Carbodiene antibody-drug conjugates and methods of use

Abstract

The present application relates to Carbodiene antibody-drug conjugates and methods of use. The present disclosure relates to linker-drug compounds and antibody-drug conjugates that bind to human oncology targets. Such linker-drug compounds and antibody-drug conjugates comprise a Carbodiene splice modulator drug moiety. The disclosure further relates to methods and compositions for treating neoplastic disorders by administering such antibody-drug conjugates provided herein. The Carberg diene itself is also claimed. Further claimed are the use thereof, as well as the use of a neoantigen produced by a Carberg diene or an ADC thereof, or a vaccine against the neoantigen.

Description

[0001] This application is a divisional application of Chinese Patent Application No. 201980081875.X, filed on December 12, 2019, with the invention title "Herboxidiene Antibody-Drug Conjugates and Methods of Use" (PCT Application No. PCT / US2019 / 066029). This disclosure claims the priority benefit of the following applications: U.S. Provisional Patent Application No. 62 / 779,400, filed on December 13, 2018; U.S. Provisional Application No. 62 / 779,406, filed on December 13, 2018; and U.S. Provisional Application No. 62 / 941,220, filed on November 27, 2019. All of the above applications are hereby incorporated by reference in their entirety.

[0002] This disclosure relates to antibody-drug conjugates (ADCs) comprising a herboxidiene splicing regulator and an antibody or an antigen-binding fragment thereof, such as antibody-drug conjugates that bind to human oncology antigen targets. This disclosure further relates to methods and compositions useful for treating or diagnosing cancer that expresses a target antigen and / or is suitable for treatment by RNA splicing disruption, and methods of making those compositions.

[0003] Most protein-coding genes in the human genome consist of multiple exons (coding regions) separated by introns (non-coding regions). Gene expression produces a single precursor messenger RNA (pre-mRNA). Subsequently, intron sequences are removed from the pre-mRNA by a process called splicing, generating mature messenger RNA (mRNA). By including different exon combinations, alternative splicing produces mRNAs encoding distinct protein isoforms.

[0004] RNA splicing is catalyzed by the spliceosome, a dynamic multi-protein-RNA complex composed of five small nuclear RNAs (snRNA U1, U2, U4, U5, and U6) and associated proteins. The spliceosome assembles on the pre-mRNA to establish a dynamic cascade of multiple RNA and protein interactions that catalyze the excision of introns and the ligation of exons (Matera and Wang (2014) Nat Rev Mol Cell Biol. 15(2):108-21). Growing evidence links human diseases to dysregulation in RNA splicing that affects many genes (Scotti and Swanson (2016) Nat Rev Genet. 17(1):19-32).

[0005] The spliceosome is an important target in cancer biology. Several studies have now documented the splicing profiles of cancer cells and numerous alterations in their own splicing factors (Agrawal et al. (2018) Curr Opin Genet Dev. 48:67-74). Alternative splicing can cause differential exon inclusion / exclusion, intron retention, or cryptic splice site usage (Seiler et al. (2018) Cell Rep. 23(1):282-296). Collectively, these events result in functional changes that may contribute to tumorigenesis or therapy resistance (Siegfried and Karni (2018) Curr Opin Genet Dev. 48:16-21).

[0006] Certain natural products can bind to the SF3b spliceosome complex. These small molecules regulate splicing by promoting intron retention and / or exon skipping (Teng et al. (2017) Nat Commun. 8:15522). For example, herboxidiene, a naturally occurring polyketide isolated from Streptomyces sp. A7847 (Isaac et al. (1992) J. Org. Chem. 57:7220-26) and its derivatives have been shown to regulate splicing. See, for example, Imaizumi et al. (2017) J. Antibiot. 70:675-79. A substantial portion of the resulting transcripts contain premature termination codons, triggering nonsense-mediated mRNA decay (NMD). In addition, because canonical splicing is impaired, canonical transcripts are significantly reduced, which may adversely affect cell function and viability. For this reason, splice modulators have become a promising class of drugs for treating cancer (Puthenveetil et al. (2016) Bioconjugate Chem. 27:1880-8).

[0007] The proto-oncogene human epidermal growth factor receptor 2 (HER2) encodes a transmembrane tyrosine kinase receptor belonging to the human epidermal growth factor receptor (EGFR) family (King et al. (1985) Science 229:974-6). Overexpression of HER2 enables constitutive activation of growth factor signaling pathways such as the PI3K-AKT-mTOR pathway and thus serves as an oncogenic driver in several types of cancers, including approximately 20% of invasive breast cancers (Slamon et al. (1989) Science 244:707-12; Gajria and Chandarlapaty (2011) Expert Rev Anticancer Ther. 11:263-75). Given that HER2 amplification mediates transformed phenotypes and because HER2 expression is largely restricted to malignant cells, HER2 is a promising antigen for targeting certain cancers and / or delivering novel cancer therapies (Parakh et al. (2017) Cancer Treat Rev. 59:1-21). Additional antigens for targeted delivery of cancer therapies include, but are not limited to, CD138 (also known as syndecan-1) and ephrin type-A receptor 2 (EPHA2).

[0008] CD138 is a cell surface heparan sulfate proteoglycan required for maintaining cell morphology and interaction with the surrounding microenvironment (Akl et al. (2015) Oncotarget 6(30):28693-715; Szatmári et al. (2015) Dis Markers 2015:796052). In general, loss of CD138 expression in cancer cells reduces cell adhesion to the extracellular matrix and enhances cell motility and invasiveness (Teng et al. (2012) Matrix Biol. 31:3-16). Increased stromal CD138 expression also alters fibronectin production and extracellular matrix organization (Yang et al. (2011) Am J Pathol. 178:325-35). Additionally, increased CD138 expression in stromal fibroblasts is associated with angiogenesis and cancer development (Maeda et al. (2006) Oncogene 25:1408-12). CD138 expression increases during B cell development, and its presence is a marker of plasma cells (Ribatti (2017) Immunol Lett. 188:64-7). CD138 expression is maintained in multiple myeloma, a plasma cell malignancy. Thus, CD138 is an attractive antigen for targeted therapy of several cancers and other hematological malignancies (Sherbenou et al. (2015) Blood Rev. 29(2):81-91; Wijdenes et al. (1996) Br J Haematol. 94(2):318-23).

[0009] EPHA2 is a transmembrane glycoprotein that is abundantly overexpressed in several malignant cancer-derived cell lines as well as in advanced cancer forms (Wykosky and Debinski (2008) Mol Cancer Ref. 6(12):1795-1806). For example, EPHA2 is strongly overexpressed in tumors of approximately 61% of GBM patients (Wykosky et al. (2008) Clin Cancer Res. 14:199-208), 76% of ovarian cancers (Thaker et al. (2004) Clin Cancer Res. 10:5145-50), and 85% of prostate adenocarcinomas (Zeng et al. (2003) Am J Pathol. 163:2271-6). The EPHA2 protein is highly overexpressed with respect to a certain percentage of patient tumors and a certain percentage of cells within the tumors, and is a plasma membrane-localized receptor that can be internalized upon ligand binding (Walker-Daniels et al. (2002) Mol Cancer Res. 1:79-87). In addition, the expression of EPHA2 is associated with poor prognosis, increased metastasis, and decreased survival. Thus, EPHA2 is another compelling antigen for targeted delivery of novel anticancer therapies due to its expression pattern, localization, and functional importance in the outcomes of cancer patients.

[0010] In various embodiments, the present disclosure provides novel hopene splicing regulators that have biological activity against neoplastic cells. The hopene splicing regulators can be used alone or as part of an ADC to slow, inhibit, and / or reverse tumor growth in mammals, and can be applicable for treating human cancer patients. In various embodiments, the present disclosure provides novel antibody-drug conjugates employing the hopene splicing regulators.

[0011] More specifically, in various embodiments, the present disclosure relates to antibody-drug conjugate (ADC) complexes that are capable of binding to and killing neoplastic cells. In various embodiments, the ADC complexes disclosed herein comprise a linker that attaches the splicing regulator to a full-length antibody or antigen-binding fragment. In various embodiments, these ADC complexes are also capable of internalizing into target cells after binding.

[0012] In some embodiments, the antibody-drug conjugate is an antibody-drug conjugate having formula (I): Ab-(L-H) p , wherein Ab is an antibody or antigen-binding fragment that targets neoplastic cells; H is a hopene splicing regulator; L is a linker that covalently attaches Ab to H; and p is an integer from 1 to 15.

[0013] In some embodiments, H as a hopadiene splicing regulator comprises a compound having the formula (I): or a pharmaceutically acceptable salt thereof, which is covalently linked to L via any atom, wherein: Y is selected from O, S, NR 6 and CR 6 R 7 ; R 1 , R 2 and R 3 are each independently selected from hydrogen, hydroxy, -O-(C1-C6 alkyl), -O-C(=O)-(C1-C6 alkyl), -C(=O)-O-(C1-C6 alkyl) and C1-C6 alkyl; R 4 is selected from hydrogen, C1-C6 alkyl, -C(=O)-(C1-C6 alkyl), -C(=O)-(C3-C8 carbocyclic group), -C(=O)-(C3-C8 heterocyclic group) and -C(=O)-NR 6 R 7 ; R 5 is selected from hydrogen, hydroxy, -CH2-OH, -CO2H, -C(=O)-O-(C1-C6 alkyl), -C(=O)-NR 6 R 7 , -NR 6 -C(=O)-R 8 , -O-C(=O)-NR 6 R 7 , -NR 6 -C(=O)-R 8 and -NR 6 -C(=O)-NR 6 R 7 ; R 6 and R 7 are each independently selected from hydrogen, -R 8 , -C(=O)-R 8 and -C(=O)-O-R 8 ; and R 8 is selected from C1-C6 alkyl, C3-C8 carbocyclic group and C3-C8 heterocyclic group, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8Each independently substituted with 0 to 3 groups independently selected from the following: halogen, hydroxy, C1-C6 alkyl, -O-(C1-C6 alkyl), -CO2H, -C(=O)-(C1-C6 alkyl), -C(=O)-(C3-C8 carbocyclic group), -C(=O)-(C3-C8 heterocyclic group), -NR 6 R 7 、C3-C8 carbocyclic group, C1-C6 alkyl hydroxy, C1-C6 alkyl alkoxy, benzyl and C3-C8 heterocyclic group, each of which may independently be substituted with 0 or 1 group selected from the following: halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, -NH-C(=O)(C1-C3 alkyl) and -NH-C(=O)-O-(C1-C3 alkyl), and wherein the valence of the atom covalently linked to L is not exceeded.

[0014] In some embodiments, H as a Herboxidiene splicing regulator comprises a compound having formula (Ia): or a pharmaceutically acceptable salt thereof, which is covalently linked to L via any atom, wherein: R 9 is selected from C3-C8 heterocyclic group; R 10 is selected from H and C1-C6 alkyl, wherein R 9 and R 10 are each independently substituted with 0 to 3 groups independently selected from the following: halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, -NH2, -NH-(C1-C3 alkyl) and -N-(C1-C3 alkyl)2, and wherein the valence of the atom covalently linked to L is not exceeded.

[0015] In some embodiments, H as a Herboxidiene splicing regulator comprises a compound having formula (Ib): or a pharmaceutically acceptable salt thereof, which is covalently linked to L via any atom, wherein: R 11 is selected from where * indicates the point of attachment of R 11 to the remainder of the compound; R 12 and R 13 are each independently selected from H and methyl; and wherein the valence of the atom covalently linked to L is not exceeded.

[0016] In some embodiments, H as a Herboxidiene splicing regulator comprises a compound having formula (II): or a pharmaceutically acceptable salt thereof, which is covalently attached to L via any atom, wherein: X is hydroxy or NR 6 R 7 ; R 6 and R 7 are each independently selected from hydrogen, -R 8 , -C(=O)-R 8 , -C(=O)-O-R 8 , -(C1-C6 alkyl)-O-C(=O)-R 8 and -(C1-C6 alkyl)-NH-C(=O)-R 8 ; and R 8 is selected from C1-C6 alkyl, C3-C8 carbocyclic group and C3-C8 heterocyclic group, wherein R 6 , R 7 and R 8 are each independently substituted with 0 to 3 groups independently selected from: halogen, hydroxy, C1-C6 alkyl, -O-(C1-C6 alkyl), -CO2H, -C(=O)-O-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)-(C3-C8 carbocyclic group), -C(=O)-(C3-C8 heterocyclic group), -NR 6 R 7 , C3-C8 carbocyclic group, C1-C6 alkyl hydroxy, C1-C6 alkyl alkoxy, benzyl and C3-C8 heterocyclic group, each of which may be independently substituted with 0 or 1 group selected from: halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, -NH-C(=O)(C1-C3 alkyl) and -NH-C(=O)-O-(C1-C3 alkyl), and wherein the valence of the atom covalently attached to L is not exceeded.

[0017] In some embodiments, H as a hopene splicing regulator comprises a compound having formula (IIa): or a pharmaceutically acceptable salt thereof, which is covalently attached to L via any atom, wherein: Z is selected from NR 9 and O; R 9 is selected from hydrogen and C1-C6 alkyl; R 10 and R 11Each independently selected from hydrogen, halogen, hydroxy, C1-C6 alkyl, -O-(C1-C6 alkyl), -CO2H, -C(=O)-O-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)-(C3-C8 carbocyclic group), -C(=O)-(C3-C8 heterocyclic group), C3-C8 carbocyclic group, C1-C6 alkyl hydroxy, C1-C6 alkyl alkoxy, benzyl and C3-C8 heterocyclic group; R 12 Selected from C1-C6 alkyl, C3-C8 carbocyclic group, C3-C8 heterocyclic group, wherein R 9 , R 10 , R 11 and R 12 Each independently substituted by 0 or 1 group selected from the following: halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy and C1-C3 haloalkyl; t is an integer selected from 1, 2, 3, 4, 5 and 6; and wherein the valence of the atom covalently linked to L is not exceeded.

[0018] In some embodiments, H as a Herberstein diene splicing regulator comprises a compound having formula (IIb): or a pharmaceutically acceptable salt thereof, which is covalently linked to L via any atom, wherein: R 13 Selected from where * indicates the point of attachment of R 13 to the remainder of the compound; R 14 and R 15 Each independently selected from hydrogen and methyl; and wherein the valence of the atom covalently linked to L is not exceeded.

[0019] In some embodiments, H as a Herberstein diene splicing regulator comprises a compound having formula (III): or a pharmaceutically acceptable salt thereof, which is covalently linked to L via any atom, wherein: R 1 , R 2 and R 3 Each independently selected from hydrogen, hydroxy, -O-(C1-C6 alkyl), -O-C(=O)-(C1-C6 alkyl), -C(=O)-O-(C1-C6 alkyl) and C1-C6 alkyl; R 6 and R 7 Each independently selected from hydrogen, -R8 、 -C(=O)-R 8 and -C(=O)-O-R 8 ; R 8 is selected from C1-C6 alkyl, C3-C8 carbocyclic group and C3-C8 heterocyclic group; and R 9 is selected from H, wherein R 1 、R 2 、R 3 、R 6 、R 7 and R 8 are each independently substituted with 0 to 3 groups independently selected from the following: halogen, hydroxyl, C1-C6 alkyl, -O-(C1-C6 alkyl), -CO2H, -C(=O)-(C1-C6 alkyl), -C(=O)-(C3-C8 carbocyclic group), -C(=O)-(C3-C8 heterocyclic group), -NR 6 R 7 、C3-C8 carbocyclic group, C1-C6 alkylhydroxy, C1-C6 alkylalkoxy, benzyl and C3-C8 heterocyclic group, each of which may be independently substituted with 0 or 1 group selected from the following: halogen, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, -NH-C(=O)(C1-C3 alkyl) and -NH-C(=O)-O-(C1-C3 alkyl), wherein the valence of the atom covalently linked to L is not exceeded; and wherein * indicates the point of attachment of R 9 to the remainder of the compound.

[0020] In some embodiments, the linker comprises a cleavable peptide moiety. In some embodiments, the cleavable peptide moiety can be cleaved by an enzyme. In some embodiments, the cleavable peptide moiety or the linker comprises amino acid units. In some embodiments, the amino acid units comprise valine-citrulline ("Val-Cit" or "VC"). In some other embodiments, the amino acid units comprise valine-alanine ("Val-Ala" or "VA"). In some other embodiments, the amino acid units comprise glutamic acid-valine-citrulline ("Glu-Val-Cit" or "EVC"). In some other embodiments, the amino acid units comprise alanine-alanine-asparagine ("Ala-Ala-Asn" or "AAN").

[0021] In some embodiments, the linker comprises a cleavable glucuronic acid moiety. In some embodiments, the cleavable glucuronic acid moiety can be cleaved enzymatically. In some embodiments, the cleavable glucuronic acid moiety can be cleaved by glucuronidase. In some embodiments, the cleavable glucuronic acid moiety can be cleaved by β-glucuronidase.

[0022] In some embodiments, the linker comprises at least one spacer unit. In some embodiments, the spacer unit or the linker comprises a polyethylene glycol (PEG) moiety. In some embodiments, the PEG moiety comprises -(PEG) m - and m is an integer from 1 to 10. In some embodiments, m is 2. In some other embodiments, the spacer unit or the linker comprises an alkyl moiety. In some embodiments, the alkyl moiety comprises -(CH2) n - and n is an integer from 1 to 10. In some embodiments, n is 2. In some embodiments, n is 5. In some embodiments, n is 6.

[0023] In some embodiments, the spacer unit is linked to the antibody or antigen-binding fragment via a maleimide (Mal) moiety (“Mal-spacer unit”). In some embodiments, the Mal-spacer unit can react with a cysteine residue on the antibody or antigen-binding fragment. In some embodiments, the Mal-spacer unit is conjugated to the antibody or antigen-binding fragment via a cysteine residue on the antibody or antigen-binding fragment.

[0024] In some embodiments, the linker comprises a Mal-spacer unit and a cleavable peptide moiety. In some embodiments, the cleavable peptide moiety comprises amino acid units. In some embodiments, the cleavable peptide moiety or the amino acid units comprise Val-Cit. In some embodiments, the cleavable peptide moiety or the amino acid units comprise Val-Ala. In some embodiments, the cleavable peptide moiety or the amino acid units comprise Glu-Val-Cit. In some embodiments, the cleavable peptide moiety or the amino acid units comprise Ala-Ala-Asn. In some embodiments, the Mal-spacer unit comprises an alkyl moiety. In some embodiments, the Mal-spacer unit comprises a PEG moiety. In some embodiments, the Mal-spacer unit comprises maleimidocaproyl (MC).

[0025] In some embodiments, the Mal-spacer subunit links an antibody or antigen-binding fragment to a cleavable moiety in the linker. In some embodiments, the cleavable moiety in the linker comprises a cleavable peptide moiety. In some embodiments, the cleavable peptide moiety comprises amino acid units. In some embodiments, the cleavable peptide moiety or amino acid units comprise Val-Cit, Val-Ala, Glu-Val-Cit, or Ala-Ala-Asn. In some embodiments, the linker comprises MC-Val-Cit. In some embodiments, the linker comprises MC-Val-Ala. In some embodiments, the linker comprises MC-Glu-Val-Cit. In some embodiments, the linker comprises MC-Ala-Ala-Asn. In some embodiments, the Mal-spacer subunit comprises an alkyl moiety. In some embodiments, the Mal-spacer subunit comprises a PEG moiety. In some embodiments, the Mal-spacer subunit comprises maleimidocaproyl (MC).

[0026] In some embodiments, the cleavable moiety in the linker directly engages the Herboxidiene splicing regulator, or the spacer subunit links the cleavable moiety in the linker to the Herboxidiene splicing regulator. In some embodiments, cleavage of the conjugate releases the Herboxidiene splicing regulator from the antibody or antigen-binding fragment and the linker. In some embodiments, the spacer subunit that links the cleavable moiety in the linker to the Herboxidiene splicing regulator is a self-ablating spacer subunit.

[0027] In some embodiments, the spacer subunit that links the cleavable moiety in the linker to the Herboxidiene splicing regulator comprises p-aminobenzyloxycarbonyl (pABC). In some embodiments, pABC links the cleavable moiety in the linker to the Herboxidiene splicing regulator. In some embodiments, the cleavable moiety in the linker comprises a cleavable peptide moiety. In some embodiments, the cleavable peptide moiety comprises amino acid units. In some embodiments, the cleavable peptide moiety or amino acid units comprise Val-Cit, Val-Ala, Glu-Val-Cit, or Ala-Ala-Asn. In some embodiments, the linker comprises Val-Cit-pABC. In some other embodiments, the linker comprises Val-Ala-pABC. In some embodiments, the linker comprises Glu-Val-Cit-pABC. In some embodiments, the linker comprises Ala-Ala-Asn-pABC.

[0028] In some embodiments, the linker's cleavable moiety linked to the spacer unit of the hopene splicing regulator contains p-aminobenzyl (pAB). In some embodiments, pAB links the cleavable moiety in the linker to the hopene splicing regulator. In some embodiments, the cleavable moiety in the linker contains a cleavable peptide moiety. In some embodiments, the cleavable peptide moiety contains amino acid units. In some embodiments, the cleavable peptide moiety or the amino acid units contain Val-Cit, Val-Ala, Glu-Val-Cit, or Ala-Ala-Asn. In some embodiments, the linker contains Val-Cit-pAB. In some other embodiments, the linker contains Val-Ala-pAB. In some other embodiments, the linker contains Glu-Val-Cit-pAB. In some other embodiments, the linker contains Ala-Ala-Asn-pAB.

[0029] In various embodiments, the linker is a non-cleavable linker. In some embodiments, the hopene splicing regulator of the ADC is released by degrading the antibody or antigen-binding fragment. In some embodiments, after internalization by the target cell and degradation within the target cell, the linker remains covalently associated with at least one amino acid of the antibody and the drug.

[0030] In some embodiments, the linker is a non-cleavable linker comprising at least one spacer unit. In some embodiments, the spacer unit or the linker contains a polyethylene glycol (PEG) moiety. In some embodiments, the PEG moiety contains -(PEG) m - and m is an integer from 1 to 10. In some embodiments, m is 2. In some other embodiments, the spacer unit or the linker contains an alkyl moiety. In some embodiments, the alkyl moiety contains -(CH2) n - or -(CH2) n -O-(CH2) n and n is an integer from 1 to 10. In some embodiments, n is 2. In some embodiments, n is 5. In some embodiments, n is 6.

[0031] In some embodiments, the spacer unit in the non-cleavable linker is connected to the antibody or antigen-binding fragment via a maleimide (Mal) moiety (“Mal-spacer unit”). In some embodiments, the Mal-spacer unit can react with a cysteine residue on the antibody or antigen-binding fragment. In some embodiments, the Mal-spacer unit is conjugated to the antibody or antigen-binding fragment via a cysteine residue on the antibody or antigen-binding fragment. In some embodiments, the Mal-spacer unit comprises an alkyl moiety. In some embodiments, the Mal-spacer unit comprises a PEG moiety. In some embodiments, the linker or Mal-spacer unit comprises maleimidocaproyl (MC). In some embodiments, the linker or Mal-spacer unit comprises maleimidocaproyl (MC) and at least one additional spacer unit. In some embodiments, the linker or Mal-spacer unit comprises MC-(PEG)2. In some embodiments, the linker or Mal-spacer unit comprises MC-(PEG)2 and at least one additional spacer unit. In some embodiments, the linker or Mal-spacer unit comprises Mal-Hex. In some embodiments, the linker or Mal-spacer unit comprises Mal-Hex and at least one additional spacer unit. In some embodiments, the linker or Mal-spacer unit comprises Mal-Et. In some embodiments, the linker or Mal-spacer unit comprises Mal-Et and at least one additional spacer unit. In some embodiments, the linker or Mal-spacer unit comprises Mal-Et-O-Et. In some embodiments, the linker or Mal-spacer unit comprises Mal-Et-O-Et and at least one additional spacer unit. In some embodiments, the Mal-spacer unit connects the antibody or antigen-binding fragment to the Hobit splicing regulator.

[0032] In some embodiments, Ab is selected from any of the antibody or binding domain sequences disclosed herein. In some embodiments, Ab is an antibody or binding domain sequence that targets neoplastic cells expressing HER2 and / or HER2. In some embodiments, Ab is an antibody or binding domain sequence that targets neoplastic cells expressing CD138 and / or CD138. In some embodiments, Ab is an antibody or binding domain sequence that targets neoplastic cells expressing EPHA2 and / or EPHA2. In some embodiments, Ab is an antibody or binding domain sequence that targets neoplastic cells expressing MSLN and / or MSLN. In some embodiments, Ab is an antibody or binding domain sequence that targets neoplastic cells expressing FOLH1 and / or FOLH1. In some embodiments, Ab is an antibody or binding domain sequence that targets neoplastic cells expressing CDH6 and / or CDH6. In some embodiments, Ab is an antibody or binding domain sequence that targets neoplastic cells expressing CEACAM5 and / or CEACAM5. In some embodiments, Ab is an antibody or binding domain sequence that targets neoplastic cells expressing CFC1B and / or CFC1B. In some embodiments, Ab is an antibody or binding domain sequence that targets neoplastic cells expressing ENPP3 and / or ENPP3. In some embodiments, Ab is an antibody or binding domain sequence that targets neoplastic cells expressing FOLR1 and / or FOLR1. In some embodiments, Ab is an antibody or binding domain sequence that targets neoplastic cells expressing HAVCR1 and / or HAVCR1. In some embodiments, Ab is an antibody or binding domain sequence that targets neoplastic cells expressing KIT and / or KIT. In some embodiments, Ab is an antibody or binding domain sequence that targets neoplastic cells expressing MET and / or MET. In some embodiments, Ab is an antibody or binding domain sequence that targets neoplastic cells expressing MUC16 and / or MUC16. In some embodiments, Ab is an antibody or binding domain sequence that targets neoplastic cells expressing SLC39A6 and / or SLC39A6. In some embodiments, Ab is an antibody or binding domain sequence that targets neoplastic cells expressing SLC44A4 and / or SLC44A4. In some embodiments, Ab is an antibody or binding domain sequence that targets neoplastic cells expressing STEAP1 and / or STEAP1. In some embodiments, Ab is an antibody or binding domain sequence that targets another cancer antigen.

[0033] In some embodiments, L is selected from any of the linkers disclosed herein or any combination of linker components disclosed herein. In some embodiments, L is a linker comprising MC-Val-Cit-pABC, Mal-(PEG)2-CO, MC-Val-Ala-pAB, MC-Val-Ala-pABC, MC-Val-Cit-pAB, Mal-Hex, Mal-Et, or Mal-Et-O-Et. In some embodiments, the linker may further comprise one or more additional spacer subunits. In some embodiments, L is an ADL1, ADL2, ADL5, ADL6, ADL7, ADL10, ADL12, ADL13, ADL14, ADL15, ADL21, ADL22, or ADL23 linker. In some embodiments, L is an ADL1, ADL2, ADL5, ADL6, ADL7, ADL12, ADL13, ADL14, ADL15, ADL21, or ADL23 linker. In some embodiments, L is an ADL12, ADL14, or ADL15 linker. In some embodiments, the ADL1, ADL2, ADL5, ADL6, ADL7, ADL12, ADL13, ADL14, ADL15, ADL21, or ADL23 linker may further comprise one or more additional spacer subunits. In some embodiments, L is an ADL1 linker and optionally comprises one or more additional spacer subunits. In some embodiments, L is an ADL2 linker and optionally comprises one or more additional spacer subunits. In some embodiments, L is an ADL5 linker and optionally comprises one or more additional spacer subunits. In some embodiments, L is an ADL6 linker and optionally comprises one or more additional spacer subunits. In some embodiments, L is an ADL7 linker and optionally comprises one or more additional spacer subunits. In some embodiments, L is an ADL12 linker and optionally comprises one or more additional spacer subunits. In some embodiments, L is an ADL14 linker and optionally comprises one or more additional spacer subunits. In some embodiments, L is an ADL15 linker and optionally comprises one or more additional spacer subunits. In different embodiments of the ADCs described herein, p is from 1 to 10. In different embodiments, p is from 2 to 8. In different embodiments, p is from 4 to 8. In some embodiments, p is 4. In some embodiments, p is 8.

[0034] In some embodiments, a set of ADCs is provided, whereby random conjugation occurs and the average p in the set is between about 2 and about 8. In some embodiments, a set of ADCs is provided, whereby random conjugation occurs and the average p in the set is between about 4 and about 8. In some embodiments, a set of ADCs is provided, whereby random conjugation occurs and the average p in the set is about 4. In some embodiments, a set of ADCs is provided, whereby random conjugation occurs and the average p in the set is about 8. Compositions (e.g., pharmaceutical compositions) are provided herein that comprise multiple copies of any of the described ADCs, wherein the average drug load (average p) of the ADCs in the composition is from about 3.5 to about 5.5 (e.g., about 4) or from about 7 to about 9 (e.g., about 8).

[0035] In some embodiments, the antibody or antigen-binding fragment (Ab) of the ADC targets neoplastic cells derived from a hematologic malignancy or a solid tumor. In some embodiments, the antibody or antigen-binding fragment targets neoplastic cells derived from a hematologic malignancy. In some embodiments, the hematologic malignancy is selected from B cell malignancies, leukemias (e.g., acute myeloid leukemia), lymphomas, and myelomas (e.g., multiple myeloma). In some embodiments, the hematologic malignancy is selected from acute myeloid leukemia and multiple myeloma. In some embodiments, the antibody or antigen-binding fragment targets neoplastic cells derived from a solid tumor. In some embodiments, the solid tumor is selected from breast cancer (e.g., HER2-positive breast cancer), gastric cancer (e.g., gastric adenocarcinoma), prostate cancer, ovarian cancer, lung cancer (e.g., lung adenocarcinoma), uterine cancer (e.g., uterine serous endometrial cancer), salivary duct carcinoma, melanoma, colorectal cancer, cervical cancer, pancreatic cancer, renal cancer, colorectal carcinoma, and esophageal cancer. In some embodiments, the solid tumor is selected from HER2-positive breast cancer, gastric adenocarcinoma, prostate cancer, and osteosarcoma.

[0036] In various embodiments, the antibody or antigen-binding fragment (Ab) of the ADC is an anti-HER2 antibody or an antigen-binding fragment thereof. In some embodiments, the antibody or antigen-binding fragment binds to HER2 and targets neoplastic cells that express HER2 (i.e., the ADC targets neoplastic cells that express HER2). In some embodiments, the antibody or antigen-binding fragment of the ADC is an internalizing anti-HER2 antibody or an internalizing antigen-binding fragment thereof.

[0037] In some embodiments, the anti-HER2 antibody or antigen-binding fragment comprises three heavy-chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) having the amino acid sequences set forth in SEQ ID NO:1 (HCDR1), SEQ ID NO:2 (HCDR2), and SEQ ID NO:3 (HCDR3); and three light-chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) having the amino acid sequences set forth in SEQ ID NO:4 (LCDR1), SEQ ID NO:5 (LCDR2), and SEQ ID NO:6 (LCDR3). In some embodiments, the anti-HER2 antibody or antigen-binding fragment is an internalizing antibody or internalizing antigen-binding fragment. In some embodiments, the anti-HER2 antibody or antigen-binding fragment comprises a human framework sequence. In some embodiments, the anti-HER2 antibody or antigen-binding fragment comprises a heavy-chain variable region having the amino acid sequence set forth in SEQ ID NO:19 and a light-chain variable region having the amino acid sequence set forth in SEQ ID NO:20. In some embodiments, the anti-HER2 antibody or antigen-binding fragment comprises a human IgG heavy-chain constant region. In some embodiments, the anti-HER2 antibody or antigen-binding fragment comprises a human IgG1 heavy-chain constant region. In some embodiments, the anti-HER2 antibody or antigen-binding fragment comprises a human Igκ or λ light-chain constant region. In some embodiments, the anti-HER2 antibody or antigen-binding fragment competes with an antibody comprising the heavy-chain variable domain of SEQ ID NO:19 and the light-chain variable domain of SEQ ID NO:20 for binding to the same epitope and / or binds to the same epitope.

[0038] In various embodiments, the antibody or antigen-binding fragment (Ab) of the ADC is an anti-CD138 antibody or an antigen-binding fragment thereof. In some embodiments, the antibody or antigen-binding fragment binds to CD138 and targets neoplastic cells that express CD138 (i.e., the ADC targets neoplastic cells that express CD138). In some embodiments, the antibody or antigen-binding fragment of the ADC is an internalizing anti-CD138 antibody or an internalizing antigen-binding fragment thereof.

[0039] In some embodiments, the anti-CD138 antibody or antigen-binding fragment comprises three heavy-chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) having the amino acid sequences set forth in SEQ ID NO:7 (HCDR1), SEQ ID NO:8 (HCDR2), and SEQ ID NO:9 (HCDR3); and three light-chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) having the amino acid sequences set forth in SEQ ID NO:10 (LCDR1), SEQ ID NO:11 (LCDR2), and SEQ ID NO:12 (LCDR3). In some embodiments, the anti-CD138 antibody or antigen-binding fragment is an internalizing antibody or internalizing antigen-binding fragment. In some embodiments, the anti-CD138 antibody or antigen-binding fragment comprises a human framework sequence. In some embodiments, the anti-CD138 antibody or antigen-binding fragment comprises a heavy-chain variable region having the amino acid sequence set forth in SEQ ID NO:21 and a light-chain variable region having the amino acid sequence set forth in SEQ ID NO:22. In some embodiments, the anti-CD138 antibody or antigen-binding fragment comprises a murine IgG2a heavy-chain constant region. In some embodiments, the anti-CD138 antibody or antigen-binding fragment comprises a murine Igκ light-chain constant region. In some embodiments, the anti-CD138 antibody or antigen-binding fragment comprises a human IgG heavy-chain constant region. In some embodiments, the anti-CD138 antibody or antigen-binding fragment comprises a human IgG2a heavy-chain constant region. In some embodiments, the anti-CD138 antibody or antigen-binding fragment comprises a human Igκ or λ light-chain constant region. In some embodiments, the anti-CD138 antibody or antigen-binding fragment competes with an antibody comprising the heavy-chain variable domain of SEQ ID NO:21 and the light-chain variable domain of SEQ ID NO:22 for binding to the same epitope and / or binds to the same epitope.

[0040] In various embodiments, the antibody or antigen-binding fragment (Ab) of the ADC is an anti-EPHA2 antibody or an antigen-binding fragment thereof. In some embodiments, the antibody or antigen-binding fragment binds to EPHA2 and targets neoplastic cells that express EPHA2 (i.e., the ADC targets neoplastic cells that express EPHA2). In some embodiments, the antibody or antigen-binding fragment of the ADC is an internalizing anti-EPHA2 antibody or an internalizing antigen-binding fragment thereof.

[0041] In some embodiments, the anti-EPHA2 antibody or antigen-binding fragment comprises three heavy-chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) having the amino acid sequences set forth in SEQ ID NO:13 (HCDR1), SEQ ID NO:14 (HCDR2), and SEQ ID NO:15 (HCDR3); and three light-chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) having the amino acid sequences set forth in SEQ ID NO:16 (LCDR1), SEQ ID NO:17 (LCDR2), and SEQ ID NO:18 (LCDR3). In some embodiments, the anti-EPHA2 antibody or antigen-binding fragment is an internalizing antibody or internalizing antigen-binding fragment. In some embodiments, the anti-EPHA2 antibody or antigen-binding fragment comprises a human framework sequence. In some embodiments, the anti-EPHA2 antibody or antigen-binding fragment comprises a heavy-chain variable region having the amino acid sequence set forth in SEQ ID NO:23 and a light-chain variable region having the amino acid sequence set forth in SEQ ID NO:24. In some embodiments, the anti-EPHA2 antibody or antigen-binding fragment comprises a human IgG heavy-chain constant region. In some embodiments, the anti-EPHA2 antibody or antigen-binding fragment comprises a human IgG1 heavy-chain constant region. In some embodiments, the anti-EPHA2 antibody or antigen-binding fragment comprises a human Igκ or λ light-chain constant region. In some embodiments, the anti-EPHA2 antibody or antigen-binding fragment competes with an antibody comprising the heavy-chain variable domain set forth in SEQ ID NO:23 and the light-chain variable domain set forth in SEQ ID NO:24 for binding to the same epitope and / or binds to the same epitope.

[0042] In some embodiments, the present disclosure provides a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: Y is selected from O, S, NR 6 and CR 6 R 7 ; R 1 , R 2 and R 3 are each independently selected from hydrogen, hydroxy, -O-(C1-C6 alkyl), -O-C(=O)-(C1-C6 alkyl), -C(=O)-O-(C1-C6 alkyl), and C1-C6 alkyl; R 4 is selected from hydrogen, C1-C6 alkyl, -C(=O)-(C1-C6 alkyl), -C(=O)-(C3-C8 carbocyclic group), -C(=O)-(C3-C8 heterocyclic group), and -C(=O)-NR 6 R 7 ; R 5Selected from hydrogen, hydroxyl, -CH2-OH, -CO2H, -C(=O)-O-(C1-C6 alkyl), -C(=O)-NR 6 R 7 、-NR 6 -C(=O)-R 8 、-OC(=O)-NR 6 R 7 、-NR 6 -C(=O)-R 8 and-NR 6 -C(=O)-NR 6 R 7 ; R 6 and R 7 are each independently selected from hydrogen, -R 8 、-C(=O)-R 8 and -C(=O)-OR 8 ;and R 8 is selected from C1-C6 alkyl, C3-C8 carbocyclic group and C3-C8 heterocyclic group, Where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each is independently substituted by 0 to 3 groups independently selected from the following: halogen, hydroxyl, C1-C6 alkyl, -O-(C1-C6 alkyl), -CO2H, -C(=O)-(C1-C6 alkyl), -C(=O)-(C3-C8 carbocyclyl), -C(=O)-(C3-C8 heterocyclyl), -NR 6 R 7 , C3-C8 carbocyclyl, C1-C6 alkylhydroxyl, C1-C6 alkylalkoxy, benzyl and C3-C8 heterocyclyl, each of which may be independently substituted by 0 or 1 groups selected from the following: halogen, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, -NH-C(=O)(C1-C3 alkyl) and -NH-C(=O)-O-(C1-C3 alkyl).

[0043] In some embodiments, provided herein are compounds having Formula (Ia): or a pharmaceutically acceptable salt thereof, wherein: R 9 is selected from C3-C8 heterocyclyl; and R 10 Selected from H and C1-C6 alkyl, Where R9 and R 10 each independently is substituted with 0 to 3 groups independently selected from the following: halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, -NH2, -NH-(C1-C3 alkyl), and -N-(C1-C3 alkyl)2.

[0044] In some embodiments, the present disclosure provides a compound having formula (Ib): or a pharmaceutically acceptable salt thereof, wherein: R 11 is selected from wherein * indicates the point of attachment of R 11 to the remainder of the compound; and R 12 and R 13 each independently is selected from H and methyl.

[0045] In some embodiments, the present disclosure provides a compound having formula (II): or a pharmaceutically acceptable salt thereof, wherein: X is NR 6 R 7 ; R 6 and R 7 each independently is selected from hydrogen, -R 8 , -C(=O)-R 8 , -C(=O)-O-R 8 , -(C1-C6 alkyl)-O-C(=O)-R 8 and -(C1-C6 alkyl)-NH-C(=O)-R 8 ; and R 8 is selected from C1-C6 alkyl, C3-C8 carbocyclic group, and C3-C8 heterocyclic group, wherein R 6 , R 7 and R 8 each independently is substituted with 0 to 3 groups independently selected from the following: halogen, hydroxy, C1-C6 alkyl, -O-(C1-C6 alkyl), -CO2H, -C(=O)-(C1-C6 alkyl), -C(=O)-(C3-C8 carbocyclic group), -C(=O)-(C3-C8 heterocyclic group), -NR 6 R 7, a C3-C8 carbocyclic group, a C1-C6 alkyl hydroxy group, a C1-C6 alkyl alkoxy group, a benzyl group, and a C3-C8 heterocyclic group, each of which may be independently substituted with 0 or 1 group selected from the following: halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, -NH-C(=O)(C1-C3 alkyl), and -NH-C(=O)-O-(C1-C3 alkyl).

[0046] In some embodiments, provided herein are compounds having the formula (IIa): or a pharmaceutically acceptable salt thereof, wherein: Z is selected from NR 9 and O; R 9 is selected from hydrogen and C1-C6 alkyl; R 10 and R 11 are each independently selected from hydrogen, halogen, hydroxy, C1-C6 alkyl, -O-(C1-C6 alkyl), -CO2H, -C(=O)-O-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)-(C3-C8 carbocyclic group), -C(=O)-(C3-C8 heterocyclic group), a C3-C8 carbocyclic group, a C1-C6 alkyl hydroxy group, a C1-C6 alkyl alkoxy group, a benzyl group, and a C3-C8 heterocyclic group; R 12 is selected from C1-C6 alkyl, C3-C8 carbocyclic group, C3-C8 heterocyclic group, wherein R 9 , R 10 , R 11 and R 12 are each independently substituted with 0 or 1 group selected from the following: halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, and C1-C3 haloalkyl; and t is an integer selected from 1, 2, 3, 4, 5, and 6.

[0047] In some embodiments, provided herein are compounds having the formula (IIb): or a pharmaceutically acceptable salt thereof, wherein: R 13 is selected from wherein * indicates the point of attachment of R 13 to the remainder of the compound; and R 14 and R 15 are each independently selected from hydrogen and methyl.

[0048] In some embodiments, provided herein are compounds having the formula (III): or a pharmaceutically acceptable salt thereof, wherein: R 1 、R 2 and R 3 are each independently selected from hydrogen, hydroxy, -O-(C1-C6 alkyl), -O-C(=O)-(C1-C6 alkyl), -C(=O)-O-(C1-C6 alkyl), and C1-C6 alkyl; R 6 and R 7 are each independently selected from hydrogen, -R 8 , -C(=O)-R 8 and -C(=O)-O-R 8 ; R 8 is selected from C1-C6 alkyl, C3-C8 carbocyclic group, and C3-C8 heterocyclic group; and R 9 is selected from H, wherein R 1 , R 2 , R 3 , R 6 , R 7 and R 8 are each independently substituted with 0 to 3 groups independently selected from the following: halogen, hydroxy, C1-C6 alkyl, -O-(C1-C6 alkyl), -CO2H, -C(=O)-(C1-C6 alkyl), -C(=O)-(C3-C8 carbocyclic group), -C(=O)-(C3-C8 heterocyclic group), -NR 6 R 7 , C3-C8 carbocyclic group, C1-C6 alkyl hydroxy, C1-C6 alkyl alkoxy, benzyl, and C3-C8 heterocyclic group, each of which may be independently substituted with 0 or 1 group selected from the following: halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, -NH-C(=O)(C1-C3 alkyl), and -NH-C(=O)-O-(C1-C3 alkyl); and wherein * indicates the point of attachment of R 9 to the remainder of the compound.

[0049] In some embodiments, the present invention provides compounds selected from the following: and pharmaceutically acceptable salts thereof, wherein L is a linker covalently linked to the antibody.

[0050] In addition, in various embodiments, the ADC compounds, hopene compounds, and compositions described herein are provided for therapeutic use, for example, in the treatment of neoplastic disorders such as cancer. In certain aspects, the present disclosure provides methods of treating neoplastic disorders such as cancers that express an antigen targeted by the antibody or antigen-binding fragment of the ADC, such as HER2, CD138, EPHA2, MSLN, FOLH1, CDH6, CEACAM5, CFC1B, ENPP3, FOLR1, HAVCR1, KIT, MET, MUC16, SLC39A6, SLC44A4, or STEAP1.

[0051] In certain aspects, the present disclosure provides methods of treating a subject having or suspected of having a neoplastic disorder by administering to the subject a therapeutically effective amount and / or a therapeutically effective regimen of any of the ADCs or compositions described herein. In some embodiments, the neoplastic disorder is a hematologic malignancy or a solid tumor. In some embodiments, the neoplastic disorder is a hematologic malignancy. In some embodiments, the hematologic malignancy is selected from B-cell malignancies, leukemias, lymphomas, and myelomas. In some embodiments, the hematologic malignancy is selected from acute myeloid leukemia and multiple myeloma. In some embodiments, the neoplastic disorder is a solid tumor. In some embodiments, the solid tumor is selected from breast cancer (e.g., HER2-positive breast cancer), gastric cancer (e.g., gastric adenocarcinoma), prostate cancer, ovarian cancer, lung cancer (e.g., lung adenocarcinoma), uterine cancer (e.g., uterine serous endometrial cancer), salivary duct carcinoma, melanoma, colorectal cancer, cervical cancer, pancreatic cancer, renal cancer, colorectal cancer, and esophageal cancer. In some embodiments, the solid tumor is selected from HER2-positive breast cancer, gastric adenocarcinoma, prostate cancer, and osteosarcoma.

[0052] In some embodiments, treatment with the antibody-drug conjugate or composition induces bystander killing of neoplastic cells that do not express the target antigen but are adjacent to neoplastic cells that express the target antigen. In some embodiments, the subject has one or more neoplastic cells that express the target antigen.

[0053] In some embodiments, the target antigen is HER2. In some embodiments, one or more neoplastic cells are in HER2-expressing breast cancer, ovarian cancer, gastric cancer, lung cancer (e.g., lung adenocarcinoma), uterine cancer (e.g., uterine serous endometrial carcinoma), osteosarcoma, or salivary duct carcinoma. In some embodiments, the subject is unresponsive or poorly responsive to treatment with (a) an anti-HER2 antibody when administered alone and / or (b) a hopene splicing regulator when administered alone. In some embodiments, the subject is intolerant, unresponsive, or poorly responsive to treatment with a hopene splicing regulator when administered alone.

[0054] In some embodiments, the target antigen is CD138. In some embodiments, one or more neoplastic cells are in CD138-expressing multiple myeloma. In some embodiments, the subject is unresponsive or poorly responsive to treatment with (a) an anti-CD138 antibody when administered alone and / or (b) a hopene splicing regulator when administered alone. In some embodiments, the subject is intolerant, unresponsive, or poorly responsive to treatment with a hopene splicing regulator when administered alone.

[0055] In some embodiments, the target antigen is EPHA2. In some embodiments, one or more neoplastic cells are in EPHA2-expressing breast cancer, prostate cancer, ovarian cancer, lung cancer, melanoma, colorectal cancer, or esophageal cancer. In some embodiments, the subject is unresponsive or poorly responsive to treatment with (a) an anti-EPHA2 antibody when administered alone and / or (b) a hopene splicing regulator when administered alone. In some embodiments, the subject is intolerant, unresponsive, or poorly responsive to treatment with a hopene splicing regulator when administered alone.

[0056] In some embodiments, the target antigen is MSLN. In some embodiments, one or more neoplastic cells are in MSLN-expressing ovarian cancer, cervical cancer, pancreatic cancer, or lung cancer (e.g., lung adenocarcinoma). In some embodiments, the subject is unresponsive or poorly responsive to treatment with (a) an anti-MSLN antibody when administered alone and / or (b) a splicing regulator when administered alone. In some embodiments, the subject is intolerant, unresponsive, or poorly responsive to treatment with a splicing regulator when administered alone.

[0057] In some embodiments, the target antigen is FOLH1. In some embodiments, one or more neoplastic cells are in FOLH1-expressing prostate cancer. In some embodiments, the subject is unresponsive or poorly responsive to treatment with (a) an anti-FOLH1 antibody when administered alone and / or (b) a splicing regulator when administered alone. In some embodiments, the subject is intolerant, unresponsive, or poorly responsive to treatment with a splicing regulator when administered alone.

[0058] In some embodiments, the target antigen is CDH6. In some embodiments, one or more neoplastic cells are in CDH6-expressing renal cell carcinoma. In some embodiments, the subject is unresponsive or poorly responsive to treatment with (a) an anti-CDH6 antibody when administered alone and / or (b) a splicing regulator when administered alone. In some embodiments, the subject is intolerant, unresponsive, or poorly responsive to treatment with a splicing regulator when administered alone.

[0059] In some embodiments, the target antigen is CEACAM5. In some embodiments, one or more neoplastic cells are in CEACAM5-expressing colorectal cancer. In some embodiments, the subject is unresponsive or poorly responsive to treatment with (a) an anti-CEACAM5 antibody when administered alone and / or (b) a splicing regulator when administered alone. In some embodiments, the subject is intolerant, unresponsive, or poorly responsive to treatment with a splicing regulator when administered alone.

[0060] In some embodiments, the target antigen is CFC1B. In some embodiments, one or more neoplastic cells are in CFC1B-expressing pancreatic cancer. In some embodiments, the subject is unresponsive or poorly responsive to treatment with (a) an anti-CFC1B antibody when administered alone and / or (b) a splicing regulator when administered alone. In some embodiments, the subject is intolerant, unresponsive, or poorly responsive to treatment with a splicing regulator when administered alone.

[0061] In some embodiments, the target antigen is ENPP3. In some embodiments, one or more neoplastic cells are in ENPP3-expressing renal cell carcinoma. In some embodiments, the subject is unresponsive or poorly responsive to treatment with (a) an anti-ENPP3 antibody when administered alone and / or (b) a splicing regulator when administered alone. In some embodiments, the subject is intolerant, unresponsive, or poorly responsive to treatment with a splicing regulator when administered alone.

[0062] In some embodiments, the target antigen is FOLR1. In some embodiments, one or more neoplastic cells are in FOLR1-expressing ovarian cancer. In some embodiments, the subject is unresponsive or poorly responsive to treatment with (a) an anti-FOLR1 antibody when administered alone and / or (b) a splicing regulator when administered alone. In some embodiments, the subject is intolerant, unresponsive, or poorly responsive to treatment with a splicing regulator when administered alone.

[0063] In some embodiments, the target antigen is HAVCR1. In some embodiments, one or more neoplastic cells are in HAVCR1-expressing renal cell carcinoma or esophageal cancer. In some embodiments, the subject is non-responsive or poorly responsive to treatment with (a) an anti-HAVCR1 antibody when administered alone and / or (b) a splicing regulator when administered alone. In some embodiments, the subject is intolerant, non-responsive, or poorly responsive to treatment with a splicing regulator when administered alone.

[0064] In some embodiments, the target antigen is KIT. In some embodiments, one or more neoplastic cells are in KIT-expressing renal cell carcinoma. In some embodiments, the subject is non-responsive or poorly responsive to treatment with (a) an anti-KIT antibody when administered alone and / or (b) a splicing regulator when administered alone. In some embodiments, the subject is intolerant, non-responsive, or poorly responsive to treatment with a splicing regulator when administered alone.

[0065] In some embodiments, the target antigen is MET. In some embodiments, one or more neoplastic cells are in MET-expressing renal cell carcinoma or esophageal cancer. In some embodiments, the subject is non-responsive or poorly responsive to treatment with (a) an anti-MET antibody when administered alone and / or (b) a splicing regulator when administered alone. In some embodiments, the subject is intolerant, non-responsive, or poorly responsive to treatment with a splicing regulator when administered alone.

[0066] In some embodiments, the target antigen is MUC16. In some embodiments, one or more neoplastic cells are in MUC16-expressing ovarian cancer, cervical cancer, or breast cancer. In some embodiments, the subject is non-responsive or poorly responsive to treatment with (a) an anti-MUC16 antibody when administered alone and / or (b) a splicing regulator when administered alone. In some embodiments, the subject is intolerant, non-responsive, or poorly responsive to treatment with a splicing regulator when administered alone.

[0067] In some embodiments, the target antigen is SLC39A6. In some embodiments, one or more neoplastic cells are in SLC39A6-expressing breast cancer or prostate cancer. In some embodiments, the subject is non-responsive or poorly responsive to treatment with (a) an anti-SLC39A6 antibody when administered alone and / or (b) a splicing regulator when administered alone. In some embodiments, the subject is intolerant, non-responsive, or poorly responsive to treatment with a splicing regulator when administered alone.

[0068] In some embodiments, the target antigen is SLC44A4. In some embodiments, one or more neoplastic cells are in SLC44A4-expressing prostate cancer. In some embodiments, the subject is unresponsive or poorly responsive to treatment with (a) an anti-SLC44A4 antibody when administered alone and / or (b) a splicing regulator when administered alone. In some embodiments, the subject is intolerant, unresponsive, or poorly responsive to treatment with a splicing regulator when administered alone.

[0069] In some embodiments, the target antigen is STEAP1. In some embodiments, one or more neoplastic cells are in STEAP1-expressing prostate cancer. In some embodiments, the subject is unresponsive or poorly responsive to treatment with (a) an anti-STEAP1 antibody when administered alone and / or (b) a splicing regulator when administered alone. In some embodiments, the subject is intolerant, unresponsive, or poorly responsive to treatment with a splicing regulator when administered alone.

[0070] In certain other aspects, the present disclosure provides methods of reducing or inhibiting tumor growth in a subject having or suspected of having a neoplastic disorder by administering to the subject a therapeutically effective amount and / or a therapeutically effective regimen of any of the described ADCs or compositions.

[0071] In some embodiments, treatment with an antibody-drug conjugate or composition induces bystander killing of neoplastic tumor cells that do not express the target antigen but are adjacent to neoplastic tumor cells that express the target antigen. In some embodiments, the tumor comprises one or more neoplastic cells that express the target antigen.

[0072] In some embodiments, the target antigen is HER2. In some embodiments, one or more neoplastic cells are from HER2-expressing breast cancer, ovarian cancer, gastric cancer, lung cancer (such as lung adenocarcinoma), uterine cancer (such as uterine serous endometrial cancer), osteosarcoma, or salivary duct carcinoma. In some embodiments, the tumor is resistant or refractory to treatment with (a) an anti-HER2 antibody when administered alone and / or (b) a hopene splicing regulator when administered alone.

[0073] In some embodiments, the target antigen is CD138. In some embodiments, one or more neoplastic cells are from CD138-expressing multiple myeloma. In some embodiments, the tumor is resistant or refractory to treatment with (a) an anti-CD138 antibody when administered alone and / or (b) a hopene splicing regulator when administered alone.

[0074] In some embodiments, the target antigen is EPHA2. In some embodiments, one or more neoplastic cells are derived from EPHA2-expressing breast cancer, prostate cancer, ovarian cancer, lung cancer, melanoma, colorectal cancer, or esophageal cancer. In some embodiments, the tumor is resistant or refractory to treatment with (a) an anti-EPHA2 antibody when administered alone and / or (b) a hopene splicing regulator when administered alone.

[0075] In some embodiments, the target antigen is MSLN. In some embodiments, one or more neoplastic cells are derived from MSLN-expressing ovarian cancer, cervical cancer, pancreatic cancer, or lung cancer (e.g., lung adenocarcinoma). In some embodiments, the tumor is resistant or refractory to treatment with (a) an anti-MSLN antibody when administered alone and / or (b) a splicing regulator when administered alone.

[0076] In some embodiments, the target antigen is FOLH1. In some embodiments, one or more neoplastic cells are derived from FOLH1-expressing prostate cancer. In some embodiments, the tumor is resistant or refractory to treatment with (a) an anti-FOLH1 antibody when administered alone and / or (b) a splicing regulator when administered alone.

[0077] In some embodiments, the target antigen is CDH6. In some embodiments, one or more neoplastic cells are derived from CDH6-expressing renal cancer. In some embodiments, the tumor is resistant or refractory to treatment with (a) an anti-CDH6 antibody when administered alone and / or (b) a splicing regulator when administered alone.

[0078] In some embodiments, the target antigen is CEACAM5. In some embodiments, one or more neoplastic cells are derived from CEACAM5-expressing colorectal cancer. In some embodiments, the tumor is resistant or refractory to treatment with (a) an anti-CEACAM5 antibody when administered alone and / or (b) a splicing regulator when administered alone.

[0079] In some embodiments, the target antigen is CFC1B. In some embodiments, one or more neoplastic cells are derived from CFC1B-expressing pancreatic cancer. In some embodiments, the tumor is resistant or refractory to treatment with (a) an anti-CFC1B antibody when administered alone and / or (b) a splicing regulator when administered alone.

[0080] In some embodiments, the target antigen is ENPP3. In some embodiments, one or more neoplastic cells are derived from ENPP3-expressing renal cancer. In some embodiments, the tumor is resistant or refractory to treatment with (a) an anti-ENPP3 antibody when administered alone and / or (b) a splicing regulator when administered alone.

[0081] In some embodiments, the target antigen is FOLR1. In some embodiments, one or more neoplastic cells are derived from FOLR1-expressing ovarian cancer. In some embodiments, the tumor is resistant or refractory to treatment with (a) an anti-FOLR1 antibody when administered alone and / or (b) a splicing regulator when administered alone.

[0082] In some embodiments, the target antigen is HAVCR1. In some embodiments, one or more neoplastic cells are derived from HAVCR1-expressing renal cancer or esophageal cancer. In some embodiments, the tumor is resistant or refractory to treatment with (a) an anti-HAVCR1 antibody when administered alone and / or (b) a splicing regulator when administered alone.

[0083] In some embodiments, the target antigen is KIT. In some embodiments, one or more neoplastic cells are derived from KIT-expressing renal cancer. In some embodiments, the tumor is resistant or refractory to treatment with (a) an anti-KIT antibody when administered alone and / or (b) a splicing regulator when administered alone.

[0084] In some embodiments, the target antigen is MET. In some embodiments, one or more neoplastic cells are derived from MET-expressing renal cancer or esophageal cancer. In some embodiments, the tumor is resistant or refractory to treatment with (a) an anti-MET antibody when administered alone and / or (b) a splicing regulator when administered alone.

[0085] In some embodiments, the target antigen is MUC16. In some embodiments, one or more neoplastic cells are derived from MUC16-expressing ovarian cancer, cervical cancer, or breast cancer. In some embodiments, the tumor is resistant or refractory to treatment with (a) an anti-MUC16 antibody when administered alone and / or (b) a splicing regulator when administered alone.

[0086] In some embodiments, the target antigen is SLC39A6. In some embodiments, one or more neoplastic cells are derived from SLC39A6-expressing breast cancer or prostate cancer. In some embodiments, the tumor is resistant or refractory to treatment with (a) an anti-SLC39A6 antibody when administered alone and / or (b) a splicing regulator when administered alone.

[0087] In some embodiments, the target antigen is SLC44A4. In some embodiments, one or more neoplastic cells are derived from SLC44A4-expressing prostate cancer. In some embodiments, the tumor is resistant or refractory to treatment with (a) an anti-SLC44A4 antibody when administered alone and / or (b) a splicing regulator when administered alone.

[0088] In some embodiments, the target antigen is STEAP1. In some embodiments, one or more neoplastic cells are derived from STEAP1-expressing prostate cancer. In some embodiments, the tumor is resistant or refractory to treatment with (a) an anti-STEAP1 antibody when administered alone and / or (b) a splicing regulator when administered alone.

[0089] In yet other aspects, the present disclosure provides methods for determining whether a subject having or suspected of having a neoplastic disorder responds to treatment with any of the described ADCs or compositions, which are carried out by providing a biological sample from the subject and contacting the biological sample with the ADC or composition. In some embodiments, the biological sample is a tumor sample. In some embodiments, the tumor sample is a tumor biopsy or a blood sample. In some embodiments, the blood sample is selected from blood, blood fractions, or cells obtained from blood or blood fractions. In some embodiments, the subject has one or more neoplastic cells that express a target antigen. In some embodiments, the target antigen is HER2. In some embodiments, the one or more neoplastic cells are derived from HER2-expressing breast cancer, ovarian cancer, gastric cancer, lung cancer (e.g., lung adenocarcinoma), uterine cancer (e.g., uterine serous endometrial cancer), osteosarcoma, or salivary duct carcinoma. In some embodiments, the target antigen is CD138. In some embodiments, the one or more neoplastic cells are derived from CD138-expressing multiple myeloma. In some embodiments, the target antigen is EPHA2. In some embodiments, the one or more neoplastic cells are derived from EPHA2-expressing breast cancer, prostate cancer, ovarian cancer, lung cancer, melanoma, colorectal cancer, or esophageal cancer. In some embodiments, the target antigen is MSLN. In some embodiments, the one or more neoplastic cells are derived from MSLN-expressing ovarian cancer, cervical cancer, pancreatic cancer, or lung cancer (e.g., lung adenocarcinoma). In some embodiments, the target antigen is FOLH1. In some embodiments, the one or more neoplastic cells are derived from FOLH1-expressing prostate cancer. In some embodiments, the target antigen is CDH6. In some embodiments, the one or more neoplastic cells are derived from CDH6-expressing renal cancer. In some embodiments, the target antigen is CEACAM5. In some embodiments, the one or more neoplastic cells are derived from CEACAM5-expressing colorectal cancer. In some embodiments, the target antigen is CFC1B. In some embodiments, the one or more neoplastic cells are derived from CFC1B-expressing pancreatic cancer. In some embodiments, the target antigen is ENPP3. In some embodiments, the one or more neoplastic cells are derived from ENPP3-expressing renal cancer. In some embodiments, the target antigen is FOLR1. In some embodiments, the one or more neoplastic cells are derived from FOLR1-expressing ovarian cancer. In some embodiments, the target antigen is HAVCR1. In some embodiments, the one or more neoplastic cells are derived from HAVCR1-expressing renal cancer or esophageal cancer. In some embodiments, the target antigen is KIT. In some embodiments, the one or more neoplastic cells are derived from KIT-expressing renal cancer. In some embodiments, the target antigen is MET. In some embodiments, the one or more neoplastic cells are derived from MET-expressing renal cancer or esophageal cancer. In some embodiments, the target antigen is MUC16.In some embodiments, one or more neoplastic cells are derived from MUC16-expressing ovarian cancer, cervical cancer, or breast cancer. In some embodiments, the target antigen is SLC39A6. In some embodiments, one or more neoplastic cells are derived from SLC39A6-expressing breast cancer or prostate cancer. In some embodiments, the target antigen is SLC44A4. In some embodiments, one or more neoplastic cells are derived from SLC44A4-expressing prostate cancer. In some embodiments, the target antigen is STEAP1. In some embodiments, one or more neoplastic cells are derived from STEAP1-expressing prostate cancer.

[0090] In various embodiments, the present disclosure further provides pharmaceutical compositions comprising an ADC and a pharmaceutically acceptable diluent, carrier, and / or excipient. Methods for producing the described ADC compounds and compositions are also disclosed. This application relates to the following items: Item 1. An antibody-drug conjugate having formula (I): Ab-(L-H) p (I) Wherein: Ab is an antibody or antigen-binding fragment that targets neoplastic cells; H is a hopene splicing regulator; L is a linker that covalently attaches Ab to H; and p is an integer from 1 to 15. Item 2. The antibody-drug conjugate according to Item 1, wherein the hopene splicing regulator comprises a compound having formula (I): Or a pharmaceutically acceptable salt thereof, which is covalently attached to L via any atom, wherein: Y is selected from O, S, NR 6 and CR 6 R 7 ; R 1 、R 2 and R 3 are each independently selected from hydrogen, hydroxy, -O-(C1-C6 alkyl), -O-C(=O)-(C1-C6 alkyl), -C(=O)-O-(C1-C6 alkyl), and C1-C6 alkyl; R 4 is selected from hydrogen, C1-C6 alkyl, -C(=O)-(C1-C6 alkyl), -C(=O)-(C3-C8 carbocyclic group), -C(=O)-(C3-C8 heterocyclic group), and -C(=O)-NR 6 R 7 ; R 5Selected from hydrogen, hydroxyl, -CH2-OH, -CO2H, -C(=O)-O-(C1-C6 alkyl), -C(=O)-NR 6 R 7 、-NR 6 -C(=O)-R 8 、-OC(=O)-NR 6 R 7 、-NR 6 -C(=O)-R 8 and-NR 6 -C(=O)-NR 6 R 7 ; R 6 and R 7 are each independently selected from hydrogen, -R 8 、-C(=O)-R 8 and -C(=O)-OR 8 ;and R 8 is selected from C1-C6 alkyl, C3-C8 carbocyclic group and C3-C8 heterocyclic group, Where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each is independently substituted by 0 to 3 groups independently selected from the following: halogen, hydroxyl, C1-C6 alkyl, -O-(C1-C6 alkyl), -CO2H, -C(=O)-(C1-C6 alkyl), -C(=O)-(C3-C8 carbocyclyl), -C(=O)-(C3-C8 heterocyclyl), -NR 6 R 7 , C3-C8 carbocyclyl, C1-C6 alkylhydroxyl, C1-C6 alkylalkoxy, benzyl and C3-C8 heterocyclyl, each of which may be independently substituted by 0 or 1 group selected from the following: halogen, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, -NH-C(=O)(C1-C3 alkyl) and -NH-C(=O)-O-(C1-C3 alkyl), and wherein the valence number of the atoms covalently bonded to L is not exceeded. Item 3. The antibody-drug conjugate of Item 1 or Item 2, wherein the HepG2 splicing regulator comprises a compound having formula (Ia): or a pharmaceutically acceptable salt thereof, which is covalently linked to L via any atom, wherein: R9 Selected from C3-C8 heterocyclic groups; R 10 Selected from H and C1-C6 alkyl groups, wherein R 9 and R 10 are each independently substituted with 0 to 3 groups independently selected from the following: halogen, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, -NH2, -NH-(C1-C3 alkyl), and -N-(C1-C3 alkyl)2, and wherein the valence of the atom covalently linked to L is not exceeded. Item 4. The antibody-drug conjugate according to any one of Items 1 to 3, wherein the Herboxidiene splicing regulator comprises a compound having the formula (Ib): or a pharmaceutically acceptable salt thereof, which is covalently linked to L via any atom, wherein: R 11 Selected from where * indicates the point of attachment of R 11 to the remainder of the compound; R 12 and R 13 are each independently selected from H and methyl; and wherein the valence of the atom covalently linked to L is not exceeded. Item 5. The antibody-drug conjugate according to any one of Items 1 to 4, wherein the Herboxidiene splicing regulator is covalently linked to L via any atom wherein the Herboxidiene splicing regulator is selected from H1, H2, H3, and H12; and wherein the valence of the atom covalently linked to L is not exceeded. Item 6. The antibody-drug conjugate according to Item 1 or Item 2, wherein L is covalently linked to the Herboxidiene splicing regulator ("L-H"), and L-H has a structure selected from the following structures: and pharmaceutically acceptable salts thereof. Item 7. The antibody-drug conjugate according to Item 1, wherein the Herboxidiene splicing regulator is a splicing regulator having the formula (II): or a pharmaceutically acceptable salt thereof, which is covalently linked to L via any atom, wherein: X is hydroxyl or NR 6 R 7 ; R 6 and R 7Each independently selected from hydrogen, -R 8 、-C(=O)-R 8 、-C(=O)-O-R 8 、-(C1-C6 alkyl)-O-C(=O)-R 8 and -(C1-C6 alkyl)-NH-C(=O)-R 8 ; and R 8 is selected from C1-C6 alkyl, C3-C8 carbocyclic group and C3-C8 heterocyclic group, wherein R 6 、R 7 and R 8 are each independently substituted with 0 to 3 groups independently selected from the following: halogen, hydroxyl, C1-C6 alkyl, -O-(C1-C6 alkyl), -CO2H, -C(=O)-O-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)-(C3-C8 carbocyclic group), -C(=O)-(C3-C8 heterocyclic group), -NR 6 R 7 、C3-C8 carbocyclic group, C1-C6 alkyl hydroxyl, C1-C6 alkyl alkoxy, benzyl and C3-C8 heterocyclic group, each of which may be independently substituted with 0 or 1 group selected from the following: halogen, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, -NH-C(=O)(C1-C3 alkyl) and -NH-C(=O)-O-(C1-C3 alkyl), and wherein the valence of the atom covalently linked to L is not exceeded. Item 8. The antibody-drug conjugate according to item 1 or item 7, wherein the Herbertene splicing regulator is a splicing regulator having formula (IIa): or a pharmaceutically acceptable salt thereof, which is covalently linked to L via any atom, wherein: Z is selected from NR 9 and O; R 9 is selected from hydrogen and C1-C6 alkyl; R 10 and R 11 are each independently selected from hydrogen, halogen, hydroxyl, C1-C6 alkyl, -O-(C1-C6 alkyl), -CO2H, -C(=O)-O-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)-(C3-C8 carbocyclic group), -C(=O)-(C3-C8 heterocyclic group), C3-C8 carbocyclic group, C1-C6 alkyl hydroxyl, C1-C6 alkyl alkoxy, benzyl and C3-C8 heterocyclic group; R 12Selected from C1-C6 alkyl, C3-C8 carbocyclic group, C3-C8 heterocyclic group, wherein R 9 , R 10 , R 11 and R 12 are each independently substituted by 0 or 1 group selected from the following: halogen, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy and C1-C3 haloalkyl; t is an integer selected from 1, 2, 3, 4, 5 and 6; and wherein the valence of the atom covalently linked to L does not exceed. Item 9. The antibody-drug conjugate according to item 1, 7 or 8, wherein the Herberdiene splicing regulator is a splicing regulator having the formula (IIb): or a pharmaceutically acceptable salt thereof, which is covalently linked to L via any atom, wherein: R 13 is selected from wherein * indicates the point of attachment of R 13 to the rest of the compound; R 14 and R 15 are each independently selected from hydrogen and methyl; and wherein the valence of the atom covalently linked to L does not exceed. Item 10. The antibody-drug conjugate according to item 1, 7, 8 or 9, wherein the Herberdiene splicing regulator is covalently linked to L via any atom; wherein the Herberdiene splicing regulator is selected from H4, H13, H14, H15, H16, H17, H18, H19, H20, H21, H23 and H24; and wherein the valence of the atom covalently linked to L does not exceed. Item 11. The antibody-drug conjugate according to item 1 or item 7, wherein L is covalently linked to the Herberdiene splicing regulator ("L-H"), and L-H has a structure selected from the following structures: , and its pharmaceutically acceptable salt. Item 12. The antibody-drug conjugate according to item 1, wherein the Herberdiene splicing regulator is a splicing regulator having the formula (III): or a pharmaceutically acceptable salt thereof, which is covalently linked to L via any atom, wherein: R 1 , R 2 and R 3each independently selected from hydrogen, hydroxy, -O-(C1-C6 alkyl), -O-C(=O)-(C1-C6 alkyl), -C(=O)-O-(C1-C6 alkyl) and C1-C6 alkyl; R 6 and R 7 each independently selected from hydrogen, -R 8 , -C(=O)-R 8 and -C(=O)-O-R 8 ; R 8 is selected from C1-C6 alkyl, C3-C8 carbocyclic group and C3-C8 heterocyclic group; and R 9 is selected from H, wherein R 1 , R 2 , R 3 , R 6 , R 7 , and R 8 each independently is substituted with 0 to 3 groups independently selected from the following: halogen, hydroxy, C1-C6 alkyl, -O-(C1-C6 alkyl), -CO2H, -C(=O)-(C1-C6 alkyl), -C(=O)-(C3-C8 carbocyclic group), -C(=O)-(C3-C8 heterocyclic group), -NR 6 R 7 , C3-C8 carbocyclic group, C1-C6 alkyl hydroxy, C1-C6 alkyl alkoxy, benzyl and C3-C8 heterocyclic group, each of which may independently be substituted with 0 or 1 group selected from the following: halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, -NH-C(=O)(C1-C3 alkyl) and -NH-C(=O)-O-(C1-C3 alkyl), wherein the valence of the atom covalently linked to L is not exceeded; and wherein * indicates the point of attachment of R 9 to the remainder of the compound. Item 13. The antibody-drug conjugate according to Item 1 or Item 12, wherein the hepsilene splicing regulator is covalently linked to L via any atom; wherein the hepsilene splicing regulator is selected from H5, H6, H7, H8, H9, H10, H11, H22 and H25; and wherein the valence of the atom covalently linked to L is not exceeded. Item 14. The antibody-drug conjugate according to item 1 or item 12, wherein the linker is covalently linked to the Herbericene splicing regulator ("L-H"), and L-H has a structure selected from the following structures: and its pharmaceutically acceptable salts. Item 15. The antibody-drug conjugate according to item 1, wherein the Herbericene splicing regulator is covalently linked to L via any atom; wherein the Herbericene splicing regulator is selected from H1, H2, H3, H4, H5, H6, H7, H8, H9, H10, H11, H12, H13, H14, H15, H16, H17, H18, H19, H20, H21, H22, H23, H24 and H25; and wherein the valence of the atom covalently linked to L is not exceeded. Item 16. The antibody-drug conjugate according to item 15, wherein the Herbericene splicing regulator is H1. Item 17. The antibody-drug conjugate according to item 15, wherein the Herbericene splicing regulator is H2. Item 18. The antibody-drug conjugate according to item 15, wherein the Herbericene splicing regulator is H3. Item 19. The antibody-drug conjugate according to item 15, wherein the Herbericene splicing regulator is H4. Item 20. The antibody-drug conjugate according to item 15, wherein the Herbericene splicing regulator is H5. Item 21. The antibody-drug conjugate according to item 15, wherein the Herbericene splicing regulator is H6. Item 22. The antibody-drug conjugate according to item 15, wherein the Herbericene splicing regulator is H7. Item 23. The antibody-drug conjugate according to item 15, wherein the Herbericene splicing regulator is H8. Item 24. The antibody-drug conjugate according to item 15, wherein the Herbericene splicing regulator is H9. Item 25. The antibody-drug conjugate according to item 15, wherein the Herbericene splicing regulator is H10. Item 26. The antibody-drug conjugate according to item 15, wherein the Herbericene splicing regulator is H11. Item 27. The antibody-drug conjugate according to item 15, wherein the Herbericene splicing regulator is H12. Item 28. The antibody-drug conjugate according to item 15, wherein the hopene splicing regulator is H13. Item 29. The antibody-drug conjugate according to item 15, wherein the hopene splicing regulator is H14. Item 30. The antibody-drug conjugate according to item 15, wherein the hopene splicing regulator is H15. Item 31. The antibody-drug conjugate according to item 15, wherein the hopene splicing regulator is H16. Item 32. The antibody-drug conjugate according to item 15, wherein the hopene splicing regulator is H17. Item 33. The antibody-drug conjugate according to item 15, wherein the hopene splicing regulator is H18. Item 34. The antibody-drug conjugate according to item 15, wherein the hopene splicing regulator is H19. Item 35. The antibody-drug conjugate according to item 15, wherein the hopene splicing regulator is H20. Item 36. The antibody-drug conjugate according to item 15, wherein the hopene splicing regulator is H21. Item 37. The antibody-drug conjugate according to item 15, wherein the hopene splicing regulator is H22. Item 38. The antibody-drug conjugate according to item 15, wherein the hopene splicing regulator is H23. Item 39. The antibody-drug conjugate according to item 15, wherein the hopene splicing regulator is H24. Item 40. The antibody-drug conjugate according to any one of items 1 to 39, wherein the linker is a cleavable linker. Item 41. The antibody-drug conjugate according to item 40, wherein the linker comprises a cleavable peptide moiety. Item 42. The antibody-drug conjugate according to item 41, wherein the cleavable peptide moiety is cleavable by an enzyme. Item 43. The antibody-drug conjugate according to any one of items 40 to 42, wherein the cleavable peptide moiety or the linker comprises amino acid units. Item 44. The antibody-drug conjugate according to item 43, wherein the amino acid unit comprises valine-citrulline (Val-Cit). Item 45. The antibody-drug conjugate according to item 43, wherein the amino acid unit comprises valine-alanine (Val-Ala). Item 46. The antibody-drug conjugate according to item 43, wherein the amino acid unit comprises glutamine-valine-citrulline (Glu-Val-Cit). Item 47. The antibody-drug conjugate according to item 43, wherein the amino acid unit comprises alanine-alanine-asparagine (Ala-Ala-Asn). Item 48. The antibody-drug conjugate according to item 40, wherein the linker comprises a cleavable glucuronide moiety. Item 49. The antibody-drug conjugate according to item 48, wherein the cleavable glucuronide moiety is cleavable by an enzyme. Item 50. The antibody-drug conjugate according to item 48 or item 49, wherein the cleavable glucuronide moiety is cleavable by glucuronidase. Item 51. The antibody-drug conjugate according to any one of items 48 to 50, wherein the cleavable glucuronide moiety is cleavable by β-glucuronidase. Item 52. The antibody-drug conjugate according to any one of items 1 to 51, wherein the linker comprises at least one spacer unit. Item 53. The antibody-drug conjugate according to item 52, wherein the spacer unit or the linker comprises a polyethylene glycol (PEG) moiety. Item 54. The antibody-drug conjugate according to item 53, wherein the PEG moiety comprises -(PEG) m - and m is an integer from 1 to 10. Item 55. The antibody-drug conjugate according to item 54, wherein m is 2. Item 56. The antibody-drug conjugate according to item 52, wherein the spacer unit or the linker comprises an alkyl moiety. Item 57. The antibody-drug conjugate according to item 56, wherein the alkyl moiety comprises -(CH2) n - and n is an integer from 1 to 10. Item 58. The antibody-drug conjugate according to item 57, wherein n is 2. Item 59. The antibody-drug conjugate according to item 57, wherein n is 5. Item 60. The antibody-drug conjugate according to item 57, wherein n is 6. Item 61. The antibody-drug conjugate according to any one of items 52 to 60, wherein the spacer unit is connected to the antibody or antigen-binding fragment via a maleimide (Mal) moiety ("Mal-spacer unit"). Item 62. The antibody-drug conjugate according to item 61, wherein the Mal-spacer unit is reactive with a cysteine residue on the antibody or antigen-binding fragment. Item 63. The antibody-drug conjugate according to item 61 or 62, wherein the Mal-spacer unit is conjugated to the antibody or antigen-binding fragment via a cysteine residue on the antibody or antigen-binding fragment. Item 64. The antibody-drug conjugate according to any one of items 61 to 63, wherein the linker comprises the Mal-spacer unit and a cleavable peptide moiety. Item 65. The antibody-drug conjugate according to item 64, wherein the cleavable peptide moiety comprises amino acid units. Item 66. The antibody-drug conjugate according to item 64 or 65, wherein the cleavable peptide moiety or amino acid units comprise Val-Cit. Item 67. The antibody-drug conjugate according to item 64 or 65, wherein the cleavable peptide moiety or amino acid units comprise Val-Ala. Item 68. The antibody-drug conjugate according to item 64 or 65, wherein the cleavable peptide moiety or amino acid units comprise Glu-Val-Cit. Item 69. The antibody-drug conjugate according to item 64 or 65, wherein the cleavable peptide moiety or amino acid units comprise Ala-Ala-Asn. Item 70. The antibody-drug conjugate according to any one of items 61 to 69, wherein the Mal-spacer unit comprises an alkyl moiety. Item 71. The antibody-drug conjugate according to any one of items 61 to 69, wherein the Mal-spacer unit comprises a PEG moiety. Item 72. The antibody-drug conjugate according to any one of items 61 to 71, wherein the Mal-spacer unit comprises maleimidocaproyl (MC). Item 73. The antibody-drug conjugate according to any one of items 61 to 72, wherein the Mal-spacer unit links the antibody or antigen-binding fragment to the cleavable portion in the linker. Item 74. The antibody-drug conjugate according to item 73, wherein the cleavable portion in the linker comprises a cleavable peptide moiety. Item 75. The antibody-drug conjugate according to item 74, wherein the cleavable peptide moiety comprises amino acid units. Item 76. The antibody-drug conjugate according to item 74 or 75, wherein the cleavable peptide moiety or amino acid units comprise Val-Cit, Val-Ala, Glu-Val-Cit or Ala-Ala-Asn. Item 77. The antibody-drug conjugate according to any one of items 73 to 76, wherein the linker comprises MC-Val-Cit. Item 78. The antibody-drug conjugate according to any one of Items 73 to 76, wherein the linker comprises MC-Val-Ala. Item 79. The antibody-drug conjugate according to any one of Items 73 to 76, wherein the linker comprises MC-Glu-Val-Cit. Item 80. The antibody-drug conjugate according to any one of Items 73 to 76, wherein the linker comprises MC-Ala-Ala-Asn. Item 81. The antibody-drug conjugate according to any one of Items 73 to 80, wherein the Mal-spacer subunit comprises an alkyl moiety. Item 82. The antibody-drug conjugate according to any one of Items 73 to 80, wherein the Mal-spacer subunit comprises a PEG moiety. Item 83. The antibody-drug conjugate according to any one of Items 73 to 82, wherein the Mal-spacer subunit comprises maleimidocaproyl (MC). Item 84. The antibody-drug conjugate according to any one of Items 52 to 83, wherein the cleavable moiety in the linker is directly conjugated to the splicing regulator, or wherein the spacer subunit connects the cleavable moiety in the linker to the splicing regulator. Item 85. The antibody-drug conjugate according to Item 84, wherein cleavage of the conjugate releases the splicing regulator from the antibody or antigen-binding fragment and the linker. Item 86. The antibody-drug conjugate according to Item 84 or Item 85, wherein the spacer subunit that connects the cleavable moiety in the linker to the splicing regulator is self-ablating. Item 87. The antibody-drug conjugate according to any one of Items 84 to 86, wherein the spacer subunit that connects the cleavable moiety in the linker to the splicing regulator comprises p-aminobenzyloxycarbonyl (pABC). Item 88. The antibody-drug conjugate according to Item 87, wherein the pABC connects the cleavable moiety in the linker to the splicing regulator. Item 89. The antibody-drug conjugate according to Item 87 or Item 88, wherein the cleavable moiety in the linker comprises a cleavable peptide moiety. Item 90. The antibody-drug conjugate according to Item 89, wherein the cleavable peptide moiety comprises amino acid units. Item 91. The antibody-drug conjugate according to Item 89 or Item 90, wherein the cleavable peptide moiety or amino acid units comprise Val-Cit, Val-Ala, Glu-Val-Cit or Ala-Ala-Asn. Item 92. The antibody-drug conjugate according to any one of Items 87 to 91, wherein the linker comprises Val-Cit-pABC. Item 93. The antibody-drug conjugate according to any one of Items 87 to 91, wherein the linker comprises Val-Ala-pABC. Item 94. The antibody-drug conjugate according to any one of Items 87 to 91, wherein the linker comprises Glu-Val-Cit-pABC. Item 95. The antibody-drug conjugate according to any one of Items 87 to 91, wherein the linker comprises Ala-Ala-Asn-pABC. Item 96. The antibody-drug conjugate according to any one of Items 84 to 86, wherein the spacer unit of the linker that connects the cleavable portion to the splicing regulator comprises p-aminobenzyl (pAB). Item 97. The antibody-drug conjugate according to Item 96, wherein the pAB connects the cleavable portion in the linker to the splicing regulator. Item 98. The antibody-drug conjugate according to Item 96 or Item 97, wherein the cleavable portion in the linker comprises a cleavable peptide portion. Item 99. The antibody-drug conjugate according to Item 98, wherein the cleavable peptide portion comprises amino acid units. Item 100. The antibody-drug conjugate according to Item 98 or Item 99, wherein the cleavable peptide portion or amino acid units comprise Val-Cit, Val-Ala, Glu-Val-Cit or Ala-Ala-Asn. Item 101. The antibody-drug conjugate according to any one of Items 96 to 100, wherein the linker comprises Val-Cit-pAB. Item 102. The antibody-drug conjugate according to any one of Items 96 to 100, wherein the linker comprises Val-Ala-pAB. Item 103. The antibody-drug conjugate according to any one of Items 96 to 100, wherein the linker comprises Glu-Val-Cit-pAB. Item 104. The antibody-drug conjugate according to any one of Items 96 to 100, wherein the linker comprises Ala-Ala-Asn-pAB. Item 105. The antibody-drug conjugate according to any one of Items 1 to 39, wherein the linker is a non-cleavable linker. Item 106. The antibody-drug conjugate according to Item 105, wherein the linker comprises at least one spacer unit. Item 107. The antibody-drug conjugate according to Item 105 or Item 106, wherein the spacer unit or the linker comprises a polyethylene glycol (PEG) moiety. Item 108. The antibody-drug conjugate according to item 107, wherein the PEG moiety comprises -(PEG) m - and m is an integer from 1 to 10. Item 109. The antibody-drug conjugate according to item 108, wherein m is 2. Item 110. The antibody-drug conjugate according to item 105 or item 106, wherein the spacer unit or linker comprises an alkyl moiety. Item 111. The antibody-drug conjugate according to item 110, wherein the alkyl moiety comprises -(CH2) n - and n is an integer from 1 to 10. Item 112. The antibody-drug conjugate according to item 111, wherein n is 2. Item 113. The antibody-drug conjugate according to item 111, wherein n is 5. Item 114. The antibody-drug conjugate according to item 111, wherein n is 6. Item 115. The antibody-drug conjugate according to any one of items 106 to 114, wherein the spacer unit is linked to the antibody or antigen-binding fragment via a maleimide (Mal) moiety ("Mal-spacer unit"). Item 116. The antibody-drug conjugate according to item 115, wherein the Mal-spacer unit is reactive with a cysteine residue on the antibody or antigen-binding fragment. Item 117. The antibody-drug conjugate according to item 115 or item 116, wherein the Mal-spacer unit is conjugated to the antibody or antigen-binding fragment via a cysteine residue on the antibody or antigen-binding fragment. Item 118. The antibody-drug conjugate according to any one of items 115 to 117, wherein the Mal-spacer unit comprises an alkyl moiety. Item 119. The antibody-drug conjugate according to any one of items 115 to 117, wherein the Mal-spacer unit comprises a PEG moiety. Item 120. The antibody-drug conjugate according to any one of items 115 to 119, wherein the linker or Mal-spacer unit comprises maleimidocaproyl (MC). Item 121. The antibody-drug conjugate according to item 120, wherein the linker or Mal-spacer unit comprises maleimidocaproyl (MC) and at least one additional spacer unit. Item 122. The antibody-drug conjugate according to any one of items 115 to 119, wherein the linker or Mal-spacer unit comprises MC-(PEG)2. Item 123. The antibody-drug conjugate according to item 122, wherein the linker or Mal-spacer subunit comprises MC-(PEG)2 and at least one additional spacer subunit. Item 124. The antibody-drug conjugate according to any one of items 115 to 119, wherein the linker or Mal-spacer subunit comprises Mal-Hex. Item 125. The antibody-drug conjugate according to item 124, wherein the linker or Mal-spacer subunit comprises Mal-Hex and at least one additional spacer subunit. Item 126. The antibody-drug conjugate according to any one of items 115 to 119, wherein the linker or Mal-spacer subunit comprises Mal-Et. Item 127. The antibody-drug conjugate according to item 126, wherein the linker or Mal-spacer subunit comprises Mal-Et and at least one additional spacer subunit. Item 128. The antibody-drug conjugate according to any one of items 115 to 119, wherein the linker or Mal-spacer subunit comprises Mal-Et-O-Et. Item 129. The antibody-drug conjugate according to item 128, wherein the linker or Mal-spacer subunit comprises Mal-Et-O-Et and at least one additional spacer subunit. Item 130. The antibody-drug conjugate according to any one of items 115 to 129, wherein the Mal-spacer subunit links the antibody or antigen-binding fragment to the splicing regulator. Item 131. The antibody-drug conjugate according to any one of items 115 to 130, wherein the linker comprises MC-Val-Cit-pABC. Item 132. The antibody-drug conjugate according to any one of items 115 to 130, wherein the linker comprises MC-(PEG)2-CO. Item 133. The antibody-drug conjugate according to any one of items 1 to 132, wherein the antibody or antigen-binding fragment targets neoplastic cells derived from a hematologic malignancy or a solid tumor. Item 134. The antibody-drug conjugate according to any one of items 1 to 133, wherein the antibody or antigen-binding fragment targets neoplastic cells derived from a hematologic malignancy. Item 135. The antibody-drug conjugate according to item 133 or item 134, wherein the hematologic malignancy is selected from B cell malignancies, leukemias, lymphomas, and myelomas. Item 136. The antibody-drug conjugate according to any one of items 133 to 135, wherein the hematologic malignancy is selected from acute myeloid leukemia and multiple myeloma. Item 137. The antibody-drug conjugate according to any one of Items 1 to 133, wherein the antibody or antigen-binding fragment targets neoplastic cells derived from a solid tumor. Item 138. The antibody-drug conjugate according to Item 133 or Item 137, wherein the solid tumor is selected from breast cancer, gastric cancer, prostate cancer, ovarian cancer, lung cancer, uterine cancer, salivary duct carcinoma, melanoma, colorectal cancer, cervical cancer, pancreatic cancer, kidney cancer, colorectal carcinoma, and esophageal cancer. Item 139. The antibody-drug conjugate according to any one of Items 1 to 138, wherein the antibody or antigen-binding fragment targets cells expressing HER2. Item 140. The antibody-drug conjugate according to Item 139, wherein the antibody or antigen-binding fragment is an anti-HER2 antibody or antigen-binding fragment. Item 141. The antibody-drug conjugate according to Item 139 or Item 140, wherein the antibody or antigen-binding fragment comprises three heavy-chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) containing the amino acid sequences of SEQ ID NO:1 (HCDR1), SEQ ID NO:2 (HCDR2), and SEQ ID NO:3 (HCDR3); and three light-chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) containing the amino acid sequences of SEQ ID NO:4 (LCDR1), SEQ ID NO:5 (LCDR2), and SEQ ID NO:6 (LCDR3). Item 142. The antibody-drug conjugate according to any one of Items 139 to 141, wherein the antibody or antigen-binding fragment comprises a heavy-chain variable region containing the amino acid sequence of SEQ ID NO:19 and a light-chain variable region containing the amino acid sequence of SEQ ID NO:20. Item 143. The antibody-drug conjugate according to any one of Items 139 to 142, wherein the antibody or antigen-binding fragment comprises a human IgG1 heavy-chain constant region. Item 144. The antibody-drug conjugate according to any one of Items 139 to 143, wherein the antibody or antigen-binding fragment comprises a human Igκ light-chain constant region. Item 145. The antibody-drug conjugate according to any one of Items 1 to 138, wherein the antibody or antigen-binding fragment targets cells expressing CD138. Item 146. The antibody-drug conjugate according to Item 145, wherein the antibody or antigen-binding fragment is an anti-CD138 antibody or antigen-binding fragment. Item 147. The antibody-drug conjugate according to item 145 or item 146, wherein the antibody or antigen-binding fragment comprises three heavy-chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) having the amino acid sequences set forth in SEQ ID NO:7 (HCDR1), SEQ ID NO:8 (HCDR2), and SEQ ID NO:9 (HCDR3); and three light-chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) having the amino acid sequences set forth in SEQ ID NO:10 (LCDR1), SEQ ID NO:11 (LCDR2), and SEQ ID NO:12 (LCDR3). Item 148. The antibody-drug conjugate according to any one of items 145 to 147, wherein the antibody or antigen-binding fragment comprises a heavy-chain variable region having the amino acid sequence set forth in SEQ ID NO:21 and a light-chain variable region having the amino acid sequence set forth in SEQ ID NO:22. Item 149. The antibody-drug conjugate according to any one of items 145 to 148, wherein the antibody or antigen-binding fragment comprises a human IgG2a heavy-chain constant region. Item 150. The antibody-drug conjugate according to any one of items 145 to 149, wherein the antibody or antigen-binding fragment comprises a human Igκ light-chain constant region. Item 151. The antibody-drug conjugate according to any one of items 1 to 138, wherein the antibody or antigen-binding fragment targets cells expressing EPHA2. Item 152. The antibody-drug conjugate according to item 151, wherein the antibody or antigen-binding fragment is an anti-EPHA2 antibody or antigen-binding fragment. Item 153. The antibody-drug conjugate according to item 151 or item 152, wherein the antibody or antigen-binding fragment comprises three heavy-chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) having the amino acid sequences set forth in SEQ ID NO:13 (HCDR1), SEQ ID NO:14 (HCDR2), and SEQ ID NO:15 (HCDR3); and three light-chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) having the amino acid sequences set forth in SEQ ID NO:16 (LCDR1), SEQ ID NO:17 (LCDR2), and SEQ ID NO:18 (LCDR3). Item 154. The antibody-drug conjugate according to any one of items 151 to 153, wherein the antibody or antigen-binding fragment comprises a heavy-chain variable region having the amino acid sequence set forth in SEQ ID NO:23 and a light-chain variable region having the amino acid sequence set forth in SEQ ID NO:24. Item 155. The antibody-drug conjugate according to any one of Items 151 to 154, wherein the antibody or antigen-binding fragment comprises a human IgG1 heavy chain constant region. Item 156. The antibody-drug conjugate according to any one of Items 151 to 155, wherein the antibody or antigen-binding fragment comprises a human Igκ light chain constant region. Item 157. The antibody-drug conjugate according to any one of Items 1 to 138, wherein the antibody or antigen-binding fragment targets cells expressing MSLN. Item 158. The antibody-drug conjugate according to Item 157, wherein the antibody or antigen-binding fragment is an anti-MSLN antibody or antigen-binding fragment. Item 159. The antibody-drug conjugate according to any one of Items 1 to 138, wherein the antibody or antigen-binding fragment targets cells expressing FOLH1. Item 160. The antibody-drug conjugate according to Item 159, wherein the antibody or antigen-binding fragment is an anti-FOLH1 antibody or antigen-binding fragment. Item 161. The antibody-drug conjugate according to any one of Items 1 to 138, wherein the antibody or antigen-binding fragment targets cells expressing CDH6. Item 162. The antibody-drug conjugate according to Item 161, wherein the antibody or antigen-binding fragment is an anti-CDH6 antibody or antigen-binding fragment. Item 163. The antibody-drug conjugate according to any one of Items 1 to 138, wherein the antibody or antigen-binding fragment targets cells expressing CEACAM5. Item 164. The antibody-drug conjugate according to Item 163, wherein the antibody or antigen-binding fragment is an anti-CEACAM5 antibody or antigen-binding fragment. Item 165. The antibody-drug conjugate according to any one of Items 1 to 138, wherein the antibody or antigen-binding fragment targets cells expressing CFC1B. Item 166. The antibody-drug conjugate according to Item 165, wherein the antibody or antigen-binding fragment is an anti-CFC1B antibody or antigen-binding fragment. Item 167. The antibody-drug conjugate according to any one of Items 1 to 138, wherein the antibody or antigen-binding fragment targets cells expressing ENPP3. Item 168. The antibody-drug conjugate according to Item 167, wherein the antibody or antigen-binding fragment is an anti-ENPP3 antibody or antigen-binding fragment. Item 169. The antibody-drug conjugate according to any one of Items 1 to 138, wherein the antibody or antigen-binding fragment targets cells expressing FOLR1. Item 170. The antibody-drug conjugate according to item 169, wherein the antibody or antigen-binding fragment is an anti-FOLR1 antibody or antigen-binding fragment. Item 171. The antibody-drug conjugate according to any one of items 1 to 138, wherein the antibody or antigen-binding fragment targets cells expressing HAVCR1. Item 172. The antibody-drug conjugate according to item 171, wherein the antibody or antigen-binding fragment is an anti-HAVCR1 antibody or antigen-binding fragment. Item 173. The antibody-drug conjugate according to any one of items 1 to 138, wherein the antibody or antigen-binding fragment targets cells expressing KIT. Item 174. The antibody-drug conjugate according to item 173, wherein the antibody or antigen-binding fragment is an anti-KIT antibody or antigen-binding fragment. Item 175. The antibody-drug conjugate according to any one of items 1 to 138, wherein the antibody or antigen-binding fragment targets cells expressing MET. Item 176. The antibody-drug conjugate according to item 175, wherein the antibody or antigen-binding fragment is an anti-MET antibody or antigen-binding fragment. Item 177. The antibody-drug conjugate according to any one of items 1 to 138, wherein the antibody or antigen-binding fragment targets cells expressing MUC16. Item 178. The antibody-drug conjugate according to item 177, wherein the antibody or antigen-binding fragment is an anti-MUC16 antibody or antigen-binding fragment. Item 179. The antibody-drug conjugate according to any one of items 1 to 138, wherein the antibody or antigen-binding fragment targets cells expressing SLC39A6. Item 180. The antibody-drug conjugate according to item 179, wherein the antibody or antigen-binding fragment is an anti-SLC39A6 antibody or antigen-binding fragment. Item 181. The antibody-drug conjugate according to any one of items 1 to 138, wherein the antibody or antigen-binding fragment targets cells expressing SLC44A4. Item 182. The antibody-drug conjugate according to item 181, wherein the antibody or antigen-binding fragment is an anti-SLC44A4 antibody or antigen-binding fragment. Item 183. The antibody-drug conjugate according to any one of items 1 to 138, wherein the antibody or antigen-binding fragment targets cells expressing STEAP1. Item 184. The antibody-drug conjugate according to item 183, wherein the antibody or antigen-binding fragment is an anti-STEAP1 antibody or antigen-binding fragment. Item 185. The antibody-drug conjugate according to any one of Items 1 to 184, wherein p is from 1 to 10. Item 186. The antibody-drug conjugate according to any one of Items 1 to 185, wherein p is from 2 to 8. Item 187. The antibody-drug conjugate according to any one of Items 1 to 186, wherein p is from 4 to 8. Item 188. The antibody-drug conjugate according to any one of Items 1 to 187, wherein p is 4. Item 189. The antibody-drug conjugate according to any one of Items 1 to 187, wherein p is 8. Item 190. A compound having formula (I), or a pharmaceutically acceptable salt thereof, wherein: Y is selected from O, S, NR 6 and CR 6 R 7 ; R 1 , R 2 and R 3 are each independently selected from hydrogen, hydroxy, -O-(C1-C6 alkyl), -O-C(=O)-(C1-C6 alkyl), -C(=O)-O-(C1-C6 alkyl) and C1-C6 alkyl; R 4 is selected from hydrogen, C1-C6 alkyl, -C(=O)-(C1-C6 alkyl), -C(=O)-(C3-C8 carbocyclic group), -C(=O)-(C3-C8 heterocyclic group) and -C(=O)-NR 6 R 7 ; R 5 is selected from hydrogen, hydroxy, -CH2-OH, -CO2H, -C(=O)-O-(C1-C6 alkyl), -C(=O)-NR 6 R 7 , -NR 6 -C(=O)-R 8 , -O-C(=O)-NR 6 R 7 , -NR 6 -C(=O)-R 8 and -NR 6 -C(=O)-NR 6 R 7 ; R 6 and R 7 are each independently selected from hydrogen, -R 8 , -C(=O)-R 8 and -C(=O)-O-R8 ; and R 8 is selected from C1-C6 alkyl, C3-C8 carbocyclic group and C3-C8 heterocyclic group, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently substituted with 0 to 3 groups independently selected from the following: halogen, hydroxy, C1-C6 alkyl, -O-(C1-C6 alkyl), -CO2H, -C(=O)-(C1-C6 alkyl), -C(=O)-(C3-C8 carbocyclic group), -C(=O)-(C3-C8 heterocyclic group), -NR 6 R 7 , C3-C8 carbocyclic group, C1-C6 alkyl hydroxy, C1-C6 alkyl alkoxy, benzyl and C3-C8 heterocyclic group, each of which may be independently substituted with 0 or 1 group selected from the following: halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, -NH-C(=O)(C1-C3 alkyl) and -NH-C(=O)-O-(C1-C3 alkyl). Item 191. The compound according to item 190, wherein the compound is a compound having formula (Ia): or a pharmaceutically acceptable salt thereof, wherein: R 9 is selected from C3-C8 heterocyclic group; and R 10 is selected from H and C1-C6 alkyl, wherein R 9 and R 10 are each independently substituted with 0 to 3 groups independently selected from the following: halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, -NH2, -NH-(C1-C3 alkyl) and -N-(C1-C3 alkyl)2. Item 192. The compound according to item 190 or item 191, wherein the compound is a compound having formula (Ib): or a pharmaceutically acceptable salt thereof, wherein: R 11 is selected from wherein * indicates the point of attachment of R 11 to the remainder of the compound; and R 12 and R 13 are each independently selected from H and methyl. Item 193. The compound as described in Item 190, wherein the compound is H1 or a pharmaceutically acceptable salt thereof. Item 194. The compound as described in Item 190, wherein the compound is H2 or a pharmaceutically acceptable salt thereof. Item 195. The compound as described in Item 190, wherein the compound is H3 or a pharmaceutically acceptable salt thereof. Item 196. The compound as described in Item 190, wherein the compound is H12 or a pharmaceutically acceptable salt thereof. Item 197. A compound having formula (II): or a pharmaceutically acceptable salt thereof, wherein: X is NR 6 R 7 ; R 6 and R 7 are each independently selected from hydrogen, -R 8 , -C(=O)-R 8 , -C(=O)-O-R 8 , -(C1-C6 alkyl)-O-C(=O)-R 8 and -(C1-C6 alkyl)-NH-C(=O)-R 8 ; and R 8 is selected from C1-C6 alkyl, C3-C8 carbocyclic group and C3-C8 heterocyclic group, wherein R 6 , R 7 and R 8 are each independently substituted with 0 to 3 groups independently selected from the following: halogen, hydroxy, C1-C6 alkyl, -O-(C1-C6 alkyl), -CO2H, -C(=O)-O-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)-(C3-C8 carbocyclic group), -C(=O)-(C3-C8 heterocyclic group), -NR 6 R 7 , C3-C8 carbocyclic group, C1-C6 alkyl hydroxy, C1-C6 alkyl alkoxy, benzyl and C3-C8 heterocyclic group, each of which may be independently substituted with 0 or 1 group selected from the following: halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, -NH-C(=O)(C1-C3 alkyl) and -NH-C(=O)-O-(C1-C3 alkyl). Item 198. The compound as described in Item 197, wherein the compound is a compound having formula (IIa): or a pharmaceutically acceptable salt thereof, wherein: Z is selected from NR9 and O; R 9 is selected from hydrogen and C1-C6 alkyl; R 10 and R 11 are each independently selected from hydrogen, halogen, hydroxy, C1-C6 alkyl, -O-(C1-C6 alkyl), -CO2H, -C(=O)-O-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)-(C3-C8 carbocyclic group), -C(=O)-(C3-C8 heterocyclic group), C3-C8 carbocyclic group, C1-C6 alkyl hydroxy, C1-C6 alkyl alkoxy, benzyl and C3-C8 heterocyclic group; R 12 is selected from C1-C6 alkyl, C3-C8 carbocyclic group, C3-C8 heterocyclic group, wherein R 9 , R 10 , R 11 and R 12 are each independently substituted with 0 or 1 group selected from: halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy and C1-C3 haloalkyl; and t is an integer selected from 1, 2, 3, 4, 5 and 6. Item 199. The compound according to item 197 or item 198, wherein the compound is a compound having the formula (IIb): or a pharmaceutically acceptable salt thereof, wherein: R 13 is selected from wherein * indicates the point of attachment of R 13 to the remainder of the compound; and R 14 and R 15 are each independently selected from hydrogen and methyl. Item 200. The compound according to item 197, wherein the compound is H4 or a pharmaceutically acceptable salt thereof. Item 201. The compound according to item 197, wherein the compound is H13 or a pharmaceutically acceptable salt thereof. Item 202. The compound according to item 197, wherein the compound is H14 or a pharmaceutically acceptable salt thereof. Item 203. The compound according to item 197, wherein the compound is H15 or a pharmaceutically acceptable salt thereof. Item 204. The compound according to item 197, wherein the compound is H16 or a pharmaceutically acceptable salt thereof. Item 205. The compound as described in Item 197, wherein the compound is H17 or a pharmaceutically acceptable salt thereof. Item 206. The compound as described in Item 197, wherein the compound is H18 or a pharmaceutically acceptable salt thereof. Item 207. The compound as described in Item 197, wherein the compound is H19 or a pharmaceutically acceptable salt thereof. Item 208. The compound as described in Item 197, wherein the compound is H20 or a pharmaceutically acceptable salt thereof. Item 209. The compound as described in Item 197, wherein the compound is H21 or a pharmaceutically acceptable salt thereof. Item 210. The compound as described in Item 197, wherein the compound is H23 or a pharmaceutically acceptable salt thereof. Item 211. The compound as described in Item 197, wherein the compound is H24 or a pharmaceutically acceptable salt thereof. Item 212. A compound having formula (III): or a pharmaceutically acceptable salt thereof, wherein: R 1 、R 2 and R 3 are each independently selected from hydrogen, hydroxy, -O-(C1-C6 alkyl), -O-C(=O)-(C1-C6 alkyl), -C(=O)-O-(C1-C6 alkyl), and C1-C6 alkyl; R 6 and R 7 are each independently selected from hydrogen, -R 8 、-C(=O)-R 8 and -C(=O)-O-R 8 ; R 8 is selected from C1-C6 alkyl, C3-C8 carbocyclic group, and C3-C8 heterocyclic group; and R 9 is selected from H, wherein R 1 、R 2 、R 3 、R 6 、R 7 and R 8 are each independently substituted with 0 to 3 groups independently selected from the following: halogen, hydroxy, C1-C6 alkyl, -O-(C1-C6 alkyl), -CO2H, -C(=O)-(C1-C6 alkyl), -C(=O)-(C3-C8 carbocyclic group), -C(=O)-(C3-C8 heterocyclic group), -NR6 R 7 , a C3-C8 carbocyclic group, a C1-C6 alkylhydroxy group, a C1-C6 alkylalkoxy group, a benzyl group, and a C3-C8 heterocyclic group, each of which may be independently substituted with 0 or 1 group selected from the following: halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, -NH-C(=O)(C1-C3 alkyl), and -NH-C(=O)-O-(C1-C3 alkyl); and where * indicates the point of attachment of R 9 to the remainder of the compound. Item 213. The compound according to Item 212, wherein the compound is H5 or a pharmaceutically acceptable salt thereof. Item 214. The compound according to Item 212, wherein the compound is H6 or a pharmaceutically acceptable salt thereof. Item 215. The compound according to Item 212, wherein the compound is H7 or a pharmaceutically acceptable salt thereof. Item 216. The compound according to Item 212, wherein the compound is H8 or a pharmaceutically acceptable salt thereof. Item 217. The compound according to Item 212, wherein the compound is H9 or a pharmaceutically acceptable salt thereof. Item 218. The compound according to Item 212, wherein the compound is H10 or a pharmaceutically acceptable salt thereof. Item 219. The compound according to Item 212, wherein the compound is H22 or a pharmaceutically acceptable salt thereof. Item 220. A pharmaceutical composition comprising the compound according to any one of Items 190 to 219 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Item 221. A composition comprising multiple copies of the antibody-drug conjugate according to any one of Items 1 to 189, wherein the average p of the antibody-drug conjugate in the composition is from about 3.5 to about 5.5. Item 222. The composition according to Item 221, wherein the average p of the antibody-drug conjugate in the composition is about 4. Item 223. A composition comprising multiple copies of the antibody-drug conjugate according to any one of Items 1 to 189, wherein the average p of the antibody-drug conjugate in the composition is from about 7 to about 9. Item 224. The composition according to Item 223, wherein the average p of the antibody-drug conjugate in the composition is about 8. Item 225. A method of treating a subject having or suspected of having a neoplastic disorder, the method comprising administering to the subject a therapeutically effective amount of an antibody-drug conjugate as described in any one of Items 1 to 189, a compound as described in any one of Items 190 to 219, or a composition as described in any one of Items 220 to 224. Item 226. The method according to Item 225, wherein the neoplastic disorder is a hematological malignancy or a solid tumor. Item 227. The method according to Item 225 or Item 226, wherein the neoplastic disorder is a hematological malignancy. Item 228. The method according to Item 227, wherein the hematological malignancy is selected from acute myeloid leukemia and multiple myeloma. Item 229. The method according to Item 225 or Item 226, wherein the neoplastic disorder is a solid tumor. Item 230. The method according to Item 229, wherein the solid tumor is selected from breast cancer, gastric cancer, prostate cancer, ovarian cancer, lung cancer, uterine cancer, salivary duct carcinoma, melanoma, colorectal cancer, cervical cancer, pancreatic cancer, renal cancer, colorectal carcinoma, and esophageal cancer. Item 231. The method according to any one of Items 225 to 230, wherein the subject has one or more neoplastic cells expressing a target antigen. Item 232. The method according to Item 231, wherein the target antigen is HER2. Item 233. The method according to Item 231 or Item 232, wherein the one or more neoplastic cells are derived from breast cancer, ovarian cancer, gastric cancer, lung cancer, uterine cancer, osteosarcoma, or salivary duct carcinoma expressing HER2. Item 234. The method according to Item 233, wherein the lung cancer is lung adenocarcinoma and / or the uterine cancer is uterine serous endometrial carcinoma. Item 235. The method according to any one of Items 232 to 234, wherein the subject is unresponsive or poorly responsive to treatment with (a) an anti-HER2 antibody when administered alone and / or (b) a splicing regulator when administered alone. Item 236. The method according to any one of Items 232 to 235, wherein the subject is intolerant, unresponsive, or poorly responsive to treatment with a splicing regulator when administered alone. Item 237. The method according to Item 231, wherein the target antigen is CD138. Item 238. The method according to Item 231 or Item 237, wherein the one or more neoplastic cells are derived from multiple myeloma expressing CD138. Item 239. The method according to item 237 or item 238, wherein the subject is non-responsive or poorly responsive to treatment with (a) an anti-CD138 antibody when administered alone and / or (b) a splicing regulator when administered alone. Item 240. The method according to any one of items 237 to 239, wherein the subject is intolerant, non-responsive or poorly responsive to treatment with a splicing regulator when administered alone. Item 241. The method according to item 231, wherein the target antigen is EPHA2. Item 242. The method according to item 231 or item 241, wherein the one or more neoplastic cells are derived from breast cancer, prostate cancer, ovarian cancer, lung cancer, melanoma, colon cancer or esophageal cancer expressing EPHA2. Item 243. The method according to item 241 or item 242, wherein the subject is non-responsive or poorly responsive to treatment with (a) an anti-EPHA2 antibody when administered alone and / or (b) a splicing regulator when administered alone. Item 244. The method according to any one of items 241 to 243, wherein the subject is intolerant, non-responsive or poorly responsive to treatment with a splicing regulator when administered alone. Item 245. A method of reducing or inhibiting tumor growth in a subject having or suspected of having a neoplastic disorder, the method comprising administering to the subject a therapeutically effective amount of an antibody-drug conjugate according to any one of items 1 to 189, a compound according to any one of items 190 to 219, or a composition according to any one of items 220 to 224. Item 246. The method according to item 245, wherein the tumor comprises one or more neoplastic cells expressing a target antigen. Item 247. The method according to item 246, wherein the target antigen is HER2. Item 248. The method according to item 246 or item 247, wherein the one or more neoplastic cells are derived from breast cancer, ovarian cancer, gastric cancer, lung cancer, uterine cancer, osteosarcoma or salivary duct carcinoma expressing HER2. Item 249. The method according to item 248, wherein the lung cancer is lung adenocarcinoma and / or the uterine cancer is uterine serous endometrial carcinoma. Item 250. The method according to any one of items 247 to 249, wherein the tumor is resistant or refractory to treatment with (a) an anti-HER2 antibody when administered alone and / or (b) a splicing regulator when administered alone. Item 251. The method according to item 246, wherein the target antigen is CD138. Item 252. The method according to item 246 or item 251, wherein the one or more neoplastic cells are derived from multiple myeloma expressing CD138. Item 253. The method according to item 251 or item 252, wherein the tumor is resistant or refractory to treatment with (a) an anti-CD138 antibody when administered alone and / or (b) a splicing regulator when administered alone. Item 254. The method according to item 246, wherein the target antigen is EPHA2. Item 255. The method according to item 246 or item 254, wherein the one or more neoplastic cells are derived from breast cancer, prostate cancer, ovarian cancer, lung cancer, melanoma, colon cancer or esophageal cancer expressing EPHA2. Item 256. The method according to item 254 or item 255, wherein the tumor is resistant or refractory to treatment with (a) an anti-EPHA2 antibody when administered alone and / or (b) a splicing regulator when administered alone. Item 257. A method for determining whether a subject having or suspected of having a neoplastic disorder responds to treatment with an antibody-drug conjugate according to any one of items 1 to 189, a compound according to any one of items 190 to 219, or a composition according to any one of items 220 to 224, the method comprising providing a biological sample from the subject and contacting the biological sample with an antibody-drug conjugate according to any one of items 1 to 189, a compound according to any one of items 190 to 219, or a composition according to any one of items 220 to 224. Item 258. The method according to item 257, wherein the biological sample is a tumor sample. Item 259. The method according to item 258, wherein the tumor sample is a tumor biopsy or a blood sample. Item 260. The method according to item 259, wherein the blood sample is selected from blood, blood fractions or cells obtained from the blood or blood fractions. Item 261. The method according to any one of items 257 to 260, wherein the subject has one or more neoplastic cells expressing a target antigen. Item 262. The method according to item 261, wherein the target antigen is HER2. Item 263. The method according to item 261 or item 262, wherein the one or more neoplastic cells are derived from breast cancer, ovarian cancer, gastric cancer, lung cancer, uterine cancer, osteosarcoma or salivary duct carcinoma expressing HER2. Item 264. The method according to item 263, wherein the lung cancer is lung adenocarcinoma and / or the uterine cancer is uterine serous endometrial carcinoma. Item 265. The method according to item 261, wherein the target antigen is CD138. Item 266. The method according to item 261 or item 265, wherein the one or more neoplastic cells are derived from multiple myeloma expressing CD138. Item 267. The method according to item 261, wherein the target antigen is EPHA2. Item 268. The method according to item 261 or item 267, wherein the one or more neoplastic cells are derived from breast cancer, prostate cancer, ovarian cancer, lung cancer, melanoma, colon cancer or esophageal cancer expressing EPHA2. Item 269. The antibody-drug conjugate according to any one of items 1 to 189, the compound according to any one of items 190 to 219, or the composition according to any one of items 220 to 224, which is used for treating neoplastic diseases. Item 270. The antibody-drug conjugate, compound or composition as used in item 269, wherein the neoplastic disease has one or more neoplastic cells expressing the target antigen. Item 271. The antibody-drug conjugate, compound or composition as used in item 270, wherein the target antigen is HER2. Item 272. The antibody-drug conjugate, compound or composition as used in item 270 or item 271, wherein the neoplastic disease is HER2-expressing breast cancer, ovarian cancer, gastric cancer, lung cancer, uterine cancer, osteosarcoma or salivary duct carcinoma. Item 273. The antibody-drug conjugate, compound or composition according to item 272, wherein the lung cancer is lung adenocarcinoma and / or the uterine cancer is uterine serous endometrial cancer. Item 274. The antibody-drug conjugate, compound or composition as used in item 270, wherein the target antigen is CD138. Item 275. The antibody-drug conjugate, compound or composition as used in item 270 or item 274, wherein the neoplastic disease is CD138-expressing multiple myeloma. Item 276. The antibody-drug conjugate, compound or composition as used in item 270, wherein the target antigen is EPHA2. Item 277. The antibody-drug conjugate, compound or composition as used in item 270 or item 276, wherein the neoplastic disease is EPHA2-expressing breast cancer, prostate cancer, ovarian cancer, lung cancer, melanoma, colorectal cancer or esophageal cancer. Item 278. Use of the antibody-drug conjugate according to any one of items 1 to 189, the compound according to any one of items 190 to 219, or the composition according to any one of items 220 to 224 for treating neoplastic diseases. Item 279. The use as described in Item 278, wherein the neoplastic disorder is characterized by neoplastic cells expressing one or more target antigens. Item 280. The use as described in Item 279, wherein the target antigen is HER2. Item 281. The use as described in Item 279 or Item 280, wherein the neoplastic disorder is HER2-expressing breast cancer, ovarian cancer, gastric cancer, lung cancer, uterine cancer, osteosarcoma or salivary duct carcinoma. Item 282. The use as described in Item 281, wherein the lung cancer is lung adenocarcinoma and / or the uterine cancer is uterine serous endometrial cancer. Item 283. The use as described in Item 279, wherein the target antigen is CD138. Item 284. The use as described in Item 279 or Item 283, wherein the neoplastic disorder is multiple myeloma expressing CD138. Item 285. The use as described in Item 279, wherein the target antigen is EPHA2. Item 286. The use as described in Item 279 or Item 285, wherein the neoplastic disorder is breast cancer, prostate cancer, ovarian cancer, lung cancer, melanoma, colon cancer or esophageal cancer expressing EPHA2. Item 287. The use of the antibody-drug conjugate as described in any one of Items 1 to 189, the compound as described in any one of Items 190 to 219 or the composition as described in any one of Items 220 to 224 in the method for manufacturing a medicament for treating a neoplastic disorder. Item 288. The use as described in Item 287, wherein the neoplastic disorder is characterized by neoplastic cells expressing one or more target antigens. Item 289. The use as described in Item 288, wherein the target antigen is HER2. Item 290. The use as described in Item 288 or Item 289, wherein the neoplastic disorder is breast cancer, ovarian cancer, gastric cancer, lung cancer, uterine cancer, osteosarcoma or salivary duct carcinoma expressing HER2. Item 291. The use as described in Item 290, wherein the lung cancer is lung adenocarcinoma and / or the uterine cancer is uterine serous endometrial cancer. Item 292. The use as described in Item 288, wherein the target antigen is CD138. Item 293. The use as described in Item 288 or Item 292, wherein the neoplastic disorder is multiple myeloma expressing CD138. Item 294. The use as described in Item 288, wherein the target antigen is EPHA2. Item 295. The use as described in Item 288 or Item 294, wherein the neoplastic disorder is breast cancer, prostate cancer, ovarian cancer, lung cancer, melanoma, colon cancer or esophageal cancer expressing EPHA2. Item 296. A method for producing an antibody-drug conjugate as described in any one of Items 1 to 189, the method comprising reacting an antibody or antigen-binding fragment with a linker conjugated to a splicing regulator under conjugation-permitting conditions. Item 297. A method for inducing at least one neoantigen, the method comprising contacting neoplastic cells with an effective amount of an antibody-drug conjugate as described in any one of Items 1 to 189, a compound as described in any one of Items 190 to 219, or a composition as described in any one of Items 220 to 224, thereby inducing the production of at least one neoantigen. Item 298. The method as described in Item 297, wherein the neoplastic cells are present in an in vitro cell culture. Item 299. The method as described in Item 297 or Item 298, wherein the neoplastic cells are obtained from a subject. Item 300. The method as described in Item 297, wherein the neoplastic cells are present in a subject. Item 301. The method as described in any one of Items 297 to 300, wherein the neoplastic cells are derived from a hematological malignancy or a solid tumor. Item 302. The method as described in Item 301, wherein the hematological malignancy is selected from B-cell malignancies, leukemias, lymphomas, and myelomas. Item 303. The method as described in Item 301 or Item 302, wherein the hematological malignancy is selected from acute myeloid leukemia and multiple myeloma. Item 304. The method as described in Item 301, wherein the solid tumor is selected from breast cancer, gastric cancer, prostate cancer, ovarian cancer, lung cancer, uterine cancer, salivary duct carcinoma, melanoma, colorectal cancer, cervical cancer, pancreatic cancer, kidney cancer, colorectal carcinoma, and esophageal cancer. Item 305. A method for inducing at least one neoantigen and / or a T-cell response in a subject having or suspected of having a neoplastic disorder, the method comprising administering to the subject an effective amount of an antibody-drug conjugate as described in any one of Items 1 to 189, a compound as described in any one of Items 190 to 219, or a composition as described in any one of Items 220 to 224. Item 306. A method for treating a subject having or suspected of having a neoplastic disorder, the method comprising administering to the subject an effective amount of an antibody-drug conjugate as described in any one of Items 1 to 189, a compound as described in any one of Items 190 to 219, or a composition as described in any one of Items 220 to 224, wherein administration of the compound, antibody-drug conjugate, or composition induces at least one neoantigen and / or a T-cell response. Item 307. The method according to item 305 or item 306, wherein the amount of the compound, antibody-drug conjugate or composition administered is reduced as compared to the standard dose of the compound, antibody-drug conjugate or composition, due to induction of at least one neoantigen and / or T cell response. Item 308. The method according to any one of items 305 to 307, wherein the amount of the compound, antibody-drug conjugate or composition administered is reduced by 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75% or 90% as compared to the standard dose of the compound, antibody-drug conjugate or composition. Item 309. The method according to any one of items 305 to 308, wherein the compound, antibody-drug conjugate or composition is administered at a frequency that is at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75% or 90% lower as compared to the standard dosing regimen of the compound, antibody-drug conjugate or composition. Item 310. The method according to any one of items 305 to 309, wherein the amount administered and / or the dose of the compound, antibody-drug conjugate or composition results in lower systemic toxicity and / or improved drug resistance. Item 311. The method according to any one of items 305 to 310, the method further comprising administering at least one additional therapy. Item 312. The method according to item 311, wherein the amount of the compound, antibody-drug conjugate, composition and / or the at least one additional therapy administered is reduced as compared to the standard dose of the compound, antibody-drug conjugate, composition and / or the at least one additional therapy, due to induction of at least one neoantigen and / or T cell response. Item 313. The method according to item 311 or item 312, wherein the amount of the compound, antibody-drug conjugate, composition and / or the at least one additional therapy administered is reduced by 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75% or 90% as compared to the standard dose of the splicing regulator, antibody-drug conjugate, composition and / or the at least one additional therapy. Item 314. The method according to any one of items 311 to 313, wherein the compound, antibody-drug conjugate, composition and / or the at least one additional therapy is administered at a frequency that is at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75% or 90% lower as compared to the standard dosing regimen of the compound, antibody-drug conjugate, composition and / or the at least one additional therapy. Item 315. The method according to any one of Items 311 to 314, wherein the dosage and / or dose of the compound, antibody-drug conjugate, composition, and / or the at least one additional therapy causes lower systemic toxicity and / or improved drug resistance. Item 316. The method according to any one of Items 311 to 315, wherein the administration of the compound, antibody-drug conjugate, or composition begins before the administration of the at least one additional therapy. Item 317. The method according to any one of Items 311 to 315, wherein the administration of the compound, antibody-drug conjugate, or composition begins after the administration of the at least one additional therapy. Item 318. The method according to any one of Items 311 to 315, wherein the administration of the compound, antibody-drug conjugate, or composition begins simultaneously with the administration of the at least one additional therapy. Item 319. The method according to any one of Items 305 to 318, wherein the administration of the compound, antibody-drug conjugate, or composition is repeated at least once after the initial administration. Item 320. The method according to Item 319, wherein the amount of the compound, antibody-drug conjugate, or composition for repeated administration is reduced compared to the amount for the initial administration. Item 321. The method according to Item 319 or Item 320, wherein the amount of the compound, antibody-drug conjugate, or composition for repeated administration is reduced compared to the standard dose of the compound, antibody-drug conjugate, or composition. Item 322. The method according to any one of Items 319 to 321, wherein the amount of the compound, antibody-drug conjugate, or composition for repeated administration is reduced by 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75%, or 90% compared to the standard dose of the compound, antibody-drug conjugate, or composition. Item 323. The method according to any one of Items 311 to 322, wherein the administration of the at least one additional therapy is repeated at least once after the initial administration. Item 324. The method according to Item 323, wherein the amount of the at least one additional therapy for repeated administration is reduced compared to the amount for the initial administration. Item 325. The method according to Item 323 or Item 324, wherein the amount of the at least one additional therapy for repeated administration is reduced compared to the standard dose of the at least one additional therapy. Item 326. The method according to any one of Items 323 to 325, wherein the amount of the at least one additional therapy for repeated administration is reduced by 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75% or 90% compared to the standard dose of the at least one additional therapy. Item 327. The method according to any one of Items 319 to 326, wherein the repeated administration of the compound, antibody-drug conjugate or composition is carried out simultaneously with the repeated administration of the at least one additional therapy. Item 328. The method according to any one of Items 319 to 326, wherein the repeated administration of the compound, antibody-drug conjugate or composition is carried out sequentially or staggered with the repeated administration of the at least one additional therapy. Item 329. The method according to any one of Items 311 to 328, wherein the at least one additional therapy comprises administering a checkpoint inhibitor. Item 330. The method according to Item 329, wherein the subject is intolerant, non-responsive or poorly responsive to the checkpoint inhibitor when administered alone. Item 331. The method according to Item 329 or Item 330, wherein the checkpoint inhibitor targets CTLA4, PD1, PDL1, OX40, CD40, GITR, LAG3, TIM3 and / or KIR. Item 332. The method according to any one of Items 329 to 331, wherein the checkpoint inhibitor targets CTLA4, OX40, CD40 and / or GITR. Item 333. The method according to any one of Items 329 to 332, wherein the checkpoint inhibitor comprises a cytotoxic T lymphocyte-associated antigen 4 pathway (CTLA4) inhibitor. Item 334. The method according to Item 333, wherein the CTLA4 inhibitor is an anti-CTLA4 antibody. Item 335. The method according to Item 334, wherein the anti-CTLA4 antibody is ipilimumab. Item 336. The method according to any one of Items 329 to 332, wherein the checkpoint inhibitor comprises a programmed death-1 pathway (PD1) inhibitor. Item 337. The method according to Item 336, wherein the PD1 inhibitor is an anti-PD1 antibody. Item 338. The method according to Item 337, wherein the anti-PD1 antibody is nivolumab. Item 339. The method according to Item 336, wherein the PD1 inhibitor is an anti-PDL1 antibody. Item 340. The method according to Item 339, wherein the anti-PDL1 antibody is atezolizumab. Item 341. The method according to any one of Items 329 to 332, wherein the checkpoint inhibitor comprises a CTLA4 inhibitor and a PD1 inhibitor. Item 342. The method according to Item 341, wherein the CTLA4 inhibitor is an anti-CTLA4 antibody. Item 343. The method according to Item 342, wherein the anti-CTLA4 antibody is ipilimumab. Item 344. The method according to Item 341, wherein the PD1 inhibitor is an anti-PD1 antibody. Item 345. The method according to Item 344, wherein the anti-PD1 antibody is nivolumab. Item 346. The method according to Item 341, wherein the PD1 inhibitor is an anti-PDL1 antibody. Item 347. The method according to Item 346, wherein the anti-PDL1 antibody is atezolizumab. Item 348. The method according to any one of Items 311 to 328, wherein the at least one additional therapy comprises administering a neoantigen vaccine. Item 349. The method according to Item 348, wherein the compound, antibody-drug conjugate or composition is administered before the administration of the neoantigen vaccine. Item 350. The method according to Item 348, wherein the compound, antibody-drug conjugate or composition is administered after the administration of the neoantigen vaccine. Item 351. The method according to Item 348, wherein the compound, antibody-drug conjugate or composition is administered simultaneously with the administration of the neoantigen vaccine. Item 352. The method according to any one of Items 348 to 351, wherein the administration of the compound, antibody-drug conjugate or composition is repeated at least once after the initial administration. Item 353. The method according to Item 352, wherein the amount of the compound, antibody-drug conjugate or composition for repeated administration is reduced compared to the amount for the initial administration. Item 354. The method according to any one of Items 348 to 353, wherein the neoantigen vaccine comprises at least one neoantigen peptide. Item 355. The method according to Item 354, wherein the length of the at least one neoantigen peptide is in the range of about 10 to about 35 amino acids. Item 356. The method according to Item 354 or Item 355, wherein the length of the at least one neoantigen peptide is in the range of about 15 to about 25 amino acids. Item 357. The method according to any one of Items 354 to 356, wherein the at least one neoantigen peptide comprises one or more neoantigen sequences. Item 358. The method according to item 357, wherein the neoantigen sequence is a neoantigen sequence specific to the subject. Item 359. The method according to item 357, wherein the neoantigen sequence is a universal neoantigen sequence. Item 360. The method according to item 358, wherein the neoantigen sequence is a personalized neoantigen vaccine for the subject. Item 361. The method according to item 360, wherein the neoantigen sequence has been identified by sequencing at least one neoantigen induced in the subject by administering an effective amount of the compound, antibody-drug conjugate or composition. Item 362. The method according to item 360 or item 361, wherein the neoantigen sequence is capable of binding to at least one HLA allele expressed in the subject. Item 363. The method according to item 359, wherein the neoantigen sequence is a universal neoantigen vaccine. Item 364. The method according to item 363, wherein the neoantigen sequence is capable of binding to at least one HLA allele expressed in at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40% or at least 45% of the subjects in the group of subjects suffering from the neoplastic disorder. Item 365. The method according to item 363 or item 364, wherein the neoantigen sequence is capable of eliciting a T cell response against tumors present in at least 1%, at least 5% or at least 10% of the group of subjects suffering from the neoplastic disorder. Item 366. The method according to any one of items 354 to 365, wherein the at least one neoantigen peptide comprises a neoantigen sequence induced by contacting neoplastic cells with an effective amount of the splicing regulator, antibody-drug conjugate or composition. Item 367. The method according to item 348, wherein the neoantigen vaccine comprises at least one neoantigen peptide and a pharmaceutically acceptable carrier. Item 368. The method according to item 367, wherein the at least one neoantigen peptide is linked to the pharmaceutically acceptable carrier. Item 369. The method according to item 367 or item 368, wherein the pharmaceutically acceptable carrier is selected from peptides, serum albumin, keyhole limpet hemocyanin, immunoglobulins, thyroglobulin, ovalbumin, toxoids or detoxified toxoid derivatives, cytokines and chemokines. Item 370. The method according to any one of items 367 to 369, wherein the neoantigen peptide and the pharmaceutically acceptable carrier are covalently linked via a linker. Item 371. The method according to any one of Items 367 to 369, wherein the neoantigen peptide and the pharmaceutically acceptable carrier are expressed in the form of a fusion protein. Item 372. The method according to Item 348, wherein the neoantigen vaccine comprises at least one neoantigen peptide and a pharmaceutically acceptable diluent. Item 373. The method according to Item 348, wherein the neoantigen vaccine comprises at least one neoantigen peptide and a pharmaceutically acceptable adjuvant. Item 374. The method according to Item 366, wherein the neoplastic cells are present in an in vitro cell culture. Item 375. The method according to Item 366 or Item 374, wherein the neoplastic cells are obtained from the subject. Item 376. The method according to Item 366, wherein the neoplastic cells are present in the subject. Item 377. The method according to any one of Items 348 to 353, wherein the neoantigen vaccine comprises at least one neoantigen mRNA. Item 378. The method according to Item 377, wherein the at least one neoantigen mRNA encodes one or more neoantigen sequences. Item 379. The method according to Item 378, wherein the neoantigen sequence is a neoantigen sequence specific to the subject. Item 380. The method according to Item 378, wherein the neoantigen sequence is a universal neoantigen sequence. Item 381. The method according to Item 379, wherein the neoantigen sequence is a personalized neoantigen vaccine for the subject. Item 382. The method according to Item 381, wherein the neoantigen sequence has been identified by sequencing at least one neoantigen induced in the subject by administering an effective amount of the compound, antibody-drug conjugate or composition. Item 383. The method according to Item 381 or Item 382, wherein the neoantigen sequence is capable of binding to at least one HLA allele expressed in the subject. Item 384. The method according to Item 380, wherein the neoantigen sequence is a universal neoantigen vaccine. Item 385. The method according to Item 384, wherein the neoantigen sequence is capable of binding to at least one HLA allele expressed in at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40% or at least 45% of the subjects in a group of subjects suffering from the neoplastic disorder. Item 386. The method according to item 384 or item 385, wherein the neoantigen sequence is capable of eliciting a T cell response against tumors present in at least 1%, at least 5%, or at least 10% of a group of subjects suffering from the neoplastic disorder. Item 387. The method according to any one of items 378 to 386, wherein the at least one neoantigen mRNA encodes a neoantigen sequence induced by contacting neoplastic cells with an effective amount of the compound, antibody-drug conjugate, or composition. Item 388. The method according to item 377, wherein the neoantigen vaccine comprises at least one neoantigen mRNA and a pharmaceutically acceptable carrier. Item 389. The method according to item 388, wherein the at least one neoantigen mRNA is linked to the pharmaceutically acceptable carrier. Item 390. The method according to item 388 or item 389, wherein the pharmaceutically acceptable carrier is selected from peptides, serum albumin, keyhole limpet hemocyanin, immunoglobulins, thyroglobulin, ovalbumin, toxoids or attenuated toxoid derivatives, cytokines, and chemokines. Item 391. The method according to item 377, wherein the neoantigen vaccine comprises at least one neoantigen mRNA and a pharmaceutically acceptable diluent. Item 392. The method according to item 377, wherein the neoantigen vaccine comprises at least one neoantigen mRNA and a pharmaceutically acceptable adjuvant. Item 393. The method according to any one of items 377 to 392, wherein the neoantigen mRNA is encapsulated by an encapsulant. Item 394. The method according to item 393, wherein the encapsulant is a liposome. Item 395. The method according to item 393, wherein the encapsulant is a nanoparticle. Item 396. The method according to item 387, wherein the neoplastic cells are present in an in vitro cell culture. Item 397. The method according to item 387 or item 396, wherein the neoplastic cells are obtained from the subject. Item 398. The method according to item 387, wherein the neoplastic cells are present in the subject. Item 399. The method according to any one of items 311 to 328, wherein the at least one additional therapy comprises administering a cytokine or cytokine analogue. Item 400. The method according to item 399, wherein the subject is intolerant, non-responsive, or poorly responsive to the cytokine or cytokine analogue when administered alone. Item 401. The method according to item 399 or item 400, wherein the cytokine or cytokine analogue comprises a T cell enhancer. Item 402. The method according to any one of Items 399 to 401, wherein the cytokine or cytokine analogue comprises IL-2, IL-10, IL-12, IL-15, IFNγ, and / or TNFα. Item 403. The method according to any one of Items 311 to 328, wherein the at least one additional therapy comprises administering engineered tumor-targeting T cells. Item 404. The method according to any one of Items 305 to 403, the method further comprising detecting one or more neoantigens and / or T cell responses in the subject after administering the compound, antibody-drug conjugate, or composition. Item 405. The method according to Item 404, the method further comprising, if one or more neoantigens and / or T cell responses are detected, continuing to administer the compound, antibody-drug conjugate, or composition. Item 406. The method according to Item 404 or Item 405, the method further comprising, if one or more neoantigens and / or T cell responses are detected, continuing to administer the compound, antibody-drug conjugate, or composition at a lower frequency and / or at a reduced dose. Item 407. The method according to any one of Items 404 to 406, wherein detecting one or more neoantigens and / or T cell responses in the subject indicates the efficacy of treatment with the compound, antibody-drug conjugate, or composition. Item 408. The method according to any one of Items 305 to 407, wherein the subject has a non-synonymous mutation burden of about 150 mutations or fewer. Item 409. The method according to any one of Items 305 to 408, wherein the subject has a non-synonymous mutation burden of about 100 mutations or fewer. Item 410. The method according to any one of Items 305 to 409, wherein the subject has a non-synonymous mutation burden of about 50 mutations or fewer. Item 411. The method according to any one of Items 305 to 410, wherein the neoplastic disorder is a hematological malignancy or a solid tumor. Item 412. The method according to Item 411, wherein the hematological malignancy is selected from B cell malignancies, leukemias, lymphomas, and myelomas. Item 413. The method according to Item 411 or Item 412, wherein the hematological malignancy is selected from acute myeloid leukemia and multiple myeloma. Item 414. The method according to Item 411, wherein the solid tumor is selected from breast cancer, gastric cancer, prostate cancer, ovarian cancer, lung cancer, uterine cancer, salivary duct carcinoma, melanoma, colorectal cancer, cervical cancer, pancreatic cancer, renal cancer, colorectal carcinoma, and esophageal cancer. Item 415. A method for treating a subject having or suspected of having a neoplastic disorder, the method comprising: (a) administering to the subject an effective amount of an antibody-drug conjugate as described in any one of Items 1 to 189, a compound as described in any one of Items 190 to 219, or a composition as described in any one of Items 220 to 224, wherein administration of the compound, antibody-drug conjugate or composition induces at least one neoantigen and / or T cell response; (b) detecting one or more neoantigens and / or T cell responses in the subject after administering the compound, antibody-drug conjugate or composition; and (c) if one or more neoantigens and / or T cell responses are detected, continuing to administer the compound, antibody-drug conjugate or composition. Item 416. The method according to Item 415, wherein detecting one or more neoantigens and / or T cell responses in the subject indicates the efficacy of treatment with the compound, antibody-drug conjugate or composition. Item 417. A method for treating a subject having or suspected of having a neoplastic disorder, the method comprising administering to the subject an effective amount of an antibody-drug conjugate as described in any one of Items 1 to 189, a compound as described in any one of Items 190 to 219, or a composition as described in any one of Items 220 to 224; and at least one additional therapy. Item 418. The method according to Item 417, wherein the at least one additional therapy comprises at least one, at least two, at least three, at least four or at least five additional therapies. Item 419. The method according to Item 417 or Item 418, wherein administration of the compound, antibody-drug conjugate or composition induces at least one neoantigen and / or T cell response. Item 420. The method according to any one of Items 417 to 419, wherein the amount of the compound, antibody-drug conjugate or composition and / or the at least one additional therapy administered is reduced by 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75% or 90% compared to the standard dose of the compound, antibody-drug conjugate or composition and / or the at least one additional therapy. Item 421. The method according to any one of Items 417 to 420, wherein the compound, antibody-drug conjugate or composition and / or the at least one additional therapy is administered at a frequency that is at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75% or 90% lower than the standard dosing regimen of the compound, antibody-drug conjugate or composition and / or the at least one additional therapy. Item 422. The method according to any one of Items 417 to 421, wherein the amount and / or dosage of the compound, antibody-drug conjugate or composition and / or the at least one additional therapy causes lower systemic toxicity and / or improved drug resistance. Item 423. The method according to any one of Items 417 to 422, wherein the administration of the compound, antibody-drug conjugate or composition begins before the administration of the at least one additional therapy. Item 424. The method according to any one of Items 417 to 422, wherein the administration of the splicing regulator, antibody-drug conjugate, or composition is initiated after the administration of the at least one additional therapy. Item 425. The method according to any one of Items 417 to 422, wherein the administration of the compound, antibody-drug conjugate or composition begins simultaneously with the administration of the at least one additional therapy. Item 426. The method according to any one of Items 417 to 425, wherein the administration of the compound, antibody-drug conjugate or composition is repeated at least once after the initial administration. Item 427. The method according to Item 426, wherein the amount of the compound, antibody-drug conjugate or composition for repeated administration is reduced compared to the amount for the initial administration. Item 428. The method according to Item 426 or Item 427, wherein the amount of the compound, antibody-drug conjugate or composition for repeated administration is reduced compared to the standard dose of the compound, antibody-drug conjugate or composition. Item 429. The method according to any one of Items 426 to 428, wherein the amount of the compound, antibody-drug conjugate or composition for repeated administration is reduced by 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75% or 90% compared to the standard dose of the compound, antibody-drug conjugate or composition. Item 430. The method according to any one of Items 417 to 429, wherein the administration of the at least one additional therapy is repeated at least once after the initial administration. Item 431. The method according to Item 430, wherein the amount of the at least one additional therapy for repeated administration is reduced compared to the amount for the initial administration. Item 432. The method according to Item 430 or Item 431, wherein the amount of the at least one additional therapy for repeated administration is reduced compared to the standard dose of the at least one additional therapy. Item 433. The method according to any one of Items 430 to 432, wherein the amount of the at least one additional therapy for repeated administration is reduced by 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75% or 90% compared to the standard dose of the at least one additional therapy. Item 434. The method according to any one of Items 426 to 433, wherein the repeated administration of the compound, antibody-drug conjugate or composition is carried out simultaneously with the repeated administration of the at least one additional therapy. Item 435. The method according to any one of Items 426 to 433, wherein the repeated administration of the compound, antibody-drug conjugate or composition is carried out sequentially or staggered with the repeated administration of the at least one additional therapy. Item 436. The method according to any one of Items 417 to 435, wherein the at least one additional therapy comprises administering a checkpoint inhibitor. Item 437. The method according to Item 436, wherein the subject is intolerant, non-responsive or poorly responsive to the checkpoint inhibitor when administered alone. Item 438. The method according to Item 436 or Item 437, wherein the checkpoint inhibitor targets CTLA4, PD1, PDL1, OX40, CD40, GITR, LAG3, TIM3 and / or KIR. Item 439. The method according to any one of Items 436 to 438, wherein the checkpoint inhibitor targets CTLA4, OX40, CD40 and / or GITR. Item 440. The method according to any one of Items 436 to 439, wherein the checkpoint inhibitor comprises a cytotoxic T lymphocyte-associated antigen 4 pathway (CTLA4) inhibitor. Item 441. The method according to Item 440, wherein the CTLA4 inhibitor is an anti-CTLA4 antibody. Item 442. The method according to Item 441, wherein the anti-CTLA4 antibody is ipilimumab. Item 443. The method according to any one of Items 436 to 439, wherein the checkpoint inhibitor comprises a programmed death-1 pathway (PD1) inhibitor. Item 444. The method according to Item 443, wherein the PD1 inhibitor is an anti-PD1 antibody. Item 445. The method according to Item 444, wherein the anti-PD1 antibody is nivolumab. Item 446. The method according to Item 443, wherein the PD1 inhibitor is an anti-PDL1 antibody. Item 447. The method according to Item 446, wherein the anti-PDL1 antibody is atezolizumab. Item 448. The method according to any one of Items 436 to 439, wherein the checkpoint inhibitor comprises a CTLA4 inhibitor and a PD1 inhibitor. Item 449. The method according to Item 448, wherein the CTLA4 inhibitor is an anti-CTLA4 antibody. Item 450. The method according to Item 449, wherein the anti-CTLA4 antibody is ipilimumab. Item 451. The method according to Item 448, wherein the PD1 inhibitor is an anti-PD1 antibody. Item 452. The method according to Item 451, wherein the anti-PD1 antibody is nivolumab. Item 453. The method according to Item 448, wherein the PD1 inhibitor is an anti-PDL1 antibody. Item 454. The method according to Item 453, wherein the anti-PDL1 antibody is atezolizumab. Item 455. The method according to any one of Items 417 to 435, wherein the at least one additional therapy comprises administering a neoantigen vaccine. Item 456. The method according to Item 455, wherein the compound, antibody-drug conjugate or composition is administered before the administration of the neoantigen vaccine. Item 457. The method according to Item 455, wherein the compound, antibody-drug conjugate or composition is administered after the administration of the neoantigen vaccine. Item 458. The method according to Item 455, wherein the compound, antibody-drug conjugate or composition is administered simultaneously with the administration of the neoantigen vaccine. Item 459. The method according to any one of Items 455 to 458, wherein the administration of the compound, antibody-drug conjugate or composition is repeated at least once after the initial administration. Item 460. The method according to Item 459, wherein the amount of the compound, antibody-drug conjugate or composition for repeated administration is reduced compared to the amount for the initial administration. Item 461. The method according to any one of Items 455 to 460, wherein the neoantigen vaccine comprises at least one neoantigen peptide. Item 462. The method according to Item 461, wherein the length of the at least one neoantigen peptide ranges from about 10 to about 35 amino acids. Item 463. The method according to Item 461 or Item 462, wherein the length of the at least one neoantigen peptide ranges from about 15 to about 25 amino acids. Item 464. The method according to any one of Items 461 to 463, wherein the at least one neoantigen peptide comprises one or more neoantigen sequences. Item 465. The method according to item 464, wherein the neoantigen sequence is a neoantigen sequence specific to the subject. Item 466. The method according to item 464, wherein the neoantigen sequence is a universal neoantigen sequence. Item 467. The method according to item 465, wherein the neoantigen sequence is a personalized neoantigen vaccine for the subject. Item 468. The method according to item 467, wherein the neoantigen sequence has been identified by sequencing at least one neoantigen induced in the subject by administering an effective amount of the compound, antibody-drug conjugate or composition. Item 469. The method according to item 467 or item 468, wherein the neoantigen sequence is capable of binding to at least one HLA allele expressed in the subject. Item 470. The method according to item 466, wherein the neoantigen sequence is a universal neoantigen vaccine. Item 471. The method according to item 470, wherein the neoantigen sequence is capable of binding to at least one HLA allele expressed in at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40% or at least 45% of the subjects in the group of subjects suffering from the neoplastic disorder. Item 472. The method according to item 470 or item 471, wherein the neoantigen sequence is capable of eliciting a T cell response against tumors present in at least 1%, at least 5% or at least 10% of the group of subjects suffering from the neoplastic disorder. Item 473. The method according to any one of items 464 to 472, wherein the at least one neoantigen peptide comprises a neoantigen sequence induced by contacting neoplastic cells with an effective amount of the compound, antibody-drug conjugate or composition. Item 474. The method according to item 455, wherein the neoantigen vaccine comprises at least one neoantigen peptide and a pharmaceutically acceptable carrier. Item 475. The method according to item 474, wherein the at least one neoantigen peptide is linked to the pharmaceutically acceptable carrier. Item 476. The method according to item 474 or item 475, wherein the pharmaceutically acceptable carrier is selected from peptides, serum albumin, keyhole limpet hemocyanin, immunoglobulins, thyroglobulin, ovalbumin, toxoids or detoxified toxoid derivatives, cytokines and chemokines. Item 477. The method according to any one of items 474 to 476, wherein the neoantigen peptide and the pharmaceutically acceptable carrier are covalently linked via a linker. Item 478. The method according to any one of Items 474 to 476, wherein the neoantigen peptide and the pharmaceutically acceptable carrier are expressed in the form of a fusion protein. Item 479. The method according to Item 455, wherein the neoantigen vaccine comprises at least one neoantigen peptide and a pharmaceutically acceptable diluent. Item 480. The method according to Item 455, wherein the neoantigen vaccine comprises at least one neoantigen peptide and a pharmaceutically acceptable adjuvant. Item 481. The method according to Item 473, wherein the neoplastic cells are present in an in vitro cell culture. Item 482. The method according to Item 473 or Item 481, wherein the neoplastic cells are obtained from the subject. Item 483. The method according to Item 473, wherein the neoplastic cells are present in the subject. Item 484. The method according to any one of Items 455 to 460, wherein the neoantigen vaccine comprises at least one neoantigen mRNA. Item 485. The method according to Item 484, wherein the at least one neoantigen mRNA encodes one or more neoantigen sequences. Item 486. The method according to Item 485, wherein the neoantigen sequence is a neoantigen sequence specific to the subject. Item 487. The method according to Item 485, wherein the neoantigen sequence is a universal neoantigen sequence. Item 488. The method according to Item 486, wherein the neoantigen sequence is a personalized neoantigen vaccine for the subject. Item 489. The method according to Item 488, wherein the neoantigen sequence has been identified by sequencing at least one neoantigen induced in the subject by administering an effective amount of the compound, antibody-drug conjugate or composition. Item 490. The method according to Item 488 or Item 489, wherein the neoantigen sequence is capable of binding to at least one HLA allele expressed in the subject. Item 491. The method according to Item 487, wherein the neoantigen sequence is a universal neoantigen vaccine. Item 492. The method according to Item 491, wherein the neoantigen sequence is capable of binding to at least one HLA allele expressed in at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40% or at least 45% of the subjects in the group of subjects suffering from the neoplastic disorder. Item 493. The method according to item 491 or item 492, wherein the neoantigen sequence is capable of eliciting a T cell response against tumors present in at least 1%, at least 5%, or at least 10% of a population of subjects having the neoplastic disorder. Item 494. The method according to any one of items 484 to 493, wherein the at least one neoantigen mRNA encodes a neoantigen sequence induced by contacting neoplastic cells with an effective amount of the compound, antibody-drug conjugate, or composition. Item 495. The method according to item 484, wherein the neoantigen vaccine comprises at least one neoantigen mRNA and a pharmaceutically acceptable carrier. Item 496. The method according to item 495, wherein the at least one neoantigen mRNA is linked to the pharmaceutically acceptable carrier. Item 497. The method according to item 495 or item 496, wherein the pharmaceutically acceptable carrier is selected from peptides, serum albumin, keyhole limpet hemocyanin, immunoglobulins, thyroglobulin, ovalbumin, toxoids or attenuated toxoid derivatives, cytokines, and chemokines. Item 498. The method according to item 484, wherein the neoantigen vaccine comprises at least one neoantigen mRNA and a pharmaceutically acceptable diluent. Item 499. The method according to item 484, wherein the neoantigen vaccine comprises at least one neoantigen mRNA and a pharmaceutically acceptable adjuvant. Item 500. The method according to any one of items 484 to 499, wherein the neoantigen mRNA is encapsulated by an encapsulant. Item 501. The method according to item 500, wherein the encapsulant is a liposome. Item 502. The method according to item 500, wherein the encapsulant is a nanoparticle. Item 503. The method according to item 494, wherein the neoplastic cells are present in an in vitro cell culture. Item 504. The method according to item 494 or item 503, wherein the neoplastic cells are obtained from the subject. Item 505. The method according to item 494, wherein the neoplastic cells are present in the subject. Item 506. The method according to any one of items 417 to 435, wherein the at least one additional therapy comprises administering a cytokine or cytokine analogue. Item 507. The method according to item 506, wherein the subject is intolerant, non-responsive, or poorly responsive to the cytokine or cytokine analogue when administered alone. Item 508. The method according to item 506 or item 507, wherein the cytokine or cytokine analogue comprises a T cell enhancer. Item 509. The method according to any one of Items 506 to 508, wherein the cytokine or cytokine analogue comprises IL-2, IL-10, IL-12, IL-15, IFNγ and / or TNFα. Item 510. The method according to any one of Items 417 to 435, wherein the at least one additional therapy comprises administering engineered tumor-targeting T cells. Item 511. The method according to any one of Items 417 to 510, wherein the subject has a non-synonymous mutation burden of about 150 mutations or less. Item 512. The method according to any one of Items 417 to 511, wherein the subject has a non-synonymous mutation burden of about 100 mutations or less. Item 513. The method according to any one of Items 417 to 512, wherein the subject has a non-synonymous mutation burden of about 50 mutations or less. Item 514. The method according to any one of Items 417 to 513, wherein the neoplastic disorder is a hematological malignancy or a solid tumor. Item 515. The method according to Item 514, wherein the hematological malignancy is selected from B cell malignancies, leukemia, lymphoma, and myeloma. Item 516. The method according to Item 514 or Item 515, wherein the hematological malignancy is selected from acute myeloid leukemia and multiple myeloma. Item 517. The method according to Item 514, wherein the solid tumor is selected from breast cancer, gastric cancer, prostate cancer, ovarian cancer, lung cancer, uterine cancer, salivary duct carcinoma, melanoma, colorectal cancer, cervical cancer, pancreatic cancer, kidney cancer, colorectal carcinoma, and esophageal cancer. Item 518. A method of identifying at least one neoantigen, the method comprising: (a) contacting neoplastic cells with an effective amount of an antibody-drug conjugate according to any one of Items 1 to 189, a compound according to any one of Items 190 to 219, or a composition according to any one of Items 220 to 224; (b) detecting at least one alternatively spliced mRNA transcript after contacting the neoplastic cells with the compound, antibody-drug conjugate, or composition; (c) predicting the translation of the at least one alternatively spliced mRNA transcript into at least one peptide; and (d) comparing the at least one peptide with a reference proteome, wherein if the at least one peptide does not match any peptide in the reference proteome, at least one neoantigen is identified. Item 519. The method according to Item 518, wherein detecting at least one alternatively spliced mRNA transcript comprises RNAseq. Item 520. The method according to item 518 or item 519, wherein predicting the translation of the at least one alternatively spliced mRNA transcript comprises quantifying a change in the percent spliced in (dPSI) value of the at least one transcript. Item 521. The method according to any one of items 518 to 520, wherein predicting the translation of the at least one alternatively spliced mRNA transcript comprises RiboSeq and / or ribosome profiling. Item 522. The method according to any one of items 518 to 521, wherein the method further comprises evaluating the at least one peptide for predicted major histocompatibility complex (MHC) binding. Item 523. The method according to item 522, wherein the predicted MHC binding is determined by measuring the binding strength by predicting the raw affinity of the at least one peptide. Item 524. The method according to item 523, wherein a raw affinity of about 500 nM or higher for predicting the binding strength indicates MHC binding. Item 525. The method according to any one of items 522 to 524, wherein the predicted MHC binding is determined by: identifying the distribution of the predicted binding strengths of a series of random peptides; and comparing the predicted binding strength of the at least one peptide with the distribution. Item 526. The method according to item 525, wherein the predicted binding strength in the top 2% of the distribution indicates weak MHC binding. Item 527. The method according to item 525, wherein the predicted binding strength in the top 0.5% of the distribution indicates strong MHC binding. Item 528. The method according to any one of items 518 to 527, wherein the neoplastic cells are present in an in vitro cell culture. Item 529. The method according to item 528, wherein the neoplastic cells are obtained from the subject. Item 530. The method according to any one of items 518 to 527, wherein the neoplastic cells are present in the subject. Item 531. The method according to any one of items 518 to 530, the method further comprising contacting one or more additional neoplastic cells to identify at least one common neoantigen. Item 532. A method of identifying at least one neoantigen, the method comprising: (a) contacting neoplastic cells with an effective amount of an antibody-drug conjugate according to any one of items 1 to 189, a compound according to any one of items 190 to 219, or a composition according to any one of items 220 to 224; (b) after contacting the neoplastic cells with the compound, antibody-drug conjugate, or composition, detecting at least one peptide comprising a potential neoantigen sequence; and (c) Compare the at least one peptide with a reference proteome, and identify at least one neoantigen if the at least one peptide does not match any peptide in the reference proteome. Item 533. The method according to item 532, wherein the method further comprises evaluating the at least one peptide for predicted major histocompatibility complex (MHC) binding. Item 534. The method according to item 533, wherein the predicted MHC binding is determined by measuring the raw affinity of the at least one peptide to predict the binding strength. Item 535. The method according to item 534, wherein a raw affinity of about 500 nM or higher to predict the binding strength indicates MHC binding. Item 536. The method according to any one of items 533 to 535, wherein the predicted MHC binding is determined by: identifying the distribution of the predicted binding strengths of a series of random peptides; and comparing the predicted binding strength of the at least one peptide with the distribution. Item 537. The method according to item 536, wherein the predicted binding strength in the top 2% of the distribution indicates weak MHC binding. Item 538. The method according to item 536, wherein the predicted binding strength in the top 0.5% of the distribution indicates strong MHC binding. Item 539. The method according to any one of items 532 to 538, wherein the neoplastic cells are present in an in vitro cell culture. Item 540. The method according to item 539, wherein the neoplastic cells are obtained from the subject. Item 541. The method according to any one of items 532 to 538, wherein the neoplastic cells are present in the subject. Item 542. The method according to any one of items 532 to 541, the method further comprising contacting one or more additional neoplastic cells to identify at least one universal neoantigen. Item 543. A method of manufacturing a neoantigen vaccine, the method comprising: (a) identifying at least one neoantigen using the method according to any one of items 518 to 542; and (b) formulating the at least one neoantigen together with a pharmaceutically acceptable carrier, diluent or adjuvant. Item 544. The method according to item 543, wherein the at least one neoantigen is linked to the pharmaceutically acceptable carrier. Item 545. The method according to item 544, wherein the pharmaceutically acceptable carrier is selected from peptides, serum albumin, keyhole limpet hemocyanin, immunoglobulins, thyroglobulin, ovalbumin, toxoids or attenuated toxoid derivatives, cytokines and chemokines. Item 546. A method of treating a subject having or suspected of having a neoplastic disorder, the method comprising: (a) administering to the subject an effective amount of an antibody-drug conjugate as described in any one of Items 1 to 189, a compound as described in any one of Items 190 to 219, or a composition as described in any one of Items 220 to 224; (b) detecting one or more neoantigens in the subject after administering the compound, antibody-drug conjugate, or composition; (c) comparing the one or more neoantigens with a panel of common neoantigens; and (d) administering to the subject a common neoantigen vaccine comprising at least one common neoantigen present in the subject. Item 547. The method according to Item 546, wherein the common neoantigen vaccine is administered alone or in combination with at least one additional therapy. Item 548. The method according to Item 547, wherein the at least one additional therapy comprises at least one, at least two, at least three, at least four, or at least five additional therapies. Item 549. The method according to Item 547 or Item 548, wherein the at least one additional therapy comprises repeated administration of the compound, antibody-drug conjugate, or composition. Item 550. The method according to Item 549, wherein the repeated administration of the compound, antibody-drug conjugate, or composition is initiated before the administration of the common neoantigen vaccine. Item 551. The method according to Item 549, wherein the repeated administration of the compound, antibody-drug conjugate, or composition is initiated after the administration of the common neoantigen vaccine. Item 552. The method according to Item 549, wherein the repeated administration of the compound, antibody-drug conjugate, or composition is initiated simultaneously with the administration of the common neoantigen vaccine. Item 553. The method according to any one of Items 549 to 552, wherein the amount of the compound, antibody-drug conjugate, or composition for repeated administration is reduced compared to the amount used for the initial administration. Item 554. The method according to any one of Items 549 to 553, wherein the amount of the compound, antibody-drug conjugate, or composition for repeated administration is reduced compared to the standard dose of the compound, antibody-drug conjugate, or composition. Item 555. The method according to any one of Items 549 to 554, wherein the amount of the compound, antibody-drug conjugate, or composition for repeated administration is reduced by 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75%, or 90% compared to the standard dose of the compound, antibody-drug conjugate, or composition. Item 556. The method according to any one of Items 547 to 555, wherein the at least one additional therapy comprises administering a checkpoint inhibitor. Item 557. The method according to Item 556, wherein the administration of the checkpoint inhibitor is initiated before the administration of the universal neoantigen vaccine and / or the repeated administration of the compound, antibody-drug conjugate or composition. Item 558. The method according to Item 556, wherein the administration of the checkpoint inhibitor is started after the administration of the universal neoantigen vaccine and / or the repetition of the compound, antibody-drug conjugate or composition. Item 559. The method according to Item 556, wherein the administration of the checkpoint inhibitor is started simultaneously with the administration of the universal neoantigen vaccine and / or the repeated administration of the compound, antibody-drug conjugate or composition. Item 560. The method according to any one of Items 556 to 559, wherein the administration of the checkpoint inhibitor is repeated at least once after the initial administration. Item 561. The method according to Item 560, wherein the amount of the checkpoint inhibitor for repeated administration is reduced compared to the amount for the initial administration. Item 562. The method according to Item 560 or Item 561, wherein the amount of the checkpoint inhibitor for repeated administration is reduced compared to the standard dose of the checkpoint inhibitor. Item 563. The method according to any one of Items 560 to 562, wherein the amount of the checkpoint inhibitor for repeated administration is reduced by 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75% or 90% compared to the standard dose of the checkpoint inhibitor. Item 564. The method according to any one of Items 556 to 563, wherein the subject is intolerant, non-responsive or poorly responsive to the checkpoint inhibitor when administered alone. Item 565. The method according to any one of Items 556 to 564, wherein the checkpoint inhibitor targets CTLA4, PD1, PDL1, OX40, CD40, GITR, LAG3, TIM3 and / or KIR. Item 566. The method according to any one of Items 556 to 565, wherein the checkpoint inhibitor targets CTLA4, OX40, CD40 and / or GITR. Item 567. The method according to any one of Items 556 to 566, wherein the checkpoint inhibitor comprises a cytotoxic T lymphocyte-associated antigen 4 pathway (CTLA4) inhibitor. Item 568. The method according to Item 567, wherein the CTLA4 inhibitor is an anti-CTLA4 antibody. Item 569. The method according to item 568, wherein the anti-CTLA4 antibody is ipilimumab. Item 570. The method according to any one of items 556 to 566, wherein the checkpoint inhibitor comprises a programmed death-1 pathway (PD1) inhibitor. Item 571. The method according to item 570, wherein the PD1 inhibitor is an anti-PD1 antibody. Item 572. The method according to item 571, wherein the anti-PD1 antibody is nivolumab. Item 573. The method according to item 570, wherein the PD1 inhibitor is an anti-PDL1 antibody. Item 574. The method according to item 573, wherein the anti-PDL1 antibody is atezolizumab. Item 575. The method according to any one of items 556 to 566, wherein the checkpoint inhibitor comprises a CTLA4 inhibitor and a PD1 inhibitor. Item 576. The method according to item 575, wherein the CTLA4 inhibitor is an anti-CTLA4 antibody. Item 577. The method according to item 576, wherein the anti-CTLA4 antibody is ipilimumab. Item 578. The method according to item 575, wherein the PD1 inhibitor is an anti-PD1 antibody. Item 579. The method according to item 578, wherein the anti-PD1 antibody is nivolumab. Item 580. The method according to item 575, wherein the PD1 inhibitor is an anti-PDL1 antibody. Item 581. The method according to item 580, wherein the anti-PDL1 antibody is atezolizumab. Item 582. The method according to any one of items 546 to 581, wherein the universal neoantigen vaccine comprises at least one neoantigen peptide. Item 583. The method according to item 582, wherein the length of the at least one neoantigen peptide ranges from about 10 to about 35 amino acids. Item 584. The method according to item 582 or item 583, wherein the length of the at least one neoantigen peptide ranges from about 15 to about 25 amino acids. Item 585. The method according to any one of items 582 to 584, wherein the at least one neoantigen peptide comprises one or more universal neoantigen sequences. Item 586. The method according to item 585, wherein the universal neoantigen sequence is capable of binding to at least one HLA allele expressed in at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40% or at least 45% of the subjects in the group of subjects suffering from the neoplastic disorder. Item 587. The method according to item 585 or item 586, wherein the universal neoantigen sequence is capable of eliciting a T cell response against tumors present in at least 1%, at least 5% or at least 10% of the group of subjects suffering from the neoplastic disorder. Item 588. The method according to item 582, wherein the universal neoantigen vaccine comprises at least one neoantigen peptide and a pharmaceutically acceptable carrier. Item 589. The method according to item 588, wherein the at least one neoantigen peptide is linked to the pharmaceutically acceptable carrier. Item 590. The method according to item 588 or item 589, wherein the pharmaceutically acceptable carrier is selected from peptides, serum albumin, keyhole limpet hemocyanin, immunoglobulins, thyroglobulin, ovalbumin, toxoids or attenuated toxoid derivatives, cytokines and chemokines. Item 591. The method according to any one of items 588 to 590, wherein the neoantigen peptide and the pharmaceutically acceptable carrier are covalently linked via a linker. Item 592. The method according to any one of items 588 to 590, wherein the neoantigen peptide and the pharmaceutically acceptable carrier are expressed as a fusion protein. Item 593. The method according to item 582, wherein the universal neoantigen vaccine comprises at least one neoantigen peptide and a pharmaceutically acceptable diluent. Item 594. The method according to item 582, wherein the universal neoantigen vaccine comprises at least one neoantigen peptide and a pharmaceutically acceptable adjuvant. Item 595. The method according to any one of items 546 to 581, wherein the universal neoantigen vaccine comprises at least one neoantigen mRNA. Item 596. The method according to item 595, wherein the at least one neoantigen mRNA encodes one or more universal neoantigen sequences. Item 597. The method according to item 596, wherein the universal neoantigen sequence is capable of binding to at least one HLA allele expressed in at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40% or at least 45% of the subjects in the group of subjects suffering from the neoplastic disorder. Item 598. The method according to item 596 or item 597, wherein the universal neoantigen sequence is capable of eliciting a T cell response against tumors present in at least 1%, at least 5%, or at least 10% of a group of subjects suffering from the neoplastic disorder. Item 599. The method according to item 595, wherein the universal neoantigen vaccine comprises at least one neoantigen mRNA and a pharmaceutically acceptable carrier. Item 600. The method according to item 599, wherein the at least one neoantigen mRNA is linked to the pharmaceutically acceptable carrier. Item 601. The method according to item 599 or item 600, wherein the pharmaceutically acceptable carrier is selected from peptides, serum albumin, keyhole limpet hemocyanin, immunoglobulins, thyroglobulin, ovalbumin, toxoids or attenuated toxoid derivatives, cytokines, and chemokines. Item 602. The method according to item 595, wherein the universal neoantigen vaccine comprises at least one neoantigen mRNA and a pharmaceutically acceptable diluent. Item 603. The method according to item 595, wherein the universal neoantigen vaccine comprises at least one neoantigen mRNA and a pharmaceutically acceptable adjuvant. Item 604. The method according to any one of items 595 to 603, wherein the neoantigen mRNA is encapsulated by an encapsulant. Item 605. The method according to item 604, wherein the encapsulant is a liposome. Item 606. The method according to item 604, wherein the encapsulant is a nanoparticle. Item 607. The method according to any one of items 546 to 606, wherein the subject has a non-synonymous mutation burden of about 150 mutations or fewer. Item 608. The method according to any one of items 546 to 607, wherein the subject has a non-synonymous mutation burden of about 100 mutations or fewer. Item 609. The method according to any one of items 546 to 608, wherein the subject has a non-synonymous mutation burden of about 50 mutations or fewer. Item 610. The method according to any one of items 546 to 609, wherein the neoplastic disorder is a hematological malignancy or a solid tumor. Item 611. The method according to item 610, wherein the hematological malignancy is selected from B cell malignancies, leukemias, lymphomas, and myelomas. Item 612. The method according to item 610 or item 611, wherein the hematological malignancy is selected from acute myeloid leukemia and multiple myeloma. Item 613. The method according to item 610, wherein the solid tumor is selected from breast cancer, gastric cancer, prostate cancer, ovarian cancer, lung cancer, uterine cancer, salivary duct carcinoma, melanoma, colorectal cancer, cervical cancer, pancreatic cancer, renal cancer, colorectal carcinoma, and esophageal cancer. Item 614. A neoantigen vaccine, the neoantigen vaccine comprising at least one neoantigen peptide, wherein the at least one neoantigen peptide comprises a neoantigen sequence induced by contacting neoplastic cells with an antibody-drug conjugate as described in any one of items 1 to 189, a compound as described in any one of items 190 to 219, or a composition as described in any one of items 220 to 224 in an effective amount. Item 615. The neoantigen vaccine according to item 614, wherein the length of the at least one neoantigen peptide ranges from about 10 to about 35 amino acids. Item 616. The neoantigen vaccine according to item 614 or item 615, wherein the length of the at least one neoantigen peptide ranges from about 15 to about 25 amino acids. Item 617. The neoantigen vaccine according to any one of items 614 to 616, the neoantigen vaccine further comprising a pharmaceutically acceptable carrier. Item 618. The neoantigen vaccine according to item 617, wherein the at least one neoantigen peptide is linked to the pharmaceutically acceptable carrier. Item 619. The neoantigen vaccine according to item 617 or item 618, wherein the pharmaceutically acceptable carrier is selected from peptides, serum albumin, keyhole limpet hemocyanin, immunoglobulins, thyroglobulin, ovalbumin, toxoids or attenuated toxoid derivatives, cytokines, and chemokines. Item 620. The neoantigen vaccine according to any one of items 617 to 619, wherein the neoantigen peptide and the pharmaceutically acceptable carrier are covalently linked via a linker. Item 621. The neoantigen vaccine according to any one of items 617 to 619, wherein the neoantigen peptide and the pharmaceutically acceptable carrier are expressed as a fusion protein. Item 622. The neoantigen vaccine according to any one of items 614 to 616, the neoantigen vaccine further comprising a pharmaceutically acceptable diluent. Item 623. The neoantigen vaccine according to any one of items 614 to 616, the neoantigen vaccine further comprising a pharmaceutically acceptable adjuvant. Item 624. The neoantigen vaccine according to any one of items 614 to 623, wherein the neoplastic cells are present in an in vitro cell culture. Item 625. The neoantigen vaccine according to any one of items 614 to 624, wherein the neoplastic cells are obtained from a subject. Item 626. The neoantigen vaccine according to any one of Items 614 to 623, wherein the neoplastic cells are present in a subject. Item 627. A neoantigen vaccine comprising at least one neoantigen mRNA, wherein the at least one neoantigen mRNA encodes a neoantigen sequence induced by contacting neoplastic cells with an antibody-drug conjugate according to any one of Items 1 to 189, a compound according to any one of Items 190 to 219, or a composition according to any one of Items 220 to 224 in an effective amount. Item 628. The neoantigen vaccine according to Item 627, further comprising a pharmaceutically acceptable carrier. Item 629. The neoantigen vaccine according to Item 628, wherein the at least one neoantigen mRNA is linked to the pharmaceutically acceptable carrier. Item 630. The neoantigen vaccine according to Item 628 or Item 629, wherein the pharmaceutically acceptable carrier is selected from peptides, serum albumin, keyhole limpet hemocyanin, immunoglobulins, thyroglobulin, ovalbumin, toxoids or attenuated toxoid derivatives, cytokines, and chemokines. Item 631. The neoantigen vaccine according to Item 627, further comprising a pharmaceutically acceptable diluent. Item 632. The neoantigen vaccine according to Item 627, further comprising a pharmaceutically acceptable adjuvant. Item 633. The neoantigen vaccine according to any one of Items 627 to 632, wherein the neoantigen mRNA is encapsulated by an encapsulant. Item 634. The neoantigen vaccine according to Item 633, wherein the encapsulant is a liposome. Item 635. The neoantigen vaccine according to Item 633, wherein the encapsulant is a nanoparticle. Item 636. The neoantigen vaccine according to any one of Items 627 to 635, wherein the neoplastic cells are present in an in vitro cell culture. Item 637. The neoantigen vaccine according to any one of Items 627 to 636, wherein the neoplastic cells are obtained from a subject. Item 638. The neoantigen vaccine according to any one of Items 627 to 635, wherein the neoplastic cells are present in a subject. Item 639. A method for treating a subject having or suspected of having a neoplastic disorder, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of Items 190 to 219 or a pharmaceutical composition according to Item 220. Item 640. A method for reducing or inhibiting tumor growth in a subject having or suspected of having a neoplastic disorder, the method comprising administering to the subject a therapeutically effective amount of a compound as described in any one of Items 190 to 219 or a pharmaceutical composition as described in Item 220. Item 641. A compound selected from: and its pharmaceutically acceptable salts, wherein L is a linker covalently linked to the antibody. Item 642. The compound according to Item 641, wherein the compound is or its pharmaceutically acceptable salt. Item 643. The compound according to Item 641, wherein the compound is or its pharmaceutically acceptable salt. Item 644. The compound according to Item 641, wherein the compound is or its pharmaceutically acceptable salt. Item 645. The compound according to Item 641, wherein the compound is or its pharmaceutically acceptable salt. Item 646. The compound according to Item 641, wherein the compound is or its pharmaceutically acceptable salt. Item 647. The compound according to Item 641, wherein the compound is or its pharmaceutically acceptable salt. Item 648. The compound according to Item 641, wherein the compound is or its pharmaceutically acceptable salt. Item 649. The compound according to Item 641, wherein the compound is or its pharmaceutically acceptable salt. Item 650. The compound according to Item 641, wherein the compound is or its pharmaceutically acceptable salt. Item 651. The compound according to Item 641, wherein the compound is or a pharmaceutically acceptable salt thereof. Item 652. The compound according to Item 641, wherein the compound is or a pharmaceutically acceptable salt thereof. Item 653. The compound according to Item 641, wherein the compound is or a pharmaceutically acceptable salt thereof. Item 654. The compound according to Item 641, wherein the compound is or a pharmaceutically acceptable salt thereof. Item 655. The compound according to Item 641, wherein the compound is or a pharmaceutically acceptable salt thereof. Item 656. The compound according to Item 641, wherein the compound is or a pharmaceutically acceptable salt thereof. Item 657. The compound according to Item 641, wherein the compound is or a pharmaceutically acceptable salt thereof. Item 658. The compound according to Item 641, wherein the compound is or a pharmaceutically acceptable salt thereof. Item 659. The compound according to Item 641, wherein the compound is or a pharmaceutically acceptable salt thereof. Item 660. The compound according to Item 641, wherein the compound is or a pharmaceutically acceptable salt thereof. Item 661. The compound according to Item 641, wherein the compound is or a pharmaceutically acceptable salt thereof. Item 662. The compound according to Item 641, wherein the compound is or a pharmaceutically acceptable salt thereof. Item 663. The compound according to Item 641, wherein the compound is or a pharmaceutically acceptable salt thereof. Item 664. The compound according to Item 641, wherein the compound is or a pharmaceutically acceptable salt thereof. Item 665. The compound according to Item 641, wherein the compound is or a pharmaceutically acceptable salt thereof. Item 666. The compound according to Item 641, wherein the compound is or a pharmaceutically acceptable salt thereof. Item 667. The compound according to Item 641, wherein the compound is or a pharmaceutically acceptable salt thereof. Item 668. The compound according to Item 641, wherein the compound is or a pharmaceutically acceptable salt thereof. Item 669. The compound according to Item 641, wherein the compound is or a pharmaceutically acceptable salt thereof. Item 670. The compound according to Item 641, wherein the compound is or a pharmaceutically acceptable salt thereof. Item 671. The compound according to Item 641, wherein the compound is or a pharmaceutically acceptable salt thereof. Item 672. The compound according to Item 641, wherein the compound is or a pharmaceutically acceptable salt thereof. Item 673. The compound according to Item 641, wherein the compound is or a pharmaceutically acceptable salt thereof. Item 674. The compound according to Item 641, wherein the compound is or a pharmaceutically acceptable salt thereof. Item 675. The compound according to Item 641, wherein the compound is or a pharmaceutically acceptable salt thereof. Item 676. The compound according to Item 641, wherein the compound is or a pharmaceutically acceptable salt thereof. Item 677. The compound according to Item 641, wherein the compound is or a pharmaceutically acceptable salt thereof. Item 678. The compound according to item 641, wherein the compound is or a pharmaceutically acceptable salt thereof. Item 679. The compound according to any one of items 641 to 678, wherein the linker is a cleavable linker. Item 680. The compound according to item 679, wherein the linker comprises a cleavable peptide moiety. Item 681. The compound according to item 680, wherein the cleavable peptide moiety is cleavable by an enzyme. Item 682. The compound according to any one of items 679 to 681, wherein the cleavable peptide moiety or the linker comprises amino acid units. Item 683. The compound according to item 682, wherein the amino acid units comprise valine-citrulline (Val-Cit). Item 684. The compound according to item 682, wherein the amino acid units comprise valine-alanine (Val-Ala). Item 685. The compound according to item 682, wherein the amino acid units comprise glutamic acid-valine-citrulline (Glu-Val-Cit). Item 686. The compound according to item 682, wherein the amino acid units comprise alanine-alanine-asparagine (Ala-Ala-Asn). Item 687. The compound according to item 679, wherein the linker comprises a cleavable glucuronic acid moiety. Item 688. The compound according to item 687, wherein the cleavable glucuronic acid moiety is cleavable by an enzyme. Item 689. The compound according to item 687 or item 688, wherein the cleavable glucuronic acid moiety is cleavable by glucuronidase. Item 690. The compound according to any one of items 687 to 689, wherein the cleavable glucuronic acid moiety is cleavable by β-glucuronidase. Item 691. The compound according to any one of items 641 to 690, wherein the linker comprises at least one spacer unit. Item 692. The compound according to item 691, wherein the spacer unit or the linker comprises a polyethylene glycol (PEG) moiety. Item 693. The compound according to item 692, wherein the PEG moiety comprises -(PEG) m - and m is an integer from 1 to 10. Item 694. The compound according to item 693, wherein m is 2. Item 695. The compound according to item 693, wherein the spacer unit or the linker comprises an alkyl moiety. Item 696. The compound according to item 695, wherein the alkyl moiety comprises -(CH2) n - and n is an integer from 1 to 10. Item 697. The compound according to item 696, wherein n is 2. Item 698. The compound according to item 696, wherein n is 5. Item 699. The compound according to item 696, wherein n is 6. Item 700. The compound according to any one of items 691 to 699, wherein the spacer unit is linked to the antibody or antigen-binding fragment via a maleimide (Mal) moiety ("Mal-spacer unit"). Item 701. The compound according to item 700, wherein the Mal-spacer unit is reactive with a cysteine residue on the antibody or antigen-binding fragment. Item 702. The compound according to item 700 or item 701, wherein the Mal-spacer unit is conjugated to the antibody or antigen-binding fragment via a cysteine residue on the antibody or antigen-binding fragment. Item 703. The compound according to any one of items 700 to 702, wherein the linker comprises the Mal-spacer unit and a cleavable peptide moiety. Item 704. The compound according to item 703, wherein the cleavable peptide moiety comprises amino acid units. Item 705. The compound according to item 703 or item 704, wherein the cleavable peptide moiety or amino acid units comprise Val-Cit. Item 706. The compound according to item 703 or item 704, wherein the cleavable peptide moiety or amino acid units comprise Val-Ala. Item 707. The compound according to item 703 or item 704, wherein the cleavable peptide moiety or amino acid units comprise Glu-Val-Cit. Item 708. The compound according to item 703 or item 704, wherein the cleavable peptide moiety or amino acid units comprise Ala-Ala-Asn. Item 709. The compound according to any one of items 700 to 708, wherein the Mal-spacer unit comprises an alkyl moiety. Item 710. The compound according to any one of items 700 to 708, wherein the Mal-spacer unit comprises a PEG moiety. Item 711. The compound according to any one of items 700 to 710, wherein the Mal-spacer unit comprises maleimidocaproyl (MC). Item 712. A compound as described in any one of Items 700 to 711, wherein the Mal-spacer unit links the antibody or antigen-binding fragment to the cleavable moiety in the linker. Item 713. A compound as described in Item 712, wherein the cleavable moiety in the linker comprises a cleavable peptide moiety. Item 714. A compound as described in Item 713, wherein the cleavable peptide moiety comprises amino acid units. Item 715. A compound as described in Item 713 or Item 714, wherein the cleavable peptide moiety or amino acid units comprise Val-Cit, Val-Ala, Glu-Val-Cit or Ala-Ala-Asn. Item 716. A compound as described in any one of Items 712 to 715, wherein the linker comprises MC-Val-Cit. Item 717. A compound as described in any one of Items 712 to 715, wherein the linker comprises MC-Val-Ala. Item 718. A compound as described in any one of Items 712 to 715, wherein the linker comprises MC-Glu-Val-Cit. Item 719. A compound as described in any one of Items 712 to 715, wherein the linker comprises MC-Ala-Ala-Asn. Item 720. A compound as described in any one of Items 712 to 719, wherein the Mal-spacer unit comprises an alkyl moiety. Item 721. A compound as described in any one of Items 7125 to 719, wherein the Mal-spacer unit comprises a PEG moiety. Item 722. A compound as described in any one of Items 712 to 721, wherein the Mal-spacer unit comprises maleimidocaproyl (MC). Item 723. A compound as described in any one of Items 691 to 722, wherein the cleavable moiety in the linker directly engages with the splicing regulator, or wherein the spacer unit links the cleavable moiety in the linker to the splicing regulator. Item 724. A compound as described in Item 723, wherein cleavage of the conjugate releases the splicing regulator from the antibody or antigen-binding fragment and the linker. Item 725. A compound as described in Item 723 or Item 724, wherein the spacer unit that links the cleavable moiety in the linker to the splicing regulator is self-ablating. Item 726. A compound as described in any one of Items 723 to 725, wherein the spacer unit that links the cleavable moiety in the linker to the splicing regulator comprises p-aminobenzyloxycarbonyl (pABC). Item 727. A compound according to item 726, wherein the pABC links the cleavable moiety in the linker to the splicing regulator. Item 728. A compound according to item 726 or item 727, wherein the cleavable moiety in the linker comprises a cleavable peptide moiety. Item 729. A compound according to item 728, wherein the cleavable peptide moiety comprises amino acid units. Item 730. A compound according to item 728 or item 729, wherein the cleavable peptide moiety or amino acid units comprise Val-Cit, Val-Ala, Glu-Val-Cit or Ala-Ala-Asn. Item 731. A compound according to any one of items 726 to 730, wherein the linker comprises Val-Cit-pABC. Item 732. A compound according to any one of items 726 to 730, wherein the linker comprises Val-Ala-pABC. Item 733. A compound according to any one of items 726 to 730, wherein the linker comprises Glu-Val-Cit-pABC. Item 734. A compound according to any one of items 726 to 730, wherein the linker comprises Ala-Ala-Asn-pABC. Item 735. A compound according to any one of items 723 to 725, wherein the spacer unit that links the cleavable moiety in the linker to the splicing regulator comprises p-aminobenzyl (pAB). Item 736. A compound according to item 735, wherein the pAB links the cleavable moiety in the linker to the splicing regulator. Item 737. A compound according to item 735 or item 736, wherein the cleavable moiety in the linker comprises a cleavable peptide moiety. Item 738. A compound according to item 737, wherein the cleavable peptide moiety comprises amino acid units. Item 739. A compound according to item 737 or item 738, wherein the cleavable peptide moiety or amino acid units comprise Val-Cit, Val-Ala, Glu-Val-Cit or Ala-Ala-Asn. Item 740. A compound according to any one of items 735 to 739, wherein the linker comprises Val-Cit-pAB. Item 741. A compound according to any one of items 735 to 739, wherein the linker comprises Val-Ala-pAB. Item 742. A compound according to any one of items 735 to 739, wherein the linker comprises Glu-Val-Cit-pAB. Item 743. A compound according to any one of Items 735 to 739, wherein the linker comprises Ala-Ala-Asn-pAB. Item 744. A compound according to any one of Items 641 to 678, wherein the linker is a non-cleavable linker. Item 745. A compound according to Item 744, wherein the linker comprises at least one spacer unit. Item 746. A compound according to Item 744 or Item 745, wherein the spacer unit or the linker comprises a polyethylene glycol (PEG) moiety. Item 747. A compound according to Item 746, wherein the PEG moiety comprises -(PEG) m - and m is an integer from 1 to 10. Item 748. A compound according to Item 747, wherein m is 2. Item 749. A compound according to Item 744 or Item 745, wherein the spacer unit or the linker comprises an alkyl moiety. Item 750. A compound according to Item 749, wherein the alkyl moiety comprises -(CH2) n - and n is an integer from 1 to 10. Item 751. A method for producing an antibody-drug conjugate, the method comprising reacting an antibody or an antigen-binding fragment with a compound according to any one of Items 641 to 750 under conditions permitting conjugation. Description of the Drawings

[0091] Figures 1A - 1D Showing the viability dose-response of exemplary payload compounds in HER2-amplified breast cancer cells (HCC1954) and gastric cancer cells (NCI-N87). Cells were incubated with the compounds for 72 hours (3 days) or 144 hours (6 days), and viability was read in 2.0 reagent. Figure 1A Showing the viability dose-response in HCC1954 cells after 72-hour incubation. Figure 1B Showing the viability dose-response in NCI-N87 cells after 72-hour incubation. Figure 1C Showing the viability dose-response in HCC1954 cells after 144-hour incubation. Figure 1D Showing the viability dose-response in NCI-N87 cells after 144-hour incubation. Data are represented as mean ± SD.

[0092] Figure 2A and Figure 2B Showing HER2-amplified breast cancer cells (HCC1954) ( Figure 2A ) and gastric cancer cells (NCI-N87) ( Figure 2B) Results of SLC25A19 splicing analysis. Cells were incubated with the compound for 6 hours, and splicing of SLC25A19 transcripts was measured in a real-time qPCR reaction using a specific Taqman primer-probe set. The y-axis represents the percentage (%) of the reaction relative to the DMSO control (0.1%). Data are represented as mean ± SD. Detailed Description

[0093] The disclosed compositions and methods can be more readily understood with reference to the following detailed description.

[0094] Throughout this document, the description relates to compositions and methods of using such compositions. When the disclosure describes or claims a feature or embodiment associated with a composition, such feature or embodiment equally applies to the method of using the composition. Similarly, when the disclosure describes or claims a feature or embodiment associated with the method of using the composition, such feature or embodiment equally applies to the composition.

[0095] When a range of values is expressed, it includes embodiments using any specific value within that range. Additionally, a reference to a value stated in a range includes every value within that range. All ranges include their endpoints and are combinable. When a value is expressed as an approximation by use of the term “about” in front, it is understood that the specific value forms another embodiment. Unless the context clearly indicates otherwise, a reference to a specific numerical value includes at least that specific value. Unless otherwise indicated in its specific use context, the use of “or” means “and / or”.

[0096] It should be understood that certain features of the disclosed compositions and methods described herein in the context of separate embodiments can also be provided in combination in a single embodiment. Conversely, the various features of the disclosed compositions and methods described in the context of a single embodiment for the sake of brevity can also be provided separately or in any sub-combination.

[0097] All references cited herein are incorporated by reference for any purpose. In the event of a conflict between a reference and this specification, this specification shall control. Definition

[0098] Throughout this specification and the claims, various terms related to the aspects described are used. Unless otherwise indicated, such terms will be given their ordinary meaning in the art. Other specifically defined terms are interpreted in a manner consistent with the definitions provided herein.

[0099] Unless the context clearly indicates otherwise, as used herein, the singular forms “a / an” and “the” include the plural forms.

[0100] As will be apparent to those of ordinary skill in the art from the teachings contained herein, in the case of numerical values and ranges, the term "about" or "approximately" means approximate or close to the recited value or range such that the embodiment can perform as expected, such as a value or range having a desired amount of nucleic acid or polypeptide in a reaction mixture. In some embodiments, about means a numerical quantity ±10%.

[0101] The terms "antibody-drug conjugate", "antibody conjugate", "conjugate", "immunoconjugate", and "ADC" are used interchangeably and refer to one or more therapeutic compounds (e.g., splicing regulators) linked to one or more antibodies or antigen-binding fragments and are defined by the following general formula: Ab-(L-H) p (Formula I), where Ab = antibody or antigen-binding fragment, L = linker moiety, H = heboxene splicing regulator (e.g., heboxene or a derivative thereof), and p = the number of drug moieties per antibody or antigen-binding fragment. An ADC comprising a heboxene splicing regulator may also be more specifically referred to herein as a "heboxene-splicing regulator-loaded antibody" or "SMLA". In an ADC comprising a heboxene splicing regulator, "p" refers to the number of heboxene splicing regulators linked to the antibody or antigen-binding fragment. In some embodiments, the linker L may include a cleavable moiety between the antibody or antigen-binding fragment and the heboxene splicing regulator. In some embodiments, the linker L may include a cleavable moiety that may be linked to either or both of the antibody or antigen-binding fragment and the heboxene splicing regulator via a spacer unit. In some embodiments, when the spacer unit links the cleavable moiety to the heboxene splicing regulator, it is a self-ablating spacer unit. In other embodiments, the linker L does not include a cleavable moiety and is an uncleavable linker. In some embodiments, the linker L may include at least one spacer unit that may be directly linked to the antibody or antigen-binding fragment and the heboxene splicing regulator. Exemplary cleavable and uncleavable linkers are described and illustrated herein.

[0102] The term "antibody" is used in the broadest sense to refer to an immunoglobulin molecule that recognizes and specifically binds to a target, such as a protein, polypeptide, carbohydrate, polynucleotide, lipid, or a combination of the foregoing, via at least one antigen recognition site within the variable region of the immunoglobulin molecule. The heavy chain of an antibody consists of a heavy chain variable domain (V H ) and a heavy chain constant region (C H ). The light chain consists of a light chain variable domain (V L ) and a light chain constant domain (C L) For the purposes of this application, the mature heavy chain variable domain and the light chain variable domain each contain three complementarity determining regions (CDR1, CDR2, and CDR3) within four framework regions (FR1, FR2, FR3, and FR4) arranged from the N-terminus to the C-terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. An "antibody" can be naturally occurring or man-made, such as monoclonal antibodies produced by conventional hybridoma techniques. The term "antibody" includes full-length monoclonal antibodies and full-length polyclonal antibodies as well as antibody fragments such as Fab, Fab’, F(ab’)2, Fv, and single-chain antibodies. Antibodies can be any of the five major classes of immunoglobulins, IgA, IgD, IgE, IgG, and IgM, or subclasses thereof (e.g., isotypes IgG1, IgG2, IgG3, IgG4). The term further encompasses human antibodies, chimeric antibodies, humanized antibodies, and any modified immunoglobulin molecule containing an antigen recognition site, provided that it exhibits the desired biological activity (e.g., binds to the target antigen, internalizes within cells expressing the target antigen).

[0103] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a substantially homogeneous population of antibodies, i.e., the individual antibodies comprising the population are identical except for possible minor variations that may be naturally occurring. Monoclonal antibodies are highly specific for a single antigenic epitope. In contrast, conventional (polyclonal) antibody preparations generally include multiple antibodies directed against different epitopes or specificities. The modifier "monoclonal" indicates the character of the antibody obtained from a substantially homogeneous population of antibodies and should not be construed as requiring that the antibody be produced by any particular method. For example, monoclonal antibodies used in accordance with this disclosure can be made by the hybridoma method first described by Kohler et al. (1975) Nature 256:495, or can be made by recombinant DNA methods (see, e.g., U.S. Patent No. 4,816,567). "Monoclonal antibodies" can also be isolated from phage antibody libraries using, for example, the techniques described in Clackson et al. (1991) Nature 352:624-8 and Marks et al. (1991) J Mol Biol. 222:581-97.

[0104] The monoclonal antibodies described herein specifically include "chimeric" antibodies in which a portion of the heavy and / or light chain is identical or homologous to the corresponding sequence in an antibody derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain is identical or homologous to the corresponding sequence in an antibody derived from another species or belonging to another antibody class or subclass; provided that they specifically bind to the target antigen and / or exhibit the desired biological activity.

[0105] As used herein, the term "human antibody" refers to an antibody produced by a human or an antibody having an amino acid sequence of an antibody produced by a human.

[0106] As used herein, the term "chimeric antibody" refers to an antibody in which the amino acid sequence of the immunoglobulin molecule is derived from two or more species. In some cases, the variable regions of both the heavy and light chains correspond to the variable regions of an antibody from one species having the desired specificity, affinity, and activity, while the constant regions are homologous to an antibody from another species (e.g., human) to minimize the immune response in the latter species.

[0107] As used herein, the term "humanized antibody" refers to an antibody form that contains sequences from non-human (e.g., murine) antibodies as well as human antibodies. Such antibodies are chimeric antibodies that contain the minimal sequence derived from a non-human immunoglobulin. Generally, a humanized antibody contains substantially all of at least one and usually two variable domains, wherein all or substantially all of the hypervariable loops correspond to the variable domains of a non-human immunoglobulin and all or substantially all of the framework (FR) regions are the variable domains of a human immunoglobulin sequence. A humanized antibody optionally also contains at least a portion of the immunoglobulin constant region (Fc), typically at least a portion of the constant region of a human immunoglobulin. A humanized antibody can be further modified by substitution of residues within the Fv framework region and / or replacement of non-human residues to improve and optimize antibody specificity, affinity, and / or activity.

[0108] As used herein, the term "antigen-binding fragment" or "antigen-binding portion" of an antibody refers to one or more fragments of an antibody or protein that retain the ability to specifically bind to an antigen (e.g., HER2, CD138, EPHA2, MSLN, FOLH1, CDH6, CEACAM5, CFC1B, ENPP3, FOLR1, HAVCR1, KIT, MET, MUC16, SLC39A6, SLC44A4, or STEAP1). The antigen-binding fragment can also retain the ability to internalize into cells expressing the antigen. In some embodiments, the antigen-binding fragment also retains immune effector activity. It has been shown that fragments of a full-length antibody can perform the antigen-binding function of the full-length antibody. Examples of binding fragments encompassed within the term "antigen-binding fragment" or "antigen-binding portion" of an antibody include (i) Fab fragment, which is a monovalent fragment consisting of the V L domain, V H domain, C L domain, and C H1 domain; (ii) F(ab’)2 fragment, which is a bivalent fragment containing two Fab fragments linked by a disulfide bond at the hinge region; (iii) a fragment consisting of the V H domain and C H1Fd fragment consisting of domains; (iv) V of a single arm of an antibody L domain and V H domain consisting of Fv fragment; (v) contains, for example, V H domain of a single variable domain dAb fragment (see, for example, Ward et al. (1989) Nature 341: 544-6; and International Publication No. WO 1990 / 005144); and (vi) isolated complementarity determining regions (CDRs). In addition, although the two domains V L and V H of the Fv fragment are encoded by separate genes, they can be joined by a synthetic linker that enables them to be made in the form of a single protein chain using recombinant methods, where the V L region and the V H region pair to form a monovalent molecule (called single-chain Fv (scFv)). See, for example, Bird et al. (1988) Science 242: 423-6; and Huston et al. (1988) Proc Natl Acad Sci. USA 85: 5879-83. Such single-chain antibodies are also intended to be encompassed within the "antigen-binding fragment" or "antigen-binding portion" of the term antibody, and are called exemplary types of binding fragments that can be internalized into cells after binding in the art (see, for example, Zhu et al. (2010) 9: 2131-41; He et al. (2010) J Nucl Med. 51: 427-32; and Fitting et al. (2015) MAbs 7: 390-402). In certain embodiments, the scFv molecule can be incorporated into a fusion protein. Other forms of single-chain antibodies such as bispecific antibodies are also encompassed. A bispecific antibody is a bivalent bispecific antibody, where the V H domain and the V L domain are expressed on a single polypeptide chain, but using a linker that is too short to allow pairing between the two domains on the same chain, thereby forcing the domain to pair with the complementary domain of another chain and generating two antigen-binding sites (see, for example, Holliger et al. (1993) Proc Natl Acad Sci. USA 90: 6444-8; and Poljak et al. (1994) Structure 2: 1121-3). Antigen-binding fragments are obtained using conventional techniques known to those of ordinary skill in the art, and the binding fragments are screened for utility (such as binding affinity, internalization) in the same manner as intact antibodies. Antigen-binding fragments can be prepared by cleaving the intact protein, for example, by protease or chemical cleavage.

[0109] As used herein with respect to an antibody or antigen-binding fragment, "internalizing" means that the antibody or antigen-binding fragment, upon binding to a cell, is capable of being taken up through the lipid bilayer membrane of the cell and entering an internal compartment (i.e., "internalized"), preferably into a degradative compartment within the cell. For example, an internalizing anti-HER2 antibody is an antibody that, upon binding to HER2 on the cell membrane, is capable of being taken up into the cell. In some embodiments, the antibody or antigen-binding fragment used in the ADCs disclosed herein targets a cell surface antigen (e.g., HER2) and is an internalizing antibody or internalizing antigen-binding fragment (i.e., the ADC is transferred through the cell membrane after antigen binding). In some embodiments, the internalizing antibody or antigen-binding fragment binds to a receptor on the cell surface. An internalizing antibody or internalizing antigen-binding fragment that targets a receptor on the cell membrane can induce receptor-mediated endocytosis. In some embodiments, the internalizing antibody or internalizing antigen-binding fragment is taken up into the cell via receptor-mediated endocytosis.

[0110] As used herein with respect to an antibody or antigen-binding fragment, "non-internalizing" means that the antibody or antigen-binding fragment remains at the cell surface upon binding to a cell. In some embodiments, the antibody or antigen-binding fragment used in the ADCs disclosed herein targets a cell surface antigen and is a non-internalizing antibody or non-internalizing antigen-binding fragment (i.e., the ADC remains at the cell surface after antigen binding and does not transfer through the cell membrane). In some embodiments, the non-internalizing antibody or antigen-binding fragment binds to a non-internalizing receptor or other cell surface antigen. Exemplary non-internalizing cell surface antigens include, but are not limited to, CA125 and CEA, and antibodies that bind to non-internalizing antigen targets are also known in the art (see, e.g., Bast et al. (1981) J Clin Invest. 68(5):1331-7; Scholler and Urban (2007) Biomark Med. 1(4):513-23; and Boudousq et al. (2013) PLoS One 8(7):e69613).

[0111] As used herein, the terms "human epidermal growth factor receptor 2", "HER2", or "HER2 / neu" refer to any native form of human HER2. The term encompasses full-length HER (e.g., UniProt reference sequence: P04626; SEQ ID NO: 31) and any form of human HER2 that can be processed by a cell. The term also encompasses functional variants or fragments of human HER2, including but not limited to splice variants, allelic variants, and isoforms that retain one or more biological functions of human HER2 (i.e., variants and fragments are encompassed unless the context indicates that the term is only used to refer to the wild-type protein). HER2 can be isolated from humans or can be produced recombinantly or by synthetic methods.

[0112] The term "anti-HER2 antibody" or "antibody that binds to HER2" refers to any form of antibody or fragment thereof that binds (e.g., specifically binds) to HER2 and encompasses monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, and biologically functional antibody fragments, provided that such biologically functional antibody fragments bind (e.g., specifically bind) to HER2. U.S. Patent No. 5,821,337 provides exemplary HER2-binding sequences, including exemplary anti-HER2 antibody sequences, and is incorporated herein by reference. In some embodiments, the anti-HER2 antibody used in the ADCs disclosed herein is an internalizing antibody or internalizing antibody fragment. Trastuzumab (U.S. Patent No. 5,821,337; Molina et al. (2001) Cancer Res. 61(12):4744-9) is an exemplary anti-human HER2 antibody.

[0113] As used herein, the terms "syndecan-1", "SDC1", or "CD138" refer to any native form of human CD138. The term encompasses full-length CD138 (e.g., UniProt reference sequence: P18827; SEQ ID NO: 32) and any form of human CD138 that can be processed by a cell. The term also encompasses functional variants or fragments of human CD138, including but not limited to splice variants, allelic variants, and isoforms that retain one or more biological functions of human CD138 (i.e., variants and fragments are encompassed unless the context indicates that the term is only used to refer to the wild-type protein). CD138 can be isolated from humans or can be produced recombinantly or by synthetic methods.

[0114] The term "anti-CD138 antibody" or "antibody that binds to CD138" refers to any form of antibody or fragment thereof that binds (e.g., specifically binds) to CD138, and encompasses monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, and biologically functional antibody fragments, provided that such biologically functional antibody fragments bind (e.g., specifically bind) to CD138. In some embodiments, the anti-CD138 antibody used in the ADCs disclosed herein is an internalizing antibody or internalizing antibody fragment. B-B4 (Tassone et al. (2004) Blood 104:3688-96) is an exemplary anti-human CD138 antibody.

[0115] As used herein, the term "erythropoietin-producing hepatocellular carcinoma A2 receptor" or "EPHA2" refers to any native form of human EPHA2. The term encompasses full-length EPHA2 (e.g., UniProt reference sequence: P29317; SEQ ID NO:33) and any form of human EPHA2 that can be processed by a cell. The term also encompasses functional variants or fragments of human EPHA2, including but not limited to splice variants, allelic variants, and isoforms that retain one or more biological functions of human EPHA2 (i.e., variants and fragments are encompassed unless the context indicates that the term is used only to refer to the wild-type protein). EPHA2 can be isolated from humans or can be produced recombinantly or by synthetic methods.

[0116] The term "anti-EPHA2 antibody" or "antibody that binds to EPHA2" refers to any form of antibody or fragment thereof that binds (e.g., specifically binds) to EPHA2, and encompasses monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, and biologically functional antibody fragments, provided that such biologically functional antibody fragments bind (e.g., specifically bind) to EPHA2. WO2007 / 030642 provides exemplary EPHA2-binding sequences, including exemplary anti-EPHA2 antibody sequences, and is incorporated herein by reference. In some embodiments, the anti-EPHA2 antibody used in the ADCs disclosed herein is an internalizing antibody or internalizing antibody fragment. 1C1 (WO 2007 / 030642; Jackson et al. (2008) Cancer Res. 68(22):9367-74) is an exemplary anti-human EPHA2 antibody.

[0117] As used herein, the term "mesothelin" or "MSLN" refers to any native form of human MSLN. The term encompasses full-length MSLN (e.g., UniProt reference sequence: Q13421; SEQ ID NO:94) and any form of human MSLN that can be processed by a cell. The term also encompasses functional variants or fragments of human MSLN, including but not limited to splice variants, allelic variants, and isoforms that retain one or more biological functions of human MSLN (i.e., variants and fragments are encompassed unless the context indicates that the term is used only to refer to the wild-type protein). MSLN can be isolated from humans or produced recombinantly or by synthetic methods.

[0118] The term "anti-MSLN antibody" or "antibody that binds to MSLN" refers to any form of antibody or fragment thereof that binds (e.g., specifically binds) to MSLN and encompasses monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, and biologically functional antibody fragments, provided that such biologically functional antibody fragments bind (e.g., specifically bind) to MSLN. WO 2011 / 074621 provides exemplary MSLN-binding sequences, including exemplary anti-MSLN antibody sequences, and is incorporated herein by reference. In some embodiments, the anti-MSLN antibody used in the ADCs disclosed herein is an internalizing antibody or internalizing antibody fragment. 11-25, IC14-30, IC7-4, IC17-35, and 2-9 are exemplary anti-human MSLN antibodies.

[0119] As used herein, the term "glutamate carboxypeptidase 2" or "FOLH1" refers to any native form of human FOLH1. The term encompasses full-length FOLH1 (e.g., UniProt reference sequence: Q04609; SEQ ID NO:95) and any form of human FOLH1 that can be processed by a cell. The term also encompasses functional variants or fragments of human FOLH1, including but not limited to splice variants, allelic variants, and isoforms that retain one or more biological functions of human FOLH1 (i.e., variants and fragments are encompassed unless the context indicates that the term is used only to refer to the wild-type protein). FOLH1 can be isolated from humans or produced recombinantly or by synthetic methods.

[0120] The term "anti-FOLH1 antibody" or "antibody that binds to FOLH1" refers to any form of antibody or fragment thereof that binds (e.g., specifically binds) to FOLH1, and encompasses monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, and biologically functional antibody fragments, provided that such biologically functional antibody fragments bind (e.g., specifically bind) to FOLH1. WO2019 / 012260 and WO 2017 / 212250 provide exemplary FOLH1-binding sequences, including exemplary anti-FOLH1 antibody sequences, and such cases are incorporated herein by reference. In some embodiments, the anti-FOLH1 antibody used in the ADCs disclosed herein is an internalizing antibody or an internalizing antibody fragment. J591 (deimmunized) is an exemplary anti-human FOLH1 antibody.

[0121] As used herein, the term "cadherin-6" or "CDH6" refers to any native form of human CDH6. The term encompasses full-length CDH6 (e.g., UniProt reference sequence: P55285; SEQ ID NO:96) and any form of human CDH6 that can be processed by cells. The term also encompasses functional variants or fragments of human CDH6, including but not limited to splice variants, allelic variants, and isoforms that retain one or more biological functions of human CDH6 (i.e., variants and fragments are encompassed unless the context indicates that the term is used only to refer to the wild-type protein). CDH6 can be isolated from humans or can be produced recombinantly or by synthetic methods.

[0122] The term "anti-CDH6 antibody" or "antibody that binds to CDH6" refers to any form of antibody or fragment thereof that binds (e.g., specifically binds) to CDH6, and encompasses monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, and biologically functional antibody fragments, provided that such biologically functional antibody fragments bind (e.g., specifically bind) to CDH6. WO 2018 / 185618 provides exemplary CDH6-binding sequences, including exemplary anti-CDH6 antibody sequences, and such case is incorporated herein by reference. In some embodiments, the anti-CDH6 antibody used in the ADCs disclosed herein is an internalizing antibody or an internalizing antibody fragment.

[0123] As used herein, the term "carcinoembryonic antigen-related cell adhesion molecule 5" or "CEACAM5" refers to any native form of human CEACAM5. The term encompasses full-length CEACAM5 (e.g., UniProt reference sequence: P06731; SEQ ID NO:97) and any form of human CEACAM5 that can be processed by cells. The term also encompasses functional variants or fragments of human CEACAM5, including but not limited to splice variants, allelic variants, and isoforms that retain one or more biological functions of human CEACAM5 (i.e., variants and fragments are encompassed unless the context indicates that the term is only used to refer to the wild-type protein). CEACAM5 can be isolated from humans or produced recombinantly or by synthetic methods.

[0124] The term "anti-CEACAM5 antibody" or "antibody that binds to CEACAM5" refers to any form of antibody or fragment thereof that binds (e.g., specifically binds) to CEACAM5, and encompasses monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, and biologically functional antibody fragments, provided that such biologically functional antibody fragments bind (e.g., specifically bind) to CEACAM5. US2015 / 0125386 provides exemplary CEACAM5-binding sequences, including exemplary anti-CEACAM5 antibody sequences, and is incorporated herein by reference. In some embodiments, the anti-CEACAM5 antibody used in the ADCs disclosed herein is an internalizing antibody or internalizing antibody fragment. hMN14 is an exemplary anti-human CEACAM5 antibody.

[0125] As used herein, the term "cryptic family protein 1B" or "CFC1B" refers to any native form of human CFC1B. The term encompasses full-length CFC1B (e.g., UniProt reference sequence: P0CG36; SEQ ID NO:98) and any form of human CFC1B that can be processed by cells. The term also encompasses functional variants or fragments of human CFC1B, including but not limited to splice variants, allelic variants, and isoforms that retain one or more biological functions of human CFC1B (i.e., variants and fragments are encompassed unless the context indicates that the term is only used to refer to the wild-type protein). CFC1B can be isolated from humans or produced recombinantly or by synthetic methods.

[0126] The term "anti-CFC1B antibody" or "antibody that binds to CFC1B" refers to any form of antibody or fragment thereof that binds (e.g., specifically binds) to CFC1B, and encompasses monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, and biologically functional antibody fragments, provided that such biologically functional antibody fragments bind (e.g., specifically bind) to CFC1B. WO2002 / 088170 provides exemplary CFC1B-binding sequences, including exemplary anti-CFC1B antibody sequences, and is incorporated herein by reference. In some embodiments, the anti-CFC1B antibody used in the ADCs disclosed herein is an internalizing antibody or an internalizing antibody fragment.

[0127] As used herein, the term "ectonucleotide pyrophosphatase / phosphodiesterase family member 3" or "ENPP3" refers to any native form of human ENPP3. The term encompasses full-length ENPP3 (e.g., UniProt reference sequence: O14638; SEQ ID NO:99) and any form of human ENPP3 that can be processed by a cell. The term also encompasses functional variants or fragments of human ENPP3, including but not limited to splice variants, allelic variants, and isoforms that retain one or more biological functions of human ENPP3 (i.e., variants and fragments are encompassed unless the context indicates that the term is used only to refer to the wild-type protein). ENPP3 can be isolated from humans or can be produced recombinantly or by synthetic methods.

[0128] The term "anti-ENPP3 antibody" or "antibody that binds to ENPP3" refers to any form of antibody or fragment thereof that binds (e.g., specifically binds) to ENPP3, and encompasses monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, and biologically functional antibody fragments, provided that such biologically functional antibody fragments bind (e.g., specifically bind) to ENPP3. Donate et al. ((2016) Clin Cancer Res. [Clinical Cancer Research] 22(8):1989-99) provides exemplary ENPP3-binding sequences, including exemplary anti-ENPP3 antibody sequences, and the document is incorporated herein by reference. In some embodiments, the anti-ENPP3 antibody used in the ADCs disclosed herein is an internalizing antibody or an internalizing antibody fragment.

[0129] As used herein, the term "folate receptor alpha" or "FOLR1" refers to any native form of human FOLR1. The term encompasses full-length FOLR1 (e.g., UniProt reference sequence: P15328; SEQ ID NO: 100) and any form of human FOLR1 that can be processed by a cell. The term also encompasses functional variants or fragments of human FOLR1, including but not limited to splice variants, allelic variants, and isoforms that retain one or more biological functions of human FOLR1 (i.e., variants and fragments are encompassed unless the context indicates that the term is only used to refer to the wild-type protein). FOLR1 can be isolated from humans or produced recombinantly or by synthetic methods.

[0130] The term "anti-FOLR1 antibody" or "antibody that binds to FOLR1" refers to any form of antibody or fragment thereof that binds (e.g., specifically binds) to FOLR1, and encompasses monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, and biologically functional antibody fragments, provided that such biologically functional antibody fragments bind (e.g., specifically bind) to FOLR1. WO2005 / 080431 and Coney et al. ((1991) Cancer Res. [Cancer Research] 51(22):6125-32) provide exemplary FOLR1-binding sequences, including exemplary anti-FOLR1 antibody sequences, and that case and the literature are incorporated herein by reference. In some embodiments, the anti-FOLR1 antibody used in the ADCs disclosed herein is an internalizing antibody or internalizing antibody fragment. Farletuzumab and MOv19 are exemplary anti-human FOLR1 antibodies.

[0131] As used herein, the term "hepatitis A virus cellular receptor 1" or "HAVCR1" refers to any native form of human HAVCR1. The term encompasses full-length HAVCR1 (e.g., UniProt reference sequence: Q96D42; SEQ ID NO: 101) and any form of human HAVCR1 that can be processed by a cell. The term also encompasses functional variants or fragments of human HAVCR1, including but not limited to splice variants, allelic variants, and isoforms that retain one or more biological functions of human HAVCR1 (i.e., variants and fragments are encompassed unless the context indicates that the term is only used to refer to the wild-type protein). HAVCR1 can be isolated from humans or produced recombinantly or by synthetic methods.

[0132] The term "anti-HAVCR1 antibody" or "antibody that binds to HAVCR1" refers to any form of antibody or fragment thereof that binds (e.g., specifically binds) to HAVCR1, and encompasses monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, and biologically functional antibody fragments, provided that such biologically functional antibody fragments bind (e.g., specifically bind) to HAVCR1. Thomas et al. ((2016) Mol Cancer Ther. [Molecular Cancer Therapeutics] 15(12):2946-54) provide exemplary HAVCR1-binding sequences, including exemplary anti-HAVCR1 antibody sequences, and this document is incorporated herein by reference. In some embodiments, the anti-HAVCR1 antibody used in the ADCs disclosed herein is an internalizing antibody or internalizing antibody fragment.

[0133] As used herein, the term "mast cell / stem cell growth factor receptor Kit" or "KIT" refers to any native form of human KIT. The term encompasses full-length KIT (e.g., UniProt reference sequence: P10721; SEQ ID NO:102) and any form of human KIT that can be processed by cells. The term also encompasses functional variants or fragments of human KIT, including but not limited to splice variants, allelic variants, and isoforms that retain one or more biological functions of human KIT (i.e., variants and fragments are encompassed unless the context indicates that the term is used only to refer to the wild-type protein). KIT can be isolated from humans or can be produced recombinantly or by synthetic methods.

[0134] The term "anti-KIT antibody" or "antibody that binds to KIT" refers to any form of antibody or fragment thereof that binds (e.g., specifically binds) to KIT, and encompasses monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, and biologically functional antibody fragments, provided that such biologically functional antibody fragments bind (e.g., specifically bind) to KIT. Shi et al. ((2016) Proc Natl Acad Sci USA [Proceedings of the National Academy of Sciences of the United States of America] 113(33):E4784-93) and Abrams et al. ((2018) Clin Cancer Res. [Clinical Cancer Research] 24(17):4297-308) provide exemplary KIT-binding sequences, including exemplary anti-KIT antibody sequences, and these documents are incorporated herein by reference. In some embodiments, the anti-KIT antibody used in the ADCs disclosed herein is an internalizing antibody or internalizing antibody fragment.

[0135] As used herein, the term "hepatocyte growth factor receptor" or "MET" refers to any native form of human MET. The term encompasses full-length MET (e.g., UniProt reference sequence: P08581; SEQ ID NO: 103) and any form of human MET that can be processed by a cell. The term also encompasses functional variants or fragments of human MET, including but not limited to splice variants, allelic variants, and isoforms that retain one or more biological functions of human MET (i.e., variants and fragments are encompassed unless the context indicates that the term is used only to refer to the wild-type protein). MET can be isolated from humans or can be produced recombinantly or by synthetic methods.

[0136] The term "anti-MET antibody" or "antibody that binds to MET" refers to any form of antibody or fragment thereof that binds (e.g., specifically binds) to MET and encompasses monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, and biologically functional antibody fragments, provided that such biologically functional antibody fragments bind (e.g., specifically bind) to MET. Yang et al. ((2019) Acta Pharmacol Sin. [Acta Pharmacologica Sinica]) provide exemplary MET-binding sequences, including exemplary anti-MET antibody sequences, and this document is incorporated herein by reference. In some embodiments, the anti-MET antibody used in the ADCs disclosed herein is an internalizing antibody or internalizing antibody fragment.

[0137] As used herein, the term "mucin-16" or "MUC16" refers to any native form of human MUC16. The term encompasses full-length MUC16 (e.g., UniProt reference sequence: Q8WXI7; SEQ ID NO: 104) and any form of human MUC16 that can be processed by a cell. The term also encompasses functional variants or fragments of human MUC16, including but not limited to splice variants, allelic variants, and isoforms that retain one or more biological functions of human MUC16 (i.e., variants and fragments are encompassed unless the context indicates that the term is used only to refer to the wild-type protein). MUC16 can be isolated from humans or can be produced recombinantly or by synthetic methods.

[0138] The term "anti-MUC16 antibody" or "antibody that binds to MUC16" refers to any form of antibody or fragment thereof that binds (e.g., specifically binds) to MUC16, and encompasses monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, and biologically functional antibody fragments, provided that such biologically functional antibody fragments bind (e.g., specifically bind) to MUC16. Liu et al. ((2016) Ann Oncol. [Annals of Oncology] 27(11):2124-30) provide exemplary MUC16-binding sequences, including exemplary anti-MUC16 antibody sequences, and this document is incorporated herein by reference. In some embodiments, the anti-MUC16 antibody used in the ADCs disclosed herein is an internalizing antibody or an internalizing antibody fragment.

[0139] As used herein, the term "zinc transporter ZIP6" or "SLC39A6" refers to any native form of human SLC39A6. The term encompasses full-length SLC39A6 (e.g., UniProt reference sequence: Q13433; SEQ ID NO: 105) and any form of human SLC39A6 that can be processed by a cell. The term also encompasses functional variants or fragments of human SLC39A6, including but not limited to splice variants, allelic variants, and isoforms that retain one or more biological functions of human SLC39A6 (i.e., variants and fragments are encompassed unless the context indicates that the term is used only to refer to the wild-type protein). SLC39A6 can be isolated from humans or can be produced recombinantly or by synthetic methods.

[0140] The term "anti-SLC39A6 antibody" or "antibody that binds to SLC39A6" refers to any form of antibody or fragment thereof that binds (e.g., specifically binds) to SLC39A6, and encompasses monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, and biologically functional antibody fragments, provided that such biologically functional antibody fragments bind (e.g., specifically bind) to SLC39A6. Sussman et al. ((2014) Mol Cancer Ther. [Molecular Cancer Therapeutics] 13(12):2991-3000) provide exemplary SLC39A6-binding sequences, including exemplary anti-SLC39A6 antibody sequences, and this document is incorporated herein by reference. In some embodiments, the anti-SLC39A6 antibody used in the ADCs disclosed herein is an internalizing antibody or an internalizing antibody fragment.

[0141] As used herein, the term "choline transporter-like protein 4" or "SLC44A4" refers to any native form of human SLC44A4. The term encompasses full-length SLC44A4 (e.g., UniProt reference sequence: Q53GD3; SEQ ID NO: 106) and any form of human SLC44A4 that can be processed by a cell. The term also encompasses functional variants or fragments of human SLC44A4, including but not limited to splice variants, allelic variants, and isoforms that retain one or more biological functions of human SLC44A4 (i.e., variants and fragments are encompassed unless the context indicates that the term is only used to refer to the wild-type protein). SLC44A4 can be isolated from humans or produced recombinantly or by synthetic methods.

[0142] The term "anti-SLC44A4 antibody" or "antibody that binds to SLC44A4" refers to any form of antibody or fragment thereof that binds (e.g., specifically binds) to SLC44A4 and encompasses monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, and biologically functional antibody fragments, provided that such biologically functional antibody fragments bind (e.g., specifically bind) to SLC44A4. Mattie et al. ((2016) Mol Cancer Ther. [Molecular Cancer Therapeutics] 15(11):2679-87) provide exemplary SLC44A4-binding sequences, including exemplary anti-SLC44A4 antibody sequences, and this document is incorporated herein by reference. In some embodiments, the anti-SLC44A4 antibody used in the ADCs disclosed herein is an internalizing antibody or internalizing antibody fragment.

[0143] As used herein, the term "metal reductase STEAP1" or "STEAP1" refers to any native form of human STEAP1. The term encompasses full-length STEAP1 (e.g., UniProt reference sequence: Q9UHE8; SEQ ID NO: 107) and any form of human STEAP1 that can be processed by a cell. The term also encompasses functional variants or fragments of human STEAP1, including but not limited to splice variants, allelic variants, and isoforms that retain one or more biological functions of human STEAP1 (i.e., variants and fragments are encompassed unless the context indicates that the term is only used to refer to the wild-type protein). STEAP1 can be isolated from humans or produced recombinantly or by synthetic methods.

[0144] The term "anti-STEAP1 antibody" or "antibody that binds to STEAP1" refers to any form of antibody or fragment thereof that binds (e.g., specifically binds) to STEAP1, and encompasses monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, and biologically functional antibody fragments, provided that such biologically functional antibody fragments bind (e.g., specifically bind) to STEAP1. WO 2008 / 052187 provides exemplary STEAP1-binding sequences, including exemplary anti-STEAP1 antibody sequences, and is incorporated herein by reference. In some embodiments, the anti-STEAP1 antibody used in the ADCs disclosed herein is an internalizing antibody or internalizing antibody fragment.

[0145] As used herein, the terms "specific," "specifically binds," and "binds specifically" refer to the binding reaction between an antibody or antigen-binding fragment (e.g., an anti-HER2 antibody) and a target antigen (e.g., HER2) in a heterogeneous population of proteins and other biologicals. The binding specificity of an antibody can be tested by comparing binding to the appropriate antigen with binding to unrelated antigens or antigen mixtures under a given set of conditions. An antibody is considered to be specific if it binds to the appropriate antigen and the affinity is at least 2, 5, 7-fold and preferably 10-fold or more than the binding affinity for unrelated antigens or antigen mixtures. A "specific antibody" or "target-specific antibody" is an antibody that binds only to the target antigen (e.g., HER2) and does not bind to other antigens (or exhibits minimal binding to other antigens). In certain embodiments, the KD of an antibody or antigen-binding fragment that specifically binds to a target antigen (e.g., HER2) D is less than 1 × 10 -6 M, less than 1 × 10 - 7 M, less than 1 × 10 -8 M, less than 1 × 10 -9 M, less than 1 × 10 -10 M, less than 1 × 10 -11 M, less than 1 × 10 -12 M or less than 1 × 10 -13 M. In some embodiments, the KD is from 1 pM to 500 pM. In some embodiments, the K D is between 500 pM and 1 μM, 1 μM and 100 nM, or 100 mM and 10 nM.

[0146] The term "epitope" refers to the part of an antigen that can be recognized and specifically bound by an antibody. When the antigen is a polypeptide, the epitope can be formed by contiguous amino acids or by non-contiguous amino acids that are brought into proximity by the tertiary folding of the polypeptide. The epitope to which an antibody binds can be identified using any epitope mapping technique known in the art, including X-ray crystallography for epitope identification, which involves direct observation of the antigen-antibody complex, and monitoring the binding of the antibody to fragments or mutant variants of the antigen, or monitoring the solvent accessibility of different parts of the antibody and the antigen. Exemplary strategies for mapping antibody epitopes include, but are not limited to, array-based oligopeptide scanning, limited proteolysis, site-directed mutagenesis, high-throughput mutagenesis mapping, hydrogen-deuterium exchange, and mass spectrometry (see, e.g., Gershoni et al. (2007) 21:145-56; and Hager-Braun and Tomer (2005) Expert Rev Proteomics 2:745-56).

[0147] Competitive binding and epitope binning can also be used to identify antibodies that share the same or overlapping epitopes. Competitive binding can be evaluated using cross-blocking assays such as those described in "Antibodies, A Laboratory Manual", Cold Spring Harbor Laboratory Press, Harlow and Lane (1st ed. 1988, 2nd ed. 2014). In some embodiments, competitive binding is identified when, in a cross-blocking assay, a test antibody or binding protein reduces the binding of a reference antibody or binding protein (e.g., a binding protein comprising a CDR and / or a variable domain selected from the variable domains identified in Tables 2-4) to a target antigen (such as HER2) by at least about 50% (e.g., 50%, 60%, 70%, 80%, 90%, 95%, 99%, 99.5% or higher or any percentage therebetween), and / or vice versa. In some embodiments, competitive binding can be attributed to shared or similar (e.g., partially overlapping) epitopes, or to steric hindrance where the antibody or binding protein binds at a site adjacent to the epitope (see, e.g., Tzartos, Methods in Molecular Biology (Morris, ed. (1998) Vol. 66, pp. 55-66)). In some embodiments, competitive binding can be used to sort groups of binding proteins that share similar epitopes. For example, binding proteins that competitively bind can be "binned" into groups of binding proteins with overlapping or adjacent epitopes, while non-competing binding proteins are grouped into separate binding protein groups that do not have overlapping or adjacent epitopes.

[0148] The term "kon "or "k a " refers to the association rate constant at which an antibody associates with an antigen to form an antibody / antigen complex. This rate can be determined using standard assays such as surface plasmon resonance, biolayer interferometry, or ELISA assays.

[0149] The term "k off " or "k d " refers to the dissociation rate constant at which an antibody dissociates from an antibody / antigen complex. This rate can be determined using standard assays such as surface plasmon resonance, biolayer interferometry, or ELISA assays.

[0150] The term "K D " refers to the equilibrium dissociation constant for a particular antibody-antigen interaction. K D is calculated by k a / k d This rate can be determined using standard assays such as surface plasmon resonance, biolayer interferometry, or ELISA assays.

[0151] In the ADCs disclosed herein, the term "p" or "halbrigen splicing regulator loading" or "halbrigen splicing regulator:antibody ratio" or "halbrigen splicing regulator to antibody ratio" or "HAR" refers to the number of halbrigen splicing regulators per antibody or antigen-binding fragment, i.e., the halbrigen splicing regulator loading, or the number of -L-H moieties per antibody or antigen-binding fragment (Ab). In an ADC containing a halbrigen splicing regulator, "p" refers to the number of halbrigen splicing regulators attached to the antibody or antigen-binding fragment. For example, if two halbrigen splicing regulators (e.g., two compounds each having an H3 structure) are attached to the antibody or antigen-binding fragment, then p = 2. In a composition containing multiple copies of an ADC as described herein, "average p" refers to the average number of -L-H moieties per antibody or antigen-binding fragment, also referred to as "average halbrigen splicing regulator loading".

[0152] "Linker" or "linker moiety" is used herein to refer to any chemical moiety capable of covalently conjugating a compound (usually a drug moiety, such as a halbrigen splicing regulator drug moiety) to another moiety (such as an antibody or antigen-binding fragment). The linker may be susceptible to or substantially resistant to acid-induced cleavage, peptidase-induced cleavage, light-based cleavage, esterase-induced cleavage, and / or disulfide cleavage under conditions that maintain the activity of the compound or antibody.

[0153] The term "agent" is used herein to refer to a compound, a mixture of compounds, a biological macromolecule, or an extract made from a biological material. The term "therapeutic agent" or "drug" refers to an agent that can modulate biological processes and / or has biological activity. The herboxidiene splicing modulators described herein are exemplary therapeutic agents.

[0154] The term "chemotherapeutic agent" or "anticancer agent" is used herein to refer to all agents that are effective in treating cancer regardless of the mechanism of action. Inhibition of metastasis or angiogenesis is often a characteristic of chemotherapeutic agents. Chemotherapeutic agents include antibodies, biomolecules, and small molecules, and encompass the herboxidiene splicing modulator compounds described herein. Chemotherapeutic agents can be cytotoxic agents or cell growth inhibitors. The term "cell growth inhibitor" refers to an agent that inhibits or curbs cell growth and / or cell proliferation. The term "cytotoxic agent" refers to a substance that causes cell death mainly by interfering with the expression activity and / or operation of cells.

[0155] As used herein, the term "herboxidiene splicing modulator / herboxidiene splice modulator" refers to a compound that has anticancer activity by interacting with components of the spliceosome and is structurally related to herboxidiene. In some embodiments, the herboxidiene splicing modulator alters the splicing rate or pattern in target cells. A herboxidiene splicing modulator that acts as an inhibitor, for example, can reduce uncontrolled cell proliferation. In some embodiments, the herboxidiene splicing modulator can act by binding to the SF3b spliceosome complex. Such modulators can be naturally occurring or synthetic herboxidiene derivatives or analogs. When referring to a herboxidiene splicing modulator or an analog thereof, the terms "derivative" and "analog" as used herein mean any such compound that retains substantially the same, similar, or enhanced biological function or activity as herboxidiene but has an altered chemical or biological structure. In some embodiments, the herboxidiene splicing modulator is a herboxidiene derivative.

[0156] As used herein, "herboxidiene splicing modulator drug moiety" refers to the component of an ADC or composition that provides the structure of the herboxidiene splicing modulator compound, such as the herboxidiene splicing modulator (H) component in an ADC having formula (I) or a composition containing -L-H.

[0157] As used herein, "spliceosome" refers to a ribonucleoprotein complex that removes introns from one or more RNA segments such as pre-mRNA segments.

[0158] The term "homolog" refers to a molecule that exhibits homology with another molecule by, for example, having a sequence with the same or similar chemical residues at corresponding positions.

[0159] As used herein, the term "inhibit" or "inhibition of" means to reduce a measurable amount and can include, but does not require, complete prevention or inhibition.

[0160] The terms "target negative", "target antigen negative", or "antigen negative" refer to the absence of target antigen expression in a cell or tissue. The terms "target positive", "target antigen positive", or "antigen positive" refer to the presence of target antigen expression. For example, a cell or cell line that does not express a target antigen can be described as target negative, while a cell or cell line that expresses a target antigen can be described as target positive.

[0161] The term "bystander killing" or "bystander effect" refers to the killing of target negative cells in the presence of target positive cells, where no killing of target negative cells is observed in the absence of target positive cells. Cell - to - cell contact or at least proximity between target positive and target negative cells enables bystander killing. Such killing can be distinguished from "off - target killing", which refers to the indiscriminate killing of target negative cells. Off - target killing can be observed in the absence of target positive cells.

[0162] The terms "neoplastic disorder" and "cancer" are used interchangeably herein to refer to the presence of cells having characteristics typical of cancer cells, such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rate, and / or certain morphological features. Generally, cancer cells can be in the form of a tumor or mass, but such cells can exist alone within a subject or can circulate in the bloodstream as individual cells such as leukemia cells or lymphoma cells. The terms "neoplastic disorder" and "cancer" include all types of cancer and cancer metastases, including hematological malignancies, solid tumors, sarcomas, carcinomas, and other solid tumor cancers and non-solid tumor cancers. Hematological malignancies can include B-cell malignancies, blood cancers (leukemias), plasma cell cancers (myelomas, such as multiple myeloma), or lymph node cancers (lymphomas). Exemplary B-cell malignancies include chronic lymphocytic leukemia (CLL), follicular lymphoma, mantle cell lymphoma, and diffuse large B-cell lymphoma. Leukemias can include acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), acute monocytic leukemia (AMoL), etc. Lymphomas can include Hodgkin's lymphoma and non-Hodgkin's lymphoma. Other hematological malignancies can include myelodysplastic syndromes (MDS). Solid tumors can include carcinomas, such as adenocarcinomas, e.g., breast cancer, pancreatic cancer, prostate cancer, colorectal cancer, lung cancer, gastric cancer, cervical cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, glioma, melanoma, etc.

[0163] The terms "tumor" and "neoplasm" refer to any mass of tissue, whether benign or malignant, caused by excessive cell growth or proliferation, including pre-cancerous lesions.

[0164] The terms "tumor cell" and "neoplastic cell" are used interchangeably and refer to individual cells or a total cell population derived from a tumor or neoplasm, including both non-tumorigenic cells and cancer stem cells. When only referring to those tumor cells lacking the ability to renew and differentiate, the term "tumor cell" as used herein is modified by the term "non-tumorigenic" to distinguish those tumor cells from cancer stem cells.

[0165] The terms "subject" and "patient" are used interchangeably herein to refer to any animal, such as any mammal, including but not limited to humans, non-human primates, rodents, and the like. In some embodiments, the mammal is a mouse. In some embodiments, the mammal is a human. In some embodiments, the subject is a mouse. In some embodiments, the subject is a human.

[0166] The term "co-administer" or "combine" the administration of one or more therapeutic agents includes simultaneous administration and sequential administration in any order.

[0167] "Pharmaceutical composition" means a preparation in a form that permits the administration of an active ingredient and subsequently provides the intended biological activity and / or achieves a therapeutic effect of the active ingredient, and that does not contain additional components with unacceptable toxicity for the subject to which the formulation is administered. The pharmaceutical composition may be sterile.

[0168] "Pharmaceutical excipient" includes substances such as adjuvants, carriers, pH regulators and buffers, tonicity regulators, wetting agents, preservatives, and similar agents.

[0169] "Pharmaceutically acceptable" means approved or approvable by a federal regulatory agency or a state government, or listed in the United States Pharmacopeia (U.S.Pharmacopeia) or other generally recognized pharmacopeias for use in animals and more particularly in humans.

[0170] "Pharmaceutically acceptable salt" is a salt that retains the desired biological activity of the parent compound and does not impart undesired toxicological effects. Examples of such salts are: (a) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and similar inorganic acids; and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, and similar organic acids; and (b) salts formed from elemental anions such as chlorine, bromine, and iodine. See, for example, Haynes et al., "Commentary: Occurrence of Pharmaceutically Acceptable Anions and Cations in the Cambridge Structural Database", J Pharmaceutical Sciences, Vol. 94, No. 10 (2005), and Berge et al., "Pharmaceutical Salts", J Pharmaceutical Sciences, Vol. 66, No. 1 (1977), which are incorporated herein by reference.

[0171] As used herein, the term "effective amount" means an amount of a compound, ADC, or composition (e.g., a hopadiene splicing regulator or ADC) described herein sufficient to effect a specifically stated purpose, e.g., sufficient to produce a therapeutic effect after administration, such as a reduction in tumor growth rate or tumor volume, alleviation of cancer symptoms, or some other indication of therapeutic efficacy. An effective amount can be determined in a conventional manner relevant to the stated purpose. The term "therapeutically effective amount" means an amount of a compound, ADC, or composition described herein that effectively and detectably kills tumor cells, reduces and / or inhibits the growth or spread of tumor cells, the size or number of tumors, and / or other measures of the extent, stage, development, and / or severity of cancer. A therapeutically effective amount can vary depending on the intended administration (in vitro or in vivo), the subject and disease condition being treated, e.g., the body weight and age of the subject, the severity of the disease condition, the mode of administration, and the like, which can be readily determined by one of ordinary skill in the art. The term also applies to the dose that induces a specific response, e.g., inhibits cell growth, in target cells. The specific dose can vary, for example, depending on the particular pharmaceutical composition, the subject and their age, and the existing health condition or risk of health condition, the dosing regimen to be followed, the severity of the disease, the timing of administration (whether administered in combination with other agents or not), the tissue to be administered to, and the physical delivery system carrying it. In the case of cancer, a therapeutically effective amount of an ADC can reduce the number of cancer cells, decrease the tumor size, inhibit (e.g., slow or stop) tumor metastasis, inhibit (e.g., slow or stop) tumor growth, and / or alleviate one or more symptoms.

[0172] A "prophylactically effective amount" means an amount effective to achieve the desired prophylactic result at the required dose and for the required period of time. Typically, since prophylactic doses are administered to a subject before or at an early stage of a disease, a prophylactically effective amount is less than a therapeutically effective amount.

[0173] As used herein, "for treating" or "therapeutic" and grammatically related terms mean any improvement in any consequence of a disease, such as an extended survival period, a lower incidence rate, and / or a reduction in side effects caused by alternative treatment modalities. As is readily understood in the art, a therapeutic procedure encompasses, but does not require, the complete eradication of a disease. As used herein, "treatment" means the administration of an ADC or composition described herein to a subject, e.g., a patient. Treatment can be used to cure, heal, alleviate, relieve, alter, remedy, improve, mitigate, enhance, or affect a disorder (e.g., cancer), the symptoms of a disorder, or the predisposition to having a disorder. In some embodiments, in addition to treating a subject having a condition, the compositions disclosed herein can also be provided prophylactically to prevent or reduce the likelihood of developing that condition.

[0174] In some embodiments, a labeled ADC is used. Suitable "labels" include radionuclides, enzymes, substrates, cofactors, inhibitors, fluorescent moieties, chemiluminescent moieties, magnetic particles, and the like.

[0175] As used herein, "protein" means at least two covalently linked amino acids. The term encompasses polypeptides, oligopeptides, and peptides. In some embodiments, two or more covalently linked amino acids are joined by peptide bonds. A protein can be composed of naturally occurring amino acids and peptide bonds, such as when a protein is made recombinantly using an expression system and a host cell. Alternatively, a protein can include synthetic amino acids (e.g., homophenylalanine, citrulline, ornithine, and norleucine) or peptidomimetic structures (i.e., "peptide or protein mimetics" such as peptoids). Peptoids are an exemplary class of peptide mimetics in which the side chains are attached to the nitrogen atom of the peptide backbone rather than to the α-carbon (as in amino acids), and have different hydrogen bonding and conformational characteristics compared to peptides (see, e.g., Simon et al. (1992) Proc Natl Acad Sci. USA 89:9367). Thus, peptoids may be resistant to proteolysis or other physiological or storage conditions and effectively penetrate cell membranes. Such synthetic amino acids can be incorporated, particularly when antibodies are synthesized in vitro by conventional methods well known in the art. In addition, any combination of peptidomimetic, synthetic, and naturally occurring residues / structures can be used. "Amino acid" also includes imino acid residues such as proline and hydroxyproline. The amino acid "R group" or "side chain" can be in the (L)- or (S)-configuration. In a specific embodiment, the amino acids are in the (L)- or (S)-configuration.

[0176] A "recombinant protein" is a protein made using recombinant techniques, using any technique and method known in the art, i.e., by expressing a recombinant nucleic acid. Methods and techniques for producing recombinant proteins are well known in the art.

[0177] An "isolated" protein is not accompanied by at least some of the materials that are normally associated with it in its native state, e.g., at least about 5% by weight or at least about 50% by weight of the total protein in a given sample. It is understood that the isolated protein can, depending on the circumstances, account for 5% to 99.9% by weight of the total protein content. For example, a protein can be made at a significantly higher concentration using an inducible promoter or a high-expression promoter such that the protein is made at an increased concentration level. This definition includes the production of antibodies in a wide variety of organisms and / or host cells known in the art.

[0178] For amino acid sequences, sequence identity and / or similarity can be determined using standard techniques known in the art, including but not limited to the local sequence identity algorithm of Smith and Waterman (1981) Adv Appl Math. 2:482, the sequence identity alignment algorithm of Needleman and Wunsch (1970) J Mol Biol. 48:443, the similarity search method of Pearson and Lipman (1988) Proc Nat Acad Sci. USA 85:2444, computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package of the Genetics Computer Group, 575 Science Drive, Madison, Wis.), the Best Fit sequence program described by Devereux et al. (1984) Nucl Acid Res. 12:387-95, preferably using default settings or determined by testing. Preferably, the percent identity is calculated by FastDB based on the following parameters: mismatch penalty 1; gap penalty 1; gap size penalty 0.33; and join penalty 30 ("Current Methods in Sequence Comparison and Analysis", Macromolecule Sequencing and Synthesis, Selected Methods and Applications, pp. 127-149 (1988), Alan R. Liss, Inc.).

[0179] An example of a suitable algorithm is PILEUP. PILEUP uses progressive pairwise alignments to generate a multiple sequence alignment from a group of related sequences. It can also draw a tree diagram showing the cluster relationships used to generate the alignment. PILEUP uses a simplified form of the progressive alignment method of Feng and Doolittle (1987) J Mol Evol. 35:351-60; this method is similar to the method described by Higgins and Sharp (1989) CABIOS 5:151-3. Suitable PILEUP parameters include a default gap weight of 3.00, a default gap length weight of 0.10, and weighted end gaps.

[0180] Another example of an applicable algorithm is the BLAST algorithm described in the following: Altschul et al. (1990) J Mol Biol. 215:403-10; Altschul et al. (1997) Nucl Acid Res. 25:3389-402; and Karin et al. (1993) Proc Natl Acad Sci. USA 90:5873-87. A particularly applicable BLAST program is the WU-BLAST-2 program obtained from Altschul et al. (1996) Methods in Enzymology 266:460-80. WU-BLAST-2 uses a number of search parameters, most of which are set to default values. The adjustable parameters are set with the following values: overlap interval = I, overlap fraction = 0.125, word threshold (T) = II. The HSP S and HSP S2 parameters are dynamic values and are established by the program itself depending on the composition of the specific sequence and the composition of the specific database against which the target sequence is searched; however, these values can be adjusted to increase sensitivity.

[0181] An additional applicable algorithm is the gapped BLAST reported by Altschul et al. (1997) Nucl Acid Res. 25:3389-402. Gapped BLAST uses the BLOSUM-62 substitution scoring; the threshold T parameter is set to 9; the two-hit method is used to trigger the ungapped extension part, with the gap length k added at a cost of 10 + k; Xu is set to 16, and Xg is set to 40 during the database search phase and 67 during the algorithm output phase. The gap alignment is triggered by a score corresponding to approximately 22 ratios.

[0182] Generally speaking, the amino acid homology, similarity or identity between the proteins and their variants disclosed herein (including variants of target antigens such as HER2, CD138 or EPHA2, MSLN, FOLH1, CDH6, CEACAM5, CFC1B, ENPP3, FOLR1, HAVCR1, KIT, MET, MUC16, SLC39A6, SLC44A4 or STEAP1) and the sequences depicted herein, and variants of the variable domains of antibodies (including individual variant CDRs) is at least 80%, for example, the homology or identity is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, approximately 100% or 100%.

[0183] In a similar manner, the "percent nucleic acid sequence identity (%)" with respect to the nucleic acid sequences of antibodies and other proteins identified herein is defined as the percentage of nucleotide residues in a candidate sequence that are identical to the nucleotide residues in the coding sequence of the antigen-binding protein. A particular method utilizes the BLASTN module of WU-BLAST-2 set to preset parameters, where the gap penalty and the match score are set to 1 and 0.125, respectively.

[0184] Although the sites or regions where amino acid sequence changes are introduced are predetermined, the mutations themselves need not be predetermined. For example, to optimize the efficacy of a mutation at a given site, random mutagenesis can be performed at the target codon or region and the best combination of the desired activities of the expressed antigen-binding protein CDR variants can be screened. Techniques for performing substitution mutations at predetermined sites in DNA having a known sequence are well known, such as MI3 primer mutagenesis and PCR mutagenesis.

[0185] As used herein, "alkyl" or "alkyl group" means a fully saturated straight-chain, branched-chain, or cyclic hydrocarbon chain. In certain embodiments, the alkyl may contain 1-8 carbon atoms ("C1-C8 alkyl"). In certain embodiments, the alkyl may contain 1-6 carbon atoms ("C1-C6 alkyl"). In certain embodiments, the alkyl contains 1-3 carbon atoms. In still other embodiments, the alkyl contains 2-3 carbon atoms, and in still other embodiments, the alkyl contains 1-2 carbon atoms.

[0186] As used herein, "alkylalkoxy" means an alkyl group substituted with an alkoxy group.

[0187] As used herein, "alkoxy" refers to an alkyl group as previously defined attached to the main carbon chain via an oxygen ("alkoxy") atom.

[0188] As used herein, "alkylhydroxy" means an alkyl group substituted with a hydroxy group.

[0189] As used herein, "hydroxy (hydroxy or hydroxyl)" refers to -OH.

[0190] As used herein, "carbocyclic" or "carbocyclic group" includes both aromatic groups (e.g., aryl) and non-aromatic groups (e.g., cycloalkyl). In certain embodiments, the carbocyclic group contains 3-10 carbon atoms ("3- to 10-membered carbocycle"). In certain embodiments, the carbocyclic group contains 3-8 carbon atoms ("3- to 8-membered carbocycle"). In certain embodiments, the carbocyclic group contains 3-6 carbon atoms ("3- to 6-membered carbocycle"). In certain embodiments, the carbocyclic group contains 3-5 carbon atoms ("3- to 5-membered carbocycle").

[0191] As used herein, "haloalkyl" refers to an alkyl group substituted with one or more halogen atoms.

[0192] "Halogen" refers to any halogen group, such as -F, -Cl, -Br, or -I.

[0193] As used herein, the terms "heterocycle (heterocycle or heterocyclyl or heterocyclic)", "heterocyclic group" mean a monocyclic heterocycle, bicyclic heterocycle, or tricyclic heterocycle containing at least one heteroatom in the ring.

[0194] A monocyclic heterocycle is a 3-, 4-, 5-, 6-, 7-, or 8-membered ring containing at least one heteroatom independently selected from O, N, and S. In some embodiments, the heterocycle is a 3- or 4-membered ring containing one heteroatom selected from O, N, and S. In some embodiments, the heterocycle is a 5-membered ring containing zero or one double bond and one, two, or three heteroatoms selected from O, N, and S. In some embodiments, the heterocycle is a 6-, 7-, or 8-membered ring containing zero, one, or two double bonds and one, two, or three heteroatoms selected from O, N, and S. Representative examples of monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, dihydropyranyl (including 3,4-dihydro-2H-pyran-6-yl), 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl (including tetrahydro-2H-pyran-4-yl), tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl.

[0195] The bicyclic heterocycles of the present disclosure may include a monocyclic heterocycle fused to an aryl group, or a monocyclic heterocycle fused to a monocyclic cycloalkyl group, or a monocyclic heterocycle fused to a monocyclic cycloalkenyl group, or a monocyclic heterocycle fused to a monocyclic heterocycle having a total of 5 to 12 ring atoms. Examples of bicyclic heterocycles include, but are not limited to, 3,4-dihydro-2H-pyranyl, 1,3-benzodioxolyl, 1,3-benzodithiolyl, 2,3-dihydro-1,4-benzodioxinyl, 2,3-dihydro-1-benzofuranyl, 2,3-dihydro-1-benzothienyl, 2,3-dihydro-1H-indolyl, and 1,2,3,4-tetrahydroquinolinyl.

[0196] The terms "heterocycle (heterocycle or heterocyclyl or heterocyclic)", "heterocyclic group" encompass heteroaryl. "Heteroaryl" refers to a cyclic moiety having one or more closed rings and having one or more heteroatoms (oxygen, nitrogen or sulfur) in at least one of such rings, wherein at least one of such rings is an aromatic ring, and wherein the ring or such rings may be independently fused and / or bridged. Examples include, but are not limited to, phenyl, thienyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl.

[0197] As described herein, the compounds of the present disclosure may contain "optionally substituted" moieties. In general, the term "substituted", whether or not preceded by the term "optionally", means that one or more hydrogens of the designated moiety are replaced by a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted by more than one substituent selected from the designated group, the substituents at each position may be the same or different. The combinations of substituents contemplated by the present disclosure are preferably combinations of substituents that result in the formation of stable or chemically viable compounds.

[0198] One of ordinary skill in the art will understand that "substituted" or "substitued" or "unsubstituted" includes the following implicit limitations: the substitution or non-substitution is in accordance with the allowed valences of the substituted atom and the substituent, and the substitution or non-substitution results in a stable compound, e.g., the stable compound does not spontaneously undergo transformations such as by rearrangement, cyclization, elimination, etc. For the purposes of the present disclosure, a heteroatom such as nitrogen may have a hydrogen substituent and / or any allowable substituent of the organic compounds described herein that satisfies the valence of the heteroatom.

[0199] "Stable" means that a compound, when subjected to conditions that permit its production, detection and in certain embodiments its recovery, purification and use for one or more of the purposes disclosed herein, is substantially unchanged chemically and / or physically. In some embodiments, a stable compound or a chemically viable compound is a compound that is substantially unchanged when maintained at a temperature of 40 °C or lower for at least one week in the absence of moisture or other chemically reactive conditions. In some embodiments, the compounds disclosed herein are stable.

[0200] The enantiomers taught herein may include "enantiomerically pure" isomers that substantially contain a single enantiomer at one or more specific asymmetric centers, e.g., greater than or equal to 90%, 92%, 95%, 98% or 99% or equal to 100% of a single enantiomer. An "asymmetric center" or "chiral center" refers to a tetrahedral carbon atom that contains four different substituents.

[0201] The compounds described herein may also contain unnatural proportions of atomic isotopes at one or more of the atoms that make up such compounds. For example, the compounds may be radiolabeled with radioactive isotopes such as deuterium ( 2 H), tritium ( 3 H), carbon-13 ( 13 C), or carbon-14 ( 14 C). All isotopic variants of the compounds disclosed herein, whether radioactive or not, are intended to be encompassed within the scope of this disclosure. Additionally, all tautomeric forms of the compounds described herein are intended to be within the scope of this disclosure. Antibody - drug conjugate

[0202] The antibody-drug conjugate (ADC) compounds of this disclosure include ADC compounds having anti-cancer activity. Specifically, the ADC compounds include an antibody or antigen-binding fragment (including antigen-binding fragments thereof) that binds (i.e., is covalently linked via a linker) to a herboxidiene splicing regulator, for example, where the herboxidiene splicing regulator has cytotoxicity or cell growth inhibitory effects when not bound to the antibody or antigen-binding fragment. In various embodiments, the herboxidiene splicing regulator is capable of binding and / or interacting with the SF3b spliceosome complex when not bound to the antibody or antigen-binding fragment. In various embodiments, the herboxidiene splicing regulator is capable of regulating RNA splicing in vitro and / or in vivo when not bound to the antibody or antigen-binding fragment. In various embodiments, the herboxidiene splicing regulators and ADCs disclosed herein are potent anti-proliferative agents by targeting RNA splicing. In various embodiments, the herboxidiene splicing regulators and ADCs disclosed herein can target both actively dividing cells and quiescent cells.

[0203] In various embodiments, the present disclosure is at least in part based on the discovery that certain bioactive hopene splicing regulators can provide improved properties when used in an ADC. Although hopene splicing regulators may display ideally improved characteristics when used alone (e.g., robust SF3b spliceosome complex binding, potent regulation of RNA splicing), in various embodiments, hopene splicing regulators may exhibit few of these ideally improved characteristics when conjugated to an antibody or antigen-binding fragment. Thus, the development and production of ADCs for use as human therapeutics, such as oncology agents, may require more than just the identification of an antibody that can bind to one or more desired targets and is conjugated to a drug used alone to treat cancer. Conjugating an antibody to a hopene splicing regulator can have a significant impact on the activity of one or both of the antibody and the hopene splicing regulator, i.e., an impact that varies depending on the type of linker and / or hopene splicing regulator selected. Thus, in some embodiments, the components of the ADC are selected to (i) maintain one or more therapeutic properties exhibited by the separate antibody and hopene splicing regulator moieties; (ii) maintain the specific binding properties of the antibody or antigen-binding fragment; (iii) optimize the hopene splicing regulator loading and the hopene splicing regulator to antibody ratio; (iv) allow delivery, e.g., intracellular delivery, of the hopene splicing regulator moiety via stable conjugation to the antibody or antigen-binding fragment; (v) maintain the stability of the ADC as an intact conjugate until transported or delivered to the target site; (vi) minimize aggregation of the ADC before or after administration; (vii) allow the therapeutic action, e.g., cytotoxic action, of the hopene splicing regulator moiety after cleavage or other release mechanism in the cellular environment; (viii) exhibit in vivo anti-cancer therapeutic efficacy equivalent to or superior to that of the separate antibody and hopene splicing regulator moieties; (ix) minimize off-target killing by the hopene splicing regulator moiety; and / or (x) exhibit desired pharmacokinetic and pharmacodynamic properties, formulatability, and toxicology / immunology profiles. Each of these properties may be required to identify an improved ADC for therapeutic use (Ab et al. (2015) Mol Cancer Ther. 14:1605-13).

[0204] In various embodiments, the ADCs disclosed herein exhibit unexpectedly favorable properties in some or each of the categories listed above. For example, in some embodiments, compared to ADCs comprising alternative linkers and / or drug moieties (e.g., alternative halbrigdine splicing regulators), the ADC constructs disclosed herein exhibit unexpectedly favorable halbrigdine splicing regulator loading, aggregation, and / or stability profiles, and / or retain antibody binding function, drug activity, and / or improved bystander killing while reducing off-target killing. In some embodiments, compared to ADCs using alternative linkers and / or halbrigdine splicing regulator moieties, the ADC constructs disclosed herein exhibit excellent stability, activity, potency, or other effects (measured in vivo or in vitro). In some embodiments, the ADC constructs disclosed herein exhibit in vivo therapeutic efficacy when administered as a single dose. In some embodiments, compared to ADCs using alternative linkers and / or halbrigdine splicing regulator moieties, the ADC constructs disclosed herein are unexpectedly stable.

[0205] The disclosed ADC compounds can selectively deliver an effective dose of a cytotoxic agent or cell growth inhibitor to cancer cells or tumor tissue. It has been found that the disclosed ADCs have potent cytotoxic and / or cell growth inhibitory activity against cells expressing respective target antigens (e.g., HER2, CD138, EPHA2, MSLN, FOLH1, CDH6, CEACAM5, CFC1B, ENPP3, FOLR1, HAVCR1, KIT, MET, MUC16, SLC39A6, SLC44A4, or STEAP1). In some embodiments, the cytotoxic and / or cell growth inhibitory activity of the ADC depends on the expression of the target antigen in the cell. In some embodiments, the disclosed ADCs are particularly effective in killing cancer cells expressing the target antigen while minimizing off-target killing. In some embodiments, the disclosed ADCs do not exhibit cytotoxic and / or cell growth inhibitory effects on cancer cells that do not express the target antigen.

[0206] Exemplary HER2-expressing cancers include, but are not limited to, breast cancer, gastric cancer, bladder cancer, urothelial carcinoma, esophageal cancer, lung cancer (e.g., lung adenocarcinoma), uterine cancer (e.g., uterine serous endometrial cancer), salivary duct carcinoma, cervical cancer, endometrial cancer, and ovarian cancer (English et al. (2013) Mol Diagn Ther. [Molecular Diagnosis and Therapy] 17:85-99).

[0207] Exemplary CD138-expressing cancers include but are not limited to intrathoracic cancers (e.g., lung cancer, mesothelioma), skin cancers (e.g., basal cell carcinoma, squamous cell carcinoma), head and neck cancers (e.g., laryngeal cancer, hypopharyngeal cancer, nasopharyngeal cancer), breast cancer, genitourinary cancers (e.g., cervical cancer, ovarian cancer, endometrial cancer, prostate cancer, bladder cancer, urothelial carcinoma), hematological malignancies (e.g., myeloma (such as multiple myeloma), B-cell malignancies, Hodgkin's lymphoma), and thyroid cancer (Szatmári et al. (2015) Dis Markers 2015:796052).

[0208] Exemplary EPHA2-expressing cancers include breast cancer, brain cancer, ovarian cancer, bladder cancer, pancreatic cancer, esophageal cancer, lung cancer, prostate cancer, melanoma, esophageal cancer, and gastric cancer (Tandon et al. (2011) Expert Opin Ther Targets 15(1):31-51).

[0209] In some embodiments, cleavage of the ADC releases the hopene splicing regulator from the antibody or antigen-binding fragment and the linker. In some embodiments, the linker and / or the hopene splicing regulator are designed to promote bystander killing (adjacent cell killing). In some embodiments, the linker and / or the hopene splicing regulator are designed to promote bystander killing via cleavage after cellular internalization and diffusion of the linker-hopene splicing regulator moiety and / or the hopene splicing regulator moiety alone to adjacent cells. In some embodiments, the linker promotes cellular internalization. In some embodiments, the linker is designed to minimize cleavage in the extracellular environment and thereby reduce toxicity to off-target tissues (e.g., non-cancerous tissues), while maintaining ADC binding to the target tissue and bystander killing of cancerous tissues that do not express the antigen targeted by the antibody or antigen-binding fragment of the ADC but surround the target cancerous tissues that express that antigen. In some embodiments, the hopene splicing regulator moiety or the catabolite of the hopene splicing regulator moiety generated by ADC cleavage is designed to promote uptake by the target cell or adjacent cells (i.e., permeable cells). Such hopene splicing regulator moieties and catabolites may be referred to herein as "bystander active", while the drug moiety or catabolite with reduced cell permeability may be referred to as "bystander inactive".

[0210] In some embodiments, the disclosed ADCs also exhibit bystander killing activity but exhibit low off-target cytotoxicity. Without being bound by theory, the bystander killing activity of the ADCs can be particularly beneficial when the penetration of the ADCs into solid tumors is limited and / or the target antigen expression in tumor cells is heterogeneous. In some embodiments, ADCs comprising a cleavable linker are particularly effective in bystander killing and / or exhibit improved bystander killing activity relative to comparable treatments with ADCs comprising a non-cleavable linker. In some embodiments, the ADCs disclosed herein exhibit improved solubility and target cell permeability relative to the drug moiety alone. In some embodiments, the ADCs disclosed herein exhibit improved cytotoxicity relative to the cytotoxicity of the Herboxidiene splicing regulator moiety alone. In some embodiments, the ADCs disclosed herein use a drug moiety that exhibits lower cytotoxicity when evaluated as a Herboxidiene splicing regulator alone, but unexpectedly performs better than ADCs comprising other Herboxidiene splicing regulator moieties that have higher cytotoxicity when evaluated as a Herboxidiene splicing regulator alone. In some embodiments, cleavage and release of the Herboxidiene splicing regulator improves the cytotoxicity of the ADC relative to comparable treatments with ADCs comprising a non-cleavable linker. In other embodiments, the ADCs do not require cleavage and release of the Herboxidiene splicing regulator to have the desired biological activity. In some embodiments, ADCs comprising a non-cleavable linker with an increased spacer length (e.g., ADL12) provide the same or similar cytotoxicity relative to comparable treatments with ADCs comprising a cleavable linker (e.g., ADL1, ADL5), and unexpectedly superior cytotoxicity relative to comparable treatments with ADCs comprising a shorter non-cleavable linker. In some embodiments, ADCs comprising a non-cleavable linker with an increased spacer length and no carbonyl group (e.g., ADL12) provide the same or similar cytotoxicity relative to comparable treatments with ADCs comprising a cleavable linker (e.g., ADL1, ADL5), and unexpectedly superior cytotoxicity relative to comparable treatments with ADCs comprising a non-cleavable linker with the same or similar spacer length and a carbonyl group (e.g., ADL10). In some embodiments, removal of the carbonyl group from a non-cleavable MC linker (e.g., ADL12) can result in an increase in cytotoxicity greater than 50-fold, greater than 75-fold, greater than 100-fold, greater than 150-fold, or greater than 200-fold relative to comparable treatments with ADCs comprising an unmodified non-cleavable MC linker (e.g., ADL10).In some embodiments, removal of a carbonyl group from a non-cleavable MC linker (e.g., ADL12) and increasing the spacer length (e.g., adding at least one spacer unit) can result in a greater than 50-fold, greater than 75-fold, greater than 100-fold, greater than 150-fold, or greater than 200-fold increase in cytotoxicity relative to a comparable treatment with an ADC comprising an unmodified non-cleavable MC linker (e.g., ADL10).

[0211] Provided herein are ADC compounds comprising an antibody or antigen-binding fragment thereof (Ab) that targets a tumor cell, a splicing regulator drug moiety (D), and a linker moiety (L) that covalently links the Ab to the D. In certain aspects, the antibody or antigen-binding fragment is capable of binding to a tumor-associated antigen (e.g., HER2, CD138, EPHA2, MSLN, FOLH1, CDH6, CEACAM5, CFC1B, ENPP3, FOLR1, HAVCR1, KIT, MET, MUC16, SLC39A6, SLC44A4, or STEAP1) with high specificity and high affinity. In certain embodiments, the antibody or antigen-binding fragment is internalized into the target cell upon binding, e.g., into a degradative compartment within the cell. In various embodiments, an ADC that internalizes, undergoes degradation, and releases a hopene splicing regulator moiety upon binding to a target cell to kill cancer cells can be used. The hopene splicing regulator moiety can be released from the antibody and / or linker moiety of the ADC by enzymatic action, hydrolysis, oxidation, or any other mechanism.

[0212] Exemplary ADCs have the formula (I): Ab-(L-H) p (I) where Ab = antibody or antigen-binding fragment, L = linker moiety, H = hopene splicing regulator drug moiety, and p = the number of splicing regulator drug moieties per antibody or antigen-binding fragment.

[0213] In certain embodiments, the moiety of the described ADCs and compositions that targets the hopene splicing regulator is an antibody or antigen-binding fragment. Also provided and described herein are moieties of other exemplary targeting agents for the described ADCs and compositions. In some embodiments, the moiety targeting the hopene splicing regulator can be any of a variety of cell-binding agents and non-antibody scaffolds. In some embodiments, the moiety targeting the hopene splicing regulator is a cell-binding agent. As used herein, the term "cell-binding agent" refers to any agent capable of binding to an animal (e.g., human) cell and delivering a hopene splicing regulator moiety (e.g., a hopene splicing regulator drug moiety as disclosed herein). The term encompasses the exemplary antibodies and antigen-binding fragments disclosed herein (e.g., monoclonal antibodies and their fragments such as Fab and scFV). The term further encompasses exemplary cell-binding agents such as DARPin, duobody, bicyclic peptides, nanobodies, centyrin, MSH (melanocyte-stimulating hormone), receptor-Fc fusion molecules, T cell receptor constructs, steroid hormones (such as androgens and estrogens), growth factors, colony-stimulating factors (such as EGF), and other non-antibody scaffolds. In different embodiments, the non-antibody scaffolds can be generally divided into two structural classes, namely domain-sized compounds (about 6-20 kDa) and constrained peptides (about 2-4 kDa). Exemplary domain-sized scaffolds include, but are not limited to, affibodies, affilins, anticalins, atrimers, DARPin, FN3 scaffolds (e.g., adnectins and centyrin), fynomors, Kunitz domains, pronectins, O-bodies, and receptor-Fc fusion proteins, while exemplary constrained peptides include avimers, bicyclic peptides, and Cys-knots. In some embodiments, the moiety of the targeting agent for the described ADCs and compositions is selected from affibodies, affilins, anticalins, atrimers, DARPin, FN3 scaffolds (such as adnectin or centyrin), fynomors, Kunitz domains, pronectins, O-bodies, avimers, bicyclic peptides, and Cys-knots. In some embodiments, the moiety of the targeting agent for the described ADCs and compositions is a receptor-Fc fusion protein, such as a HER2-Fc chimeric fusion protein. Non-antibody scaffolds are reviewed, for example, in Vazquez-Lombardi et al. (2015) Drug Dis Today 20(10):1271-83. Antibody

[0214] The antibody or antigen-binding fragment (Ab) of formula (I) includes within its scope any antibody or antigen-binding fragment that specifically binds to a target antigen on a cancer cell. The antibody or antigen-binding fragment can bind to the target antigen, where the dissociation constant (K ) ≤ 1 mM, ≤ 100 nM, or ≤ 10 nM or any amount therebetween as measured by, for example D analysis. In certain embodiments, K D is from 1 pM to 500 pM. In some embodiments, K D is between 500 pM to 1 μM, 1 μM to 100 nM, or 100 mM to 10 nM.

[0215] In some embodiments, the antibody or antigen-binding fragment is a four-chain antibody (also referred to as an immunoglobulin or full-length antibody or intact antibody) comprising two heavy chains and two light chains. In some embodiments, the antibody or antigen-binding fragment is a two-chain half-antibody (one light chain and one heavy chain) or an antigen-binding fragment of an immunoglobulin. In some embodiments, the antibody or antigen-binding fragment is an antigen-binding fragment of an immunoglobulin that retains the ability to bind to the target cancer antigen and / or the ability to provide immunoglobulin function.

[0216] In some embodiments, the antibody or antigen-binding fragment is an antibody or an antigen-binding fragment thereof. In some embodiments, the antibody or antigen-binding fragment is an internalizing antibody or an internalizing antigen-binding fragment thereof. In some embodiments, the internalizing antibody or an internalizing antigen-binding fragment thereof binds to a target cancer antigen expressed on the cell surface and enters the cell after binding. In some embodiments, after the ADC enters and is present in a cell expressing the target cancer antigen (i.e., after the ADC has been internalized), the payload of the ADC, the heptadiene splicing regulator drug moiety, is released from the antibody or antigen-binding fragment of the ADC, for example, by cleavage, by degradation of the antibody or antigen-binding fragment, or by any other suitable release mechanism.

[0217] The amino acid sequences of exemplary antibodies of the present disclosure are set forth in Tables 2-4. Table 1. Antibodies mAb Type Target Trastuzumab (AB185) Humanized HER2 / neu B - B4 (AB205) Mouse CD138 (Syndecan - 1) 1C1 (AB206) Humanized EPHA2 Table 2. Amino Acid Sequences of mAb Variable Regions Table 3. Amino Acid Sequences of mAb CDRs Table 4. Amino Acid Sequences of Full-Length mAb Ig Chains Table 5. Exemplary target antigen amino acid sequences

[0218] In various embodiments, the ADCs disclosed herein can comprise any set of the heavy and light chain variable domains listed in the table above, or a set of the six CDR sequences from the heavy and light chain sets, for example, obtained by grafting the six CDRs into a selected human donor antibody framework. In various embodiments, the ADCs disclosed herein can comprise amino acid sequences homologous to the sequences listed in the table above, provided that the ADC retains the ability to bind to its target cancer antigen (e.g., where K D is less than 1×10 -8 M) and retains one or more functional properties of the ADCs disclosed herein (e.g., the ability to internalize, modulate RNA splicing, inhibit cell growth, etc.).

[0219] In some embodiments, the ADC further comprises human heavy and light chain constant domains or fragments thereof. For example, the ADC can comprise a human IgG heavy chain constant domain (such as IgG1) and a human κ or λ light chain constant domain. In various embodiments, the antibody or antigen-binding fragment of the described ADC comprises a human immunoglobulin G subtype 1 (IgG1) heavy chain constant domain and a human Igκ light chain constant domain.

[0220] In various other embodiments, the target cancer antigen of the ADC is human epidermal growth factor receptor 2 (HER2).

[0221] In various embodiments, the anti-HER2 antibody or antigen-binding fragment thereof comprises the following three heavy-chain CDRs and three light-chain CDRs: heavy-chain CDR1 (HCDR1) consisting of SEQ ID NO:1, heavy-chain CDR2 (HCDR2) consisting of SEQ ID NO:2, and heavy-chain CDR3 (HCDR3) consisting of SEQ ID NO:3, as defined by the Kabat numbering system; ...

Claims

1. An antibody-drug conjugate having formula (I): Ab-(L-H) p (I) Wherein: Ab is an antibody or antigen-binding fragment targeting neoplastic cells; H is a hopadiene splicing regulator; L is a linker that covalently links Ab to H; And p is an integer from 1 to 15.

2. The antibody-drug conjugate according to claim 1, wherein the hopadiene splicing regulator comprises a compound having formula (I): or a pharmaceutically acceptable salt thereof, which is covalently linked to L via any atom, wherein: Y is selected from O, S, NR 6 and CR 6 R 7 ; R 1 、R 2 and R 3 are each independently selected from hydrogen, hydroxy, -O-(C1-C6 alkyl), -O-C(=O)-(C1-C6 alkyl), -C(=O)-O-(C1-C6 alkyl), and C1-C6 alkyl; R 4 Selected from hydrogen, C1-C6 alkyl, -C(=O)-(C1-C6 alkyl), -C(=O)-(C3-C8 carbocyclic group), -C(=O)-(C3-C8 heterocyclic group), and -C(=O)-NR 6 R 7 ; R 5 selected from hydrogen, hydroxy, -CH2-OH, -CO2H, -C(=O)-O-(C1-C6 alkyl), -C(=O)-NR 6 R 7 、-NR 6 -C(=O)-R 8 、-O-C(=O)-NR 6 R 7 、-NR 6 -C(=O)-R 8 and -NR 6 -C(=O)-NR 6 R 7 ; R 6 and R 7 each independently selected from hydrogen, -R 8 , -C(=O)-R 8 and -C(=O)-O-R 8 ; and R 8 selected from C1-C6 alkyl, C3-C8 carbocyclic group and C3-C8 heterocyclic group, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently substituted with 0 to 3 groups independently selected from the following: halogen, hydroxy, C1-C6 alkyl, -O-(C1-C6 alkyl), -CO2H, -C(=O)-(C1-C6 alkyl), -C(=O)-(C3-C8 carbocyclic group), -C(=O)-(C3-C8 heterocyclic group), -NR 6 R 7 , C3-C8 carbocyclic group, C1-C6 alkyl hydroxy, C1-C6 alkyl alkoxy, benzyl and C3-C8 heterocyclic group, each of which may be independently substituted with 0 or 1 group selected from the following: halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, -NH-C(=O)(C1-C3 alkyl) and -NH-C(=O)-O-(C1-C3 alkyl), and Wherein the valence of the atom covalently linked to L is not exceeded.

3. The antibody-drug conjugate according to claim 1 or claim 2, wherein the hopadiene splicing regulator comprises a compound having formula (Ia): or a pharmaceutically acceptable salt thereof, which is covalently linked to L via any atom, wherein: R 9 selected from C3-C8 heterocyclic groups; R 10 selected from H and C1-C6 alkyl, wherein R 9 and R 10 are each independently substituted with from 0 to 3 groups independently selected from the following: halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, -NH2, -NH-(C1-C3 alkyl), and -N-(C1-C3 alkyl)2, and Wherein the valence of the atom covalently linked to L is not exceeded.

4. The antibody-drug conjugate according to any one of claims 1 to 3, wherein the hopene splicing regulator comprises a compound having the formula (Ib): or a pharmaceutically acceptable salt thereof, which is covalently linked to L via any atom, wherein: R 11 selected from and where * indicates the point of attachment of R 11 to the remainder of the compound; R 12 and R 13 each independently selected from H and methyl; and Wherein the valence of the atom covalently linked to L is not exceeded.

5. The antibody-drug conjugate according to any one of claims 1 to 4, Wherein the hopadiene splicing regulator is covalently linked to L via any atom Wherein the hopadiene splicing regulator is selected from H1, H2, H3 and H12; and Wherein the valence of the atom covalently linked to L is not exceeded.

6. The antibody-drug conjugate according to claim 1 or claim 2, wherein L is covalently linked to the hopadiene splicing regulator ("L-H"), and L-H has a structure selected from the following structures: And its pharmaceutically acceptable salts.

7. The antibody-drug conjugate according to claim 1, wherein the hopadiene splicing regulator is a splicing regulator having formula (II): or a pharmaceutically acceptable salt thereof, which is covalently linked to L via any atom, wherein: X is a hydroxyl group or NR 6 R 7 ; R 6 and R 7 each independently selected from hydrogen, -R 8 , -C(=O)-R 8 , -C(=O)-O-R 8 , -(C1-C6 alkyl)-O-C(=O)-R 8 and -(C1-C6 alkyl)-NH-C(=O)-R 8 ; and R 8 selected from C1-C6 alkyl, C3-C8 carbocyclic group and C3-C8 heterocyclic group, wherein R 6 , R 7 and R 8 are each independently substituted with from 0 to 3 groups independently selected from the following: halogen, hydroxy, C1-C6 alkyl, -O-(C1-C6 alkyl), -CO2H, -C(=O)-O-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)-(C3-C8 carbocyclic group), -C(=O)-(C3-C8 heterocyclic group), -NR 6 R 7 , C3-C8 carbocyclic group, C1-C6 alkyl hydroxy, C1-C6 alkyl alkoxy, benzyl and C3-C8 heterocyclic group, each of which may be independently substituted with 0 or 1 group selected from the following: halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, -NH-C(=O)(C1-C3 alkyl) and -NH-C(=O)-O-(C1-C3 alkyl), and Wherein the valence of the atom covalently linked to L is not exceeded.

8. The antibody-drug conjugate according to claim 1 or claim 7, wherein the hopene splicing regulator is a splicing regulator having formula (IIa): or a pharmaceutically acceptable salt thereof, which is covalently linked to L via any atom, wherein: Z is selected from NR 9 and O; R 9 selected from hydrogen and C1-C6 alkyl groups; R 10 and R 11 each independently selected from hydrogen, halogen, hydroxy, C1-C6 alkyl, -O-(C1-C6 alkyl), -CO2H, -C(=O)-O-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)-(C3-C8 carbocyclic group), -C(=O)-(C3-C8 heterocyclic group), C3-C8 carbocyclic group, C1-C6 alkyl hydroxy, C1-C6 alkyl alkoxy, benzyl and C3-C8 heterocyclic group; R 12 selected from C1-C6 alkyl, C3-C8 carbocyclic group, C3-C8 heterocyclic group, wherein R 9 , R 10 , R 11 and R 12 are each independently substituted by 0 or 1 group selected from the following: halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy and C1-C3 haloalkyl; t is an integer selected from 1, 2, 3, 4, 5 and 6; and Wherein the valence of the atom covalently linked to L is not exceeded.

9. The antibody-drug conjugate according to claim 1, 7 or 8, wherein the hopadiene splicing regulator is a splicing regulator having formula (IIb): or a pharmaceutically acceptable salt thereof, which is covalently linked to L via any atom, wherein: R 13 selected from and wherein * indicates the point of attachment to the remainder of the compound; 13 the point of attachment to the remainder of the compound; R 14 and R 15 are each independently selected from hydrogen and methyl; and Wherein the valence of the atom covalently linked to L is not exceeded.

10. The antibody-drug conjugate according to claim 1, 7, 8 or 9, wherein the hopadiene splicing regulator is covalently linked to L via any atom; Wherein the hopadiene splicing regulator is selected from H4, H13, H14, H15, H16, H17, H18, H19, H20, H21, H23 and H24; and Wherein the valence of the atom covalently linked to L is not exceeded.

Images