15(CH2)q-, -NR15(C6H4)-, -CONR15-, -NR15CO-, -C(O)O-, -OC(O)-, -O-, -S-, -S(O)-, -SO2-, -SO2NR15-, -NR15SO2- and -P(O)OH-, wherein q is an integer from 1 to 6; wherein:integer from 1 to 30;EDA is an ethylene diamine moiety having the following structure:where y is an integer from 1 to 6 and r is 0 or 1;4-amino-piperidineAA is an amino acid residue, where p is an integer from 1 to 20; and each R12is independently selected from hydrogen, an alkyl, a substituted alkyl, a polyethylene glycol moiety, an aryl, and a substituted aryl, wherein any two adjacent R12groups may be cyclically linked to form a piperazinyl ring; each R13is independently selected from hydrogen, alkyl, substituted alkyl, aryl, and substituted aryl; andeach R15is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, carboxyl, carboxyl ester, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl.

[0399] In some embodiments, LAcomprises:-(T1-V1)a-(T2-V2)b-(T3-V3)c-(T4-V4)d-(T5-V5)e-(T6-V6)f-, wherein: a, b, c, d, e, and f are each independently 0 or 1, provided at least one of a, b, c, d, e, and f is 1;T1, T2, T3, T4, T5and T6are each independently selected from a covalent bond, (Ci- Cn)alkyl, substituted (Ci-Ci2)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, (EDA)W, (PEG)n, (AA)P, -(CR13OH)X-, 4-amino-piperidine (4AP), meta-amino-benzyloxy (MABO), meta-amino-benzyloxycarbonyl (MABC), para-amino-benzyloxy (PABO), para-amino- benzyloxycarbonyl (PABC), para-aminobenzyl (PAB), para-amino-benzylamino (PABA), para-amino-phenyl (PAP), para-hydroxy-phenyl (PHP), an acetal group, a hydrazine, a disulfide, and an ester, wherein EDA is an ethylene diamine moiety, PEG is a polyethylene glycol, and AA is an amino acid residue or an amino acid analog, wherein each w is an integer from 1 to 20, each n is an integer from 1 to 30, each p is an integer from 1 to 20, and each x is an integer from 1 to 12;V1, V2, V3, V4, V5and V6are each independently selected from the group consisting of a covalent bond, -CO-, -NR15-, -NR15(CH2)q-, -NR15(C6H4)-, -CONR15-, -NR15CO-, -C(O)O-, -OC(O)-, -O-, -S-, -S(O)-, -SO2-, -SO2NR15-, -NR15SO2- and -P(O)OH-, wherein each q is an integer from 1 to 6; each R13is independently selected from hydrogen, an alkyl, a substituted alkyl, an aryl, and a substituted aryl; and each R15is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, carboxyl, carboxyl ester, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl.

[0400] In some embodiments of LA:T1is selected from a (Ci-Ci2)alkyl and a substituted (Ci-Ci2)alkyl;T2, T3, T4, T5and T6are each independently selected from a covalent bond, (Ci- Cn)alkyl, substituted (Ci-Ci2)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, (EDA)W, (PEG)n, (AA)p, -(CR13OH)X-, 4-amino-piperidine (4AP), MABO, MABC, PABO, PABC, PAB, PABA, PAP, PHP, an acetal group, a hydrazine, and an ester; andV1, V2, V3, V4, V5and V6are each independently selected from the group consisting of a covalent bond, -CO-, -NR15-, -NR15(CH2)q-, -NR15(CeH4)-, -CONR15-, -NR15CO-, -C(O)O-, -OC(O)-, -O-, -S-, -S(O)-, -SO2-, -SO2NR15-, -NR15SO2-, and -P(O)OH-; wherein:integer from 1 to 30;EDA is an ethylene diamine moiety having the following structure:where y is an integer from 1 to 6 and r is 0 or 1;4-amino-piperidineeach R12is independently selected from hydrogen, an alkyl, a substituted alkyl, a polyethylene glycol moiety, an aryl, and a substituted aryl, wherein any two adjacent R12groups may be cyclically linked to form a piperazinyl ring; a, b, c, and d are each 1; and e and f are 0.

[0401] In some embodiments, T1, T2, T3, T4, T5and T6are each optionally substituted with a glycoside.

[0402] In some embodiments, MABO, MABC, PABO, PABC, PAB, PABA, PAP and PHP are each optionally substituted with a glycoside.

[0403] In some embodiments, the glycoside is selected from a glucuronide, a galactoside, a glucoside, a mannoside, a fucoside, O-GlcNAc, and O-GalNAc.

[0404] In certain embodiments, T1, T2, T3, T4, T5and T6and V1, V2, V3, V4, V5and V6are selected from the following: wherein:T1is (Ci-Ci2)alkyl and V1is -CO-;T2is (AA)Pand V2is absent (e.g., a covalent bond);T3is PABC and V3is absent (e.g., a covalent bond); p is an integer from 1 to 10; and d, e, and f are each 0; or wherein:T1is (Ci-Ci2)alkyl and V1is -CONH-;T2is (PEG)nand V2is -CO-;T3is (AA)Pand V3is absent (e.g., a covalent bond);T4is PABC and V4is absent (e.g., a covalent bond); p is an integer from 1 to 10; and e and f are each 0; or wherein:T1is (Ci-Ci2)alkyl and V1is -CO-;T2is an amino acid analog and V2is -NH-;T3is (PEG)nand V3is -CO-;T4is (AA)Pand V4is absent (e.g., a covalent bond);T5is PABC and V5is absent (e.g., a covalent bond); p is an integer from 1 to 10; and f is 0; or wherein:T1is (Ci-Ci2)alkyl and V1is -CONH-;T2is (PEG)nand V2is -CO-;T3is (AA)Pand V3is absent (e.g., a covalent bond);T4is PABC and V4is absent (e.g., a covalent bond); p is an integer from 1 to 10; and e and f are each 0; or wherein:T1is (Ci-Ci2)alkyl and V1is -CONH-;T2is substituted (Ci-Ci2)alkyl and V2is -CO-;T3is (AA)Pand V3is absent (e.g., a covalent bond);T4is PABC and V4is absent (e.g., a covalent bond); p is an integer from 1 to 10; and e and f are each 0; or wherein:T1is (Ci-Ci2)alkyl and V1is -CONH-;T2is (PEG)n and V2is -CO-;T3is (AA)Pand V3is absent (e.g., a covalent bond);T4is PABA and V4is -CO-;T5is (Ci-Ci2)alkyl and V5is absent (e.g., a covalent bond); p is an integer from 1 to 10; and f is 0; or wherein:T1is (Ci-Ci2)alkyl and V1is -CO-;T2is 4AP and V2is -CO-;T3is (Ci-Ci2)alkyl and V3is -CO-;T4is (AA)Pand V4is absent (e.g., a covalent bond);T5is PABC and V5is absent (e.g., a covalent bond); p is an integer from 1 to 10; and f is 0; or wherein:T1is (Ci-Ci2)alkyl and V1is -CO-;T2is 4AP and V2is -CO-;T3is (Ci-Ci2)alkyl and V3is -O-;T4is (Ci-Ci2)alkyl and V4is -CO-;T5is (AA)Pand V5is absent (e.g., a covalent bond); p is an integer from 1 to 10; andT6is PABC and V6is absent (e.g., a covalent bond); or wherein:T1is (Ci-Ci2)alkyl and V1is -CO-;T2is an amino acid analog and V2is absent (e.g., a covalent bond);T3is (AA)Pand V3is absent (e.g., a covalent bond);T4is PABC and V4is absent (e.g., a covalent bond); p is an integer from 1 to 10; and e and f are each 0; or wherein:T1is (Ci-Ci2)alkyl and V1is -CONH-;T2is (PEG)n and V2is -CONH-;T3is substituted (Ci-Ci2)alkyl and V3is -CO-;T4is (AA)Pand V4is absent (e.g., a covalent bond);I l lT5is PABC and V5is absent (e.g., a covalent bond); p is an integer from 1 to 10; and f is 0; or wherein:T1is (Ci-Ci2)alkyl and V1is -CO-;T2is an (AA)Pand V2is -NH-;T3is (PEG)nand V3is -CO-;T4is (AA)Pand V4is absent (e.g., a covalent bond);T5is PABC and V5is absent (e.g., a covalent bond); p is an integer from 1 to 10; and f is 0; or wherein:T1is (Ci-Ci2)alkyl and V1is -CONH-;T2is (PEG)nand V2is -CO-;T3is (AA)Pand V3is absent (e.g., a covalent bond);T4is PAP and V4is -C(O)O-; p is an integer from 1 to 10; and e and f are each 0; or wherein:T1is (Ci-Ci2)alkyl and V1is -CONH-;T2is substituted (Ci-Ci2)alkyl and V2is -CO-;T3is (AA)Pand V3is absent (e.g., a covalent bond);T4is PABC and V4is absent (e.g., a covalent bond); p is an integer from 1 to 10; and e and f are each 0; or wherein:T1is (Ci-Ci2)alkyl and V1is -CONH-;T2is substituted (Ci-Ci2)alkyl and V2is -CO-;T3is PABC and V3is absent (e.g., a covalent bond); and d, e, and f are each 0.

[0405] In certain embodiments, the left-hand side of the above linker structure for the first linker LAis attached to the hydrazinyl-indolyl or a hydrazinyl-pyrrolo-pyridinyl conjugation moiety, and the right-hand side of the above linker structure for the first linker LAis attached to the first drug or active agent.

[0406] As described above, in some embodiments, LBis a second linker comprising: -(T7-V7)g-(T8-V8)h-(T9-V9)i-(T10-V10)j-(T11-V11)k-(T12-V12)i-(T13-V13)m-, wherein g, h, i, j, k, 1, and m are each independently 0 or 1, provided that at least one of g, h, i, j, k, 1, and m is 1.

[0407] In some embodiments, in the second linker LB:T7is selected from a (Ci-Cnjalkyl and a substituted (Ci-Ci2)alkyl;T8, T9, T10, T11, T12and T13are each independently selected from (Ci-Ci2)alkyl, substituted (Ci-Ci2)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, (EDA)W, (PEG)n, (AA)P, -(CR13OH)X-, 4AP, MABO, MABC, PABO, PABC, PAB, PABA, PAP, PHP, an acetal group, a disulfide, a hydrazine, and an ester; andV7, V8, V9, V10, V11, V12and V13are each independently selected from a covalent bond, -CO-, -NR15-, -NR15(CH2)q-, -NR15(C6H4)-, -CONR15-, -NR15CO-, -C(O)O-, -OC(O)-, -O-, -S-, -S(O)-, -SO2-, -SO2NR15-, -NR15SO2- and -P(O)OH-, wherein q is an integer from 1 to 6; wherein:integer from 1 to 30;EDA is an ethylene diamine moiety having the following structure:where y is an integer from 1 to 6 and r is 0 or 1;4-amino-piperidineAA is an amino acid residue, where p is an integer from 1 to 20; and each R12is independently selected from hydrogen, an alkyl, a substituted alkyl, a polyethylene glycol moiety, an aryl, and a substituted aryl, wherein any two adjacent R12groups may be cyclically linked to form a piperazinyl ring; each R13is independently selected from hydrogen, alkyl, substituted alkyl, aryl, and substituted aryl; and each R15is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, carboxyl, carboxyl ester, acyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl.

[0408] Any convenient tether groups may be utilized for T7, T8, T9, T10, T11, T12and T13. For example, any of the tether groups described above in relation to T1, T2, T3, T4, T5and T6may be used for the tether groups T7, T8, T9, T10, T11, T12and T13.

[0409] Any convenient linking functional groups may be utilized for V7, V8, V9, V10, V11, V12and V13. For example, any of the linking functional groups described above in relation to V1, V2, V3, V4, V5and V6may be used for the linking functional groups V7, V8, V9, V10, V11, V12and V13.

[0410] In certain embodiments, each R13is independently selected from hydrogen, alkyl, substituted alkyl, aryl, and substituted aryl. In these embodiments, alkyl, substituted alkyl, aryl, and substituted aryl are as described above for R13.

[0411] In certain embodiments, each R15is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, carboxyl, carboxyl ester, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl. In these embodiments, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, carboxyl, carboxyl ester, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl are as described above for R15. In these embodiments, various possible substituents are as described above for R15.

[0412] In certain embodiments of the second linker LB, one or more of the tether groups T7, T8, T9, T10, T11, T12and T13is each optionally substituted with a glycoside or glycoside derivative. In certain embodiments, the glycoside or glycoside derivative is selected from a glucuronide, a galactoside, a glucoside, a mannoside, a fucoside, O-GlcNAc, and O-GalNAc.

[0413] In certain embodiments of the second linker LB, the MABO, MABC, PABO, PABC, PAB, PABA, PAP, and PHP tether structures shown above may be substituted with one or more additional groups selected from a glycoside and a glycoside derivative. For example, in some embodiments of the MABO, MABC, PABO, PABC, PAB, PABA, PAP, and PHP tether structures shown above, the phenyl ring may be substituted with one or more additional groups selected from a glycoside and a glycoside derivative. In certain embodiments, the glycoside or glycoside derivative is selected from a glucuronide, a galactoside, a glucoside, a mannoside, a fucoside, O-GlcNAc, and O-GalNAc.

[0414] In some embodiments, T7, T8, T9, T10, T11, T12and T13are each optionally substituted with a glycoside.

[0415] In some embodiments, MABO, MABC, PABO, PABC, PAB, PABA, PAP and PHP are each optionally substituted with a glycoside.

[0416] In some embodiments, the glycoside is selected from a glucuronide, a galactoside, a glucoside, a mannoside, a fucoside, O-GlcNAc, and O-GalNAc.

[0417] In some embodiments of LB: g, h, i, j, and k are each 1;1 and m are each 0;T7is a covalent bond;T8, T9, T10, T11and T12are each independently selected from a covalent bond, (Ci- Cn)alkyl, substituted (Ci-Ci2)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, (EDA)W, (PEG)n, (AA)p, -(CR13OH)X-, 4-amino-piperidine (4AP), MABO, MABC, PABO, PABC, PAB, PABA, PAP, PHP, an acetal group, a hydrazine, and an ester; andV7, V8, V9, V10, V11and V12are each independently selected from the group consisting of a covalent bond, -CO-, -NR15-, -NR15(CH2)q-, -NR15(CeH4)-, -CONR15-, -NR15CO-, -C(O)O-, -OC(O)-, -O-, -S-, -S(O)-, -SO2-, -SO2NR15-, -NR15SO2-, and -P(O)OH-; wherein:integer from 1 to 30;EDA is an ethylene diamine moiety having the following structure:where y is an integer from 1 to 6 and r is 0 or 1;4-amino-piperidineeach R12is independently selected from hydrogen, an alkyl, a substituted alkyl, a polyethylene glycol moiety, an aryl, and a substituted aryl, wherein any two adjacent R12groups may be cyclically linked to form a piperazinyl ring.

[0418] In some embodiments, T1, T2, T3, T4, T5, T6, T7, T8, T9, T10, T11, and T12are each optionally substituted with a glycoside.

[0419] In some embodiments, MABO, MABC, PABO, PABC, PAB, PABA, PAP and PHP are each optionally substituted with a glycoside.

[0420] In some embodiments, the glycoside is selected from a glucuronide, a galactoside, a glucoside, a mannoside, a fucoside, O-GlcNAc, and O-GalNAc.

[0421] In certain embodiments, T7, T8, T9, T10, T11, T12and T13and V7, V8, V9, V10, V11,V12and V13are selected from the following: wherein:T7is absent (e.g., a covalent bond) and V7is -NHCO-;T8is (Ci-Ci2)alkyl and V8is -CO-;T9is (AA)Pand V9is absent (e.g., a covalent bond);T10is PABC and V10is absent (e.g., a covalent bond); and k, 1, and m are each 0; or wherein:T7is absent (e.g., a covalent bond) and V7is -NHCO-;T8is (Ci-Ci2)alkyl and V8is -CONH-;T9is (PEG)nand V9is -CO-;T10is (AA)Pand V10is absent (e.g., a covalent bond); andT11is PABC and V11is absent (e.g., a covalent bond); and1 and m are each 0; or wherein:T7is absent (e.g., a covalent bond) and V7is -NHCO-;T8is (Ci-Ci2)alkyl and V8is -CO-;T9is an amino acid analog and V9is -NH-;T10is (PEG)nand V10is -CO-;T11is (AA)Pand V11is absent (e.g., a covalent bond);T12is PABC and V12is absent (e.g., a covalent bond); and m is 0; or wherein:T7is absent (e.g., a covalent bond) and V7is -NHCO-;T8is (Ci-Ci2)alkyl and V8is -CONH-;T9is (PEG)nand V9is -CO-;T10is (AA)Pand V10is absent (e.g., a covalent bond);T11is PABC and V11is absent (e.g., a covalent bond); and1 and m are each 0; orwherein:T7is absent (e.g., a covalent bond) and V7is -NHCO-;T8is (Ci-Ci2)alkyl and V8is -CONH-;T9is substituted (Ci-Ci2)alkyl and V9is -CO-;T10is (AA)Pand V10is absent (e.g., a covalent bond);T11is PABC and V11is absent (e.g., a covalent bond); and1 and m are each 0; or wherein:T7is absent (e.g., a covalent bond) and V7is -NHCO-;T8is (Ci-Ci2)alkyl and V8is -CONH-;T9is (PEG)nand V9is -CO-;T10is (AA)Pand V10is absent (e.g., a covalent bond);T11is PABA and V11is -CO-;T12is (Ci-Ci2)alkyl and V12is absent (e.g., a covalent bond); and m is 0; or wherein:T7is absent (e.g., a covalent bond) and V7is -NHCO-;T8is (Ci-Ci2)alkyl and V8is -CO-;T9is 4AP and V9is -CO-;T10is (Ci-Ci2)alkyl and V10is -CO-;T11is (AA)Pand V11is absent (e.g., a covalent bond);T12is PABC and V12is absent (e.g., a covalent bond); and m is 0; or wherein:T7is absent (e.g., a covalent bond) and V7is -NHCO-;T8is (Ci-Ci2)alkyl and V8is -CO-;T9is 4AP and V9is -CO-;T10is (Ci-Ci2)alkyl and V10is -O-;T11is (Ci-Ci2)alkyl and V11is -CO-;T12is (AA)Pand V12is absent (e.g., a covalent bond); andT13PABC and V13is absent (e.g., a covalent bond); or wherein:T7is absent (e.g., a covalent bond) and V7is -NHCO-;T8is (Ci-Ci2)alkyl and V8is -CO-;T9is an amino acid analog and V9is absent (e.g., a covalent bond);T10is (AA)Pand V10is absent (e.g., a covalent bond);T11is PABC and V11is absent (e.g., a covalent bond); and1 and m are each 0; or wherein:T7is absent (e.g., a covalent bond) and V7is -NHCO-;T8is (Ci-Ci2)alkyl and V8is -CONH-;T9is (PEG)n and V9is -CONH-;T10is substituted (Ci-Ci2)alkyl and V10is -CO-;T11is (AA)Pand V11is absent (e.g., a covalent bond);T12is PABC and V12is absent (e.g., a covalent bond); and m is 0; or wherein:T7is absent (e.g., a covalent bond) and V7is -NHCO-;T8is (Ci-Ci2)alkyl and V8is -CO-;T9is (AA)Pand V9is -NH-;T10is (PEG)nand V10is -CO-;T11is (AA)Pand V11is absent (e.g., a covalent bond);T12is PABC and V12is absent (e.g., a covalent bond); and m is 0; or wherein:T7is absent (e.g., a covalent bond) and V7is -NHCO-;T8is (Ci-Ci2)alkyl and V8is -CONH-;T9is (PEG)nand V9is -CO-;T10is (AA)Pand V10is absent (e.g., a covalent bond);T11is PAP and V11is -C(O)O-; and1 and m are each 0; or wherein:T7is absent (e.g., a covalent bond) and V7is -NHCO-;T8is (Ci-Ci2)alkyl and V8is -CO-;T9is (AA)Pand V9is absent (e.g., a covalent bond);T10is PABC and V10is absent (e.g., a covalent bond);T11is PAP and V11is -C(O)O-; and1 and m are each 0; orwherein:T7is absent (e.g., a covalent bond) and V7is -NHCO-;T8is (Ci-Ci2)alkyl and V8is -CONH-;T9is substituted (Ci-Ci2)alkyl and V9is -CO-;T10is PABC and V10is absent (e.g., a covalent bond); and k, 1, and m are each 0; or wherein:T7is absent (e.g., a covalent bond) and V7is -NHCO-;T8is (Ci-Ci2)alkyl and V8is absent (e.g., a covalent bond);T9is heteroaryl and V9is absent (e.g., a covalent bond);T10is (Ci-Ci2)alkyl and V10is -CONH-;T11is (PEG)nand V11is -CO-; and1 and m are each 0; or wherein:T7is absent (e.g., a covalent bond) and V7is -NHCO-;T8is (Ci-Ci2)alkyl and V8is absent (e.g., a covalent bond);T9is heteroaryl and V9is absent (e.g., a covalent bond);T10is (Ci-Ci2)alkyl and V10is -CONH-;T11is substituted (Ci-Ci2)alkyl and V11is -CO-;T12is (AA)Pand V12is absent (e.g., a covalent bond); andT13PAB and V13is absent (e.g., a covalent bond); or wherein:T7is absent (e.g., a covalent bond) and V7is -NHCO-;T8is (Ci-Ci2)alkyl and V8is absent (e.g., a covalent bond);T9is heteroaryl and V9is absent (e.g., a covalent bond);T10is (Ci-Ci2)alkyl and V10is -CONH-;T11is substituted (Ci-Ci2)alkyl and V11is -CO-;T12is (AA)Pand V12is absent (e.g., a covalent bond); andT13PABC and V13is absent (e.g., a covalent bond).

[0422] In certain embodiments, the left-hand side of the above linker structure for the second linker LBis attached to the hydrazinyl-indolyl or a hydrazinyl-pyrrolo-pyridinyl conjugation moiety, and the right-hand side of the above linker structure for the second linker LBis attached to the second drug or active agent.

[0423] In certain embodiments, the conjugate is an antibody-drug conjugate where the IL13Ra2 antibody and the drugs are linked together by linkers as described above. In some instances, the linker m (e.g., LAand / or LB) is a cleavable linker. A cleavable linker is a linker that includes one or more cleavable moieties, where the cleavable moiety includes one or more bonds that can dissociate under certain conditions, thus separating the cleavable linker into two or more separable portions. For example, the cleavable moiety may include one or more covalent bonds, which under certain conditions, can dissociate or break apart to separate the cleavable linker into two or more portions. As such the linkers that are included in an antibody-drug conjugate can be cleavable linkers, such that under appropriate conditions, the cleavable linker is cleaved to separate or release the drug from the antibody at a desired target site of action for the drug.

[0424] In some instances, a cleavable linker includes two cleavable moieties, such as a first cleavable moiety and a second cleavable moiety. The cleavable moieties can be configured such that cleavage of both cleavable moieties is needed in order to separate or release the drug from the IL13Ra2 antibody at a desired target site of action for the drug. For example, cleavage of a cleavable linker can be achieved by initially cleaving one of the two cleavable moieties and then cleaving the other of the two cleavable moieties. In certain embodiments, a cleavable linker includes a first cleavable moiety and a second cleavable moiety that hinders cleavage of the first cleavable moiety. By “hinders cleavage” is meant that the presence of an uncleaved second cleavable moiety reduces the likelihood or substantially inhibits the cleavage of the first cleavable moiety, thus substantially reducing the amount or preventing the cleavage of the cleavable linker. For instance, the presence of uncleaved second cleavable moiety can hinder cleavage of the first cleavable moiety. The hinderance of cleavage of the first cleavable moiety by the presence of the second cleavable moiety, in turn, substantially reduces the amount or prevents the release of the drug from the antibody. For example, the premature release of the drug from the antibody can be substantially reduced or prevented until the antibody-drug conjugate is at or near the desired target site of action for the drug.

[0425] In some cases, since the second cleavable moiety hinders cleavage of the first cleavable moiety, cleavage of the cleavable linker can be achieved by initially cleaving the second cleavable moiety and then cleaving the first cleavable moiety. Cleavage of the second cleavable moiety can reduce or eliminate the hinderance on the cleavage of the first cleavable moiety, thus allowing the first cleavable moiety to be cleaved. Cleavage of the first cleavable moiety can result in the cleavable linker dissociating or separating into two or more portions as described above to release the drug from the antibody-drug conjugate. In some instances,cleavage of the first cleavable moiety does not substantially occur in the presence of an uncleaved second cleavable moiety. By substantially is meant that about 10% or less cleavage of the first cleavable moiety occurs in the presence of an uncleaved second cleavable moiety, such as about 9% or less, or about 8% or less, or about 7% or less, or about 6% or less, or about 5% or less, or about 4% or less, or about 3% or less, or about 2% or less, or about 1% or less, or about 0.5% or less, or about 0.1% or less cleavage of the first cleavable moiety occurs in the presence of an uncleaved second cleavable moiety.

[0426] Stated another way, the second cleavable moiety can protect the first cleavable moiety from cleavage. For instance, the presence of uncleaved second cleavable moiety can protect the first cleavable moiety from cleavage, and thus substantially reduce or prevent premature release of the drug from the antibody until the antibody-drug conjugate is at or near the desired target site of action for the drug. As such, cleavage of the second cleavable moiety exposes the first cleavable moiety (e.g., deprotects the first cleavable moiety), thus allowing the first cleavable moiety to be cleaved, which results in cleavage of the cleavable linker, which, in turn, separates or releases the drug from the antibody at a desired target site of action for the drug as described above. In certain instances, cleavage of the second cleavable moiety exposes the first cleavable moiety to subsequent cleavage, but cleavage of the second cleavable moiety does not in and of itself result in cleavage of the cleavable linker (e.g., cleavage of the first cleavable moiety is still needed in order to cleave the cleavable linker).

[0427] The cleavable moieties included in the cleavable linker may each be an enzymatically cleavable moiety. For example, the first cleavable moiety can be a first enzymatically cleavable moiety and the second cleavable moiety can be a second enzymatically cleavable moiety. An enzymatically cleavable moiety is a cleavable moiety that can be separated into two or more portions as described above through the enzymatic action of an enzyme. The enzymatically cleavable moiety can be any cleavable moiety that can be cleaved through the enzymatic action of an enzyme, such as, but not limited to, an ester, a peptide, a glycoside, and the like. In some instances, the enzyme that cleaves the enzymatically cleavable moiety is present at a desired target site of action, such as the desired target site of action of the drug that is to be released from the antibody-drug conjugate. In some cases, the enzyme that cleaves the enzymatically cleavable moiety is not present in a significant amount in other areas, such as in whole blood, plasma, or serum. As such, the cleavage of an enzymatically cleavable moiety can be controlled such that substantial cleavage occurs at the desired site of action, whereas cleavage does not significantly occur in other areas or before the antibody-drug conjugate reaches the desired site of action.

[0428] For example, as described herein, antibody-drug conjugates of the present disclosure can be used for the treatment of cancer, such as for the delivery of a cancer therapeutic drug to a desired site of action where the cancer cells are present. In some cases, enzymes, such as an esterase that cleaves ester bonds or a glycosidase that cleaves glycosidic bonds, can be a biomarker for cancer that is overexpressed in cancer cells. The overexpression, and thus localization, of certain enzymes in cancer can be used in the context of the enzymatically cleavable moieties included in the cleavable linkers of the antibody-drug conjugates of the present disclosure to specifically release the drug at the desired site of action (e.g., the site of the cancer (and overexpressed enzyme)). Thus, in some embodiments, the enzymatically cleavable moiety is a cleavable moiety (e.g., an ester or a glycoside) that can be cleaved by an enzyme that is overexpressed in cancer cells. For instance, the enzyme can be an esterase. As such, in some instances, the enzymatically cleavable moiety is a cleavable moiety (e.g., an ester) that can be cleaved by an esterase enzyme. In some instances, the enzyme can be a glycosidase. As such, in some instances, the enzymatically cleavable moiety is a cleavable moiety (e.g, a glycoside or glycoside derivative) that can be cleaved by a glycosidase enzyme.

[0429] In certain embodiments, the enzymatically cleavable moiety is an ester bond. For example, the first cleavable moiety described above (e.g, the cleavable moiety protected from premature cleavage by the second cleavable moiety) can include an ester. The presence of uncleaved second cleavable moiety can protect the first cleavable moiety (ester) from cleavage by an esterase enzyme, and thus substantially reduce or prevent premature release of the drug from the antibody until the antibody-drug conjugate is at or near the desired target site of action for the drug. In some instances, a portion of the linker adjacent to the first cleavable moiety is linked to or includes a substituent, where the substituent comprises the second cleavable moiety. In some instances, the second cleavable moiety includes a glycoside or glycoside derivative.

[0430] In some embodiments, the enzymatically cleavable moiety is sugar moiety, such as a glycoside (or glyosyl) or glycoside derivative. In some cases, the glycoside or glycoside derivative can facilitate an increase in the hydrophilicity of the cleavable linker as compared to a cleavable linker that does not include the glycoside or glycoside derivative. The glycoside or glycoside derivative can be any glycoside or glycoside derivative suitable for use in the cleavable linker and that can be cleaved through the enzymatic action of an enzyme. For example, the second cleavable moiety (e.g., the cleavable moiety that protects the first cleavable moiety from premature cleavage) can be a glycoside or glycoside derivative. Forinstance, in some embodiments, the first cleavable moiety includes an ester, and the second cleavable moiety includes a glycoside or glycoside derivative. In certain embodiments, the second cleavable moiety is a glycoside or glycoside derivative selected from a glucuronide, a galactoside, a glucoside, a mannoside, a fucoside, O-GlcNAc, and O-GalNAc. In some instances, the second cleavable moiety is a glucuronide. In some instances, the second cleavable moiety is a galactoside. In some instances, the second cleavable moiety is a glucoside. In some instances, the second cleavable moiety is a mannoside. In some instances, the second cleavable moiety is a fucoside. In some instances, the second cleavable moiety is O-GlcNAc. In some instances, the second cleavable moiety is O-GalNAc.

[0431] The glycoside or glycoside derivative can be attached (covalently bonded) to the cleavable linker through a glycosidic bond. The glycosidic bond can link the glycoside or glycoside derivative to the cleavable linker through various types of bonds, such as, but not limited to, an O-glycosidic bond (an O-glycoside), an N-glycosidic bond (a glycosylamine), an S-glycosidic bond (a thioglycoside), or C-glycosidic bond (a C-glycoside or C-glycosyl). In some instances, the glycosidic bond is an O-glycosidic bond (an O-glycoside). In some cases, the glycoside or glycoside derivative can be cleaved from the cleavable linker it is attached to by an enzyme (e.g., through enzymatically mediated hydrolysis of the glycosidic bond). A glycoside or glycoside derivative can be removed or cleaved from the cleavable linker by any convenient enzyme that is able to carry out the cleavage (hydrolysis) of the glycosidic bond that attaches the glycoside or glycoside derivative to the cleavable linker. An example of an enzyme that can be used to mediate the cleavage (hydrolysis) of the glycosidic bond that attaches the glycoside or glycoside derivative to the cleavable linker is a glycosidase, such as a glucuronidase, a galactosidase, a glucosidase, a mannosidase, a fucosidase, and the like. Other suitable enzymes may also be used to mediate the cleavage (hydrolysis) of the glycosidic bond that attaches the glycoside or glycoside derivative to the cleavable linker. In some cases, the enzyme used to mediate the cleavage (hydrolysis) of the glycosidic bond that attaches the glycoside or glycoside derivative to the cleavable linker is found at or near the desired site of action for the drug of the antibody-drug conjugate. For instance, the enzyme can be a lysosomal enzyme, such as a lysosomal glycosidase, found in cells at or near the desired site of action for the drug of the antibody-drug conjugate. In some cases, the enzyme is an enzyme found at or near the target site where the enzyme that mediates cleavage of the first cleavable moiety is found.

[0432] In some embodiments, an IL13Ra2-ADC is represented by Formula (I):wherein:Ab represents the antibody that binds to IL13Ra2;Z1, Z2, and Z4are each independently CR4;Z3is C-LB-W2;R1, R2, R3and R4are each selected from hydrogen and (Ci-Ci2)alkyl;LAis a first linker comprising:-(T1-V1)a-(T2-V2)b-(T3-V3)c-(T4-V4)d-(T5-V5)e-(T6-V6)f-, wherein:T1is (Ci-Ci2)alkyl and V1is -CONH-;T2is substituted (Ci-Ci2)alkyl and V2is -CO-;T3is (AA)Pwhere p is an integer from 1-20 and V3is a covalent bond;T4is PABC and V4is a covalent bond; a, b, c, and d are each 1; e and f are each 0; andLBis a second linker comprising:-(T7-V7)g-(T8-V8)h-(T9-V9)i-(T10-V10)j-(T11-V11)k-(T12-V12)i-(T13-V13)m-, wherein:T7is a covalent bond and V7is -NHCO-;T8is (Ci-Ci2)alkyl and V8is -CONH-;T9is substituted (Ci-Ci2)alkyl and V9is -CO-;T10is (AA)Pwhere p is an integer from 1-20 and V10is a covalent bond;T11is PABC and V11is a covalent bond; and h, i, j, and k are each 1; and1 and...

Claims

CLAIMSWhat is claimed is:

1. An antibody-drug conjugate (ADC) of Formula (A):whereinAb represents an antibody that binds to interleukin- 13 receptor subunit alpha-2 (IL13Ra2) and Ab comprises any one or more of (i)-(iii):(i) a heavy chain variable region (VH) complementarity determining region 1 (CDR1), a VH complementarity determining region 2 (CDR2), and a VH complementarity determining region 3 (CDR3) as set forth in a VH comprising the amino acid sequence of SEQ ID NO:25 and a light chain variable region (VL) CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:26; or(ii) a VH CDR1 , a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:48 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:49; or(iii) a VH CDR1 , a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:73 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 74;L represents a linker; s is an integer from 1 to 10; andW1represents a drug.

2. The ADC of claim 1, wherein L comprises a pyridazine-pyrrolo coupling moiety optionally a hydrazinyl-indolyl or a hydrazinyl-pyrrolo-pyridinyl compound, or a derivative of each thereof.

3. The ADC of claim 1 or 2, wherein L comprises:(L-T) wherein: t is 0 or 1; represents the point of attachment to Ab;# represents the point of attachment to W1;Z1, Z2, Z3, and Z4are each independently selected from CR4, N, and C-LB-$, and $ represents the point of attachment to a second drug W2;R1, R2, R3, and R4are each selected from hydrogen and alkyl;LAis a first linker comprising:-(T1-V1)a-(T2-V2)b-(T3-V3)c-(T4-V4)d-(T5-V5)e-(T6-V6)f-, wherein: a, b, c, d, e, and f are each independently 0 or 1, provided at least one of a, b, c, d, e, and f are 1 ;T1, T2, T3, T4, T5and T6are each independently selected from a covalent bond, (Ci-Ci2)alkyl, substituted (Ci-Ci2)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, (EDA)w, (PEG)n, (AA)P, -(CR13OH)X-, 4-amino-piperidine (4AP), meta-amino-benzyloxy (MABO), meta-amino-benzyloxycarbonyl (MABC), para-amino-benzyloxy (PABO), para-amino-benzyloxycarbonyl (PABC), para-aminobenzyl (PAB), para-amino- benzylamino (PAB A), para-amino-phenyl (PAP), para-hydroxy-phenyl (PHP), an acetal group, a hydrazine, a disulfide, and an ester, wherein EDA is an ethylene diamine moiety, PEG is a polyethylene glycol, and AA is an amino acid residue or an amino acid analog, wherein each w is an integer from 1 to 20, each n is an integer from 1 to 30, each p is an integer from 1 to 20, and each x is an integer from 1 to 12;V1, V2, V3, V4, V5and V6are each independently selected from the group consisting of a covalent bond, -CO-, -NR15-, -NR15(CH2)q-, -NR15(CeH4)-, -CONR15-, -NR15CO-, -C(O)O-, -OC(O)-, -O-, -S-, -S(O)-, -SO2-, -SO2NR15-, -NR15SO2- and -P(O)OH-, wherein each q is an integer from 1 to 6; each R13is independently selected from hydrogen, an alkyl, a substituted alkyl, an aryl, and a substituted aryl; and each R15is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, carboxyl, carboxyl ester, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl;LBis a second linker comprising: -(T7-V7)g-(T8-V8)h-(T9-V9)i-(T10-V10)j-(T11-V11)k-(T12-V12)i-(T13-V13)m-, wherein: g, h, i, j, k, 1, and m are each independently 0 or 1, provided that at least one of g, h, i, j, k, 1, and m is 1;T7, T8, T9, T10, T11, T12and T13are each independently selected from a covalent bond, (Ci-Ci2)alkyl, substituted (Ci-Ci2)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, (EDA)W, (PEG)n, (AA)P, -(CR13OH)X-, 4-amino-piperidine (4AP), meta- amino-benzyloxy (MABO), meta-amino-benzyloxycarbonyl (MABC), para-amino- benzyloxy (PABO), para-amino-benzyloxycarbonyl (PABC), para-aminobenzyl (PAB), para-amino-benzylamino (PABA), para-amino-phenyl (PAP), para-hydroxy-phenyl (PHP), an acetal group, a hydrazine, a disulfide, and an ester, wherein EDA is an ethylene diamine moiety, PEG is a polyethylene glycol, and AA is an amino acid residue or an amino acid analog, wherein each w is an integer from 1 to 20, each n is an integer from 1 to 30, each p is an integer from 1 to 20, and each x is an integer from 1 to 12;V7, V8, V9, V10, V11, V12and V13are each independently selected from the group consisting of a covalent bond, -CO-, -NR15-, -NR15(CH2)q-, -NR15(CeH4)-, -CONR15-, - NR15CO-, -C(O)O-, -OC(O)-, -O-, -S-, -S(O)-, -SO2-, -SO2NR15-, -NR15SO2- and - P(O)OH-, wherein each q is an integer from 1 to 6; each R13is independently selected from hydrogen, an alkyl, a substituted alkyl, an aryl, and a substituted aryl; and each R15is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, carboxyl, carboxyl ester, acyl,aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl.

4. The ADC of claim 3, wherein at least one of Z1, Z2, Z3, and Z4is C-LB-$, and $ represents the point of attachment to a second drug W2, optionally wherein Z3is C-LB-$.

5. The ADC of claim 3 or 4, wherein W2comprises:(i) a camptothecin or an analog thereof, optionally belotecan; or(ii) an auristatin or an analog thereof, optionally MMAE.

6. The ADC of any one of claims 3 to 5, wherein W1and W2are the same.

7. The ADC of any one of claims 1 to 6, wherein W1comprises:(i) a camptothecin or an analog thereof, optionally belotecan; or(ii) an auristatin or an analog thereof, optionally MMAE.

8. The ADC of any one of claims 1-7, wherein s is 2 or 4.

9. The ADC of any one of claims 1-8, wherein s is 2.

10. The ADC of any one of claims 1-8, wherein s is 4.

11. An ADC of Formula (I) comprising: a. an antibody that binds to interleukin- 13 receptor subunit alpha-2 (IL13Ra2); and b. two or more drugs conjugated to a pyridazine-pyrrolo coupling moiety, each via a linkerwherein:Ab represents the antibody that binds to IL13Ra2;Z1, Z2, and Z4are each independently CR4;Z3is C-LB-W2;R1, R2, R3, and R4are each selected from hydrogen and alkyl;LAis a first linker comprising: -(T1-V1)a-(T2-V2)b-(T3-V3)c-(T4-V4)d-(T5-V5)e-(T6-V6)f-, wherein: a, b, c, d, e, and f are each independently 0 or 1, provided at least one of a, b, c, d, e, and f are 1 ;T1, T2, T3, T4, T5and T6are each independently selected from a covalent bond, (Ci-Ci2)alkyl, substituted (Ci-Ci2)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, (EDA)w, (PEG)n, (AA)P, -(CR13OH)X-, 4-amino-piperidine (4AP), meta-amino-benzyloxy (MABO), meta-amino-benzyloxycarbonyl (MABC), para-amino-benzyloxy (PABO), para-amino-benzyloxycarbonyl (PABC), para-aminobenzyl (PAB), para-amino- benzylamino (PAB A), para-amino-phenyl (PAP), para-hydroxy-phenyl (PHP), an acetal group, a hydrazine, a disulfide, and an ester, wherein EDA is an ethylene diamine moiety, PEG is a polyethylene glycol, and AA is an amino acid residue or an amino acid analog, wherein each w is an integer from 1 to 20, each n is an integer from 1 to 30, each p is an integer from 1 to 20, and each x is an integer from 1 to 12;V1, V2, V3, V4, V5and V6are each independently selected from the group consisting of a covalent bond, -CO-, -NR15-, -NR15(CH2)q-, -NR15(CeH4)-, -CONR15-, -NR15CO-, -C(O)O-, -OC(O)-, -O-, -S-, -S(O)-, -SO2-, -SO2NR15-, -NR15SO2- and -P(O)OH-, wherein each q is an integer from 1 to 6;each R13is independently selected from hydrogen, an alkyl, a substituted alkyl, an aryl, and a substituted aryl; and each R15is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, carboxyl, carboxyl ester, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl;LBis a second linker comprising: -(T7-V7)g-(T8-V8)h-(T9-V9)i-(T10-V10)j-(T11-V11)k-(T12-V12)i-(T13-V13)m-, wherein: g, h, i, j, k, 1, and m are each independently 0 or 1, provided that at least one of g, h, i, j, k, 1, and m is 1;T7, T8, T9, T10, T11, T12and T13are each independently selected from a covalent bond, (Ci-Ci2)alkyl, substituted (Ci-Ci2)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, (EDA)W, (PEG)n, (AA)P, -(CR13OH)X-, 4-amino-piperidine (4AP), meta- amino-benzyloxy (MABO), meta-amino-benzyloxycarbonyl (MABC), para-amino- benzyloxy (PABO), para-amino-benzyloxycarbonyl (PABC), para-aminobenzyl (PAB), para-amino-benzylamino (PABA), para-amino-phenyl (PAP), para-hydroxy-phenyl (PHP), an acetal group, a hydrazine, a disulfide, and an ester, wherein EDA is an ethylene diamine moiety, PEG is a polyethylene glycol, and AA is an amino acid residue or an amino acid analog, wherein each w is an integer from 1 to 20, each n is an integer from 1 to 30, each p is an integer from 1 to 20, and each x is an integer from 1 to 12;V7, V8, V9, V10, V11, V12and V13are each independently selected from the group consisting of a covalent bond, -CO-, -NR15-, -NR15(CH2)q-, -NR15(CeH4)-, -CONR15-, - NR15CO-, -C(O)O-, -OC(O)-, -O-, -S-, -S(O)-, -SO2-, -SO2NR15-, -NR15SO2- and - P(O)OH-, wherein each q is an integer from 1 to 6; each R13is independently selected from hydrogen, an alkyl, a substituted alkyl, an aryl, and a substituted aryl; and each R15is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, carboxyl, carboxyl ester, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl; s is an integer from 1 to 10;W1is a first drug; andW2is a second drug.

12. The ADC of claim 11, wherein:T1is selected from a (Ci-Cnjalkyl and a substituted (Ci-Ci2)alkyl;T2, T3, T4, T5and T6are each independently selected from a covalent bond, (Ci- Cnjalkyl, substituted (Ci-Cnjalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, (EDA)W, (PEG)n, (AA)p, -(CR13OH)X-, 4-amino-piperidine (4AP), MABO, MABC, PABO, PABC, PAB, PAB A, PAP, PHP, an acetal group, a hydrazine, and an ester; andV1, V2, V3, V4, V5and V6are each independently selected from the group consisting of a covalent bond, -CO-, -NR15-, -NR15(CH2)q-, -NR15(C6H4)-, -CONR15-, -NR15CO-, -C(O)O-, -OC(O)-, -O-, -S-, -S(O)-, -SO2-, -SO2NR15-, -NR15SO2-, and -P(O)OH-;4-amino-piperidineeach R12is independently selected from hydrogen, an alkyl, a substituted alkyl, a polyethylene glycol moiety, an aryl, and a substituted aryl, wherein any two adjacent R12groups may be cyclically linked to form a piperazinyl ring; q is an integer from 1 to 6; r is 0 or 1; and y is an integer from 1 to 6.

13. The ADC of claims 11 or 12, wherein:T1is (Ci-Ci2)alkyl and V1is -CONH-;T2is substituted (Ci-Ci2)alkyl and V2is -CO-;T3is (AA)Pand V3is absent;T4is PABC and V4is absent; p is an integer from 1 to 10; and a, b, c, and d are each 1; ande and f are each 0.

14. The ADC of any one of claims 11-13, wherein:T7is a covalent bond;T8, T9, T10, T11and T12are each independently selected from a covalent bond, (Ci- Cn)alkyl, substituted (Ci-Ci2)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, (EDA)W, (PEG)n, (AA)p, -(CR13OH)X-, 4-amino-piperidine (4AP), MABO, MABC, PABO, PABC, PAB, PAB A, PAP, PHP, an acetal group, a hydrazine, and an ester; andV7, V8, V9, V10, V11and V12are each independently selected from the group consisting of a covalent bond, -CO-, -NR15-, -NR15(CH2)q-, -NR15(CeH4)-, -CONR15-, -NR15CO-, -C(O)O-, -OC(O)-, -O-, -S-, -S(O)-, -SO2-, -SO2NR15-, -NR15SO2-, and -P(O)OH-, wherein:integer from 1 to 30;EDA is an ethylene diamine moiety having the following structure:integer from 1 to 6 and r is 0 or 1;4-amino-piperidineeach R12is independently selected from hydrogen, an alkyl, a substituted alkyl, a polyethylene glycol moiety, an aryl, and a substituted aryl, wherein any two adjacent R12groups may be cyclically linked to form a piperazinyl ring; g, h, i, j, and k are each 1; and1 and m are each 0.

15. The ADC of any one of claims 11-14, wherein:T7is absent and V7is -NHCO-;T8is (Ci-Ci2)alkyl and V8is -CONH-;T9is substituted (Ci-Ci2)alkyl and V9is -CO-;T10is (AA)Pand V10is absent;T11is PABC and V11is absent; p is an integer from 1 to 10; andg, h, i, j, and k are each 1; and1 and m are each 0.

16. The ADC of any one of claims 11-15 wherein one or both of T2and T9is (Ci-Ce)alkylene substituted with -NHCO(PEG)ki, wherein (integer from 2 to 10, optionally 8.

17. The ADC of any one of claims 11-16, wherein one or both T3and T10have a p of 2.

18. The ADC of any one of claims 11-17, wherein MABO, MABC, PABO, PABC, PAB, PABA, PAP and PHP are each optionally substituted with a glycoside, optionally wherein the glycoside is selected from a glucuronide, a galactoside, a glucoside, a mannoside, a fucoside, O-GlcNAc, and O-GalNAc.

19. The ADC of any one of claims 11-18, wherein one or both of W1and W2is a camptothecin analog, optionally wherein the camptothecin analog is belotecan.

20. The ADC of any one of claims 11-19, wherein each of W1and W2is belotecan.

21. An ADC represented by F ormula (II) :wherein:Ab represents an antibody that binds to IL13Ra2; and s is an integer from 1 to 10.

22. The ADC of any one of claims 11-21, wherein s is 2 or 4.

23. The ADC of any one of claims 11-22, wherein s is 2.

24. The ADC of any one of claims 11-22, wherein s is 4.

25. An antibody-drug conjugate (ADC) of Formula (III) comprising: a. an antibody that binds to IL13Ra2; and b. one or more drugs conjugated to one or more pyridazine-pyrrolo coupling moieties via a linkerwherein:Ab represents the antibody that binds to IL13Ra2;W1is the drug; s is an integer from 1 to 10; t is 0 or 1;R2and R3are each independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acyl amino, amino acyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl; or R2and R3are cyclically linked to form a 5- or 6-membered heterocyclyl;X1, X2, X3, and X4are each independently selected from the group consisting of C, N, O and S;Y1, Y2, Y3, and Y4are each independently selected from the group consisting of hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acyl amino, amino acyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, and absent when adjacent to N; or Y1and Y2, Y2and Y3, or Y3and Y4are cyclically linked; andwherein:'AA / represents attachment to the nitrogen of the pyridazine-pyrrolo coupling moiety;* represents attachment to W1; each R5is independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, or substituted heterocyclyl; each R6is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl;R7is a cleavable moiety; k is an integer from 1 to 10;Llacomprises -(T-1-V1)a-(T2-V2)b-(T3-V3)c-(T4-V4)d-;L2acomprises -(T-5-V5)e-(T6-V6)f-(T7-V7)g-(T8-V8)h-; each of a, b, c, d, e, f, g, and h are independently 1 or 0;T1, T2, T3T4, T5, T6, T7, and T8are each independently selected from the group consisting of a covalent bond, C1-C12 alkyl, substituted C1-C12 alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, (EDA)W, (PEG)n, (AA)P, -(CR13OH)m-, P4A-R12, acetal, a hydrazine, a disulfide, and an ester; each w is an integer from 1 to 20; each n is an integer from 1 to 30; each p is an integer from 1 to 20; each m is an integer from 1 to 12;V1, V2, V3, V4, V5, V6, V7, and V8are each independently selected from the group consisting of a covalent bond, -CO-, -NR15-, -NR15(CH2)q-, -NR15(CeH4)-, -CONR15-, -NR15CO-, -C(O)O-, -OC(O)-, -O-, -S-, -S(O)-, -SO2-, -SO2NR15-, -NR15SO2-, and -P(O)OH-; each q is an integer from 1 to 6;R12is selected from the group consisting of hydrogen, alkyl, substituted alkyl, a polyethylene glycol moiety, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acyl amino, amino acyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl; each R13is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, and substituted aryl; and each R15is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, carboxyl, carboxyl ester, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl.

26. The ADC of claim 25, wherein R2and R3are each alkyl.

27. The ADC of claim 26, wherein R2and R3are each methyl.

28. The ADC of any one of claims 25-27, wherein each of X1, X2, X3, and X4are independently selected from C and N.

29. The ADC of any one of claims 25-28, represented by Formula (V-3):

30. The ADC of any one of claims 25-29, whereinrepresents the point of attachment to the phenyl group in LAor Formula (V-3).

31. The ADC of any one of claims 25-30, represented by Formula (IV-5):(IV-5) wherein R6and R6are each independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, or substituted heterocyclyl.

32. The ADC of any one of claims 25-31, represented by Formula (V-5):(V-5) wherein X1is CH or N, wherein R6and R6are each independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, or substituted heterocyclyl.

33. The ADC of any one of claims 25-32, represented by Formula (V-6):(V-6)34. The ADC of any one of claims 25-33, wherein:Llacomprises -(T1-V1)a-(T2-V2)b-(T3-V3)c-(T4-V4)d-; a, b, and c are each 1; d is 0 and therefore T4and V4are absent;T1, T2, and T3are each independently selected from the group consisting of C1-C12 alkyl, (PEG)n, and (AA)P, n is an integer from 1 to 10; p is an integer from 1 to 10;V1, V2, and V3are each independently selected from the group consisting of-C(=O)- and -NR11-; andR11is selected from hydrogen, alkyl, substituted alkyl, a polyethylene glycol moiety, aryl, and substituted aryl.

35. The ADC of any one of claims 25-33, wherein:Llacomprises -(T1-V1)a-(T2-V2)b-(T3-V3)c-(T4-V4)d-; a, b, and c are each 1; d is 0 and therefore T4and V4are absent;T1, T2, and T3are each independently selected from the group consisting of C1-C12 alkyl, substituted C1-C12 alkyl, and (PEG)n; n is an integer from 1 to 10;V1, V2, and V3are each independently selected from the group consisting of-C(=O)-, -CONR15-, and -NR15CO-; andR15is selected from hydrogen, alkyl, substituted alkyl, and alkenyl.

36. The ADC of any one of claims 25-35, wherein Llais:wherein represents the point of attachment to the nitrogen of a pyridazine-pyrrolo coupling moiety and wherein * represents a point of attachment in any direction to a remaining portion of the linker.

37. The ADC of any one of claims 25-36, represented by Formula (V-7):(V-7) wherein X1is CH or N.

38. The ADC of any one of claims 25-37, wherein L2ais a carbonyl group.

39. The ADC of any one of claims 25-38, wherein W1is an auristatin, optionally, MMAE.

40. The ADC of any one of claims 25-39, wherein X1is N and W1is MMAE.

41. The ADC of any one of claims 25-40, represented by Formula (Vb-82):(Vb-82)42. The ADC of any one of claims 25-41, wherein s is 2 or 4.

43. The ADC of any one of claims 25-42, wherein s is 2.

44. The ADC of any one of claims 25-42, wherein s is 4.

45. The ADC of any one of claims 25-43, represented by Formula (Vb-82-1):(Vb-82-1)46. The ADC of any one of claims 11-45, wherein Ab comprises any one or more of (i)- (iii):(i) a heavy chain variable region (VH) complementarity determining region 1 (CDR1), a VH complementarity determining region 2 (CDR2), and a VH complementarity determining region 3 (CDR3) as set forth in a VH comprising the amino acid sequence of SEQ ID NO:25 and a light chain variable region (VL) CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:26; or(ii) a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:48 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:49; or(iii) a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:73 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:74.

47. The ADC of any one of claims 1-46, wherein Ab comprises:(a) a VH comprising:(1) a VH CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1, 2, 3, 4, and 5;(2) a VH CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 6, 7, 8, 9, and 10; and(3) a VH CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 11, 12, 13, and 14;(b) a V comprising:(1) a VL CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 15, 16, 17, and 18;(2) a VL CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 19, 20, and 21; and(3) a VL CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22, 23, and 24.

48. The ADC of any one of claims 1-47, wherein Ab comprises one or more of (i)-(vi):(i) a VH comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:6, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 11; and a VL comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 15, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 19, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:22;(ii) a VH comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:2, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:7, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 12; and a VL comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 16, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:20, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:22;(iii) a VH comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:3, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:6, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 11; and a VL comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 15, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 19, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:22;(iv) a VH comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:4, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:8, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 13; and a VL comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 17, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:20, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:23;(v) a VH comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:5, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:9, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 14; and a VL comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 18, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:21, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:24; or(vi) a VH comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 10, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 11; and a VL comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 15, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 19, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:22.

49. The ADC of any one of claims 1-46, wherein Ab comprises:(a) a VH comprising:(1) a VH CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 27, 28, 29, 30, and 31;(2) a VH CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 32, 33, 34, 35, and 36; and(3) a VH CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 37, 38, 39, and 40; and(b) a VL comprising:(1) a VL CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 41, 42, 43, and 44;(2) a VL CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 19, 20, and 21; and(3) a VL CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 45, 46, and 47.

50. The ADC of any one of claims 1-46 and 49, wherein Ab comprises one or more of (i)- (vi):(i) a VH comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:27, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:32, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VLcomprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:41, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 19, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:45;(ii) a VH comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:28, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:33, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:38; and a VL comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:42, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:20, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:45;(iii) a VH comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:29, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:32, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:41, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 19, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:45;(iv) a VH comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:30, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:34, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:39; and a VL comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:43, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:20, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:46;(v) a VH comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:31, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:35, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:40; and a VL comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:44, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:21, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:47; or(vi) a VH comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:27, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:36, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:37; and a VL comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:41, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 19, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:45.

51. The ADC of any one of claims 1-46, wherein Ab comprises:(a) a VH comprising:(1) a VH CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 50, 51, 52, 53, and 54;(2) a VH CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 55, 56, 57, 58, and 59; and(3) a VH CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 60, 61, 62, and 63; and(b) a VL comprising:(1) a VL CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 64, 65, 66, and 67;(2) a VL CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 68, 20, and 69; and(3) a VL CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 70, 71, and 72.

52. The ADC of any one of claims 1-46 and 51, wherein Ab comprises one or more of (i)- (vi):(i) a VH comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:50, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:55, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:60; and a VL comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:64, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:68, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:70;(ii) a VH comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:51, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:56, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:61; and a VL comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:65, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:20, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:70;(iii) a VH comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:52, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:55, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:60; and a VLcomprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:64, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:68, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:70;(iv) a VH comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:53, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:57, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:62; and a VL comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:66, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:20, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:71;(v) a VH comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:54, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:58, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:63; and a VL comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:67, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:69, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:72; or(vi) a VH comprising a VH CDR1 comprising the amino acid sequence of SEQ ID NO:50, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:59, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:60; and a VL comprising a VL CDR1 comprising the amino acid sequence of SEQ ID NO:64, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:68, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:70.

53. The ADC of any one of claims 1-52, wherein Ab further comprises a framework 1 (FR1), a framework 2 (FR2), a framework 3 (FR3) and / or a framework 4 (FR4) sequence.

54. The ADC of any one of claims 1 to 53, wherein Ab further comprises human framework sequences, optionally an FR1, an FR2, an FR3 and / or an FR4 sequence as set forth in any one or more of SEQ ID NOs: 25, 26, 48, 49, 73 and 74.

55. The ADC of any one of claims 1-54, wherein the antibody Ab comprises a sequence of Formula (X) x'(fGly’)X2z20x z0(X) wherein: fGly’ is the amino acid residue coupled to the drug through a linker;Z20is either a proline (P) or alanine (A) residue;Z30is a basic amino acid residue optionally selected from the group consisting of: arginine (R), lysine (K), and histidine (H), or an aliphatic amino acid residue optionally selected from the group consisting of: alanine (A), glycine (G), leucine (L), valine (V), isoleucine (I), and proline (P);X1is present or absent and, when present, can be any amino acid residue, with the proviso that when the sequence of Formula (X) is at the N-terminus of the antibody Ab, X1is present; andX2and X3independently is any amino acid residue, optionally wherein, the sequence of Formula (X) is selected from the group consisting of: L(fGly’)TPSR (SEQ ID NO: 146), M(fGly’)TPSR (SEQ ID NO: 147), V(fGly’)TPSR (SEQ ID NO: 148), L(fGly’)SPSR (SEQ ID NO: 149), L(fGly’)APSR (SEQ ID NO: 150), L(fGly’)VPSR (SEQ ID NO: 151), L(fGly’)GPSR (SEQ ID NO: 152), I(fGly’)TPAR (SEQ ID NO: 153), L(fGly’)TPSK (SEQ ID NO: 154), M(fGly’)TPSK (SEQ ID NO: 155), V(fGly’)TPSK (SEQ ID NO: 156), L(fGly’)SPSK (SEQ ID NO: 157), L(fGly’)APSK (SEQ ID NO: 158), L(fGly’)VPSK (SEQ ID NO: 159), L(fGly’)GPSK (SEQ ID NO: 160), L(fGly’)TPSA (SEQ ID NO: 161), I(fGly’)TPAA (SEQ ID NO: 162), M(fGly’)TPSA (SEQ ID NO: 163), V(fGly’)TPSA (SEQ ID NO: 164), L(fGly’)SPSA (SEQ ID NO: 165), L(fGly’)APSA (SEQ ID NO: 166), L(fGly’)VPSA (SEQ ID NO: 167), and L(fGly’)GPSA (SEQ ID NO: 168); further optionally wherein the sequence of Formula (X) comprises L(fGly’)TPSR (SEQ ID NO: 146).

56. The ADC of any one of claims 1-55, wherein the antibody Ab is an IgGl antibody, optionally an IgGl kappa antibody.

57. The ADC of any one of claims 1 to 56, wherein Ab comprises any one of:(i) a VH comprising the amino acid sequence of SEQ ID NO:48 and a VL comprising the amino acid sequence of SEQ ID NO:49; or(ii) a VH comprising the amino acid sequence of SEQ ID NO:73 and a VL comprising the amino acid sequence of SEQ ID NO:74; or(iii) a VH comprising the amino acid sequence of SEQ ID NO:25 and a VL comprising the amino acid sequence of SEQ ID NO:26.

58. The ADC of any one of claims 1 to 57, wherein Ab comprises any one of:(i) a heavy chain comprising the amino acid sequence of SEQ ID NO:201, and a light chain comprising the amino acid sequence of SEQ ID NO:76; or(ii) a heavy chain comprising the amino acid sequence of SEQ ID NO:208, and a light chain comprising the amino acid sequence of SEQ ID NO:80; or(iii) a heavy chain comprising the amino acid sequence of SEQ ID NO:217, and a light chain comprising the amino acid sequence of SEQ ID NO:82; or(iv) a heavy chain comprising the amino acid sequence of SEQ ID NO:203, and a light chain comprising the amino acid sequence of SEQ ID NO:76; or(v) a heavy chain comprising the amino acid sequence of SEQ ID NO:211, and a light chain comprising the amino acid sequence of SEQ ID NO:80; or(vi) a heavy chain comprising the amino acid sequence of SEQ ID NO:220, and a light chain comprising the amino acid sequence of SEQ ID NO:82; or(vii) a heavy chain comprising the amino acid sequence of SEQ ID NO:205, and a light chain comprising the amino acid sequence of SEQ ID NO:76; or(viii) a heavy chain comprising the amino acid sequence of SEQ ID NO:214, and a light chain comprising the amino acid sequence of SEQ ID NO:80; or(ix) a heavy chain comprising the amino acid sequence of SEQ ID NO:223, and a light chain comprising the amino acid sequence of SEQ ID NO:82.

59. The ADC of any one of claims 1-58, wherein Ab is a monoclonal antibody.

60. The ADC of any one of claims 1-59, wherein Ab is a humanized, human, or chimeric antibody.

61. The ADC of any one of claims 1-55, wherein Ab is any one of a Fab, Fab’, F(ab’)2, Fv, scFv, (SCFV)2, single chain antibody molecule, dual variable region antibody, single variable region antibody, linear antibody, V region, or a multispecific antibody formed from antibody fragments.

62. A pharmaceutical composition comprising the ADC of any one of claims 1-61 and a pharmaceutically acceptable excipient.

63. The pharmaceutical composition of claim 62, characterized by an ADC drug-to- antibody ratio (DAR) of about 1 to about 20.

64. The pharmaceutical composition of claim 63, wherein the DAR is about 2 to about 8.

65. The pharmaceutical composition of claim 63 or 64, wherein the DAR is about 4 to about 8.

66. The pharmaceutical composition of claim 63 or 64, wherein the DAR is about 2.

67. The pharmaceutical composition of any one of claims 63-65, wherein the DAR is about 4.

68. The pharmaceutical composition of any one of claims 63-65, wherein the DAR is about 8.

69. A method for treating a disease or disorder in a subject, the method comprising administering a therapeutically effective amount of the ADC of any one of claims 1-61 or the pharmaceutical composition of any one of claims 62-68 to the subject.

70. The method of claim 69, wherein the disease or disorder is a cancer.

71. The method of claim 70, wherein the cancer expresses IL13Ra2.

72. The method of claim 70 or 71, wherein the cancer overexpresses IL13Ra2.

73. The method of any one of claims 70-72, wherein the cancer is selected from the group consisting of melanoma, lung cancer, breast cancer, colon cancer, ovarian cancer, and head and neck cancer.

74. The method of any one of claims 70-73, wherein the cancer is non-small cell lung cancer (NSCLC), or head and neck squamous cell carcinoma (HNSCC).

75. The method of any one of claims 69-73, wherein the subject is a human subject.

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